KR100424393B1 - Process for the preparation of oxiracetam - Google Patents
Process for the preparation of oxiracetam Download PDFInfo
- Publication number
- KR100424393B1 KR100424393B1 KR10-2001-0073696A KR20010073696A KR100424393B1 KR 100424393 B1 KR100424393 B1 KR 100424393B1 KR 20010073696 A KR20010073696 A KR 20010073696A KR 100424393 B1 KR100424393 B1 KR 100424393B1
- Authority
- KR
- South Korea
- Prior art keywords
- formula
- compound
- preparation
- acid
- hours
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
Abstract
본 발명은 중간체로서 N-(2-t-부톡시카보닐아세틸)이미노디아세테이트 유도체를 거쳐 목적하는 옥시라세탐(Oxiracetam, 1-카바모일메틸-4-히드록시-2-옥소피롤리딘)을 고순도 및 고수율로 제조하는 개선된 방법에 관한 것이다.The present invention passes through N- (2-t-butoxycarbonylacetyl) iminodiacetate derivative as an intermediate to the desired oxyracetam (1-carbamoylmethyl-4-hydroxy-2-oxopyrrolidine). The present invention relates to an improved process for the preparation of high purity and high yield.
Description
본 발명은 중간체로서 N-(2-t-부톡시카보닐아세틸)이미노디아세테이트 유도체를 거쳐 목적하는 옥시라세탐을 고순도 및 고수율로 제조하는 개선된 방법에 관한 것이다.The present invention relates to an improved process for producing the desired oxyracetam in high purity and high yield via an N- (2-t-butoxycarbonylacetyl) iminodiacetate derivative as an intermediate.
하기 화학식 1의 옥시라세탐(1-카바모일메틸-4-히드록시-2-옥소피롤리딘)은 뇌기능 개선작용과 치매 치료 효과를 나타내는 화합물로 알려져 있다.Oxyacetam of Formula 1 (1-carbamoylmethyl-4-hydroxy-2-oxopyrrolidine) is known as a compound that exhibits brain function improving and dementia treatment effects.
옥시라세탐을 제조하는 종래의 기술로서, 미국 특허 제4,118,396호는 에틸 이미노디아세테이트와 에톡시카보닐아세틸클로라이드를 출발물질로 사용하여 옥시라세탐을 제조하는 방법을 개시하고 있다. 이 방법은, 중간체로서 3-에톡시카보닐-4-옥소-2-피롤리돈 유도체를 생성하는 반응과 이 유도체를 탈탄산화하는 반응을 포함하는데, 상기 유도체의 생성을 위해 에틸 N-에톡시카보닐아세틸이미노디아세테이트 및 에톡시화나트륨을 벤젠과 에탄올의 혼합용매에서 환류교반하고, 또한 탈탄산화를 위해 상기 유도체를 물과 아세토니트릴의 혼합용매에서 환류교반하고 있어, 공정이 복잡하고 수율이 낮아지는 문제가 있으며, 탈탄산화를 통해 생성된 4-옥소-2-피롤리돈 유도체가 상기 온도 및 용매조건 하에서는 불안정하여 다른 화합물로 쉽게 전환되는 문제점을 갖는다.As a conventional technique for preparing oxyracetams, US Pat. No. 4,118,396 discloses a process for preparing oxyracetams using ethyl iminodiacetate and ethoxycarbonylacetylchloride as starting materials. The process includes the reaction of producing 3-ethoxycarbonyl-4-oxo-2-pyrrolidone derivatives as intermediates and the decarbonation of these derivatives, which are used to produce ethyl N-ethoxy Carbonylacetyliminodiacetate and sodium ethoxylate were refluxed and stirred in a mixed solvent of benzene and ethanol, and the derivatives were refluxed and stirred in a mixed solvent of water and acetonitrile for decarbonation, resulting in a complicated process and a low yield. There is a problem, and the 4-oxo-2-pyrrolidone derivative produced through decarbonation is unstable under the above temperature and solvent conditions and has a problem of being easily converted to another compound.
미국 특허 제5,371,237호는 중간체로서 4-알콕시-3-피롤린-2-온 유도체 및 4-옥소-2-피롤리돈 유도체를 거쳐 옥시라세탐을 제조하는 방법을 개시하고 있다. 그러나, 이 방법 또한 4-알콕시-3-피롤린-2-온 유도체로부터 4-옥소-2-피롤리돈 유도체를 제조하는 산성조건이 반응중에 생성되는 4-옥소-2-피롤리돈 유도체를 화학적으로 불안정하게 만든다는 문제점을 갖는다.U.S. Pat.No. 5,371,237 discloses a process for preparing oxyracetam via 4-alkoxy-3-pyrroline-2-one derivatives and 4-oxo-2-pyrrolidone derivatives as intermediates. However, this method also provides a method for producing 4-oxo-2-pyrrolidone derivatives from 4-alkoxy-3-pyrroline-2-one derivatives in which It has the problem of making it chemically unstable.
