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WO2016062212A1 - 一种用回收制备3-异丁基戊二酸单酰胺的方法 - Google Patents

一种用回收制备3-异丁基戊二酸单酰胺的方法 Download PDF

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Publication number
WO2016062212A1
WO2016062212A1 PCT/CN2015/091836 CN2015091836W WO2016062212A1 WO 2016062212 A1 WO2016062212 A1 WO 2016062212A1 CN 2015091836 W CN2015091836 W CN 2015091836W WO 2016062212 A1 WO2016062212 A1 WO 2016062212A1
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temperature
monoamide
hours
mother liquor
chiral separation
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PCT/CN2015/091836
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English (en)
French (fr)
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王曙东
游学海
张文灵
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浙江华海药业股份有限公司
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Priority to ES15853118T priority Critical patent/ES2916810T3/es
Priority to EP15853118.6A priority patent/EP3210967B1/en
Priority to US15/521,021 priority patent/US10131625B2/en
Publication of WO2016062212A1 publication Critical patent/WO2016062212A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01D—COMPOUNDS OF ALKALI METALS, i.e. LITHIUM, SODIUM, POTASSIUM, RUBIDIUM, CAESIUM, OR FRANCIUM
    • C01D1/00—Oxides or hydroxides of sodium, potassium or alkali metals in general
    • C01D1/04—Hydroxides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • the invention relates to a method for recovering a pharmaceutical intermediate, in particular to a key intermediate of chiral separation of 3-isobutylglutarate monoamide for recovering the key intermediate of pregabalin 3-isobutylglutaric acid monoamide Methods.
  • Pregabalin English name Pregalalin, is a novel gamma-aminobutyric acid (GABA) receptor antagonist developed by Pfizer. Partial seizures approved for treatment of adult patients in the first time in July 2004, under the trade name Lyrica. Approved in the United States in June 2005 by the US Food and Drug Administration (FDA). In March 2006, it increased its indications to treat generalized anxiety disorder and social anxiety disorder. In 2009, it was approved to treat spinal cord injury, trauma, and multiple sclerosis. Symptoms, diabetic neuropathic pain and herpes zoster neuropathic pain have further expanded its clinical application.
  • GABA gamma-aminobutyric acid
  • pregabalin has better anti-epilepsy, anti-anxiety and treatment of neuropathic pain, it has been widely used in clinical practice, and the market demand has further increased. According to research, most of the current market uses synthetic methods to synthesize pregabalin.
  • 3-Isobutylglutaric acid monoamide is an important intermediate for the synthesis of pregabalin.
  • the structural formula is as follows:
  • the (S) isomer of 3-isobutylglutaric acid monoamide is used in the synthesis of pregabalin. It has been reported in the literature that the levo isomer is obtained by resolution of a resolving agent. But 3-isobutyl The yield of (s)-3-isobutylglutarate monoamide resolved to glutaric acid monoamide is only about 35%, and a large amount of raw materials remain in the split mother liquor (that is, 3-isobutyl group) The utilization rate of glutaric acid monoamide is about 35%). In the commercial large-scale production of pregabalin, if 6% of the intermediates are not considered, the intermediates will remain in the mother liquor, causing waste, which will greatly increase the cost of producing pregabalin.
  • This method usually involves adding a lye to the mother liquor, layering, adjusting the pH, filtering the wet product and then adding toluene, and then adding diisopropylamine and 1,8-diazabicycloundec-7-ene ( DBU), diisopropylethylamine and other reflux reaction racemic, and then open the ring with a base, adjust the pH, filtration, ethyl acetate purification, drying, etc. (total yield: about 50%, put into the split when 3- Isobutylglutaric acid monoamide).
  • the method step is cumbersome and cumbersome, and the operation is complicated. Two times of acid and alkali adjustment, a large amount of inorganic salt is introduced and waste water is generated.
  • the utilization of glutaric acid monoamide is increased, thereby reducing production costs.
  • the 3-isobutylglutaric acid monoamide chiral separation mother liquid is directly distilled, and after distillation, an aromatic hydrocarbon such as toluene or p-xylene is directly refluxed, and the mixture is dehydrated and crystallized, and the product is obtained by filtration and drying.
  • the method of the invention greatly reduces the operation steps, simplifies the process, reduces the loss, improves the utilization rate of the raw materials (the improved utilization rate of 3-isobutylglutaric acid monoamide is 70-80%), reduces the cost, and protects the environment. And is atomic and suitable for commercial production.
