CN107383035A - 2‑((1S3aR7aR)‑5‑叔丁氧羰基四氢呋喃并[3,4]哌啶‑1)乙酸制法 - Google Patents

2‑((1S3aR7aR)‑5‑叔丁氧羰基四氢呋喃并[3,4]哌啶‑1)乙酸制法 Download PDF

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CN107383035A
CN107383035A CN201710530560.1A CN201710530560A CN107383035A CN 107383035 A CN107383035 A CN 107383035A CN 201710530560 A CN201710530560 A CN 201710530560A CN 107383035 A CN107383035 A CN 107383035A
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1s3ar7ar
acetic acid
tertbutyloxycarbonyls
piperidines
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CN107383035B (zh
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陈远丽
韩冰洋
杨云龙
王冰
杜天源
石美奂
陆绘联
于凌波
马汝建
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Changzhou Hequan Pharmaceutical Co ltd
Shanghai SynTheAll Pharmaceutical Co Ltd
Shanghai STA Pharmaceutical R&D Ltd
Wuxi STA Pharmaceutical Co Ltd
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Changzhou Hequan Pharmaceutical Co Ltd
Changzhou Whole New Drug Research And Development Co Ltd
Shanghai Sta Pharmaceutical R & D Co Ltd
Wuxi Wuxi Pharmaceutical Co Ltd
Shanghai SynTheAll Pharmaceutical Co Ltd
Wuxi Apptec Biopharmaceuticals Co Ltd
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Abstract

本发明涉及一种2‑((1S3aR7aR)‑5‑叔丁氧羰基四氢呋喃并[3,4]哌啶‑1)乙酸的合成方法，本发明分11步，由二羧酸吡啶化合物1在二氯亚砜中进行酯化得到二酯化合物2，再用钯碳还原吡啶环得到化合物3，然后与Boc酸酐反应得到boc保护的化合物4，用氢氧化锂水解得到二羧酸化合物5，在乙酸酐中关环得到化合物6，用NaBH4还原开环得到位置异构化合物7A和7B混合物，在碘甲烷，碳酸钾条件下，关环生成位置异构的内酯8A和8B，第八步，过柱分离出来的8A用DIBAH还原得到化合物9，再经过叶立德反应得到化合物10，在碱性条件下进行麦克尔加成得到化合物11，最后化合物11在碱性条件下水解得到最终化合物。

