KR100606534B1 - An improved synthetic method of sibutramine - Google Patents

An improved synthetic method of sibutramine Download PDF

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KR100606534B1
KR100606534B1 KR1020040087765A KR20040087765A KR100606534B1 KR 100606534 B1 KR100606534 B1 KR 100606534B1 KR 1020040087765 A KR1020040087765 A KR 1020040087765A KR 20040087765 A KR20040087765 A KR 20040087765A KR 100606534 B1 KR100606534 B1 KR 100606534B1
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sibutramine
chlorophenyl
cyclobutyl
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ether
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권혁일
김영웅
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한올제약주식회사
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    • C07C209/48Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of nitriles
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Abstract

본 발명은 시부트라민의 개선된 합성방법에 관한 것으로, 특히 최종 단계의 공정을 개선하여 생산단가를 절감하고 반응시간을 크게 줄여 생산성을 향상시킨 시부트라민의 개선된 합성방법에 관한 것이다. 본 발명에서는 종래 시부트라민의 합성방법에 있어서 세 단계로 진행되던 반응을 한 단계로 진행시켜 공정을 크게 줄이고, 특히 합성의 마지막 단계에서 종전에 사용되던 37% 포름알데히드 대신 파라포름알데히드를 사용하여 전단계의 수득물을 염기(free base) 상태에서 그대로 반응시켜 생산단가를 절감하고 반응시간을 크게 줄인 시부트라민의 개선된 합성방법이 제공된다. 본 발명에 따르면 전체 수율면에서 종래 합성방법의 3배에 가까운 수율개선 효과를 보이게 되며, 생산단가가 절감되고, 반응시간이 단축되어 생산성을 크게 향상시킬 수 있다. 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.

시부트라민, sibutramine, 비만치료제, 합성방법, 공정개선, 파라포름알데히드Sibutramine, sibutramine, obesity drug, synthetic method, process improvement, paraformaldehyde

Description

생산성을 향상시킨 시부트라민의 개선된 합성방법 {AN IMPROVED SYNTHETIC METHOD OF SIBUTRAMINE}Improved Synthesis of Sibutramine Enhances Productivity {AN IMPROVED SYNTHETIC METHOD OF SIBUTRAMINE}

본 발명은 시부트라민의 개선된 합성방법에 관한 것으로, 특히 최종 단계의 공정을 개선하여 생산단가를 절감하고 반응시간을 크게 줄여 생산성을 향상시킨 시부트라민의 개선된 합성방법에 관한 것이다. 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.

시부트라민 염산염(Sibutramine HCl : C17H26CIN HCl)은 화학명 {1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸}-디메틸아민 염산염으로, 하기 화학식 1의 구조를 갖는다. 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 .

Figure 112004050293490-pat00001
Figure 112004050293490-pat00001

시부트라민은 본래 우울증 치료제로 개발되던 중 이 약을 복용한 환자의 체 중이 준다는 사실이 발견되어 비만치료제로 개발된 약물로, 뇌에서 식욕을 조절하는 신경호르몬인 세로토닌과 노르아드레날린의 재흡수를 억제시켜 식욕을 떨어뜨리게 한다. 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.

대한민국 특허공보 특1990-274호(대응특허 DE3212682 (Boots), 1982.10.21. 출원; 우선권 GB 1981.4.6.)에 시부트라민을 포함하는 1-(1-아릴사이클로부틸)알킬아민 유도체의 제조방법이 기재되어 있다. 본 문헌에 기재된 시부트라민의 합성 방법은 다음과 같이 총 5단계로 진행된다.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.

제 1 단계First step

Figure 112004050293490-pat00002
Figure 112004050293490-pat00002

4-클로로벤질 시아나이드(4-Chlorobenzyl cyanide)로부터 1-(4-클로로페닐)-1-사이클로부틸 시아나이드를 얻는다. 본 문헌에 기재된 실제 합성방법의 예는 다음과 같다.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.

