Amino-acid amide derivatives, agricultural or horticultural fungicides, and method for producing the same

FIELD OF THE INVENTION
The present invention relates to an amino-acid amide derivative as well as to an agricultural or horticultural fungicide containing the same as an active ingredient. The present invention also relates to a process for preparing the same.
BACKGROUND OF THE ART
Amino-acid amide derivatives have been disclosed as intermediates for medicines in Japanese Patent Application, First Publication Nos. Sho 56-8352 and Sho 62-89696. However, these documents fail to disclose the utility of the amino-acid amide derivatives. Although Japanese Patent Application First Publication Nos. Hei 3-5451, Hei 3-153657, Hei 4-230652, Hei 4-230653, Hei 4-283554, Hei 4-308507, and Hei 4-338372 disclose that some amino-acid amides are useful for biocides, the compounds disclosed in these documents are different from the amino-acid amide derivatives according to the present invention.
DISCLOSURE OF THE INVENTION
The present inventors have synthesized various amino-acid amide derivatives and have carried out extensive research in connection with their effects on the physiological activities of fungi. As a result, we have found that the compounds according to the present invention exhibit a broad spectrum of anti-fungal activity especially against cucumber downy mildew, grape downy mildew, and tomato late blight, and at the same time they do not hinder desirable plant growth.
According to an aspect of the present invention, there is provided an amino-acid amide derivative represented by the formula: ##STR2## wherein R.sup.1 represents a lower alkyl group (optionally having at least one same or different substituent selected from the group consisting of a halogen atom, an alkoxy group, and a cyano group),
a lower alkenyl group,
a lower alkynyl group,
a cycloalkyl group (optionally having at least one same or different substituent selected from the group consisting of methyl group and a halogen atom),
a cycloalkylalkyl group,
a cycloalkenyl group,
an alkylene oxide group,
an aralkyl group (optionally having at least one same or different substituent selected from the group consisting of a methyl group, a cyano group, and a nitro group),
a phenyl group (optionally having at least one same or different substituent selected from the group consisting of a halogen atom,
a lower alkyl group which may be substituted with a same or different halogen atom,
a lower alkoxy group which may be substituted with a same or different halogen atom,
a cyano group, and
a nitro group), or
a heterocyclic group,
R.sup.2 represents an ethyl group, an n-propyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an alkenyl group, a cycloalkyl group, a phenyl group (optionally having at least one substituent of halogen atom),
R.sup.3 represents a hydrogen atom or a lower alkyl group,
R.sup.4 represents a hydrogen atom, a lower alkyl group, or a cyano group,
R.sup.5, R.sup.6, and R.sup.7 independently represent a hydrogen atom or a lower alkyl group,
R.sup.8 represents a hydrogen atom, a lower alkyl group, an aralkyl group, a phenyl group, an alkoxycarbonyl group, or a cyano group,
Z.sup.1 and Z.sup.2 independently represent an oxygen atom or a sulfur atom,
Z.sup.3 represents an oxygen atom, a sulfur atom, a group N--R.sup.10 (wherein R.sup.10 represents a hydrogen atom, a methyl group, a methylcarbonyl group, a phenylcarbonyl group, a methoxycarbonyl group, or a methoxymethyl group), a sulfinyl group, a sulfonyl group, a group COO, a group CONR.sup.11 (wherein R.sup.11 represents a hydrogen atom or a lower alkyl group),
Q represents
a phenyl group [optionally having at least one same or different substituent selected from the group consisting of
a halogen atom,
a lower alkyl group which may be substituted with at least one same or different halogen atom,
a lower alkoxy group which may be substituted with a same or different halogen atom,
a cyano group,
a nitro group,
a lower alkoxycarbonyl group,
a methylsulfonyl group,
a methylsulfinyl group,
a methylthio group which may be substituted with a halogen atom,
a dimethylamino group,
a phenylsulfonyl group,
an acyl group, and a phenyl group],
an alkylene oxide group,
a heterocyclic group (optionally having a substituent selected from the group consisting of a halogen atom, an alkyl group, a trifluoromethyl group, and a nitro group), or
a condensed heterocyclic group optionally having a substituent selected from the group consisting of a halogen atom and a nitro group,
m represents an integer from 0 to 2, and
n represents 0 or 1, and an agricultural or horticultural fungicide containing the same as the active ingredient.
The terms employed in the present invention are defined as follows. The term "alkyl group" is used herein to mean a straight or branched alkyl group possessing 1 to 6 carbon atoms including, but not limited to, a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 2,2-dimethylpropyl group, 1,1-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group, or the like.
The term "halogen atom" is used herein to mean a fluorine atom, chlorine atom, bromine atom, or iodine atom.
The term "lower alkenyl group" is used herein to mean a straight or branched alkenyl group possessing 2 to 6 carbon atoms and including, but not limited to, a vinyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 2-methylpropenyl group, 1-ethylvinyl group, or the like.
The term "lower alkynyl group" is used herein to mean a straight or branched alkynyl group possessing 2 to 6 carbon atoms and including, for example, an ethynyl group, propynyl group, butynyl group, 1-methyl-2-propynyl group, or the like.
The term "cycloalkyl group" is used herein to mean a cycloalkyl group possessing 3 to 8 carbon atoms and including, but not limited to, a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, or the like.
The term "cycloalkenyl group" is used herein to mean a cycloalkenyl group possessing 4 to 8 carbon atoms and including, for example, a cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group, or the like.
The term "aralkyl group" is used herein to mean an aralkyl group possessing 7 to 8 carbon atoms and including, but not limited to, a benzyl group, phenethyl group, or the like.
The term "alkylene oxide group" is used herein to mean an alkylene oxide group possessing 2 to 6 carbon atoms and including, for example, an oxiranyl group, oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group, or the like.
The preferred compounds of the present invention are represented by formula [I], wherein R.sup.1 represents a straight or branched alkyl group possessing 2 to 6 carbon atoms, a straight or branched alkenyl group possessing 3 carbon atoms, a cycloalkyl group possessing 5 to 6 carbon atoms, or a phenyl group optionally having a substituent; R.sup.2 represents an ethyl group, an n-propyl group, an isopropyl group, or a sec-butyl group; R.sup.3 represents a hydrogen atom or a methyl group; R.sup.4 represents a hydrogen atom or a methyl group; R.sup.5 represents a hydrogen atom or a methyl group; R.sup.6 represents a hydrogen atom or a methyl group; Q represents a phenyl group optionally having a substituent; m represents an integer of 0 or 1; n represents 0; Z.sup.1, Z.sup.2, and Z.sup.3 represent an oxygen atom or a sulfur atom; and the amino acid is an L-isomer.
The compounds represented by formula [I] according to the present invention can exist in stereoisomers by virtue of the presence of two or more chiral centers. The present invention relates to all such stereoisomers, including diastereomers, enantiomers, and mixtures thereof, which can be separated by appropriate methods.
Next, the compounds represented by formula [I] according to the present invention are listed in Tables 1 to 12. However, it should be understood that the invention is not limited to these compounds. The compound Numbers given in Tables 1 to 12 will be referred to in the subsequent description.
In Tables 1 to 12, Compound Nos. 108, 433, 456, 459, 460, 461, 462, 464, 467, 470, 471,472, and 475 possess D,L-configurational amino acid moieties; Compound No. 109 possesses a D-configurational amino acid moiety; Compound Nos. 233, 234, 235, 236, 237, 238, 425, 426, 427 possess (2S)-butyric acid moieties; and the compounds other than the compounds described above possess L-configurational amino acid moieties. Compound Nos. 33, 345, and 346; Compound Nos. 107, 116, and 117; Compound Nos. 135, 395, and 396; Compound Nos. 228, 414, and 415; and Compound Nos. 452, 453, and 454 are mixtures of diastereomers, and are also individual diastereomers. In addition, Compound Nos. 26 and 27; Compound Nos. 45 and 356; Compound Nos. 335 and 336; Compound Nos. 397 and 401; and Compound Nos. 409 and 410 are mixtures of diastereomers, and are also one of the individual diastereomers, respectively. Compound No. 108 is a mixture of four isomers and Compound No. 433 is a mixture of two isomers. Compound Nos. 483 to 501,504, 505, 510 to 518, 521, and 522 are L-Val-DL-Ala; Compound Nos. 502, 503, 508, 509, 519, and 525 are L-Val-D-Ala; Compound No. 520 is L-Val-L-Ala; Compound Nos. 506 and 523 are L-Ile-D-Ala; Compound No. 526 is L-Val-Gly; and Compound Nos. 507 and 524 are (2S)-butylyl-D-Ala.
In the tables of the present specification, the expressions "C.sub.3 H.sub.7 -i", "C.sub.4 H.sub.9 -t", "C.sub.4 H.sub.9 -s", and "C.sub.4 H.sub.9- i" are used to indicate an isopropyl group, a tert-butyl group, a sec-butyl group, and an isobutyl group, respectively.
TABLE 1__________________________________________________________________________ ##STR3##Com- Melting Pointpound (.degree.C.) or ReflactiveNo. R.sup.1 R.sup.9 Z.sup.1 Z.sup.2 Z.sup.3 A Index (n.sub.D .sup.20)__________________________________________________________________________ 1 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR4## 88-92 2 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR5## 98-100 3 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR6## 1.5051 4 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR7## 97-98 5 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR8## 77-80 6 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR9## 1.5051 7 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR10## 99-101 8 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR11## 86-89 9 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR12## 1.4899 10 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR13## 86-89 11 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR14## 12 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR15## 83-87 13 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR16## 53-56 14 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR17## 1.5081 15 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR18## 112-114 16 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR19## 105-107 17 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR20## 95-97 18 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR21## 89-92 19 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR22## 85-89 20 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR23## 99-100 21 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR24## 102-104 22 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR25## 87-91 23 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR26## 88-90 24 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR27## 98-103 25 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR28## 120-125 26 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR29## 108-110 27 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR30## 143-146 28 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR31## 115-117 29 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR32## 94-98 30 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR33## 31 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR34## 32 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR35## 33 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR36## 149-152 34 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR37## 35 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR38## 36 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR39## 37 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR40## 38 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR41## 39 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR42## 40 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR43## 41 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR44## 42 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR45## 149-152 43 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR46## 44 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR47## 45 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR48## not determined 46 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR49## 47 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR50## 48 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR51## 49 C.sub.2 H.sub.5 CH.sub.3 O O O ##STR52## 50 C.sub.2 H.sub.5 CH.sub.3 O O O ##STR53## 51 C.sub.2 H.sub.5 CH.sub.3 O O O ##STR54## 52 C.sub.2 H.sub.5 CH.sub.3 O O O ##STR55## 53 C.sub.2 H.sub.5 CH.sub.3 O O O ##STR56## 54 C.sub.2 H.sub.5 CH.sub.3 O O O ##STR57## 112-115 55 C.sub.2 H.sub.5 CH.sub.3 O O O ##STR58## 56 C.sub.2 H.sub.5 CH.sub.3 O O O ##STR59## 57 C.sub.2 H.sub.5 CH.sub.3 O O O ##STR60## 58 C.sub.4 H.sub.9 -s CH.sub.3 O O O ##STR61## 59 C.sub.4 H.sub.9 -s CH.sub.3 O O O ##STR62## 60 C.sub.4 H.sub.9 -s CH.sub.3 O O O ##STR63## 61 C.sub.4 H.sub.9 -s CH.sub.3 O O O ##STR64## 62 C.sub.4 H.sub.9 -s CH.sub.3 O O O ##STR65## 63 C.sub.4 H.sub.9 -s CH.sub.3 O O O ##STR66## 140-143 64 C.sub.4 H.sub.9 -s CH.sub.3 O O O ##STR67## 65 C.sub.4 H.sub.9 -s CH.sub.3 O O O ##STR68## 66 C.sub.4 H.sub.9 -s CH.sub.3 O O O ##STR69## 67 C.sub.4 H.sub.9 -s CH.sub.3 O O O ##STR70## 68 C.sub.4 H.sub.9 -s CH.sub.3 O O O ##STR71## 69 ##STR72## CH.sub.3 O O O ##STR73## 70 ##STR74## CH.sub.3 O O O ##STR75## 71 ##STR76## CH.sub.3 O O O ##STR77## 72 ##STR78## CH.sub.3 O O O ##STR79## 73 ##STR80## CH.sub.3 O O O ##STR81## 74 ##STR82## CH.sub.3 O O O ##STR83## 75 ##STR84## CH.sub.3 O O O ##STR85## 76 ##STR86## CH.sub.3 O O O ##STR87## 77 ##STR88## CH.sub.3 O O O ##STR89## 82-86 78 ##STR90## CH.sub.3 O O O ##STR91## 79 ##STR92## CH.sub.3 O O O ##STR93## 80 ##STR94## CH.sub.3 O O O ##STR95## 81 ##STR96## CH.sub.3 O O O ##STR97## 82 ##STR98## CH.sub.3 O O O ##STR99## 83 ##STR100## CH.sub.3 O O O ##STR101## 84 ##STR102## CH.sub.3 O O O ##STR103## 85 ##STR104## CH.sub.3 O O O ##STR105## 86 ##STR106## CH.sub.3 O O O ##STR107## 87 ##STR108## CH.sub.3 O O O ##STR109## 88 ##STR110## CH.sub.3 O O O ##STR111## 145-148 89 ##STR112## CH.sub.3 O O O ##STR113## 90 ##STR114## CH.sub.3 O O O ##STR115## 91 ##STR116## CH.sub.3 O O O ##STR117## 92 ##STR118## CH.sub.3 O O O ##STR119## 93 ##STR120## CH.sub.3 O O O ##STR121## 94 ##STR122## CH.sub.3 O O O ##STR123## 