JPS63253058A - Production of aminocarboxylic acid derivative - Google Patents

Abstract

PURPOSE:To industrially and economically obtain the titled compound having antiulcer action in high yield and purity, by reducing p-(trans-4- cyanocyclohexylcarbonyl)phenylpropionic acids. CONSTITUTION:p-(trans-4-Cyanocyclohexylcarbonyl)phenylpropionic acid expres sed by formula I (R1 is H or lower alkyl) or lower alkyl ester thereof is reduced to provide p-(trans-4-aminomethylcyclohexylcarbonyl)phenylpropionic acid and salt thereof. The reaction is preferably carried out using a catalyst such as Ni, Co and Pd and in case of using Ni, Co and Ru, the by product is reduced when catalytic reduction is carried out in the presence of a base such as NH3.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel method for producing p-()trans-4-aminomethylcyclohexylcarbonyl)phenylpropionic acid or its salts. The object of the present invention is to industrially produce a salt of p-(trans-4-7minomethylcyclohexylcarbonyl) 7z nilpion #ma which has an anti-ulcer effect.

and can be produced with high yield.

(Prior art) The aminocarboxylic acid derivative represented by the following formula (IV)
This is a compound described in JP-A-3442 or JP-A-57-24557.

This aminocarboxylic acid derivative is composed of an acid addition salt of an aminocarboxylic acid halide represented by the primary formula (V) and a primary formula (III
) (wherein, R represents a lower alkyl group).

It is produced by performing an acylation reaction in the presence of a Lewis acid and then hydrolyzing the ester.

(Problem that @Ming is trying to solve) When an acid addition salt of an aminocarboxylic acid nolide whose amine group is not protected, as shown in formula (V) above, is used in the acylation reaction, it self-condenses and produces nine by-products. I can't avoid it.

9. In the acylation reaction carried out using a Lewis acid, a complex of the Lewis acid is formed. , the Lewis acid complex and the remaining Lewis acid were decomposed by adding a large amount of water.

A method has been adopted in which the nine-acylated product is extracted under acidic conditions with the same solvent used in the acylation reaction or with another organic solvent.

However, the acylation product in the conventional method represented by the linear formula (Vl) (wherein R represents a lower alkyl group) is a basic substance, and under acidic conditions, the starting material aminocarboxylic acid [formula (■)〕
It is difficult to separate from the

Under neutral or basic conditions, a gel of hydroxide compounds derived from Lewis acids precipitates, making extraction with organic solvents extremely difficult.
Formula (III) ] is difficult to separate.

(Problem tl - Means and action for solving the problem) The present inventors solved the above problem? p-(1-lance-4-cyanocyclohexylcarbonyl) represented by the quintic formula (I) (where RI represents a hydrogen atom and each represents a lower alkyl group) Phenylpropion I! ! The only thing left to do is to reduce the lower alkyl ester.

Mano has discovered a method for producing the salt of p-()trans-4-aminomethylcyclohexylcarbonyl)phenylpropionic acid represented by the following formula ([I).

Firstly, the implementation method 'f: will be explained in detail.

Nickel, radium, and platinum are used as catalysts.

Ruthenium, rhodium, and ruthenium can be used, but nickel, nickel, and radium are preferred. When nickel or ruthenium is used, catalytic reduction is performed in the presence of a base such as ammonia to reduce the generation of by-products.

The amount of the base to be used is 1 to 10 times the mole, preferably 1 to 5 times the amount of the compound of formula (I). moreover.

Alkali metal hydroxides such as hydroxide, potassium hydroxide, lithium hydroxide, etc. are used to prevent a decrease in catalytic activity and promote the hydrolysis reaction of esters, preferably hydroxide. Hysodium is 0.1 to 5 times the mole of the compound of formula CI), preferably 0.8 to 1.2
It is carried out using twice the molar amount.

The reaction is carried out at normal pressure to 100 kg/c11. It is suitable to conduct the reaction preferably at a hydrogen pressure of normal pressure to 40 kg/cd and at a temperature of 0 to 200C, preferably 0 to 100C'O@degree.

Solvents include methanol, ethanol, impropatol, acetone, and tetrahydrofuran.

Organic solvents such as dioxane or ethyl acetate, mixed solvents of these and water, and water can be used, but water is preferred as a mixed solvent of organic solvents and water in view of the solubility of the target product.

After the reaction is complete, add an acid such as hydrochloric acid to make it acidic.

After filtering the catalyst, the F solution is tanned, and the resulting nine crystals are recrystallized, whereby the desired product can be easily obtained with high purity and high yield.

The compound of formula (I), which is the raw material of the present invention, has the linear formula (■)
trans-4-cyanocyclohexanecarboxylic acid chloride represented by the formula (III) and a phenylpropionate ester represented by the primary formula (III) (in the formula, Rq represents a lower alkyl group).

