KR20130051146A - The new process for the preparation of (+)-duloxetine hcl via (s)-3-methyl-6-(2-thienyl)-1,3-oxazinan-2-one - Google Patents
The new process for the preparation of (+)-duloxetine hcl via (s)-3-methyl-6-(2-thienyl)-1,3-oxazinan-2-one Download PDFInfo
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Abstract
Description
본 발명은 (+)염산 둘록세틴, 즉 (S)-(+)-N-메틸-3-(1-나프탈레닐옥시)-3-(2-티에닐)프로필아민 히드로클로라이드 새로운 제조방법에 관한 것이다.
The present invention provides a new process for preparing duloxetine (+) hydrochloride, ie (S)-(+)-N-methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propylamine hydrochloride. It is about.
(+)염산 둘록세틴, 즉 (S)-(+)-N-메틸-3-(1-나프탈레닐옥시)-3-(2-티에닐)프로필아민 히드로클로라이드는 노르에피네프린 및 세로토닌의 재흡수를 억제한다. (+)염산 둘록세틴은 항우울제로서 특별한 치료학적 유용성을 가진다.
(+) Duloxetine hydrochloride, i.e. (S)-(+)-N-methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propylamine hydrochloride, is used to reconstitute norepinephrine and serotonin. Suppresses absorption. Duloxetine hydrochloride has particular therapeutic utility as an antidepressant.
본 발명은 (+)염산 둘록세틴의 새로운 제조 방법에 대한 것으로, 대량 생산 시 반응 공정이 용이하고 반응 부산물의 생성 없이 염산 둘록세틴을 합성할 수 있는 개선된 방법에 관한 것이다.The present invention relates to a novel process for the preparation of duloxetine (+) hydrochloride, and to an improved process that facilitates the reaction process in mass production and can synthesize duloxetine hydrochloride without the production of reaction byproducts.
하기 [구조식 1]의 구조를 갖는 (+)염산 둘록세틴을 제조하는 방법은 유럽특허 EP650965에 개시되어 있다.[반응식 1]
A method for preparing (+) hydrochloric acid duloxetine having the structure of [Formula 1] is disclosed in European Patent EP650965.
[구조식 1] [Structural formula 1]
화합물(7)인 2-아세틸티오펜으로부터 출발하여 디메틸아민 및 포름알데히드와의 아미노메틸화 반응을 진행하여 화합물(8)을 제조하고, 화합물(8)은 소듐 보로하이드리드에 의하여 상응하는 알콜인 N,N-디메틸-3-히드록시-3-(2-티에닐)-프로판아민으로 환원된다. 이를 (S)-(+)-만델린산을 이용하여 분해(resolution)함으로써 화합물(2)를 제조한다. 다음 1-플루오로나프탈렌과의 커플링 반응을 진행하여 화합물(9)로 전환하고, 아미노기의 탈메틸화를 진행하여 최종 (+)염산 둘록세틴(1)을 제조한다. 바람직한 (+)염산 둘록세틴은 히드로클로라이드 형태의 생성물의 (S)-(+) 거울상 이성질체이다.
Starting with 2-acetylthiophene, which is compound (7), an aminomethylation reaction with dimethylamine and formaldehyde was carried out to prepare compound (8), and compound (8) was reacted with sodium borohydride to give N, the corresponding alcohol. , N-dimethyl-3-hydroxy-3- (2-thienyl) -propanamine. Compound (2) was prepared by resolution using (S)-(+)-mandelic acid. Next, a coupling reaction with 1-fluoronaphthalene was carried out to convert to compound (9), and demethylation of the amino group was carried out to produce final (+) duloxetine hydrochloride (1). Preferred (+) hydrochloric acid duloxetine is the (S)-(+) enantiomer of the product in hydrochloride form.
[반응식 1][Reaction Scheme 1]
이러한 상기 종래 기술에 따른 (+)염산 둘록세틴의 제조 방법에서는 화합물(9)를 제조하기 위해 사용되는 소듐 히드리드를 사용하는데 이 물질은 강염기로 상업적 대량생산 시 안전상 위험을 악화시키고 환경오염과 같은 문제를 유발할 수 있다. 또한 소듐 히드리드는 DMSO와 같은 양성자성 극성 용매의 존재하에, 축합된 산물의 부분적이거나 완전한 라세미화를 야기할 수 있는 딤실 음이온이 생성될 수 있다. 또한, 화합물(9)에서 (+)염산 둘록세틴을 제조하는 과정은 30%대의 저조한 제조 수율을 보이는 단점이 있다. In the method for preparing (+) hydrochloric acid duloxetine according to the prior art, the sodium hydride used to prepare the compound (9) is used, which is a strong base, which worsens the safety risks in commercial mass production, such as environmental pollution. It can cause problems. Sodium hydride can also produce dimsil anions that can cause partial or complete racemization of the condensed product in the presence of a protic polar solvent such as DMSO. In addition, the process of preparing (+) duloxetine hydrochloride in compound (9) has a disadvantage of showing a poor production yield of 30%.
실제 실시예의 방법으로 해당 공정의 합성을 수행하여 화합물(9)를 제조하는 과정에서 1-플루오로나프탈렌과의 커플링 동안 상당한 라세미화를 겪는다는 것을 발견하였고, 화합물(9)의 인산염은 물성이 좋지 않아 결정화가 어렵고, 보관 시 색 변성이 일어나는 문제점이 있었다. 또한 순수한 (+)염산 둘록세틴은 부산물을 함유한 상태에서 결정화되기가 어려워 컬럼크로마토그래피를 사용하여 분리, 정제 후 30~40%의 저조한 수율로 (+)염산 둘록세틴을 얻을 수 있었다. 이러한 제조 방법은 인체에 유해한 물질을 사용하고, 대량생산 시 사용이 불가능한 방법인 컬럼크로마토그래피 정제 방법과 컬럼크로마토그래피 적용 후에도 30%대의 저조한 제조 수율로 인해 많은 문제점이 있음을 확인할 수 있었다.
In the preparation of compound (9) by carrying out the synthesis of the process by the method of the actual example, it was found that during the coupling with 1-fluoronaphthalene, significant racemization occurs. Not good crystallization is difficult, there was a problem that color change occurs during storage. In addition, pure (+) hydrochloric acid duloxetine was difficult to crystallize in the presence of by-products, it was possible to obtain (+) duloxetine hydrochloride in a low yield of 30-40% after separation and purification using column chromatography. This manufacturing method was confirmed that there are many problems due to the low production yield of 30% even after applying the column chromatography purification method and column chromatography, which is a method that is harmful to the human body and is not available for mass production.
그러므로, 전술한 바와 같은 선행 기술 방법과 관련된 문제를 줄이는 (+)염산 둘록세틴의 개선된 제조 방법이 요구된다.
Therefore, there is a need for an improved process for the preparation of duloxetine (+) hydrochloride that reduces the problems associated with the prior art methods as described above.
한편, (+)염산 둘록세틴의 다른 제조 방법으로서, 특허 WO 04/056795 호에 개시된 것이 있다.[반응식 2]
On the other hand, as another method for producing duloxetine (+) hydrochloride, there is one disclosed in patent WO 04/056795.
