KR20060010000A - Process for preparation of (s) or (r)-oxiracetam - Google Patents
Process for preparation of (s) or (r)-oxiracetam Download PDFInfo
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- KR20060010000A KR20060010000A KR1020040058550A KR20040058550A KR20060010000A KR 20060010000 A KR20060010000 A KR 20060010000A KR 1020040058550 A KR1020040058550 A KR 1020040058550A KR 20040058550 A KR20040058550 A KR 20040058550A KR 20060010000 A KR20060010000 A KR 20060010000A
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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Abstract
본 발명은 뇌기능 개선작용 및 치매 치료 효과를 나타내는 1-카바모일메틸-4-하이드록시-2-피롤리디논(옥시라세탐)의 광학 (S)-이성체 또는 (R)-이성체를 용이하게 제조하는 방법에 관한 것으로, 본 발명에 따라 1-(S 또는 R)-페닐에틸-4-(S 또는 R)-히드록시-2-피롤리디논을 유기용매 존재 하에 아세틸화시키고, 생성된 1-(S 또는 R)-페닐에틸-4-(S 또는 R)-아세톡시-2-피롤리디논을 유기용매 존재 하에 탈벤질화 시킨 후, 생성된 4-(S 또는 R)-알콕시-2-피롤리디논을 유기용매 및 염기 존재 하에 할로겐으로 치환된 아세테이트와 반응시킨 다음, 생성된 1-에톡시카보닐메틸-4-(S 또는 R)-2-피롤리디논을 암모니아와 반응시키는 단계를 포함하는 1-카바모일-4-(S 또는 R)-히드록시-2-피롤리디논의 제조방법은 저가의 원료물질들을 사용하여 산업적 적용이 용이한 공정으로 (S)-옥시라세탐 또는 (R)-옥시라세탐을 고수율 및 고순도로 제조할 수 있으므로 뇌기능 개선 및 치매 치료제 개발에 유용하게 활용될 수 있다.The present invention readily facilitates the optical (S) -isomer or (R) -isomer of 1-carbamoylmethyl-4-hydroxy-2-pyrrolidinone (oxyracetam), which exhibits brain function improving and dementia treatment effects. A process for the preparation, wherein according to the invention 1- (S or R) -phenylethyl-4- (S or R) -hydroxy-2-pyrrolidinone is acetylated in the presence of an organic solvent and produced 1 4- (S or R) -alkoxy-2 produced after debenzylation of-(S or R) -phenylethyl-4- (S or R) -acetoxy-2-pyrrolidinone in the presence of an organic solvent Reacting pyrrolidinone with acetate substituted with halogen in the presence of an organic solvent and a base, and then reacting the resulting 1-ethoxycarbonylmethyl-4- (S or R) -2-pyrrolidinone with ammonia 1-carbamoyl-4- (S or R) -hydroxy-2-pyrrolidinone production method comprising a (S)- Shirakawa setam or (R) -, so that the oxy-La ride can be produced in a high yield and a high purity can be useful in improving brain function and development of dementia.
Description
본 발명은 1-카바모일메틸-4-히드록시-2-옥소피롤리딘(옥시라세탐)의 광학 활성을 갖는 (S)-이성체 또는 (R)-이성체를 용이하게 제조하는 방법에 관한 것이다.The present invention relates to a method for easily preparing (S) -isomers or (R) -isomers having the optical activity of 1-carbamoylmethyl-4-hydroxy-2-oxopyrrolidine (oxyracetam). .
옥시라세탐은 우수한 뇌기능 개선작용 및 치매 치료 효과를 나타내며, 현재 치매치료제의 원료로 폭넓게 활용되고 있는 물질이다. 이러한 옥시라세탐의 광학 활성을 갖는 (S) 또는 (R)-옥시라세탐을 제조하는 기존의 기술들로는, M. Cruz Carballero, Tetrahedron: Asymmetry, 3(11),1431-1440, 1992; 국제출원공개 제 WO 93-06826호; M. Larcheveque 외, Tetraedron, 46, 4277, 1990; 및 대한민국 특허공개 제 2000-9465호 등이 있다.Oxyracetam exhibits excellent brain function improvement and dementia treatment effects, and is currently widely used as a raw material for dementia treatment. Existing techniques for preparing (S) or (R) -oxyracetams with the optical activity of such oxyracetams include M. Cruz Carballero, Tetrahedron: Asymmetry , 3 (11), 1431-1440, 1992; International Application Publication No. WO 93-06826; M. Larcheveque et al., Tetraedron , 46, 4277, 1990; And Korean Patent Publication No. 2000-9465.
구체적으로, M. Cruz Carballero, Tetrahedron: Asymmetry, 3(11),1431-1440, 1992에서는 하기 반응식 1에 나타낸 바와 같이, (S)-말릭산을 출발물질로 사용하여 (S)-옥시라세탐을 제조하는 방법을 제공하고 있으나, 고가의 실란화합물 및 불소화합물의 사용 및 까다로운 반응조건으로 산업적 적용이 어려운 실정이다. Specifically, in M. Cruz Carballero, Tetrahedron: Asymmetry , 3 (11), 1431-1440, 1992, as shown in Scheme 1, (S) -maleic acid was used as a starting material (S) -oxyracetam. Although it provides a method for preparing the present invention, it is difficult to apply industrially due to the use of expensive silane compounds and fluorine compounds and difficult reaction conditions.
또한, 국제출원공개 제 WO 93-06826호 및 M. Larcheveque 외, Tetrahedron, 46, 4277, 1990에서는 하기 반응식 2에서와 같이, (S)-2-히드록시-감마-부티로락톤을 출발물질로 사용하여 (S)-옥시라세탐을 제조하는 방법을 제공하고 있으나, 산화은 및 락톤 등과 같은 고가의 화합물질의 사용, 및 요오드 사용으로 인한 설비의 제한성 등으로 역시 산업적 적용이 어려운 결점을 가지고 있다.Furthermore, in WO 93-06826 and M. Larcheveque et al., Tetrahedron , 46, 4277, 1990, (S) -2-hydroxy-gamma-butyrolactone is used as starting material, as shown in Scheme 2 below. It provides a method for producing (S)-oxyracetam, but also has the disadvantage that industrial application is also difficult due to the use of expensive compounds such as silver oxide and lactone, and the limitation of equipment due to the use of iodine.
또한, 대한민국 특허공개 제 2000-9465호는 하기 반응식 3과 같이 (S)-2-히드록시-감마-부티로락톤을 출발물질로 사용하여 (S)-옥시라세탐을 제조하는 방법을 개시하고 있으나, 고가의 락톤, 브롬화수소산과 초산의 혼합산의 사용으로 산업적 적용이 어렵고 최종 제품의 정제가 용이하지 못한 문제점을 가지고 있다.In addition, Korean Patent Publication No. 2000-9465 discloses a method of preparing (S) -oxyracetam using (S) -2-hydroxy-gamma-butyrolactone as a starting material as in Scheme 3 below. However, the use of expensive lactones, hydrobromic acid and acetic acid mixed acid is difficult to apply industrially and the final product is not easy to purify.
본 발명의 목적은 산업적 적용이 용이한 공정을 사용하여 뇌기능 개선작용 및 치매치료 효과를 나타내는 1-카바모일메틸-4-히드록시-2-옥소피롤리딘(옥시라세 탐)의 광학활성을 갖는 (S)-이성체 또는 (R)-이성체를 고수율 및 고순도로 제조하는 방법을 제공하는 것이다.
An object of the present invention is to provide an optical activity of 1-carbamoylmethyl-4-hydroxy-2-oxopyrrolidine (oxyracetam), which shows an improvement in brain function and treatment of dementia by using an industrially easy process. It is to provide a method for producing the (S) -isomer or the (R) -isomer having high yield and high purity.
