CN1115338C - 4-[(2′,5′-二氨基-6′-卤代嘧啶-4′-基)氨基]-环戊-2-烯基甲醇的制备方法 - Google Patents
4-[(2′,5′-二氨基-6′-卤代嘧啶-4′-基)氨基]-环戊-2-烯基甲醇的制备方法 Download PDFInfo
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- CN1115338C CN1115338C CN99812845A CN99812845A CN1115338C CN 1115338 C CN1115338 C CN 1115338C CN 99812845 A CN99812845 A CN 99812845A CN 99812845 A CN99812845 A CN 99812845A CN 1115338 C CN1115338 C CN 1115338C
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
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Abstract
本发明涉及通式(I)表示的4-[(2’,5’-二氨基-6’-卤代嘧啶-4’-基)氨基]-环戊-2-烯基甲醇的新颖制备方法,式中X表示卤原子。按照本发明方法,在碱的存在下和在极性质子溶剂中使通式(II)的2,5-二氨基-4,6-卤代嘧啶(式中X的定义同上)与式(III)的4-氨基环戊-2-烯基甲醇或其盐反应。
Description
说明
本发明涉及通式I的4-[(2’,5’-二氨基-6’-卤代嘧啶-4’-基)氨基]-环戊-2-烯基甲醇的新制备方法
4-[(2’,5’-二氨基-6’-卤代嘧啶-4’-基)氨基]-环戊-2-烯基甲醇是制备抗病毒核苷酸衍生物的重要中间体(WO91/01310)。
以4-乙酰氨基环戊-2-烯基甲醇为原料,将二异丙基乙基胺用作碱,通过在丁醇中与2-氨基-4,6-二氯嘧啶反应合成4-[(2’,5’-二氨基-6’-卤代嘧啶-4’-基)氨基]-环戊-2-烯基甲醇的三步法是已知的。在该方法中,先形成[(2’-氨基-6’-氯嘧啶-4’-基)氨基]-环戊-2-烯基甲醇,然后在一个后续步骤中通过重氮化转化成相应的胺,再水解成最终产物(J.Chem.Soc.Perkin.Trans.,1,1992)。该方法的缺点是成本太高,而所需最终产物的收率仅为一般。
本发明的任务是提供一种4-[(2’,5’-二氨基-6’-卤代嘧啶-4’-基)氨基]-环戊-2-烯基甲醇的一步制备方法。该方法的成本较低,且能高收率地得到所需的最终产物。
这个任务由权利要求1所述的方法加以解决。
令人惊奇地发现,当用通式II的2,5-二氨基-4,6-二卤代嘧啶代替2-氨基-4,6-二氯嘧啶用作原料,且在碱的存在下和在极性质子溶剂中使其与式III的4-氨基环戊-2-烯基甲醇或其盐反应时,可以低几倍的成本和高收率地得到所需的通式I最终产物。取代基X是指卤原子,如F、Cl、Br或I。
2,5-二氨基-4,6-二卤代嘧啶,如2,5-二氨基-4,6-二氯嘧啶可根据EP-A-0684326所述的方法进行制备。
外消旋的和光学活性的化合物如(1R,4S)-、(1S,4R)-、(1R,4R)-或(1S,4S)-4-氨基环戊-2-烯基甲醇可用作4-氨基环戊-2-烯基甲醇。其合适的盐是酸加成盐,特别是氢卤酸盐,如盐酸盐或氢溴酸盐。4-氨基环戊-2-烯基甲醇,特别是(1R,4S)-或(1S,4R)-对映体可按WO97/45529所述的方法制备。
该反应宜在碱金属或碱土金属碳酸盐、碱金属或碱土金属碳酸氢盐或氮碱(如叔胺)(均用作碱)的存在下进行。碳酸钠、碳酸钾、碳酸氢钠或碳酸氢钾可用作碱金属碳酸盐或碱金属碳酸氢盐。碳酸钙、碳酸镁、碳酸氢钙可用作碱金属碳酸盐或碱金属碳酸氢盐。三乙胺和二异丙基乙基胺可适用作叔胺。该反应较好地在碱金属碳酸氢盐(如碳酸氢钠)或叔胺(二异丙基乙基胺)的存在下进行。
相对于2,5-二氨基-4,6-二卤代嘧啶,上述的碱宜过量使用,较好每摩尔2,5-二氨基-4,6-二卤代嘧啶使用1-4摩尔的碱。
适用作极性质子溶剂的特别是C1-4烷醇,如甲醇、乙醇、丙醇及其异构体和丁醇及其异构体。
该反应宜在20℃至相应溶剂的回流温度之间的一个温度进行,较好在50℃至回流温度之间的一个温度进行。宜等摩尔地使用4-氨基环戊-2-烯基甲醇和2,5-二氨基-4,6-二卤代嘧啶。
在2-20小时的常规反应时间后,可以用常规的后处理方法得到式I的最终产物,较好是(1S,4R)-4-[(2’,5’-二氨基-6’-卤代嘧啶-4’-基)氨基]-环戊-2-烯基甲醇。
实施例
实施例1
在碳酸氢钠的存在下制备4-[(2’,5’-二氨基-6’-氯嘧啶-4’-基)氨基]-环戊-2-烯基甲醇
在一个干燥的反应器中加入(1S,4R)-4-氨基环戊-2-烯基甲醇盐酸盐(0.14摩尔,23.25克)、乙醇(3摩尔,138.12克、176毫升)、2,5-二氨基-4,6-二氯嘧啶(0.14摩尔,25克)和碳酸氢钠(0.34摩尔,28.68克)。在回流温度(约80℃)将该混合物加热16小时。然后用薄层色谱法(TLC)检测转化率。13/1二氯甲烷:甲醇用作展开剂。将该反应混合物冷却至室温,搅拌45分钟。过滤除去盐,用乙醇(0.86摩尔,39.5克,50毫升)将滤饼洗涤两次。
通过真空蒸馏除去2/3有机相后,滴加己烷(150毫升)。将该悬浮液冷却至10℃以下。过滤后在50℃真空干燥。
得到21.5克(0.08摩尔)产物,相当于60%的收率。
实施例2
在二异丙基乙基胺的存在下制备4-[(2’,5’-二氨基-6’-氯嘧啶-4’-基)氨基]-环戊-2-烯基甲醇
