CN1020604C - 制备(S)-α-乙基-2-氧代-1-吡咯烷基乙酰胺的方法 - Google Patents
制备(S)-α-乙基-2-氧代-1-吡咯烷基乙酰胺的方法 Download PDFInfo
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- 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
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Abstract
于NaBH4/NiCl2·6H2O2,阮内镍W-2或优选阮内镍T-1之类脱硫剂存在下氢解(S)-α-(2-(甲硫基)乙基)-2-氧代-1-吡咯烷基乙酰胺制备(S)-α-乙基-2-氧代-1-吡咯烷基乙酰胺,此化合物可用于治疗和预防中枢神经系统氧不足和局部缺血型攻击行为。
Description
本发明涉及一种制备(S)-α-乙基-2-氧代-1-吡咯烷基乙酰胺的新方法,所说酰胺的结构式为
在4,696,943和4,837,223号美国专利中代表本申请人介绍了具有绝对S构型的上述化合物,并指出该化合物具有使之完全出乎意料的不同于外消旋形式的特殊治疗性能。正是由于这种性能,此S对映体比外消旋形式更适于治疗和预防中枢神经系统的供氧不足和局部缺血发作。
在上述美国专利(U.S.4,696,943和4,837,223)中披露了(S)-α-乙基-2-氧代-1-吡咯烷基乙酰胺的制备方法。根据这两份美国专利文献,此化合物不能采用分离该两种对映异构体的方法直接从其外消旋混合物中得到。制备此化合物必须采用其它方法,而且上述美国专利具体介绍了制备该化合物用的两种方法。第一种方法是,依次使(S)-
-乙基-2-氧代-1-吡咯烷基乙酸同卤代甲酸烷基酯(优选氯甲酸乙酯)和氨反应;第二种方法是,使(S)-4-〔〔1-(氨基羰基)丙基〕氨基〕丁酸烷基酯或(S)-N-〔1-(氨基羰基)丙基〕-4-卤丁酰胺环化,而此两种化合物本身是由(S)-2-氨基丁酰胺制备的。
此两种方法都有同样的缺点,都需要制备已经具有合适的立体化学构型的初始反应物。在上述的第一种方法中,这种初始反应物通过拆开相应的外消旋化合物(±)-α-乙基-2-氧代-1-吡咯烷基乙酸获得,而在第二种方法中,通过拆开外消旋化合物(±)-2-氨基-丁酰胺而得到。从相应的外消旋化合物中事先分离具有所需构型的对映异构体时必然从一开始就使所用原料损失50%。而且如果考虑到回收旋光异构体难于在定量产率下进行,则使原料的总损失远远大于初始外消旋化合物的50%。
因此急需一种无上述缺点而操作又相当容易的方法。
本发明提供了一种无前述方法弊端,因而又较经济的制备(S)-α-乙基-2-氧代-1-吡咯烷基乙酰胺用方法。而且这种新方法还有一个优点,即使用天然存在的氨基酸L-(蛋氨酸)或其容易获得的酰胺作为初始物料。
根据本发明的制备(S)-α-乙基-2-氧代-1-吡咯烷基乙酰用方法包括采用脱硫剂按下式对(S)-α-〔2-(甲甲硫基)乙基〕-2-氧代-1-吡咯烷基乙酰胺进行氢解。
(S)-α-〔2-(甲硫基)乙基〕-2-氧代-1-吡咯烷基乙酰胺的脱硫化反应是立体有择的。此反应一般在水中,50-100℃温度下,脱硫剂(例如NaBH4/NiCl2·6H2O(R.B BOAR等人,化学会志,Perkin译Ⅰ(1973年),654页),阮内镍W-2或优选阮内镍T-1)存在下,常压或加压下(X.DOMINGUEZ等人,有机化学杂志,26,(1961年)1625页)进行。
本方法中的初始化合物(S)-α-〔2-(甲硫基)乙基〕-2-氧代-1-吡咯烷基乙酰胺是一种新化合物。可采用下述两方法之一制备此化合物:
1)使(S)-2-氨基-4-(甲硫基)丁酰胺盐酸盐同4-卤丁酰卤HalCH2CH2CH2CoHal(其中Hal是卤原子,优选氯原子)按下式进行反应
此反应一般在惰性溶剂(如二氯甲烷)中,约0℃下,溴化四丁铵之类催化剂存在下和粉末氢氧化钾存在下进行。
2)a)先使(S)-2-氨基-4-(甲硫基)丁酰胺与4-卤丁酸烷基酯XCH2CH2CH2COOR(其中X为卤素原子,R是1-4个碳原子的烷基),按下式进行反应:
此反应一般利用在甲苯之类惰性溶剂中,有机叔碱(如三乙胺)之类酸受体存在下及在80-100℃温度下加热几小时的方式进行。
b)然后使a)步中制得的(S)-4-〔〔1-(氨基羰基)-3-(甲硫基)丙基〕氨基〕丁酸烷基酯按下式环化
此环化反应一般在甲苯或二甲苯之类惰性溶剂中,利用在100-130℃温度下和2-羟基吡啶之类催化剂存在下加热几小时的方法进行。
作为游离碱的(S)-2-氨基-4-(甲硫基)丁酰胺可以由L-蛋氨酸采用文献(E.SANDRIN和R.A.BOISSONNAS,Helv.Chim.Aeta,46,(1963),1637-1669)中介绍的方法加以制备。熔
点50-51℃,比旋光度(α)22 D=-27.7°(C=2,二甲基甲酰胺)。
可以用此碱作原料,按A.EBERLE等人在文献(Helv.Chim.Acta,61,(1978),2360-74)中所介绍的方法制备已知化合物(S)-2-氨基-4-(甲硫基)丁酰胺盐酸盐,熔点212~215℃,比旋光度[α]25 D=+26.4°(C=1,二甲基甲酰胺)。
下面的实施例旨在用于说明本发明。
在此实施例中,最终产品的旋光纯度是通过差示热函的量热法测定予以证实的(C.FOUQUEY和J.JACQUES,Tetrahedron,23,(1967),4009-19)。
实施例
Ⅰ.制备初始化合物(S)-α-(2-(甲硫基)乙基)-2-氧代-1-吡咯烷基乙酰胺。
1)以4-卤丁酰卤为原料
