KR100461859B1 - The manufacturing method of Oxiracetam - Google Patents
The manufacturing method of Oxiracetam Download PDFInfo
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- KR100461859B1 KR100461859B1 KR10-2002-0022150A KR20020022150A KR100461859B1 KR 100461859 B1 KR100461859 B1 KR 100461859B1 KR 20020022150 A KR20020022150 A KR 20020022150A KR 100461859 B1 KR100461859 B1 KR 100461859B1
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Abstract
본 발명은 옥시라세탐의 제조방법에 관한 것으로서, 더욱 상세하게는 비닐 아세트산과 글리신 에틸 에스테르를 출발물질로 하여 에폭시 화합물을 중간물질로 합성하는 과정을 거치도록 한 것으로, 상온 중에서 매우 완만한 반응조건 하에 고수율로 옥시라세탐을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing oxyracetam, and more particularly, to a process of synthesizing an epoxy compound into an intermediate material using vinyl acetic acid and glycine ethyl ester as starting materials, and very gentle reaction conditions at room temperature. To a process for the preparation of oxyracetam in high yield.
Description
본 발명은 옥시라세탐(Oxiracetam)의 제조방법에 관한 것으로서, 더욱 상세하게는 뇌혈관 질환, 노인성 치매 등에 효과가 있는 것으로 밝혀진 옥시라세탐을 공업적 측면에서 매우 간편하고 고효율로 생산할 수 있는 제조방법에 관한 것이다.The present invention relates to a method for producing oxyracetam (Oxiracetam), more specifically, a manufacturing method that can be produced in a very simple and highly efficient manner in the industrial aspect of oxyracetam found to be effective in cerebrovascular disease, senile dementia, etc. It is about.
옥시라세탐은 뇌 대사기능 촉진제로서 뇌신경 세포막을 안정화시키고, 뇌 내의 ATP 유효율을 증가시키며 콜린성 신경전달을 촉진하여 뇌 대사 기능을 개선해주는 물질이다.Oxyracetam is a brain metabolic promoter that stabilizes neuronal cell membranes, increases the rate of ATP in the brain, and promotes cholinergic neurotransmission, thereby improving brain metabolism.
이러한 기능을 가진 옥시라세탐은 현재 여러 가지의 임상적 용도로 활용되고 있는데, 주로 뇌혈관 질환, 뇌손상 등 뇌기능 부전으로 인한 뇌증후군에 사용되거나 뇌의 인식기능, 기억력, 주의집중력, 언어행동력 등의 개선을 목적으로 사용되며, 또한 노인성 치매에도 효과가 있는 것으로 알려져 있다.Oxyracetam with this function is currently used in various clinical uses, mainly used in brain syndrome due to brain dysfunction such as cerebrovascular disease, brain injury, or brain cognitive function, memory, attention concentration, verbal behavior It is used for the purpose of improving the back and is also known to be effective for senile dementia.
현재까지 본 화합물의 합성법으로서 여러 가지 방법이 알려져 있는데, 그중대표적인 방법으로서 에틸이미노디아세테이트(ethyliminodiacetate)와 에톡시카보닐아세틸 클로라이드(ethoxycarbonylacetyl chloride)를 출발물질로 사용하는 방법(USP No, 4118396), 감마-아미노-베타-하이드록시부티릭 애시드(r-amino-b-hydroxybutyric acid)를 출발물질로 사용하는 방법(Italian Patent 20227A), 글리신아미드(glycinamide)와 3,4-에폭시부티릭 애시드 에스테르(3,4-epoxybutyric acid ester)를 출발물질로 사용하는 방법(Italian Patent 19802A) 및 최근의 감마-클로로-베타-하이드럭시 부티릭 애시드(r-chloro-b-hydroxy butyric acid) 유도체와 글리신아미드(glycinamide)를 축합시키는 방법(European Patent 223328A) 등이 보고돼 있다.To date, various methods have been known for synthesizing the present compounds, among which ethyliminodiacetate and ethoxycarbonylacetyl chloride are used as starting materials (USP No, 4118396), Method of using gamma-amino-beta-hydroxybutyric acid (r-amino-b-hydroxybutyric acid) as a starting material (Italian Patent 20227A), glycinamide (glycinamide) and 3,4-epoxybutyric acid ester ( 3,4-epoxybutyric acid ester) as a starting material (Italian Patent 19802A) and recent gamma-chloro-beta-hydroxy butyric acid derivatives and glycineamides (Glycinamide) condensation method (European Patent 223328A) and the like have been reported.
