JPH0333151B2 - - Google Patents

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 cyanomethyl esters, and more particularly, to a method for producing cyanomethyl esters having chiral centers in both the acid and alcohol moieties, and methods for producing these products. A novel catalyst and optically active optionally substituted S-
The present invention relates to a method for producing an α-cyano-3-phenoxybenzyl alcohol intermediate (to the ester). PRIOR ART Stereoisomers of alpha-chiral carboxylic acid chiral cyanomethyl ester or the acid itself usually have different effects in biological systems. The corresponding chiral α
-Hydroxynitrile is not easily available;
Direct production of optically active cyanomethyl esters has not been straightforward in the past, as synthetic methods have yielded products at low to no concentrations. Even when optically active alpha-hydroxynitriles became available or relatively readily available, optically active acids were not readily available. Optically active acids have been obtained by classical resolution, but this is time consuming and cannot be carried out on a large scale. Optically active α-hydroxybenzene acetonitriles are known to those skilled in the art and are of interest both as such and as intermediates (eg to esters). Among the alcohol-derived pyrethroid esters, those with an (α-S)-α-hydroxy-nitrile moiety combined with the appropriate pyrethroid acid usually have the highest insecticidal activity. However, such (α-S)-α-hydroxy-
Since nitrile was usually produced by splitting,
In the past, it was not easy to obtain. The method of the present invention provides a method for producing chiral cyanomethyl esters of α-chiral carboxylic acids in high yields by direct synthesis, avoiding the cumbersome classical resolution of the corresponding optically active acids and alcohols. SUMMARY OF THE INVENTION The present invention provides optically active cyanomethyl esters of α-chiral (optically active) carboxylic acids (i.e. (alpha-chiral cyanomethyl ester) or a rich mixture thereof. The optically active cyanomethyl ester product has the formula [In the formula, R ¹ , R ² , R ³ and R ⁴ are substituents, *
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 are alkanes containing from 5 to 10 carbon atoms, such as n-pentane, n-hexane, n-heptane, n-octane, n-nonane, n-decane and their isomers. Alkane-rich petroleum fractions are also suitable, e.g. boiling ranges 40-65 °C, 60-80 °C or 80-80 °C at atmospheric pressure.
One example is gasoline at 110°C. Petroleum ethers are also suitable. Cyclohexane and methylcyclohexane are examples of useful cycloalkanes containing 6 to 8 carbon atoms. Aromatic hydrocarbon solvents may have from 6 to 10 carbon atoms and include, for example, benzene, toluene, o-, m- and p-xylene, 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, such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, trichloroethane, perchloroethane,
Chlorobenzene and 1,2- or 1,3-
Examples include dichlorobenzene. Ethers generally have 4 to 6 carbon atoms, such as diethyl ether, methyl-t-butyl ether and diisopropyl ether. As the solvent, aromatic solvents, especially toluene, are preferred. All unsymmetrical ketenes can be used (if they do not contain substituents that create other stable reaction products with alpha-hydroxynitrile). The asymmetric ketene is the formula [In the formula, R ¹ and R ² are different and each represents an alkyl, aralkyl, alkoxy, aryloxy, alkylthio, alkylsulfonyl, arylthio or arylsulfonyl group having 1 to 10 carbon atoms, or 3 to 7 carbon atoms. or R ² is an alkenyl or alkynyl group having 2 to 10 carbon atoms, or a naphthyl group, a phenyl group, in which one heteroatom is oxygen, sulfur, or nitrogen, and the remainder are carbon atoms. represents a 5- to 6-membered heterocyclic group or an acyl or alkyl group having up to 10 carbon atoms, or an amino group di-substituted with a phenyl group, or R ¹ and R ² are When they are combined via a carbon atom between them, they form an asymmetric cycloalkyl group having 4 to 7 carbon atoms in the ring and having 4 to 14 carbon atoms. R ¹ and R ² groups are optionally halogen atoms having an atomic number of 9 to 35, alkyl or haloalkyl having 1 to 4 carbon atoms, and 2 to 3 carbon atoms.
4 alkenyl or haloalkenyl, haloalkoxy or alkoxy having 1 to 4 carbon atoms, haloalkylthio or alkylthio having 1 to 4 carbon atoms, or one substituent of equivalent type and size having the same or more carbon atoms. or more may be substituted. One embodiment of the asymmetric ketene used in the method of the present invention is described in U.S. Pat. No. 4,062,968;
4137324 and 4199595, which produce pyrethroid esters containing esters with acid moieties. Examples of such ketenes include formula () in which R ¹ is isopropyl or cyclopropyl and R ² has 1 to 1 carbon atoms.
6 alkyl group, an alkenyl group having 2 to 6 carbon atoms, each optionally containing one or more halogens, alkyl groups, in which the halogen is bromine, chlorine or fluorine, and the alkyl group has 1 to 4 carbon atoms;
A naphthyl group, a phenyl group, or a (benzyloxycarbonyl)phenylamino group whose ring is substituted with haloalkyl, alkoxy, or haloalkoxy. Of particular interest as asymmetric ketene reactants, since the resulting esters usually have high insecticidal activity, are those of formula () in which R ¹ is isopropyl and R ²
is a phenyl group para-substituted by halogen, alkyl or haloalkoxy, where halogen is for example chlorine or fluorine and alkyl has 1 to 4 carbon atoms (eg methyl). For example, unsymmetrical ketenes include (4-chlorophenyl)-isopropylketene, (4-(difluoromethoxy)phenyl)isopropylketene and ((4-(trifluoromethyl)-3-chlorophenyl)(benzyloxycarbonyl)amino)isopropylketene. etc. All racemic or optically active α-hydroxynitriles can be used (if they do not contain unsymmetrical ketenes or substituents that create stable reaction products with the catalyst present). Preferably, the α-hydroxynitrile has the formula [wherein R ³ is an optionally substituted hydrocarbyl or heterocyclic group, R ⁴ is an optionally substituted hydrocarbyl group or a hydrogen atom, or R ³ and R ⁴ are as indicated by the dashed line] ,
They come together via the carbon atom to which they are bonded to form a carbocyclic group.] Symmetrical or asymmetrical, racemic or optically active α-hydroxynitrile. The hydrocarbyl group represented by R ³ and R ⁴ of the formula () may be, for example, an alkyl, cycloalkyl or aryl group of up to 20 carbon atoms, preferably up to 10 carbon atoms, or a hydrocarbyl group of the formula () R ³ may be a carbocyclic or O or S-heterocyclic aryl group. Examples of carbocyclic aryl groups are phenyl, 1-naphthyl, 2-naphthyl and 2-anthryl groups. Heteroaromatic groups are described in Kirk Othmer's Encyclopedia of Chemical Technology, Vol.
