JPS59116256A - Manufacture of optically active cyanomethyl ester - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

BACKGROUND OF THE INVENTION (Field of the Invention) The present invention relates to a method for producing optically active cyan methyl esters, and more particularly, to a method for producing cyano methyl esters having chiral centers in both the acid and alcohol moieties, and methods for producing these products. The present invention relates to novel catalysts and methods for preparing optically active optionally substituted S-α-cyano-3-phenoxybenzyl alcohol intermediates (to said esters). PRIOR ART Stereoisomers of alpha-chiral carboxylic acid chiral cyanomethiesters or the acid itself usually have different effects in biological systems. Direct production of optically active cyanomethyl esters has not been straightforward in the past because the corresponding xyl α-hydroxynitrile was not readily available and synthetic methods did not yield the product at low or no concentrations. Ta. Contains optically active α-hydroxynitrile-J
Optically active acids were not readily available, even when 4'-triple acids became relatively readily available. Optically active acids have been obtained by classical resolution, but this is time consuming and cannot be performed on a large scale. Optically active α-hydroxybenzene acetonitriles are known to those skilled in the art and are of interest as such and as intermediates (eg to esters). Among the alcohol-derived pyrethroid esters, those having an (α-5)-σ-hydroxynitrile moiety combined with a suitable pyrethroid acid usually have the highest insecticidal activity. However, such (α-5)-α-hydroxy-nitriles were not readily available in the past, since they were usually produced by splitting. The method of the present invention provides a method for producing chiral cyanomethiesters of α-chiral carboxylic acids in high yields by a direct synthesis method, avoiding the hassle of using the corresponding optically active acids and alcohols and C) classical resolution. be. []Summary of the Invention] The present invention provides a method for converting asymmetric ketene into racemic or optically active α-
A method for producing an optically active cyan methyl ester of an alpha-chiral (optically active) carboxylic acid (i.e., a monochiral cyanomethyl ester of an alpha-chiral carboxylic acid) or a rich mixture thereof, comprising treatment with hydroxynitrile. The optically active cyan methyl ester product comprises a compound represented by the following formula: (wherein kl, R2, R3, and 4 represent substituents, 棢 represents an asymmetrically substituted carbon atom, and the dashed line represents an optional bond). The reaction is carried out in the presence or absence of a solvent. If a solvent is used, the solvent is preferably a non-hydroxyl solvent such as a hydrocarbon, chlorinated hydrocarbon, ether, and the like. For example, suitable solvents include those having 5 to 10 carbon atoms, such as n-pentane, n-hexane, n-hebutane, n-octane, n-nonane, n-decane and their isomers.
is an alkane. Alkane-rich petroleum fractions are also suitable, e.g. boiling ranges 40-65°C, 60-80°C at atmospheric pressure.
Alternatively, gasoline at 80 to 110°C may be used. Petroleum ethers are also suitable. Cyclohexane and methylcyclohexane are examples of useful cycloalkanes containing 6 to 8 carbon atoms. The aromatic hydrocarbon solvent has 6 to 1 carbon atoms.
0, for example benzene, toluene, o −1
Contains m-p--1-silene, trimethylbenzene, and P-ethyltoluene. Suitable chlorinated hydrocarbons include alkane chains of 1 to 4 carbon atoms or benzene rings to which 1 to 4 chlorine atoms are attached, for example:
Carbon tetrachloride, chloroform, dichloromethane, 1゜2-
Dichloroethane, trichloroethane, perchloroethane, chlorobenzene and H1, 2-4+L, < is 1,3-
Examples include dichlorobenzene. Ethers generally have 4 to 6 carbon atoms, such as diethyl ether, methyl-t-butyl ether and diimpropyl ether. As the solvent, aromatic solvents, especially toluene, are preferred. All unsymmetrical ketenes (if they do not contain substituents that create α-hydroxynitrile and other stable reaction products)
Can be used. The asymmetric ketene has the formula () % formula % [where ml and 2 are different, and each is an alkyl having 1 to 10 carbon atoms, aralkyl, alkoxy, ori-ruoxy, alkylthio, alkylsulfonyl, arylthio or aryl] represents a sulfonyl group, or a cycloalkyl group having 3 to 7 carbon atoms, or 2 represents an alkenyl or alkynyl group having 2 to 10 carbon atoms, or a naphthyl group, a phenyl group, one hetero atom is oxygen, sulfur , or a 5- to 6-membered heterocyclic group consisting of nitrogen and the remainder being carbon atoms or having 10 carbon atoms
represents an acyl or alkyl group up to, or an amino group di-substituted with a phenyl group, or when R1 and R2 are taken together via the carbon atom to which they are bonded, a ring carbon atom The number is 4-7 and the number of carbon atoms is 4-1.
form an asymmetric cycloalkyl group of 4]. kl and ρ groups optionally have atomic number 9
~35 halogen atoms, alkyl or haloalkyl having 1 to 4 carbon atoms, alkenyl or haloalkenyl having 2 to 4 carbon atoms, haloalkoxy or alkoxy having 1 to 4 carbon atoms, haloalkylthio having 1 to 4 carbon atoms or may be substituted with alkylthio or one or more substituents of equivalent type and size having the same or more carbon atoms. One embodiment of the asymmetric ketene used in the method of the invention is
U.S. Patent No. 4,062,968, No. 4,1
37,324 and 4,199,595, including esters with acid moieties. An example of such a ketene is that in formula (11), R1 is isopropyl or cyclopropyl, and K group (alkyl group having 1 to 6 carbon atoms, alkenyl group having 2 to 6 carbon atoms, each optionally containing a halogen is bromine, chlorine or fluorine, and the ring is substituted with one or more halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, where the alkyl group has 1 to 4 carbon atoms, phenyl group (benzyl) Of particular interest as asymmetric ketene reactants, since the resulting esters usually have high insecticidal activity, are those of the formula For example, phenyl radicals substituted by halogen, alkyl or haloalkoxy, where alkyl has 1 to 4 carbon atoms (e.g. methyl), with chlorine or fluorine. For example, unsymmetrical ketene is (4-chlorophenyl)-isopropyl ketene, (4-(difluoromethoxy)phenyl)inpropylketene and ((4-(trifluoromethyl)-3-chlorophenyl)(benzyloxycarbonyl)amino)inpropylketene, etc. All racemic or optically active α-Hydroxy'J2)
IJ ul/ is (if it does not contain an asymmetric ketene or a substituent that creates a stable reaction product with the catalyst present)
Can be used. Preferably, the α-hydroxynitrile is
Formula [wherein R3 is an optionally substituted hydrocarbyl or heterocyclic group, R4 is an optionally substituted hydrocarbyl group or a hydrogen atom, or
are symmetrical or asymmetrical, racemic or optically active α-hydroxynitriles, taken together via the carbon atoms to which they are attached to form a carbocyclic group, as indicated by the dashed line. . The hydrocarbyl group represented by formula (III) (7) R and ← may be, for example, an alkyl, cycloalkyl, or aryl group of up to 20 carbon atoms, preferably up to 10 carbon atoms, or of the formula ( III) Noni 3
may be a carbocyclic or O or S-heterocyclic aryl group. Examples of carbocyclic aryl groups are pheninope 1-naphthyl, 2-naphthyl and 2-an I-IJ
is a group. Heteroaromatic groups are derived from the heteroaromatic compounds defined in Kirk Osmer's Encyclopedia of Chemical Technology, 2nd edition, Volume 2, page 702. It is a 5-membered ring obtained by replacing one or more carbon atoms of a carbocyclic aromatic compound by a heteroatom selected from 0 or S, and which is a 5-membered ring exhibiting aromatic character. and is described on page 703 of the above-mentioned document. The optional substituent is a halogen atom having an atomic number of 9 to 35 (including the numbers at both ends; the same applies hereinafter), or an alkyl having 1 to 6 carbon atoms, each optionally substituted with one or more halogen atoms; Alkenyl or alkoxy groups, including one or more optionally substituted phenoxy, phenyl, benzyl or benzoyl, and equivalent groups. An example of an optically active α-hydroxynitrile is α-hydroxy-α-methylbutyronide IJ/α-
Includes hydroxy-α-methylbenzeneacetonitrile and α-hydroxyinbutyronitrile. Preferably, the α-hydroxynitrile compound has the formula [wherein each A is the same or different, a hydrogen atom,
B represents an alkyl, alkenyl or alkoxy group having 1 to 6 carbon atoms optionally substituted with one or more halogen atoms having an atomic number of 9 to 35; , a hydrogen atom, a hydrogen atom having an atomic number of 9 to 35, an alkyl, alkenyl or alkoxy group having 1 to 6 carbon atoms, each optionally substituted with one or more halogen atoms having an atomic number of 9 to 35, or a group [wherein Y is 0, CH2 or c(o), m is 0 or 1, D and E are the same or different, each a hydrogen atom, a 7X rogen atom with an atomic number of 9 to 35, each as desired represents an alkyl, alkenyl or alkoxy group having 1 to 6 carbon atoms substituted with one or more atomic atoms having an atomic number of 9 to 35. Preferably, α-hydroxynitrile is K- or S
- configuration, having the formula, I ( [wherein Y is 0, CH2 or C(0), A, D and E are the same or different, a hydrogen atom, atomic number 9
~35 halogen atoms, each optionally with atomic number 9
represents an alkyl, alkenyl or alkoxy group having 1 to 6 carbon atoms substituted with one or more halogen atoms of 1] or preferably S
- Contains α-hydroxynitrile. Preferably, Y represents 0. Preferably, A, D and E are the same or different and represent a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group or a methoxy group. (2) and one of E is preferably a hydrogen atom. Particularly preferred types of S-α-hydroxyl are those of the type 2) in which A and E are the same or different and are a fluorine atom or a hydrogen atom; or when E is fluorine, in the 4-position of the ring relative to the benzylic carbon in the case of A or to the carbon atom with Y=-0 in the case of E; Particularly suitable alcohols are those in which A is a fluorine atom in the 4-position and E is a hydrogen atom. Examples of α-hydroxynitrile of the above formula include S-α-
Cyano-3-phenoxybenzyl alcohol, S-α-
Included are cyano-4-fluoro-3-phenoxybenzyl alcohol, S-α-cyano-3-(4-fluorophenoxy)benzyl alcohol and the corresponding enantiomers. The present invention provides a method for converting unsymmetrical ketenes into racemic or optically active monohydroxynitriles (where hydroxy and nitrile substituents both are bonded to the same carbon atom) to produce stereoisomer-enriched cyan methyl ester. The optically active (chiral) tertiary amine catalyst has 4 carbon atoms.