4-클로로벤질 시아나이드 25g과 1,3-디브로모프로판 15㎖를 DMSO 150㎖에 용해시킨 후 이 용액을 질소하에 실온(20-35℃)에서 광유(mineral oil) 중에 분산된 NaH 7.5g과 DMSO 200㎖의 교반혼합물에 적가한다. 혼합물을 실온에서 2시간 교반 하고 IPA 8㎖를 적가한 후 물 110㎖를 적가한다. 혼합물을 셀라이트(CELITE™)로 여과시킨 후 고체 잔사를 에테르로 세척한다. 에테르 층을 분리하고 물로 세척하고 건조, 증발시킨 후, 고온에서 진공 증류시켜 목적하는 1-(4-클로로페닐)-1-사이클로부틸 시아나이드를 분리시킨다. 본 단계의 총 반응시간은 5시간이며, 출발물질로부터의 수율은 78%이다. 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%.

제 2 단계2nd step

Figure 112004050293490-pat00003
Figure 112004050293490-pat00003

1-(4-클로로페닐)-1-사이클로부틸 시아나이드로부터 1-[1-(4-클로로페닐)-시아노부틸]-3-메틸-부탄-1-온을 얻는다. 구체적인 합성예는 다음과 같다. 1-(4-클로로페닐)-1-사이클로부틸 시아나이드 35.2g을 에테르 100㎖ 중에 용해시키고 이 용액을 프로필브로마이드 32g과 마그네슘 6.36g과의 반응으로 제조된 생성물에 가한다. 에테르를 톨루엔으로 대치하고 혼합물을 환류하에 1시간 동안 가열한다. 물을 가한 후 농염산을 가하고, 혼합물을 환류하에 1시간 동안 가열한다. 전 단계와 마찬가지 방법으로 얻어진 혼합물을 에테르, 물로 처리하고 건조, 증발시킨 후 진공 증류시켜 목적하는 1-[1-(4-클로로페닐)-시아노부틸]-3-메틸-부탄-1-온을 분리시킨다. 본 단계의 반응시간은 총 22시간이며, 수율은 81%이다. 목적물은 bp 100-120℃/0.2 ㎜/Hg 이다. 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.

제 3 단계3rd step

Figure 112004050293490-pat00004
Figure 112004050293490-pat00004

1-[1-(4-클로로페닐)-시아노부틸]-3-메틸-부탄-1-온으로부터 N-{1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸}포름아미드를 얻는다. 구체적인 합성예는 다음과 같다. 포름아미드 23.5㎖에, 1-[1-(4-클로로페닐)-시아노부틸]-3-메틸-부탄-1-온 37g(0.14mol)과 HCOOH 9㎖를 160-170℃에서 적가한다. 온도를 175℃ 내지 180℃에서 24시간 동안 유지시킨다. 혼합물을 에테르로 추출하고 농축하여 오일을 수득하고, 석유 에테르로부터 목적하는 N-{1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸}포름아미드를 결정화한다. 본 단계의 반응시간은 총 24시간이며, 수율은 39%이다. 목적물은 mp 110-112℃ 이다. 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.

제 4 단계4th step

Figure 112004050293490-pat00005
Figure 112004050293490-pat00005

N-{1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸}포름아미드로부터 1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸아민 염산염을 얻는다. 구체적인 합성예는 다음과 같다. N-{1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸}포름아미드 4g, 2-메톡시에틸 에테르 25㎖, 물 10㎖, 농염산 22㎖를 18시간 동안 환류하에 교반한다. 물로 희석하고, 에테르로 세척하고, 5M NaOH 수용액 35㎖를 가한다. 에테르, 물, 식염수로 처리하여 공정을 마무리한 후 황산마그네슘으로 처리하고 여과한 후 농축한다. 농축된 조생성물을 에테르 20㎖에 녹인 염산으로 포화시킨다. 생성된 고형물을 여과, 농축하고 석유 에테르로 결정화하여 목적물인 1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸아민 염산염을 얻는다. 본 단계의 반응시간은 총 20시간이며, 수율은 오일 96%, 염산염 46%이다. 목적물은 mp 163-165℃ 이다. 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.