ed., Volume 2, page 702. This is O or S
703 of the above-mentioned document, including heterocyclic compounds which are five-membered rings exhibiting aromatic character obtained by replacing one or more carbon atoms of a carbocyclic aromatic compound by a heteroatom selected from stated on the page. 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; Includes one or more alkenyl or alkoxy groups, optionally substituted phenoxy, phenyl, benzyl or benzoyl, and equivalent groups. Examples of optically active α-hydroxynitriles include α-hydroxy-α-methylbutyronitrile, α-hydroxy-α-methylbenzeneacetonitrile, α-hydroxyisobutyronitrile, and the like. Preferably, the α-hydroxynitrile compound has the formula [In the formula, each A is the same or different, and is a hydrogen atom, a halogen atom with an atomic number of 9 to 35, and the number of carbon atoms optionally substituted with one or more halogen atoms with an atomic number of 9 to 35. 1-6
represents an alkyl, alkenyl or alkoxy group, and B is a hydrogen atom, a halogen atom having an atomic number of 9 to 35, and optionally a halogen atom having an atomic number of 9 to 35.
an alkyl, alkenyl or alkoxy group having 1 to 6 carbon atoms, or a group substituted with 5 or more halogen atoms [In the formula, Y is O, CH ₂ or C(O), 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, and each optionally an atom Number 9-35 1
represents an alkyl, alkenyl or alkoxy group having 1 to 6 carbon atoms substituted with one or more halogen atoms; Preferably, the α-hydroxynitrile is R-
or has the S-configuration and has the formula, [In the formula, Y is O, CH ₂ or C(O), A, D and E are the same or different, and a hydrogen atom,
R represents a halogen atom with an atomic number of 9 to 35, an alkyl, alkenyl or alkoxy group having 1 to 6 carbon atoms optionally substituted with one or more halogen atoms with an atomic number of 9 to 35] - or preferably S-α-hydroxynitrile. Preferably, Y represents O. 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. Preferably, one of D and E is a hydrogen atom. Particularly preferred types of S-α-hydroxynitrile are those of the above formula, where D is a hydrogen atom, A and E are the same or different, and are a fluorine atom or a hydrogen atom, and preferably,
If A or E is fluorine, it is located in the 4-position of the ring relative to the benzylic carbon in the case of A or to the carbon atom with Y=O 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. As an example of α-hydroxynitrile of the above formula,
S-α-cyano-3-phenoxybenzyl alcohol, S-α-cyano-4-fluoro-3-phenoxybenzyl alcohol, S-α-cyano-3
-(4-fluorophenoxy)benzyl alcohol and the corresponding enantiomer, and the like. The present invention provides a method for converting unsymmetrical ketenes into racemic or optically active α-hydroxynitriles (where hydroxy and nitrile substituted (both groups are bonded to the same carbon atom) to produce stereoisomerically enriched cyanomethyl esters. The optically active (chiral) tertiary amine catalyst is an optionally substituted alkyl having up to 40 carbon atoms,
A cycloalkyl, aromatic or heterocyclic mono- or polyamine (including polymers, copolymers, amine salts, etc.) that does not interfere with the reaction. The amine is preferably a medium to weakly basic amine. optically active amine,
The polymers and copolymers are of the conventional type known in the art and are made by known methods, with the exception of the novel ketene reaction products described below. For example, many optically active amines are
"Procedures for Chemical Compounds," Volume 1, "Amines and Related Compounds," Optical Resolution Information Center, Manhattan College Riverdale, New York;
Individually listed in Library of Congress Catalog Card Number 78-61452. This document also describes optically active mono-G and polyamines that 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 is a substituted optically active amino acid, preferably an acyclic amino acid having up to 20 carbon atoms, preferably up to 10 carbon atoms, substituted with a substituent of a medium to weakly basic nitrogen base, carbon cyclic amino acids, aromatic amino acids or heterocyclic amino acids, or the reaction products thereof with about 1 to about 3 moles of ketene. Suitable nitrogen base substituents each optionally contain 1 carbon atom.
-6 alkyl or cycloalkyl groups, or nitrogen heterocyclic groups or amino groups substituted with optionally substituted phenyl. Other optional substituents include hydroxy, alkyl,
Includes alkoxy, amino, alkylthio, phosphoryloxy and amido. Examples of nitrogen heterocyclic groups include thiazolyl, imidazolyl,
Includes pyrrolyl and benzopyrrolyl. Examples of optically active catalysts are β-aminoalanine, ornithine, canavanine, anserine, kynurenine, mimosine, cystathionine, efuedrin,
These include, but are not limited to, acylated ephedrin, histidinol, citrulline, carbamoylserine, cinchonine, quinine or acylated quinuclidinyl alcohol. Another embodiment of amine catalysts are heterocyclic amines and polymers of heterocyclic amines. An example is
di- and polyaziridines, polymers of acryloyl cinchonine alone or polymers of acryloyl cinchonine with N,N-diacryloylhexamethylene diamine, di- and poly(iminoisobutylethylene), acrylates or lower alkanoic acids with (N-benzyl-2 -pyrrolidinyl methyl ester) and the like, but are not limited to these. In other embodiments of the invention, the catalyst comprises free N-H of at least one histidine and free N-H of at least one histidine.
Optically active histidine-containing peptides, or histidine-containing di- or polypeptides, in which the COOH group has been optionally changed with a protecting group into an amide (or acid addition salt thereof) and an ester group, respectively, or ketene per mole of histidine group. Approximately 1
It is the reaction product of 1 mole of histidine or a histidine-containing di- or polypeptide. A di- or polypeptide can 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 di- and polypeptides, are described, for example, in Greenstein and Winitz, Chemistry of the
Amino Acids, John Willey & Sons, Inc., New York, 1961
It is produced by the known peptide synthesis method described in 2010. Dipeptides, especially cyclic dipeptide forms of histidine-containing catalysts are preferred. Di- or polypeptides containing alanine and di- or polypeptides produced using alanine, feralanine or alanine derivatives are preferred. In one embodiment of the invention, the asymmetric carbon atom in the histidine-containing peptide is catalytic in the D-configuration, although the L-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 amic acid catalyst may include protecting groups, and any conventional amic 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 COOH. 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. Although all amino acids may be used, preferably the amino acids are non-heterocyclic, mono- or diamino alkanoic 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. , suitable for forming salts. When producing a di- or polypeptide catalyst having alanine (including the moiety), it is produced from alanine or a derivative thereof, which derivative is
These include alanine, β-aminoalanine, β-phenylalanine, 3,4-dihydroxyphenylalanine, and the like. Histidine (including moieties)
Histidine, 3-methylhistidine, 1-methylhistidine, 1-ethylhistidine, 1-propylhistidine or 1
-benzylhistidine and the like are preferred. The catalyst is
Cyclic dipeptides containing a histidine moiety and an alanine moiety are preferred. Peptide adducts (reaction products) with ketene are novel and constitute another part of the invention. The adduct contains about 1 to 3 moles of ketene per mole of peptide;
Preferably it is prepared to contain about 2 moles of ketene per mole of (cyclic) dipeptide, especially about 1 mole. 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, 1-methyl-histidine, 3-methylhistidine, cyclo(histidine-histidine), (benzyloxycarbonylalanyl), in free or protected form. Histidine methyl ester, cyclo(alanyl-histidine), dichloro(β-phenylalanyl-histidine), histidine methyl ester hydrochloride, histidine ethyl ester dihydrochloride, anserine,
Cyclo(valyl-histidine), glycyl-histidine, cyclo(phenylalanyl-glycyl-
histidine), cyclo(leucyl-histidine),
cyclo(homophenylalanyl-histidine),
cyclo(phenylalanyl-methylhistidine),
N-α-(β-naphthoyl)histidine, histidyl-alanine, histidyl-phenylalanamide hydrochloride, histidyl-phenylalanine, cyclo(histidyl-proline), cyclo(glycyl-histidine) or these substances and ketene ( (4-chlorophenyl)isopropylketene)
including, but not limited to, reaction products with (4-(difluoromethoxy)phenyl)isopropylketene and cyclo(β-phenylalanyl-histidine) adduct, dimethylketene and histidine adduct, (4-(difluoromethoxy)phenyl)isopropylketene and cyclo(glycyl-histidine) It also includes adducts of dimethylketene and histidyl-alanine. In one type of the invention, the peptide catalyst has the formula [wherein,

Each of the n units of the formula is identically or differently substituted, where Y is hydrogen, acyl, alkyl or arylalkyl of up to 10 carbon atoms, Z is benzyl, 3-carboxypropyl, Represents common amino acid residues that do not interfere with the reaction of the present invention, including 3-amino-propyl, mercaptomethyl, 4-hydroxybenzyl, imidazol-4-ylmethyl, where each m is 0
or 1, n represents 2 to 16, and both m are 0
In this case, 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. When the peptide catalyst is in the presence of a solvent (e.g. water),
If produced by conventional methods, the catalyst may contain a crystallization solvent (eg, water) if solid. Catalysts of the invention of optically active nitrogen-based amino acids (eg, histidine-containing peptides), when solid, include those in the presence or absence of a crystallizing solvent (eg, water). Non-chiral tertiary amine catalysts have a carbon atom count of ca.
