WO2009037230A2

WO2009037230A2 - Improved process for preparing (e)-2-(2-chloromethylphenyl)-2-alkoximinoacetic esters

Info

Publication number: WO2009037230A2
Application number: PCT/EP2008/062261
Authority: WO
Inventors: Karsten Luettgen; Martin Lassnig
Original assignee: DSM Fine Chemicals Austria Nfg GmbH and Co KG
Current assignee: Patheon Austria GmbH and Co KG
Priority date: 2007-09-17
Filing date: 2008-09-15
Publication date: 2009-03-26
Anticipated expiration: 2010-03-17
Also published as: WO2009037230A3

Abstract

An improved process for preparing (E)-2-(2-chloromethylphenyl)-2-alkoximinoacetic esters of Formula (I), in which R is a radical inert to the reaction, n is 0 to 4 and R1 and R5 may each independently be C1-C8-alkyl radicals, which comprises reacting a compound of Formula (II), in which n, R and R1 are each as defined above with o-methylhydroxylammonium hydrochloride (CH3ONH2-HCI) in a solvent mixture at a pH of from 0 to 7, which is established by adding an inorganic base, to give an isomer mixture of Formula (III), in which n, R, R1 and R5 are each as defined above, then extracting with cyclohexane, then isomerizing the isomer mixture by introducing gaseous hydrochloric acid, neutralizing the reaction mixture and crystallizing the compound of the formula (I) after adding a cosolvent.

Description

IMPROVED PROCESS FOR PREPARING (EV2-(2-CHLOROMETHYLPHENYϋ-2-

ALKOXIMINOACETIC ESTERS

The present invention relates to an improved process for preparing (E)-2-(2-chloromethylphenyl)-2-alkoximinoacetic esters.

(E)-2-(2-Chloromethylphenyl)-2-alkoximinoacetic esters are important intermediates for the preparation of active agrochemical ingredients and/or microbicides of the methoximinophenylglyoxylic ester series, as described, for example, in EP 0 254 426, EP 0 782 982, WO 95/18789 and WO 95/21153. According to EP 0 782 982, for example, methyl o-(N,N- dimethylaminomethyl)-phenylglyoxylate or methyl o-piperidinomethylphenylglyoxylate are obtained by reaction of N-benzyldimethylamine or N-benzylpiperidine with an organolithium compound and subsequent reaction with a dialkyl oxalate compound, with a chloroformic ester to give the corresponding o-chloromethylphenylglyoxylic esters, which are then oximated with o-methylhydroxlamine or hydroxylamine and then methylated, fluoromethylated or difluoromethylated and reacted with a chloroformic ester.

According to this publication, methyl (E)-2-(2-chloromethylphenyl)-2- methoximinoacetate is obtained, for example, by treating a solution of the (E/Z) isomer mixture of methyl 2-(2-chloromethylphenyl)-2-methoximinoacetate in methylcyclohexane with hydrogen chloride gas.

It was an object of the present invention to provide an improved process for preparing (E)-2-(2-chloromethylphenyl)-2-alkoximinoacetic esters, in which the desired (E)-isomer is obtained in a very favorable ratio and particularly high purity. The present invention therefore provides an improved process for preparing (E)-2-(2-chloromethylphenyl)-2-alkoximinoacetic esters of the formula

in which

R is a radical inert to the reaction, n is 0 to 4 and

R1 and R5 may each independently be C-i-Cβ-alkyl radicals, which comprises reacting a compound of the formula

with o-methylhydroxylammonium hydrochloride (CH₃ONH₂-HCI) or sulfate in a solvent mixture at a pH of from 0 to 7, which is established by adding an inorganic base if necessary, to give an isomer mixture of the formula

in which n, R, R1 and R5 are each as defined above, then extracting with cyclohexane, then isomerizing the isomer mixture by introducing gaseous hydrochloric acid, neutralizing the reaction mixture and crystallizing the compound of the formula I using a cosolvent.

