JPS5883663A - Isomerization of 3-(p-(4-aminomethylcyclohexylcarbonyl) phenyl)propionic acid - Google Patents

Abstract

NEW MATERIAL:The compound of formula (R is H or lower alkyl). EXAMPLE:3-[p-(trans-4-Aminomethylcyclohexylcarbonyl)phenyl]propionic acid. USE:Antiulcer agent. PROCESS:The compound of formula (R is H or lower alkyl) can be prepared by the Friedel-Crafts reaction of 4-aminomethylcyclohexanecarboxylic acid chloride with a phenylpropionic acid ester, and if necessary, the hydrolysis of the ester. The cis-isomer or a mixture of cis-isomer and trans-isomer of the acid addition salt of the compound of formula can be isomerized to the compound of formula rich in the trans-isomer, by contacting the cis-isomer, etc. with an acidic aqueous solution (preferably an aqueous solution of hydrochloric acid) having a pH of <=3.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for isomerizing 3(,p-(47minomethylsic-hexylcarbonyl)phenyl) p-hyono. a −(p −(4-7
minomethylcyclohexylcarbonyl)phenyl)purpion ml 1iIl f) By contacting the acid addition salt with an acidic aqueous solution under specific conditions, a higher proportion of the trans isomer can be converted into ttr3-(p-(4-amino/methylcyclohexyl) The present invention relates to a method for isomerizing so-called 3-(Tl-(4-7minomethylcyclohexylcarbonyl)phenyl)ppionic acids to produce carbonyl)phenyl]propions.

3-(p-(4-amino/methylcyclohexylcarbonyl)phenylpropionic acid eA is a new compound synthesized for the first time by the present inventors (Il#1111 1973).
No. 5-98636 and Japanese Patent Application No. 163231/1982).

Aminocarboxylic acid derivatives are extremely useful compounds as excellent anti-ulcer therapeutic agents. Such a-(p-(4-7
In the case of 5゛methylcyclohexylcarbonyl)phenylpropion #, the two bonds across the 7 1,4-cyclohexyl groups in the molecule can be coordinated in a trans or cis relationship, Among them, trans-coordinated one, 3-(p-()trans-4-7minomethylcyclohexylcarbonyl)phenylpropion a
The second type is baking soda as a new digestive treatment agent.

Conventionally, 3-(
There is no known method for isomerizing p-(4-7minomethylcyclohexylcarponyl).

The present inventors have discovered such a useful 3-(p-()lance-4
-aminomethylcyclohexylcarbonyl)phenyl]
As a result of intensive research on a method that can advantageously produce propion #s by isomerizing the cis form or a mixture of the cis form and the trans form, we found that 3-(p -(4-7-methylcyclohexylcarbonyl)phenyl p-pionic acids can be isomerized very easily by contacting them with an acidic aqueous solution under specific conditions, thus increasing the content of the trans isomer. The inventors have discovered that it is possible to produce Lta3-(p-(4-7minomethylcyclohexylcarbonyl)phenylpropion) and have arrived at the present invention.

・・・・・・・・・ (1) [In the formula, R is a hydrogen atom or a lower alkyl group] Acid addition of 3-CP-(4-7minomethylcyclohexylcarbonyl) 4111 Contacting the cis-form of the salt or a mixture of the cis-form and the trans-form with an acidic aqueous solution having a pH of 3 or less is the preparation of 3-(p-(4-7minomethylcyclohexylcarbonyl)phenyl) p-pionic acids. (by isomerization method).

Ru used as raw material in carrying out the present invention 3-
(p-('4-7minomethylcyclohexylcarbonyl)phenyl)fropionic acids are cis form + oo
% to a mixture of cis and trans isomers in any proportion. Moreover, it may be synthesized by any method, for example, it can be easily produced by the method proposed by the present inventors (Japanese Patent Application No. 1986-98636).

That is, one example is as follows.

4-7/Methylcyclohexanecarphonic acid chloride and phenylpropionate ester
Attached to the crack reaction 1-necessary gj! It can be easily obtained by hydrolyzing the ester depending on the conditions.

