KR20080062276A - Method for preparing sumatriptan - Google Patents

Abstract

A method for preparing 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide(sumatriptan) is provided to mass-produce the sumatriptan economically with high purity and high yield through a simple reaction without using a non-toxic organic solvent. A method for preparing sumatriptan represented by a formula(1) comprises a step of reacting 4-hydrazino-N-methyl-benzene methanesulfonamide hydrochloride represented by a formula(2) with 4-(N,N-dimethylamino)butanal dimethyl acetal represented by a formula(3) in the presence of an aqueous solution of sulfuric acid, wherein the aqueous solution of sulfuric acid is 4% aqueous solution of sulfuric acid and 2-10ml of the aqueous solution of sulfuric acid is used regarding 1mmol of the 4-hydrazino-N-methyl-benzene methane sulfone amide hydrochloride.

Description

Method for preparing sumatriptan {Method for preparing sumatriptan}

The invention provides 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide (3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5- methanesulfonamide (hereinafter referred to as sumatriptan), and more particularly, to a novel method for preparing sumatriptan, an indole derivative useful for treating migraine and cluster headache, in high purity and high yield.

Sumatriptan acts specifically and selectively on the 5HT1B / 1D receptors distributed in the cerebrovascular system, exhibiting cerebrovascular contraction without affecting coronary and peripheral blood vessels, thereby rapidly improving the symptoms of migraine and cluster headaches. It works. In addition, the drug has been in the spotlight as a breakthrough therapeutic agent with significantly less side effects. Thus, methods for preparing sumatriptan have been proposed in various literatures.

Korean Patent No. 10-0040084 issued by Glaxo Group discloses 3-cyanopropane dimethyl acetal using 4-hydrazino-N-methyl benzene methanesulfonamide hydrochloride as starting material. Was reacted under acidic conditions to synthesize 4- [2- (3-cyanopropylidene) hydrazino] -benzenemethanesulfonamide, the compound was closed using polyphosphate ester, and then palladium catalyst was used. Disclosed is a method for preparing sumatriptan, a target compound, by hydrogenating a cyano group and introducing a dimethyl group. However, this method has a disadvantage of using an expensive noble metal catalyst and having a very low overall yield of about 6%, thereby decreasing the industrial value.

Later, in the Republic of Korea Patent No. 10-0066515, Glaxo Group has variously disclosed a method for producing sumatriptan via various intermediates. In the first method, N-methyl-1H-indole-5-methanesulfonamide is synthesized using 4-hydrazino-benzenemethanesulfonamide hydrochloride and phenylthioacetaldehyde as starting materials. It is a method of preparing sumatriptan through an additional step process. However, the manufacturing process includes a dangerous process that requires the use of Raney Ni and a reducing agent, and has a disadvantage in that mass production and economic production are difficult because of the low yield and purification process using column chromatography.

The second method is to prepare sumatriptan from 3- [2- (methylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide in two additional steps, but this method also yields low yields. In addition, there is a disadvantage in using a noble metal catalyst and a reducing agent in the reaction process.

The third method is to prepare sumatriptan by using a 3- (cyanomethyl) -N-methyl-1H-indole-5-methanesulfonamide as a starting material through two to three additional steps. This method requires a further step in the process of preparing 3- (cyanomethyl) -N-methyl-1H-indole-5-methanesulfonamide, which is used as a starting material. Hazardous processes that require the use of expensive precious metal catalysts or reducing agents have been added, which is difficult to use industrially.

The fourth method is a relatively short process with starting materials of 4-hydrazino-N-methyl-benzenemethanesulfonamide hydrochloride and 4- (N, N-dimethylamino) butanal dimethylacetal (4- (N, N-dimethylamino). ) butanal dimetyl acetal) to give 4- [2- [4- (dimethylamino) butylidene] hydrazino] -N-methylbenzene-methanesulfonamide, followed by reaction with polyphosphate ester in chloroform solvent. It is a method for producing sumatriptan. This method can produce sumatriptan in a short process of two-step reaction, compared to the existing processes, but because of the use of highly toxic organic solvents, the residual problem of the residual solvent is severe, and the yield is as low as 29%. The method is also difficult to use industrially.

The fifth method is a method of introducing methylamine of methanesulfonyl group at the 5th position of 1H-indole nucleus at the last step, but this method must also be prepared using existing methods to prepare 1H-indole nucleus. That is, there is no economic value because it has a fundamental problem of the sumatriptan synthesis methods.

In International Patent Publication No. WO01 / 34561, proposed by KNOLL, Germany, 3- [2-aminoethyl is reacted by reacting 4-hydrazino-N-methyl-benzenemethanesulfonamide hydrochloride with 4-chlorobutanal dimethylacetal. ] -N-methyl-1H-indole-5-methanesulfonamide was prepared and this compound was reacted with water-soluble formaldehyde and sodium borohydride to synthesize sumatriptan. However, this method has a problem in commercial use because of the complicated reaction process and low yield.

