KR20030061474A - Improved process for the preparation of a cis-racemate compound used as an intermediate in preparing a sertraline - Google Patents
Improved process for the preparation of a cis-racemate compound used as an intermediate in preparing a sertraline Download PDFInfo
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- C07C209/52—Preparation 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 imines or imino-ethers
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Abstract
Description
본 발명은 서트랄린(Sertraline) 제조용 중간체로서 사용되는 시스-라세메이트(cis-racemate) 화합물을 온화한 반응조건 하에서 고순도 및 고수율로 제조할 수 있는 개선된 제조방법에 관한 것이다.The present invention relates to an improved process for the production of cis-racemate compounds used as intermediates for the preparation of Sertraline in high purity and high yield under mild reaction conditions.
서트랄린((1S),(4S)-시스-4-(3,4-디클로로페닐)-1,2,3,4-테트라하이드로-N-메틸-나프탈렌아민)은 선택적인 세로토닌 재흡수 억제제(Selective Serotonin Reuptake Inhibitor ; SSRI)로서 항우울제, 식욕감퇴제로 유용할 뿐만 아니라, 불안관련 질환, 강박성 질환, 외상 후 스트레스 질환, 화학약품 중독증, 암, 심근경색증 및 조루증의 치료에 유용한 것으로 잘 알려져 있다.Sertraline ((1S), (4S) -cis-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-naphthalenamine) is a selective serotonin reuptake inhibitor Selective Serotonin Reuptake Inhibitor (SSRI) is not only useful as an antidepressant, anorexia nervosa, but also useful for the treatment of anxiety-related disorders, obsessive compulsive disorder, post-traumatic stress disorder, chemical poisoning, cancer, myocardial infarction and premature ejaculation.
하기 화학식 1의 시스-라세메이트 화합물은 서트랄린의 제조에 중간체로서 사용될 수 있다:The cis-racemate compound of formula 1 can be used as intermediate in the preparation of sertraline:
화학식 1Formula 1
상기 화학식 1의 시스-라세메이트 화합물을 제조하기 위한 방법은 다양하게 공지되어 있는데, 그 중 하기 화학식 2의 케티민(ketimine) 화합물을 가수소반응시켜 제조하는 방법을 살펴보면, 대한민국 특허공고공보 제84-2001호에는 상온, 상압 하에서 화학식 2의 케티민 화합물을 10%-Pd을 촉매로 하여 테트라하이드로퓨란 중에서 가수소반응시키는 방법이 개시되어 있다.A method for preparing the cis-racemate compound of Chemical Formula 1 is known in various ways. Among them, the method for preparing a cis-racemate compound of Chemical Formula 2 by hydrogenation of the ketimine compound of Chemical Formula 2 is disclosed in Korean Patent Publication No. 84 -2001 discloses a method in which a ketimine compound of the formula (2) is hydrogenated in tetrahydrofuran at room temperature and atmospheric pressure using 10% -Pd as a catalyst.
대한민국 특허공고공보 제84-2001호에 따른 방법은 상압이라는 비교적 온화한 조건에서 가수소반응을 수행할 수 있다는 장점은 있으나, 부산물인 트랜스-라세메이트(trans-racemate) 화합물이 반응산물 중에 30%나 함유되어 있어 메탄올-에테르 혼합용매 중에서 재결정시키는 정제공정을 거쳐야 하므로, 목적 화합물의 수율이 40% 내외에 불과하다는 문제점을 갖는다. 또한, 고가의 촉매인 Pd을 중량비로 10%나 사용하여 많은 제조비용이 소요된다는 단점이 있다.Although the method according to Korean Patent Publication No. 84-2001 has the advantage that the hydrogen reaction can be carried out under relatively mild conditions of atmospheric pressure, the by-product trans-racemate compound is 30% in the reaction product. It has a problem that the yield of the target compound is only about 40% since it must be subjected to a purification step of recrystallization in a methanol-ether mixed solvent. In addition, there is a disadvantage in that a large manufacturing cost is required by using 10% by weight of Pd, which is an expensive catalyst.