이 특허에 따르면, 화합물(10)인 N,N-디메틸-3-히드록시-3-(2-티에닐)-프로판아민을 출발물질로 사용하여 염기 및 상전이 촉매의 존재하에, 고온에서 1-플루오로나프탈렌을 가하여 반응시켜 화합물(11) 옥살산염을 수득한 후, 탈메틸화하여 라세미 둘록세틴을 얻는다. 이 후 (-)디-ρ-톨루일 타르타르산을 이용하여 라세미 둘록세틴을 분해하여 (+)-둘록세틴 디-ρ-톨루일 타르타르산염을 수득하고, 이를 (+)-둘록세틴 히드로클로라이드로 전환하여 최종 (+)염산 둘록세틴(1)을 제조한다. According to this patent, compound (10), N, N-dimethyl-3-hydroxy-3- (2-thienyl) -propanamine, is used as a starting material in the presence of a base and a phase transfer catalyst at 1- at high temperature. Fluoronaphthalene is added to the reaction to give compound (11) oxalate, followed by demethylation to obtain racemic duloxetine. Thereafter, the racemic duloxetine was digested with (-) di-ρ-toluyl tartaric acid to obtain (+)-duloxetine di-ρ-toluyl tartarate, which was converted into (+)-duloxetine hydrochloride. Conversion is made to final duloxetine hydrochloride (1).
[반응식 2][Reaction Scheme 2]
그러나, 이러한 [반응식 2]에 나타난 (+)염산 둘록세틴의 제조 방법 역시 다음과 같은 문제점을 가진다. 1-플루오로나프탈렌과의 반응에서 라세미화를 방지하기 위해 사용한 18-크라운-6 에테르와 같은 상전이촉매는 유독하여 상업적 대량생산시 안전상 위험하고(Takayama, K. et al, chem. Pharm. Bull. 25(11), 3125(1977), 및 Hendrixson, R. et. al, Toxicol. Appl. Pharmacol., 44, 263(1978), 특허 WO 00/61540), 1-플루오로나프탈렌을 고온에서 첨가하는 것은 증기에 노출 될 우려가 있어 작업자의 안전에 영향을 끼치는 위험한 공정이다. 또한 탈메틸화 후 라세미 둘록세틴을 최종단계에서 분해하여 (+) 둘록세틴을 수득하는 것은, (-) 둘록세틴이 풍부한 모액을 수득하더라도 이를 다시 라세미화한 후 분해를 진행을 해야 하는 추가 공정이 필요하게 되고, 제조 수율 또한 약 40%대로 저조하여 경제적이지 못하므로 상업적 대량생산에 적합하지 않다.
However, the method for preparing (+) hydrochloric acid duloxetine shown in [Scheme 2] also has the following problems. Phase transfer catalysts such as 18-crown-6 ethers used to prevent racemization in reaction with 1-fluoronaphthalene are toxic and are dangerous for commercial mass production (Takayama, K. et al, chem. Pharm. Bull. 25 (11), 3125 (1977), and Hendrixson, R. et. Al, Toxicol. Appl. Pharmacol., 44, 263 (1978), patent WO 00/61540), adding 1-fluoronaphthalene at high temperature This is a dangerous process that may expose you to steam and affect your safety. In addition, after demethylation, racemic duloxetine is decomposed in the final step to obtain (+) duloxetine, even if a mother liquor rich in (-) duloxetine is obtained. It is not suitable for commercial mass production because it is necessary, and the production yield is also low, about 40%, which is not economical.
이 때문에, 상기의 종래 기술에 의한 (+)염산 둘록세틴의 제조 방법 역시, 전술한 것과 같은 문제점으로 인하여 개선된 조건으로 고순도의 (+)염산 둘록세틴을 제조할 수 있는 방법이 계속적으로 요구되어 왔다.
For this reason, the method for producing (+) hydrochloric acid duloxetine according to the prior art, there is a continuous need for a method for producing high purity (+) hydrochloric acid duloxetine under improved conditions due to the problems described above. come.
한편, 특허 EP1506965에는 (+)염산 둘록세틴의 또 다른 제조 방법이 개시된 바 있다.[반응식 3]
On the other hand, patent EP1506965 discloses another method for producing duloxetine (+) hydrochloride.
[반응식 3]Scheme 3
(S)-3-N,N-디메틸-3-히드록시-3-(2-티에닐)-프로판아민(2)을 클로로포메이트류를 사용하여 반응 후 가수분해하여 (S)-3-N-메틸-3-히드록시-3-(2-티에닐)-프로판아민(13)을 수득한 후 1-플루오로나프탈렌과 반응하여 최종 (+)염산 둘록세틴(1)을 얻는 제조방법이다.
(S) -3-N, N-dimethyl-3-hydroxy-3- (2-thienyl) -propanamine (2) was hydrolyzed after the reaction using chloroformates (S) -3- A process for obtaining N-methyl-3-hydroxy-3- (2-thienyl) -propanamine (13) and then reacting with 1-fluoronaphthalene to obtain the final (+) duloxetine hydrochloride (1). .
이러한 [반응식 3]에 나타난 화합물(13)을 통한 (+)염산 둘록세틴의 제조 방법에서도 역시 다음과 같은 문제점을 가진다. 화합물(13)을 제조하기 위해 사용되는 용매인 t-부틸 메틸 에테르는 폭발성이 있는 에테르류의 용매 중 하나로 상업적 대량생산 시 용매의 인화성으로 인해 취급이 용이하지 않으며, 50%대의 저조한 제조 수율의 문제로 인해 상업적인 방법으로 이용하기 힘든 문제점이 있다.
Also in the method for preparing (+) hydrochloric acid duloxetine through the compound (13) shown in [Reaction Scheme 3] also has the following problems. T-butyl methyl ether, a solvent used to prepare compound (13), is one of the solvents of explosive ethers, which is not easy to handle due to the flammability of the solvent in commercial mass production, and has a problem of low production yield of 50%. Due to this problem is difficult to use in a commercial way.
실제 실시예의 방법으로 화합물(13)을 얻기 위해 해당 공정의 합성을 수행하여 본 결과, (S)-3-N-메틸-3-히드록시-3-(2-티에닐)-프로판아민(13)이 물에서 녹는 성질로 인하여 유기용매로의 추출이 잘 되지 않아 손실이 발생하고, 부산물을 함유하고 있는 액상에서 헵탄을 사용한 화합물(13)의 결정화 또한 재현성있게 잘 진행되지 않았으며, 물성이 불안정하여 다량의 부산물 발생 우려가 있고, 구조적으로 (+)둘록세틴과 비슷하여 반응 후 제거되기 어려운 문제점이 있었다.
As a result of the synthesis of the process for obtaining compound (13) by the method of the practical example, (S) -3-N-methyl-3-hydroxy-3- (2-thienyl) -propanamine (13 ) Is insoluble in water, which causes loss due to poor extraction with organic solvents. Crystallization of compound (13) using heptane in liquid phase containing by-products did not proceed reproducibly, and physical properties were unstable. There is a concern that a large amount of by-products are generated, and structurally similar to (+) duloxetine, there was a problem that is difficult to remove after the reaction.