It can be produced by reacting in the presence of a condensing agent.

Examples of condensing agents include Lewis acids, aluminum compounds such as aluminum chloride and aluminum bromide, iron compounds such as ferric chloride, and zinc compounds such as zinc chloride.
Examples include tin compounds such as stannic salts, titanium compounds such as titanium chloride, and the like. Among these, aluminum compounds such as aluminum chloride and aluminum bromide are preferred.

To carry out the acylation reaction using these compounds, a method similar to that employed in a conventional 7-LiDerkraut reaction is used.

That is, the acid chloride of the above formula (■) is converted into the acid chloride of the above formula (II).
0.9 to phenylpropionate of I)
1.1 times the mole of the Lewis acid is used, and the Lewis acid is used in an equimolar amount to 10 times the mole of the acid chloride, preferably 2 to 5 times the mole of the acid chloride.

In addition, as one reaction solvent, chloroform, carbon tetrachloride,
Halogen hydrocarbons such as dichloromethane, dichloroethane, and tetrachloroethane. The liquid is benzene, disulfuric acid, and
Inert solvents such as arsenic are preferably used.

For anti-E tri, a method of adding phenylpropionic acid ester of formula 1 (Lll) to a mixed solution of acid chloride of formula (■) and the above condensing agent is preferably taken;
The condensing agent may be added little by little to a solution of the acid chloride of ) and the phenylpropionate ester of formula (lft),
Alternatively, the acid chloride of formula 1 (VID (7)) may be added to a mixed solution of the phenylpropionate ester of formula (LIE) and the condensing agent.

The reaction temperature can usually be carried out at a temperature ranging from 1°C to the boiling point of the solvent used, but preferably from room temperature to 70G.

After the reaction was completed, one reaction solution was added to an aqueous hydrochloric acid solution.

The target compound of formula (D) can be easily obtained by performing ordinary extraction operations.

Trans-4-amine methylcyclohexanecarboxylic acid, which is a raw material for the conventional method, is obtained by reducing 4-cyanocyclohexanecarboxylic acid, but since it is a mixture of cis-trans, only trans-4-aminemethylcyclohexanecarboxylic acid is used. In order to isolate μ, a very complicated operation is required. However, since the cis-trans form of 4-cyanocyclohexanecarboxylic acid has better solubility in water, the trans form can be easily isolated. The formula (
Reducing the compound I) to obtain the target compound of formula (2) can simplify complicated operations. 9, formula (I
) is hydrolyzed by the base added during one reaction, making it possible to cut out the hydrolysis step of conventional methods.

(Effects of the Invention) The present invention enables isolation and purification to be performed using conventional techniques.
Our goal is to industrially and economically produce p-()lance-4-7minomethylcyclohexylcarbonyl)-phenylpropionic acid.

(Examples) Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples in any way.

Reference Example 1 Trans-4-cyanocyclohexanecarbonyl chloride 5. Of (29 mmot) in dichloroethane.

Aluminum chloride 11.
Gradually add 7f (87,5 mmot). Phenylpropionic acid methyl ester 4.7 on a stone rack under ice cooling
50 tml'l of a dichloroethane solution containing 9 (28,6 mmot)' was gradually added dropwise. Then 5 at 50C
Time reaction money goes nine. After the reaction is complete, add 50ml of concentrated hydrochloric acid to the reaction solution.
and 50 m of ice to decompose excess aluminum chloride and add 1
Perform all liquid separation operations. The organic layer was washed 5 times with 50% of 2N hydrochloric acid, and the aqueous layer was extracted 5 times with 50% of dichloroethane. Wash the layer 5 times with 50% of aqueous solution of 7 um, and then 5 times with 50wtt of water. After drying the organic layer, all the solvent was distilled off to give a crude crystal of 8.2
I got 2 and nine.

Recrystallization from enal-acetic acid-hexane system gave p-(trans-4-cyanocyclohexylcarbonyl)phenylpropionic acid methyl ester 6.6y (yield 76%). Melting point: 98-100 CI R, NMR, elemental analysis, all shown below, support the structure of the target product.

I R (KBr) 2220 Ichigo (CN) 1720cW1-1 (C=O) 1660I-Fff-” (C=,O)N M R
(CDCl2) δ (p-)1.2~2.5 (m
, 10 K, cyclohexane) 2.5-3.2
(m, 4H, CMt)3.7 (S
, 5H, CHl)7゜7 (dd,
4) i, phenyl) Elemental analysis theoretical value Analysis value C72, 24% 72. m3%) 1 7.02 壬 7.24% N 4.68 沾 4,58 Section 016, (16% 16.15 Section Reference Example 2 p-(trans-4-cyanocyclohexyl obtained in Reference Example 1) carbonyl)phenylpropionic acid methyl ester 2f (6,7mmot) in methanol 20TI
Then, 10wItl of IN-sodium hydroxide was added, and the mixture was stirred at room temperature for 5 hours. Thereafter, methanol was distilled off and 50% of water was added.

