WO2017097193A1 - 一种赖诺普利氢化物的精制方法 - Google Patents

一种赖诺普利氢化物的精制方法 Download PDF

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WO2017097193A1
WO2017097193A1 PCT/CN2016/108814 CN2016108814W WO2017097193A1 WO 2017097193 A1 WO2017097193 A1 WO 2017097193A1 CN 2016108814 W CN2016108814 W CN 2016108814W WO 2017097193 A1 WO2017097193 A1 WO 2017097193A1
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lisinopril
hydride
cooling
crystallization
crude
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PCT/CN2016/108814
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French (fr)
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胡佳兴
黄文锋
涂国良
林恩敏
王安宇
方玉玲
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浙江华海药业股份有限公司
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    • 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
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic

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  • the invention relates to a method for purifying and purifying lisinopril hydride which is an important intermediate of lisinopril.
  • Lisinopril is a new generation of angiotensin-converting enzyme inhibitors that lowers blood pressure mainly by inhibiting the renin-angiotensin-aldosterone system, and lisinopril also has a hypotensive effect on low renin hypertension.
  • Lisinopril hydride is the main intermediate in the synthesis of lisinopril. The structural formula is as shown in formula I:
  • the synthesis of lisinopril hydride is mainly obtained by using an addition-hydrogenation process using trifluoroacetyl lysine and a phenyl ester as a raw material, and the crude lisinopril hydride synthesized by the route contains A large number of impurities such as lisinopril hydride isomer (II), lisinopril hydrogenation transition state (III), lisinopril hydrogenation hydrolysate (IV), the specific structural formula is as follows:
  • the known system for refining crude lisinopril hydride is mainly ethanol-water, which has high energy consumption and fineness.
  • the problems of poor production, low purification yield, and large amount of hydride remaining in the mother liquor have caused problems such as high production cost, material waste, and environmental pollution.
  • the invention provides a method for separating and refining crude lisinopril hydride by solvent crystallization, so as to solve the problems of high energy consumption, poor purification effect and low purification yield of the existing refined lisinopril hydride.
  • the problem of residual large amount of hydride in the mother liquor, the method provided by the invention can efficiently separate lisinopril hydride from the crude product, the yield is more than 80%, and the purity of the hydride is as high as 97%, and more than 98%.
  • the invention provides a method for refining crude lisinopril hydride, comprising the following steps:
  • the crude lisinopril hydride is added to the ketone solvent, dissolved by heating, and the first time the temperature is crystallized to a certain temperature, the crystal is crystallized, the crystal is further cooled, and the lisinopril hydride product is obtained by suction filtration.
  • a preferred technical solution of the present invention is to add a crude lisinopril hydride to a ketone solvent, heat and dissolve, and firstly reduce the temperature and crystallize to a certain temperature, then add the seed crystal, then reduce the temperature, crystallize, continue to cool and crystallize, and filter.
  • a lisinopril hydride product is obtained.
  • the purified solvent (ketone solvent) described therein is selected from the group consisting of acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone, cyclohexanone or a combination thereof.
  • the ketone solvent is used in an amount of 5 to 10 mL/g, preferably 6 to 8 mL/g, based on the weight of the crude lisinopril hydride.
  • the certain temperature described in the first temperature reduction to a certain temperature is 25-35 ° C, preferably 28-33 ° C, more preferably 30-32 ° C.
  • the temperature at which the seed crystal is added is 25 to 35 ° C, preferably 28 to 33 ° C, more preferably 30 to 32 ° C.
  • the temperature-lowering crystallization is a gradient cooling, and the cooling rate is 5 to 10 ° C / h, preferably 7 to 8 ° C / h.
  • the addition of the seed crystal followed by the temperature reduction crystallization is a cooling temperature of 15-25 ° C, preferably 17-23 ° C.
  • the crystal growth time is 3 to 10 hours, preferably 5 to 7 hours.
  • the continued cooling and crystallization is a cooling temperature of 0 to 5 ° C, preferably 2 to 5 ° C.
  • the invention also provides a lisinopril hydride compound prepared according to the purification method of the invention for synthesizing an angiotensin converting enzyme inhibitor lisinopril, the specific synthetic route is as follows:
  • the beneficial technical effect of the present invention is that the crude lisinopril hydride is refined by adding a ketone solvent, which can significantly improve the purification yield and the purification efficiency, and effectively reduce the lisinopril hydride isomer and lisinopril.
  • the purity can be as high as 97%, and it can reach 98% (HPLC) or more.
  • Buffer 2.5g potassium dihydrogen phosphate dissolved in 1000ml water, adjust the pH to 4.5
  • the source of the seed crystal of the present invention is disclosed, and the seed crystal is a purified product obtained by repeated recrystallization using a 65% aqueous ethanol solution, and has a purity of 98% or more.
  • the crude lithopril hydride (the content of lisinopril hydride isomer (II) is 18.2%, the transition state of lisinopril hydrogenation (III) is 0.16%, and the content of lisinopril hydrolyzate (IV) 1.40%) 200g, liquid chromatography showed that the content of lisinopril hydride in the crude product was 76.2%, added 1600mL of acetone, heated to 60 ° C, stirred and dissolved, stirred and reduced to 35 ° C at a cooling rate of 8 ° C / h, Add 2g of seed crystals, continue and stir at 5 ⁇ 10°C/h to 25°C, raise the crystal for 8h, continue to stir at 5 ⁇ 10°C/h and cool to 5°C, stir the crystal, filter and dry to obtain solid.
  • the white product was 127 g, lisinopril hydride purity (HPLC) 98.1%.
  • the crude ruthenide hydride was 200 g, and the liquid chromatogram showed that the content of lisinopril hydride in the crude product was 78.1%, and 2000 mL of methyl ethyl ketone was added, and the mixture was heated to 65 ° C, stirred and dissolved, and stirred at 10 ° C / h.
  • the crude ruthenide hydride was 200 g, and the liquid chromatogram showed that the content of lisinopril hydride in the crude product was 77.8%, 1000 mL of methyl isobutyl ketone was added, and the mixture was heated to 60 ° C, stirred and dissolved, and stirred at 8 ° C / The cooling rate of h is reduced to 30 ° C, seed crystal 2g is added, continue and stirred at 5 ⁇ 10 ° C / h to 20 ° C, crystal growth for 3h, continue and stir at 5 ⁇ 10 ° C / h to 2 ° C, stir The crystals were suction filtered and dried to give a solid white product (133 g), purity (HPLC) 98.1%.
  • the crude ruthenide hydride was 200 g, and the liquid chromatogram showed that the content of lisinopril hydride in the crude product was 81.0%, 1400 mL of diisobutyl ketone was added, and the mixture was heated to 65 ° C, stirred and dissolved, and stirred at 9 ° C / h.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

