Optically active amine derivatives and preparation process therefor

Abstract
A readily available and inexpensive natural α-amino acid is converted into a compound represented by formula (1), which is then reacted with an organometallic reagent represented by formula (2) to give an optically active 5-hydroxyoxazolidine represented by formula (3), which is then treated with an acid to provide an optically active aminoketone represented by formula (4). The product is then converted into an optically active aminoalcohol represented by formula (5) or (6) by, for example reduction.
Description
BACKGROUND OF THE INVENTION

1. Field of the Invention


This invention relates to a process for preparing an optically active aminoalcohol derivative useful as a production intermediate for medicines, agricultural agents and so forth; for example, a process for preparing erythro-(1R,2S)-p-hydroxynorephedrine. This invention also relates to an optically active 5-hydroxyoxazolidine derivative as an important intermediate for production of the above optically active aminoalcohol derivative or a number of other optically active amine derivatives as well as a preparing process therefor. For example, an optically active 5-hydroxyoxazolidine derivative according to this invention is also very useful as a production intermediate for an azole antibacterial agent. A compound defined by general formula (1), (3) or (4) which has an asymmetric carbon having R1 and an amino substituent represents a R— or S-form, but not a racemic mixture of the R and S forms. A compound defined by general formula (5) or (6) having two adjacent asymmetric carbons which have an amino and hydroxy substituents represents a R—S or S—R form, but not an R—R or S—S form.


2. Description of the Prior Art


Recently, optically active compounds have been increasingly needed in many applications including medicines and agricultural agents. For industrial applications, there has been strongly needed for a convenient and inexpensive process for preparing an optically active material.


The following three processes are those according to the prior art for preparing an optically active aminoalcohol derivative relating to this invention:


[1] A method, in which, after a racemic compound of the desired compound is chemically synthesized, it is then optically resolved via, for example, a diastereomer salt to give the desired optically active compound. [2] A method, in which a technique for chemical or biological asymmetric synthesis is employed to give an optically active compound from an optically inactive material.


[3] A method by a so-called “chiral pool method”, in which it starts from an optically active material and the optical active compound is obtained under prevention of racemization.


Regarding the process in [1] as “A method, in which, after a racemic compound of the desired compound is chemically synthesized, it is then optically resolved via, for example, a diastereomer salt to give the desired optically active compound”, an example may be a process according to the prior art for preparing erythro-(1R,2S)-p-hydroxynorephedrine within a category of desired optically active aminoalcohol derivatives in this invention, in which after a racemate having the desired structure is first chemically synthesized, its optical resolution is carried out using an optically active carboxylic acid such as D-tartaric acid (J. Med. Chem., 1977, 20, 7, 978).


However, as long as using a preparation process on the basis of optical resolution, it is theoretically impossible to increase the yield over 50%, unless an enantiomer is recovered and subject to a special treatment such as racemization. Furthermore, an optically active carboxylic acid and the other compounds required in resolution are generally expensive, and it is often necessary to repeat several times a process such as recrystallization. In other words, the optical resolution process requires an expensive resolving agent(s) and a multiple-stage operation, and is, therefore, industrially a high-cost preparation process.


The process in [2] as “A method, in which a technique for chemical or biological asymmetric synthesis is employed to give an optically active compound from an optically inactive material” has been significantly advanced. As examples, there are mentioned an asymmetric synthesis technique based on a chemical synthesis including the uses of asymmetric reduction catalysts or the other agents (J. Am. Chem. Soc., 1980, 102, 7932) and an asymmetric synthesis technique based on a biotechnological synthesis using an enzyme or the other agents (Japanese Patent Laid-open No. 62-29998). Unfortunately, specificity for each substrate is significantly involved in practical production and thus the process cannot be applied to all kinds of production. Furthermore, the process cannot be always inexpensive when requiring an expensive asymmetric catalyst. In practice, for an optically active aminoalcohol derivative as a desired compound in this invention, there has been available no industrially reasonable preparation processes on the basis of chemical or biotechnological technique as described above.


For the process in [3] as “A method by a so-called “chiral pool method”, in which it starts from an optically active material and the optical active compound is obtained under prevention of racemization”, there have been many problems to be solved; for example, control of racemization is difficult till now and furthermore, practical production requires multiple steps. Regarding the aminoalcohol derivatives as the desired compounds in the present invention, no processes have been reported till now, which is fully satisfactory in the industrial viewpoint.


Regarding the prior art techniques for production of the optically active aminoalcohol derivatives, only the processes, which are difficult in the industrial viewpoint and require considerably high cost. Therefore, a novel, inexpensive and more convenient processes for the production are strongly desired.


Furthermore, only the following processes [4] to [6] are known in the prior art for preparation of an optically active 5-hydroxyoxazolidine derivative as an important production intermediate in the process of this invention:


[4] A method, in which (4S)-N-(ethoxycarbonyl)-4-(2-phenylethyl)-5-oxazolidinone is reacted with 4-chloro-3-methoxyphenyl magnesium bromide (WO 95/09155).


[5] A method, in which a 5-oxazolidinone derivative is reacted with a halomethyl lithium (WO 00/53571).


[6] A method, in which a 5-oxazolidinone derivative is reacted with (trifluoromethyl)trimethylsilane (J. Org. Chem. 1998, 63 (15), 5179).


In the above [4], the compound as a starting material is a special synthetic, non-naturally, compound relating to amino-acids, which has a phenylethyl group in its side chain. The compound is, therefore, prepared by a multistep reaction and it is difficult to obtain the compound in general. In addition, it is not an inexpensive material in the viewpoint of its production cost and the process maintains a significant problem in raw material supply. Furthermore, in the above process [4], the process is extremely limited, as a single production example, to that of the compound having a 4-chloro-3-methoxyphenyl group at 5-position in the oxazolidinone ring as a principal structure, and the product is used only as a starting material for a limited application to produce a medicine (Sch39166). It cannot be said that the preparation process as an example described in [4] is a universal process, and that, regarding an optically active 5-hydroxyoxazolidine derivative, which is widely useful, its preparation process has been fully established.


Regarding the compounds described in above [5] or [6], a special functional group such as a haloalkyl group (for example, a chloromethyl group) and a trifluoromethyl group is reacted at the 5-position of the oxazolidine as a main structure, but neither aryl nor hetero ring, which are widely useful for an intermediate of a medicine and agricultural agent are not included.


Although an optically active aminoalcohol derivative having an aryl group or heterocycle has been increasingly demanded in many applications such as in the pharmaceutical and agricultural fields, no general production methods has been found in the prior art, regarding the optically active 5-hydroxyoxazolidine derivative having an aryl group or heterocycle at the 5-position as its important production intermediate.


As a known prior art for preparation of an optically active aminoketone relating to this invention, a process is known, which uses a reaction where a carboxyl group in an N-protected amino acid is converted into an acid chloride, which then undergoes Friedel-Crafts reaction (J. Am. Chem. Soc. 1981, 103, 6157). Acylation using Friedel-Crafts reaction is, however, not considered to be a general preparation method for the reasons that the reaction causes racemization, that the reaction is considerably restricted by a structure to be acylated and that sometimes an aminoketone produced cannot be isolated. Thus, an industrially practical process is needed.


SUMMARY OF THE INVENTION

An objective of this invention is to provide a stereoselective process for preparing an optically active aminoalcohol derivative represented by the general formula (5), which is useful as a production intermediate for a medicine or agricultural agent using a “readily available and inexpensive natural α-amino acid” as a starting material without racemization. Another objective is to provide technique to prepare the compound stably in a large scale with an adequate optical purity and a lower cost in an industrial viewpoint. Another objective is to provide a novel optically active 5-hydroxyoxazolidine derivative represented by general formula (3) and a novel aminoketone derivative represented by general formula (4) as important intermediates for production of the above optically active aminoalcohol derivative or many optically active amine derivatives other than the above compound as well as a novel preparation process therefor.


After intensive investigation to achieve the above objects, the present inventors have found a process for preparing an optically active aminoalcohol derivative represented by general formula (5), as a very important production intermediate for a medicine or agricultural agent, from an inexpensive and easily available starting material. Specifically, the present inventors have newly found a process for preparing the compound stereoselectively by a short process while preventing racemization, using a “natural α-L-amino acid which is industrially available with a lower cost in a large amount” and a “natural α-D-amino acid which is industrially available with a lower cost in a large amount by racemization and optical resolution of a natural α-L-amino acid or selective assimilation (Japanese Patent Laid-open No. 63-198997) as starting materials.


In other words, the present inventors have found an industrially very useful novel preparation process for an optically active aminoalcohol derivative, which is produced stably even in a large scale production, as well as with a higher optical purity and at a lower cost.


Furthermore, the present inventors have found a novel optically active 5-hydroxyoxazolidine derivative represented by general formula (3) having an aryl group or heterocycle at the 5-position in an oxazolidine ring, which is an important intermediate for preparing the above optically active aminoalcohol derivative and a novel preparation process therefore; and a novel aminoketone derivative represented by general formula (4) and a novel preparation process therefore.


Thus, the present invention has been completed.


This invention includes the following embodiments:


(I) A process for preparing an optically active aminoalcohol derivative, wherein an optically active 5-oxazolidinone derivative represented by a general formula (1):




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wherein R1 represents an unprotected or optionally protected side chain in a natural α-amino acid; and R2 represents optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl; is reacted with an organometallic reagent represented by general formula (2):

R3—M  (2)


wherein R3 represents optionally substituted aryl or optionally substituted heterocycle; M represents one selected from the group consisting of Li, MgX, ZnX, TiX3 and CuX; and X represents halogen;


to form an optically active 5-hydroxyoxazolidine derivative represented by general formula (3):




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wherein R1, R2 and R3 have the same meaning as defined above; which is then treated under acidic conditions to give an optically active aminoketone derivative represented by general formula (4):




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wherein R1 and R3 have the same meanings as defined above; and R4 represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group;


which is then treated with a reducing agent or catalytically hydrogenated with a metal catalyst to stereoselectively provide an optically active aminoalcohol derivative represented by general formula (5):




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wherein R1, R3 and R4 have the same meanings as defined above; provided that configuration of R1 attached to the asymmetric carbon at 4-position and the substituent represented by a nitrogen atom in the optically active 5-oxazolidinone derivative represented by general formula (1) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol derivative represented by general formula (5) is an erythro configuration.


(II) A process for preparing an aminoalcohol derivative, wherein an optically active 5-oxazolidinone derivative represented by a general formula (1):




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wherein R1 represents an unprotected or optionally protected side chain in a natural α-amino acid; and R2 represents optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl; is reacted with an organometallic reagent represented by general formula (2):

R3—M  (2)


wherein R3 represents optionally substituted aryl or optionally substituted heterocycle; M represents one selected from the group consisting of Li, MgX, ZnX, TiX3 and CuX; and X represents halogen,


to form an optically active 5-hydroxyoxazolidine represented derivative by general formula (3):




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wherein R1, R2 and R3 have the same meanings as defined above;


which is then treated under acidic conditions to give an optically active aminoketone derivative represented by general formula (4):




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wherein R1 and R3 have the same meanings as defined above; and R4 represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group;


which is then treated with a reducing agent or catalytically hydrogenated with a metal catalyst to provide an optically active aminoalcohol derivative represented by general formula (5):




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wherein R1, R3 and R4 have the same meanings as defined above,


and then, when R4 is a protective group, the amino group in the product is deprotected to give an optically active aminoalcohol derivative represented by general formula (6):




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wherein R1 and R3 have the same meanings as defined above;


provided that configuration of R1 attached to the asymmetric carbon at 4-position and the substituent represented by a nitrogen atom in the optically active 5-oxazolidinone derivative represented by general formula (1) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol derivative represented by general formula (6) is an erythro configuration.


(III) The process for preparing an optically active aminoalcohol derivative as described in (I) or (II), wherein R1 represents methyl, isopropyl, isobutyl, benzyl, hydroxymethyl, benzyloxymethyl, phenylthiomethyl, methylthiomethyl, alkyloxycarbonylmethyl or alkyloxycarbonylethyl; R2 represents benzyl, tert-butyl, methyl, ethyl, isopropyl or 9-fluorenylmethyl.


(IV) The process for preparing an optically active aminoalcohol as described in (I) or (II), wherein R3 is represented by general formula (7):




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wherein Y represents halogen; or by general formula (8):




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wherein R5 represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl.


(V) The process for preparing an optically active aminoalcohol as described in (I) or (II) wherein R1 represents methyl; and R3 is represented by general formula (8).


(VI) An optically active 5-hydroxyoxazolidine derivative represented by general formula (3):




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wherein R1 represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R2 represents optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl; and R3 represents optionally substituted aryl or optionally substituted heterocycle.


(VII) The optically active 5-hydroxyoxazolidine derivative as described in (VI), wherein R1 represents methyl, isopropyl, isobutyl, benzyl, hydroxymethyl, benzyloxymethyl, phenylthiomethyl, methylthiomethyl, alkyloxycarbonylmethyl or alkyloxycarbonylethyl.


(VIII) The optically active 5-hydroxyoxazolidine derivative as described in (VI) or (VII) wherein R2 represents benzyl, tert-butyl, methyl, ethyl, isopropyl or 9-fluorenylmethyl.


(IX) The optically active 5-hydroxyoxazolidine as described in (VIII) wherein R3 is represented by general formula (7):




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wherein Y represents halogen; or general formula (8):




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wherein R5 represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl.


(X) The optically active 5-hydroxyoxazolidine as described in (IX) wherein R1 is methyl.


(XI) A process for preparing an optically active 5-hydroxyoxazolidine wherein an optically active 5-oxazolidinone derivative represented by general formula (1):




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wherein R1 represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R2 represents optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl;


is reacted with an organometallic reagent represented by general formula (2):

R3—M  (2)


wherein R3 represents optionally substituted aryl or optionally substituted heterocycle; M is one selected from the group consisting of Li, MgX, ZnX, TiX3 and CuX; and X represents halogen; to provide an optically active 5-hydroxyoxazolidine derivative represented by general formula (3):




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wherein R1, R2 and R3 have the same meanings as defined above.


(XII) The process for preparing an optically active 5-hydroxyoxazolidine derivative as described in (XI) wherein R1 represents methyl, isopropyl, isobutyl, benzyl, hydroxymethyl, benzyloxymethyl, phenylthiomethyl, methylthiomethyl, alkyloxycarbonylmethyl or alkyloxycarbonylethyl.


(XIII) The process for preparing an optically active 5-hydroxyoxazolidine derivative as described in (XI) or (XII) wherein R2 represents benzyl, tert-butyl, methyl, ethyl, isopropyl or 9-fluorenylmethyl.


(XIV) The process for preparing an optically active 5-hydroxyoxazolidine derivative as described in (XIII) wherein R3 is represented by general formula (7):




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wherein Y represents halogen; or general formula (8):




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wherein R5 represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl.


(XV) The process for preparing an optically active 5-hydroxyoxazolidine derivative as described in (XIV) wherein R1 is methyl.


(XVI) The process for preparing an optically active 5-hydroxyoxazolidine derivative as described in (XI) or (XII) wherein M in general formula (2) is MgX wherein X is as defined above.


(XVII) An aminoketone represented by general formula (4a):




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wherein R1a represents methyl: R4a represents hydrogen, benzyloxycarbonyl, tert-butoxycarbonyl or 9-fluorenylmethoxycarbonyl; R3a represents 4-benzyloxyphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl or 3-indolyl.


(XVIII) A process for preparing an aminoketone derivative wherein a 5-hydroxyoxazolidine derivative represented by general formula (3):




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wherein R1 represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R2 represents optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl; and R3 represents optionally substituted aryl or optionally substituted heterocycle;


is treated under acidic conditions to form an aminoketone derivative represented by general formula (4):




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wherein R1 and R3 are as defined above; R4 represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group.


(XIX) An optically active alcohol derivative represented by general formula (5a):




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wherein R1a represents methyl; R3b represents 4-benzyloxyphenyl; R4b represents benzyloxycarbonyl; and configuration between the amino group and the hydroxy group is erythro.


(XX) A process for preparing an optically active aminoalcohol derivative wherein an optically active aminoketone represented by general formula (4b):




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wherein R1 represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R4 represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group; R3c is represented by general formula (8):




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R5 represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl;


is treated with a reducing agent or catalytically hydrogenated with a metal catalyst, to stereoselectively form an optically active aminoalcohol derivative represented by general formula (5b):




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wherein R1, R3c and R4 are as defined above; provided that configuration of R1 attached to the asymmetric carbon at the 2-position and the substituent represented by a nitrogen atom in the optically active aminoketone derivative represented by general formula (4b) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol derivative represented by general formula (5b) is erythro.


