KR100606534B1 - An improved synthetic method of sibutramine - Google Patents

Abstract

The present invention relates to an improved method for synthesizing sibutramine, and more particularly, to an improved method for synthesizing sibutramine, which improves productivity by reducing the production cost and significantly reducing the reaction time by improving the final step process. In the present invention, in the conventional method for synthesizing sibutramine, the reaction proceeded in three steps to a single step, greatly reducing the process, and in particular, using paraformaldehyde instead of 37% formaldehyde, which was previously used in the last step of the synthesis, An improved method for synthesizing sibutramine is provided in which the obtained product is reacted as it is in a free base state, thereby reducing production cost and greatly reducing the reaction time. According to the present invention, the yield can be improved by nearly three times as much as the conventional synthesis method in terms of overall yield, the production cost is reduced, and the reaction time is shortened, which can greatly improve productivity.

Sibutramine, sibutramine, obesity drug, synthetic method, process improvement, paraformaldehyde

Description

Improved Synthesis of Sibutramine Enhances Productivity {AN IMPROVED SYNTHETIC METHOD OF SIBUTRAMINE}

The present invention relates to an improved method for synthesizing sibutramine, and more particularly, to an improved method for synthesizing sibutramine, which improves productivity by reducing the production cost and significantly reducing the reaction time by improving the final step process.

Sibutramine hydrochloride (Sibutramine HCl: C ₁₇ H ₂₆ CIN HCl) is a chemical name {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -dimethylamine hydrochloride, and has the structure of Formula 1 .

Sibutramine was originally developed as a drug for the treatment of depression and was found to give weight to patients taking this drug. It was developed as an anti-obesity drug. Let your appetite decrease.

Korean Patent Publication No. 1990-274 (corresponding patent DE3212682 (Boots), filed Oct. 21, 1982; priority GB 1981.4.6.) For the preparation of 1- (1-arylcyclobutyl) alkylamine derivative comprising sibutramine It is described. The method for synthesizing sibutramine described in this document proceeds in a total of five steps as follows.

First step

1- (4-chlorophenyl) -1-cyclobutyl cyanide is obtained from 4-Chlorobenzyl cyanide. Examples of the actual synthesis method described in this document are as follows.

After dissolving 25 g of 4-chlorobenzyl cyanide and 15 ml of 1,3-dibromopropane in 150 ml of DMSO, the solution was dissolved in nitrogen at room temperature (20-35 ° C.) and 7.5 g of NaH dispersed in mineral oil. And 200 ml of DMSO was added dropwise. The mixture was stirred at room temperature for 2 hours, 8 ml of IPA was added dropwise, and 110 ml of water was added dropwise. The mixture is filtered through CELITE ™ and the solid residue is washed with ether. The ether layer is separated, washed with water, dried, evaporated and vacuum distilled at high temperature to separate the desired 1- (4-chlorophenyl) -1-cyclobutyl cyanide. The total reaction time of this step is 5 hours and the yield from the starting material is 78%.

2nd step

1- [1- (4-chlorophenyl) -cyanobutyl] -3-methyl-butan-1-one is obtained from 1- (4-chlorophenyl) -1-cyclobutyl cyanide. Specific synthesis examples are as follows. 35.2 g of 1- (4-chlorophenyl) -1-cyclobutyl cyanide are dissolved in 100 ml of ether and this solution is added to the product prepared by the reaction of 32 g of propylbromide and 6.36 g of magnesium. The ether is replaced with toluene and the mixture is heated under reflux for 1 hour. After adding water, concentrated hydrochloric acid is added, and the mixture is heated under reflux for 1 hour. The mixture obtained in the same manner as in the previous step was treated with ether, water, dried and evaporated and then vacuum distilled to give the desired 1- [1- (4-chlorophenyl) -cyanobutyl] -3-methyl-butan-1-one. To separate. The reaction time of this step is a total of 22 hours, the yield is 81%. The target product is bp 100-120 ° C / 0.2 mm / Hg.

3rd step

N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl from 1- [1- (4-chlorophenyl) -cyanobutyl] -3-methyl-butan-1-one } Formamide is obtained. Specific synthesis examples are as follows. To 23.5 ml of formamide, 37 g (0.14 mol) of 1- [1- (4-chlorophenyl) -cyanobutyl] -3-methyl-butan-1-one and 9 ml of HCOOH were added dropwise at 160-170 ° C. The temperature is maintained at 175 ° C. to 180 ° C. for 24 hours. The mixture is extracted with ether and concentrated to afford an oil, which crystallizes the desired N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} formamide from petroleum ether. The reaction time of this step is a total of 24 hours, the yield is 39%. The target is mp 110-112 ° C.

