CN1099389A - N-乙酰基神经氨酸衍生物的合成 - Google Patents
N-乙酰基神经氨酸衍生物的合成 Download PDFInfo
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Abstract
5-乙酰氨基-2,3,4,5-四脱氧-4-胍基-D-甘
油基-D-乳壬-2-烯吡喃糖酸的制备方法,它包括在
水性介质中将5-乙酰氨基-2,3,4,5-四脱氧-4-氨
基-D-甘油基-D-乳壬-2-烯吡喃糖酸与吡唑-1H-
羟酰胺或其衍生物反应。
Description
本发明涉及N-乙酰基神经氨酸衍生物的制备方法。具体地说,本发明涉及5-乙酰氨基-2,3,4,5-四脱氧-4-胍基-D-甘油基-D-乳壬-2-烯吡喃糖酸(DANA的4-胍基类似物;也称为5-(乙酰氨基)-2,6-脱水-4-胍基-D-甘油基-D-甘油基-D-乳壬-2-烯酸)及其衍生物的制备方法。
PCT/AU91/00161(公开号WO91/16320)描述了多种包括DANA的4-胍基类似物在内的5-乙酰氨基-2,3,5-三脱氧-D-甘油基-D-乳壬-2-烯吡喃糖酸(2,3-二脱氧-2,3-二脱水-N-乙酰基-神经氨酸;DANA)衍生物。DANA的4-胍基类似物是通过将对应的0-酰基保护的DANA的4-氨基类似物与S-甲基异脲反应,随后去保护而制得的。
我们现在发现了直接从未保护的DANA的4-氨基类似物制备DANA的4-胍基类似物的方法。
DANA的4-氨基和4-胍基类似物结构如下:
因此,首先本发明提供5-乙酰氨基-2,3,4,5-四脱氧-4-胍基-D-甘油基-D-乳壬-2-烯吡喃糖酸的制备方法,它包括将5-乙酰氨基-4-氨基-2,3,4,5-四脱氧-D-甘油基-D-乳壬-2-烯吡喃糖酸与式(Ⅰ)化合物反应,式(Ⅰ)如下:
式中X1,X2,X3和X4至少有一个是C-R,其余为C-R或N;各R可相同或不同并且是H、C1-6烷基、未取代或取代的苯基、未取代或取代的苯基C1-4烷基或吸电子基团。
在式(Ⅰ)化合物中,当R是吸是子基团时,可以使用任何这样的基团。这样的基团是本领域技术人员所熟知的,例如羧基、硝基和氰基。
式(Ⅰ)化合物可以游离碱或酸加成盐的形式使用。适宜的盐包括从下列无机或有机酸衍生而来的盐:例如盐酸、氢溴酸、硫酸、硝酸、过氯酸、富马酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、甲苯对苯磺酸、酒石酸、乙酸、柠檬酸、甲磺酸、甲酸、苯甲酸、丙二酸、萘-2-磺酸和苯磺酸。
优选的式(Ⅰ)化合物是吡唑环上带有一个C1-6烷基的吡唑-1H-羧酰胺。
特别优选的式(Ⅰ)化合物是游离碱或者最好是酸加成盐形式的吡唑-1H-羧酰胺,例如吡唑-1H-羧酰胺盐酸盐(PCH)。
该反应可方便地在水性介质中进行。所谓水性介质是指包括大量(例如≥50%)水的任何液体介质。优选仅含水的水性介质。
该反应可在室温或高温如30-70℃下进行。该反应最好在约50-55℃进行。
