WO2016008285A1 - 一种手性1-苄基-3-羟基哌啶的消旋回收方法 - Google Patents
一种手性1-苄基-3-羟基哌啶的消旋回收方法 Download PDFInfo
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- WO2016008285A1 WO2016008285A1 PCT/CN2015/070184 CN2015070184W WO2016008285A1 WO 2016008285 A1 WO2016008285 A1 WO 2016008285A1 CN 2015070184 W CN2015070184 W CN 2015070184W WO 2016008285 A1 WO2016008285 A1 WO 2016008285A1
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- hydroxypiperidine
- benzyl
- reaction
- chiral
- racemization
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
Definitions
- the invention relates to the field of compound synthesis, in particular to a racemic recovery method of chiral 1-benzyl-3-hydroxypiperidine.
- Chiral 1-benzyl-3-hydroxypiperidine is an important pharmaceutical intermediate.
- the prior art relates to chiral 1-benzyl-3-hydroxypiperidine, which is prepared by chiral synthesis or chemical resolution.
- the chemical resolution method has the problem of recycling of chiral hydroxyl groups in a non-target configuration, and is generally recovered by indirect racemization.
- the indirect racemization method specifically oxidizes a hydroxyl group to a ketone, and then reduces it to an alcohol with sodium borohydride.
- the above methods have various defects such as complicated process and low yield. Therefore, an improved method for recycling chiral 1-benzyl-3-hydroxypiperidine has yet to be proposed.
- the object of the present invention is to provide a novel racemic recovery method of chiral 1-benzyl-3-hydroxypiperidine, which solves the difficulty in recycling and the indirect elimination of chiral hydroxyl groups in a non-target configuration in the chemical resolution method.
- the spin method operates with a cumbersome and low yield defect. This method has not been reported in the literature, and the reaction is clean and suitable for industrial large-scale production.
- the present invention adopts the following technical solutions:
- a racemic recovery method of chiral N-benzyl-3-hydroxypiperidine which uses a chiral N-benzyl-3-hydroxypiperidine as a raw material to undergo a racemic reaction under the action of a strong base and a high temperature to form a racemic reaction. Racemic product.
- chiral N-benzyl-3-hydroxypiperidine is (R)-N-benzyl-3-hydroxypiperidine, (S)-N-benzyl-3-hydroxypiperidine or both mixture.
- the ee value of (R)-N-benzyl-3-hydroxypiperidine and (S)-N-benzyl-3-hydroxypiperidine in the mixture ranges from 0 to 100%.
- the strong base comprises sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably strong potassium oxide, Such strong bases facilitate the racemization faster.
- the temperature of the racemization reaction of the present invention is 120 to 300 ° C, preferably 180 to 200 ° C; the reaction time is 1 to 100 hours, preferably 10 to 20 hours, most preferably 15 hours, under which the reaction can be carried out. Fully completed, while taking into account the cost and efficiency of the reaction.
- the method of the present invention wherein the molar ratio of the chiral N-benzyl-3-hydroxypiperidine to the strong base is from 1:1 to 5, preferably from 1:2.5 to 1:4, more preferably 1:2.54.
- the occurrence of the racemization reaction can be effectively performed, and it can be made more fully.
- the method of the present invention further comprises a post-treatment process of the racemization reaction, specifically, after the racemization reaction is finished, the reaction liquid is cooled to 50 ° C, diluted with water, and then MTBE dissolved product is added; the reaction liquid is cooled to room temperature. The liquid phase was separated, and the aqueous phase was extracted once with MTBE; the organic phase was combined, washed with a small amount of water; and concentrated to give N-benzyl-3-hydroxypiperidine.
