DD231344A5 - PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE CYANOMETHYL ESTERS - Google Patents

Abstract

The invention relates to a process for the preparation of an optically active cyanomethyl ester or a mixture enriched thereon by treatment of an alpha-chiral carboxylic acid halide or a reactive derivative thereof with an optically active alpha-hydroxynitrile. The process allows the preparation of the compounds mentioned in high yield and avoids the time-consuming classical synthesis of the corresponding optically active acids and alcohols as a direct synthesis process. Stereoisomers of chiral cyanomethyl esters of alphachiral carboxylic acids or the acids themselves generally have different effects in biological systems.

Description

Berlin, 21.12.1984 64 799/11 (Elimination from AP C 07 C / 256 815/1 63 193/11)

Process for the preparation of optically active cyanomethyl esters

Field of application of the invention

The invention relates to a process for the preparation of cyanomethyl esters with chiral centers in both the acid and the alcohol molecule parts.

Characteristic of the known technical solutions

Stereoisomers of chiral cyanomethyl esters of alphachiral carboxylic acids or the acids themselves generally have different effects in biological systems. In the past, it has generally not been possible to directly prepare such optically active cyanomethyl esters, since the corresponding chiral alpha-hydroxynitriles were not always readily available or the synthetic methods yielded products with little or no enrichment. Even if these optically active alpha-hydroxynitriles were available or more readily available, the optically active acids were not always readily available. Often, the optically active acids have been obtained by classical dissolution, which normally takes a long time and can not be practiced on a large scale. Optically active alpha-hydroxybenzene acetonitriles are known and per se as intermediates, for example, esters, of interest. In pyrethroid esters which are derived from an alcohol, those having an (alpha-S) -alpha-hydroxynitrile molecular moiety, coupled

pelt with the appropriate pyrethroic acid "generally the highest activity as a pesticide. In addition, such (alpha-S) -alpha-hydroxynitriles could not be readily prepared in the past because they were generally prepared only by resolution.

Object of the invention

The present invention is based on the object to provide a process for the preparation of chiral Cyanomethylestern of alpha-chiral carboxylic acids in high yield * The method should be suitable as a direct synthesis method, and the painstaking classical resolution of the corresponding optically active acids and alcohols should be avoided.

Explanation of the essence of the invention

The invention relates to a process for the preparation of an optically active cyanomethyl ester of an alpha-chiral (optically active) carboxylic acid (ie of alpha-chiral Cyanomethylestern of alpha-chiral carboxylic acids) or a mixture enriched thereon, which is characterized in that a non-symmetrical Keten is treated with a racemic or an optically active alpha-hydroxynitrile. The optically active cyanoethyl ester products include those of the following formula I:

0 CN

Il I " ³ ", CH-COC i I

V-J

wherein R, R, R ³ and R ^{4 are} substituents, * is an asymmetrically substituted carbon atom and the broken lines represent bonds which may be present.

The reaction is carried out in the presence or absence of a solvent. When a solvent is used, the solvent is preferably a non-hydroxylic solvent such as hydrocarbons, chlorinated hydrocarbons, ethers, and the like. For example, suitable solvents are alkanes containing from 5 to 10 carbon atoms, such as n-pentane, η-hexane, n-heptane, n-octane, n-nonane, n-decane and their isomers, petroleum fractions rich in alkanes, are also suitable For example, gasoline or mineral spirits with a boiling range at atmospheric pressure between 40 and 65 ⁰ C, between 60 and 80 ⁰ C or between 80 and 110 ⁰ C, petroleum ether is also suitable, cyclohexane and methylcyclohexanes are examples of suitable cycloalkanes, the 6 to 8 Contain carbon atoms. Aromatic hydrocarbon solvents may contain from 6 to 10 carbon atoms, for example, benzene, toluene, o-, m- and p-xylene, the trimethylbenzenes, p-ethyltoluene and the like. Suitable chlorinated hydrocarbons contain from 1 to 4 chlorine atoms together with the alkane chain containing 1 to 4 carbon atoms or with a benzene ring, for example carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, trichloroethane, perchloroethane, chlorobenzene and 1,2- or 1,3-dichlorobenzene and the like. Ethers are generally those containing from 4 to 6 carbon atoms, such as diethyl ether, methyl tertiary butyl ether and diisopropyl ether, and the like. Preferred is an aromatic solvent, more preferably toluene is used.

Any non-symmetric ketene may be used (provided that it does not contain substituent groups that form other stable reaction products with the alpha-hydroxynitrile). The non-symmetric ketene has the formula II:

R ¹

R ² -C = C = 0 II »

Wherein R and R are independently a different alkyl, aralkyl, alkoxy, aryloxy, alkylthio, alkylsulfonyl, arylthio or arylsulfonyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 7

Ring carbon atoms, or wherein R is also 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, one of which is oxygen, sulfur or nitrogen and the remaining carbon atoms, or an amino group disubstituted by acyl or alkyl of up to 10 carbon atoms, or a phenyl group or wherein

1 2

R and R together with the carbon atom to which they are attached denote a non-symmetrical cycloalkyl group having 4 to 7 ring atoms and 4 to 14 carbon atoms.

The groups R and R may be optionally substituted by one or more halogen atoms having an atomic number of 9 to 35, alkyl or haloalkyl of 1 to 4 carbon atoms, alkenyl or haloalkenyl of 2 to 4 carbon atoms, haloalkoxy or alkoxy of 1 to 4 carbon atoms, haloalkylthio or alkylthio of 1 to 4 carbon atoms or equivalent types and sizes of substituents containing the same or higher carbon number.

A type of non-symmetric ketenes that can be used in the process of the invention; is that which yields pyrethroid esters, including those esters containing an acid moiety, as described in US Pat. Nos. 4,062,968, 4,137,324 and 4,199,595. Examples of such ketene include those of formula II wherein R is isopropyl or Cyclopropyl, R represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a naphthyl group, a phenyl group or a (benzyloxycarbonyl) -phenylamino group, each optionally substituted on the ring by one or more substituents, such as halogens, alkyl, Haloalkyl, alkoxy, Haloaikoxy, wherein the halogens are bromine, chlorine or fluorine, and the Alky! Groups may contain 1 to 4 carbon atoms, may be substituted »

Of particular interest as non-symmetrical ketene reactants are ketenes of the formula II, where R is iso-

2 is propyl and R is a phenyl group, para-substituted

by halogen, alkyl or halogenooxy, in which the halogen can be, for example, chlorine or fluorine and the alkyl group contains from 1 to 4 carbon atoms, for example methyl, since their resulting esters are highly active as pesticides «

For example, the non-symmetric ketene may be (4-chlorophenyl) isopropyl ketene, (4- (difluoromethoxy) phenyl) isopropyl ketene, ((4- (trifluoromethyl) -3-chlorophenyl) - (benzyloxycarbonyl) amino) isopropyl ketene or a be a similar connection «

Any racemic or optically active alpha-hydroxynitrile is useful (provided that it does not contain substituent groups "which form other stable reaction products with the non-symmetric ketene or catalyst * if present)." Preferably, the alpha-hydroxynitrile is a symmetric or non-symmetrical, racemic or optically active alphaf-hydroxynitrile of the formula III:

CN

R *

HO-C III,

wherein R represents an optionally substituted hydrocarbon, hydrocarbyl or heterocyclic group and R represents an optionally substituted hydrocarbyl group or a hydrogen atom, or wherein R and R together with the carbon atom to which they are attached form a carbocyclic group, as is indicated by the dashed line,

The hydrocarbon groups represented by R and R in the formula III may be, for example, an alkyl, a cycloalkyl or an aryl group having up to 20 carbon atoms "preferably having up to 10 carbon atoms, or R may be a carbocyclic group in the formula III Examples of carbocyclic aryl groups are phenyl, 1-naphthyl, 2-naphthyl and 2-anthryl groups. Heterocyclic aromatic groups are those which are derived from heteroaromatic compounds and which are described in Other, "Encyclopedia

pedia of Chemical Technology, Vol. 2 (1963), p. 702, and are obtained by replacing one or more carbons of a carbocyclic aromatic compound with a heteroatom selected from O or S, and which are also heterocyclic Compounds which have five-membered rings which have aromatic properties and are mentioned on page 703 of the abovementioned band. Possible substituents are one or more halogen atoms having an atomic number of from 9 to 35 and including 35 or an alkyl, alkenyl or alkoxy group. containing 1 to 6 carbon atoms, each of which may optionally be substituted by one or more halogen atoms, optionally substituted phenoxy, phenyl, benzyl or benzoyl groups and equivalent types of these substituents. Illustrative examples of optically active alpha-hydroxynitriles include alpha-hydroxy alpha-methylbutyronitrile, alpha-hydroxy-alpha Methylbenzeneacetonitrile, alpha-hydroxyisobutyronitrile and similar compounds.

