WO1997014688A1 - A PROCESS FOR THE PREPARATION OF α-CHLOROMETHYLPHENYLACETIC ACID DERIVATIVES - Google Patents

A PROCESS FOR THE PREPARATION OF α-CHLOROMETHYLPHENYLACETIC ACID DERIVATIVES Download PDF

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WO1997014688A1
WO1997014688A1 PCT/EP1996/004332 EP9604332W WO9714688A1 WO 1997014688 A1 WO1997014688 A1 WO 1997014688A1 EP 9604332 W EP9604332 W EP 9604332W WO 9714688 A1 WO9714688 A1 WO 9714688A1
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formula
compound
reaction
process according
acid ester
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PCT/EP1996/004332
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French (fr)
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Albert Pfiffner
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Novartis Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
    • C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups

Definitions

  • the invention relates to a process for the preparation of ⁇ -chloromethylphenylacetic acid derivatives of formula I
  • X is a radical inert towards the reaction; m is from 0 to 4.;
  • R 3 is CH 3l CH 2 F or CHF 2 ;
  • R 4 is C,-C 6 alkyl
  • R 5 is hydrogen or C 1 -C 4 alkyl; n is 0 or 1 ; which process comprises reacting a tert-benzylamine of formula II
  • X, m and Z are as defined for formula I and R-i and R 2 are each independently of the other C Cealkyl, C C 6 alkenyl, C T -C ⁇ alkoxyalkyl,
  • Ri and R 2 together with the nitrogen atom are an unsubstituted or substituted 6- or 7- membered ring that in addition to the nitrogen atom may also contain a further hetero atom
  • Suitable substituents for benzyl and on the substituted 6- or 7-membered ring are: halogen, C T -C ⁇ alkyl, C-rC ⁇ alkoxyalkyl, halo-CrC ⁇ alkyl and halo-d-Cgalkoxyalkyl.
  • alkyl groups are straight-chain or branched and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, sec-amyl, tert-amyl, 1 -hexyl or 3-hexyl.
  • alkenyl straight-chain or branched alkenyl e.g. allyl, methallyl
  • Alkenyl radicals having a chain length of 3 or 4 carbon atoms are preferred.
  • Halogen and halo denote fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
  • Haloalkyl may contain identical or different halogen atoms, e.g. fluoromethyl, difluoromethyl, difluorochloromethyl, trifiuoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trichloroethyl or 3,3,3-trifluoropropyl.
  • fluoromethyl difluoromethyl, difluorochloromethyl
  • trifiuoromethyl chloromethyl, dichloromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trichloroethyl or 3,3,3-trifluoropropyl.
  • Alkoxy is, for example, methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy or tert-butyloxy; preferably methoxy or ethoxy.
  • Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the compounds of formula I are important intermediates for the preparation of microbicides.
  • tert-benzylamines can be converted into the corresponding benzyl chlorides with a chloroformic acid ester.
  • an o-hydroxybenzyldiethylamine is reacted with ethyl chloroformate to form the corresponding benzyl chloride, the yield being only 80% and the hydroxy group on the phenyl ring also reacting with the ethyl chloroformate.
  • the reaction according to the invention may be carried out in an anhydrous, aprotic solvent or without solvent, it being possible also for a chloroformic acid ester to be used as solvent.
  • Preferred solvents are hydrocarbons, halogenated hydrocarbons, ethers and carboxylic acid esters, especially preferably benzene, toluene, xylene, chlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, trichloromethane, dichloroethane, trichloroethane, tert-butyl methyl ether, tetrahydrofuran, dioxane, ethyl acetate or ethyl chloroformate.
  • the reaction temperature is preferably from 0°C to the boiling point of the solvent, especially 20-120 ⁇ C.
  • the reaction is advantageously carried out in the presence of a base that is used e.g. in an amount of from 1 to 50 mol % based on the compound of formula II.
  • a base that is used e.g. in an amount of from 1 to 50 mol % based on the compound of formula II.
  • Preferred bases are alkali metal or alkaline earth metal hydrogen carbonates or carbonates.
  • the chloroformic acid ester may be used in any excess and the unreacted portion can be recovered; the use of 100-200 mol % based on the compound of formula II is advantageous.
  • the alcohol moiety of the chloroformic acid ester may be chosen as desired provided it does not enter into any undesired reactions; expediently it consists of a maximum of 8 carbon atoms, with an unsubstituted or halogenated C C 4 alkyl ester, an unsubstituted or halogenated C 1 -C 4 alkenyl ester or an unsubstituted or substituted benzyl or phenyl ester being preferred and with ethyl chloroformate being especially preferred.
  • R T and R are preferably C C ⁇ alkyl or
  • R T and R 2 together with the nitrogen atom are piperidine, piperazine, hexahydroazepine or tetrahydroisoquinoline, especially piperidine.
  • both amino groups can be utilised for the reaction according to the invention, that is to say in that case only half a molar equivalent of the amine is required.
  • Z is the group b) and
  • R 3 and R 4 are CH 3 .
