CN1742003A - 3-甲氨基-1-(2-噻吩基)-1-丙酮及其制备和应用 - Google Patents
3-甲氨基-1-(2-噻吩基)-1-丙酮及其制备和应用 Download PDFInfo
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- CN1742003A CN1742003A CNA2004800026862A CN200480002686A CN1742003A CN 1742003 A CN1742003 A CN 1742003A CN A2004800026862 A CNA2004800026862 A CN A2004800026862A CN 200480002686 A CN200480002686 A CN 200480002686A CN 1742003 A CN1742003 A CN 1742003A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
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- Organic Chemistry (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本发明涉及3-甲氨基-1-(2-噻吩基)-1-丙酮的制备及其用于制备药物(+)-(S)-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)丙胺草酸盐(商标名为度洛西汀)的应用。
Description
本发明涉及3-甲氨基-1-(2-噻吩基)-1-丙酮的制备和应用。
氨基醇1(图1)[(1 S)-3-甲氨基-1-(2-噻吩基)-丙-1-醇]是药物((+)-(S)-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)丙胺草酸盐-商标名为度洛西汀(Duloxetine))制备中受欢迎的中间体。迄今为止,所使用的制备上述中间体的方法复杂且需要昂贵的、不稳定的试剂。此外,还需要技术复杂的色谱法制备纯的化合物。参考,例如,EP 273658 A1;Liu等,Chirality 2000,12(1),26~29;Wheeler等,J.Labelled Comp.Radiopharm.1995,36(3),213-23;US5362886、EP457559,Deeter等,Tet.Lett.1990,31(49),7101-4;EP0650965;L.A.Sorbera,R.M.Castaner,J.Castaner,Drugs of the Future2000,25(9):907~916。
因此,本发明的目的在于提供更简单经济的方法制备度洛西汀。
本发明描述了一种新颖的、经济的获得异构(isomerically)纯的化合物1的方法。本发明方法采用新的酮5(图1)[3-甲氨基-1-(2-噻吩基)-1-丙酮]作为各方法共有的中间体,所述酮5通过对映选择性(enantioselective)还原可制得氨基醇1。氨基醇1随后生成度洛西汀的反应已为技术人员所熟知,并可以类似于EP0457559A2中所述的方法(与1-氟代萘反应)进行。
本发明涉及3-甲氨基-1-(2-噻吩基)-1-丙酮(图1,化合物5)及其酸加成盐。化合物5的酸加成盐是化合物5与无机酸或有机酸反应的产物。就上述目的而言,特别适用的酸有盐酸、硫酸、磷酸、草酸、富马酸、马来酸和乙酸。
制备酮5或氨基醇1的原料化合物可为噻吩或2-乙酰基噻吩。图1描述了制备酮5的三种路线(路线1~3),如下所述:
路线1
化合物4由乙酰基噻吩、甲醛和二甲胺通过经典的曼尼希反应(Mannich reaction)制得(EP0457559A2,实施例1)。 单甲氨基酮5由制得的4与过量的甲胺通过逆迈克尔/迈克尔反应(Michaelreaction)制得。
路线2
化合物6由乙酰基噻吩、甲醛和甲胺通过经典的曼尼希反应制得(Blicke;Burckhalter;JACSAT;J.Amer.Chem.Soc.;64;1942;451,453)。单甲氨基酮5由制得的6与过量的甲胺通过逆迈克尔/迈克尔反应制得。
路线3
化合物7由噻吩8与3-氯丙酰氯通过经典的弗瑞德-克来福酰化作用(Friedel-crafts acylation)制得(如El-Khagawa,Ahmed M.;El-Zohry,Maher F.;Ismail,Mohamed T.;PREEDF;Phosphorus Sulfur;EN;33;1987;25~32所述)。单甲氨基酮5由7与甲胺反应制得。
本发明还涉及3-甲氨基-1-(2-噻吩基)-1-丙酮或其酸加成盐制备外消旋形式或对映异构(enantiomerically)纯形式的N-甲基-3-(1-萘氧基)-3-(2-噻吩基)丙胺或其酸加成盐的应用。特别优选制备(+)-(S)-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)丙胺草酸盐(度洛西汀)的应用。
本发明还涉及制备外消旋形式、或优选对映异构纯形式的N-甲基-3-(1-萘氧基)-3-(2-噻吩基)-丙胺或其酸加成盐的方法,所述方法首先制备3-甲氨基-1-(2-噻吩基)-1-丙酮或其酸加成盐作为中间体,然后将所述中间体还原为相应的醇。
所述还原可在外消旋条件下或对映选择性地进行。优选对映选择性还原,特别是生成的产物为(S)-对映异构体1的还原。
所述还原可使用经典的对映选择性氢化方法化学方式实现,或者使用含有过渡金属的氢化催化剂或使用酶还原作用实现,所述氢化方法使用例如具有手性配体的NaBH4或LiAlH4以获得对映选择性,所述酶还原作用使用例如微生物脱氢酶,特别是细菌或真菌脱氢酶。
