KR0143805B1 - Method for preparing (+)-(2s,3s)-3-rydroxg-2-(4-methoxy phenyl)-2,3-dihydro-5h-1.5-bengothiage pine-4-one and chlorinated derivatives thereof - Google Patents
Method for preparing (+)-(2s,3s)-3-rydroxg-2-(4-methoxy phenyl)-2,3-dihydro-5h-1.5-bengothiage pine-4-one and chlorinated derivatives thereofInfo
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- KR0143805B1 KR0143805B1 KR1019900010155A KR900010155A KR0143805B1 KR 0143805 B1 KR0143805 B1 KR 0143805B1 KR 1019900010155 A KR1019900010155 A KR 1019900010155A KR 900010155 A KR900010155 A KR 900010155A KR 0143805 B1 KR0143805 B1 KR 0143805B1
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- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
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Abstract
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Description
본 발명의 목적은 방향족 고리에 임의적으로 염소 원자를 지니는 (+)-(2S, 3S)-3-히드록시-2-(4-메톡시페닐)-2, 3-디 히드로-5H-1,5-벤조티아제핀-4-온 의 제조방법이다. 이들의 광학적으로 순수한 화합물은 (+)-(2S, 3S)-3-아세틸옥시-5-(2-디메틸아미노에틸)-2-(4-메톡시페닐)-2, 3-디 히드로-5H-1, 5-벤조티아제핀-4-온 및 그의 염소화 유도체와 같은 치료학적 활성을 갖는 화합물들의 합성 중간체이다. 반응도를 다음 페이지에 나타내었다. 식에서 X는 수소 또는 염소를 나타낸다.It is an object of the present invention to provide (+)-(2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2, 3-dihydro-5H-1, optionally having a chlorine atom in the aromatic ring, It is a manufacturing method of 5-benzothiazepin-4-one. Their optically pure compounds are (+)-(2S, 3S) -3-acetyloxy-5- (2-dimethylaminoethyl) -2- (4-methoxyphenyl) -2, 3-dihydro-5H Synthetic intermediates of therapeutically active compounds such as -1, 5-benzothiazepin-4-one and chlorinated derivatives thereof. The reactivity is shown on the next page. In the formula, X represents hydrogen or chlorine.
제1단계는 일반식 II의 2-아미노티오페놀 유도체를 식 III의 (-)-(2R, 3S)-2, 3-에폭시-3-(4-메톡시페닐) 프로피오네이트와 반응시키는 것으로 이루어진다. 에폭시드 고리의 개환을 통해 일반식 IV의 메틸(2S, 3S)-3- [ (2-아미노페닐 )티오]-2-히드록시-3-(4-메톡 시페닐)프로피오네이트가 얻어진다. 제2단계는 산의 존재하에 이 화합물의 고리화로 이루어진다. 두 단계 각각의 반응 원리는 잘 공지되어 있다. 그것들은 예를 들면, Chem, Pharm, Bull., 18, 2028-2037(1970)에서 발견되며 여기서 식III의 에스테르는 라세미 형태로 사용된다. 제1단계는 150-160%로 수시간 가열을 필요로 하며 식 IV의 에스테르의 분리 및 정제후, 제2단계는 이 에스테르를 가수분해하고 환류하는 크실렌 중에서 황산 또는 아세트산의 존재하에 얻어진 산을 고리화함으로써 수행된다. 미국 특허 제4,116,819로는 제1단계를 기술하는 데, 여기서 식 III의 (라세미체) 에스테르를 환류하에 6시 간 가열후 톨루엔에서 아미노티오페놀(II)과 반응시킨다. 일본 특허 출원 제145160/1986호는 식 III의 광학적으로 순수한 에스테르의 합성을 기술하며, 마찬가지로 톨루엔 환류하에 10시간 동안 후자의 식 II의 아미노티오페놀과의 반응을 기술하고 있다. 마지막으로, 유럽 특허 출원 제0154838호는 다른 것들 중 두단계를 합하는 방법을 기술한다. 반응은 용매 없이 수행되며 160℃로 16시간의 가열을 요하며 최종 화합물의 광학 이성질체들과 중간체의 혼합물을 제공한다. 따라서, 공지 방법들의 어떤 것도 여러가지 이유 즉, 불량한 수율, 고온, 중간체 및/또는 최종 화합물을 정재할 필요 및 긴 반응 시간 때문에 식 I의 화합물의 경제적인 공업적 제조에 적합한 것은 없음이 분명하다. 본 발명은 따라서, 공지 기술의 단점을 극복하고 다음의 이점을 제공하는 방법을 제안한다. 