In addition, US Patent No. 6,281,475 proposed by Cargill (USA) discloses a method for preparing sumatriptan through a six-step reaction process using 5-bromoindole as a starting material. However, the raw materials used in each step are difficult to use in the mass production such as oxalyl chloride, lithium aluminum hydride, sodium hydride, tetrakis (triphenylphosphine) palladium, sodium / liquid nitrogen, or expensive There is a disadvantage of using a noble metal catalyst, the yield of the six-stage pre-process less than 5%, was not commercially available.

Republic of Korea Patent No. 10-056562 is a manufacturing method proposed by Chirogenix, 4-hydrozino-N-methyl-benzenemethanesulfonamide hydrochloride and 4- (N, N-dimethylamino) butanal dimethylacetal acetonitrile solvent Production of a ring closure process in one step via an intermediate of 4- [2- [4- (dimethylamino) butylidene] hydrazino] -N-methylbenzene-methanesulfonamide in a polyphosphate ester The method is disclosed. However, this manufacturing method has a higher yield than the conventional process, but still has a low yield for commercial use, and there is a risk of using a flammable material such as P ₂ O ₅ to prepare a polyphosphate ester reagent, which is a raw material used for the reaction. There is this. In addition, contamination of high-boiling impurities derived from polyphosphate esters interferes with crystallization of sumatriptan, and acetonitrile solvents, which are used as solvents, are also highly toxic solvents. Have

Thus, the above-mentioned disadvantages of the existing methods are solved: low yield, use of intractable reducing agents in mass production, complicated process steps, use of expensive precious metal catalysts, quality problems caused by the use of toxic solvents, and the like. New manufacturing methods for sumatriptan need to be developed.

Accordingly, it is an object of the present invention to provide a new method for preparing sumatriptan, which is capable of synthesizing high purity and high yield sumatriptan through a simple reaction process step without risk, and is economically easy to mass produce.

It is also an object of the present invention to provide a method for preparing sumatriptan that can solve the residual solvent and purity problems of sumatriptan at a time through a safe production process that does not use a highly toxic organic solvent.

In order to achieve the above object, the present invention is 4-hydrazino-N-methyl-benzene methanesulfonamide hydrochloride represented by the following formula (2) and 4- (N, N-dimethylamino) butanal represented by the following formula (3) Reacting dialkyl acetal under aqueous sulfuric acid solution to obtain 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide (sumatriptan) represented by the following formula (1): It provides a method for producing sumatriptan.

In Formula 3, R is a methyl group or an ethyl group.

Hereinafter, the present invention will be described in more detail.

Method for preparing sumatriptan according to the present invention, 4-hydrazino-N-methyl-benzene methanesulfonamide hydrochloride (Formula 2) and 4- (N, N-dimethylamino) butanal dialkylacetal (Formula 3) 4- [2- [4- (dialkylamino) butylidene] hydrazino] -N-methylbenzene-methanesulfonamide intermediate represented by the following Chemical Formula 4 by reaction under sulfuric acid (H ₂ SO ₄ ) aqueous solution conditions Through, obtaining a sumatriptan (Formula 1) as a target compound.

In the present invention, since it is completed in a one-pot reaction without separating and purifying the intermediate (Formula 4) generated during the reaction process, it is possible to obtain a superior effect compared to the conventional method in terms of purity and yield. have. In addition, in order for the ring to be closed in the intermediate, isomerization with N-hydrazine is required. In this case, the sulfuric acid aqueous solution used in the present invention has a higher yield since the effect of isomerization is much higher than that of other acids such as hydrochloric acid and acetic acid. It is possible to produce sumatriptan.

Preparation of sumatriptan according to the present invention can be made according to the following Scheme 1. In the following scheme, R is a methyl group or an ethyl group.

4-hydrazino-N-methyl-benzenemethanesulfonamide hydrochloride (Formula 2), which is used as a starting material in the present invention, can be prepared by the method disclosed in British Patent No. 2123210 and Tetrahedron Letters, 1992, 33, 8011. 4- (N, N-dimethylamino) butanal dialkylacetal (Formula 3) may be prepared from J. Org. Chem., 1994, 3788.

Since 4- (N, N-dimethylamino) butanal dialkylacetal (Formula 3) has a substituent (R) being a methyl group or an ethyl group, 4- (N, N-dimethylamino) butanal dimethylacetal or 4- (N , N-dimethylamino) butanal diethylacetal can be used. In the preparation method of the present invention, the amount of acetal used may be the same or higher than that of 4-hydrazino-N-methyl-benzenemethanesulfonamide hydrochloride, preferably 1 to 1.5 equivalents.

The range of possible concentrations of the aqueous sulfuric acid solution used in the present invention is a wide range of 2 to 20%, and most preferably, when the reaction is performed in a 4% aqueous sulfuric acid solution, it is possible to minimize the production of unreacted materials and acid decomposition products. The reason for this is that the concentration of unreacted material is increased at a concentration of less than 4%, and the production of acid decomposition products increases due to the influence of high acidity at a concentration of more than 4%. When 4% sulfuric acid aqueous solution is used in the present invention, the amount of the 4% sulfuric acid aqueous solution used is 2 to 10 ml, preferably 5 to 6 ml, per 1 mmol of 4-hydrazino-N-methyl-benzenemethanesulfonamide hydrochloride. If less than 2ml of 4% aqueous solution of sulfuric acid is used, a lot of unreacted substances are generated and the reaction time is long.