  • the present invention provides a method for recovering high purity 3-isobutylglutaric acid monoamide from a chiral separation mother liquor of 3-isobutylglutarate monoamide, comprising the steps of:
  • step (c) After the heat preservation reaction in the above step (b) is completed, the temperature is lowered to 20 to 30 ° C, layered, and the separated aqueous layer is adjusted to pH 1-2, and after extraction with an organic solvent, the organic phase is subjected to vacuum distillation. Then, it was subjected to crystallization at a temperature of 0 ⁇ 5 ° C to obtain 3-isobutylglutaric acid monoamide.
  • the 3-isobutylglutarate monoamide chiral separation mother liquor in step (a) is a 3-isobutylglutarate monoamide in the use of a resolving agent (The mother liquor obtained after cleavage of R-phenylethylamine.
  • the aromatic hydrocarbon added to the 3-isobutylglutaric acid monoamide chiral separation mother liquor after the distillation in step (a) is a C 6 -C 12 aromatic hydrocarbon; It is benzene, toluene, xylene, p-xylene; more preferably toluene or xylene.
  • the heating dissolution temperature in step (a) is from 80 to 150 °C, more preferably from 100 to 120 °C.
  • the ratio of the mass of the 3-isobutylglutaric acid monoamide chiral separation mother liquor to the volume of the aromatic hydrocarbon solvent after the distillation in step (a) is 1:10 ⁇ 1:20 g/ml, preferably 1:13 to 1:18 g/ml.
  • the incubation temperature in step (a) is from 90 to 130 ° C, more preferably from 100 to 120 ° C.
  • the incubation time in step (a) is from 20 to 48 h, further preferably from 24 to 34 h.
  • the incubation temperature in step (b) is from 90 to 130 ° C, more preferably from 100 to 120 ° C.
  • the incubation time in step (b) is from 20 to 48 h, further preferably from 24 to 34 h.
  • the end temperature of the cooling in step (b) is from 30 to 60 ° C, more preferably from 40 to 50 ° C.
  • the lye in step (b) is an aqueous solution of an alkali metal hydroxide and/or an aqueous solution of an alkali metal carbonate, such as sodium hydroxide, sodium carbonate, potassium carbonate,
  • the aqueous solution of potassium hydroxide is preferably an aqueous solution of sodium hydroxide or potassium carbonate, and the concentration of the alkali liquid is preferably 20 to 30% by mass.
  • the amount of the lye in the step (b) is 1- to 4-butyl glutaric acid monoamide in the 3-isobutylglutarate monoamide chiral separation mother liquor. 3 times (mass ratio, based on the amount of monoamide before separation), more preferably 2 to 3 times.
  • the temperature at which the alkali solution is added dropwise in the step (b) is 30 to 60 ° C, and more preferably 30 to 50 ° C.
  • the cooling mode in step (b) is reduced by 1 ° C every 5 minutes and the crystallization time is controlled between 3 and 5 hours.
  • the end temperature of the cooling in step (b) is from 40 to 50 °C.
  • the cooling mode after the vacuum distillation in step (c) is reduced by 1 ° C every 5 minutes and the crystallization time is controlled to 3 to 5 hours.
  • the extraction solvent in step (c) is a water-immiscible organic solvent, preferably selected from the group consisting of n-hexane, cyclohexane, n-heptane, toluene, ethyl acetate or Ethyl ether is further preferably n-heptane, ethyl acetate or toluene.
  • the present invention relates to the recovery of the reactant 3-isobutylglutaric acid monoamide as exemplified below:
  • the invention provides a purification method with simple operation and low operation cost; and the product quality is good and refined.
  • the post-3-isobutylglutaric acid monoamide is white with a purity (HPLC) ⁇ 99.8%, which meets the requirements for the production of high quality intermediates by pregabalin.
  • an aromatic hydrocarbon refers to a hydrocarbon having a benzene ring structure in its molecule, especially a C 6 -C 12 aromatic hydrocarbon, including but not limited to benzene, toluene, xylene, p-xylene, o-xylene, and m-. Toluene, ethylbenzene, cumene, naphthalene, and the like.
  • xylene refers to a mixture of three isomers of o-xylene, m-xylene, and p-xylene.
  • the filtrate (about 1.7 L) obtained in the above Reference Example was taken in, decompressed, controlled at a temperature of 30 to 40 ° C, concentrated to 300-500 mL, cooled to 15 to 25 ° C, 200 mL of water was added, and the temperature was controlled to 30. ⁇ 40 ° C, Concentrate to no significant fractions. Add 700 mL of toluene and raise the temperature. The temperature was raised to 110 to 120 ° C in 1 to 2 hours, and the water was separated. From the 24th hour, HPLC detection was performed every 4 hours until 3-isobutylglutaic acid ⁇ 1% was stopped. The temperature was lowered to 40 to 50 ° C in 1 to 2 hours.