따라서, 상기의 종래 기술에 의한 (+)염산 둘록세틴의 제조 방법 역시, 화합물(13)의 50%대의 저조한 제조 수율과 폭발성있는 용매의 사용으로 인한 상업적 대량생산에 도입하기 힘든 문제점이 있어, 보다 고수율, 고순도의 (+)염산 둘록세틴을 제조할 수 있는 방법이 계속적으로 요구되고 있다.
Therefore, the above-mentioned method for preparing (+) hydrochloride duloxetine according to the prior art also has a problem that it is difficult to introduce into commercial mass production due to the low production yield of 50% of compound (13) and the use of explosive solvents. There is a continuing need for a method capable of producing high yield, high purity duloxetine hydrochloride.
한편, 특허 WO 04/011452에는 (+)염산 둘록세틴의 또 다른 제조 방법이 개시되어 있다.[반응식 4]
On the other hand, patent WO 04/011452 discloses another method for producing (+) duloxetine hydrochloride.
[반응식 4][Reaction Scheme 4]
상기 제조 방법은, 3-N-에톡시카보닐-N-메틸아미노-1-(2-티에닐)-1-프로파논(14)을 오토클레이브에서 (R)-TolBINAP-RuCl2-(1R,2R)-디페닐에틸렌디아민 촉매와 포타슘 t-부티레이트를 사용하여 반응 후 10bar의 수소 분위기에서 상응하는 알콜인 화합물(15)을 비대칭 환원하여 수득하고, 오랜 시간 자연 방치하여 시클릭 카바메이트 화합물(5)을 얻는다. 이 화합물(5)를 가수분해한 화합물(13)을 1-플루오르나프탈렌과 반응하여 최종 (+)염산 둘록세틴(1)을 제조하는 방법이다.
The above production method comprises (R) -TolBINAP-RuCl 2- (1R) in a 3-N-ethoxycarbonyl-N-methylamino-1- (2-thienyl) -1-propanone (14) in an autoclave. (2R) -diphenylethylenediamine catalyst and potassium t-butyrate were obtained by asymmetric reduction of the compound (15) which is the corresponding alcohol in a hydrogen atmosphere of 10 bar after the reaction, and left for a long time by cyclic carbamate compound ( 5) get A compound (13) obtained by hydrolyzing this compound (5) is reacted with 1-fluornaphthalene to prepare a final (+) duloxetine hydrochloride (1).
이러한 [반응식 4]로 제조되는 (+)염산 둘록세틴의 제조 과정에서도 다음과 같은 문제점이 있다. 화합물(14)의 비대칭환원 과정에서 사용되는 고가의 금속촉매의 사용으로 인해서 생산단가가 크게 상승하며, 오토클레이브 내에서 수소분위기 하에 알콜을 수득하는 과정 또한 특수 생산 설비의 사용으로 상업적인 대량생산에는 적합하지 않은 문제점을 가지고 있다.
In the manufacturing process of (+) hydrochloric acid duloxetine prepared by the above [Reaction Scheme 4] has the following problems. Due to the use of expensive metal catalysts used in the asymmetric reduction process of the compound (14), the production cost is greatly increased, and the process of obtaining alcohol in the hydrogen atmosphere in the autoclave is also suitable for commercial mass production by using special production equipment. I have a problem that is not.
또한, 화합물 (15)를 오랜 시간 자연 방치하여 시클릭 카바메이트 화합물(5)를 수득하는 공정에서, 불특정한 오랜 시간 동안 방치하는 것은 정확한 제조 수율 파악에 문제가 있을 뿐 아니라 부산물 발생의 우려가 있다. 또한 제조 수율이 34%로 매우 저조하며 거울상 이성질체의 순도가 낮은 문제점 역시 존재한다.
In addition, in the process of leaving the compound (15) naturally left for a long time to obtain the cyclic carbamate compound (5), leaving it for an unspecified long time not only has a problem in determining an accurate manufacturing yield but also a possibility of generation of by-products. . In addition, the manufacturing yield is very low as 34% and there is also a problem of low purity of the enantiomer.
따라서, 상기의 종래 기술에 의한 (+)염산 둘록세틴의 제조 방법 역시, 경제적 비효율성 및 저조한 수율과 같은 문제점으로 인하여 보다 용이한 제조 조건으로 고순도, 고수율의 (+)염산 둘록세틴을 효과적으로 제조할 수 있는 반응 조건을 찾는 연구가 계속적으로 요구되고 있다.
Therefore, the method for preparing (+) hydrochloride duloxetine hydrochloride according to the prior art also effectively produces high purity, high yield (+) hydrochloride duloxetine with easier manufacturing conditions due to problems such as economic inefficiency and poor yield. There is a continuing need for research to find possible reaction conditions.
이에, (+)염산 둘록세틴을 제조하는 경제적으로 효과적인 제조방법을 제공하고자 한다. Accordingly, an object of the present invention is to provide an economically effective method for preparing duloxetine hydrochloride.
이와 같이 기존 (+)염산 둘록세틴을 제조하는 방법은, 취급하기 어려운 시약을 사용하며 고가의 금속 촉매 및 고압의 수소반응을 위한 특수 생산 설비 사용으로 인한 경제적인 비효율성과, 대량 생산 시 폭발의 위험으로 취급이 용이하지 않은 반응 용매 및 조건, 환경오염의 문제, 낮은 거울상 이성질체 순도 및 수율 등의 많은 문제점을 안고 있다.
This method of preparing duloxetine hydrochloride is economically inefficient due to the use of difficult-to-handling reagents, the use of expensive metal catalysts and special production equipment for high-pressure hydrogen reactions, and the risk of explosion in mass production. It has many problems such as reaction solvents and conditions that are not easy to handle, problems of environmental pollution, low enantiomeric purity, and yields.
본 발명은 이러한 각 종래 기술에 의한 (+)염산 둘록세틴 제조 방법의 문제점을 해소하고, 보다 용이하고 새로운 제조 공정으로 고수율, 고순도의 (+)염산 둘록세틴을 경제적, 효과적으로 제조하는 데 그 목적이 있다.
The present invention solves the problems of the method for producing (+) hydrochloride duloxetine hydrochloride according to each of the prior art, and the objective is to produce a high yield, high purity (+) duloxetine hydrochloride economically and effectively with an easier and new production process. There is this.
따라서 본 발명자들은 상기 기술한 방법들의 단점을 해소하고 고가의 시약을 사용하지 않으면서 짧은 제조과정을 통하여 부산물의 생성 없이 경제적이고 효율적인 방법으로 (+)염산 둘록세틴을 고수율, 고순도로 제조할 수 있는 방법을 찾기 위한 다양한 연구를 진행하였다.
Therefore, the present inventors can solve the disadvantages of the above-described methods and can manufacture (+) duloxetine hydrochloride in high yield and high purity in an economical and efficient manner without producing by-products through a short manufacturing process without using expensive reagents. Various studies have been conducted to find a way.