95 ##STR124## CH.sub.3 O O O ##STR125## 96 ##STR126## CH.sub.3 O O O ##STR127## 97 ##STR128## CH.sub.3 O O O ##STR129## 158-162 98 ##STR130## CH.sub.3 O O O ##STR131## 123-126 99 ##STR132## CH.sub.3 O O O ##STR133##100 ##STR134## CH.sub.3 O O O ##STR135##101 ##STR136## CH.sub.3 O O O ##STR137## 165-170102 ##STR138## CH.sub.3 O O O ##STR139##103 ##STR140## CH.sub.3 O O O ##STR141##104 ##STR142## CH.sub.3 O O O ##STR143## 166-169105 ##STR144## CH.sub.3 O O O ##STR145##106 ##STR146## CH.sub.3 O O O ##STR147##107 ##STR148## CH.sub.3 O O O ##STR149## 142-146108 ##STR150## CH.sub.3 O O O ##STR151## 158-162109 ##STR152## CH.sub.3 O O O ##STR153## 128-133110 ##STR154## CH.sub.3 O O O ##STR155##111 ##STR156## CH.sub.3 O O O ##STR157##112 ##STR158## CH.sub.3 O O O ##STR159## 137-142113 ##STR160## CH.sub.3 O O O ##STR161##114 ##STR162## CH.sub.3 O O O ##STR163## 151-155115 ##STR164## CH.sub.3 O O O ##STR165## 144-147116 ##STR166## CH.sub.3 O O O ##STR167## 145-147117 ##STR168## CH.sub.3 O O O ##STR169## 166-170118 ##STR170## CH.sub.3 O O O ##STR171##119 ##STR172## CH.sub.3 O O O ##STR173##120 ##STR174## CH.sub.3 O O O ##STR175##121 ##STR176## CH.sub.3 O O O ##STR177##122 ##STR178## CH.sub.3 O O O ##STR179##123 ##STR180## CH.sub.3 O O O ##STR181##124 ##STR182## CH.sub.3 O O O ##STR183## 137-142125 ##STR184## CH.sub.3 O O O ##STR185##126 ##STR186## CH.sub.3 O O O ##STR187##127 ##STR188## CH.sub.3 O O O ##STR189##128 ##STR190## CH.sub.3 O O O ##STR191##129 ##STR192## CH.sub.3 O O O ##STR193## 114-117130 ##STR194## CH.sub.3 O O O ##STR195##131 ##STR196## CH.sub.3 O O O ##STR197##132 ##STR198## CH.sub.3 O O O ##STR199##133 ##STR200## CH.sub.3 O O O ##STR201##134 ##STR202## CH.sub.3 O O O ##STR203## 133-138135 ##STR204## CH.sub.3 O O O ##STR205## 156-160136 ##STR206## CH.sub.3 O O O ##STR207##137 ##STR208## CH.sub.3 O O O ##STR209##138 ##STR210## CH.sub.3 O O O ##STR211##139 ##STR212## CH.sub.3 O O O ##STR213##140 ##STR214## CH.sub.3 O O O ##STR215##141 ##STR216## CH.sub.3 O O O ##STR217##142 ##STR218## CH.sub.3 O O O ##STR219##143 ##STR220## CH.sub.3 O O O ##STR221##144 ##STR222## CH.sub.3 O O O ##STR223##145 ##STR224## CH.sub.3 O O O ##STR225##146 ##STR226## CH.sub.3 O O O ##STR227##147 ##STR228## CH.sub.3 O O O ##STR229##148 ##STR230## CH.sub.3 O O O ##STR231##149 ##STR232## CH.sub.3 O O O ##STR233##150 ##STR234## CH.sub.3 O O O ##STR235##151 ##STR236## CH.sub.3 O O O ##STR237##152 ##STR238## CH.sub.3 O O O ##STR239##153 ##STR240## CH.sub.3 O O O ##STR241##154 ##STR242## CH.sub.3 O O O ##STR243## 146-150155 ##STR244## CH.sub.3 O O O ##STR245##156 ##STR246## CH.sub.3 O O O ##STR247##157 ##STR248## CH.sub.3 O O O ##STR249## 97-100158 ##STR250## CH.sub.3 O O O ##STR251##159 ##STR252## CH.sub.3 O O O ##STR253##160 ##STR254## CH.sub.3 O O O ##STR255## 152-155161 ##STR256## CH.sub.3 O O O ##STR257##162 ##STR258## CH.sub.3 O O O ##STR259##163 ##STR260## CH.sub.3 O O O ##STR261## 137-140164 ##STR262## CH.sub.3 O O O ##STR263##165 ##STR264## CH.sub.3 O O O ##STR265##166 ##STR266## CH.sub.3 O O O ##STR267## 134-137167 ##STR268## CH.sub.3 O O O ##STR269##168 ##STR270## CH.sub.3 O O O ##STR271##169 ##STR272## CH.sub.3 O O O ##STR273## 139-145170 ##STR274## CH.sub.3 O O O ##STR275##171 ##STR276## CH.sub.3 O O O ##STR277##172 ##STR278## CH.sub.3 O O O ##STR279##173 ##STR280## CH.sub.3 O O O ##STR281##174 ##STR282## CH.sub.3 O O O ##STR283##175 ##STR284## CH.sub.3 O O O ##STR285##176 ##STR286## CH.sub.3 O O O ##STR287##177 ##STR288## CH.sub.3 O O O ##STR289##178 ##STR290## CH.sub.3 O O O ##STR291##179 ##STR292## CH.sub.3 O O O ##STR293##180 ##STR294## CH.sub.3 O O O ##STR295##181 ##STR296## CH.sub.3 O O O ##STR297##182 ##STR298## CH.sub.3 O O O ##STR299##183 ##STR300## CH.sub.3 O O O ##STR301##184 CH.sub.2 CH.sub.2 Cl CH.sub.3 O O O ##STR302## 170-175185 CH.sub.2 Cl CH.sub.3 O O O ##STR303##186 CH(Cl)CH.sub.3 CH.sub.3 O O O ##STR304##187 CH.sub.2 CF.sub.3 CH.sub.3 O O O ##STR305##188 ##STR306## CH.sub.3 O O O ##STR307##189 CH.sub.2 CH.sub.2 OCH.sub.3 CH.sub.3 O O O ##STR308##190 CH.sub.2 CH.sub.2 OCH.sub.3 CH.sub.3 O O O ##STR309##191 CH.sub.2 CH.sub.2 OCH.sub.3 CH.sub.3 O O O ##STR310##192 ##STR311## CH.sub.3 O O O ##STR312##193 ##STR313## CH.sub.3 O O O ##STR314## 125-128194 ##STR315## CH.sub.3 O O O ##STR316##195 ##STR317## CH.sub.3 O O O ##STR318## 98-101196 ##STR319## CH.sub.3 O O O ##STR320##197 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR321##198 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR322##199 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR323##200 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR324##201 ##STR325## CH.sub.3 O O O ##STR326##202 ##STR327## CH.sub.3 O O O ##STR328##203 ##STR329## CH.sub.3 S O O ##STR330## 111-113204 ##STR331## CH.sub.3 S O O ##STR332## 149-152205 ##STR333## CH.sub.3 S O O ##STR334## 146-149206 ##STR335## CH.sub.3 O S O ##STR336##207 ##STR337## CH.sub.3 O S O ##STR338##208 ##STR339## CH.sub.3 O S O ##STR340## not determined209 ##STR341## CH.sub.3 S S O ##STR342##210 ##STR343## CH.sub.3 S S O ##STR344##211 ##STR345## CH.sub.3 S S O ##STR346## not determined212 ##STR347## CH.sub.3 O O S ##STR348## 140-144213 ##STR349## CH.sub.3 O O S ##STR350## 136-140214 ##STR351## CH.sub.3 O O S ##STR352## 123-126215 ##STR353## CH.sub.3 O O S ##STR354## 144-146216 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR355## 74-78217 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR356## 109-112218 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR357##219 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR358## 122-126220 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR359## 165-169221 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR360## 158-160222 C.sub.4 H.sub.9 -t CH.sub.3 O O NCH.sub.3 ##STR361##223 ##STR362## CH.sub.3 O O NCOCH.sub.3 ##STR363##224 ##STR364## CH.sub.3 O O ##STR365## ##STR366##225 ##STR367## CH.sub.3 O O NCO.sub.2 CH.sub.3 ##STR368##226 C.sub.4 H.sub.9 -t C.sub.2 H.sub.5 O O O ##STR369## 101-104227 C.sub.4 H.sub.9 -t C.sub.2 H.sub.5 O O O ##STR370## 128-130228 C.sub.4 H.sub.9 -t C.sub.2 H.sub.5 O O O ##STR371## 100-106229 C.sub.4 H.sub.9 -t C.sub.2 H.sub.5 O O O ##STR372##230 ##STR373## C.sub.2 H.sub.5 O O O ##STR374## 149-154231 ##STR375## C.sub.2 H.sub.5 O O O ##STR376## 152-154232 ##STR377## C.sub.2 H.sub.5 O O O ##STR378## 108-112233 C.sub.4 H.sub.9 -t H O O O ##STR379## 1.5081234 C.sub.4 H.sub.9 -t H O O O ##STR380##235 C.sub.4 H.sub.9 -t H O O O ##STR381## not determined236 ##STR382## H O O O ##STR383## 125-130237 ##STR384## H O O O ##STR385##238 ##STR386## H O O O ##STR387## 43-46239 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR388##240 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR389##241 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR390##242 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR391##243 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR392##244 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR393##245 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR394##246 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR395## 104-109247 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR396##248 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR397##249 ##STR398## CH.sub.3 O O O ##STR399##250 ##STR400## CH.sub.3 O O O ##STR401##251 ##STR402## CH.sub.3 O O O ##STR403##252 ##STR404## CH.sub.3 O O O ##STR405##253 ##STR406## CH.sub.3 O O O ##STR407##254 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR408##255 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR409##256 ##STR410## CH.sub.3 O O O ##STR411##257 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR412##258 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR413##259 ##STR414## CH.sub.3 O O O ##STR415##260 C.sub.4 H.sub.9 -t CH.sub.3 O O NH ##STR416##261 C.sub.4 H.sub.9 -t CH.sub.3 O O NH ##STR417##262 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR418##263 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR419##264 ##STR420## CH.sub.3 O O NH ##STR421##265 ##STR422## CH.sub.3 O O NH ##STR423##266 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR424##267 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR425##268 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR426##269 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR427##270 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR428##271 ##STR429## CH.sub.3 O O O ##STR430##272 ##STR431## CH.sub.3 O O O ##STR432##273 ##STR433## CH.sub.3 O O O ##STR434##274 ##STR435## CH.sub.3 O O O ##STR436##275 ##STR437## CH.sub.3 O O O ##STR438## 60-65276 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR439##277 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR440##278 ##STR441## CH.sub.3 O O O ##STR442##279 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR443##280 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR444##281 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR445##282 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR446##283 ##STR447## CH.sub.3 O O O ##STR448##284 ##STR449## CH.sub.3 O O O ##STR450##285 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR451##286 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR452##287 ##STR453## CH.sub.3 O O O ##STR454##288 ##STR455## CH.sub.3 O O S ##STR456##289 ##STR457## CH.sub.3 O O NH ##STR458##290 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR459##291 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR460##292 ##STR461## CH.sub.3 O O NH ##STR462##293 ##STR463## CH.sub.3 O O NH ##STR464##294 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR465##295 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR466##296 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR467##297 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR468##298 ##STR469## CH.sub.3 O O O ##STR470##299 ##STR471## CH.sub.3 O O O ##STR472##300 ##STR473## CH.sub.3 O O O ##STR474##301 ##STR475## CH.sub.3 O O NH ##STR476##302 ##STR477## CH.sub.3 O O NH ##STR478##303 ##STR479## CH.sub.3 O O NH ##STR480##304 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR481##305 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR482##306 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR483##307 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR484##308 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR485##309 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR486##310 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR487##311 ##STR488## CH.sub.3 O O NCH.sub.2 OCH.sub.3 ##STR489##312 ##STR490## CH.sub.3 O O SO ##STR491##313 ##STR492## CH.sub.3 O O SO.sub.2 ##STR493##314 ##STR494## CH.sub.3 O O NH ##STR495##315 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR496##316 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR497##317 ##STR498## CH.sub.3 O O O ##STR499##318 ##STR500## CH.sub.3 O O O ##STR501##319 ##STR502## CH.sub.3 O O O ##STR503##320 ##STR504## CH.sub.3 O O O ##STR505##321 ##STR506## CH.sub.3 O O O ##STR507##322 ##STR508## CH.sub.3 O O O ##STR509##323 ##STR510## CH.sub.3 O O O ##STR511## 115-117324 ##STR512## CH.sub.3 O O O ##STR513##325 ##STR514## CH.sub.3 O O O ##STR515##326 ##STR516## CH.sub.3 O O O ##STR517## 127-129327 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR518## 93-96328 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR519## 48-51329 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR520## 122-125330 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR521## 74-77331 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR522## 1.5164332 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR523## 1.5319333 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR524## 1.5361334 C.sub.4 H.sub.9 -t CH.sub.3 O O NH ##STR525## 102-104335 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR526## 80-84336 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR527## 133-137337 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR528## 1.5360338 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR529## 1.5361339 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR530## 1.5274340 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR531## 1.5245341 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR532## 1.5269342 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR533## 66-69343 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR534## 71-74344 C.sub.4 H.sub.9 -t CH.sub.3 O O S ##STR535## 1.5312345 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR536## 161-163346 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR537## 167-171347 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR538## 166-172348 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR539## 121-123349 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR540## 125-129350 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR541## 103-106351 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR542## 122-125352 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR543## 155-158353 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR544## 130-134354 C.sub.3 H.sub.7 -i CH.sub.3 O O SO ##STR545## 119-123355 C.sub.3 H.sub.7 -i CH.sub.3 O O SO.sub.2 ##STR546## 151-153356 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR547## 177-180357 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR548## 137-140358 C.sub.3 H.sub.7 -i CH.sub.3 O O NCH.sub.3 ##STR549## 145-148359 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR550## 155-156360 C.sub.3 H.sub.7 -i CH.sub.3 O O NCH.sub.3 ##STR551## 141-143361 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR552## 85-90362 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR553## 143-145363 C.sub.3 H.sub.7 -i CH.sub.3 O O NCH.sub.3 ##STR554## 65-67364 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR555## 146-149365 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR556## 115-118366 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR557## 124-127367 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR558## 119-121368 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR559## 107-110369 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR560## 111-115370 C.sub.3 H.sub.7 -i CH.sub.3 O O S ##STR561## 109-112371 C.sub.4 H.sub.9 -i CH.sub.3 O O O ##STR562## 125-130372 C.sub.5 H.sub.11 CH.sub.3 O O O ##STR563## 109-111373 C.sub.6 H.sub.13 CH.sub.3 O O O ##STR564## 107-110374 ##STR565## CH.sub.3 O O O ##STR566## 122-125375 C.sub.3 H.sub.7 -i CH.sub.3 O O NCOCH.sub.3 ##STR567## 56-60376 ##STR568## CH.sub.3 O O O ##STR569## 181-184377 ##STR570## CH.sub.3 O O O ##STR571## 201-204378 ##STR572## CH.sub.3 O O O ##STR573## 111-116379 ##STR574## CH.sub.3 O O O ##STR575## 141-142380 ##STR576## CH.sub.3 O O O ##STR577## 133-136381 ##STR578## CH.sub.3 O O O ##STR579## 148-151382 ##STR580## CH.sub.3 O O O ##STR581## 161-164383 ##STR582## CH.sub.3 O O O ##STR583## 102-107384 ##STR584## CH.sub.3 O O O ##STR585## 159-162385 ##STR586## CH.sub.3 O O NH ##STR587## 130-134386 ##STR588## CH.sub.3 O O S ##STR589## 