  • the compounds of formula III are known (e.g. J. Heterocycl. Chem. Vol.16, p.1443, 1979).
  • Preferred leaving groups are chlorine, bromine, iodine, trifluoromethanesulfonyloxy and p- toluenesulfonyloxy.
  • organic nitrite e.g. tert-butyl nitrite, n-pentyl nitrite or isopentyl nitrite
  • the compounds of formulae Ila, lib, lie and lid are reacted according to the invention to form the corresponding compounds of formula I which are then reacted, as described e.g. in WO 94/26700 and WO 95/18789, to form the ⁇ -(subst.methyl)-phenylacetic acid derivatives.
  • the present invention relates also to that entire reaction sequence.
  • the described reactions are carried out in a manner known perse, e.g.
  • solvents or diluents aromatic, aliphatic and alicyclic hydrocarbons and halogenated hydrocarbons, such as benzene, toluene, xylene, chlorobenzene, bromobenzene, nitrobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, trichloromethane, dichloroethane or trichloroethane; ethers, such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; alcohols, such as methanol, ethanol, propanol, butanol, ethylene glycol or glycerol; esters, such as ethyl acetate or butyl acetate; amides, such as N,N- dimethylformamide, N
  • Leaving groups are, e.g., chlorine, bromine, iodine, C ⁇ -C 8 alkylthio, such as methylthio, ethylthio or propylthio, C C ⁇ alkanoyloxy, such as acetoxy, (halo- ⁇ -Ce-alkanesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy or trifluoromethanesulfonyloxy, or unsubstituted or substituted phenylsulfonyloxy, such as benzenesulfonyloxy or p-toluene- sulfonyloxy, imidazolyl, hydroxy or water; preferably chlorine, bromine, iodine or p-toluene- sulfonyloxy.
  • Suitable bases are e.g. alkali metal or alkaline earth metal hydroxides, hydrides, amides, alkanolates, carbonates, dialkylamides or alkylsilylamides, alkylamines, alkylenediamines, or unsubstituted or N-alkylated, saturated or unsaturated cycloalkylamines, basic heterocycles, ammonium hydroxides and also carbocyclic amines.
  • DBU 1 ,8-diazabicyclo[5.4.0]undec-5- ene
  • the reaction may also be carried out with phase transfer catalysis in an organic solvent, e.g. methylene chloride or toluene, in the presence of an aqueous basic solution, e.g. sodium hydroxide solution, and also in the presence of a phase transfer catalyst, e.g. tetrabutyl ⁇ ammonium hydrogen sulfate.
  • organic solvent e.g. methylene chloride or toluene
  • an aqueous basic solution e.g. sodium hydroxide solution
  • phase transfer catalyst e.g. tetrabutyl ⁇ ammonium hydrogen sulfate
  • the invention relates also to a process for the preparation of ⁇ -chloromethylphenylacetic acid derivatives of formula Ib according to Reaction Scheme 2
  • X, m and R-i to R 4 are as defined for formulae I and II, which process comprises b) hydrolysis and subsequent esterification of a compound of formula VI, wherein X, m, R, and R 2 are as defined for formula I, to form a compound of formula lib; h) reaction of the compound so obtained with a chloroformic acid ester or phosgene in the absence of water.
  • the invention relates also to a process for the preparation of ⁇ -chloromethylphenylacetic acid derivatives of formulae Ib, Ic and Id according to Reaction Scheme 3 Reaction Scheme 3
  • ⁇ -chloromethylphenylacetic acid derivatives of formula Ib are prepared wherein m is 0, and
  • R 3 and R 4 are CH 3 .
  • the invention relates also to a process for the preparation of ⁇ -chloromethylphenylacetic acid denvatives of formula la according to Reaction Scheme 4
  • X, m, n and Ri to R 4 are as defined for formulae I and II, which process comprises f) hydrolysis of a compound of formula IV and subsequent esterification to form a compound of formula V; g) reaction of the compound so obtained with a formic acid ester and subsequent methylation e.g. with methyl iodide, methyl chloride or dimethyl sulfate; or fluoromethylation with BrCH 2 F; or difluoromethylation with CICHF 2 ; under basic conditions to form a compound of formula Ila; h) reaction of the compound so obtained with a chloroformic acid ester or phosgene in the absence of water.
  • the invention relates also to the novel compounds of formulae II, IV and VI, especially the compounds
  • Example 1 2-Bromomethvlbenzvl cvanide .111.1 .
  • the conversion of the piperidinomethylbenzyl cyanide into the methoxyiminobenzyl cyanide can be carried out also without isolation of the intermediate without losses of yield by distilling off tert-butanol after the oximation (proceeds quantitatively) and methylating the resulting potassium salt in situ with diethyl sulfate in acetone or DMF.
  • the mixture is then poured into 250 ml of water, exhaustively extracted with ethyl acetate and worked up in customary manner.
  • reaction requires 15 hours' reflux and the HCl consumption is 85 g.
  • the reaction time depends on the size of the batch, on the amount of HCl introduced per unit of time and on the water content. There is no conversion without the addition of water.
