CN103739483B - 一种反式-(1r,2r)-2-(3,4-二氟苯基)-1-环丙烷甲酸的制备方法 - Google Patents
一种反式-(1r,2r)-2-(3,4-二氟苯基)-1-环丙烷甲酸的制备方法 Download PDFInfo
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Abstract
本发明属于药物合成技术领域，具体涉及一种反式-(1R，2R)-2-(3，4-二氟苯基)-1-环丙烷甲酸的制备方法。本发明是以(E)-3-(3，4-二氟苯基)丙-2-烯-1-醇为起始原料，通过手性配体的诱导作用，高度立体选择性的得到反式-(1R，2R)-2-(3，4-二氟苯基)-1-环丙烷甲醇，氧化该醇得到反式-(1R，2R)-2-(3，4-二氟苯基)-1-环丙烷甲酸。该制备方法简便，经济环保，原料易得，收率高，得到的产品纯度好且立体选择性好。
Description
技术领域
本发明涉及一种反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸的制备方法，属于药物合成技术领域。
背景技术
替卡格雷，化学名为(1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-二氯苯基)环丙氨基]-5-(硫丙基)-3H-[1,2,3]三唑[4,5-d]嘧啶-3-基]-5-(2-羟基乙氧基)环戊烷-1,2-二醇。该药是由美国阿斯利康(AstraZeneca)公司研发的一种新型的、具有选择性的小分子抗凝血药。口服使用后起效迅速，能有效改善急性冠心病患者的症状。替卡格雷的抗血小板作用是可逆的，其对于那些需要在先期进行抗凝治疗后再行手术的病人尤为适用。是一种前景广阔的抗凝血药。
替卡格雷的合成路线和制备方法已有报道：CN1334816、CN1680340、CN101143864、CN102731467、CN102659815、CN102675321、WO2010030224、WO2011036479、WO2012138981等专利中均使用不同的合成路线研究了替卡格雷的制备方法。分析已公开的合成路线和制备方法后发现，反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸在合成其中间体反式-(1R,2S)-2-(3,4-二氟苯基)-1-环丙胺中起着重要的作用，已有的合成反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸或其异构体的方法主要有以下几种：
1、专利CN1431992和CN1200940采用的路线：
以3,4-二氟苯甲醛为原料，制成丙烯酸和丙烯酸酰氯衍生物，再通过L-薄荷醇的手性诱导和硫叶立得的环丙烷化,最后水解得到目标产物。该路线反应步骤较长，用到的酰氯对设备有腐蚀作用，收率上也不高，不利于工业化。
2、WO2011017108采用的路线：
该路线号改用樟脑磺内酰胺代替L-薄荷醇进行手性诱导反应，配体樟脑磺内酰胺和醋酸钯价格昂贵，后处理过程涉及柱层析。因而，该法同样存在不易工业化的问题。
3、CN103003231采用的路线：
以3,4-二氟苯甲醛为原料，经过磷叶立得反应制得3,4-二氟苯乙烯，该烯烃在手性催化剂作用下和重氮基乙酸乙酯反应环丙化，该环丙化合物经水解得到。该步反应用了昂贵的拔氢试剂1,8-二氮杂双环[5.4.0]十一碳-7-烯和手性配体，增加了成本。
4、WO2013144295采用的路线：
以3,4-二氟苯甲醛为原料，制成丙烯酸和丙烯酸酰氯衍生物，再通过与N,O-二甲基羟胺盐酸盐反应形成酰胺，硫叶立得环丙烷化,最后水解得到目标产物。该路线反应步骤较长，用到的酰氯对设备有腐蚀作用，且得到的为消旋化的产物，不利于工业化。
5、WO2013124280采用的路线一：
该步骤中傅-克酰基化的条件苛刻，纯化过程用到层析柱，路线较长，且得到的产物为消旋体，需进一步分体纯化才能得到目标产物，整体收率很低。
6、WO2013124280采用的路线二：
该步骤中傅-克酰基化的条件苛刻，手性还原用到的配体较贵重，且不可回收，整体收率很低。
综上所述，虽然对反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸的制备研究较多，但都或多或少存在缺陷，如步骤较长、原料难得、收率偏低、分离困难、污染较重和成本较高等，这些不利因素使得上述工艺的工业化受到一定的制约。
发明内容
本发明的目的在于提供一种替卡格雷中间体反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸的制备方法，具体地，以(E)-3-(3,4-二氟苯基)丙-2-烯-1-醇为起始原料，通过手性配体(1R,2R)-1,2-N,N'-二(3,5-二氯苯磺酰胺基)环己烷的诱导作用，高度立体选择性的得到反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲醇，氧化该醇得到目标产物。
