CN101098863B - 提纯(1s)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的方法 - Google Patents
提纯(1s)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的方法 Download PDFInfo
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- CN101098863B CN101098863B CN2005800459793A CN200580045979A CN101098863B CN 101098863 B CN101098863 B CN 101098863B CN 2005800459793 A CN2005800459793 A CN 2005800459793A CN 200580045979 A CN200580045979 A CN 200580045979A CN 101098863 B CN101098863 B CN 101098863B
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- Prior art keywords
- thienyl
- methylamino
- propyl alcohol
- reaction mixture
- propanol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000000034 method Methods 0.000 title claims abstract description 17
- YEJVVFOJMOHFRL-ZETCQYMHSA-N (1s)-3-(methylamino)-1-thiophen-2-ylpropan-1-ol Chemical compound CNCC[C@H](O)C1=CC=CS1 YEJVVFOJMOHFRL-ZETCQYMHSA-N 0.000 title abstract 3
- 239000011541 reaction mixture Substances 0.000 claims abstract description 11
- 238000004821 distillation Methods 0.000 claims abstract description 6
- 238000000746 purification Methods 0.000 claims description 7
- 238000000199 molecular distillation Methods 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- -1 3-methylamino-1-(2-thienyl)-1-propyl Chemical group 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000009834 vaporization Methods 0.000 description 3
- 230000008016 vaporization Effects 0.000 description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000000526 short-path distillation Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D3/00—Distillation or related exchange processes in which liquids are contacted with gaseous media, e.g. stripping
- B01D3/12—Molecular distillation
-
- 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
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
本发明涉及一种通过将包含25-99重量％(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的反应混合物进行蒸馏而提纯(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的方法。
Description
本发明涉及提纯(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的方法。
现有技术
(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇是用于制备药物的重要中间体，所述药物特别是是一种来自EliLilly&Co，USA的药物活性化合物。
已经公开了(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的制备方法。一种在DE 103 48 479A1中详细描述的常见制备方法包括使噻吩与3-氯丙酰氯在AlCl3的存在下反应，随后将酮基对映异构选择性地还原成羟基，并直接胺化，得到(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇。(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇随后通过重结晶提纯，优选从甲基叔丁基醚中重结晶。
(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的制备也描述在WO2004/031168中。在这种情况下，(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇也通过从甲基叔丁基醚中结晶来提纯。
(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的制备也描述在WO2004/005307中。在这种情况下，(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇也通过从甲基叔丁基醚中结晶来提纯。
上述提纯(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的方法的特征在于显著的产率损失。
发明目的
本发明的目的是提供一种提纯(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的方法，该方法能同时以高的化学和对映异构纯度以及高产率提供有价值的产品，并也应该能以可接受的成本在工业规模上实施。
本发明的详细描述
我们发现该目的通过一种提纯(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的方法实现，其中将包含25-99重量％(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的反应混合物进行蒸馏。
术语“反应混合物”表示以下含义：该反应混合物可以是从用于制备(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的反应衍生得到的未纯化的混合物，即例如由甲基胺和(1S)-3-氯-1-(2-噻吩基)-1-丙醇组成的反应混合物。但是，根据制备(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的反应路线，该反应混合物可以是由其它共反应物组成的混合物。但是，术语“反应混合物”也包括(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的提纯或部分提纯的反应产物。(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇在一种或多种溶剂中的溶液也被理解为属于“包含(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的反应混合物”。
如上所述，一种制备(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的路线详细公开在DE 103 48 479A1中，将其中关于制备(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的内容明确引入这里供参考。
但是，本发明的方法也可以非常成功地用于以其它方式制备的(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇，例如在WO 2004/031168和WO2004/005307中所述的方式，其中的公开内容也明确引入这里供参考。也可以考虑制备(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的其它路线，例如通过酶催方式将酮基对映选择性地还原成羟基，或将DE 103 48 479中所述的顺序反转，即直接将3-氯-1-(2-噻吩基)-1-丙酮胺化，随后还原得到(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇。本发明的方法适用于所有这些制备方法以及其它在这里没有具体提到的制备(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的方法。
