WO2020252662A1 - 一种缬沙坦化合物的精制方法 - Google Patents

一种缬沙坦化合物的精制方法 Download PDF

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WO2020252662A1
WO2020252662A1 PCT/CN2019/091743 CN2019091743W WO2020252662A1 WO 2020252662 A1 WO2020252662 A1 WO 2020252662A1 CN 2019091743 W CN2019091743 W CN 2019091743W WO 2020252662 A1 WO2020252662 A1 WO 2020252662A1
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valsartan
acid
organic solvent
organic
add
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PCT/CN2019/091743
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English (en)
French (fr)
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王毅峰
朱晓仁
朱元勋
颜峰峰
王鹏
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浙江华海药业股份有限公司
浙江华海天诚药业有限公司
浙江华海致诚药业有限公司
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Priority to CN201980095818.7A priority Critical patent/CN113727976B/zh
Priority to PCT/CN2019/091743 priority patent/WO2020252662A1/zh
Publication of WO2020252662A1 publication Critical patent/WO2020252662A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • 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
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This application belongs to the field of medical technology, and particularly relates to a method for refining valsartan.
  • Valsartan (Valsartan), the chemical name is N-(1-pentanoyl)-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- Yl]methyl]-L-valine, the structural formula is as follows:
  • Valsartan was developed by Novartis (Novatis) and was first approved for listing in Germany on July 1, 1996. It is the second non-peptide angiotensin II (A-TII) type I receptor approved for clinical treatment of hypertension. Body antagonist. Valsartan can affect vasoconstriction and the blood pressure effect of aldosterone by blocking the binding of angiotensin II to AT1 receptors in many tissues (such as vascular smooth muscle and glomeruli). Valsartan is used for various types of hypertension, and it has a good protective effect on the heart, brain and kidney. It does not affect the heart rhythm, and does not affect the total cholesterol, triglyceride, blood sugar and uric acid levels of hypertensive patients. It has small side effects. Good application and market prospects.
  • Patent document WO2005021535A2 uses L-valine methyl ester hydrochloride and tetrazolium protected 2'-tetrazolyl-4-bromomethyl biphenyl as starting materials, and undergoes condensation, valerylation, and saponification , Acidification, deprotection and other operations to obtain valsartan.
  • Patent document US5399578 uses L-valine methyl ester hydrochloride and 4-formyl-2'-cyanobiphenyl as starting materials, and undergoes reductive amination reaction, n-valerylation reaction, and upper tetrazolium reaction. After saponification and acidification, valsartan is formed.
  • Patent document WO2004026847A1 takes L-valine benzyl ester p-methanesulfonate and 4-bromomethyl-2'-cyanobiphenyl as starting materials, and undergoes condensation, valerylation, upper tetrazolium and hydrogenation reduction, Get valsartan.
  • the above-mentioned synthetic routes all involve the synthesis of tetrazolium ring, and the reaction principle is the cyclization reaction of organic nitrile and sodium azide under the action of a catalyst. Because the cyclization reaction requires a higher reaction temperature and a longer reaction time, a high boiling point aprotic polar solvent DMF (N,N-dimethylformamide) is often used as a solvent to improve the reaction efficiency.
  • aprotic polar solvent DMF N,N-dimethylformamide
  • the DMF in the reaction system may be decomposed into dimethylamine, and sodium nitrite is often used in the post-treatment step to quench the excess sodium azide, and the decomposition product of sodium nitrite and DMF, dimethylamine
  • Lewis acid catalysts such as zinc chloride, etc.
  • amines will generate trace by-products of N-dimethylnitrosamine (molecular formula C 2 H 6 N 2 O, structural formula (CH 3 ) 2 NNO, The molecular weight is 74.08, abbreviated as NDMA).
  • NDMA N-dimethylnitrosamine
  • NDMA is a typical nitrosamine compound. It has shown carcinogenic effects on rodents and other 7 animals tested through different routes (including oral and inhalation). It has been identified as an animal carcinogen. The target organ is mainly the liver. And kidney. The American Association of Governmental Industrial Hygienists (ACGIH) has listed NDMA as a suspected chemical carcinogen for humans.
