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CN114736196A - 一种维兰特罗主链与侧链偶联后处理提纯工艺 - Google Patents

一种维兰特罗主链与侧链偶联后处理提纯工艺 Download PDF

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CN114736196A
CN114736196A CN202210524300.4A CN202210524300A CN114736196A CN 114736196 A CN114736196 A CN 114736196A CN 202210524300 A CN202210524300 A CN 202210524300A CN 114736196 A CN114736196 A CN 114736196A
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bromohexyloxy
dichlorobenzene
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CN114736196B (zh
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张启龙
许坤
王红磊
汪崇文
李登阳
史帅帅
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Anhui Dexinjia Biopharm Co ltd
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

本发明公开了一种维兰特罗主链与侧链偶联后处理提纯工艺，属于药物合成领域。维兰特罗主链2‑[2‑(6‑溴己氧基)乙氧基甲基]‑1,3‑二氯苯与侧链(5R)‑5‑(2,2‑二甲基‑4H‑1,3‑苯并二氧杂环己‑6‑基)‑1,3‑恶唑烷‑2‑酮发生偶联反应，过量的主链2‑[2‑(6‑溴己氧基)乙氧基甲基]‑1,3‑二氯苯与吡啶衍生物反应成盐，之后用50℃热水洗去盐。本发明使用价廉易得的吡啶衍生物成盐反应条件温和，操作简单，杂质易于除去，避免了硅胶色谱柱提纯和蒸馏方法提纯产品，适合工业化生产。