또한, 국제특허공개 WO 99/36394호에는 테트라론 화합물과 메틸아민을 에탄올 중에서 반응시켜 화학식 2의 케티민 화합물을 제조한 후, 여기에 곧바로 Pd-탄산칼슘 촉매를 2% 내외로 가하여 3기압 이상의 가압 하에서 가수소반응시키는 방법이 개시되어 있다.In addition, WO 99/36394 discloses a ketimine compound represented by Chemical Formula 2 by reacting a tetraron compound with methylamine in ethanol, and immediately adding a Pd-calcium carbonate catalyst to about 2% or more to add 3 atm or more. A method of hydrogenating under pressure is disclosed.
이 방법은 반응시 고가의 Pd 촉매를 소량 사용하므로 제조단가에 대한 부담이 크지 않다는 장점은 있으나, 3기압 이상의 고압을 견딜 수 있는 내압용기가 필요하며, 그에 따라 대량생산이 어렵다는 문제가 있다. 또한, 부산물로서 트랜스-라세메이트 뿐만이 아니라 하기 화학식 3의 일탈염소 화합물(n=1) 또는 이탈염소 화합물(n=0)이 5 내지 10% 가량 생성되는데, 이 물질은 목적 화합물과 물리적 성질이 유사하여 제거가 매우 어렵다.This method has a merit that the burden on manufacturing cost is not high because a small amount of expensive Pd catalyst is used during the reaction, but a pressure resistant container capable of withstanding a high pressure of 3 atm or higher is required, and thus, mass production is difficult. In addition, as a by-product, not only trans-racemate but also 5-10% of a chlorine dechlorination compound (n = 1) or a dechlorination compound (n = 0) of formula (3) are produced, which have similar physical properties to the target compound. It is very difficult to remove.
상기 식에서,Where
n은 0 또는 1이다.n is 0 or 1;
이와 같이, 화학식 2의 케티민 화합물을 가수소반응시켜 화학식 1의 시스-라세메이트를 제조하는 기존의 방법은 트랜스-라세메이트 화합물 및 탈염소 화합물과 같은 부산물이 다량 생성되는 문제, Pd 촉매를 과량 사용하는 문제, 고압하에서 반응시켜야 하는 문제 등을 가지고 있으므로, 이러한 문제가 개선된 제조방법에 대한 개발요구가 절실하였다.As such, the conventional method of preparing the cis-racemate of Formula 1 by hydrogenation of the ketimine compound of Formula 2 has a problem of generating a large amount of by-products such as a trans-racemate compound and a dechlorinated compound, and an excessive amount of Pd catalyst. Since there are problems to be used and a problem to be reacted under high pressure, there is an urgent need for development of a manufacturing method in which these problems are improved.
따라서, 본 발명의 목적은 서트랄린 제조용 중간체로서 유용한 시스-라세메이트 화합물을 보다 온화한 조건 하에서 부산물의 생성을 최소화시키면서 고순도 및 고수율로 제조할 수 있는 개선된 제조방법을 제공하는 것이다.Accordingly, it is an object of the present invention to provide an improved process for the preparation of cis-racemate compounds useful as intermediates for preparation of sertraline in high purity and high yield with minimal production of by-products under milder conditions.
상기 목적에 따라 본 발명에서는, 하기 화학식 2의 케티민(ketimine) 화합물을 가수소반응시켜 하기 화학식 1의 시스-라세메이트(cis-racemate) 화합물 또는 이의 산부가염을 제조하는 방법에 있어서, 상기 가수소반응을 알콜과 디클로로메탄의 혼합용매 중에서 수행하는 것을 특징으로 하는, 화학식 1의 시스-라세메이트 화합물 또는 이의 산부가염의 제조방법을 제공한다:In the present invention according to the above object, in the method for producing a cis-racemate compound of formula (1) or an acid addition salt thereof by hydrogenation of a ketimine compound of formula (2) Provided is a process for preparing a cis-racemate compound of formula (1) or an acid addition salt thereof, wherein the minor reaction is carried out in a mixed solvent of alcohol and dichloromethane:
화학식 1Formula 1
화학식 2Formula 2
이하 본 발명을 더욱 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in more detail.