在反应中,DANA的4-氨基类似物与所用的式(Ⅰ)化合物的摩尔比可以是约1∶1到1∶10,例如1∶1到1∶3,式(Ⅰ)化合物最好摩尔过量约1.5-2倍,例如约1.8倍。
反应在约PH6-9的范围内进行。在反应过程中PH可在此范围内变化。
当式(Ⅰ)化合物以酸加成盐的形式使用时,可通过加入一种或多种无机或有机碱而PH值保持在期望的范围内。这样的碱包括例如碱金属氢氧化物和碳酸盐,例如氢氧化锂、碳酸钠或碳酸氢钠;和胺类,例如三乙胺、咪唑或1,8-二氮二环[5.4.0]十一-7-烯(DBU)。保持期望PH所需的碱的量取决于具体所用的碱。控制PH所需的碱的量对于本领域专业人员来说是显而易见的。
可以用任何常规方法从反应混合物中分离所需的DANA的4-胍基类似物,例如用结晶或层析的方法。尤其是可用下述方法分离DANA的4-胍基类似物:即用与水不相溶的并且不能溶解该化合物的有机溶剂处理水性溶液。这样的溶剂包括例如脂肪醇(如甲醇和异丙醇(IPA))和丙酮。
下述实施例仅用来进一步说明本发明,不应该理解为对本发明的限定。
实施例1
5-乙酰氨基-2,3,4,5-四脱氧-4-胍基-D-甘油基-D-乳壬-2-烯吡喃糖酸
将5-乙酰氨基-4-氨基-2,3,4,5-四脱氧-D-甘油基-D-乳壬-2-烯吡喃糖酸三水合物(58.05g;169mmol)的水(300ml)溶液在33℃下搅拌,再一次加入吡唑-1H-羧酰胺盐酸盐(600mmol,87.95g),随后加入三乙胺(60ml,PH=8.4),搅拌5小时。
将此反应混合物粗品加入高速搅拌的甲醇(900ml)中。继续搅拌过夜,收集沉淀固体,用4∶1甲醇/水(250ml)洗涤,空气干燥,于42℃的真空烘箱干燥2小时。产量=46.7g。
将如此制得的产物(45.5g)悬浮于水(518ml)中,高速搅拌的同时加热。将所得溶液迅速过滤,自然冷却至室温。将溶液进一步冷却(冰-水浴)至3℃,用1小时的时间向该冷溶液中滴加异丙醇(450ml),继续搅拌1.5小时以上。滤出沉淀固体,于40℃干燥,得到与真实样本相同的标题化合物(30.49g)。
实施例2
5-乙酰氨基-2,3,4,5-四脱氧-4-胍基-D-甘油基-D-乳壬-2-烯吡喃糖酸
将5-乙酰氨基-4-氨基-2,3,4,5-四脱氧-D-甘油基-D-乳壬-2-烯吡喃糖酸三水合物(15.0g)、吡唑-1H-羧酰胺盐酸盐(7.55g)和咪唑(11.55g)与水(52.5ml)的混合物于50-55℃加热搅拌。18小时后,用丙酮(150ml)处理所得浆液15分钟,同时保持容器内物料温度为50-55℃。然后将混合物冷却至15-20℃,再过3小时,真空滤集产物。滤饼依次用4∶1丙酮/水(2×25ml)和丙酮(25ml)洗涤。产物在室温空气干燥,得标题化合物(10.98g)。
PMR(D2O) 2.04(3H,s),3.67(2H,m),3.93(2H,m),4.23(1H,m),4.42(2H,m),5.63(1H,d,J2.5Hz)
IR(Nujol) 3428,3338,3253:NH,OH
1692,1666,1646,1619,1575,CO(CH3CONH,CO2),CN.