本发明提供了一种通过溶剂结晶，对赖诺普利氢化物粗品进行精制的方法，具体为利用将含有赖诺普利氢化物（Ι）、赖诺普利异构体（II）以及其它杂质（如杂质III、IV）的粗品加入酮类溶剂，加热溶解，首次降温析晶，选择性地加入晶种接着降温析晶，养晶、继续降温析晶，抽滤即可得到赖诺普利氢化物，收率达80％，纯度达97％以上，更能达98％以上。该方法可将赖诺普利氢化物粗品中的氢化物进行分离精制，提高赖诺普利氢化物精制产率，在工业应用上具有明显的利用价值。

Description

一种赖诺普利氢化物的精制方法 技术领域
本发明涉及一种赖诺普利的重要中间体赖诺普利氢化物纯化精制方法。
背景技术
赖诺普利是新一代血管紧张素转化酶抑制剂，主要通过抑制肾素－血管紧张素－醛固酮系统降低血压，同时赖诺普利亦对低肾素性高血压有降压作用。赖诺普利氢化物为赖诺普利合成工艺中的主要中间体，结构式如式I所示：
Figure PCTCN2016108814-appb-000001
目前，赖诺普利氢化物的合成主要以三氟乙酰基赖氨酸与苯酯类化合物为原料，通过加成－氢化过程得到，通过该路线合成得到的赖诺普利氢化物粗品中含有大量的赖诺普利氢化物异构体(II)、赖诺普利氢化过渡态(III)、赖诺普利氢化水解物(IV)等杂质，具体结构式如下：
Figure PCTCN2016108814-appb-000002
已知的对赖诺普利氢化物粗品进行精制的体系主要有乙醇－水，该体系存在能耗高、精 制效果差、精制收率低、母液中残留大量氢化物等问题，这些问题极大的造成了生产成本高、物料浪费以及环境污染等问题。
发明内容
本发明提供了一种通过溶剂结晶，对赖诺普利氢化物粗品进行分离精制的方法，以解决现有精制赖诺普利氢化物存在的能耗高、精制效果差、精制收率低、母液中残留大量氢化物等问题，本发明提供的方法可从粗品中高效的分离得到赖诺普利氢化物，收率大于80％，且氢化物纯度高达97％，更能达到98％以上。
本发明提供一种赖诺普利氢化物粗品的精制方法，包括以下步骤：
将赖诺普利氢化物粗品加入酮类溶剂，加热溶解，首次降温析晶至一定温度后，养晶、继续降温析晶，抽滤得到赖诺普利氢化物精制品。
本发明优选的技术方案是将赖诺普利氢化物粗品加入酮类溶剂，加热溶解，首次降温析晶至一定温度后加入晶种，接着降温析晶、养晶、继续降温析晶，抽滤得到赖诺普利氢化物精制品。
其中所述的精制溶剂(酮类溶剂)选自：丙酮、丁酮、甲基乙基酮、甲基异丁基酮、二异丁酮、环己酮或其组合物。
作为本发明的进一步改进，其中所述酮类溶剂的使用体积量相对于赖诺普利氢化物粗品重量为5～10mL/g，优选6～8mL/g。
作为本发明的进一步改进，其中首次降温析晶至一定温度中所述的一定温度为25-35℃，优选28-33℃，更优选30-32℃。
作为本发明的进一步改进，其中加入晶种时的温度为25-35℃，优选28-33℃，更优选30-32℃。
作为本发明的进一步改进，所述降温析晶均为梯度降温，降温速度为5～10℃/h，优选为7～8℃/h。
作为本发明的进一步改进，加入晶种后接着降温析晶是冷却温度至15-25℃，优选17-23℃。
作为本发明的进一步改进，养晶时间3～10小时，优选5-7小时。
作为本发明的进一步改进，继续降温析晶是冷却温度至0～5℃，优选2-5℃。
本发明还提供根据本发明精制方法制备得到的赖诺普利氢化物化合物用于合成制备血管紧张素转化酶抑制剂赖诺普利，具体合成路线如下：
Figure PCTCN2016108814-appb-000003
本发明有益的技术效果是通过加入酮类溶剂对赖诺普利氢化物粗品进行精制，可以显著提高精制收率和精制效率，有效地降低赖诺普利氢化物异构体及赖诺普利氢化水解物等杂质，通过简单的重结晶方法得到合格成品，降低了生产成本、提高了精制效率，生产工艺和所需设备适合工业大生产；该方法纯化后赖诺普利氢化物外观为白色，纯度能高达97％，更能达到98％(HPLC)以上。