3-(p-(4-
In the 7minomethylcyclohexylcarbonyl)phenyl)propionic acids, R represents a hydrogen atom or a lower alkyl group. The lower alkyl group is not particularly limited;
, C1 to Cta are preferred, and methyl and ethyl groups are particularly preferred. Propyl group. Mention may be made of the butyl group. Specific examples of the compound represented by the above formula rl) include the following compounds.

3-(p-(4-7minomethylcyclohexylcarponyl)phenyl)p-pionic acid.

3-(p'-(4-7minomethylcyclohexylcarponyl)phenyl)pionic acid methyl ester.

3-(p-(4-7minomethylcyclohexylcarponyl)phenyl)pionic acid ethyl ester.

3-FP-(4-ami,methylcyclohexylcarbonyl)phenyl]propionic acid n-propyl ester.

3-Cp-(4-7minomethyllaclohexylcarponyl)phenyl]propionic acid isopropyl ester.

It is the cis form or a mixture of the cis form and the trans form of 5-CP-(4-aminomethylcyclohexynylcarbonyl)phenyl]propionic acid phthyl ester.

In the practice of the present invention, the compounds of formula CI) above are not used in the form of acid addition salts, such as mineral salts such as hydrochlorides, hydrobromides, sulfates, phosphates, etc. acid salt;
or formate, acetate.

Monochloroacetate, trichloroacetate, trifluoropi
! Examples include organic acid salts such as salt removal, oxalate, and citrate; or organic sulfonates such as paratoluenesulfonate and benzenesulfonate. Among these, hydrochloride is preferably used from the viewpoint of ease of handling and pharmaceutical stability.

After subjecting a compound with a free ano group that is not in the form to an isomerization reaction as it is to form an addition salt with the acid used in the preparation of the acidic aqueous solution at pH 3u as described above to essentially turn it into an acid addition salt. The invention may be implemented.

The acidic aqueous solution suitable for the method of the present invention may have a pH of 3 or less, but industrially preferably an aqueous solution of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, etc.
% is preferably an aqueous salt solution. The aqueous solution may also contain an inert organic solvent that is substantially miscible with water, such as acetic acid or chloric acid.

7 Setone, tetrahydrofuran, dimethyl sulfoxide, :) methylformamide, etc. in an aqueous solution of 50% by weight.
There is no problem even if it contains the following.

The strength of the acidic aqueous solution used is not particularly limited (for example, it is 1 to 1000 parts (11 preferably 2 to 50 parts (by weight) per 1 part (by weight) of the compound represented by the above formula CI). .

Isomerization is carried out by bringing the acid addition salt of the compound of the formula CI' into contact with an acidic aqueous solution of pl (3 or less); contact here refers to the acid addition salt of the compound of the formula CI'. This means that it is suspended or dissolved in an acidic aqueous solution.

The isomerization temperature can be carried out at a temperature in the range of 0°C to 100°C, but preferably in the range of 10°C to 90°C,
The isomerization time can be appropriately selected depending on the type and amount of the acidic aqueous solution used and the isomerization temperature, but it is usually carried out in the range of 30 minutes to 1 week, preferably in the range of 1 hour to 24 hours.

The type S of the acid of the acid addition salt of the compound represented by the above formula CI) and the type of acid used to make the acidic water bath liquid I4 may be the same or different, but the acidic water @ liquid consisting of different liquids may be the same or different. When used, acid exchange reaction of partial addition salt may occur due to acid type 1 isomerization, etc., so N1- is preferable.

In addition, when R in the compound represented by formula (1'J) above is lower alkyl, a hydrolysis reaction of the ester group may occur simultaneously with isomerization to give a carboxylic acid as a product.
As described above, horse mackerel, in which the hydrolysis reaction of ester groups occurs along with isomerization, is naturally included in the isomerization method of the present invention. In this case, if necessary, the ester can be easily obtained by subjecting the product to a conventional esterification reaction.

Further, K, which converts the type of acid addition salt of a compound obtained by isomerization, can be easily converted by neutralizing the compound with an alkali and then treating it with the desired acid.