  • the product is chromatographed on silica gel with ethyl acetate/hexane 1 :6 and the carbamate (7.18 g) carried along with the product is distilled off under a high vacuum with gentle heating.
  • Crystallisate 3.26 g of dark green crystals.

Abstract

A process for the preparation of α-chloromethylphenylacetic acid derivatives of formula (I), wherein X is a radical inert towards the reaction; m is from 0 to 4; Z is a group (a), (b), (c) or (d); R3 is CH3, CH2F or CHF2; R4 is C1-C6alkyl; R5 is hydrogen or C1-C4alkyl; n is 0 or 1; which process comprises reacting a tert-benzylamine of formula (II), wherein X, m and Z are as defined for formula (I) and R1 and R2 are each independently of the other C1-C6alkyl, C1-C6alkenyl, C1-C6alkoxyalkyl, C3-C6cycloalkyl or unsubstituted or substituted benzyl, or R1 and R2 together with the nitrogen atom are an unsubstituted or substituted 6- or 7-membered ring that in addition to the nitrogen atom may also contain a further hetero atom O, S or N, with a chloroformic acid ester or phosgene in the absence of water. The compounds of formula (I) are important intermediates for the preparation of microbicides.

Description

A process for the preparation of α-chloromethylphenylacetic acid derivatives
The invention relates to a process for the preparation of α-chloromethylphenylacetic acid derivatives of formula I
Figure imgf000003_0001
wherein:
X is a radical inert towards the reaction; m is from 0 to 4;
Z is a group
Figure imgf000003_0002
R3 is CH3l CH2F or CHF2;
R4 is C,-C6alkyl;
R5 is hydrogen or C1-C4alkyl; n is 0 or 1 ; which process comprises reacting a tert-benzylamine of formula II
Figure imgf000003_0003
Rι" "R2
wherein X, m and Z are as defined for formula I and R-i and R2 are each independently of the other C Cealkyl, C C6alkenyl, CT-Cβalkoxyalkyl,
C3-C6cycloalkyl or unsubstituted or substituted benzyl, or
Ri and R2 together with the nitrogen atom are an unsubstituted or substituted 6- or 7- membered ring that in addition to the nitrogen atom may also contain a further hetero atom
O, S or N, with a chloroformic acid ester or phosgene in the absence of water.
Suitable substituents for benzyl and on the substituted 6- or 7-membered ring are: halogen, CT-Cβalkyl, C-rCβalkoxyalkyl, halo-CrCβalkyl and halo-d-Cgalkoxyalkyl.
The radical X may be selected as desired, provided it is inert with respect to the reaction conditions, e.g. alkyl, alkenyl, phenyl, benzyl, nitro, halogen or alkoxy; R is preferably C C4alkyl or halogen; preferably m = 0.
Depending on the number of carbon atoms, alkyl groups are straight-chain or branched and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, sec-amyl, tert-amyl, 1 -hexyl or 3-hexyl.
There is to be understood by alkenyl straight-chain or branched alkenyl, e.g. allyl, methallyl,
1 -methylvinyl or but-2-en- 1-yl. Alkenyl radicals having a chain length of 3 or 4 carbon atoms are preferred.
Halogen and halo denote fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
Haloalkyl may contain identical or different halogen atoms, e.g. fluoromethyl, difluoromethyl, difluorochloromethyl, trifiuoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trichloroethyl or 3,3,3-trifluoropropyl.
Alkoxy is, for example, methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy or tert-butyloxy; preferably methoxy or ethoxy.
Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The compounds of formula I are important intermediates for the preparation of microbicides.
It is known that tert-benzylamines can be converted into the corresponding benzyl chlorides with a chloroformic acid ester. For example, in the Indian Journal of Chemistry, Vol.31 B, p.626 (1992), an o-hydroxybenzyldiethylamine is reacted with ethyl chloroformate to form the corresponding benzyl chloride, the yield being only 80% and the hydroxy group on the phenyl ring also reacting with the ethyl chloroformate. In the Indian Journal of Chemistry, Vol.24B, p.360 (1985), a benzyldimethylamine is reacted with an approximately 12-fold molar excess of ethyl chloroformate to form the corresponding benzyl chloride but no yields are indicated.
It is also known, e.g. from J.Org. Chem. Vol.49, p.2081 (1984) and Chem. Pharm. Bull. 24(2), 342 (1976), that the alkyl and benzyl group can be removed from tert-N-alkyl- piperidines and N-benzylpiperidines, respectively, using chloroformic acid esters; in that literature source, however, the purpose is to obtain the N-unsubstituted piperidines, and the corresponding alkyl chlondes and benzyl chlorides are regarded as by-products with no figures being given in respect of their yields.
It has now been found that tert-benzylamines of formula II can be reacted with a chloroformic acid ester or phosgene in the absence of water to obtain compounds of formula I in good yields. This opens up a new method for the synthetic preparation of microbicidal α- (subst.methyl)phenylacetic acid derivatives as described, for example, in WO 94/26700 and WO 95/18789, which is distinguished by ready availability of the starting materials and good yields of the individual stages.