Up to 40 optionally substituted alkyl, cycloalkyl, aromatic or heterocyclic tertiary amines (including polymers, copolymers, amine salts) that do not interfere with the reaction. As the amine, one with medium to strong basicity is used. Non-chiral tertiary amines, polymers and copolymers 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-luzidine, triethylamine, trimethylamine,
N,N-dimethylaniline, diisopropylethylamine and 1,4-diazabicyclo[2,
2,2] Octane, etc. 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 method of the invention optionally comprises a previously defined non-chiral or chiral (optically active)
It consists of treating said ketene with an aldehyde or ketone and a source of cyanide ions in the presence of a catalyst. The reaction is preferably carried out in a non-hydroxyl solvent of the type described above. Any aldehyde or ketone (carbonyl compound) may be used, provided it does not contain substituents that form cyanide ions or other stable reaction products with the catalyst. Preferably, the aldehyde or ketone has the formula [In the formula, R ³ represents an optionally substituted hydrocarbyl or heterocyclic group, R ⁴ represents an optionally substituted hydrocarbyl group or a hydrogen atom, or R ³ and R ⁴ represent the carbon atom to which they are bonded. together to form a carbocyclic group. ] It is indicated by. The hydrocarbyl group represented by R ³ and R ⁴ in formula () may be, for example, an alkyl, cycloalkyl or aryl group having up to 20 carbon atoms, preferably up to 10 carbon atoms, and R ³ in formula () is a carbocyclic group. may be a heterocyclic aryl group of the formula O or S. Examples of carbocyclic aryl groups are phenyl,
1-naphthyl, 2-naphthyl and 2-anthryl groups. Heteroaromatic groups are described in Kirk Othmer's Encyclopedia of Chemicals.
2nd Edition, Volume 2 (1963), page 702. It includes heterocyclic compounds having a five-membered ring, obtained by replacing one or more carbon atoms of a carbocyclic aromatic compound by a heteroatom selected from O or S, and exhibiting aromatic character;
It is described on page 703 of the aforementioned document. Such aldehyde and ketone compounds are described in US Pat. No. 4,132,728. Optional substituents include one or more halogen atoms having an atomic number of 9 to 35, or alkyls, alkenyls having 1 to 6 carbon atoms, each optionally substituted with one or more halogen atoms;
Alkoxy groups include optionally substituted phenoxy, phenyl, benzyl, benzoyl or equivalent types of substituents. Preferably, the aromatic aldehyde has the formula [In the formula, each A is the same or different, and is a hydrogen atom, a halogen atom with an atomic number of 9 to 35, and the number of carbon atoms optionally substituted with one or more halogen atoms with an atomic number of 9 to 35. 1-6
represents an alkyl, alkenyl or alkoxy group, and B is a hydrogen atom, a halogen atom having an atomic number of 9 to 35, and optionally a halogen atom having an atomic number of 9 to 35.
an alkyl, alkenyl or alkoxy group having 1 to 6 carbon atoms, or a group optionally substituted with 5 or more halogen atoms [In the formula, Y is O, CH ₂ or C(O), 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 Number 9-35 1
represents an alkyl, alkenyl or alkoxy group having 1 to 6 carbon atoms substituted with 1 or more halogen atoms] is used. Preferably, the aldehyde corresponds to an α-hydroxynitrile as defined above, thus having the formula [In the formula, A, D, E and Y represent the same meanings as in the above formula]. Examples of suitable aldehydes of the above formula are 3-phenoxybenzaldehyde, 4-fluoro-3-phenoxybenzaldehyde, and the like. The cyanide ion source is hydrogen cyanide or
It is a reagent that produces hydrogen cyanide under reaction conditions, such as α-hydroxynitrile and cyanohydrin. The molar ratio of hydrogen cyanide per mole of aldehyde or ketone is from about 1.0 to about 3.0, preferably about
1.1 to about 2.0. The preparation 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, mixing the mixture, e.g. by stirring, and producing the optically active ester. This is done by maintaining the reaction conditions for a time to achieve the formation of . 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 be from about 1 to about 100%, preferably from about 1 to about 10 mol%, 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 mole %, preferably about 0.1 to about 5 mole %, especially about 1.5 mole %, based on the weight of alpha-hydroxynitrile, aldehyde or ketone present. It is used in a range of about 5 mol%. 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 1:
5, preferably about 2:1 to about 1:2. However, it is desirable to use from about 1:1.1 to about 1:1.5 molar excess of ketone to alpha-hydroxynitrile, aldehyde or ketone. Reaction temperatures for producing cyanomethyl esters can vary, as can pressure. At normal pressure,
The temperature is around -10 to about 50°C. Approximately 0 to approximately 35
Room temperature of 0.degree. C. is convenient, especially from about 0 to about 15.degree. α-Hydroxynitriles and the corresponding aldehydes or ketones are generally known in the literature. U.S. Patent Nos. 3,649,457 and 4,273,727
No., Ok et al., Journal of Chemical Society, Chemical Communication, 229
~230 pages, and Betzker et al., Journal
of the American Chemical Society, Vol. 88, pp. 4299-4300, these are directly synthesized chemically, often enzymatically, and in the case of optically active α-hydroxynitrile, the divided in a manner known in the art. Optically active optionally substituted S-α-cyano-3-phenoxybenzyl alcohols can also be synthesized by cyclo(D
-phenyl-alanyl-D-histidine) dipeptide by treating the corresponding aldehyde or ketone with hydrogen cyanide in the presence of a catalyst. Such optionally substituted S-α-
Also included in this invention is a method for producing cyano-3-phenoxybenzyl alcohol. The catalyst is prepared by known peptide synthesis as described, for example, in Greenstein and Winitz, Chemistry of Diamine Assemblies, John Wiley and Sons, Inc., 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% by volume. For example, the solvent is a hydrocarbon or ether solvent containing aliphatic, cycloaliphatic or aromatic materials. 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-heptane, n-octane, n-nonane,
Alkanes having 5 to 10 carbon atoms, such as n-decane and their isomers. Petroleum fractions rich in alkanes are also suitable (e.g. 40 to 65
℃, gasoline with a boiling point range of 60-80℃ or 80-110℃). Petroleum ethers are also suitable. Cyclohexane and methylcyclohexane are examples of useful cycloalkanes containing 6 to 8 carbon atoms. Aromatic hydrocarbon solvents have 6 to 10 carbon atoms (e.g. benzene, toluene, o-, m-, p-
