CN1285571C - 2-乙氧基-3-[4-(2-{甲磺酰氧苯基}乙氧基)苯基]丙酸的制备工艺 - Google Patents
2-乙氧基-3-[4-(2-{甲磺酰氧苯基}乙氧基)苯基]丙酸的制备工艺 Download PDFInfo
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
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Abstract
式(Ⅰ)化合物的制备工艺,式中R代表H或一种酸保护基团,该工艺包含使一种式中R同以上定义的式(Ⅱ)化合物与一种式中X是一种适用离去基团的式(Ⅲ)化合物在一种碱的存在下反应和使用水作为稀释剂。
Description
本发明涉及以下式I所示化合物2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸或其(R)或(S)对映体或其医药上可接受盐及其溶剂合物的一种改善制备工艺:
以上化合物意在用于包括2型糖尿病在内的胰岛素抗性综合征(IRS)的治疗用途,该综合征系指一群表现,包括有伴随高胰岛素血的胰岛素抗性,可能的2型糖尿病,动脉高血压,中央(内脏)肥胖,作为以VLDL(甚低密度脂蛋白)偏高、稠密LDL微粒小和HDL(高密度脂蛋白)浓度降低的典型特征的脂蛋白水平紊乱观察到的血脂异常,和血纤维蛋白溶解减少。
最近的流行病学研究已经表明,有胰岛素抗性的个体有大大增加心血管发病率和死亡率的风险,尤其会发生心肌梗塞和中风。在2型糖尿病中,与动脉粥样硬化相关的病症引起所有死亡数的可高达80%。
在临床医学中,人们认识到需要提供高IRS患者的胰岛素敏感性,从而矫正被视为造成加速动脉粥样硬化进展的血脂异常。然而,目前,这并不是一种普遍十分明确的疾病。
式I化合物公开于PCT公报No.WO 99/62872。该申请的实施例1和2中公开了式I化合物的两种替代制备工艺。我们已经发现了与所公开的工艺之一有关的改进。
具体地说,我们已经找到了前末端酯化中间体合成的一种改进方法,该反应的最终步骤是酯基转化成最终产物的酸。
因此,本发明提供一种式I化合物制备工艺
式中R代表H或一种酸保护基,该工艺包含使一种式II化合物
式中R同以上定义,与一种式III化合物
式中X是一种适用离去基团,在一种碱的存在下反应并使用水作为稀释剂。
适当地,该反应是在0℃~250℃范围内、较好在50℃~150℃范围内的温度进行的。更好该工艺是在80℃~130℃范围内、最好在90℃~110℃范围内的温度进行的。
“酸保护基”这一术语系指该酸通过生成一种适当酸衍生物例如酯或酰胺或者用业内已知的其它羧酸基保护手段进行保护而免于反应。适用保护手段和酸衍生物(以及生成手段和最终脱保护手段)的实例可以参阅T.W.Greene and P.G.M.Wuts,“Protective Groups inOrganic Synthesis”,Third Edition,John Wiley & Sons,New York,1999。在该工艺的执行中酯的性质并不重要,因为它的功能是充当保护基。这些改进涉及相转移催化对该工艺的应用。较好,R是H、苄基或C1-C4烷基例如甲基、乙基或丙基。更好,R是一个C1-C4烷基。最好,R是乙基。
适用地,X是卤素例如溴、氯或碘,任选地有取代的苯磺酰氧基、尤其(4-甲基苯基)磺酰氧基或2,4,6-三异丙基苯基磺酰氧基,或烷磺酰氧基例如甲磺酰氧基。较好,X是一个甲磺酰氧基。
适用的碱包括尤其碱金属的碳酸盐、碳酸氢盐或氢氧化物。较好,该碱是碳酸钠、碳酸氢钠、碳酸钾或碳酸氢钾。
适用地,式III化合物与式II化合物的摩尔比是在0.5~10的范围内、较好在0.8~4的范围内、更好在1.0~3的范围内、最好在1.2~1.8、例如1.2~1.6的范围内。
适用地,该碱与式II化合物的摩尔比是在0.5~10的范围内、较好在0.8~7例如0.8~4的范围内、更好在1.0~5的范围内,最好在1.2~4.2的范围内。
本发明的工艺有以下优点。反应时间比先有技术上已知的反应更快,因而该工艺运行费用不太昂贵。此外,与以前公开的式I化合物制备工艺相比,本工艺给出更高的产率且产品有更高的纯度。而且,就废物处置、环境理由和用水代替有机液体作为稀释剂的费用而言,它也有可观的优点。进而,该工艺始终是可再现的和稳健的。
该酸酯衍生物的转化只需通过酯变成酸的水解(酸性的或碱性的或酶促的)就可以实现,这样一个步骤是业内人士已知的,例如以下实施例中和WO 99/62872的实施例2i)中所述。
另一方面,本发明提供一种式中R代表H的式I化合物的制备工艺:
该工艺包含使式中R代表一种酸保护基团的式II化合物
与式中X是一种适用离去基团的式III化合物
在一种碱的存在下反应并使用水作为稀释剂,给出式中R是一种酸保护基的式I化合物,然后脱除该保护基,给出一种式中R是H的式I化合物。
在一个较好的方面,该保护基是一种酯且该保护基脱除步骤包含一个水解步骤。该水解步骤可以是酸催化的或碱催化的。较好该碱是氢氧化锂。优选地,在该水解步骤可以存在一种有机液体,例如丙酮、2-丁酮、甲醇、乙醇、四氢呋喃或二烷。
在一个较好的方面,该工艺通过使用式中R代表H或一种酸保护基的式II化合物的S-对映体、随后当R是一种酸保护基时水解,提供式中R是H的式I化合物的S-对映体。
式中R是H的式I化合物可以通过重结晶精制。适用的重结晶溶剂包括乙醇、水、乙酸异丙酯、异丙醇、异辛烷和甲苯中一种或多种。