其中，(E)-3-(3,4-二氟苯基)丙-2-烯-1-醇可通过购买或参考专利CN1431992和文献J.Chem.Res.,2003,8,522-525制备，手性配体(1R,2R)-1,2-N,N'-二(3,5-二氯苯磺酰胺基)环己烷可通过购买或以相应的磺酰氯与(1R,2R)-(-)-1,2-环己二胺反应得到。
本发明采用的技术方案如下：一种反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸的制备方法，
该方法包括以下步骤：
(1)(E)-3-(3,4-二氟苯基)丙-2-烯-1-醇与Zn(Et)2和CH2I2及(1R,2R)-1,2-N,N'-二(3,5-二氯苯磺酰胺基)环己烷反应得到反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲醇；
(2)反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲醇与H5IO6和CrO3反应成为反-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸，反应式如下：
步骤(1)中的反应温度为-15-0℃，反应所采用的溶剂不为醚类，在乙醚、四氢呋喃等醚类溶剂中，该反应不能发生，优选的反应溶剂为甲苯、正己烷、二氯甲烷中的一种或多种，其中在二氯甲烷中，反应的收率较好，故最优选的反应溶剂为二氯甲烷。
步骤(1)中(E)-3-(3,4-二氟苯基)丙-2-烯-1-醇：Zn(Et)2：CH2I2：(1R,2R)-1,2-N,N'-二(3,5-二氯苯磺酰胺基)环己烷的摩尔配比为：1.0:2.0-3.0:2.5-3.5:0.05-0.1；
步骤(2)中采用的反应温度为0-10℃，溶剂为含水量为1.0％-2.0％(体积比)的乙腈，此含水量的乙腈，大大缩短了H5IO6和CrO3的溶解时间，且对反应没有影响。
步骤(2)中反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲醇：H5IO6：CrO3的摩尔配比为：1.0:2.0-3.0:0.003-0.005，较小催化量的CrO3，既能很好的促进反应，又减少了环境的污染，采用H5IO6和CrO3的氧化组合，以超高的收率得到了目标产物，且没有检测到酯类副产物。
本发明的有益效果是：该制备方法简便，经济环保，原料易得，收率高，得到的产品纯度好且立体选择性好。
具体实施例
通过以下实施例来进一步说明本发明，以下实施例仅用于例证，而不限制本发明。
实施例1、制备反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲醇：
(E)-3-(3,4-二氟苯基)丙-2-烯-1-醇(1.70g，10mmol)和(1R,2R)-1,2-N,N'-二(3,5-二氯苯磺酰胺基)环己烷(5mmol％)的100mL无水CH2Cl2溶液，保持温度-15-0℃，加入Et2Zn(1mol/L正己烷溶液20mL，20mmol)和CH2I2(8.04g，30mmol)，保温反应5小时，升至室温，加入2mol/L的NaOH溶液50mL，用100mL CH2Cl2提取3次，催化剂可以通过酸化水层得到回收。合并有机层，并用饱和氯化钠水溶液洗涤一次，无水Na2SO4干燥，减压蒸出溶剂，即得反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲醇1.66g，收率90％，ee值:97％(HPLC，手性柱，3％异丙醇正己烷)。IR(KBr)：3450,362,3012,2927,1865,1605,1498,1461,1090,1413,1020；1HNMR(400MHz,CDCl3,):δ7.21-7.26(m,1H),7.07-7.14(m,2H),3.41-3.50(m,2H),1.68-1.81(m,1H),1.46(br,1H),1.23-1.36(m,1H),0.71-0.98(m,2H)。
实施例2、制备反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲醇：
(E)-3-(3,4-二氟苯基)丙-2-烯-1-醇(1.70g，10mmol)和(1R,2R)-1,2-N,N'-二(3,5-二氯苯磺酰胺基)环己烷(5mmol％)的100mL无水CH2Cl2溶液，保持温度-15-0℃，加入Et2Zn(1mol/L正己烷溶液21mL，21mmol)和CH2I2(8.04g，30mmol)，保温反应5小时，后处理过程参考实施例1，收率94％，ee值:98.9％。
实施例3、制备反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲醇
(E)-3-(3,4-二氟苯基)丙-2-烯-1-醇(1.70g，10mmol)和(1R,2R)-1,2-N,N'-二(3,5-二氯苯磺酰胺基)环己烷(10mmol％)的100mL无水CH2Cl2溶液，保持温度-15-0℃，加入Et2Zn(1mol/L正己烷溶液25mL，25mmol)和CH2I2(9.4g，35mmol)，保温反应5小时，后处理过程参考实施例1，收率98％，ee值:99.8％。