  • the European Pharmacopoeia Commission (EDQM) currently defines nitrosamine compounds as genotoxic impurities with warning structures in accordance with the requirements of ICH-M7.
  • the acceptable limit of NDMA is tentatively set at 0.3 ppm, and it is required to transition to The final 0.03ppm.
  • tetrazolium ring is an indispensable key step in the synthesis process of valsartan, and azide, as an indispensable cyclization reagent, must be quenched after the reaction is completed due to its special explosive properties ;
  • sodium nitrite can oxidize sodium azide to safe and harmless nitrogen in an acidic environment and terminate the reaction at the same time. Therefore, unless DMF is not used or other quenchers are used in the synthesis of valsartan, there is bound to be a risk of NDMA production.
  • DMF can greatly improve the reaction efficiency; other quenchers have poor quenching effects (such as a large amount of sodium hypochlorite solution to quench completely), so it is necessary to design a system that can effectively remove nitrosamines
  • the post-treatment method of impurities to eliminate the restriction on the production process and improve the quality and safety of valsartan bulk medicine.
  • the purpose of this application is to provide a new valsartan refining method, which is mainly used to remove nitrosamine impurities in valsartan.
  • a method for refining valsartan which may include the following steps:
  • Step 1 Dissolve the valsartan to be refined in the first organic solvent, add water and the first acid, or add a pre-prepared aqueous solution of the first acid for extraction, separate and remove the water phase, and retain the organic phase;
  • Step 2 Add water and alkaline reagent to the organic phase obtained in step 1, or add the pre-prepared aqueous solution of alkaline reagent to make valsartan salt and dissolve in the water phase, separate and remove the organic phase, and retain the water phase;
  • Step 3 Add a second acid to the aqueous phase obtained in step 2, and perform an acidification reaction to re-acidify and precipitate valsartan, and then add a second organic solvent to dissolve the precipitated valsartan in the second organic solvent, and separate Remove the water phase and keep the organic phase;
  • Step 4 Drying the organic phase obtained in Step 3, cooling and crystallizing, filtering and vacuum drying to obtain a refined valsartan product.
  • nitrosamine impurities are extracted three times, and then valsartan refined products are obtained through crystallization; specifically,
  • step 1 First dissolve valsartan with a good solvent (first organic solvent), then add a poor solvent for valsartan (acidic aqueous solution), and extract and remove Most nitrosamine impurities.
  • first organic solvent a good solvent
  • second organic solvent acidic aqueous solution
  • the inventor found that a small amount of nitrosamine impurities will inevitably remain in the organic phase after step 1 extraction.
  • the inventors tried to repeat the extraction process to increase the impurity removal effect, but the experimental results show that continuous acidic aqueous solution extraction has almost no superimposing effect on the removal of nitrosamine impurities. For example, using valsartan to be refined with an NDMA residue of 108 ppm as the test material, The results of 3 extractions with acidic aqueous solution are as follows:
  • step 2 Perform the second impurity extraction (organic solvent washing) in step 2: add water and alkaline reagent to the organic phase obtained in step 1, or directly add a pre-prepared aqueous solution of alkaline reagent to form a salt
  • the reaction turns the valsartan molecules dissolved in the organic phase into valsartan salt and dissolves in the water phase.
  • the inventor found that the distribution ratio of nitrosamine impurities in the organic phase is relatively large under non-acidic conditions. At this time, the original organic phase becomes the extraction solvent, which has a good extraction and removal effect on the residual small amount of nitrosamine impurities.
  • the experimental results are as follows:
  • NDMA residue before extraction/ppm NDMA residue/ppm after extraction Test sample: organic phase concentrate after step 1 extraction
  • Test sample aqueous phase concentrate after step 2 extraction 10.1 2.6
  • step 3 the third impurity extraction (water washing): through two washings with water and organic solvent, most of the nitrosamine impurities have been removed.