The reaction temperature during the preparation of sumatriptan is 0 to 200 ° C, preferably 90 to 120 ° C. If the reaction temperature is too low, the reaction time is long, on the contrary, if the reaction temperature is too high, there is a fear that the generation of impurities is increased.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples. The following examples are intended to illustrate the present invention more specifically, but the present invention is not limited by the following examples.

Example 1 Preparation of Sumatriptan

5.07 (20 mmol) of 4-hydrazino-N-methyl-benzenemethanesulfonamide hydrochloride and 3.87 g (24 mmol) of 4- (N, N-dimethylamino) butanal dimethylacetal were dissolved in 120 ml of a 4% aqueous sulfuric acid solution and reacted. After the solution was refluxed at 100 ° C. for 2 hours, the reaction was terminated by thin layer chromatography. The reaction compound was cooled to room temperature, treated with 15 ml of 30% ammonia water, and extracted three times with methylene chloride (20 ml each). The extracted organic layer was depressurized to remove the solvent, and the residue was crystallized using 15 ml of isopropyl alcohol. The resulting crystals were filtered off, washed with a small amount of cooled isopropyl alcohol, and dried in vacuo at 40 ° C. to obtain 4.84 g of a light white sumatriptan (yield: 82%).

Example 2 Preparation of Sumatriptan

5.07 (20 mmol) of 4-hydrazino-N-methyl-benzenemethanesulfonamide hydrochloride and 4.35 g (24 mmol) of 4- (N, N-dimethylamino) butanal diethylacetal are dissolved in 120 ml of a 4% aqueous sulfuric acid solution, After the reaction solution was refluxed at 100 ° C. for 2 hours, the reaction was terminated by thin layer chromatography. The reaction compound was cooled to room temperature, treated with 15 ml of 30% ammonia water, and extracted three times with methylene chloride (20 ml each). The extracted organic layer was depressurized to remove the solvent, and the residue was crystallized using 15 ml of isopropyl alcohol. The resulting crystals were stirred at 10 DEG C or less for 1 hour, filtered, washed with a small amount of cooled isopropyl alcohol, and dried in vacuo at 40 DEG C to obtain 4.6 g (yield: 78%) of white white sumatriptan.

Comparative Example 1 Preparation of sumatriptan

10 g of 4-hydrazino-N-methyl-benzenemethanesulfonamide hydrochloride was added to 25 ml of water and 5 ml of 2N hydrochloric acid. 8.32 g of 4- (N, N-dimethylamino) butanal dimethylacetal was added to the suspension and stirred. 15 ml of 2N hydrochloric acid was further added to the reaction compound, and the mixture was stirred at room temperature for 3 hours. 150 ml of chloroform was added thereto, and then 150 ml of 2N sodium carbonate solution was added little by little. The aqueous layer was separated and the aqueous layer was extracted with 150 ml of chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and then the solvent was concentrated under reduced pressure to give 12.4 g of 4- [2- [4- (dialkylamino) butylidene] hydrazino] -N-methylbenzene-methanesulfonamide. Got it.

4 g of the obtained compound and 20 g of polyphosphate ester were dissolved in 80 ml of chloroform, and stirred at room temperature for 4 hours. The reaction mixture was extracted twice with water (100 ml each). The aqueous layer was washed with 50 ml of chloroform, the pH was adjusted to 11 using solid potassium carbonate, and then extracted three times using ethyl acetate (10 ml each). The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 2.5 g of a solid in the form of a bubble. Then, chromatograph 1.13 g (yield from starting material: 29.8%) was obtained by chromatography.

As described above, the manufacturing method of sumatriptan according to the present invention minimizes the reaction process step, eliminates the use of highly toxic organic solvents, and is a method for obtaining high purity sumatriptan in high yield, and commercial mass production is possible. In addition, it is possible to minimize the risk factors that may occur in the reaction process, and the yield, purity, economics and process safety are significantly improved compared to the existing methods.

Claims (2)

4-hydrazino-N-methyl-benzene methanesulfonamide hydrochloride represented by the following Chemical Formula 2 and 4- (N, N-dimethylamino) butanal dialkylacetal represented by the following Chemical Formula 3 are reacted under sulfuric acid aqueous solution A method for preparing sumatriptan, comprising the step of obtaining 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide (sumatriptan) represented by the following Chemical Formula 1. [Formula 1]

[Formula 2]

[Formula 3]

In Formula 3, R is a methyl group or an ethyl group. The preparation of sumatriptan according to claim 1, wherein the aqueous sulfuric acid solution is a 4% aqueous sulfuric acid solution, and the amount of the aqueous 4% sulfuric acid solution is 2 to 10 ml per 1 mmol of the 4-hydrazino-N-methyl-benzenemethanesulfonamide hydrochloride. Way.