상기 목적에 따라, 본 발명에서는 하기 반응식 4에 나타낸 바와 같이, According to the above object, in the present invention, as shown in Scheme 4,
1) 1-(S 또는 R)-페닐에틸-4-(S 또는 R)-히드록시-2-피롤리디논(화합물 1)을 유기용매 존재 하에 아세틸화시키는 단계; 1) acetylating 1- (S or R) -phenylethyl-4- (S or R) -hydroxy-2-pyrrolidinone (Compound 1) in the presence of an organic solvent;
2) 상기 단계 1에서 생성된 1-(S 또는 R)-페닐에틸-4-(S 또는 R)-아세톡시-2-피롤리디논(화합물 2)을 유기용매 존재 하에 탈벤질화 시키는 단계; 2) debenzylating 1- (S or R) -phenylethyl-4- (S or R) -acetoxy-2-pyrrolidinone (Compound 2) produced in step 1 in the presence of an organic solvent;
3) 상기 단계 2에서 생성된 4-(S 또는 R)-알콕시-2-피롤리디논(화합물 3)을 유기용매 및 염기 존재 하에 할로겐으로 치환된 아세테이트와 반응시키는 단계; 및 3) reacting 4- (S or R) -alkoxy-2-pyrrolidinone (compound 3) produced in step 2 with acetate substituted with halogen in the presence of an organic solvent and a base; And
4) 상기 단계 3에서 생성된 1-에톡시카보닐메틸-4-(S 또는 R)-2-피롤리디논(화합물 4)을 암모니아와 반응시키는 단계를 포함하는 1-카바모일-4-(S 또는 R)-히드록시-2-피롤리디논((S)-옥시라세탐 또는 (R)-옥시라세탐)의 제조방법을 제공한다.4) 1-carbamoyl-4- (comprising reacting 1-ethoxycarbonylmethyl-4- (S or R) -2-pyrrolidinone (Compound 4) produced in step 3 with ammonia) Provided are methods for the preparation of S or R) -hydroxy-2-pyrrolidinone ((S) -oxyracetam or (R) -oxyracetam).
상기 식에서, R2는 메틸 또는 에틸이다.Wherein R 2 is methyl or ethyl.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 방법에 있어서, 단계 1에서 출발물질로 사용되는 1-(S 또는 R)-페닐에틸-4-(S)-히드록시-2-피롤리디논(화합물 1)은 하기 반응식 5에 나타낸 바와 같이, 대한민국 특허공개 제 2004-58612 호에 제시된 방법에 따라 수득될 수 있다. In the process of the present invention, 1- (S or R) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone (Compound 1) used as starting material in step 1 is represented by the following scheme 5. As such, it may be obtained according to the method disclosed in Korean Patent Publication No. 2004-58612.
상기 식에서, R은 메틸, 에틸, n-프로필, i-프로필 또는 t-부틸로 임의 치환된 C1-4의 저급알킬기이고; R1은 메틸 또는 에틸이고; X는 염소 원자 또는 히드록시기이다.Wherein R is a C 1-4 lower alkyl group optionally substituted with methyl, ethyl, n-propyl, i-propyl or t-butyl; R 1 is methyl or ethyl; X is a chlorine atom or a hydroxyl group.
구체적으로, 상기 말론산 모노알킬(화합물 5, alkyl malonate)을 1,1-카보닐다이이미다졸(CDI)의 존재 하에 DMF 또는 아세토니트릴과 같은 유기용매 중에서 N-((S 또는 R)-1-페닐에틸)글라이신 알킬에스테르(화합물 6)와 반응시켜 알킬 N-(2-에톡시카보닐아세틸)-N-(2-알콕시카보닐메틸)아미노아세테이트(화합물 7)를 제조한 후, 이를 용매 중에서 포타슘 t-부톡사이드와 반응시켜 실온에서 고리화한 다음(화합물 8), 탈탄산(화합물 9) 및 환원 반응시켜 N-((S 또는 R)-1-페닐에틸)-4-(S 또 는 R)-히드록시-2-옥소피롤리딘(화합물 1)을 제조할 수 있다.Specifically, the malonic acid monoalkyl (compound 5, alkyl malonate) in the organic solvent such as DMF or acetonitrile in the presence of 1,1-carbonyldiimidazole (CDI) N-((S or R) -1- Phenylethyl) glycine alkylester (Compound 6) to produce alkyl N- (2-ethoxycarbonylacetyl) -N- (2-alkoxycarbonylmethyl) aminoacetate (Compound 7), which is then dissolved in a solvent Reaction with potassium t-butoxide to cyclize at room temperature (compound 8), followed by decarboxylation (compound 9) and reduction reaction to N-((S or R) -1-phenylethyl) -4- (S or R) -hydroxy-2-oxopyrrolidine (Compound 1) can be prepared.
본 발명에 따른 방법의, 단계 1의 아세틸화 반응에서는 1-(S 또는 R)-페닐에틸-4-(S 또는 R)-히드록시-2-피롤리디논(화합물 1)을 유기용매 및 염기 존재 하에 무수초산 또는 아세틸클로라이드와 반응시킨다. 이때, 사용가능한 유기용매로는 염화메틸렌 및 클로로포름 등이 있으며, 화합물 1을 기준으로 15 내지 30 중량배, 바람직하게는 15 내지 20 중량배 범위로 사용할 수 있다. 사용가능한 염기의 예로는 N,N-다이메틸아미노피리다인(DMAP), 피리딘 및 트리에틸아민 등이 있으며, 화합물 1을 기준으로 1 내지 2 당량, 바람직하게는 1 내지 1.2 당량 범위로 사용할 수 있다. 또한, 무수초산은 화합물 1의 1 내지 10 당량, 바람직하게는 1 내지 3 당량 범위로 사용할 수 있으며, 상기 반응은 -10 내지 30℃, 바람직하게는 0 내지 30℃에서 2 내지 24시간, 바람직하게는 2 내지 10시간 동안 수행할 수 있다.In the acetylation reaction of step 1 of the process according to the invention, 1- (S or R) -phenylethyl-4- (S or R) -hydroxy-2-pyrrolidinone (Compound 1) is converted into an organic solvent and a base. In the presence of acetic anhydride or acetylchloride. In this case, usable organic solvents include methylene chloride and chloroform, and may be used in a range of 15 to 30 weight times, preferably 15 to 20 weight times, based on Compound 1. Examples of bases that can be used include N, N-dimethylaminopyridine (DMAP), pyridine and triethylamine, and the like, and can be used in the range of 1 to 2 equivalents, preferably 1 to 1.2 equivalents based on compound 1. . In addition, acetic anhydride may be used in the range of 1 to 10 equivalents, preferably 1 to 3 equivalents of compound 1, the reaction is -10 to 30 ℃, preferably 0 to 30 ℃ 2 to 24 hours, preferably It can be performed for 2 to 10 hours.
단계 2의 탈벤질화 반응에서는 상기 아세틸화 반응으로 생성된 1-(S 또는 R)-페닐에틸-4-(S 또는 R)-아세톡시-2-피롤리디논(화합물 2)을 유기용매 존재 하에 양성자산과 반응시킨다. 이때, 사용가능한 유기용매로는 톨루엔, 염화메틸렌 및 에탄올 등이 있으며, 화합물 2를 기준으로 10 내지 30 중량배, 바람직하게는 12 내지 20 중량배 범위로 사용할 수 있다. 또한, 상기 반응에 사용가능한 양성자산으로는 메탄설폰산 및 삼불초산 등이 있으며, 화합물 2의 3 내지 15 당량, 바람직하게는 3 내지 8 당량 범위로 사용할 수 있다. 반응은 20 내지 150℃, 바람직하게는 30 내지 140℃에서 2 내지 30시간, 바람직하게는 2 내지 10시간 동안 수행할 수 있 다. In the debenzylation reaction of step 2, 1- (S or R) -phenylethyl-4- (S or R) -acetoxy-2-pyrrolidinone (Compound 2) produced by the acetylation reaction is present in an organic solvent. React with a positive asset under At this time, usable organic solvents include toluene, methylene chloride and ethanol, and can be used in the range of 10 to 30 times by weight, preferably 12 to 20 times by weight, based on Compound 2. In addition, the amphoteric assets usable in the reaction include methanesulfonic acid, trifluoroacetic acid, and the like, and may be used in the range of 3 to 15 equivalents, preferably 3 to 8 equivalents of compound 2. The reaction can be carried out at 20 to 150 ℃, preferably 30 to 140 ℃ for 2 to 30 hours, preferably 2 to 10 hours.