제 5 단계5th step

Figure 112004050293490-pat00006
Figure 112004050293490-pat00006

1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸아민 염산염으로부터 최종 목적물인 {1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸}-디메틸아민 염산염, 즉 시부트라민 염산염을 얻는다. 구체적인 합성예는 다음과 같다. 1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸아민 염산염 3.3g, HCOOH 2.99g 및 물 1㎖를 냉각시키면서 혼합한다. 37% 수성 포름알데히드 3.93㎖를 가하고 85-95℃에서 18시간 동 안 가열한다. 과량의 염산을 가하고 용액을 증발 건조시킨다. 5N NaOH 용액을 가하고, 에테르로 추출하고 농축하여 담황색의 오일을 수득한다. 이 오일을 IPA 4㎖, 에테르 20㎖의 혼합물에 용해시키고 염산 2㎖를 적가한다. 농축하고, 에탄올에 반복적으로 용해시키고, 다시 농축한다. 석유 에테르로 연마하여 황색고체를 수득하고 아세톤으로 재결정시켜 최종 목적물인 시부트라민 염산염을 얻는다. 본 단계의 반응시간은 총 18시간이며, 수율은 80%이다. 목적물은 mp 195-197℃ 이다. 다섯 단계의 전체 수율은 18.9%이다. 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%.

상기와 같은 종래의 시부트라민 합성방법은, 총 다섯 단계를 거치도록 되어 있어 공정이 복잡하고, 시간이 오래 걸리며, 대량생산이 어렵고, 수율이 낮다는 문제점이 있었다. 실제 종래의 시부트라민 합성방법을 적용하여 합성을 수행한 결과 전체수율이 18.9%로 매우 낮게 나왔다.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%.

이에 본 발명은 종래 시부트라민의 복잡한 합성방법을 개선하여 공정을 간소화하고, 대량생산이 가능하도록 반응조건을 용이하게 하며, 수율과 생산성을 크게 향상시키는 것을 목적으로 한다. 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.

본 발명에서는, 종래 시부트라민의 합성방법에 있어서 제2단계, 제3단계, 제4단계의 세 단계로 진행되던 반응을 한 단계로 진행시켜 공정을 크게 줄이고, 특히 합성의 마지막 단계에서 종전에 사용되던 37% 포름알데히드 대신 파라포름알데히드를 사용하여 전단계의 수득물을 염기(free base) 상태에서 그대로 반응을 진행시킴 으로써 생산단가를 절감하고 반응시간을 크게 줄인 시부트라민의 개선된 합성방법을 제공하고자 한다. 아울러 본 발명에서는, 최종단계(c)에서, 종래의 복잡한 재결정과정을 단순화하여 최종 목적물인 시부트라민 염산염을 얻는 보다 간편한 방법을 제공하고자 한다. 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.

본 발명의 다른 목적 및 장점들은 하기에 설명될 것이며, 본 발명의 실시에 의해 더 잘 알게 될 것이다.
Other objects and advantages of the invention will be described below, and will be better understood by practice of the invention.

본 발명에서는,In the present invention,

4-클로로벤질 시아나이드(4-Chlorobenzyl cyanide)로부터 {1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸}-디메틸아민을 합성하는 방법에 있어서,In the method for synthesizing {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -dimethylamine from 4-chlorobenzyl cyanide,

(a) 4-클로로벤질 시아나이드(4-Chlorobenzyl cyanide)와 1,3-디브로모프로판을 반응시켜 1-(4-클로로페닐)-1-사이클로부틸 시아나이드를 얻는 단계와; (a) reacting 4-chlorobenzyl cyanide with 1,3-dibromopropane to obtain 1- (4-chlorophenyl) -1-cyclobutyl cyanide;

(b) 톨루엔에 용해시킨 1-(4-클로로페닐)-1-사이클로부틸 시아나이드에, 디에틸에테르에 용해시킨 이소부틸마그네슘 브로마이드를 가하고, 이 혼합물을 105℃ 이상의 온도에서 환류하에 1-3 시간 가열하고, 냉각시킨 후 0-25℃에서 NaBH4를 가하고 1시간 이상 교반 반응시켜 1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸아민을 얻는 단계와;(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) 상기 단계에서 얻어진 1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸 아민을 염기(free base) 상태에서 포름산과 혼합한 후 파라포름알데히드를 가하고 85-95℃에서 6-9 시간 가열반응시켜 시부트라민을 얻는 단계;를 포함하는 3단계 반응으로 이루어진 시부트라민의 개선된 합성방법이 제공된다. (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.