Description

2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸 制法
技术领域
本发明涉及化合物2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸合成方法。
背景技术
化合物2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸(CAS：646518-35-6 )及相关的衍生物在药物化学及有机合成中具有广泛应用。目前2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸合成方法没有文献报道。因此，需要开发一个原料易得，操作方便，反应易于控制，总体收率适合，适合工业化生产的合成方法。
发明内容
本发明的目的是开发一种具有原料易得，操作方便，反应易于控制，收率较高的2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸的合成方法。主要解决目前没有适合工业化合成方法的技术问题。
本发明的技术方案：一种2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸的合成方法，本发明分11步，第一步，首先由二羧酸吡啶化合物1在二氯亚砜中进行酯化得到二酯化合物2，第二步，化合物2用钯碳还原吡啶环得到化合物3，第三步，化合物3与Boc酸酐反应得到boc保护的化合物4，第四步，化合物4用氢氧化锂水解得到二羧酸化合物5，第五步，化合物5在乙酸酐中关环得到化合物6，第六步，化合物6用NaBH4还原开环得到位置异构化合物7A和7B混合物，第七步，7A和7B混合物在碘甲烷，碳酸钾条件下，关环生成位置异构的内酯8A和8B，第八步，过柱分离出来的8A用DIBAH还原得到化合物9，第九步，化合物9经过叶立德反应得到化合物10，第十步，化合物10在碱性条件下进行麦克尔（Michael）加成得到化合物11，第十一步，化合物11在碱性条件下水解得到最终化合物。反应式如下：
第一步回流反应过夜；第二步用到钯碳在50℃50psi下反应；第四步使用了氢氧化锂室温条件下进行水解；第六步，化合物6在四氢呋喃溶液中还原；第八步反应温度为-70℃；用(乙酯基甲基)三苯基磷溴化进行叶立德反应；第十步，所述的碱性条件是加入乙醇钠；第十一步，所述的碱性条件是加入采用氢氧化钠进行水解。
本发明缩写的中文释义：SOCl2 ：二氯亚砜；NaBH4 ：硼氢化钠；Ac2O： 乙酸酐；DIBAH： 二异丁基氢化铝；Boc2O ：Boc酸酐；DMF： N,N-二甲基甲酰胺； [Ph3PCH2CO2Et]+Br-：(乙酯基甲基)三苯基磷溴化。
本发明的有益效果：本发明反应工艺设计合理，其采用了易得、能规模化生产的原料吡啶-3,4-二羧酸，通过11步合成2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸，该方法路线简单，每步都是简单反应，重复操作性强，反应易于放大。
具体实施方式
本发明反应式如下
实施例1：
零度时，SOCl2 (400 mL) 慢慢滴加到甲醇中(2.0 L)，滴加完后，溶液在室温搅拌15分钟，化合物1 (200 g, 1.2 mol) 分批加入到上述溶液中，然后滴加入2,2-二甲氧基丙烷(400 mL)。滴加完后，反应液回流过夜。TLC（二氯甲烷/甲醇的体积比为10:1）显示反应完毕。反应液减压浓缩，弄过残留物中加入乙酸乙酯(2.0 L)并用二甲胺调节pH值到8。混合物用水洗三次，每次用1.0 L水，分离出来的有机相用无水硫酸钠干燥并真空浓缩，最后得到的残留物用硅胶柱色谱纯化（梯度洗脱：石油醚/乙酸乙酯体积比由10/1 到 5/1 到 2/1）得到纯品化合物2为黄色油状物（108 g），收率：46%。
化合物2 (100 g, 0.512 mol)溶于乙酸(1.5 L)中，在氩气保护下加入钯碳 (25g)，混合物在氢气氛(50 psi)和50度下反应24小时。TLC（石油醚/乙酸乙酯的体积比为2:1）显示反应完毕。抽滤漏斗里加上硅藻体对反应液进行抽滤，滤饼用乙酸洗三次，每次用300毫升，滤液减压浓缩得到黄色油状的化合物3(240.5 g, >100%)直接进行下一步反应。
化合物3(195 g, 0.97 mol)溶于甲醇(1.5 L)中，在搅拌及控温零度时滴加三乙胺(589 g, 5.82 mol)，滴加完后零度滴加BOC2O (314 g, 1.46 mol)。滴加完后，反应液在室温下搅拌过夜。TLC（二氯甲烷/甲醇的体积比为10:1）显示反应完毕。反应液减压浓缩，残留物溶于乙酸乙酯(2.0 L)中，并用水洗三次，每次用800毫升。有机相用无水硫酸钠干燥后减压浓缩得到黄色油状的化合物4(178 g), 两步反应的收率为61%。
化合物4(215 g, 0.71 mol)中加入600毫升甲醇和600毫升水，氢氧化锂(150 g,3.55 mol)控温0℃下分批加入。加完后，反应液室温搅拌过夜。TLC（石油醚/乙酸乙酯的体积比为2:1）显示反应完毕。然后反应液用6N盐酸调节pH到3并用水稀释(500 mL)，混合物用二氯甲烷萃取三次，每次用500毫升。合并的有机相用无水硫酸钠干燥并减压浓缩得到黄色油状的化合物5(199.3 g)，收率100%。
化合物5(200 g, 0.73 mol)加入到四氢呋喃(1.5 L)中，室温下滴加入乙酸酐(740 mL)，滴加完后，室温下搅拌2小时。TLC（二氯甲烷/甲醇的体积比为10:1）显示反应完毕。反应液减压浓缩得到黄色油状化合物6 (167 g)，收率92%。
化合物6(167 g, 0.655 mol)加入四氢呋喃(1.5 L)，在搅拌并控温0℃分批加入硼氢化钠(24.6 g, 0.655 mol)。加完后，反应液在0℃搅拌3小时。TLC（二氯甲烷/甲醇的体积比为10:1）显示反应完毕。反应液用饱和柠檬酸溶液(500 mL)和水(1.5 L)淬灭。然后用乙酸乙酯萃取三次，每次用1.0L。合并的有机相用无水硫酸钠干燥并减压浓缩得到黄色油状的化合物7A和7B的混合物(152 g)，收率89%。
7A和7B的混合物(166.5 g, 0.643 mol)中加入DMF (2.0 L)，在搅拌下滴加碘甲烷(183 g, 1.29 mol)，然后分批加入碳酸钾(178 g, 1.29 mol)。加完后，反应混合物室温搅拌3小时。TLC（二氯甲烷/甲醇的体积比为10:1）显示反应完毕。漏斗垫上硅藻土对反应液进行抽滤，滤液减压浓缩，最后得到的残留物用硅胶柱色谱纯化（梯度洗脱：石油醚/乙酸乙酯体积比由10/1 到 5/1 到 2/1）得到纯品化合物8A(62 g)，收率40%，化合物8B(65 g)，收率42%。
在化合物8A (103 g, 0.427 mol)中加入四氢呋喃(1.5 L)，搅拌下控温-70℃时，DIBAH (855 mL, 0.855 mol, 1M 甲苯溶液)滴加入反应液，滴加完后，反应混合物在氮气保护和-70℃下搅拌1.5小时。TLC（石油醚/乙酸乙酯的体积比为2:1）显示反应完毕，反应混合物用甲醇(500 mL)淬灭并在室温下搅拌30分钟。然后漏斗垫上硅藻土把反应混合物抽滤，滤饼用二氯甲烷/甲醇体积比为20/1的溶液洗洗直到把产物完全从滤饼里洗出来。滤液减压浓缩，最后得到的残留物用硅胶柱色谱纯化（梯度洗脱：二氯甲烷/甲醇体积比由200/1~100/1 到 50/1 到 20/1）得到黄色油状化合物9(67 g)，收率64%。
在三苯基磷中加入乙酸乙酯(5.0 L)，混合物在搅拌下滴加入溴乙酸乙酯(665 g,4.01 mol)，滴加完后，反应混合物室温搅拌24小时。然后混合物抽滤，滤饼用乙酸乙酯洗三次，每次用500毫升。滤饼真空干燥得到[Ph3PCH2CO2Et]+Br- (1500 g)白色固体直接用于下一步反应，收率92%。
在[Ph3PCH2CO2Et]+Br- (706.6 g, 1.646 mol)中加入二氯甲烷(2.0 L)，混合物搅拌下滴加入氢氧化钠(98.7 g, 2.469 mol)和水(500 mL)配成的混合液。滴加完后，混合物室温搅拌10分钟。然后分出有机相，水相用二氯甲烷萃取两次，每次用200毫升。合并的有机相用无水硫酸钠干燥并减压浓缩。浓缩残留物加入到化合物9 (200 g, 0.823 mol) 和甲苯 (1.0 L)的混合液中，最后的反应混合物在60℃下搅拌5个小时。TLC（石油醚/乙酸乙酯的体积比为2:1）显示反应完毕，反应混合物减压浓缩得到黄色油状不纯的化合物10(800g)，产率大于100%直接用于下一步反应。
化合物10(800 g, 0.824 mol, 32.2%)溶于无水乙醇(1.5 L)中，搅拌下分批加入乙醇钠(62 g, 0.906 mol)，加完后，反应混合物室温搅拌1.5小时。TLC（石油醚/乙酸乙酯的体积比为2:1）显示反应完毕，反应混合物用水(2.0 L)稀释并用乙酸乙酯萃取三次，每次1.5升。合并的有机相用饱和食盐水洗三次，每次1.5升，然后用无水硫酸钠干燥并减压浓缩。最后得到的残留物用硅胶柱色谱纯化（梯度洗脱：石油醚/乙酸乙酯体积比由20/1~10/1到 5/1 到 2/1）得到黄色油状化合物11(192.6 g)，两步收率75%。
在化合物11 (566 g, 1.81 mol)中加入乙醇（2 L）和水（2 L）的混合液，然后0℃下分批加入氢氧化钠（(108 g, 2.71 mol)。反应混合物室温下搅拌2小时。TLC（石油醚/乙酸乙酯的体积比为2:1）显示反应完毕，反应混合物用1N的盐酸溶液调节pH到4, 然后用二氯甲烷萃取三次，每次用3 L。合并的有机相用饱和食盐水洗三次，每次用3 L，然后有机相用无水硫酸钠干燥并减压浓缩得到最终化合物WX111163(496 g)为黄色油状物，收率96%。