또한, 단계 3에서는 상기 단계 2에서 생성된 4-(S 또는 R)-아세톡시-2-피롤리디논(화합물 3)을 유기용매 및 염 존재 하에 할로겐 치환된 아세테이트와 반응시킨다. 이때, 유기용매로는 메탄올 등의 저급 알콜 또는 테트라하이드로퓨란 등이 사용될 수 있으며, 화합물 3을 기준으로 10 내지 40 중량배, 바람직하게는 12 내지 30 중량배 범위로 사용될 수 있다. 또한, 사용가능한 염으로는 포타시움카보네이트 및 소디움하이드라이드 등이 있으며, 화합물 3을 기준으로 1 내지 10 당량, 바람직하게는 1.2 내지 10 당량 범위로 사용할 수 있다. 할로겐 치환된 아세테이트로는 브로모아세테이트 또는 클로로아세테이트 등이 있으며, 화합물 3의 1 내지 2 당량, 바람직하게는 1.1 내지 1.5 당량으로 사용할 수 있다. 반응은 -30 내지 80℃, 바람직하게는 0 내지 75℃에서 2 내지 20시간, 바람직하게는 2 내지 12시간 동안 수행할 수 있다. In addition, in step 3, 4- (S or R) -acetoxy-2-pyrrolidinone (compound 3) produced in step 2 is reacted with halogen-substituted acetate in the presence of an organic solvent and a salt. In this case, a lower alcohol such as methanol or tetrahydrofuran may be used as the organic solvent, and may be used in a range of 10 to 40 weight times, preferably 12 to 30 weight times, based on Compound 3. In addition, salts that can be used include potassium carbonate, sodium hydride, and the like, and can be used in the range of 1 to 10 equivalents, preferably 1.2 to 10 equivalents, based on compound 3. Halogen-substituted acetates include bromoacetate or chloroacetate, and can be used in the amount of 1 to 2 equivalents, preferably 1.1 to 1.5 equivalents of compound 3. The reaction can be carried out at -30 to 80 ° C, preferably 0 to 75 ° C for 2 to 20 hours, preferably 2 to 12 hours.
단계 4에서는 단계 3에서 생성된 1-에톡시카보닐메틸-4-(S 또는 R)-2-피롤리디논(화합물 4)을 유기용매 중에서 암모니아와 반응시켜 본 발명에 따른 1-카바모일-4-(S)-히드록시-2-피롤리디논을 제조한다. 이때, 사용가능한 유기용매로는 메탄올 등의 저급 알콜이 있으며, 화합물 4를 기준으로 10 내지 40 중량배, 바람직하게는 12 내지 35 중량배 범위로 사용할 수 있다. 또한, 암모니아는 화합물 4의 2 내지 15 당량, 바람직하게는 5 내지 12 당량으로 사용할 수 있으며, 상기 반응은 -30 내지 30℃, 바람직하게는 -20 내지 25℃에서 2 내지 20시간, 바람직하게는 3 내지 16시간 동안 수행할 수 있다. In step 4, 1-ethoxycarbonylmethyl-4- (S or R) -2-pyrrolidinone (Compound 4) produced in step 3 is reacted with ammonia in an organic solvent to prepare 1-carbamoyl- according to the present invention. Prepare 4- (S) -hydroxy-2-pyrrolidinone. At this time, usable organic solvents include lower alcohols such as methanol, and may be used in the range of 10 to 40 weight times, preferably 12 to 35 weight times, based on compound 4. In addition, ammonia can be used in 2 to 15 equivalents, preferably 5 to 12 equivalents of compound 4, and the reaction is carried out at -30 to 30 ° C, preferably at -20 to 25 ° C, for 2 to 20 hours, preferably It may be performed for 3 to 16 hours.
상기 단계들을 포함하는 본 발명의 1-카바모일-4-(S 또는 R)-히드록시-2-피롤리디논의 제조방법은 저가의 원료물질들을 사용하여 산업적 적용이 용이한 공정으로 (S)-옥시라세탐 또는 (R)-옥시라세탐을 고수율 및 고순도로 제조할 수 있으므로 뇌기능 개선 및 치매 치료제 개발에 유용하게 활용될 수 있다.The method for preparing 1-carbamoyl-4- (S or R) -hydroxy-2-pyrrolidinone of the present invention comprising the above steps is a process that is easy to apply industrially using inexpensive raw materials (S). -Oxyracetam or (R) -oxyracetam can be prepared in high yield and high purity, so it can be usefully used for improving brain function and developing dementia treatment.
이하, 본 발명을 실시예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by way of examples.
단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.
제조예 1: 1-(R)-페닐에틸-4-(S 또는 R)-히드록시-2-피롤리디논의 제조Preparation Example 1 Preparation of 1- (R) -phenylethyl-4- (S or R) -hydroxy-2-pyrrolidinone
<단계 1> N-에톡시카보닐메틸-N-((R)-1-페닐에틸)말로나믹산 에틸 에스테르의 제조<Step 1> Preparation of N-ethoxycarbonylmethyl-N-((R) -1-phenylethyl) malonamic acid ethyl ester
실온에서 에틸 말론산 42.2 g을 아세토니트릴 500 ㎖에 희석한 후 물중탕 조건에서 1,1-카보닐다이이미다졸 46.73 g을 천천히 가하여 실온에서 20분간 반응시켰다. 반응 혼합물에 N-((R)-1-페닐에틸)글라이신 에틸 에스테르 54.3 g을 아세토니트릴 20 ㎖에 희석한 것을 천천히 가한 후 2시간 정도 방치하여 출발물질이 모두 없어지면, 감압 증류하여 용매를 제거하였다. After diluting 42.2 g of ethyl malonic acid in 500 ml of acetonitrile at room temperature, 46.73 g of 1,1-carbonyldiimidazole was slowly added under water bath and reacted at room temperature for 20 minutes. After diluting 54.3 g of N-((R) -1-phenylethyl) glycine ethyl ester in 20 ml of acetonitrile, the reaction mixture was slowly added to the mixture and left for about 2 hours to remove the starting materials. .
남은 잔여물에 에틸 아세테이트 500 ㎖을 가한 후 차가운 5% HCl 수용액 50 ㎖로 2회 세척하였으며, 유기용매 층을 무수 황산마그네슘으로 건조시킨 후 여과 및 감압농축을 수행하였다. 결과물을 컬럼크로마토그라피(용리액: 에틸 아세테이트/헥산=1/5)로 분리하여 76.19 g의 표제화합물인 N-에톡시카보닐메틸-N-((R)-1-페닐에틸)말로나믹산 에틸 에스테르를 얻었다. 500 ml of ethyl acetate was added to the residue, followed by washing twice with 50 ml of a cold 5% aqueous HCl solution. The organic solvent layer was dried over anhydrous magnesium sulfate, and then filtered and concentrated under reduced pressure. The resultant was separated by column chromatography (eluent: ethyl acetate / hexane = 1/5), and 76.19 g of the title compound N-ethoxycarbonylmethyl-N-((R) -1-phenylethyl) malonamic acid ethyl An ester was obtained.
1H NMR (200MHz, CDCl3) : δ 1.14~1.25 (3H, m), 1.45, 1.64 (3H, d, J=7Hz), 1.47 (9H, d, J=1Hz), 3.37~4.16 (6H, m), 5.15 (0.5H, q, J=7Hz), 6.08 (0.5H, q, J=7Hz), 7.26~7.36 (5H, m) 1 H NMR (200 MHz, CDCl 3 ): δ 1.14-1.25 (3H, m), 1.45, 1.64 (3H, d, J = 7 Hz), 1.47 (9H, d, J = 1 Hz), 3.37-4.16 (6H, m), 5.15 (0.5H, q, J = 7Hz), 6.08 (0.5H, q, J = 7Hz), 7.26 ~ 7.36 (5H, m)
<단계 2-1> 1-(R)-페닐에틸-4-(S)-히드록시-2-피롤리디논의 제조<Step 2-1> Preparation of 1- (R) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone
상기 단계 1에서 제조한 N-에톡시카보닐메틸-N-((R)-1-페닐에틸)말로나믹산 에틸 에스테르 20 g을 톨루엔 400 ㎖에 희석한 후 온도를 0℃ 이하로 유지하였으며, 포타슘 t-부톡사이드 7.7 g을 천천히 가한 후 서서히 실온으로 올려 10시간 동안 방치하였다.20 g of N-ethoxycarbonylmethyl-N-((R) -1-phenylethyl) malonamic acid ethyl ester prepared in step 1 was diluted in 400 ml of toluene, and the temperature was maintained at 0 ° C or below. 7.7 g of potassium t-butoxide was slowly added and then slowly raised to room temperature and left for 10 hours.