在一个干燥的反应器中加入(1S,4R)-4-氨基环戊-2-烯基甲醇盐酸盐(0.14摩尔,23.18克)、丁醇(1.26摩尔,93.39克、115.3毫升)、2,5-二氨基-4,6-二氯嘧啶(0.14摩尔,25.67克)和二异丙基乙基胺(0.29摩尔,37.09克,49.99毫升)。在回流温度(约115℃)将该混合物加热过夜。然后用薄层色谱法(TLC)检测转化率。13/1二氯甲烷:甲醇用作展开剂。将该反应混合物冷却至室温。然后加入水,最后用乙酸乙酯萃取两次。
有机相用水洗涤两次,然后用C盐(Celite)过滤有机相。通过真空蒸馏除去2/3有机相后,滴加己烷。将该悬浮液冷却至10℃以下。过滤后在50℃真空干燥。
得到21.47克(0.08摩尔)产物,相当于60%的收率。
Claims (3)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP98120529 | 1998-10-30 | ||
EP98120529.7 | 1998-10-30 | ||
US14610599P | 1999-07-29 | 1999-07-29 | |
US60/146,105 | 1999-07-29 |
Publications (2)
Publication Number | Publication Date |
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CN1325386A CN1325386A (zh) | 2001-12-05 |
CN1115338C true CN1115338C (zh) | 2003-07-23 |
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Application Number | Title | Priority Date | Filing Date |
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CN99812845A Expired - Fee Related CN1115338C (zh) | 1998-10-30 | 1999-10-29 | 4-[(2′,5′-二氨基-6′-卤代嘧啶-4′-基)氨基]-环戊-2-烯基甲醇的制备方法 |
Country Status (14)
Country | Link |
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EP (1) | EP1124805B1 (zh) |
JP (1) | JP4457496B2 (zh) |
CN (1) | CN1115338C (zh) |
AT (1) | ATE240945T1 (zh) |
AU (1) | AU1158000A (zh) |
CA (1) | CA2348374C (zh) |
CZ (1) | CZ300155B6 (zh) |
DK (1) | DK1124805T3 (zh) |
ES (1) | ES2200594T3 (zh) |
HU (1) | HU227559B1 (zh) |
IL (1) | IL142760A (zh) |
PL (1) | PL198180B1 (zh) |
SK (1) | SK285271B6 (zh) |
WO (1) | WO2000026193A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103626745A (zh) * | 2013-12-04 | 2014-03-12 | 青岛黄海制药有限责任公司 | 一种替卡格雷中间体的制备方法 |
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Publication number | Priority date | Publication date | Assignee | Title |
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KR100606625B1 (ko) | 1998-10-30 | 2006-07-28 | 론자 아게 | 4-[(2',5'-디아미노-6'-할로피리미딘-4'-일)아미노]-시클로펜트-2-에닐메탄올의 제조 방법 |
MX2009007200A (es) | 2007-01-10 | 2009-07-15 | Angeletti P Ist Richerche Bio | Indazoles sustituidos con amida como inhibidores de poli(adp-ribosa)polimerasa (parp). |
US8436185B2 (en) | 2008-01-08 | 2013-05-07 | Merck Sharp & Dohme Corp. | Pharmaceutically acceptable salts of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide |
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YU47791B (sr) * | 1988-01-20 | 1996-01-09 | Regents Of The University Of Minnesota | Postupak za dobijanje dideoksihidrokar-bocikličnih nukleozida |
GB8916698D0 (en) * | 1989-07-21 | 1989-09-06 | Beecham Group Plc | Novel process |