(XXI) A process for preparing an optically active aminoalcohol wherein an optically active aminoketone derivative represented by general formula (4b):




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wherein R1 represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R4 represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group; R3c is represented by general formula (8):




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R5 represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl;


is treated with a reducing agent or catalytically hydrogenated with a metal catalyst, to stereoselectively form an optically active aminoalcohol derivative represented by general formula (5b):




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wherein R1, R3c and R4 are as defined above, and when R4 is a protective group, the amino group in the product is deprotected to give an optically active aminoalcohol derivative represented by general formula (6a):




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wherein R1 and R3c are as defined above; provided that configuration of R1 attached to the asymmetric carbon at the 2-position and the substituent represented by a nitrogen atom in the optically active aminoketone derivative represented by general formula (4b) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol derivative represented by general formula (6a) is erythro.







DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

This invention will be detailed.


The term “unprotected side chain or optionally protected side chain in a natural α-amino acid” as used herein refers to a side chain on an α-carbon such as alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, hydroxylysine, arginine, cysteine, cystine, methionine, phenylalanine, tyrosine, tryptophan, histidine and ornithine for, for example, an “unprotected side chain in a natural α-amino acid”.


An “optionally protected side chain” may be a side chain on an α-carbon in any of the above natural α-amino acid in which a given functional group is protected by a protective group. The protective group may be any of those commonly used in a process known by those skilled in the art. For example, it may be a protective group for an amino, thiol, hydroxy, phenol or carboxyl group used in common preparation of an amino acid.


An “optionally substituted alkyl” means a substituted alkyl at an optional position(s). Examples of the alkyl group include methyl, ethyl, isopropyl, tert-butyl, pentyl, hexyl, octyl, decyl and allyl. Examples of the substituents used include hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine, chlorine, bromine and iodine.


An “optionally substituted aryl” means a substituted aryl at an optional position(s). Examples of the aryl group include phenyl, naphthyl, anthracenyl, fluorenyl and phenanthrenyl. Examples of a substituent(s) used include alkyls such as methyl, tert-butyl and benzyl; cycloalkyls such as cyclopropyl, cyclopentyl and cyclohexyl; phenyl; hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine, chlorine, bromine and iodine.


An “optionally substituted aralkyl” means a substituted aralkyl at an optional position(s). Examples of the aralkyl group include benzyl, naphthylmethyl, phenylethyl and 9-fluorenylmethyl. Examples of a substituent(s) used include alkyls such as methyl, tert-butyl and benzyl; cycloalkyls such as cyclopropyl, cyclopentyl and cyclohexyl; phenyl; hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine, chlorine, bromine and iodine.


An “optionally substituted heterocycle” means an substituted heterocycle at an optional position(s).


Examples of the heterocycle include tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, piperidyl, morpholinyl, piperazinyl, pyrrolyl, furyl, thienyl, pyridyl, furfuryl, thenyl, pyridylmethyl, pyrimidyl, pyrazyl, imidazoyl, imidazoylmethyl, indolyl, indolylmethyl, isoquinolyl, quinolyl and thiazolyl. Examples of a substituent used include alkyls such as methyl, tert-butyl and benzyl; cycloalkyls such as cyclopropyl, cyclopentyl and cyclohexyl; phenyl; hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine, chlorine, bromine and iodine.


A “heterocyclealkyl” in an optionally substituted heterocyclealkyl means an alkyl substituted with one or more heterocycles at one or more positions, and the “heterocyclealkyl” itself is optionally substituted. Examples of the heterocycle, the alkyl and the substituent therefor may be those described above for an “optionally substituted alkyl” and an “optionally substituted heterocycle”.


An “optionally substituted alkyloxycarbonyl” means an optionally substituted alkyloxycarbonyl at given one or more positions. Examples of the alkyloxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl and allyloxycarbonyl. Examples of the substituent(s) used include hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine, chlorine, bromine and iodine.


An “optionally substituted aryloxycarbonyl” means an optionally substituted aryloxycarbonyl at given one or more positions. Examples of the aryloxycarbonyl include phenoxycarbonyl, naphthyloxycarbonyl, anthracenyloxycarbonyl, fluorenyloxycarbonyl and phenanthrenyloxycarbonyl. Examples of the substituent(s) used include alkyls and aralkyls such as methyl, tert-butyl and benzyl; cycloalkyls derived from cyclopropane, cyclopentane and cyclohexane (for example, cyclopropyl, cyclopentyl and cyclohexyl); phenyl; hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine, chlorine, bromine and iodine.


An “optionally substituted aralkyloxycarbonyl” means an optionally substituted aralkyloxycarbonyl at given one or more positions. Examples of the aralkyloxycarbonyl include benzyloxycarbonyl, naphthylmethyloxycarbonyl, phenylethyloxycarbonyl and 9-fluorenylmethyloxycarbonyl. Examples of the substituent(s) used include alkyls and aralkyls; such as methyl, tert-butyl and benzyl; cycloalkyls derived from cyclopropane, cyclopentane and cyclohexane (for example, cyclopropyl, cyclopentyl and cyclohexyl); phenyl; hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine, chlorine, bromine and iodine.


Each of the above optionally substituted groups may have one or more substituents. When it has a plurality of substituents, each substituent may be independently selected from those described above.


A “halogen” may be fluorine, chlorine, bromine or iodine. Two “Ys” in general formula (7) may be the same or different.


A “reducing agent” means a reagent which can reduce a ketone moiety in the aminoketone derivative represented by general formula (4) into an alcohol moiety, including borane reagents such as borane-tetrahydrofuran complex; borohydride reagents such as sodium borohydride, zinc borohydride and sodium trimethoxy borohydride; alkylaluminum reagents such as diisopropylaluminum hydride; aluminum hydride reagents such as lithium aluminum hydride and lithium trialkoxyaluminum hydride; silane reagents such as trichlorosilane and triethylsilane; sodium metal in liquid ammonia; and magnesium metal in an alcohol.


“Catalytic hydrogenation with a metal catalyst” means reduction of a ketone moiety in the aminoketone derivative represented by general formula (4) into an alcohol moiety by catalytic hydrogenation in the presence of a metal catalyst. Examples of the metal catalyst include nickel catalysts such as Raney nickel, platinum catalysts such as platinum oxide, palladium catalysts such as palladium-carbon or rhodium catalysts such as chlorotris(triphenylphosphine)rhodium which is also known as a Wilkinson catalyst.


“Erythro configuration” is a term indicating a relative configuration of two adjacent asymmetric carbons. For a compound represented by general formula (5) or (6), when the amino and the hydroxy groups as substituents are in the same side in a Ficher projection formula, they have erythro configuration.


Tables 1 to 21 show representative optically active 5-hydroxyoxazolidine derivatives within general formula (3); Tables 22 to 27 show representative optically active aminoketone derivatives within general formula (4); and Tables 28 to 39 show representative optically active aminoalcohol derivatives within general formula (5) or (6), but this invention is not limited to these exemplified compounds. In these Tables, Ph is phenyl or phenylene; Me is methyl; Boc is tert-butoxycarbonyl as a protective group.