  • the liquid was separated, and 167.0 g of toluene was added to the aqueous phase, and the mixture was stirred for 0.5 to 1 hour, and allowed to stand for 0.5 to 1 hour.
  • the water phase is separated.
  • the filtrate (about 1.7 L) obtained in the above Reference Example was taken in, decompressed, controlled at a temperature of 30 to 40 ° C, concentrated to 300-500 mL, cooled to 15 to 25 ° C, 200 mL of water was added, and the temperature was controlled to 30. At ⁇ 40 ° C, concentrate until no significant fractions flow out. 700 mL of xylene was added, the temperature was raised, and the temperature was raised to 110 to 120 ° C in 1 to 2 hours while stirring, and water was separated. From the 24th hour, HPLC detection was performed every 4 hours until 3-isobutylglutaic acid ⁇ 1% was stopped. The temperature was lowered to 40 to 50 ° C in 1 to 2 hours.
  • the liquid was separated, and 167.0 g of toluene was added to the aqueous phase, and the mixture was stirred for 0.5 to 1 hour, and allowed to stand for 0.5 to 1 hour.
  • the water phase is separated.
  • Add 600 mL of n-heptane stir for 20 to 30 minutes, let stand for 30 minutes, and add 300 mL of n-heptane to the aqueous phase.
  • the filtrate (about 1.7 L) obtained in the above Reference Example was taken in, decompressed, controlled at a temperature of 30 to 40 ° C, concentrated to 300-500 mL, cooled to 15 to 25 ° C, 200 mL of water was added, and the temperature was controlled to 30. At ⁇ 40 ° C, concentrate until no significant fractions flow out. 700 mL of p-xylene was added, the temperature was raised, and the temperature was raised to 110 to 120 ° C in 1 to 2 hours while stirring, and water was separated. From the 24th hour, HPLC detection was performed every 4 hours until 3-isobutylglutaic acid ⁇ 1% was stopped. The temperature was lowered to 40 to 50 ° C in 1 to 2 hours.
  • the liquid was separated, and 167.0 g of toluene was added to the aqueous phase, and the mixture was stirred for 0.5 to 1 hour, and allowed to stand for 0.5 to 1 hour.
  • the water phase is separated.
  • the filtrate (about 1.7 L) obtained in the above Reference Example was taken in, decompressed, controlled at a temperature of 30 to 40 ° C, concentrated to 300-500 mL, cooled to 15 to 25 ° C, 200 mL of water was added, and the temperature was controlled to 30. At ⁇ 40 ° C, concentrate until no significant fractions flow out. 700 mL of p-xylene was added, the temperature was raised, and the temperature was raised to 110 to 120 ° C in 1 to 2 hours while stirring, and water was separated. From the 24th hour, HPLC detection was performed every 4 hours until 3-isobutylglutaic acid ⁇ 1% was stopped. The temperature was lowered to 40 to 50 ° C in 1 to 2 hours.
  • the liquid was separated, and 167.0 g of toluene was added to the aqueous phase, and the mixture was stirred for 0.5 to 1 hour, and allowed to stand for 0.5 to 1 hour.
