CN109320485B - 合成特戈拉赞手性醇的方法 - Google Patents
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
本发明涉及一条制备特戈拉赞(Tegoprazan)手性醇的方法,具体涉及(S)‑5,7‑二氟‑3,4‑二氢‑2H‑色原烯‑4‑醇的制备方法。该方法以5,7‑二氟‑4H‑苯并吡喃‑4‑酮为起始物料，通过手性试剂对酮羰基的不对称还原和随后的常规氢化反应，实现(S)‑5,7‑二氟‑3,4‑二氢‑2H‑色原烯‑4‑醇的制备。
Description
技术领域
本发明属于合成原料药手性片段技术领域，具体涉及特戈拉赞手性氟醇的制备。
背景技术
特戈拉赞，又名替戈拉生、Tegoprazan、CJ-12420，于2018年7月获韩国食品药品安全部(MFDS)批准上市，用于治疗胃食管反流疾病和糜烂性食管炎的治疗。
特戈拉赞最初由辉瑞公司研发，2008年授权给RaQualia Pharma(从辉瑞脱离)合作开发，2014年由RaQualia Pharma授权给CJ Health Care，最终由CJ Health Care在韩国研发成功并上市销售。特戈拉赞是一种竞争性钾离子酸阻滞剂(P-CAB)和氢离子/钾离子交换ATP酶(H+/K+ATPase)抑制剂，该药首先在韩国上市，是一款全新的用于治疗胃食管反流病及糜烂性食管炎的药物。
胃质子泵氢离子/钾离子交换ATP酶是治疗胃酸相关疾病的主要药理靶点。钾竞争性酸阻断剂(P-CAB)，能够通过与K+竞争性结合H+/K+-ATP酶来抑制胃酸分泌。研究发现Tegoprazan就是这样一种钾竞争性酸阻断剂，被认为是目前治疗胃食管反流疾病最先进的药物，因为质子泵抑制剂是最常用的治疗胃食管反流病的药物，而特戈拉赞恰好能克服质子泵抑制剂的缺点。特戈拉赞的有效性和安全性主要基于两项III期临床试验。其中一项是双盲，主动控制的III期研究(NCT02456935)，该研究在韩国进行，以280名糜烂性食管炎患者为研究对象，第8周糜烂性食管炎的累积愈合率作为主要终点，比较特戈拉赞与质子泵抑制剂埃索美拉唑的安全性和有效性。另外一项III期临床试验，是双盲、随机、安慰剂对照试验(NCT02556021)。该试验在韩国324名患者中进行，主要终点是使用反流疾病问卷(RDQ)确定的4周时主要症状(胃灼热和反流)完全消退的患者百分比，从而评估每日一次特戈拉赞片剂(50mg和100mg)在非糜烂性反流病患者中的安全性和有效性。该药的批准上市为该类疾病的治疗提供了新的选择，并且一定程度弥补了其它药物的缺点，使该类疾病能得到更好的治疗。
特戈拉赞化学名为(S)-4-((5，7-二氟色满-4-基)氧)-N，N，2-三甲基-1H-苯并[d]咪唑-6-甲酰胺，化学结构中含有苯并咪唑结构和手性5，7-二氟色满-4-氧基结构，具体化学结构如下：
专利CN101341149B公开了特戈拉赞的制备方法，具体为4-羟基-N，N，2-三甲基-1-[(4-甲苯基)磺酰基]-1H-苯并咪唑-6-甲酰胺和(S)-5，7-二氟-3，4-二氢-2H-色原烯-4-醇在三丁基膦/ADDP作用下发生缩合反应，制备得到(-)-4-[((4S)-5，7-二氟-3，4-2H-色原烯-4-基)氧基]-N，N，2-三甲基-1-[(4-甲苯基)磺酰基]-1H-苯基咪唑-6-甲酰胺中间体，后者在碱作用下脱除保护基完成特戈拉赞的制备，具体合成路线如下：
基于上述专利的描述，特戈拉赞的制备主要涉及到两个片段，其中一个为手性氟醇片段，即(S)-5，7-二氟-3，4-二氢-2H-色原烯-4-醇。CJ Health Care专利CN101341149B和CN107849003A公开了(S)-5，7-二氟-3，4-二氢-2H-色原烯-4-醇的制备方法，但是CN101341149B描述的方法手性纯度比较差(86％ee)(重结晶虽然能够提高产品ee值，但是重结晶收率只有58％)，CN107849003A涉及到商业化难以采购的手性Ru试剂(价格昂贵)，专利CN101341149B和CN 107849003A描述的方法如下：
鉴于目前公开的两条制备(S)-5，7-二氟-3，4-二氢-2H-色原烯-4-醇的方法都存在一定的缺陷，因此开发新的适合产业化、成本具有优势的合成(S)-5，7-二氟-3，4-二氢-2H-色原烯-4-醇的方法将使特戈拉赞更具有市场竞争力。
发明内容
本发明的目的在于提供一种制备(S)-5，7-二氟-3，4-二氢-2H-色原烯-4-醇的新方法，旨在避免目前原研专利中手性试剂昂贵、产品手性纯度低以及收率低的缺陷。专利CN101341149B和CN107849003A都是采用5，7-二氟-2，3-二氢-4H-色原烯-4-酮作为氢化前体，虽然这样的底物在特殊的手性试剂作用下能够达到一定的不对称氢化效果，但是由于色原烯的氧杂环还不具有特别的刚性，所以导致一些常规的手性试剂诱导的酮羰基不对称还原效果差。