-xylene, trimethylbenzene and p-ethyltoluene). Useful ethers include diethyl ether, diisopropyl ether, methyl-t-butyl ether, and the like. Preferably,
The solvent is an aromatic hydrocarbon, especially toluene, diisopropyl ether or dimethyl ether or mixtures thereof (for example 25/75 diethyl ether/toluene). The reaction for producing optically active S-α-cyano-3-phenoxybenzyl alcohol involves cyclo(D-
(phenylalanyl-D-histidine) catalyst, add aldehyde and solvent and disperse (mixture
Grind mechanically or mix, for example by stirring. ), adding hydrogen cyanide and maintaining reaction conditions for a time to achieve the formation of optically active α-hydroxynitrile. That is, preferably,
Hydrogen cyanide can be added simultaneously with or after the solvent and/or aldehyde, or can be added 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°C to about 80°C. Preferably, a room temperature of about 5 to about 35°C is convenient, giving good yields, good reaction rates, and good enantiomeric excess of the desired optically active product; temperatures below 5°C give good results. give. Optically active α-hydroxynitrile (e.g. S
The amount of catalyst used to produce -α-hydroxynitrile) can vary. For example, the catalyst is
Based on the weight of aldehyde present, from about 0.1 to
It is used in a range of about 10 mol%, preferably about 0.1 to about 5 mol%, especially about 1.5 to about 7.5 mol%. Preferably, the catalyst is well dispersed in the reaction mixture. When the catalyst is prepared by conventional methods in the presence of a solvent (eg, water), the catalyst, if solid, may contain a crystallization solvent (eg, water). As described above, when the optically active cyclo(D-phenylalanyl-D-histidine) dipeptide catalyst of the present invention is solid,
Includes the presence or absence of a crystallizing solvent (eg, water). Asymmetric ketenes used to make cyanomethyl esters are generally known in the art. The ketene used in the present invention is produced by treating the corresponding acid halide with a tertiary amine. Suitable tertiary amines include alkyl, aryl or heterocyclic tertiary nitrogen bases including mono- or polyamines and the like. Preferably, the tertiary amine is an amine having any alkyl group of 1 to 10 carbon atoms, any aryl or arylalkyl group of 6 to 20 carbon atoms and 1 to 2 hydrocarbyl rings, and optionally sulfur. ,
Any heterocyclic amine containing at least one ring nitrogen atom in a 5- or 6-membered heterocyclic ring containing oxygen or a further nitrogen atom, including trimethylamine, triethylamici, tri-n-propylamine and pyridine. It will be done. Preferably, the tertiary amine is one containing 3 alkyl groups of 1 to 4 carbon atoms, such as trimethylamine, tri-n-propylamine, and especially triethylamine or trimethylamine. Reactions to produce asymmetric ketenes are carried out in the presence or absence of a solvent. When using a solvent,
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-
Alkanes having 5 to 10 carbon atoms such as hexane, n-heptane, n-octane, n-nonane, n-decane and their isomers. Petroleum fractions rich in alkanes, e.g., at atmospheric pressure, 40-65 °C,
Gasoline with a boiling range of 60-80°C or 80-110°C are also suitable. Petroleum ethers are also suitable. Cyclohexane and methylcyclohexane are examples of useful cycloalkanes containing 6 to 8 carbon atoms. Aromatic hydrocarbon solvents include those having 6 to 10 carbon atoms, such as benzene, toluene, o-, m-
and p-xylene, trimethylbenzene and p-ethyltoluene. Suitable chlorinated hydrocarbons include C1-4 alkane chains or benzene rings to which 1-4 chlorine atoms are attached, 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 t-butyl ether and diisopropyl 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 about 10:1 to about 1:10, preferably about 5:1 to about 1:5. However, it is desirable to use a 1 molar excess of base to acid halide. Thus, the molar ratio of acid halide to base is conveniently from about 1:1.2 to about 1:2,
The ratio is preferably about 1:1 to about 1:5. In the production of asymmetric ketenes, temperatures can vary widely. For example, at normal pressure, the reaction temperature is about 75~
Although 95°C has been found to be very useful, e.g.
It can change around 40℃. 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 has the formula [In the formula, X is a halogen atom such as chlorine or bromine, R ¹ and R ² are the same or different,
A carbon atom that represents an alkyl, aralkyl, alkoxy, aryloxy, alkylthio, alkylsulfonyl, arylthio, arylsulfonyl group having 1 to 10 carbon atoms, or a cycloalkyl group having 3 to 7 ring carbon atoms, or to which they are bonded. When taken together via a ring, an asymmetric cycloalkyl group having 3 to 7 ring atoms is formed, and R ² is an alkenyl or alkynyl group having 2 to 10 carbon atoms, a naphthyl group, a phenyl group, a ring atom group. Heterocyclic groups containing 5 or 6 ring atoms, one of which is oxygen, sulfur or nitrogen and the remainder carbon atoms, or di-substituted with acyl, alkyl or phenyl groups of up to 10 carbon atoms represents an amino group] The R ¹ and R ² groups 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. , a haloalkoxy or alkoxy group having 1 to 4 carbon atoms, a haloalkylthio or alkylthio group having 1 to 4 carbon atoms, or an equivalent type of substituent. One type of acid halides are pyrethroid acid halides, including those described in US Pat. Examples of such acid halides include, in formula (), R ¹ is isopropyl or cyclopropyl, R ² is an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 2 to 6 carbon atoms;
alkenyl group of 6, optionally halogen is bromine,
one or more halogens which are chlorine or fluorine and whose alkyl group has 1 to 4 carbon atoms;
Includes naphthyl, phenyl, or (benzyloxycarbonyl)phenylamino groups ring-substituted by alkyl, haloalkyl, alkoxy, or haloalkoxy. For example, acid halides include isopropyl (4-chlorophenyl) acetyl chloride, isopropyl (4-(difluoromethoxy) phenyl) acetyl chloride, isopropyl ((4-(trifluoromethyl)-3-chlorophenyl) (benzyloxycarbonyl) aminoacetyl chloride, etc. Preferably, in formula (), R ¹ is isopropyl, and R ² is preferably halogen at the para position, optionally alkyl having 1 to 4 carbon atoms,
Particularly useful are phenyl groups substituted with haloalkyl, alkoxy, haloalkoxy groups, such as 4-chlorophenyl, 4-(difluoromethoxyphenyl), 4-methylphenyl or 4-t-butylphenyl. A number of asymmetric ketones of the present invention are known, such as (4-chlorophenyl)isopropyl ketone in US Pat. No. 4,199,527. Some other unsymmetrical ketenes may be generally known, but of special kinds, e.g.