Description

一种维兰特罗主链与侧链偶联后处理提纯工艺
技术领域
本发明属于药物中间体合成领域，涉及一种维兰特罗主链与侧链偶联后处理提纯工艺。
背景技术
维兰特罗三苯乙酸盐(Vilanterol trifenatate)是由葛兰素史克公司(GSK)开发的长效β2受体激动剂。其与糠酸氟替卡松的复方制剂，与芜地溴铵的复方制剂分别于2013年5月和12月获FDA批准，用于阻塞性肺病和哮喘的治疗。其中，(5R)-3-[6-[2-[(2,6-二氯苯基)甲氧基]乙氧基]己基]-5-(2,2-二甲基-4H-1,3-苯并二噁英-6-基)-2-噁唑烷酮是合成维兰特罗的关键中间体，CAS：503068-36-8，分子式：C28H35Cl2NO6，分子量：552.49，其经过两步反应即可得到维兰特罗，具体反应如下所示：
Figure BDA0003643452360000011
目前，关于(5R)-3-[6-[2-[(2,6-二氯苯基)甲氧基]乙氧基]己基]-5-(2,2-二甲基-4H-1,3-苯并二噁英-6-基)-2-噁唑烷酮的合成主要采用以下工艺(参考文献：US2015239862A)：
Figure BDA0003643452360000012
该路线以维兰特罗主链2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯与侧链(5R)-5-(2,2-二甲基-4H-1,3-苯并二氧杂环己-6-基)-1,3-恶唑烷-2-酮在叔丁醇钾作用下发生偶联反应得到(5R)-3-[6-[2-[(2,6-二氯苯基)甲氧基]乙氧基]己基]-5-(2,2-二甲基-4H-1,3-苯并二噁英-6-基)-2-噁唑烷酮。由于维兰特罗侧链中间体(5R)-5-(2,2-二甲基-4H-1,3-苯并二氧杂环己-6-基)-1,3-恶唑烷-2-酮具有手性，并且需要至少7步反应合成，因此价格较高，工艺上通常加入过量的维兰特罗主链中间体以保证侧链中间体完全转化。但是，合成的产物(5R)-3-[6-[2-[(2,6-二氯苯基)甲氧基]乙氧基]己基]-5-(2,2-二甲基-4H-1,3-苯并二噁英-6-基)-2-噁唑烷酮与主链原料常温下都是一种粘性较大的液体，难以采用重结晶的方式进行提纯，同时由于这两个化合物具有较高的沸点，沸点大约为420.8±45.0℃(760Torr)，产物在高温下易分解，因此，难以采用蒸馏的方式进行提纯。目前工业上主要依靠硅胶色谱柱提纯，生产效率有限，难以实现工业化。
发明内容
本发明针对现有技术上的不足，提供了一种维兰特罗主链与侧链偶联后处理提纯工艺，维兰特罗主链2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯与侧链(5R)-5-(2,2-二甲基-4H-1,3-苯并二氧杂环己-6-基)-1,3-恶唑烷-2-酮发生偶联反应，过量的主链2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯与吡啶衍生物反应成盐，之后用热水洗去盐，达到除去杂质的目的，具体成盐反应如下：
Figure BDA0003643452360000021
所述的吡啶衍生物为吡啶、2-吡啶甲酸、2-吡啶甲醛、2-羟基吡啶、2-氨基吡啶、3-吡啶甲酸、3-吡啶甲醛、3-羟基吡啶、3-氨基吡啶、4-吡啶甲酸、4-吡啶甲醛、4-羟基吡啶、4-氨基吡啶中的一种，优选为2-吡啶甲酸、3-吡啶甲酸、4-吡啶甲酸；所述的主链与侧链偶联反应结束后，加入的吡啶衍生物的量为2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯摩尔量的10％；所述吡啶衍生物在主链与侧链偶联反应结束后直接加入到反应体系中；所述反应溶剂为DMF；所述的热水温度为50℃；所述的加入吡啶衍生物后反应时间为2h。
本发明的有益效果：
(1)本发明采用吡啶衍生物将过量的主链2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯成盐后热水洗掉，无需硅胶色谱柱或蒸馏方式提纯，产品纯度可达到99％以上。
(2)本发明操作简单，去除彻底，具有大规模工业化生产的可行性。
具体实施方式
实施例1：
在100L反应釜中加入(5R)-5-(2,2-二甲基-4H-1,3-苯并二氧杂环己-6-基)-1,3-恶唑烷-2-酮(2.5kg,10.0mol)，DMF(20kg)。将叔丁醇钾(1.2kg,10.5mol)，在低于30℃的条件下，1小时内分批加入反应体系中，加毕，搅拌反应1小时。在30-35℃下，1.5小时内滴加2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯(4.2kg,11.0mol，加入5kg的DMF稀释)，30-35℃下搅拌2小时，液相中控，直到(5R)-5-(2,2-二甲基-4H-1,3-苯并二氧杂环己-6-基)-1,3-恶唑烷-2-酮完全消耗。之后，4-吡啶甲酸(0.135kg)加入到反应体系中，加热50℃继续搅拌2h。乙酸乙酯(25kg)和水(25kg)加入到反应体系中，保持50℃，搅拌1h。分层，有机相用饱和NaCl(10kg+10kg)溶液洗涤两次，再用水(10kg+10kg)洗涤两次。有机相加入Na2SO4(2kg)干燥，过滤，滤液减压蒸馏除去溶剂，得到(5R)-3-[6-[2-[(2,6-二氯苯基)甲氧基]乙氧基]己基]-5-(2,2-二甲基-4H-1,3-苯并二噁英-6-基)-2-噁唑烷酮，为淡黄色油(5.1kg，产率92％，液相纯度99.1％，2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯含量＜0.1％)。
实施例2：
在100L反应釜中加入(5R)-5-(2,2-二甲基-4H-1,3-苯并二氧杂环己-6-基)-1,3-恶唑烷-2-酮(2.5kg,10.0mol)，DMF(20kg)。将叔丁醇钾(1.2kg,10.5mol)，在低于30℃的条件下，1小时内分批加入反应体系中，加毕，搅拌反应1小时。在30-35℃下，1.5小时内滴加2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯(4.2kg,11.0mol，加入5kg的DMF稀释)，30-35℃下搅拌2小时，液相中控，直到(5R)-5-(2,2-二甲基-4H-1,3-苯并二氧杂环己-6-基)-1,3-恶唑烷-2-酮完全消耗。之后，4-吡啶甲酸(0.135kg)加入到反应体系中，加热50℃继续搅拌1h。乙酸乙酯(25kg)和水(25kg)加入到反应体系中，保持50℃，搅拌1h。分层，有机相用饱和NaCl(10kg+10kg)溶液洗涤两次，再用水(10kg+10kg)洗涤两次。有机相加入Na2SO4(2kg)干燥，过滤，滤液减压蒸馏除去溶剂，得到(5R)-3-[6-[2-[(2,6-二氯苯基)甲氧基]乙氧基]己基]-5-(2,2-二甲基-4H-1,3-苯并二噁英-6-基)-2-噁唑烷酮，为淡黄色油(5.1kg，产率92％，液相纯度98.8％，2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯含量0.6％)。
实施例3：
在10L反应釜中加入(5R)-5-(2,2-二甲基-4H-1,3-苯并二氧杂环己-6-基)-1,3-恶唑烷-2-酮(250g,1.0mol)，DMF(2kg)。将叔丁醇钾(120g,1.05mol)，在低于30℃的条件下，1小时内分批加入反应体系中，加毕，搅拌反应1小时。在30-35℃下，1.5小时内滴加2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯(420g,1.1mol，加入500g的DMF稀释)，30-35℃下搅拌2小时，液相中控，直到(5R)-5-(2,2-二甲基-4H-1,3-苯并二氧杂环己-6-基)-1,3-恶唑烷-2-酮完全消耗。之后，4-羟基吡啶(104g)加入到反应体系中，加热50℃继续搅拌2h。乙酸乙酯(25kg)和水(25kg)加入到反应体系中，保持25℃，搅拌1h。乙酸乙酯(2.5kg)和水(2.5kg)加入到反应体系中，保持25℃，搅拌1h。分层，有机相用饱和NaCl(1kg+1kg)溶液洗涤两次，再用水(1kg+1kg)洗涤两次。有机相加入Na2SO4(200g)干燥，过滤，滤液减压蒸馏除去溶剂，得到(5R)-3-[6-[2-[(2,6-二氯苯基)甲氧基]乙氧基]己基]-5-(2,2-二甲基-4H-1,3-苯并二噁英-6-基)-2-噁唑烷酮，为淡黄色油(497g，产率91％，液相纯度98.3％，2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯含量0.8％)。
实施例4：
在10L反应釜中加入(5R)-5-(2,2-二甲基-4H-1,3-苯并二氧杂环己-6-基)-1,3-恶唑烷-2-酮(250g,1.0mol)，DMF(2kg)。将叔丁醇钾(120g,1.05mol)，在低于30℃的条件下，1小时内分批加入反应体系中，加毕，搅拌反应1小时。在30-35℃下，1.5小时内滴加2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯(420g,1.1mol，加入500g的DMF稀释)，30-35℃下搅拌2小时，液相中控，直到(5R)-5-(2,2-二甲基-4H-1,3-苯并二氧杂环己-6-基)-1,3-恶唑烷-2-酮完全消耗。乙酸乙酯(2.5kg)和水(2.5kg)加入到反应体系中，保持50℃，搅拌1h。分层，有机相用饱和NaCl(1kg+1kg)溶液洗涤两次，再用水(1kg+1kg)洗涤两次。有机相加入Na2SO4(200g)干燥，过滤，滤液减压蒸馏除去溶剂，得到(5R)-3-[6-[2-[(2,6-二氯苯基)甲氧基]乙氧基]己基]-5-(2,2-二甲基-4H-1,3-苯并二噁英-6-基)-2-噁唑烷酮，为淡黄色油(514g，产率93％，液相纯度92.6％，2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯含量7.3％)。
上述虽然对本发明的具体实施方式进行了描述，但并非对本发明保护范围的限制，所属领域技术人员应该明白，在本发明的技术方案的基础上，本领域技术人员不需要付出创造性劳动即可做出的各种修改或变形仍在本发明的保护范围以内。