그러나 상기와 같은 합성방법은, 출발물질의 확보가 어렵고 반응조작이 까다로우며 수율이 낮고 가열조작 등으로 인하여 제조공정상 특별한 장치가 필요하다는 점 등, 공업적 제법으로서는 개선되어야 할 단점을 가지고 있다.However, the synthesis method as described above has disadvantages that need to be improved as an industrial production method, such that it is difficult to secure starting materials, the reaction operation is difficult, the yield is low, and special equipment is required in the manufacturing process due to the heating operation.
본 발명은 상기한 문제점을 해결하기 위하여 안출된 것으로서, 본 발명의 목적은 종래 방법이 갖는 단점을 보완하여 저렴한 출발물질인 비닐아세트산(vinylacetic acid)과 글리신 에틸 에스테르(ethyl glycinate)를 출발물질로 하고, 각각의 단계가 상온에서 진행되며, 구하기 쉽고 공업적으로 흔하게 사용되는 시약을 사용하고, 또한 회수가 가능한 반응 용매를 이용함으로써, 고수율로 반응이 진행되어 공업적인 측면에서 경제성이 있는 옥시라세텀의 합성경로를 제공하기 위한 것이다.The present invention has been made to solve the above problems, the object of the present invention is to compensate for the disadvantages of the conventional method as a starting material, vinyl acetate (vinylacetic acid) and glycine ethyl ester (ethyl glycinate) as an inexpensive starting material Each step is carried out at room temperature, by using a reagent which is easy to obtain and commonly used industrially, and by using a reaction solvent that can be recovered. To provide a synthetic route of the.
도 1은 본 발명에 따른 옥시라세탐의 제조공정을 도시한 도면.1 is a view showing a manufacturing process of the oxyracetam according to the present invention.
상기한 목적을 달성하기 위한 본 발명에 따른 제조방법은 도 1과 같은 과정을 거쳐 옥시라세탐을 제조하는 것을 특징으로 한다.The production method according to the present invention for achieving the above object is characterized in that to prepare the oxyracetam through the same process as in FIG.
즉, 비닐 아세트산(1)을 원료 물질로 하여 글리신 에틸 에스테르와 축합한 후, 에폭시화를 시켜 3과 같은 에폭시 화합물(3)을 합성한 후, 염기를 첨가하여 고리화 반응을 거쳐 5각형 환(4)을 형성하고, 최종적으로 암모니아수를 이용하여 옥시라세탐(5)을 합성한다.That is, after condensation with glycine ethyl ester using vinyl acetic acid (1) as a raw material, epoxidation is performed to synthesize an epoxy compound (3) such as 3, and then a base is added to undergo a cyclization reaction to give a pentagonal ring ( 4) is formed, and finally, the oxyracetam (5) is synthesized using ammonia water.
상기 과정들은 모두 상온에서, 구하기 쉬운 시약을 이용하여 반응되며, 각 단계 모두 고수율로 진행된다.The above processes are all reacted at room temperature using easy to obtain reagents, and each step proceeds in high yield.
본 제조방법에 따른 제조과정 중 화합물 2(3-bytenoylamino-acetic ethyl ester)의 합성과정은, 트리에틸아민(triethylamine)의 양을 1.2당량(eq)에서 2당량 정도로 변화시키면서 반응을 진행하여 본 결과, 약 2당량을 사용하였을 경우 TLC(박층 크로마토그래피) 상에서 가장 양호하게 반응이 진행되는 것으로 나타났다.Synthesis of compound 2 (3-bytenoylamino-acetic ethyl ester) during the preparation process according to the present method was carried out by changing the amount of triethylamine from 1.2 equivalents (eq) to about 2 equivalents. The reaction proceeded best on TLC (thin layer chromatography) when about 2 equivalents were used.
본 반응은 트리에틸아민 외에 다른 3급 아민이나, 피리딘 및 기타 염기의 사용이 가능하다. 또한 비닐 아세틸 클로라이드(Vinyl acetyl Chloride) 및 글리신 유도체와의 직접 축합 반응으로도 합성이 가능하다.In addition to triethylamine, this reaction may use other tertiary amines, but also pyridine and other bases. It can also be synthesized by direct condensation reaction with vinyl acetyl chloride and glycine derivatives.