미국 특허 제4,686,296호는 4-클로로-3-히드록시부타노익산 또는 3,4-에폭시부타노익산 에스테르와 글리신아미드를 출발물질로 사용하여 옥시라세탐을 제조하는 방법을 개시하고 있다. 이 방법은 단일 단위반응만으로 가능하다는 장점은 있으나, 고가의 출발물질을 사용하며 정제가 용이하지 않고 제조 수율이 25-35%로 저조한 단점을 가지고 있다.US Pat. No. 4,686,296 discloses a process for preparing oxyracetam using 4-chloro-3-hydroxybutanoic acid or 3,4-epoxybutanoic acid ester and glycineamide as starting materials. This method has the advantage of being possible by only a single unit reaction, but uses expensive starting materials, is not easy to purify, and has a low production yield of 25-35%.
따라서, 본 발명자들은 상기 문제점을 해소하기 위해 연구하던 중, 중요 제조 중간체로서 N-(2-t-부톡시카보닐아세틸)이미노디아세테이트 유도체를 거치는 공정으로 옥시라세탐을 고수율 및 고순도로 간편하게 제조할 수 있음을 발견하고 본 발명을 완성하게 되었다.Therefore, the present inventors have been studying to solve the above problems, the oxyracetam in a high yield and high purity by a step of passing through the N- (2-t-butoxycarbonylacetyl) iminodiacetate derivative as an important manufacturing intermediate It has been found that it can be produced to complete the present invention.
본 발명의 목적은 뇌기능 개선작용과 치매 치료 효과를 나타내는 옥시라세탐을 고순도 및 고수율로 간편하게 제조하는 개선된 방법을 제공하는 것이다.It is an object of the present invention to provide an improved method for the simple production of high purity and high yield of oxacetam, which exhibits brain function improving and dementia treatment effects.
상기 목적을 달성하기 위하여 본 발명에서는,In the present invention to achieve the above object,
a) 유기용매 중에서 하기 화학식 4의 화합물과 하기 화학식 5의 화합물을 반응시켜 하기 화학식 2의 3급 아미드 화합물을 제조하는 단계,a) reacting a compound of Formula 4 with a compound of Formula 5 to prepare a tertiary amide compound of Formula 2 in an organic solvent,
b) 유기용매 중에서 화학식 2의 화합물을 연속적으로 고리화, 탈탄산화 및 환원시켜 하기 화학식 3의 화합물을 제조하는 단계, 및b) continuously cyclizing, decarbonizing and reducing the compound of formula 2 in an organic solvent to prepare a compound of formula 3, and
c) 물 또는 알콜 중에서 화학식 3의 화합물을 암모니아와 반응시키는 단계c) reacting the compound of formula 3 with ammonia in water or alcohol
를 포함하는, 하기 화학식 1의 옥시라세탐의 제조방법을 제공한다:It provides a method of preparing an oxalase of Formula 1, comprising:
화학식 1Formula 1
상기 식에서, R은 메틸기 또는 에틸기이고, X는 히드록시기 또는 할로겐화물이다.Wherein R is a methyl group or an ethyl group and X is a hydroxy group or a halide.
이하 본 발명에 대하여 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 옥시라세탐 제조방법을 반응식으로 나타내면 다음과 같다.Representation method of the oxyracetam production method of the present invention is as follows.
상기 식에서, R 및 X는 상기 정의한 바와 같다.Wherein R and X are as defined above.
본 발명의 출발물질인 화학식 4 및 5의 화합물은 공지된 방법에 따라 용이하게 제조하거나 구입하여 사용할 수 있다.The compounds of formulas (4) and (5), which are starting materials of the present invention, can be easily prepared or purchased according to known methods.
본 발명의 제조방법의 단계 (a)에 따르면, 일반적인 아미드결합 생성 방법인 DCC(디시클로헥실카보디이미드)법, CDI(카보닐디이미다졸)법 또는 산할로겐화물을 이용하여 유기용매(예: 아세토니트릴, 염화메틸렌, 클로로포름) 중에서 화학식 4 및 5의 화합물을 -30 내지 80℃에서 0.5 내지 10시간 동안 반응시켜 본 발명의 중요 중간체인 화학식 2의 3급 아미드 화합물을 제조한다.According to step (a) of the preparation method of the present invention, an organic solvent (eg, using a DCC (dicyclohexylcarbodiimide) method, CDI (carbonyldiimidazole) method or an acid halide), which is a general amide bond production method, may be used. In the acetonitrile, methylene chloride, chloroform), the compounds of formulas 4 and 5 are reacted at −30 to 80 ° C. for 0.5 to 10 hours to prepare tertiary amide compounds of formula 2 which are important intermediates of the present invention.