本发明的合成路线如下：
本发明的起始物料5，7-二氟-4H-苯并吡喃-4-酮可以通过5，7-二氟-2，3-二氢-4H-色原烯-4-酮的氧化得到(ChemComm.，2016，52，14314-14317)或者按照文献(Org.Lett.，2016，18，4986-4989)报道的类似方法进行合成。
反应第一步涉及5，7-二氟-4H-苯并吡喃-4-酮在手性试剂存在下使用硼烷-二甲硫醚络合物对酮羰基进行不对称还原，高选择性地得到(S)-5，7-二氟-4H-苯并吡喃-4-醇。
反应第一步使用的手性试剂包括(S)-四氢-1-甲基-，3，3-二苯基-1H，3H-吡咯并[1，2-c][1，3，2]恶唑硼烷、(S)-四氢-1，3，3-三苯基-1H，3H-吡咯并[1，2-c][1，3，2]恶唑硼烷。
反应第二步涉及(S)-5，7-二氟-4H-苯并吡喃-4-醇在催化剂和溶剂存在下进行氢化反应，得到(S)-5，7-二氟-3，4-二氢-2H-色原烯-4-醇。
反应第二步是使用的催化剂包括Pd/C、Pd(OH)2。
反应第二步使用的溶剂包括甲醇、乙醇。
本发明使用的起始物料合成方法简单，使用的试剂易于采购，工艺操作简单，手性选择性高，适合(S)-5，7-二氟-3，4-二氢-2H-色原烯-4-醇的产业化制备。
具体实施方式
以下典型实施例用来说明本发明，在本领域内的技术人员对本发明所做的简单替换和改进等均属于本发明所保护的技术方案之内。
实施例一：(S)-5，7-二氟-4H-苯并吡喃-4-醇的制备
氮气保护下向3L的反应瓶中加入无水THF(400mL)和(S)-四氢-1-甲基-，3，3-二苯基-1H，3H-吡咯并[1，2-c][1，3，2]恶唑硼烷的甲苯溶液(1M in Toluene，55mL，55mmol)。加入完毕后体系冰盐浴降温至0±2℃，然后向体系中加入硼烷二甲硫醚络合物(1M in THF，575mL，0.575mol)，体系0±2℃搅拌10min后加入5，7-二氟-4H-苯并吡喃-4-酮(100g，0.549mol)的THF(500mL)溶液，加入过程维持体系反应温度0±2℃，加入完毕后体系反应至TLC跟踪起始物料5，7-二氟-4H-苯并吡喃-4-酮消失。反应完毕后，体系加入MeOH(200mL)淬灭，体系自然升温至室温剧烈搅拌1小时。高真空脱除体系的有机溶剂，残余物硅胶柱层析纯化(正庚烷/EA＝5∶1)纯化得(S)-5，7-二氟-4H-苯并吡喃-4-醇(83.9g，83％，98.5％ee)。
实施例二：(S)-5，7-二氟-4H-苯并吡喃-4-醇的制备
氮气保护下向500mL的反应瓶中加入无水THF(80mL)和(S)-四氢-1，3，3-三苯基-1H，3H-吡咯并[1，2-c][1，3，2]恶唑硼烷的甲苯溶液(1M in Toluene，11.0mL，11.0mmol)。加入完毕后体系冰盐浴降温至0±2℃，然后向体系中加入硼烷二甲硫醚络合物(1M inTHF，121mL，121mmol)。体系0±2℃搅拌10min后加入5，7-二氟-4H-苯并吡喃-4-酮(20.0g，109.8mmol)的THF(100mL)溶液，加入过程维持体系反应温度0±2℃，加入完毕后体系反应至TLC跟踪物料5，7-二氟-4H-苯并吡喃-4-酮消失。反应完毕后，体系加入MeOH(50mL)淬灭，体系自然升温至室温剧烈搅拌1小时。高真空脱除体系的有机溶剂，残余物硅胶柱层析纯化(正庚烷/EA＝5∶1)纯化得(S)-5，7-二氟-4H-苯并吡喃-4-醇(17.7g，87.6％，99.1％ee)。
实施例三：(S)-5，7-二氟-3，4-二氢-2H-色原烯-4-醇的制备
向反应瓶中加入(S)-5，7-二氟-4H-苯并吡喃-4-醇(5.0g，27.15mmol)和乙醇(100mL)，体系搅拌，然后氮气保护下加入5％Pd/C(含水量65％，5.8g)。加入完毕后体系氮气置换三次，然后室温常压氢化至HPLC跟踪反应原料消失。过滤，高真空脱除有机溶剂，残余物柱层析纯化(正庚烷/EA＝5∶1)得(S)-5，7-二氟-3，4-二氢-2H-色原烯-4-醇(4.65g，92％)。
Claims (1)
1.制备(S)-5,7-二氟-3,4-二氢-2H-色原烯-4-醇的方法,反应式如下：
其中，上述方法中使用的手性试剂选自(S)-四氢-1-甲基-3,3-二苯基-1H,3H-吡咯并[1,2-c][1,3,2]恶唑硼烷或(S)-四氢-1,3,3-三苯基-1H,3H-吡咯并[1,2-c][1,3,2]恶唑硼烷；使用的催化剂选自Pd/C或Pd(OH)2。
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