반응이 완결되면 얼음냉각조로 냉각한 다음 냉수 100 ㎖을 넣고 격렬하게 교반시킨 후 정치하여 물층을 분리하였으며, 톨루엔 층은 물 30 ㎖로 3회 추출하였다. 5℃ 이하의 얼음냉각조에서 물층에 진한 염산을 pH 1이 될 때까지 천천히 가하고 상온에서 30분 더 교반하여 생성된 고체를 여과하였으며, 정제과정 없이 건조하여 40 내지 50 ℃의 아세토니트릴/물(100/1, v/v) 200 ㎖과 혼합하여 1시간 동안 가열환류시켰다.After the reaction was completed, the mixture was cooled with an ice cooling bath, 100 ml of cold water was added thereto, stirred vigorously, and left standing to separate the water layer. The toluene layer was extracted three times with 30 ml of water. In an ice cooling bath below 5 ° C, concentrated hydrochloric acid was slowly added to the water layer until pH 1 and stirred for 30 minutes at room temperature, and the resulting solid was filtered and dried without refining. 100/1, v / v) was mixed with 200 ml and heated to reflux for 1 hour.
기포가 더 이상 발생하지 않으면 반응 혼합물을 식히고 용매를 감압농축하여 진공펌프에서 건조시켰으며, 이를 에탄올 200 ㎖에 녹여 내부온도 0℃ 이하에서 소듐보로하이드라이드(NaBH4) 3.0 g을 천천히 가하였다. 2시간 후 반응이 완결되면, 얼음냉각조 조건에서 반응 혼합물의 pH가 6 내지 7이 되도록 18% 염산을 가하고 이를 30분 동안 교반하였다. 생성된 고체를 여과한 후 수득된 여액을 감압농축 하였으며, 남은 잔여물에 염화메틸렌 200 ㎖을 첨가하였다. 반응혼합물에 무수 황산마그네슘을 가하고 격렬하게 교반하여 충분히 건조시켰으며, 이를 여과한 여액을 감압농축하였다. 남은 잔여물에 메탄올 200 ㎖ 및 활성탄 5.0 g을 첨가하여 2시간 동안 환류교반 반응시켰으며, 이를 여과한 여액을 감압농축하여 1-(R)-페닐에틸-4-(S)-히드록시-2-피롤리디논 및 1-(R)-페닐에틸-4-(R)-히드록시-2-피롤리디논의 라세믹 혼합물 7.1 g을 얻었다.When no more bubbles were generated, the reaction mixture was cooled, the solvent was concentrated under reduced pressure, dried in a vacuum pump, and dissolved in 200 ml of ethanol, and 3.0 g of sodium borohydride (NaBH 4 ) was slowly added at an internal temperature of 0 ° C. or lower. . When the reaction was completed after 2 hours, 18% hydrochloric acid was added so that the pH of the reaction mixture was 6 to 7 under ice-cooling bath conditions and stirred for 30 minutes. The resulting solid was filtered and the filtrate was concentrated under reduced pressure, and 200 ml of methylene chloride was added to the residue. Anhydrous magnesium sulfate was added to the reaction mixture, followed by vigorous stirring and drying sufficiently, and the filtrate was filtered under reduced pressure. To the residue was added 200 ml of methanol and 5.0 g of activated charcoal, and the mixture was stirred under reflux for 2 hours, and the filtrate was concentrated under reduced pressure to give 1- (R) -phenylethyl-4- (S) -hydroxy-2. 7.1 g of a racemic mixture of -pyrrolidinone and 1- (R) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone were obtained.
수득된 1-(R)-페닐에틸-4-(S)-히드록시-2-피롤리디논 및 1-(R)-페닐에틸-4-(R)-히드록시-2-피롤리디논의 라세믹 혼합물을 아세토니트릴 10 ㎖로 2회 재결정하여 표제화합물인 화합물 1-(R)-페닐에틸-4-(S)-히드록시-2-피롤리디논 2.9 g을 제조하였다. Of 1- (R) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone and 1- (R) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone obtained The racemic mixture was recrystallized twice with 10 ml of acetonitrile to prepare 2.9 g of the title compound Compound 1- (R) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone.
1H NMR (300MHz, CDCl3) : δ 1.50 (3H, d, J=7Hz), 2.39 (1H, dd, J1=3Hz, J2=18Hz), 2.65~2.73(2H, m), 2.96 (1H, dd, J1=2Hz, J2=11Hz), 3.53 (1H, dd, J1=5Hz, J2=11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J=7Hz), 7.23~7.36 (5H, m) 1 H NMR (300MHz, CDCl 3 ): δ 1.50 (3H, d, J = 7Hz), 2.39 (1H, dd, J1 = 3Hz, J2 = 18Hz), 2.65 ~ 2.73 (2H, m), 2.96 (1H, dd, J1 = 2Hz, J2 = 11Hz), 3.53 (1H, dd, J1 = 5Hz, J2 = 11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J = 7Hz), 7.23 ~ 7.36 (5H, m)
<단계 2-2> 1-(R)-페닐에틸-4-(R)-히드록시-2-피롤리디논의 제조<Step 2-2> Preparation of 1- (R) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone
상기 단계 2-1에서 생성된 1-(R)-페닐에틸-4-(S)-히드록시-2-피롤리디논 및 1-(R)-페닐에틸-4-(R)-히드록시-2-피롤리디논의 라세믹 혼합물을 아세토니트릴로 재결정하여 화합물 1-(R)-페닐에틸-4-(S)-히드록시-2-피롤리디논을 여과한 후, 여액을 감압 증발하여 얻은 잔여물을 컬럼크로마토그라피(에틸 아세테이트/메탄올 = 10/1, v/v)로 분리하여 표제화합물인 1-(R)-페닐에틸-4-(R)-히드록시-2-피롤리디논 3.2 g을 얻었다. 이를 에틸아세테이트로 재결정하였다.1- (R) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone and 1- (R) -phenylethyl-4- (R) -hydroxy- produced in step 2-1 The racemic mixture of 2-pyrrolidinone was recrystallized from acetonitrile to filter Compound 1- (R) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone, and the filtrate was obtained by evaporation under reduced pressure. The residue was separated by column chromatography (ethyl acetate / methanol = 10/1, v / v) to give the title compound 1- (R) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone 3.2 g was obtained. It was recrystallized from ethyl acetate.
1H NMR (300MHz, CDCl3) : δ 1.50 (3H, d, J=7Hz), 2.39 (1H, dd, J1=3Hz, J2=18Hz), 2.65~2.73(2H, m), 2.96 (1H, dd, J1=2Hz, J2=11Hz), 3.53 (1H, dd, J1=5Hz, J2=11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J=7Hz), 7.23~7.36 (5H, m) 1 H NMR (300MHz, CDCl 3 ): δ 1.50 (3H, d, J = 7Hz), 2.39 (1H, dd, J1 = 3Hz, J2 = 18Hz), 2.65 ~ 2.73 (2H, m), 2.96 (1H, dd, J1 = 2Hz, J2 = 11Hz), 3.53 (1H, dd, J1 = 5Hz, J2 = 11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J = 7Hz), 7.23 ~ 7.36 (5H, m)
제조예 2: 1-(S)-페닐에틸-4-(S 또는 R)-히드록시-2-피롤리디논의 제조Preparation Example 2 Preparation of 1- (S) -phenylethyl-4- (S or R) -hydroxy-2-pyrrolidinone
<단계 1> N-에톡시카보닐메틸-N-((S)-1-페닐에틸)말로나믹산 에틸 에스테르의 제조<Step 1> Preparation of N-ethoxycarbonylmethyl-N-((S) -1-phenylethyl) malonamic acid ethyl ester
N-((R)-1-페닐에틸)글라이신 에틸 에스테르 대신에 N-((S)-1-페닐에틸)글라이신 에틸 에스테르을 사용하는 것 외에는 제조예 1의 단계 1과 동일한 방법에 의하여 N-에톡시카보닐메틸-N-((S)-1-페닐에틸)말로나믹산 에틸 에스테르를 제조할 수 있다.Except for using N-((S) -1-phenylethyl) glycine ethyl ester in place of N-((R) -1-phenylethyl) glycine ethyl ester, The oxycarbonylmethyl-N-((S) -1-phenylethyl) malonamic acid ethyl ester can be prepared.
