FR2490218A1 - PROCESS FOR THE PREPARATION OF 4-AMINOMETHYLCYCLOHEXANECARBOXYLIC ACID AND ITS SALTS WITH MINERAL ACIDS - Google Patents

Abstract

PROCESS FOR PREPARATION OF 4-AMINOMETHYLCYCLOHEXANECARBOXYLIC ACID OR ITS SALTS WITH MINERAL ACIDS. IT CONSISTS OF CATALYTICALLY HYDROGENING 4-HYDROXYIMINOMETHYLBENZOIC ACID DISPERSE IN AN AQUEOUS MEDIUM CONTAINING A MINERAL ACID IN THE PRESENCE OF A CATALYST OBTAINED FROM A COMPOUND OF PALLADIUM, A COMPOUND OF PLATINUM AND OF RHODIUM.

Description

The present invention relates to a method of

  preparation of 4-aminomethylcyclohexanecarboxylic acid

  or its salts with the mineral acids from 4hydroxyiminomethylbenzoic acid. It relates more particularly to a process for the preparation of 4-aminomethylcyclohexanecarboxylic acid or its salts with mineral acids, which acid is useful for

  the preparation of trans-4-aminomethylcyclohexane-

  carboxylic acid which is useful as a medicine having a

  antiplasmin action, from 4-hydroxyimino acid

  methylbenzoic by catalytic hydrogenation.

  Until now, we knew

  for the preparation of 4-aminomethylcyclohexanecarboxylic acid

  from 4-hydroxyiminomethylbenzoic acid or its derivatives, the following processes (1) and (2): (1) a process for preparing an acetyl compound or

  of an esterified compound of 4-aminomethylcyclohexa-

  Necarboxylic acid by catalytic reduction of 4hydroxyiminomethylbenzoic acid or an alkyl ester thereof in the presence of palladium as catalyst

  in acetic anhydride (see Japanese patent application

but published 51-52159).

  (2) a process comprising (a) reducing the oximic structure of methyl 4-hydroxyiminomethyl benzoate with a palladium catalyst in a lower alcohol solvent, (b) hydrogenating the benzene ring of the thus reduced ester, and c) deacetylating the ester linkage (by hydrolyzing the methyl ester) to obtain 4-aminomethylcyclohexanecarboxylic acid (see

  published Japanese Patent Application No. 50-88042).

  However, as the process (]) requires to operate at high temperature (150 C) under pressure

  (100 kg / cm2) and using an organic solvent

  that such as acetic anhydride or acetic acid as reaction medium, the process (1) is difficult

  to industrialize for reasons of economy and safety

  rite. Process (2) is too complicated to be

industrially applied.

  In his studies to find a new way

  for the preparation of 4-aminomethylcyclohexanecarboxylic acid

  Hereinafter (hereinafter abbreviated to 4-AMCHA) or a salt thereof with mineral acids, the applicant has found a simple process for preparing 4-2ACHA and / or a salt thereof with mineral acids with a good

  yield, and has resulted in the present invention.

  One of the aims of the invention is therefore to provide a process for preparing 4-AMCHA and / or a salt thereof with mineral acids. This process comprises a step of catalytically hydrogenating 4hydroxyiminomethylbenzoic acid dispersed in an aqueous medium containing a mineral acid in the presence

  of a catalyst obtained from a palladium compound

  dium, a platinum compound or a rhodium compound.

  Other goals will appear below.

  The present invention relates to a process for preparing 4-AMCHA and / or a salt thereof with mineral acids, which comprises aminomethylation and reduction of the benzene ring by a reaction.

  in a single stage, in which 4-hydroxyiminoacetic acid

  methylbenzoic acid (hereinafter abbreviated as 4-HBA) and catalytically reduced in an aqueous medium using a catalyst containing three noble metals,

  palladium, platinum and rhodium at a temperature of

  relatively low temperature from ambient temperature

  bient at about 60 C in mineral acid medium.