[구조식 3] [Structural Formula 3]
그 결과 상기 [구조식 3]의 (S)-3-N,N-디메틸-3-히드록시-3-(2-티에닐)-프로판아민(2)으로부터 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)을 제조하여 (+)염산 둘록세틴(1)을 제조하면 상기 기술한 방법들의 문제점을 해결 가능함을 알게 되었다.
As a result, (S) -3-methyl-6- from (S) -3-N, N-dimethyl-3-hydroxy-3- (2-thienyl) -propanamine (2) of the above [Formula 3] It was found that the preparation of (+) hydrochloric acid duloxetine (1) by preparing (2-thienyl) -1,3-oxazinan-2-one (5) can solve the problems of the above-described methods.
이 방법은 상기 [반응식 4]에서 비효율적인 장시간 방치를 통해 30%대의 낮은 수율로 얻을 수 있었던 시클릭 카바메이트 화합물(5)을 용이하게 고순도, 고수율로 제조하고, 이 후 화합물(13)의 추출, 분리 과정 없이 시클릭 카바메이트 화합물(5)로부터 (+)염산 둘록세틴을 제조함으로써 화합물(13)으로 인해 발생되는 문제점이 해소될 수 있다. 따라서 이 제조 방법은 기존 선행 기술의 단점을 개선한 공업적으로 대량생산이 용이한 새로운 제조 방법임을 발견하였다. In this method, the cyclic carbamate compound (5), which was obtained in a low yield of about 30% through long time of inefficient standing in [Scheme 4], was easily prepared in high purity and high yield. The problem caused by the compound (13) can be solved by preparing (+) duloxetine hydrochloride from the cyclic carbamate compound (5) without extraction and separation. Therefore, this manufacturing method has been found to be a new manufacturing method that is easy to mass-produce industrially, which improves the disadvantages of the existing prior art.
따라서 본 발명은 시클릭 카바메이트 화합물(5)를 통한 (+)염산 둘록세틴, 즉 (S)-(+)-N-메틸-3-(1-나프탈레닐옥시)-3-(2-티에닐)프로필아민 히드로클로라이드(1)의 신규한 제조 방법 및 대량생산에 적합한 제조 방법을 제공한다.
Thus, the present invention provides (+) hydrochloric acid duloxetine via cyclic carbamate compound (5), namely (S)-(+)-N-methyl-3- (1-naphthalenyloxy) -3- (2- A novel process for the preparation of thienyl) propylamine hydrochloride (1) and a process suitable for mass production are provided.
상기한 바와 같이, 본 발명은 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)을 통한 (S)-(+)-N-메틸-3-(1-나프탈레닐옥시)-3-(2-티에닐)프로필아민 히드로클로라이드(1)의 새로운 합성에 관한 것으로써, 구체적으로 (S)-3-N,N-디메틸-3-히드록시-3-(2-티에닐)-프로판아민(2)으로부터 페닐(S)-N-[3-페닐옥시카르보닐옥시-3-(2-티에닐)프로필]-N-메틸카바메이트(4)를 제조하고 알코올 용매에서 수산화칼륨을 사용하여 핵심 중간체인 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)을 제조한 후 수산화칼륨을 사용하여 1-플루오로나프탈렌과 반응하여 (+)염산 둘록세틴(1)을 고순도, 고수율로 제조한다.
As described above, the present invention provides (S)-(+)-N- via (S) -3-methyl-6- (2-thienyl) -1,3-oxazinan-2-one (5). New synthesis of methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propylamine hydrochloride (1), specifically (S) -3-N, N-dimethyl- Phenyl (S) -N- [3-phenyloxycarbonyloxy-3- (2-thienyl) propyl] -N-methyl from 3-hydroxy-3- (2-thienyl) -propanamine (2) Carbamate (4) was prepared and potassium hydroxide in an alcohol solvent was used to prepare (S) -3-methyl-6- (2-thienyl) -1,3-oxazinan-2-one (5) as a key intermediate. After the preparation, the mixture is reacted with 1-fluoronaphthalene using potassium hydroxide to prepare (+) duloxetine hydrochloride (1) in high purity and high yield.
본 발명에 따른, (+)염산 둘록세틴 제조 핵심 중간체인 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)을 통한 (+)염산 둘록세틴의 제조 방법은 다음과 같은 장점을 가진다.
(+) Through (S) -3-methyl-6- (2-thienyl) -1,3-oxazinan-2-one (5), the key intermediate for preparing duloxetine hydrochloride according to the invention The method for preparing duloxetine hydrochloride has the following advantages.
첫째, (S)-N-메틸-3-히드록시-3-(2-티에닐)-프로판아민(13)은 물에 녹는 성질을 가지고 있어 반응 후 처리과정(work up)인 추출 시 손실이 발생한다. 또한 결정화 수득률이 30%대로 저조하고, 상온에서도 상변성이 일어나는 물성이 불안정한 성질을 가지고 있다. 이에 비해 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)은 제조 수율이 90%대로 훨씬 높고, 60~80℃ 보관시에도 물성이 변하지 않고 안정하다. 따라서 (S)-N-메틸-3-히드록시-3-(2-티에닐)-프로판아민(13)의 추출, 분리과정 없이 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)을 통해 (+)염산 둘록세틴(1)을 제조하는 것은 상기 언급한 (S)-N-메틸-3-히드록시-3-(2-티에닐)-프로판아민(13)으로 인한 문제점을 해소할 수 있다.
First, (S) -N-methyl-3-hydroxy-3- (2-thienyl) -propanamine (13) has a water-soluble property, which causes loss during extraction, which is a work-up after reaction. Occurs. In addition, the yield of crystallization is as low as 30%, and the physical properties of phase change at room temperature are unstable. On the other hand, (S) -3-methyl-6- (2-thienyl) -1,3-oxazinan-2-one (5) has a much higher yield of 90%, and physical properties even when stored at 60 to 80 ° C. It is stable without change. Thus, the extraction and separation of (S) -N-methyl-3-hydroxy-3- (2-thienyl) -propanamine (13) without (S) -3-methyl-6- (2-thienyl) Preparation of (+) hydrochloric acid duloxetine (1) via -1,3-oxazinan-2-one (5) has been described above with (S) -N-methyl-3-hydroxy-3- (2- The problem caused by thienyl) -propanamine (13) can be solved.
둘째, 합성 공정이 길거나 고가의 금속 촉매 및 고압 수소반응을 할 수 있는 특수 생산 설비를 사용하는 기존 선행기술과 비교하여 용이하고 경제적이다.
Second, the synthesis process is easy and economical compared to the existing prior art using a long or expensive metal catalyst and special production equipment capable of high-pressure hydrogen reaction.
셋째, 기존 선행기술의 소듐 히드리드와 18-크라운-6 에테르와 같은 상전이촉매와 같은 작업자의 안전에 영향을 끼치는 시약이나 폭발성이 있는 용매를 사용하지 않고, 특허 WO 04/056795와 같이 고온에서 첨가하지 않으므로 고온의 증기에 노출되는 위험한 공정을 포함하지 않는다.