Up to 0 optionally substituted alkyl, cycloalkyl, aromatic or heterocyclic mono- or polyamines (including polymers, copolymers and amine salts, etc.) that do not interfere with the reaction. The amine is preferably a medium to weakly basic amine. The optically active amines, polymers and copolymers are of a conventional type known in the art and are prepared by known methods, with the exception of the novel ketene reaction products described below. For example, a large number of optically active amines are described in Newman, Optical Resolution Procedures for Chemical Compounders, Volume 1, Amines and Related Compounders, Optical Resolution I/F. Mation Center, Manhattan Calendar Liverpool, New York, Library of Combres Catalog. Individually listed on card number 78-61452. This document also describes optically active mono-, di- and poly-amines which can be polymerized or copolymerized by known methods to produce the optically active amine polymers used in the present invention. One embodiment of the optically active amine catalyst comprises a substituted optically active amino acid, preferably up to 20 carbon atoms, preferably 1 carbon atom, substituted with a substituent of a medium to weakly basic nitrogen base.
o acyclic amino acids, carbocyclic amino acids, aromatic amino acids or heterocyclic amino acids, or the reaction products thereof with about 1 to about 3 moles of ketene. Suitable nitrogenous base substituents include nitrogen heterocyclic groups or amino groups substituted by optionally substituted alkyl or cycloalkyl groups, or optionally substituted phenyl, respectively. Other optional substituents include hydroxy, alkyl, alkoxy, amino,
Includes alkylthio, phosphoryloxy, amido, and the like. Examples of nitrogen heterocyclic groups include thiazolyl, imidazolyl, pyrrolyl, benzopyrrolyl, and the like. Examples of optically active catalysts are β-aminoalanine, ornithine, canavanine, anserine, kynurenine, mimosine, cystathionine, ephedrine, acylated ephedrine,
These include, but are not limited to, histidinol, citrulline, carbamoylserine, cinchonine, quinine or acylated quinuclidinyl alcohol. Another embodiment of amine catalysts are heterocyclic amines and polymers of heterocyclic amines. Examples are di- and poly-aziridines, polymers of acryloyl cinchonine alone or with N,N-diacryloylhexamethylene diamine and acryloyl cinchonine, di- and poly-aziridines, acrylates or lower alkanoic acids. (N-benzyl-2-pyrrolidinyl methyl ester) and the like, but are not limited thereto. In another embodiment of the invention, the catalyst is characterized in that the free N-H and free C0OH groups of at least one histidine are optionally converted with protecting groups to amide (or acid addition salts thereof) and ester groups, respectively. It is an optically active histidine-containing peptide, or a histidine-containing di- or polypeptide, or a reaction product of about 1 mole of ketene per mole of histidine groups with 1 mole of histidine or histidine-containing di- or polypeptide. Polypeptides can also be linear or cyclic. The peptide usually contains about 2 to 16 peptide units, preferably 2 to 4 peptide units. Nitrogen-substituted amino acids, including histidine-containing enzymes and polypeptides, are described, for example, in Greenstein and Reinilla, Chemistry of the Amino Acids, John Wiley and Nunns, Inc., New York, 1999.
It is produced by the known peptide synthesis method described in 1961. Dipeptides, especially cyclic dipeptide forms of histidine-containing catalysts are preferred. Preferred are di- or polypeptides containing alanine, and di- or polypeptides produced using alanine, feralanine or alanine derivatives. In one embodiment of the invention, the asymmetric carbon atom in the histidine-containing peptide is catalytic in the D-configuration, although the D-configuration in the histidine-containing peptide is also useful. The choice of chirality in the catalyst is made to impart the desired chirality to the product. The functional groups in the amino acid catalyst may include protecting groups, and any conventional amino acid protecting group known in the art may be used. For example, the protecting group is an organic acid for free N-H and an alcohol for free C00I-I. All organic acids and alcohols that do not interfere with the reaction may be used as protecting groups. Preferably, the protecting group is another amino acid. All amino acids are used (14), but preferably the amino acids are
Non-heterocyclic mono- or diamino alkanoic acids or arylalkanoic acids such as alanine, phenylalanine, glutamic acid and glycine. Acid addition salts of amine catalysts are made with any acid that does not interfere with the reaction. Hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric acids such as sulfuric acid or toluenesulfonic acid, inorganic acids including phosphorous acids such as phosphoric acid or phenylphosphonic acid, and organic acids such as oxalic acid. are suitable for forming salts. When preparing a di- or polypeptide catalyst having alanine (including the moiety), it is prepared from alanine or a derivative thereof, which derivatives include 77=, β-aminoalanine, β-phenylalanine and 3.4- Contains dihydroxyphenylalanine, etc. When producing a catalyst from histidine (including moieties), histidine, 3-
Methylhistidine, -methylhistidine, 1-ethylhistidine, 1-propylhistidine or 1-benzylhistidine are preferred. The catalyst is preferably a cyclic cyheftide containing a histidine moiety and an alanine moiety. Peptide adducts (reaction products) with ketene are novel and constitute another part of the invention. The adduct is peptide 1
It is prepared to contain about 1 to 3 moles of ketene per mole, preferably about 2 moles, especially about 1 mole of ketene per mole of (cyclic) dipeptide. Obviously, it is preferred to form an adduct in the reaction liquid with the asymmetric ketene reactant in the process described below for the preparation conditions. However, a process in which the optically active catalyst is treated with about 1 to 3 moles of ketene, preferably in the absence of a solvent or in the presence of any solvent used to prepare the ketene, is suitable. The ketene may be a homologous but symmetrical ketene, such as dimethylketene, diphenylketene, etc., or a ketene itself. Examples of optically active histidine-containing catalysts include histidine, α-methylhistidine, in free or protected form,
1-Methyl-histidine, 3-methylhistidine, cyclo(histidyl-histidine), (benzyloxycarbonylalanyl)histidine methyl ester, cyclo(
alanyl-histidine), cyclo(β-phenylalanyl-histidine), histidine methyl ester hydrochloride,
Histidine ethyl ester dihydrochloride, anserine, cyclo(baryl-histidine), cricyl-histidine, cyclo(phenylalanyl-glycyl-histidine), cyclo(leucyl-histidine), cyclo(homophenylalanyl-histidine), cyclo( Phenylalanyl-
methylhistidine), N-α-(β-naphthoyl)histidine, histidyl-alanine, histidyl-phenylalanamide hydrochloride L histidyl-phenylalanine, cyclo(histidyl-proline), cyclo(glycyl-histidine) or these substances and ketene ( (4-chlorophenyl)isopropyl ketene). (4-(difluoromethoxy)phenyl)isopropylketone and cyclo(β-phenylalanyl-histidine) adduct,
Also included are adducts of dimethylketene and histidine, adducts of (4-(difluoromethoxy)phenyl)isopropylketene and cyclo(glycyl-histidine), or adducts of dimethylketene and histidyl-alanine. In one type of the invention, the peptide catalyst is
X represents H, alkyl or R-CO, each being the same or different, each of the n units having up to 7 carbon atoms being the same or differently substituted, where Y is hydrogen, Acyl, alkyl or arylalkyl of up to 10 carbon atoms, l is benzyl, 3-carboxypropyl, 3-amino-propyl, mercaptomethyl, 4-
Represents a common amino acid residue that does not interfere with the reaction of the present invention, including hydroxybenzyl and imidazol-4-ylmethyl, each m represents 0 or 1, n represents 2 to 16, and when both m are O , the catalyst has a cyclic structure as shown by the broken line. wherein at least one histidine or substituted histidine unit is included in the catalyst], and the catalyst represents the reaction product of 1 to 3 moles of ketene with the aforementioned catalyst. If the peptide catalyst is prepared by conventional methods in the presence of a solvent (eg, water), the catalyst may contain a crystallizing solvent (eg, water) if solid. Optically active nitrogen-based amino acids (
For example, the catalyst of the invention (histidine-containing peptide)
In the case of a solid, it includes the presence or absence of a crystallizing solvent (eg, water). Non-chiral tertiary amine catalysts include optionally substituted alkylloalkyl, aromatic or heterocyclic tertiary amines (polymers, copolymers, etc.) having up to about 40 carbon atoms.
Contains amine salts. ) and does not interfere with the reaction. As the amine, one with medium to strong basicity is used. Non-chiral tertiary amines, polymers and copo IJmers are of a conventional type known in the art and prepared by known methods. Examples of non-chiral tertiary amine catalysts include 1-methylimidazole, pyridine, 2+6'residine, triethylamine, trimethylamine, N,N-dimethylaniline, diimpropylethylamine, and the like. In one embodiment of the invention, the non-chiral tertiary amine is an acyclic, carbocyclic, aromatic or heterocyclic amine having up to about 20 carbon atoms. Preferably, the tertiary amine is an aliphatic or aromatic amine of 3 to 8 carbon atoms, conveniently an aliphatic tertiary amine such as triethylamine or trimethylamine. The non-chiral tertiary amine herein includes its acid addition salts. Acid addition salts are formed with any acid that does not interfere with the reaction. suitable inorganic acids including hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfur acids such as sulfuric acid or sulfonic acids, phosphorous acids such as phosphoric acid or phosphonic acids, and organic acids such as oxalic acid, etc. Acids are suitable for forming salts. Alternatively, the process of the invention consists of treating said ketene with an aldehyde or ketone and a source of cyanide ions, optionally in the presence of a non-chiral or chiral (optically active) catalyst as defined above. The reaction is preferably carried out in a non-hydroxyl solvent of the type described above. Any aldehyde or ketone (carbonyl compound)
are used (provided they do not contain substituents that form cyanide ions or other stable reaction products with the catalyst). Preferably, the aldehyde or ketone is of the formula [wherein R3 represents an optionally substituted hydrocarbyl or heterocyclic group, R4 represents an optionally substituted hydrocarbyl group or a hydrogen atom, or R3 and come together through the bonding carbon atoms,
Forms a carbocyclic group. ]. The hydrocarbyl group represented by ρ and 4 in formula (iv) may be, for example, an alkyl, cycloalkyl or aryl group having up to 20 carbon atoms, preferably up to 10 carbon atoms; formula or 0 or S
may be a heterocyclic aryl group. Examples of carbocyclic aryl groups are phenyl, 1-naphthyl, 2-naphthyl and 2-anthryl groups. Heteroaromatic groups are described in Kiln Osmer, Encyclopedia of Chemical Technology, 2nd edition, Volume 2 (1963), 702.
