CN1041918C - 芳基哌啶甲醇的制法 - Google Patents
芳基哌啶甲醇的制法 Download PDFInfo
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- CN1041918C CN1041918C CN94191430A CN94191430A CN1041918C CN 1041918 C CN1041918 C CN 1041918C CN 94191430 A CN94191430 A CN 94191430A CN 94191430 A CN94191430 A CN 94191430A CN 1041918 C CN1041918 C CN 1041918C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
通过用乙硼烷还原式(II)化合物来制备式(I)化合物的方式,式(I)中R3是氢、R1-6烷基或R1-6烷芳基;式(II)中R3如对式(Ⅰ)所定义,R4为R1-6烷基。
Description
本发明涉及新的制备芳基哌啶甲醇的方法。
美国专利4,007,196描述了一些据说具有抗抑郁活性的化合物。
式(A)化合物被描述为具有可以使它们用作抗抑郁剂的药理性质。
已发现一种特别的式(A)化合物作为抗抑郁剂是特别有效的。该化合物被称为帕罗西汀,具有下式结构:美国专利4,902,801描述了通过式(C)化合物的还原制备式(B)化合物。式中Ar表示芳基或取代的芳基,R表示氢、烷基或芳烷基;式中Ar和R如对式(B)所定义,Ra是烷基。
这样一种方法被说成是适于制备帕罗西汀的前体式(B)化合物。
唯一特别公开的用于进行美国专利4,902,801中所述方法的还原剂是氢化铝锂或氢化铝。这些还原剂昂贵,难以操作,并伴随着大量放热,这在大规模进行反应时产生过程控制问题。
本发明通过使用乙硼烷作为还原剂令人惊奇地克服或减轻了上述问题,它也给出了较好的收率且更为经济。
优选地,R3是甲基。
优选地,R4是乙基或甲基或乙基和甲基的混合物。
该反应适当地在惰性溶剂如四氢呋喃或二甲氧基乙烷(DME)中进行。
乙硼烷通过在降低的温度如-10~20℃、优选0-5℃的温度下在式(Ⅱ)化合物存在下将三氟化硼醚合物加到氢硼化钠中适当地就地产生。或者,也是就安全和操作理由而言较优选地,通过在降低的温度如-10~20℃、优选0~5℃的温度下在式(Ⅱ)化合物存在下将氯化氢气体(它可适当地溶于惰性溶剂如DME中)加到氢硼化钠中产生。
一旦加完了三氟化硼醚合物或氯化氢气体,就让反应物适当地温热到环境温度或升高的温度如20~60℃、较优选地20℃~40℃。
然后可以通过将反应混合物加到无机酸如盐酸水溶液中或将无机酸如盐酸水溶液加到反应混合物中终止反应或使反应物“骤冷”。然后可以滤掉产生的任何固体,可以通过蒸掉反应溶剂,用合适的、产物可从中沉出的溶剂如甲苯代替反应溶剂,并适当的话在浓缩产物溶液之后,通过加入合适的使产物沉淀的溶剂如庚烷使产物沉出,由此分离产物即式(Ⅰ)化合物。
本发明还提供了一种制备帕罗西汀或其可药用的盐尤其是其盐酸盐半水合物的方法,它包括如上所述形成式(Ⅰ)化合物,然后用常规技术,尤其是美国专利4,902,801和4,721,723中所述的技术,将所述化合物转化成帕罗西汀或其可药用的盐。
下述实施例用来说明本发明。
实施例1
(±)-反式-4-(4′-氟苯基)-3-羟甲基-N-甲基哌啶进料
(±)-反式-3-乙氧基/甲氧基羰基-4-(4′-氟苯基)-N-甲基哌啶-2,6-二酮*
13.5g定量分析(assay)93.7%
氢硼化钠6.3g
三氟化硼醚合物18ml
四氢呋喃(THF)75ml
甲苯200ml
3N HCl 40ml
庚烷70ml
40%氢氧化钠溶液25ml方法-进行下述方法
1)向50mlTHF中加入6.3g氢硼化钠
2)将溶液冷却到0~5℃
3)将15.3g(±)-反式-3-乙氧基/甲氧基羰基-4-(4′-氟苯基)-N-甲基哌啶-2,6-二酮溶于25ml THF中。在大约15分钟内缓慢地加到保持在0~5℃的氢硼化物溶液中
4)保持温度在0~5℃下,缓慢地将18ml醚合物加到溶液中
5)在大约1小时内使温度升到20℃
6)将溶液温热到35~40℃保持2小时
7)将溶液冷却到0~5℃
8)反过来将溶液缓慢地加到40ml 3N HCl中,允许温度升至20~25℃
9)将溶液冷却至5℃,滤掉硼酸固体
10)用20ml水洗涤滤器
11)在65℃回流溶液,收集THF
12)允许溶液温度升至100℃
13)加入50ml水/75ml甲苯将溶液冷却至60℃
14)分离下面的水层
15)向甲苯中,加入另外50ml水,同时保持在60℃温度
16)分离并收集水性各部分
17)向水性部分加入75ml甲苯。将pH值调至12~12.5,分离各层
18)向水性部分加入另外50ml甲苯并分离
19)合并甲苯相并蒸发至大约20g
20)加入50ml庚烷,冷却至5℃,过滤
21)用20ml庚烷洗涤滤器
22)在真空炉中于40℃下干燥过夜。
分离的重量 9.6g
定量分析 97%
收率 85%
定量分析是用高效液相色谱法进行的。
*按照美国专利4,902,801中概括的步骤制备的。
实施例2
(±)-反式-4-(4′-氟苯基)-3-羟甲基-N-甲基哌啶的合成进料
(+,-)-反式-3-乙氧基/甲氧基羰基-4-(4′-氟苯基)-3-羟甲基-N-甲基哌啶-2,6-二酮*15.3g
氢硼化钠 8.0g
氯化氢气体 6.5g
二甲氧基乙烷(DME) 150ml
甲苯 50ml
3N盐酸溶液 60ml
庚烷 20ml
40%氢氧化钠溶液 25ml方法-进行下述方法
1.将氢硼化钠(8.0g)加到DME(75ml)中。
2.将溶液冷却至0~5℃。
3.将(+,1)-反式-3-乙氧基/甲氧基羰基-4-(4’-氟苯基)-N-甲基哌啶-2,6-二酮(15.3g)溶于DME(25ml)中,加到保持在0~5℃的氢硼化钠浆状物中。