본 발명의 시부트라민 합성방법은, 종래 시부트라민의 합성방법에서 (1-(4-클로로페닐)-1-사이클로부틸 시아나이드로부터 1-[1-(4-클로로페닐)-시아노부틸]-3-메틸-부탄-1-온을 얻는 단계(제2단계); 1-[1-(4-클로로페닐)-시아노부틸]-3-메틸-부탄-1-온으로부터 N-{1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸}포름아미드를 얻는 단계(제3단계); N-{1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸}포름아미드로부터 1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸아민 염산염을 얻는 단계(제4단계)의 세 단계를, 본 발명에서는 하나의 단계, 즉 상기 단계(b)로 단순화하여 공정을 획기적으로 단축한다. 동시에 본 발명에서는 최종 단계에서 종전에 사용되던 37% 포름알데히드 대신 파라포름알데히드를 사용하여 전단계에서 수득된 1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸아민을 염기(free base) 상태로 반응시켜 생산단가를 절감하고 반응시간을 크게 줄이게 된다. 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.

즉, 본 발명에서는 37% 포름알데히드 대신 파라포름알데히드를 사용하여 물을 사용하지 않음으로써 반응성이 크게 증가하여 반응시간이 종전 18시간에서 6-9시간으로 줄어 들고 이에 따라 생산성이 2배에서 많게는 3배까지 크게 증가하게 된다. 또, 37% 포름알데히드에 비해 상대적으로 저가이며 적은 양을 사용하는 파라포름알데히드를 사용함으로써 이 부분의 원료비용을 1/5 이상 절감하게 된다. 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.

또한 본 발명에서는, 최종단계(c)에서 종래의 복잡한 재결정과정을 단순화하 여, 가열반응이 끝난 후 오일 상태로 얻어진 수득물을 에테르에 용해시키고 HCl가스가 포화된 에테르로 결정화하여 보다 간편한 방법으로 최종 목적물인 시부트라민 염산염을 얻는다. 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.

하기에 설명하는 본 발명의 바람직한 실시예에 따르면, 공정 전체의 총 수율이 53%로 종래 합성방법의 18.9%에 비해 거의 3배 가까이 향상된다. 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.

이하, 본 발명의 시부트라민 합성방법을 각 단계별로 바람직한 실시예를 들어 상세히 설명한다. 그러나 다음의 바람직한 실시예에 의해 본 발명의 범위가 한정되는 것은 아니며, 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에 의해 본 발명의 기술사상과 아래에 기재될 특허청구범위의 균등범위내에서 다양한 수정 및 변형이 가능한 것은 물론이다. 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.

단계 AStep A

4-클로로벤질 시아나이드(4-Chlorobenzyl cyanide)와 1,3-디브로모프로판을 반응시켜 1-(4-클로로페닐)-1-사이클로부틸 시아나이드를 얻는다. 4-Chlorobenzyl cyanide is reacted with 1,3-dibromopropane to give 1- (4-chlorophenyl) -1-cyclobutyl cyanide.

Figure 112004050293490-pat00007
Figure 112004050293490-pat00007

실온(20-35℃)에서 플라스크에 광유(mineral oil) 중에 분산(60%)된 NaH 14.1g(352mmol)과 DMSO 200㎖를 넣고, 4-클로로벤질 시아나이드 25g(160mmol)과 1,3-디브로모프로판 36g(176mmol)을 DMSO 200㎖에 용해시킨 용액을 적가한다. 혼합물을 실온에서 2시간 교반하고 IPA 10㎖를 적가한 후 물 200㎖를 적가한다. 혼합물을 셀라이트(CELITE™) 필터로 여과한 후 고체 잔사를 에테르로 세척한다. 에테르 층을 분리하고 물로 세척한 후 여과, 농축, 건조하여 1-(4-클로로페닐)-1-사이클로부틸 시아나이드의 조생성물을 34.72g 얻는다. 조생성물의 수율은 109.8%이다. 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%.

단계 BStep B

1-(4-클로로페닐)-1-사이클로부틸 시아나이드와 이소부틸마그네슘 브로마이드를 반응시켜 1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸아민을 얻는다. 1- (4-chlorophenyl) -1-cyclobutyl cyanide isobutyl magnesium bromide is reacted to obtain 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine.

Figure 112004050293490-pat00008
Figure 112004050293490-pat00008

실온에서 1-(4-클로로페닐)-1-사이클로부틸 시아나이드 10g(52mmol)을 톨루엔 25㎖에 녹인 다음, 디에틸에테르 40㎖에 용해시킨 이소부틸마그네슘 브로마이드 2.0M 용액을 가한다. 이 혼합물을 105℃ 이상의 온도에서 환류하에 2시간 동안 가열한다. 메탄올로 0℃에서 반응을 종결시킨 후 혼합물에 NaBH4 2.4g을 0-25℃에서 넣고 1시간 이상 교반한다. 농축하고 에테르, 물로 처리한 후 다시 농축하고 진공건조하여 1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸아민 12g을 얻는다. 조생성물의 수득율은 91.6%이다. 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%.