After the isomerization reaction is completed, the target product containing an increased number of trans isomers is usually processed by filtration, evaporation of the aqueous solution, distillation, and recrystallization of the residue depending on the situation, or ion conversion.
It can be easily isolated and purified by chromatography or column chromatography.

It is also possible to isolate the desired product by direct extraction with a suitable solvent, neutralization with a #1 aqueous alkali solution, and the like.

As detailed above, according to the present invention, 3-(
It is possible to produce extremely #AI effects by producing p-(,) lance-4-7minomethylcyclohexylcarbonyl)phenyl]propionic acids. In addition, in the present invention, the cis isomer or the
is a mixture of cis and trans forms, 3-rp-(4 ami,
Nomethylsinlohexylcarbonyl)phetylpion*a can be easily obtained from 4-7=minomethylcyclohexanecarboxylic acid, which is easily and inexpensively available in the cis form or a mixture of the cis and trans forms. Therefore, the isomerization of the present invention is industrially very advantageous.Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 3-(p-(4-7minomethylcyclohexylcarbonyl)phenyl) pbio7@* containing 10% of cis isomer
Suspend rllk salt 30G11 in 3N #1 acid 4゛V and add 80
Stir at ℃ for 2 hours. After the reaction is completed, hydrochloric acid is distilled off under reduced pressure.
When solidified, white crystals of 3.0 (jalP) are obtained.

,・This is a high-performance liquid vaporography analysis l(u
PTC), Thin Layer P Madography Analysis Chamber 2 (TLC)
, and 3-[・P-(4-N-7cetylaminomethylcyclohexylcarponyl)phenyl]propionyl methyl ester, followed by NMR analysis, etc., revealed that 3-(p-() containing 03 cis-isomers) lance-4-7minomethylcyclohexylka, rubonyl) phenyl)
It was confirmed that it was a pionic hydrochloride.

+1 Separation conditions for cis and trans forms: Column: N
uc'leo s eyes @ s CIs (Machere
y-Nagj1), 15csc Effluent solvent: water-methanol system with sodium 1-pentanesulfonate added to adjust the flow rate to 35% Flow rate: tcc/min.

Detection: UV' Under the above conditions, the trans isomer was confirmed at 29 minutes, and the cis isomer was confirmed at 32 minutes.

Appetizer 2 Separation conditions for cis and trans isomers Thickness of Nijirica gel as carrier: 025. Using a dilute ym* of m, when chloroform dimeth/-ol: formic acid is related to about 151' using a developing solvent of 25:8:4, the trans isomer has an Rf of about 58 J.
The cis isomer can be confirmed at Rf approximately 063 by UV or ninhydrin color development.

Example 2 3-(p-(4-7minomethylcyclohexylcarbonyl)phenyl containing 10 qb of cis isomer) 1100 ml of propionic salt was suspended in N salt @21 @80°C.
Stir for hours. Below, the same aK treatment as in Example 1 was carried out, and the cis isomer was 0.
．． 3-(p-(trans-4-7mi/
99 da of methylcyclohexylcarbonyl)phenyl 1-propionic hydrochloride was obtained.

Example 3 Example 206N Hydrochloric acid was replaced with filtrated acid, and the rest was Example 2 and tffl kJ! As a result of the sexualization reaction, 100 da of trans isomer containing 03% of cis isomer was obtained.

Example 4 3'-(p-(4-Arnomethylcyclohexyl-luponyl)phenyl) propionic salt 1[oo* containing 10% of the cis-isomer] was dissolved in 3Njf[29 liters of stomach at 80°C, then 45 The temperature was lowered to ℃ and stirred for 5 hours.

After the reaction is complete, the resulting crystals are separated and dried to give white crystals 92
■ was obtained. This one is 3-[p-(trans-4-
It was 7minomethylcyclohexylcarponyl)phenyl]propionate hydrochloride, and no cis form was observed.

Example 5 Sulphur 3-(p-(4-7minomethylcyclohexylcarbonyl)fe21) containing cis isomer 1oQfk was suspended and stirred at room temperature (approximately 20°C) for 24 hours.The following treatment was carried out in the same manner as in Example 1. and 3-(p-
100 Iv of ()trans-4-aminomethylcyclohexylcarbonyl(7t)phenyl]propionate hydrochloride was recovered.