The reaction according to the invention may be carried out in an anhydrous, aprotic solvent or without solvent, it being possible also for a chloroformic acid ester to be used as solvent. Preferred solvents are hydrocarbons, halogenated hydrocarbons, ethers and carboxylic acid esters, especially preferably benzene, toluene, xylene, chlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, trichloromethane, dichloroethane, trichloroethane, tert-butyl methyl ether, tetrahydrofuran, dioxane, ethyl acetate or ethyl chloroformate.
The reaction temperature is preferably from 0°C to the boiling point of the solvent, especially 20-120βC.
The reaction is advantageously carried out in the presence of a base that is used e.g. in an amount of from 1 to 50 mol % based on the compound of formula II. Preferred bases are alkali metal or alkaline earth metal hydrogen carbonates or carbonates. The chloroformic acid ester may be used in any excess and the unreacted portion can be recovered; the use of 100-200 mol % based on the compound of formula II is advantageous.
The alcohol moiety of the chloroformic acid ester may be chosen as desired provided it does not enter into any undesired reactions; expediently it consists of a maximum of 8 carbon atoms, with an unsubstituted or halogenated C C4alkyl ester, an unsubstituted or halogenated C1-C4alkenyl ester or an unsubstituted or substituted benzyl or phenyl ester being preferred and with ethyl chloroformate being especially preferred.
RT and R are preferably C Cβalkyl or
RT and R2 together with the nitrogen atom are piperidine, piperazine, hexahydroazepine or tetrahydroisoquinoline, especially piperidine.
If an amine having two amino groups is used, e.g. piperazine, both amino groups can be utilised for the reaction according to the invention, that is to say in that case only half a molar equivalent of the amine is required.
In a preferred embodiment of the process according to the invention, in compounds of formulae I and II m is 0;
Z is the group b) and
Figure imgf000006_0001
R3 and R4 are CH3.
Starting from known compounds of formula III according to Reaction Scheme 1 wherein X, m, Z and R-i to R5 are as defined for formulae I and II, the novel synthesis of microbicidal α- (subst.methyl)-phenylacetic acid derivatives rendered possible by the reaction according to the invention may be illustrated as follows : Reaction Scheme 1
Figure imgf000007_0001
0) A compound of formula III, wherein W is a leaving group, is reacted with a secondary amine of formula HNR1R2, wherein R! and R2 are as defined for formula I. The compounds of formula III are known (e.g. J. Heterocycl. Chem. Vol.16, p.1443, 1979). Preferred leaving groups are chlorine, bromine, iodine, trifluoromethanesulfonyloxy and p- toluenesulfonyloxy. There then follows either
a) oximation of a compound of formula IV wherein X, m, R, and R2 are as defined for formula I with an organic nitrite, e.g. tert-butyl nitrite, n-pentyl nitrite or isopentyl nitrite, in the presence of an anhydrous base, e.g. potassium tert-butanolate, sodium alcoholate; and subsequent methylation e.g. with methyl iodide, methyl chloride or dimethyl sulfate; or fluoromethylation with BrCH2F; or difluoromethylation with CICHF2 ; under basic conditions, to form a compound of formula VI; b) hydrolysis and subsequent esterification to form a compound of formula lib; c) if desired, amidation of the compound so obtained with an alkylamine of formula NH2Rs, wherein R5 is as defined for formula I, to form a compound of formula lie; d) if desired, reaction of the compound so obtained with a thionating agent, especially phosphorus pentasulfide or Lawesson's reagent, to form a compound of formula lid wherein n=0; e) if desired, reaction of the compound so obtained with an oxidizing agent, especially hydrogen peroxide, to form a compound of formula lid wherein n=1 ; or
f) hydrolysis of a compound of formula IV and subsequent esterification to form a compound of formula V; g) reaction of the compound so obtained with a formic acid ester and subsequent methylation e.g. with methyl iodide, methyl chloride or dimethylsulfate; or fluoromethylation with BrCH2F; or difluoromethylation with CICHF2 ; under basic conditions to form a compound of formula Ila.
The compounds of formulae Ila, lib, lie and lid are reacted according to the invention to form the corresponding compounds of formula I which are then reacted, as described e.g. in WO 94/26700 and WO 95/18789, to form the α-(subst.methyl)-phenylacetic acid derivatives. The present invention relates also to that entire reaction sequence. The described reactions are carried out in a manner known perse, e.g. in the absence or presence of a suitable solvent or diluent or a mixture thereof, and, as required, with cooling, at room temperature or with heating, for example in a temperature range of approximately from 0°C to the boiling temperature of the reaction medium, preferably from approximately 20°C to approximately +150°C, and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and/or under anhydrous conditions.
There may be mentioned as examples of solvents or diluents: aromatic, aliphatic and alicyclic hydrocarbons and halogenated hydrocarbons, such as benzene, toluene, xylene, chlorobenzene, bromobenzene, nitrobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, trichloromethane, dichloroethane or trichloroethane; ethers, such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; alcohols, such as methanol, ethanol, propanol, butanol, ethylene glycol or glycerol; esters, such as ethyl acetate or butyl acetate; amides, such as N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or hexamethylphosphoric acid triamide; nitriles, such as acetonitrile; and sulfoxides, such as dimethyl sulfoxide. Also bases used in excess, such as triethylamine, pyridine, N-methylmorpholine or N,N- diethylaniline, may serve as solvents or diluents.