Third, without the use of reagents or explosive solvents affecting the safety of the operator, such as phase transition catalysts such as sodium hydride and 18-crown-6 ethers of the prior art, they are added at high temperatures as in patent WO 04/056795. And does not include hazardous processes that are exposed to hot steam.
따라서, 본 발명은 공업적으로 생산이 용이하고, 반응 부산물의 생성 없이 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)을 통하여 고순도의 (+)염산 둘록세틴을 고수율로 합성 가능한 효율적이고 개량된 새로운 제조 방법이다.
Therefore, the present invention is easy to produce industrially, and is produced through (S) -3-methyl-6- (2-thienyl) -1,3-oxazinan-2-one (5) without producing reaction byproducts. It is an efficient and improved new production method capable of synthesizing high purity duloxetine (+) hydrochloride in high yield.
이하, 본 발명이 이루고자하는 기술적 과제를 자세히 설명하면 다음과 같다.
Hereinafter, described in detail the technical problem to be achieved by the present invention.
[반응식 5]Scheme 5
본 발명은 상기 [반응식 5]와 같이 (S)-3-N,N-디메틸-3-히드록시-3-(2-티에닐)-프로판아민(2)으로부터 페닐(S)-N-[3-페닐옥시카르보닐옥시-3-(2-티에닐)프로필]-N-메틸카바메이트(4)를 제조하고 알코올 용매에서 수산화칼륨을 사용하여 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)을 제조한 후 수산화칼륨을 염기로 사용하여 1-플루오로나프탈렌(6)과 반응하여 (+)염산 둘록세틴(1)을 제조한다. The present invention relates to the phenyl (S) -N- [from (S) -3-N, N-dimethyl-3-hydroxy-3- (2-thienyl) -propanamine (2) as shown in [Scheme 5]. 3-phenyloxycarbonyloxy-3- (2-thienyl) propyl] -N-methylcarbamate (4) was prepared and (S) -3-methyl-6- (2 using potassium hydroxide in alcohol solvent -Thienyl) -1,3-oxazinan-2-one (5) was prepared, and then reacted with 1-fluoronaphthalene (6) using potassium hydroxide as a base to form (+) duloxetine (1). Manufacture.
본 발명은 모든 제조 공정이 공업적인 대량 생산에 적용하기 용이한 조건으로, 하기 [구조식 3]을 시작물질로 하여 소정의 반응 공정을 통해 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)을 거쳐 부반응 또는 부산물의 발생 없이 고순도, 고수율로 (+)염산 둘록세틴, 즉 (S)-(+)-N-메틸-3-(1-나프탈레닐옥시)-3-(2-티에닐)프로필아민 히드로클로라이드(1)를 제조할 수 있다.
The present invention is a condition that all the manufacturing process is easy to apply to industrial mass production, and through the predetermined reaction process (S) -3-methyl-6- (2-thienyl) starting from [Formula 3] as a starting material ) -1,3-oxazinan-2-one (5) with high purity, high yield of duloxetine hydrochloride, i.e. (S)-(+)-N-methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propylamine hydrochloride (1) may be prepared.
[구조식 3] [Structural Formula 3]
본 발명은 (S)-3-N,N-디메틸-3-히드록시-3-(2-티에닐)-프로판아민(2)을 비극성용매에서 염기의 존재하에서 페닐 클로로포메이트(3)와 반응하여 페닐(S)-N-[3-페닐옥시카르보닐옥시-3-(2-티에닐)프로필]-N-메틸카바메이트(4)를 제조하는 단계; 페닐(S)-N-[3-페닐옥시카르보닐옥시-3-(2-티에닐)프로필]-N-메틸카바메이트(4)를 알코올 용매에서 염기와 반응하여 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)을 제조하는 단계; (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)을 양성자성 극성용매와 비극성용매의 혼합용매에서 수산화칼륨을 첨가하고 1-플루오로나프탈렌(6)과 반응하여 (S)-(+)-N-메틸-3-(1-나프탈레닐옥시)-3-(2-티에닐)프로필아민 히드로클로라이드((+)염산 둘록세틴(1))를 제조하는 단계를 포함하는 [반응식 5]로 표시되는 (+)염산 둘록세틴의 제조 방법을 제공한다.
The present invention relates to (S) -3-N, N-dimethyl-3-hydroxy-3- (2-thienyl) -propanamine (2) with phenyl chloroformate (3) in the presence of a base in a nonpolar solvent. Reacting to prepare phenyl (S) -N- [3-phenyloxycarbonyloxy-3- (2-thienyl) propyl] -N-methylcarbamate (4); Phenyl (S) -N- [3-phenyloxycarbonyloxy-3- (2-thienyl) propyl] -N-methylcarbamate (4) is reacted with a base in an alcohol solvent to give (S) -3-methyl Preparing -6- (2-thienyl) -1,3-oxazinan-2-one (5); (S) -3-methyl-6- (2-thienyl) -1,3-oxazinan-2-one (5) was added potassium hydroxide in a mixed solvent of a protic polar solvent and a nonpolar solvent, Reaction with Ronaphthalene (6) (S)-(+)-N-methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propylamine hydrochloride ((+) duloxetine hydrochloride It provides a method for producing (+) duloxetine hydrochloride represented by [Scheme 5] comprising the step of preparing (1)).
이하, 본 발명을 더욱 상세히 설명한다. Hereinafter, the present invention will be described in more detail.
페닐(S)-N-[3-페닐옥시카르보닐옥시-3-(2-티에닐)프로필]-N-메틸카바메이트(4)의 제조는 하기 [반응식 6]과 같이 진행한다. The preparation of phenyl (S) -N- [3-phenyloxycarbonyloxy-3- (2-thienyl) propyl] -N-methylcarbamate (4) proceeds as in Scheme 6 below.
[반응식 6] [Reaction Scheme 6]
상기 반응에 있어서 화합물(2)와 트리에틸아민을 톨루엔용매에 교반하면서 냉각한 후 페닐 클로로포메이트(3)를 천천히 가하고 2시간~6시간 상온 교반시켜 반응을 완결시킨다. In the reaction, the compound (2) and triethylamine are cooled with stirring in a toluene solvent, and then phenyl chloroformate (3) is slowly added, followed by stirring at room temperature for 2 to 6 hours to complete the reaction.
상기 반응의 제조 조건은, 톨루엔 용매하에서 염기로는 트리알킬아민, 디알킬아민, 모노알킬아민, 알칼리금속의 히드록시드를 사용할 수 있고, 바람직하게는 트리알킬아민, 가장 바람직하게는 트리에틸아민을 사용한다. 염기의 사용량은 (S)-3-N,N-디메틸-3-히드록시-3-(2-티에닐)-프로판아민(2) 몰당량의 0 내지 5.0 몰당량, 바람직하게는 0.2 내지 3.0 몰당량, 가장 바람직하게는 1.0당량이다.