127-130387 ##STR590## CH.sub.3 O O S ##STR591## 108-110388 ##STR592## CH.sub.3 O O NH ##STR593## 154-156389 ##STR594## CH.sub.3 O O NCH.sub.3 ##STR595## 125-130390 ##STR596## CH.sub.3 O O NH ##STR597## 147-149391 ##STR598## CH.sub.3 O O NCH.sub.3 ##STR599## 64-70392 ##STR600## CH.sub.3 O O NH ##STR601## 117-119393 ##STR602## CH.sub.3 O O NH ##STR603## 156-160394 ##STR604## CH.sub.3 O O O ##STR605## 156-162395 ##STR606## CH.sub.3 O O O ##STR607## 137-140396 ##STR608## CH.sub.3 O O O ##STR609## 174-179397 ##STR610## CH.sub.3 O O O ##STR611## 153-156398 ##STR612## CH.sub.3 O O O ##STR613## 130-134399 ##STR614## CH.sub.3 O O O ##STR615## 156-161400 ##STR616## CH.sub.3 O O O ##STR617## 125-129401 ##STR618## CH.sub.3 O O O ##STR619## 155-158402 ##STR620## CH.sub.3 O O O ##STR621## 141-144403 ##STR622## CH.sub.3 O O O ##STR623## 153-154404 ##STR624## CH.sub.3 O O O ##STR625## 144-148405 ##STR626## CH.sub.3 O O O ##STR627## 129-133406 ##STR628## CH.sub.3 O O NH ##STR629## 60-62407 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR630## 90-93408 ##STR631## CH.sub.3 O O O ##STR632## 129-130409 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR633## 111-112410 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR634## 129-131411 ##STR635## CH.sub.3 O O O ##STR636## 163-164412 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR637## 118-120413 ##STR638## CH.sub.3 O O O ##STR639## 123-124414 C.sub.4 H.sub.9 -t C.sub.2 H.sub.5 O O O ##STR640## 122-125415 C.sub.4 H.sub.9 -t C.sub.2 H.sub.5 O O O ##STR641## 135-137416 C.sub.3 H.sub.7 -i C.sub.2 H.sub.5 O O S ##STR642## 85-86417 C.sub.3 H.sub.7 -i C.sub.2 H.sub.5 O O O ##STR643## 145-148418 ##STR644## C.sub.2 H.sub.5 O O O ##STR645## 139-141419 ##STR646## C.sub.2 H.sub.5 O O S ##STR647## 105-107420 ##STR648## C.sub.2 H.sub.5 O O S ##STR649## 130-133421 ##STR650## C.sub.2 H.sub.5 O O NH ##STR651## 137-139422 ##STR652## C.sub.2 H.sub.5 O O NCH.sub.3 ##STR653## 53-56423 ##STR654## C.sub.2 H.sub.5 O O O ##STR655## 159-163424 ##STR656## C.sub.2 H.sub.5 O O O ##STR657## 150-153425 C.sub.3 H.sub.7 -i H O O O ##STR658## 118-121426 ##STR659## H O O O ##STR660## 127-132427 ##STR661## H O O O ##STR662## 141-145428 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR663## 217-220429 ##STR664## CH.sub.3 O O O ##STR665## 65-68430 C.sub.3 H.sub.7 -i CH.sub.3 S O O ##STR666## 161-163431 C.sub.2 H.sub.5 CH.sub.3 S O O ##STR667## 152-154432 C.sub.2 H.sub.5 CH.sub.3 S O O ##STR668## 164-166433 ##STR669## CH.sub.3 O O O ##STR670## 118-120434 ##STR671## CH.sub.3 O O NCOCH.sub.3 ##STR672##435 C.sub.3 H.sub.7 -i CH.sub.3 O O NCO.sub.2 CH.sub.3 ##STR673##436 C.sub.3 H.sub.7 -i CH.sub.3 O O ##STR674## ##STR675## 71-73437 C.sub.3 H.sub.7 -i CH.sub.3 O O NCH.sub.2 OCH.sub.3 ##STR676##438 ##STR677## CH.sub.3 O O O ##STR678##439 ##STR679## CH.sub.3 O O O ##STR680## 135-138440 ##STR681## CH.sub.3 O O O ##STR682## 112-114441 C.sub.3 H.sub.7 -i CH.sub.3 O O NH ##STR683##__________________________________________________________________________
TABLE 2__________________________________________________________________________ ##STR684## Melting Point (.degree.C.) orCompound No. R.sup.1 R.sup.9 Z.sup.1 Z.sup.2 Z.sup.3 A Reflactive Index (n.sub.D.sup.20)__________________________________________________________________________442 ##STR685## CH.sub.3 O O O ##STR686##443 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR687##444 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR688##445 ##STR689## CH.sub.3 O O O ##STR690##446 ##STR691## CH.sub.3 O O O ##STR692##447 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR693##448 ##STR694## CH.sub.3 O O O ##STR695##449 C.sub.4 H.sub.9 -t CH.sub.3 O O O ##STR696##450 C.sub.3 H.sub.7 -i CH.sub.3 O O O ##STR697##__________________________________________________________________________
TABLE 3__________________________________________________________________________ ##STR698## Melting PointCom- (.degree.C.) orpound ReflactiveNo. R.sup.1 R.sup.2 Q Index (n.sub.D .sup.20)__________________________________________________________________________451 ##STR699## C.sub.3 H.sub.7 ##STR700## 117-119452 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 ##STR701## 78-80453 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 ##STR702## 105-107454 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 ##STR703## 93-95455 C.sub.4 H.sub.9 -t C.sub.4 H.sub.9 -i ##STR704## not determined456 C.sub.4 H.sub.9 -t ##STR705## ##STR706## 140-142457 C.sub.4 H.sub.9 -t C.sub.4 H.sub.9 -t ##STR707## 68-71458 C.sub.4 H.sub.9 -t ##STR708## ##STR709## 61-64459 C.sub.4 H.sub.9 -t ##STR710## ##STR711## 124-126460 C.sub.4 H.sub.9 -t ##STR712## ##STR713## 1.5132461 C.sub.4 H.sub.9 -t ##STR714## ##STR715## 107-109462 C.sub.3 H.sub.7 -i ##STR716## ##STR717## 155-158463 C.sub.3 H.sub.7 -i ##STR718## ##STR719## 149-151464 C.sub.3 H.sub.7 -i ##STR720## ##STR721## 158-161465 ##STR722## C.sub.3 H.sub.7 ##STR723## 88-91466 ##STR724## C.sub.4 H.sub.9 -i ##STR725## 43-47467 ##STR726## ##STR727## ##STR728## 153-156468 ##STR729## C.sub.4 H.sub.9 -t ##STR730## 75-78469 ##STR731## ##STR732## ##STR733## 68-71470 ##STR734## ##STR735## ##STR736## 152-155471 ##STR737## ##STR738## ##STR739## 141-145472 ##STR740## ##STR741## ##STR742## 170-174473 ##STR743## C.sub.4 H.sub.9 -t ##STR744## 46-49474 ##STR745## ##STR746## ##STR747## 155-157475 ##STR748## ##STR749## ##STR750## 128-129476 ##STR751## C.sub.3 H.sub.7 -i ##STR752## 127-129477 ##STR753## C.sub.3 H.sub.7 -i ##STR754## 152-154478 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 -i ##STR755## 100-103479 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 -i ##STR756## 105-106480 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 -i ##STR757## 109-112481 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i ##STR758## 173-175482 ##STR759## C.sub.3 H.sub.7 -i ##STR760## 128-129__________________________________________________________________________
TABLE 4__________________________________________________________________________ ##STR761## Melting Point (.degree.C.) orCompound No. R.sup.1 R.sup.2 R.sup.4 Z.sup.3 A Reflactive Index__________________________________________________________________________ (n.sub.D.sup.20)483 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 i CH.sub.3 ##STR762## ##STR763## 82-87484 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 -i CH.sub.3 ##STR764## ##STR765## 156-159485 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 -i CH.sub.3 ##STR766## ##STR767## 145-149486 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 -i CH.sub.3 ##STR768## ##STR769## 96-100487 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 -i CH.sub.3 ##STR770## ##STR771## 157-158488 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 -i CH.sub.3 ##STR772## ##STR773## 83-86489 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 -i CH.sub.3 ##STR774## ##STR775## 144-146490 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 -i CH.sub.3 ##STR776## ##STR777## 70-73491 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 -i CH.sub.3 ##STR778## ##STR779## 140--143492 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i CH.sub.3 ##STR780## ##STR781## 179-182493 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i CH.sub.3 ##STR782## ##STR783## 251-255494 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i CH.sub.3 ##STR784## ##STR785## 219--222495 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i CH.sub.3 ##STR786## ##STR787## 88-92496 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i CH.sub.3 ##STR788## ##STR789## 211-212497 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i CH.sub.3 ##STR790## ##STR791## 210-213498 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i CH.sub.3 ##STR792## ##STR793## 200-203499 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i CH.sub.3 ##STR794## ##STR795## 68-72500 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i CH.sub.3 ##STR796## ##STR797## 205-210501 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i CH.sub.3 ##STR798## ##STR799## 113-115502 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i CH.sub.3 ##STR800## ##STR801## 184-186503 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i CH.sub.3 ##STR802## ##STR803## 73-75504 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i CH.sub.3 COO ##STR804## 184-185505 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i CH.sub.3 COO ##STR805## 151-153506 C.sub.3 H.sub.7 -i C.sub.4 H.sub.9 -i CH.sub.3 ##STR806## ##STR807## 197-198507 C.sub.3 H.sub.7 -i C.sub.2 H.sub.5 CH.sub.3 ##STR808## ##STR809## 84-87508 C.sub.4 H.sub.9 -s C.sub.3 H.sub.7 -i CH.sub.3 ##STR810## ##STR811## 165-167509 ##STR812## C.sub.3 H.sub.7 -i CH.sub.3 ##STR813## ##STR814## 197-199510 ##STR815## C.sub.3 H.sub.7 -i CH.sub.3 ##STR816## ##STR817## 201-204511 ##STR818## C.sub.3 H.sub.7 -i CH.sub.3 ##STR819## ##STR820## 219-221512 ##STR821## C.sub.3 H.sub.7 -i CH.sub.3 ##STR822## ##STR823## 245-250513 ##STR824## C.sub.3 H.sub.7 -i CH.sub.3 ##STR825## ##STR826## 225-230514 ##STR827## C.sub.3 H.sub.7 -i CH.sub.3 ##STR828## ##STR829## 199-202515 ##STR830## C.sub.3 H.sub.7 -i CH.sub.3 ##STR831## ##STR832## 194-197516 ##STR833## C.sub.3 H.sub.7 -i CH.sub.3 ##STR834## ##STR835## 173-175517 ##STR836## C.sub.3 H.sub.7 -i CH.sub.3 ##STR837## ##STR838## 69-71518 ##STR839## C.sub.3 H.sub.7 -i CH.sub.3 ##STR840## ##STR841## 149-153519 ##STR842## C.sub.3 H.sub.7 -i CH.sub.3 ##STR843## ##STR844## 158-161520 ##STR845## C.sub.3 H.sub.7 -i CH.sub.3 ##STR846## ##STR847## 202-203521 ##STR848## C.sub.3 H.sub.7 -i CH.sub.3 COO ##STR849## 168-170522 ##STR850## C.sub.3 H.sub.7 -i CH.sub.3 COO ##STR851## 175-178523 ##STR852## C.sub.4 H.sub.9 -s CH.sub.3 ##STR853## ##STR854## 157-159524 ##STR855## C.sub.2 H.sub.5 CH.sub.3 ##STR856## ##STR857## 156-158525 ##STR858## C.sub.3 H.sub.7 -i CH.sub.3 ##STR859## ##STR860## 182-184526 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i H ##STR861## ##STR862## 181-185
TABLE 5__________________________________________________________________________ ##STR863## Melting Point (.degree.C.) orCompound No. R.sup.1 Z.sup.1 Z.sup.2 Z.sup.3 A Reflactive Index (n.sub.D.sup.20)__________________________________________________________________________527 C.sub.4 H.sub.9 -t O O O ##STR864## 158-160528 C.sub.4 H.sub.9 -t O O O ##STR865##529 C.sub.4 H.sub.9 -t O O O ##STR866##530 C.sub.4 H.sub.9 -t O O O ##STR867##531 C.sub.4 H.sub.9 -t O O O ##STR868##532 C.sub.3 H.sub.7 -i O O O ##STR869##533 C.sub.3 H.sub.7 -i O O O ##STR870##534 C.sub.3 H.sub.7 -i O O O ##STR871##535 ##STR872## O O O ##STR873##536 ##STR874## O O O ##STR875##537 ##STR876## O O O ##STR877##538 ##STR878## O O O ##STR879##539 ##STR880## O O O ##STR881##540 ##STR882## O O O ##STR883##541 ##STR884## O O O ##STR885##542 ##STR886## O O O ##STR887##543 ##STR888## O O O ##STR889##544 ##STR890## S O O ##STR891##545 ##STR892## O S O ##STR893##546 ##STR894## S S O ##STR895##547 ##STR896## O O S ##STR897##548 ##STR898## O O S ##STR899##549 ##STR900## O O S ##STR901##550 ##STR902## O O S ##STR903##551 C.sub.4 H.sub.9 -t O O S ##STR904## 75-77552 C.sub.4 H.sub.9 -t O O S ##STR905##553 C.sub.4 H.sub.9 -t O O S ##STR906##554 ##STR907## O O O ##STR908##555 ##STR909## O O O ##STR910##556 ##STR911## O O O ##STR912##557 ##STR913## O O O ##STR914##558 ##STR915## O O O ##STR916##559 ##STR917## O O O ##STR918##560 ##STR919## O O O ##STR920##561 ##STR921## O O O ##STR922##562 ##STR923## O O O ##STR924##563 ##STR925## O O O ##STR926##564 ##STR927## O O O ##STR928##565 ##STR929## O O O ##STR930##566 ##STR931## O O O ##STR932##567 ##STR933## O O O ##STR934##568 C.sub.3 H.sub.7 -i O O O ##STR935##569 C.sub.3 H.sub.7 -i O O O ##STR936##570 ##STR937## O O O ##STR938##571 ##STR939## O O O ##STR940##572 C.sub.3 H.sub.7 -i O O NH ##STR941##573 C.sub.3 H.sub.7 -i O O NH ##STR942##574 C.sub.3 H.sub.7 -i O O NH ##STR943##575 C.sub.3 H.sub.7 -i O O NH ##STR944##576 C.sub.3 H.sub.7 -i O O NCH.sub.3 ##STR945##577 C.sub.3 H.sub.7 -i O O NCH.sub.3 ##STR946##578 C.sub.3 H.sub.7 -i O O NCH.sub.3 ##STR947##579 ##STR948## O O NH ##STR949##580 ##STR950## O O NH ##STR951##581 ##STR952## O O NCH.sub.3 ##STR953##582 ##STR954## O O NCH.sub.3 ##STR955##583 C.sub.3 H.sub.7 -i O O S ##STR956##584 C.sub.3 H.sub.7 -i O O S ##STR957##585 C.sub.3 H.sub.7 -i O O S ##STR958##586 C.sub.3 H.sub.7 -i O O S ##STR959##587 C.sub.3 H.sub.7 -i O O O ##STR960##588 ##STR961## O O O ##STR962##589 C.sub.3 H.sub.7 -i O O O ##STR963##590 C.sub.3 H.sub.7 -i O O O ##STR964##591 ##STR965## O O O ##STR966##592 C.sub.3 H.sub.7 -i O O O ##STR967##593 C.sub.3 H.sub.7 -i O O O ##STR968##594 C.sub.3 H.sub.7 -i O O O ##STR969##595 ##STR970## O O O ##STR971##596 ##STR972## O O O ##STR973##597 C.sub.3 H.sub.7 -i O O O ##STR974##598 C.sub.3 H.sub.7 -i O O O ##STR975##599 ##STR976## O O O ##STR977##600 C.sub.3 H.sub.7 -i O O O ##STR978##601 C.sub.3 H.sub.7 -i O O O ##STR979##__________________________________________________________________________
TABLE 6__________________________________________________________________________ ##STR980##Compound Melting Point (.degree.C.) orNo. R.sup.1 Z.sup.1 Z.sup.2 Z.sup.3 A Reflactive Index (n.sub.D.sup.20)__________________________________________________________________________602 C.sub.4 H.sub.9 -t O O O ##STR981## not determined603 C.sub.4 H.sub.9 -t O O O ##STR982##604 C.sub.4 H.sub.9 -t O O O ##STR983##605 C.sub.4 H.sub.9 -t O O O ##STR984## 1.4784606 C.sub.4 H.sub.9 -t O O O ##STR985## 1.5109607 C.sub.4 H.sub.9 -t O O O ##STR986## not determined608 C.sub.3 H.sub.7 -i O O O ##STR987##609 C.sub.3 H.sub.7 -i O O O ##STR988##610 C.sub.3 H.sub.7 -i O O O ##STR989##611 ##STR990## O O O ##STR991##612 ##STR992## O O O ##STR993##613 ##STR994## O O O ##STR995##614 ##STR996## O O O ##STR997##615 ##STR998## S O O ##STR999##616 ##STR1000## S O O ##STR1001##617 ##STR1002## O S O ##STR1003##618 ##STR1004## O S O ##STR1005##619 ##STR1006## S S O ##STR1007##620 ##STR1008## S S O ##STR1009##621 C.sub.3 H.sub.7 -i O O S ##STR1010##622 C.sub.3 H.sub.7 -i O O S ##STR1011##623 ##STR1012## O O S ##STR1013##624 ##STR1014## O O S ##STR1015##625 ##STR1016## O O S ##STR1017##626 ##STR1018## O O O ##STR1019##627 ##STR1020## O O O ##STR1021##628 ##STR1022## O O O ##STR1023##629 ##STR1024## O O O ##STR1025##630 ##STR1026## O O O ##STR1027##631 ##STR1028## O O O ##STR1029##632 ##STR1030## O O O ##STR1031##633 ##STR1032## O O O ##STR1033##634 C.sub.3 H.sub.7 -i O O O ##STR1034##635 ##STR1035## O O O ##STR1036##636 C.sub.3 H.sub.7 -i O O O ##STR1037##637 ##STR1038## O O O ##STR1039##638 C.sub.3 H.sub.7 -i O O O ##STR1040##639 C.sub.3 H.sub.7 -i O O O ##STR1041##__________________________________________________________________________