즉,The first step is to react the 2-aminothiophenol derivative of formula II with (-)-(2R, 3S) -2, 3-epoxy-3- (4-methoxyphenyl) propionate of formula III. Is done. Ring opening of the epoxide ring results in methyl (2S, 3S) -3-[(2-aminophenyl) thio] -2-hydroxy-3- (4-methoxyphenyl) propionate of general formula IV. . The second step consists of the cyclization of this compound in the presence of an acid. The reaction principle of each of the two steps is well known. They are found, for example, in Chem, Pharm, Bull., 18, 2028-2037 (1970), wherein the esters of formula III are used in racemic form. The first step requires heating for several hours to 150-160% and after separation and purification of the ester of formula IV, the second step is a ring of the acid obtained in the presence of sulfuric acid or acetic acid in xylene hydrolyzing and refluxing the ester. Is done by US Pat. No. 4,116,819 describes the first step, wherein the (racemic) ester of formula III is reacted with aminothiophenol (II) in toluene after heating for 6 hours under reflux. Japanese Patent Application No. 145160/1986 describes the synthesis of optically pure esters of formula III and likewise describes the reaction with the latter aminothiophenols of formula II for 10 hours under toluene reflux. Finally, European patent application 0154838 describes a method of combining two steps among others. The reaction is carried out without solvent and requires 16 hours of heating to 160 ° C. to give a mixture of optical isomers and intermediates of the final compound. Thus, it is evident that none of the known methods are suitable for the economical industrial preparation of the compounds of formula I for a variety of reasons: poor yield, high temperature, intermediate and / or final compound needs and long reaction times. The present invention therefore proposes a method which overcomes the disadvantages of the known art and provides the following advantages. In other words,
-두 반응 단계가 하나의 같은 반응기에서 수행될 수 있으므로 두 단계 사이에 반응기를 비우고 세척하거나 제2의 반응기를 사용하는 것이 불필요하다. (편리상, 두 단계는 별도의 반응기에서 수행 될 수 있으나 어쨋든 중간체 에스테르를 분리하는 것을 필요로 하지 않는다.) -총 수율은 공지 방법의 수율과 비교하여 높다.Since two reaction steps can be carried out in one and the same reactor, it is unnecessary to empty and wash the reactor or use a second reactor between the two steps. (Conveniently, the two steps can be carried out in separate reactors, but do not require any separation of intermediate esters.)-The total yield is high compared to the yield of known methods.
-에너지 소비가 제1단계의 동안에 특히 감소된다.The energy consumption is particularly reduced during the first phase.
-반응 시간이 짧다.-Short reaction time.
-최종 화합물이 순수하다.The final compound is pure.