이어, 본 발명의 제조방법의 단계 (b)에서, 유기용매(예: 벤젠, 톨루엔, 에탄올) 중에서 -30 내지 50℃에서, 상기 단계 (a)에서 생성된 화학식 2의 3급 아미드 화합물을 1 내지 15시간 동안 수소화물 또는 알콕시화물과 반응시켜 고리화시킨 다음, 유기산 또는 무기산을 첨가하여 1 내지 6시간 동안 탈탄산화시킨 후, 붕수소화물과 같은 환원제로 20분 내지 14시간 동안 환원시켜, 화학식 3의 화합물을 제조한다.Subsequently, in step (b) of the preparation method of the present invention, the tertiary amide compound of Formula 2 produced in step (a) at -30 to 50 ° C in an organic solvent (eg, benzene, toluene, ethanol) is 1 After cyclization by reacting with a hydride or alkoxide for 15 to 15 hours, followed by decarboxylation for 1 to 6 hours by adding an organic acid or an inorganic acid, and then reducing for 20 minutes to 14 hours with a reducing agent such as borohydride, To prepare a compound.
상기 단계 (b) 중 고리화 반응에 사용되는 수소화물 또는 알콕시화물의 구체적인 예로는 t-부톡시화칼륨, 에톡시화나트륨, 메톡시화나트륨 및 수소화나트륨을 들 수 있고, 탈탄산화 반응에 사용되는 유기산 또는 무기산의 구체적인 예로는 염산, 황산, 메탄술폰산, 삼불화메탄술폰산 및 톨루엔술폰산을 들 수 있으며, 환원 반응에 사용되는 붕수소화물의 구체적인 예로는 수소화붕소나트륨을 들 수 있다.Specific examples of the hydride or alkoxide used in the cyclization reaction in step (b) include t-butoxide, sodium ethoxylate, sodium methoxide and sodium hydride, and the organic acid used in the decarbonation reaction, or Specific examples of the inorganic acid include hydrochloric acid, sulfuric acid, methanesulfonic acid, methanesulfonic trifluoride and toluenesulfonic acid. Specific examples of the boride hydride used in the reduction reaction include sodium borohydride.
이때, 탈탄산화시 제거되는 기인 t-부톡시카보닐기는, 종래의 방법에서는 고온 및 특정 용매조건 하에서 제거하여야 했던 C1-3알콕시카보닐기와는 달리, 상온에서 산에 의해 용이하게 제거가능할 뿐만 아니라, 탈탄산화를 통해 생성되는 화합물 또한 이러한 온도 및 용매조건 하에서는 화학적으로 매우 안정하다.At this time, unlike the C 1-3 alkoxycarbonyl group which had to be removed under high temperature and specific solvent conditions in the conventional method, the t-butoxycarbonyl group that is removed during decarbonization can be easily removed by acid at room temperature. In addition, compounds produced through decarbonation are also chemically very stable under these temperature and solvent conditions.
이어, 본 발명의 제조방법의 단계 (c)에 따르면, 물 또는 알콜 중에서, 상기 단계 (b)에서 생성된 화학식 3의 화합물을 -40 내지 50℃에서 30분 내지 24시간 동안 암모니아와 반응시켜, 목적 화합물인 화학식 1의 옥시라세탐(1-카바모일메틸-4-히드록시-2-옥소피롤리딘)을 제조한다.Then, according to step (c) of the preparation method of the present invention, the compound of formula 3 produced in step (b) is reacted with ammonia for 30 minutes to 24 hours at -40 to 50 ℃ in water or alcohol, Oxyacetam (1-carbamoylmethyl-4-hydroxy-2-oxopyrrolidine) of the formula (1) as a target compound is prepared.
이와 같은 본 발명의 방법에 의하면, 기존 방법과 달리 저온 조건에서 탈탄산화반응을 수행하여 목적 화합물인 옥시라세탐을 고순도 및 고수율로 간편하게 제조할 수 있다.According to the method of the present invention, unlike the existing method, the decarboxylation reaction can be performed under low temperature conditions to easily prepare the desired compound, oxyracetam, in high purity and high yield.
이하에서 본 발명을 실시예에 의거하여 보다 구체적으로 설명한다. 단, 이들 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명이 이들만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, these Examples are only for illustrating the present invention, the present invention is not limited to these.