1H NMR (200MHz, CDCl3) : δ 1.15∼1.29 (3H, m), 1.45, 1.64 (3H, d, J=7Hz), 1.48 (9H, d, J=1Hz), 3.37∼4.17 (6H, m), 5.16 (0.5H, q, J=7Hz), 6.09 (0.5H, q, J=7Hz), 7.25∼7.36 (5H, m) 1 H NMR (200 MHz, CDCl 3 ): δ 1.15-1.29 (3H, m), 1.45, 1.64 (3H, d, J = 7 Hz), 1.48 (9H, d, J = 1 Hz), 3.37-4.17 (6H, m), 5.16 (0.5H, q, J = 7Hz), 6.09 (0.5H, q, J = 7Hz), 7.25-7.36 (5H, m)
<단계 2-1> 1-(S)-페닐에틸-4-(S)-히드록시-2-피롤리디논의 제조<Step 2-1> Preparation of 1- (S) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone
상기 단계 1에서 제조한 N-에톡시카보닐메틸-N-((S)-1-페닐에틸)말로나믹산 에틸 에스테르를 사용하여 제조예 1의 단계 2-1의 방법에 따라 1-(S)-페닐에틸-4-(S)-히드록시-2-피롤리디논 및 1-(S)-페닐에틸-4-(R)-히드록시-2-피롤리디논의 라세믹 혼합물을 얻었다.1- (S according to the method of Step 2-1 of Preparation Example 1 using N-ethoxycarbonylmethyl-N-((S) -1-phenylethyl) malonamic acid ethyl ester prepared in Step 1 A racemic mixture of) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone and 1- (S) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone was obtained.
수득된 1-(S)-페닐에틸-4-(S)-히드록시-2-피롤리디논 및 1-(S)-페닐에틸-4-(R)-히드록시-2-피롤리디논의 라세믹 혼합물을 아세토니트릴로 재결정하여 표제화합물인 화합물 1-(S)-페닐에틸-4-(S)-히드록시-2-피롤리디논을 제조하였다. Of 1- (S) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone and 1- (S) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone obtained The racemic mixture was recrystallized with acetonitrile to prepare the title compound Compound 1- (S) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone.
1H NMR (200MHz, CDCl3) : 1.50 (3H, d, J=7Hz), 2.39 (1H, dd, J1=2Hz, J2=7Hz), 2.51 (1H, d, J=4Hz), 2.70 (1H, dd, J1=7Hz, J2=17Hz), 2.95 (1H, dd, J1=2Hz, J2=11Hz), 3.53 (1H, dd, J1=6Hz, J2=11Hz), 4.40 (1H, bs), 5.44 (1H, q, J=7Hz), 7.21∼7.29 (5H, m) 1 H NMR (200 MHz, CDCl 3 ): 1.50 (3H, d, J = 7 Hz), 2.39 (1H, dd, J 1 = 2 Hz, J 2 = 7 Hz), 2.51 (1H, d, J = 4 Hz), 2.70 (1H, dd, J 1 = 7Hz, J 2 = 17Hz), 2.95 (1H, dd, J 1 = 2Hz, J 2 = 11Hz), 3.53 (1H, dd, J 1 = 6Hz, J 2 = 11Hz), 4.40 (1H, bs), 5.44 (1H, q, J = 7 Hz), 7.21-7.29 (5H, m)
<단계 2-2> 1-(S)-페닐에틸-4-(R)-히드록시-2-피롤리디논의 제조<Step 2-2> Preparation of 1- (S) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone
상기 단계 2-1에서 생성된 1-(S)-페닐에틸-4-(S)-히드록시-2-피롤리디논 및 1-(S)-페닐에틸-4-(R)-히드록시-2-피롤리디논의 라세믹 혼합물을 아세토니트릴로 재결정하여 화합물 1-(S)-페닐에틸-4-(S)-히드록시-2-피롤리디논을 여과한 후, 여액을 감압 증발하여 얻은 잔여물을 컬럼크로마토그라피(에틸 아세테이트/메탄올 = 10/1, v/v)로 분리하여 표제화합물인 1-(S)-페닐에틸-4-(R)-히드록시-2-피롤리디논 을 얻었다.1- (S) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone and 1- (S) -phenylethyl-4- (R) -hydroxy- produced in step 2-1 The racemic mixture of 2-pyrrolidinone was recrystallized from acetonitrile, and the compound 1- (S) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone was filtered, and the filtrate was obtained by evaporation under reduced pressure. The residue was separated by column chromatography (ethyl acetate / methanol = 10/1, v / v) to give the title compound 1- (S) -phenylethyl-4- (R) -hydroxy-2-pyrrolidinone. Got it.
1H NMR (300MHz, CDCl3) : δ 1.50 (3H, d, J=7Hz), 2.39 (1H, dd, J1=3Hz, J2=18Hz), 2.65~2.73(2H, m), 2.96 (1H, dd, J1=2Hz, J2=11Hz), 3.53 (1H, dd, J1=5Hz, J2=11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J=7Hz), 7.23~7.36 (5H, m) 1 H NMR (300MHz, CDCl 3 ): δ 1.50 (3H, d, J = 7Hz), 2.39 (1H, dd, J1 = 3Hz, J2 = 18Hz), 2.65 ~ 2.73 (2H, m), 2.96 (1H, dd, J1 = 2Hz, J2 = 11Hz), 3.53 (1H, dd, J1 = 5Hz, J2 = 11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J = 7Hz), 7.23 ~ 7.36 (5H, m)
실시예 1: 1-카바모일-4-(S)-히드록시-2-피롤리디논((S)-옥시라세탐)의 제조Example 1: Preparation of 1-carbamoyl-4- (S) -hydroxy-2-pyrrolidinone ((S) -oxyracetam)
<단계 1-1> 1-(R)-페닐에틸-4-(S)-아세톡시-2-피롤리디논의 제조<Step 1-1> Preparation of 1- (R) -phenylethyl-4- (S) -acetoxy-2-pyrrolidinone
상기 제조예 1의 단계 2-1에서 생성된 1-(R)-페닐에틸-4-(S)-히드록시-2-피 롤리디논 4.5 g을 클로로포름 80 ㎖에 현탁시킨 후 0℃ 이하에서 무수초산 8.4 ㎖ 및 N,N-다이메틸아미노피리딘(DMAP) 0.54 g을 가하여 온도를 서서히 실온까지 올리면서 3시간 동안 반응시켰다. 반응 혼합물을감압증류하여 용매를 제거하였으며, 잔여물은 컬럼크로마토그라피(용리액: 에틸 아세테이트/메탄올 = 10/1, v/v)로 분리하여 표제화합물인 1-(R)-페닐에틸-4-(S)-아세톡시-2-피롤리디논 5.98 g을 얻었다. 4.5 g of 1- (R) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone produced in Step 2-1 of Preparation Example 1 was suspended in 80 ml of chloroform, followed by anhydrous at 0 ° C. or lower. 8.4 mL of acetic acid and 0.54 g of N, N-dimethylaminopyridine (DMAP) were added thereto, and the mixture was allowed to react for 3 hours while gradually raising the temperature to room temperature. The reaction mixture was distilled under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluent: ethyl acetate / methanol = 10/1, v / v) to give the title compound 1- (R) -phenylethyl-4- 5.98 g of (S) -acetoxy-2-pyrrolidinone was obtained.
1H NMR (300MHz, CDCl3) : δ 1.50 (3H, d, J=7Hz), 2.02(3H, s), 2.39 (1H, dd, J1=3Hz, J2=18Hz), 2.65~2.73(2H, m), 2.96 (1H, dd, J1=2Hz, J2=11Hz), 3.53 (1H, dd, J1=5Hz, J2=11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J=7Hz), 7.23~7.36 (5H, m) 1 H NMR (300MHz, CDCl 3 ): δ 1.50 (3H, d, J = 7Hz), 2.02 (3H, s), 2.39 (1H, dd, J1 = 3Hz, J2 = 18Hz), 2.65 ~ 2.73 (2H, m), 2.96 (1H, dd, J1 = 2Hz, J2 = 11Hz), 3.53 (1H, dd, J1 = 5Hz, J2 = 11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J = 7Hz) , 7.23 ~ 7.36 (5H, m)
<단계 1-2> 1-(S)-페닐에틸-4-(S)-아세톡시-2-피롤리디논의 제조<Step 1-2> Preparation of 1- (S) -phenylethyl-4- (S) -acetoxy-2-pyrrolidinone
상기 제조예 2의 단계 2-1에서 생성된 1-(S)-페닐에틸-4-(S)-히드록시-2-피롤리디논을 실시예 1의 단계 1-1과 동일한 방법으로 처리하여 1-(S)-페닐에틸-4-(S)-아세톡시-2-피롤리디논을 얻었다.1- (S) -phenylethyl-4- (S) -hydroxy-2-pyrrolidinone produced in Step 2-1 of Preparation Example 2 was treated in the same manner as in Step 1-1 of Example 1 1- (S) -phenylethyl-4- (S) -acetoxy-2-pyrrolidinone was obtained.