본 발명에 사용되는 화학식 2의 케티민 화합물은 공지된 방법에 따라 하기 화학식 4의 테트랄론(tetralone) 화합물을 메틸아민과 반응시켜 용이하게 제조할 수 있다(국제특허공개 WO 99/36394호 참조).The ketamine compound of the formula (II) used in the present invention can be easily prepared by reacting a tetralone compound of the following formula (4) with methylamine according to a known method (see WO 99/36394). ).
본 발명에 따른 방법은 반응용매로서 알콜과 디클로로메탄의 혼합용매를 사용하는데 기술구성상 특징이 있으며, 에탄올, 메탄올, 디클로로메탄, 테트라하이드로퓨란, 에틸 아세테이트 등을 단독으로 사용하는 기존의 방법에 비하여 트랜스-라세메이트 화합물이나 탈염소 화합물과 같은 부산물의 생성이 현저히 억제되고, 시스-라세메이트 화합물이 선택적으로 생성되는 뚜렷한 효과를 보여준다.The method according to the present invention has a technical feature of using a mixed solvent of alcohol and dichloromethane as a reaction solvent, and compared with conventional methods using ethanol, methanol, dichloromethane, tetrahydrofuran, ethyl acetate, etc. alone. The production of by-products such as trans-racemate compounds and dechlorine compounds is significantly inhibited and the pronounced effect of the selective production of cis-racemate compounds is shown.
본 발명에서 사용하는 알콜과 디클로로메탄의 혼합용매에 있어서, 사용가능한 알콜로는 메탄올 및 에탄올을 들 수 있으며, 그 중 메탄올을 사용하는 것이 바람직하다. 이때, 알콜 : 디클로로메탄은 1.0 : 1.0∼3.0, 바람직하게는 1.0 : 1.2∼1.8의 부피비로 혼합될 수 있다. 또한, 혼합용매는 화학식 2의 케티민 화합물에 대하여 5 내지 20배(v/wt), 바람직하게는 8 내지 13배(v/wt)의 양으로 사용할 수 있다.In the mixed solvent of alcohol and dichloromethane used in the present invention, usable alcohols include methanol and ethanol, of which methanol is preferable. At this time, the alcohol: dichloromethane may be mixed in a volume ratio of 1.0: 1.0 to 3.0, preferably 1.0: 1.2 to 1.8. In addition, the mixed solvent may be used in an amount of 5 to 20 times (v / wt), preferably 8 to 13 times (v / wt) with respect to the ketimine compound of the formula (2).
본 발명의 가수소반응은 10%-Pd/C 촉매 존재하에서 상온 및 상압의 온화한 조건에서 수행할 수 있다.The hydrogenation reaction of the present invention can be carried out under mild conditions of room temperature and atmospheric pressure in the presence of 10% -Pd / C catalyst.
본 발명에 있어서, 10%-Pd/C 촉매는 화학식 2의 케티민 화합물에 대하여 1.0내지 3.0 중량%, 바람직하게는 1.5 내지 2.0 중량%의 양으로 사용할 수 있으며, 이러한 범위의 사용량은 기존의 사용량에 비해 현저히 적은 것으로서 적은 양으로도 반응이 완결되는 장점을 갖는다. 또한, 본 발명의 가수소반응은 알콜과 디클로로메탄의 혼합비 및 촉매의 사용량에 따라 다소 차이는 있으나, 대략 6 내지 12시간이면 반응이 완결된다.In the present invention, 10% -Pd / C catalyst can be used in an amount of 1.0 to 3.0% by weight, preferably 1.5 to 2.0% by weight relative to the ketimine compound of formula (2), the amount of use of this range is Remarkably less as compared to having the advantage that the reaction is completed in a small amount. In addition, the hydrogen reaction of the present invention is somewhat different depending on the mixing ratio of alcohol and dichloromethane and the amount of catalyst used, but the reaction is completed in about 6 to 12 hours.