具体实施方式
以下实施例中HPLC的仪器型号：Agilent 1100series
色谱条件如下:
检测器：高效液相仪器配备紫外检测器
色谱柱：shim-pack CLC-ODS 150x6.0mm 5um
缓冲液：2.5g磷酸二氢钾溶于1000ml水中，调节pH为4.5
流动相：缓冲液：乙腈＝60:40
流速：1.0ml/min 柱温：25℃ 检测波长：210nm
实施例1：赖诺普利粗品的精制
取赖诺普利氢化物粗品(赖诺普利氢化物异构体(II)含量为18.0％，赖诺普利氢化过渡态(III)0.15％，赖诺普利氢化水解物(IV)含量为1.50％)200g，液相色谱显示粗品中赖诺普利氢化物的含量为77.0％，加入甲基异丁基酮1500mL，加热至66℃搅拌溶解，搅拌并以5℃/h搅拌降温至25℃，养晶7h，继续并以5～10℃/h搅拌降温至2℃，搅拌析晶，抽 滤、烘干，得固体白色产物128g，赖诺普利氢化物纯度(HPLC)97.5％。
披露本发明晶种的来源，晶种是使用65％乙醇水溶液反复重结晶得到的精制产品，纯度98％以上。
实施例2：赖诺普利粗品的精制
取赖诺普利氢化物粗品(赖诺普利氢化物异构体(II)含量为18.2％，赖诺普利氢化过渡态(III)0.16％，赖诺普利氢化水解物(IV)含量为1.40％)200g，液相色谱显示粗品中赖诺普利氢化物的含量为76.2％，加入丙酮1600mL，加热至60℃搅拌溶解，搅拌并以8℃/h的降温速度降至35℃，加入晶种2g，继续并以5～10℃/h搅拌降温至25℃，养晶8h，继续以5～10℃/h搅拌降温至5℃，搅拌析晶，抽滤、烘干，得固体白色产物127g，赖诺普利氢化物纯度(HPLC)98.1％。
实施例3：赖诺普利粗品的精制
取赖诺普利氢化物粗品200g，液相色谱显示粗品中赖诺普利氢化物的含量为76.4％，加入丁酮1600mL，加热至60℃搅拌溶解，搅拌并以5℃/h的降温速度降至28℃，加入晶种2g，继续并以5～10℃/h搅拌降温至15℃，养晶10h，继续并以5～10℃/h搅拌降温至2℃，搅拌析晶，抽滤、烘干，得固体白色产物134g，纯度(HPLC)98.2％。
实施例4：赖诺普利粗品的精制
取赖诺普利氢化物粗品200g，液相色谱显示粗品中赖诺普利氢化物的含量为78.1％，加入甲基乙基酮2000mL，加热至65℃搅拌溶解，搅拌并以10℃/h的降温速度降至33℃，加入晶种2g，继续并以5～10℃/h搅拌降温至25℃，养晶5h，继续并以5～10℃/h搅拌降温至0℃，搅拌析晶，抽滤、烘干，得固体白色产物129g，纯度(HPLC)98.0％。
实施例5：赖诺普利粗品的精制
取赖诺普利氢化物粗品200g，液相色谱显示粗品中赖诺普利氢化物的含量为77.8％，加入甲基异丁基酮1000mL，加热至60℃搅拌溶解，搅拌并以8℃/h的降温速度降至30℃，加入晶种2g，继续并以5～10℃/h搅拌降温至20℃，养晶3h，继续并以5～10℃/h搅拌降温至2℃，搅拌析晶，抽滤、烘干，得固体白色产物133g，纯度(HPLC)98.1％。
实施例6：赖诺普利粗品的精制
取赖诺普利氢化物粗品200g，液相色谱显示粗品中赖诺普利氢化物的含量为81.0％，加入二异丁酮1400mL，加热至65℃搅拌溶解，搅拌并以9℃/h的降温速度降至25℃，加入晶种2g，继续并以5～10℃/h搅拌降温至15℃，养晶5h，继续并以5～10℃/h搅拌降温至0℃，搅拌析晶，抽滤、烘干，得固体白色产物141g，纯度(HPLC)98.4％。
表1 HPLC检测实验结果
Figure PCTCN2016108814-appb-000004
实施结果：表明经本发明提供在酮类溶剂中精制纯化后，赖诺普利氢化物纯度能达到97.0％以上，更能达到98.0％以上，其中赖诺普利氢化物异构体(II)、赖诺普利氢化过渡态(III)及赖诺普利氢化水解物(IV)都有明显的降低，为得到高质量的赖诺普利产品提供有力的保证。