  The process of the invention is based on the following reaction scheme: HON = CH COOH aa P e H2N-CH2 C. COOH Catalyst 2

(Pd, Pt and Rh) ,.

mineral acid

> H2N-CH2 -K - COOH

(4-AMCHA)

  4-HBA, the starting substance of the invention

  can be easily and cheaply obtained as an industrial raw material, for

  react the p-formylbenzoic acid obtained as

  product of the preparation of terephthalic acid,

  with hydroxylamine hydrochloride.

  The amount of water used as a reaction medium in the process of the invention advantageously represents 10 to 20 times the weight of the 4-HBA serving as starting material, and a mineral acid is added to the water which forms with the product obtained. (4-AMCHA) a water-soluble salt, for example hydrochloric acid,

  sulfuric acid and nitric acid, in one

  not less than one molar equivalent per mol

  4-HBA, preferably in a proportion of 1 to 3 times the Ncm-

  of molar equivalents of 4-HBA, the concentration of the acid

  mineral in the water being advantageously from 3 to 5% by weight.

  The addition of the mineral acid to the water as a reaction medium results in: (1) the formation of a very water-soluble mineral acid salt of 4-aminomethylbenzoic acid formed as an intermediate in the reduction of 4-HBA and its dissolution in the reaction medium to facilitate the hydrogenation of the benzene ring, and (2) the protection of the aminomethyl group by the mineral acid to avoid side reactions such as deamination, thus providing the salt acid

  mineral of 4-AMCHA with a good yield.

  In the absence of mineral acid in the medium

  reaction, the product of the reduction of acid 4-

  hydroxyiminomethylbenzoic acid is 4-aminomethyl-

  benzoic, because 4-AMCHA can not be formed.

  The addition of the mineral acid is therefore a

  indispensable conditions of the process of the invention.

  Another essential condition of the process of the invention is the use of a catalyst comprising 3 metals, palladium, platinum and rhodium. When using a catalyst consisting of a single metallic element, palladium, platinum

  or rhodium and when using a conventional catalyst

  With only two metal elements such as palladium and platinum, platinum and rhodium, ruthenium and palladium, a salt of 4-aminomethylbenzoic acid is formed by the reduction of the structure of the oxime, but the hydrogenation of the benzene ring

does not happen at all.

  The catalyst used in the process of the invention comprises three new metals, palladium, platinum and rhodium, and although the catalyst may contain others, this is economically disadvantageous. These three metals - may be in metallic form or in the form of a metal compound, such as oxide, or as an alloy of two or three of them. It is preferable to use the catalyst deposited on a support such as activated carbon or diatomaceous earth, the activated carbon being particularly preferred. The amount of metal deposited on the support is usually from 2 to 10% by weight relative to

total weight of the catalyst.

  The proportion of each of the three active constituents of the catalyst used in the invention can be

  greater than about 0.25% by weight of metal by

  the weight of the starting material, 4-HBA, and although the ratio of palladium, platinum and rhodium may be any, it is preferred that the ratio Pd: Pt: Rh be about 1: 1: 1 , given

  the activity obtained and economic considerations.

  With regard to the conditions of the

  catalytic hydrogenation reaction of the process of the invention.

  vention, the temperature is relatively low,

  is 10 to 60 ° C, a temperature above 60 ° C does not

  not so favorable because it promotes side reactions such as deamination. For the hydrogen used in the reduction, a pressure higher than 1 bar may be sufficient, and in general, the reaction is easily carried out under low pressure (1 bar). The reaction time depends on the amount of catalyst, the reaction temperature and the hydrogen pressure in the reaction system. In any case, the reaction is continued until the absorption of hydrogen ceases. The reaction time

  is usually 2 to 10 hours.

  When the reduction is complete, the catalyst is removed by filtration and the filtrate is concentrated.

  under reduced pressure (after having neutralized it,

  that it is desired to prepare the free acid), then, if necessary, acetone is added to the concentrated filtrate and the mixture is allowed to cool. The separating and settling substance is collected by filtration, washed with a suitable solvent and dried. We get the

  4-AMCHA or a salt thereof with mineral acids.