4th step

1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride from N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} formamide Get Specific synthesis examples are as follows. 4 g of N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} formamide, 25 ml of 2-methoxyethyl ether, 10 ml of water and 22 ml of concentrated hydrochloric acid were refluxed for 18 hours. Stir under. Dilute with water, wash with ether, and add 35 ml of 5M aqueous NaOH solution. After completion of the process by treatment with ether, water and brine, treated with magnesium sulfate, filtered and concentrated. The concentrated crude product is saturated with hydrochloric acid dissolved in 20 ml of ether. The resulting solid is filtered, concentrated and crystallized with petroleum ether to give the desired product 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride. The reaction time of this step is a total of 20 hours, the yield is 96% oil, 46% hydrochloride. The target product is mp 163-165 ° C.

5th step

The final target from 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -dimethyl Amine hydrochloride, ie sibutramine hydrochloride, is obtained. Specific synthesis examples are as follows. 3.3 g of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride, 2.99 g of HCOOH and 1 ml of water are mixed while cooling. 3.93 ml of 37% aqueous formaldehyde is added and heated at 85-95 ° C. for 18 hours. Excess hydrochloric acid is added and the solution is evaporated to dryness. 5N NaOH solution is added, extracted with ether and concentrated to give a pale yellow oil. This oil is dissolved in a mixture of 4 mL IPA, 20 mL ether and 2 mL hydrochloric acid is added dropwise. Concentrate, repeatedly dissolve in ethanol and concentrate again. Polishing with petroleum ether gives a yellow solid and recrystallizes with acetone to give the final target sibutramine hydrochloride. The reaction time of this step is a total of 18 hours, the yield is 80%. The target product is mp 195-197 ° C. The overall yield for the five stages is 18.9%.

The conventional sibutramine synthesis method as described above has a problem that the process is complicated, takes a long time, is difficult to mass-produce, and the yield is low because it is to go through a total of five steps. In fact, the synthesis was performed by applying the conventional sibutramine synthesis method, the total yield was very low as 18.9%.

Accordingly, the present invention aims to simplify the process by improving the conventional method of synthesizing sibutramine, to facilitate the reaction conditions to enable mass production, and to greatly improve the yield and productivity.

In the present invention, in the conventional method for synthesizing sibutramine, the reaction proceeded in three steps of the second step, the third step, and the fourth step in one step to greatly reduce the process, in particular, which was previously used in the last step of the synthesis. By using paraformaldehyde instead of 37% formaldehyde, the reaction of the previous step is carried out in a free base state, thereby providing an improved method for synthesizing sibutramine, which reduces production cost and greatly reduces the reaction time. In addition, the present invention, in the final step (c), to simplify the conventional complex recrystallization process to provide a simpler method for obtaining the final target sibutramine hydrochloride.

Other objects and advantages of the invention will be described below, and will be better understood by practice of the invention.

In the present invention,

In the method for synthesizing {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -dimethylamine from 4-chlorobenzyl cyanide,

(a) reacting 4-chlorobenzyl cyanide with 1,3-dibromopropane to obtain 1- (4-chlorophenyl) -1-cyclobutyl cyanide;

(b) To isobutyl magnesium bromide dissolved in diethyl ether is added to 1- (4-chlorophenyl) -1-cyclobutyl cyanide dissolved in toluene, and the mixture is refluxed at a temperature of 105 ° C. or higher at 1-3 ° C. Heating and cooling for a period of time, followed by addition of NaBH ₄ at 0-25 ° C., followed by stirring for at least 1 hour to obtain 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine;

(c) 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl amine obtained in the above step is mixed with formic acid in a free base state, and then paraformaldehyde is added and 85-95 ° C. An improved method for synthesizing sibutramine, comprising a three-step reaction, is provided.

The sibutramine synthesis method of the present invention is conventionally synthesized from (1- (4-chlorophenyl) -1-cyclobutyl cyanide 1- [1- (4-chlorophenyl) -cyanobutyl] -3- in the method for synthesizing sibutramine. Obtaining methyl-butan-1-one (second step): N- {1- [1 from 1- [1- (4-chlorophenyl) -cyanobutyl] -3-methyl-butan-1-one Obtaining ((3-step)-(4-chlorophenyl) -cyclobutyl] -3-methylbutyl} formamide; N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methyl In the present invention, three steps of obtaining 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride from butyl} formamide (step 4) are performed in one embodiment, that is, the step The process is dramatically shortened by simplifying to (b) In the present invention, 1- [1- (4-chlorophenyl) obtained in the previous step using paraformaldehyde instead of 37% formaldehyde used in the final step. -Cyclobutyl] -3-methylbutyl By reacting with a base min (free base) conditions reduce the production cost and greatly reduces the reaction time.

In other words, in the present invention, by using paraformaldehyde instead of 37% formaldehyde, water is not used, and the reactivity is greatly increased, thereby reducing the reaction time from the previous 18 hours to 6-9 hours, thereby increasing the productivity from 2 to 3 times. It is greatly increased up to 2 times. In addition, the use of paraformaldehyde, which is relatively inexpensive and uses less than 37% formaldehyde, reduces the raw material cost of this portion by more than one fifth.

In addition, in the present invention, in the final step (c), the conventional complicated recrystallization process is simplified, and after the heating reaction is completed, the obtained product obtained in the oil state is dissolved in ether and crystallized with ether saturated with HCl gas. Obtain the final target sibutramine hydrochloride.

