JPH0296555A - Production of 4-carboxyamidecyclohexane carboxylic acid esters - Google Patents

Abstract

PURPOSE:To obtain the subject compound in a high yield by a simple and mild process by reacting an inexpensive 1,4-cyclohexanedicarboxylic acid diester with ammonia in the presence of an alkali metal alkoxide catalyst under an anhydrous condition. CONSTITUTION:A 1,4-cyclohexanedicarboxylic acid diester such as trans-1,4- cylohexanedicarboxylic acid dimethyl ester is reacted with ammonia gas or liquid ammonia in an amount of 1-4mol based on the compound in the presence of an alkali metal alkoxide catalyst such as CH3ONa in an amount of 0.1-2 times mol based on the dicarboxylic acid diester in an organic solvent such as anhydrous methanol or a mixture thereof with a solvent such as toluene at -10-150 deg.C for 1-100hr under atmospheric pressure or an increased pressure to provide the objective compound useful as an intermediate for synthesizing a drug trans-4-aminomethylcyclohexanecarboxylic acid having an antiplasmin action.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention provides 4-cal-11 useful as a synthetic intermediate for pharmaceuticals.
1 Preparation of cyclohexane carboxylic acid esters 3
m method.

More specifically, trans-4-aminomethylcyclohekylene carmine 1v24,1 anti-7' rasmin 1' [
Is the compound useful as a 6-stone compound and can also be used as a pharmaceutical intermediate?
- Method for manufacturing carboxyrimide cyclohexane carboxylic acid ester lamp 1 (relating to this).

[Conventional techniques (・I'+ 33 and its problems] Conventional, 4-
There are almost no known methods for obtaining carboxyrimide cyclol\kirincal''j (carboxyrimide cyclol\kirincar) esters at high yields.Also,
For example, the only known method for its hydrolysis product, 4-carboxamide cyclohexylcarboxylic acid, is a method in which 1,4-cyclohexylcyclohexylcarphonic acid diester is reacted with aqueous ammonia. 43-142
October, Japanese Patent Publication No. 58-144353).

Trans-4-amitsume 5) Recylohexanecarboxylic acid is produced (by reduction) via 4-cyanocyclohexanecarboxylic acid, or converted to 4-cyanocyclo, which is its precursor (raw material), When V1 noncarboxylic acid is prepared by the dehydration reaction of 4-carboxamide cyclohylcarboxylic acid, the reaction between the dehydrating agent and the carboxylic acid also occurs, and the dehydration reaction does not proceed smoothly. multiple times are required.

On the other hand, 4-cyanocyclohexylinecarboxylic acid ester is a small kyrimide derivative having a carboxylic acid Nisder group, so it can be easily and highly yielded by the dehydration reaction. It is possible to lead to
- In order to lead to cyanocyclo to 4-sancarboxylic acid and 1q,
It is a more useful intermediate.

Therefore, the present inventors have obtained 1,4-Schiff[1-hekyline sicaphonic acid diesters, -[nocarboxamito7)T stellates, which are readily available, inexpensive and advantageous raw materials, in high yields. I did my best to save δ(1).

[Means for Solving the Problems] In order to obtain heptanocal small kyrimide and notospures from di-earth ster compounds in a high yield, some means for increasing selectivity is required. As a method for converting an ester group into a carpokyrimyl group, there is a method of heating an ester compound with an amine. For example, even when reacted with ammonia in a methanol solvent, there is no significant conversion above 100°C, and the selectivity for mono-ster compounds is extremely low. In addition, if water is present, the reaction with ammonia is relatively slow or involves a water decomposition reaction of 11[1] of the ester group, so that almost no endogenous compounds are reacted with [1].

The present inventors have discovered that by using an alkali metal alkoxylide as a catalyst under anhydrous conditions, the reaction proceeds extremely reproducibly even at low temperatures, and the amount of ammonia can be reduced from 21 to 1. The present inventors have discovered that by rolling, the selectivity can be increased and 4-carboxyrimidocyclotocarboxylic acid methyls can be produced in high yield, and the present invention has been completed.

Specifically, the present invention provides a 4-carboxylene dicarboxylic acid diester, which is characterized by reacting 1,4-cyclohekyline dicarboxylic acid diester and unpure in the presence of an alkali metal alkali metal alkali oxide in an anhydrous fire extinguishing medium. This is one method for midocycloto-4-phosphoric acid esters.

The method of the present invention will be explained in detail below.

In the present invention, alkali metal alkali is used as a catalyst.
Use Kirito.

Examples of alkali metal alkoxides include
Lium methoxide, potassium 11, methoxide, sodium methoxide, sodium methoxide, sodium methoxide, potassium 11, lithium methoxide, potassium 11, lithium
J-thorium propoxylide, J-thorium propoxylate, and the like.

There is no strict limit on the catalyst skewer.
~2 times the molar amount is used. Alkali metal alkoxides can be prepared by using commercially available products as they are, by adding an alkali metal to alcohol, or by reacting alcohol with alkanometal hydrides or alkali metal amides. You can also use the

1? Examples of the 1,4-cyclohekyline dicarboxylic acid diesters of 11 include ], ]4-cyclohenyline dicarboxylic acid cymel ester, '1,4-cycloL1 hekyline dicarboxylic acid cymel ester, It is also possible to use a lower alkylnisdale such as 1°4-cyclohexylcarphonate dipropyl earth suar. In addition, the raw material 1,4
- Cyclohekirin cycal small phosphatide - esters, there are two stereoisomers, cis form and 1 herans form,
The raw material used in the present invention may be any isomer or may be a mixture of both isomers.