TABLE 7__________________________________________________________________________ ##STR1042## Melting Point (.degree.C.) orCompound No. R.sup.1 Z.sup.3 A Reflactive Index (n.sub.D.sup.20)__________________________________________________________________________640 C.sub.4 H.sub.9 -t O ##STR1043##641 C.sub.4 H.sub.9 -t O ##STR1044##642 C.sub.4 H.sub.9 -t O ##STR1045##643 C.sub.3 H.sub.7 -i O ##STR1046## 153-155644 C.sub.3 H.sub.7 -i O ##STR1047##645 C.sub.3 H.sub.7 -i O ##STR1048##646 ##STR1049## O ##STR1050##647 ##STR1051## O ##STR1052##648 ##STR1053## O ##STR1054## 157-160649 ##STR1055## O ##STR1056##650 ##STR1057## O ##STR1058##651 ##STR1059## O ##STR1060##652 ##STR1061## O ##STR1062##653 ##STR1063## O ##STR1064##654 ##STR1065## O ##STR1066##655 ##STR1067## O ##STR1068##656 ##STR1069## O ##STR1070##657 ##STR1071## O ##STR1072##658 ##STR1073## O ##STR1074##659 ##STR1075## O ##STR1076##660 ##STR1077## O ##STR1078##661 ##STR1079## S ##STR1080##662 ##STR1081## S ##STR1082##663 ##STR1083## S ##STR1084##664 ##STR1085## O ##STR1086##665 ##STR1087## O ##STR1088##__________________________________________________________________________
TABLE 8__________________________________________________________________________ ##STR1089## Melting Point (.degree.C.) orCompound No. R.sup.1 Z.sup.3 A Reflactive Index (n.sub.D.sup.20)__________________________________________________________________________666 C.sub.4 H.sub.9 -t O ##STR1090##667 C.sub.4 H.sub.9 -t O ##STR1091##668 C.sub.4 H.sub.9 -t O ##STR1092##669 C.sub.4 H.sub.9 -t O ##STR1093##670 C.sub.3 H.sub.7 -i O ##STR1094##671 C.sub.3 H.sub.7 -i O ##STR1095##672 C.sub.3 H.sub.7 -i O ##STR1096## 1.5111673 ##STR1097## O ##STR1098##674 ##STR1099## O ##STR1100##675 ##STR1101## O ##STR1102##676 ##STR1103## O ##STR1104##677 ##STR1105## O ##STR1106##678 ##STR1107## O ##STR1108##679 ##STR1109## O ##STR1110##680 ##STR1111## O ##STR1112##681 ##STR1113## O ##STR1114##682 ##STR1115## O ##STR1116##683 ##STR1117## O ##STR1118##684 ##STR1119## O ##STR1120##685 ##STR1121## O ##STR1122##686 ##STR1123## O ##STR1124##687 ##STR1125## O ##STR1126##688 ##STR1127## O ##STR1128##689 ##STR1129## O ##STR1130##690 ##STR1131## O ##STR1132##691 ##STR1133## O ##STR1134##692 ##STR1135## S ##STR1136##693 ##STR1137## S ##STR1138##694 ##STR1139## S ##STR1140##695 C.sub.3 H.sub.7 -i O ##STR1141##696 C.sub.3 H.sub.7 -i O ##STR1142##697 ##STR1143## O ##STR1144##698 ##STR1145## O ##STR1146##__________________________________________________________________________
TABLE 9__________________________________________________________________________ ##STR1147## Melting Point (.degree.C.) orCompound No. R.sup.1 Z.sup.3 A Reflactive Index (n.sub.D.sup.20)__________________________________________________________________________699 C.sub.4 H.sub.9 -t O ##STR1148##700 C.sub.4 H.sub.9 -t O ##STR1149##701 C.sub.4 H.sub.9 -t O ##STR1150##702 C.sub.4 H.sub.9 -t O ##STR1151##703 C.sub.3 H.sub.7 -i O ##STR1152##704 C.sub.3 H.sub.7 -i O ##STR1153##705 C.sub.3 H.sub.7 -i O ##STR1154##706 ##STR1155## O ##STR1156##707 ##STR1157## O ##STR1158##708 ##STR1159## O ##STR1160## 128-130709 ##STR1161## O ##STR1162##710 ##STR1163## O ##STR1164##711 ##STR1165## O ##STR1166##712 C.sub.3 H.sub.7 -i O ##STR1167##713 C.sub.3 H.sub.7 -i O ##STR1168##714 C.sub.3 H.sub.7 -i O ##STR1169##715 ##STR1170## O ##STR1171##716 ##STR1172## O ##STR1173##717 C.sub.3 H.sub.7 -i O ##STR1174##718 C.sub.3 H.sub.7 -i O ##STR1175##719 ##STR1176## O ##STR1177##720 ##STR1178## O ##STR1179##721 C.sub.3 H.sub.7 -i S ##STR1180##722 C.sub.3 H.sub.7 -i S ##STR1181##723 C.sub.3 H.sub.7 -i S ##STR1182##724 ##STR1183## S ##STR1184##725 ##STR1185## S ##STR1186##726 ##STR1187## S ##STR1188##__________________________________________________________________________
TABLE 10__________________________________________________________________________ ##STR1189## Melting Point (.degree.C.) orCompound No. R.sup.1 Z.sup.3 A Reflactive Index (n.sub.D.sup.20)__________________________________________________________________________727 C.sub.4 H.sub.9 -t O ##STR1190##728 C.sub.4 H.sub.9 -t O ##STR1191##729 C.sub.4 H.sub.9 -t O ##STR1192##730 C.sub.3 H.sub.7 -i O ##STR1193##731 C.sub.3 H.sub.7 -i O ##STR1194##732 C.sub.3 H.sub.7 -i O ##STR1195##733 ##STR1196## O ##STR1197##734 ##STR1198## O ##STR1199##735 ##STR1200## O ##STR1201##736 C.sub.3 H.sub.7 -i S ##STR1202##737 C.sub.3 H.sub.7 -i S ##STR1203##738 ##STR1204## S ##STR1205##__________________________________________________________________________
TABLE 11__________________________________________________________________________ ##STR1206## Melting Point (.degree.C.) orCompound No. R.sup.1 Z.sup.3 A Reflactive Index (n.sub.D.sup.20)__________________________________________________________________________739 ##STR1207## O ##STR1208##740 C.sub.3 H.sub.7 -i O ##STR1209##741 C.sub.3 H.sub.7 -i O ##STR1210## 150-151742 ##STR1211## O ##STR1212##743 ##STR1213## O ##STR1214##744 ##STR1215## O ##STR1216##745 C.sub.3 H.sub.7 -i S ##STR1217##746 ##STR1218## S ##STR1219##747 C.sub.3 H.sub.7 -i O ##STR1220##748 C.sub.3 H.sub.7 -i O ##STR1221##749 C.sub.3 H.sub.7 -i O ##STR1222##__________________________________________________________________________
TABLE 12__________________________________________________________________________ ##STR1223## Melting Point (.degree.C.) orCompound No. R.sup.1 R.sup.4 R.sup.5 R.sup.6 A Reflactive Index (n.sub.D.sup.20)__________________________________________________________________________750 ##STR1224## H H CH.sub.3 ##STR1225## not determined751 C.sub.4 H.sub.9 -t H H CH.sub.3 ##STR1226## 46-50752 C.sub.3 H.sub.7 -i H H CH.sub.3 ##STR1227##753 ##STR1228## H H CH.sub.3 ##STR1229##754 C.sub.4 H.sub.9 -t H H CH.sub.3 ##STR1230##755 C.sub.3 H.sub.7 -i H H CH.sub.3 ##STR1231##756 ##STR1232## H H CH.sub.3 ##STR1233##757 C.sub.4 H.sub.9 -t H H CH.sub.3 ##STR1234##758 C.sub.3 H.sub.7 -i H H CH.sub.3 ##STR1235##759 ##STR1236## H CH.sub.3 CH.sub.3 ##STR1237##760 C.sub.4 H.sub.9 -t H CH.sub.3 CH.sub.3 ##STR1238##761 C.sub.3 H.sub.7 -i H CH.sub.3 CH.sub.3 ##STR1239##762 ##STR1240## H CH.sub.3 CH.sub.3 ##STR1241##763 C.sub.4 H.sub.9 -t H CH.sub.3 CH.sub.3 ##STR1242##764 C.sub.3 H.sub.7 -i H CH.sub.3 CH.sub.3 ##STR1243##765 ##STR1244## H CH.sub.3 CH.sub.3 ##STR1245##766 C.sub.4 H.sub.9 -t H CH.sub.3 CH.sub.3 ##STR1246##767 C.sub.3 H.sub.7 -i H CH.sub.3 CH.sub.3 ##STR1247##768 ##STR1248## C.sub.3 H.sub.7 -i H H ##STR1249## 150-152769 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 -i H H ##STR1250##770 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i H H ##STR1251## 154-157771 ##STR1252## C.sub.3 H.sub.7 -i H H ##STR1253##772 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 -i H H ##STR1254##773 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i H H ##STR1255##774 ##STR1256## C.sub.3 H.sub.7 -i H H ##STR1257##775 C.sub.4 H.sub.9 -t C.sub.3 H.sub.7 -i H H ##STR1258##776 C.sub.3 H.sub.7 -i C.sub.3 H.sub.7 -i H H ##STR1259##__________________________________________________________________________
The compounds represented by Formula [I] according to the present invention can be prepared, for example, in the following manner. ##STR1260## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, Z.sup.1, Z.sup.2, Z.sup.3, Q, m, and n have the same meanings as defined above.
The compounds represented by Formula [I] according to the present invention can be prepared by reacting an amino acid derivative represented by Formula [IX] or the amino acid derivative wherein the carboxyl group is activated, with an amine represented by Formula [X] in the presence of a base and/or a catalyst, if necessary.
In the present reaction, as the amino acid derivative represented by Formula [IX] with an activated carboxyl group, there can be mentioned, for example, an acid halide such as an acid chloride, an acid anhydride derived from the two molecules of the amino acid derivatives represented by Formula [IX], a mixed acid anhydride derived from the amino acid derivative represented by Formula [IX] and other acid or an O-alkyl carbonic acid, and an activated ester such as p-nitrophenyl ester, 2-tetrahydropyranyl ester, and 2-pyridyl ester and the like. These amino acid derivatives with activated carboxyl groups can be synthesized according to conventional methods [for example, see Methoden der Organischen Chemie, Vol. 15, No. 2, from page 2; Georg Thieme Verlag Stuttgart: 1974; Chemische Berichte, Vol. 38, page 605 (1905); Journal of the American Chemical Society, Vol. 74, page 676 (1952); and Journal of the American Chemical Society, Vol. 86, page 1839 (1964)].
In addition, it is also possible to perform the present reaction using a condensing agent such as N,N'-dicyclohexylcarbodiimide, carbonyldiimidazole, 2-chloro- 1,3-dimethylimidazolium chloride, or the like.
The present reaction can be performed in a conventional solvent: this solvent can be any solvent that does not hinder the reaction, for example, hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene and the like, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene and the like, ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane and the like, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone and the like, esters such as methyl acetate, ethyl acetate and the like, nitriles such as acetonitrile, propionitrile, benzonitrile and the like aprotic polar solvents such as dimethylsulfoxide, dimethylformamide, sulfolane and the like, and mixed solvents combining solvents selected from the aforementioned.
The base can be any type of base generally used in this type of reaction. For example, there can be mentioned hydroxides of alkaline metals such as sodium hydroxide, potassium hydroxide and the like, hydroxides of alkaline earth metals such as calcium hydroxide and the like, carbonates of alkaline metals such as sodium carbonate, potassium carbonate and the like, bicarbonates of alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like, organic bases such as triethylamine, trimethylamine, dimethylaniline, pyridine, N-methylmorpholine, N-methylpiperidine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU), and the like, and preferably tertiary amines such as triethylamine, pyridine, N-methylpiperidine and the like.
As the catalyst, there can be mentioned 4-dimethylaminopyridine, 1-hydroxybenzotriazole, dimethylformamide and the like. The present reaction is carried out at a temperature of -75.degree. C. to 100.degree. C., preferably -60.degree. C. to 40.degree. C. The reaction time is preferably 1 to 20 hours.
Furthermore, compounds represented by formula [IX] as the starting material can generally be synthesized by conventional methods [for example, see Methoden der Organischen Chemie, Vol. 15, No. 2, from page 2; Georg Thieme Verlag Stuttgart: 1974; Chemistry of the Amino Acids, vol. 2, page 891; John Wiley & Sons, New York (1964); and Journal of the American Chemical Society, Vol. 79, page 4686 (1957)]. Various manufacturing methods for compounds [X] can also be considered such as those methods stated in Japanese patent application First Publication No. Sho 63-146876, Tetrahedron Letters, page 21, 1973, and Japanese Patent Application, First Publication, No. Hei 5-271206). ##STR1261## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, Z.sup.1, Z.sup.2, Z.sup.3, Q, m n have the same meanings as defined above, and Y represents a halogen atom, a 4,6-dimenylpyrimidinylthio group, an R.sup.1 OC(O)O-- group, or an --ON.dbd.C(CN)Ph group (in which Ph represents a phenyl group).
Compounds of the present invention represented by Formula [I] can be manufactured by means of reacting the compound represented by Formula [XI] with an amine represented by Formula [XII] or the salt of the amine derivative with an inorganic acid such as hydrochloride and the like, or a salt of the amine derivative with an organic acid such as rosylate and the like, in the presence of a base when required.
The present reaction can be performed in a conventional solvent: this solvent can be any solvent that does not hinder the reaction, for example, hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene and the like, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene and the like, ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane and the like, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone and the like, esters such as methyl acetate, ethyl acetate and the like, nitriles such as acetonitrile, propionitrile, benzonitrile and the like, aprotic polar solvents such as dimethylsulfoxide, dimethylformamide, sulfolane and the like, water, and mixed solvents combining solvents selected from the aforementioned.
The base can be any type of base generally used in this type of reaction. For example, there can be mentioned hydroxides of alkaline metals such as sodium hydroxide, potassium hydroxide and the like, hydroxides of alkaline earth metals such as calcium hydroxide and the like, carbonates of alkaline metals such as sodium carbonate, potassium carbonate and the like, bicarbonates of alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like, organic bases such as triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, pyridine, N-methylpiperidine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0]-undec-7-ene (DBU), and the like, and preferably tertiary amines such as triethylamine, pyridine, N-methylpiperidine and the like. The present reaction is carried out at a temperature of -20.degree. C. to 100.degree. C., preferably 0.degree. C. to 40.degree. C. The reaction time is preferably 30 minutes to 20 hours.
Compounds represented by Formula [XII] as the starting material represent novel compounds, and can be manufactured, for example, by means of treating carbamates of compounds [I] synthesized by the procedure of preparation process A using a conventional process for removing the amino protecting group of the amino acid such as catalytic reduction, or by treating with acids such as liquid hydrofluoric acid, sulfonic acids, hydrochloric acid, hydrobromic acid, formic acid and the like.

In the following, synthesis examples of amino-acid amide derivatives, which are novel intermediates of the compounds of the present invention represented by Formulae [X] and [XII], are provided as reference examples.
REFERENCE EXAMPLE 1
Synthesis of 2-(4-cyanophenoxy)-1-methylethylamine (Intermediate Compound No. 1)
293 g of ammonium acetate and 16.7 g of sodium cyanoborohydride were added to a solution containing 66.5 g of 4-cyanophenoxyacetone dissolved in 1500 mL of methanol, and the resultant mixture was stirred for 30 hours at room temperature. The reaction mixture was then concentrated under reduced pressure, and acidified with concentrated hydrochloric acid. 500 mL of diethyl ether and 300 mL of water were then added thereto. Subsequently, the resultant water layer was made basic with a 5% aqueous solution of sodium hydroxide, the solution was extracted with 1000 mL of diethyl ether, and then washed with water. The organic layer was then dried over anhydrous sodium sulfate, and the diethyl ether was removed under reduced pressure. The obtained residue was distilled under reduced pressure to yield 13.0 g of the desired product (19%). Boiling point: 132.degree. C./0.26 mmHg.