1H NMR (200MHz, CDCl3) : 1.50 (3H, d, J=7Hz), 2.02(3H, s), 2.39 (1H, dd, J1=2Hz, J2=7Hz), 2.51 (1H, d, J=4Hz), 2.70 (1H, dd, J1=7Hz, J2 =17Hz), 2.95(1H, dd, J1=2Hz, J2=11Hz), 3.53 (1H, dd, J1=6Hz, J2=11Hz), 4.40 (1H, bs), 5.44 (1H, q, J=7Hz), 7.21∼7.29 (5H, m) 1 H NMR (200 MHz, CDCl 3 ): 1.50 (3H, d, J = 7 Hz), 2.02 (3H, s), 2.39 (1H, dd, J 1 = 2 Hz, J 2 = 7 Hz), 2.51 (1H, d , J = 4Hz), 2.70 (1H, dd, J 1 = 7Hz, J 2 = 17Hz), 2.95 (1H, dd, J 1 = 2Hz, J 2 = 11Hz), 3.53 (1H, dd, J 1 = 6Hz , J 2 = 11 Hz), 4.40 (1H, bs), 5.44 (1H, q, J = 7 Hz), 7.21-7.29 (5H, m)
<단계 2-1> 4-(S)-아세톡시-2-피롤리디논의 제조<Step 2-1> Preparation of 4- (S) -acetoxy-2-pyrrolidinone
1-(R)-페닐에틸-4-(S)-아세톡시-2-피롤리디논 3.5 g에 톨루엔 30 ㎖ 및 메탄설폰산(MsOH) 4.58 ㎖을 가하고 서서히 가열하면서 6시간 동안 환류시켰다. 반응 생성물을 실온으로 식히고 중탄산소다를 가하여 중화시킨 다음, 여과하여 여분의 중탄산소다를 제거하였으며, 감압 농축 후 칼럼크로마토그라피(에틸 아세테이트/메탄올 = 10/1)로 분리하여 표제화합물인 4-(S)-아세톡시-2-피롤리디논 1.38 g을 얻었다.To 3.5 g of 1- (R) -phenylethyl-4- (S) -acetoxy-2-pyrrolidinone was added 30 ml of toluene and 4.58 ml of methanesulfonic acid (MsOH), and the mixture was refluxed for 6 hours while heating slowly. The reaction product was cooled to room temperature, neutralized by adding sodium bicarbonate, filtered to remove excess sodium bicarbonate, concentrated under reduced pressure and separated by column chromatography (ethyl acetate / methanol = 10/1) to obtain the title compound 4- (S. 1.38 g of) -acetoxy-2-pyrrolidinone was obtained.
1H NMR (300MHz, CDCl3) : δ2.08 (3H, s), 2.40 (1H, dd, J1=3Hz, J2=18Hz), 2.72 (1H, dd, J1=6Hz, J2=18Hz), 3.41 (1H, d, J=12Hz), 3.76 (1H, dd, J1=6Hz, J2=12Hz), 5.35~5.40 (1H, m), 6.95 (1H, bs) 1 H NMR (300MHz, CDCl 3 ): δ2.08 (3H, s), 2.40 (1H, dd, J1 = 3Hz, J2 = 18Hz), 2.72 (1H, dd, J1 = 6Hz, J2 = 18Hz), 3.41 (1H, d, J = 12Hz), 3.76 (1H, dd, J1 = 6Hz, J2 = 12Hz), 5.35 ~ 5.40 (1H, m), 6.95 (1H, bs)
[α]27 = -56.4°(c=1. EtOH)[α] 27 = -56.4 ° (c = 1.EtOH)
<단계 2-2> 4-(S)-아세톡시-2-피롤리디논의 제조<Step 2-2> Preparation of 4- (S) -acetoxy-2-pyrrolidinone
상기 실시예 1의 단계 1-2에서 생성된 1-(S)-페닐에틸-4-(S)-아세톡시-2-피롤리디논을 실시예 1의 단계 2-1과 동일한 방법으로 처리하여 4-(S)-아세톡시-2-피 롤리디논을 얻었다.1- (S) -phenylethyl-4- (S) -acetoxy-2-pyrrolidinone produced in step 1-2 of Example 1 was treated in the same manner as in step 2-1 of Example 1 4- (S) -acetoxy-2-pyrrolidinone was obtained.
<단계 3> 1-에톡시카보닐메틸-4-(S)-아세톡시-2-피롤리디논의 제조 <Step 3> Preparation of 1-ethoxycarbonylmethyl-4- (S) -acetoxy-2-pyrrolidinone
4-(S)-아세톡시-2-피롤리디논 1 g을 건조된 테트라하이드로퓨란 20 ㎖에 녹이고, 여기에 60% 포타시움카보네이트 1.07 g을 상온에서 천천히 가하여 기포가 발생하지 않을 때까지 계속 교반시켰다. 20분간 더 교반시킨 후, 에틸 브로모아세테이트 0.85 ㎖을 천천히 적하하여 상온에서 3시간 동안 반응시켰다. 1 g of 4- (S) -acetoxy-2-pyrrolidinone was dissolved in 20 ml of dried tetrahydrofuran, and 1.07 g of 60% potassium fortium carbonate was slowly added thereto at room temperature and the stirring was continued until no bubbles were generated. . After further stirring for 20 minutes, 0.85 ml of ethyl bromoacetate was slowly added dropwise and reacted at room temperature for 3 hours.
반응 혼합물을 여과하여 여액을 감압농축하였으며, 칼럼크로마토그라피(용리액: 에틸 아세테이트/n-헥산 = 2/1, v/v)로 분리하여 표제화합물인 1-에톡시카보닐메틸-4-(S)-아세톡시-2-피롤리디논 1.25 g을 얻었다.The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, and separated by column chromatography (eluent: ethyl acetate / n-hexane = 2/1, v / v) to give the title compound 1-ethoxycarbonylmethyl-4- (S 1.25 g of) -acetoxy-2-pyrrolidinone was obtained.
1H NMR (300MHz, CDCl3): δ1.28 (3H, t, J=7Hz), 1.79 (1H, d, J=5Hz), 2.08 (3H, s), 2.52 (1H, dd, J1=2Hz, J2=18Hz), 2.83 (1H, dd, J1=8Hz, J2=18Hz), 3.46 (1H, dd, J1=2Hz, J2=11Hz), 3.88~3.99 (2H, m), 4.17~4.24 (3H, m), 5.31~5.36 (1H, m) 1 H NMR (300 MHz, CDCl 3 ): δ 1.28 (3H, t, J = 7 Hz), 1.79 (1H, d, J = 5 Hz), 2.08 (3H, s), 2.52 (1H, dd, J1 = 2 Hz , J2 = 18Hz), 2.83 (1H, dd, J1 = 8Hz, J2 = 18Hz), 3.46 (1H, dd, J1 = 2Hz, J2 = 11Hz), 3.88 ~ 3.99 (2H, m), 4.17 ~ 4.24 (3H , m), 5.31-5.36 (1H, m)
<단계 4> 1-카바모일-4-(S)-히드록시-2-피롤리디논((S)-옥시라세탐)의 제조Step 4 Preparation of 1-carbamoyl-4- (S) -hydroxy-2-pyrrolidinone ((S) -oxyracetam)
1-에톡시카보닐에틸-4-(S)-아세톡시-2-피롤리디논 1 g을 메탄올 10 ㎖에 희 석하고 0℃ 이하에서 암모니아를 주입하였다. 암모니아 0.78 g이 포화되면 마개를 잘 막은 뒤 서서히 실온으로 올려 밤새 교반하였으며, 이를 감압 증류하여 용매를 제거하고 아세톤/메탄올(5/1, v/v) 혼합용매를 4 ㎖ 가한 후 교반하여 연한 회색을 가진 고체 0.417 g을 얻었다. 1 g of 1-ethoxycarbonylethyl-4- (S) -acetoxy-2-pyrrolidinone was diluted in 10 ml of methanol and ammonia was injected at 0 ° C or lower. When 0.78 g of ammonia was saturated, the stopper was well sealed and then slowly raised to room temperature and stirred overnight. The solvent was distilled under reduced pressure to remove the solvent, and 4 ml of acetone / methanol (5/1, v / v) mixed solvent was added thereto, followed by stirring. 0.417 g of solid was obtained.