  • the water phase is separated.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明提供一种从3-异丁基戊二酸单酰胺手性拆分母液回收3-异丁基戊二酸单酰胺的方法，包括以下步骤：(a)将3-异丁基戊二酸单酰胺手性拆分母液蒸馏，然后加入芳香烃，加热溶解，保温搅拌；(b)在上述步骤(a)的保温反应结束后，将反应液降温至30～60℃，再滴加碱液，保温反应；(c)在上述步骤(b)的保温反应完毕后，降温到20～30℃，分层，分出的水层调节pH至1-2，用有机溶剂萃取后，对有机相进行减压蒸馏，然后在0±5℃的温度下析晶以获得3-异丁基戊二酸单酰胺。本发明提供的方法操作简便，获得回收的产品纯度高(≥99.8％)，且收率较高。

Description

一种用回收制备3-异丁基戊二酸单酰胺的方法
本申请要求于2014年10月24日提交中国专利局、申请号为201410589184.X发明名称为“一种用回收制备3-异丁基戊二酸单酰胺的方法”的中国专利申请的优先权，其全部内容通过引用并入本申请中。
技术领域
本发明涉及一种回收药物中间体的方法，特别是涉及一种从3-异丁基戊二酸单酰胺手性拆分母液回收普瑞巴林关键中间体3-异丁基戊二酸单酰胺的方法。
背景技术
普瑞巴林，英文名Pregabalin，是由Pfizer公司开发的新型γ-氨基丁酸(GABA)受体拮抗剂。2004年7月首次经欧盟批准用于治疗成年患者的部分癫痫发作，商品名为Lyrica。2005年6月经美国食品与药品管理局(FDA)批准在美国上市，2006年3月增加适应症，治疗广泛性焦虑障碍和社交性焦虑障碍，2009年又获准治疗脊髓损伤、外伤、多发性硬化症、糖尿病性神经疼痛和带状疱疹神经疼痛，使其临床应用得到进一步扩展。由于普瑞巴林具有较好的抗癫痫、抗焦虑和治疗神经性疼痛等作用，目前已在临床中得到广泛应用，市场的需求量进一步加大。经调研，目前市场上大多采用化学合成的方法合成普瑞巴林。
3-异丁基戊二酸单酰胺是合成普瑞巴林的重要中间体，结构式如下所示：
Figure PCTCN2015091836-appb-000001
在合成普瑞巴林过程中用到的是3-异丁基戊二酸单酰胺的(S)型异构体，目前文献中多报道采用拆分剂拆分的办法获得该左旋异构体。但是3-异丁基 戊二酸单酰胺拆分至(S)-3-异丁基戊二酸单酰胺的收率仅在35％左右，大量的原料留在拆分母液中(也就是说，3-异丁基戊二酸单酰胺的利用率约为35％)。在商业化大规模生产普瑞巴林时，如不考虑母液回收，约65％的中间体将留在母液中，造成浪费，从而使生产普瑞巴林的成本大大提高。印度Anil B.Chavan等人在期刊“Organic Process Research and Development”(2009年5月18日出版)的第13卷第4期第812-814页的文章《An Efficient Process of Racemization of 3-(Carbamoylmethyl)-5-methylhexanoic acid：A Pregabalin Intermediate》中提到用消旋回收的方法，重新利用母液中的3-异丁基戊二酸单酰胺。该类方法通常是在母液中先加入碱液，分层，再调节pH，过滤湿品再加入甲苯，再加入二异丙胺、1，8-二氮杂二环十一碳-7-烯(DBU)、二异丙基乙胺等回流反应消旋，再用碱开环，调节pH，过滤、乙酸乙酯精制，烘干等(总收率：约50％，以拆分时投入3-异丁基戊二酸单酰胺计)。该方法步骤繁琐冗长，操作复杂，两次调酸碱，会引入大量无机盐并产生废水。
发明内容
本发明的目的是提供一种从3-异丁基戊二酸单酰胺手性拆分母液回收3-异丁基戊二酸单酰胺的方法，该方法适合工业化生产并且使3-异丁基戊二酸单酰胺的利用率提高，从而降低生产成本。
本发明将3-异丁基戊二酸单酰胺手性拆分母液直接蒸馏，蒸馏后加入芳香烃例如甲苯、对二甲苯等溶剂直接回流分水消旋并析晶，过滤烘干得产品。本发明的方法大幅减少操作步骤，简化工艺过程，减少损耗，提高原料的利用率(改进后3-异丁基戊二酸单酰胺总的利用率为70～80％)，降低成本，保护环境，并且是原子经济的，适用于商业化生产。
更具体而言，本发明提供了一种从3-异丁基戊二酸单酰胺手性拆分母液回收高纯度的3-异丁基戊二酸单酰胺的方法，包括以下步骤：
(a)将3-异丁基戊二酸单酰胺手性拆分母液蒸馏，然后加入芳香烃，加热溶解，保温搅拌；
(b)在上述步骤(a)的保温反应结束后，将上述反应液降温，再滴加碱液， 保温反应；
(c)在上述步骤(b)的保温反应完毕后，降温到20～30℃，分层，分出的水层调节pH至1-2，用有机溶剂萃取后，对有机相进行减压蒸馏，然后在0±5℃的温度下析晶以获得3-异丁基戊二酸单酰胺。