Leaving groups are, e.g., chlorine, bromine, iodine, Cι-C8alkylthio, such as methylthio, ethylthio or propylthio, C Cβalkanoyloxy, such as acetoxy, (halo-^-Ce-alkanesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy or trifluoromethanesulfonyloxy, or unsubstituted or substituted phenylsulfonyloxy, such as benzenesulfonyloxy or p-toluene- sulfonyloxy, imidazolyl, hydroxy or water; preferably chlorine, bromine, iodine or p-toluene- sulfonyloxy.
Suitable bases are e.g. alkali metal or alkaline earth metal hydroxides, hydrides, amides, alkanolates, carbonates, dialkylamides or alkylsilylamides, alkylamines, alkylenediamines, or unsubstituted or N-alkylated, saturated or unsaturated cycloalkylamines, basic heterocycles, ammonium hydroxides and also carbocyclic amines. There may be mentioned by way of example sodium hydroxide, hydride, amide, methanolate or carbonate, potassium tert- butanolate or carbonate, lithium diisopropylamide, potassium bis(trimethylsilyl)-amide, caicium hydride, triethylamine, triethylenediamine, cyclohexylamine, N-cyclohexyl-N,N- dimethylamine, N,N-diethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, N-methyl¬ morpholine, benzyltrimethylammonium hydroxide and also 1 ,8-diazabicyclo[5.4.0]undec-5- ene (DBU).
The reaction may also be carried out with phase transfer catalysis in an organic solvent, e.g. methylene chloride or toluene, in the presence of an aqueous basic solution, e.g. sodium hydroxide solution, and also in the presence of a phase transfer catalyst, e.g. tetrabutyl¬ ammonium hydrogen sulfate. Typical reaction conditions are disclosed in the Examples.
The invention relates also to a process for the preparation of α-chloromethylphenylacetic acid derivatives of formula Ib according to Reaction Scheme 2
Reaction Scheme 2
Figure imgf000010_0001
wherein X, m and R-i to R4 are as defined for formulae I and II, which process comprises b) hydrolysis and subsequent esterification of a compound of formula VI, wherein X, m, R, and R2 are as defined for formula I, to form a compound of formula lib; h) reaction of the compound so obtained with a chloroformic acid ester or phosgene in the absence of water.
The invention relates also to a process for the preparation of α-chloromethylphenylacetic acid derivatives of formulae Ib, Ic and Id according to Reaction Scheme 3 Reaction Scheme 3
Figure imgf000011_0001
wherein X, m, n and R-, to R5 are as defined for formulae I and II, which process comprises a) oximation of a compound of formula IV, wherein X, m, R, and R2 are as defined for formula I, with an organic nitnte, and subsequent methylation or fluoromethylation or difluoromethylation to form a compound of formula VI, as described above; b) hydrolysis and subsequent esterification to form a compound of formula lib; c) if desired, amidation of the compound so obtained with an alkylamine to form a compound of formula lie; d) if desired, reaction of the compound so obtained with a thionating agent, especially phosphorus pentasulfide or Lawesson's reagent, to form a compound of formula lid wherein n=0; e) if desired, reaction of the compound so obtained with an oxidizing agent, especially hydrogen peroxide, to form a compound of formula Hd wherein n=1 ; h) reaction of the compound of formula lib, He or Hd obtained according to b), c), d) or e) with a chloroformic acid ester or phosgene in the absence of water
In a preferred embodiment according to Reaction Scheme 3, α-chloromethylphenylacetic acid derivatives of formula Ib are prepared wherein m is 0, and
R3 and R4 are CH3.
The invention relates also to a process for the preparation of α-chloromethylphenylacetic acid denvatives of formula la according to Reaction Scheme 4
Reaction Scheme 4
Figure imgf000013_0001
•1
Figure imgf000013_0002
wherein X, m, n and Ri to R4 are as defined for formulae I and II, which process comprises f) hydrolysis of a compound of formula IV and subsequent esterification to form a compound of formula V; g) reaction of the compound so obtained with a formic acid ester and subsequent methylation e.g. with methyl iodide, methyl chloride or dimethyl sulfate; or fluoromethylation with BrCH2F; or difluoromethylation with CICHF2 ; under basic conditions to form a compound of formula Ila; h) reaction of the compound so obtained with a chloroformic acid ester or phosgene in the absence of water.
The invention relates also to the novel compounds of formulae II, IV and VI, especially the compounds
Figure imgf000014_0001
Figure imgf000014_0002
Examples
Abbreviations: RT: room temperature
Example 1 : 2-Bromomethvlbenzvl cvanide .111.1 .
