KR100606533B1 - An improved synthetic method of sibutramine - Google Patents

Abstract

The present invention relates to an improved method for synthesizing sibutramine, and in the present invention, the reaction proceeded in three steps in the conventional method for synthesizing sibutramine in one step, greatly reducing the process, and omitting the high temperature distillation process of the conventional synthesis method. Proceed to the next step, mass production is possible. In addition, step-by-step process improvements provide an improved synthesis method that greatly increases yield and significantly reduces production time and production costs. According to the present invention, the production yield can be greatly reduced by showing a yield improvement effect nearly three times that of the conventional synthesis method in terms of overall yield.

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

Description

Improved Synthesis of Sibutramine {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 greatly improves the yield while greatly reducing the process and facilitating reaction conditions.

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%.

As described above, the conventional sibutramine synthesis method has a total of five steps, which makes the process complicated and time-consuming, and requires high temperature vacuum distillation (first step). Since the reaction proceeds under the conditions there was a problem that the yield is reduced by high temperature modification of the raw material. 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.

In particular, 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, and the high temperature distillation process of the conventional synthesis method (see By eliminating step 1), the next step is to proceed to the next step, and mass production is possible. In addition, step by step process improvement is intended to provide an improved synthesis method which greatly increases the yield and greatly reduces the production time and production cost.

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) Dimethylating the amine group of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine to yield {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methyl There is provided an improved method for synthesizing sibutramine consisting of a three step reaction comprising: obtaining butyl} -dimethylamine.

Sibutramine synthesis method of the present invention in the conventional method for synthesizing sibutramine, the second step, that is 1- [1- (4-chlorophenyl) -cyano from (1- (4-chlorophenyl) -1-cyclobutyl cyanide Butyl] -3-methyl-butan-1-one; the third step, ie N- from 1- [1- (4-chlorophenyl) -cyanobutyl] -3-methyl-butan-1-one Obtaining {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} formamide; the fourth step, ie N- {1- [1- (4-chlorophenyl) -cyclobutyl ] 3-methylbutyl} formamide to obtain 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride in one step, i.e. The process is dramatically shortened.

In addition, in the present invention, by increasing the yield step by step, such as enabling the mass production by skipping the high-temperature distillation process in the first step of the conventional synthesis method, and proceeding to the next step, the yield is greatly increased and the production time and production costs are greatly reduced. Improved synthesis methods are provided. That is, in step (a), a solution of 4-chlorobenzyl cyanide and 1,3-dibromopropane dissolved in DMSO is added dropwise to a mixture of NaH and DMSO dispersed in mineral oil to react. After filtration, washing, concentration, and drying, a crude product of 1- (4-chlorophenyl) -1-cyclobutyl cyanide was obtained, and the crude product was subjected to the next step (b) as it is without high temperature distillation. And yields are increased as can be seen below.

In the present invention, in step (c), after mixing 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine with formic acid in a free base state, unlike the prior art, 37% aqueous formaldehyde is added and heated at 85-95 ° C. for 15-22 hours followed by hydrochloric acid to obtain sibutramine hydrochloride. That is, the present invention can improve the solubility by reacting 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine in a free base state rather than hydrochloride, unlike the prior art. And avoid the hassle of using water.

As described above, the present invention improves the reaction which was performed in the conventional three steps to an efficient one-step reaction, thereby greatly reducing the process, and in addition to the step-by-step process improvement, greatly reducing the production time and production cost, which will be described below. According to a preferred embodiment of the present invention, the overall yield is 52.7%, and the yield is improved almost three times 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.

5.02 g of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine and 10 ml of HCOOH are mixed with cooling. 6 ml of 37% aqueous formaldehyde is added and heated at 85-95 ° C. for 18 hours. Excess 2M HCl 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. 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 5.12 g of sibutramine hydrochloride as the final target. Yield of the product is 92%, mp 193.5-194.8 ° C. The total yield of steps A to C is 52.7%. 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 is to shorten the process that was conventionally carried out in five steps to three steps to greatly shorten the process as well as to eliminate the difficult and time-consuming high-temperature vacuum distillation process to enable mass production In addition, it is possible to greatly reduce production time and production costs by improving the process step by step, and to reduce the production cost by showing a yield improvement effect nearly three times that of the conventional synthesis method in terms of overall yield.

Claims (3)

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) Dimethylating the amine group of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine to yield {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methyl Improved synthesis method of sibutramine consisting of a three-step reaction comprising the step of obtaining butyl} -dimethylamine. The method according to claim 1, In step (a), the solution of 4-chlorobenzyl cyanide and 1,3-dibromopropane dissolved in DMSO is added dropwise to the mixture of NaH and DMSO dispersed in mineral oil, followed by filtration. , Washing, concentrating and drying to obtain a crude product of 1- (4-chlorophenyl) -1-cyclobutyl cyanide, and proceeding to the next step (b) as it is without distillation at high temperature. Improved Synthesis of Sibutramine. The method according to claim 1, In step (c), 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine is mixed with formic acid in the free base state, and then 37% aqueous formaldehyde is added and 85- An improved method for synthesizing sibutramine, characterized in that sibutramine hydrochloride is obtained by adding hydrochloric acid after heating at 95 ° C. for 15-22 hours.