在根据本发明方法的一个实施方案中，步骤(a)中所述3-异丁基戊二酸单酰胺手性拆分母液是3-异丁基戊二酸单酰胺在利用拆分剂(R-苯乙胺)拆分后甩滤得到的母液。
在根据本发明方法的一个实施方案中，步骤(a)中所述蒸馏后3-异丁基戊二酸单酰胺手性拆分母液中加入的芳香烃为C6-C12芳香烃；优选为苯、甲苯、二甲苯、对二甲苯；更优选为甲苯或二甲苯。
在根据本发明方法的一个实施方案中，步骤(a)中所述加热溶解温度为80～150℃，进一步优选为100～120℃。
在根据本发明方法的一个实施方案中，步骤(a)中所述蒸馏后3-异丁基戊二酸单酰胺手性拆分母液的质量与芳香烃溶剂的体积之比为1∶10～1∶20g/ml，优选为1∶13～1∶18g/ml。
在根据本发明方法的一个实施方案中，步骤(a)中所述保温反应温度为90～130℃，进一步优选为100～120℃。
在根据本发明方法的一个实施方案中，步骤(a)中所述保温反应时间为20～48h，进一步优选为24～34h。
在根据本发明方法的一个实施方案中，步骤(b)中所述保温反应温度为90～130℃，进一步优选为100～120℃。
在根据本发明方法的一个实施方案中，步骤(b)中所述保温反应时间为20～48h，进一步优选为24～34h。
在根据本发明方法的一个实施方案中，步骤(b)中所述降温的终点温度为30～60℃，进一步优选为40～50℃。
在根据本发明方法的一个实施方案中，步骤(b)中所述碱液为碱金属氢氧化物的水溶液和/或碱金属碳酸盐的水溶液，例如氢氧化钠、碳酸钠、碳酸钾、氢氧化钾的水溶液，优选为氢氧化钠或碳酸钾的水溶液，碱液质量百分比浓度优选为20～30％。
在根据本发明方法的一个实施方案中，步骤(b)中碱液用量为3-异丁基戊二酸单酰胺手性拆分母液中3-异丁基戊二酸单酰胺含量的1～3倍(质量比，以拆分前的单酰胺量计)，进一步优选为2～3倍。
在根据本发明方法的一个实施方案中，步骤(b)中所述滴加碱液时的温度30～60℃，进一步优选为30～50℃。
在根据本发明方法的一个实施方案中，步骤(b)中所述降温方式为每5分钟降低1℃，析晶时间控制在3～5小时。
在根据本发明方法的一个实施方案中，步骤(b)中所述降温的终点温度为40～50℃。
在根据本发明方法的一个实施方案中，步骤(c)中所述减压蒸馏后的降温方式为每5分钟降低1℃，析晶时间控制在3～5小时。
在根据本发明方法的一个实施方案中，步骤(c)中所述萃取溶剂为与水不混溶的有机溶剂，优选选自正己烷、环己烷、正庚烷、甲苯、乙酸乙酯或乙醚，进一步优选为正庚烷、乙酸乙酯或甲苯。
由3-异丁基戊二酸单酰胺制备普瑞巴林的反应式中，本发明涉及如下示例的反应物3-异丁基戊二酸单酰胺的回收：
Figure PCTCN2015091836-appb-000002
本发明提供纯化方法操作简便，运行成本低；且获得产品质量好，精制 后3-异丁基戊二酸单酰胺为白色，纯度(HPLC)≥99.8％，能够满足生产普瑞巴林对高质量中间体的要求。
具体实施方式
为使本发明的目的、技术方案、及优点更加清楚明白，以下参照实施例，对本发明进行进一步的详细说明。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
定义：
本文中所用的芳香烃是指分子中含有苯环结构的碳氢化合物，尤其是C6-C12芳香烃，包括但不限于苯、甲苯、二甲苯、对二甲苯、邻二甲苯、间二甲苯、乙苯、异丙苯、萘等。
本文中所用的二甲苯是指邻二甲苯、间二甲苯和对二甲苯三种异构体的混合物。
参考实施例：3-异丁基戊二酸单酰胺母液的获得
在15～25℃下，往一个3L反应釜中依次抽入三氯甲烷2139.0g、乙醇26.7g，搅拌下用固体加料器加入142.0g 3-异丁基戊二酸单酰胺，用300.0g三氯甲烷洗涤加料器。在1～2小时内加热至55～60℃。在55～60℃下滴加R(+)-α-苯乙胺50.0g，约3～4小时，在55～60℃下继续搅拌0.5～1小时。在55～60℃下滴加R(+)-α-苯乙胺16.7g，约2～3小时，滴完后，在55～60℃下继续搅拌1～2小时，降温至28～32℃，速率为10～20℃/小时。在28～32℃下继续搅拌1～2小时，在28～32℃下过滤，湿品用184.0g三氯甲烷洗二次，合并滤液，备用。
实施例1：从3-异丁基戊二酸单酰胺手性拆分母液回收3-异丁基戊二酸单酰胺