실시예 1 : 디에틸 N-(2-t-부톡시카보닐아세틸)이미노디아세테이트(화합물 2)의 제조Example 1 Preparation of Diethyl N- (2-t-butoxycarbonylacetyl) iminodiacetate (Compound 2)
아세토니트릴 400ml에 2-t-부톡시카보닐아세트산 17.6g을 녹이고, 여기에 CDI 19.5g을 넣고 실온에서 교반하면서 디에틸 이미노디아세테이트 18.9g을 아세토니트릴 100ml에 녹인 용액을 적가하였다. 반응 혼합물을 10시간 동안 교반하고, 감압하에서 용매를 제거한 다음, 염화메틸렌에 녹여 묽은 중탄산나트륨 수용액으로 세척하였다. 이어, 용액을 무수 황산나트륨으로 건조하고, 감압하에서 용매를 제거하여 점성이 높은 목적 화합물 29.76g을 얻었다(수율: 94.1%).17.6 g of 2-t-butoxycarbonyl acetic acid was dissolved in 400 ml of acetonitrile, and 19.5 g of CDI was added thereto, and a solution of 18.9 g of diethyl iminodiacetate in 100 ml of acetonitrile was added dropwise while stirring at room temperature. The reaction mixture was stirred for 10 hours, the solvent was removed under reduced pressure, then dissolved in methylene chloride and washed with dilute aqueous sodium bicarbonate solution. The solution was then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 29.76 g of a highly viscous target compound (yield: 94.1%).
H1-NMR(CDCl3): δ1.28(6H, t, t), 1.47(9H, s), 3.39(2H, s), 4.21(8H, m)H 1 -NMR (CDCl 3 ): δ 1.28 (6H, t, t), 1.47 (9H, s), 3.39 (2H, s), 4.21 (8H, m)
실시예 2 : 디에틸 N-(2-t-부톡시카보닐아세틸)이미노디아세테이트(화합물 2)의 제조Example 2 Preparation of Diethyl N- (2-t-butoxycarbonylacetyl) iminodiacetate (Compound 2)
염화메틸렌 400ml에 2-t-부톡시카보닐아세트산 17.6g을 녹이고, 여기에 DCC 22.6g을 넣고 실온에서 교반하면서 디에틸 이미노디아세테이트 18.9g을 가한 후,12시간 동안 교반하였다. 반응 혼합물을 여과하고, 여액을 묽은 중탄산나트륨 수용액으로 세척한 후, 무수 황산나트륨으로 건조하고, 감압하에서 용매를 제거하여 점성이 높은 목적 화합물 29.67g을 얻었다(수율: 93.8%).17.6 g of 2-t-butoxycarbonyl acetic acid was dissolved in 400 ml of methylene chloride, 22.6 g of DCC was added thereto, and 18.9 g of diethyl iminodiacetate was added while stirring at room temperature, followed by stirring for 12 hours. The reaction mixture was filtered, the filtrate was washed with dilute aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 29.67 g of a highly viscous target compound (yield: 93.8%).
H1-NMR(CDCl3): δ1.28(6H, t, t), 1.47(9H, s), 3.39(2H, s), 4.21(8H, m)H 1 -NMR (CDCl 3 ): δ 1.28 (6H, t, t), 1.47 (9H, s), 3.39 (2H, s), 4.21 (8H, m)
실시예 3 : 디메틸 N-(2-t-부톡시카르보닐아세틸)이미노디아세테이트(화합물 2)의 제조Example 3 Preparation of Dimethyl N- (2-t-butoxycarbonylacetyl) iminodiacetate (Compound 2)
클로로포름 100ml에 2-t-부톡시카보닐아세트산 8.8g을 녹이고, 여기에 CDI 9.8g를 넣고 실온에서 5시간 동안 교반하였다. 이 혼합물에 디메틸 이미노디아세테이트 8.1g을 가하여 10시간 동안 교반하였다. 반응 혼합물을 묽은 중탄산나트륨 수용액으로 세척하고, 무수 황산마그네슘으로 건조하고, 감압하에서 용매를 제거하여 점성이 높은 목적 화합물 13.66g을 얻었다(수율: 90.1%).8.8 g of 2-t-butoxycarbonyl acetic acid was dissolved in 100 ml of chloroform, and 9.8 g of CDI was added thereto, followed by stirring at room temperature for 5 hours. 8.1 g of dimethyl iminodiacetate was added to the mixture, followed by stirring for 10 hours. The reaction mixture was washed with dilute aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 13.66 g of a highly viscous target compound (yield: 90.1%).