TABLE 1









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Example




Compound No.
R2—
R3—





1001
PhCH2
p-PhCH2OPh—


1002
CH3
p-PhCH2OPh—


1003
9-Fluorenylmethyl-
p-PhCH2OPh—


1004
(CH3)3C—
o-PhCH2OPh—


1005
CH3
m-PhCH2OPh—


1006
PhCH2
p-NO2Ph—


1007
(CH3)3C—
p-MeOPh—


1008
PhCH2
p-HOPh—


1009
(CH3)3C—
Ph—


1010
PhCH2
p-FPh


1011
PhCH2
3-Indolyl-


1012
CH3
3-Indolyl-





1013
PhCH2


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1014
PhCH2


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1015
(CH3)3C—
p-PhCH2OPh—


1016
CH3CH2
p-PhCH2OPh—


1017
PhCH2
o-PhCH2OPh—


1018
(CH3)3C—
m-PhCH2OPh—


1019
CH3CH2
o-PhCH2OPh—


1020
PhCH2
p-MeOPh—


1021
(CH3)3C—
m-MeOPh—


1022
PhCH2
Ph


1023
PhCH2
p-CH3Ph—


1024
(CH3)3C—
p-ClPh—


1025
(CH3)3C—
3-Indolyl-


1026
9-Fluorenylmethyl-
3-Indolyl-





1027
(CH3)3C—


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1028
9-Fluorenylmethyl-


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1029
(CH3)3C—


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1030
PhCH2


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1031
(CH3)2CH—


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TABLE 2









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Example




Compound No.
R2—
R3—





2001
PhCH2
p-PhCH2OPh—


2002
CH3
p-PhCH2OPh—


2003
9-Fluorenylmethyl-
p-PhCH2OPh—


2004
(CH3)3C—
o-PhCH2OPh—


2005
CH3
m-PhCH2OPh—


2006
PhCH2
p-NO2Ph—


2007
(CH3)3C—
p-MeOPh—


2008
PhCH2
p-HOPh—


2009
(CH3)3C—
Ph—


2010
PhCH2
p-FPh


2011
PhCH2
3-Indolyl-


2012
CH3
3-Indolyl-





2013
PhCH2


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2014
PhCH2


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2015
(CH3)3C—
p-PhCH2OPh—


2016
CH3CH2
p-PhCH2OPh—


2017
PhCH2
o-PhCH2OPh—


2018
(CH3)3C—
m-PhCH2OPh—


2019
CH3CH2
o-PhCH2OPh—


2020
PhCH2
p-MeOPh—


2021
(CH3)3C—
m-MeOPh—


2022
PhCH2
Ph


2023
PhCH2
p-CH3Ph—


2024
(CH3)3C—
p-ClPh—


2025
(CH3)3C—
3-Indolyl-


2026
9-Fluorenylmethyl-
3-Indolyl-





2027
(CH3)3C—


embedded image







2028
9-Fluorenylmethyl-


embedded image







2029
(CH3)3C—


embedded image







2030
PhCH2


embedded image







2031
(CH3)2CH—


embedded image


















TABLE 3









embedded image














Example




Compound No.
R2—
R3—





3001
PhCH2
p-PhCH2OPh—


3002
CH3
p-PhCH2OPh—


3003
9-Fluorenylmethyl-
p-PhCH2OPh—


3004
(CH3)3C—
o-PhCH2OPh—


3005
CH3
m-PhCH2OPh—


3006
PhCH2
p-NO2Ph—


3007
(CH3)3C—
p-MeOPh—


3008
PhCH2
p-HOPh—


3009
(CH3)3C—
Ph—


3010
PhCH2
p-FPh


3011
PhCH2
3-Indolyl-


3012
CH3
3-Indolyl-





3013
PhCH2


embedded image







3014
PhCH2


embedded image







3015
(CH3)3C—
p-PhCH2OPh—


3016
CH3CH2
p-PhCH2OPh—


3017
PhCH2
o-PhCH2OPh—


3018
(CH3)3C—
m-PhCH2OPh—


3019
CH3CH2
o-PhCH2OPh—


3020
PhCH2
p-MeOPh—


3021
(CH3)3C—
m-MeOPh—


3022
PhCH2
Ph


3023
PhCH2
p-CH3Ph—


3024
(CH3)3C—
p-ClPh—


3025
(CH3)3C—
3-Indolyl-


3026
9-Fluorenylmethyl-
3-Indolyl-





3027
(CH3)3C—


embedded image







3028
9-Fluorenylmethyl-


embedded image







3029
(CH3)3C—


embedded image







3030
PhCH2


embedded image







3031
(CH3)2CH—


embedded image


















TABLE 4









embedded image














Example




Compound No.
R2—
R3—





4001
PhCH2
p-PhCH2OPh—


4002
CH3
p-PhCH2OPh—


4003
9-Fluorenylmethyl-
p-PhCH2OPh—


4004
(CH3)3C—
o-PhCH2OPh—


4005
CH3
m-PhCH2OPh—


4006
PhCH2
p-NO2Ph—


4007
(CH3)3C—
p-MeOPh—


4008
PhCH2
p-HOPh—


4009
(CH3)3C—
Ph—


4010
PhCH2
p-FPh


4011
PhCH2
3-Indolyl-


4012
CH3
3-Indolyl-





4013
PhCH2


embedded image







4014
PhCH2


embedded image







4015
(CH3)3C—
p-PhCH2OPh—


4016
CH3CH2
p-PhCH2OPh—


4017
PhCH2
o-PhCH2OPh—


4018
(CH3)3C—
m-PhCH2OPh—


4019
CH3CH2
o-PhCH2OPh—


4020
PhCH2
p-MeOPh—


4021
(CH3)3C—
m-MeOPh—


4022
PhCH2
Ph


4023
PhCH2
p-CH3Ph—


4024
(CH3)3C—
p-ClPh—


4025
(CH3)3C—
3-Indolyl-


4026
9-Fluorenylmethyl-
3-Indolyl-





4027
(CH3)3C—


embedded image







4028
9-Fluorenylmethyl-


embedded image







4029
(CH3)3C—


embedded image







4030
PhCH2


embedded image







4031
(CH3)2CH—


embedded image


















TABLE 5









embedded image














Example




Compound No.
R2—
R3—





5001
PhCH2
p-PhCH2OPh—


5002
CH3
p-PhCH2OPh—


5003
9-Fluorenylmethyl-
p-PhCH2OPh—


5004
(CH3)3C—
o-PhCH2OPh—


5005
CH3
m-PhCH2OPh—


5006
PhCH2
p-NO2Ph—


5007
(CH3)3C—
p-MeOPh—


5008
PhCH2
p-HOPh—


5009
(CH3)3C—
Ph—


5010
PhCH2
p-FPh


5011
PhCH2
3-Indolyl-


5012
CH3
3-Indolyl-





5013
PhCH2


embedded image







5014
PhCH2


embedded image







5015
(CH3)3C—
p-PhCH2OPh—


5016
CH3CH2
p-PhCH2OPh—


5017
PhCH2
o-PhCH2OPh—


5018
(CH3)3C—
m-PhCH2OPh—


5019
CH3CH2
o-PhCH2OPh—


5020
PhCH2
p-MeOPh—


5021
(CH3)3C—
m-MeOPh—


5022
PhCH2
Ph


5023
PhCH2
p-CH3Ph—


5024
(CH3)3C—
p-ClPh—


5025
(CH3)3C—
3-Indolyl-


5026
9-Fluorenylmethyl-
3-Indolyl-





5027
(CH3)3C—


embedded image







5028
9-Fluorenylmethyl-


embedded image







5029
(CH3)3C—


embedded image







5030
PhCH2


embedded image







5031
(CH3)2CH—


embedded image


















TABLE 6









embedded image














Example




Compound No.
R2—
R3—





6001
PhCH2
p-PhCH2OPh—


6002
CH3
p-PhCH2OPh—


6003
9-Fluorenylmethyl-
p-PhCH2OPh—


6004
(CH3)3C—
o-PhCH2OPh—


6005
CH3
m-PhCH2OPh—


6006
PhCH2
p-NO2Ph—


6007
(CH3)3C—
p-MeOPh—


6008
PhCH2
p-HOPh—


6009
(CH3)3C—
Ph—


6010
PhCH2
p-FPh


6011
PhCH2
3-Indolyl-


6012
CH3
3-Indolyl-





6013
PhCH2


embedded image







6014
PhCH2


embedded image







6015
(CH3)3C—
p-PhCH2OPh—


6016
CH3CH2
p-PhCH2OPh—


6017
PhCH2
o-PhCH2OPh—


6018
(CH3)3C—
m-PhCH2OPh—


6019
CH3CH2
o-PhCH2OPh—


6020
PhCH2
p-MeOPh—


6021
(CH3)3C—
m-MeOPh—


6022
PhCH2
Ph


6023
PhCH2
p-CH3Ph—


6024
(CH3)3C—
p-ClPh—


6025
(CH3)3C—
3-Indolyl-


6026
9-Fluorenylmethyl-
3-Indolyl-





6027
(CH3)3C—


embedded image







6028
9-Fluorenylmethyl-


embedded image







6029
(CH3)3C—


embedded image







6030
PhCH2


embedded image







6031
(CH3)2CH—


embedded image


















TABLE 7









embedded image














Example




Compound No.
R2—
R3—





7001
PhCH2
p-PhCH2OPh—


7002
CH3
p-PhCH2OPh—


7003
9-Fluorenylmethyl-
p-PhCH2OPh—


7004
(CH3)3C—
o-PhCH2OPh—


7005
CH3
m-PhCH2OPh—


7006
PhCH2
p-NO2Ph—


7007
(CH3)3C—
p-MeOPh—


7008
PhCH2
p-HOPh—


7009
(CH3)3C—
Ph—


7010
PhCH2
p-FPh


7011
PhCH2
3-Indolyl-


7012
CH3
3-Indolyl-





7013
PhCH2


embedded image







7014
PhCH2


embedded image







7015
(CH3)3C—
p-PhCH2OPh—


7016
CH3CH2
p-PhCH2OPh—


7017
PhCH2
o-PhCH2OPh—


7018
(CH3)3C—
m-PhCH2OPh—


7019
CH3CH2
o-PhCH2OPh—


7020
PhCH2
p-MeOPh—


7021
(CH3)3C—
m-MeOPh—


7022
PhCH2
Ph


7023
PhCH2
p-CH3Ph—


7024
(CH3)3C—
p-ClPh—


7025
(CH3)3C—
3-Indolyl-


7026
9-Fluorenylmethyl-
3-Indolyl-





7027
(CH3)3C—


embedded image







7028
9-Fluorenylmethyl-


embedded image







7029
(CH3)3C—


embedded image







7030
PhCH2


embedded image







7031
(CH3)2CH—


embedded image


















TABLE 8









embedded image














Example




Compound No.
R2—
R3—





8001
PhCH2
p-PhCH2OPh—


8002
CH3
p-PhCH2OPh—


8003
9-Fluorenylmethyl-
p-PhCH2OPh—


8004
(CH3)3C—
o-PhCH2OPh—


8005
CH3
m-PhCH2OPh—


8006
PhCH2
p-NO2Ph—


8007
(CH3)3C—
p-MeOPh—


8008
PhCH2
p-HOPh—


8009
(CH3)3C—
Ph—


8010
PhCH2
p-FPh


8011
PhCH2
3-Indolyl-


8012
CH3
3-Indolyl-





8013
PhCH2


embedded image







8014
PhCH2


embedded image







8015
(CH3)3C—
p-PhCH2OPh—


8016
CH3CH2
p-PhCH2OPh—


8017
PhCH2
o-PhCH2OPh—


8018
(CH3)3C—
m-PhCH2OPh—


8019
CH3CH2
o-PhCH2OPh—


8020
PhCH2
p-MeOPh—


8021
(CH3)3C—
m-MeOPh—


8022
PhCH2
Ph


8023
PhCH2
p-CH3Ph—


8024
(CH3)3C—
p-ClPh—


8025
(CH3)3C—
3-Indolyl-


8026
9-Fluorenylmethyl-
3-Indolyl-





8027
(CH3)3C—


embedded image







8028
9-Fluorenylmethyl-


embedded image







8029
(CH3)3C—


embedded image







8030
PhCH2


embedded image







8031
(CH3)2CH—


embedded image


















TABLE 9









embedded image














Example




Compound No.
R2—
R3—





9001
PhCH2
p-PhCH2OPh—


9002
CH3
p-PhCH2OPh—


9003
9-Fluorenylmethyl-
p-PhCH2OPh—


9004
(CH3)3C—
o-PhCH2OPh—


9005
CH3
m-PhCH2OPh—


9006
PhCH2
p-NO2Ph—


9007
(CH3)3C—
p-MeOPh—


9008
PhCH2
p-HOPh—


9009
(CH3)3C—
Ph—


9010
PhCH2
p-FPh


9011
PhCH2
3-Indolyl-


9012
CH3
3-Indolyl-





9013
PhCH2


embedded image







9014
PhCH2


embedded image







9015
(CH3)3C—
p-PhCH2OPh—


9016
CH3CH2
p-PhCH2OPh—


9017
PhCH2
o-PhCH2OPh—


9018
(CH3)3C—
m-PhCH2OPh—


9019
CH3CH2
o-PhCH2OPh—


9020
PhCH2
p-MeOPh—


9021
(CH3)3C—
m-MeOPh—


9022
PhCH2
Ph


9023
PhCH2
p-CH3Ph—


9024
(CH3)3C—
p-ClPh—


9025
(CH3)3C—
3-Indolyl-


9026
9-Fluorenylmethyl-
3-Indolyl-





9027
(CH3)3C—


embedded image







9028
9-Fluorenylmethyl-


embedded image







9029
(CH3)3C—


embedded image







9030
PhCH2


embedded image







9031
(CH3)2CH—


embedded image


















TABLE 10









embedded image














Example




Compound No.
R2—
R3—





10001
PhCH2
p-PhCH2OPh—


10002
CH3
p-PhCH2OPh—


10003
9-Fluorenylmethyl-
p-PhCH2OPh—


10004
(CH3)3C—
o-PhCH2OPh—


10005
CH3
m-PhCH2OPh—


10006
PhCH2
p-NO2Ph—


10007
(CH3)3C—
p-MeOPh—


10008
PhCH2
p-HOPh—


10009
(CH3)3C—
Ph—


10010
PhCH2
p-FPh


10011
PhCH2
3-Indolyl-


10012
CH3
3-Indolyl-





10013
PhCH2


embedded image







10014
PhCH2


embedded image







10015
(CH3)3C—
p-PhCH2OPh—


10016
CH3CH2
p-PhCH2OPh—


10017
PhCH2
o-PhCH2OPh—


10018
(CH3)3C—
m-PhCH2OPh—


10019
CH3CH2
o-PhCH2OPh—


10020
PhCH2
p-MeOPh—


10021
(CH3)3C—
m-MeOPh—


10022
PhCH2
Ph


10023
PhCH2
p-CH3Ph—


10024
(CH3)3C—
p-ClPh—


10025
(CH3)3C—
3-Indolyl-


10026
9-Fluorenylmethyl-
3-Indolyl-





10027
(CH3)3C—


embedded image







10028
9-Fluorenylmethyl-


embedded image







10029
(CH3)3C—


embedded image







10030
PhCH2


embedded image







10031
(CH3)2CH—


embedded image


















TABLE 11









embedded image














Example




Compound No.
R2—
R3—





11001
PhCH2
p-PhCH2OPh—


11002
CH3
p-PhCH2OPh—


11003
9-Fluorenylmethyl-
p-PhCH2OPh—


11004
(CH3)3C—
o-PhCH2OPh—


11005
CH3
m-PhCH2OPh—


11006
PhCH2
p-NO2Ph—


11007
(CH3)3C—
p-MeOPh—


11008
PhCH2
p-HOPh—


11009
(CH3)3C—
Ph—


11010
PhCH2
p-FPh


11011
PhCH2
3-Indolyl-


11012
CH3
3-Indolyl-





11013
PhCH2


embedded image







11014
PhCH2


embedded image







11015
(CH3)3C—
p-PhCH2OPh—


11016
CH3CH2
p-PhCH2OPh—


11017
PhCH2
o-PhCH2OPh—


11018
(CH3)3C—
m-PhCH2OPh—


11019
CH3CH2
o-PhCH2OPh—


11020
PhCH2
p-MeOPh—


11021
(CH3)3C—
m-MeOPh—


11022
PhCH2
Ph


11023
PhCH2
p-CH3Ph—


11024
(CH3)3C—
p-ClPh—


11025
(CH3)3C—
3-Indolyl-


11026
9-Fluorenylmethyl-
3-Indolyl-





11027
(CH3)3C—


embedded image







11028
9-Fluorenylmethyl-


embedded image







11029
(CH3)3C—


embedded image







11030
PhCH2


embedded image







11031
(CH3)2CH—


embedded image


















TABLE 12









embedded image














Example




Compound No.
R2—
R3—





12001
PhCH2
p-PhCH2OPh—


12002
CH3
p-PhCH2OPh—


12003
9-Fluorenylmethyl-
p-PhCH2OPh—


12004
(CH3)3C—
o-PhCH2OPh—


12005
CH3
m-PhCH2OPh—


12006
PhCH2
p-NO2Ph—


12007
(CH3)3C—
p-MeOPh—


12008
PhCH2
p-HOPh—


12009
(CH3)3C—
Ph—


12010
PhCH2
p-FPh


12011
PhCH2
3-Indolyl-


12012
CH3
3-Indolyl-





12013
PhCH2


embedded image







12014
PhCH2


embedded image







12015
(CH3)3C—
p-PhCH2OPh—


12016
CH3CH2
p-PhCH2OPh—


12017
PhCH2
o-PhCH2OPh—


12018
(CH3)3C—
m-PhCH2OPh—


12019
CH3CH2
o-PhCH2OPh—


12020
PhCH2
p-MeOPh—


12021
(CH3)3C—
m-MeOPh—


12022
PhCH2
Ph


12023
PhCH2
p-CH3Ph—


12024
(CH3)3C—
p-ClPh—


12025
(CH3)3C—
3-Indolyl-


12026
9-Fluorenylmethyl-
3-Indolyl-





12027
(CH3)3C—


embedded image







12028
9-Fluorenylmethyl-


embedded image







12029
(CH3)3C—


embedded image







12030
PhCH2


embedded image







12031
(CH3)2CH—


embedded image


















TABLE 13









embedded image














Example




Compound No.
R2—
R3—





13001
PhCH2
p-PhCH2OPh—


13002
CH3
p-PhCH2OPh—


13003
9-Fluorenylmethyl-
p-PhCH2OPh—


13004
(CH3)3C—
o-PhCH2OPh—


13005
CH3
m-PhCH2OPh—


13006
PhCH2
p-NO2Ph—


13007
(CH3)3C—
p-MeOPh—


13008
PhCH2
p-HOPh—


13009
(CH3)3C—
Ph—


13010
PhCH2
p-FPh


13011
PhCH2
3-Indolyl-


13012
CH3
3-Indolyl-





13013
PhCH2


embedded image







13014
PhCH2


embedded image







13015
(CH3)3C—
p-PhCH2OPh—


13016
CH3CH2
p-PhCH2OPh—


13017
PhCH2
o-PhCH2OPh—


13018
(CH3)3C—