  As indicated, the process of the invention is an excellent industrial process for the preparation of 4-AMCHA and its salts with mineral acids. The following non-limiting examples are

  given by way of illustration of the invention.

Example 1

  In a 500 ml autoclave made of resistant glass

  16.5 g (0.1 mole) of 4-hydroxyiminomethylbenzoic acid are suspended in 200 ml of aqueous 30% strength aqueous hydrochloric acid solution in the presence of pressure, and a mixed catalyst consisting of 5% of activated palladium on carbon, 5% of platinum on activated carbon and 5% of activated rhodium on the proportions indicated in the table, and the hydrogenation is carried out under an initial pressure of hydrogen.

  5 bar, at a temperature between

  room temperature and 45 C, until hydrogen uptake is complete, which takes 6 hours. Then we

  removes the catalyst from the reaction mixture by filtration.

  tion. After checking the absence in the filtrate

  specific absorbance of 4- hydrochloride hydrochloride

  aminomethylbenzoic at 228 nm, the filtrate is concentrated under reduced pressure and acetone is added to the concentrate. The acetone mixture is allowed to cool, the crystals which are deposited are collected by filtration and dried. 15.9 g of a pulverulent white product having a melting point of 175-177 ° C. are obtained.

  the IR spectrum of the product to that of an authentic sample

  the product is identified as chlorhydrin

  4-AMCHA drate. The yield is 82% of the theory.

  By esterifying the product to N-acetyl esters

  and N-butyl and analyzing the ester by chromato-

  gas phase to determine the formation ratio of the cis and trans isomers, it is found that the product is composed of 62 to 66% cis isomer and 34

at 38% trans isomer.

Examples 2 and 3.

  In the same way as in example 1, but

  using each of the indicated mixed catalysts -

  in the table, the hydrogenation of 4hydroxyiminomethylbenzoic acid is carried out. The product of Example 2 and that of Example 3 have the same melting point as the product of Example 1, ie 175-177 C, and both identify with 4-AMCHA hydrochloride by their spectrum. IR. The ratio of the cis and trans isomers of each of the products of Examples 2 and 3 is in

  the same interval as for the product of Example 1.

Example 4

  The hydrogenation is carried out in the same manner as in Example 1, except that 4-hydroxyiminomethylbenzoic acid is suspended in 5% aqueous sulfuric acid solution at a temperature between room temperature and 50 ° C. By treating the reaction mixture in the same manner as in Example 1, 15.5 g of a powdery white product melting at 205-206 ° C. are obtained. The product is identified as being 4-AMCHA sulfate by the same method as in Example 1. The ratio of isomers

  cis and trans in the product is 68:32.

Comparative Example 1

  In the same way as in Example 1, except

  that the 4-hydroxyiminomethyl acid is suspended

  benzoic acid in 200 ml of water containing no aqueous hydrochloric acid at 3.5% as in Example 1, the hydrogenation is carried out until the absorption of hydrogen ends, after 4 hours. When the hydrogen uptake is complete, 20 ml of concentrated hydrochloric acid are added to the mixture to dissolve the crystals which have settled in the reaction mixture, and the mixture is filtered to remove the catalyst. The filtrate is concentrated, acetone is added to it, the crystals which are deposited are filtered off and dried.

  14.5 g of a powdery white product melting at 284 -

  286 C (decomp.). The product is identified as 4-aminomethyl benzoic acid hydrochloride by comparing its IR absorption spectrum with that of a sample

  authentic of this compound. The yield is 77%.

Comparative Examples 2 to 5.

  In the same way as in Example 1, but using each of the mixed catalysts of the table, a series of hydrogenations is carried out. The hydrogenation of the structure of the oxime and that of the benzene ring can be followed by the decrease of the pressure of the hydrogen in the autoclave. Each of the products of the hydrogenation series is identified as 4-aminomethyl benzoic acid hydrochloride by its UV absorption spectrum at 228 nm and by its infrared absorption spectrum. The operating conditions and the results of comparative examples 2 and 5

also in the table.