Claims (12)

  1. 一种赖诺普利氢化物的精制方法，所述赖诺普利氢化物如下式1：
    Figure PCTCN2016108814-appb-100001
    具体方法：包含将赖诺普利氢化物粗品加入酮类溶剂，加热溶解，首次降温析晶至一定温度后，养晶、继续降温析晶，抽滤得到赖诺普利氢化物精制品；其中赖诺普利氢化物粗品至少还包含以下3种化合物中的一种：
    Figure PCTCN2016108814-appb-100002
  2. 根据权利要求1所述的精制方法，其特征在于：所述的赖诺普利氢化物粗品加入酮类溶剂，加热溶解，首次降温析晶至一定温度后加入晶种，接着降温析晶、养晶、继续降温析晶，抽滤得到赖诺普利氢化物精制品。
  3. 根据权利要求1或2所述的精制方法，其特征在于：所述的酮类溶剂选自：丙酮、丁酮、甲基乙基酮、甲基异丁基酮、二异丁酮、环己酮或其组合物。
  4. 根据权利要求1或2所述的精制方法，其特征在于：其中所述酮类溶剂的使用体积量相对于赖诺普利氢化物粗品重量为5～10mL/g，优选6～8mL/g。
  5. 根据权利要求1所述的精制方法，其特征在于，其中首次降温析晶至一定温度中所述的一定温度为25-35℃，优选28-33℃，更优选30-32℃。
  6. 根据权利要求2所述的精制方法，其特征在于：其中加入晶种时的温度为25-35℃，优选28-33℃，更优选30-32℃。
  7. 根据权利要求1或2或5或6所述的精制方法，其特征在于：所述降温析晶均为梯度降温，降温速度为5～10℃/h，优选为7～8℃/h。
  8. 根据权利要求2或6所述的精制方法，其特征在于：接着降温析晶是冷却温度至15-25℃，优选17-23℃。
  9. 根据权利要求1或2或5或6所述的精制方法，其特征在于：养晶时间3～10小时，优选5-7小时。
  10. 根据权利要求1或2或5或6所述的精制方法，其特征在于：继续降温析晶是冷却温度至0～5℃，优选2-5℃。
  11. 根据权利要求1或2或5或6所述的精制方法，其特征在于，其中赖诺普利氢化物粗品还包含以下3种化合物：
    Figure PCTCN2016108814-appb-100003
    Figure PCTCN2016108814-appb-100004
  12. 一种如权利要求1至11任一项所述的精制方法制备得到的赖诺普利氢化物用于合成制备血管紧张素转化酶抑制剂赖诺普利。
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CN101973904A (zh) * 2010-09-28 2011-02-16 苏州雅本化学股份有限公司 一种具有高光学纯度的n2-[1-(s)-乙氧羰基-3-苯丙基]-n6-三氟乙酰基-l-赖氨酸的制备方法
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CN101239923A (zh) * 2007-12-31 2008-08-13 浙江工业大学 (s,s)n-(1-乙氧羰基-3-苯丙基)-l-氨基酸衍生物的制备方法与精制方法
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