Derived from heteroaromatic compounds as defined on page. It is obtained by replacing one or more carbon atoms of a carbocyclic aromatic compound by a heteroatom selected from O or S, and is a heterocyclic compound having a 5-membered ring exhibiting aromatic character. and is described on page 703 of the above-mentioned document. Such aldehyde and ketone compounds are described in US Pat. No. 4,132,728. The optional substituents include one or more halogen atoms having atomic numbers 9 to 35, or each optionally one or more halogen atoms.
C1-C6 alkyl, alkenyl, alkoxy groups substituted with 1 to 6 halogen atoms, optionally substituted phenoxy, phenyl, benzyl, benzoyl or equivalent types of substituents. Preferably, the aromatic aldehyde has the formula [wherein each A is the same or different, a hydrogen atom,
B represents an alkyl, alkenyl or alkoxy group having 1 to 6 carbon atoms optionally substituted with 1 or more halogen atoms with an atomic number of 9 to 35; B is hydrogen; a norogen atom with atomic number 9 to 35, an alkynopearkenyl or alkoxy group having 1 to 6 carbon atoms, each optionally substituted with one or more halogen atoms with atomic number 9 to 35, or group [wherein Y is O, CH2 or C(0), m is 0 or 1, D and E are the same or different, each a hydrogen atom, a halogen atom with an atomic number of 9 to 35, each an atom as desired Represents an alkyl, alkenyl or alkoxy group having 1 to 6 carbon atoms substituted with one or more halogen atoms with numbers 9 to 35. Preferably, the aldehyde is α-hyde as defined above [wherein
A, D, E and Y have the same meanings as in the above formula]. Examples of suitable aldehydes of formula 2 are 3-phenoxybenzaldehyde, 4-fluoro-3-phenoxybenzaldehyde, and the like. The cyanide ion source is hydrogen cyanide or a reagent that produces hydrogen cyanide under the reaction conditions, such as alpha-hydroxynitrile or cyanohydrin. The molar ratio of hydrogen cyanide per mole of aldehyde or ketone is approximately 1.0
to about 3.0, preferably about J1 to about 2.0. The production of the cyanomethyl ester is preferably carried out by adding the asymmetric ketene to the α-hydroxynitrile dissolved in a solvent containing the catalyst or to the aldehyde or ketone and a source of cyanide ions and mixing the mixture, e.g. by stirring,
This is done by maintaining reaction conditions for a time to achieve the formation of an optically active ester. Separation and recovery of the optically active ester product is performed by conventionally known methods such as extraction. The amount of catalyst can vary. For example, depending on the tertiary non-chiral amine used, the amount of catalyst may range from about 1 to about 100%, preferably from about 1 to about 10 molar percentages, based on the weight of alpha-hydroxynitrile, aldehyde or ketone present. Varies within the range of . When the catalyst is a chiral tertiary amine, the catalyst contains about 0.1 to about 10 moles, preferably about 0.1 to about 5 moles, based on the weight of alpha-hydroxynitrile, aldehyde or ketone present; In particular, it is used in a range of about 1.5 to about 5 molar. The molar ratio of the starting materials (asymmetric ketene and α-hydroxynitrile, aldehyde or ketene) can be varied. For example, the molar ratio of ketene to alpha-hydroxynitrile is from about 5:1 to about 5, preferably from about 2=1 to about 1:
It is 2. However, it is desirable to use from about 1:1.1 to about 1215 molar excess of ketone to alpha-hydroxynitrile, aldehyde or ketone. The reaction temperature for producing cyanogen methyl ester can vary, as can the pressure. At normal pressure, the temperature is approximately -1
The temperature is around 0 to about 50°C. Room temperatures of about 0 to about 35°C are convenient, especially about 0 to about 15°C. α-Hydroxynitriles and the corresponding aldehydes or ketones are generally known in the literature. U.S. Patent No. 3,649,457, No. 4,2
73.727, Off et al., Journal of Chemical Communication, 22.
9-230, and Beraker et al., Journal of the American Chemical Society, Vol. 88, pages 4299-4300.
These are directly synthesized chemically and enzymatically,
In the case of optically active α-hydroxyl I-IJ, resolution is accomplished by methods known in the art. 5-α-cyano-3- optionally substituted for optical activity
phenoxybenzyl alcohol, prepared by treatment of the corresponding aldehyde or ketone with hydrogen cyanide in the presence of a cyclo(1)-phenyl-alanyl-D-histidine)cyheftide catalyst in a substantially water-immiscible aprotic solvent be done. The present invention also includes a method for producing such optionally substituted S-α-cyT/-3-phenoxybenzyl alcohol. Catalysts are prepared by known peptide syntheses as described, for example, in Greenstein and Reinilla, Chemistry of Di Amino Acids, John Wiley and Nuns Incorporated, New York, 1961. Substantially water-immiscible aprotic solvents for use in the present invention are defined as aprotic solvents whose solubility in water does not exceed 5 parts by volume. For example, the solvent is a hydrocarbon or ether solvent containing aliphatic, cycloaliphatic or aromatic substances. Preferably, the solvent has a boiling point below about 150°C (and does not interfere with the reaction) at the reaction temperature. For example, suitable solvents include n-pentane, n-hexane, n-
-Alkanes having from 5 to 10 carbon atoms, such as hebutane, n-octane, n-nonane, n-decane and their isomers. Petroleum fractions rich in alkanes are also suitable (e.g. 40-65°C, 60-80°C or 80°C at atmospheric pressure).
-110°C boiling point range). Petroleum ethers are also suitable. Cyclohexane and methylcyclohexane are examples of useful cycloalkanes containing 6 to 8 carbon atoms. Aromatic hydrocarbon solvents are those having 6 to 10 carbon atoms (e.g. benzene, toluene, 0-1m-1p-+silene,
trimethylbenzene, p-ethyltoluene, etc.). Useful ethers include diethyl ether, diimpropyl ether, methyl-1-butyl ether, and the like. Preferably, the solvent is an aromatic hydrocarbon, especially toluene, diisopropyl ether or dimethyl ether or a mixture thereof (eg 25/75 diethyl ether/toluene). The reaction for producing optically active S-α-cyano-3-phenoxybenzyl alcohol involves adding an aldehyde and a solvent to a cyclo(1)-phenylalanyl-1)-histidine) catalyst and dispersing it (the mixture is mechanically dispersed). (by grinding or mixing, for example by stirring), adding hydrogen cyanide and maintaining reaction conditions for a time to achieve the formation of optically active α-hydroxynide IJ. That is, hydrogen cyanide is preferably added simultaneously with or after the solvent and/or aldehyde, or immediately following the hydrogen cyanide to increase conversion and stereoselectivity. The presence of cyanide ions has a negative effect on the catalyst in this reaction, and competitive racemization is reduced by protecting the catalyst from cyanide ions. It is useful to form and maintain a well-dispersed, but not necessarily homogeneous, reaction mixture. Separation and recovery of the optically active alcohol product is accomplished by conventional techniques such as extraction. The reaction temperature, as well as the pressure, can vary. At normal pressure, the temperature is about -10 to about 80°C. Preferably about 5 to about 3
A room temperature of 5° C. is convenient, giving good yields, good reaction rates and good enantiomeric excess of the desired optically active product;
A zero temperature below 5° C. gives good results. The amount of catalyst used to produce optically active α-hydroxynitrile (eg, S-σ-hydroxynitrile) can vary. For example, the catalyst is used in a range of about 0.1 to about 10 molar, preferably about 0.1 to about 5 molar, especially about 15 to about 7.5 molar, based on the weight of aldehyde present. . Preferably, the catalyst is well dispersed in the reaction mixture. When the catalyst is prepared by conventional methods in the presence of a solvent (e.g. water), the catalyst, if solid, is prepared in the presence of a crystallizing solvent (e.g. water).
water). When the optically active cyclo(D-phenylalanyl-D-histidine) dipeptide catalyst of the present invention is solid, it includes those with or without a crystallization solvent (eg, water). Asymmetric ketenes used to make cyanomethyl esters are generally known in the art. The ketenes used in the present invention are produced by treating the corresponding acid nitride with a tertiary amine. Suitable tertiary amines include alkyl, tertiary or heterocyclic tertiary nitrogen bases including heptano- or polyamines and the like. Preferably, the tertiary amine is any alkyl group having from 1 to 10 carbon atoms, from 6 to 2 carbon atoms.
Amines having any aryl or arylalkyl group with 0 and 1 to 2 hydrocarbinol rings, and optionally containing sulfur, oxygen or further nitrogen atoms, 5
or any heterocyclic amine containing at least one ring nitrogen atom in a 6-membered heterocyclic ring, including trimethylamine, triethylamine, tri-n-propylamine, and pyridine. Preferably, the tertiary amine is one containing 3 alkyl groups of 1 to 4 carbon atoms, such as trimethylamine, trilopropylamine, and especially triethylamine or trimethylamine. Reactions to produce asymmetric ketenes are carried out in the presence or absence of a solvent. If a solvent is used, the solvent is preferably a non-hydroxyl solvent such as hydrocarbons, chlorinated hydrocarbons, ethers, and the like. For example, suitable solvents include n-pentane, n-hexane,
Alkanes having 5 to 10 carbon atoms such as n-hebutane, n-octane, n-nonane, 1]-decane and their isomers. Petroleum fractions rich in alkanes, e.g.
At atmospheric pressure, 40-65℃, 60-80℃ or 80-1
Gasoline with a boiling range of 10°C is also suitable. Petroleum ethers are also suitable. Cyclohexane and methylcyclohexane are examples of useful cycloalkanes containing 6 to 8 carbon atoms. The aromatic hydrocarbon solvent has 6 to 10 carbon atoms.
