Patent Grant
10227286
This invention relates to certain 3-oxo-3-(arylamino)propanoates, their salts and compositions, a process to prepare them and their use in preparing certain pyrrolidinones useful as herbicides.
This invention is directed to a compound of Formula I and salts thereof
wherein
This invention also relates to a method for preparing a compound of Formula I, comprising contacting a compound of Formula II
with a compound of Formula III
optionally in the presence of a catalyst or a base to form a compound of Formula I.
This invention further relates to a method for preparing a compound of Formula IV
comprising reductively cyclizing a compound of Formula I in the presence of a reducing agent.
As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains”, “containing,” “characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus.
The transitional phrase “consisting of” excludes any element, step, or ingredient not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase “consisting of” appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.
The transitional phrase “consisting essentially of” is used to define a composition, method or apparatus that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term “consisting essentially of” occupies a middle ground between “comprising” and “consisting of”.
Where applicants have defined an invention or a portion thereof with an open-ended term such as “comprising,” it should be readily understood that (unless otherwise stated) the description should be interpreted to also describe such an invention using the terms “consisting essentially of” or “consisting of.”
Further, unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
Also, the indefinite articles “a” and “an” preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore “a” or “an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.
In the above recitations, the term “alkyl”, used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl or hexyl isomers. “Alkenyl” includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. “Alkenyl” also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. “Alkynyl” includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. “Alkynyl” can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
“Alkoxy” includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. “Alkoxyalkyl” denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. “Alkoxyalkoxy” denotes alkoxy substitution on alkoxy. “Alkenyloxy” includes straight-chain or branched alkenyloxy moieties. Examples of “alkenyloxy” include H2C═CHCH2O, (CH3)2C═CHCH2O, (CH3)CH═CHCH2O, (CH3)CH═C(CH3)CH2O and CH2═CHCH2CH2O. “Alkynyloxy” includes straight-chain or branched alkynyloxy moieties. Examples of “alkynyloxy” include HC≡CCH2O, CH3C≡CCH2O and CH3C≡CCH2CH2O. “Alkylthio” includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. “Alkylsulfinyl” includes both enantiomers of an alkylsulfinyl group. Examples of “alkylsulfinyl” include CH3S(O)—, CH3CH2S(O)—, CH3CH2CH2S(O)—, (CH3)2CHS(O)— and the different butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers. Examples of “alkyl sulfonyl” include CH3S(O)2—, CH3CH2S(O)2—, CH3CH2CH2S(O)2—, (CH3)2CHS(O)2—, and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers. “Alkylthioalkyl” denotes alkylthio substitution on alkyl. Examples of “alkylthioalkyl” include CH3SCH2, CH3SCH2CH2, CH3CH2SCH2, CH3CH2CH2CH2SCH2 and CH3CH2SCH2CH2. “Alkylamino”, “Alkylaminoalkyl”, and the like, are defined analogously to the above examples.
“Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “alkylcycloalkyl” denotes alkyl substitution on a cycloalkyl moiety and includes, for example, ethylcyclopropyl, i-propylcyclobutyl, 3-methylcyclopentyl and 4-methylcyclohexyl. The term “cycloalkylalkyl” denotes cycloalkyl substitution on an alkyl moiety. Examples of “cycloalkylalkyl” include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups. The term “cycloalkoxy” denotes cycloalkyl linked through an oxygen atom such as cyclopentyloxy and cyclohexyloxy. “Cycloalkylalkoxy” denotes cycloalkylalkyl linked through an oxygen atom attached to the alkyl chain. Examples of “cycloalkylalkoxy” include cyclopropylmethoxy, cyclopentylethoxy, and other cycloalkyl moieties bonded to straight-chain or branched alkoxy groups.