According to a preferred embodiment of the present invention described below, the overall yield of the process is 53%, which is almost three times improved compared to 18.9% of the conventional synthesis method.

Hereinafter, the sibutramine synthesis method of the present invention will be described in detail with reference to preferred examples for each step. However, the scope of the present invention is not limited by the following preferred embodiments, and those skilled in the art to which the present invention pertains should be within the equivalent scope of the technical spirit of the present invention and the claims to be described below. Of course, various modifications and variations are possible.

Step A

4-Chlorobenzyl cyanide is reacted with 1,3-dibromopropane to give 1- (4-chlorophenyl) -1-cyclobutyl cyanide.

In a flask at room temperature (20-35 ° C.), 14.1 g (352 mmol) of NaH dispersed in mineral oil (200%) and 200 ml of DMSO were added. 25 g (160 mmol) of 4-chlorobenzyl cyanide and 1,3- A solution of 36 g (176 mmol) of dibromopropane dissolved in 200 ml of DMSO was added dropwise. The mixture is stirred at room temperature for 2 hours, 10 ml of IPA is added dropwise and 200 ml of water is added dropwise. The mixture is filtered through a CELITE ™ filter and the solid residue is washed with ether. The ether layer is separated, washed with water, filtered, concentrated and dried to give 34.72 g of crude product of 1- (4-chlorophenyl) -1-cyclobutyl cyanide. The yield of crude product is 109.8%.

Step B

1- (4-chlorophenyl) -1-cyclobutyl cyanide isobutyl magnesium bromide is reacted to obtain 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine.

10 g (52 mmol) of 1- (4-chlorophenyl) -1-cyclobutyl cyanide was dissolved in 25 ml of toluene at room temperature, followed by addition of a 2.0 M solution of isobutyl magnesium bromide dissolved in 40 ml of diethyl ether. The mixture is heated at reflux at a temperature of at least 105 ° C. for 2 hours. After completion of the reaction at 0 ° C. with methanol, 2.4 g of NaBH ₄ was added to the mixture at 0-25 ° C. and stirred for 1 hour or more. Concentrate, treat with ether, water, concentrate again and dry under vacuum to obtain 12 g of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine. The yield of crude product is 91.6%.

Step C

The amine group of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine was dimethylated to obtain {1- [1- (4-chlorophenyl) -cyclobutyl]-which is the final object of the present invention. 3-methylbutyl} -dimethylamine hydrochloride, ie sibutramine hydrochloride, is obtained.

5.81 g of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine and 10 ml of HCOOH are mixed with cooling. 1.7 g paraformaldehyde is added and heated at 85-95 ° C. for 8 hours. Extract with ether and concentrate to give a pale yellow oil. After dissolving in a small amount of ether, ether saturated with HCl gas is slowly added dropwise at 0 ° C. The solid obtained was filtered and dried in vacuo to give 5.93 g of sibutramine hydrochloride as the final target. Yield of the product is 92%, mp 193.5-194.8 ° C. The total yield of the first to third stages is 53%. The H ¹ NMR results of the final product are as follows: H ¹ NMR (CDCl ₃ ) 1.058 (6H, dd), 1.400 (2H, m), 1.508 (2H, m), 2.193 (3H, d), 2.316 (2H , m), 2.784 (2H, m), 2.910 (3H, d), 2.967 (1H, m), 3.568 (1H, m), 7.386 (2H, d), 7.638 (2H, d), 10.771 (1H, s)

The present invention greatly reduces the process, which has been carried out in five stages, to three stages, greatly shortening the process and improving the yield, and in particular, in the final stage of the synthesis, it is produced by reacting with paraformaldehyde instead of 37% formaldehyde. Productivity can be greatly improved by reducing the reaction time and reducing the reaction time from the previous 18 hours to 8 hours.

Claims (2)

In the method for synthesizing {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -dimethylamine from 4-chlorobenzyl cyanide, (a) reacting 4-chlorobenzyl cyanide with 1,3-dibromopropane to obtain 1- (4-chlorophenyl) -1-cyclobutyl cyanide; (b) To isobutyl magnesium bromide dissolved in diethyl ether is added to 1- (4-chlorophenyl) -1-cyclobutyl cyanide dissolved in toluene, and the mixture is refluxed at a temperature of 105 ° C. or higher at 1-3 ° C. Heating and cooling for a period of time, followed by addition of NaBH ₄ at 0-25 ° C., followed by stirring for at least 1 hour to obtain 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine; (c) 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine obtained in the above step is mixed with formic acid in a free base state, paraformaldehyde is added thereto, and 85-95 ° C. An improved synthesis method of sibutramine consisting of a three-step reaction comprising the step of obtaining a sibutramine by heating for 6-9 hours. The method according to claim 1, In step (c), after the heating reaction is completed, the obtained product obtained in an oil state is dissolved in ether and HCl gas saturated ether is added to obtain sibutramine hydrochloride.