4.将氯化氢气体(6.5g)溶于DME(50ml)。
5.将氯化氢/DME溶液加到保持在0~5℃温度下的氢硼化物浆状物中。在此期间,反应用氮气保护,放出氢气。
6.在0~5℃温度下搅拌反应混合物30分钟。
7.将混合物温热至35~40℃,搅拌2小时。
8.将反应物冷却至0~5℃。
9.将温度保持在20℃以下通过加入3N盐酸溶液(60ml)骤冷反应物。
10.将温度保持在20℃以下向反应混合物中加入水(50ml)。
11.对溶液进行蒸馏,温度最高升至95℃,收集湿的DME溶液(大约150ml)。
12.加入甲苯(50ml),允许温度降到80℃。
13.分离各相。
14.将水相冷却至50~55℃,加入庚烷(20ml)。
15.在保持温度为50~55℃的同时,加入氢氧化钠溶液将溶液pH值调至11.0~11.5。
16.在至少30分钟时间内将混合物冷却至5~10℃。
17.滤出产物。
18.用水(2×20ml)洗涤产物。
19.在大约40℃干燥产物。
通常分离重量9.1g
通常的纯度90~95%
通常的收率78~80%*按照美国专利4,902,801中概括的方法制备。
Claims (6)
1.制备式(Ⅰ)化合物的方法,式中R3为氢、C1-6烷基或C1-6烷基芳基,所述方法包括在-10℃至20℃、在惰性溶剂中用就地产生的乙硼烷还原式(Ⅱ)化合物,式中R3如对式(Ⅰ)中所定义,R4为C1-6烷基。
2.根据权利要求1的方法,其中R3是甲基。
3.根据权利要求1或2的方法,其中R4是乙基或甲基。
4.根据权利要求1的方法,其中反应在四氢呋喃或二甲氧基乙烷中进行的。
5.根据权利要求1的方法,其中乙硼烷是在式(Ⅱ)化合物存在下将三氟化硼醚合物加到氢硼化钠中产生的。
6.根据权利要求1的方法,其中乙硼烷是在式(Ⅱ)化合物存在下将氯化氢气体加到氢硼化钠中产生的。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB939305175A GB9305175D0 (en) | 1993-03-13 | 1993-03-13 | Novel process |
GB9305175.3 | 1993-03-13 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN98109273A Division CN1055470C (zh) | 1993-03-13 | 1998-05-21 | 帕罗西汀或其可药用盐的制法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1119012A CN1119012A (zh) | 1996-03-20 |
CN1041918C true CN1041918C (zh) | 1999-02-03 |
Family
ID=10731995
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN94191430A Expired - Fee Related CN1041918C (zh) | 1993-03-13 | 1994-03-08 | 芳基哌啶甲醇的制法 |
CN98109273A Expired - Fee Related CN1055470C (zh) | 1993-03-13 | 1998-05-21 | 帕罗西汀或其可药用盐的制法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN98109273A Expired - Fee Related CN1055470C (zh) | 1993-03-13 | 1998-05-21 | 帕罗西汀或其可药用盐的制法 |
Country Status (27)
Country | Link |
---|---|
US (1) | US5681962A (zh) |
EP (1) | EP0688317B1 (zh) |
JP (1) | JPH08507540A (zh) |
KR (1) | KR100296719B1 (zh) |
CN (2) | CN1041918C (zh) |
AP (1) | AP452A (zh) |
AT (1) | ATE207898T1 (zh) |
AU (1) | AU682497B2 (zh) |
BR (1) | BR9406035A (zh) |
CA (1) | CA2158175A1 (zh) |
CZ (1) | CZ235595A3 (zh) |
DE (1) | DE69428886T2 (zh) |
DZ (1) | DZ1758A1 (zh) |
ES (1) | ES2164700T3 (zh) |
FI (1) | FI954272A0 (zh) |
GB (1) | GB9305175D0 (zh) |
HU (1) | HUT72087A (zh) |
IL (1) | IL108946A (zh) |
MA (1) | MA23134A1 (zh) |
NO (1) | NO306717B1 (zh) |
NZ (1) | NZ262735A (zh) |
PH (1) | PH31434A (zh) |
PL (1) | PL176907B1 (zh) |
RU (1) | RU2141477C1 (zh) |
SK (1) | SK281977B6 (zh) |
WO (1) | WO1994021609A1 (zh) |
ZA (1) | ZA941716B (zh) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6444190B2 (en) | 1995-08-03 | 2002-09-03 | Fmc Corporation | Reduction compositions and processes for making the same |