(7) Examples include evaporative, benzene, toluene, 〇-m- and P-xylene, trimethylbenzene and P-ethyltoluene. Suitable chlorinated hydrocarbons are
Alkane chains or benzene rings having 1 to 4 carbon atoms bonded with 1 to 4 chlorine atoms, such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, trichloroethane, perchloroethane, chlorobenzene, 1
, 2- or 1,3-chlorobenzene. Ethers are generally diethyl ether, methyl-

[-- those having 4 to 6 carbon atoms, such as butyl ether and diimpropyl ether. Tetrahydrofuran and dioxane are also used. Preferably, the solvent, if used, is an aromatic hydrocarbon, especially toluene. In the production of asymmetric ketenes, the molar ratios of the starting materials can vary widely. For example, the molar ratio of acid halide to base is from about 10-1 to about 1:10, preferably from about 5:1 to
The ratio is approximately 1:5. However, it is desirable to use a 1 molar excess of base to acid halide. Thus, the molar ratio of acid to base is conveniently about 1:1.
2 to about 1:2, preferably about 1:1 to about 1:5. In the production of asymmetric ketenes, temperatures can vary widely. For example, at normal pressure, reaction temperatures of about 75-95°C have been found to be very useful, but can vary, for example, from about 10-40°C. Separation and recovery of the product asymmetric ketene is accomplished by conventional methods including crystallization and the like. The method of the invention can be used to prepare unsymmetrical ketenes from any acid halide that does not contain substituents that react with bases. For example, the acid halide can be an acyclic, alicyclic, aromatic or heterocyclic acid halide. Preferably, the acid halide is [wherein X is a halogen atom such as chlorine or bromine; kl and R2 are the same or different; represents a sulfonyl, arylthio, arylsulfonyl group, a cycloalkyl group having 3 to 7 ring carbon atoms, or when they are taken together via the carbon atom to which they are bonded;
It forms an asymmetric cycloalkyl group having 3 to 7 carbon atoms in the ring, and alkenyl or alkynyl group having 2 to 10 carbon atoms, naphthyl group, phenyl group, in which one ring atom is oxygen, sulfur or nitrogen. represents a heterocyclic group containing 5 or 6 ring atoms, the remainder being carbon atoms, or an amino group di-substituted with an acyl, alkyl, or phenyl group having up to 10 carbon atoms. The kl and i groups optionally represent one or more halogens with atomic numbers 9 to 35, alkyl of up to 7 carbon atoms, haloalkyl or cycloalkyl groups, alkenyl or haloalkenyl groups of 2 to 4 carbon atoms, carbon Haloalkoxy or alkoxy group having 1 to 4 atoms, 1 to 4 carbon atoms
haloalkylthio or alkylthio groups, or substituents of an equivalent type. One type of acid halide is described in U.S. Pat.
062,968 and 4,199,595. Examples of such acid halides include formula (V) where R1 is isopropyl or cyclopropyl, IMi is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and optionally halogen is bromine , chlorine or fluorine, and the alkyl group is ring-substituted by one or more halogens, alkyl, haloalkyl, alkoxy, haloalkoxy, phenyl group matah (benzyloxycarbonyl) Including those that are phenylamino groups. For example, the acid halide is inpropyl (4-chlorophenyl) acetyl chloride,
Isopropyl (4-(difluoromethoxy)phenyl)
Acetyl chloride, isopropyl ((4=(trifluoromethyl)-3-chlorophenyl)(benzyloxycarbonyl)aminoacetyl chloride, etc.) Preferably, in formula (V), the foot is isopropyl, and 1e is preferably The rose position is Haroken as desired,
Phenyl radicals substituted with alkyl, haloalkyl, alkoxy, haloalkoxy groups having 1 to 4 carbon atoms, particularly useful are 4-chlorophenyl, 4-(difluoromethoxyphenyl), 4-methylphenyl or 4-t-butylphenyl etc. A number of asymmetric ketones of the present invention, such as (4-chlorophenyl) in U.S. Pat. No. 4,199,527
Isopropyl ketone is known. Some other unsymmetrical ketenes are believed to be generally known, but special types such as (4-(difluoromethoxy)
Phenyl) isopropyl ketone is new. Another embodiment of the present invention provides an optically active optionally substituted S- A process for producing an optically active cyanoethyl ester or a mixture rich in the same, comprising treating with a rich mixture thereof. The method of the invention is useful for making esters from any optically active acid halide, which does not contain substituents that react with bases. For example, the acid halide can be an acyclic, cycloaliphatic, aromatic or heteroaromatic acid halide. The reaction is carried out in the presence of an organic solvent appropriately selected from the same types of non-hydroxyl solvents as those mentioned above in the method for producing esters by treating asymmetric ketones, or in the absence of a solvent. Preferably the solvent is an aromatic solvent such as toluene. Reactions using acid halides are usually added slowly under stirring after the other reactants are well mixed, preferably in the presence of a hydrogen halide acceptor such as a tertiary amine such as triethylamine or pyridine. It is done below. The reaction to produce optically active cyanomethyl esters from S-alcohols and alpha-chiral carboxylic acid halides or their reactive derivatives also involves the crossing of ions or other reactive or functional species across phase interfaces in heterogeneous systems. It is carried out in a phase transfer state in the presence of a phase transfer catalyst that effectively promotes the transfer. Examples of phase transfer catalysts include, but are not limited to, organic quaternary salts of Group VA elements of the Periodic Table of the Elements (eg, nitrogen, phosphorus, arsenic, antimony, and bismuth). Preferred phase transfer catalysts include tetra-n-butylphosphonium chloride, tri-n-butyl-n-octylphosphonium bromide, hexadecyltributylphosphonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide,
They are trioctylethylammonium bromide, tetraheptylammonium iodite, triphenyldecylphosphonium iodite, tribenzyldecyl ammonium chloride, tetranonylammonium hydroxide, tricaprylylmethylammonium chloride, and dimethyldicocoammonium chloride. last 2
The two were manufactured by General Mills Company, Chemical Division, Kankaki-1111 and were named "Aliquot 336 (R)J, [Aliquot 221 (R)
R) It is named J. In the production of esters, the molar ratios of the starting materials can vary widely. For example, the molar ratio of acid halide to alcohol is from about 10:1 to about 1:10, preferably about 5:1.
~about 1=5. However, it is desirable to use a 1 molar excess of acid halide to alcohol. therefore,
The molar ratio of alcohol to acid halide is desirably from about 1:1 to about 1:5, conveniently from about 1:1 to about 1:1.
It is 2. In the production of esters, temperatures can vary widely. At normal pressure, the reaction temperature may vary, for example, from about 0 to about 70<0>C, but is preferably after about 10 to 40'CfnJ. Separation and recovery of the product ester is accomplished by conventional methods including recrystallization and the like. This method of the invention is used to prepare esters from any acid halide or reactive derivative thereof that does not contain substituents that react with bases. For example, acid halides or reactive derivatives thereof are conventionally known in the art and include acyclic, cycloaliphatic, aromatic or heteroaromatic acids and their reactive derivatives; is preferably the formula % formula % () [wherein, , aryloxy, alkylthio, alkylsulfonyl, arylthio, arylsulfonyl group, ring with 3 or more carbon atoms
7 represents a cycloalkyl group, or when taken together via the carbon atom to which they are attached, forms an asymmetric cycloalkyl group with 3 to 7 ring carbon atoms, and 2 represents a cycloalkyl group with 2 to 7 carbon atoms; 10 alkenyl or alkynyl groups,
Naphthyl group, phenyl group, heterocyclic group containing 5 or 6 ring atoms in which one of the ring atoms is oxygen, sulfur or nitrogen and the remainder are carbon atoms, or acyl, alkyl group having up to 10 carbon atoms or represents an amine group di-substituted with a phenyl group]. kl and one group optionally include one or more halogens with atomic numbers 9 to 35, alkyl, haloalkyl or cycloalkyl groups having up to 7 carbon atoms, alkenyl or haloalkenyl groups having 2 to 4 carbon atoms, carbon haloalkoxy or alkoxy group having 1 to 4 atoms, haloalkylthio or alkylthio group having 1 to 4 carbon atoms,
or may be substituted with an equivalent type of substituent. The reactive derivative is preferably a halide, ie, X, chlorine or bromine in the above formula (1). One type of acid halide is described in U.S. Pat.
No. 024,163, No. 4,062,968, No. 4.2
No. 20,591, No. 3,835,176, No. 4,24
No. 3.819, No. 4,316,913 and No. 4.1
Pyrethroid acid halides including those described in No. 99.595. Examples of such acid halides or reactive derivatives thereof include the formula
6 alkyl, 2 to 6 alkenyl groups, each optionally) one or more halogens, alkyl, 10 alkyl, in which 10 is bromine, chlorine or fluorine, and the alkyl group has 1 to 4 carbon atoms; Alkoxy ring-substituted by haloalkoxy and is a thanaphthyl group, phenyl group or (benzyloxycarbonyl)phenylamino group,
or ml and % (combined with R1 and % through the bonded carbon atom, formula [wherein W, X, Y and Z are the same or different, hydrogen atom, atomic number represents a 9-35 halogen atom or a C1-4 alkyl group, or Y and Z are the same or different and each represents a C1-4 alkyl group, W is a hydrogen atom, and X is a pentyl group; /10 ethyl, dihalovinyl, inbutenyl, parts\
lomethylviny/I/, 2-phenyl-2-halobinyl,
2-phenyl-11212- ) IJ haloethyl group, or alkoxyiminomethyl or ((cycloalkyl)alkoxy)iminomethyl having 1 to 10 carbon atoms. For example, acid halides include isopropyl (4-chlorophenyl) acetyl chloride, isopropyl (4-(difluoromethoxy) phenyl) acetyl chloride, isopropyl ( ( , 4-1-lifluoromethyl-3
-chlorophenyl)(benzyloxycarbonyl)amino)acetyl chloride, 2,2-dimethyl-3-(2
．． 2-chlorovinyl) cyclopropane carbonyl chloride, 2,2-dimethyl-3-(2,2-dibromovinyl) cyclopropane carbonyl chloride, 2+2
') methyl-3-(1,2-dibromo-2,2-dichloroethyl)cyclopropanecarbonylchloride l',
1-(4-ethoxyphenyl)-2,2-dichlorocyclopropanecarbonyl chloride, 2,2-dimethyl-
3-(2-(1-lifluoromethyl)-2-chlorovinyl)cyclopropanecarbonyl chloride, 2,2-dimethyl-3-((imbutoximino)methyl)cyclopropanecarbonyl chloride, 2,2-dimethyl- 3
-((neopentoxyimino)methyl)cyclopropanecarbonyl chloride, 2,2-dimethyl-3-( (
(cyclobutyl)methoxyimino)methyl)cyclopropanecarbonyl chloride or chrysanthemyl chloride. Preferably, in the formula (V), kl is isopropyl, and R2 is preferably a phenyl group optionally substituted at the para position with a halogen, an alkyl having 1 to 4 carbon atoms, a haloalkyl, an alkoxy, a haloalkoxy group, Particularly useful are 4-chlorophenyl, 4-(difluoromethoxyphenyl), 4-methylphenyl or 4-t-
Butylphenyl, etc. In one embodiment of the invention, S-α-cya/-3-phenoxybenzyl alcohol or a rich mixture thereof is treated with S-α-isopropylphenylacetic acid chloride or an optionally substituted chiral cyclopropanecarboxylic acid chloride. An optically active cyanomethyl ester or a rich mixture thereof is obtained. The shea/methyl esters, the optically active forms of which are prepared by one or more embodiments of the process of the invention, are described in Francis et al., Journal of
Chemical, Vol. 95, pp. 1403-1409, (1909), which is generally known in the art, and U.S. Patent No. 4.151,195, No.