Figure imgf000014_0003
111.1
In a 4.5 litre sulfonating flask, a mixture of 296.2 g (1.664 mol) of N-bromosuccinimide and 4.1 g of benzoyl peroxide in 1500 ml of carbon tetrachloride is heated to reflux and, with vigorous stirring, a solution of 216 g (1.647 mol) of 2-methylbenzyl cyanide in 825 ml of carbon tetrachloride is added dropwise and the mixture is refluxed for a further 12 h. The mixture is then cooled to RT, the succinimide is filtered off and the yellow reaction solution is is concentrated by evaporation. The residue is crystallised from petroleum ether 123.7 g of white crystals; 36% of the theoretical yield. Chromatography on silica gel with hexane/ethyl acetate (6:1) yields a further 21.3 g. Total yield: 145 g or 42.9% of the theoretical yield.
Example 2: 2-Piperidinomethylbenzyl cyanide (IV.1)
Figure imgf000015_0001
In a 2.5 litre sulfonating flask, 104.3 g (0.75 mol) of pulverised potassium carbonate are suspended in 1440 ml of ethanol, and 81.7 g of piperidine (94.75 ml; 0.96 mol) are added thereto. 144 g of 2-bromomethylbenzyl cyanide (0.685 mol) are then added in portions at RT, the temperature rising to 35-40°C. The mixture is then stirred at 60°C until the starting material can no longer be detected by gas chromatography or thin-layer chromatography (approximately 2 h). The mixture is then concentrated by evaporation in vacuo in a rotary evaporator, water is added to the residue and exhaustive extraction is carried out with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation. For the purpose of purification the crude product is distilled. Yield: 136.2 g; 93% of the theoretical yield; b.p.: 139-141 °C / 0.66 mbar
Example 3: Methoxviminobenzyl cvanide fVI.1.
Figure imgf000016_0001
In a 2.5 litre sulfonating flask, 136 g (0.634 mol) of 2-piperidinomethylbenzyl cyanide are dissolved in 110 ml of tert-butanol under N2 and 145.6 g of tert-butyl nitrite (c. 90%; 1.27 mol) are added thereto. While cooling with an ice bath, a solution of 72 g (0.64 mol) of potassium tert-butanolate in 735 ml of tert-butanol is added dropwise at 20°C in the course of approximately 30 min., and the mixture is subsequently stirred at RT for 4 hours until the starting material can no longer be detected. Tert-butanol and the excess tert-butyl nitrite are then evaporated off in vacuo, the residue is poured into a solution of 54 ml (0.650 mol) of 37% hydrochloric acid in 800 ml of water, and 5 g of sodium carbonate (0.047 mol) are added. The hydroxyiminobenzyl cyanide is then exhaustively extracted with ethyl acetate, washed with sodium chloride solution, dried, filtered and concentrated by evaporation.
Crude yield: 167 g of brown, highly viscous oil, or 108% of the theoretical yield (still contains solvent) [E/Z]-mixture.
In a 1.5 litre sulfonating flask, 83.5 g (0.317 mol) of crude hydroxyiminobenzyl cyanide are dissolved in 500 ml of dimethylformamide and, while cooling with ice, 22.97 g (0.348 mol) of 85% pulv. potassium hydroxide are added thereto. The mixture is then stirred for 1 h at RT, 400 ml of toluene are added and subsequently, at 10°C, 44 g (0.35 mol) of dimethyl sulfate are added dropwise. The mixture is then stirred at RT until the starting material (E/Z-mixture) can no longer be detected by TLC (ethyl acetate/hexane 1 :1) (3 h). The mixture is then poured into ice-water, exhaustively extracted with ethyl acetate and worked up in customary manner; crude yield 85 g, reddish oil; after distillation: 68.3 g or 84% of the theoretical yield; yellow-orange oil; b.p.: 130-140°C / 0.3 mbar. Becomes solid, m.p.: 48-59°C. GC: [E/Z]-ratio
25/75.
The conversion of the piperidinomethylbenzyl cyanide into the methoxyiminobenzyl cyanide can be carried out also without isolation of the intermediate without losses of yield by distilling off tert-butanol after the oximation (proceeds quantitatively) and methylating the resulting potassium salt in situ with diethyl sulfate in acetone or DMF.
Example 4: Methoxviminocarboxamide (llc.1.
Figure imgf000017_0001
VI.1 llc.1
In a 100 ml sulfonating flask, 33.9 g (0.132 mol) of methoxyiminobenzyl cyanide are dissolved warm in 110 ml of ethanol and then a solution of 8.7 g (0.132 mol) of 85% potassium hydroxide in 28.3 ml of water is added. The reaction mixture is heated at 60°C until the starting material (E/Z-mixture) can no longer be detected by TLC (MeOH) (c. 5/4 h).
The mixture is then poured into 250 ml of water, exhaustively extracted with ethyl acetate and worked up in customary manner.
Crude yield: 33.9 g of a pale yellow crystallisate; purity: 95.6%, corresponds to 89% of the theoretical yield.