본 발명에 따르는 방법의 조작 조건은 상기 열거한 이 점들을 달성하는 것을 가능하게 하는데, 이하에 기술한다. 식 III의 출발 에스테르는 광학적으로 순수한 형태로 사용된다. 그것은 일본 특허 출원 제 145159/1986호, 145160/1986호 및 145174/1986호에 기재되어 있다. 중간체를 다른 용기에 비우지 않고 같은 용기에서 두 단계의 반응을 수행하는 가능성은 두 단계 각각에 크게 적합한 독특한 용매의 선택에 기인한다. 두 단계 각각에 특이적인 용매는 그대로 이미 공지되어 있으나 (디클로로에탄, 톨루엔, 크실렌 등) 그것들은 각 단계에 대해 다르며, 따라서 같은 반응기 내에서 전체 방법이 일어나도록 허용하지 않는다. 본 발명에 따라 사용되는 용매는 70℃ 이상의 비점을 갖는 염소화된 유기 용매이다. 적당한 용매의 예들은 1, 2, 3-트리클로로프로판, 디클로로벤젤 및 바람직하게는 클로로벤젠이다. 이들 용매는 양호한 전체 수율로 예상외로 크게 바람직할 뿐만 아니라, 더 나아가서 그것들은 제1단계는 반응의 발열 성질이 외부에너지의 참가없이 유지되기에 충분하기 때문에 출발시에만 가열을 필요로 할만큼 효율적이다. 이 구체적인 특징은 다른 용매들로는 결코 발견되지 못하였기 때문에 전혀 예상하지 못한 것이다. 추가로, 이들 용매의 사용은 제1단계의 트레오-에리트로 선택성을 촉진한다. 다른 용매로는 식 IV의 부분 입체 이성질체의 바람직하지 못한 혼합물이 얻어짐이 실제로 발견된다. 본 발명이 또 다른 구체적 특징은 제2단계에서 사용되는 촉매에 기인한다. 고리화는 산매제(황산 또는 아세트산)에서 더 잘 일어나는 것이 공지되어 있는 한편, 본 발명에 따라 사용되는 촉매는 메탄 술폰산, 인산,트리플루오로 아세트산,트리플루오로 메탄술폰산, 과염소산,파라톨루엔 술폰산으로부터 선택된다. 바람직한 촉매는 메탄술폰산이다. 이들 산은 탁월한 수율의 고리화된 화합물(I)의 얻는 것을 가능하게 하는 데, 제1단계가 완결되자마자 반응 매제에 간단히 첨가된다. 다음의 실시 예들은 본 발명에 따르는 방법의 상세한 예시를 제공한다.The operating conditions of the method according to the invention make it possible to achieve these points listed above, which are described below. The starting ester of formula III is used in optically pure form. It is described in Japanese Patent Application Nos. 145159/1986, 145160/1986 and 145174/1986. The possibility of carrying out two stage reactions in the same vessel without emptying the intermediates in another vessel is due to the selection of a unique solvent which is highly suitable for each of the two stages. Solvents specific for each of the two steps are already known as such (dichloroethane, toluene, xylene, etc.) but they are different for each step and thus do not allow the whole process to occur in the same reactor. Solvents used according to the invention are chlorinated organic solvents having a boiling point of at least 70 ° C. Examples of suitable solvents are 1, 2, 3-trichloropropane, dichlorobenzel and preferably chlorobenzene. These solvents are unexpectedly highly desirable with good overall yields, and furthermore they are efficient enough to require heating only at the start, since the first step is sufficient to maintain the exothermic nature of the reaction without participation of external energy. This specific feature is unexpected because it was never found in other solvents. In addition, the use of these solvents promotes the selectivity with the threo-erythrite of the first step. It is actually found that other solvents result in undesirable mixtures of the diastereomers of formula IV. Another specific feature of the invention is due to the catalyst used in the second step. It is known that cyclization is better at acidic solvents (sulfuric acid or acetic acid), while the catalysts used according to the invention are from methane sulfonic acid, phosphoric acid, trifluoro acetic acid, trifluoro methanesulfonic acid, perchloric acid, paratoluene sulfonic acid Is selected. Preferred catalyst is methanesulfonic acid. These acids make it possible to obtain excellent yields of the cyclized compound (I), which are simply added to the reaction medium as soon as the first step is completed. The following examples provide a detailed illustration of the method according to the invention.