Preferably, the alpha-hydroxynitrile compound has the formula:

AB CN Il

¹ fr W

HOC-V y -A

wherein each of the substituents A is independently a hydrogen atom, a halogen atom of 9 to 35 inclusive, or an alkyl, alkenyl or alkoxy group.

pe having 1 to 6 carbon atoms * each of which may optionally be substituted by one or more halogen atoms having an atomic number of 9 to 35, inclusive, B represents a hydrogen atom, a halogen atom of 9 to 35 inclusive, or an alkyl, alkenyl Or alkoxy group having 1 to 6 carbon atoms, each of which may be optionally substituted by one or more halogen atoms having an atomic number of 9 to 35 inclusive, or a group of the formula:

where Y is O, CH- or C (O), m is 0 or 1, and D and E are independently a hydrogen atom, a halogen atom of 9 to 35 inclusive or an alkyl, alkenyl or alkoxy group of 1 to 6 carbon atoms, each of which may be optionally substituted by one or more halogen atoms having an atomic number of 9 to 35, inclusive.

Preferably, the alpha-hydroxynitrile has the R or S configuration and thus comprises either R- or, preferably, S-alpha-hydroxynitrile of the formula:

CN .JYV

4 \ Ä W

wherein Y is O, CH ₂ or C (O) * each of the substituents A, D and E is independently a hydrogen atom, a halogen atom of 9 to 35 inclusive or an alkyl, alkenyl or alkoxy group of 1 to 6 carbon atoms, each of which may be optionally substituted by one or more halogen atoms having an atomic number of 9 to inclusive inclusive. Preferably, Y represents 0,

Preferably, each of the substituents A, D or E is independently a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group or a methoxy group. Preferably, one of the substituents D and E is a hydrogen atom. A particularly preferred subclass of S-alpha-hydroxynitriles are those of the above formula wherein D represents a hydrogen atom and A and E each independently represent a fluorine atom or a hydrogen atom, and preferably when A or E is fluoro, each in the 4-position of the ring relative to the benzyl carbon atom when A is present or relative to the Y = O bearing carbon atom when E is present. "Particularly suitable alcohols are those when A is a fluorine atom at the 4-position and E is a hydrogen atom."

Examples of alpha-hydroxynitriles of the above formula include S-alpha-cyano-3-phenoxybenzyl alcohol, S-alpha-cyano-4-

- IO -

fluoro-3-phenoxybenzyl alcohol, S-alpha-cyano-3 * - (4-fluorophenoxy) -benzyl alcohol and their corresponding enantiomers and similar compounds «

The present invention relates to a process for the preparation of stereoisomerically enriched cyanomethyl esters by treating a non-symmetrical ketene with a racemic or optically active alpha-hydroxynitrile (wherein both the hydroxy and nitrile substituents are attached to the same carbon atom) in the absence of a catalyst or in the presence of an achiral tertiary amine catalyst or an optically active (chiral) tertiary amine catalyst »

The optically active (chiral) tertiary amine catalyst is any optionally substituted alkyl, cycloalkyl, aromatic or heterocyclic mono- or polyamine "containing up to 40 carbon atoms (including the polymers and copolymers and amine salts and the like) that do not interfere with the reaction." The amine is preferably a moderate to weakly basic amine. The optically active amines * polymers and copolymers are known types of materials and can be prepared by methods known per se, except for the particular novel ketene reaction products which will be illustrated below * For example, numerous optically active amines are disclosed specifically in Newman, P * , "Optical Resolution Procedures for Chemical Compounds," Volume 1, Amines and Related Compounds, Optical Resolution Information Center, Manhattan College, Riverdale, NY, Library of Congress Catalog Card No. 78-61452.

Also described in this reference are optically active mono-, di- and polyamines which can be polymerized and copolymerized according to methods known per se to form optically active polymeric amines which can be used in the present invention.

One embodiment of optically active amine catalysts comprises a substituted optically active amino acid, which is preferably any acyclic, carbocyclic, aromatic or heterocyclic amino acid containing up to 20 carbon atoms, preferably up to 10 carbon atoms, and which additionally is moderately to slightly basic Suitable nitrogen base substituents are optionally substituted nitrogen heterocyclic groups or amino groups optionally substituted by alkyl or cycloalkyl groups containing from 1 to 6 carbon atoms or by optionally substituted phenyl groups. Other possible substituents are hydroxy, alkyl, alkoxy, amino, 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, but are not limited to, beta-aminoalanine, ornithine, canavanine, anserine, kynurenine, mimosine, cystathionine, ephedrine, acylated ephedrines, histidinol, citrulline, carbamoylserine, cinchonine, quinine or acylated quinuclidinyl alcohols.

Another embodiment of amine catalysts are heterocyclic amines and heterocyclic amine polymers. Examples which are not intended to be limiting, however, are di- and polyaziridines, polymers of acryloylcinchonines alone or with Ν, Ν-diacryloylhexamethylenediamine, di- and poly (iminoisobutylethylene), polymers of (N-3enzyl-2-pyrrolidinylmethylester) with acrylate or a low alkane carboxylic acid, and similar materials *

In another embodiment, the catalyst is a peptide containing optically active histidine, or is a histidine-containing di- or polypeptide wherein at least one of the histidinyl-free NH and free COOH groups is optionally modified with a protecting group in the form of an amide (or a) Acid addition salt thereof) or an ester group, or it is the reaction product of 1 mole of histidine or "a histidine-containing di- or polypeptides with about 1 mole of a ketenes per mole of histridine" group.

The di- or polypeptide is linear or cyclic. These peptides generally contain from about 2 to about 16 peptide units, preferably from 2 to 4 peptide units. Nitrogen substituted amino acids including these histidine-containing di- and polypeptides are synthesized by per se known peptide synthesis methods as described, for example, in Greenstein, P, and M, Winitz , "Chemistry of the Amino Acids," Dohn Wiley & Sons, Inc., New York, 1961, "

The dipeptides of the histidine-containing catalysts are

preferred, especially in the cyclic dipeptide form. The di- or polypeptides may also contain an alanine and the one that raises. Alanine, phenylalanine or alanine derivatives have been prepared, are preferred »

In another embodiment, the asymmetric carbon atoms in the histidine-containing peptide used as the catalyst are in the D configuration, although the L configuration in the histidine-containing peptide is also suitable. The choice of chirality in the catalyst can be made to provide the desired chirality in the product.

In the amino acid catalysts, the functional groups may contain protecting groups. Any known protecting group for the amino acid can be used. For example, the protecting group may be an organic acid in the case of the free N-H group or an alcohol in the case of the free COOH group. "Any organic acid and any alcohol which does not disturb the reaction may be used as a protecting group." Preferably, the protecting group is another amino acid. One may use any amino acid, but it is preferred that the amino acid is a non-heterocyclic, and that it is a monoamino or diaminoalkanecarboxylic acid or aralkanecarboxylic acid, such as alanine, phenylalanine, glutamic acid, glycine or a similar connection,

Acid addition salts of the amine catalysts can be formed with any acid that does not interfere with the reaction. Suitable inorganic acids are hydrohalic acids, such as

Hydrochloric or hydrobromic acid, sulfuric acids such as sulfuric acid or toluenesulfonic acid and phosphoric acids such as phosphoric acid or phenylphosphonic acid, and organic acids such as oxalic acid and the like are also suitable for the formation of the salts.

In the preparation of the di- or polypeptide catalyst "having an alanine-containing moiety" this is made of alanine or its derivatives. These include alanine beta-aminoalanine, beta-phenylalanine, 3,4-dihydroxyphenyl alanine, and similar compounds. In preparing the catalyst having a histidine-containing moiety, it is preferable to use histidine, 3-methyl-histidine, 1-methyl-histidine, 1-ethyl-histidine, 1-propyl-histidine, or 1-benzyl-histidine, or the like. It is preferable to use a catalyst which is a cyclic dipeptide containing a histidine molecule part and an alanine molecule part.