  • Test sample organic phase concentrate after step 3 extraction
  • Test sample step 4 valsartan after crystallization and drying ⁇ 0.3 ⁇ 0.03
  • the first organic solvent used in step 1 is an organic solvent that is polar and immiscible with water; preferably, the first organic solvent is selected from the group consisting of diethyl ether, isopropyl ether, methyl ether One or at least two of methyl tert-butyl ether, 2-methyltetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, butyl acetate, isopropyl acetate, and tert-butyl acetate; More preferably, the first organic solvent is selected from methyl tert-butyl ether or chloroform.
  • the ratio of the volume of the first organic solvent used in step 1 to the mass of valsartan to be refined is (1-30) mL/g; preferably (3-10) mL/g.
  • the first acid used in step 1 is selected from inorganic acids and/or organic acids; preferably, the inorganic acid is selected from one or at least two of hydrochloric acid, sulfuric acid, and phosphoric acid;
  • the organic acid is selected from one or at least two of formic acid, acetic acid, propionic acid, oxalic acid, and citric acid; more preferably, the first acid is an inorganic acid, further preferably hydrochloric acid.
  • the ratio of the volume of water used in step 1 to the mass of valsartan to be refined is (1-50) mL/g; preferably (5-10) mL/g.
  • the ratio of the volume of water used in step 2 to the mass of valsartan to be refined is (1-30) mL/g; preferably (5-10) mL/g.
  • the alkaline reagent in step 2 is selected from one or at least two of inorganic bases, organic bases, strong bases and weak acid salts; preferably, the inorganic bases are selected from alkali metal Hydroxide and/or ammonia; the organic base is selected from one or at least two of phenethylamine, triethylamine, diethylamine, and isopropylamine; the strong base and weak acid salt are selected from sodium carbonate, carbonic acid One or at least two of potassium, calcium carbonate, sodium bicarbonate, and potassium bicarbonate; more preferably, the alkali metal hydroxide is selected from one of sodium hydroxide, potassium hydroxide, and calcium hydroxide Or at least two.
  • the inorganic bases are selected from alkali metal Hydroxide and/or ammonia
  • the organic base is selected from one or at least two of phenethylamine, triethylamine, diethylamine, and isopropylamine
  • the strong base and weak acid salt are selected
  • the alkaline reagent in step 2 is selected from alkali metal hydroxides, preferably sodium hydroxide and potassium hydroxide.
  • the pH value of the water phase in step 2 is pH ⁇ 8, preferably pH value 8-12.
  • the second acid in step 3 is selected from inorganic acids and/or organic acids; preferably, the inorganic acid is selected from one or at least two of hydrochloric acid, sulfuric acid, and phosphoric acid;
  • the organic acid is selected from one or at least two of formic acid, acetic acid, propionic acid, oxalic acid, and citric acid.
  • the second acid in step 3 is an inorganic acid, more preferably hydrochloric acid.
  • the final pH value of the acidification reaction in step 3 is pH ⁇ 3; preferably, the pH value is 0.5-2.
  • the second organic solvent used in step 3 is an organic solvent that is polar and immiscible with water; preferably, the second organic solvent is selected from the group consisting of diethyl ether, isopropyl ether, and methyl ether.
  • the second organic solvent is selected from the group consisting of diethyl ether, isopropyl ether, and methyl ether.
  • the ratio of the volume of the second organic solvent used to the mass of valsartan to be refined is (3-30) mL/g.
  • the second organic solvent used in step 3 is ethyl acetate; preferably, the ratio of the volume of ethyl acetate to the mass of valsartan to be refined is (5-10) mL/g.
  • the water used may be purified water, such as deionized water, distilled water or double distilled water.
  • the drying method in step 4 may be selected from desiccant drying or distillation drying.
  • this application combines extraction technology and crystallization technology, uses the method of acid-base conversion, and uses water and organic solvents for multiple alternate washings, which is simple and effective.
  • Refined valsartan Experiments have proved that the method provided in this application can efficiently eliminate the nitrosamine impurities in valsartan and reduce the residual level to less than 10ppb; and the method has the characteristics of simple and efficient, and is suitable for industrialized production and improvement of drug quality and drug Security provides a new approach.
  • the valsartan used in step 1 is all NDMA that Zhejiang Huahai Pharmaceutical has detected and identified NDMA impurities during the process of optimizing the production process of valsartan API, and has been returned and isolated after the voluntary recall at home and abroad Excess batch of valsartan.