m-PhCH2OPh—


13019
CH3CH2
o-PhCH2OPh—


13020
PhCH2
p-MeOPh—


13021
(CH3)3C—
m-MeOPh—


13022
PhCH2
Ph


13023
PhCH2
p-CH3Ph—


13024
(CH3)3C—
p-ClPh—


13025
(CH3)3C—
3-Indolyl-


13026
9-Fluorenylmethyl-
3-Indolyl-





13027
(CH3)3C—


embedded image







13028
9-Fluorenylmethyl-


embedded image







13029
(CH3)3C—


embedded image







13030
PhCH2


embedded image







13031
(CH3)2CH—


embedded image


















TABLE 14









embedded image














Example




Compound No.
R2—
R3—





14001
PhCH2
p-PhCH2OPh—


14002
CH3
p-PhCH2OPh—


14003
9-Fluorenylmethyl-
p-PhCH2OPh—


14004
(CH3)3C—
o-PhCH2OPh—


14005
CH3
m-PhCH2OPh—


14006
PhCH2
p-NO2Ph—


14007
(CH3)3C—
p-MeOPh—


14008
PhCH2
p-HOPh—


14009
(CH3)3C—
Ph—


14010
PhCH2
p-FPh


14011
PhCH2
3-Indolyl-


14012
CH3
3-Indolyl-





14013
PhCH2


embedded image







14014
PhCH2


embedded image







14015
(CH3)3C—
p-PhCH2OPh—


14016
CH3CH2
p-PhCH2OPh—


14017
PhCH2
o-PhCH2OPh—


14018
(CH3)3C—
m-PhCH2OPh—


14019
CH3CH2
o-PhCH2OPh—


14020
PhCH2
p-MeOPh—


14021
(CH3)3C—
m-MeOPh—


14022
PhCH2
Ph


14023
PhCH2
p-CH3Ph—


14024
(CH3)3C—
p-ClPh—


14025
(CH3)3C—
3-Indolyl-


14026
9-Fluorenylmethyl-
3-Indolyl-





14027
(CH3)3C—


embedded image







14028
9-Fluorenylmethyl-


embedded image







14029
(CH3)3C—


embedded image







14030
PhCH2


embedded image







14031
(CH3)2CH—


embedded image


















TABLE 15









embedded image














Example




Compound No.
R2—
R3—





15001
PhCH2
p-PhCH2OPh—


15002
CH3
p-PhCH2OPh—


15003
9-Fluorenylmethyl-
p-PhCH2OPh—


15004
(CH3)3C—
o-PhCH2OPh—


15005
CH3
m-PhCH2OPh—


15006
PhCH2
p-NO2Ph—


15007
(CH3)3C—
p-MeOPh—


15008
PhCH2
p-HOPh—


15009
(CH3)3C—
Ph—


15010
PhCH2
p-FPh


15011
PhCH2
3-Indolyl-


15012
CH3
3-Indolyl-





15013
PhCH2


embedded image







15014
PhCH2


embedded image







15015
(CH3)3C—
p-PhCH2OPh—


15016
CH3CH2
p-PhCH2OPh—


15017
PhCH2
o-PhCH2OPh—


15018
(CH3)3C—
m-PhCH2OPh—


15019
CH3CH2
o-PhCH2OPh—


15020
PhCH2
p-MeOPh—


15021
(CH3)3C—
m-MeOPh—


15022
PhCH2
Ph


15023
PhCH2
p-CH3Ph—


15024
(CH3)3C—
p-ClPh—


15025
(CH3)3C—
3-Indolyl-


15026
9-Fluorenylmethyl-
3-Indolyl-





15027
(CH3)3C—


embedded image







15028
9-Fluorenylmethyl-


embedded image







15029
(CH3)3C—


embedded image







15030
PhCH2


embedded image







15031
(CH3)2CH—


embedded image


















TABLE 16









embedded image














Example




Compound No.
R2—
R3—





16001
PhCH2
p-PhCH2OPh—


16002
CH3
p-PhCH2OPh—


16003
9-Fluorenylmethyl-
p-PhCH2OPh—


16004
(CH3)3C—
o-PhCH2OPh—


16005
CH3
m-PhCH2OPh—


16006
PhCH2
p-NO2Ph—


16007
(CH3)3C—
p-MeOPh—


16008
PhCH2
p-HOPh—


16009
(CH3)3C—
Ph—


16010
PhCH2
p-FPh


16011
PhCH2
3-Indolyl-


16012
CH3
3-Indolyl-





16013
PhCH2


embedded image







16014
PhCH2


embedded image







16015
(CH3)3C—
p-PhCH2OPh—


16016
CH3CH2
p-PhCH2OPh—


16017
PhCH2
o-PhCH2OPh—


16018
(CH3)3C—
m-PhCH2OPh—


16019
CH3CH2
o-PhCH2OPh—


16020
PhCH2
p-MeOPh—


16021
(CH3)3C—
m-MeOPh—


16022
PhCH2
Ph


16023
PhCH2
p-CH3Ph—


16024
(CH3)3C—
p-ClPh—


16025
(CH3)3C—
3-Indolyl-


16026
9-Fluorenylmethyl-
3-Indolyl-





16027
(CH3)3C—


embedded image







16028
9-Fluorenylmethyl-


embedded image







16029
(CH3)3C—


embedded image







16030
PhCH2


embedded image







16031
(CH3)2CH—


embedded image


















TABLE 17









embedded image














Example




Compound No.
R2—
R3—





17001
PhCH2
p-PhCH2OPh—


17002
CH3
p-PhCH2OPh—


17003
9-Fluorenylmethyl-
p-PhCH2OPh—


17004
(CH3)3C—
o-PhCH2OPh—


17005
CH3
m-PhCH2OPh—


17006
PhCH2
p-NO2Ph—


17007
(CH3)3C—
p-MeOPh—


17008
PhCH2
p-HOPh—


17009
(CH3)3C—
Ph—


17010
PhCH2
p-FPh


17011
PhCH2
3-Indolyl-


17012
CH3
3-Indolyl-





17013
PhCH2


embedded image







17014
PhCH2


embedded image







17015
(CH3)3C—
p-PhCH2OPh—


17016
CH3CH2
p-PhCH2OPh—


17017
PhCH2
o-PhCH2OPh—


17018
(CH3)3C—
m-PhCH2OPh—


17019
CH3CH2
o-PhCH2OPh—


17020
PhCH2
p-MeOPh—


17021
(CH3)3C—
m-MeOPh—


17022
PhCH2
Ph


17023
PhCH2
p-CH3Ph—


17024
(CH3)3C—
p-ClPh—


17025
(CH3)3C—
3-Indolyl-


17026
9-Fluorenylmethyl-
3-Indolyl-





17027
(CH3)3C—


embedded image







17028
9-Fluorenylmethyl-


embedded image







17029
(CH3)3C—


embedded image







17030
PhCH2


embedded image







17031
(CH3)2CH—


embedded image


















TABLE 18









embedded image














Example




Compound No.
R2—
R3—





18001
PhCH2
p-PhCH2OPh—


18002
CH3
p-PhCH2OPh—


18003
9-Fluorenylmethyl-
p-PhCH2OPh—


18004
(CH3)3C—
o-PhCH2OPh—


18005
CH3
m-PhCH2OPh—


18006
PhCH2
p-NO2Ph—


18007
(CH3)3C—
p-MeOPh—


18008
PhCH2
p-HOPh—


18009
(CH3)3C—
Ph—


18010
PhCH2
p-FPh


18011
PhCH2
3-Indolyl-


18012
CH3
3-Indolyl-





18013
PhCH2


embedded image







18014
PhCH2


embedded image







18015
(CH3)3C—
p-PhCH2OPh—


18016
CH3CH2
p-PhCH2OPh—


18017
PhCH2
o-PhCH2OPh—


18018
(CH3)3C—
m-PhCH2OPh—


18019
CH3CH2
o-PhCH2OPh—


18020
PhCH2
p-MeOPh—


18021
(CH3)3C—
m-MeOPh—


18022
PhCH2
Ph


18023
PhCH2
p-CH3Ph—


18024
(CH3)3C—
p-ClPh—


18025
(CH3)3C—
3-Indolyl-


18026
9-Fluorenylmethyl-
3-Indolyl-





18027
(CH3)3C—


embedded image







18028
9-Fluorenylmethyl-


embedded image







18029
(CH3)3C—


embedded image







18030
PhCH2


embedded image







18031
(CH3)2CH—


embedded image


















TABLE 19









embedded image














Example




Compound No.
R2—
R3—





19001
PhCH2
p-PhCH2OPh—


19002
CH3
p-PhCH2OPh—


19003
9-Fluorenylmethyl-
p-PhCH2OPh—


19004
(CH3)3C—
o-PhCH2OPh—


19005
CH3
m-PhCH2OPh—


19006
PhCH2
p-NO2Ph—


19007
(CH3)3C—
p-MeOPh—


19008
PhCH2
p-HOPh—


19009
(CH3)3C—
Ph—


19010
PhCH2
p-FPh


19011
PhCH2
3-Indolyl-


19012
CH3
3-Indolyl-





19013
PhCH2


embedded image







19014
PhCH2


embedded image







19015
(CH3)3C—
p-PhCH2OPh—


19016
CH3CH2
p-PhCH2OPh—


19017
PhCH2
o-PhCH2OPh—


19018
(CH3)3C—
m-PhCH2OPh—


19019
CH3CH2
o-PhCH2OPh—


19020
PhCH2
p-MeOPh—


19021
(CH3)3C—
m-MeOPh—


19022
PhCH2
Ph


19023
PhCH2
p-CH3Ph—


19024
(CH3)3C—
p-ClPh—


19025
(CH3)3C—
3-Indolyl-


19026
9-Fluorenylmethyl-
3-Indolyl-





19027
(CH3)3C—


embedded image







19028
9-Fluorenylmethyl-


embedded image







19029
(CH3)3C—


embedded image







19030
PhCH2


embedded image







19031
(CH3)2CH—


embedded image


















TABLE 20









embedded image














Example




Compound No.
R2—
R3—





20001
PhCH2
p-PhCH2OPh—


20002
CH3
p-PhCH2OPh—


20003
9-Fluorenylmethyl-
p-PhCH2OPh—


20004
(CH3)3C—
o-PhCH2OPh—


20005
CH3
m-PhCH2OPh—


20006
PhCH2
p-NO2Ph—


20007
(CH3)3C—
p-MeOPh—


20008
PhCH2
p-HOPh—


20009
(CH3)3C—
Ph—


20010
PhCH2
p-FPh


20011
PhCH2
3-Indolyl-


20012
CH3
3-Indolyl-





20013
PhCH2


embedded image







20014
PhCH2


embedded image







20015
(CH3)3C—
p-PhCH2OPh—


20016
CH3CH2
p-PhCH2OPh—


20017
PhCH2
o-PhCH2OPh—


20018
(CH3)3C—
m-PhCH2OPh—


20019
CH3CH2
o-PhCH2OPh—


20020
PhCH2
p-MeOPh—


20021
(CH3)3C—
m-MeOPh—


20022
PhCH2
Ph


20023
PhCH2
p-CH3Ph—


20024
(CH3)3C—
p-ClPh—


20025
(CH3)3C—
3-Indolyl-


20026
9-Fluorenylmethyl-
3-Indolyl-





20027
(CH3)3C—


embedded image







20028
9-Fluorenylmethyl-


embedded image







20029
(CH3)3C—


embedded image







20030
PhCH2


embedded image







20031
(CH3)2CH—


embedded image


















TABLE 21









embedded image














Example




Compound No.
R2—
R3—





21001
PhCH2
p-PhCH2OPh—


21002
CH3
p-PhCH2OPh—


21003
9-Fluorenylmethyl-
p-PhCH2OPh—


21004
(CH3)3C—
o-PhCH2OPh—


21005
CH3
m-PhCH2OPh—


21006
PhCH2
p-NO2Ph—


21007
(CH3)3C—
p-MeOPh—


21008
PhCH2
p-HOPh—


21009
(CH3)3C—
Ph—


21010
PhCH2
p-FPh


21011
PhCH2
3-Indolyl-


21012
CH3
3-Indolyl-





21013
PhCH2


embedded image







21014
PhCH2


embedded image







21015
(CH3)3C—
p-PhCH2OPh—


21016
CH3CH2
p-PhCH2OPh—


21017
PhCH2
o-PhCH2OPh—


21018
(CH3)3C—
m-PhCH2OPh—


21019
CH3CH2
o-PhCH2OPh—


21020
PhCH2
p-MeOPh—


21021
(CH3)3C—
m-MeOPh—


21022
PhCH2
Ph


21023
PhCH2
p-CH3Ph—


21024
(CH3)3C—
p-ClPh—


21025
(CH3)3C—
3-Indolyl-


21026
9-Fluorenylmethyl-
3-Indolyl-





21027
(CH3)3C—


embedded image







21028
9-Fluorenylmethyl-


embedded image







21029
(CH3)3C—


embedded image







21030
PhCH2


embedded image







21031
(CH3)2CH—


embedded image


















TABLE 22









embedded image














Example




Compound No.
R2—
R3—





22001
PhCH2
p-PhCH2OPh—


22002
CH3
p-PhCH2OPh—


22003
9-Fluorenylmethyl-
p-PhCH2OPh—


22004
(CH3)3C—
o-PhCH2OPh—


22005
CH3
m-PhCH2OPh—


22006
PhCH2
p-NO2Ph—


22007
(CH3)3C—
p-MeOPh—


22008
PhCH2
p-HOPh—


22009
(CH3)3C—
Ph—


22010
PhCH2
p-FPh


22011
PhCH2
3-Indolyl-


22012
CH3
3-Indolyl-





22013
PhCH2


embedded image







22014
PhCH2


embedded image







22015
H—
p-PhCH2OPh—


22016
CH3CH2
p-PhCH2OPh—


22017
PhCH2
o-PhCH2OPh—


22018
(CH3)3C—
m-PhCH2OPh—


22019
CH3CH2
o-PhCH2OPh—


22020
PhCH2
p-MeOPh—


22021
(CH3)3C—
m-MeOPh—


22022
PhCH2
Ph


22023
PhCH2
p-CH3Ph—


22024
(CH3)3C—
p-ClPh—


22025
(CH3)3C—
3-Indolyl-


22026
9-Fluorenylmethyl-
3-Indolyl-





22027
(CH3)3C—


embedded image







22028
9-Fluorenylmethyl-


embedded image







22029
(CH3)3C—


embedded image







22030
PhCH2


embedded image







22031
(CH3)2CH—


embedded image


















TABLE 23









embedded image














Example




Compound No.
R2—
R3—





23001
PhCH2
p-PhCH2OPh—


23002
CH3
p-PhCH2OPh—


23003
9-Fluorenylmethyl-
p-PhCH2OPh—


23004
(CH3)3C—
o-PhCH2OPh—


23005
CH3
m-PhCH2OPh—


23006
PhCH2
p-NO2Ph—


23007
(CH3)3C—
p-MeOPh—


23008
PhCH2
p-HOPh—


23009
(CH3)3C—
Ph—


23010
PhCH2
p-FPh


23011
PhCH2
3-Indolyl-


23012
CH3
3-Indolyl-





23013
PhCH2


embedded image







23014
PhCH2


embedded image







23015
H—
p-PhCH2OPh—


23016
CH3CH2
p-PhCH2OPh—


23017
PhCH2
o-PhCH2OPh—


23018
(CH3)3C—
m-PhCH2OPh—


23019
CH3CH2
o-PhCH2OPh—


23020
PhCH2
p-MeOPh—


23021
(CH3)3C—
m-MeOPh—


23022
PhCH2
Ph


23023
PhCH2
p-CH3Ph—


23024
(CH3)3C—
p-ClPh—


23025
(CH3)3C—
3-Indolyl-


23026
9-Fluorenylmethyl-
3-Indolyl-





23027
(CH3)3C—


embedded image







23028
9-Fluorenylmethyl-


embedded image







23029
(CH3)3C—


embedded image







23030
PhCH2


embedded image







23031
(CH3)2CH—


embedded image


















TABLE 24









embedded image














Example




Compound No.
R2—
R3—





24001
PhCH2
p-PhCH2OPh—


24002
CH3
p-PhCH2OPh—


24003
9-Fluorenylmethyl-
p-PhCH2OPh—


24004
(CH3)3C—
o-PhCH2OPh—


24005
CH3
m-PhCH2OPh—


24006
PhCH2
p-NO2Ph—


24007
(CH3)3C—
p-MeOPh—


24008
PhCH2
p-HOPh—


24009
(CH3)3C—
Ph—


24010
PhCH2
p-FPh


24011
PhCH2
3-Indolyl-


24012
CH3
3-Indolyl-





24013
PhCH2


embedded image







24014
PhCH2


embedded image







24015
H—
p-PhCH2OPh—


24016
CH3CH2
p-PhCH2OPh—


24017
PhCH2
o-PhCH2OPh—


24018
(CH3)3C—
m-PhCH2OPh—


24019
CH3CH2
o-PhCH2OPh—


24020
PhCH2
p-MeOPh—


24021
(CH3)3C—
m-MeOPh—


24022
PhCH2
Ph


24023
PhCH2
p-CH3Ph—


24024
(CH3)3C—
p-ClPh—


24025
(CH3)3C—
3-Indolyl-


24026
9-Fluorenylmethyl-
3-Indolyl-





24027
(CH3)3C—


embedded image







24028
9-Fluorenylmethyl-


embedded image







24029
(CH3)3C—


embedded image







24030
PhCH2


embedded image







24031
(CH3)2CH—


embedded image


















TABLE 25









embedded image














Example




Compound No.
R2—
R3—





25001
PhCH2
p-PhCH2OPh—


25002
CH3
p-PhCH2OPh—


25003
9-Fluorenylmethyl-
p-PhCH2OPh—


25004
(CH3)3C—
o-PhCH2OPh—


25005
CH3
m-PhCH2OPh—


25006
PhCH2
p-NO2Ph—


25007
(CH3)3C—
p-MeOPh—


25008
PhCH2
p-HOPh—


25009
(CH3)3C—
Ph—


25010
PhCH2
p-FPh


25011
PhCH2
3-Indolyl-


25012
CH3
3-Indolyl-





25013
PhCH2


embedded image







25014
PhCH2


embedded image







25015
H—
p-PhCH2OPh—


25016
CH3CH2
p-PhCH2OPh—


25017
PhCH2
o-PhCH2OPh—


25018
(CH3)3C—
m-PhCH2OPh—


25019
CH3CH2
o-PhCH2OPh—


25020
PhCH2
p-MeOPh—


25021
(CH3)3C—
m-MeOPh—


25022
PhCH2
Ph


25023
PhCH2
p-CH3Ph—


25024
(CH3)3C—
p-ClPh—


25025
(CH3)3C—
3-Indolyl-


25026
9-Fluorenylmethyl-
3-Indolyl-





25027
(CH3)3C—


embedded image







25028
9-Fluorenylmethyl-


embedded image







25029
(CH3)3C—


embedded image







25030
PhCH2


embedded image







25031
(CH3)2CH—


embedded image


















TABLE 26









embedded image














Example




Compound No.
R2—
R3—





26001
PhCH2
p-PhCH2OPh—


26002
CH3
p-PhCH2OPh—


26003
9-Fluorenylmethyl-
p-PhCH2OPh—