, No. 737, No. 4,328,167, No. 4,133,
826 and British Patent No. 2,014.137. All of the α-cyanomethyl esters produced can be hydrolyzed to the corresponding acid. Preferably, the optically active ester of the product is S-α-cyano-3-phenoxybenzyl S-α-inpropyl (
P-chlorophenyl)acetate, S-α-cyano-3
-Phenoxybenzyl S-α-inpropyl (P-(difluoromethoxy)phenyl)acetate, S-α-cyano-3-phenoxybenzyl (IR. cis)-3-(2,2-dichlorovinyl)-2,2 -dimethylcyclopropanecarboxylene 3S-α-cyano-3-phenoxybenzyl (IR, cis)-3-(2,
2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate, S-α-cyan-3-phenoxybenzyl (IR, cis)-3-(1,2-dibromo-2
,2-dichloroethyl)-2,2-dimethylcycloprono(carboxylate, S-α-cyan-3-phenoxybenzyl(IR,cis)-2,2-dimethyl-3
-(neopentoxyiminomethyl)cyclopronocarpoxylate, and the like. The present invention will be explained in more detail below with reference to Examples. Example I Preparation of N-(benzyloxycarbonyl)-〇-phenylalanine. 45 d of an aqueous solution containing 15.0 g of D-phenylalanine sample and 7.26 g of 50% I-IJ hydroxide
dissolved in. This solution was stirred at 0 to 10°C, and 16.3 g of pendylchloroformate was quickly added in several portions. The reaction was mildly exothermic and a solid precipitated immediately after the addition. An additional 45- and 3.61' of water and 3.61' of sodium hydroxide were added to redissolve most of the solids. The reaction mixture was stirred for 20 minutes and then acidified with 6N hydrochloric acid. The resulting solid was filtered, washed with water and then hexane, suctioned, and dried in vacuo to yield 47 g of a white solid. This solid was etherealed as a colorless oil to yield 27.79 of the desired product. Example 2 Preparation of N-(benzyloxycarbonyl)-1)-phenylalanine P-nitrophenyl ester. In a 300d three-bottle flask equipped with a stirrer and addition funnel, add 135 ml of pyridine. and acid 2 of Example 1 above.
79 was charged under a nitrogen stream, and then 13.2 g of p-nitrophenol was added. The reaction solution was cooled to 0 to 10°C, and 14.6 g of phosphorus oxychloride was added. The reaction mixture was warmed to 25 °C, stirred for 15 min, then poured with cold water at 300 rn
Pour it into I. The resulting solid was filtered, washed with water, and dried under reduced pressure to obtain 33 g of product. Crystallization was effected by cooling to -5°C from hot ethyl alcohol. The product was filtered, washed with cold ethyl alcohol then hexane, and dried under vacuum to give the desired product 2B, 7f. Melting point: 23
゜122.5~124.5℃, [α] ・+24.7(
C; = 2.0, solvent dimethylformamide). Example 3 Preparation of N-(benzyloxycarbonyl)-D-phenylalanyl-I)-histidine methyl ester. [)-Histidine methyl ester5. 40 me of triethylamine and 40 me of methylene chloride with stirring.
17. Furthermore, 8.27 f/ of the nitrophenyl ester produced in Example 2 above was added. The reaction mixture quickly turned light yellow and solids began to precipitate. The reaction mixture was stirred for 2 hours and left at -10°C overnight. The reaction mixture was warmed to room temperature and 0.6 ml of triethylamine was added. Then, D-histidine methyl ester hydrochloride 490 ME/
was added and stirring continued for 2 hours. Pour the reaction mixture into 20WL of water.
eThen, it was washed twice with 20 ml of 10% ammonium hydroxide and then twice with 20 mJ of water. All washings were sequentially back-extracted with 20 ml of methylene chloride, and the combined organic layers were dried over MgSO,i, concentrated to 100 ml, filtered over silica, and extracted with methanol/ethyl acetate (20/80).
) 25IIle of the mixture was added. The resulting eluent was
It was concentrated to 1 ml and made up to 120 ml with diethyl ether. The precipitated solid was filtered, washed with diethyl ether and dried under vacuum to give the desired product 5.661 as a white solid. Melting point: 114.5-117°C, [α':]: -5
5.5 (C2, solvent: CHCd3). Example 4 Production of cyclo(D-phenylalanyl-D-histidine). The methyl ester 5.601i' of Example 3 above was hydrogenated at atmospheric pressure using 220 mg of 10 cfo palladium on carbon in 100 ytl of methanol under stirring. After 3 hours, solids began to precipitate. An additional 2.5 ml of methanol was added to facilitate stirring. After 7 hours, an additional 280 rrtl of methanol was added and the mixture was heated to reflux. The mixture was filtered under heat, and the P solution was concentrated to a gel mass, and mixed with 100 ml of diethyl ether. The resulting solid was filtered, washed with diethyl ether and dried under suction and under high vacuum at 35°C to give the desired product 3.29f as a slightly off-white powder 23°. [α]13. →
68.5 (C2,0, solvent: CH3CO0H). Example 5 Preparation of (4-chlorophenyl)isopropyl ketone. To a 1 volume solution of methylene chloride LO#rl and 2.31 g of isopropyl (4-chlorophenyl) acetyl chloride was added 1.5 g of triethylamine in one portion. After 18 hours, 15 g of heptane was added to the mixture and trimethylamine hydrochloride was removed by filtration. The solvent was removed from the liquid, 10me of heptane was added, the mixture was filtered and the solvent was removed to give a yellow residue. This residue was dissolved in 5 rnl of heptane for GLC analysis. The reaction solution was heated to 125 to 150 using Pantamwear's short neck head.
By oil bath at ℃, 0.2~0.05 F ■ g1110~
When distilled at a head temperature of 1oooC, 0.95g of distillate
And 0.81 g of rubber was obtained. The distillate was crystallized twice at -80°C from two volumes of hexane. The solid was melted and distilled at about 40 °C Q, 5*gf (g) to give 0.42 g of the desired product as a yellow liquid. Example 6 Preparation of (4-chlorophenyl)isopropyl ketene. 500 ml flask In the solution, inpropyl (4-chlorophenyl) vinegar e53.29 was added to thionyl chloride 21.5vt.
1 and slowly heated to 80°C and held at 80°C for 20 minutes. The reaction mixture was left at room temperature for 2 days. Volatiles were removed at 0.5 rxmHf at 75°C. The resulting yellow liquid was diluted with 250 parts of methylene chloride, followed by 3'8 parts of triethylamine. Added Of. The mixture was stirred until triethylamine hydrochloride began to precipitate after 30 minutes. After 16 hours, the reaction mixture was filtered and the solid triethylamine hydrochloride was washed with heptane. Most of the solvent was removed from the p-liquid on a rotary evaporator at 50'C. The residue was diluted with 75 ml of Heflin and the triethylamine hydrochloride was removed by filtration as described above. The solvent was removed from the p solution again, diluted again with 75 ml of heptane, added with 25 M/h of heptane, and refiltered. The P solution was cooled in dry ice, inoculated, and crystallized. The resulting crystals were filtered using a p filter and washed with cold hebutane. The filtered solid was dissolved in 1.5 volumes of hebutane, diluted and crystallized at -80°C, and the collected solid was melted and stored at -80°C. Warm the P solution, remove most of the solvent, and dry it in an oil bath using a Pantamware short path head.
Distilled at 05-0.06 mm H9, 90-120°C. The total distillate was collected at a head temperature of 60-85° C. and weighed 14.5 g as a bright yellow-orange liquid. The distillate was crystallized from an equal volume of pentane at -80°C, filtered as before, washed twice with Heflin, and warmed to give a second melt. A total of 5.979 desolvented p-fluids were crystallized as above in a 6 inch test tube, and the learning melt was immediately recrystallized as above to give a third melt. The three melts were combined and distilled for 5 mat-ip at 50<0>C to yield 29.4 g of the desired ketene as a yellow liquid. Example 7 Preparation of (4-chlorophenyl)isopropyl ketene. 69.4 ml of triethylamine was added to 57.75 y of isopropyl (4-chlorophenyl) acetyl chloride. The mixture was left at 20°C overnight. The resulting soft lump solid was crushed, diluted with 300 me of distilled hexane, and filtered. The solid was washed 3 times with 75 m/h of hexane, filtered and suction dried with calcium chloride dry air to yield 32 g of triethylamine hydrochloride. - More solids slowly precipitated from the combined hexane solution of ketene. The flask was wrapped in aluminum foil and the mixture was left at room temperature overnight and filtered, yielding an additional 0.75 solids! I got f. Remove the solvent from solution F by rotary evaporation and then evaporate for 1 hour.