MY104575A (en) * | 1989-12-22 | 1994-04-30 | The Wellcome Foundation Ltd | Therapeutic nucleosides. |
CA2145928C (en) * | 1994-04-27 | 2007-10-09 | Gerhard Stucky | N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide, and a process for its preparation |
IL127235A (en) * | 1996-05-30 | 2003-04-10 | Lonza Ag | Process for the preparation of amino alcohols and derivatives thereof |
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- 1999-10-29 DK DK99971416T patent/DK1124805T3/da active
- 1999-10-29 PL PL347503A patent/PL198180B1/pl unknown
- 1999-10-29 EP EP99971416A patent/EP1124805B1/de not_active Expired - Lifetime
- 1999-10-29 CA CA002348374A patent/CA2348374C/en not_active Expired - Fee Related
- 1999-10-29 WO PCT/EP1999/008270 patent/WO2000026193A1/de active IP Right Grant
- 1999-10-29 AU AU11580/00A patent/AU1158000A/en not_active Abandoned
- 1999-10-29 JP JP2000579582A patent/JP4457496B2/ja not_active Expired - Fee Related
- 1999-10-29 IL IL14276099A patent/IL142760A/en not_active IP Right Cessation
- 1999-10-29 CZ CZ20011486A patent/CZ300155B6/cs not_active IP Right Cessation
- 1999-10-29 HU HU0104045A patent/HU227559B1/hu not_active IP Right Cessation
- 1999-10-29 SK SK569-2001A patent/SK285271B6/sk not_active IP Right Cessation
- 1999-10-29 AT AT99971416T patent/ATE240945T1/de active
- 1999-10-29 CN CN99812845A patent/CN1115338C/zh not_active Expired - Fee Related
- 1999-10-29 ES ES99971416T patent/ES2200594T3/es not_active Expired - Lifetime
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103626745A (zh) * | 2013-12-04 | 2014-03-12 | 青岛黄海制药有限责任公司 | 一种替卡格雷中间体的制备方法 |
CN103626745B (zh) * | 2013-12-04 | 2016-02-24 | 青岛黄海制药有限责任公司 | 一种替卡格雷中间体的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
WO2000026193A1 (de) | 2000-05-11 |
JP4457496B2 (ja) | 2010-04-28 |
SK5692001A3 (en) | 2001-12-03 |
HUP0104045A3 (en) | 2002-07-29 |
AU1158000A (en) | 2000-05-22 |
HU227559B1 (en) | 2011-08-29 |
PL198180B1 (pl) | 2008-06-30 |
IL142760A (en) | 2005-12-18 |
ATE240945T1 (de) | 2003-06-15 |
CZ300155B6 (cs) | 2009-02-25 |
IL142760A0 (en) | 2002-03-10 |
CA2348374A1 (en) | 2000-05-11 |
ES2200594T3 (es) | 2004-03-01 |
CA2348374C (en) | 2009-04-07 |
HUP0104045A2 (hu) | 2002-05-29 |
EP1124805A1 (de) | 2001-08-22 |
CZ20011486A3 (cs) | 2001-10-17 |
CN1325386A (zh) | 2001-12-05 |
SK285271B6 (sk) | 2006-10-05 |
EP1124805B1 (de) | 2003-05-21 |
PL347503A1 (en) | 2002-04-08 |
JP2003500333A (ja) | 2003-01-07 |
DK1124805T3 (da) | 2003-09-15 |
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