26004
(CH3)3C—
o-PhCH2OPh—


26005
CH3
m-PhCH2OPh—


26006
PhCH2
p-NO2Ph—


26007
(CH3)3C—
p-MeOPh—


26008
PhCH2
p-HOPh—


26009
(CH3)3C—
Ph—


26010
PhCH2
p-FPh


26011
PhCH2
3-Indolyl-


26012
CH3
3-Indolyl-





26013
PhCH2


embedded image







26014
PhCH2


embedded image







26015
H—
p-PhCH2OPh—


26016
CH3CH2
p-PhCH2OPh—


26017
PhCH2
o-PhCH2OPh—


26018
(CH3)3C—
m-PhCH2OPh—


26019
CH3CH2
o-PhCH2OPh—


26020
PhCH2
p-MeOPh—


26021
(CH3)3C—
m-MeOPh—


26022
PhCH2
Ph


26023
PhCH2
p-CH3Ph—


26024
(CH3)3C—
p-ClPh—


26025
(CH3)3C—
3-Indolyl-


26026
9-Fluorenylmethyl-
3-Indolyl-





26027
(CH3)3C—


embedded image







26028
9-Fluorenylmethyl-


embedded image







26029
(CH3)3C—


embedded image







26030
PhCH2


embedded image







26031
(CH3)2CH—


embedded image


















TABLE 27









embedded image














Example




Compound No.
R2—
R3—





27001
PhCH2
p-PhCH2OPh—


27002
CH3
p-PhCH2OPh—


27003
9-Fluorenylmethyl-
p-PhCH2OPh—


27004
(CH3)3C—
o-PhCH2OPh—


27005
CH3
m-PhCH2OPh—


27006
PhCH2
p-NO2Ph—


27007
(CH3)3C—
p-MeOPh—


27008
PhCH2
p-HOPh—


27009
(CH3)3C—
Ph—


27010
PhCH2
p-FPh


27011
PhCH2
3-Indolyl-


27012
CH3
3-Indolyl-





27013
PhCH2


embedded image







27014
PhCH2


embedded image







27015
H—
p-PhCH2OPh—


27016
CH3CH2
p-PhCH2OPh—


27017
PhCH2
o-PhCH2OPh—


27018
(CH3)3C—
m-PhCH2OPh—


27019
CH3CH2
o-PhCH2OPh—


27020
PhCH2
p-MeOPh—


27021
(CH3)3C—
m-MeOPh—


27022
PhCH2
Ph


27023
PhCH2
p-CH3Ph—


27024
(CH3)3C—
p-ClPh—


27025
(CH3)3C—
3-Indolyl-


27026
9-Fluorenylmethyl-
3-Indolyl-





27027
(CH3)3C—


embedded image







27028
9-Fluorenylmethyl-


embedded image







27029
(CH3)3C—


embedded image







27030
PhCH2


embedded image







27031
(CH3)2CH—


embedded image


















TABLE 28









embedded image














Example




Compound No.
R1—
R3—












28001
CH3
p-HOPh—


28002
CH3
o-HOPh—


28003
CH3
m-HOPh—


28004
CH3
p-MeOPh—


28005
CH3
o-MeOPh—


28006
CH3
m-MeOPh—


28007
CH3
p-MePh—


28008
CH3
p-(CH3)2NPh—


28009
CH3
Ph—


28010
CH3
p-FPh


28011
CH3
3-Indolyl-





28012
CH3
p-AcNHPh





28013
CH3


embedded image







28014
CH3


embedded image







28015
CH3


embedded image







28016
(CH3)2CH—
p-HOPh—


28017
(CH3)2CH—
o-HOPh—


28018
(CH3)2CH—
m-HOPh—


28019
(CH3)2CH—
p-MeOPh—


28020
(CH3)2CH—
o-MeOPh—


28021
(CH3)2CH—
m-MeOPh—


28022
(CH3)2CH—
p-MePh—


28023
(CH3)2CH—
p-(CH3—)2NPh—


28024
(CH3)2CH—
Ph—


28025
(CH3)2CH—
p-FPh


28026
(CH3)2CH—
3-Indolyl-


28027
(CH3)2CH—
p-AcNHPh





28028
(CH3)2CH—


embedded image







28029
(CH3)2CH—


embedded image







28030
(CH3)2CH—


embedded image


















TABLE 29









embedded image














Example




Compound No.
R1—
R3—












29001
PhCH2
p-HOPh—


29002
PhCH2
o-HOPh—


29003
PhCH2
m-HOPh—


29004
PhCH2
p-MeOPh—


29005
PhCH2
o-MeOPh—


29006
PhCH2
m-MeOPh—


29007
PhCH2
p-MePh—


29008
PhCH2
p-(CH3)2NPh—


29009
PhCH2
Ph—


29010
PhCH2
p-FPh


29011
PhCH2
3-Indolyl-





29012
PhCH2
p-AcNHPh





29013
PhCH2


embedded image







29014
PhCH2


embedded image







29015
PhCH2


embedded image







29016
HOCH2
p-HOPh—


29017
HOCH2
o-HOPh—


29018
HOCH2
m-HOPh—


29019
HOCH2
p-MeOPh—


29020
HOCH2
o-MeOPh—


29021
HOCH2
m-MeOPh—


29022
HOCH2
p-MePh—


29023
HOCH2
p-(CH3)2NPh—


29024
HOCH2
Ph—


29025
HOCH2
p-FPh


29026
HOCH2
3-Indolyl-


29027
HOCH2
p-AcNHPh





29028
HOCH2


embedded image







29029
HOCH2


embedded image







29030
HOCH2


embedded image


















TABLE 30









embedded image














Example




Compound No.
R1—
R3—












30001
CH3
p-HOPh—


30002
CH3
o-HOPh—


30003
CH3
m-HOPh—


30004
CH3
p-MeOPh—


30005
CH3
o-MeOPh—


30006
CH3
m-MeOPh—


30007
CH3
p-MePh—


30008
CH3
p-(CH3)2NPh—


30009
CH3
Ph—


30010
CH3
p-FPh


30011
CH3
3-Indolyl-





30012
CH3
p-AcNHPh





30013
CH3


embedded image







30014
CH3


embedded image







30015
CH3


embedded image







30016
(CH3)2CH—
p-HOPh—


30017
(CH3)2CH—
o-HOPh—


30018
(CH3)2CH—
m-HOPh—


30019
(CH3)2CH—
p-MeOPh—


30020
(CH3)2CH—
o-MeOPh—


30021
(CH3)2CH—
m-MeOPh—


30022
(CH3)2CH—
p-MePh—


30023
(CH3)2CH—
p-(CH3)2NPh—


30024
(CH3)2CH—
Ph—


30025
(CH3)2CH—
p-FPh


30026
(CH3)2CH—
3-Indolyl-


30027
(CH3)2CH—
p-AcNHPh





30028
(CH3)2CH—


embedded image







30029
(CH3)2CH—


embedded image







30030
(CH3)2CH—


embedded image


















TABLE 31









embedded image














Example Compound No.
R1—
R3—





31001
PhCH2
p-HOPh—


31002
PhCH2
o-HOPh—


31003
PhCH2
m-HOPh—


31004
PhCH2
p-MeOPh—


31005
PhCH2
o-MeOPh—


31006
PhCH2
m-MeOPh—


31007
PhCH2
p-MePh—


31008
PhCH2
p-(CH3)2NPh—


31009
PhCH2
Ph—


31010
PhCH2
p-FPh


31011
PhCH2
3-Indolyl-


31012
PhCH2
p-AcNHPh





31013
PhCH2


embedded image







31014
PhCH2


embedded image







31015
PhCH2


embedded image







31016
HOCH2
p-HOPh—


31017
HOCH2
o-HOPh—


31018
HOCH2
m-HOPh—


31019
HOCH2
p-MeOPh—


31020
HOCH2
o-MeOPh—


31021
HOCH2
m-MeOPh—


31022
HOCH2
p-MePh—


31023
HOCH2
p-(CH3)2NPh—


31024
HOCH2
Ph—


31025
HOCH2
p-FPh


31026
HOCH2
3-Indolyl-


31027
HOCH2
p-AcNHPh





31028
HOCH2


embedded image







31029
HOCH2


embedded image







31030
HOCH2


embedded image


















TABLE 32









embedded image














Example Compound No.
R1—
R3—





32001
CH3
p-HOPh—


32002
CH3
p-PhCH2OPh—


32003
CH3
p-MeOCH2CH2OPh—


32004
CH3
p-MeOPh—


32005
CH3
o-MeOPh—


32006
CH3
m-MeOPh—


32007
CH3
p-MePh—


32008
CH3
p-(CH3)2NPh—


32009
CH3
Ph—


32010
CH3
p-FPh


32011
CH3
3-Indolyl-


32012
CH3
p-AcNHPh





32013
CH3


embedded image







32014
CH3


embedded image







32015
CH3


embedded image







32016
(CH3)2CH—
p-HOPh—


32017
(CH3)2CH—
p-PhCH2OPh—


32018
(CH3)2CH—
p-MeOCH2CH2OPh—


32019
(CH3)2CH—
p-MeOPh—


32020
(CH3)2CH—
o-MeOPh—


32021
(CH3)2CH—
m-MeOPh—


32022
(CH3)2CH—
p-MePh—


32023
(CH3)2CH—
p-(CH3)2NPh—


32024
(CH3)2CH—
Ph—


32025
(CH3)2CH—
p-FPh


32026
(CH3)2CH—
3-Indolyl-


32027
(CH3)2CH—
p-AcNHPh





32028
(CH3)2CH—


embedded image







32029
(CH3)2CH—


embedded image







32030
(CH3)2CH—


embedded image


















TABLE 33









embedded image














Example Compound No.
R1—
R3—





33001
PhCH2
p-HOPh—


33002
PhCH2
p-PhCH2OPh—


33003
PhCH2
p-MeOCH2CH2OPh—


33004
PhCH2
p-MeOPh—


33005
PhCH2
o-MeOPh—


33006
PhCH2
m-MeOPh—


33007
PhCH2
p-MePh—


33008
PhCH2
p-(CH3)2NPh—


33009
PhCH2
Ph—


33010
PhCH2
p-FPh


33011
PhCH2
3-Indolyl-


33012
PhCH2
p-AcNHPh





33013
PhCH2


embedded image







33014
PhCH2


embedded image







33015
PhCH2


embedded image







33016
HOCH2
p-HOPh—


33017
HOCH2
p-PhCH2OPh—


33018
HOCH2
p-MeOCH2CH2OPh—


33019
HOCH2
p-MeOPh—


33020
HOCH2
o-MeOPh—


33021
HOCH2
m-MeOPh—


33022
HOCH2
p-MePh—


33023
HOCH2
p-(CH3)2NPh—


33024
HOCH2
Ph—


33025
HOCH2
p-FPh


33026
HOCH2
3-Indolyl-


33027
HOCH2
p-AcNHPh





33028
HOCH2


embedded image







33029
HOCH2


embedded image







33030
HOCH2


embedded image


















TABLE 34









embedded image














Example Compound No.
R1—
R3—





34001
CH3
p-HOPh—


34002
CH3
p-PhCH2OPh—


34003
CH3
p-MeOCH2CH2OPh—


34004
CH3
p-MeOPh—


34005
CH3
o-MeOPh—


34006
CH3
m-MeOPh—


34007
CH3
p-MePh—


34008
CH3
p-(CH3)2NPh—


34009
CH3
Ph—


34010
CH3
p-FPh


34011
CH3
3-Indolyl-


34012
CH3
p-AcNHPh





34013
CH3


embedded image







34014
CH3


embedded image







34015
CH3


embedded image







34016
(CH3)2CH—
p-HOPh—


34017
(CH3)2CH—
p-PhCH2OPh—


34018
(CH3)2CH—
p-MeOCH2CH2OPh—


34019
(CH3)2CH—
p-MeOPh—


34020
(CH3)2CH—
o-MeOPh—


34021
(CH3)2CH—
m-MeOPh—


34022
(CH3)2CH—
p-MePh—


34023
(CH3)2CH—
p-(CH3)2NPh—


34024
(CH3)2CH—
Ph—


34025
(CH3)2CH—
p-FPh


34026
(CH3)2CH—
3-Indolyl-


34027
(CH3)2CH—
p-AcNHPh





34028
(CH3)2CH—


embedded image







34029
(CH3)2CH—


embedded image







34030
(CH3)2CH—


embedded image


















TABLE 35









embedded image














Example Compound No.
R1—
R3—





35001
PhCH2
p-HOPh—


35002
PhCH2
p-PhCH2OPh—


35003
PhCH2
p-MeOCH2CH2OPh—


35004
PhCH2
p-MeOPh—


35005
PhCH2
o-MeOPh—


35006
PhCH2
m-MeOPh—


35007
PhCH2
p-MePh—


35008
PhCH2
p-(CH3)2NPh—


35009
PhCH2
Ph—


35010
PhCH2
p-FPh


35011
PhCH2
3-Indolyl-


35012
PhCH2
p-AcNHPh





35013
PhCH2


embedded image







35014
PhCH2


embedded image







35015
PhCH2


embedded image







35016
HOCH2
p-HOPh—


35017
HOCH2
p-PhCH2OPh—


35018
HOCH2
p-MeOCH2CH2OPh—


35019
HOCH2
p-MeOPh—


35020
HOCH2
o-MeOPh—


35021
HOCH2
m-MeOPh—


35022
HOCH2
p-MePh—


35023
HOCH2
p-(CH3)2NPh—


35024
HOCH2
Ph—


35025
HOCH2
p-FPh


35026
HOCH2
3-Indolyl-


35027
HOCH2
p-AcNHPh





35028
HOCH2


embedded image







35029
HOCH2


embedded image







35030
HOCH2


embedded image


















TABLE 36









embedded image














Example Compound No.
R1—
R3—





36001
CH3
p-HOPh—


36002
CH3
p-PhCH2OPh—


36003
CH3
p-MeOCH2CH2OPh—


36004
CH3
p-MeOPh—


36005
CH3
o-MeOPh—


36006
CH3
m-MeOPh—


36007
CH3
p-MePh—


36008
CH3
p-(CH3)2NPh—


36009
CH3
Ph—


36010
CH3
p-FPh


36011
CH3
3-Indolyl-


36012
CH3
p-AcNHPh





36013
CH3


embedded image







36014
CH3


embedded image







36015
CH3


embedded image







36016
(CH3)2CH—
p-HOPh—


36017
(CH3)2CH—
p-PhCH2OPh—


36018
(CH3)2CH—
p-MeOCH2CH2OPh—


36019
(CH3)2CH—
p-MeOPh—


36020
(CH3)2CH—
o-MeOPh—


36021
(CH3)2CH—
m-MeOPh—


36022
(CH3)2CH—
p-MePh—


36023
(CH3)2CH—
p-(CH3)2NPh—


36024
(CH3)2CH—
Ph—


36025
(CH3)2CH—
p-FPh


36026
(CH3)2CH—
3-Indolyl-


36027
(CH3)2CH—
p-AcNHPh





36028
(CH3)2CH—


embedded image







36029
(CH3)2CH—


embedded image







36030
(CH3)2CH—


embedded image


















TABLE 37









embedded image














Example Compound No.
R1—
R3—





37001
PhCH2
p-HOPh—


37002
PhCH2
p-PhCH2OPh—


37003
PhCH2
p-MeOCH2CH2OPh—


37004
PhCH2
p-MeOPh—


37005
PhCH2
o-MeOPh—


37006
PhCH2
m-MeOPh—


37007
PhCH2
p-MePh—


37008
PhCH2
p-(CH3)2NPh—


37009
PhCH2
Ph—


37010
PhCH2
p-FPh


37011
PhCH2
3-Indolyl-


37012
PhCH2
p-AcNHPh





37013
PhCH2


embedded image







37014
PhCH2


embedded image







37015
PhCH2


embedded image







37016
HOCH2
p-HOPh—


37017
HOCH2
p-PhCH2OPh—


37018
HOCH2
p-MeOCH2CH2OPh—


37019
HOCH2
p-MeOPh—


37020
HOCH2
o-MeOPh—


37021
HOCH2
m-MeOPh—


37022
HOCH2
p-MePh—


37023
HOCH2
p-(CH3)2NPh—


37024
HOCH2
Ph—


37025
HOCH2
p-FPh


37026
HOCH2
3-Indolyl-


37027
HOCH2
p-AcNHPh





37028
HOCH2


embedded image







37029
HOCH2


embedded image







37030
HOCH2


embedded image


















TABLE 38









embedded image














Example Compound No.
R1—
R3—





38001
CH3
p-HOPh—


38002
CH3
p-PhCH2OPh—


38003
CH3
p-MeOCH2CH2OPh—


38004
CH3
p-MeOPh—


38005
CH3
o-MeOPh—


38006
CH3
m-MeOPh—


38007
CH3
p-MePh—


38008
CH3
p-(CH3)2NPh—


38009
CH3
Ph—


38010
CH3
p-FPh


38011
CH3
3-Indolyl-


38012
CH3
p-AcNHPh





38013
CH3


embedded image







38014
CH3


embedded image







38015
CH3


embedded image







38016
(CH3)2CH—
p-HOPh—


38017
(CH3)2CH—
p-PhCH2OPh—


38018
(CH3)2CH—
p-MeOCH2CH2OPh—


38019
(CH3)2CH—
p-MeOPh—


38020
(CH3)2CH—
o-MeOPh—


38021
(CH3)2CH—
m-MeOPh—


38022
(CH3)2CH—
p-MePh—


38023
(CH3)2CH—
p-(CH3)2NPh—


38024
(CH3)2CH—
Ph—


38025
(CH3)2CH—
p-FPh


38026
(CH3)2CH—
3-Indolyl-


38027
(CH3)2CH—
p-AcNHPh





38028
(CH3)2CH—


embedded image







38029
(CH3)2CH—


embedded image







38030
(CH3)2CH—


embedded image


















TABLE 39









embedded image














Example Compound No.
R1—
R3—





39001
PhCH2
p-HOPh—


39002
PhCH2
p-PhCH2OPh—


39003
PhOH2
p-MeOCH2CH2OPh—


39004
PhCH2
p-MeOPh—


39005
PhCH2
o-MeOPh—


39006
PhCH2
m-MeOPh—


39007
PhCH2
p-MePh—


39008
PhCH2
p-(CH3)2NPh—


39009
PhCH2
Ph—


39010
PhCH2
p-FPh


39011
PhCH2
3-Indolyl-


39012
PhCH2
p-AcNHPh





39013
PhCH2


embedded image







39014
PhCH2


embedded image







39015
PhCH2


embedded image







39016
HOCH2
p-HOPh—


39017
HOCH2
p-PhCH2OPh—


39018
HOCH2
p-MeOCH2CH2OPh—


39019
HOCH2
p-MeOPh—


39020
HOCH2
o-MeOPh—


39021
HOCH2
m-MeOPh—


39022
HOCH2
p-MePh—


39023
HOCH2
p-(CH3)2NPh—


39024
HOCH2
Ph—


39025
HOCH2
p-FPh


39026
HOCH2
3-Indolyl-


39027
HOCH2
p-AcNHPh





39028
HOCH2


embedded image







39029
HOCH2


embedded image







39030
HOCH2


embedded image











There will be described representative preparation processes according to this invention.