In the production conditions of the reaction, trialkylamine, dialkylamine, monoalkylamine, hydroxide of alkali metal may be used as a base in a toluene solvent, preferably trialkylamine, and most preferably triethylamine. Use The amount of the base used is 0 to 5.0 molar equivalents, preferably 0.2 to 3.0 molar equivalents of (S) -3-N, N-dimethyl-3-hydroxy-3- (2-thienyl) -propanamine (2) Molar equivalents, most preferably 1.0 equivalent.
상기 [반응식 6]에서 톨루엔 용매에 용해된 (S)-3-N,N-디메틸-3-히드록시-3-(2-티에닐)-프로판아민(2)에 트리에틸아민을 처리한 후 페닐 클로로포메이트(3)를 첨가할 때의 온도는 10~30℃에서 진행하고, 그 이후에 2시간~6시간, 바람직하게는 2시간동안의 상온교반으로 반응을 진행한다. Triethylamine was treated with (S) -3-N, N-dimethyl-3-hydroxy-3- (2-thienyl) -propanamine (2) dissolved in a toluene solvent in [Scheme 6]. The temperature at the time of adding phenyl chloroformate (3) advances at 10-30 degreeC, and after that, reaction advances by normal temperature stirring for 2 hours-6 hours, Preferably it is 2 hours.
상기 반응에서 생성된 페닐(S)-N-[3-페닐옥시카르보닐옥시-3-(2-티에닐)프로필]-N-메틸카바메이트(4)로부터 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)의 제조는 하기 [반응식 7]과 같이 진행한다.
(S) -3-methyl-6 from phenyl (S) -N- [3-phenyloxycarbonyloxy-3- (2-thienyl) propyl] -N-methylcarbamate (4) produced in the above reaction The preparation of-(2-thienyl) -1,3-oxazinan-2-one (5) proceeds as in the following [Scheme 7].
[반응식 7] [Reaction Scheme 7]
상기 반응에 있어서 화합물(4)를 알콜 용매에 교반하면서 냉각한 후 염기를 천천히 가하고 30분~3시간 상온 교반하여 반응을 완결시킨다.
In the reaction, the compound (4) is cooled with stirring in an alcohol solvent, and then a base is slowly added, followed by stirring at room temperature for 30 minutes to 3 hours to complete the reaction.
상기 반응의 제조조건에서 용매는 알코올 용매를 사용하고, 바람직하게는 메탄올을 사용한다.
In the preparation conditions of the reaction, the solvent is an alcohol solvent, preferably methanol.
상기 [반응식 7]에서 이용되는 염기는 수산화칼륨을 사용하고, 사용량은 (S)-3-N,N-디메틸-3-히드록시-3-(2-티에닐)-프로판아민(2) 몰당량의 2 내지 10.0 몰당량, 바람직하게는 3.0 몰당량이다.
The base used in [Scheme 7] uses potassium hydroxide, and the amount used is (S) -3-N, N-dimethyl-3-hydroxy-3- (2-thienyl) -propanamine (2) mol 2 to 10.0 molar equivalents, preferably 3.0 molar equivalents.
상기 [반응식 7]에서 알콜 용매에 용해된 페닐(S)-N-[3-페닐옥시카르보닐옥시-3-(2-티에닐)프로필]-N-메틸카바메이트(4)에 수산화칼륨을 첨가할 때의 온도는 10~30℃에서 진행하고, 그 이후에 상온 교반으로 진행한다. 반응시간은 30분~3시간, 바람직하게는 1시간 동안 교반하여 반응을 진행한다. Potassium hydroxide is added to phenyl (S) -N- [3-phenyloxycarbonyloxy-3- (2-thienyl) propyl] -N-methylcarbamate (4) dissolved in an alcohol solvent in the above [Scheme 7]. The temperature at the time of addition advances at 10-30 degreeC, and it progresses by normal temperature stirring after that. The reaction time is 30 minutes to 3 hours, preferably stirred for 1 hour to proceed with the reaction.
이러한 반응 공정을 통해 제조된 생성물은 후처리 반응(work up) 과정 후 반응 용매를 감압하에 농축하여 제거하고 혼합 유기용매를 사용하여 결정화할 수 있으며, 혼합 유기용매는 이소프로판올과 노르말헥산이 가장 바람직하다.
The product produced through this reaction process can be removed by concentration after removal of the reaction solvent under reduced pressure after the work-up process (crystallization) using a mixed organic solvent, isopropanol and normal hexane is most preferred. .
상기 반응 조건은 기존 선행 기술들의 제조 방법상 존재하는 대량생산 시 비경제적인 고가의 금속촉매 및 고압 수소 반응을 위한 특수 생산 설비를 사용하거나 작업자의 안전에 영향을 끼치는 위험한 공정을 포함하지 않으며, 상온에서 단시간에 용이한 방법으로 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)을 90% 이상의 높은 수율과 99.8~99.9%의 고순도로 얻을 수 있다.
The reaction conditions do not include the use of special production equipment for expensive metal catalysts and high-pressure hydrogen reactions that are inexpensive during mass production that exist in the manufacturing methods of the existing prior art, or include dangerous processes that affect the safety of the workers. (S) -3-methyl-6- (2-thienyl) -1,3-oxazinan-2-one (5) was prepared in a short time and with a high yield of more than 90% and high purity of 99.8 to 99.9%. You can get it.
상기 반응에서 제조된 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)으로부터 (S)-(+)-N-메틸-3-(1-나프탈레닐옥시)-3-(2-티에닐)프로필아민 히드로클로라이드((+)염산 둘록세틴(1))의 제조는 하기 [반응식 8]과 같이 진행한다.
(S)-(+)-N-methyl-3- from (S) -3-methyl-6- (2-thienyl) -1,3-oxazinan-2-one (5) prepared in the above reaction Preparation of (1-naphthalenyloxy) -3- (2-thienyl) propylamine hydrochloride ((+) duloxetine hydrochloride (1)) proceeds as in Scheme 8 below.
[반응식 8] [Reaction Scheme 8]
상기 반응에 있어서 화합물(5)를 디메틸술폭시드 용매에 교반하면서 수산화칼륨을 첨가하고 2시간~5시간 교반((S)-N-메틸-3-히드록시-3-(2-티에닐)-프로판아민(13) 형성) 한 후 1-플루오로나프탈렌을 톨루엔에 희석하여 1시간 동안 천천히 가하여 반응을 진행 후 산성화하여 (+)염산 둘록세틴(1)을 고수율로 제조한다.
In the reaction, potassium hydroxide is added to the compound (5) in a dimethyl sulfoxide solvent while stirring, followed by stirring for 2 hours to 5 hours ((S) -N-methyl-3-hydroxy-3- (2-thienyl)- After propanamine (13) is formed, 1-fluoronaphthalene is diluted in toluene and slowly added for 1 hour to proceed with the reaction, followed by acidification to prepare (+) duloxetine hydrochloride (1) in high yield.
상기 반응의 제조조건은, 디메틸술폭시드와 같은 양성자성 극성 용매에서 염기, 바람직하게는 수산화칼륨을 가하고 2시간~5시간, 바람직하게는 3시간 교반한 후 1-플루오로나프탈렌을 톨루엔에 희석하여 1시간 동안 첨가하여 진행하고, 반응온도는 40~110℃, 바람직하게는 75~85℃의 온도에서 진행한다.