反应混合物通常包含25-99重量％、优选40-98重量％、特别优选超过50重量％的有价值产物(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇。
如果(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇以小于25重量％的量存在于反应混合物中，则通常建议在蒸馏之前进行浓缩步骤，例如通过除去溶剂或通过萃取来浓缩(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇。
蒸馏可以按照本领域技术人员公知的许多方式进行，例如描述在化学技术手册如Ullmann或Winnacker-Küchler中。
本发明方法的特别优选的形式是所谓的短路蒸馏或分子蒸馏，其中使用在蒸发和冷凝空间之间尽可能短和直线形的的路径进行蒸馏。
商业上可得的分子蒸馏设备(例如以专业级别销售)也是特别合适的。
本发明的方法使得有可能在单个操作中以出人意料的高化学产率并且同时以高纯度分离(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇。
实验部分
实施例1：
将500g的包含约90％(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的浅黄色原料在0.05毫巴和120℃蒸发温度下在分子蒸馏设备中蒸馏。获得420g(93％产率)的纯白色馏出物，是含量＞99％的无色固体。
实施例2：
将500g的包含约50％(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的深褐色原料在0.05毫巴和150℃蒸发温度下在分子蒸馏设备中蒸馏。获得221g(88％产率)的纯白色馏出物，是含量＞99％的无色固体。
实施例3：
将500g的包含约98％(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的浅黄色原料在0.05毫巴和100℃蒸发温度下在分子蒸馏设备中蒸馏。获得455g(93％产率)的纯白色馏出物，是含量＞99％的无色固体。
Claims (4)
1.一种提纯(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的方法，包括将包含25-99重量％(1S)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的反应混合物进行蒸馏。
2.权利要求1的方法，其中所述蒸馏在0.0001-1毫巴的压力下进行。
3.权利要求2的方法，其中所述蒸馏作为分子蒸馏进行。
4.权利要求1-3中任一项的方法，其中所述蒸馏在50-250℃的温度下进行。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102005000867A DE102005000867A1 (de) | 2005-01-05 | 2005-01-05 | Verfahren zur Reinigung von (1S)-3-methylamino-1-(2-thienyl)-1-propanol |
| DE102005000867.4 | 2005-01-05 | ||
| PCT/EP2005/014161 WO2006072465A1 (de) | 2005-01-05 | 2005-12-31 | Verfahren zur reinigung von (1s)-3-methylamino-1-(2-thienyl)-1-propanol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101098863A CN101098863A (zh) | 2008-01-02 |
| CN101098863B true CN101098863B (zh) | 2010-09-15 |
Family
ID=35788364
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005800459793A Expired - Fee Related CN101098863B (zh) | 2005-01-05 | 2005-12-31 | 提纯(1s)-3-甲基氨基-1-(2-噻吩基)-1-丙醇的方法 |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US20080108835A1 (zh) |
| EP (1) | EP1836185A1 (zh) |
| JP (1) | JP2008526703A (zh) |
| CN (1) | CN101098863B (zh) |
| CA (1) | CA2590660A1 (zh) |
| DE (1) | DE102005000867A1 (zh) |
| WO (1) | WO2006072465A1 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107417663B (zh) * | 2017-09-25 | 2019-05-28 | 台州职业技术学院 | 一种高纯(s)-3-甲基氨基-1-(噻吩-2-基)丙醇的制备方法 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004005307A1 (en) * | 2002-07-09 | 2004-01-15 | Lonza Ag | Process for the preparation of optically active 3-n-methylamino-1-(2-thienyl)-1-propanol |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003276066A1 (en) * | 2002-10-07 | 2004-04-23 | Lonza Ag | Processes and intermediates for the preparation of optically active 3-amino-1-(2-thienyl)-1-propanol derivatives |
-
2005
- 2005-01-05 DE DE102005000867A patent/DE102005000867A1/de not_active Withdrawn
- 2005-12-31 US US11/814,253 patent/US20080108835A1/en not_active Abandoned
- 2005-12-31 JP JP2007548766A patent/JP2008526703A/ja not_active Withdrawn
- 2005-12-31 WO PCT/EP2005/014161 patent/WO2006072465A1/de active Application Filing
- 2005-12-31 CN CN2005800459793A patent/CN101098863B/zh not_active Expired - Fee Related
- 2005-12-31 CA CA002590660A patent/CA2590660A1/en not_active Abandoned
- 2005-12-31 EP EP05820701A patent/EP1836185A1/de not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004005307A1 (en) * | 2002-07-09 | 2004-01-15 | Lonza Ag | Process for the preparation of optically active 3-n-methylamino-1-(2-thienyl)-1-propanol |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2590660A1 (en) | 2006-07-13 |
| EP1836185A1 (de) | 2007-09-26 |
| WO2006072465A1 (de) | 2006-07-13 |
| CN101098863A (zh) | 2008-01-02 |
| US20080108835A1 (en) | 2008-05-08 |
| JP2008526703A (ja) | 2008-07-24 |
| DE102005000867A1 (de) | 2006-07-13 |
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