REFERENCE EXAMPLE 2
Synthesis of 2-(4-chloro-2-methylphenoxy)-1-methylethylamine (Intermediate Compound No. 2)
120 g of ammonium acetate and 9.8 g of sodium cyanoborohydride were added to a solution containing 31 g of (4-chloro-2-methylphenoxy)acetone dissolved in 700 mL of methanol, and the resultant mixture was stirred for 20 hours at room temperature. After the reaction mixture was concentrated under reduced pressure, 180 mL of concentrated hydrochloric acid and 100 mL of water were added to the residue. The whole mixture was stirred for 1 hour, and then extracted with 300 mL of diethyl ether. The water layer was alkalifled using a 5% aqueous solution of sodium hydroxide, and then extracted with 500 mL of ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. A fraction possessing a low boiling point was removed from the obtained oily products to afford 25 g (yield 81%) of the desired product. Refractive index: 1.5360.
REFERENCE EXAMPLE 3
Synthesis of 2-(4-chlorophenoxy)-1-methylpropylamine (Intermediate Compound No. 3)
82 g of ammonium acetate and 6.7 g of sodium cyanoborohydridc were added to a solution containing 21 g of 3-(4-chlorophenoxy)-2-butanone dissolved in 500 mL of methanol, and the reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was then concentrated under reduced pressure, and 180 mL of concentrated hydrochloric acid and 100 mL of water were added to the residue. The whole mixture was extracted with 300 mL of diethyl ether. The obtained water layer was alkalifled using a 5% aqueous solution of sodium hydroxide, and then extracted with 500 mL of ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulphate, and then concentrated under reduced pressure. A fraction possessing a low boiling point was removed from the obtained oily products to afford 18 g (yield 86%) of the desired product. Refractive index: 1.5360.
REFERENCE EXAMPLE 4
Synthesis of 1-methyl-2-(2-methylphenoxy)ethylamine (Intermediate Compound No. 4)
A solution containing 36 g of 2-(2-methylphenoxy)acetone oxime O-methyl ether dissolved in 150 mL of dimethoxyethane was added dropwise to a suspension containing 13 g of sodium borohydride in 500 mL of dimethoxyethane at room temperature. After the mixture was stirred for 15 minutes at room temperature, a solution containing 66 g of trifluoroborane diethyl ether complex dissolved in 100 mL of dimethoxyethane was added dropwise to the mixture at room temperature. The reaction mixture was stirred for 30 minutes at room temperature and then refluxed for 3 hours. The resultant mixture was allowed to sit and cool naturally to room temperature and then acidified using a 10% hydrochloric acid. The dimethoxyethane layer was concentrated and combined with the water layer. The mixture was alkalified using sodium carbonate, and then extracted with dichloromethane, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and then the dichloromethane was removed under reduced pressure. The residue was distilled under reduced pressure to obtain 6.4 g (yield 21%) of the desired product. Boiling point: 65.degree. C./0.08 mmHg.
REFERENCE EXAMPLE 5
Synthesis of 2-(4-cyanophenoxy)- 1-methylethylamine (Intermediate Compound No. 1)
50.0 g of 2-amino-1-propanol was added dropwise to a stirred mixture of 29.3 g of 60% sodium hydride and 300 mL of N,N-dimethylformamide at 0.degree. C. After the reaction mixture was stirred for 30 minutes at 0.degree. C., a solution containing 121.2 g of 4-bromobenzonitrile dissolved in N,N-dimethylformamide was added dropwise to the reaction mixture. The resultant mixture was stirred for 20 hours at room temperature. After completion of the reaction, the resultant mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure. The residue was distilled under reduced pressure to obtain 48.0 g of the desired product (yield 41%). Boiling point: 132.degree. C./0.26 mmHg.
REFERENCE EXAMPLE 6
Synthesis of (-)-2-(4-cyanophenoxy)-1-methylethylamine (Intermediate Compound No. 5)
25.0 g of R-(-)-2-amino-1-propanol was added dropwise to a stirred mixture of 14.0 g of 60% sodium hydride and 200 mL of N,N-dimethylformamide at a temperature of 5.degree. C. to 10.degree. C. After the reaction mixture was stirred for 30 minutes, a solution containing 45.0 g of 4-chlorobenzonitrile dissolved in N,N-dimethylformamide was added dropwise to the reaction mixture. The reaction mixture was stirred for 20 hours at room temperature. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure. The residue was distilled under reduced pressure to obtain 33.0 g of the desired product (yield: 56%). Boiling point: 60.degree.-66.degree. C./0.08 mmHg, [.alpha.]D.sup.20 -15.7.degree. (C1.0 CH.sub.3 OH).
REFERENCE EXAMPLE 7
Synthesis of 1-methyl-2-(2-pyrimidyloxy)ethylamine (Intermediate Compound No. 6)
2.0 g of 2-amino-1-propanol was added dropwise to a stirred mixture of 1.3 g of 60% sodium hydride and 30 mL of N,N-dimethylformamide at room temperature. After the reaction mixture was stirred for 30 minutes, a solution containing 3.7 g of 2-chloropyrimidine dissolved in N,N-dimethylformamide was added dropwise to the reaction mixture. The mixture was stirred for 2 hours at 100.degree. C. After completion of the reaction, the reaction mixture was cooled. The solids were filtered off. The solvent in the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 2.1 g of the desired product (yield: 50%). Refractive index: 1.5481.
REFERENCE EXAMPLE 8
Synthesis of 1-methyl-2-(4-pyridyloxy)ethylamine (Intermediate Compound No. 7)
6.2 g of 2-amino-1-propanol was added dropwise to a stirred mixture of 4.0 g of 60% sodium hydride and 50 mL of N,N-dimethylformamide at 5.degree. C.-10.degree. C. After the reaction mixture was stirred for 30 minutes, 12.5 g of 4-chloropyridine hydrochloride in limited amounts was added to the reaction mixture. The mixture was stirred for 20 hours at room temperature. After completion of the reaction, the solids were filtered off. The solvent in the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 3.8 g of the desired product (yield: 30%). Refractive index: 1.5469.
Specific examples of intermediate [X] obtained through the operations of Reference Examples 1 to 8 are shown in Table 13.
TABLE 13______________________________________ ##STR1262##Inter-mediateCom- Reflactive Index (n.sub.D .sup.20)pound orNo. R.sup.6 Xp Boiling Point (.degree.C./mmHg)______________________________________ 8 H 2-OCH.sub.3 96.5/0.15 9 H 3-OCH.sub.3 1.515810 H 4-OCH.sub.3 95/0.1011 H 2-CN 1.556612 H 3-CN 1.540913 H 2-F 70/0.2214 H 3-F 74/0.1515 H 2-NO.sub.2 1.558216 H 2,4-Cl.sub.2 1.547517 H 3,4-Cl.sub.2 107/0.1618 H 3,5-Cl.sub.2 100/0.1219 H 3,4-(OCH.sub.3).sub.2 1.536120 H 3,5-(OCH.sub.3).sub.2 12.5/0.1021 CH.sub.3 4-CN 1.548022 CH.sub.3 4-NO.sub.2 1.6263______________________________________
REFERENCE EXAMPLE 9
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide hydrochloride (Intermediate Compound No. 23)
Hydrogen chloride gas was introduced into a solution containing 3.7 g of N2-tert-butoxycarbonyl-N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide dissolved in 100 mL of methylene chloride for 1 hour at room temperature. After completion of the reaction, the methylene chloride was removed under reduced pressure, thus obtaining a crude crystal. The crude crystal was washed with acetone to afford 3.1 g of the desired product (yield: 100%). Melting point: 59.degree.-63.degree. C.
REFERENCE EXAMPLE 10
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-isoleucinamide (Intermediate Compound No. 24)
Hydrogen chloride gas was introduced into a solution containing 15.0 g of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-isoleucinamide dissolved in 300 mL of methylene chloride for 1 hour at room temperature. After completion of the reaction, the methylene chloride was removed under reduced pressure, thus obtaining a crude crystal. 200 ml of a saturated aqueous solution of sodium bicarbonate and 200 ml of methylene chloride were added to the crude crystal, and the mixture was stirred for 30 minutes and extracted with methylene chloride. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The methylene chloride was removed under reduced pressure. The obtained crude product was washed with acetone to afford 10.0 g of the desired product (yield: 90%). Melting point: 64.degree.-67.degree. C.
Specific examples of Intermediate [XII] obtained through the operations of Reference Examples 9 and 10 are shown in Table 14.
TABLE 14______________________________________ ##STR1263##Inter-mediate Reflactive Index (n.sub.D .sup.20)Com- orpound Boiling PointNo. R.sup.2 Q (.degree.C./mmHg)______________________________________25 C.sub.3 H.sub.7 -i ##STR1264## 73-7526 C.sub.2 H.sub.5 ##STR1265## 43-4427 C.sub.2 H.sub.5 ##STR1266## 1.539128 C.sub.3 H.sub.7 ##STR1267## 1.529929 C.sub.4 H.sub.9 -t ##STR1268## 1.525130 C.sub.3 H.sub.7 -i ##STR1269## 1.5250______________________________________
The Best Mode for Carrying Out the Invention
The methods for producing the compounds according to the present invention as well as the use of the compounds will be described in detail in the following Synthesis Examples.
SYNTHESIS EXAMPLE 1
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[1-methyl-2-(4-nitrophenoxy)ethyl]-L-valinamide (Compound No. 16)
0.5 g of N-methylpiperidine was added to a solution containing 1.1 g of N-tert-butoxycarbonyl-L-valine dissolved in 40 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 0.7 g of isobutyl chloroformate was added to the mixture at -40.degree. C., and stirred for 1 hour at -20.degree. C. 1 g of 1-methyl-2-(4-nitrophenoxy)ethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the dichloromethane layer was successively washed with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue, which was a crude crystal, was purified by column chromatography on silica gel, thus obtaining 0.7 g of the desired product in the form of a yellow powder (yield: 55%).
SYNTHESIS EXAMPLE 2
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -isopropenyloxycarbonyl-L-valinamide (Compound No. 77)
0.6 g of N-methylmorpholine, and subsequently 0.4 g of isopropyl chloroformate were added to a solution containing 0.9 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]L-valinamide hydrochloride dissolved in 50 ml of methylene chloride at -15.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the dichloromethane layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.23 g of the desired product in the form of colorless grains (yield: 13% ).
SYNTHESIS EXAMPLE 3
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -phenoxycarbonyl-L-valinamide (Compound No. 107)
1.3 g of N-methylpiperidine was added to a solution containing 3 g of N-phenoxycarbonyl-L-valine dissolved in 50 mL of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 1.7 g of isobutyl chloroformate was added to the mixture at -40.degree. C., and stirred for 1 hour at -20.degree. C. 2.2 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature, with stirring, and stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue, which was a crude crystal, was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of a white powder (yield: 22%).
SYNTHESIS EXAMPLE 4
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-isoleucinamide (Compound No. 228)
1.3 g of N-methylpiperidine was added to a solution containing 3 of N-tert-butoxycarbonyl-L-isoleucine dissolved in 60 mL of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 1.8 g of isobutyl chloroformate was added to the mixture at -40.degree. C., and stirred for 1 hour at -20.degree. C. 2.3 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of a white powder (yield: 12% ).
Synthesis Example 5
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -(2-phenylthioethyl)-L-valinamide (Compound No. 551)
1 g of N-methylpiperidine was added to a solution containing 2.1 g of N-tert-butoxycarbonyl-L-valine dissolved in 40 mL of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 1.3 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 1.5 g of 2-phenylthioethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.4 g of the desired product in the form of cream yellow grains (yield: 12%).
SYNTHESIS EXAMPLE 6
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[1-methyl-2-(4-nitrophenoxy)propyl]-L-valinamide (Compound No. 606)
0.5 g of N-methylpiperidine was added to a solution containing 1 g of N-tert-butoxycarbonyl-L-valine dissolved in 40 mL of methylene chloride, at -20.degree. C. After the mixture was stirred for 15 minutes at the same temperature, 0.7 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 1 g of 1-methyl-2-(4-nitrophenoxy)propylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue, which was an oily substance, was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of yellow viscous liquid (yield: 56%).
SYNTHESIS EXAMPLE 7
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[2-(3,5-dimethoxyphenoxy)-1-methylethyl]-L-valinamide (Compound No. 22)
0.5 g of N-methylpiperidine was added to a solution containing 1.0 g of N-tert-butoxycarbonyl-L-valine dissolved in 100 mL of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 0.7 g of isobutyl chloroformate was added to the mixture at -40.degree. C., and stirred for 1 hour at -20.degree. C. 1 g of 2-(3,5-cyanophenoxy)-1-methylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue, which was a crude crystal, was purified by column chromatography on silica gel, thus obtaining 1.3 g of the desired product in the form of white powder (yield: 64%).
SYNTHESIS EXAMPLE 8
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[1-methyl-2-(2,4,6-trichlorophenoxy)ethyl]-L-valinamide (Compound No. 25)
1.7 g of N-methylpiperidine was added to a solution containing 3.8 g of N-tert-butoxycarbonyl-L-valine dissolved in 80 mL of methylene chloride, at -20.degree. C. After the mixture was stirred for 15 minutes at the same temperature, 2.4 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 4.5 g of 1-methyl-2-(2,4,6-trichlorophenoxy)ethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 4.6 g of the desired product in the form of a colorless needle crystal (yield: 58%).
SYNTHESIS EXAMPLE 9
Synthesis of N.sup.2 -isopropoxycarbonyl-N.sup.1 -[1-methyl-2-(4-nitrophenoxy)ethyl]-L-valinamide (Compound No. 45)
1.2 g of N-methylpiperidine was added to a solution containing 2.5 g of N-isopropoxycarbonyl-L-valine dissolved in 100 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 1.7 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 2.2 g of 2-(4-nitrophenoxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.3 g of the desired product in the form of a yellow vitrified substance (yield: 6%).
______________________________________.sup.1 H-NMR: (CDCl.sub.3, .delta.)______________________________________ 1.16-1.33 (6H, m) 1.43-1.36 (9H, m) 2.56 (1H, m) 4.01 (2H, m) 4.00-5.33 (3H, m) 6.17 (1H, d) 6.87 (2H, d) 8.06 (2H, d)______________________________________
SYNTHESIS EXAMPLE 10
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -cyclohexyloxycarbonyl-L-valinamide (Compound No. 97)
0.8 g of N-methylpiperidine was added to a solution containing 2.0 g of N-cyclohexyloxycarbonyl-L-valine dissolved in 150 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 1.1 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 1.5 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.5 g of the desired product in the form of light brown powder (yield: 16%).
SYNTHESIS EXAMPLE 11
Synthesis of N.sup.1 -[1-methyl-2-(4-trifluoromethylphenoxy)ethyl]-N.sup.2 -phenoxycarbonyl-L-valinamide (Compound No. 114)
1.6 g of N-methylpiperidine was added to a solution containing 4.0 g of N-phenoxycarbonyl-L-valine dissolved in 80 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 15 minutes at the same temperature, 2.2 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 3.5 g of 1-methyl-2-(4-trifluoromethylphenoxy)ethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 2.8 g of the desired product in the form of a white crystal (yield: 40%).
SYNTHESIS EXAMPLE 12
Synthesis of N.sup.1 -[1-methyl-2-(4-trifluoromethoxyphenoxy)ethyl]-N.sup.2 -phenoxycarbonyl-L-valinamide (Compound No. 115)
1.7 g of N-methylpiperidine was added to a solution containing 4.0 g of N-phenoxycarbonyl-L-valine dissolved in 80 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 15 minutes at the same temperature, 2.3 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C.
4.0 g of 1-methyl-2-(4-trifluoromethoxyphenoxy)ethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 3.4 g of the desired product in the form of a white crystal (yield: 45%).