(4-(difluoromethoxy)phenyl)isopropylketone is new. Another aspect of the invention is to provide alpha chiral (optically active) carboxylic acid halides, reactive derivatives thereof, or mixtures enriched therein, prepared as described above.
A process for producing optically active cyanoethyl esters or mixtures enriched therein comprising treatment with an optically active optionally substituted S-α-cyano-3-phenoxybenzyl alcohol or an enriched 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 may 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 usually involve the addition of a hydrogen halide acceptor, preferably a tertiary amine such as triethylamine or pyridine, which is added slowly under stirring after the other reactants are well mixed. done in the presence of The reaction to produce optically active cyanomethyl esters from S-alcohols and α-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. The process 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 A elements of the Periodic Table of the Elements (eg, nitrogen, phosphorus, arsenic, antimony, and bismuth). Preferred phase transfer catalysts are tetra-n-butylphosphonium chloride, tri-n-butyl-n
-Octylphosphonium bromide, hexadecyltributylphosphonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, trioctylethylammonium bromide, tetraheptylammonium iodide, triphenyldecylphosphonium iodide, tribenzyldecyl ammonium chloride, tetranonylammonium hydroxide side, tricaprylylmethylammonium chloride, and dimethyldicocoammonium chloride. The last two are manufactured by General Mills Company, Chemical Division, Kankakee, I11, and are named "Aliquot 336(R)" and "Aliquot 221(R)," respectively. 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 about 10:1 to about 1:10, preferably about 5:1 to about 1:5. However, it is desirable to use a 1 molar excess of acid halide to alcohol. Accordingly, 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 1:1.2. In the production of esters, temperatures can vary widely. At normal pressure, the reaction temperature is, for example, about 0 to about 70
The temperature may vary, but is preferably around 10 to 40°C. 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, alicyclic,
including aromatic or heteroaromatic acids and their reactive derivatives, preferably having the formula [ ^{wherein ,}
represents an alkoxy, aryloxy, alkylthio, alkylsulfonyl, arylthio, arylsulfonyl group, a cycloalkyl group having 3 to 7 carbon atoms in the ring, or when they are taken together via a carbon atom to which they are bonded, the carbon atoms in the ring Number of atoms: 3~
7 to form an asymmetric cycloalkyl group, and also R ²
is an alkenyl or alkynyl group having 2 to 10 carbon atoms, a naphthyl group, a phenyl group, a 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 an amino group di-substituted with an acyl, alkyl, or phenyl group having up to 10 carbon atoms]. The R ¹ and R ² groups optionally have an atomic number of 9 to 35
one or more halogens of 7 carbon atoms
an alkyl, haloalkyl or cycloalkyl group, an alkenyl or haloalkenyl group having 2 to 4 carbon atoms, a haloalkoxy or alkoxy group having 1 to 4 carbon atoms, a haloalkylthio or alkylthio group having 1 to 4 carbon atoms, or May be substituted with equivalent types of substituents. As the reactive derivative, a halide, that is, chlorine or bromine in the above formula () is preferred. One type of acid halide is described in U.S. Pat.
No. 3835176, No. 4243819, No. 4316913 and No.
Pyrethroid acid halides including those described in No. 4199595. Examples of such acid halides or reactive derivatives thereof include, in formula (),
R ¹ is isopropyl or cyclopropyl;
R ² is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, each of which is optionally halogen is bromine, chlorine or fluorine, and the alkyl group is 1 to 4 carbon atoms. or a naphthyl group, phenyl group or (benzyloxycarbonyl)phenylamino group ring-substituted by more than one halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or the carbon atom to which R ¹ and R ² are bonded. R ¹ and R ² come together through the formula [In the formula, W, X, Y and Z are the same or different and each represents a hydrogen atom, a halogen atom with an atomic number of 9 to 35, or an alkyl group having 1 to 4 carbon atoms, or Y and Z are the same or different, each an alkyl group having 1 to 4 carbon atoms, W is a hydrogen atom, 2,2-trihaloethyl 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-trifluoromethyl-3-chlorophenyl) (benzyloxycarbonyl) amino) acetyl chloride. ,
2,2-dimethyl-3-(2,2-chlorovinyl)cyclopropanecarbonyl chloride, 2,
2-dimethyl-3-(2,2-dibromovinyl)
Cyclopropane carbonyl chloride, 2,2-
Dimethyl-3-(1,2-dibromo-2,2-dichloroethyl)cyclopropanecarbonyl chloride, 1-(4-ethoxyphenyl)-2,2-dichlorocyclopropanecarbonyl chloride,
2,2-dimethyl-3-(2-(trifluoromethyl)-2-chlorovinyl)cyclopropanecarbonyl chloride, 2,2-dimethyl-3-((isobutoxyimino)methyl)cyclopropanecarbonyl chloride, 2, 2-dimethyl-3-((neopentoxyimino)methyl)cyclopropanecarbonyl chloride, 2,2-dimethyl-3-
(((cyclobutyl)methoxyimino)methyl)cyclopropanecarbonyl chloride or chrysanthemyl chloride, etc. Preferably, in formula (), R ¹ is isopropyl, and R ² is preferably a para-position optionally halogen, alkyl having 1 to 4 carbon atoms,
Particularly useful are phenyl groups substituted with haloalkyl, alkoxy, haloalkoxy groups, such as 4-chlorophenyl, 4-(difluoromethoxyphenyl), 4-methylphenyl or 4-t-butylphenyl. In one embodiment of the invention, S-α-cyano-3-phenoxybenzyl alcohol or an enriched mixture thereof is combined with S-α-isopropylphenyl acetic acid chloride or an optionally substituted chiral cyclopropanecarboxylic acid chloride. Processing yields optically active cyanomethyl esters or rich mixtures thereof. The cyanomethyl ester, the optically active form of which is prepared by one or more embodiments of the process of the invention, i.e. is indicated by Francis et al.
Of Chemical Society Volume 95 1403-1409
(1909), and are commonly known in the art, such as U.S. Pat.
4328167, 4133826 and British Patent No.
It is known as the optical type, such as in No. 2014137. All of the alpha-cyanomethyl esters produced can be hydrolyzed to the corresponding acids by conventional hydrolysis methods known in the art. Preferably, the optically active ester of the product is S-α-cyano-3-phenoxybenzyl S-α-isopropyl (p-chlorophenyl) acetate, S-α-cyano-3-
Phenoxybenzyl S-α-isopropyl (p-
(difluoromethoxy)phenyl)acetate,
S-α-cyano-3-phenoxybenzyl (1R,
cis)-3-(2,2-dichlorovinyl)-2,2
-dimethylcyclopropane carboxylate, S
-α-cyano-3-phenoxybenzyl (1R,
cis)-3-(2,2-dibromovinyl)-2,2
-dimethylcyclopropane carboxylate, S
-α-cyano-3-phenoxybenzyl (1R,
cis)-3-(1,2-dibromo-2,2-dichloroethyl)-2,2-dimethylcyclopropanecarboxylate, S-α-cyano-3-phenoxybenzyl (1R, cis)-2, 2-dimethyl-3
-(neopentoxyiminomethyl)cyclopropanecarbosylate, etc. The present invention will be explained in more detail below with reference to Examples. Example 1 Production of N-(benzyloxycarbonyl)-D-phenylalanine. A 15.0 g sample of D-phenylalanine was dissolved in 45 ml of an aqueous solution containing 7.26 g of 50% sodium hydroxide. This solution was stirred at 0-10°C, and 16.3 g of benzyl chloroformate was quickly added in several portions. The reaction was mildly exothermic and a solid precipitated immediately after the addition. 45ml water and
An additional 3.63 g of 50% sodium hydroxide was added to redissolve most of the solids. The reaction mixture was stirred for 20 minutes and then acidified with 6N hydrochloric acid. The solid that forms is filtered, washed with water and then with hexane,
After suction and further vacuum drying, 47 g of a white solid was obtained. The solid was dissolved in ether, washed twice with 1N hydrochloric acid and then water, dried over MgSO ₄ and incubated at 35°C.