In a process for preparing a compound represented by general formula (5) or (6) from a compound represented by general formula (1) as a starting material in this invention, the meaning of the phrase “configuration of R1 attached to the carbon at 4-position and the substituent represented by a nitrogen atom in the optically active 5-oxazolidinone is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol represented by general formula (5) is erythro” may be described in the following reaction equations 1 and 2 in detail:




embedded image


Specifically, as shown in reaction equation 1, S-form optically active 5-oxazolidinone derivative represented by general formula (9) selectively gives a 1R,2S-optically active aminoalcohol derivative of erythro configuration represented by general formula (12) or (13). Furthermore, as shown in reaction formula 2, an R-form optically active 5-oxazolidinone derivative represented by general formula (14) can provide a 1S,2R-optically active aminoalcohol derivative of erythro configuration represented by general formula (17) or (18).


Each preparation step will be detailed.


Preparation of an Optically Active 5-Oxazolidinone Derivative Represented by General Formula (1)


An optically active 5-oxazolidinone derivative represented by general formula (1) can be provided according to a well-known process where an N-urethane protected compound derived from a readily available and inexpensive natural α-amino acid is reacted with paraformaldehyde in the presence of a catalytic amount of an acid (J. Am. Chem. Soc. 1957, 79, 5736).


Preparation of an Organometallic Reagent Represented by General Formula (2)


An organometallic reagent represented by general formula (2) may be easily prepared by a well-known process; for example, oxidative addition of a metal to a corresponding halogenated compound or transmetallation with an organometallic reagent.


In preparation of an organometallic reagent, there is no limitation of the solvent, as long as it is inert to the reaction, and, for example, ethers such as tetrahydrofuran, diethyl ether, dioxane and diglyme; toluene; and xylenes can be used. Among these, preferred is tetrahydrofuran alone or a mixture of tetrahydrofuran and another solvent in the light of solubility of a substrate. A reaction temperature may be generally −78° C. to a boiling point of the solvent used. Furthermore, an organometallic reagent, particularly a Grignard reagent can be used to give good results in a preparation process according to this invention.


A Grignard reagent may be easily prepared by, for example, adding dropwise a halogenated compound represented by R3X where X is as defined above, after initiating the reaction by adding a catalytic amount of an initiator such as 1,2-dibromoethane, ethyl bromide and iodine to magnesium dispersed in a solvent.


Preparation of an Optically Active 5-Hydroxyoxazolidine Derivative Represented by General Formula (3)


In a reaction of an optically active 5-oxazolidinone derivative represented by general formula (1) with an organometallic reagent represented by general formula (2), a reaction solvent may be, but not limited to, the same solvent as that used in preparing the organometallic reagent or a solvent mixture which does not significantly affect the reaction. The amount of the organometallic reagent is preferably, but not limited to, an equal to a five-fold moles, more preferably 1.0 to 2-fold moles per one mole of the 5-oxazolidinone derivative as a substrate. A reaction temperature may be preferably, but not limited to, an ambient temperature, room temperature, to −78° C. In this reaction, there are no restrictions to the order of adding the optically active 5-oxazolidinone derivative and the organometallic reagent. That is, the organometallic reagent may be added to the optically active 5-oxazolidinone derivative or vice versa. At the end of the reaction, for obtaining the optically active 5-hydroxyoxazolidine derivative produced, the excessive organometallic reagent in the reaction solution is decomposed using, for example, an aqueous diluted hydrochloric acid, diluted sulfuric acid, acetic acid, ammonium chloride, citric acid or potassium hydrogen sulfate solution and then the product can be isolated from the resulting mixture by a common separation/purification process such as extraction, concentration, neutralization, filtration, recrystallization and column chromatography.


Furthermore, as described above, a Grignard reagent can be used as an organometallic reagent to give particularly good results in this reaction. When using a Grignard reagent as an organometallic reagent, the conditions including a reaction solvent, the amount of the materials used, a reaction temperature, the order of adding the reagents, work-up of the reaction and isolation and purification of the product are as described for the above general preparation process when using an organometallic reagent.


The optically active 5-oxazolidine derivative prepared as described above is generally obtained as a mixture of two diastereomers because both R- and S-forms are formed for configuration at the 5-position in the oxazolidine. Depending on the conditions, high performance liquid chromatography or nuclear magnetic spectrometry may be performed to determine a diastereomer ratio. A diastereomer ratio may vary depending on the reaction conditions and properties of the product, and the diastereomers may be individually isolated or may be obtained as a mixture. However, a diastereomer mixture may be converted into an optically active aminoketone derivative represented by the same general formula (4) by, for example, treatment with an acid described below. It is, therefore, not necessary to separate the diastereomers as production intermediates in the light of a production cost.


Preparation of an Optically Active Aminoketone Derivative Represented by General Formula (4)


A process for converting an optically active 5-hydroxyoxazolidine derivative into an optically active aminoketone derivative represented by general formula (4) under an acidic condition can be generally conducted in a solvent. Examples of a solvent which can be used include, but not limited to, alcohols such as methanol and ethanol; acetonitrile; tetrahydrofuran; benzene; toluene; and water. These solvents may be used alone or in combination of two or more in a given mixing ratio. Examples of an acid which can be used include, but not limited to, inorganic acids such as hydrochloric acid, sulfuric acid and perchloric acid; organic acids such as p-toluenesulfonic acid and methanesulfonic acid; acidic resins such as Amberlite IR-120 and Amberlist; and Lewis acids such as boron trifluoride and zinc chloride. The amount of an acid used is an equal to 30-fold moles, preferably 1.5- to 10-fold moles per one mole of the optically active 5-hydroxyoxazolidine derivative. When using a resin, its amount is 5 to 200% by weight, preferably 10 to 100% by weight. A reaction temperature may be −30° C. to a boiling point of a solvent, particularly 0° C. to 100° C. An aminoketone derivative may be easily isolated from a reaction mixture by a common separation/purification method such as extraction, concentration, neutralization, filtration, recrystallization and column chromatography.


Preparation of an Optically Active Aminoalcohol Derivative Represented by General Formula (5)


A process for reducing an aminoketone derivative represented by general formula (4) with a reducing agent to give an optically active alcohol derivative represented by general formula (5) is generally conducted in a solvent. Examples of the solvent, which can be used include, but not limited to, methanol, ethanol, 2-propanol, tetrahydrofuran and water. These solvents may be used alone or in combination of two or more in a given mixing ratio.


Examples of the reducing agent include borane reagents such as borane-tetrahydrofuran complex; borohydride reagents such as sodium borohydride, zinc borohydride and sodium trimethoxyborohydride; alkylaluminum reagents such as diisopropylaluminum hydride; aluminum hydride reagents such as lithium aluminum hydride and lithium trialkoxyaluminum hydride; silane reagents such as trichlorosilane and triethylsilane; sodium metal in liquid ammonia; and magnesium metal in an alcohol. In particular, borohydride reagents such as sodium borohydride, zinc borohydride and sodium trimethoxyborohydride are suitable.


The amount of the reducing agent may be an equal to 10-fold moles per one mole of a material to be reduced. A reaction temperature is appropriately selected within the range of −78° C. to a boiling point of the solvent, preferably −40° C. to 80° C.


Alternatively, an aminoketone derivative represented by general formula (4) may be catalytically hydrogenated in the presence of an appropriate metal catalyst in an appropriate solvent under an atmosphere of hydrogen, to give an optically active aminoalcohol derivative represented by general formula (5). A hydrogen pressure may be, but not limited to, an ambient pressure to 3 MPa, preferably 0.3 MPa to 1 MPa. Any solvent may be used as long as it does not adversely affect the reaction; for example, methanol, ethanol, n-propanol, 2-propanol, n-butanol and water. These solvents may be used alone or in combination of two or more in a given mixing ratio. The amount of a solvent is 1 to 50 parts (wt/wt), preferably 3 to 20 parts per one part of the compounds.


Examples of the metal catalyst which can be used include nickel catalysts such as Raney nickel; platinum catalysts such as platinum-alumina, platinum-carbon and platinum oxide; palladium catalysts such as palladium-alumina, palladium-carbon and palladium hydroxide-carbon; ruthenium catalysts such as ruthenium oxide; and rhodium catalysts such as chlorotris(triphenylphosphine)rhodium which is also known as a Wilkinson catalyst, more suitably palladium catalysts. A reaction temperature may be, but not limited to, −20 to 200° C., preferably 0 to 60° C.


A process for deprotecting a compound represented by general formula (5) having a protected amino group as appropriate to give a free amine derivative represented by general formula (6) may be conducted by, for example, hydrolysis using an acid or base. Examples of an acid, which can be used include, but not limited to, inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid; and organic acids such as trifluoromethanesulfonic acid, is trifluoroacetic acid, p-toluenesulfonic acid and acetic acid. Examples of a base, which can be used, include inorganic bases such as sodium hydrogen carbonate, potassium carbonate, lithium hydroxide and sodium hydroxide; and organic bases such as triethylamine, morpholine, tetrabutylammonium fluoride and tetraethylammonium hydroxide.


An optically active aminoalcohol derivative represented by general formula (5) or (6) thus obtained may be isolated as crystals of the free amine or as a salt by adding, if necessary, an appropriate acid. A diastereomeric purity or optical purity of the compound may be improved by recrystallization.


When the compound is obtained as crystals of a free amine, any solvent which is suitable to such purification can be used for crystallization. Examples of such a solvent include alcohols such as methanol, ethanol, n-propanol and 2-propanol; esters such as ethyl acetate and butyl acetate; halogenated solvents such as chloroform and methylene chloride; ethers such as 1,4-dioxane and tetrahydrofuran; water; acetonitrile; 2-butanone; and toluene, which can be used alone or in combination of two or more.


Any acid which can form a crystalline salt suitable for purification may be used for salt formation. Examples of such an acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfuric acid and phosphoric acid; and organic acids such as acetic acid, tartaric acid, citric acid, fumaric acid, methanesulfonate and p-toluenesulfonate.


Any solvent which is suitable for purification may be used for recrystallization. Examples of such solvent include alcohols such as methanol, ethanol, n-propanol and 2-propanol; esters such as ethyl acetate and butyl acetate; halogenated solvents such as chloroform and methylene chloride; ethers such as 1,4-dioxane and tetrahydrofuran; water; acetonitrile; 2-butanone; and toluene, which may be used alone or in combination of two or more.


A salt purified by recrystallization may be treated with an alkaline solution by a common procedure to be isolated as a free amine.


EXAMPLES

This invention will be more specifically described with reference to, but not limited to, Reference Examples and Examples.


Reference Example 1

Preparation of (4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone




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Benzyloxycarbonyl-L-alanine (19.3 g), paraformaldehyde (6.56 g) and p-toluenesulfonic acid monohydrate (0.17 g) were suspended in toluene (190 mL), and the mixture was heated at reflux while removing water produced. At the end of the reaction, the reaction mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and then saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, the resulting crystals were filtrated to give the title compound (19.0 g) as white crystals in an yield of 93%.


Melting point: 91–93° C. 1H NMR (CDCl3, 400 MHz) δ ppm: 1.54 (d, 3H, J=6.4 Hz), 4.29–4.31 (m, 1H), 5.18 (s, 2H), 5.28–5.29 (m, 1H), 5.47 (br, 1H), 7.33–7.41 (m, 5H); IR (KBr) νmax 1778, 1685 cm−1.


Reference Example 2

Preparation of 4-benzyloxybromobenzene




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p-Bromophenol (25.0 g) and anhydrous potassium carbonate (20.0 g) were suspended in N,N-dimethylformamide (250 mL). To the suspension was added dropwise benzyl chloride (20.2 g) at room temperature. After heating at 95 to 100° C. for one hour, the reaction mixture was cooled to room temperature and water (400 mL) was added. After extraction with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give the title compound (34.3 g) as milk-white crystals in a yield of 90%.


Melting point: 55–57° C.; 1H-NMR (CDCl3, 400 MHz) δ ppm: 5.04 (s, 2H), 6.83–6.87 (m, 2H), 7.31–7.43 (m, 2H).


Example 1

Preparation of (4S)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-methyl-5-hydroxyoxazolidine (Compound No. 1001)




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Preparation of a Grignard Reagent


To magnesium metal (1.16 g) in anhydrous tetrahydrofuran (20 mL) was added ethyl bromide (0.26 g) under nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. At reflux of the solvent, a solution of 4-benzyloxybromobenzene (10.5 g) prepared in Reference Example 2 dissolved in anhydrous tetrahydrofuran (20 mL) was added dropwise over about 1 hour. At the end of addition, the mixture was stirred at reflux for further 40 min to prepare a Grignard reagent.


Grignard Reaction


In anhydrous tetrahydrofuran (40 mL) was dissolved (4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (7.84 g) prepared in Reference Example 1 and the solution was cooled to −20° C. To the solution under nitrogen atmosphere was added dropwise the Grignard reagent prepared above while maintaining the internal temperature at −20° C. At the end of addition, the mixture was stirred for further 1 hour at that temperature, and then treated with an aqueous 5% hydrochloric acid solution. The solution was warmed to room temperature and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solution was concentrated in vacuo. The residue was purified by silica column chromatography (eluent: chloroform) to give the title compound (9.85 g) as a diastereomer mixture as white crystals in a yield of 71%.


Melting point: 83–86° C. 1H-NMR (CDCl3, 400 MHz) indicated that a diastereomer ratio was about 2:1.


Major Diastereomer Product



1H-NMR (CDCl3, 400 MHz) δ ppm: 1.47 (d, 3H, J=7.3 Hz), 3.81–3.84 (m, 1H), 4.79–5.07 (m, 2H), 5.14 (s, 2H), 5.14 (d, 1H, J=8.4 Hz), 5.20 (d, 1H, J=8.4 Hz), 5.87 (q, 1H, J=7.3 Hz), 7.02 (d, 2H, J=8.8 Hz), 7.23–7.44 (m, 10H), 8.01 (d, 2H, J=8.8 Hz)


Sub Diastereomer Product



1H-NMR (CDCl3, 400 MHz) δ ppm: 1.49 (d, 3H, J=7.3 Hz), 3.60–3.70 (m, 1H), 4.79–5.15 (m, 4H), 5.13 (s, 2H), 5.57 (q, 1H, J=7.3 Hz), 6.91 (d, 2H, J=8.8 Hz), 7.23–7.44 (m, 10H), 7.83 (d, 2H, J=8.8 Hz); IR (neat) νmax 3436, 3033, 1671, 1603, 1508 cm−1.


Example 2

Preparation of (2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone (Compound No.: 22001)




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In toluene (50 mL) was dissolved (4S)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-methyl-5-hydroxyoxazolidine (3.8 g) prepared in Example 1. After adding Amberlist (300 mg), the mixture was reacted at room temperature. At the end of the reaction, Amberlist was filtered off, the filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (eluent: chloroform) to give the title compound (3.1 g) as pale yellow crystals in a yield of 88%.


Melting point: 89–91° C.; 1H-NMR (CDCl3, 400 MHz) δ ppm: 1.43 (d, 3H, J=6.83 Hz), 5.13 (s, 2H), 5.15 (s, 2H), 5.28–5.31 (m, 1H), 5.88 (br, 1H), 7.03 (d, 2H, J=9.0 Hz), 7.31–7.44 (m, 10H), 7.96 (d, 2H, J=9.0 Hz); IR (KBr) νmax 3374, 1712, 1690 cm−1;


Optical purity: 93%ee


HPLC Analysis Conditions:






    • Column: Daicel Chiral-Pak AD-RH (4.6 mmφ×150 mm);

    • Mobile phase: methanol;

    • Flow rate: 0.5 mL/min;

    • Wavelength: 254 nm;

    • Temperature: room temperature;

    • tR: (2S-form); 19.8 min;
      • (2R-form); 24.3 min.





Example 3

Preparation of (2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone (Compound No. 22001)




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Preparation of a Grignard Reagent


To anhydrous tetrahydrofuran (15 mL) under nitrogen atmosphere were added magnesium metal (1.16 g) and ethyl bromide (0.05 g), and the mixture was stirred at room temperature for 30 min. To the mixture at reflux of the solvent was added dropwise a solution of 4-benzyloxybromobenzene (10.92 g) prepared in Reference Example 2 dissolved in anhydrous tetrahydrofuran (10 mL) over about 1 hour. At the end of addition, the mixture was stirred at reflux for further 30 min to prepare a Grignard reagent.


Grignard Reaction


In anhydrous tetrahydrofuran (26 mL) was dissolved (4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (6.97 g) prepared in Reference Example 1 and the mixture was cooled to −20° C. To the solution under nitrogen atmosphere was added dropwise the Grignard reagent prepared above while maintaining the internal temperature at −20° C. At the end of addition, the mixture was stirred for further 1 hour at that temperature.