I made it p. 500 ml of hexane was added to the mixture, and after P filtration, the solvent of the P liquid was removed to obtain a yellow oil. This oil is passed through the Pantamwear short pass head.
, 5 mml (g) to give the desired ketene 2 as a yellow liquid.
8.61 g was obtained. d20: 1.10° Example 8 Production of S-α-cyano-3-phenoxybenzyl alcohol. Cyclo (
1)-phenylalanyl-D-histidine) 43 m
y was charged, and the flask was placed under a nitrogen stream. Then add 3.51me of hydrogen cyanide with a syringe,
The catalyst swelled and became a gel. 5 minutes later, 30m of toluene
When 1 was added, excess catalyst precipitated. Immediately all 5.95 g of 3-phenoxybenzaldehyde was added. The reaction mixture f was stirred for 4.75 hours, then concentrated hydrochloric acid 10
The reaction was stopped with 20 ml of water dropwise. Separate the toluene solution, wash twice with water, and add toluene “E-50#” for analysis.
Diluted with Il. Analysis revealed that 80% S-α-cyano-3-phenoquine benzyl alcohol isomer was produced. Example 9 Preparation of S-α-cyano-3-phenoxybenzyl alcohol. Cyclo(I]-phenylalanyl-D-histidine) 1
The reaction of Example 8 above was repeated using 71'T9. After a while, take a sample of 0.25 yte,
It was analyzed by gas-liquid chromatography and the following results were obtained. After 7 hours, 10 rnl of IN hydrochloric acid was added to the reaction mixture to stop the reaction. Separate the organic layer, wash twice with water, Mg
Dry over S04, filter and keep at -10'C. The P solution was diluted with 50 ml of toluene and the optical rotation was measured.
-1,54'(7) results were obtained at 21°C in a 0 cm cell. A sample of the product was acetylated with P-nitrophenyl acetic anhydride, and the stereoisomer ratio was determined by IP of the chiral Bark column.
Determined by LC, 71% S-α-cyano-3-phenoxybenzyl alcohol and 29% monoα-cyano-3-phenoxybenzyl alcohol.
Phenoxybenzyl Alcohol Example 10 Preparation of S-α-cyano-3-phenoxybenzyl alcohol. Into two small round-bottomed flasks with magnetic stirrers and septum covers, each was charged with cyclo(D-phenylalanyl-
histidine) and placed under a nitrogen stream. Dilute 0.98 d of hydrogen cyanide with 25 ml of toluene and pour 5 ml of this solution into two flasks. After about 5 minutes, 3-phenoxybenzaldehyde (POAL) Q, 87D was added to the two flasks. Flask, reed, 1 in oil bath 3
At 5°C, flask boil 2 was stirred in a water bath at 24-26°C. The results of this experiment are shown in Table 1. Example 11 Preparation of S-α-cyano-3-phenoxybenzyl alcohol. Cyclo(D-phenylalanyl-D-histidine) 0.
0099m/# to 3-phenoxybenzaldehyde 0.
99 m1k (j, followed by hydrogen cyanide 22 m/kL
The reaction was carried out in contact with J.j. and 190 PPm of water. The reaction was carried out in toluene at 25°C. aldehyde 9
The product obtained at 3% conversion was 88% S-α-cyano-3-phenoxybenzyl alcohol isomer. Example 12 Preparation of S-α-cyano-3-phenoxybenzyl alcohol. To 0.29339 cyclo(D-phenylalanyl-D-histidine) and 15 m/l of diethyl ether at 25°C were added 2.90711 l of 3-phenoxybenzaldehyde followed by 0.940 f of hydrogen cyanide. 94% after 2 hours
of 3-phenoxybenzaldehyde was converted and the product was S-α-cyano-3-phenoxybenzyl alcohol with 84% enantiomeric excess. After 4-20 hours, 99
．． 4% of 3-phenoxybenzaldehyde was converted and the product was S-σ-cyano 3-phenoxybenzyl alcohol with 67-68% enantiomeric excess. Example 13 Preparation of S-α-cyano-3-phenoxybenzyl alcohol. Cyclo(D-phenylalanyl-D-histidine) 0.
0200 g was treated with 1.4037 g of 3-phenoxybenzaldehyde at 25° C. under a nitrogen stream to disperse the catalyst, and then treated with 13.65% hydrogen cyanide-containing toluene solution 2.
．． The reaction was carried out by injecting and working up 1812 g. After 2.7 hours, 93% of the 3-phenoxybenzaldehyde had been converted and the product was 5-phenoxybenzaldehyde in 77% enantiomeric excess.
Attach with a-cyano-3-phenoxybenzyl alcohol. Example 14 Preparation of S-α-cyano-3-phenoxybenzyl alcohol. cyclo(1)-phenylalanyl-D-histidine)0
．． 05199 and diethyl ether) and 9.32 rl
3-phenoxybenzaldehyde to 1. s i i
y and subsequently with 0.617 fj of hydrogen cyanide to carry out the reaction at 25°C. 3.6 hours later, 9
9.4% of 3-phenoxybenzaldehyde was converted,
The product was S-α-cyano-3-phenoxybenzyl alcohol with 72% enantiomeric excess. Example 15 Preparation of S-α-cyano-3-phenoxybenzyl S-isopropyl (4-chlorophenyl) acetate. S-α-cyano-3-phenoxybenzyl alcohol 0.134M in two 1-dram vials containing toluene solution
1 m-1 of a solution of
4 m/ was charged. 0.07 ml'i of 2,6-lutidine in the first vial
::'&Added to ■. The reaction mixture warmed quickly and a solid precipitated. Stirring was continued for 10 minutes, but there was no change. The mixture was washed successively with water, -) dihydrochloric acid, water and dried over MgS04. The oil produced is 75
．． 5% S-α-cyano-3-phenoxybenzyl S-
Contained isopropyl (4-chlorophenyl) acetate isomer. 0.083 m/triethylamine was added to the second vial with stirring. The reaction occurred immediately and the product was recovered as above and 72.0% of S-α-cyano-3-phenoxybenzyl S-isopropyl(4-chlorophenyl)
Acetate isomer obtained. Example 16 Preparation of S-α-cyano-3-phenoxybenzyl (1, cis)-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylate. (1 to cis)-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylic acid 1 g of methylene chloride 25 tyl! To the solution, 0.5 g of thionyl chloride,
A few drops of dimethylformamide were then added. The reaction mixture was refluxed overnight and the solvent was removed under pressure at 40°C. The residue was dissolved in 20 ml of benzene and mixed with a solution of 0.4 g of S-α-cyano-3-phenoxybenzyl alcohol (90% S-isomer enantiomeric excess) in 2 ml of benzene, followed by 0.5 ml of pyridine in 2 ml of benzene. liquid was added. The reaction mixture was stirred for 5 hours. The reaction mixture was poured into water, extracted with ether, and the ether layer was washed with dilute hydrochloric acid and then with hydrogen carbonate bath solution. The organic layer was washed with water, dried over M g S 04 and concentrated to give a yellow oil. This was chromatographed to obtain 0.53 g of the desired product. [α] 0
:26.55°(0,558f/me, solvent: CH2C
e2). Example 17 Preparation of S-α-cyano-3-phenoxybenzyl S-isopropyl (4-chlorophenyl) acetate. To a 1 dram vial was added 1 ml of α-cyano-3-phenoxybenzyl alcohol solution with an R/S ratio of approximately 72/28 and 0.121/ml of (4-chlorophenyl)isopropyl ketene. Next, cyclo(D-phenylalanyl-D-histidine) was added. The reaction mixture was stirred for 20 hours at room temperature to obtain a colorless product liquid containing white insoluble mass. Centrifuge the reaction mixture to remove the undissolved gel mass.
Washed 4 times with ml hexane and centrifuged. The organic extract was washed with dilute hydrochloric acid and water, dried, concentrated to 1y6 or less,
Diluted to 2 ml with toluene. The desired product was determined by Pircle column analysis to be 63% S-α-cyano-3-phenoxybenzyl S-isopropyl (4-chlorophenyl) acetate and 15% (7) R-α-cyano-3-
It contained monoisopropyl (4-chlorophenyl) acetate in phenoxybenzyl. Example 19 Preparation of S-α-cyano-3-phenoxybenzyl S-isopropyl (4-chlorophenyl) acetate. The catalyst gel recovered from Example 18 above was mixed with hexa:/1.
It was washed with 5 ml and charged into a 1 dram bicelle. The S-α-cyano-3-phenoxybenzyl alcohol solution 11rLl and (41
0.121 ml of Improhyrketene (0 lophenyl) was charged. The reaction mixture was stirred for 16 h, then extracted 5 times with 1-hexane, the extracts were concentrated and diluted to 2 w with toluene for analysis. The desired product was determined to have 62.4% S-α-cyano-3 by Particle column analysis.
-phenoxybenzyl S-iso7'o-pyl (4-chlorophenyl) acetate and 14.1% of α-cyano-3-phenoxybenzyl-inpropyl (4-
10 lophenyl) acetate. Example 20 Preparation of S-α-cyano-3-phenoxybenzyl S-isopropyl (4-chlorophenyl) acetate. Magnetic stirring bar and cyclo(D-phenylalani/l/
-D-Histidine) 41'll! A 0.5 dram vial containing ' was filled with nitrogen and stoppered. Add 0.17 i of 3-phenoxybenzaldehyde to this ear. Subsequently, 0.04411 g of hydrogen cyanide was injected. After stirring for 5 minutes, 0.18 ml of (4-chlorophenyl)inpropylketene was added. After 2 days, the reaction mixture was diluted with toluene, washed with IN hydrochloric acid, water, dried over MgSO4, and filtered. A 1 ml solution of this in toluene was analyzed and found to be rich in the desired compound. Examples 21-103 0.6 Ml of 13.5% w/v racemic α-cyano-3-phenoxybenzyl alcohol in a vial
The toluene solution was charged followed by a 5% weight/volume excess of (4-chlorophenyl)isopropylketene and 4m% catalyst. The reaction mixture was stirred at 25° C. until the reaction was essentially complete or complete. Table 2 shows the major isomers produced when various catalysts are used. The symbols used here to represent catalysts are common in peptide chemistry, such as those in Schroeder and Rabke's "The Peptide", Volumes ■-X.