- the invention obtains a novel chiral 3-hydroxypiperidine racemic recovery method, which can stably and batchly obtain high quality racemic N-benzyl-3-hydroxypiperidine, and the reaction is safe. Efficient; isomers are easy to recycle, less waste.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
本发明涉及了一种手性1-苄基-3-羟基哌啶的消旋回收方法,具体以拆分回收的手性N-苄基-3-羟基哌啶(I)为原料,在强碱的作用下消旋回收得N-苄基--3-羟基哌啶。该消旋回收方案未见文献报道,反应简单,适合工业化大生产。
Description
本发明涉及化合物合成领域,具体涉及一种手性1-苄基-3-羟基哌啶的消旋回收方法。
手性1-苄基-3-羟基哌啶是一种重要的医药中间体,现有技术有关于手性1-苄基-3-羟基哌啶多采用手性合成或化学拆分法制备,化学拆分法存在非目标构型的手性羟基的回收利用问题,一般采用间接消旋法回收。间接消旋法具体为把羟基氧化成酮,再用硼氢化钠还原成醇。但上述方法存在工艺复杂,产率低等多种缺陷。因此,仍有待提出改进的手性1-苄基-3-羟基哌啶的回收利用方法。
发明内容
本发明的目的在于提供一种新的手性1-苄基-3-羟基哌啶的消旋回收方法,解决化学拆分法中,非目标构型的手性羟基的回收利用难以及间接消旋法操作繁琐产率低的缺陷。该方法未见文献报道,反应清洁,适合工业化大生产。
为实现上述目的,本发明采用如下技术方案:
一种手性N-苄基-3-羟基哌啶的消旋回收方法,以手性N-苄基-3-羟基哌啶为原料,在强碱及高温的作用下发生消旋反应,形成消旋产物。
上述制备方法用化学反应方程式表示如下:
其中,所述的手性N-苄基-3-羟基哌啶为(R)-N-苄基-3-羟基哌啶、(S)-N-苄基-3-羟基哌啶或二者混合物。
所述混合物中(R)-N-苄基-3-羟基哌啶与(S)-N-苄基-3-羟基哌啶的ee值范围为:0~100%。
本发明所述的方法,其中所述的强碱包括氢氧化钠、氢氧化钾或氢氧化锂,优选强氧化钾,
此类强碱有利于消旋更快进行。
本发明所述的消旋反应的温度为120~300℃,优选为180-200℃;反应时间为1~100小时,优选10~20小时,最优选15小时,在该反应条件下,反应能够充分完成,且同时兼顾到反应成本及效率。
本发明所述的方法,其中所述手性N-苄基-3-羟基哌啶与强碱的摩尔用量比为1:1~5,优选1:2.5-1:4,更优选1:2.54,在该用例范围内,能够有效消旋反应的发生,能够使其进行的更充分。
此外,本发明所述的方法还包括消旋反应的后处理过程,具体为消旋反应结束后,反应液冷却至50℃,滴加水稀释,再流加MTBE溶解产物;反应液冷至室温,分液,水相以MTBE补充提取一次;合并有机相,少量水洗涤;浓缩得消旋N-苄基-3-羟基哌啶。
采用上述技术方案,本发明得到了一种全新的手性3-羟基哌啶的消旋回收方法可以稳定、批量化得到高质量的消旋N-苄基-3-羟基哌啶,反应安全,高效;异构体方便回收利用,三废较少。
以下是本发明的具体实施例,对本发明的技术方案作进一步的描述,但本发明并不限于此实施例。
实施例1(R)-N-苄基-3-羟基哌啶的消旋(一)
1000ml三口瓶中,加入(R)-N-苄基-3-羟基哌啶(95.6g,0.5mol),氢氧化钠50g(1.25mol),升温190℃,反应15小时,HPLC监控,基本消旋,反应液冷却至~50℃(表示约50℃),滴加水稀释,再流加甲基叔丁基醚(MTBE)溶解产物。反应液冷至室温,分液,水相以MTBE补充提取一次。合并有机相,少量水洗涤。浓缩得消旋N-苄基-3-羟基哌啶:96g,收率:100%。(HPLC:R/S=51.9/48.1)。
实施例2(R)-N-苄基-3-羟基哌啶的消旋(二)
1000ml三口瓶中,加入(R)-N-苄基-3-羟基哌啶(95.6g,0.5mol),90%氢氧化钾75g(1.27mol),升温180℃,反应15小时,HPLC监控,基本消旋,反应液冷却至~50℃,滴加水稀释,再流加MTBE溶解产物。反应液冷至室温,分液,水相以MTBE补充提取一次。合并有机相,少量水洗涤。浓缩得消旋N-苄基-3-羟基哌啶:96g,收率:100%。(HPLC:R/S=50.8/49.2)。
实施例3(R)-N-苄基-3-羟基哌啶的消旋(三)
1000ml三口瓶中,加入(R)-N-苄基-3-羟基哌啶(95.6g,0.5mol),氢氧化锂84g(2mol),升温200℃,升温过程,分去水,再保温200℃,反应15小时,HPLC监控,基本消旋,反应液冷却至~50℃,滴加水稀释,再流加MTBE溶解产物。反应液冷至室温,分液,水相以MTBE补充提取一次。合并有机相,少量水洗涤。浓缩得消旋N-苄基-3-羟基哌啶:96g,收率:100%。(HPLC:R/S=52.1/47.9)。
实施例4(S)-N-苄基-3-羟基哌啶的消旋
1000ml三口瓶中,加入(S)-N-苄基-3-羟基哌啶(95.6g,0.5mol),90%氢氧化钾75g(1.27mol),升温180℃,反应15小时,HPLC监控,基本消旋,反应液冷却至~50℃,滴加水稀释,再流加MTBE溶解产物。反应液冷至室温,分液,水相以MTBE补充提取一次。合并有机相,少量水洗涤。浓缩得消旋N-苄基-3-羟基哌啶:96g,收率:100%。(HPLC:S/R=50.6/49.4)。