SYNTHESIS EXAMPLE 3
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -phenoxycarbonyl-L-valinamide (Compound Nos. 116 and 117)
1.8 g of N-methylpiperidine was added to a solution containing 4.2 g of N-phenoxycarbonyl-L-valine dissolved in 100 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 2.4 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 3.1 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.0 g of a white powder. 0.6 g of the obtained white powder was purified using high pressure liquid chromatography (hereinafter, referred to as "HPLC") (YMC-063-15, hexane/ethyl acetate=55/45) to separate two fractions. The ingredient of the first fraction possessing a short retention time was 0.3 g of a white powder (yield: 7%) possessing 145.degree. to 147.degree. C. of melting point and the ingredient of the second fraction possessing a long retention time was 0.3 g of a white powder (yield: 7%) possessing a melting point of 166.degree. to 170.degree. C. of melting point.
SYNTHESIS EXAMPLE 14
Synthesis of N.sup.2 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -(3-methoxyphenoxycarbonyl)-L-valinamide (Compound No. 166)
1.0 g of N-methylmorpholine was added to a solution containing 1.5 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide hydrochloride dissolved in 100 ml of methylene chloride, at -20.degree. C. After 0.9 g of 3-methoxyphenyl chloroformate was added to the mixture at -20.degree. C., the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 2 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.25 g of the desired product in the form of a white plated crystal (yield: 12%).
SYNTHESIS EXAMPLE 15
Synthesis of N.sup.2 -(2-chloroethoxycarbonyl)-N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide (Compound No. 184)
0.5 g of N-methylpiperidine was added to a solution containing 1.1 g of N-(2-chloroethoxycarbonyl)-L-valine dissolved in 40 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 15 minutes at the same temperature, 0.7 g of isobutyl chloroformate was added to the mixture at -40.degree. C., and stirred for 1 hour at -20.degree. C. 0.9 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue, which was an oily substance, was purified by column chromatography on silica gel, thus obtaining 1.0 g of the desired product in the form of colorless grains (yield: 52%).
SYNTHESIS EXAMPLE 16
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -(4-methylbenzyloxycarbonyl)-L-valinamide (Compound No. 195)
0.6 g of N-methylpiperidine was added to a solution containing 1.5 g of N-(4-methylbenzyloxycarbonyl)-L-valine dissolved in 100 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 0.8 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 1.0 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue, which was a crude crystal, was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of light white powder (yield: 28%).
SYNTHESIS EXAMPLE 17
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -phenoxythiocarbonyl-L-valinamide (Compound No. 208)
0.4 g of N-methyhnorpholine was added to a suspension containing 1.1 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 40 ml of methylene chloride, at -15.degree. C. After 0.7 g of phenyl chlorothionoformate was added to the mixture at -15.degree. C., the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.2 g of the desired product in the form of a yellow glutinous substance (yield: 75%).
______________________________________.sup.1 H-NMR: (CDCl.sub.3, .delta.)______________________________________ 1.05 (6H, m) 1.35 (3H, m) 2.30 (1H, m) 4.00 (2H, m) 4.44 (1H, m) 4.54 (1H, m) 6.16, 6.25 (1H, d) 7.26 (9H, m) 7.51 (1H, br)______________________________________
SYNTHESIS EXAMPLE 18
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -(phenylthio)thiocarbonyl-L-valinamide (Compound No. 211)
0.5 g of N-methylmorpholine was added to a suspension containing 1.4 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 40 ml of methylene chloride, at -15.degree. C. After 0.9 g of phenyl chlorodithioformate was added to the mixture at -15.degree. C., the reaction mixture was allowed to sit and, warm naturally to room temperature while being stirred, and was stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.4 g of the desired product in the form of a yellow glutinous substance (yield: 66%).
______________________________________.sup.1 H-NMR: (CDCl.sub.3, .delta.)______________________________________ 0.83 (6H, m) 1.30, 1.32 (3H, d) 2.13 (1H, m) 3.96 (2H, m) 4.35 (1H, m) 4.78 (1H, dd) 6.04, 6.13 (1H, d) 6.93, 6.98 (2H, d) 7.15, 7.22 (1H, d) 7.57 (7H, m)______________________________________
SYNTHESIS EXAMPLE 19
Synthesis of N.sup.1 -(1-methyl-2-phenylthioethyl)-N.sup.2 -phenoxycarbonyl-L-valinamide (Compound No. 212)
1.3 g of N-methylmorpholine was added to a suspension containing 3.0 g of N.sup.1 -(1-methyl-2-phenylthioethyl)-L-valinamide hydrochloride suspended in 80 ml of methylene chloride, at -15.degree. C. After 1.9 g of phenyl chloroformate was added to the mixture at -15.degree. C., the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 2.3 g of the desired product in the form of a white crystal (yield: 54%).
SYNTHESIS EXAMPLE 20
Synthesis of N.sup.1 -[2-(4-chloroanilino)-1-methylethyl]-N.sup.2 -isopropoxycarbonyl-L-valinamide (Compound No. 221)
1.9 g of N-methylpiperidine was added to a solution containing 3.8 g of N-isopropoxycarbonyl-L-valine dissolved in 80 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 15 minutes at the same temperature, 2.6 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 3.5 g of 2-(4-chloroanilino)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 3.3 g of the desired product in the form of a white crystal (yield: 47%).
SYNTHESIS EXAMPLE 21
Synthesis of 2-tert-butoxycarbonylamino-N-[2-(4-chlorophenoxy)-1-methylethyl]-(2S)-butyramide (Compound No. 233)
2.0 g of N-methylpiperidine was added to a solution containing 4.1 g of (2S)-2-tert-butoxycarbonylaminobutyric acid dissolved in 60 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 2.7 g of isobutyl chloroformate was added to the mixture at -40.degree. C., and stirred for 1 hour at -20.degree. C. 3.7 g of 2-(4-chlorophenoxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 5.6 g of the desired product in the form of a colorless glutinous substance (yield: 76%).
SYNTHESIS EXAMPLE 22
Synthesis of 2-tert-butoxycarbonylamino-N-[2-(4-cyanophenoxy)-1-methylethyl]-(2S)-butyramide (Compound No. 235)
0.5 g of N-methylpiperidine was added to a solution containing 1.0 g of (2S)-2-tert-butoxycarbonylaminobutyric acid dissolved in 40 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 0.7 g of isobutyl chloroformate was added to the mixture at -20.degree. C., and stirred for 1 hour at -20.degree. C. 0.9 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.0 g of the desired product in the form of a glutinous substance (yield: 54%).
______________________________________.sup.1 H-NMR: (CDCl.sub.3, .delta.)______________________________________ 0.94 (3H, t) 1.20-1.50 (12H, m) 1.69 (2H, m) 3.83-4.56 (4H, m) 5.30 (1H, d) 6.60 (1H, m) 6.90 (2H, d) 7.50 (2H, d)______________________________________
SYNTHESIS EXAMPLE 23
Synthesis of N.sup.1 -[2-(4-chlorobenzyloxy)-1methylethyl]-N.sup.2 -isopropoxycarbonyl-L-valinamide (Compound No. 246)
0.5 g of N-methylpiperidine was added to a solution containing 1 g of N-isopropoxycarbonyl-L-valine dissolved in 40 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 15 minutes at the same temperature, 0.7 g of isobutyl chloroformate was added to the mixture at -40.degree. C., and stirred for 1 hour at -20.degree. C. 1 g of 2-(4-chlorobenzyloxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained oily residue was purified by column chromatography on silica gel, thus obtaining 0.9 g of the desired product in the form of a colorless plated crystal (yield: 48%).
SYNTHESIS EXAMPLE 24
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[1-methyl-2-(4-methylthiophenoxy)ethyl]-L-valinamide (Compound No. 327)
3.4 g of N-methylpiperidine was added to a solution containing 7.5 g of N-tert-butoxycarbonyl-L-valine dissolved in 100 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 4.7 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 6.8 g of 1-methyl-2-(4-methylthiophenoxy)ethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The obtained oily residue was purified by column chromatography on silica gel, thus obtaining 6.2 g of the desired product in the form of a colorless prism-shaped crystal (yield: 46%).
SYNTHESIS EXAMPLE 25
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[1-methyl-2-(4-methylsulfinylphenoxy)ethyl]-L-valinamide (Compound No. 328)
1.5 g of m-chloroperbenzoic acid was added to a solution containing 3.0 g of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[1-methyl-2-(4-methylthiophenoxy)ethyl]-L-valinamide dissolved in 60 ml of methylene chloride, at 0.degree. C. After the mixture was stirred for 5 hours at room temperature, the reaction mixture was filtered. The filtrate was washed successively with a saturated aqueous solution of potassium carbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The obtained oily residue was purified by column chromatography on silica gel, thus obtaining 1.7 g of the desired product in the form of a colorless crystal (yield: 56%).
SYNTHESIS EXAMPLE 26
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[1-methyl-2-(4-methylsulfonylphenoxy)ethyl]-L-valinamide (Compound No. 329)
2.1 g of m-chloroperbenzoic acid was added to a solution containing 2.0 g of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[1-methyl-2-(4-methylthiophenoxy)ethyl]-L-valinamide dissolved in 50 ml of methylene chloride, at 0.degree. C. After the mixture was stirred for 8 hours at a reflux temperature, the reaction mixture was allowed to sit and cool naturally to room temperature and filtered. The filtrate was washed successively with a saturated aqueous solution of potassium carbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The obtained residue was purified by column chromatography on silica gel, thus obtaining 1.3 g of the desired product in the form of a colorless prism-shaped crystal (yield: 60%).
SYNTHESIS EXAMPLE 27
Synthesis of N.sup.1 -[2-(4-fluorophenylsulfinyl)-1-methylethyl]-N.sup.2 -isopropoxycarbonyl-L-valinamide (Compound No. 354)
1.3 g of m-chloroperbenzoic acid was added to a solution containing 2.5 g of N.sup.1 -[2-(4-fluorophenylthio)-1-methylethyl]-N.sup.2 -isopropoxycarbonyl-L-valinamide dissolved in 50 ml of methylene chloride, at 0.degree. C. After the mixture was stirred for 5 hours at room temperature, the reaction mixture was filtered. The filtrate was washed successively with a saturated aqueous solution of potassium carbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The obtained residue was purified by column chromatography on silica gel, thus obtaining 1.8 g of the desired product in the form of a colorless prism-shaped crystal (yield: 69%).
SYNTHESIS EXAMPLE 28
Synthesis of N.sup.1 -[2-(4-fluorophenylsulfonyl)-1-methylethyl]-N.sup.2 -isopropoxycarbonyl-L-valinamide (Compound No. 355)
3.4 g of m-chloroperbenzoic acid was added to a solution containing 2.2 g of N.sup.1 -[2-(4-fluorophenylthio)-1-methylethyl]-N.sup.2 -isopropoxycarbonyl-L-valinamide dissolved in 50 ml of methylene chloride, at 0.degree. C. After the mixture was stirred for 8 hours at a reflux temperature, the reaction mixture was allowed to sit and cool to room temperature, and then filtered. The filtrate was washed successively with a saturated aqueous solution of potassium carbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The obtained residue was purified by column chromatography on silica gel, thus obtaining 2.0 g of the desired product in the form of a white crystal (yield: 83%).
SYNTHESIS EXAMPLE 29
Synthesis of N.sup.2 -isopropoxycarbonyl-N.sup.1 -[1-methyl-2-(2-methylphenylthio)ethyl]-L-valinamide (Compound No. 367)
1.9 g of N-methylpiperidine was added to a solution containing 3.9 g of N-isopropoxycarbonyl-L-valine dissolved in 80 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 2.6 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 3.5 g of 1-methyl-2-(2-methylphenylthio)ethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 3.6 g of the desired product in the form of a white crystal (yield: 51%).
SYNTHESIS EXAMPLE 30
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl)-N.sup.2 -(3-tetrahydrofuranyl)oxycarbonyl-L-valinamide (Compound No. 376)
1.0 g of N-methylmorpholine, and subsequently 0.7 g of 3-tetrahydrofuranyl chloroformate were added to a suspension containing 1.5 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide hydrochloride suspended in 100 ml of methylene chloride at -20.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 2 hours at room temperature. Water was subsequently added to the reaction mixture. After the dichloromethane layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of white powder (yield: 61%).
SYNTHESIS EXAMPLE 31
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -(3-methylcyclohexyloxycarbonyl)-L-valinamid (Compound No. 379)
0.4 g of N-methylmorpholine, and subsequently 0.8 g of 3-methylcyclohexyl chloroformate were added to a suspension containing 1.0 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 50 ml of methylene chloride at -15.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.2 g of the desired product in the form of a white crystal (yield: 80% ).
SYNTHESIS EXAMPLE 32
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -propargyloxycarbonyl-L-valinamide (Compound No. 381)
0.2 g of N-methylmorpholine, and subsequently 0.2 g of propargyl chloroformate were added to a suspension containing 0.5 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 30 ml of methylene chloride at -15.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.5 g of the desired product in the form of white powder (yield: 78%).
SYNTHESIS EXAMPLE 33
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -(2-methoxy-1-methylethyl)oxycarbonyl-L-valinamide (Compound No. 383)
1.0 g of N-methylmorpholine, and subsequently 0.7 g of 2-methoxy-1-methylethyl chloroformate were added to a suspension containing 1.5 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 150 ml of methylene chloride at -20.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 2 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.37 g of the desired product in the form of a white plated crystal (yield: 20%).
SYNTHESIS EXAMPLE 34
Synthesis of N.sup.1 -[2-(4-fluoro-N-methylanilino)-1-methylethyl]-N.sup.2 -phenoxycarbonyl-L-valinamide (Compound No. 391)
1.6 g of N-methylpiperidine was added to a solution containing 3.9 g of N-phenoxycarbonyl-L-valine dissolved in 80 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 2.2 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 3.0 g of 2-(4-fluoro-N-methylanilino)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.2 g of the desired product in the form of a white crystal (yield: 19%).
SYNTHESIS EXAMPLE 35
Synthesis of N.sup.2 -(4-chlorophenoxycarbonyl)-N.sup.1 -[2-(4-cyanophenoxy-1-methylethyl]-L-valinamide (Compound Nos. 395 and 396)
1.7 g of N-methylpiperidine was added to a solution containing 4.7 g of N-(4-chlorophenoxycarbonyl)-L-valine dissolved in 250 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 2.3 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 3.0 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 0.4 g of the desired product in the form of white powder. In addition, the powder was purified by HPLC (YMC-063-15, hexane/ethyl acetate=55/45) to separate two fractions. One fraction possessing a short retention time was 0.17 g of white powder possessing 137.degree.-140.degree. C. of melting point (yield: 2%), and another fraction possessing a long retention time was 0.17 g of white powder possessing a melting point of 174.degree.-179.degree. C. (yield: 2%).
SYNTHESIS EXAMPLE 36
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -(2-nitrophenoxycarbonyl-L-valinamide (Compound No. 400)
1.3g of N-methylmorpholine, and subsequently 2.5 g of 2nitrophenyl chloroformate were added to a suspension containing 3.4 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 100 ml of methylene chloride at -20.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 2 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.0 g of the desired product in the form of a yellow plated crystal (yield: 18%).
SYNTHESIS EXAMPLE 37
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -(4-fluorophenoxycarbonyl)-L-valinamide (Compound. No. 401)
1.2 g of N-methylpiperidine was added to a solution containing 3.0 g of N-(4-fluorophenoxycarbonyl)-L-valine dissolved in 80 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 15 minutes at the same temperature, 1.6 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 2.3 g of (-)-2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of a white crystal (yield: 23% ).
SYNTHESIS EXAMPLE 38
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -(3,4-dimethylphenoxycarbonyl)-L-valinamide (Compound No. 403)
0.6 g of N-methylmorpholine, and subsequently 1.2 g of 3,4-dimethylphenyl chloroformate were added to a suspension containing 1.5 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 50 ml of methylene chloride at -15.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.7 g of the desired product in the form of a white crystal (yield: 74%).