Claims (13)
2、权利要求1的方法,其中式(Ⅰ)化合物是吡唑-1H-羧酰胺或其在吡唑环上带有C1-6烷基的衍生物。
3、权利要求2的方法,其中式(Ⅰ)化合物是吡唑-1H-羧酰胺。
4、权利要求1-3任一项的方法,其中式(Ⅰ)化合物是酸加成盐的形式。
5、权利要求1-4任一项的方法,其中所述盐是盐酸盐。
6、权利要求1-5任一项的方法,其中反应在水性介质中进行。
7、权利要求6的方法,其中水性介质是水。
8、权利要求1-7任一项的方法,其中该过程在30-70℃的温度下进行。
9、权利要求8的方法,其中温度是50-55℃。
10、权利要求1-9任一项的方法,其中5-乙酰氨基-2,3,4,5-四脱氧-4-氨基-D-甘油基-D-乳壬-2-烯吡喃糖酸与式(Ⅰ)化合物的摩尔比在1∶1到1∶10的范围内。
11、权利要求10的方法,其中摩尔比是约1∶1.8。
12、权利要求1-11任一项的方法,其中PH值在6-9的范围内。
13、用权利要求1-12任一项的方法制备5-乙酰氨基-2,3,4,5-四脱氧-4-胍基-D-甘油基-D-乳壬-2-烯吡喃糖酸。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9220327.2 | 1992-09-25 | ||
GB929220327A GB9220327D0 (en) | 1992-09-25 | 1992-09-25 | Process |
Publications (2)
Publication Number | Publication Date |
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CN1099389A true CN1099389A (zh) | 1995-03-01 |
CN1041416C CN1041416C (zh) | 1998-12-30 |
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Application Number | Title | Priority Date | Filing Date |
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CN93118291A Expired - Lifetime CN1041416C (zh) | 1992-09-25 | 1993-09-24 | N-乙酰基神经氨酸衍生物的合成 |
Country Status (21)
Country | Link |
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EP (1) | EP0662967B1 (zh) |
CN (1) | CN1041416C (zh) |
AT (1) | ATE162188T1 (zh) |
AU (1) | AU672634B2 (zh) |
CA (1) | CA2144342C (zh) |
CY (1) | CY2110B1 (zh) |
DE (1) | DE69316382T2 (zh) |
DK (1) | DK0662967T3 (zh) |
ES (1) | ES2112433T3 (zh) |
FI (1) | FI112224B (zh) |
GB (1) | GB9220327D0 (zh) |
GR (1) | GR3026298T3 (zh) |
IL (1) | IL107069A (zh) |
IS (1) | IS4071A (zh) |
MX (1) | MX9305902A (zh) |
NO (1) | NO308743B1 (zh) |
PL (1) | PL174446B1 (zh) |
SG (1) | SG50642A1 (zh) |
TW (1) | TW282464B (zh) |
WO (1) | WO1994007886A1 (zh) |
ZA (1) | ZA937032B (zh) |
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AU720933B2 (en) | 1995-02-27 | 2000-06-15 | Gilead Sciences, Inc. | Novel selective inhibitors of viral or bacterial neuraminidases |
US5866601A (en) * | 1995-02-27 | 1999-02-02 | Gilead Sciences, Inc. | Carbocyclic compounds |
US5763483A (en) * | 1995-12-29 | 1998-06-09 | Gilead Sciences, Inc. | Carbocyclic compounds |
US5859284A (en) | 1996-08-23 | 1999-01-12 | Gilead Sciences, Inc. | Preparation of carbocyclic compounds |
US6518438B2 (en) | 1996-08-23 | 2003-02-11 | Gilead Sciences, Inc. | Preparation of cyclohexene carboxylate derivatives |
US5994377A (en) | 1996-10-21 | 1999-11-30 | Gilead Sciences, Inc. | Piperidine compounds |
US5886213A (en) * | 1997-08-22 | 1999-03-23 | Gilead Sciences, Inc. | Preparation of carbocyclic compounds |
TW480247B (en) * | 1997-12-12 | 2002-03-21 | Gilead Sciences Inc | Novel compounds useful as neuraminidase inhibitors and pharmaceutical compositions containing same |
DE10230780A1 (de) * | 2002-07-09 | 2004-02-05 | Degussa Ag | Verfahren zur Herstellung von 1-Methylcyclopropylguanidin bzw. dessen Salzen |
AU2009321347A1 (en) | 2008-11-28 | 2010-06-03 | Cipla Limited | Process for preparing zanamivir and intermediates for use in the process |
US20140073804A1 (en) | 2011-02-24 | 2014-03-13 | Ganpat Dan Shimbhu CHARAN | Process for the preparation of zanamivir |