The solvent was removed at 2.5 mm Hg to yield 27.7 g of the desired product as a colorless oil. Example 2 Preparation of N-(benzyloxycarbonyl)-D-phenylalanine p-nitrophenyl ester. In a 300 ml three-necked flask equipped with a stirrer and addition funnel, add 135 ml of pyridine and the acid from Example 1 above.
27 g was charged under a nitrogen stream, and then 13.2 g of p-nitrophenol was added. The reaction solution was cooled to 0-10°C, and 14.6g of phosphorus oxychloride was added. The reaction mixture was warmed to 25 °C, stirred for 15 min, then poured with cold water.
Pour into 300ml. The resulting solid was filtered, washed with water, and dried under reduced pressure to obtain 33 g of product. Crystallization was achieved 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 yield 28.7 g of the desired product. Melting point: 122.5-124.5℃ [α]
^23D : +24.7 (C=2.0 _, solvent: dimethylformamide). Example 3 Preparation of N-(benzyloxycarbonyl)-D-phenylalanyl-D-histidine methyl ester. Add triethylamine to 5.0 g of D-histidine methyl ester and 40 ml of methylene chloride with stirring.
4.18 g and an additional 8.27 g of the nitrophenyl ester prepared in Example 2 above were 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 triethylamine 0.6
Added ml. Then 490 mg of D-histidine methyl ester hydrochloride was added and stirring continued for 2 hours.
The reaction mixture was washed with 20 ml of water, then twice with 20 ml of 10% ammonium hydroxide, and then twice with 20 ml of water. All washes were sequentially back-extracted with 20 ml of methylene chloride and the combined organic layers were dried with _MgSO4 and extracted with 100 ml of methylene chloride.
The mixture was concentrated to 100 ml, filtered through silica, and 25 ml of methanol/ethyl acetate (20/80) mixture was added. The resulting eluate was concentrated to 40 ml and diluted with diethyl ether to 120 ml.
I made it. The precipitated solid was filtered, washed with diethyl ether, and dried under vacuum to give 5.66 g of the desired product as a white solid. Melting point: 114.5-117℃,
[α] ²⁰ _D : −55.5 (c2, solvent: CHCl ₃ ). Example 4 Preparation of cyclo(D-phenylalanyl-D-hysterine). 5.60 g of the methyl ester of Example 3 above was added to 10% palladium on carbon 220 in 100 ml of methanol under stirring.
Hydrogenation was carried out at atmospheric pressure using After 3 hours, solids began to precipitate. An additional 2.5 ml of methanol was added to facilitate stirring. After 7 hours, methanol
A further 280ml was added and the mixture was heated to reflux. The mixture was heated, concentrated to a gel mass, and mixed with 100 ml of diethyl ether. The resulting solid is filtered, washed with diethyl ether and dried under suction and under high vacuum at 35°C to give the desired product as a slightly off-white powder.
Obtained 3.29g. [α] ²³ _D : +68.5 (c2.0, solvent:
_CH3COOH ). Example 5 Preparation of (4-chlorophenyl)isopropyl ketone. To a solution of 10 ml of methylene chloride and 2.31 g of isopropyl (4-chlorophenyl) acetyl chloride was added 1.5 g of triethylamine in one portion. After 18 hours, 15 ml of heptane was added to the mixture and trimethylamine hydrochloride was removed by filtration. The solvent was removed from the liquid, 10 ml of heptane was added, the mixture was filtered and the solvent was removed to give a yellow residue. This residue
Dissolved in 5 ml heptane for GLC analysis. The reaction solution was heated to 0.2 to 0.05 mmHg using a bantam wear short neck head in an oil bath at 125 to 150°C.
When distilled at a head temperature of 110-100℃, the distillate
0.95 g and 0.81 g of rubber were obtained. The distillate was crystallized twice at -180°C from two volumes of hexane. The solid was melted and distilled at approximately 40° C. and 0.5 mm Hg to yield 0.42 g of the desired product as a yellow liquid. Example 6 Preparation of (4-chlorophenyl)isopropyl ketene. In a 500 ml flask, treat 53.2 g of isopropyl (4-chlorophenyl)acetic acid with 21.5 ml of thionyl chloride and gently heat to 80°C for 20 minutes at 80°C.
I kept it. The reaction mixture was left at room temperature for 2 days.
Volatiles were removed at 0.5 mmHg and 75°C. The resulting yellow liquid was diluted with 250 ml of methylene chloride, followed by the addition of 38.0 g of triethylamine. 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 liquid on a rotary evaporator at 50°C. The residue was diluted with 75 ml of heptane and triethylamine hydrochloride was removed by filtration as described above. Remove the solvent from the solution again and add heptane 75
ml, added 25 ml of heptane, and refiltered. The liquid was cooled in dry ice and inoculated to crystallize. The resulting crystals were filtered through a filter and washed with cold heptane. The supersolid was dissolved in 1.5 times the volume of heptane, diluted, and crystallized at -80°C.
The collected solids were melted and stored at -80°C. The liquid solution was warmed, most of the solvent removed, and heated in an oil bath at 0.05-0.06 mmHg at 90-120°C using a bantamware shot path head. Distilled. The total distillate was collected at a head temperature of 60-85°C and weighed 14.5 g as a light yellow-orange liquid. The distillate was crystallized at −80° C. from an equal volume of pentane, filtered as above, washed twice with heptane, and warmed to give a second melt. A total of 5.97g of solvent removed liquid was added to 6
The melt was immediately recrystallized as described above to give a third melt. Combine the three melts, 5mmHg,
29.4 g of desired ketene distilled at 50°C as a yellow liquid
I got it. Example 7 Preparation of (4-chlorophenyl)isopropyl ketene. 69.4 ml of triethylamine was added to 57.75 g of isopropyl (4-chlorophenyl) acetyl chloride. The mixture was left at 20°C overnight. Crush the resulting soft lump solids, dilute with 300ml of distilled hexane,
passed. Wash the solids three times with 75ml of hexane,
The mixture was filtered and dried under suction using calcium chloride dry air to obtain 32 g of triethylamine hydrochloride. More solids slowly precipitated from the combined hexane solutions of ketene. The flask was wrapped in aluminum foil and the mixture was left at room temperature overnight and filtered to give an additional 0.75 g of solid. The solution was freed from solvent by rotary evaporation and brought to 1 mm Hg. Add 500ml of hexane to the mixture, and after filtering,
The solvent was removed from the solution to obtain a yellow oil. This oil was distilled at 0.5 mm Hg using a bantamware short pass head to yield 28.61 g of the desired ketene as a yellow liquid.
