JPS5927333B2 - Process for producing clemastine fumarate useful as a medicine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 2-(2'-[(parachloro-α-methyl-α-phenylbenzyl)oxy]ethyl)-1-methyl-pyrrolidine fumarate, that is, “clemastine fumarate”. The present invention relates to a manufacturing method, and particularly to a method for optical resolution of isomers useful as pharmaceuticals from stereoisomer mixtures.

Clemastine has two asymmetric carbon atoms and therefore has four optical isomers.

These four isomers and organic acid salts have different standard specific rotations, but isomer ① exhibits antihistamine action and is particularly important as a medicine.

As a recently proposed optical resolution method for clemastine, there is a method described in JP-A-51-105054.

In this known method, when a general optically active organic acid used for optical resolution, such as tartaric acid or malic acid, is used, the cremastate obtained is non-crystalline, and dibenzoyl as a resolving agent is used. Or H-tartaric acid is used.

In view of this known method, we investigated the use of various organic acids as resolving agents...Although H-tartaric acid is effective when acetone is used as a solvent, when pure acetone is used as a recrystallization solvent during purification. In order to obtain the desired isomer (2) of clemastine fumarate, it was found that problems occurred in reproducibility, yield, etc.

Therefore, the object of the present invention is to provide (1) or (d) a method for producing the above isomer, ie, clemastine fumarate useful as a pharmaceutical, from a mixture of isomers of clemastine using monotartaric acid as a resolving agent and acetone as a solvent, The object of the present invention is to provide a manufacturing method with good reproducibility and high yield.

According to the invention, this object is achieved by a method characterized in that, in the method described above, aqueous acetone or aqueous ethanol is used as the recrystallization solvent for purification.

In the present invention, aqueous acetone or aqueous ethanol is 7
Means 0 to 95% acetone or ethanol aqueous solution.

The method of the present invention can be carried out in various ways as described below.

First, in the first method, a mixture of isomers of clemastine and (4
) with monotartaric acid in the presence of acetone, filtered,
This is a method in which acetone is distilled off from the resulting tartrate salt, and then recrystallized from aqueous acetone or aqueous ethanol.

In this method, if acetone is added to the filter cake after filtering off the tartrate and refluxing it, isomer 1 and the tartrate are obtained, and the tartrate of these isomers is released by neutralizing the filtered filtrate. If (d) monotartaric acid is added and reacted after forming a base, the isomer (d) monotartrate is obtained, and the filtered residue from which the tartrate of this isomer is filtered off is again neutralized to form a free base. If so, it can be used again as starting material for the first method. The second method involves refluxing a mixture of clemastine isomers and (4)-tartaric acid in the presence of acetone, filtering the reaction mixture, distilling off the acetone from the filter, and then hydrating the resulting tartrate. This method involves recrystallization from acetone or aqueous ethanol.

In this second method, the reflux treatment requires about 6 hours,
The resulting solid is a tartrate mixture with isomer 1. The third method uses a mixture of isomers of clemastine and (
d) Tartaric acid is refluxed in the presence of acetone, the reaction mixture is filtered, and acetone is distilled off from the filtrate to produce (d)
In this method, tartrate is recovered as a free base, reacted with monotartaric acid in the presence of acetone, acetone is distilled off from the reaction mixture, and then recrystallized from aqueous acetone or aqueous ethanol.

The fourth method is to purify crude clemastine with an organic acid salt such as succinate or fumarate, react the resulting clemastine free base with monotartrate, and then recrystallize from aqueous acetone or aqueous ethanol. be. However, as a result of examining the possibility of using various organic acids as resolving agents, we found that (4) monotartaric acid and (d) tartaric acid are effective when acetone is used as a solvent, and pure acetone is used as a solvent during recrystallization. It has been found that in some cases, problems arise in reproducibility, yield, etc., or that these problems can be improved if aqueous acetone or aqueous ethanol is used as a solvent.

Thus, an object of the present invention is to provide (4) a method for producing clemastine fumarate using monotartaric acid as a resolving agent and aqueous acetone or aqueous ethanol as a recrystallization solvent.

The first method of the present invention comprises a mixture of isomers of clemastine and...
It is characterized in that it is reacted with monotartaric acid in the presence of acetone, filtered, and acetone is distilled from the resulting tartrate and recrystallized from aqueous acetone or aqueous ethanol.

In this method, if acetone is added to the liquid from which the tartrate has been separated and the liquid is refluxed, isomer 1 and tartrate can be obtained. When the isomer (d) monotartrate is obtained by adding (d) monotartrate and reacting, the toya which has removed the tartrate of the isomer is again neutralized. If it is made into a free base,
This can again be used as starting material for this first method.