将上述参考实施例中所得的滤液(约1.7L)抽入，减压，控制温度30～40℃，浓缩至300-500mL，冷却到15～25℃，加入200mL水，减压，控制温度30～40℃， 浓缩至无明显馏分流出。加入甲苯700mL，升高温度。在1～2小时内升温至110～120℃搅拌，同时分水。从第24小时开始，每4小时HPLC检测，直到3-异丁基戊二酸＜1％停止。在1～2小时内降温至40～50℃。在40～50℃下滴加入284.0g水以及284.0g 10％NaOH水溶液，温度控制在35～55℃。在40～50℃下搅拌3～4小时，降温至20～30℃，静置分层1～2小时。分液，水相分出后，有机相加入140.0g水，搅拌0.5～1小时，静置分层1～2小时。分液，水相分出后合并。水相加入167.0g甲苯，搅拌0.5～1小时，静置分层0.5～1小时。分液，水相加入167.0g甲苯，搅拌0.5～1小时，静置分层0.5～1小时。分出水相。在水相中滴加100.0g浓盐酸调pH 1.5～2(加入盐酸的量以实际用量为准)，控制温度0～10℃。在0～5℃搅拌1～2小时。加入600mL乙酸乙酯，搅拌20～30分钟，静置30分钟分层，再向水相中加入300mL乙酸乙酯，搅拌20～30分钟，静置30分钟分层，合并有机相，将有机相在40～50℃下减压蒸馏至240mL，缓慢降温至0±5℃，过滤，干燥，得一次回收3-异丁基戊二酸单酰胺(白色固体约67.9g，收率72.5％，纯度99.81％)。
实施例2：从3-异丁基戊二酸单酰胺手性拆分母液回收3-异丁基戊二酸单酰胺
将上述参考实施例中所得的滤液(约1.7L)抽入，减压，控制温度30～40℃，浓缩至300-500mL，冷却到15～25℃，加入200mL水，减压，控制温度30～40℃，浓缩至无明显馏分流出。加入二甲苯700mL，升高温度，在1～2小时内升温至110～120℃搅拌，同时分水。从第24小时开始，每4小时HPLC检测，直到3-异丁基戊二酸＜1％停止。在1～2小时内降温至40～50℃。在40～50℃下滴加入284.0g水以及284.0g 10％NaOH水溶液，温度控制在35～55℃。在40～50℃下搅拌3～4小时，降温至20～30℃，静置分层1～2小时。分液，水相分出后，有机相加入140.0g水，搅拌0.5～1小时，静置分层1～2小时。分液，水相分出后合并。水相加入167.0g甲苯，搅拌0.5～1小时，静置分层0.5～1小时。分液，水相加入167.0g甲苯，搅拌0.5～1小时，静置分层0.5～1小时。分出水相。在水相中滴加100.0g浓盐酸调pH 1.5～2(加入盐酸的量以实际用量为准)，控制温度0～10℃。在0～5℃搅拌1～2小时。加入600mL正庚烷，搅拌20～30分钟，静置30分钟分层，再向水相中加入300mL正庚烷， 搅拌20～30分钟，静置30分钟分层，合并有机相，将有机相在60～70℃下减压蒸馏至240mL，缓慢降温至0±5℃，过滤，干燥，得一次回收3-异丁基戊二酸单酰胺(白色固体约67.3g，收率71.8％，纯度99.79％)。
实施例3：从3-异丁基戊二酸单酰胺手性拆分母液回收3-异丁基戊二酸单酰胺
将上述参考实施例中所得的滤液(约1.7L)抽入，减压，控制温度30～40℃，浓缩至300-500mL，冷却到15～25℃，加入200mL水，减压，控制温度30～40℃，浓缩至无明显馏分流出。加入对二甲苯700mL，升高温度，在1～2小时内升温至110～120℃搅拌，同时分水。从第24小时开始，每4小时HPLC检测，直到3-异丁基戊二酸＜1％停止。在1～2小时内降温至40～50℃。在40～50℃下滴加入284.0g水以及284.0g 10％NaOH水溶液，温度控制在35～55℃。在40～50℃下搅拌3～4小时，降温至20～30℃，静置分层1～2小时。分液，水相分出后，有机相加入140.0g水，搅拌0.5～1小时，静置分层1～2小时。分液，水相分出后合并。水相加入167.0g甲苯，搅拌0.5～1小时，静置分层0.5～1小时。分液，水相加入167.0g甲苯，搅拌0.5～1小时，静置分层0.5～1小时。分出水相。在水相中滴加100.0g浓盐酸调pH 1.5～2(加入盐酸的量以实际用量为准)，控制温度0～10℃。在0～5℃搅拌1～2小时。加入600mL环己烷，搅拌20～30分钟，静置30分钟分层，再向水相中加入300mL环己烷，搅拌20～30分钟，静置30分钟分层，合并有机相，将有机相在40～50℃下减压蒸馏至240mL，缓慢降温至0±5℃，过滤，干燥，得一次回收3-异丁基戊二酸单酰胺(白色固体约66.9g，收率70.5％，纯度99.84％)。
实施例4：从3-异丁基戊二酸单酰胺手性拆分母液回收3-异丁基戊二酸单酰胺