[실시예1]Example 1
질소로 정화된 에나멜로된 25-리터 반응기에 3kg의 메틸(-)-(2R, 3S)-2, 3- 에폭실-(4-메톡시페닐)프로피오네이트와 10ℓ의 클로로벤젠을 도입하고 혼합물을 100℃로 가열한다. 가열을 중지하고, 1.5ℓ의 클로로벤젠중의 20아미노티오페놀 1900g의 용액을 30분의 간격으로 도입하고 온도가 120℃를 넘지 않도록 하고 3.5ℓ의 클로로벤젠을 또한 첨가하여 입구 깔대기와 관을 헹군다. 온도를 대략 115℃에서 30분 더 유지시킨 다음 37.5ml의 메탄술폰산을 첨가하고 혼합물을 환류하에 8시간 동안 가열하되, 온도가 132℃(클로로벤젠의 비점)아래로 떨어지지 않도록 증류에 의해 메탄올과 클로로벤젠의 혼합물을 제거한다. 가열을 중지하고 혼합물을 20℃로 돌아오도록 두고 5℃로 1시간동안 냉각시키고 형성된 결정을 여과하고 클로로벤젠으로 헹구고 100℃의 진공에서 건조시킨다. 순수한 (+)-(2S, 3S)-3-히드록시-2-(4-메톡시페닐)-2, 3-디 히드로-5H-1,5-벤조티아제핀-4-온 3463g의 수율이 얻어진다. 융점: 200.3 -201.8℃.[ α]2 D 0-+114°(c=0.1;DMF).3 kg of methyl (-)-(2R, 3S) -2, 3-epoxyl- (4-methoxyphenyl) propionate and 10 liters of chlorobenzene were introduced into a 25-liter reactor purged with nitrogen. The mixture is heated to 100 ° C. The heating is stopped, a solution of 1900 g of 20 aminothiophenol in 1.5 l of chlorobenzene is introduced at an interval of 30 minutes, the temperature not exceeding 120 ° C., and 3.5 l of chlorobenzene also added to rinse the inlet funnel and tube. . Maintain the temperature for approximately 30 minutes at 115 ° C, then add 37.5 ml of methanesulfonic acid and heat the mixture under reflux for 8 hours, but distill the methanol and chloro by distillation so that the temperature does not drop below 132 ° C (boiling point of chlorobenzene). Remove the mixture of benzene. The heating is stopped and the mixture is returned to 20 ° C. and cooled to 5 ° C. for 1 hour and the crystals formed are filtered off, rinsed with chlorobenzene and dried in vacuo at 100 ° C. Yield of 3463 g of pure (+)-(2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2, 3-dihydro-5H-1,5-benzothiazepin-4-one Obtained. Melting point: 200.3 -201.8 ° C. [α] 2 D 0- + 114 ° (c = 0.1; DMF).