ES2121685B1 (es) * | 1996-04-10 | 1999-09-16 | Vita Invest Sa | Procedimiento para la obtencion de (+)-trans-4(4-fluoro-fenil)-3-hidroximetil-1-metilpiperidina. |
JP3446468B2 (ja) | 1996-04-15 | 2003-09-16 | 旭硝子株式会社 | ピペリジンカルビノール類の製造方法 |
US5936090A (en) * | 1996-05-24 | 1999-08-10 | Fmc Corporation | Processes for the reduction of imide ester functionality |
EP1384711A1 (en) | 1996-06-13 | 2004-01-28 | SUMIKA FINE CHEMICALS Co., Ltd. | Optical resolution of a piperidine derivative |
GB9623359D0 (en) * | 1996-11-09 | 1997-01-08 | Smithkline Beecham Plc | Novel process |
GB9710004D0 (en) * | 1997-05-17 | 1997-07-09 | Knoll Ag | Chemical process |
HUP0003958A3 (en) | 1997-05-29 | 2001-06-28 | Smithkline Beecham Plc | Process for preparation of 4-aryl-piperidines and intermediates |
ES2149687B1 (es) * | 1998-04-08 | 2001-05-16 | Medichem Sa | Procedimiento de obtencion de (+-)-trans-4-(4-fluorofenil)-3-hidroximetilpiperidinas e intermedios de sintesis para las mismas. |
GB0003232D0 (en) * | 2000-02-11 | 2000-04-05 | Smithkline Beecham Plc | Novel composition |
US6720003B2 (en) | 2001-02-16 | 2004-04-13 | Andrx Corporation | Serotonin reuptake inhibitor formulations |
WO2003024918A1 (es) * | 2001-09-14 | 2003-03-27 | Medichem S.A. | Compuestos intermedios para la preparación de mirtazapina y sus procedimientos de obtención |
WO2008013248A1 (fr) * | 2006-07-24 | 2008-01-31 | Sumitomo Chemical Company, Limited | Procédé de production de (±)-trans-4-(4- fluorophényl)-3-hydroxyméthylpipéridine |
JP5165951B2 (ja) * | 2006-07-24 | 2013-03-21 | 住友化学株式会社 | (±)−トランス−4−(4−フルオロフェニル)−3−ヒドロキシメチルピペリジンの製造方法 |
CN109020872B (zh) * | 2018-06-26 | 2020-05-12 | 浙江邦富生物科技有限责任公司 | 一种盐酸帕罗西汀关键中间体的制备方法 |
Citations (3)
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US4007196A (en) * | 1973-01-30 | 1977-02-08 | A/S Ferrosan | 4-Phenylpiperidine compounds |
US4902801A (en) * | 1985-08-10 | 1990-02-20 | Beecham Group Plc. | Process for preparing aryl-piperidine carbinols and novel intermediates used in the process |
EP0374675A2 (en) * | 1988-12-22 | 1990-06-27 | Novo Nordisk A/S | Reduction of piperidine-dion-derivatives and intermediates |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5470262A (en) * | 1977-11-09 | 1979-06-05 | Daiichi Kagaku Yakuhin Kk | Manufacture of pyrrolidinee22methanol |
FR2581242B1 (fr) * | 1985-04-24 | 1988-08-26 | Telemecanique Electrique | Dispositif de commande electrique adaptable a un dispositif de commutation a deux etats |