实验:
路线1:
首先在25ml的乙醇中引入5g盐酸盐形式的二甲氨基酮4,然后逐滴加入20当量的甲胺(40%,于水中)并在60~70℃搅拌混合物6小时。反应结束后,除去部分乙醇,即得到白色结晶固体状的产物5(产量为3.45g的盐酸盐)。
路线2:
首先在25ml的乙醇中引入5g盐酸盐形式的二酮6,然后逐滴加入20当量的甲胺(40%,于水中)并在70~80℃搅拌混合物6小时。反应结束后,除去部分乙醇即得到白色结晶固体状的产物5(产量为3.87g的盐酸盐)。
路线3:
首先在25ml的THF中引入5g氯代酮7,然后逐滴加入20当量的甲胺(40%,于水中)并在30~40℃搅拌混合物6小时。反应结束后,移除大部分THF并分离出白色结晶固体状的产物5(产量为4.10g的盐酸盐)。
在路线1~3中,甲胺水溶液还可用气态或液化的甲胺代替。
盐酸盐形式的单甲氨基酮5的光谱数据如下:
13C NMR(D2O,125MHz)自旋回波的峰裂数示于括号中:
δ(ppm)=188.5(s),140.4(s),139.2(d),137.8(d),131.9(d),46.9(t),37.3(t),36.0(q)
1H NMR(D2O,500MHz):
δ(ppm)=8.00(m,1H),7.95(m,1H),7.25(m,1H),3.40(m,2H),2.75(m,2H),2.62(s,3H)
还原化合物5以生成化合物1(图1)
NaBH4(外消旋):
首先在20ml的乙醇中引入5g甲氨基酮5,然后在20℃下分批加入0.8当量的NaBH4。混合物搅拌6小时后用水进行后处理。得到淡黄色固体状的外消旋单甲氨基醇1(产量为3.9g)
1H NMR(500MHz,CDCl3)
δ(ppm)=2.1(m,2H),2.5(s,3H),2.9(m,2H),4.5(br s,2H),5.25(m,1H),6.94(m,1H),7.00(m,1H),7.22(m,1H)
13-C-NMR(125MHz,CDCl3)
δ(ppm)=35.4,36.3,49.7,71.4,122.5,123.8,126.6,149.3
采用LiAlH4(手性修饰的)的方法如EP 0457559A2,实施例1B中所述的(对映选择性地)进行。
1的产率为74%,对映异构的纯度为72%ee。
Claims (8)
1.3-甲氨基-1-(2-噻吩基)-1-丙酮及其酸加成盐。
2.3-甲氨基-1-(2-噻吩基)-1-丙酮盐酸盐。
3.3-甲氨基-1-(2-噻吩基)-1-丙酮或其酸加成盐用于制备N-甲基-3-(1-萘氧基)-3-(2-噻吩基)丙胺或其酸加成盐的应用。
4.根据权利要求3的应用,用于制备(+)-(S)-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)丙胺草酸盐(度洛西汀)。
5.根据权利要求3的应用,其中3-甲氨基-1-(2-噻吩基)-1-丙酮或其酸加成盐还原为(1S)-3-甲氨基-1-(2-噻吩基)-丙-1-醇或其酸加成盐。
6.一种制备(+)-(S)-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)-丙胺草酸盐(度洛西汀)的方法,其中3-甲氨基-1-(2-噻吩基)-1-丙酮或其酸加成盐作为中间体制备。
7.根据权利要求6的方法,其中3-甲氨基-1-(2-噻吩基)-1-丙酮或其酸加成盐还原为(1S)-3-甲氨基-1-(2-噻吩基)-丙-1-醇或其酸加成盐。
8.根据权利要求7的方法,其中还原作用采用微生物脱氢酶进行。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10302595.2 | 2003-01-22 | ||
DE10302595A DE10302595A1 (de) | 2003-01-22 | 2003-01-22 | 3-Methylamino-1-(2-thienyl)-1-proganon, seine Herstellung und Verwendung |
Publications (2)
Publication Number | Publication Date |
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CN1742003A true CN1742003A (zh) | 2006-03-01 |
CN100432069C CN100432069C (zh) | 2008-11-12 |
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CNB2004800026862A Expired - Fee Related CN100432069C (zh) | 2003-01-22 | 2004-01-15 | 3-甲氨基-1-(2-噻吩基)-1-丙酮及其制备和应用 |
Country Status (10)
Country | Link |
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US (1) | US7259264B2 (zh) |
EP (1) | EP1587802B1 (zh) |
JP (1) | JP4837552B2 (zh) |
KR (1) | KR101070977B1 (zh) |
CN (1) | CN100432069C (zh) |
AT (1) | ATE378326T1 (zh) |