Example 6 150% of 3-(p-(4-7minomethylcyclohexylcarbonyl)phenyl)propionic hydrochloride containing cis-isomer 1O2 was suspended in an aqueous solution of IN sulfuric acid, 760" The mixture was stirred at C for 3 hours.

After cooling, concentrated hydrochloric acid of 5- was added, and the precipitated crystals were separated by P. The crude crystals were recrystallized with 7 tons of water to obtain 3-(p-() lance-) containing the cis isomer of o54. Example 7 3-('p-(4-7minomethylcyclohexylcarbonyl)raenyl)propiosic acid containing 45% of the cis-isomer was obtained. Hydrochloride (100 da
-7minomethylcyclohexylcarponyl)phenyl]
Polypionic acid! /Ii acid salt, 100 Da was recovered.

Example 8 3-(p-(4-amylomethylcyclohexylcarbonyl)p-bio?/acid 11501v containing 25 cis isomers was suspended in 6N salt #31 and stirred at 60°C for 5 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain 3-(p-
() lance-4-7minomethylcyclohexylcarbonyl)phenyl)propionate acid' salt 148 was recovered.

Example 9 3-C p-(4-7
200 das of minomethylcyclohexylcarbonyl phenyl pionic acid methyl ester hydrochloride. 2 N@
@1. sm'H was dissolved and stirred at 80°C for 05 hours. After the reaction, the reaction mixture was cooled on ice and the resulting crystals were separated to obtain 142 white crystals. This crystal was separated by pre-bar tape thin layer chromatography and 3-(p-(
) lance-4-7minomethylcyclohexylcarbonyl)phenyl]propionic acid methyl ester hydrochloride 76M
3-(p-() lance-4- containing 8 g and cis isomers
7minomethylcyclohexylcarponyl)phenyl 1butrho pionate #tJ[63# was obtained.

Example 10 3. containing 70% cis isomer. -(p-(4-7minomethylcyclohexylcarbonyl)7enyl)propionic acid methyl ester hydrochloride 20G drops of 6N salt was suspended in 92dlK and stirred at 80'C for 4 hours. At the end of the reaction, hydrochloric acid was added under reduced pressure. Distillation gave white crystals 180IIIi+. This was recrystallized in a water-77t system to give 3-(p-()lans-4-7minomethylcyclohexylcarbonyl)phenyl containing 02% of the cis isomer. ]p pionic acid #its
sMg was obtained.

Example 11 3-(p'-, (4-7minomethylcyclohexylcarbonyl)propionic acid ethyl ester hydrochloride 150 cape containing 10 qb of cis isomer
Salt @ 2. The suspension was suspended in 5 m4 and stirred at 80°C for 5 hours. Thereafter, the same treatment as in Example 1O was carried out, and 0. 2
% of 3-(p-()-4-7minomethylcyclohexylcarponylphenyl)propionate hydrochloride was obtained.

Example 12 (+) 20 Jl of 4-aminomethylcyclohexanecarboxylic acid having 10% of the cis isomer (determination and amount according to the Japanese Pharmacopoeia Act, 10th revision) was suspended in Bezizene 201, and thionyl chloride 4. 6 Ii was added and stirred at 49°C for 2 hours. After the reaction was completed, the pressure was reduced to 7 1 (benzene was distilled off to obtain 2.70 I of the acid chloride in the form of white crystals.
-Suspended in 2 osl of dichloroethane and 515j under ice-cooling.
(anhydrous salt of 1) aluminum chloride then 3-phenylpq methi pionate 5
A solution of 198 g of ester dissolved in 41 1,2-dichloroethane was added, and the mixture was reacted at 30°C for 2 hours. The reaction mixture was then ice-cooled again and stirred thoroughly for 8 a.
t of water was added to 1O2 seedlings, and when P was precipitated as white crystals, 3-(p-(4-7minomethylcyclohexylcarbonyl)phenyl)propionic acid methyl ester hydrochloric acid containing 8 t of Schiff bodies was obtained. Salt 3.65 II was obtained.