나아가, 가수소반응을 통해 형성된 반응물을 예를 들어, 염산, 브롬산 또는 요오드산으로 처리함으로써 보다 안정한 염산염, 브롬산염 또는 요오드산염 형태의 목적 화합물을 수득할 수 있다.Furthermore, by treating the reactants formed through the hydrogenation reaction with, for example, hydrochloric acid, bromic acid or iodic acid, the target compounds in the form of more stable hydrochloride, bromate or iodide salts can be obtained.
이와 같은 본 발명의 방법에 의하면, 부산물인 트랜스-라세메이트 화합물이나 탈염소 화합물의 생성이 현저히 억제되어 별도의 정제공정 없이도 고순도의 목적하는 시스-라세메이트 화합물을 얻을 수 있으며, 촉매를 소량 사용하여도 상압에서 반응이 완결되므로, 별도의 고압 장치가 필요 없고 목적 화합물의 제조비용을 낮출 수 있다.According to the method of the present invention, the production of a by-product trans-racemate compound or dechlorination compound is significantly suppressed, so that a high-purity desired cis-racemate compound can be obtained without a separate purification process. Since the reaction is completed at normal pressure, no separate high pressure device is required and the cost of preparing the target compound can be lowered.
한편, 서트랄린은 본 발명에 따라 제조된 화학식 1의 시스-라세메이트 화합물 또는 이의 산부가염을 만델산 염으로 전환시키고, 이를 중화한 후 에테르 또는 이소프로판올 중에서 염화수소가스로 처리하는 공지의 방법을 통하여 제조할 수 있다.On the other hand, sertraline converts the cis-racemate compound of Formula 1 or acid addition salt thereof prepared according to the present invention into a mandelic acid salt, and neutralizes it, and then, through a known method of treating with hydrogen chloride gas in ether or isopropanol. It can manufacture.
이하, 본 발명을 실시예에 의거하여 보다 상세하게 설명하고자 하나, 이는 본 발명의 구성 및 작용의 이해를 돕기 위한 것일 뿐이며 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, which are only intended to assist in understanding the configuration and operation of the present invention, and the scope of the present invention is not limited to these Examples.
제조예Production Example
N-[4-(3,4-디클로로페닐)-3,4-디하이드로-1(2H)-나프탈레닐리덴]메탄아민의 제조Preparation of N- [4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenylidene] methanamine
디클로로메탄 100㎖를 질소 기류하에서 -30℃ 이하로 냉각하고 사염화티탄 2.0㎖를 가하였다. 이 용액에 메틸아민 가스 9.5g을 포집시킨 다음, 화학식 4의 화합물 10g을 가하고 실온에서 24시간 동안 교반하였다. 이어, 반응액에 디클로로메탄 20㎖를 가하고 2시간 동안 추가로 교반한 다음, 반응물을 셀라이트 상에서 여과하고, 디클로로메탄으로 세척하였다. 여액을 감압 증류하고 헥산 40㎖를 가하여 2시간 동안 교반한 후, 여과, 세척 및 건조하여 미황색의 고체로서 목적 화합물 10.1g(수율: 96%)을 수득하였다.100 mL of dichloromethane was cooled to -30 DEG C or lower under a stream of nitrogen, and 2.0 mL of titanium tetrachloride was added thereto. 9.5 g of methylamine gas was collected in this solution, and then 10 g of a compound of Formula 4 was added and stirred at room temperature for 24 hours. Then, 20 ml of dichloromethane was added to the reaction solution, and further stirred for 2 hours, and then the reaction was filtered over Celite and washed with dichloromethane. The filtrate was distilled under reduced pressure, 40 ml of hexane was added thereto, stirred for 2 hours, filtered, washed and dried to give 10.1 g (yield: 96%) of the title compound as a pale yellow solid.