The Peptidaddukte (reaction products) with ketene are novel _# They are prepared so 'that about 1 mole to 3 moles of ketene per mole of peptide and preferably about 2 and most preferably about 1 mole of ketene per mole of cyclic dipeptide contained * Obviously, it is preferred However, the treatment of the optically active catalyst with about 1 to 3 moles of a ketene, preferably in the absence of the solvent or in the presence of any solvent, is also possible. which was used to prepare the ketene suitable. The ketene

may be similar, but a symmetric ketene, for example dimethylketene, diphenylketene etc., or ketene itself is preferred,

Examples of optically active histidine-containing catalysts are, but are not intended to be limiting, histidine, alpha-methylhistidine, 1-methylhistidine, 3-methylhistidine, cyclo (histidylhistidine), (benzyloxycarbonylalanylj-histidine methyl ester, cyclo (alanylhistidine), cyclo ( beta-phenylalanylhistidine), histidine methyl ester hydrochloride, histidine ethyl ester dihydrochloride »anserine, cyclo (vallyi histidine), tidine» glycylhistidine, cyclo (phenylalanylglycylhistidine), cyclo (leucylhistidine), cyclo (homophenylalanylhistidine), cyclo (phenylalanylmethylhistidine), N-alpha (beta ^ naphthoyl) histidine, histidylalanine, histidylphenylalanamide hydrochloride, histidylphenylalanine, cyclo (histidylproline), cyclo (glycylhistidine) in free or protected form or the reaction product of these materials with a ketene, in particular (4-chlorophenyl) isopropyl ketene, Further examples are the cyclo (beta-phenylalanylhistidine) adduct with (4- (difluoromethoxy) phenyl) isopropyl ketene, histidina dduct with dimethylketene, the cyclo- (glycylhistidine) adduct with (4- (difluoromethoxy) phenyl) isopropyl ketene or the Histidylalaninaddukt with dimethyl ketene and the like.

A subclass of peptide catalysts used has the formula:

¹ YZO

0 η in which X is H, alkyl or R-C, each of the substituents

R independently alkyl or cycloalkyl with up to 7 carbon atoms

Substituents, optionally substituted phenyl, benzyl

YZO

or similar mean each of the η units of (-N-CH-C-) is independently substituted j wherein Y is hydrogen, acyl »alkyl or aralkyl having up to 10 carbon atoms, Z is the residue of conventional amino acids which in the inventive Do not disturb processes, including benzyl, 3-. Carboxypropyl, 3-aminopropyl, mercaptomethyl, 4-hydroxybenzyl, imidazol-4-ylmethyl, means that each of the numbers m is O or 1, η is 2 to 16, and wherein when m is O, the catalyst has a cyclic structure, which indicated by the dashed line, with the proviso that at least one histidine? or substituted histidine moiety is present in the catalyst, or the reaction products of the above catalysts with 1 to 3 moles of ketene,

When prepared by methods known per se in the presence of a solvent (e.g., water), the peptide catalysts may also contain, if solid, a crystallization solvent (e.g., water). The optically active catalyst based on a nitrogen-containing amino acid, e.g. Histidine-containing peptide may or may not contain a crystallization solvent (e.g., water) when solid.

The achiral tertiary amine catalyst may be any optionally substituted alkyl, cycloalkyl, aromatic, or heterocyclic tertiary amine containing up to about 40 carbon atoms (including the polyhydric amine).

kidneys and copolymers and amine salts), where the substituents are not allowed to interfere with the reaction. "The amine is a moderately to strongly basic amine. The achiral tertiary amines; Polymers and copolymers are any known types of materials known in the art and can be prepared by methods known per se.

Illustrative examples of the achiral tertiary amine catalyst are 1-methyliraidazole "pyridine" 2,6-lutidine, triethylamine, trimethylamine, Ν, Ν-dimethylaniline, diisopropylethylamine, 1,4-diazabicyclo [2,2,2] octane, and the like.

In one embodiment, the achiral tertiary amine catalyst is an acyclic, carbocyclic, aromatic or heterocyclic amine containing up to about 20 carbon atoms. Preferably, the tertiary amine is an acyclic or aromatic amine containing 3 to 8 carbon atoms and suitably an acyclic tertiary amine such as triethylamine or triethylamine or a similar compound.

The term "achiral tertiary amine" in the present application also encompasses the acid addition salts. The acid addition salts can be formed with any acid which does not disturb the reaction. Suitable inorganic acids are hydrogen halides, such as hydrochloric or hydrobromic acid. Sulfuric acids, such as sulfuric or sulphonic acids and phosphoric acids, such as phosphoric or phosphonic acids and organic acids, such as oxalic

Acid and the like, are also suitable for the formation of the salts.

Alternatively, the process described comprises treating a non-symmetric ketene as defined above with an aldehyde or ketone and a source of cyanide ions, optionally in the presence of the previously defined achiral or chiral (optically active) catalyst -hydroxylic solvents of the kind mentioned above »

Any aldehyde or ketone (carbonyl compound) is useful (provided that it contains no substituent groups "which form other stable reaction products with cyanide ions or with the catalyst). Preferably, the aldehyde or the ketone has the formula:

I. IV

'- c-R H O

wherein R represents an optionally substituted hydrocarbyl or hydrocarbyl or heterocyclic group and R represents an optionally substituted hydrocarbyl group or a hydrogen atom, or alternatively wherein R and R together with the carbon atom to which they are attached form a carbocyclic group.

The hydrocarbyl or hydrocarbyl groups, which by

3 4 R and R can be represented in the formula IV, can bei-

for example, an alkyl-, a cycloalkyl- or an aryl group having up to 20 carbon atoms, preferably up to 10 carbon atoms, or R in the formula IV can be a carbocyclic or an O- or S-heterocyclic aryl group. Examples of cadbocyclic aryl groups are phenyl, 1-naphthyl-V 2-naphthyl and 2-anthryl groups. Heterocyclic aromatic groups can be derived from heteroaromatic compounds which are described in Kirk-Other, "Encyclopaedia of Chemical Technology", 2nd Edition, Volume 2 (1963). , Page 702, which is obtained by replacing one or more carbons of a carbocyclic aromatic compound with a heteroatom selected from O or S. Also included are those five-membered ring heterocyclic compounds which have aromatic properties and are described on page 703 of the tape. Such aldehydes and ketone compounds are described in U.S. Patent 4,132. Substituents which may optionally be present include one or more halogen atoms having an atomic number of 9 to 35, inclusive, or an alkyl, alkenyl or alkoxy group of 1 to 6 carbon atoms, each optionally substituted by one or more halogenating agents, or optionally may be substituted by a phenoxy, phenyl, benzyl or benzoyl group or equivalent types of substituents.

Preference is given to an aromatic aldehyde of the formula:

A B

ο ι ι

HC

• ι »- · ¹¹ //

-O-

A A

wherein each of the substituents A independently represents a hydrogen atom, a halogen atom having an atomic number of 9 to 35 inclusive, or an alkyl, alkenyl or alkoxy group having 1 to 6 carbon atoms each represented by one or more halogen atoms having an atomic number of 9 to including 35, B represents a hydrogen radical, a halogen atom of 9 to 35 inclusive or an alkyl radical; Alkenyl or alkoxy group having 1 to 6 carbon atoms, each of which may be substituted by one or more halogen atoms having an atomic number of 9 to 35 inclusive, or a group of the formula:

• 4 ·

where Y is O, CH "or C (O), ra is 0 or 1, and D and E are independently hydrogen, halogen of 9 to 35 inclusive, or alkyl, alkenyl or alkoxy of 1 to 6 carbon atoms, each of which may be substituted by one or more halogen atoms having an atomic number of 9 to 35, inclusive.

Preferably, the aldehyde is used, the above-defined alpha-hydroxynitrile corresponds, and thus has the formula:

wherein A ^ D, E and Y have the meaning given in the above formula

Examples of suitable aldehydes of the formula given above are 3-phenoxybenzaldehyde, 4-fluoro-3-phenoxybenzaldehyde and similar compounds,

The source of cyanide ions is hydrogen cyanide or an agent which generates hydrogen cyanide at the reaction conditions, such as an alpha-hydroxynitrile such as acetone cyanohydrin. The molar ratio of hydrogen cyanide to 1 mole of aldehyde or ketone is from about 1.0 to about 3.0, and preferably from from about 1.1 to about 2.0,

The preparation of the cyanomethyl esters according to the invention is carried out by adding the non-symmetric Ke.ten to the alpha-hydroxynitrile or to the aldehyde or ketone and a source of cyanide ions, preferably dissolved in a catalyst-containing solvent, moves the mixture, for example stirring, and the reaction conditions during a time so selected that the formation of the optically active ester is ensured. The separation and recovery of the optically active ester product is carried out according to known methods, such as extraction and similar methods.