The second method of the present invention uses a mixture of isomers of clemastine and...
The method is characterized by refluxing monotartaric acid in the presence of acetone, filtering the reaction mixture, distilling off acetone from the distilled liquid, and recrystallizing the resulting tartrate from aqueous acetone or aqueous ethanol.

In the second method, the reflux treatment requires about 6 hours.

The solid resulting from this treatment is a tartrate mixture with isomer 1. The third method of the present invention is to reflux a mixture of clemastine isomers and (d) tartaric acid in the presence of acetone, filter the reaction mixture, and distill off acetone from the bottom liquid to produce (d) tartrate. Recovered as free base...
It is characterized by reacting in the presence of monotartaric acid and acetone, distilling off the acetone, and recrystallizing from hydrous acetone or ethanol.

In the fourth method of the present invention, crude clemastine is purified using an organic acid salt such as succinate and fumarate, and the isomer separated from four types of isomers (1)...The specific rotation of tartrate is +
A purity of 23 to +25 is desirable, but a purity of +21 to +26.5 is required as a raw material for clemastine fumarate, which is useful as a medicine. Next, the present invention will be explained in more detail with reference to reference examples and examples.

Reference Example Synthesis of Clemastine;) Synthesis of α-methyl-p-chlorobenzhydrol Magnesium 60.89 (2.5 gram atoms), Iodine 2,
59. Add bromobenzene 3709 (2.35 mono(c)) and 400 ml of ether to 700 ml of anhydrous ether with stirring.
A Grignard reagent is prepared by adding 1 of the solution dropwise to the solution until it gently refluxes, and then refluxing for an additional 2 hours.

The Grignard reagent was cooled to below 0°C, and a solution consisting of p-chloroacetophenone 2809 (1.81 mono(III) and 400 ml of ether) was added dropwise at 0 to -5°C. After that, the mixture was refluxed for 15 minutes, cooled again to below 0°C, and decomposed by dropping about 400 ml of a saturated aqueous ammonium chloride solution.The ether layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. By doing so, the target product approximately 4109 (yield 973%) is obtained as a residual liquid.11) 2-
(Synthesis of 2-chloroethyno(c)-1-methylpyrrolidine 1-methyl-2-pyrrolidine ethanol 103.29 (0.8 mono(c) and chloroform 500
The solution consisting of a was saturated with dry hydrogen chloride gas at room temperature, cooled to below 10°C, and then 196.5 g of thionyl chloride (1.65 mono(c)) was added dropwise over about 10 minutes. Heat and reflux for 2 hours at a bath temperature of 7°C.

After that, the solvent was distilled off and 3N sodium monohydroxide solution 55%
0 ml was added, extracted with 340 ml of ether, and solid potassium hydroxide 1009 was added to the aqueous layer under strong cooling.
The combined ether extracts were extracted three times with 340 ml each of ether, dried over sodium sulfate, the solvent was distilled off, and the residue was separated from boiling point 47°C/5Hg to boiling point 65-6°C/
Distillation under reduced pressure at 11 mmHg yields the target product 1069 (yield 89.8%).

111) Synthesis of clemastine Sodium amide powder 399 (1
．． α-methyl-p-chlorobenzhydrol 20 obtained by the method described in section ;
09 (dropping 0.86 mono(c) (benzene 100 m
After gradually adding the mixture and refluxing for 1 to 4 hours, the method described in section ii) can be applied.
Add 2-(2-chloroethino(c)-1-methylpyrrolidine 1069 (0.72 mono(c)) dropwise over about 30 minutes (washing the dropping funnel etc. with 50 ml of benzene),
Reflux treatment for 0 hours 5. After cooling, wash with 200 ml of water, add 300 ml of ether to the organic layer, and add 43 ml each of 2N monohydrochloric acid.
The combined hydrochloric acid extract was washed with ether again, made alkaline with 500ml of 6N sodium monohydroxide aqueous solution, extracted twice with 300ml each of ether, and the combined extract was washed with potassium carbonate. Dry, evaporate the solvent and reduce the residue to a boiling point of 154°C/0. Distilled under reduced pressure at 02 mmHg to obtain 191 g of the crude target substance as an oil (
A yield of 77.4%) is obtained.

lV) Purification of Crude Clemastine Using Wako Gel C-200, 7009, crude oil (obtained by the method described in Section 111) above 259 was separated and purified by column chromatography.

The developing solvent and distillation amount are as follows, and the recovery rate is 95
The % free base was 80-85%. 1. Developing solvent triethylamine, ethyl acetate, and n-hexane.
2:2:10 Mixture Example 1', tJL1-1? ? T? , Dissolve 1.0059 of the oily substance in 10 ml of acetone,
To this... 0.4379 of monotartaric acid was added and dissolved by heating, then the solvent was distilled off, and the resulting tartrate was recrystallized from 3 ml of an 80% acetone aqueous solution at 4°C.
Recrystallization (at 4° C.) from 1 ml of an aqueous solution of % acetone gives 258 η of the crude tartrate of the isomer (yield: 119%).