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SK282950B6 (sk) * | 1990-04-24 | 2003-01-09 | Biota Scientific Management Pty Ltd | Deriváty alfa-D-neuramínovej kyseliny, spôsob ich prípravy, ich použitie a farmaceutické prípravky na ich báze |
CA2081068C (en) * | 1991-10-23 | 2005-11-29 | Laurence Mark Von Itzstein | Antiviral 4-substituted-2-deoxy-2,3-didehydro-derivatives of .alpha.-d-neuraminic acid |
GB9126725D0 (en) * | 1991-12-17 | 1992-02-12 | Glaxo Group Ltd | Process |
-
1992
- 1992-09-25 GB GB929220327A patent/GB9220327D0/en active Pending
-
1993
- 1993-09-17 TW TW082107635A patent/TW282464B/zh not_active IP Right Cessation
- 1993-09-20 IS IS4071A patent/IS4071A/is unknown
- 1993-09-22 IL IL107069A patent/IL107069A/en not_active IP Right Cessation
- 1993-09-23 ES ES93921840T patent/ES2112433T3/es not_active Expired - Lifetime
- 1993-09-23 AT AT93921840T patent/ATE162188T1/de active
- 1993-09-23 SG SG1996007544A patent/SG50642A1/en unknown
- 1993-09-23 EP EP93921840A patent/EP0662967B1/en not_active Expired - Lifetime
- 1993-09-23 AU AU51088/93A patent/AU672634B2/en not_active Expired
- 1993-09-23 WO PCT/EP1993/002575 patent/WO1994007886A1/en active IP Right Grant
- 1993-09-23 ZA ZA937032A patent/ZA937032B/xx unknown
- 1993-09-23 CA CA002144342A patent/CA2144342C/en not_active Expired - Lifetime
- 1993-09-23 PL PL93308203A patent/PL174446B1/pl unknown
- 1993-09-23 DK DK93921840T patent/DK0662967T3/da active
- 1993-09-23 DE DE69316382T patent/DE69316382T2/de not_active Expired - Lifetime
- 1993-09-24 MX MX9305902A patent/MX9305902A/es unknown
- 1993-09-24 CN CN93118291A patent/CN1041416C/zh not_active Expired - Lifetime
-
1995
- 1995-03-23 FI FI951378A patent/FI112224B/fi not_active IP Right Cessation
- 1995-03-24 NO NO951136A patent/NO308743B1/no not_active IP Right Cessation
-
1998
- 1998-03-06 GR GR980400469T patent/GR3026298T3/el unknown
- 1998-09-10 CY CY9800026A patent/CY2110B1/xx unknown
Also Published As
Publication number | Publication date |
---|---|
DK0662967T3 (da) | 1998-09-14 |
ATE162188T1 (de) | 1998-01-15 |
DE69316382T2 (de) | 1998-07-23 |
EP0662967A1 (en) | 1995-07-19 |
CA2144342C (en) | 2000-05-16 |
TW282464B (zh) | 1996-08-01 |
CA2144342A1 (en) | 1994-04-14 |
FI112224B (fi) | 2003-11-14 |
WO1994007886A1 (en) | 1994-04-14 |
AU5108893A (en) | 1994-04-26 |
NO308743B1 (no) | 2000-10-23 |
PL308203A1 (en) | 1995-07-24 |
EP0662967B1 (en) | 1998-01-14 |
NO951136D0 (no) | 1995-03-24 |
IL107069A0 (en) | 1993-12-28 |
ZA937032B (en) | 1994-05-16 |
ES2112433T3 (es) | 1998-04-01 |
AU672634B2 (en) | 1996-10-10 |
DE69316382D1 (de) | 1998-02-19 |
IS4071A (is) | 1994-03-26 |
NO951136L (no) | 1995-05-08 |
FI951378A (fi) | 1995-03-23 |
GB9220327D0 (en) | 1992-11-11 |
CY2110B1 (en) | 2002-04-26 |
GR3026298T3 (en) | 1998-06-30 |
SG50642A1 (en) | 1999-04-27 |
IL107069A (en) | 1998-01-04 |
PL174446B1 (pl) | 1998-07-31 |
CN1041416C (zh) | 1998-12-30 |
FI951378A0 (fi) | 1995-03-23 |
MX9305902A (es) | 1994-05-31 |
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