GC: [E/Z]-ratio 16 / 84; m.p. [E/Z]-mixture: 139-143°C; m.p. [E]-form: 144-146°C. Example 5: Methoxviminocarboxylic acid ester (llb.1^
Figure imgf000018_0001
In a 750 ml sulfonating flask having a gas introduction tube, 37.6 g of methoxyimino- carboxamide (c. 95.6%; 0.131 mol) are dissolved in 375 ml of methanol, and 2.2 ml
(0.122 mol) of water are added. While cooling with an ice bath, HCl gas is introduced at 20-
30°C. As soon as the exothermic reaction has subsided, the cooling bath is removed and, with the continued introduction of HCl gas, the mixture is refluxed (GC monitoring) until the starting material can no longer be detected (Note 1).The cooled reaction mixture is poured into ice-water and adjusted to a pH of 8-9 with a solution of 40 g (1 mol) of sodium hydroxide in 200 ml of water. The mixture is then exhaustively extracted with ethyl acetate and worked up in customary manner.
Crude product: 39.2 g, orange oil; purity: 95.9%; (77.6% [E] + 18.3% [Z] + 1.5% starting material)
For the purpose of purification, distillation under a high vacuum is carried out (Note 2): b.p.:
128-132°C / 0.06 mbar; pale-yellow oil; purity: 91%.
Yield: 32.51 g [E/Z]-mixture; 78% of the theoretical yield; GC: [E Z]-ratio = 80:20.
Notes:
1) The reaction requires 15 hours' reflux and the HCl consumption is 85 g. The reaction time depends on the size of the batch, on the amount of HCl introduced per unit of time and on the water content. There is no conversion without the addition of water.
2) Since the distillation results in a loss of purity of about 5% (increased formation of by¬ products), the distillation is advantageously dispensed with and the resulting product is purified by crystallisation. Examnle 6: 2-.α-Chlnromethylphenyl,-2-methoxyiminoacetic acid methyl ester (lb 1 .
Figure imgf000019_0001
Ilb 1 Ib 1
In a 100 ml sulfonating flask, 15.7 g of methoxyiminocarboxylic acid ester (dist., 91.3%;
49.4 mmol) are dissolved in 20 ml of toluene, and 0.3 g (2.15 mmol) of pulv. potassium carbonate is added thereto. Subsequently, 7.1 ml of ethyl chloroformate (74.6 mmol) are rapidly added dropwise at RT, the temperature rising to 41°C in the course of 10 min. After the exothermic reaction has subsided, the reaction mixture is heated to 95°C and the conversion is determined by means of GC: 86%. A further 1.41 ml of ethyl chloroformate
(14.8 mmol) is then added and after 1/4 h the conversion is determined again: 98%. After a total reaction time of 1 hour, the reaction mixture is cooled, poured into sodium chloride solution and rendered weakly acidic with 1 N hydrochloric acid. The mixture is then exhaustively extracted with ethyl acetate and worked up in customary manner.
Crude yield: 22.4 g of orange oil.
For the purpose of accurate determination of the yield of the [E/Z]-isomers, the product is chromatographed on silica gel with ethyl acetate/hexane 1 :6 and the carbamate (7.18 g) carried along with the product is distilled off under a high vacuum with gentle heating.
Yield: 11.81 g, viscous yellow oil, or 99% of the theoretical yield; purity: 96.5%; total yield:
95.4% of the theoretical yield; [E/Z]-ratio (GC): = 80:20.
Based on the starting material, 4 mol% potassium carbonate and 180 mol% ethyl chloroformate are used in this Example.
Isomerisation:
On standing overnight, the [E]-form crystallises out in the oil, and can be filtered off and washed with methylcyclohexane/tert-butyl methyl ether and then dried under a high vacuum to a constant weight. 1. Crystallisate: 6.37 g of white crystals.
5.44 g of [E/Z]-mixture from the mother liquor are dissolved hot in 20 ml of methylcyclo- hexane, cooled to room temperature, and a gentle stream of HCl gas is introduced for 5 h. The solution, which is initially dark violet, turns dark green, and the [E]-isomer precipitates and can be filtered off.
2. Crystallisate: 3.26 g of dark green crystals.
Total yield of [E]-isomer: 9.63 g or 81% of the theoretical yield.

Claims

What is claimed is:
1. A process for the preparation of an α-chloromethylphenylacetic acid derivative of formula I
Figure imgf000021_0001
wherein:
X is a radical inert towards the reaction; m is from 0 to 4;
Z is a group
Figure imgf000021_0002
R3 is CH3, CH2F or CHF2;
Figure imgf000021_0003
R5 is hydrogen or C-|-C4alkyl; n is 0 or 1 ; which process comprises reacting a tert-benzylamine of formula II
Figure imgf000021_0004
R2 wherein X, m and Z are as defined for formula I and
Ri and R2 are each independently of the other
Figure imgf000021_0005
C Cβalkoxyalkyl,
C3-C6cycloalkyl or unsubstituted or substituted benzyl, or Rf and R2 together with the nitrogen atom are an unsubstituted or substituted 6- or 7- membered ring that in addition to the nitrogen atom may also contain a further hetero atom O, S or N, with a chloroformic acid ester or phosgene in the absence of water.