将上述参考实施例中所得的滤液(约1.7L)抽入，减压，控制温度30～40℃，浓缩至300-500mL，冷却到15～25℃，加入200mL水，减压，控制温度30～40℃，浓缩至无明显馏分流出。加入对二甲苯700mL，升高温度，在1～2小时内升温至110～120℃搅拌，同时分水。从第24小时开始，每4小时HPLC检测，直到3-异丁基戊二酸＜1％停止。在1～2小时内降温至40～50℃。在40～50℃ 下滴加入284.0g水以及284.0g 10％NaOH水溶液，温度控制在35～55℃。在40～50℃下搅拌3～4小时，降温至20～30℃，静置分层1～2小时。分液，水相分出后，有机相加入140.0g水，搅拌0.5～1小时，静置分层1～2小时。分液，水相分出后合并。水相加入167.0g甲苯，搅拌0.5～1小时，静置分层0.5～1小时。分液，水相加入167.0g甲苯，搅拌0.5～1小时，静置分层0.5～1小时。分出水相。在水相中滴加100.0g浓盐酸调pH 1.5～2(加入盐酸的量以实际用量为准)，控制温度0～10℃。在0～5℃搅拌1～2小时。加入600mL乙酸乙酯，搅拌20～30分钟，静置30分钟分层，再向水相中加入300mL乙酸乙酯，搅拌20～30分钟，静置30分钟分层，合并有机相，将有机相在40～50℃下减压蒸馏至240mL，缓慢降温至0±5℃，过滤，干燥，得一次回收3-异丁基戊二酸单酰胺(白色固体约75.1g，收率80.1％，纯度99.81％)。以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明保护的范围之内。

Claims (15)

  1. 一种从3-异丁基戊二酸单酰胺手性拆分母液回收3-异丁基戊二酸单酰胺的方法，包括以下步骤：
    (a)将3-异丁基戊二酸单酰胺手性拆分母液蒸馏，然后加入芳香烃，加热溶解，保温搅拌；
    (b)在上述步骤(a)的保温反应结束后，将反应液降温至30～60℃，再滴加碱液，保温反应；
    (c)在上述步骤(b)的保温反应完毕后，降温到20～30℃，分层，分出的水层调节pH至1-2，用有机溶剂萃取后，对有机相进行减压蒸馏，然后在0±5℃的温度下析晶以获得3-异丁基戊二酸单酰胺。
  2. 根据权利要求1所述的方法，其特征在于步骤(a)中所述蒸馏后3-异丁基戊二酸单酰胺手性拆分母液中加入的芳香烃为C6-C12芳香烃；优选为苯、甲苯、二甲苯、对二甲苯；更优选为甲苯或二甲苯。
  3. 根据权利要求1或2所述的方法，其特征在于步骤(a)中所述加热溶解温度为80～150℃，进一步优选为100～120℃。
  4. 根据权利要求1至3中任一项所述的方法，其特征在于步骤(a)中所述蒸馏后3-异丁基戊二酸单酰胺手性拆分母液的质量与芳香烃溶剂的体积之比为1∶10～1∶20g/ml，优选为1∶13～1∶18g/ml。
  5. 根据权利要求1至4中任一项所述的方法，其特征在于步骤(a)中所述保温反应温度为90～130℃，进一步优选为100～120℃。
  6. 根据权利要求1至5中任一项所述的方法，其特征在于步骤(a)中所述保温反应时间为20～48h，进一步优选为24～34h。
  7. 根据权利要求1至6中任一项所述的方法，其特征在于步骤(b)中所述保温反应温度为90～130℃，进一步优选为100～120℃。
  8. 根据权利要求1至7中任一项所述的方法，其特征在于步骤(b)中所述 保温反应时间为20～48h，进一步优选为24～34h。
  9. 根据权利要求1至8中任一项所述的方法，其特征在于步骤(b)中所述碱液为碱金属氢氧化物的水溶液和/或碱金属碳酸盐的水溶液，例如，氢氧化钠、碳酸钠、碳酸钾、氢氧化钾的水溶液，优选为氢氧化钠或碳酸钾的水溶液，碱液质量百分比浓度优选为20～30％。
  10. 根据权利要求1至9中任一项所述的方法，其特征在于步骤(b)中滴加碱液时的温度为30～50℃。
  11. 根据权利要求1至10中任一项所述的方法，其特征在于步骤(b)中所述降温的终点温度为40～50℃。
  12. 根据权利要求1至11中任一项所述的方法，其特征在于步骤(c)中所述减压蒸馏后的降温方式为每5分钟降低1℃，析晶时间控制在3～5小时。
  13. 根据权利要求1至12中任一项所述的方法，其特征在于步骤(c)中所述萃取溶剂为与水不混溶的有机溶剂，优选选自正己烷、环己烷、正庚烷、甲苯、乙酸乙酯或乙醚，进一步优选为正庚烷、乙酸乙酯或甲苯。
  14. 根据权利要求1至13中任一项所述的方法，其特征在于步骤(b)中碱液用量与3-异丁基戊二酸单酰胺手性拆分母液中3-异丁基戊二酸单酰胺含量的质量比为1～3∶1，进一步优选为2～3∶1。
  15. 根据权利要求1至14中任一项所述的方法，其特征在于步骤(a)中所述3-异丁基戊二酸单酰胺手性拆分母液是3-异丁基戊二酸单酰胺在利用拆分剂R-苯乙胺拆分后甩滤得到的母液。