以下用非限定性实施例说明本发明。
缩略语
EtOAc=乙酸乙酯
HPLC=高压液体色谱法
i-PrOAc=乙酸异丙酯
EtOH=乙醇
起始原料的制备
如WO 99/62872中所述那样制备甲磺酸2-(4-甲磺酰氧基苯基)乙酯。
实施例1
(S)-2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸
甲磺酸2-(4-甲磺酰氧基苯基)乙酯(9.88g/33.57mmol)、(S)-2-乙氧基-3-(4-羟基苯基)丙酸乙酯(5.0g/20.98mmol)、Na2CO3(2.96g/27.9mmol eq)和水(10ml)的混合物在剧烈搅拌下回流沸腾4.5h。使混合物冷却到2℃,添加丙酮(13.5ml)。让含有(S)-2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸乙酯的混合物回升到常温。使丙酮溶液在反应器中保持在Ti=25℃。在25±5℃,在剧烈搅拌下,用30分钟时间连续加入溶解于水(20ml)中的LiOH×H2O粉末(1.144g/27.27mmol)。该反应继续进行7小时。在Ti=25±5℃添加EtOAc(1.5ml)使反应猝灭。在相分离之后向水混合物中添加乙酸,再用硫酸水溶液将pH调整到1~3。接种晶种使粗标题化合物结晶。采用HPLC证实该产品的同一性,给出76%的相对面积。
Claims (7)
3.按照权利要求2的工艺,其中,该酸保护基是通过水解脱除的。
4.按照权利要求1-3任一项的工艺,其中,R是苄基或C1-C4烷基。
5.按照权利要求1-3任一项的工艺,其中,X是卤素、任选取代的苯磺酰氧基或烷磺酰氧基。
6.按照权利要求1-3任一项的工艺,其中,该碱选自碱金属的碳酸盐、碳酸氢盐或氢氧化物。
7.按照权利要求1-3任一项的工艺,其中,式I化合物是S对映体。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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SE02010056 | 2002-04-02 | ||
SE0201005A SE0201005D0 (sv) | 2002-04-02 | 2002-04-02 | New Process |
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Publication Number | Publication Date |
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CN1646487A CN1646487A (zh) | 2005-07-27 |
CN1285571C true CN1285571C (zh) | 2006-11-22 |
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CNB038076853A Expired - Fee Related CN1285571C (zh) | 2002-04-02 | 2003-03-28 | 2-乙氧基-3-[4-(2-{甲磺酰氧苯基}乙氧基)苯基]丙酸的制备工艺 |
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US (1) | US20050215808A1 (zh) |
EP (1) | EP1492764B1 (zh) |
JP (1) | JP2005521725A (zh) |
KR (1) | KR20050002918A (zh) |
CN (1) | CN1285571C (zh) |
AT (1) | ATE331704T1 (zh) |
AU (1) | AU2003226523A1 (zh) |
BR (1) | BR0308297A (zh) |
CA (1) | CA2478650A1 (zh) |
DE (1) | DE60306506T2 (zh) |
ES (1) | ES2266842T3 (zh) |
HK (1) | HK1071353A1 (zh) |
IL (1) | IL164334A0 (zh) |
MX (1) | MXPA04009686A (zh) |
NO (1) | NO20044045L (zh) |
NZ (1) | NZ534989A (zh) |
SE (1) | SE0201005D0 (zh) |
WO (1) | WO2003082812A2 (zh) |
ZA (1) | ZA200406589B (zh) |
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SE9801992D0 (sv) * | 1998-06-04 | 1998-06-04 | Astra Ab | New 3-aryl-2-hydroxypropionic acid derivative I |
US6358850B1 (en) * | 1999-12-23 | 2002-03-19 | International Business Machines Corporation | Slurry-less chemical-mechanical polishing of oxide materials |