^d20 :1.10. Example 8 Preparation of S-α-cyano-3-phenoxybenzyl alcohol. Cyclo(D-phenylalanyl-D-histidine) in a 100 ml three-necked bantamware flask.
After charging 43 mg, the flask was placed under a nitrogen stream. Then 3.51 ml of hydrogen cyanide was added via syringe, and the catalyst swelled into a gel. 5 minutes later,
Addition of 30 ml toluene precipitated excess catalyst. A total of 5.95 g of 3-phenoxybenzaldehyde was added immediately. The reaction mixture was stirred for 4.75 hours;
The reaction was then quenched with 20 ml of water containing 10 drops of concentrated hydrochloric acid. The toluene solution was separated, washed twice with water and diluted with 50 ml of toluene for analysis. From analysis, 80%
It was found that S-α-cyano-3-phenoxybenzyl alcohol isomer was produced. Example 9 Preparation of S-α-cyano-3-phenoxybenzyl alcohol. The reaction of Example 8 above was repeated using 171 mg of cyclo(D-phenylalanyl-D-histidine). After a period of time, 0.25 ml of the sample was taken and analyzed by gas-liquid chromatography, and the following results were obtained.

[Table] After 7 hours, add 10 ml of 1N hydrochloric acid to the reaction mixture,
I stopped reacting. Separate the organic layer, wash twice with water,
Dry over _MgSC4 , filter and keep at -10 °C. Dilute the liquid with 50 ml of toluene and measure the optical rotation.
A result of -1.54° was obtained at 21°C in the cell. A sample of the product was acetylated with p-nitrophenyl acetic anhydride, and the stereoisomer ratio was determined using a chiral perkle column.
It was determined by HPLC and the results were 71% S-α-cyano-3-phenoxybenzyl alcohol and 29% R-α-cyano-3-phenoxybenzyl alcohol. Example 10 Preparation of S-α-cyano-3-phenoxybenzyl alcohol. Cyclo(D-phenylalanyl-D-histidine) was charged into two small round-bottomed flasks with a magnetic stirrer and a diaphragm cover, and placed under a nitrogen stream. 0.98ml of hydrogen cyanide and 25ml of toluene
5 ml of this solution was added to two flasks. After about 5 minutes, 0.87 ml of 3-phenoxybenzaldehyde (POAL) was added to the two flasks. Flask No. 1 was stirred in an oil bath at 35°C and flask No. 2 was stirred in a water bath at 24-26°C. The results of this experiment are shown in Table 1.

[Table] Example 11 Production of S-α-cyano-3-phenoxybenzyl alcohol. A reaction was carried out by contacting 0.0099 m/Kg of cyclo(D-phenylalanyl-D-histidine) with 0.99 m/Kg of 3-phenoxybenzaldehyde, followed by 22 m/Kg of hydrogen cyanide and 190 ppm of water. The reaction was carried out in toluene at 25°C. aldehyde 93
The product obtained at a conversion of 88% S-α-
It was a cyano-3-phenoxybenzyl alcohol isomer. Example 12 Preparation of S-α-cyano-3-phenoxybenzyl alcohol. 0.2933 g of cyclo(D-phenylalanyl-D-histidine) and 15 ml of diethyl ether at 25°C
2.907 g of 3-phenoxybenzaldehyde was added to the solution, followed by 0.940 g of hydrogen cyanide. After 2 hours, 94%
of 3-phenoxybenzaldehyde is converted and the product is S-α-cyano-3 with an enantiomeric excess of 84%.
- It was phenoxybenzyl alcohol. 4~
After 20 hours, 99.4% of the 3-phenoxybenzaldehyde had been converted and the product was S-α-cyano-3-phenoxybenzyl alcohol with an enantiomeric excess of 67-68%. Example 13 Preparation of S-α-cyano-3-phenoxybenzyl alcohol. 0.0200 g of cyclo(D-phenylalanyl-D-histidine) was treated with 1.4037 g of 3-phenoxybenzaldehyde at 25°C under a nitrogen stream to disperse the catalyst, and then 2.1812 g of a toluene solution containing 13.65% hydrogen cyanide was injected. The reaction was carried out by treatment. After 2.7 hours, 93% of the 3-phenoxybenzaldehyde had been converted and the product was S-α-cyano-3-phenoxybenzyl alcohol in 77% enantiomeric excess. Example 14 Preparation of S-α-cyano-3-phenoxybenzyl alcohol. 3 in 0.0519 g of cyclo(D-phenylalanyl-D-histidine) and 9.32 ml of diethyl ether.
The reaction was carried out at 25°C by contacting 1.811 g of -phenoxybenzaldehyde followed by 0.617 g of hydrogen cyanide. After 3.6 hours, 99.4% of the 3-phenoxybenzaldehyde had been converted and the product was S-α-cyano-3-phenoxybenzyl alcohol in 72% enantiomeric excess. Example 15 S-α-cyano-3-phenoxybenzyl S-
Production of isopropyl (4-chlorophenyl) acetate. S in two 1-dram vials containing toluene
1 ml of a solution of 0.135 g of -α-cyano-3-phenoxybenzyl alcohol was charged, followed by 0.504 ml of a toluene solution of S-isopropyl (4-chlorophenyl) acetyl chloride. 0.07 ml of 2,6-lutidine was added to the first vial under stirring. The reaction mixture warmed quickly and a solid precipitated. Stirring was continued for 10 minutes,
There was no change. The mixture was washed successively with water, dilute hydrochloric acid, water, and dried over _MgSO4 . The resulting oil contains 75.5% S-α-cyano-3-phenoxybenzyl S-isopropyl (4-chlorophenyl)
Contains acetate isomer. 0.083 ml of triethylamine was added to the second vial with stirring. The reaction occurred immediately and the product was recovered as above and 72.0% S-α-cyano-
3-Phenoxybenzyl S-isopropyl (4-
The chlorophenyl)acetate isomer was obtained. Example 16 S-α-cyano-3-phenoxybenzyl (1R, cis)-2,2-dimethyl-3-(2,2-
Production of (dichlorovinyl) cyclopropane carboxylate. (1R, cis)-2,2-dimethyl-3-(2,
2-dichlorovinyl)cyclopropanecarboxylic acid
Thionyl chloride in a 25 ml solution of 1 g of methylene chloride.
0.5 g followed by a few drops of dimethylformamide. The reaction mixture was refluxed overnight and the solvent was removed under pressure at 40°C. Dissolve the residue in 20 ml of benzene and add S-
A solution of 0.4 g of 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.
