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 PDF

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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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diamino
amino
methyl alcohol
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CN1325386A (zh
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W·布里登
E·塞卡利
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Lonza AG
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—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
    • 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

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
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)

1.通式I表示的4-[(2’，5’-二氨基-6’-卤代嘧啶-4’-基)氨基]-环戊-2-烯基甲醇的制备方法，式中X表示卤原子，其特征在于在碱金属或碱土金属碳酸盐的存在下或在碱金属或碱土金属碳酸氢盐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
Figure C9981284500022
式中X的定义同上，与式III的4-氨基环戊-2-烯基甲醇
Figure C9981284500023
或其盐反应，产生通式I的最终产物。
2.如权利要求1所述的方法，其特征在于C1-4链烷醇用作极性质子溶剂。
3.如权利要求1或2所述的方法，其特征在于反应在20℃至相应溶剂的回流温度之间的一个温度下进行。
CN99812845A 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 Expired - Fee Related CN1115338C (zh)

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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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DE59905679D1 (de) 1998-10-30 2003-06-26 Lonza Ag Verfahren zur herstellung von 4-[(2',5'-diamino-6'-halogenpyrimidin-4'-yl)amino]-cyclopent-2-enylmethanolen
EP2336120B1 (en) 2007-01-10 2014-07-16 MSD Italia S.r.l. Combinations containing amide substituted indazoles as poly(adp-ribose)polymerase (parp) inhibitors
BRPI0906020A2 (pt) 2008-01-08 2015-06-30 Merck Sharp & Dohme Sais farmaceuticamente aceitáveis de 2-{4-[ (3s) - piperidina-3-il ] fenil} -2h - indazol - 7 - carboxamida, uso e método de tratamento

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IT1229531B (it) * 1988-01-20 1991-09-04 Univ Minnesota Composti nucleosidi dideossidideidrocarbociclici e formulazione farmaceutica che li contiene
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
US6368850B1 (en) * 1996-05-30 2002-04-09 Lonza Ag Process for the preparation of amino alcohols and derivatives thereof

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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

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CZ20011486A3 (cs) 2001-10-17
PL198180B1 (pl) 2008-06-30
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JP4457496B2 (ja) 2010-04-28
AU1158000A (en) 2000-05-22
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ES2200594T3 (es) 2004-03-01
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PL347503A1 (en) 2002-04-08
CN1325386A (zh) 2001-12-05
CA2348374C (en) 2009-04-07
IL142760A0 (en) 2002-03-10
EP1124805A1 (de) 2001-08-22
ATE240945T1 (de) 2003-06-15
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