단계 CStep C

1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸아민의 아민기를 디메틸화하여 본 발명의 최종 목적물인 {1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸}-디메틸아민 염산염, 즉 시부트라민 염산염을 얻는다. 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.

Figure 112004050293490-pat00009
Figure 112004050293490-pat00009

1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸아민 5.81g과 HCOOH 10㎖를 냉각시키면서 혼합한다. 파라포름알데히드 1.7g을 가하고 85-95℃에서 8시간 동안 가열한다. 에테르로 추출하고, 농축하여 담황색의 오일을 수득한다. 소량의 에테르에 녹인 후 HCl 가스가 포화된 에테르를 0℃에서 천천히 적가한다. 얻어진 고체를 여과하고 진공건조하여 최종 목적물인 시부트라민 염산염 5.93g을 얻는다. 생성물의 수율은 92%, mp 193.5-194.8℃이다. 제1단계 내지 제3단계의 총 수율은 53%이다. 최종 생성물의 H1 NMR 결과는 다음과 같다 : H1 NMR(CDCl3) 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)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)

본 발명은 기존 다섯 단계로 진행되던 공정을 세 단계로 줄여 공정을 크게 단축하고, 수율을 향상시키며, 특히 합성의 마지막 단계에서 종전의 37% 포름알데 히드 대신 파라포름알데히드를 사용하여 반응시킴으로써 생산단가를 절감하고 종전 18시간에서 8시간 정도로 반응시간을 줄여 생산성을 크게 향상시킬 수 있다.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)

4-클로로벤질 시아나이드(4-Chlorobenzyl cyanide)로부터 {1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸}-디메틸아민을 합성하는 방법에 있어서,In the method for synthesizing {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -dimethylamine from 4-chlorobenzyl cyanide, (a) 4-클로로벤질 시아나이드(4-Chlorobenzyl cyanide)와 1,3-디브로모프로판을 반응시켜 1-(4-클로로페닐)-1-사이클로부틸 시아나이드를 얻는 단계와; (a) reacting 4-chlorobenzyl cyanide with 1,3-dibromopropane to obtain 1- (4-chlorophenyl) -1-cyclobutyl cyanide; (b) 톨루엔에 용해시킨 1-(4-클로로페닐)-1-사이클로부틸 시아나이드에, 디에틸에테르에 용해시킨 이소부틸마그네슘 브로마이드를 가하고, 이 혼합물을 105℃ 이상의 온도에서 환류하에 1-3 시간 가열하고, 냉각시킨 후 0-25℃에서 NaBH4를 가하고 1시간 이상 교반 반응시켜 1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸아민을 얻는 단계와;(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) 상기 단계에서 얻어진 1-[1-(4-클로로페닐)-사이클로부틸]-3-메틸부틸아민을 염기(free base) 상태에서 포름산과 혼합한 후 파라포름알데히드를 가하고 85-95℃에서 6-9 시간 가열반응시켜 시부트라민을 얻는 단계;를 포함하는 3단계 반응으로 이루어진 시부트라민의 개선된 합성방법.(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. 청구항 1에 있어서,The method according to claim 1, 단계(c)에서, 상기 가열반응이 끝난 후 오일 상태로 얻어진 수득물을 에테르에 용해시키고 HCl가스가 포화된 에테르를 가하여 시부트라민 염산염을 얻는 것을 특징으로 하는 시부트라민의 개선된 합성방법.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.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2098602A (en) 1981-04-06 1982-11-24 Boots Co Plc Therapeutic agents
US6476078B2 (en) * 1999-08-11 2002-11-05 Sepracor, Inc. Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction
KR20040087765A (en) * 2003-04-09 2004-10-15 주식회사 일산 Pipe forming method and the device

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2098602A (en) 1981-04-06 1982-11-24 Boots Co Plc Therapeutic agents
US6476078B2 (en) * 1999-08-11 2002-11-05 Sepracor, Inc. Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction
KR20040087765A (en) * 2003-04-09 2004-10-15 주식회사 일산 Pipe forming method and the device

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