US5258517A (en) * | 1992-08-06 | 1993-11-02 | Sepracor, Inc. | Method of preparing optically pure precursors of paroxetine |
-
1993
- 1993-03-13 GB GB939305175A patent/GB9305175D0/en active Pending
-
1994
- 1994-03-07 PH PH47890A patent/PH31434A/en unknown
- 1994-03-08 DE DE69428886T patent/DE69428886T2/de not_active Expired - Fee Related
- 1994-03-08 KR KR1019950703844A patent/KR100296719B1/ko not_active IP Right Cessation
- 1994-03-08 CZ CZ952355A patent/CZ235595A3/cs unknown
- 1994-03-08 HU HU9502661A patent/HUT72087A/hu unknown
- 1994-03-08 BR BR9406035A patent/BR9406035A/pt not_active Application Discontinuation
- 1994-03-08 PL PL94310469A patent/PL176907B1/pl unknown
- 1994-03-08 WO PCT/EP1994/000694 patent/WO1994021609A1/en not_active Application Discontinuation
- 1994-03-08 CA CA002158175A patent/CA2158175A1/en not_active Abandoned
- 1994-03-08 AT AT94909935T patent/ATE207898T1/de not_active IP Right Cessation
- 1994-03-08 US US08/522,403 patent/US5681962A/en not_active Expired - Fee Related
- 1994-03-08 SK SK1140-95A patent/SK281977B6/sk unknown
- 1994-03-08 RU RU95121634A patent/RU2141477C1/ru active
- 1994-03-08 ES ES94909935T patent/ES2164700T3/es not_active Expired - Lifetime
- 1994-03-08 JP JP6520592A patent/JPH08507540A/ja active Pending
- 1994-03-08 AU AU62587/94A patent/AU682497B2/en not_active Ceased
- 1994-03-08 NZ NZ262735A patent/NZ262735A/en unknown
- 1994-03-08 CN CN94191430A patent/CN1041918C/zh not_active Expired - Fee Related
- 1994-03-08 EP EP94909935A patent/EP0688317B1/en not_active Expired - Lifetime
- 1994-03-09 DZ DZ940019A patent/DZ1758A1/fr active
- 1994-03-10 AP APAP/P/1994/000624A patent/AP452A/en active
- 1994-03-11 ZA ZA941716A patent/ZA941716B/xx unknown
- 1994-03-11 MA MA23441A patent/MA23134A1/fr unknown
- 1994-03-11 IL IL108946A patent/IL108946A/xx active IP Right Grant
-
1995
- 1995-09-12 NO NO953598A patent/NO306717B1/no not_active IP Right Cessation
- 1995-09-12 FI FI954272A patent/FI954272A0/fi unknown
-
1998
- 1998-05-21 CN CN98109273A patent/CN1055470C/zh not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4007196A (en) * | 1973-01-30 | 1977-02-08 | A/S Ferrosan | 4-Phenylpiperidine compounds |
US4902801A (en) * | 1985-08-10 | 1990-02-20 | Beecham Group Plc. | Process for preparing aryl-piperidine carbinols and novel intermediates used in the process |
EP0374675A2 (en) * | 1988-12-22 | 1990-06-27 | Novo Nordisk A/S | Reduction of piperidine-dion-derivatives and intermediates |
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