XVI page (1966). The isomers are 1 Aα-8-acid S-alcohol 1. Aβ=S-
Acid R-alcohol isomer, Bα= monoacid S-alcohol isomer, Bβ-R-acid monoalcohol isomer. By selecting various reaction conditions within the scope of this invention, the rate of reaction and the amount of major isomer can be varied. Of course, it is within the scope of the present invention to replace in Examples 21-109 with pure optically active ni- or S-α-cyano-3-phenoxybenzyl alcohol or mixtures in which it is highly enriched, and Increase the amount of isomeric product. EXAMPLE 10 Preparation of α-cyano-3-phenoxybenzyl α-isopropyl (4-chlorophenyl) acetate. A mixture of 2.311 i' of isopropyl (4-chlorophenyl) acetyl chloride was treated with 2.78 ml of anhydrous triethylamine in the same manner as in Examples 5-7 to obtain a solution of isopropyl (4-chlorophenyl) isopropyl ketone in 8 ml of toluene. . 3-phenoxybenzaldehyde 2.0012. A mixture of 8 m,e of toluene and 0.559 m of hydrogen cyanide was stirred under a nitrogen stream. Add 0.5 me of water to this cooling solution. Subsequently, 0.86 ml of concentrated hydrochloric acid was slowly added. The reaction mixture was stirred at room temperature for 10 minutes and concentrated hydrochloric acid was added dropwise. Separate the organic layer with a pipette and add 3 ml of toluene.
was added and passed through Mg50439. This p solution was added to the above ketone solution (containing triethyltriamine) cooled to -50°C. The reaction was warmed to room temperature, allowed to stand for 10 minutes, washed successively with water, 5% sodium carbonate solution, water, then dilute hydrochloric acid, placed in a column of silica gel, and washed with diethyl ether/toluene-36/'64.
It was eluted with The eluent was dried over MgS04 and the solvent was removed to yield 3.98 g of a brown oil. This is 65
% enantiomeric pair, S-α-cyano-3-phenoxybenzyl tech-improvir (4-chlorophenyl) acetate, k-α-cyano-3-phenoxybenzyl S-isopropyl (4-chlorophenyl) acetate and 35%
It had an enantiomeric pair of PR and SS. Example 111 α-cyano-3-phenoxybenzyl inpropyl (4
-Production of chlorophenyl) acetate. ■ 1 drum vial, 1 toluene solution of 0.6 mmol of α-cyano-3-phenoxybenzyl alcohol with isomer ratio R/S = 72/28 prepared in Example 9.
ml was added. To this was added 0.121 me of (4-chlorophenyl)isopropyl ketene followed by 0.0084 ml of triethylamine. The reaction mixture became warm and the reaction was complete within 1 minute. The mixture was washed with 1N HCl, water, dried over MgS04 and diluted to 2 ml with toluene. According to liquid chromatography analysis of a chiral Barkle column, S-α
-cyano-3-phenoxybenzyl and monoisopropyl (
4-chlorophenyl) acetate/R5 isomer/SS isomer/RR isomer-13,6/42.2/30.6/1
The isomer ratio was 3.6. Examples 112-121 Preparation of S-α-cyano-3-phenoxybenzyl isoprobyl (410 lophenyl) acetate. In the same manner as in Examples 110 and 111 above, equal amounts of the non-chiral tertiary amine, (4-chlorophenyl)inpropyl ketene and S-σ-cyano 3-phenoxybenzyl alcohol were reacted at 0°C. The results of this experiment are shown in Table 3. Here, the capital letters A and B indicate the absolute configuration of S or R, respectively, in the acid moiety of the ester product, and α indicates the absolute configuration of S in the alcohol moiety of the ester product. The same sample of α-cyano-3-phenoxybenzyl alcohol, approximately 86% S-isomer, was used in all reactions. By selecting various reaction conditions within the scope of this invention, the rate of reaction and the amount of major isomer can be varied. Of course, it is within the scope of the present invention to replace in Examples 110-121 with pure optically active ni- or S~-cyano-3-phenoxybenzyl alcohol or mixtures that are highly enriched with the same. Increase the amount of K or S isomer. Procedural Amendment (Chief) 1985, Section M7, Commissioner of the Patent Office, Mr. 1゜Indication of Case, 1982 Patent Application No. 220485 2, Name of Invention Process for Producing Optically Active Cyanomethyl Ester 3, Person Making Amendment Case and Relationship between Patent Applicant 4 and Agent 5 Date of amendment order: Voluntary 1, Sun 1 Stop V Kadoya: Separate rules. Claims 1. Substantially water-immiscible aprotic solvents and cyclo(
I) Optionally substituted S-α-cyano consisting of treating optionally substituted 3-phenoxybenzaldehyde with hydrogen cyanide feed in the presence of a dipeptide-phenylazonyl-D-histidine catalyst. −
A method for producing 3-phenoxybenzyl alcohol or a rich mixture thereof. 2. The method according to item 1, wherein the solvent is an aromatic Yl hydrocarbon, an ether, or a mixture thereof. 3. The method according to item 2, wherein the solvent is toluene, diethyl ether or a mixture thereof. 4. The method of claim 1, wherein from about 1 to about 3 moles of hydrogen cyanide are used per mole of optionally substituted 3-phenxybenzaldehyde. 5. The method according to item 1, wherein hydrogen cyanide is introduced simultaneously with or after the addition of the solvent and/or aldehyde, or the addition is carried out rapidly after the introduction of hydrogen cyanide. 6. The method according to item 1, wherein the aldehyde is 3-phenoxybenzaldehyde. 7. α-chiral (optically active) carboxylic acid halide or a reactive derivative thereof or an enriched mixture thereof is added to the first
Optically active S-α-cyano- produced by the method described in section
A process for producing an optically active cyanomethyl ester or a rich mixture thereof, comprising treatment with 3-phenoxybenzyl alcohol or a rich mixture thereof. 8. The method according to item 7, which is carried out using an acid halide in the presence of a solvent and a hydrogen halide acceptor. 9. The method according to item 7, which is carried out under phase transfer conditions. 10. The method according to item 7, wherein the acid halide is optionally substituted S-α-isopropylbenzene acetic acid chloride or optionally substituted chiral cyclopropanecarboxylic acid chloride. 11. A process for preparing cyanomethyl esters of α-chiral carboxylic acids, which comprises treating an unsymmetrical ketene with an α-hydroxynitrile or with an aldehyde or ketone and a source of cyanide ions. 12. The method according to item 511, which is carried out in the presence of a pro-active tertiary amine catalyst. 13. The method according to item 12, in which lithium is treated with optically active α-hydroxynitrile. 14. The method according to item 13, wherein the amine is an optically active histidine-containing peptide catalyst. 15. The method according to item 14, which is carried out in the presence of a non-hydroxyl solvent. 16. The method according to item 15, wherein the asymmetric ketene is treated with α-hydroxynitrile having an S configuration. 17. The catalyst is free N-H and free C0 of histidine.
Histidine or a histidine-containing polypeptide in which at least one of the OH groups is optionally changed into an amide or its acid addition salt and ester group, respectively, with a cleaving group, or about 1 mole or more of ketene and histidine or 17. The method of claim 16, wherein the reaction product is 1 mole of histidine-containing di- or polypeptide. 18. The method according to item 17, wherein the histidine moiety in the melting medium is 3-methinobi-histidine, 1-methyl-histidine, 1-ethyl-histidine, 1-propyl-histidine or 1-benzyl-histidine. 19. The method according to item 18, wherein the catalyst is a cyclic dipeptide containing a histidine moiety and an alanine moiety. The 2α catalyst is optically active, and histidine in free or hazy form, α-methyl-histidine, 1-methyl-histidine, 3-methyl-histidine, cyclo(histidyl-histidine), (benzyloxycarbonylalanyl) Histidine methyl ester, cyclo(alanyl-histidine), cyclo(β-phenylalanyl-histidine), cyclo(β-phenylalanyl-1-methyl-histidine), cyclo(β-phenylalanyl-3-methyl-histidine) ), histidine methyl ester hydrochloride,
histidine ethyl ester dihydrochloride, anserine, cyclo(paryl-histidine), glycyl-histidine, cyclo(phenyl-7ranyl-glycyl-histidine),
Cyclo(leucyl-histidine), cyclo(homophenylalanyl-histidine), cyclo(phenylalanyl-methylhistidine), N-α-(β-naphthoyl)histidine, histidyl-alanine, histidyl-phenylalaninamide hydrochloride, histidyl 18. The method according to claim 17, wherein the β-phenylalanine is selected from cyclo(histidyl-proline) or cyclo(glycyl-histidine) or ketones and their reaction products. 2.1. ct-hydroxynitrile has the formula [wherein Y is 0. A%D and E may be the same or different (respectively, a hydrogen atom, a halogen atom with an atomic number of 9 to 35 (inclusive), or each as desired with an atomic number of 9 to 3)
5 (inclusive) alkyl having 1 to 6 carbon atoms substituted with one or more halogen atoms or 7
f) Represents a lekoxy group] The method according to item 11, wherein the S-α-cyan alcohol is represented by the following formula. 22, s-α-cyano alcohol is S-α-cyano-
22. The method of claim 21, wherein the 3-phenoxybenzyl alcohol is 3-phenoxybenzyl alcohol. 23.5-α-cyanoalcohol, /7(5-α-cyano-4-fluoro-3-phenoxybenzylalcohol-/
lzalsol;is-α-nonano-3-4-fluoro7
The 21st M which is f-/xy)benzyl alcohol
According to the method described in 24, the optically active ester product or S-α-cyano-3-
18. The method of claim 17, wherein the phenoxybenzyl S-α-inpropyl-4-chlorophenylacetate or a rich mixture thereof. Drink-C20 = 0 [In the formula, loss is isopropyl or cyclopropyl R
2 is different from R1, and is an alkyl group having 1 to 6 carbon atoms, a pulkenyl group having 2 to 6 carbon atoms, and optionally halogen is bromine, chlorine or fluorine, and the alkyl group has 1 to 4 carbon atoms. Naphthyl group, phenyl group or (
12. The method according to item 11, wherein the benzyloxycarbonyl) phenyl 1-mino group is represented by 26, R1 of the asymmetric ketene is isopropyl and R2
However, when halogen or alkyl contains 1 to 4 carbon atoms, it is alkyl or haloalkyl! 18. The method according to item 17, wherein the phenyl group is para-substituted with . 27. The method according to item 11, wherein the asymmetric ketene is (4-chlorophenyl)isopropylketene. 28. The method of paragraph 11, wherein the ketene is produced by treating an acid hafide with a tertiary amine. 29, cyclo(
12. The method of claim 11 for producing an optically active α-hydroxynitrile by treating the corresponding aldehyde or ketone with a cyanide ion source in the presence of a D-phenyl-alanyl-〇-histidine) dipeptide catalyst. 30. A composition comprising a reaction product of about 1 to about 3 moles of ketene per mole of the nitrogen base-substituted amino acid and an optically active nitrogen base-substituted amino acid or its di- or polypeptide. 31. Histidine or histidine-containing polypeptide and histidine group 1 in which at least one histidine free N-H free C00) group is converted into an amide or its acid salt or ester group with a protecting group. About 1 mole per mole of the reaction product of ketene, G5
The composition according to item 30. 32, cyclo(alanyl-histidine, ) or cyclo(phenylalanyl-histidine) and about 1 mole of valve seal 1
32. The composition of claim 31, which is a reaction product of ketene. 33, Item 30 in which the unsymmetrical ketene is represented by the formula 薯误-(, = to = Q [wherein R1 represents inpropyl and 2 represents a phenyl group para-substituted with halogen, alkyl, haloalkoxy or haloalkyl] 34. The composition according to item 31, wherein 'r'tene is (4-chlorophenyl)inpropylketene. 35. An optically active nitrogen base-substituted amino acid or di- or polypeptide thereof and per mole of the nitrogen-substituted amino acid. Approximately 1
A catalyst composition comprising from to about 3 moles of a reaction product of ketene. 36, a histidine or histidine-containing dipeptide in which at least one free N-H group and a free C00H group of histidine are each converted into an amide or an acid addition salt or ester group thereof with a collusive group, and about 1 mole of the above dipeptide 36. Catalyst composition according to clause 35, which is a reaction product of asymmetric ketene in a proportion of 1 molar. ': 32 shots (! 110 group thin go ■

Claims (1)

[Claims] 1. A substantially water-immiscible aprotic solvent and a cyclo(
1) Optionally substituted S-α-cyano-3- consisting of treating an optionally substituted 3-phenoxybenzaldehyde with a source of hydrogen cyanide in the presence of a -phenyl77-D-histidine) dipeptide catalyst.