The process according to the invention is suitable for preparing (E)-2-

(2-chloromethylphenyl)-2-alkoximinoacetic esters of the formula (I). In the formula (I) R is a radical inert to the reaction, i.e. the R radical can be selected as desired, provided that it is inert with respect to the reaction conditions. Examples thereof are Ci-Ci₂-alkyl radicals, preferably Ci-C₆-alkyl radicals,

Ci-Ci₂-alkenyl radicals, preferably Ci-C₆-alkenyl radicals, Ci-Ci₂-alkoxy radicals, preferably Ci-C₆-alkoxy radicals, phenyl, benzyl, nitro, etc. n may be 0, 1 , 2, 3 or 4; preferably, n = 0.

R1 and R5 are each independently a C-pCe-alkyl radical, for instance methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, etc. R1 and R5 are preferably each independently a C₁-C₂-alkyl radical, more preferably methyl. The starting compound used for the process according to the invention is a compound of the formula (II) in which n, R, R and R1 are each as defined above.

In the process according to the invention, the compound of the formula (II) is converted to the compound of the formula (III) by reaction with o- methylhydroxylammonium hydrochloride or sulfate.

For this purpose, from 0.5 to 20 equivalents, preferably from 0.9 to 5 equivalents, based on the compound of the formula (II), of o-methylhydroxylammonium hydrochloride or sulfate are added in the presence of a suitable solvent or solvent mixture at a temperature of from 0⁰C to 100⁰C, preferably from 20⁰C to 65°C.

The pH of the o-methylhydroxylammonium hydrochloride solution is adjusted by means of an inorganic base to from 0 to 7, preferably from 2.5 to 4.5.

Suitable solvents are, for example alcohol (R2OH)/water mixtures, where R2 is a C1 to C4 alkyl radical which may be linear or branched, or solvents such as DMF, acetonitrile, MTBE and mixtures thereof. Preference is given to using methanol/water or ethanol/water mixtures.

Subsequently, the reaction solution is extracted with cyclohexane at a temperature of from 0⁰C to 100⁰C, preferably from 20°C to 65°C.

The resulting organic phase is treated with gaseous HCI while maintaining the reaction temperature.

Subsequently, the reaction temperature is lowered, preferably to 18 - 25°C, and the introduction of gaseous hydrochloric acid is continued.

Subsequently, the reaction mixture is neutralized with addition of a basic solution, for example solutions of NaHCO₃ NaCO₃, K₂HCO₃, K₂CO₃, NaOH, KOH. The phase separation subsequently takes place at elevated temperature (from about 40 to 60 ⁰C).

For the crystallization, the organic phase (solution of the product in cyclohexane) is adjusted to a concentration of about 30 - 50% by weight by removing the solvent, and a cosolvent, for example alcohols R2-OH, esters R2COOR2, ketones R2COR2 where R2 is a C1- to C4-alkyl radical which may be linear or branched, is added. Preference is given to adding methanol as the cosolvent. The molar ratio of cyclohexane to methanol is preferably 98:2 to 80:20.

At a temperature of preferably from 30 to 40°, the crystallization of the (E)-isomer now commences. Subsequently, the temperature is lowered slowly, preferably to a temperature of from -10 to 10⁰C. The resulting suspension is preferably filtered under inert gas, for example nitrogen, and the resulting crystals are washed with cyclohexane/methanol and then with methanol while cooling and dried under reduced pressure.

The process according to the invention affords the corresponding E-isomer in an advantageous manner in an improved isomer ratio and in high quality with at least the same rate of isomerization.

As a result of use of cyclohexane, in contrast to the extractants and solvents used to date, no solvent exchange is necessary between oximation step and crystallization. Moreover, it allows the temperature in the isomerization to be kept low (about 30⁰C lower than usual) and hence a greater temperature separation from that temperature at which the decomposition of the corresponding (2-chloromethylphenyl)- 2-alkoximinoacetic ester sets in to be maintained, which further minimizes losses of product. Of much greater significance is, however, the gain in safety in the context of an industrial scale production campaign.