The term “halogen”, either alone or in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” or “alkyl substituted with halogen” include F3C, ClCH2, CF3CH2 and CF3CCl2. The terms “halocycloalkyl”, “haloalkoxy”, “haloalkylthio”, “haloalkenyl”, “haloalkynyl”, and the like, are defined analogously to the term “haloalkyl”. Examples of “haloalkoxy” include CF3O—, CCl3CH2O—, HCF2CH2CH2O— and CF3CH2O—. Examples of “haloalkylthio” include CCl3S—, CF3S—, CCl3CH2S— and ClCH2CH2CH2S—. Examples of “haloalkylsulfinyl” include CF3S(O)—, CCl3S(O)—, CF3CH2S(O)— and CF3CF2S(O)—. Examples of “haloalkylsulfonyl” include CF3S(O)2—, CCl3S(O)2—, CF3CH2S(O)2— and CF3CF2S(O)2—. Examples of “haloalkenyl” include (Cl)2C═CHCH2— and CF3CH2CH═CH═CH2—. Examples of “haloalkynyl” include HC≡CCHCl—, CF3C≡C—, CCl3C≡C— and FCH2C≡CCH2—. Examples of “haloalkoxyalkoxy” include CF3OCH2O—, ClCH2CH2OCH2CH2O—, Cl3CCH2OCH2O— as well as branched alkyl derivatives.
“Alkylcarbonyl” denotes a straight-chain or branched alkyl moieties bonded to a C(═O) moiety. Examples of “alkylcarbonyl” include CH3C(═O)—, CH3CH2CH2C(═O)— and (CH3)2CHC(═O)—. Examples of “alkoxycarbonyl” include CH3OC(═O)—, CH3CH2OC(═O)—, CH3CH2CH2OC(═O)—, (CH3)2CHOC(═O)— and the different butoxy- or pentoxycarbonyl isomers.
The total number of carbon atoms in a substituent group is indicated by the “Ci-Cj” prefix where i and j are numbers from 1 to 12. For example, C1-C4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl; C2 alkoxyalkyl designates CH3OCH2—; C3 alkoxyalkyl designates, for example, CH3CH(OCH3)—, CH3OCH2CH2— or CH3CH2OCH2—; and C4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH3CH2CH2OCH2— and CH3CH2OCH2CH2—.
When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1, said substituents (when they exceed 1) are independently selected from the group of defined substituents, e.g., ([R1)n], n is 0, 1, 2, 3, 4 or 5). When a group contains a substituent which can be hydrogen, for example Q1, then when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted. When a variable group is shown to be optionally attached to a position, for example R1, then hydrogen may be at the position even if not recited in the variable group definition. When one or more positions on a group are said to be “not substituted” or “unsubstituted”, then hydrogen atoms are attached to take up any free valency.
The expression “fully saturated” in relation to a ring of atoms means that the bonds between the atoms of the ring are all single. The expression “fully unsaturated” in relation to a ring means that the bonds between the atoms in the ring are single or double bonds according to valence bond theory and furthermore the bonds between the atoms in the ring include as many double bonds as possible without double bonds being cumulative (i.e. no C═C═C, N═C═C, etc.). The term “partially unsaturated” in relation to a ring denotes a ring comprising at least one ring member bonded to an adjacent ring member though a double bond and which conceptually potentially accommodates a number of non-cumulated double bonds through adjacent ring members (i.e. in its fully unsaturated counterpart form) greater than the number of double bonds present (i.e. in its partially unsaturated form). When a fully unsaturated ring satisfies Hückel's rule then it can also be described as aromatic.
Unless otherwise indicated, a “ring” or “ring system” as a component of Formula I (e.g., substituent Q1) is carbocyclic or heterocyclic. The term “ring system” denotes two or more fused rings. The term “bicyclic ring system” denotes a ring system consisting of two fused rings, in which either ring can be saturated, partially unsaturated, or fully unsaturated unless otherwise indicated. The term “heteroaromatic bicyclic ring system” denotes a bicyclic ring system in which at least one ring atom is not carbon. The term “ring member” refers to an atom or other moiety (e.g., C(═O), C(═S), S(O) or S(O)2) forming the backbone of a ring or ring system.
The terms “carbocyclic ring” denotes a ring or ring system wherein the atoms forming the ring backbone are selected only from carbon. Unless otherwise indicated, a carbocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. When a fully unsaturated carbocyclic ring satisfies Hückel's rule, then said ring is also called an “aromatic ring”.
The term “heterocyclic ring” denotes a ring or ring system in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or sulfur. Typically a heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs. Unless otherwise indicated, a heterocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. When a fully unsaturated heterocyclic ring satisfies Hückel's rule, then said ring is also called a “heteroaromatic ring” or “aromatic heterocyclic ring”. Unless otherwise indicated, heterocyclic rings and ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
“Aromatic” indicates that each of the ring atoms is essentially in the same plane and has a p-orbital perpendicular to the ring plane, and that (4n+2) π electrons, where n is a positive integer, are associated with the ring to comply with Hückel's rule.