H1-NMR(CDCl3): δ1.48(9H, s), 3.39(2H, s), 3.81(6H, s), 4.21(4H, s)H 1 -NMR (CDCl 3 ): δ 1.48 (9H, s), 3.39 (2H, s), 3.81 (6H, s), 4.21 (4H, s)
실시예 4 : 1-에톡시카보닐메틸-4-히드록시-2-피롤리돈(화합물 3)의 제조Example 4 Preparation of 1-Ethoxycarbonylmethyl-4-hydroxy-2-pyrrolidone (Compound 3)
톨루엔 200ml에 상기 실시예 1에서 제조된 디에틸 N-(2-t-부톡시카보닐아세틸)이미노디아세테이트 15.8g을 녹인 후, 얼음중탕에서 에톡시화나트륨 3.8g을 조금씩 나누어 0.5시간 동안 가하고 5시간 동안 교반하였다(고리화 반응). 반응 혼합물에 물 100ml를 넣고 격렬하게 교반한 후, 물층을 묽은 염산으로 산성화하여 3시간 동안 교반하였다(탈탄산 반응). 이 수용액을 에틸 아세테이트로 추출하고 황산마그네슘으로 건조하여 감압하에서 용매를 제거하고, 잔류물에 메탄올 100ml를 가하고 얼음중탕에서 수소화붕소나트륨 4.5g을 조금씩 천천히 가한 다음 3시간 동안 교반하였다(환원 반응). 얻어진 반응 혼합물에 물 10ml를 가한 다음, 감압하에서 용매를 제거하고, 잔류물을 크로마토그래피하여 목적 화합물 7.21g을 얻었다(수율: 77.1%).After dissolving 15.8 g of diethyl N- (2-t-butoxycarbonylacetyl) iminodiacetate prepared in Example 1 in 200 ml of toluene, 3.8 g of sodium ethoxylate was added little by little in an ice bath for 0.5 hour. Stir for time (ring reaction). 100 ml of water was added to the reaction mixture, followed by vigorous stirring. The aqueous layer was acidified with dilute hydrochloric acid and stirred for 3 hours (decarbonation reaction). The aqueous solution was extracted with ethyl acetate, dried over magnesium sulfate, the solvent was removed under reduced pressure, 100 ml of methanol was added to the residue, and 4.5 g of sodium borohydride was slowly added slowly in an ice bath, followed by stirring for 3 hours (reduction reaction). 10 ml of water was added to the obtained reaction mixture, the solvent was removed under reduced pressure, and the residue was chromatographed to obtain 7.21 g of the target compound (yield: 77.1%).
H1-NMR(CDCl3): δ1.28(3H, t), 2.41(1H, d x d), 2.78(1H, d x d), 3.09(1H, d), 3.38(1H, d x d), 3.80(1H, ABx), 4.10(2H, ABq), 4.19(2H, q), 4.52(2H, m)H 1 -NMR (CDCl 3 ): δ 1.28 (3H, t), 2.41 (1H, dxd), 2.78 (1H, dxd), 3.09 (1H, d), 3.38 (1H, dxd), 3.80 (1H, ABx), 4.10 (2H, ABq), 4.19 (2H, q), 4.52 (2H, m)
실시예 5 : 1-메톡시카보닐메틸-4-히드록시-2-피롤리돈(화합물 3)의 제조Example 5 Preparation of 1-methoxycarbonylmethyl-4-hydroxy-2-pyrrolidone (Compound 3)
톨루엔 150ml에 상기 실시예 3에서 제조된 디메틸 N-(2-t-부톡시카보닐아세틸)이미노디아세테이트 15.2g을 녹인 후, 얼음중탕에서 t-부톡시화칼륨 6.6g을 조금씩 나누어 1시간 동안 가하고 7시간 동안 교반하였다(고리화 반응). 반응 혼합물에 물 50ml를 넣고 격렬하게 교반한 후, 물층을 묽은 염산으로 산성화하여 3시간 동안 교반하였다(탈탄산 반응). 이 수용액을 에틸 아세테이트로 추출하고 황산마그네슘으로 건조하여 감압하에서 용매를 제거하고, 잔류물에 메탄올 50ml을 가하고 얼음중탕에서 수소화나트륨 4.2g을 조금씩 천천히 가한 다음 3시간 동안 교반하였다(환원 반응). 얻어진 반응 혼합물에 물 5ml를 가한 다음, 감압하에서 용매를 제거하고, 잔류물에 에틸 아세테이트와 물을 가하였다. 유기층을 황산마그네슘으로 건조하고, 감압하에서 용매를 제거하고, 잔류물을 크로마토그래피하여 목적 화합물 6.56g을 얻었다(수율: 75.8%).15.2 g of dimethyl N- (2-t-butoxycarbonylacetyl) iminodiacetate prepared in Example 3 was dissolved in 150 ml of toluene, and then, in an ice bath 6.6 g of t-butoxylated portion was added in small portions for 1 hour and stirred for 7 hours (ring reaction). 50 ml of water was added to the reaction mixture, followed by vigorous stirring. The water layer was acidified with dilute hydrochloric acid and stirred for 3 hours (decarbonation reaction). The aqueous solution was extracted with ethyl acetate, dried over magnesium sulfate, the solvent was removed under reduced pressure, 50 ml of methanol was added to the residue, and 4.2 g of sodium hydride was slowly added slowly in an ice bath, followed by stirring for 3 hours (reduction reaction). 5 ml of water was added to the obtained reaction mixture, the solvent was removed under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer was dried over magnesium sulfate, the solvent was removed under reduced pressure, and the residue was chromatographed to give 6.56 g of the target compound (yield: 75.8%).