(-) Suspend this in 3N salt @40-80℃
The mixture was stirred for 4 hours. After the reaction was completed, hydrochloric acid was distilled off under reduced pressure to obtain white crystals. I got 509. This product was recrystallized in a water-a7tone system, and 3 containing the cis isomer of 04eIb was obtained.
- (p!() lance-4-7minomethylcyclohexylcarbonyl)phenyl]propionate hydrochloride3. 0 2 11. Obtained.

The yield was 73%.

Example 13 (+) 4-7minomethylcyclohexanecarboxylic acid having 70 cis-isomers 2. 5 jl benzene 25-
5. Suspend in thionyl chloride. 8 II In addition chamber'
Stirred for 1 hour. Benzene was distilled off under reduced pressure, and 337 g of the resulting white crystals of the acid chloride were mixed into 1. 2-' dino 2 no 112 fu 25 chloride, 644 anhydrous salt hyaluminum and then 2.48Ii 3-phenylbrohionic acid methyl ester were dissolved in 5-1,2-dip/reethane under water cooling. The solution was added. After reacting the ゛koiL at room temperature for 4 hours, it was cooled on ice again, and while stirring thoroughly, water was added for 10 hours.
Added t to lO branch child. When the precipitated white crystals were extracted, 3, - (p -
(4-aminomethylcyclohexylcarbonyl)phenyl]bu-p-hionic acid methyl ester salt desalting4. o
3g force; Obtained (-) Suspend this in 3N hydrochloric acid Soil/s
.

After stirring at ℃ for 5 hours, hydrochloric acid was distilled off under reduced pressure to give 38
6 g of white crystalline car was obtained. Furthermore, this product was re-crystallized in a water-a-7t system, and a 3-pyrite containing 0 and 6 cine bodies was added.
(p'-()lans-4-7minomethylcyclohexylcarbonyl)phenyl]furopionic acid3. 2 0 1
The yield obtained was 62%.

Example 14 (1) 4-7minomethylcyclohexanecarboxylic acid containing 70% cis isomer2. s I. In the same manner as in Example 13, acid p-lide was first prepared and then Friedel-Crach reaction was carried out.

After adding 10 g of water to the reaction mixture under water cooling, the mixture was stirred at 60°C for 2 hours. This was then cooled with water, and the crystalline P that precipitated was
Upon taking, 464II 3-(p-(4-7minomethylcyclohexylcarponyl)phenyl)pionic hydrochloride and its methyl ester were obtained in a ratio of 6:4.

(1) Add this stuff with 3N salt @4on7! Ic was suspended and stirred at 80°C for 4 hours. After the reaction was completed, the salt pentaacid was distilled off under reduced pressure to obtain 453 g of white crystals. This product was recrystallized in a water-77 ton system to obtain 3-+p containing 0.3 mo of cis isomer.
-()Lance-4-aminomethylcyclohexylcarbonyl)phenyl]propionic acid hydrochloride 3.679 was obtained.

The yield was 71%.

Claims (1)

[Claims] l Following formula (1) -NHa-mountain (VC kai CH HzCH heavy C0OR...
... [11 [wherein R is a hydrogen atom or a lower alkyl group] 3-(p-(4-ami7/methylcyclohexylcarbonyl)phenyl]bupion 1liliIl/)Wk
3-(p-(4-7minomethylcyclohexylcarponyl)phenyl 1-propionic acid m- o Isomerization method. When contacting with acidic water purifier with a pH of 1 or less, the temperature l
The isomerization method according to claim 1, wherein the contact is carried out at a temperature in the range of 0° C. to 100”C. 3. Claim 1
Or the isomerization method of Section 2. 4, 3 (p~(4-7minomethylcyclohexylcarbonyl)phenyl) acid addition salts of pionic acids,
3-(p-(4-amidimethylcyclohexylcarbonyl)phenyl 1propio/acid methyl/toester salt salt) Claims 1 to $1311 (.) Any isomerization method. 5, 3- The acid addition salt of (P-(4-7minomethylcyclohexylcarbonyl)phenyl) pion is 3
-(p-(4-amidimethylcyclohexylcarbonyl)phenyl)fropionic acid hydrochloride, the isomerization method according to any one of claims 1 to 3.