SYNTHESIS EXAMPLE 39
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[2-(2-pyridyloxy)-1-methylethyl]-L-valinamide (Compound No. 409)
2.0 g of N-methylpiperidine was added to a solution containing 4.3 g of N-tert-butoxycarbonyl-L-valine dissolved in 80 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 2.7 g of isobutyl chloroformate was added to the mixture at -40.degree. C., and stirred for 1 hour at -20.degree. C. 3.3 g of 2-(2-pyridyloxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 2.0 g of the desired product in the form of colorless grains (yield: 28%).
SYNTHESIS EXAMPLE 40
Synthesis of N.sup.1 -[2-(5-chloro-2-pyridyloxy)-1-methylethyl]-N.sup.2 -isopropyloxycarbonyl-L-valinamide (Compound No. 412)
0.8 g of N-methylmorpholine, and subsequently 0.5 g of isopropyl chloroformate were added to a suspension containing 1.4 g of N.sup.1 -[2-(5-chloro-2-pyridyloxy)-1-methylethyl]-L-valinamide hydrochloride suspended in 50 ml of methylene chloride at -15.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of colorless grains (yield: 38%).
SYNTHESIS EXAMPLE 41
Synthesis of N.sup.1 -[2-(5-chloro-2-pyridyloxy)-1-methylethyl]-N.sup.2 -phenoxycarbonyl-L-valinamide (Compound No. 413)
0.8 g of N-methylmorpholine, and subsequently 0.7 g of phenyl chloroformate were added to a suspension containing 1.4 g of N.sup.1 -[2-(5-chloro-2-pyridyloxy)-1-methylethyl]-L-valinamide hydrochloride suspended in 50 ml of methylene chloride at -15.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of colorless grains (yield: 34%).
SYNTHESIS EXAMPLE 42
Synthesis of N.sup.1 -[2-(4-fluoro-N-methylanilino)-1-methylethyl]-N.sup.2 -phenoxycarbonyl-L-isoleucinamide (Compound No. 422)
1.9 g of N-methylpiperidine was added to a solution containing 4.8 g of N-phenoxycarbonyl-L-isoleucine dissolved in 80 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 2.6 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 3.5 g of 2-(4-fluoro-N-methylanilino)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of a white crystal (yield: 13%).
SYNTHESIS EXAMPLE 43
Synthesis of N.sup.2 -(ethylthio)carbonyl-N.sup.1 -[1-methyl-2-(4-nitrophenoxy)ethyl]-L-valinamide (Compound No. 432)
0.3 g of N-methylmorpholine, and subsequently 0.4 g of ethyl chlorothioformate were added to a suspension containing 0.9 g of N.sup.1 -[1-methyl-2-(4-nitrophenoxy)ethyl]-L-valinamide suspended in 50 ml of methylene chloride at -15.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.0 g of the desired product in the form of yellow grains (yield: 79%).
SYNTHESIS EXAMPLE 44
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-leucinamide (Compound No. 455)
1.5 g of N-methylpiperidine was added to a solution containing 3.4 g of N-tert-butoxycarbonyl-L-leucine dissolved in 60 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 2.0 g of isobutyl chloroformate was added to the mixture at -40.degree. C., and stirred for 1 hour at -20.degree. C. 2.6 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 5.1 g of the desired product in the form of a colorless glutinous substance (yield: 86%).
______________________________________.sup.1 H-NMR: (CDCl.sub.3, .delta.)______________________________________ 0.92 (6H, m) 1.28, 1.32 (3H, d) 1.39, 1.43 (9H, s) 1.46, 1.65 (2H, m) 1.65 (1H, m) 3.98 (2H, m) 4.06 (1H, m) 4.35 (1H, m) 4.91 (1H, br) 6.46 (1H, br) 6.97 (2H, d) 7.57 (2H, dd)______________________________________
SYNTHESIS EXAMPLE 45
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-tert-leucinamide (Compound No. 457)
1.7 g of N-methylpiperidine was added to a solution containing 4 g of N-tert-butoxycarbonyl-L-tert-leucine dissolved in 50 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 2.4 g of isobutyl chloroformate was added to the mixture at -40.degree. C., and stirred for 1 hour at -20.degree. C. 3.1 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 3.9 g of the desired product in the form of a colorless amorphous substance (yield: 58%).
SYNTHESIS EXAMPLE 46
Synthesis of 2-tert-butoxycarbonylamino-3-methyl-N-[2-(4-cyanophenoxy)-1-methylethyl]-3-butenic acid amide (Compound No. 460)
0.5 g of N-methylpiperidine was added to a solution containing 1.1 g of 2-tert-butoxycarbonylamino-3-methyl-3-butenic acid dissolved in 40 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 0.7 g of isobutyl chloroformate was added to the mixture at -40.degree. C., and stirred for 1 hour at -20.degree. C. 1.9 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 0.3 g of the desired product in the form of a colorless glutinous substance (yield: 32%).
SYNTHESIS EXAMPLE 47
Synthesis of N-[2-(4-cyanophenoxy)-1-methylethyl]-2-isopropoxycarbonylaminocyclopentylacetic acid amide (Compound No. 462)
0.4 g of N-methyhnorpholine, and subsequently 0.5 g of isopropyl chloroformate were added to a suspension containing 1.2 g of 2-amino-N-[2-(4-cyanophenoxy)-1-methylethyl]cyclopentylacetic acid amide suspended in 40 ml of methylene chloride at -15.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.4 g of the desired product in the form of a colorless plated crystal (yield: 90%).
SYNTHESIS EXAMPLE 48
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -phenoxycarbonyl-L-norvalinamide (Compound No. 465)
0.5 g of N-methylmorpholine, and subsequently 0.8 g of phenyl chloroformate were added to a suspension containing 1.4 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-norvalinamide suspended in 40 ml of methylene chloride at -15.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of a colorless plated crystal (yield: 57%).
SYNTHESIS EXAMPLE 49
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-N.sup.2 -phenoxycarbonyl-L-leucinamide (Compound No. 466)
0.5 g of N-methylmorpholine, and subsequently 0.8 g of phenyl chloroformate were added to a suspension containing 1.5 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-leucinamide suspended in 40 ml of methylene chloride at -15.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed tinder reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.5 g of the desired product in the form of colorless powder (yield: 73%)
SYNTHESIS EXAMPLE 50
Synthesis of 2-(4-chlorophenoxycarbonylamino)-N-[2-(4-cyanophenoxy)-1-methylethyl]cyclopentylacetic acid amide (Compound No. 471)
0.4 g of N-methylmorpholine, and subsequently 0.8 g of 4-chlorophenyl chloroformate were added to a suspension containing 1.2 g of 2-amino-N-[2-(4-cyanophenoxy)-1-methylethyl]cyclopentylacetic acid amide suspended in 40 ml of methylene chloride at -15.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of colorless grains (yield: 30%).
SYNTHESIS EXAMPLE 51
Synthesis of N.sup.2 -benzyloxycarbonyl-N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-(4-chlorophenyl)glycinamide (Compound No. 475)
0.4 g of N-methyhnorpholine, and subsequently 0.6 g of benzyl chloroformate were added to a suspension containing 1.3 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-(4-chlorophenyl)glycinamide suspended in 40 ml of methylene chloride at -15.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.2 g of the desired product in the form of colorless grains (yield: 70%).
SYNTHESIS EXAMPLE 52
Synthesis of N.sup.2 -(1-cyano-1-methylethoxycarbonyl)-N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide (Compound No. 476)
0.5 g of N-methylmorpholine, and subsequently 0.4 g of 1-cyano-1-methylethyl chloroformate were added to a suspension containing 0.7 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide hydrochloride suspended in 50 ml of methylene chloride at -20.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 3 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of colorless grains (yield: 71%).
SYNTHESIS EXAMPLE 53
Synthesis of N.sup.2 -(2-chlorocyclohexyloxycarbonyl)-N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide (Compound No. 477)
0.4 g of N-methylmorpholine, and subsequently 0.9 g of 2-chlorocyclohexyl chloroformate were added to a suspension containing 1.0 g of N.sup.1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide hydrochloride suspended in 50 ml of methylene chloride at -20.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of a white crystal (yield: 71%).
SYNTHESIS EXAMPLE 54
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[2-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-1-methylethyl]-L-valinamide (Compound No. 479)
2.0 g of N-methylpiperidine was added to a solution containing 5.6 g of N-tert-butoxycarbonyl-L-valine dissolved in 100 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 2.7 g of isobutyl chloroformate was added to the mixture at -40.degree. C., and stirred for 1 hour at -20.degree. C. 1.5 g of 2-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-1-methylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature, with stirring, and stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 7.0 g of the desired product in the form of colorless grains (yield: 77%).
SYNTHESIS EXAMPLE 55
Synthesis of N.sup.1 -[1-(5-chloro-6-ethyl-4-pyrimidinyloxy)-2-propyl]-N.sup.2 -isopropoxycarbonyl-L-valinamide (Compound No. 481)
0.34 g of N-methylpiperidine was added to a solution containing 0.7 g of N-isopropoxycarbonyl-L-valine dissolved in 50 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 0.47 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 0.74 g of 1-(5-chloro-6-ethyl-4-pyrimidinyloxy)-2-propylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of a white prism-shaped crystal (yield: 43%).
SYNTHESIS EXAMPLE 56
Synthesis of N-tert-butoxycarbonyl-L-valyl-N-(4-chlorophenyl)-N-methyl-DL-alaninamide (Compound No. 490)
0.9 g of N-methylpiperidine was added to a solution containing 2.0 g of N-tert-butoxycarbonyl-L-valine dissolved in 40 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 1.3 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 2.0 g of N.sup.1 -(4-chlorophenyl)-N.sup.1 -methyl-DL-alaninamide was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 3.4 g of the desired product in the form of a colorless needle crystal (yield: 87%).
SYNTHESIS EXAMPLE 57
Synthesis of N-isopropoxycarbonyl-L-isoleucyl-N-(4-cyanophenyl)-D-alaninamide (Compound No. 506)
0.26 g of N-methylpiperidine was added to a solution containing 0.57 g of N-isopropoxycarbonyl-L-isoleucine dissolved in 60 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 0.36 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 0.5 g of N.sup.1 -(4-cyanophenyl)-D-alaninamide was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.5 g of the desired product in the form of white powder (yield: 49%).
SYNTHESIS EXAMPLE 58
Synthesis of N-cyclohexyloxycarbonyl-L-valyl-N-(4-cyanophenyl)-D-alaninamide (Compound No. 509)
0.6 g of N-methyhnorpholine, and subsequently 0.6 g of cyclopentyl chloroformate were added to a suspension containing 1.0 g of L-valyl-N-(4-cyanophenyl)alaninamide, hydrochloride suspended in 50 ml of methylene chloride at -20.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of a white crystal (yield: 49% ).
SYNTHESIS EXAMPLE 59
Synthesis of N-phenoxycarbonyl-L-valyl-N-(4-chlorobenzyl)-DL-alaninamide (Compound No. 516)
0.55 g of N-methyhnorpholine, and subsequently 0.43 g of phenyl chloroformate were added to a suspension containing 0.95 g of L-valyl-N-(4-chlorobenzyl)-DL-alaninamide, hydrochloride suspended in 50 ml of methylene chloride at -15.degree. C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.9 g of the desired product in the form of white powder (yield: 75%).
SYNTHESIS EXAMPLE 60
Synthesis of N-phenoxycarbonyl-L-valyl-DL-alanine phenyl ester (Compound No. 522)
0.24 g of N-methylpiperidine was added to a solution containing 0.57 g of N-phenoxycarbonyl-L-valine dissolved in 40 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 0.33 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 0.5 g of DL-alanine phenyl ester was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.2 g of the desired product in the form of white powder (yield: 20%).
SYNTHESIS EXAMPLE 61
Synthesis of N.sup.1 -(4-cyanophenyl)-N.sup.2 -(2-phenoxycarbonylamino)-(2S)-butyryl-D-alaninamide (Compound No. 524)
0.45 g of N-methylpiperidine was added to a solution containing 1.0 g of (2S)-2-phenoxycarbonylaminobutyric acid dissolved in 50 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 0.61 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 0.85 g of N.sup.1 -(4-cyanophenyl)-D-alaninamide was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 0.8 g of the desired product in the form of white powder (yield: 45%).
SYNTHESIS EXAMPLE 62
Synthesis of N-isopropoxycarbonyl-L-valyl-N-(4-cyanophenyl)glycinamide (Compound No. 526)
0.3 g of N-methylpiperidine was added to a solution containing 0.6 g of N-isopropoxycarbonyl-L-valine dissolved in 40 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 0.4 g of isobutyl chloroformate was added to the n-fixture, and stirred for 1 hour at -20.degree. C. 0.5 g of N.sup.1 -(4-cyanophenyl)glycinamide was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.5 g of the desired product in the form of colorless powder (yield: 49%).
SYNTHESIS EXAMPLE 63
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -(1,2-dimethyl-2-phenoxyethyl)-L-valinamide (Compound No. 602)
0.6 g of N-methylpiperidine was added to a solution containing 1.3 g of N-tert-butoxycarbonyl-L-valine dissolved in 40 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 15 minutes at the same temperature, 0.8 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 1 g of 1,2-dimethyl-2-phenoxyethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained oily substance was purified by column chromatography on silica gel, thus obtaining 1.3 g of the desired product in the form of a white glutinous substance (yield: 57%).
______________________________________.sup.1 H-NMR: (CDCl.sub.3, .delta.)______________________________________ 0.8-1.02 (6H, m) 1.18-1.45 (15H, m) 2.10 (1H, m) 3.65-4.45 (3H, m) 5.18 (1H, m) 6.38 (1H, m) 6.72-7.35 (5H, m)______________________________________
SYNTHESIS EXAMPLE 64
Synthesis of N.sup.2 -tert-butoxycarbonyl-N.sup.1 -[2-(4-cyanophenoxy)-1,2-dimethylethyl]-L-valinamide (Compound No. 607)
0.5 g of N-methylpiperidine was added to a solution containing 1.1 g of N-tert-butoxycarbonyl-L-valine dissolved in 60 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 0.7 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20.degree. C. 1.0 g of 2-(4-cyanophenoxy)-1,2-dimethylethylamine was added to this mixture at -60.degree. C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.2 g of the desired product in the form of a colorless glassy substance (yield: 61%).
______________________________________.sup.1 H-NMR: (CDCl.sub.3, .delta.)______________________________________ 0.79-1.03 (6H, m) 1.15-1.46 (15H, m) 2.03 (1H, m) 3.63-4.72 (3H, m) 5.06 (1H, m) 6.30 (1H, m) 6.83-7.60 (4H, m)______________________________________
SYNTHESIS EXAMPLE 65
Synthesis of N.sup.1 -[2-(4-cyanophenoxy)propyl]-N.sup.2 -phenoxycarbonyl-L-valinamide (Compound No. 750)
0.16 g of N-methylpiperidine was added to a suspension containing 0.25 g of N.sup.1 -[2-(4-cyanophenoxy)propyl]-L-valinamide hydrochloride suspended in 20 ml of methylene chloride, at -20.degree. C. After the mixture was stirred for 10 minutes at the same temperature, 0.13 g of phenyl chloroformate was added drop by drop to the mixture, and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 3 hours at room temperature. After the methylene chloride was removed under reduced pressure, the residue was purified by column chromatography on silica gel, thus obtaining 0.2 g of the desired product in the form of a white glutinous substance (yield: 63%).
______________________________________.sup.1 H-NMR: (CDCl.sub.3, .delta.)______________________________________ 1.00 (6H, m) 1.23 (3H, d) 2.13 (1H, m) 3.31 (1H, m) 4.00 (2H, m) 4.49 (1H, m) 5.93 (1H, d) 6.52 (1H, m) 6.80-7.56 (9H, m)______________________________________
The agricultural or horticultural fungicide according to the present invention is a composition containing an amino acid amide derivative represented by Formula [I] as an active ingredient. In the case where the compounds according to the present invention are employed as an agricultural or horticultural fungicide, the compounds acting as the active ingredient can be formulated appropriately, depending on the purpose. The active ingredient is usually diluted in an inert liquid or a solid carrier, and a surfactant or the like is added thereto, if necessary. The mixture is then formulated in a known manner into, for example, a fine powder, a wettable powder, an emulsifiable concentrate, granules, or the like.