[실시예2]Example 2
아르곤 분위기하에 1리터 플라스크에 50g의 메틸 (-)-(2R, 3S)-2, 3-에폭시-3-(4-메톡시페닐) 프로피오네이트와 350㎖의 디클로로벤젠(0-, m- 및 p-이성질체의 시중 구입되는 혼합물)을 도입 하고 혼합물을 l15℃에서 가열한다. 다음에, 30분의 간격으로, 온도가 120℃를 넘지 않도록 하면서, 31.8g의 2-아미노티오페놀을 도입한다. 온도를 120℃에서 30분 더 유지시킨 다음 0.62㎖의 메 탄술폰산을 첨가하고, 혼합물을 150℃에서 3시간 가열한다. (반응은 2시간후 완결된다.) 혼합물을 냉각되도록 두고 5℃로 1시간 동안 냉각시키고 결정을 여과하고 디클로로벤젠으로 세척하고 진공에서 건조시킨다. 49.5g의 순수한 (+)-(2S, 3S)-3-히드록시-2(4-메톡시페닐)-2, 3-디 히드로-5H-1, 5-벤조티아제핀-4-온이 얻어진다. 융점 : 203-2O4℃50 g of methyl (-)-(2R, 3S) -2, 3-epoxy-3- (4-methoxyphenyl) propionate and 350 ml of dichlorobenzene (0-, m- in a 1 liter flask under argon atmosphere And a commercially available mixture of p-isomers) and the mixture is heated at l15 ° C. Next, 31.8 g of 2-aminothiophenol is introduced at an interval of 30 minutes while the temperature does not exceed 120 ° C. The temperature is held at 120 ° C. for another 30 minutes and then 0.62 ml of methasulfonic acid is added and the mixture is heated at 150 ° C. for 3 hours. (The reaction is complete after 2 hours.) The mixture is left to cool and cooled to 5 ° C. for 1 hour, the crystals are filtered off, washed with dichlorobenzene and dried in vacuo. 49.5 g of pure (+)-(2S, 3S) -3-hydroxy-2 (4-methoxyphenyl) -2, 3-dihydro-5H-1, 5-benzothiazepin-4-one are obtained Lose. Melting Point: 203-2O4 ℃
[실시예3]Example 3
18.8g의 2-아미노티오테놀을 110-l15℃에서 200㎖의 1, 2, 3- 트리클로로프로판중의 30g의 메틸 (-)-(2R, 3S)-2, 3-에폭시-3-(4-메톡시페닐) 프로피오네이트의 용액에 적가한다. 30분후 0.35g의 메탄술폰산을 첨가하고, 혼합물을 145-l5O℃에서 6시간 동안 가열한다. 혼합물을 냉각되도록 둔 다음 냉각시키고 여과한다. 결정을 1, 2, 3 - 트리클로로프로판으로 세척하고 50℃에서 진공에서 건조시킨다. 33.8g의 순수한 (+)-(2S, 3S)-3-히드록시-2-(4-메톡시페닐)-2, 3-디 히드로-5H-1, 5-벤조티아제핀-4-온이 얻어진다. 융점: 202.8 - 204.1℃18.8 g of 2-aminothiothenol was mixed with 30 g of methyl (-)-(2R, 3S) -2, 3-epoxy-3- () in 200 ml of 1, 2, 3-trichloropropane at 110-l15 ° C. Dropwise to a solution of 4-methoxyphenyl) propionate. After 30 minutes 0.35 g of methanesulfonic acid is added and the mixture is heated at 145-1 50 ° C. for 6 hours. Allow the mixture to cool, then cool and filter. The crystals are washed with 1, 2, 3-trichloropropane and dried in vacuo at 50 ° C. 33.8 g of pure (+)-(2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2, 3-dihydro-5H-1, 5-benzothiazepin-4-one Obtained. Melting Point: 202.8-204.1 ℃
[실시예4]Example 4
실시 예1에서와 같은 방법으로, 2-아미노-5-클로로티오페놀과 메틸(-)-(2R, 3S)-2, 3-에폭시-3-(4-메톡시페닐) 프로피오네이트간의 반응은 (+)-(2S, 3S)-8-클로로-3-히드록시-2-(4-메톡시페닐)-2, 3- 디 히드로-5H-1, 5-벤조티아제핀-4-온을 재공한다. 융점:237-241℃ [ α]2 D 0=+91.9。 (c=0.1; DMF)In the same manner as in Example 1, the reaction between 2-amino-5-chlorothiophenol and methyl (-)-(2R, 3S) -2, 3-epoxy-3- (4-methoxyphenyl) propionate Silver (+)-(2S, 3S) -8-chloro-3-hydroxy-2- (4-methoxyphenyl) -2, 3-dihydro-5H-1, 5-benzothiazepin-4-one Provide for. Melting point: 237-241 ° C. [α] 2 D 0 = + 91.9。 (c = 0.1; DMF)
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