The term “optionally substituted” in connection with the heterocyclic rings refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog. As used herein, the following definitions shall apply unless otherwise indicated. The term “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” or with the term “(un)substituted.” Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
When Q1 and Q2 is a 5- or 6-membered nitrogen-containing heterocyclic ring, it may be attached to the remainder of Formula I though any available carbon or nitrogen ring atom, unless otherwise described. As noted above, Q1 or Q2 can be (among others) phenyl optionally substituted with one or more substituents selected from a group of substituents as defined in the Summary of the Invention. An example of phenyl optionally substituted with one to five substituents is the ring illustrated as U-1 in Exhibit 1, wherein, for example, Rv is R1 as defined in the Summary of the Invention for Q1, or Rv is R4 as defined in the Summary of the Invention for Q2, and r is an integer (from 0 to 5).
As noted above, Q1 and Q2 can be (among others) 5- or 6-membered fully unsaturated heterocyclic ring, optionally substituted with one or more substituents selected from a group of substituents as defined in the Summary of the Invention. Examples of a 5- or 6-membered fully unsaturated heterocyclic ring optionally substituted with from one or more substituents include the rings U-2 through U-61 illustrated in Exhibit 1 wherein Rv is any substituent as defined in the Summary of the Invention for Q1 (i.e. R1 or R3) or Q2 (i.e. R4 or R5) and r is an integer from 0 to 4, limited by the number of available positions on each U group. As U-29, U-30, U-36, U-37, U-38, U-39, U-40, U-41, U-42 and U-43 have only one available position, for these U groups r is limited to the integers 0 or 1, and r being 0 means that the U group is unsubstituted and a hydrogen is present at the position indicated by (Rv)r.
As noted above, Q1 and Q2 can be (among others) an 8- to 10-membered heteroaromatic bicyclic ring system optionally substituted with one or more substituents selected from a group of substituents as defined in the Summary of the Invention for Q1 and Q2. Examples of an 8- to 10-membered heteroaromatic bicyclic ring system optionally substituted with one or more substituents include the rings U-62 through U-100 illustrated in Exhibit 2 wherein Rv is any substituent as defined in the Summary of the Invention for Q1 or Q2, and r is typically an integer from 0 to 4.
Although Rv groups are shown in the structures U-1 through U-100, it is noted that they do not need to be present since they are optional substituents. Note that when Rv is H when attached to an atom, this is the same as if said atom is unsubstituted. The nitrogen atoms that require substitution to fill their valence are substituted with H or Rv. Note that when the attachment point between (Rv)r and the U group is illustrated as floating, (Rv)r can be attached to any available carbon atom or nitrogen atom of the U group. Note that when the attachment point on the U group is illustrated as floating, the U group can be attached to the remainder of Formula I through any available carbon or nitrogen of the U group by replacement of a hydrogen atom. Note that some U groups can only be substituted with less than 4 Rv groups (e.g., U-2 through U-5, U-7 through U-48, and U-52 through U-61).
A wide variety of synthetic methods are known in the art to enable preparation of aromatic and nonaromatic heterocyclic rings and ring systems; for extensive reviews see the eight volume set of Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees editors-in-chief, Pergamon Press, Oxford, 1984 and the twelve volume set of Comprehensive Heterocyclic Chemistry II, A. R. Katritzky, C. W. Rees and E. F. V. Scriven editors-in-chief, Pergamon Press, Oxford, 1996.
Compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. Stereoisomers are isomers of identical constitution but differing in the arrangement of their atoms in space and include enantiomers, diastereomers, cis-trans isomers (also known as geometric isomers) and atropisomers. Atropisomers result from restricted rotation about single bonds where the rotational barrier is high enough to permit isolation of the isomeric species. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
For example the C(O)N(Q2)(R6) moiety (bonded to the carbon at the 3-position of the pyrrolidinone ring) and Q1 (bonded to the carbon at the 4-position of the pyrrolidinone ring) are generally found in the trans configuration. These two carbon atoms (i.e. at the 3- and 4-positions each posses the pyrroldinone ring of Formula IV) both possess a chiral center. The two most prevelant pairs of enantiomers are depicted as Formula IV′ and Formula IV″ where the chiral centers are identified (i.e. as 3R, 4S or as 3S, 4R). While this invention pertains to all stereoisomers, the preferred enantiomeric pair for biological operability is identified as Formula IV′ (i.e. the 3R, 4S configuration). For a comprehensive discussion of all aspects of stereoisomerism, see Ernest L. Eliel and Samuel H. Wilen, Stereochemistry of Organic Compounds, John Wiley & Sons, 1994.