또한 화합물 3의 제조과정은 반응 용매를 클로로포름(Chloroform)이나 메틸렌 클로라이드(methylene chloride, CH2Cl2)로 하는 경우 모두에서 별반 차이 없이 양호하게 반응이 진행되었으며, 반응온도를 환류(reflux)시켰을 경우 5시간 이내에서 반응이 완결되었으나 박층 크로마토그래피 상에서 다소 부반응이 진행되는 것으로 나타났다. 또한 본 에폭시화 반응은 메타클로로퍼벤조익 애시드(meta-chloroperbenzoic acid, MCPBA) 외에 HO-X(X: 할로겐 원소), 고사산화 수소 등 에폭시화 반응에 이용되는 여타 시약을 사용하여도 합성이 가능하다.In addition, the process of preparing compound 3 was performed well without any difference in the case of using chloroform or methylene chloride (CH 2 Cl 2 ) as a reaction solvent, and when the reaction temperature was refluxed. The reaction was completed within 5 hours, but some side reactions were observed in thin layer chromatography. In addition, the epoxidation reaction can be synthesized using meta-chloroperbenzoic acid (MCPBA) as well as other reagents used for the epoxidation reaction such as HO-X (X: halogen element) and high hydrogen tetraoxide. Do.
4번 화합물의 제조과정에서는, 사용되는 수소화나트륨(Sodium hydride, NaH)의 양을 1당량(eq)에서 2당량(eq)으로, 반응시간을 4시간에서 10시간 정도로 조건을 바꾸어 반응을 진행하여 보았으나, 별반 반응의 차이를 보이지 않음을 알 수 있었다. 또한 본 과정은 수소화나트륨(Sodium hydride) 외에 탄산나트륨(Sodium carbonate) 등 여타 염기를 이용하여도 목적 화합물의 합성이 가능하다.In the preparation process of compound 4, the reaction was performed by changing the amount of sodium hydride (NaH) used from 1 equivalent (eq) to 2 equivalents (eq) and changing the reaction time from 4 hours to 10 hours. It was found, but did not show a difference in response. In addition, the present process can be synthesized using other bases such as sodium carbonate in addition to sodium hydride.
5번 화합물의 합성과정에서 사용되는 암모니아수의 양을 바꾸어 반응을 진행시켜 본 결과, 약 10배 정도의 암모니아수를 사용할 경우 비교적 양호하게 반응이 진행되는 것으로 나타났다.When the reaction proceeded by changing the amount of ammonia water used in the synthesis of compound 5, it was found that the reaction proceeded relatively well when using about 10 times of ammonia water.
본 제조방법은 타 방법과는 다르게 모든 반응이 상온에서 진행되며, 사용되는 시약도 매우 저렴한 시약이 사용되고, 전 반응공정의 수율도 박층 크로마토그래피 상에서 거의 부반응 없이 높은 수율로 진행되는 장점이 있어 매우 경제적인 제조공정이라고 할 수 있겠다.Unlike the other methods, all the reactions proceed at room temperature, and the reagents used are very inexpensive, and the yield of the entire reaction process is also very economical because it has a high yield with little side reaction on thin layer chromatography. Phosphorus manufacturing process.
본 반응의 실험예는 다음과 같다.The experimental example of this reaction is as follows.
1. 실험예 1 (화합물 2의 제조방법)Experimental Example 1 (Manufacturing Method of Compound 2)
글라이신 에틸에스테르 하이드로클로라이드(Glycine ethylester hydrochloride) 1.0당량을 약 10배(W/V)의 디엠에프(DMF, N,N-Dimethylformamide)에 현탁시키고, 그 용액에 비닐 아세트산(vinylacetic acid) 1.2당량, 디에틸포스포로시아니데이트(DEPC, diethyphosphorocyanidate) 1.2당량과 트리에틸아민(triethylamine) 2당량을 계속하여 주입한 후, 상온에서 7시간 정도 교반한다. 반응이 끝난 후 반응용액을 반응액의 약 10배 정도의 에틸아세테이트(ethylacetate)에 희석하고, 에틸아세테이트 용액을 전체 용액의 약 10분의 1정도의 물, 10%의 염산(Hydrochloric acid) 수용액, 10%의 중조(Sodium Bicarbonate) 수용액과 포화 식염수로 각각 2회씩 세척한 후 감압 증발시켜 오일상의 목적화합물 2를 얻는다.1.0 equivalent of glycine ethylester hydrochloride is suspended in about 10 times (W / V) of DMF (N, N-Dimethylformamide), and 1.2 equivalents of vinyl acetic acid (vinylacetic acid) in the solution 1.2 equivalent of ethylphosphorocyanidate (DEPC) and 2 equivalents of triethylamine were continuously added, followed by stirring at room temperature for 7 hours. After the reaction, the reaction solution is diluted with about 10 times ethylacetate, and the ethyl acetate solution is about one tenth of the total water, 10% aqueous hydrochloric acid solution, After washing twice with 10% aqueous sodium bicarbonate solution and saturated brine, and evaporating under reduced pressure to obtain the desired compound 2 as an oil.