The amount of catalyst may vary. For example, depending on the tertiary achiral amine used, it may vary slightly in the range of from about 1 to about 100 percent based on the weight of the alpha-hydroxynitrile aldehyde or ketone present, and is preferably about one to about 10 mol%, when the catalyst is a chiral tertiary amine, it may be present in an amount ranging from about 0.1 to about 10 % by weight, and preferably from about 0.1 to about 5% by mole , based on the Weight of the alpha-hydroxynitrile, aldehyde or ketone present, and is preferably about 1.5 to about 5 mol% _#

The molar ratio of starting materials, non-symmetric ketene and alpha-hydroxynitrile, aldehyde or ketone can vary. For example, the molar ratio of ketene to alpha-hydroxynitrile may be from about 5: 1 to about 1: 5, and preferably from about 2: 1 to about 1: 2. However, it is preferred to use a molar excess of ketene to alpha-hydroxynitrile, aldehyde or ketone of about 1: 1.1 to about 1: 1.5 ·

The reaction temperature for the preparation of the cyanomethyl esters as well as the pressure may vary. At normal pressures, the temperature is from about -10 to about 50 ^° C., more or less. Ambient temperatures from about 0 to about 35 ^° C. are preferred, and most preferably about 0 to about 15 ° C _#

The alpha-hydroxynitriles and their corresponding aldehydes or ketones are generally known and are described in the literature. They can be either directly or chemically

In the case of the optically active alpha-hydroxynitrile, the resolution is carried out according to methods known per se, including those described in US Pat. Nos. 3,649,457 and 4,273,727, by Oku et al., 3, C _# S *, Chemi. Cömnuv pages 229 and 230 (1981) and by Becker et al., "CJ, Amer. Chem. Soc." 88 * pp. 4299 to 4300 (1966) and in similar references.

The optically active, optionally substituted S-alpha-cyano-3-phenoxybenzyl alcohols are also prepared by treating the corresponding aldehyde or ketone with hydrogen cyanide in a substantially water-immiscible aprotic solvent and in the presence of a cyclo- (D-phenylalanyl-D-histidine). prepared dipeptide catalyst.

The catalyst is prepared by a per se known peptide synthesis method, for example as described in Greenstein, 3 _# P # and M, Winitz, "Chemistry of the Amino Acids", Oohn Wiley & Sons, Inc., New York, 1961 , manufactured.

A substantially water-immiscible aprotic solvent which can be used in the present invention is described as an aprotic solvent in which the solubility in water is not more than 5 % in terms of volume. For example, the solvent may be a hydrocarbon or ether solvent including the acyclic, alicyclic or aromatic materials. Preferred because of

the reaction temperature, the solvent has a boiling point below about 150 ⁰ C (and does not interfere with the reaction). For example, suitable solvents are alkanes of 5 to 10 carbon atoms, such as n-pentane, n-hexane n-heptane, n-octane, n-nonane, n-decane and their isomers. Oil-rich petroleum fractions are also suitable For example, gasoline or motor gasoline having a boiling range at atmospheric pressure between 40 and 65 ⁰ C ₁ between 60 and 80 ⁰ C or between 80 and 110 ⁰ C, petroleum ether is also suitable. "Cyclohexane and methylcyclohexanes are examples of useful cycloalkanes having 6 to 8 carbon atoms Aromatic hydrocarbon solvents may contain from 6 to 10 carbon atoms, for example, benzene, toluene, o-> m- and p-xylene, trimethylbenzenes, p-ethyltoluene and the like. Useful ethers include diethyl ether, diisopropyl ether, methyl t-butyl ether and the like. Preferably, the solvent is an aromatic hydrocarbon, in particular toluene, diisopropyl ether or diethyl ether or mixtures thereof (for example 25/75 of diethyl ether / toluene) *

The reaction for the preparation of the optically active S-alpha-cyano-3-phenoxybenzyl alcohols is suitably carried out by adding the aldehyde and the solvent to the cyclo (D-phenylalanyl-D-histidine) catalyst, dispersing the mixture (mechanical or the mixture is agitated, for example stirred), hydrogen cyanide is added and the reaction conditions are chosen such that the optically active alpha-hydroxynitrile is formed within a certain time. It is preferred to use the hydrogen cyanide simultaneously

after or immediately after the solvent and / or the aldehyde to increase the conversion and stereoselectivity. The presence of cyanide ions has an adverse effect on the catalyst in this reaction, and the competitive racemization is reduced by protecting the catalyst from the cyanide ions. The formation and maintenance of a well-dispersed but not necessarily homogeneous reaction mixture is useful and recovery of the optically active alcohol product is carried out by methods known per se, including extraction and similar processes,

The reaction temperature as well as the pressure can vary. At normal pressure, the temperature is from about -10 to about 80 ^° C, more or less. Ambient temperatures of from about 5 to about 35 C are preferably used to obtain a good yield, suitable reaction rates and an enantiomeric excess of the desired optically active product. The low temperature of 5 ⁰ C gives the best results,

The amount of catalyst used to prepare the optically active alpha-hydroxynitriles, for example, S-alpha-hydroxynitrile, may vary. For example, it may be in the range of about 0.1 to about 10 mol% and preferably 0.1 to about 5 mol %, based on the weight of the aldehyde present, in particular in an amount of about 1.5 to about 7.5 mol% »are used. The catalyst is preferably well dispersed in the reaction mixture.

When the catalysts are prepared by methods known per se in the presence of a solvent (for example, water), if they are solid, they may also contain a crystallization solvent (for example, water). The optically active cyolo (D-phenylalanyl-D-histidine) dipeptide catalyst according to the invention can thus contain or not contain a crystallization solvent (for example water) if it is solid.

The non-symmetric ketenes used to prepare the cyano-methyl esters are generally known. Ketenes used in the present invention can be prepared by treating the corresponding acid halide with a tertiary amine.

Suitable tertiary amines are alkyl, aryl or heterocyclic tertiary nitrogen bases including the mono- or polyamines and similar compounds. Preferably, the tertiary amine is an amine in which the alkyl groups have from 1 to 10 carbon atoms, any aryl or aralkyl groups having from 6 to 20 carbon atoms and from 1 to 2 hydrocarbon rings, and any heterocyclic amines at least one ring nitrogen atom in a 5- or 6-membered heterocyclic ring optionally, a sulfur or oxygen atom or another nitrogen atom may contain , such as trimethylamine, triethylamine, tri-n-propylamine, pyridine and the like. A tertiary amine preferably contains three alkyl groups having 1 to 4 carbon atoms, for example trimethylamine, tri-n-propylamine and in particular triethylamine or trimethylamine,

The reaction for producing the non-symmetrical ketene is carried out in the presence or absence of a solvent. When a solvent is used, the solvent is preferably a non-hydroxylic solvent * such as hydrocarbons, chlorinated hydrocarbons, ethers and similar compounds. 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, Alkanene rich petroleum fractions are also suitable, for example motor gasoline, or gasoline with a boiling range at atmospheric pressure of between 40 and 65 ⁰ C, between 60 and 80 ⁰ C or between SO and 110 ⁰ C, petroleum ether is also suitable, cyclohexane and Methyl-cyclohexanes are examples of useful cycloalkanes containing 6 to 8 carbon atoms. Aromatic hydrocarbon solvents may contain from 6 to 10 carbon atoms, examples being benzene, toluene, o-, m- and p-xylene _# trimethylbenzenes, p-ethyltoluene and the like. Suitable chlorinated hydrocarbons contain 1 to 4 chlorine atoms together with an alkane chain containing 1 to 4 carbon atoms or with a benzene ring, for example carbon tetrachloride, chloroform * dichloromethane, 1,2-dichloroethane, trichloroethane, perchloroethane, chlorobenzene and 1,2- or 1 , 3-dichlorobenzene and similar compounds, ethers are generally those containing 4 to 6 carbon atoms, such as diethyl ether, methyl tert-butyl ether and diisopropyl ether, and similar compounds, tetrahydrofuran and dioxane are also suitable. If a solvent is used, this is preferably an aromatic hydrocarbon, particularly preferably toluene,

In preparing the non-symmetric ketene, the molar ratio of the starting materials can be widely varied. For example, the mole ratio of acid halide to base may be from about 10: 1 to about 1:10, and preferably from about 5: 1 to about 1: 5. However, it is preferred to use a molar excess of base based on the acid halide. Thus, the mole ratio of acid halide to base is suitably from about 1: 1.2 to about 1: 2, and preferably from about 1: 1 to about 1: 5.