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- 2003-03-28 CA CA002478650A patent/CA2478650A1/en not_active Abandoned
- 2003-03-28 IL IL16433403A patent/IL164334A0/xx unknown
- 2003-03-28 US US10/509,654 patent/US20050215808A1/en not_active Abandoned
- 2003-03-28 MX MXPA04009686A patent/MXPA04009686A/es not_active Application Discontinuation
- 2003-03-28 KR KR10-2004-7015590A patent/KR20050002918A/ko not_active Application Discontinuation
- 2003-03-28 DE DE60306506T patent/DE60306506T2/de not_active Expired - Fee Related
- 2003-03-28 CN CNB038076853A patent/CN1285571C/zh not_active Expired - Fee Related
- 2003-03-28 WO PCT/GB2003/001395 patent/WO2003082812A2/en active IP Right Grant
- 2003-03-28 AU AU2003226523A patent/AU2003226523A1/en not_active Abandoned
- 2003-03-28 ES ES03745340T patent/ES2266842T3/es not_active Expired - Lifetime
- 2003-03-28 NZ NZ534989A patent/NZ534989A/en unknown
- 2003-03-28 BR BR0308297-0A patent/BR0308297A/pt not_active IP Right Cessation
- 2003-03-28 JP JP2003580280A patent/JP2005521725A/ja not_active Withdrawn
- 2003-03-28 AT AT03745340T patent/ATE331704T1/de not_active IP Right Cessation
- 2003-03-28 EP EP03745340A patent/EP1492764B1/en not_active Expired - Lifetime
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- 2004-08-18 ZA ZA200406589A patent/ZA200406589B/en unknown
- 2004-09-24 NO NO20044045A patent/NO20044045L/no unknown
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Also Published As
Publication number | Publication date |
---|---|
DE60306506D1 (de) | 2006-08-10 |
EP1492764A2 (en) | 2005-01-05 |
EP1492764B1 (en) | 2006-06-28 |
SE0201005D0 (sv) | 2002-04-02 |
KR20050002918A (ko) | 2005-01-10 |
WO2003082812A3 (en) | 2004-01-08 |
JP2005521725A (ja) | 2005-07-21 |
CA2478650A1 (en) | 2003-10-09 |
AU2003226523A1 (en) | 2003-10-13 |
WO2003082812A2 (en) | 2003-10-09 |
ATE331704T1 (de) | 2006-07-15 |
ZA200406589B (en) | 2005-09-21 |
DE60306506T2 (de) | 2007-01-18 |
NZ534989A (en) | 2006-04-28 |
HK1071353A1 (en) | 2005-07-15 |
IL164334A0 (en) | 2005-12-18 |
BR0308297A (pt) | 2004-12-28 |
MXPA04009686A (es) | 2005-01-11 |
ES2266842T3 (es) | 2007-03-01 |
NO20044045L (no) | 2004-10-18 |
CN1646487A (zh) | 2005-07-27 |
US20050215808A1 (en) | 2005-09-29 |
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