H1-NMR(CDCl3): δ2.42(1H, d x d), 2.75(1H, d x d), 3.05(1H, br s), 3.38(1H, d x d), 3.78(3H, s), 3.80(2H, ABx), 4.19(2H, ABq), 4.53(1H, m)H 1 -NMR (CDCl 3 ): δ 2.42 (1H, dxd), 2.75 (1H, dxd), 3.05 (1H, br s), 3.38 (1H, dxd), 3.78 (3H, s), 3.80 (2H , ABx), 4.19 (2H, ABq), 4.53 (1H, m)
실시예 6 : 1-카바모일메틸-4-히드록시-2-옥소피롤리딘(화합물 1)의 제조Example 6: Preparation of 1-carbamoylmethyl-4-hydroxy-2-oxopyrrolidine (Compound 1)
상기 실시예 4에서 제조된 1-에톡시카보닐메틸-4-히드록시-2-피롤리돈 9.4g을 메탄올 60 ml에 녹이고, 이 용액을 -10℃에서 암모니아로 포화시켜 실온에서 10시간 동안 정치시켰다. 반응 혼합물을 감압 증발시켜 얻은 고체를 메탄올 30ml에 녹이고, 디이소프로필 에테르를 천천히 적가하여 재결정화하여 목적 화합물 7.83g을 얻었다(수율: 99.1%).9.4 g of 1-ethoxycarbonylmethyl-4-hydroxy-2-pyrrolidone prepared in Example 4 was dissolved in 60 ml of methanol, and the solution was saturated with ammonia at −10 ° C. for 10 hours at room temperature. Let it stand. The reaction mixture was evaporated under reduced pressure, and the solid obtained was dissolved in 30 ml of methanol, and diisopropyl ether was slowly added dropwise to recrystallize to obtain 7.83 g of the target compound (yield: 99.1%).
H1-NMR(DMSO-d6): δ2.07(1H, d), 2.54(1H, d x d), 3.14(1H, d), 3.61(1H, d), 3.78(2H, ABq), 4.28(1H, m), 5.21(1H, br s), 7.10(1H, br s), 7.30(1H, br s)H 1 -NMR (DMSO-d 6 ): δ 2.07 (1H, d), 2.54 (1H, dxd), 3.14 (1H, d), 3.61 (1H, d), 3.78 (2H, ABq), 4.28 ( 1 H, m), 5.21 (1 H, br s), 7.10 (1 H, br s), 7.30 (1 H, br s)
실시예 7 : 1-카바모일메틸-4-히드록시-2-옥소피롤리딘(화합물 1)의 제조Example 7: Preparation of 1-carbamoylmethyl-4-hydroxy-2-oxopyrrolidine (Compound 1)
상기 실시예 5에서 제조된 1-메톡시카보닐메틸-4-히드록시-2-피롤리돈 8.66g을 메탄올 50ml에 녹이고, 이 용액을 -10℃에서 암모니아로 포화시켜 실온에서 10시간 동안 정치시켰다. 반응 혼합물을 감압 증발시켜 얻은 고체를 메탄올 30ml에 녹이고, 얼음중탕에서 천천히 냉각시켜 흰색 고체의 목적 화합물 7.87g을 얻었다(수율: 99.6%).8.66 g of 1-methoxycarbonylmethyl-4-hydroxy-2-pyrrolidone prepared in Example 5 was dissolved in 50 ml of methanol, and the solution was saturated with ammonia at −10 ° C. and left at room temperature for 10 hours. I was. The reaction mixture was evaporated under reduced pressure, and the solid was dissolved in 30 ml of methanol, and cooled slowly in an ice bath to give 7.87 g of the target compound as a white solid (yield: 99.6%).