In the preparation of the non-symmetric element, the temperature can vary widely. For example, at atmospheric pressure, the reaction temperature may be varied, and, for example, is suitably from about 10 to 40 C, more or less, although higher temperatures of about 75 to about 95 ° C are also useful.

The separation and recovery of the non-symmetrical ketene product is carried out according to methods known per se, including crystallization and similar processes,

The process of the invention is useful for the preparation of non-symmetric ketenes from any acid halides containing no substituent groups that react with the base. For example, the acid halide may be that of an acyclic, alicyclic, aromatic or heteroaromatic acid. The acid halide preferably has the formula V:

R ¹ 0

p I »»

R CH-C-X V,

wherein X is a halogen atom, such as a chlorine or bromine atom,

1 2 R and R each independently represent an alkyl, aralkyl, alkoxy, aryl oxy, alkylthio, alkylsulfonyl, arylthio or arylsulfonyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 7 ring carbon atoms, or wherein they together with the carbon atom to which they are attached *. a non-symmetrical cycloalkyl group with

3 to 7 form ring carbon atoms, R is an alkenyl or

Alkynyl group having 2 to 10 carbon atoms, a naphthyl group, phenyl group, a heterocyclic group, which

Contains 5 or 6 ring atoms »one of which is an oxygen, sulfur or nitrogen atom and the remaining carbon atoms, or an amino group which is disubstituted by acyl, alkyl having up to 10 carbon atoms,

Or a phenyl group means "The R and R groups may optionally be substituted by one or more halogens having an atomic number of 9 to 35, an alkyl, haloalkyl or cycloalkyl group of up to 7 carbon atoms, an alkenyl or haloalkenyl group of 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 equivalent kinds of substituents.

One class of acid halides are the halides of the pyrethroic acids including those described in US Pat

4 062 968 and 4 199 595, examples of

such acid halides include those of the formula V wherein

1 * 2

R isopropyl or cyclopropyl, "R is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to

6 carbon atoms, a naphthyl group, a phenyl group

or a (benzyloxycarbonyl) -phenylamino group each optionally substituted on the ring with one or more halogen atoms, alkyl, haloalkyl, alkoxy, haloalkoxy groups wherein the halogens are bromine, chlorine or fluorine and the alkyl groups contain from 1 to 4 carbon atoms can mean. For example, the acid halide may be isopropyl (4-chlorophenyl) acyl chloride, isopropyl (4-difluoromethoxy) phenyl) acetyl chloride, isopropyl ((4- (trifluoromethyl) -3-chlorophenyl) - (benzyloxycarbonyl) amino) acetyl chloride and similar compounds,

It is preferred that in the formula V R is isopropyl

2 and R represents a phenyl group optionally substituted by halogen, an alkyl or haloalkyl group having 1 to 4 carbon atoms, or an alkoxy or haloalkoxy group having 1 to 4 carbon atoms, preferably in the para position. Particularly useful are 4-chlorophenyl, 4- (difluoromethoxyphenyl), 4-methylphenyl, 4-tert-butylphenyl and like compounds,

Many of the non-symmetric ketenes are known per se, for example, (4-chlorophenyl) isopropyl ketene, which is described in U.S. Patent No. 4,199,527. Some other nonsymmetrical ketenes are known, but it may be that specific species are new, including, for example, (4- (difluoromethoxy) phenyl) isopropyls.

The invention relates, in accordance with a further embodiment of the invention, to a process for the preparation of an optically active cyanomethyl ester or an attached thereto.

richer mixture characterized in that an alpha-chiral (optically active) carboxylic acid halide or a reactive derivative thereof or an enriched mixture with an optically active, optionally substituted S-alpha-cyano-3-phenoxybenzylalkohol or an enriched Mixture prepared as above, treated.

The process of the invention is useful for preparing esters of any optically active acid halides (which do not contain substituted groups that react with the base, if present). * For example, the acid halide may be that of an acyclic, alicyclic, aromatic or heteroaromatic acid. "

The reaction is carried out in the absence of a solvent or in the presence of an organic solvent suitably selected from the same types of non-hydroxylic solvents described above for the process of preparing esters by treatment of the non-symmetric ketene Solvent an aromatic solvent, such as toluene.

The reaction with the acid halide is preferably carried out in the presence of a hydrogen halide acid acceptor, which is suitably a tertiary amine such as triethylamine or pyridine, and added slowly with stirring and generally after the other reactants are well mixed.

The reaction for the preparation of the optically active cyanomethyl esters from the S-alcohols and alpha-chiral carboxylic acid halides or their reactive derivatives is also suitably carried out at phase transfer conditions in the presence of a phase transfer catalyst whereby the transfer of ions or other reactive or functional chemical species along the phase interface such as in heterogeneous systems, examples which are not intended to be limiting of phase transfer catalysts include certain organic quaternary salts of Group VA elements of the Periodic Table of Elements, for example, nitrogen, phosphorus, arsenic, antimony and bismuth.

The preferred phase transfer catalysts are tetra-butylphosphonium chloride, tri-n-butyl-n-octylphosphoniumbroride "hexadecyltributylphosphonium bromide", benzyltriethylammonium chloride, benzyltriethylammonium bromide, trioctylethylammonium bromide, tetraheptylaramonium iodide, triphenyldecylphosphonium iodide, tribenzyldecylammonium chloride, tetranonylammonium hydroxide, tricaprylylmethylammonium chloride, and dimethyldicocoammonium chloride. The last two catalysts are manufactured by General Mills Company "Chemical Division" Kankakee "III.," And they are alternatively identified by the designations "Aliquat 336 ^" and "Aliquat 221 ^".

In the preparation of the esters, the molar ratio of the starting materials can be varied widely. For example, the molar ratio of acid halide to alcohol of

from about 10: 1 to about 1:10, and preferably from about 5: 1 to about 1: 5. However, it is preferred to have a molar excess of acid halide to alcohol. Therefore, the molar ratio of alcohol to acid halide is preferably from about 1: 1 to about 1: 5 and suitably from about 1: 1 to about 1: 1.2,

In the production of the ester, the temperature can be varied widely. For example, at atmospheric pressure, the temperature in the reaction of, for example, about 0 to about 70 ⁰ C can be varied. However, it is preferably about 10 to 40 C, more or less.

The separation and recovery of the ester product can be carried out by methods known per se, including crystallization and similar processes.

This embodiment of the process of the invention is useful for the preparation of esters from acid halides or their reactive derivatives which contain no substituted groups which react with the base. For example, the acid halides or their reactive derivatives are well known and include acyclic, alicyclic, aromatic or heteroaromatic acids and their reactive derivatives, and they preferably have the formula VI:

R 10 R ¹ CH-OX VI,

where X is a reactive derivative of the corresponding carboxylic

1 2 acid, R and R each independently

Alkyl, aralkyl, alkoxy, aryloxy, alkylthio, alkylsulfonyl, arylthio or Arylsulfonylgruppe having 1 to 10 carbon atoms or a Cycloalkylgruppe rait 3 to 7 ring carbon atoms mean or together with the carbon atom to which they are attached, a non-symmetrical cycloalkyl group having 3 to 7 ring carbon atoms

R 2 represents an alkenyl or alkynyl group having 2 to 10 carbon atoms, a naphthyl group, a phenyl group, a heterocyclic group having 5 or 6 ring atoms, one of which is an oxygen, sulfur or nitrogen atom and the rest are carbon atoms, or an amino group, disubstituted by acyl, alkyl with up to 10 carbon atoms

1 2 atoms, or a phenyl group means "The R and R groups may optionally be replaced by one or more halogen atoms having an atomic number of 9 to 35, an alkyl, haloalkyl or cycloalkyl group of up to 7 carbon atoms, an alkenyl or Haloalkeny! group with 2 to 4, haloalkoxyT or alkoxy group having 1 to 4 carbon atoms, Haloalkylthio- or alkylthio group having 1 to 4 carbon atoms or equivalent types of substituents substituted as "reactive derivatives, the halides are preferred, for example those of the above formula VI, wherein X is chlorine or bromine means.