Claims (6)

1.一种维兰特罗主链与侧链偶联后处理提纯工艺，主链与侧链偶联反应结束后，加入吡啶衍生物与过量的2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯反应成盐，加热除盐，具体成盐反应如下：
Figure FDA0003643452350000011
其中，R＝H；2-COOH；2-CHO；2-OH；2-NH2；3-COOH；3-CHO；3-OH；3-NH2；4-COOH；4-CHO；4-OH；4-NH2。
2.根据权利要求1中所述的一种维兰特罗主链与侧链偶联后处理提纯工艺，其特征在于，所述的主链与侧链偶联反应结束后，加入的吡啶衍生物的量为2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯摩尔量的10％。
3.根据权利要求1中所述的一种维兰特罗主链与侧链偶联后处理提纯工艺，其特征在于，所述的加热温度为50℃。
4.根据权利要求1中所述的一种维兰特罗主链与侧链偶联后处理提纯工艺，其特征在于，所述的主链与侧链偶联反应结束后，吡啶衍生物直接加入到反应体系中。
5.根据权利要求1中所述的一种维兰特罗主链与侧链偶联后处理提纯工艺，其特征在于，所述反应溶剂为DMF。
6.根据权利要求1中所述的一种维兰特罗主链与侧链偶联后处理提纯工艺，其特征在于，所述的主链与侧链偶联反应结束后，加入吡啶衍生物后反应时间为2h。
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