Extracted 3 times with ether 50wt. The first aqueous layer was quenched with hydrochloric acid, extracted 5 times with 50% ether, and after drying the ether layer, all the ether was distilled off, and p-() lance-4-cyanocyclohexylcarbonyl)phenylpropion fi
1.7 tf obtained. Melting point: 189-91C IR, NMR, and elemental analysis are shown below, which support the structure of the target product.

I R (KBr) 2250, -' (CN) 1700 crn-1 (C=O) 1670 crn"" (C=O) NMR (COOm) δ (narrowness) 1.2-2.5 (m, 10 H, cyclohexane) 2.5-3.2 (m, 4H, CHl)5.
9 (s, IH, Co, H) 7.6
(dd, 4H, phenyl) Elemental analysis theoretical value Analysis value C71,58471,45壬H6,67Q6 6.74% N 4.91% 4.86 cs016.84%
16.97% Example 1 p-(trans-4-7minomethylcyclohexylcarbonyl)phenylpropionic hydrochloride p-(trans-
4-cyanocyclohexylcarbonyl)phenylpropionic acid methyl ester 2, Of (6,7mmot,
) f, 25% ammonia water 1. ? Pig 1N was dissolved in a mixture of 6.7rse of sodium hydroxide and 50rnt of water, and 0.21ml of Raney nickel was added to it.
C, 20 kg/crIL(i') catalytic reduction for 4 hours under hydrogen pressure9. Boil the reducing solution to pH 2 with concentrated hydrochloric acid.

After separation of Raney nickel t-F, nine crystals obtained by condensing P liquid t-a were recrystallized in a water-77 ton system, p-(trans-4-aminemethylcyclohexylcarbonyl) phenylpropion a salt (1! , salt 1.a s t (yield 85
) was obtained. Melting point 245C (decomposition) IR, NMR,
Elemental analysis is shown below and supports the structure of the object.

I R (KBr) 1680α-1 (C=O) 1660cWI-' (C=O) N M R (D, O) δ (solution) 1.0-2.5 (m, 10 H, cyclohexane)2. 5-3.2 (m, 4H, CHl) 7.8
(dd, 4H, phenyl) Elemental analysis theoretical value Analysis value C62,67% 62.59 section) (7,37% 7.44 tatami N 4.50 width 4.22 regret Q14.75%
14.78% C610,91 10.974 Example 2 p-(trans-4-aminomethylcyclohexylcarbonyl) phenylpropionate a salt p-(trans-
4-cyanocyclohexylcarbonyl)phenylpropion fi 1.5? (5,5mmot)k,
Dissolved in a mixture of 1.2 ntt of 25% ammonia water, 5.3 m of IN-sodium hydroxide, 20 mg of methanol, and 20 m of water, and added 0.19 f of Raney nickel to this.
, yo c, zo kg/ado water IX under pressure 4
Time contact reduction friend. Adjust the reducing solution to pH 2 using a salt pan,
After separation of Raney nickel kP, the next crystal obtained by a-condensation is water-
When recrystallized in acetone system.

p-()Lance-4-aminemethylcyclohexylcarbonyl)phenylpropio71112m acid! 1.342
(Yield: 78 pieces) was obtained.

Melting point, IR, NMR, and elemental analysis support the structure of the object.

Example 5 p-(trans-4-aminemethylcyclohexylcarbonyl)phenylpropion m hydrochloride p-c trans-
4-cyanocyclohexylcarbonyl)phenylpropionic acid methyl ester 2.0 ? (6,7mm mot)
was dissolved in a mixture of 1.9 d of 25% aqueous ammonia, 6.7 m of 1N sodium hydroxide and 50 m of water, and 0.42 w of Raney cobalt was added thereto, and the solution was heated at 100C, 20k.
Catalytic reduction was carried out under hydrogen pressure of g/cd for 6 hours. The reducing solution was adjusted to pH 2 with hydrochloric acid, and after separating the Raney cobalt gold P, the P solution was a-condensed and the resulting crystals were recrystallized in a water-acetone system.

p-()trans-4-aminomethylcyclohexylcarbonyl)phenylpropion m hydrochloric acid m 1.57y (yield: 72 g) was obtained. Melting point, IR, NMR.

Elemental analysis supports the structure of the object.

Claims (1)

[Claims] The following formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 represents a hydrogen atom or a lower alkyl group.) p-(trans-4- p-(trans-4-amino) represented by the following formula (II) ▲Mathematical formulas, chemical formulas, tables, etc. are available▼(II) A method for producing methylcyclohexylcarbonyl)phenylpropionic acid or a salt thereof.