얻어진 고체를 메탄올 1.2 ㎖로 재결정하여 연한 색의 고체 0.231 g을 얻었으며, 이를 메탄올 10 ㎖에 녹인 후 활성탄 0.05 g을 가하여 30분 동안 가열환류 시켰다. 반응 생성물을 여과하고 실온으로 식힌 후, 감압증류하여 용매를 제거하였으며, 생성된 시럽상태의 혼합물에 메탄올 0.2 ㎖ 및 아세톤 1 ㎖를 가해 생성된 고체를 여과하여 표제화합물인 1-카바모일-4-(S)-히드록시-2-피롤리디논 0.564 g을 얻었다. The obtained solid was recrystallized with 1.2 ml of methanol to obtain 0.231 g of a light colored solid, which was dissolved in 10 ml of methanol and heated to reflux for 30 minutes with addition of 0.05 g of activated carbon. The reaction product was filtered, cooled to room temperature, and distilled under reduced pressure to remove the solvent. 0.2 ml of methanol and 1 ml of acetone were added to the resulting syrup mixture, and the resulting solid was filtered to give the title compound, 1-carbamoyl-4-. 0.564 g of (S) -hydroxy-2-pyrrolidinone was obtained.
1H NMR(500MHz, DMSO-d6): δ 2.05 (1H, dd, J1=3Hz, J1=17Hz), 2.54 (1H, dd, J1=7Hz, J1=17Hz), 3.14 (1H, dd, J1=2Hz, J1=10Hz), 3.60 (1H, dd, J1=6Hz, J1=10Hz), 3.64 (1H, d, J1=17Hz), 3.85 (1H, d, J1=17Hz), 4.26~4.30 (1H, m), 5.21 (1H, d, J1=4Hz), 7.11 (1H, s), 7.30 (1H, s) 1 H NMR (500 MHz, DMSO-d 6 ): δ 2.05 (1H, dd, J1 = 3 Hz, J1 = 17 Hz), 2.54 (1H, dd, J1 = 7 Hz, J1 = 17 Hz), 3.14 (1H, dd, J1 = 2Hz, J1 = 10Hz), 3.60 (1H, dd, J1 = 6Hz, J1 = 10Hz), 3.64 (1H, d, J1 = 17Hz), 3.85 (1H, d, J1 = 17Hz), 4.26 ~ 4.30 (1H , m), 5.21 (1H, d, J 1 = 4 Hz), 7.11 (1 H, s), 7.30 (1 H, s)
13C NMR(125MHz, DMSO-d6): δ 40.30, 44.71, 56.69, 63.26, 169.73, 172.81 13 C NMR (125 MHz, DMSO-d 6 ): δ 40.30, 44.71, 56.69, 63.26, 169.73, 172.81
[α]27 = -37.25. (c=1, water)[a] 27 = -37.25. (c = 1, water)
mp : 134.8 ~ 136.0 ℃mp: 134.8 ~ 136.0 ℃
순도:99.9%(HPLC, Waters Carbohydrate Column, 5% water in acetonitrile))Purity: 99.9% (HPLC, Waters Carbohydrate Column, 5% water in acetonitrile)
실시예 2: 1-카바모일-4-(R)-히드록시-2-피롤리디논((R)-옥시라세탐)의 제조Example 2: Preparation of 1-carbamoyl-4- (R) -hydroxy-2-pyrrolidinone ((R) -oxyracetam)
<단계 1> 1-(R)-페닐에틸-4-(R)-아세톡시-2-피롤리디논의 제조<Step 1> Preparation of 1- (R) -phenylethyl-4- (R) -acetoxy-2-pyrrolidinone
상기 제조예 1의 단계 2-2에서 생성된 1-(R)-페닐에틸-4-(5)-히드록시-2-피롤리디논 4.5 g을 클로로포름 80 ㎖에 현탁시킨 후, 반응 혼합물에 0℃에서 무수초산 8.4 ㎖ 및 N,N-디메틸아미노피리딘(DMAP) 0.54 g을 가하고 서서히 온도를 실온까지 올리면서 3시간 동안 반응시켰다.4.5 g of 1- (R) -phenylethyl-4- (5) -hydroxy-2-pyrrolidinone produced in step 2-2 of Preparation Example 1 was suspended in 80 ml of chloroform, and then, 0 was added to the reaction mixture. 8.4 mL of acetic anhydride and 0.54 g of N, N-dimethylaminopyridine (DMAP) were added thereto, and the mixture was allowed to react for 3 hours while gradually raising the temperature to room temperature.
반응 생성물을 감압 증류하여 용매를 제거하였으며, 잔여물을 컬럼크로마토그라피(에틸 아세테이트/메탄올 = 10/1, v/v)로 분리하여 표제화합물인 1-(R)-페닐에틸-4-(R)-아세톡시-2-피롤리디논 5.21 g을 수득하였다. 이를 에틸 아세테이트로 재결정하였다.The reaction product was distilled under reduced pressure to remove the solvent, and the residue was separated by column chromatography (ethyl acetate / methanol = 10/1, v / v) to give the title compound 1- (R) -phenylethyl-4- (R 5.21 g of) -acetoxy-2-pyrrolidinone was obtained. It was recrystallized from ethyl acetate.
1H NMR (300MHz, CDCl3) : δ 1.50 (3H, d, J=7Hz), 2.39 (1H, dd, J1=3Hz, J2=18Hz), 2.65~2.73(2H, m), 2.96 (1H, dd, J1=2Hz, J2=11Hz), 3.53 (1H, dd, J1=5Hz, J2=11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J=7Hz), 7.23~7.36 (5H, m) 1 H NMR (300MHz, CDCl 3 ): δ 1.50 (3H, d, J = 7Hz), 2.39 (1H, dd, J1 = 3Hz, J2 = 18Hz), 2.65 ~ 2.73 (2H, m), 2.96 (1H, dd, J1 = 2Hz, J2 = 11Hz), 3.53 (1H, dd, J1 = 5Hz, J2 = 11Hz), 4.4 (bs, 1H), 5.47 (1H, q, J = 7Hz), 7.23 ~ 7.36 (5H, m)
<단계 2-1> 4-(R)-아세톡시-2-피롤리디논의 제조<Step 2-1> Preparation of 4- (R) -acetoxy-2-pyrrolidinone
1-(R)-페닐에틸-4-(R)-아세톡시-2-피롤리디논 3.5 g에 톨루엔 30 ㎖ 및 메탄설폰산(MsOH) 4.58 ㎖을 가하여 6시간 동안 서서히 가열환류시켰다. 이를 실온으로 식힌 후 중탄산소다를 가하여 중화시킨 다음, 여과하여 여분의 중탄산소다를 제거하였으며, 남은 여액을 감압농축한 후 칼럼크로마토그라피(에틸 아세테이트/메탄올 = 10/1)로 분리하여 표제화합물인 4-(R)-아세톡시-2-피롤리디논 1.21 g을 얻었다.To 3.5 g of 1- (R) -phenylethyl-4- (R) -acetoxy-2-pyrrolidinone was added 30 ml of toluene and 4.58 ml of methanesulfonic acid (MsOH), and the mixture was slowly heated to reflux for 6 hours. The mixture was cooled to room temperature, neutralized by adding sodium bicarbonate, and then filtered to remove excess sodium bicarbonate. The remaining filtrate was concentrated under reduced pressure, and then separated by column chromatography (ethyl acetate / methanol = 10/1) to obtain the title compound (4). 1.21 g of-(R) -acetoxy-2-pyrrolidinone was obtained.
1H NMR (300MHz, CDCl3) : δ2.08 (3H, s), 2.40 (1H, dd, J1=3Hz, J2=18Hz), 2.72 (1H, dd, J1=6Hz, J2=18Hz), 3.41 (1H, d, J=12Hz), 3.76 (1H, dd, J1=6Hz, J2=12Hz), 5.35~5.40 (1H, m), 6.95 (1H, bs) 1 H NMR (300MHz, CDCl 3 ): δ2.08 (3H, s), 2.40 (1H, dd, J1 = 3Hz, J2 = 18Hz), 2.72 (1H, dd, J1 = 6Hz, J2 = 18Hz), 3.41 (1H, d, J = 12Hz), 3.76 (1H, dd, J1 = 6Hz, J2 = 12Hz), 5.35 ~ 5.40 (1H, m), 6.95 (1H, bs)
[α]27 = +56.1°(c=1. EtOH)[α] 27 = +56.1 ° (c = 1.EtOH)
<단계 2-2> 4-(R)-아세톡시-2-피롤리디논의 제조<Step 2-2> Preparation of 4- (R) -acetoxy-2-pyrrolidinone
1-(S)-페닐에틸-4-(R)-아세톡시-2-피롤리디논을 실시예 1의 단계 2-1과 동일한 방법으로 처리하여 4-(S)-아세톡시-2-피롤리디논을 얻었다.1- (S) -phenylethyl-4- (R) -acetoxy-2-pyrrolidinone was treated in the same manner as in Step 2-1 of Example 1 to 4- (S) -acetoxy-2-py Obtained Lollidinone.