Deformylation


To the mixture was added a 6.5% aqueous hydrochloric acid solution, and the reaction was stirred at 35 to 40° C. for 6 hours. The aqueous layer was discarded after separation. Then to the organic layer was added a 5% aqueous hydrochloric acid solution, and the mixture was stirred at 45 to 50° C. for 4 hours. The reaction mixture was extracted with toluene and the organic layer was washed with water. The solution was concentrated in vacuo, 2-propanol (70 g) was added, and then the mixture was stirred at room temperature for 6 hours. The reaction mixture was cooled to 0 to 5° C. to precipitate crystals, which were then filtered to give the title compound (8.61 g) as pale yellow crystals in a yield of 80%.


Melting point: 89–91° C.; 1H-NMR (CDCl3, 400 MHz) δ ppm: 1.43 (d, 3H, J=6.8 Hz), 5.13 (s, 2H), 5.15 (s, 2H), 5.28–5.31 (m, 1H), 5.88 (br, 1H), 7.03 (d, 2H, J=9.0 Hz), 7.31–7.44 (m, 10H), 7.96 (d, 2H, J=9.3 Hz); IR (KBr) νmax 3374, 1712, 1690 cm−1; Specific rotation: [α]D24=+26° (C=1.00, CHCl3) Optical purity: 99%ee (analytical conditions are as described in Example 2).


Example 4

Preparation of erythro-(1R,2S)-p-hydroxynorephedrine (Compound No. 28001)




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A mixture of (2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone (4.8 g) prepared in Example 2 or 3, methanol (100 mL), water (50 mL) and 5% Pd/C (50% water-containing) (1.0 g) was stirred below 20° C. under hydrogen atmosphere (0.5 MPa) for 28 hours. The catalyst was filtered off, the filtrate was concentrated in vacuo, and the residue was slushed with 2-propanol to give the title compound (1.44 g) as white crystals in a yield of 70%.


Melting point: 163–165° C.; 1H-NMR (DMSO-d6, 400 MHz) δ ppm: 0.85 (d, 3H, J=6.3 Hz), 2.77–2.83 (m, 1H), 4.17 (d, 1H, J=5.3 Hz), 4.96 (brs, 1H), 6.70 (d, 2H, J=8.3 Hz), 7.09 (d, 2H, J=8.3 Hz), 8.31 (s, 1H); IR (KBr) νmax 3470, 1593, 1484, 1242 cm−1; Specific rotation: [α]D24=−18° (C=0.2, MeOH);


Erythro:threo=99.5:0.5;


HPLC Analysis Conditions:






    • Column: YMC TMS A-102 (6 mmφ×150 mm)

    • Mobile phase: acetonitrile:water=3:97 (each of NaH2PO4 and Na2HPO4 is 10 mM, pH 6.9);

    • Detection wavelength: 275 nm;

    • Flow rate: 0.5 mL/min;

    • Column temperature: 40° C.;

    • tR: erythro form; 6.9 min;
      • threo form; 7.1 min;

    • Optical purity: 99%ee


      HPLC Analysis Conditions:

    • Column: Daicel Crown-Pak CR(−) (4 mmφ×150 mm);

    • Mobile phase: HClO4 aq (pH 3.5);

    • Detection wavelength: 275 nm;

    • Flow rate: 0.1 mL/min;

    • Column temperature: 25° C.





Example 5

Preparation of erythro-(1R,2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanol (Compound No.: 36002)




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To methanol (25 mL) was added sodium borohydride (0.32 g), and the mixture was cooled to 0 to 5° C. To the solution was added (2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone (2.00 g) prepared in Example 2 or 3, and the mixture was stirred at room temperature. Precipitated crystals were filtered, washed with methanol and then dried to give the title compound (1.39 g) as white crystals in a yield of 69%.


Melting point: 85–91° C.; 1H-NMR (DMSO-d6, 400 MHz) δ ppm: 0.99 (d, 3H, J=6.59 Hz), 3.61–3.62 (m, 1H), 4.46–4.49 (m, 1H), 4.95 (s, 2H), 5.07 (s, 2H), 5.23 (m, 1H), 6.93 (d, 2H, J=7.08), 7.19–7.40 (m, 10H), 7.44 (d, 2H, J=7.08), 8.30 (s, 1H); IR (KBr) νmax 3334, 1690 cm−1.


Example 6

Preparation of erythro-(1R,2S)-p-hydroxynorephedrine (Compound No.: 28001)




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In methanol was dissolved erythro-(1R,2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanol (1.39 g) prepared in Example 5, and the solution was stirred with 5% Pd/C (50% water-containing) (0.03 g) under hydrogen atmosphere (ambient pressure) at room temperature for 2 hours. After removing the catalyst by filtration, the filtrate was concentrated in vacuo. The residue was crystallized with 2-propanol to give the title compound (0.65 g) as white crystals in a yield of 75%.


Melting point: 163–165° C.; 1H-NMR (DMSO-d6, 400 MHz) δ ppm: 0.85 (d, 3H, J=6.3 Hz), 2.77–2.83 (m, 1H), 4.17 (d, 1H, J=5.3 Hz), 4.96 (brs, 1H), 6.70 (d, 2H, J=8.3 Hz), 7.09 (d, 2H, J=8.3 Hz), 8.31 (s, 1H); IR (KBr) νmax 3470, 1593, 1484, 1242 cm−1; Specific rotation: [α]D24=−18° (C=0.2, MeOH); Erythro:threo=97.5:2.5 (analysis conditions are as described in Example 4);


Optical purity: 99%ee (analysis conditions are as described in Example 4).


Reference Example 3

Preparation of (4S)-N-tert-butoxycarbonyl-4-methyl-5-oxazolidinone




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In toluene (250 mL) were suspended tert-butoxycarbonyl-L-alanine (18.9 g), paraformaldehyde (6.70 g) and p-toluenesulfonic acid monohydrate (0.19 g), and the suspension was heated at reflux while removing water produced. At the end of the reaction, the mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the crystals obtained were filtered to give the title compound (14.2 g) white crystals in a yield of 71%.


Melting point: 66–68° C.; 1H NMR (CDCl3, 400 MHz) δ ppm: 1.49 (s, 9H), 1.52 (d, 2H, J=7.1 Hz), 4.23 (br, 1H), 5.23 (br, 1H), 5.41 (br, 1H); IR (KBr) νmax 1798, 1698 cm−1.


Example 7

Preparation of (4S)-5-(4-benzyloxyphenyl)-N-tert-butoxycarbonyl-4-methyl-5-hydroxyoxazolidine (Compound No.: 1015)




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In anhydrous tetrahydrofuran (40 mL) was dissolved (4S)-N-tert-butoxycarbonyl-4-methyl-5-oxazolidinone (6.64 g) prepared in Reference Example 3, and the solution was cooled to −20° C. To the solution under nitrogen atmosphere was added dropwise a Grignard reagent prepared as described in Example 1 while maintaining the internal temperature at −20° C. At the end of addition, the mixture was stirred at that temperature for 1 hour and then treated with a 5% aqueous hydrochloric acid solution. The solution was warmed to room temperature and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solution was concentrated in vacuo and the residue was purified by silica column chromatography (eluent: chloroform) to give the title compound (10.2 g) as a diastereomer mixture as a pale yellow syrup in an yield of 80%.



1H-NMR (CDCl3, 400 MHz) δ ppm: 1.35–1.38 (m, 3H), 1.44–1.49 (m, 9H), 4.90–5.85 (m, 5H), 6.99–7.03 (m, 2H), 7.35–7.44 (m, 5H), 7.80–8.00 (m, 2H); IR (KBr) νmax 3422, 1683 cm−1.


Reference Example 4

Preparation of (4S)-N-benzyloxycarbonyl-4-isopropyl-5-oxazolidinone




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In toluene (250 mL) were suspended benzyloxycarbonyl-L-valine (25.1 g), paraformaldehyde (6.70 g) and p-toluenesulfonic acid monohydrate (0.19 g), and the suspension was heated at reflux while removing water produced. At the end of the reaction, the mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give the title compound (23.7 g) as colorless transparent syrup in an yield of 90%.



1H-NMR (CDCl3, 400 MHz) δ ppm: 1.00 (d, 3H, J=6.6 Hz), 1.07 (d, 3H, J=6.6 Hz), 2.30–2.40 (m, 1H), 4.22 (bs, 1H), 5.15–5.22 (m, 3H), 5.56 (bs, 1H), 7.15–7.40 (m, 5H); IR (KBr) νmax 1798, 1698 cm−1.


Example 8

Preparation of (4S)-5-(4-benzyloxyphenyl)-N-benzyloxycarbonyl-4-isopropyl-5-hydroxyoxazolidine (Compound No.: 2001)




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In anhydrous tetrahydrofuran (22 mL) was dissolved (4S)-benzyloxycarbonyl-4-isopropyl-5-oxazolidinone (5.20 g) prepared in Reference Example 4, and the solution was cooled to −20° C. To the solution under nitrogen atmosphere was added dropwise a Grignard reagent prepared as described in Example 1 while maintaining the internal temperature at −10 to 20° C. At the end of addition, the mixture was stirred at that temperature for 1 hour and then treated with a 12.5% aqueous hydrochloric acid solution. The solution was warmed to room temperature, extracted with toluene. The organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=2/1) to give the title compound (4.72 g) as a diastereomer mixture as a pale yellow syrup in an yield of 53%.



1H-NMR (CDCl3, 400 MHz) indicated that a diastereomer ratio was about 1.9:1.


Major Diastereomer Product



1H-NMR (CDCl3, 400 MHz) δ ppm: 0.85 (d, 3H, J=6.6 Hz), 0.98 (d, 2H, J=6.6), 2.29–2.40 (m, 1H), 3.29 (m, 1H), 4.79 (m, 1H), 5.10–5.50 (m, 6H), 7.02 (d, 2H, J=8.7 Hz), 7.28–7.45 (m, 10H), 8.11 (d, 2H, J=8.7 Hz);


Sub Diastereomer Product



1H-NMR (CDCl3, 400 MHz) δ ppm: 0.83 (d, 3H, J=6.2 Hz), 1.00 (d, 2H, J=6.2), 2.29–2.40 (m, 1H), 3.55 (m, 1H), 4.79 (m, 1H), 5.10–5.50 (m, 6H), 6.81 (d, 2H, J=9.0 Hz), 7.28–7.45 (m, 10H), 7.85 (d, 2H, J=9.0 Hz); IR (KBr) νmax 3422, 1683 cm−1


Example 9

Preparation of (2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-3-methyl-1-butanone (Compound No.: 23001)




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In tetrahydrofuran (4 mL) was dissolved (4S)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-isopropyl-5-hydroxyoxazolidine (1.38 g) prepared in Example 8, and to the solution were added water (5 mL) and conc. hydrochloric acid (2 mL). The mixture was stirred at room temperature for 24 hours. The reaction was diluted with toluene and the aqueous layer was discarded. The organic layer was washed with water three times. The organic layer was dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=2/1) to give the title compound (466 mg) as pale yellow crystals in a yield of 36%.


Melting point: 75–77° C.; 1H-NMR (CDCl3, 400 MHz) δ ppm: 0.76 (d, 3H, J=6.8 Hz), 1.04 (d, 3H, J=6.8 Hz), 2.16 (m, 1H), 5.11 (s, 1H), 5.14 (s, 1H), 5.24 (dd, 1H, J=8.8, 4 Hz), 5.70 (d, 1H, J=8.8 Hz), 7.03 (d, 2H, J=8.8 Hz), 7.30–7.45 (m, 10H), 7.96 (d, 2H, J=8.8 Hz); IR (KBr) νmax 3422, 1683 cm−1.


Example 10

Preparation of (4S)-N-benzyloxycarbonyl-5-(4-methoxyphenyl)-4-methyl-5-hydroxyoxazolidine (Compound No.: 1020)




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Preparation of a Grignard Reagent


To anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere were added magnesium metal (756 mg) and ethyl bromide (0.1 g), and the mixture was stirred at room temperature for 1 hour. To the mixture at reflux of the solvent was added dropwise a solution of 4-bromoanisole (3.76 g) dissolved in anhydrous tetrahydrofuran (20 mL) over 1 hour. At the end of addition, the mixture was stirred at reflux for further 40 min to prepare a Grignard reagent.


Grignard Reaction


In anhydrous tetrahydrofuran (30 mL) was dissolved (4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (7.70 g) prepared in Reference Example 1, and the solution was cooled to −20° C. To the solution under nitrogen atmosphere was added dropwise the Grignard reagent while maintaining the internal temperature at −20° C. At the end of addition, the mixture was stirred for 1 hour at that temperature and then treated with a 5% aqueous hydrochloric acid solution. The solution was warmed to room temperature and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solution was concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=2/1 to 3/2), to give the title compound (4.56 g) as a diastereomer mixture as a colorless transparent syrup in a yield of 66%.



1H-NMR (CDCl3, 400 MHz) indicated that a diastereomer ratio was about 2:1.


Major Diastereomer Product



1H-NMR (CDCl3, 400 MHz) δ ppm: 1.47 (d, 3H, J=7 Hz), 3.70–3.75 (m, 1H), 3.87 (s, 3H), 4.80–5.20 (m, 2H), 5.16 (d, 1H, J=12.4 Hz), 5.25 (d, 1H, J=12.4 Hz), 5.88 (q, 1H, J=7 Hz), 6.95 (d, 2H, J=9.0 Hz), 7.23–7.36 (m, 5H), 8.02 (d, 2H, J=9.0 Hz);


Minor Diastereomer Product



1H-NMR (CDCl3, 400 MHz) δ ppm: 1.48 (d, 3H, J=7 Hz), 3.70–3.75 (m, 1H), 3.86 (s, 3H), 4.80–5.20 (m, 2H), 5.16 (d, 1H, J=12.4 Hz), 5.25 (d, 1H, J=12.4 Hz), 5.57 (q, 1H, J=7 Hz), 6.83 (d, 2H, J=8.8 Hz), 7.23–7.36 (m, 5H), 8.83 (d, 2H, J=8.8 Hz) IR (neat) νmax 3443, 1697, 1601 cm−1.


Example 11

Preparation of (2S)-2-(benzyloxycarbonyl)amino-1-(4-methoxyphenyl)-1-propanone (Compound No.: 22020)




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In tetrahydrofuran (4 mL) was dissolved (4S)-N-benzyloxycarbonyl-5-(4-methoxyphenyl)-4-methyl-5-hydroxyoxazolidine (1.72 g) prepared in Example 10 and then water (5 mL) and conc. hydrochloric acid (2 mL) were added. The mixture was stirred at room temperature for 24 hours. The reaction was diluted with toluene, the aqueous layer was discarded, and then the organic layer was dried over anhydrous magnesium sulfate. After concentration under a reduced pressure, the residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=3/1) to give the title compound (1.40 mg) as white crystals in a yield of 89%.


Melting point: 46–48° C.; 1H-NMR (CDCl3, 400 MHz) δ ppm: 1.43 (d, 3H, J=6.8 Hz), 3.88 (s, 3H), 5.13 (s, 2H), 5.30 (dq, 1H, J=7.1, 6.8 Hz), 5.91 (d, 1H, J=7.1 Hz), 6.96 (d, 2H, J=8.8 Hz), 7.29–7.37 (m, 5H), 7.96 (d, 2H, J=8.8 Hz); IR (KBr) νmax 3458, 2958, 1714, 1676, 1597, 1527 cm−1.


Example 12

Preparation of (4S)-N-benzyloxycarbonyl-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine (Compound No.: 1030)




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Preparation of a Grignard Reagent


To anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere were added magnesium metal (2.56 g) and iodine (30 mg). To the mixture at room temperature was added one-fifth of a solution of 2,4-difluorobromobenzene (19.3 g) dissolved in anhydrous tetrahydrofuran (60 mL) in one portion. Five minutes after addition, Grignard reagent formation was initiated as indicated by temperature rising of the reaction. While maintaining a reaction temperature below 45° C., the remaining four-fifths of the reagent was added dropwise over about 30 min. At the end of addition, the mixture was stirred at 25 to 40° C. for 30 min to give a Grignard reagent.