室温下把84克无水硫酸钠加到由92.25克(0.5摩尔)(S)-2-氨基-4-(甲硫基)丁酰胺和600毫升二氯甲烷配制和悬浮液中。将此混合物冷却到0℃后相继加入115克粉末氢氧化钾和溶有8.1克(0.025摩尔)溴化四丁铵的二氯甲烷(100毫升)溶液。于同一温度并快速搅拌下滴加含77.5克(0.55摩尔)4-氯丁酰氯的二氯甲烷(100毫升)溶液。加料期间同时加入550毫升二氯甲烷稀释此反应介质。0℃下搅拌2小时后向此混合物中加入29克粉末氢氧化钾。
反应进行四个半小时后,再加29克粉末氢氧化钾并于0℃继续搅拌1小时。然后用Hyflocel过滤此反应混合物,对滤液进行减压蒸发,残留物经氧化硅色谱(以二氯甲烷/甲醇/氨水∶95.5/4.5/0.2(V/V/V)混合物作为洗脱液)纯化得到白色粉状化合物(S)-α-(2-甲硫基)乙基)-2-氧代-1-吡咯烷基乙酰胺(66克),比旋光度(α)25 D=-39.1°(C=1,甲醇),产率61%。
对C9H16N2O2S的分析(%):
计算值:C 50.00 H 7.41 N 12.96
测量值:C 50.15 H 7.80 N 12.94
2)以4-卤丁酸烷基酯为原料
a)制备(S)-4-〔〔1-氨基羰基)-3-(甲硫基)丙基〕氨基〕丁酸乙酯
于由10克(68毫摩尔)(S)-2-氨基-4-(甲硫基)丁酰胺和100毫升甲苯配制的悬浮液中加入10.57毫升(76毫摩尔)三乙胺。快速搅拌下将此混合物加热到80-85℃并滴加13.26克(68毫摩尔)4-溴丁酸乙酯。维持此温度8小时,减压蒸发除去溶剂后,使残留物溶于100毫升二氯甲烷中。加热回流此混合物30分钟,趁热过滤,蒸干滤液得到的残留物经氧化硅色谱(乙酸乙酯/甲醇/氨水∶10/0.1/0.1(V/V/V)混合物作洗脱液)得到6.2克(S)-4-〔〔1-(氨基羰基)-3-(甲硫基)丙基〕氨基〕丁酸乙酯,比旋光度(α)25 436=-14.1°(C=1,甲醇),产率
35%。
此中间化合物不需进一步纯化直接用于最后的环化反应。
b)把a)步中得到的0.6克(2.29毫摩乐)粗产品和21.3毫克(0.225毫摩尔)2-羟基吡啶混合于1.15毫升对二甲苯中。在氮气氛中130℃下将此混合物加热4.5小时。冷却后在室温下将其搅拌30分钟。滤出形成的沉淀并用乙酸乙酯进行重结晶,得到0.18克(S)-α-〔(2-甲硫基)乙基〕-2-氧代-1-吡咯烷基乙酰胺,比旋光度(α)25 D=-36.5°(C=1,甲醇),产率36%。
对C9H16N2O2S的分析(%)。
计算值:C 50.00 H 7.41 N 12.96
测量值:C 49.88 H 7.49 N 12.68
Ⅱ.制备(S)-α-乙基-2-氧代-1-吡咯烷基乙酰胺
于一升三颈园底烧瓶中相继加入50克阮内镍T-1(X.A.DOMINGUEZ等人,有机化学杂志26,(1961年),1625页),386毫升水和7克(0.0324摩尔)(S)-α-〔2-(甲硫基)乙基〕-2-氧代-1-吡咯烷基乙酰胺。将此混合物加热到75℃,在此温度下搅拌1小时,过滤后减压蒸发除去水,残留物(5.3克)用60毫升乙酸乙酯进行重结晶得到3.87克(S)-α-乙基-2-氧代-1-吡咯烷基乙酰胺,熔点112-115℃,比旋光度(α)25 D=-90°(C=1,丙酮),产率69%。
对C8H14N2O2的分析(%):
计算值:C 56.45 H 8.29 N 16.46
测量值:C 56.30 H 8.42 N 16.18。
Claims (2)
1、一种制备(S)-a-乙基-2-氧代-1-吡咯烷基乙酰胺的方法,其特征在于,在水中和50-100℃下,使用脱硫剂使(S)-a-(2-(甲硫基)乙基-2-氧代-1-吡咯烷基乙酰胺氢解。
2、权利要求1的方法,其中所说的脱硫剂是阮内镍T-1。
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GB888827389A GB8827389D0 (en) | 1988-11-23 | 1988-11-23 | Process for preparation of(s)alpha-ethyl-2-oxo-1-pyrrolidineacetamide |
GB88.27389 | 1988-11-23 |
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CN1042904A CN1042904A (zh) | 1990-06-13 |
CN1020604C true CN1020604C (zh) | 1993-05-12 |
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KR (1) | KR0157610B1 (zh) |
CN (1) | CN1020604C (zh) |
AT (1) | AT392781B (zh) |
BG (1) | BG51041A3 (zh) |
CY (1) | CY1672A (zh) |
ES (1) | ES2023532A6 (zh) |
FI (1) | FI91961C (zh) |
GB (2) | GB8827389D0 (zh) |
GR (1) | GR1000719B (zh) |
HK (1) | HK102492A (zh) |
HU (1) | HU204508B (zh) |
NO (1) | NO173823C (zh) |
PH (1) | PH26332A (zh) |
PL (1) | PL161781B1 (zh) |
PT (1) | PT92365B (zh) |
RU (1) | RU1797607C (zh) |
SG (1) | SG89392G (zh) |