<단계 3> 1-에톡시카보닐메틸-4-(R)-아세톡시-2-피롤리디논의 제조 <Step 3> Preparation of 1-ethoxycarbonylmethyl-4- (R) -acetoxy-2-pyrrolidinone
4-(R)-아세톡시-2-피롤리디논 2 g을 건조된 테트라하이드로퓨란 30 ㎖에 녹이고 상온에서 60% 포타슘카보네이트 2.2 g을 천천히 넣은 다음 기포가 발생하지 않을 때까지 상온에서 계속 교반시켰다. 기포 발생이 중지되면 20분간 더 교반시킨 후 에틸 브로모아세테이트 1.7 ㎖을 천천히 적가하였으며, 이를 상온에서 3시간 동안 반응시킨 후 반응 생성물을 여과하였다. 여과액을 감압농축한 후 칼럼크로마토그라피(에틸 아세테이트/n-헥산 = 2/1, v/v)로 분리하여 표제화합물인 1-에톡시카보닐메틸-4-(R)-아세톡시-2-피롤리디논 2.71 g을 얻었다.2 g of 4- (R) -acetoxy-2-pyrrolidinone was dissolved in 30 ml of dried tetrahydrofuran and slowly added 2.2 g of 60% potassium carbonate at room temperature, followed by continued stirring at room temperature until no bubbles were generated. . After the bubble was stopped, the solution was further stirred for 20 minutes, and 1.7 ml of ethyl bromoacetate was slowly added dropwise. The reaction product was filtered after reacting at room temperature for 3 hours. The filtrate was concentrated under reduced pressure, and then separated by column chromatography (ethyl acetate / n-hexane = 2/1, v / v) to give the title compound 1-ethoxycarbonylmethyl-4- (R) -acetoxy-2. 2.71 g of pyrrolidinone was obtained.
1H NMR (300MHz, CDCl3) : δ1.28 (3H, t, J=7Hz), 1.79 (1H, d, J=5Hz), 2.08 (3H, s), 2.52 (1H, dd, J1=2Hz, J2=18Hz), 2.83 (1H, dd, J1=8Hz, J2=18Hz), 3.46 (1H, dd, J1=2Hz, J2=11Hz), 3.88~3.99 (2H, m), 4.17~4.24 (3H, m), 5.31~ 5.36 (1H, m) 1 H NMR (300 MHz, CDCl 3 ): δ 1.28 (3H, t, J = 7 Hz), 1.79 (1H, d, J = 5 Hz), 2.08 (3H, s), 2.52 (1H, dd, J1 = 2 Hz , J2 = 18Hz), 2.83 (1H, dd, J1 = 8Hz, J2 = 18Hz), 3.46 (1H, dd, J1 = 2Hz, J2 = 11Hz), 3.88 ~ 3.99 (2H, m), 4.17 ~ 4.24 (3H , m), 5.31-5.36 (1H, m)
<단계 4> 1-카바모일-4-(R)-히드록시-2-피롤리디논((R)-옥시라세탐)의 제조Step 4 Preparation of 1-carbamoyl-4- (R) -hydroxy-2-pyrrolidinone ((R) -oxyracetam)
1-에톡시카보닐에틸-4-(R)-아세톡시-2-피롤리디논 1 g을 메탄올 10 ㎖에 희석하고 0℃ 이하에서 암모니아를 주입하였다. 암모니아 0.78 g이 포화되면 마개를 잘 막은 뒤 서서히 실온으로 올려 밤새 교반반응 시켰다. 반응생성물을 감압 증류하여 용매를 제거하였으며, 여기에 아세톤/메탄올(5/1, v/v) 혼합용매를 4 ㎖ 가하 여 교반시켜 연한 회색을 가진 고체 0.417 g을 얻었다. 수득된 고체를 메탄올 1.2 ㎖로 재결정한 후 연한 색을 가진 고체 0.231 g 얻었으며, 이를 메탄올 10 ㎖에 녹인 후 활성탄 0.05 g을 가하여 30분 동안 가열환류시켰다. 이를 여과하고 실온으로 식힌 후, 감압 증류하여 용매를 제거하였으며, 생성된 시럽상태의 혼합물에 메탄올 0.2 ㎖ 및 아세톤 1 ㎖을 가하였다. 생성된 백색고체를 여과하여 표제화합물인 1-카바모일-4-(R)-히드록시-2-피롤리디논 0.632 g을 얻었다. 1 g of 1-ethoxycarbonylethyl-4- (R) -acetoxy-2-pyrrolidinone was diluted in 10 ml of methanol and ammonia was injected at 0 ° C. or lower. When 0.78 g of ammonia was saturated, the stopper was well blocked, and then slowly raised to room temperature, followed by stirring overnight. The reaction product was distilled under reduced pressure to remove the solvent, and 4 ml of acetone / methanol (5/1, v / v) mixed solvent was added thereto, followed by stirring to obtain 0.417 g of a light gray solid. The obtained solid was recrystallized with 1.2 ml of methanol to obtain 0.231 g of a light colored solid, which was dissolved in 10 ml of methanol and heated to reflux for 30 minutes by adding 0.05 g of activated carbon. After filtration and cooling to room temperature, the solvent was removed by distillation under reduced pressure, and 0.2 ml of methanol and 1 ml of acetone were added to the resulting syrup. The resulting white solid was filtered to obtain 0.632 g of 1-carbamoyl-4- (R) -hydroxy-2-pyrrolidinone as the title compound.
1H NMR(500MHz, DMSO-d6): δ 2.05 (1H, dd, J1=3Hz, J1=17Hz), 2.54 (1H, dd, J1=7Hz, J1=17Hz), 3.14 (1H, dd, J1=2Hz, J1=10Hz), 3.60 (1H, dd, J1=6Hz, J1=10Hz), 3.64 (1H, d, J1=17Hz), 3.85 (1H, d, J1=17Hz), 4.26~4.30 (1H, m), 5.21 (1H, d, J1=4Hz), 7.11 (1H, s), 7.30 (1H, s) 1 H NMR (500 MHz, DMSO-d 6 ): δ 2.05 (1H, dd, J1 = 3 Hz, J1 = 17 Hz), 2.54 (1H, dd, J1 = 7 Hz, J1 = 17 Hz), 3.14 (1H, dd, J1 = 2Hz, J1 = 10Hz), 3.60 (1H, dd, J1 = 6Hz, J1 = 10Hz), 3.64 (1H, d, J1 = 17Hz), 3.85 (1H, d, J1 = 17Hz), 4.26 ~ 4.30 (1H , m), 5.21 (1H, d, J 1 = 4 Hz), 7.11 (1 H, s), 7.30 (1 H, s)
13C NMR(125MHz, DMSO-d6): δ 40.30, 44.71, 56.69, 63.26, 169.73, 172.8 13 C NMR (125 MHz, DMSO-d 6 ): δ 40.30, 44.71, 56.69, 63.26, 169.73, 172.8
[α]27 = +37.18. (c=1, water)[a] 27 = +37.18. (c = 1, water)
mp : 135.8~136.7℃mp: 135.8 ~ 136.7 ℃
순도:99.8%(HPLC, Waters Carbohydrate Column, 5% water in acetonitrile))Purity: 99.8% (HPLC, Waters Carbohydrate Column, 5% water in acetonitrile)
본 발명에 따른 1-카바모일메틸-4-(S 또는 R)-히드록시-2-옥소피롤리딘((S)- 옥시라세탐 또는 (R)-옥시라세탐)을 제조하는 방법은 저가의 원료물질들을 사용하여 산업적 적용이 용이한 공정으로 (S)-옥시라세탐 및 (R)-옥시라세탐을 고수율 및 고순도((S 또는 R)-옥시라세탐의 특성치에 순도 표시하였음)로 제조할 수 있으므로 뇌기능 개선 및 치매 치료제 개발에 유용하게 활용될 수 있다.The process for preparing 1-carbamoylmethyl-4- (S or R) -hydroxy-2-oxopyrrolidine ((S) -oxyracetam or (R) -oxyracetam) according to the invention is inexpensive. (S) -Oxyracetam and (R) -Oxyracetam have high yield and high purity (Purity is indicated in the properties of (S or R) -Oxyracetam) by using industrial raw materials Because it can be prepared as may be useful in improving brain function and developing dementia treatment.
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