CA (1) | CA2513542C (zh) |
DE (2) | DE10302595A1 (zh) |
ES (1) | ES2294457T3 (zh) |
WO (1) | WO2004065376A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113912582A (zh) * | 2020-07-10 | 2022-01-11 | 南京桦冠生物技术有限公司 | 度洛西汀中间体的制备方法 |
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Publication number | Priority date | Publication date | Assignee | Title |
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EP2044049A2 (en) | 2006-07-03 | 2009-04-08 | Ranbaxy Laboratories Limited | Process for the preparation of enantiomerically pure salts of n-methyl- 3 -( 1-naph-thaleneoxy)- 3 - (-2-thienyl) propanamine |
ATE552250T1 (de) | 2006-12-22 | 2012-04-15 | Synthon Bv | Verfahren zur herstellung von duloxetin und verwandten verbindungen |
US8168805B2 (en) * | 2007-10-29 | 2012-05-01 | Sci Pharmtech, Inc | Optically active methylhydroxylaminopropanol compound and its use as intermediate for preparation of (S)-(−)-3-methylamino-1-(2-thienyl)propan-1-ol |
US7829731B2 (en) * | 2007-10-29 | 2010-11-09 | Sci Pharmtech, Inc. | Methylhydroxylaminopropanol derivative and its use as intermediate for preparation of 3-methylamino-1-(2-thienyl)propan-1-OL |
WO2009147687A2 (en) * | 2008-06-03 | 2009-12-10 | Shodhana Laboratories Limited | An improved process for the separation of enantiomerically pure compounds |
SI2329013T1 (sl) | 2008-08-27 | 2016-03-31 | Codexis, Inc. | Polipeptidi ketoreduktaze za proizvodnjo 3-aril-3-hidroksipropanamina iz 3-aril-3-ketopropanamina |
WO2010025287A2 (en) | 2008-08-27 | 2010-03-04 | Codexis, Inc. | Ketoreductase polypeptides for the production of 3-aryl-3-hydroxypropanamine from a 3-aryl-3-ketopropanamine |
WO2011128370A1 (en) | 2010-04-13 | 2011-10-20 | Krka, D.D., Novo Mesto | Synthesis of duloxetine and/or pharmaceutically acceptable salts thereof |
ES2425379T3 (es) | 2010-08-30 | 2013-10-15 | Saltigo Gmbh | Procedimiento para la preparación de (S)-3-N-metilamino-1-(2-tienil)-1-propanol |
CN103214452B (zh) * | 2013-05-07 | 2014-08-06 | 浙江丽晶化学有限公司 | N-甲基-3-羟基-3-(2-噻吩基)-丙胺的制备方法 |
CN111793056A (zh) * | 2020-07-27 | 2020-10-20 | 广州康瑞泰药业有限公司 | 一种度洛西汀中间体的制备方法 |
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KR880007433A (ko) | 1986-12-22 | 1988-08-27 | 메리 앤 터커 | 3-아릴옥시-3-치환된 프로판아민 |
US5057339A (en) * | 1988-12-29 | 1991-10-15 | Matsushita Electric Industrial Co., Ltd. | Metallized polyacetylene-type or polyacene-type ultralong conjugated polymers and process for producing the same |