Molecular depictions drawn herein follow standard conventions for depicting stereochemistry. To indicate stereoconfiguration, bonds rising from the plane of the drawing and towards the viewer are denoted by solid wedges wherein the broad end of the wedge is attached to the atom rising from the plane of the drawing towards the viewer. Bonds going below the plane of the drawing and away from the viewer are denoted by dashed wedges wherein the narrow end of the wedge is attached to the atom further away from the viewer. Constant width lines indicate bonds with a direction opposite or neutral relative to bonds shown with solid or dashed wedges; constant width lines also depict bonds in molecules or parts of molecules in which no particular stereoconfiguration is intended to be specified. This invention comprises racemic mixtures, for example, equal amounts of the enantiomers of Formulae IV′ and IV″. In addition, this invention includes compounds that are enriched compared to the racemic mixture in an enantiomer of Formula IV. Also included are the essentially pure enantiomers of compounds of Formula I, for example, Formula IV′ and Formula IV″.
When enantiomerically enriched, one enantiomer is present in greater amounts than the other, and the extent of enrichment can be defined by an expression of enentiomeric ratio (ER) expressed as the relative area % of the two entantiomers determined by chiral high-performance liquid chromatography.
Preferably the compositions of this invention have at least a 50% ER; more preferably at least a 75% ER; still more preferably at least a 90% ER; and the most preferably at least a 94% ER of the more active isomer. Of particular note are enantiomerically pure embodiments of the more active isomer.
Compounds of Formula IV can comprise additional chiral centers. For example, substituents and other molecular constituents such as R1, R3, R4 and R5 may themselves contain chiral centers. This invention comprises racemic mixtures as well as enriched and essentially pure stereoconfigurations at these additional chiral centers.
Compounds of this invention can exist as one or more conformational isomers due to restricted rotation about the amide bond (e.g., C(O)—N) in Formula I and IV. This invention comprises mixtures of conformational isomers. In addition, this invention includes compounds that are enriched in one conformer relative to others.
Compounds of Formula I typically exist in more than one form, and Formula I thus include all crystalline and non-crystalline forms of the compounds they represent. Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts. Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e. different crystalline types). The term “polymorph” refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice. Although polymorphs can have the same chemical composition, they can also differ in composition due the presence or absence of co-crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability. One skilled in the art will appreciate that a polymorph of a compound of Formula I can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound of Formula I. Preparation and isolation of a particular polymorph of a compound of Formula I can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures. For a comprehensive discussion of polymorphism see R. Hilfiker, Ed., Polymorphism in the Pharmaceutical Industry, Wiley-VCH, Weinheim, 2006.
One skilled in the art will appreciate that not all nitrogen-containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen-containing heterocycles which can form N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist in Comprehensive Organic Synthesis, vol. 7, pp 748-750, S. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keene in Advances in Heterocyclic Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.
One skilled in the art recognizes that because in the environment and under physiological conditions salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms. Thus a wide variety of salts of a compound of Formula I are useful for control of undesired vegetation (i.e. are agriculturally suitable). The salts of a compound of Formula I include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. When a compound of Formula I contains an acidic moiety such as a carboxylic acid or phenol, salts also include those formed with organic or inorganic bases such as pyridine, triethylamine or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium or barium. Accordingly, the present invention comprises compounds selected from Formula I, N-oxides and agriculturally suitable salts thereof.
Embodiments of the present invention as described in the Summary of the Invention include (where Formula I as used in the following Embodiments includes N-oxides and salts thereof):
Embodiments of this invention, including any one of Embodiments A1 through A34, B1 through B41 and C1 through C35 above as well as any other embodiments described herein, can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula I and IV but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula I and IV.