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CN104693052A (zh) * 2014-12-30 2015-06-10 云南大学 一种绿色转化毒品冰毒制备美沙酮的工艺
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CN105152954B (zh) * 2015-07-22 2020-12-08 浙江华海药业股份有限公司 一种无溶剂回收3-异丁基戊二酸单酰胺的方法
CN109761838B (zh) * 2019-02-22 2024-12-31 浙江华海药业股份有限公司 一种制备普瑞巴林中间体和回收拆分剂的方法
CN111747862B (zh) * 2020-06-22 2025-02-28 浙江华海药业股份有限公司 一种回收普瑞巴林中间体3-异丁基戊二酸单酰胺的方法
CN113735732A (zh) * 2021-09-08 2021-12-03 江西金丰药业有限公司 一种高纯度r-(-)-3-氨甲酰甲基-5-甲基己酸的精制方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996038405A1 (en) * 1995-06-02 1996-12-05 Warner-Lambert Company Methods of making (s)-3-(aminomethyl)-5-methylhexanoic acid
CN101500985A (zh) * 2006-07-04 2009-08-05 化学实验室国际股份公司 (r)-(-)-3-(氨甲酰基甲基)-5-甲基己酸以及普瑞巴林和合成中间体的制备方法
WO2011077463A1 (en) * 2009-12-24 2011-06-30 Msn Laboratories Limited Process for preparing pregabalin and its intermediate
CN103980144A (zh) * 2014-05-16 2014-08-13 浙江华海药业股份有限公司 一种普瑞巴林中间体母液的套用方法
CN104086439A (zh) * 2014-06-30 2014-10-08 浙江华海药业股份有限公司 一种pregabalin中间体拆分剂(R)-(+)-α-苯乙胺的回收方法
CN104356016A (zh) * 2014-10-24 2015-02-18 浙江华海药业股份有限公司 一种用回收制备3-异丁基戊二酸单酰胺的方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2012342084A1 (en) * 2011-11-24 2014-06-26 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
CN102898320A (zh) * 2012-10-26 2013-01-30 浙江省天台县奥锐特药业有限公司 (3r)-(-)-3-(2-乙酰氨基)-5-甲基己酸的制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996038405A1 (en) * 1995-06-02 1996-12-05 Warner-Lambert Company Methods of making (s)-3-(aminomethyl)-5-methylhexanoic acid
CN101500985A (zh) * 2006-07-04 2009-08-05 化学实验室国际股份公司 (r)-(-)-3-(氨甲酰基甲基)-5-甲基己酸以及普瑞巴林和合成中间体的制备方法
WO2011077463A1 (en) * 2009-12-24 2011-06-30 Msn Laboratories Limited Process for preparing pregabalin and its intermediate
CN103980144A (zh) * 2014-05-16 2014-08-13 浙江华海药业股份有限公司 一种普瑞巴林中间体母液的套用方法
CN104086439A (zh) * 2014-06-30 2014-10-08 浙江华海药业股份有限公司 一种pregabalin中间体拆分剂(R)-(+)-α-苯乙胺的回收方法
CN104356016A (zh) * 2014-10-24 2015-02-18 浙江华海药业股份有限公司 一种用回收制备3-异丁基戊二酸单酰胺的方法

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