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GB9319732D0 (en) | 1993-09-24 | 1993-11-10 | Ucb Sa | Use of (s)-alpha-ethyl-2-oxo-l-pyrrolidineacetamide for the treatment of anxiety |
US6107492A (en) * | 1998-05-08 | 2000-08-22 | Ucb, S.A. | Process for the preparation of levetiracetam |
HUP0204023A3 (en) | 1999-12-01 | 2005-03-29 | Ucb Sa | A pyrrolidineacetamide derivative alone or in combination for treatment of cns disorders and pharmaceutical compositions containing them |
GB0004297D0 (en) | 2000-02-23 | 2000-04-12 | Ucb Sa | 2-oxo-1 pyrrolidine derivatives process for preparing them and their uses |
CN1802352A (zh) * | 2003-02-03 | 2006-07-12 | 特瓦制药工业有限公司 | 制备左乙拉西坦的方法 |
ES2214147B1 (es) * | 2003-02-28 | 2005-10-01 | Farma-Lepori S.A. | Procedimiento de obtencion de un agente antiepileptico. |
ES2390455T3 (es) * | 2003-09-24 | 2012-11-13 | Ucb Pharma, S.A. | Procedimiento para la preparación de derivados de 2-oxo-1-pirrolidina |
CA2488325C (en) | 2004-11-22 | 2010-08-24 | Apotex Pharmachem Inc. | Improved process for the preparation of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide and (r)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide |
EP1912966A2 (en) | 2005-06-01 | 2008-04-23 | Ucb, S.A. | 2-oxo-1-pyrrolidine derivatives and their therapeutic use on the central nervous system |
US8338621B2 (en) | 2005-12-21 | 2012-12-25 | Ucb S.A. | Process for the preparation of 2-oxo-1-pyrrolidine derivatives |
WO2009050735A1 (en) * | 2007-10-15 | 2009-04-23 | Lupin Limited | A novel polymorph of levetiracetam and a process for its preparation |
EP2147911A1 (en) | 2008-07-24 | 2010-01-27 | ZaCh System S.p.A. | Process for the preparation of levetiracetam |
US7939676B2 (en) | 2009-09-17 | 2011-05-10 | Zach System S.P.A. | Process for the preparation of levetiracetam |
HUE045610T2 (hu) | 2014-01-21 | 2020-01-28 | Janssen Pharmaceutica Nv | 2-es altípusú metabotróp glutamáterg receptor pozitív allosztérikus modulátorait vagy ortosztérikus agonistáit tartalmazó kombinációk és alkalmazásuk |
MX2016009471A (es) | 2014-01-21 | 2016-10-13 | Janssen Pharmaceutica Nv | Combinaciones que comprenden agonistas ortostericos o moduladores alostericos positivos del receptor glutamatergico metabotropico de subtipo 2 y su uso. |
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GB1309692A (en) * | 1970-02-13 | 1973-03-14 | Ucb Sa | N-substituted lactams |
GB8412357D0 (en) * | 1984-05-15 | 1984-06-20 | Ucb Sa | Pharmaceutical composition |