Combinations of Embodiments A1 through A34, B1 through B41 and C1 through C35 are illustrated by:
Specific embodiments include compounds of Formula I selected from the group consisting of:
The pyrrolidinones of Formula IV are useful as herbicides as disclosed in PCT/US14/68073.
The compounds of Formula I and IV can be prepared by general methods known in the art of synthetic organic chemistry. One or more of the following methods and variations as described in Schemes 1-5 can be used to prepare the compounds of Formula I and IV. The definitions of Q1, Q2, R in the compounds of Formulae I, II, III, IV, a, b, c, d, e and f below are as defined above in the Summary of the Invention unless otherwise noted. All substituents for Formulae a, b, c, d, e and f are as defined above for Formulae I, II, III and IV unless otherwise noted.
As shown in Scheme 1, a compound of Formula IV can be obtained by the reduction of a compound of Formula I and subsequent in situ cyclization of the resulting intermediate amine. A wide variety of methods for reduction of the aliphatic nitro group in compounds of Formula I are known in the literature. Methods well known to those skilled in the art include catalytic hydrogenation in the presence of palladium on carbon, reduction using Raney nickel, iron or zinc metal in acidic medium (see, for example, Berichte der Deutschen Chemischen Gesellschaft 1904, 37, 3520-3525) and reduction using lithium aluminum hydride. Reduction can also be achieved with samarium(II) iodide in the presence of a proton source such as methanol (see for example, Tetrahedron Letters 1991, 32 (14), 1699-1702). Alternatively sodium borohydride in the presence of a nickel catalyst such as nickel(II) acetate or nickel(II) chloride can be used (see for example, Tetrahedron Letters 1985, 26 (52), 6413-6416). The method of utilizing sodium borohydride in the presence of nickel(II) chloride is illustrated by Step C of Synthesis Example 1.
As shown in Scheme 2, a compound of Formula I can be prepared by reacting compounds of Formula a with nitromethane in the presence of a base. Suitable bases for the reaction include alkali metal lower alkoxides such as sodium methoxide in methanol or sodium ethoxide in ethanol.
Alternatively, as shown in Scheme 3, a compound of Formula I can be prepared by reacting nitroalkenes of Formula II with malonates of Formula III in the presence of a catalyst, a base or both a catalyst and a base. Suitable catalysts for this reaction include, but are not limited to, a Ni(II) complex with vicinal diamine ligrands such as Ni(II) Bis[(R,R)—N,N′-dibenzylcyclohexane-1,2-diamine]bromide or Ni(II)Br2 complexed with chiral 1,1′-Bi(tetrahydroisoquinoline)-diamines. Suitable bases for this reaction include, but are not limited to, alkali metal lower alkoxides such as sodium methoxide in methanol or sodium ethoxide in ethanol, organic bases such as piperidine, morpholine, triethyl amine, N-methyl morpholine or N, N-diisopropylehtyl amine, or bases such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and lithium diisopropylamide in solvents such as tetrahydrofuran, toluene or dichloromethane. Typically, the reaction is carried out at a temperature from about −78° C. to about 23° C. optionally in the presence of 0 to 2 equivalents of catalyst or/and base. See Synthesis 2005, 2239-2245 for conditions for effecting this transformation and see J. Am. Chem. Soc. 2005, 9958-9959 or Eur. J. Org. Chem. 2011, 5441-5446 for conditions to accomplish this transformation stereoselectively. Conditions for effecting this transformation in refluxing water in the absence of catalyst have been reported in Synthetic Communications 2013, 43, 744-748. Nitroalkenes of Formula II can readily be prepared from aldehydes and nitromethane by methods known to those skilled in the art.
As shown in Scheme 4, compounds of Formula a can be prepared by reaction of malonates of Formula d with aldehydes of Formula e by methods known to those skilled in the art, e.g., by Knoevenagel condensation of aldehydes and malonates (see for example, Jones, G., Organic Reactions; Volume 15, John Wiley & Sons, 1967). As also shown in Scheme 4, malonates of Formula d can readily be prepared from lower alkyl malonyl chlorides of Formula b such as methyl malonyl chloride and amines of Formula c by methods known to those skilled in the art.