Example 1 : Preparation of methyl (E)-2-(2-chloromethylphenyl)2-methyloximino- acetate

met phe nyl)-

1. OXIMATION

A reaction vessel is initially charged with 97 g (70.84% = 68.71 g of pure substance, 0.323 mol) of methyl o-chloromethylphenylglyoxylate and 343.5 g of methanol and the mixture is heated to 55°C. In a further vessel, 116.3 g (1.3 eq) of o-methylhydroxylammonium hydrochloride solution are adjusted to pH 3.1 with 22.8 g of 50% sodium hydroxide solution and added to the reaction mixture. After the mixture has been stirred for 2 hours, 343.4 g of water are added and the reaction mixture is cooled to 0⁰C. Even during the addition of water, the separation of a brown-black oil is observed, which is completed by the cooling. After the oil has been removed, the reaction mixture is heated again to 55°C and extracted twice with 103.1 g each time of cyclohexane at 55°C. The combined organic phases and the oil are heated together to 55°C, which affords a brown solution (E/Z isomer ratio CLMO = 55:45).

2. ISOMERIZATION

While maintaining the reaction temperature, first the gas phase present over the reaction mixture is saturated with hydrogen chloride gas and then further hydrogen chloride gas is introduced into the liquid (1 bubble per second). At the same time, by means of downstream bubblers, a slightly elevated pressure of approx. 10-20 mbar is attained. After hydrogen chloride has been introduced at 55°C for two hours, the temperature is reduced to 20⁰C and the introduction is continued for a further 2 hours (E/Z isomer ratio CLMO = 92:8). After the hydrogen chloride has been displaced from the gas phase by introducing nitrogen, the reaction mixture is neutralized with saturated NaHCO₃ solution and heated to 55°C, and the phases are separated.

3. CRYSTALLIZATION The solution of CLMO in cyclohexane is adjusted to a concentration of 40% by removing solvent, and methanol is added such that the molar ratio of cyclohexane to methanol is 95:5. The temperature of the solution is now adjusted to 35°C and the crystallization of CLMO is started by adding a few seed crystals. Within the next 15 hours, the temperature of the solution is lowered to 5°C (-2⁰C per hour) and the resulting dark brown suspension is filtered under nitrogen. The resulting brown- black crystals are washed with 68 g of a solution of cyclohexane and methanol at 5°C (molar ratio 95:5) and three times with 34 g each time of methanol cooled to 0⁰C, in the course of which the color of the crystals changes from brown to colorless. The resulting colorless crystals (content >99.5%) are dried under reduced pressure.

Claims

CLAIMS:

An improved process for preparing (E)-2-(2-chloromethylphenyl)-2- alkoximinoacetic esters of the formula (I)

in which

R is a radical inert to the reaction, n is 0 to 4 and

R1 and R5 may each independently be Ci-C₈-alkyl radicals, which comprises reacting a compound of the formula (II)

in which n, R and R1 are each as defined above with o-methylhydroxylammonium hydrochloride (CH₃ONH₂-HCI) or sulfate in a solvent mixture at a pH of from 0 to 7, which is established by adding an inorganic base, to give an isomer mixture of the formula (III)

in which n, R, R1 and R5 are each as defined above, then extracting with cyclohexane, then isomerizing the isomer mixture by introducing gaseous hydrochloric acid, neutralizing the reaction mixture and crystallizing the compound of the formula I after adding a cosolvent.

2. The process as claimed in claim 1 , wherein an aqueous solution of an alcohol (R2OH) where R2 is a C1 to C4-alkyl radical which may be linear or branched is used as a solvent in the first step.

3. The process as claimed in claim 2, wherein an aqueous solution of methanol is used as the solvent.

4. The process as claimed in any one of claims 1 to 3, wherein sodium hydroxide solution is used as the inorganic base to establish the pH in the first step.

5. The process as claimed in any one of claims 1 to 4, wherein the reaction solution is neutralized with a solution of NaHCO₃ NaCO₃, K₂HCO₃, K₂CO₃, NaOH, KOH.

6. The process as claimed in any one of claims 1 to 5, wherein the crystallization is effected from a mixture of cyclohexane/cosolvent.

7. The process as claimed in claim 6, wherein the cosolvents used are alcohols R2-OH, esters R2COOR2, ketones R2COR2 where R2 is a C1- to C4-alkyl radical which may be linear or branched.

8. The process as claimed in claim 6, wherein the molar cyclohexane/cosolvent ratio is from 98:2 to 80:20.