One class of acid halides are those of the pyrethroic acids, including those described in U.S. Patent Nos. 4,024,163, 4,062,968, 4,220,591, 3,835,176, 4,243,819, 4,316,913 and 4,199,595 Such acid halides or their reactive derivatives include those of formula VI, wherein R is isopropyl or cyclopropyl,

2 R is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a naphthyl group, a phenyl group or a (benzyloxycarbonyl) -phenylamino each of which is optionally substituted on the ring by one or more halogens, alkyl, haloalkyl, alkoxy, Haloalkoxy, wherein the halogens are bromine, chlorine or fluorine and the alkyl groups contain 1 to 4 carbon atoms, may be substituted * or wherein R

and R together with the carbon atom to which they are attached form a cyclopropyl group of the formula:

X W \ /

ν_ / Λ-

in which VV, X "Y and Z each independently represent a hydrogen atom, a halogen atom having an atomic number of up to 35 or an alkyl group having 1 to 4 carbon atoms, wherein Y and Z each independently represent an alkyl group having 1 to 4 carbon atoms, W is a hydrogen atom and X is pentahaloethyl, dihalovinyl, isobutenyl, perhalomethylvinyl, 2-phenyl-2-halovinyl-2-phenyl-1, 2,2-trihaloethyl or alkoxyiminomethyl or ((cycloalkyl) alkoxy) -iminomethyl having 1 to 10 carbon atoms , For example, the acid halide may be 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 _f 2-dichlorovinyl) -cyclopropanecarbonyl chloride _# 2., 2-dimethyl-3- (2,2-dibromovinyl) -cyclopropanecarbonyl chloride _i 2,2-dimethyl-3- (1,2-dibromo-2,2-dichloroethyl) -cyclopropancarbonylchlorid, l- (4-ethoxyphenyl) ~ 2 _# 2-dichlorcyclopropancarbonylchlorid, 2,2-dimethyl-3- (2- (trifluoromethyl) -2-chlorovinyl) -cyclopropancarbonylchlorid, 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 chrysantheryl chloride or the like Be connections.

1 2

Preferably in the formula VI R is isopropyl and R is a phenyl group which is optionally substituted by halogen, an alkyl or haloalkyl group of 1 to 4 carbon atoms or an alkoxy or haloalkoxy group of 1 to 4 carbon atoms, preferably in the para position. Particularly useful are 4-chlorophenyl, 4- (difluoromethoxyphenyl), 4-methylphenyl, 4-tert-butylphenyl and similar compounds,

According to one embodiment of the invention, an S-alpha-cyano-3-phenoxybenzyl alcohol or a diet enriched therewith is treated with S-alpha-isopropylphenylacetyl chloride or an optionally substituted chiral cyclopropanecarboxylic acid chloride to form an optically active cyanomethyl ester or a mixture enriched therewith.

The cyanomethyl esters for which the optically active form is prepared according to one or more embodiments of the method of the invention, d. h of the formula I:

O CN

CH-C-O-C

are well known, cf., for example, Francis et al. Chem. See, 95, pp. 1403-1409 (1909) and the like, and the optical forms are disclosed in US Pat. Nos. 4,151,195, 4,239,737, 4,328,167, and 4,133,826, and GB-PS 2 014 137 and similar references "Any of the alpha-cyanomethyl esters produced can be hydrolyzed into their corresponding acids by hydrolysis methods known per se. Preferably, the optically active ester product is S-alpha-cyano-S-phenoxybenzyl-s-alpha. , (isopropyl- (p-chlorophenyl) -acetate, S-alpha-cyano-3-phenoxybenzyl-S-alpha-isopropyl- (p- (difluoromethoxy) -phenyl) -acetate, S-alpha-cyano-3-phenoxybenzyl (lR, cis) -3- (2,2-dichlorovinyl) - 2,2-dimethyl-cyclopropanecarboxylate, S-alpha-cyano-3-phenoxybenzyl (lR _i cis) -3- (2,2-dibroravinyl) - 2 _{l of} 2-dimethylcyclopropane carboxylate , S-alpha-cyano-3-phenoxybenzyl (1R, cis) -3- (1- _t- 2-dibromo-2,2-dichloroethyl) -2,2-dimethylcyclopropanecarboxylate, S-alpha Cyano-3-phenoxybenzyl (IR, ice) -2,2-dimethy1-3- (neopentoxyiminomethyl) cyclopropanecarboxylate or the like he similar connections *

The following embodiments illustrate the invention without limiting it.

embodiments example 1

S-alpha-cyano-3-phenoxybenzyl-S-isopropyl-f4-chlorophenyl) acetate

1 liter of a solution containing 0.135 g of S-alpha-cyano-3-phenoxybenzyl alcohol in toluene is added to two 1-dram ampoules, followed by the addition of 0.504 ml of S-isopropyl (4-chlorophenyl) acetyl chloride solution Toluene too.

0.07 ml of 2,3-lutidine are added to the first ampoule with stirring. The resulting mixture heats up immediately and a solid separates out. Stirring is continued for 10 minutes, no change occurs. The mixture is washed successively with water, dilute hydrochloric acid and water and dried over MgSO 4. dried. The resulting oil contains 75.5 % S-alpha-cyano-3-phenoxybenzyl-S-isopropyl- (4-chlorophenyl) -acetate isomer.

0.083 ml of triethylamine are added to the second ampoule with stirring. An immediate reaction occurs and the product is recovered as described above. An oil containing 72.0 % S-alpha-cyano-3-phenoxybenzyl-S-xsopropyl (4-chlorophenylacetate isomer is obtained.

Example 2

S-alpha-cyano-3-phenoxybenzyl (lR, cis) -2,2-dimethyl-3- (2,2-dichlorovinyl) cyclopropanecarboxylate

To a solution of 1 g of (1R, cis) -2,2-dimethyl-3- (2,2-dichlorovinyl) -cyclopropanecarboxylic acid, dissolved in 25 ml of methylene chloride, is added 0.5 g of thionyl chloride and then a few drops of dimethylformamide. The reaction mixture is heated at reflux overnight, and the solvent is under pressure at 40 ⁰ C away "the residue in

Dissolve 20 ml of benzene and add 0.4 g of S-alpha-cyano-3-phenoxybenzyl alcohol (90% enantiomeric excess of the S-isomer) in 2 ml of benzene, then add 0-5 ml of pyridine in 2 ml of benzene. The reaction mixture is stirred for 1.5 h »The resulting solution is poured into water, extracted with ether ¹ * the ether layer is washed with dilute hydrochloric acid and then with sodium bicarbonate solution. The organic layer is washed with water, dried (MgSO 4) and condensed. A yellow oil is obtained, which is chromatographed. 0.53 g of the desired product is obtained, * 0g = 26.55 ° (CH ₂ Cl ₂ 0.558 g / ml),

Example 3

S-alpha-cyano-S-phenoxybenzyl-S-isopropyl-M-chlorophenyl) -acetate ,

In a 1-Dram ampoule, add 1 ml of a solution of alpha-cyano-3-phenoxybenzyl alcohol with an R / S ratio of ca, 72/28 and 0.121 ml (4-chlorophenyl) isopropyl ketene, then 7, 5 mg cyclo (D-phenylalanyl-D-histidine) added. The reaction mixture is stirred at ambient temperature for 24 h. A colorless product is obtained which contains white insoluble flakes. The reaction mixture is centrifuged to remove the solids. The liquid phase is decanted off and washed with 1 N hydrochloric acid and twice with water, dried with MgSO ₄ , filtered and diluted to room temperature with a solvent for analysis. The desired product, as shown by the analysis on the Pirkle column, has a ratio of 55.1 % S-alpha.