이때 수율은 70-95%로 나타났다.Yield was 70-95%.
적외선분광계(케이비알법)[IR-KBr법) cm-1:Infrared spectrometer (cabby method) [IR-KBr method) cm-1:
1650(CO, amide), 1750(CO, ester), 3100(C-H, ethylene), 3300(NH)1650 (CO, amide), 1750 (CO, ester), 3100 (C-H, ethylene), 3300 (NH)
2. 실험예 2 (화합물 2의 제조방법)2. Experimental Example 2 (Manufacturing Method of Compound 2)
염산글라이신 에틸에스테르(Glycine ethylester hydrochloride) 1.0 당량을약 10배(W/V)의 메틸렌 클로라이드(methylene chloride)에 현탁시키고, 그 용액에 비닐아세트산(vinylacetic acid) 1.2 당량, 디사이클로헥실카보디이미드(DCC, dicyclohexylcarbodiimide) 1.2 당량과 트리에틸아민(triethylamine) 2.0 당량을 계속하여 주입한 후, 상온에서 3시간 정도 교반한다. 반응이 끝난 후 반응용액을 전체 용액의 약 10분의 1정도의 물, 10%의 염산 수용액, 10%의 중조 수용액과 포화 식염수로 각각 2회씩 세척한 후 감압 증발시켜 오일상의 목적화합물 2를 얻는다.1.0 equivalent of glycine ethylester hydrochloride was suspended in about 10 times (W / V) of methylene chloride, and 1.2 equivalent of vinylyacetic acid and dicyclohexylcarbodiimide were dissolved in the solution. 1.2 equivalents of dicyclohexylcarbodiimide (DCC) and 2.0 equivalents of triethylamine are continuously added, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction solution was washed twice with about one tenth of water, 10% aqueous hydrochloric acid solution, 10% aqueous sodium bicarbonate solution and saturated brine, and evaporated under reduced pressure to obtain the target compound 2 as an oil. .
이때 수율은 80-95%로 나타났다.Yield was 80-95%.
3. 실험예 3 (화합물 3의 제조방법)3. Experimental Example 3 (Manufacturing Method of Compound 3)
실험예 1 또는 2의 제조방법으로 합성된 화합물 2를 약 10배의 메틸렌 클로라이드(methylene chloride) 혹은 클로로포름(chloroform)에 녹인 후, 메타클로로퍼벤조익 애시드(meta-chloroperbenzoic acid, 1.2 당량)의 메틸렌 클로라이드(methylene chloride) 용액(10%, w/v)을 주입한 후 상온에서 약 10시간 정도 교반한다. 박층 크로마토그래피 상에서 출발물질이 소실됨을 확인한 후 10%의 아황산수소나트륨(sodium bisulfite) 수용액, 10% 중조 수용액, 포화 식염수로 각각 2회씩 세척한 후 감압 증발시켜 목적화합물 3을 얻는다.Compound 2 synthesized by the preparation method of Experimental Example 1 or 2 was dissolved in about 10-fold methylene chloride or chloroform, and then methylene of meta-chloroperbenzoic acid (1.2 equivalents). Chloride (methylene chloride) solution (10%, w / v) is injected and stirred at room temperature for about 10 hours. After confirming the disappearance of the starting material in thin layer chromatography, 10% aqueous sodium bisulfite solution, 10% aqueous sodium bicarbonate solution, and two times washed with saturated brine, and then evaporated under reduced pressure to obtain the target compound 3.
이때의 수율은 정량적으로 나온다.Yield at this time is quantitative.
이 화합물의 융점(녹는점)은 156-158℃이다.Melting | fusing point (melting point) of this compound is 156-158 degreeC.