As shown in Scheme 5, compounds of Formula II can be prepared by reaction of nitromethane with an aldehyde of Formula e in the presence of a base. Dehydration of the intermediate f may be accomplished by azeotropic distillation of water from the reaction mixture or reacting with methanesulfonyl chloride in the presence of a base such as triethylamine. Suitable bases for this reaction include, but are not limited to, alkali metal lower alkoxides such as sodium hydroxide, sodium methoxide in methanol or sodium ethoxide in ethanol, ammonium acetate; or organic bases such as piperidine, morpholine or triethyl amine in solvents such as methanol, toluene, acetic acid or 1-chlorobutane. Typically, the reaction is carried out at a temperature from about −78° C. to 130° C. in the presence of 0 to 2 equivalents of catalyst or base. For representative conditions to prepare nitrostyrenes, see WO 2012/158413, US2011/207944 and WO2004/18455.
It is recognized by one skilled in the art that various functional groups can be converted into others to provide different compounds of Formula I. For a valuable resource that illustrates the interconversion of functional groups in a simple and straightforward fashion, see Larock, R. C., Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Ed., Wiley-VCH, New York, 1999. For example, intermediates for the preparation of compounds of Formula I may contain aromatic nitro groups, which can be reduced to amino groups, and then be converted via reactions well known in the art such as the Sandmeyer reaction, to various halides, providing compounds of Formula I. The above reactions can also in many cases be performed in alternate order
It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula I may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula I. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular presented to prepare the compounds of Formula I.
One skilled in the art will also recognize that compounds of Formula I and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.
Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Steps in the following Examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step may not have necessarily been prepared by a particular preparative run whose procedure is described in other Examples or Steps. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. 1H NMR spectra are reported in ppm downfield from tetramethylsilane in CDCl3 solution unless indicated otherwise; “s” means singlet, “d” means doublet, “t” means triplet, “q” means quartet, “m” means multiplet and “br s” means broad singlet. 19F NMR spectra are reported in ppm downfield from CFCl3 in CDCl3 unluess indicated otherwise. The enentiomeric ratio (ER) was determined by chiral high performance liquid chromatography analysis using a Chiralpak AD-RH column and eluting with a 50:50 isopropanol/water mixture at 40° C. at 0.3 mL/min.
To a stirred solution of 3-(trifluoromethyl)benzaldehyde (12.2 g, 70.1 mmol) in methanol (50 mL) was added nitromethane (4.34 g, 71.1 mmol). The mixture was cooled to 2° C. and sodium hydroxide (5.65 g, 70.6 mmol) was added as a 50% solution in 24.3 mL of water dropwise over 15 min. An exotherm was noted and additional ice was added to maintain the internal temperature below 10° C. while stirring for an additional 1 h. The reaction mixture was poured into 75 mL of 1 N hydrochloric acid, rinsing the flask with 10 mL of methanol/water. The quenched reaction mixture was transferred to a separatory funnel and extracted with 150 mL of toluene. The aqueous layer was separated and the organic layer was concentrated under vacuum to yield 15.84 g of a yellow oil.
The yellow oil (15.84 g, 67.3 mmol) thus obtained was taken up in 160 mL of dichloromethane. The solution was cooled to 3° C. and methanesulfonyl chloride (8.03 g, 71.1 mmol) was added via pipette as a solution in 50 mL of dichloromethane. A solution of triethylamine (14.2 g, 140 mmol) in 50 ml of dichloromethane was then added dropwise over 50 min. The mixture was stirred for 2 h and then poured into 150 mL of 1 N hydrochloric acid and transferred to a separatory funnel. The layers were separated and the organic layer was washed with 150 mL water and then filtered. The organic layer was concentrated under reduced pressure and the crude solid was triturated with hexanes to yield 12.09 g (79.4% yield over two steps) of product as a yellow solid.
1H NMR (500 MHz) δ 7.96-8.08 (m, 1H), 7.69-7.84 (m, 3H), 7.54-7.66 (m, 2H).
To a stirred solution of 2-fluoroaniline (10 g, 90.0 mmol) and triethylamine (9.1 g, 90.0 mmol) in dichloromethane (50 mL) at 0° C. was added dropwise over 10 minutes a solution of ethyl malonyl chloride (15.5 g, 90.0 mmol) in dichloromethane (30 mL). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then poured into water (100 mL), and the organic layer was separated, washed with water (50 mL) and brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to provide the title compound as an amber oil (19.0 g).