实施例4、制备反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸
H5IO6(11.4g，50mmol)和CrO3(5.8mg，0.3mmol％)加入MeCN(1.0％H2O体积比)至114mL，搅拌直至完全溶解后，缓慢滴加到含有反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲醇(3.68g，20mmol)的100mL乙腈溶液中，保持温度0-10℃，滴毕，保温反应1小时，反应完毕后，用Na2HPO4溶液淬灭，100mL甲苯提取3次，有机层饱1:1食盐水，NaHSO3(5mol/L)水溶液以及饱和食盐水洗涤，干燥并浓缩，得到反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸3.77g，收率95％，纯度：99.5％(HPLC，面积归一化法)。1H-NMR(CDCl3,δ):1.33-1.40(1H,m)，1.64-1.69(1H,m)，1.82-1.87(1H,m)，2.55-2.62(1H,m)，6.82-6.92(2H,m)，7.03-7.11(1H,m)，10.0(1H,br)。
实施例5、制备反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸
H5IO6(13.7g，60mmol)和CrO3(9.5mg，0.5mmol％)加入MeCN(1.0％H2O体积比)至100mL，搅拌直至完全溶解后，缓慢滴加到含有反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲醇(3.68g，20mmol)的100mL乙腈溶液中，保持温度0-10℃，滴毕，保温反应1小时，后处理参考实施例4，收率100％，纯度：99.8％。
实施例6、制备反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸
H5IO6(13.7g，60mmol)和CrO3(9.5mg，0.5mmol％)加入MeCN(2.0％H2O体积比)至100mL，搅拌直至完全溶解后，缓慢滴加到含有反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲醇(3.68g，20mmol)的100mL乙腈溶液中，保持温度0-10℃，滴毕，保温反应1小时，后处理参考实施例4，收率100％，纯度：99.7％。
Claims (6)
1.一种反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸的制备方法，
其特征在于包括如下步骤：
(1)(E)-3-(3,4-二氟苯基)丙-2-烯-1-醇与Zn(Et)2和CH2I2及配体(1R,2R)-1,2-N,N'-二(3,5-二氯苯磺酰胺基)环己烷反应得到反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲醇；
(2)反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲醇与H5IO6和CrO3反应成为反-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸
2.如权利要求1所述的反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸的制备方法，其特征在于：
步骤(1)中所采用的溶剂不为醚类，(E)-3-(3,4-二氟苯基)丙-2-烯-1-醇：Zn(Et)2：CH2I2：(1R,2R)-1,2-N,N'-二(3,5-二氯苯磺酰胺基)环己烷的摩尔配比为：1.0:1.0-3.0:2.0-4.0:0.01-0.5；
步骤(2)中采用的溶剂为含水量为1.0％-2.0％体积比的乙腈，反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲醇：H5IO6：CrO3的摩尔配比为：1.0:2.0-3.0:0.003-0.005。
3.如权利要求1所述的反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸的制备方法，其特征在于：步骤(1)中所采用的溶剂为甲苯、正己烷、二氯甲烷中的一种或多种。
4.如权利要求3所述的反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸的制备方法，其特征在于：步骤(1)中所采用的溶剂为二氯甲烷。
5.如权利要求1所述的反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸的制备方法，其特征在于：步骤(1)的反应温度为-15-0℃；步骤(2)的反应温度为0-10℃。
6.如权利要求1所述的反式-(1R,2R)-2-(3,4-二氟苯基)-1-环丙烷甲酸的制备方法，其特征在于：步骤(2)的反应温度为0-10℃。
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