实施例5回收N-苄基-3-羟基哌啶的消旋
1000ml三口瓶中,加入拆分回收R/S-N-苄基-3-羟基哌啶(95.6g,0.5mol;R/S=10/90),90%氢氧化钾75g(1.27mol),升温180℃,反应15小时,HPLC监控,基本消旋,反应液冷却至~50℃,滴加水稀释,再流加MTBE溶解产物。反应液冷至室温,分液,水相以MTBE补充提取一次。合并有机相,少量水洗涤。浓缩得消旋N-苄基-3-羟基哌啶:96g,收率:100%。(HPLC:S/R=50.4/49.6)。
实施例61000ml不锈钢高压釜中,加入拆分回收R/S-N-苄基-3-羟基哌啶(95.6g,0.5mol;R/S=30/70),90%氢氧化钾75g(1.27mol),升温300℃,反应1小时,HPLC监控,基本消旋,反应液冷却至~50℃,滴加水稀释,再流加MTBE溶解产物。反应液冷至室温,分液,水相以MTBE补充提取一次。合并有机相,少量水洗涤。浓缩得消旋N-苄基-3-羟基哌啶:96g,收率:100%。(HPLC:S/R=50.5/49.5)。
实施例7
1000ml三口瓶中,加入拆分回收R/S-N-苄基-3-羟基哌啶(95.6g,0.5mol;R/S=30/70),90%氢氧化钾75g(1.27mol),升温120℃,反应100小时,HPLC监控,基本消旋,反应液冷却
至~50℃,滴加水稀释,再流加MTBE溶解产物。反应液冷至室温,分液,水相以MTBE补充提取一次。合并有机相,少量水洗涤。浓缩得消旋N-苄基-3-羟基哌啶:96g,收率:100%。(HPLC:S/R=51.5/48.5)。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (10)
- 一种手性N-苄基-3-羟基哌啶的消旋回收方法,其特征在于:以手性N-苄基-3-羟基哌啶为原料,在强碱及高温的作用下发生消旋反应,形成消旋产物。
- 根据权利要求1所述的方法,其特征在于:所述的手性N-苄基-3-羟基哌啶为(R)-N-苄基-3-羟基哌啶、(S)-N-苄基-3-羟基哌啶或二者混合物。
- 根据权利要求2所述的方法,其特征在于:所述混合物中(R)-N-苄基-3-羟基哌啶、(S)-N-苄基-3-羟基哌啶的ee值范围为:0~100%。
- 根据权利要求1或2所述的方法,其特征在于:所述的强碱包括氢氧化钠、氢氧化钾或氢氧化锂。
- 根据权利要求1或2所述的方法,其特征在于:所述的消旋反应的温度为120~300℃。
- 根据权利要求5所述的方法,其特征在于:所述的消旋反应的温度为180-200℃。
- 根据权利要求1或2所述的方法,其特征在于:所述的消旋反应的时间为1~100小时。
- 根据权利要求7所述的方法,其特征在于:所述的消旋反应的时间为15小时。
- 根据权利要求1或2所述的方法,其特征在于:所述手性N-苄基-3-羟基哌啶与强碱的摩尔用量比为1:1~5,优选1:2.5-1:4。
- 根据权利要求1或2所述的方法,其特征在于:还包括消旋反应的后处理过程,具体为消旋反应结束后,反应液冷却至50℃,滴加水稀释,再流加MTBE溶解产物;反应液冷至室温,分液,水相以MTBE补充提取一次;合并有机相,少量水洗涤;浓缩得消旋N-苄基-3-羟基哌啶。
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WO2013076630A1 (en) * | 2011-11-24 | 2013-05-30 | Lupin Limited | Novel process for racemization of an optically active (s)-3-carbamoylmethyl-5-methyl-hexanoic acid to corresponding 3-carbamoylmethyl-5-methyl-hexanoic acid racemate |
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CN101817779B (zh) * | 2010-05-19 | 2012-12-19 | 安徽盛东化工有限公司 | N-苄基-3-哌啶醇的合成工艺、镍基催化剂及制备方法 |
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EP3115358B1 (en) * | 2014-03-04 | 2019-09-11 | ABA Chemicals Corporation | Method of preparation and chiral inversion of chiral-1-t-butoxycarbonyl-3-hydroxy piperidine |
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CN1280981A (zh) * | 1999-07-06 | 2001-01-24 | 拜尔公司 | R,s-二氧代-苄基吡咯并哌啶的外消旋化 |
CN101284789A (zh) * | 2007-04-09 | 2008-10-15 | 浙江京新药业股份有限公司 | 外消旋化舍曲林异构体的新方法 |
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CN104140390B (zh) | 2016-06-08 |
EP3170809A1 (en) | 2017-05-24 |
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