Claims (9)

1.一种2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸的合成方法，其特征是包括以下步骤：第一步，首先由二羧酸吡啶化合物1在二氯亚砜中进行酯化得到二酯化合物2，第二步，化合物2用钯碳还原吡啶环得到化合物3，第三步，化合物3与Boc酸酐反应得到boc保护的化合物4，第四步，化合物4用氢氧化锂水解得到二羧酸化合物5，第五步，化合物5在乙酸酐中关环得到化合物6，第六步，化合物6用NaBH4还原开环得到位置异构化合物7A和7B混合物，第七步，7A和7B混合物在碘甲烷，碳酸钾条件下，关环生成位置异构的内酯8A和8B，第八步，8A用二异丁基氢化铝还原得到化合物9，第九步，化合物9经过叶立德反应得到化合物10，第十步，化合物10在碱性条件下进行麦克尔加成得到化合物11，第十一步，化合物11碱性条件下水解得到最终化合物,反应式如下：
。
2.根据权利要求1所述的一种2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸的合成方法，其特征是：第一步回流反应过夜。
3.根据权利要求1所述的2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸的合成方法，其特征是：第二步用到钯碳在50℃50psi下反应。
4.根据权利要求1所述的2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸的合成方法，其特征是：第四步使用了氢氧化锂室温条件下进行水解。
5.根据权利要求1所述的2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸的合成方法，其特征是：第六步，化合物6在四氢呋喃溶液中进行还原反应。
6.根据权利要求1所述的2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸的合成方法，其特征是：第八步，化合物8A用二异丁基氢化铝低温-70℃还原。
7.根据权利要求1所述的2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸的合成方法，其特征是：第九步，用(乙酯基甲基)三苯基磷溴化进行叶立德反应。
8.根据权利要求1所述的2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸的合成方法，其特征是：第十步，所述的碱性条件是加入乙醇钠。
9.根据权利要求1所述的2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸的合成方法，其特征是：第十一步，所述的碱性条件是加入采用氢氧化钠进行水解。
CN201710530560.1A 2017-06-29 2017-06-29 2-((1S3aR7aR)-5-叔丁氧羰基四氢呋喃并[3,4]哌啶-1)乙酸制法 Active CN107383035B (zh)

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