  As can be seen from Comparative Examples 1 and 2 to 5, (a) even in the presence of a catalyst containing 3 metallic elements, palladium, platinum and

  rhodium, the hydrogenation of 4-hydroxyiminomethyl

  Benzolque stops at the stage of 4-aminomethyl

  benzole and (b) even in the presence of a mineral acid in the aqueous reaction medium, the hydrogenation of 4hydroxyiminomethylbenzoic acid stops at the 4-aminomethylbenzoic acid stage when the system

  catalytic system does not meet the conditions of the

  tion. ) o9GZ Q t8z ap am nqe.l_, a-atm v ed = p os gsouo m (5 * 9ATqe auoqo ms UlaTuLtrnq ap% S (br 9AT: pe ave years yOur% 5 (ú * gA,; ORF4vld op% S (Z * 9AT4 auo = ams umTPUIT'd ap% S (1 *: soN

- 5'úT. 0 - S'Z, S 9'1 '- 9'I 5

  - 1'0 0 - S. 9'1 9'1 - b-_ / .. "E1 0 S" '"ar., Sap - 9'T 9'T ú - /.L'91 0 -p pe . -''E S'0 98Z-D8Z D-9't 9 "[9'1 T g is T 'saidnzx OrLb

  08 0 SD 90Z-SOZ 9 Ta "years epToe 9 'T 9' 1 9'1i.

  D8 0 ú'9T LLt-SLT 9 ,, 9l 9 '[9 8'b E 6L 0 ú'ST LLT-SLI S'S ", eTaP: 0'8 9" T 9 "TZ Z8 0 6'ST LLI-SLI 9 -Aqzoi OPTDe 9'1 9'T g "9 1

enblozutct 'd--

  -IKR'i.uTv-np lTeu (%) apTOVI O) p TIL. -Tpu Opto luamu-puaiD-ruTm Wle:, p Tas -e, p Tes no uoTsnj (no ({i) 9RTRueZ ap luTo e ap uOcI pi9te u epTsV (Ce-U% S (zD-% S (T DP% -d.osqe, () nua4: o iTnpo.T: p ema znasATWe np uo4Tsocxt I Co Cu o> N% SVI sTqelaedwoD saladuixe saT pv I seEdmaxa se Suep. uoTqeugboapAqI op se; lnsga 1s sIlTsuuoTIoega suoT $ TpuoD: nvaEavi

Claims (9)

  1. Process for the preparation of 4-amino acid   methylcyclohexanecarboxylic acid or a salt thereof with mineral acids, characterized in that it consists   to catalytically hydrogenate 4-hydroxyiminoic acid   benzyl alcohol dispersed in an aqueous medium containing a mineral acid in the presence of a catalyst obtained from a palladium compound, a   platinum and a rhodium compound.   2. The process of claim 1, wherein   characterized in that said mineral acid is selected from hydrochloric acid, sulfuric acid and nitric acid.   3. Process according to any one of the   1 or 2, characterized in that this mineral acid   ral is contained in this aqueous medium in a proportion of not less than 1 molar equivalent per mole of 4-hydroxyiminomethylbenzoic acid.   4. Process according to claim 3, characterized   rised in that this mineral acid is contained in this   aqueous medium at a rate of 1 to 3 times the number of equi-   molar values of 4-hydroxyiminomethylbenzois- than.   5. Process according to claim 1, characterized   rised in that the concentration of this mineral acid.   is from 3 to 5% by weight of this aqueous medium.   6. The process of claim 1, wherein   in that the 4-hydroyimiinomethylbenzoic acid is catalytically hydrogenated at a temperature of 10 at 60 C.   7. The process of claim 1, wherein   characterized in that the 4-hydroxyiminomethylbenzoic acid is catalytically hydrogenated under an initial pressure hydrogen from 1 to 10 bar.   8. A process according to claim 1, characterized   rised in that 4-hydroxyiminomethylbenzolucic acid   is catalytically hydrogenated for 2 to 10 hours.   9. The process of claim 1 wherein   characterized in that the catalyst is a mixture of palladium on activated carbon, platinum on activated carbon and rhodium on active carbon.