Process for producing phenoxybenzyl alcohol or rich mixtures thereof. 2. The method according to item 1, wherein the solvent is an aromatic hydrocarbon, an ether, or a mixture thereof. 3. The method according to item 2, wherein the solvent is toluene, diethyl ether or a mixture thereof. 4. The process of claim 1, wherein from about 1 to about 3 moles of hydrogen cyanide are used per mole of optionally substituted 3-phenoxybenzaldehyde. 5. The method according to item 1, wherein hydrogen cyanide is introduced simultaneously with or after the addition of the solvent and/or aldehyde, or the above addition is carried out rapidly after the introduction of hydrogen cyanide. 2. The method according to claim 1, wherein the 6-aldehyde is 3-phenoxybenzaldehyde. 7. α-chiral (optically active) carboxylic acid halide or a reactive derivative thereof or an enriched mixture thereof is added to the first
Optically active 5-α-cyano produced by the method described in section
A method for preparing optically active cyan methyl esters or rich mixtures thereof, comprising treatment with 3-phenoxybenzyl alcohol or rich mixtures thereof, using an acid halide in the presence of a solvent and a hydrogen halide acceptor. The method according to paragraph 7, which is carried out by 9. The method according to item 7, which is carried out under phase transfer conditions. 10. The method according to item 7, wherein the acid halide is optionally substituted S-α-inpropylbenzene acetic acid chloride or optionally substituted chiral cyclopropanecarboxylic acid chloride. 11. A process for the preparation of cyan methyl esters of α-chiral carboxylic acids, which comprises treating an unsymmetrical ketene with an α-hydroxynitrile or with an aldehyde or ketone and a source of cyanide ions. 12. The method according to item 11, which is carried out in the presence of an optically active tertiary amine catalyst. 13. The method according to item 12, wherein ketene is treated with optically active α-hydroxynitrile. 14. The method according to item 13, wherein the amine or optically active histidine-containing peptide catalyst is used. 15. The method according to item 14, which is carried out in the presence of a non-hydroxyl solvent. 16. The method of claim 15, wherein the 16-unsymmetric ketene is treated with α-hydroxyni)IJ having S configuration. 17, the catalyst is free N-I of histidine (and free C
histidine or a histidine-containing polypeptide in which at least one of the 00H groups is optionally changed with a protecting group into the form of an amide or its acid addition salt and ester group, respectively, or about 1 mole or more of ketene and histidine or histidine 17. The method of claim 16, wherein the reaction product is 1 mole of polypeptide containing di- or polypeptide. 18. The method according to item 17, wherein the histidine moiety in the catalyst is 3-methyl-histidine, 1-methyl-histidine, -ethyl-histidine, 1-propyl-histidine or 1-benzyl-histidine. 19.8 The method according to paragraph 18, wherein the medium is a cyclic dipeptide comprising a histidine moiety and an alanine moiety. 20. The catalyst is optically active, and histidine in free or captured form, α-methyl-histidine, 1-methyl-
histidine, 3-methyl-histidine, cyclo(histidyl-histidine), (benzyloxycarbonylalanyl)histidine methyl ester, cyclo(alanyl-
histidine), cyclo(β-phenylalanyl-histidine), cyclo(β-phenylalanyl-1-methyl-
histidine), cyclo(β-phenylalanyl-3-methyl-histidine), histidine methyl ester hydrochloride, histidine ethyl ester dihydrochloride, anserine, cyclo(valyl-histidine), glycyl-histidine,
Cyclo(phenyl-alanyl-glycyl-histidine)
, cyclo(leucyl-histidine), cyclo(homophenylalanyl-histidine), cyclo(phenylalanyl-methylhistidine), N-α-(β-naphthoyl)
Item 17 selected from histidine, histidyl-alanine, histidyl-phenylalaninamide hydrochloride, histidyl-β-phenylalanine, cyclo(histidyl-proline) or cyclo(glycyl-histidine) or ketones and reaction products thereof. The method described. 21, α-hydroxynitrile force, formula [wherein, Y is O, A, D and E may be the same or different, and each is a hydrogen atom, a halogen atom with an atomic number of 9 to 35 (including numbers at both ends), or Each represents an alkyl or alkoxy group having 1 to 6 carbon atoms optionally substituted with one or more halogen atoms having atomic numbers 9 to 35 (inclusive) S-α-cyan represented by 12. The method according to item 11, wherein the alcohol is alcohol. 22, S-α-cyanoalcohol is S-α-cyano-3
- Phenoxybenzyl alcohol. 23, S-α-cyano alcohol is S-α-cyano-4
-Fluoro-3-phenoxybenzyl alcohol or S-α-cyano-3-(4-fluorophenoxy)benzyl alcohol. 24, the optically active ester product is S-α-cyano-3-
18. The method of claim 17, wherein the phenoxybenzyl S-α-inpropyl-4-chlorophenylacetate or a rich mixture thereof. R2-C C=O [In the formula, Iυ is inpropyl or cyclopropyl,
R2 is different from 1 and has 1 to 6 carbon atoms.
/l/ 4 Jl/ group, an alkenyl group having 2 to 6 carbon atoms, each optionally containing one or more halogen, alkyl group, in which the halogen is bromine, chlorine or fluorine and the alkyl group has 1 to 4 carbon atoms. /lz, haloalkynohair alkoxy, naphthyl group substituted with haloalkoxy, phenyl group or (benzyloxycarbonyl)
12. The method according to item 11, wherein 26, 1 of the asymmetric ketene is isopropyl, R2
is a phenyl group substituted with halogen, alkyl or haloalkyltehara containing 1 to 4 carbon atoms. 27. The method according to item 19, wherein the asymmetric ketene is (4-chlorophenyl)inpropylketene. 28. The method of paragraph 11, wherein the ketene is prepared by treating an acid halide with a tertiary amine. 29 Cyclo(D
-Phenyl-alanyl-1]-histidine) dipeptide The method of claim 11 for producing an optically active α-hydroxynitrile by treating the corresponding aldehyde or ketone with a cyanide ion source in the presence of a dipeptide catalyst. 30. A composition comprising a reaction product of about 1 to about 3 moles of ketene per mole of the nitrogen base-substituted amino acid and an optically active nitrogen base-substituted amino acid or its di- or polypeptide. 31, histidine or histidine-containing di- or polypeptide in which at least one histidine free N-H and free C00H group is converted into an amide or its acid addition salt or ester group with a protecting group, respectively, and about 1 per mole of histidine group; The tertiary reaction product of moles of ketene
The composition according to item 0. 32, cyclo(alanyl-histidine) or cyclo(
32. The composition of claim 31, wherein the composition is the reaction product of phenylalanyl-histidine) and about 1 mole of an asymmetric ketene. 33. The composition according to item 30, wherein the asymmetric ketene is represented by the formula % % [wherein R1 represents inpropyl and R2 represents a phenyl group substituted with hala by halogen, alkyl, haloalkoxy or haloalkyl]. 34. The composition according to item 31, wherein the ketene is (4-chlorophenyl)inpropylketene. 35, optically active nitrogen base-substituted amino acid or its di- or polypeptide and about 1 mole of nitrogen-substituted amino acid
A catalyst composition comprising from to about 3 moles of a reaction product of ketene. 36. At least one free WIN-H and free C00II group of histidine is converted into an amide or an acid addition salt or ester group thereof with a protecting group, respectively. 36. A catalyst composition according to clause 35, which is a reaction product of a molar proportion of asymmetric ketene.