The mixture was added. The reaction mixture was stirred for 1.5 hours. The reaction solution was poured into water, extracted with ether, and the ether layer was washed with dilute hydrochloric acid and then with sodium bicarbonate solution. The organic layer was washed with water, dried with _MgSO4 ,
Concentration gave a yellow oil. This was chromatographed to give 0.53 g of the desired product. [α] ²⁰ _D :
26.55° (0.558g/ml, solvent: CH ₂ Cl ₂ ). Example 17 S-α-cyano-3-phenoxybenzyl S-
Production of isopropyl (4-chlorophenyl) acetate. One drum vial has an R/S ratio of approximately 72/
1 ml of α-cyano-3-phenoxybenzyl alcohol solution of No. 28 and 0.121 ml of (4-chlorophenyl)isopropyl ketene were added. 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. The reaction mixture was centrifuged and the undissolved gel mass was washed four times with 1 ml hexane and centrifuged. Organic extract, diluted hydrochloric acid,
Washed with water, dried, concentrated to less than 1 ml, and 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% R-α-cyano-3-phenoxy. Benzyl R-isopropyl (4
-chlorophenyl) acetate. Example 19 S-α-cyano-3-phenoxybenzyl S-
Production of isopropyl (4-chlorophenyl) acetate. The catalyst gel recovered from Example 18 above was dissolved in hexane.
It was washed with 1.5 ml and placed in a 1 dram bicelle.
S-α-cyano-3 as described in Example 14 in a vial
- 1ml of phenoxybenzyl alcohol solution and 0.121ml of (4-chlorophenyl)isopropylketene
I prepared ml. The reaction mixture was stirred for 16 hours, then extracted five times with 1 ml of hexane, the extract was concentrated and diluted to 2 ml with toluene for analysis. Desired product: 62.4% by Pircle column analysis
S-α-cyano-3-phenoxybenzyl S-
It contained isopropyl (4-chlorophenyl) acetate and 14.1% R-α-cyano-3-phenoxybenzyl R-isopropyl (4-chlorophenyl) acetate. Example 20 S-α-cyano-3-phenoxybenzyl S-
Production of isopropyl (4-chlorophenyl) acetate. A magnetic stir bar and a 0.5 dram vial containing 4 mg of cyclo(D-phenylalanyl-D-histidine) was filled with nitrogen and stoppered. This vial contains 0.174g of 3-phenoxybenzaldehyde.
Subsequently, 0.044 ml of hydrogen cyanide was injected. After stirring for 5 minutes, 0.18 ml of (4-chlorophenyl)isopropyl ketene was added. After 2 days, the reaction mixture was diluted with toluene, washed with 1N hydrochloric acid, water, dried over MgSO ₄ and filtered. A 1 ml solution of this in toluene was analyzed and found to be rich in the desired compound. Examples 21-103 A vial of 13.5% w/v racemic α-cyano-3-phenoxybenzyl alcohol solution
A 0.6M toluene solution was charged followed by a 5% weight/volume excess of (4-chlorophenyl)isopropylketene and 4m% catalyst. Reaction mixture at 25℃
and stirring 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, and are described, for example, in Schroeder and Rabke, "The Peptide," Volume, Pages XI-- (1966). The isomer is Aα=S−
Acid S-alcohol isomer, Aβ=S-acid R-alcohol isomer, Bα=R-acid S-alcohol isomer, Bβ=R-acid R-alcohol 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, in Examples 20 to 109,
Pure optically active R- or S-α-cyano-
It is within the scope of the invention to replace 3-phenoxybenzyl alcohol or mixtures that are very rich in it, increasing the amount of major isomeric product.

【table】

【table】

【table】

[Table] Example 110 Preparation of α-cyano-3-phenoxybenzyl α-isopropyl (4-chlorophenyl) acetate. A mixture of 2.31 g of isopropyl (4-chlorophenyl) acetyl chloride was treated with 2.78 ml of anhydrous triethylamine in the same manner as in Examples 5-7,
A solution of isopropyl (4-chlorophenyl) isopropyl ketone in 8 ml of toluene was obtained. A mixture of 2.00 g of 3-phenoxybenzaldehyde, 8 ml of toluene and 0.55 g of hydrogen cyanide was stirred under a nitrogen stream. To this cooled solution was added 0.5 ml of water followed by 0.86 ml of concentrated hydrochloric acid. 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.
ml and passed through 3 _g of MgSO4. This liquid was added to the above ketone solution (containing triethylamine) 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, loaded onto a column of silica gel, and eluted with diethyl ether/toluene = 36/64. . The eluent was dried with MgSO ₄ and the solvent was removed to give 3.98 g of a brown oil. It contains 65% of the enantiomeric pair, S-α-cyano-3-phenoxybenzyl R-isopropyl (4-chlorophenyl) acetate, R-α-cyano-3-phenoxybenzyl S-isopropyl (4- chlorophenyl) acetate and 35% PR, which had an enantiomeric pair of SS. Example 11 Preparation of α-cyano-3-phenoxybenzylisopropyl (4-chlorophenyl) acetate. A 1-dram vial was charged with 1 ml of a toluene solution containing 0.6 mmol of α-cyano-3-phenoxybenzyl alcohol having an isomer ratio R/S=72/28 prepared in Example 9. To this was added 0.121 ml 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 1NHCl, water, dried over MgSO ₄ and diluted to 2 ml with toluene. According to liquid chromatography analysis of a chiral perkle column, S-α-cyano-3-phenoxybenzyl R-isopropyl (4-chlorophenyl) acetate/RS isomer/
The isomer ratio was SS isomer/RR isomer = 13.6/42.2/30.6/13.6. Examples 112-121 Preparation of S-α-cyano-3-phenoxybenzylisopropyl (4-chlorophenyl) acetate. In the same manner as Examples 110 and 111 above, an equivalent amount of non-chiral tertiary amine, (4-chlorophenyl)
Isopropyl ketene and S-α-cyano-3-
Phenoxybenzyl alcohol was reacted at 0°C. The results of this experiment are shown in Table 3. where the capital letters A and B represent the S of the acid portion of the ester product.
or the absolute configuration of R, respectively, and α is
The absolute configuration of S in the alcohol moiety of the ester product is shown. In all reactions, approximately 86% of the S-isomer α-
The same sample of cyano-3-phenoxybenzyl alcohol was used. 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 invention to replace in Examples 110-121 with pure optically active R- or S-α-cyano-3-phenoxybenzyl alcohol or mixtures in which it is highly enriched. , increasing the amount of R or S isomer.

[Table] Min

【table】

Claims (1)

[Scope of Claims] 1. Optionally substituted 3-phenoxybenzaldehyde in the presence of a substantially water-immiscible aprotic solvent and a cyclo(D-phenylalanyl-D-histidine) dipeptide catalyst. 1. A process for producing optionally substituted S-α-cyano-3-phenoxybenzyl alcohol or a mixture enriched therein, comprising treating S-α-cyano-3-phenoxybenzyl alcohol with a hydrogen cyanide source. 2. The method according to claim 1, wherein the solvent is an aromatic hydrocarbon, an ether, or a mixture thereof. 3. The method according to claim 2, wherein the solvent is toluene or 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-phenoxybenzaldehyde. 5. The method according to claim 1, wherein hydrogen cyanide is introduced simultaneously with or after the introduction of the solvent and/or aldehyde, or the solvent and/or aldehyde is introduced rapidly after the introduction of hydrogen cyanide. 6. The method according to claim 1, wherein the aldehyde is 3-phenoxybenzaldehyde.