융점 : 144∼146℃Melting Point: 144 ~ 146 ℃
1H-NMR(δ, CDCl3) : 8.15(d, 1H), 7.3-7.2(m, 3H),7.1(d, 1H), 6.8(dd, 2H), 4.1(m, 1H), 3.2(s, 3H), 2.46(m, 2H), 2.25(m, 1H), 2.1(m, 1H) 1 H-NMR (δ, CDCl 3 ): 8.15 (d, 1H), 7.3-7.2 (m, 3H), 7.1 (d, 1H), 6.8 (dd, 2H), 4.1 (m, 1H), 3.2 ( s, 3H), 2.46 (m, 2H), 2.25 (m, 1H), 2.1 (m, 1H)
실시예 1Example 1
N-메틸-4-(3,4-디클로로페닐)-1,2,3,4-테트라하이드로-1-나프탈렌아민 염산염의 제조Preparation of N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride
상기 제조예에서 제조된 화학식 2의 케티민 화합물 100g을 디클로로메탄 700㎖와 메탄올 500㎖의 혼합물에 용해시키고, 질소 충진후 10%-Pd/C 3.0g을 가한 다음, 수소가스를 버블링하면서 상온에서 24시간 동안 충분히 교반하였다. 반응액을 셀라이트 상에서 여과한 후, 진한 염산 30㎖를 가하고 감압 증류하였다. 잔사에메탄올 800㎖ 및 에테르 400㎖를 가하고 2시간 동안 교반한 후 여과하여 백색의 고체로서 목적 화합물 92g(수율: 81%)을 수득하였다.100 g of the ketamine compound of Formula 2 prepared in the above preparation was dissolved in a mixture of 700 ml of dichloromethane and 500 ml of methanol, and charged with 10% -Pd / C after filling with nitrogen, followed by bubbling hydrogen gas at room temperature. The mixture was stirred sufficiently for 24 hours. The reaction solution was filtered over celite, and 30 ml of concentrated hydrochloric acid was added thereto, followed by distillation under reduced pressure. 800 ml of residue and 400 ml of ether were added and stirred for 2 hours, followed by filtration to give 92 g (yield: 81%) of the title compound as a white solid.
융점 : 287∼289℃Melting Point: 287 ~ 289 ℃
1H-NMR (δ, DMSO) : 9.5(bs, 1H), 7.6(m, 3H),7.3(m, 3H), 6.7(d, 1H), 4.4(t,1H), 4.1(t, 1H), 3.35(s, 3H), 2.2-2.0(m, 4H) 1 H-NMR (δ, DMSO): 9.5 (bs, 1H), 7.6 (m, 3H), 7.3 (m, 3H), 6.7 (d, 1H), 4.4 (t, 1H), 4.1 (t, 1H ), 3.35 (s, 3H), 2.2-2.0 (m, 4H)
실시예 2 내지 4 및 비교예 1 내지 5Examples 2-4 and Comparative Examples 1-5
N-메틸-4-(3,4-디클로로페닐)-1,2,3,4-테트라하이드로-1-나프탈렌아민 염산염의 제조Preparation of N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride
실시예 2 내지 4에 있어서 디클로로메탄과 메탄올 또는 에탄올의 혼합비를 하기 표 1과 같이 변화시키고, 비교예 1 내지 5에 있어서 하기 표 1에 나타낸 바와 같은 다른 용매를 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법을 수행하여 목적 화합물을 수득하였다.Except for changing the mixing ratio of dichloromethane and methanol or ethanol in Examples 2 to 4 as shown in Table 1, except for using a different solvent as shown in Table 1 in Comparative Examples 1 to 5, The same method as in 1 was carried out to obtain the target compound.