2. A process according to claim 1 , wherein the reaction is carried out in an anhydrous aprotic solvent at from 0°C to the boiling point of the solvent.
3. A process according to claim 2, wherein the solvent is a hydrocarbon, a halogenated hydrocarbon, an ether or a carboxylic acid ester.
4. A process according to claim 3, wherein the solvent is benzene, toluene, xylene, chlorobenzene, nitrobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, trichloromethane, dichloroethane, trichloroethane, tert-butyl methyl ether, tetrahydrofuran, dioxane, ethyl acetate or ethyl chloroformate.
5. A process according to claim 1 , wherein the reaction is carried out in the presence of a base.
6. A process according to claim 5, wherein the base is used in an amount of from 1 to 50 mol% based on the compound of formula II.
7. A process according to claim 5, wherein the base is an alkali metal or alkaline earth metal hydrogen carbonate or carbonate.
8. A process according to claim 1 , wherein the chloroformic acid ester is used in an amount of from 100 to 200 mol% based on the compound of formula II.
9. A process according to claim 1 , wherein the chloroformic acid ester is an unsubstituted or halogenated C-ι-C4alkyl ester, an unsubstituted or halogenated C,-C4alkenyl ester or an unsubstituted or substituted benzyl or phenyl ester.
10. A process according to claim 9, wherein the chloroformic acid ester is ethyl chloro¬ formate.
11. A process according to claim 1 , wherein in formula II R1 and R2 are C^Cealkyl or
Rt and R2 together with the nitrogen atom are piperidine, piperazine, hexahydroazepine or tetrahydroisoquinoline.
12. A process according to claim 11, wherein in formula II R, and R2 together with the nitrogen atom are piperidine.
13. A process according to claim 1 , wherein in compounds of formulae I and II m is 0;
Z is the group b) and
Figure imgf000023_0001
R3 and R4 are CH3.
14. A process for the preparation of an α-chloromethylphenylacetic acid derivative of formula Ib wherein X, m and R-\ to R are as defined for formulae I and II
Figure imgf000023_0002
which comprises b) hydrolysis and subsequent esterification of a compound of formula VI, wherein X, m, R, and R2 are as defined for formula I, to form a compound of formula lib; h) reaction of the compound so obtained with a chloroformic acid ester or phosgene in accordance with claim 1.
15. A process for the preparation of an α-chloromethylphenylacetic acid derivative of formula Ib, Ic or Id wherein X, m, n and R*, to R5 are as defined for formulae I and II
Figure imgf000024_0001
which compri! ses a) oximation of a compound of formula IV, wherein X, m, R and R2 are as defined for formula I, with an organic nitrite, and subsequent methylation or fluoromethylation or difluoromethylation to form a compound of formula VI; b) hydrolysis and subsequent esterification to form a compound of formula Mb; c) if desired, amidation of the compound so obtained with an alkylamine to form a compound of formula lie; d) if desired, reaction of the compound so obtained with a thionating agent, especially phosphorus pentasulfide or Lawesson's reagent, to form a compound of formula lid wherein n=0; e) if desired, reaction of the compound so obtained with an oxidizing agent, especially hydrogen peroxide, to form a compound of formula lid wherein n=1; h) reaction of the compound of formula lib, lie or Hd obtained according to b), c), d) or e) with a chloroformic acid ester or phosgene in accordance with claim 1.
16. A process according to claim 15 for the preparation of an α-chloromethylphenylacetic acid derivative of formula Ib wherein m is 0; and
R3 and R4 are CH3.
17. A process for the preparation of an α-chloromethylphenylacetic acid derivative of formula la wherein X, m, n and R to R4 are as defined for formulae I and II
Figure imgf000026_0001
which comprises f) hydrolysis of a compound of formula IV and subsequent esterification to form a compound of formula V; g) reaction of the compound so obtained with a formic acid ester and subsequent methylation or fluoromethylation or difluoromethylation to form a compound of formula Ila; h) reaction of the compound so obtained with a chloroformic acid ester or phosgene in accordance with claim 1.
18. A compound of formula
Figure imgf000027_0001
Figure imgf000027_0002
PCT/EP1996/004332 1995-10-13 1996-10-04 A PROCESS FOR THE PREPARATION OF α-CHLOROMETHYLPHENYLACETIC ACID DERIVATIVES WO1997014688A1 (en)

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WO2011113884A1 (en) 2010-03-18 2011-09-22 Basf Se N-carbomethoxy-n-methoxy-(2-chloromethyl)-anilines, their preparation and their use as precursors for preparing 2-(pyrazol-3'-yloxymethylene)-anilides
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WO2000037432A1 (en) * 1998-12-18 2000-06-29 Bayer Aktiengesellschaft Method of producing aromatic halogen methyl compounds
WO2011113884A1 (en) 2010-03-18 2011-09-22 Basf Se N-carbomethoxy-n-methoxy-(2-chloromethyl)-anilines, their preparation and their use as precursors for preparing 2-(pyrazol-3'-yloxymethylene)-anilides
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