적외분광계(케이비알법)[IR-KBr법]cm-1:Infrared spectrometer (Cavial method) [IR-KBr method] cm-1:
1650(CO, amide), 1750(CO, ester), 3300(NH)1650 (CO, amide), 1750 (CO, ester), 3300 (NH)
1HNMR(DMSO-d6) δ : 1.15(CH3, t, J=7.5Hz), 2.20-2.50(5H, m), 2.50-2.62(1H, m), 3.40-3.60(1H, br), 4.10(2H, q, J=7.5Hz), 8.18-8.25(1H, br.)1 HNMR (DMSO-d6) δ: 1.15 (CH3, t, J = 7.5 Hz), 2.20-2.50 (5H, m), 2.50-2.62 (1H, m), 3.40-3.60 (1H, br), 4.10 (2H , q, J = 7.5 Hz), 8.18-8.25 (1H, br.)
4. 실험예 4 (화합물 4의 제조방법)4. Experimental Example 4 (Manufacturing Method of Compound 4)
실험예 2의 제조방법으로 제조한 3 화합물의 약 1.2 당량의 수소화나트륨(Sodium hydride)을 반응용기에 넣은 후, 소량의 벤젠으로 수소화나트륨을 세척하고, 아세토니트릴(acetonitrile)을 주입하여 약 10%의 현탁액으로 만들고, 그 용액에 3 화합물의 10% 아세토니트릴(acetonitrile) 용액을 주입한 후 상온에서 6시간 정도 교반한다. 반응이 끝난 후 5%의 염산(hydrochloric acid) 수용액으로 산성화시키고 감압 증발시켜 잔유물을 얻고, 다시 그 잔유물을 10배 정도의 아세토니트릴(acetonitrile)에 현탁시킨 후 여과하여 감압증발시켜 목적 화합물 4를 오일상으로 얻었다.About 1.2 equivalents of sodium hydride of 3 compounds prepared by the preparation method of Experimental Example 2 were added to the reaction vessel, followed by washing with sodium hydride with a small amount of benzene, followed by injection of acetonitrile (acetonitrile). It is made into a suspension of, and the solution is injected with a 10% acetonitrile solution of 3 compounds, followed by stirring at room temperature for about 6 hours. After the reaction, the mixture was acidified with 5% hydrochloric acid aqueous solution and evaporated under reduced pressure to obtain a residue. The residue was suspended in about 10 times acetonitrile, filtered and evaporated under reduced pressure to give the desired compound 4. Got it everyday.
이때 수율은 약 70-85%로 나타났다.The yield was about 70-85%.
적외분광계(니트법)[IR-neat법]cm-1:Infrared spectrometer (knit method) [IR-neat method] cm-1:
1680(CO, r-lactam), 1730(CO, ester), 3250(OH)1680 (CO, r-lactam), 1730 (CO, ester), 3250 (OH)
5. 실험예 5 (화합물 4의 제조방법)5. Experimental Example 5 (Manufacturing Method of Compound 4)
실험예 2의 제조방법으로 제조한 3 화합물의 약 1.2 당량의 수소화나트륨을반응용기에 넣은 후, 소량의 벤젠으로 수소화나트륨을 세척하고, 아세토니트릴(acetonitrile)을 주입하여 약 10%의 현탁액으로 만들고, 그 용액에 3 화합물의 10% 아세토니트릴(acetonitrile) 용액을 주입한 후 상온에서 6시간 정도 교반한다. 반응이 끝난 후 초산(acetic acid)을 사용하여 중화시키고 감압 증발시켜 잔유물을 얻고, 다시 그 잔유물을 10배 정도의 아세토니트릴(acetonitrile)에 현탁시킨 후 여과하여 감압증발시켜 목적 화합물 4를 오일상으로 얻었다.About 1.2 equivalents of sodium hydride of the three compounds prepared by the preparation method of Experimental Example 2 were added to the reaction vessel, and sodium hydride was washed with a small amount of benzene, and acetonitrile was injected to make a suspension of about 10%. After injecting 10% acetonitrile solution of 3 compounds into the solution, the mixture was stirred at room temperature for about 6 hours. After the reaction was neutralized with acetic acid and evaporated under reduced pressure to obtain a residue. The residue was suspended in about 10 times acetonitrile, filtered and evaporated under reduced pressure to give the desired compound 4 as an oil phase. Got it.
이때 수율은 약 75-85 %로 나타났다.The yield was about 75-85%.