Cyano-3-phenoxybenzyl-S-isopropyl- (4-chlorophenyl) -acetate and 16.6 % R-alpha-cyano-3-phenoxybenzyl-R-isopropyl- (4-chlorophenyl) -acetate «

Example 4

S-alpha-cyano-3-phenoxybenzyl S-isopropyl- (4-chlorophenyl) acetate

In a 1-Dram ampoule are added 1 ml of alpha-cyano-3-phenoxybenzylalkohollösung as described in Example 17, and then 0.121 ml (4-chlorophenyl) isopropyl ketene and then 7.5 mg cyclo-CD-phenylalanyl-D histidine) ♦ The resulting mixture is stirred at ambient temperature for 20 h. A colorless product is obtained which contains white flakes. This reaction product mixture is centrifuged and the insoluble gel cake is washed and centrifuged four times with 1 ml portions of hexane. The combined organic extracts are washed with dilute hydrochloric acid and water, dried, concentrated to less than 1 ml and then diluted to 2 ml with toluene »The desired product has, as the analysis with the Pirkle column shows a ratio of 63, 0 % S-alpha-cyano-3-phenoxybenzyl-S-isopropyl- (4-chlorophenyl) -acetate and 12.5 % R-alpha-cyano-3-phenoxybenzyl-R-isopropyl- (4-chlorophenyl) -acetate »

Example 5

S-alpha-Cvano-3-phenoxvbenzvl-S-isopropyl- (4-chlorophenyl) acetate

The catalyst gel, which in the embodiment 18 above

.- 41 -

is washed with 1.5 ml of hexane and then placed in a 1-dram vial »The ampoule is rait 1 ml of S-alpha-cyano-3-phenoxybenzylalkohollösung as described in Example 14, and 0.121 ml (4 The reaction mixture is stirred for 16 h and then extracted five times with 1 ml of hexane. The combined extracts are stripped and diluted to 2 ml with toluene for analysis. The desired product, as shown by the analysis on the Pirkle column, has a ratio of 62.4 % S-alpha'-cyano-S-phenoxybenzyl-S-isopropyl- (4-chlorophenyl) -acetate and 14.1 %. R-alpha-cyano-3-phenoxybenzyl R-isopropyl ~ acetate (4-chlorophenyl),

Example 6

S-alpha-cyano-3-phenoxybenzyl S-isopropyl- ~ (4-chlorophenyl) acetate

A 0.5 dram vial containing a magnetic stir bar and 4 mg of cyclo (D-.phenylalanyl-D-histidine) is filled with nitrogen and capped with a septum cap. In this vial is injected 0.174 ml After stirring for 5 minutes, 0.18 ml of (4-chlorophenyl) isopropyl ketene is added. After 2 days, the reaction mixture is diluted with toluene, washed with 1N-hydrochloric acid and water, dried (MgSO 4) A solution thereof in 1 ml of toluene is analyzed and found to be enriched in the desired material.

Examples 7 to 95

Into a vial is added 13.5 % w / v racemic alpha-cyano-3-phenoxybenzyl alcohol solution in 0.6 M toluene, followed by a 5 % w / v excess of (4-chlorophenyl) isopropyl ketene and 4 % catalyst The resulting mixture is stirred at 25 ^° C. for a time such that the reaction is substantially complete.

The catalyst used and the predominant isomers are given in the following table, wherein the symbols used to describe the catalyst are standard symbols in peptide chemistry, for example as described by Schröder and Lubke in "The Peptide", Volume II, pages XI to XXVI (1966), and the isomers are Api = S-acid-S-alcohol isomer, Aβ = S-acid-R-alcohol isomer, Bist = R-acid-S-alcohol isomer and Bβ = R-acid R-alcohol isomer,

table

Exemplary embodiment catalyst Time (h) Percentage of the predominant Iso mers = 29.8 7 cyc (2-pyridylala-L-Phe) 4 3 "* = 38.0 8th cyc (D-Phe-L-His) <28 3S = 28.1 9 cyc (L-Trp-L-Trp) > 36 bß = 32.4 10 Z-L-Leu-L-His-Me ester 6.5 aod = 30.0 11 .. D-histidine (free base) ? 36 bß = 29.3 12 D-His-Me ester, 2 HCl 30 A * = 30.0 13 L-Phe > 30 ate = 27.0 each 14 Ser-ΜΜ ester , HCl > 35 Α? *, Bß

Continued table

Execution example catalyst Time (h) Percentage of the predominant Iso mers = 29.4 15 eye (L-Leu-L-His) , 30 A * = 36.7 16 eye (Gly-L-Trp) > 36 bß = 36.7 17 eye (D-Phe-D-Trp) > 52 ate = 36.4 18 eye (D-Phe-L-His) <36 bß , B4> = 27.8 each = 31.8 19 20 eye (L-Phe-L-Phe) eye (L-Phe-L-Mst) > 52> 52 Aß, Bß = 32.6 21 eye (D-Phe-D-His)> 8 <22 AoC = 30.6 22 N-acetyl-L-His.H ₃ O 30 bß = 28.5 23 Z-D-Phe-L-His ester 28 bß = 29.9 24 eye (L-HoraoPhe-L-His) ^^ JL O A * = 35.8 25 eye (L-Phe-L-3-Me-His) 1.5 bß = 27.0 26 (L-Phe) ⁴ , 3H ₂ O > 100 Bk. BoC = 29.9 each 27 BOC-D-Phe 6.5 ate, = 29.2 23 N-acetyl-L-Trp 120 at = 30.9 29 N-Acetyl-L-Trp Et ester 120 ate H 0 t It

(+) -cis_ f [

120

= 32.6

COOH

N-CH ₀ CH-

> 100

BoC

= 28.7

Continued table

Execution example catalyst Time Ch) > 6 <24 80 > 54 <72 Percentage with the predominant Iso mers = 26.3 32 N-alpha-acetyl-L-Orn > 120 30 5 days BeC = 25.5 33 L-phenylalaninol > 120 0.25 <22 AeC = 36.8 34 L-Camosine 80 1 > 50 <74 AoC = 28.8 35 L - (-) - sparteine 1 eye (N-Ac-L-Phe-N-Ac-Gly) 74 24 In. = 33.0 36 N-benzyl-in-benzyl-L-His 0.5 eye (L-Val-L-His) 6.5 bß = 38.4 37 N-Z-His-p-NO-L-Phe-L-Phe- 6.5 OMe eye (L-Phe-Gly) > 8 <22 Ad. = 32.7 38 eye (L-Tyr-L-His) eye (L-Phe-L-His) > 100 bß = 32.4 39 N-Z-L-His L-benzyl hydantoin 100 Act = 32.4 40 brucine alpha-N-Me-L-His 100 BoC = 28.8 41 Nicotine alpha-N-benzyl-L-His > 8 <22 ate = 25.8 each 42 ZL-His-L-Leu. H ₃ O > 22 <72 BcC, Bd = 38.1 43 N-Z-L-His-Gly > 8 <22 ΑΛ = 26.8 44 Gly-L-His ♦ HCl 4 B <* = 38.1 45 L-beta-aspartyl-L-His t-BOC-N- ^1- benzyl-L-His 1. bß = 26.9 46 Z-L-His-L-Phe t-BOC-N ⁱⁿ -tosyl-L-His ate = 31.0 47 BOC-L-Phe-L-His-OMe bß = 30.6 each 48 AOC-L-Ph e -L-His-OMe Aet.Bß = 36.6 49 BOC-D-PhGly-D-His-OMe B ₀ C = 37.4 50 AeC = 27.3 51 AiK = 31.3 52 bß = 30.0 53 ΑΛ = 27.6 54 AeC = 29.5 55 AoC = 34.2 56 bß = 31.0 57 bß = 27.0 58 bß

Continued table

Execution example Time catalyst (h) Percentage with the predominant Iso mers = 28.4 59 0 Ah L- I II N _n '^, 46 ^^ M ^^ - LJ bß = 30.5 60 L-histidinol. 2HCl 28 AoC = 32.2 61 L-beta-Imidazole Lactic 22-100 acid bß = 28.5 62 N-Z-L-Trp> 100 BoJ .. = 31.8 = 28.5 63 64 NZL-Trp-p-N0 ₂ Ph ester> 100 ZD-Phe-D-Trp-OMe> 100 Ate Bai = 28.8 65 alpha-N-L-Arginine-3enzoyl> 100 = 28.2 56 N-alpha-benzoyl-L-arginine amides. HCl.H ₂ O> 100 B ₀ C = 29.2 67 N-alpha-acetyl-L-lysines> 100 at = 28.2 68 N-alpha-acetyl-L-lysine 100 OMe.HCl ate = 28.6 69 Cyc (L-Vali-Gly) 100 3Λ. = 31.2 70 3-Me-His-0Me.2HCl> 8 4.22 AeC = 32.9 71 Cyc (Gly-L-His) 30 bß = 31.4 72 Poly-L-histidine <46 ate = 32.9 73 Z-L-Hls-L-Phe-L-Phe.CEt 6.5 bß = 31.5 74 N-alpha-benzoyl-L-His-> 10 <22 OMe.HCl eel = 5 30.8 75 t-BOC-L-His> 30 <46 A * = 35.6 76 L-pGlu-L-His-Gly-NH ₂ 9 bß = 30.2 77 L-pGlu-L-His-Gly-HOAc 0.5 ate

- 46 - Time (h) ' Percentage with the predominant Iso mers 6 Act = 35.3 Implementation example Continuation table > 6 <54 A <* = 28.8 78 catalyst 79 L-beta-Ala-L-3-Me-His HNO ₃ 3.5 Bβ = 26.9 N-3,5-DNPyr-L-His 80 OH CH, ^ -Ph-CH-CHN (Me) ₀

Z-D-Phe-NHCH.