GB8412358D0 (en) * | 1984-05-15 | 1984-06-20 | Ucb Sa | Pharmaceutical composition |
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1988
- 1988-11-23 GB GB888827389A patent/GB8827389D0/en active Pending
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1989
- 1989-11-20 GR GR890100769A patent/GR1000719B/el not_active IP Right Cessation
- 1989-11-20 BG BG90398A patent/BG51041A3/xx unknown
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- 1989-11-21 GB GB8926244A patent/GB2225322B/en not_active Expired - Lifetime
- 1989-11-22 RU SU4742434A patent/RU1797607C/ru active
- 1989-11-22 AT AT2666/89A patent/AT392781B/de not_active IP Right Cessation
- 1989-11-22 CN CN89108764A patent/CN1020604C/zh not_active Expired - Fee Related
- 1989-11-22 FI FI895562A patent/FI91961C/fi active IP Right Grant
- 1989-11-22 HU HU896132A patent/HU204508B/hu not_active IP Right Cessation
- 1989-11-22 PL PL89282413A patent/PL161781B1/pl unknown
- 1989-11-22 ES ES8903978A patent/ES2023532A6/es not_active Expired - Lifetime
- 1989-11-22 NO NO894649A patent/NO173823C/no unknown
- 1989-11-23 KR KR1019890017038A patent/KR0157610B1/ko not_active IP Right Cessation
- 1989-11-23 PH PH39568A patent/PH26332A/en unknown
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1992
- 1992-09-05 SG SG893/92A patent/SG89392G/en unknown
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Publication number | Publication date |
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CY1672A (en) | 1993-05-14 |
HK102492A (en) | 1992-12-24 |
NO894649L (no) | 1990-05-25 |
SG89392G (en) | 1992-12-04 |
PL161781B1 (en) | 1993-07-30 |
HUT53072A (en) | 1990-09-28 |
GR1000719B (el) | 1992-11-23 |
AT392781B (de) | 1991-06-10 |
PH26332A (en) | 1992-04-29 |
GB8926244D0 (en) | 1990-01-10 |
BG51041A3 (en) | 1993-01-15 |
GB8827389D0 (en) | 1988-12-29 |
PT92365A (pt) | 1990-05-31 |
GB2225322B (en) | 1992-03-25 |
NO173823B (no) | 1993-11-01 |
CN1042904A (zh) | 1990-06-13 |
KR0157610B1 (ko) | 1998-11-16 |
GR890100769A (en) | 1990-12-31 |
KR900007797A (ko) | 1990-06-02 |
HU896132D0 (en) | 1990-02-28 |
ES2023532A6 (es) | 1992-01-16 |
FI91961C (fi) | 1994-09-12 |
FI895562A0 (fi) | 1989-11-22 |
PT92365B (pt) | 1995-07-18 |
GB2225322A (en) | 1990-05-30 |
HU204508B (en) | 1992-01-28 |
NO173823C (no) | 1994-02-09 |
NO894649D0 (no) | 1989-11-22 |
ATA266689A (de) | 1990-11-15 |
FI91961B (fi) | 1994-05-31 |
RU1797607C (ru) | 1993-02-23 |
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