CA2042346A1 (en) | 1990-05-17 | 1991-11-18 | Michael Alexander Staszak | Chiral synthesis of 1-aryl-3-aminopropan-1-ols |
EP0571685A1 (en) * | 1992-05-27 | 1993-12-01 | Novo Nordisk A/S | Aryloxyheteroarylpropylamines, their preparation and use |
US5362886A (en) | 1993-10-12 | 1994-11-08 | Eli Lilly And Company | Asymmetric synthesis |
DE60329640D1 (de) | 2002-07-09 | 2009-11-19 | Lonza Ag | Verfahren zur Herstellung von N-Monoalkyl-Beta-Aminoalkoholen |
DE10240026A1 (de) * | 2002-08-27 | 2004-03-11 | Merck Patent Gmbh | Verfahren zur Herstellung von Monoalkylaminoketonen |
RU2340594C2 (ru) * | 2002-08-27 | 2008-12-10 | Мерк Патент Гмбх | Способ энантиоселективного гидрирования аминоспиртов |
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- 2003-01-22 DE DE10302595A patent/DE10302595A1/de not_active Withdrawn
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2004
- 2004-01-15 CN CNB2004800026862A patent/CN100432069C/zh not_active Expired - Fee Related
- 2004-01-15 ES ES04702333T patent/ES2294457T3/es not_active Expired - Lifetime
- 2004-01-15 WO PCT/EP2004/000237 patent/WO2004065376A1/de active IP Right Grant
- 2004-01-15 AT AT04702333T patent/ATE378326T1/de active
- 2004-01-15 CA CA2513542A patent/CA2513542C/en not_active Expired - Fee Related
- 2004-01-15 EP EP04702333A patent/EP1587802B1/de not_active Expired - Lifetime
- 2004-01-15 KR KR1020057013433A patent/KR101070977B1/ko active IP Right Grant
- 2004-01-15 US US10/542,003 patent/US7259264B2/en not_active Expired - Lifetime
- 2004-01-15 DE DE502004005491T patent/DE502004005491D1/de not_active Expired - Lifetime
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113912582A (zh) * | 2020-07-10 | 2022-01-11 | 南京桦冠生物技术有限公司 | 度洛西汀中间体的制备方法 |
Also Published As
Publication number | Publication date |
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ES2294457T3 (es) | 2008-04-01 |
US20060128791A1 (en) | 2006-06-15 |
CN100432069C (zh) | 2008-11-12 |
DE10302595A1 (de) | 2004-07-29 |
KR20050098253A (ko) | 2005-10-11 |
EP1587802A1 (de) | 2005-10-26 |
JP4837552B2 (ja) | 2011-12-14 |
CA2513542A1 (en) | 2004-08-05 |
WO2004065376A1 (de) | 2004-08-05 |
EP1587802B1 (de) | 2007-11-14 |
CA2513542C (en) | 2012-01-03 |
JP2006515878A (ja) | 2006-06-08 |
ATE378326T1 (de) | 2007-11-15 |
DE502004005491D1 (de) | 2007-12-27 |
KR101070977B1 (ko) | 2011-10-06 |
US7259264B2 (en) | 2007-08-21 |
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