1H NMR δ 9.46 (br s, 1H), 8.28 (m, 1H), 7.10 (m, 2H), 4.26 (m, 2H), 3.51 (s, 2H), 1.32 (t, 3H).
A stirred solution of 1-[(E)-2-nitrovinyl]-3-(trifluoromethyl)benzene (i.e. the product of Step A, 12 g, 55 mmol) and ethyl 3-[(2-fluorophenyl)amino]-3-oxopropanote (i.e. the product of Step B, 12.4 g, 55 mmol) in anhydrous tetrahydrofuran (55 mL) was cooled to −5° C. under an atmosphere of nitrogen. To this mixture was added triethylamine (7.7 mL, 55 mmol) as a solution in anhydrous tetrahydrofuran (15 mL) over the course of 10 min. The reaction was stirred and allowed to warm to ambient temperature over the course of 1.5 h. The solution was concentrated under reduced pressure. The resulting crude solid was triturated with Et2O, filtered and washed with a small amount of Et2O and then hexanes. After drying with suction under nitrogen, 16.25 g of a white solid was isolated. Concentration of the filtrate and trituration with 1-chlorobutane at 50° C. yielded 3.45 g of additional product (NMR data is a 1:1 mixture of two diastereomers).
1H NMR (500 MHz, DMSO-d6) δ 10.16 (s, 1H), 10.03 (s, 1H), 7.44-7.88 (m, 8H), 6.85-7.33 (m, 8H), 4.95-5.16 (m, 4H), 4.10-4.38 (m, 6H), 3.84-4.01 (m, 2H), 1.17-1.24 (m, 3H), 0.90-1.00 (m, 3H); 19F NMR (471 MHz, DMSO-d6) δ−124.41-−124.17 (m, 2F), −61.56-−60.99 (m, 6F).
To a solution of Ethyl α-[[(2-fluorophenyl)amino]carbonyl]-β-(nitromethyl)-3-(trifluoromethyl)benzenepropanoate (i.e. the product of Step C, 15.1 g, 34 mmol) in anhydrous N,N-dimethyformamide (30 mL) and methanol (160 mL) was added NiCl2.6H2O dust (8.1 g, 34 mmol) in one portion. After the solution became clear the mixture was cooled to −7° C. NaBH4 (3.8 g, 100 mmol) was added in 0.5 g portions maintaining the internal temperature below 0° C. The reaction mixture was warmed to ambient temperature with stirring overnight. The solution was concentrated under reduced pressure and the crude material was suspended in dichloromethane (300 ml) and adsorbed onto of mixture of silica gel (60 g) and celite (25 g). Following concentration in vacuo, the sample was filtered through a plug of silica gel (160 g), eluting with ethyl acetate until no more product came through the plug. Concentration under reduced pressure gave 9.55 g of the desired product as an oily, off white solid. 1H NMR (500 MHz) δ 9.70 (br s, 1H), 8.15-8.25 (m, 1H), 7.42-7.68 (m, 4H), 6.97-7.12 (m, 3H), 6.49 (br s, 1H), 4.23-4.34 (m, 1H), 3.81-3.89 (m, 1H), 3.56-3.67 (m, 1H), 3.41-3.53 (m, 1H);
19F NMR (471 MHz) δ ppm −129.69-−129.51 (m, 1F), −62.56 (s, 3F).
To a mechanically stirred solution of 1-[(E)-2-nitroethenyl]-3-(trifluoromethyl)benzene (i.e. the product of Step A in Synthesis Example 1, 70 g, 0.32 mol) and ethyl 3-[(2-fluorophenyl)amino]-3-oxopropanote (i.e. the product of Step B in Synthesis Example 1, 72.6 g, 0.3225 mol) in toluene (350 mL) was added Ni(II)-Bis[(R,R)—N,N′-dibenzylcyclohexane-1,2-diamine]bromide (3.9 g, 0.0048 mol). The resulting mixture was stirred for 48 h at ambient temperature. The solution was then diluted with dichloromethane (500 mL) and adsorbed onto silica gel and purified by chromatography (70/30 petroleum ether/ethyl acetate). After standing at ambient temperature, 130 g of a white solid was obtained. Analysis by chiral HPLC (Chiral Pak IA (250×4.6) mm 5μ, 0.1% diethylamine in hexane:ethanol (90:10) at 1.0 mL/min) showed an ER of 89:10.