After separating the tartrate of isomer 1V, the solvent of the solution was distilled off, refluxed with 5 ml of acetone for several hours, and after separating the precipitated crystals, the F5 solution was neutralized with 1N sodium monohydroxide solution. and extract with ether to obtain the free base.

If you convert this base into (d) monotartrate and repeat the same operation as above, you will obtain the crude isomer (d) monotartrate, so treat this solution and convert it to monotartrate again. ,
By carrying out the same treatment as above, the crude tartrate of the isomer is obtained.

(Yield 6.4%) The crude isomer tartrate was prepared using ethanol/
It can be purified by recrystallization from hexane.

The purified crystals are suspended in water, made alkaline with sodium hydroxide, and extracted with ether to obtain the isomer as an oil.

(b) D=+36.5 (in 1-2% methanol) When this isomer is converted into a fumarate salt in ethanol and recrystallized from ethanol, the width is obtained.

+16.9 (2% methanol) melting point 176-180C
(decomposition) of clemastine fumarate is obtained.

Example 2 Clemastine oil 1 that can be obtained by the method described in Reference Example
．． 219 and 0.539 bitartaric acid were dissolved in 5 ml of acetone, refluxed for 6 hours, and then aged at a temperature to give 8.
Crystals of 287r19 (yield 47.6%) are obtained.

This crystal has a melting point of 141-180°C and is a mixture of tartaric acid and isomer 1.

Acetone was distilled off from the above crystals from Fuchiya, and 80%
Recrystallization from 1.7 ml of acetone aqueous solution at 4 DEG C. yields crystals of 374~ (yield 21.5%).

If recrystallized from 1 ml of 90% acetone solution, 2
The isomeric tartrate salt of 05W19 (yield 11.8%) is obtained.

When treated in the same manner as in Example 1, Mpl76-180℃
(Decomposition) (Company) D+16.6 clemastine fumarate is obtained.

Examples 3 to 6 10.059 ml of purified clemastine oil obtained by the method described in Reference Examples is dissolved in 100 ml of acetone, 4.371 ml of monotartaric acid is added and dissolved by heating, and then the solvent is distilled off.

This was separated using aqueous acetone and aqueous ethanol, and the results were as follows.

Example 7 Purified clemastine oil 59 obtained by the method described in Reference Example was dissolved in 18 ml of acetone, 2.189 g of (d)tartaric acid was added thereto, refluxed for 5 hours, and after cooling, precipitated crystals were removed, The solvent was distilled off, the residue was made alkaline with 1N sodium hydroxide solution and extracted with ether, and the resulting free base (approximately 2.49) and tartaric acid 1. O5
After heating and dissolving 9 in 8 ml of acetone and distilling off the solvent, 8
If recrystallized from 3.5ml of 0% acetone, the melting point will be 77-1.
00°C isomer ■...tartrate 1.185g (yield 16.
5%) is obtained.

1.09 of this tartrate was made alkaline with 1N sodium hydroxide and extracted with ether. To the resulting free base, 0.2359 of fumaric acid and 12 ml of ethanol were added, dissolved by heating, and after cooling, the precipitated fumarate was again removed. If recrystallized from ethanol, clemastine fumarate 0.7259 (yield 77.9%) with a melting point of 178 to 1800 C (decomposition) is obtained.

Example 8 Reference Example 11j) To the crude clemastine oil obtained by the method described in 59, 15 ml of acetone and 1 succinic acid were added.
．． 759 was added and dissolved by heating, and the succinate that precipitated by standing at room temperature was mixed with ethanol:n-hexane (3:1) 3
Recrystallization in 0 ml yields 3.29 succinates (yield 47.64%) with a melting point of 127-130°C.

Clemastine free base obtained by making 2.99 of these crystals alkaline with 10% sodium hydroxide solution and extracting with ether...tartaric acid 0.9439, 95% acetone 9.3m
1, dissolved by heating, and left to stand at room temperature to precipitate crystals.
When recrystallized from 0% acetone, the melting point is 74-110℃.
Isomer ■(t)tartrate 0.8589 (yield 27.7
%) (company).

Claims (1)

[Claims] 1. In a method for producing clemastine fumarate useful as a pharmaceutical from a mixture of clemastine isomers using (+) or (-)-tartaric acid as a resolving agent and acetone as a solvent, aqueous acetone or aqueous ethanol is used as a recrystallization solvent for purification. A method for producing clemastine fumarate useful as a medicine, characterized in that it is used as a medicine.