H1-NMR(DMSO-d6): δ2.07(1H, d), 2.54(1H, d x d), 3.14(1H, d), 3.61(1H, d), 3.78(2H, ABq), 4.28(1H, m), 5.21(1H, br s), 7.10(1H, br s), 7.30(1H, br s)H 1 -NMR (DMSO-d 6 ): δ 2.07 (1H, d), 2.54 (1H, dxd), 3.14 (1H, d), 3.61 (1H, d), 3.78 (2H, ABq), 4.28 ( 1 H, m), 5.21 (1 H, br s), 7.10 (1 H, br s), 7.30 (1 H, br s)
비교예 : 1-카바모일메틸-4-히드록시-2-옥소피롤리딘(화합물 1)의 제조(미국 특허 제4,118,396호에 따른 방법)Comparative Example: Preparation of 1-carbamoylmethyl-4-hydroxy-2-oxopyrrolidine (Compound 1) (method according to US Pat. No. 4,118,396)
무수 벤젠 500ml에 디에틸 N-(2-t-에톡시카보닐아세틸)이미노디아세테이트 30.3g을 녹인 용액에, 에탄올 90ml에 나트륨 2.53g을 녹여 제조한 용액을 실온에서 가하고 6시간 동안 환류교반하였다. 반응 혼합물을 냉각시켜 물로 추출한 다음, 얻어진 추출액에 염산을 가해 pH 1로 산성화하여 고체 11.2g을 얻었다(고리화 반응). 얻어진 고체를 아세토니트릴 110ml와 물 1ml의 혼합 용매에 넣고, 20분 동안 환류교반한 후 감압하에서 용매를 제거하였다(탈탄산 반응). 이어, 잔류물에 무수 디메톡시에탄 200ml를 가하고 0℃에서 수소화붕소나트륨 0.8g을 가한 다음, 얼음중탕에서 10분간, 실온에서 30분간 정치하였다(환원 반응). 얻어진 반응 혼합물을20% 염산으로 산성화한 다음, 감압하에서 용매를 제거하였다. 잔류물을 염화메틸렌에 녹인 후, 무수 황산마그네슘으로 건조하여 용매를 감압증발시키고, 크로마토그래피하여 목적 화합물 7.19g을 얻었다(수율: 38.4%).To a solution of 30.3 g of diethyl N- (2-t-ethoxycarbonylacetyl) iminodiacetate in 500 ml of anhydrous benzene, a solution prepared by dissolving 2.53 g of sodium in 90 ml of ethanol was added at room temperature and stirred under reflux for 6 hours. . The reaction mixture was cooled and extracted with water. Then, hydrochloric acid was added to the obtained extract and acidified to pH 1 to obtain 11.2 g of a solid (ring reaction). The obtained solid was put into the mixed solvent of 110 ml of acetonitrile and 1 ml of water, and stirred under reflux for 20 minutes, and then the solvent was removed under reduced pressure (decarbonation reaction). Then, 200 ml of anhydrous dimethoxyethane was added to the residue, 0.8 g of sodium borohydride was added at 0 ° C, and then allowed to stand for 10 minutes in an ice bath and 30 minutes at room temperature (reduction reaction). The reaction mixture obtained was acidified with 20% hydrochloric acid and then the solvent was removed under reduced pressure. The residue was dissolved in methylene chloride, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and chromatographed to give 7.19 g of the target compound (yield: 38.4%).