· = N

4.5 ate

= 29.2

N-benzoyl-L-His <46

N-S-acetyl-L-lysines> 72

alpha-N-benzoyl-L-Arg,

OEt.HCl> 46 <54

Z-D-Phe

^ NH {' N

3.5

ate

= 30.3 = 31.4

= 26.5

Lp-Glu-L-His-L-Pro.NH ₂ 6 Bβ = 35.3

Cyc (L - + - Phegly-L-His) 24 Aet = 32.4

Cyc (1-Me-L-His-L-Phe) 10 min Bβ = 41.3

Cyc (2-naphthylala-L-His)> 6 <24 Bβ = 34.6

ZL-Phegly-L-His-OMe 7 Ni = 32.8

Z-L-Homophe-L-His-OMe <23 Bβ = 30.6

- 47 Continuation of the table

Execution time percentage

Example catalyst (h) with the over

weighing Iso '. _{i tt} 'mers

92 cyc (D-Phe-D-His) -CtG ₄ H _g > 7 <22 AoC = 38.9

93 angiotensin II pentapeptides 48 atf. = 34.4 (Tyr-Ile-His-Pro-Phe)

94 Z-Renin Substrates> 24 <48 Ac *. = 42.1 (Z-Pro-Phe-His-Leu ~ Leu

Val-Tyr-Ser-beta-naphthy1 amidej

95 glucagon hexapeptides> 24 < 48 AeC = 31.1 (L-His-L-Ser-L-Glu-Gly-

L-Thr-L-Phe)

The choice of the various reaction conditions within the scope of the present invention may effect a change in the reaction rate and a change in the amount of the predominant isomer. Of course, the substitution of pure optically active R- or S-alpha-cyano-3-phenoxybenzylalcohol or a strongly enriched one Mixture thereof in Embodiments 7 to 95 within the scope of the present invention, and the amount of the predominant isomer product increases »

Example 96

alpha-cyano-3-phenoxybenzyl-alpha-isopropyl- (4-chlorophenyl) -acetate

A mixture of 2.31 g of isopropyl (4-chlorophenyl) -acetyl chloride is treated with 2 _f 78 ml dry triethylamine.

Isopropyl (4-chlorophenyl) isopropyl ketene is obtained in 8 ml of toluene.

A mixture of 2.00 g of 3-phenoxybenzaldehyde in 8 ml of toluene with 0.55 g of sodium cyanide is stirred under nitrogen. To this cooled solution is added O ₁ S ml of water »and then added slowly 0.86 ml of concentrated hydrochloric acid to. The resulting mixture is stirred at room temperature for 10 minutes and then 0.2 ml of concentrated hydrochloric acid is added dropwise. The organic phase is separated with a pipette, filtered over 3 g of magnesium sulfate using an additional 3 ml of toluene. The entire filtrate is added to the ketene solution prepared above (containing triethylamine) pre-cooled to -50 ° C. The reaction mixture is warmed to room temperature, allowed to stand for 10 minutes and then sequentially with water, 5% sodium carbonate solution, water and dilute Washed hydrochloric acid, added to a column of silica gel and eluted with 36 / öigem diethyl ether in toluene. The eluate is dried (MgSO 4) and stripped of solvent. This gives 3.98 g of a brown oil having an isomeric ratio of 65 % of the enantiomeric pair S-alpha-cyano-3-phenoxybenzyl-R-isopropyl- (4-chlorophenyl) -acetate and .R-alpha-cyano-3-phenoxybenzyl- S-isopropyl- (4-chlorophenyl) -acetate and 35 % of the R _# R and S, S-enantiomers "

Example 97

alpha-cyano-3-phenoxybenzyl-isopropyl- (4 ~ chlorophenyl) acetate

In an I-Dram ampoule, 1 ml of a toluene solution of

0.6 mmol of alpha-cyano-3-phenoxybenzyl alcohol with an isomer ratio of 'R / S = 72/28, to this are added 0.121 ml of (4-chlorophenyl) isopropyl ketene and then 0.0084 ml.' Triethylamine, the reaction mixture warms The reaction is completed in less than 1 minute The mixture is washed with 1N HCl, water, dried (MgSO 4) and diluted to 2 ml with toluene Analysis by liquid chromatography on a Chiral Pirkle column gives the following isomer ratio: S -alpha-cyanogen ~ 3-phenoxybenzyl-R-isopropyl- (4-chlorophenyl) -acetate / -R, S-isomer / S, S-isomer / R, R-isomer = 13,6 / 42,2 / 30, 6 / 13.6,

Examples 98 to 107

S-alpha-cyano-3-phenoxybenzylisopropyl- (4-chlorophenyl) acetate

According to the methods described in the above embodiments 96 and 97, equimolar amounts of non-chiral tertiary amines (4-chlorophenyl) -. isopropyl ketene and S-alpha-cyano-3-phenoxybenzyl alcohol reacted at 0 ⁰ C,

The results of these experiments are listed in the following Table II, where the capital letters A and B denote the S or R absolute configuration in the acid molecular moiety of the ester product, and oL the S-absolute configuration in the alcohol moiety of the ester product.

Table II

Execution tertiary amine yield selectivity example%% _t to

98 1, 4 ~ diazabicyclo - / 2,2,2; j - 60,8 Bot B <* »68,1 octane

99 1-methylimidazole 46.4 Act. AeI, 52.0

100 2,6-Lutidine 63.7 W Bet, 71.1

101 dinethylbenzylamine 53.8 bot bot, 58.9

102 dimethyldodecylamine 57.6 BoL Bot »53.3

103 imidazole 42.3 BeC Bed, 50.7

104 Tricapylamine 54.2 Bot Bet, 60.4

105 pyridine 58.9 BJ. At, 64.6

106 pyridine (Keten overhead) 55.5 BqL Bd ₁ 61.3

107 dimethylaniline 44.9 bot at, 50.4

In alveolar reactions, aliquots of the same sample of alpha-cyano-3-phenoxybenzyl alcohol containing about 86 % of the S-isomer are used.

The choice of other reaction conditions within the scope of the present invention can effect a change in the reaction rate and amount of the predominantly formed isomer. Of course, the substitution of pure optically active R- or S-alpha-cyano-3-phenoxybenzyl alcohol or a more enriched mixture thereof in the embodiments 96 to 107 within the scope of the present invention, and thereby increasing the amount of the R or S isomer product.

Claims (4)

Invention claim} 1 »A process for the preparation of an optically active Cyanomethylesters or a mixture enriched thereon, characterized in that an alpha-chiral (optically active) carboxylic acid halide or a reactive derivative thereof or an enriched mixture with an optically active S-alpha-cyano-3 phenoxybenzyl alcohol or a mixture enriched therewith, the alcohol or mixture thereof being prepared by reacting an optionally substituted 3-phenoxybenzaldehyde with a source of hydrogen cyanide in the presence of a substantially water immiscible aprotic solvent and a cyclo (D -phenylalanyl-D-histidine) ~ dipeptide ~ l <atalysators, 2. The method according to item 1, characterized in that it is carried out using an acid halide in the presence of a solvent and a hydrogen halide acceptor. 3. Method according to item 1, characterized in that it is carried out under phase transfer conditions, A method according to item 1, characterized in that the acid halide is an optionally substituted S-alpha-isopropylbenzeneacetic acid chloride or an optionally substituted chiral cyclopropanecarboxylic acid chloride.