The reaction conditions were prepared by adding a base, preferably potassium hydroxide, in a protic polar solvent such as dimethyl sulfoxide, stirring for 2 hours to 5 hours, preferably 3 hours, and then diluting 1-fluoronaphthalene in toluene. The addition proceeds for 1 hour, and the reaction temperature is carried out at a temperature of 40 ~ 110 ℃, preferably 75 ~ 85 ℃.
1-플루오로나프탈렌을 첨가한 후 반응 시간은 1시간~48시간, 바람직하게는 15~20시간동안 진행하고, 수산화칼륨은 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)의 몰당량의 3 내지 6.0 몰당량, 바람직하게는 3.0 몰당량을 사용한다.
After addition of 1-fluoronaphthalene, the reaction time proceeds for 1 hour to 48 hours, preferably 15 to 20 hours, and potassium hydroxide is (S) -3-methyl-6- (2-thienyl) -1 3 to 6.0 molar equivalents, preferably 3.0 molar equivalents, of molar equivalents of, 3-oxazinan-2-one (5) are used.
이러한 반응 공정을 통해 제조된 반응물은 톨루엔과 과량의 상수를 가해 교반시켜 디메틸술폭시드를 제거한 다음, 염산 수용액으로 산성화시켜 결정화하여 (+)염산 둘록세틴을 제조한다.
The reactant prepared through this reaction process is added with toluene and an excess of constant to stir to remove dimethyl sulfoxide, and then acidified with aqueous hydrochloric acid solution to crystallize to produce (+) duloxetine hydrochloride.
이하 본 발명을 다음의 실시 예에 의거하여 더욱 상세히 설명하는 바, 본 발명이 이에 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
실시예 1 : 페닐(S)-N-[3-페닐옥시카르보닐옥시-3-(2-티에닐)프로필]-N-메틸카바메이트(4)의 제조 Example 1 Preparation of Phenyl (S) -N- [3-phenyloxycarbonyloxy-3- (2-thienyl) propyl] -N-methylcarbamate (4)
(S)-3-N,N-디메틸-3-히드록시-3-(2-티에닐)-프로판아민(2) 50.0g과 트리에틸아민 37.6mL를 톨루엔 250mL에 용해하고, 10℃ 이하로 냉각한 뒤 페닐 클로로포메이트 92.1mL를 천천히 가하고 상온에서 2시간 교반하여 반응을 진행시킨다. 반응액을 10℃ 이하로 냉각한 뒤 5.0% 수산화나트륨 수용액 583mL를 가하여 30분 교반하고 층분리하여 유기층을 무수황산마그네슘으로 건조한 후 여과, 농축하여 표제 화합물 111g(수율:100%)을 액으로 수득하였다.
50.0 g of (S) -3-N, N-dimethyl-3-hydroxy-3- (2-thienyl) -propanamine (2) and 37.6 mL of triethylamine were dissolved in 250 mL of toluene, After cooling, 92.1 mL of phenyl chloroformate was slowly added, followed by stirring at room temperature for 2 hours to proceed with the reaction. The reaction solution was cooled to 10 ° C. or lower, 583 mL of 5.0% aqueous sodium hydroxide solution was added thereto, stirred for 30 minutes, and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give 111 g (yield: 100%) of the title compound as a liquid. It was.
실시예 2 : (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5)의 제조 Example 2 Preparation of (S) -3-methyl-6- (2-thienyl) -1,3-oxazinan-2-one (5)
페닐(S)-N-[3-페닐옥시카르보닐옥시-3-(2-티에닐)프로필]-N-메틸카바메이트(4) 130g을 메탄올 250mL에 용해하고, 10℃ 이하로 냉각한 뒤 수산화칼륨을 첨가한 뒤 상온에서 1시간 반응을 진행시킨다. 고체잔여물을 여과하고, 유기용매를 감압 농축한 뒤 농축된 잔사에 상수 250mL와 메탄올 250mL를 첨가하여 층분리한다. 유기층을 상수 100mL, 염화나트륨 포화 수용액 100mL 각 1회 세척하고 무수황산마그네슘으로 건조한 후 여과, 농축한 잔사에 이소프로판올 100mL 가하여 환류한 뒤 노르말헥산을 500mL 가하여 생성된 결정을 상온에서 1시간 교반하고 여과하여 노르말헥산으로 세척하고 60℃에서 건조하여 순도 99.8~99.9%의 표제 화합물 50.5g(수율: 95%)을 얻었다.
130 g of phenyl (S) -N- [3-phenyloxycarbonyloxy-3- (2-thienyl) propyl] -N-methylcarbamate (4) was dissolved in 250 mL of methanol and cooled to 10 DEG C or lower. After adding potassium hydroxide, the reaction is performed at room temperature for 1 hour. The solid residue is filtered, the organic solvent is concentrated under reduced pressure, and 250 mL of constant water and 250 mL of methanol are added to the concentrated residue, and the layers are separated. The organic layer was washed once with 100 mL of constant water and 100 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to 100 mL of isopropanol and added to the concentrated residue to reflux. 500 mL of normal hexane was added, and the resulting crystals were stirred at room temperature for 1 hour and filtered. Washing with hexane and drying at 60 ℃ to give 50.5g (yield: 95%) of the title compound with a purity of 99.8 ~ 99.9%.
녹는점: 110~115℃Melting Point: 110 ~ 115 ℃
1H-NMR(400MHz, CDCl3): δ 7.32-7.31(m, 1H), 7.08-7.07(m, 1H), 7.01-6.99(m, 1H), 5.55-5.52(m, 1H), 3.51-3.44(m, 1H), 3.35-3.29(m, 1H), 3.02(s, 3H), 2.40-2.28(m, 2H) 1 H-NMR (400 MHz, CDCl 3 ): δ 7.32-7.31 (m, 1H), 7.08-7.07 (m, 1H), 7.01-6.99 (m, 1H), 5.55-5.52 (m, 1H), 3.51- 3.44 (m, 1H), 3.35-3.29 (m, 1H), 3.02 (s, 3H), 2.40-2.28 (m, 2H)
13C-NMR(100MHz, CDCl3): δ 153.2, 141.7, 126.8, 125.7, 125.1, 74.3, 46.1, 36.5, 29.4 13 C-NMR (100 MHz, CDCl 3 ): δ 153.2, 141.7, 126.8, 125.7, 125.1, 74.3, 46.1, 36.5, 29.4
HPLC 순도: 99.8~99.9%HPLC purity: 99.8-99.9%
거울상 이성질체 순도: 99.78 eeEnantiomeric Purity: 99.78 ee
실시예 3 : (S)-(+)-N-메틸-3-(1-나프탈레닐옥시)-3-(2-티에닐)프로필아민 히드로클로라이드((+)염산 둘록세틴(1))의 제조 Example 3 : (S)-(+)-N-methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propylamine hydrochloride ((+) duloxetine hydrochloride (1)) Manufacture
(S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온(5) 38.3g을 디메틸술폭시드 230mL에 용해하고 수산화칼륨 32.7g을 가한 뒤 상온에서 3시간 교반한다. 1-플루오로나프탈렌 32.4mL을 톨루엔 76.6mL에 희석하여 천천히 가하고 75~85℃에서 일야 반응을 진행시킨다. 냉각하여 상수 575mL에 천천히 붓고 30분 교반한 뒤 톨루엔을 115mL 가하고 유기층을 분리하여 염화나트륨 포화 수용액을 380mL 가하여 세척하고 유기용매를 감압 농축하여 제거한다. 농축된 잔사에 에탄올 38.3mL와 상수 192mL를 가하고 6N 염산 수용액으로 산성화하여 디클로로메탄을 192mL 가하고 층분리하여 유기층을 무수황산마그네슘으로 건조한 뒤 여과하고 농축한 잔사에 에틸 아세테이트 38.3mL와 시클로헥산 192mL을 가하여 생성된 결정을 상온에서 2시간 교반하여 여과하고 시클로헥산으로 세척한 뒤 60℃에서 건조하여 표제 화합물 55.1g(수율: 85%)을 얻었다.