H1-NMR(CDCl3): δ1.28(3H, t), 2.41(1H, d x d), 2.78(1H, d x d), 3.09(1H, d), 3.38(1H, d x d), 3.80(1H, ABx), 4.10(2H, ABq), 4.19(2H, q), 4.52(2H, m)H 1 -NMR (CDCl 3 ): δ 1.28 (3H, t), 2.41 (1H, dxd), 2.78 (1H, dxd), 3.09 (1H, d), 3.38 (1H, dxd), 3.80 (1H, ABx), 4.10 (2H, ABq), 4.19 (2H, q), 4.52 (2H, m)
본 발명의 방법에 따르면, 기존 방법에 비해 옥시라세탐을 고순도 및 고수율로 간편하게 제조할 수 있다.According to the method of the present invention, oxyracetam can be easily prepared in high purity and high yield as compared to the existing method.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2001-0073696A KR100424393B1 (en) | 2001-11-26 | 2001-11-26 | Process for the preparation of oxiracetam |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2001-0073696A KR100424393B1 (en) | 2001-11-26 | 2001-11-26 | Process for the preparation of oxiracetam |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20030042883A KR20030042883A (en) | 2003-06-02 |
| KR100424393B1 true KR100424393B1 (en) | 2004-03-24 |
Family
ID=29571313
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR10-2001-0073696A KR100424393B1 (en) | 2001-11-26 | 2001-11-26 | Process for the preparation of oxiracetam |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR100424393B1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4331579A1 (en) * | 2021-04-26 | 2024-03-06 | KSB Tugen Inc. | Composition comprising oxiracetam for preventing or treating muscular disease |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4173569A (en) * | 1977-02-11 | 1979-11-06 | I.S.F. Spa | Preparation of pyrrolidine and pyrrolidin-2-one derivatives |
| EP0154490A2 (en) * | 1984-02-27 | 1985-09-11 | I.S.F. Socièta per Azioni | Process for the preparation of pyrrolidone derivatives |
| JPS62286964A (en) * | 1986-06-03 | 1987-12-12 | Denki Kagaku Kogyo Kk | Production of oxiracetam |
| KR20000009465A (en) * | 1998-07-24 | 2000-02-15 | 박영구 | Process for preparing (s)-oxylacetam having optical activities |
-
2001
- 2001-11-26 KR KR10-2001-0073696A patent/KR100424393B1/en not_active IP Right Cessation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4173569A (en) * | 1977-02-11 | 1979-11-06 | I.S.F. Spa | Preparation of pyrrolidine and pyrrolidin-2-one derivatives |
| EP0154490A2 (en) * | 1984-02-27 | 1985-09-11 | I.S.F. Socièta per Azioni | Process for the preparation of pyrrolidone derivatives |
| JPS62286964A (en) * | 1986-06-03 | 1987-12-12 | Denki Kagaku Kogyo Kk | Production of oxiracetam |
| KR20000009465A (en) * | 1998-07-24 | 2000-02-15 | 박영구 | Process for preparing (s)-oxylacetam having optical activities |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20030042883A (en) | 2003-06-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2397164C2 (en) | INTERMEDIATE COMPOUNDS FOR SYNTHESIS OF TRANS-5-CHLORO-2-METHYL-2,3,3a,12b-TETRAHYDRO-1H-DIBENZ[2,3:6,7]-OXEPINO[4,5-c]PYRROLE | |
| JP4108130B2 (en) | Stereoselective production method of 4-acetoxyazetidinone | |
| CZ292123B6 (en) | Process for preparing mofetil mycophenolate | |
| JP2003506425A (en) | Method for producing nitroxyalkyl ester of naproxen | |
| JP2010510253A (en) | Novel process for the preparation of 4,4 '-(1-methyl-1,2-ethanediyl) -bis- (2,6-piperazinedione) | |
| KR20080030692A (en) | Process for preparing 3-acylaminobenzofuran-2-carboxylic acid derivative | |
| KR100424393B1 (en) | Process for the preparation of oxiracetam | |
| KR101063146B1 (en) | Method for preparing pitavastatin intermediate and method for preparing pitavastatin hemicalcium salt | |
| JP4783998B2 (en) | Preparation of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid | |
| EA000122B1 (en) | Aminotetralone derivatives and process for producing the same | |
| GB2036744A (en) | Eburnane derivatives | |
| JP3166017B2 (en) | Method for producing alkyl tetronate | |
| KR102218320B1 (en) | Method of preparing(3r,5r)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxymethylphenylamino)carbonyl)-pyrrol-1-yl)-3,5-dihydroxy-heptanoic acid hemi calcium salt, and method of preparing intermediates used therein | |
| JP2769058B2 (en) | Preparation of cyclopropane derivatives | |
| KR100856133B1 (en) | Improved process for preparing atorvastatin | |
| JP2771257B2 (en) | Preparation of imidazole derivatives | |
| KR100413172B1 (en) | A process for the preparation of quinolinone derivatives | |
| US5344942A (en) | Reagents for racmate resolution | |
| KR20050056252A (en) | Process for making spirolactone compounds | |
| KR101086039B1 (en) | Novel process for preparing 3,4-dihydro-pyrano[3,4-c]pyridin-1-one derivatives | |
| KR950013852B1 (en) | Process for preparing 4-ethoxycarbonyl-1-methyl-5-pyrazole mercaptan | |
| WO2022075347A1 (en) | Method for producing octahydrothienoquinoline compound, and production intermediate of same | |
| JP3283959B2 (en) | D-biotin intermediate and method for producing the same | |
| KR900004909B1 (en) | Preparation for dehydro -3-methyl -1,4-oxathine derivatives | |
| JPH0667942B2 (en) | Tetrahydro tricyclic compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| FPAY | Annual fee payment |
Payment date: 20100104 Year of fee payment: 7 |
|
| LAPS | Lapse due to unpaid annual fee |