제조된 화합물의 융점 및1H-NMR 데이터는 상기 실시예 1과 동일하였으며, 반응 완결 후 반응액의 고성능 액체 크로마토그래피(HPLC) 결과를 하기 표 1에 나타내었다. 이때, 표 1의 결과값은 목적 산물인 시스-라세메이트, 및 부산물인 트랜스-라세메이트와 탈염소 화합물 간의 상대적 중량%를 나타낸다.Melting point and 1 H-NMR data of the prepared compound were the same as in Example 1, the results of high performance liquid chromatography (HPLC) of the reaction solution after completion of the reaction are shown in Table 1 below. The results in Table 1 represent the relative weight percents between cis-racemate as the desired product and trans-racemate and the dechlorine compound as byproducts.
상기 표 1로부터 알 수 있듯이, 본 발명의 실시예에 따르면 부반응이 현저히 억제되고 목적하는 반응이 선택적으로 진행됨으로써 목적하는 시스-라세메이트 화합물을 80% 이상의 고수율, 98% 이상의 고순도로 수득할 수 있으며, 반응 후처리를 통해 초고순도의 시스-라세메이트 화합물을 얻을 수 있다.As can be seen from Table 1, according to the embodiment of the present invention, the side reaction is significantly suppressed and the desired reaction is selectively performed, so that the desired cis-racemate compound can be obtained in high yield of 80% or higher and 98% or higher. And, through the reaction post-treatment can be obtained a very high-purity cis- racemate compound.
본 발명의 방법에 의하면, 부산물인 트랜스-라세메이트 화합물이나 탈염소 화합물의 생성이 현저히 억제되어 별도의 정제공정 없이도 고순도의 목적하는 시스-라세메이트 화합물을 얻을 수 있으며, 촉매를 소량 사용하여도 상압에서 반응이 완결되므로, 별도의 고압 장치가 필요 없고 목적 화합물의 제조비용을 낮출 수 있다.According to the method of the present invention, the production of by-product trans-racemate compound or dechlorination compound is remarkably suppressed, so that the desired cis-racemate compound of high purity can be obtained without a separate purification process, and even if a small amount of catalyst is used, the atmospheric pressure is reduced. Since the reaction is completed at, a separate high pressure device is not required and the cost of preparing the target compound can be lowered.
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| KR100462288B1 (en) * | 2002-04-02 | 2004-12-17 | 한국과학기술연구원 | Method for determination of sertraline in plasma |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR840002001A (en) * | 1981-10-16 | 1984-06-11 | 에이.엔.리에디 | Process for preparing phenyl-substituted sulfonamide |
| WO1999036394A1 (en) * | 1998-01-16 | 1999-07-22 | Pfizer Products Inc. | Novel process for preparing a ketimine |
| WO2001034117A1 (en) * | 1999-11-08 | 2001-05-17 | The University Of Tennessee Research Corporation | A method for chemoprevention of prostate cancer |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR840002001A (en) * | 1981-10-16 | 1984-06-11 | 에이.엔.리에디 | Process for preparing phenyl-substituted sulfonamide |
| WO1999036394A1 (en) * | 1998-01-16 | 1999-07-22 | Pfizer Products Inc. | Novel process for preparing a ketimine |
| US6232500B1 (en) * | 1998-01-16 | 2001-05-15 | Pfizer Inc | Process for preparing a ketimine |
| WO2001034117A1 (en) * | 1999-11-08 | 2001-05-17 | The University Of Tennessee Research Corporation | A method for chemoprevention of prostate cancer |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100462288B1 (en) * | 2002-04-02 | 2004-12-17 | 한국과학기술연구원 | Method for determination of sertraline in plasma |
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