Suitable examples of carriers employed in the formulation are solid carriers such as talc, bentonite, clay, kaolin, diatomaceous earth, white carbon, vermiculite, slaked lime, siliceous sand, ammonium sulfate, urea, or the like; and liquid carriers such as isopropyl alcohol, xylene, cyclohexanone, methylnaphthalene, and the like. Illustrative examples of the surfactants and dispersants include salts of dinaphthylmethanesulfonic acid, sulfate esters of alcohol, alkylarylsulfonic acid, and ligninesulfonic acid, polyoxyethylene glycol ethers, polyoxyethylene alkyl aryl ethers, polyoxyethylenesorbitan monoalkylates, and the like. Suitable examples of auxiliary agents include carboxymethylcellulose, and the like. These preparations can be applied directly, or after diluting the preparation to a suitable concentration.
The agricultural or horticultural fungicide according to the present invention can be employed for a number of purposes: for example, treating seeds, spraying of stem and leaf portions, injection into irrigation water, and applying to the soil. The proportion of the active ingredient is selected as needed. When formulated into a fine powder or granules, 0.1% by weight to 20% by weight of the active ingredient is preferred. For an emulsifiable concentrate or wettable powder, 5% by weight to 80% by weight of the active ingredient is adequate.
The rate of application of the agricultural or horticultural fungicide according to the present invention may vary depending on the type of active compound employed, the kind of the pest or disease to be controlled, the nature of occurrence of the pest or disease, the degree of damage, environmental conditions, the form of preparation to be used, and the like. When the agricultural or horticultural fungicide of the present invention is applied directly in the form of fine powder or granules, it is recommended that the rate of application of the active ingredient be suitably chosen within the range of 0.1 g to 5 kg per 10 ares, preferably, in the range of 1 g to I kg per 10 ares. In addition, when the fungicide of the present invention is in the form of a liquid such as an emulsifiable concentrate or a wettable powder, it is recommended that the ratio for application of the active ingredient be suitably chosen within the range of 0.1 ppm to 10,000 ppm, and preferably within the range of 10 ppm to 3,000 ppm.
The compounds according to the present invention in the formulation described above can control plant diseases caused by fungi in the Oomycetes, Ascomycetes, Deuteromycetes, and Basidiomycetes or other pathogenic fungi. The fungi include, but are not limited to, Pseudoperonospora such as cucumber downy mildew (Pseudoperonospora cubensis), Phytophthora such as tomato late blight (Phytophthora infestans), and Plasmopara such as grape downy mildew (Plasmopara viticola).
The agricultural or horticultural fungicide according to the present invention may be employed alone or in combination with other fungicides, insecticides, herbicides, plant growth modifiers, fertilizers or the like.
Next, the representative formulations are illustrated with reference to the following Formulation Examples, wherein all "%" represent "percent by weight".
Formulation Example 1
Fine powder
2% of Compound No. 15, 5% of diatomaceous earth, and 93% of clay were uniformly mixed and ground into a fine powder.
Formulation Example 2
Wettable powder
50% of Compound No. 16, 45% of diatomaceous earth, 2% of sodium dinaphthylmethanedisulfonate, and 3% of sodium ligninsulfonate were uniformly mixed and ground into a wettable powder.
Formulation Example 3
Emulsifiable concentrate
30% of Compound No. 19, 20% of cyclohexanone, 11% of polyoxyethylene alkylaryl ether, 4% of calcium alkylbenzenesulfonate, and 35% of methylnaphthalene were uniformly dissolved, thus obtaining an emulsifiable concentrate.
Formulation Example 4
Granules
5% of Compound No. 101, 2% of sodium lauryl alcohol sulfonate, 5% of sodium lignin sulfonate, 2% of carbomethylcellulose, and 86% of clay were mixed and ground. 20% of water was added to the ground mixture. The resulting mixture was kneaded and formed into granules of 14 mesh to 32 mesh by means of an extrusion granulator, and then dried into the desired granules.
Effects of the Invention
The agricultural or horticultural fungicides according to the present invention exhibit high ability to control the growth or spread of cucumber downy mildew (Pseudoperonospora cubensis), tomato late blight (Phytophthora infestans), and grape downy mildew (Plasmopara viticola), and are effective for potato late blight (Phytophthora infestans). In addition, the agricultural or horticultural fungicides according to the present invention not only exhibit the ability to prevent fungal infection, but also exhibit the ability to eliminate pathogenic fungi after it has invaded a host plant. Furthermore, the agricultural or horticultural fungicides of the present invention are also characterized in that they are not harmful chemicals and exhibit excellent characteristics such as systemic action, residual activity, and persistence after rain-fall.
The effects of the compounds according to the present invention are now illustrated with reference to the following Test Examples. Comparative Compound X and Comparative Compound Y employed in the Test Examples are the compounds disclosed as synthesis intermediates for drugs in Japanese Patent Application, First Publication, No. Sho 62-89696. These Comparative Compounds were employed after being formulated in the same manner as the compounds of the present invention to be tested.
Comparative Compound X: N.sup.2 -tert-butoxycarbonyl-N.sup.1 -(2-phenoxyethyl)-D-alaninamide
Comparative Compound Y: N.sup.2 -tert-butoxycarbonyl-N.sup.1 -(2-phenylthioethyl)-D-alaninamide
Test Example 1
Test on the Effect of Preventing Infection by Cucumber Downy Mildew (Pseudoperonospora cubensis)
Cucumber seeds (variety: "Sagami hanjiro") were sown at a rate of 10 seeds each in a square PVC (polyvinyl chloride) pot, wherein each side is 9 cm wide. The seeds were allowed to grow in a greenhouse, for 7 days, to the cotyledonous stage. A wettable powder prepared as in Formulation Example 2 was diluted with water to a concentration of 500 ppm of the active ingredient, and the aqueous preparation obtained was then applied at a rate of 10 ml per pot to the cucumber seedlings at their cotyledonous stage. After drying in the air, the plant was inoculated with a spore suspension of cucumber downy mildew (Pseudoperonospora cubensis) fungi using a spray and then placed in a moist chamber at 22.degree. C. for 24 hours, and then placed in a greenhouse. On the seventh day after the inoculation, the extent of lesion was rated in accordance with the standards of evaluation as shown in Table 15 in order to secure the preventive effects of the compounds according to the present invention. The results of the test are given in Table 16.
TABLE 15______________________________________Standard of evaluation: Affected areaClass A: No lesions were observedClass B: Affected area is less than 25%Class C: Affected area is 25% or more and less than 50%Class D: Affected area is 50% or more______________________________________
TABLE 16______________________________________CompoundNo. Evaluation______________________________________ 1 B 2 A 4 A 6 A 7 A 8 B 10 A 13 A 14 B 16 A 17 A 18 B 19 A 23 A 24 B 26 B 27 A 29 A 33 A 42 A 45 A 54 B 63 A 77 A 88 A 98 A101 A104 A107 A108 A112 A114 A115 A116 A124 B129 A134 A135 A154 A157 A160 A163 A166 A169 A184 A193 A195 B204 B205 A208 A211 A212 A213 A214 A215 A216 A217 A219 A220 A221 A227 A228 A230 A231 A232 A235 A236 A238 A246 B323 A326 A327 A328 A329 B331 B333 B335 A336 A338 A339 A340 A341 A342 A343 A344 B345 A347 A348 B349 A350 B351 A352 A353 A354 A355 A356 A357 B358 A359 A360 A361 B362 B363 A364 B365 A366 A367 A368 A369 A370 A371 A372 A373 A374 A376 A377 A378 A379 A380 A381 A382 A383 A385 A386 A387 B388 A389 A390 A391 A392 A393 A394 A395 A397 A399 A401 A402 A403 A405 A408 A410 A411 B412 A413 A414 A416 A417 A418 A419 A421 A422 A423 A424 A425 A426 A427 A429 A430 A431 A432 A439 A440 A451 A452 A453 A455 A456 A462 A465 A466 A467 A468 A471 B477 A482 A486 A492 A493 A495 A496 B499 B502 A506 A508 A509 A510 A511 A512 A513 A517 A519 A523 A525 A605 A606 A607 A708 A768 A770 AComparative DExample XComparative DExample Y______________________________________
Test Example 2
Test on the Effect of Treating Infection by Cucumber Downy Mildew (Pseudoperonospora cubensis)
Cucumber seeds (variety: "Sagami hanjiro") were sown at a rate of 10 seeds each in a square PVC (polyvinyl chloride) pot, wherein each side is 9 cm wide. The seeds were allowed to grow in a greenhouse, for 7 days, to the cotyledonous stage. The seedlings were inoculated with a spore suspension of cucumber downy mildew (Pseudoperonospora cubensis) fungi and then placed in a moist chamber at 22.degree. C. for 24 hours. After drying in the air, a wettable powder prepared as in Formulation Example 2 was diluted with water to a concentration of 500 ppm of the active ingredient, and the aqueous preparation obtained was then applied at a rate of 10 ml per pot to the cucumber seedlings. The seedlings were then placed in a green house. On the seventh day after the inoculation, the extent of lesions was rated in accordance with the standards of evaluation shown in Table 15 in order to secure the effect of treating with the compounds according to the present invention. The results of the test are given in Table 17.
TABLE 17______________________________________CompoundNo. Evaluation______________________________________ 4 B 10 A 13 A 16 A 19 B 29 A 33 A 42 A 45 A 54 B 63 A 77 A 88 B104 A107 A108 B114 B115 A116 A124 A129 B134 A135 A154 A157 A160 A163 A184 B212 A213 A215 A216 B219 A220 B221 A228 B230 B231 A232 A238 A333 A335 A336 A340 B341 B342 A345 A348 B349 A351 A352 A353 A354 A355 A356 A358 A360 B365 A367 B368 A369 A371 A374 A376 A378 A381 B382 A383 A385 A386 A388 B394 A395 A397 A399 A401 A402 B405 B414 A416 A417 A418 A419 B423 A424 A425 A427 A429 A439 A451 A452 A453 A455 A456 A462 A465 A466 A467 B468 A477 B486 B492 A495 A499 B502 A506 A508 A509 A513 A517 A519 B523 A606 A607 B708 A768 B770 BComparative DExample XComparative DExample Y______________________________________
Test Example 3
Test on the Effect of Preventing Infection by Tomato Late Blight (Phytophthora infestans)
One tomato seedling (variety: "Ponterosa") was transplanted into each porcelain pot (diameter: 12 cm) and grown in a greenhouse. A wettable powder prepared as in Formulation Example 2 was diluted with water to a concentration of 500 ppm of the active ingredient, and the aqueous preparation obtained was then applied at a rate of 20 ml per pot to the tomato seedlings at their 6- or 7-leaf stage. After drying in the air, the plant was inoculated with a zoosporangium suspension of tomato late blight (Phytophthora infestans) fungi and then placed in a moist chamber at 22.degree. C. On the fourth day after the inoculation, index of incidence was determined based on the size of the affected area as shown in Table 18. The degree of damage was calculated according to Equation (1) and the index of incidence and the ability to prevent the disease (controlling activity) was calculated according to Equation (2). The results are shown in Table 19.
TABLE 18______________________________________Incidence Index Affected Area______________________________________0 No lesions1 Less than 5%2 5% or more and less than 33.3%3 33.3% or more and less than 66.6%4 66.6% or more______________________________________ ##EQU1##
TABLE 19______________________________________ ControllingCompound ActivityNo. (%)______________________________________ 2 100 4 100 6 100 7 100 10 100 13 100 16 100 17 100 19 100 23 100 27 100 29 100 33 100 42 100 45 100 63 100 77 100 88 100 98 100101 100104 100107 100108 100112 100115 100116 100129 100134 100135 100154 100157 100160 100163 100166 100169 100184 100193 100213 100215 100217 100220 100221 100228 100231 100232 100235 100238 100323 100326 100336 100345 100352 100356 100359 100360 100364 100365 100369 100371 100372 100373 100374 100378 100379 100380 100381 100382 100386 100388 100390 100391 100393 100394 100395 100397 100399 100401 100402 100403 100404 100405 100408 100414 100417 100418 100423 100424 100427 100430 100439 100440 100451 100462 100465 100466 100467 100477 100482 100492 100495 100502 100508 100509 100513 100519 100523 100605 100606 100607 100708 100768 100770 100Comparative 0Example XComparative 0Example Y______________________________________
Test Example 4
Test on the Effect of Preventing Infection by Grape Downy Mildew (Plasmopara viticola)
Grape rooted cuttings (variety: "Kyoho"), each grown from a cutting and pruned, was grown in a porcelain pot (diameter: 12 cm) and maintained in a greenhouse. A wettable powder prepared as in Formulation Example 2 was diluted with water to a concentration of 500 ppm of the active ingredient, and the aqueous preparation obtained was then applied at a rate of 20 ml per pot to the grape seedlings at their 4- or 5-leaf stage. After drying in the air, the plant was inoculated with a zoosporangium suspension of grape downy mildew (Plasmopara viticola) fungi and then placed in a moist chamber at 22.degree. C. for 24 hours. On the seventh day in the greenhouse after the inoculation, the plant was again placed in a moist chamber at 22.degree. C. for 24 hours to cultivate conidiospores. The incidence area where conidiospores grew on each leaf was examined and the incidence index determined according to the standards shown in Table 18. The degree of damage was calculated according to Equation (1) and the incidence index and the ability to prevent the disease (controlling activity) was calculated according to Equation (2). The results of the test are shown in Table 20.
TABLE 20______________________________________ ControllingCompound ActivityNo. (%)______________________________________ 2 100 4 100 6 100 7 100 10 100 13 100 16 100 17 100 19 100 23 100 27 100 29 100 33 100 42 100 45 100 63 100 77 100 88 100 98 100101 100104 100107 100108 100112 100115 100116 100129 100134 100135 100154 100157 100160 100163 100166 100169 100184 100193 100213 100215 100217 100220 100221 100228 100231 100232 100235 100238 100323 100326 100336 100345 100352 100356 100359 100360 100364 100365 100369 100371 100372 100373 100374 100378 100379 100380 100381 100382 100386 100388 100390 100391 100393 100394 100395 100397 100399 100401 100402 100403 100404 100405 100408 100414 100417 100418 100423 100424 100427 100430 100439 100440 100451 100462 100465 100466 100467 100477 100482 100492 100495 100502 100508 100509 100513 100519 100523 100605 100606 100607 100708 100768 100770 100Comparative 0Example XComparative 0Example Y______________________________________

Number	Date	Country
0554729	Aug 1993	EPX
0587110	Mar 1994	EPX
4308507	Aug 1992	JPX
4230653	Aug 1992	JPX
4230652	Aug 1992	JPX

Amino-acid amide derivatives, agricultural or horticultural fungicides, and method for producing the same

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Entry
Jamontaite et al. CA:437540, 1974.
Analytical Biochemistry, vol. 192, No. 2, Feb. 1, 1991, pp. 419-425, Jair R. Chagas, et al., "Intramolecularly Quenched Fluorogenic Tetrapeptide Substrates for Tissue and Plasma Kallikreins".
Chemical Abstracts, vol. 106, No. 9, Mar. 2, 1987, p. 649, AN-67647s.
Chemical Abstracts, vol. 81, No. 7, Aug. 19, 174, p. 388, AN-37540z.
Acta Chemica Scandinavica, vol. B42, No. 8, 1988, pp. 556-562, Christer Sahlberg, et al., "Synthesis of a Tritiated LPS Inhibitor Derived From 3-Deoxy-D-Manno-2-Octulosonic acid (KDO). A Cautionary Note Regarding Amide Synthesis from Azides Via Phosphine Imines".