Grignard Reaction


In anhydrous tetrahydrofuran (68 mL) was dissolved (4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (21.2 g) prepared in Reference Example 1, and the solution was cooled to −20° C. To the solution under nitrogen atmosphere was added dropwise the Grignard reagent prepared while maintaining the internal temperature at −20° C. At the end of addition, the mixture was stirred at that temperature for one hour and treated with a 5% aqueous hydrochloric acid solution. The solution was warmed to room temperature and extracted with toluene. The organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=2/1) to give the title compound (21.4 g) as a diastereomer mixture as a pale yellow syrup in a yield of 68%.



1H-NMR (CDCl3, 400 MHz) δ ppm: 1.52 and 1.51 (2d, 3H, J=6.8 Hz), 3.20–3.45 (m, 1H), 4.30–4.50 (m, 1H), 4.70–5.45 (m, 4H), 6.55–6.90 (m, 2H), 7.30–7.40 (m, 5H), 7.50–7.90 (m, 1H); IR (KBr) νmax 3402, 1803, 1701, 1614 cm−1.


Example 13

Preparation of (2S)-2-(benzyloxycarbonyl)amino-1-(2,4-difluorophenyl)-1-propanone (Compound No.: 22030)




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In tetrahydrofuran (70 mL) was dissolved (4S)-2-(benzyloxycarbonyl)amino-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine (14.0 g) prepared in Example 12, and water (50 mL) and conc. hydrochloric acid (20 mL) were added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with toluene, the aqueous layer was discarded, and the organic layer was washed with water three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=3/1) to give the title compound (11.7 g) as a pale yellow syrup in a yield of 92%.



1H-NMR (CDCl3, 400 MHz) δ ppm: 1.40 (d, 3H, J=7.0 Hz), 5.10 (s, 2H), 5.05–5.20 (m, 1H), 5.75–5.80 (m, 1H), 6.88–6.94 (m, 1H), 6.98–7.02 (m, 1H), 7.30–7.37 (m, 5H), 7.95–8.01 (m, 1H); IR (neat) νmax 3358, 1718, 1681, 1611, 1532 cm−1, Optical purity: 90%ee;


HPLC Analysis Conditions






    • Column: Daicel Chiral-Pak AD-RH (4.6 mmφ×150 mm);

    • Mobile phase: methanol;

    • Flow rate: 0.5 mL/min;

    • Wavelength: 254 nm;

    • Temperature: room temperature;

    • tR: (2R-form); 6.5 min
      • (2S-form); 7.5 min.





Reference Example 5

Preparation of (4R)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone




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In toluene (190 mL) were suspended benzyloxycarbonyl-D-alanine (19.3 g), paraformaldehyde (6.56 g) and p-toluenesulfonic acid monohydrate (0.17 g), and the mixture was heated at reflux while removing water produced. At the end of the reaction, the mixture was cooled to room temperature, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The precipitated crystals were filtered to give the title compound (17.4 g) as white crystals in a yield of 85%.


Melting point: 89–91° C.; 1H NMR (CDCl3, 400 MHz) δ ppm: 1.54 (d, 3H, J=6.4 Hz), 4.29–4.31 (m, 1H), 5.18 (s, 2H), 5.28–5.29 (m, 1H), 5.47 (br, 1H), 7.33–7.41 (m, 5H); IR (KBr) νmax 1778, 1685 cm−1.


Example 14

Preparation of (4R)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-methyl-5-hydroxyoxazolidine (Compound No.: 19001)




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(4R)-N-Benzyloxycarbonyl-4-methyl-5-oxazolidinone (2.61 g) prepared in Reference Example 5 was processed as described in Example 1 to give the title compound (9.0 g) as a diastereomer mixture as white crystals in an yield of 65%.


Melting point: 82–86° C. 1H-NMR (CDCl3, 400 MHz) indicated that a diastereomer ratio was about 2:1.


Major Diastereomer Product



1H-NMR (CDCl3, 400 MHz) δ ppm: 1.47 (d, 3H, J=7.3 Hz), 3.81–3.84 (m, 1H), 4.79–5.07 (m, 2H), 5.14 (s, 2H), 5.14 (d, 1H, J=8.4 Hz), 5.20 (d, 1H, J=8.4 Hz), 5.87 (q, 1H, J=7.3 Hz), 7.02 (d, 2H, J=8.8 Hz), 7.23–7.44 (m, 10H), 8.01 (d, 2H, J=8.8 Hz);


Sub Diastereomer Product



1H-NMR (CDCl3, 400 MHz) δ ppm: 1.49 (d, 3H, J=7.3 Hz), 3.60–3.70 (m, 1H), 4.79–5.15 (m, 4H), 5.13 (s, 2H), 5.57 (q, 1H, J=7.3 Hz), 6.91 (d, 2H, J=8.8 Hz), 7.23–7.44 (m, 10H), 7.83 (d, 2H, J=8.8 Hz); IR (neat) νmax 3436, 3033, 1671, 1603, 1508 cm−1.


Example 15

Preparation of (2R)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone (Compound No. 25001)




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(4R)-N-Benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-methyl-5-hydroxyoxazolidine (2.1 g) prepared in Example 14 was processed as described in Example 9 to give the title compound (1.85 g) as pale yellow crystals in an yield of 95%.


Melting point: 88–90° C.; 1H-NMR (CDCl3, 400 MHz) δ ppm: 1.43 (d, 3H, J=6.83 Hz), 5.13 (s, 2H), 5.15 (s, 2H), 5.28–5.31 (m, 1H), 5.88 (br, 1H), 7.03 (d, 2H, J=9.0 Hz), 7.31–7.44 (m, 10H), 7.96 (d, 2H, J=9.0 Hz); IR (KBr) νmax 3374, 1712, 1690 cm−1; Specific rotation: [α]D24=−25° (C=1.00, CHCl3); Optical purity: 98%ee (analysis conditions are as described in Example 3).


Example 16

Preparation of (4R)-N-benzyloxycarbonyl-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine (Compound No.: 19030)




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Preparation of a Grignard Reagent


To anhydrous tetrahydrofuran (10 mL) under nitrogen atmosphere were added magnesium metal (1.28 g) and iodine (20 mg). A solution of 2,4-difluorobromobenzene (9.65 g) in anhydrous tetrahydrofuran (30 mL) at room temperature was used as described in Example 12 to give a Grignard reagent.


Grignard Reaction


In anhydrous tetrahydrofuran (34 mL) was dissolved (4R)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (10.6 g). The mixture was processed as described in Example 12 to give the title compound (10.7 g) as a diastereomer mixture as a pale yellow syrup in a yield of 68%.



1H-NMR (CDCl3, 400 MHz) δ ppm: 1.52 and 1.51 (2d, 3H, J=6.8 Hz), 3.20–3.45 (m, 1H), 4.30–4.50 (m, 1H), 4.70–5.45 (m, 4H), 6.55–6.90 (m, 2H), 7.30–7.40 (m, 5H), 7.50–7.90 (m, 1H); IR (KBr) νmax 3402, 1803, 1701, 1614 cm−1.


Example 17

Preparation of (2R)-2-(benzyloxycarbonyl)amino-1-(2,4-difluorophenyl)-1-propanone (Compound No.: 25030)




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In tetrahydrofuran (35 mL) was dissolved (4R)-2-(benzyloxycarbonyl)amino-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine (6.98 g) prepared in Example 16, and water (25 mL) and conc. hydrochloric acid (10 mL) were added. The mixture was processed as described in Example 13 to give the title compound (5.87 g) as pale yellow syrup in a yield of 92%.



1H-NMR (CDCl3, 400 MHz) δ ppm: 1.40 (d, 3H, J=7.0 Hz), 5.10 (s, 2H), 5.05–5.20 (m, 1H), 5.75–5.80 (m, 1H), 6.88–6.94 (m, 1H), 6.98–7.02 (m, 1H), 7.30–7.37 (m, 5H), 7.95–8.01 (m, 1H); IR (neat) νmax 3358, 1718, 1681, 1611, 1532 cm−1; Optical purity: 90%ee (analysis conditions are as described in Example 12).


INDUSTRIAL APPLICABILITY

According to the present invention, an optically active aminoalcohol derivative represented by general formula (5) or (6), which is useful as a production intermediate for a medicine or agricultural agent, can be produced stably in a large scale with an industrially adequate optical purity and a lower cost. This invention also provides an optically active 5-hydroxyoxazolidine derivative represented by general formula (3) as an important intermediate for production of the above optically active aminoalcohol derivative or other optically active amine derivatives and a generally usable preparation process therefor, as well as an optically aminoketone derivative represented by general formula (4) and a generally usable preparation process therefor. The production technique may be extensively applicable to preparation of optically active amine derivatives in addition to preparation of the above optically active aminoalcohol derivative, and thus is industrially excellent technique.

Claims
  • 1. A process for preparing an optically active aminoalcohol wherein an optically active 5-oxazolidinone derivative represented by general formula (1): wherein R1 represents an unprotected or optionally protected side chain in a natural α-amino acid; and R2 represents optionally substituted aryl, optionally substituted alkyl, or optionally substituted aralkyl, is reacted with an organometallic reagent represented by general formula (2): R3—M  (2)wherein R3 represents optionally substituted aryl or optionally substituted heterocycle; M represents one selected from the group consisting of Li, MgX, ZnX, TiX3 and CuX; and X represents halogen,to form an optically active 5-hydroxyoxazolidine derivative represented by general formula (3): wherein R1, R2 and R3 are as defined above,which is then treated under acidic conditions to give an optically active aminoketone derivative represented by general formula (4): wherein R1 and R3 are as defined above; and R4 represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group,which is then treated with a reducing agent or catalytically hydrogenated with a metal catalyst to stereoselectively provide an optically active aminoalcohol derivative represented by general formula (5): wherein R1, R3 and R4 are as defined above;provided that configuration of R1 attached to the asymmetric carbon at 4-position and the substituent represented by a nitrogen atom in the optically active 5-oxazolidinone represented by general formula (1) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol represented by general formula (5) is an erythro configuration.
  • 2. A process for preparing an aminoalcohol wherein an optically active 5-oxazolidinone derivative represented by a general formula (1): wherein R1 represents an unprotected or optionally protected side chain in a natural α-amino acid; and R2 represents optionally substituted aryl, optionally substituted alkyl, or optionally substituted aralkyl,is reacted with an organometallic reagent represented by general formula (2): R3—M  (2)wherein R3 represents optionally substituted aryl or optionally substituted heterocycle; M represents one selected from the group consisting of Li, MgX, ZnX, TiX3 and CuX; and X represents halogen,to form an optically active 5-hydroxyoxazolidine derivative represented by general formula (3): wherein R1, R2 and R3 are as defined above,which is then treated under acidic conditions to give an optically active aminoketone derivative represented by general formula (4): wherein R1 and R3 are as defined above; and R4 represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group,which is then treated with a reducing agent or catalytically hydrogenated with a metal catalyst to provide an optically active aminoalcohol derivative represented by general formula (5): wherein R1, R3 and R4 are as defined above,and then, when R4 is a protective group, the amino group in the product is deprotected to give an optically active aminoalcohol derivative represented by general formula (6): wherein R1 and R3 are as defined above;provided that configuration of R1 attached to the asymmetric carbon at 4-position and the substituent represented by a nitrogen atom in the optically active 5-oxazolidinone represented by general formula (1) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol represented by general formula (6) is an erythro configuration.
  • 3. The process for preparing an optically active aminoalcohol as claimed in claim 1 or 2 wherein R1 represents methyl, isopropyl, isobutyl, benzyl, hydroxymethyl, benzyloxymethyl, phenylthiomethyl, methylthiomethyl, alkyloxycarbonylmethyl or alkyloxycarbonylethyl; R2 represents benzyl, tert-butyl, methyl, ethyl, isopropyl or 9-fluorenylmethyl.
  • 4. The process for preparing an optically active aminoalcohol as claimed in claim 1 or 2 wherein R3 is represented by general formula (7): wherein Y represents halogen; or by general formula (8): wherein R5 represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocycloalkyl.
  • 5. The process for preparing an optically active aminoalcohol derivative as claimed in claim 1 or 2 wherein R1 represents methyl; and R3 is represented by general formula (8): wherein R5 represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl.
  • 6. An optically active 5-hydroxyoxazolidine derivative represented by general formula (3): wherein R1 represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; andwherein R2 represents benzyl, tert-butyl, methyl, ethyl, isopropyl or 9-fluorenylmethyl.
  • 7. The optically active 5-hydroxyoxazolidine derivative as claimed in claim 6 wherein R3 is represented by general formula (7): wherein Y represents halogen; or general formula (8): wherein R5 represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl.
  • 8. The optically active 5-hydroxyoxazolidine derivative as claimed in claim 7 wherein R1 is methyl.
  • 9. A process for preparing an optically active 5-hydroxyoxazolidine derivative wherein an optically active 5-oxazolidinone derivative represented by general formula (1): wherein R1 represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; wherein R2 represents benzyl, tert-butyl, methyl, ethyl, isopropyl or 9-fluorenylmethyl,is reacted with an organometallic reagent represented by general formula (2): R3—M  (2)wherein R3 represents optionally substituted aryl or optionally substituted heterocycle; M is one selected from the group consisting of Li, MgX, ZnX, TiX3 and CuX; and X represents halogen,to provide an optically active 5-hydroxyoxazolidine derivative represented by general formula (3): wherein R1, R2 and R3 are as defined above.
  • 10. The process for preparing an optically active 5-hydroxyoxazolidine derivative as claimed in claim 9 wherein R3 is represented by general formula (7): wherein Y represents halogen; or general formula (8): wherein R5 represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl.
  • 11. The process for preparing an optically active 5-hydroxyoxazolidine derivative as claimed in claim 10 wherein R1 is methyl.
  • 12. The process for preparing an optically active 5-hydroxyoxazolidine derivative as claimed in claim 9 wherein M in general formula (2) is MgX wherein X is as defined above.
  • 13. An aminoketone derivative represented by
  • 14. A process for preparing an aminoketone derivative wherein a 5-hydroxyoxazolidine derivative represented by general formula (3): wherein R1 represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R2 represents optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl; and R3 represents optionally substituted aryl or optionally substituted heterocycle,is treated under acidic conditions to form an aminoketone derivative represented by general formula (4): wherein R1 and R3 are as defined above; R4 represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group.
  • 15. An optically active alcohol derivative represented by general formula (5a): wherein R1a represents methyl; R3b represents 4-benzyloxyphenyl; R4b represents benzyloxycarbonyl; and configuration between the amino group and the hydroxy group is an erythro configuration.
  • 16. A process for preparing an optically active aminoalcohol derivative wherein an optically active aminoketone derivative represented by general formula (4b): wherein R1 represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R4 represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group; R3c is represented by general formula (8): wherein, R5 represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl,is catalytically hydrogenated with a metal catalyst, to stereoselectively form an optically active aminoalcohol derivative
  • 17. A process for preparing an optically active aminoalcohol derivative wherein an optically active aminoketone derivative represented by general formula (4b): wherein R1 represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R4 represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group; R3c is represented by general formula (8): wherein, R5 represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl,is catalytically hydrogenated with a metal catalyst, to stereoselectively form an optically active aminoalcohol represented by general formula (5b): wherein R1, R3c and R4 are as defined above,and when R4 is a protective group, the amino group in the product is deprotected to give an optically active aminoalcohol derivative represented by general formula (6a): wherein R1 and R3c are as defined above;provided that configuration of R1 attached to the asymmetric carbon at 2-position and the substituent represented by a nitrogen atom in the optically active aminoketone derivative represented by general formula (4b) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol derivative represented by general formula (6a) is an erythro configuration.
PCT Information
Filing Document Filing Date Country Kind 371c Date
PCT/JP01/09830 11/9/2001 WO 00 5/9/2003
Publishing Document Publishing Date Country Kind
WO02/38532 5/16/2002 WO A
US Referenced Citations (3)
Number Name Date Kind
5116858 Hayashi et al. May 1992 A
5449694 Yamazaki et al. Sep 1995 A
6770642 Cole et al. Aug 2004 B1
Foreign Referenced Citations (7)
Number Date Country
1087079 May 1994 CN
77983 May 1983 EP
396973 Nov 1990 EP
603414 Jun 1994 EP
62-29998 Dec 1987 JP
WO 9509155 Apr 1995 WO
WO 9932483 Jul 1999 WO
Related Publications (1)
Number Date Country
20040030144 A1 Feb 2004 US