38.3 g of (S) -3-methyl-6- (2-thienyl) -1,3-oxazinan-2-one (5) was dissolved in 230 mL of dimethylsulfoxide, 32.7 g of potassium hydroxide was added thereto, followed by 3 at room temperature. Stir for time. Dilute 32.4 mL of 1-fluoronaphthalene in 76.6 mL of toluene, add slowly, and proceed with the overnight reaction at 75 ~ 85 ℃. After cooling, slowly poured into a constant 575 mL, stirred for 30 minutes, toluene was added to 115 mL, the organic layer was separated, washed with 380 mL of saturated aqueous sodium chloride solution, and the organic solvent was concentrated under reduced pressure to remove the organic solvent. 38.3 mL of ethanol and a constant 192 mL were added to the concentrated residue, acidified with 6N aqueous hydrochloric acid solution, 192 mL of dichloromethane was added and the layers separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and 38.3 mL of ethyl acetate and 192 mL of cyclohexane were added to the concentrated residue. The resulting crystals were stirred at room temperature for 2 hours, filtered, washed with cyclohexane and dried at 60 ° C. to give 55.1 g (yield: 85%) of the title compound.
녹는점: 158~160℃Melting Point: 158 ~ 160 ℃
1H-NMR(400MHz, CDCl3): δ 8.30-8.28(m, 1H), 7.77-7.30(m, 1H), 7.51-7.44(m, 2H), 7.37-7.35(m, 1H), 7.25-7.21(m, 1H), 7.15-7.13(m, 1H), 7.11-7.10(m, 1H), 6.87-6.84(m, 2H), 5.93-5.90(m, 1H), 3.20-3.12(m, 2H), 2.83-2.74(m, 1H), 2.60(s, 3H), 2.67-2.59(m, 1H) 1 H-NMR (400 MHz, CDCl 3 ): δ 8.30-8.28 (m, 1H), 7.77-7.30 (m, 1H), 7.51-7.44 (m, 2H), 7.37-7.35 (m, 1H), 7.25- 7.21 (m, 1H), 7.15-7.13 (m, 1H), 7.11-7.10 (m, 1H), 6.87-6.84 (m, 2H), 5.93-5.90 (m, 1H), 3.20-3.12 (m, 2H ), 2.83-2.74 (m, 1H), 2.60 (s, 3H), 2.67-2.59 (m, 1H)
13C-NMR(100MHz, CDCl3): δ 152.5, 142.9, 134.5, 127.5, 126.8, 126.4, 125.8, 125.7, 125.6, 125.5, 125.4, 121.9, 121.1, 107.2, 73.1, 46.1, 34.8, 33.0 13 C-NMR (100 MHz, CDCl 3 ): δ 152.5, 142.9, 134.5, 127.5, 126.8, 126.4, 125.8, 125.7, 125.6, 125.5, 125.4, 121.9, 121.1, 107.2, 73.1, 46.1, 34.8, 33.0
HPLC 순도: 99.95%HPLC purity: 99.95%
거울상 이성질체 순도: 99.96 ee
Enantiomeric Purity: 99.96 ee
Claims (5)
b) [구조식 4]로 표시되는 페닐(S)-N-[3-페닐옥시카르보닐옥시-3-(2-티에닐)프로필]-N-메틸카바메이트를 알코올용매 중에서 염기와 반응시켜 하기 [구조식 2]로 표시되는 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온을 제조하는 단계;
c) [구조식 2]로 표시되는 (S)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온을 디메틸술폭시드와 톨루엔의 혼합용매에서 수산화칼륨을 첨가하고 1-플루오로나프탈렌과 반응시켜 (+)염산 둘록세틴을 제조하는 단계;
를 포함하는 것을 특징으로 하는 하기 [구조식 1]로 표시되는 (S)-(+)-N-메틸-3-(1-나프탈레닐옥시)-3-(2-티에닐)프로필아민 히드로클로라이드((+)염산 둘록세틴)의 제조방법
[구조식 1]
[구조식 2]
[구조식 3]
[구조식 4]
a) (S) -3-N, N-dimethyl-3-hydroxy-3- (2-thienyl) -propanamine represented by the following [formula 3] is substituted with phenyl chlorophore in toluene in the presence of triethylamine. Reacting with a mate to prepare phenyl (S) -N- [3-phenyloxycarbonyloxy-3- (2-thienyl) propyl] -N-methylcarbamate represented by the following [Formula 4];
b) by reacting phenyl (S) -N- [3-phenyloxycarbonyloxy-3- (2-thienyl) propyl] -N-methylcarbamate represented by [Formula 4] with a base in an alcohol solvent Preparing (S) -3-methyl-6- (2-thienyl) -1,3-oxazinan-2-one represented by [Formula 2];
c) Potassium hydroxide is added to (S) -3-methyl-6- (2-thienyl) -1,3-oxazinan-2-one represented by [Formula 2] in a mixed solvent of dimethyl sulfoxide and toluene. And reacting with 1-fluoronaphthalene to prepare (+) duloxetine hydrochloride;
(S)-(+)-N-methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propylamine hydrochloride represented by the following [Formula 1] Method for preparing ((+) hydrochloric acid duloxetine)
[Structural formula 1]
[Structural formula 2]
[Formula 3]
[Structure 4]
The process according to claim 1, wherein the alcohol solvent in step b) is methanol.
The process according to claim 1, wherein the base in step b) is potassium hydroxide.
The method of claim 1 or 3, wherein the base in step b) is potassium hydroxide and the amount thereof used is (S) -3-N, N-dimethyl-3-hydroxy-3 represented by [Formula 3] of claim 1. A manufacturing method characterized by 2 to 10 molar equivalents relative to the molar equivalent of-(2-thienyl) -propanamine
(S) -3-methyl-6- (2-thienyl) -1,3-oxazinan-2-one represented by [Formula 2] of claim 1 is added with potassium hydroxide in a mixed solvent of dimethyl sulfoxide and toluene. A method for producing (+) duloxetine hydrochloride, which is added and reacted with 1-fluoronaphthalene.
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