1H NMR (500 MHz) δ 8.66 (br s, 2H), 8.16-8.25 (m, 1H), 7.99-8.09 (m, 1H), 7.52-7.62 (m, 3H), 7.39-7.51 (m, 5H), 7.01-7.20 (m, 6H), 5.04-5.09 (m, 2H), 4.87-5.01 (m, 2H), 4.39-4.46 (m, 1H), 4.30 (q, J=7.15 Hz, 3H), 4.02 (q, J=7.20 Hz, 2H), 3.82-3.91 (m, 2H), 1.28-1.37 (m, 3H), 0.93-1.05 (m, 3H);
19F NMR (471 MHz) δ−130.24-−130.09 (m, 1F), −129.92-−129.76 (m, 1F), −62.84 (s, 3F), −62.80 (s, 3F); NMR data is a 1:1 mixture of two diastereomers.
MP: 130.6-134.6° C.: ESI [M+1] 443.6.
To a solution of Ethyl (βS)-α-[[(2-fluorophenyl)amino]carbonyl]-β-(nitromethyl)-3-(trifluoromethyl)benzenepropanoate (i.e. the product of Step C, 100 g, 0.226 mol) in ethanol (1000 mL) was added zinc dust (144.7 g, 2.26 mol) in one portion. The reaction mixture was heated to 80° C. Acetic acid (108 g, 1.81 mol) was added dropwise over a period of 45 min. After the addition of acetic acid, the solution was heated to 90° C. and stirred for 3 h. The solution was cooled to ambient temperature and diluted with ethyl acetate (1 L) and filtered through a bed of Celite® diatomaceous earth filter aid. The filtrate was concentrated under reduced pressure and the residue was taken up in ethyl acetate (2 L). The organic layer was washed with 0.5 N HCl, water and brine and then dried over Na2SO4, filtered and concentrated in vacuo. The thick liquid obtained was triturated with 500 mL of 10% methyl tert-butyl ether/petroleum ether to give a white solid. Filtration and drying provided the title compound as an white solid (56 g, 67% yield). Analysis by chiral HPLC (Chiral Pak IA (250×4.6) mm 5μ, 0.1% DEA in hexane:ethanol (90:10) at 1.0 mL/min) showed an ER of 86:14.
1H NMR (500 MHz, Acetone-d6) δ 10.05 (br s, 1H), 8.24-8.33 (m, 1H), 7.78-7.90 (m, 2H), 7.57-7.65 (m, 2H), 7.52 (br s, 1H), 7.00-7.22 (m, 3H), 4.20-4.29 (m, 1H), 3.96-4.02 (m, 1H), 3.83-3.92 (m, 1H), 3.41-3.53 (m, 1H);
19F NMR (471 MHz, Acetone-d6) δ ppm −131.19-−131.01 (m, 1F), −62.93 (s, 3F); MP 141.8-144.7° C.; ESI [M+1] 367.0.
By the procedures described herein together with methods known in the art, the following compounds of Tables 1 to 688 can be prepared. The following abbreviations are used in the Tables which follow: t means tertiary, n means normal, i means iso, c means cyclo, Me means methyl, Et means ethyl, Pr means propyl, Bu means butyl, i-Pr means isopropyl, Bu means butyl, c-Pr cyclopropyl, c-Bu means cyclobutyl, Ph means phenyl, OMe means methoxy, OEt means ethoxy, SMe means methylthio, SEt means ethylthio, NHMe methylamino, —CN means cyano, —NO2 means nitro, TMS means trimethylsilyl, S(O)Me means methylsulfinyl, and S(O)2Me means methylsulfonyl.
Table 2 is constructed in the same manner except that the Row Heading “R is Me; Q2 is Ph(2-F) and Q1 is” is replaced with the Row Heading listed for Table 2 below (i.e. “R is Me; Q2 is Ph(2,3-diF) and Q1 is”). Therefore the first entry in Table 2 is a compound of Formula I wherein R is Me; Q2 is Ph(2,3-diF) and Q1 is Ph(2-C1) (i.e. 2-chlorophenyl). Tables 3 through 688 are constructed similarly.
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| Publishing Document | Publishing Date | Country | Kind |
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| WO2016/094117 | 6/16/2016 | WO | A |
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