The organic solvent used in the present invention generally includes 1, which is a raw material.
, it is reasonable to use a lower alcohol corresponding to the ester group of the 4-cycloD-hekyline dicarboxylic acid diester. Specifically, methanol, ethanol, propatool, and isopanol can be used. In this case, the lower alcohol may be optionally mixed with other solvents such as methylene chloride, chloroborum, toluene, benzene, cyclone, 1゜2-dichloroethane, etc., which have low reactivity with ammonia and are used. It is also possible to use a mixture of common general-purpose solvents.

The reaction is carried out, for example, by adding a catalyst alkali metal alkali oxide and 1,4-cyclohekyline dicarboxylic acid diester to an anhydrous organic solvent, and then adding ammonia scum or liquid ammonia to react.

The reaction temperature is 110'C to 150'C.
By carrying out the reaction at a temperature of 100'C to 100°C, 1q of the target compound can be obtained with better selectivity.

The amount of ammonia has an important influence on the selectivity as well as the temperature, and it is usually sufficient to use ammonia in an amount of 1 to 4 times the mole of the raw ester.

When the amount of ammonia is increased, a large amount of 1,4-cyclohekirindiruboxamide is produced and the selectivity is decreased.

Although the reaction does not need to be particularly pressurized, it is carried out under normal pressure or under increased pressure depending on the temperature in the system.

The progress of the reaction can be confirmed by scrontographies, etc., and the reaction is usually determined at intervals of 1 to 100 [1,'j].

The product after the reaction can be isolated by, for example, adding condensate water from which the solvent has been distilled off, neutralizing it with acid, reading the precipitated crude crystals, dissolving the crude crystals in a solvent, and filtering out insoluble matter. After that, the i1 running solution is concentrated and the excess ammonia is removed by introducing an inert ↑1 gas, the insoluble matter is filtered off, and the filtrate is concentrated to precipitate. If necessary, it can be purified by means such as washing with a solvent, recrystallization, column chromatography, etc.

[Effect of the invention] According to the present invention, C4JrtJ% is used as a pharmaceutical synthesis intermediate.
4-Carboxy V mitocyclohekylinecarphonic acid esters can be produced in high yields using a simple and mild process.

[Examples] The present invention will be described below in more detail with reference to Examples, but the present invention is not limited by the following examples.

Actual h(!!Example 1 Trans-1,4-cyclohexanedicarboxylic acid simebru ester 25!7 (125 mmol>, sodium methoxylide 6.75'j (125 mmol)
), a mixture of 5 g of metamelf (!-stir, 15 °C
Then, 6.4y (375mmol) of ammonia was introduced in gaseous form over about 1 hour. Thereafter, the mixture was stirred at 20°C for 30 hours. After the reaction, methanol was distilled off under reduced pressure.
100 parts of water was added, and the mixture was neutralized to p)-14.5 with aqueous hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain white crystals. The crystals were added to 200 ml of hot methanol, insoluble crystals were removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting white crystals were recrystallized with toluene.
Add 16.2 Ij (8.75 mmol, 70%) of Kirin carboxylic acid methyl ester to Callebokirimide 99 days.
It's q. The raw material dimethyl ester 2y (10 mmol,
8% recovery) was recovered.

Example 2 1.84 g (80 mmol) of metal notorium was added to 5
Dissolved in 0 ml methanol, then 25 g (
125 mmol) of trans-1,4-cycloLl/\kirinshical dimethyl phosphate was added and stirred, and 50
It was kept at °C. Ammonia was introduced into the tube at a rate of 25 m/min in the form of a 25 m/min. Thereafter, the mixture was stirred at 50°C for 211 minutes. After the reaction was completed, the same isolation procedure as in Example 1 was carried out to obtain trans-4-calilζkyrimitocyclohexylinecarboxylic acid methyl ester 16 LJ (86 mmol, 69% yield).

Example 3 25 g (125 mmol) of transl 1,4-cyclohekyline cyclohexyl dimethyl ester, 8.75'J (125 mmol) of potassium methoxylide, 10 (M) of methanol, 100 parts of toluene, 4.25 g of liquid ammonia. (250 mmol) was placed in an autoclave and stirred with IJ heat at 80'C for 3 hours. After the reaction was completed, the pressure was returned to normal pressure and nitrogen gas was introduced at 60'C to remove excess an-[nia]. Then, filter at 60°C,
After removing insoluble matter, the filtrate was distilled off under reduced pressure to obtain 1 white crystal.
It was. This was washed with water, rl + L/, and then washed with hexadiene, l~ lance ~ 4-carboquinamide cyclohexylcarboxylic acid methyl ester 17 (j (92 mm
ol, 73%).

Mochihe9 Applicant: Showa Denko Co., Ltd.

Claims (1)

[Claims] 1) A method for producing 4-carboxamide cyclohexanecarboxylic acid esters, which comprises reacting 1,4-cyclohexanedicarboxylic acid diesters with ammonia in an anhydrous organic solvent in the presence of an alkali metal alkoxide. . 2) The method according to claim 1, wherein the 1,4-cyclohexanedicarboxylic acid diesters are 1,4-cyclohexanecarboxylic acid di-lower alkyl esters.