6. 실험예 6 (화합물 5의 제조방법)6. Experimental Example 6 (Preparation method of compound 5)
실험예 3의 방법으로 얻은 화합물을 약 10배의 암모니아수에 녹인 후 상온에서 5시간 정도 교반하여 박층 크로마토그래피 상에서 출발물질이 소실됨을 확인한 후, 감압 증발시켜 조생성물을 얻는다. 생성된 조생성물을 소량의 메탄올(methanol)에 용해시킨 후 냉장고에 하루 정도 방치하여 고체를 얻는다(옥시라세탐). 본 실험에서 얻어진 화합물은 표준품과 박층 크로마토그래피(클로로포름 : 메탄올 = 1 : 1)상에서 같은 전개양상(Rf값, rate flow value)을 보였다.After dissolving the compound obtained by the method of Experimental Example 3 in about 10 times of ammonia water and stirred for about 5 hours at room temperature to confirm that the starting material is lost on thin layer chromatography, the crude product is obtained by evaporation under reduced pressure. The resulting crude product is dissolved in a small amount of methanol and left in the refrigerator for about one day to obtain a solid (oxyracetam). The compound obtained in this experiment showed the same development pattern (Rf value, rate flow value) on standard product and thin layer chromatography (chloroform: methanol = 1: 1).
이때 수율은 65-75%로 나타났다.Yield was 65-75%.
이 화합물(옥시라세탐)의 융점은 165-172℃이다. (lit. : 161-163℃)Melting | fusing point of this compound (oxyracetam) is 165-172 degreeC. (lit.:161-163℃)
적외분광계(케이비알법)[IR-KBr법]cm-1:Infrared spectrometer (Cavial method) [IR-KBr method] cm-1:
1650(C=O, lactam), 3200, 3250 (N-H), 3300(OH)1650 (C = O, lactam), 3200, 3250 (N-H), 3300 (OH)
1H NMR(DMSO-d6) δ : 2.33(2H, m), 3.46(2H, m), 3.90(2H, m), 4.50(1H, m), 7.10-7.40(2H, br)1 H NMR (DMSO-d6) δ: 2.33 (2H, m), 3.46 (2H, m), 3.90 (2H, m), 4.50 (1H, m), 7.10-7.40 (2H, br)
상기 실험예에서 보듯이 본 반응공정은 여타 반응공정과는 달리 모든 공정이 상온에서 진행되므로 공업적 생산측면에서 타 방법에 비해 매우 간편한 방법이다. 또한 사용되는 출발물질, 시약 및 반응 용매도 공업적으로 경제적인 물질들로 사용되었으며 특히 매 공정의 수율이 높고, 여타 부반응 없이 반응이 진행되므로 중간과정에서 특별한 정제과정 없이 전 공정을 진행할 수 있어 매우 효율적이며 경제적인 공업적 제조방법이다.As shown in the experimental example, this reaction process is very simple compared to other methods in terms of industrial production because all processes proceed at room temperature unlike other reaction processes. In addition, starting materials, reagents, and reaction solvents are used as industrially economical materials. In particular, the yield of each process is high, and the reaction proceeds without any side reactions. It is an efficient and economical industrial manufacturing method.
상기한 바와 같이 이루어진 본 발명에 따르면, 현재 뇌 관련 질환에 유용하게 사용되는 옥시라세탐을 매우 저렴하고 용이하게 합성하는 것이 가능해지므로, 관련 질환자를 저렴한 비용으로 치료할 수 있는 효과를 도모할 수 있다.According to the present invention made as described above, since it is possible to synthesize the oxacetam which is currently useful for brain-related diseases very cheaply and easily, it is possible to achieve the effect of treating the related diseases at low cost.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62185069A (en) * | 1986-02-07 | 1987-08-13 | Denki Kagaku Kogyo Kk | Production of oxiracetam |
| JPS62286964A (en) * | 1986-06-03 | 1987-12-12 | Denki Kagaku Kogyo Kk | Production of oxiracetam |
| JPS63132872A (en) * | 1986-11-25 | 1988-06-04 | Denki Kagaku Kogyo Kk | 4-hydroxy-2-oxo-1-pyrrolidineacetonitrile and production thereof |
| JPH03181458A (en) * | 1989-12-12 | 1991-08-07 | Kyowa Yuka Kk | Production of oxiracetam |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62185069A (en) * | 1986-02-07 | 1987-08-13 | Denki Kagaku Kogyo Kk | Production of oxiracetam |
| JPS62286964A (en) * | 1986-06-03 | 1987-12-12 | Denki Kagaku Kogyo Kk | Production of oxiracetam |
| JPS63132872A (en) * | 1986-11-25 | 1988-06-04 | Denki Kagaku Kogyo Kk | 4-hydroxy-2-oxo-1-pyrrolidineacetonitrile and production thereof |
| JPH03181458A (en) * | 1989-12-12 | 1991-08-07 | Kyowa Yuka Kk | Production of oxiracetam |
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