  • NDMA is detected by GC-MS (referring to gas chromatography-mass spectrometry), and the detection conditions are as follows:
  • Step 1 Add 50g to be refined valsartan (NDMA content is 108ppm), 250ml methyl tert-butyl ether, 250ml volume fraction of 5% dilute hydrochloric acid aqueous solution (pH value 1) into the reaction flask, stir until the solution is clear After that, let it stand for stratification, discard the water phase and keep the organic phase;
  • pH value 1 5% dilute hydrochloric acid aqueous solution
  • Step 3 Add 6mol/L hydrochloric acid solution dropwise to the water phase obtained in step 2, adjust the pH to 0.5-2, precipitate insoluble matter, stir and crystallize for 1 to 2 hours, add 250ml ethyl acetate, dissolve and clarify, and then stand still Separate, discard the water phase and keep the organic phase;
  • Step 4 Add 5 g of anhydrous magnesium sulfate to the organic phase obtained in step 3, stir for 1 to 2 hours, filter, slowly cool the filtrate to 0-10°C, stir for crystallization for 1 to 2 hours, filter, and vacuum dry to obtain valsa Tan Jing products.
  • the product yield is 90%, the HPLC purity is 99.9%, and the NDMA content: ⁇ 30ppb.
  • Step 1 Add 50g to be refined valsartan (NDMA content of 108ppm), 500ml of chloroform, 500ml of 10% phosphoric acid aqueous solution (pH value of 1) into the reaction flask, stir to dissolve and clarify, then stand for stratification, discard Remove the water phase and keep the organic phase;
  • Step 3 Add 50% volume fraction of glacial acetic acid aqueous solution to the water phase obtained in step 2, adjust the pH to 2, precipitate insoluble matter, stir and crystallize for 2 hours, add 500ml of isopropyl acetate, dissolve and clarify, and then stand still Separate the layers, discard the water phase and keep the organic phase;
  • Step 4 Distill the organic phase obtained in step 3 under reduced pressure to remove part of the solvent, add fresh isopropyl acetate and then distill off part of the solvent again, add fresh isopropyl acetate and dissolve and clarify, then filter, and the filtrate is slowly cooled to 10°C , Stir and crystallize for 1 to 2 hours, filter and dry in vacuum to obtain refined valsartan products.
  • the product yield is 88%
  • HPLC purity is 99.9%
  • NDMA content ⁇ 30ppb.
  • Step 1 Add 50g to be refined valsartan (NDMA content 108ppm), 200ml isopropyl acetate, 500ml 10% acetic acid aqueous solution (pH 2) into the reaction flask, stir to dissolve and clarify, then let stand for Layer, discard the water phase and keep the organic phase;
  • Step 3 Add dropwise a 40% citric acid aqueous solution to the water phase obtained in step 2, adjust the pH to 2, precipitate insoluble materials, stir and crystallize for 1 hour, add 500ml of isopropyl acetate, dissolve and clarify, then stand for separation. Discard the water phase and keep the organic phase;
  • Step 4 Distill the organic phase obtained in step 3 under reduced pressure to remove part of the solvent, add fresh tert-butyl acetate and then distill off part of the solvent again, add fresh isopropyl acetate and dissolve and clarify, then filter, and the filtrate is slowly cooled to 5 °C, stirring and crystallization for 2 hours, filtration, and vacuum drying to obtain a refined product of valsartan.
  • Product yield is 81%
  • HPLC purity is 99.9%
  • NDMA content ⁇ 30ppb.
  • Step 1 Add 50g to be refined valsartan (NDMA content is 108ppm), 500ml 2-methyltetrahydrofuran, 500ml purified water into the reaction flask, add concentrated hydrochloric acid dropwise to adjust the pH value to 1, stir to dissolve and clarify and then stand for separation. , Discard the water phase and keep the organic phase;
  • Step 3 Add a 5% sulfuric acid aqueous solution dropwise to the water phase obtained in step 2, adjust the pH to 3, precipitate insoluble materials, stir and crystallize for 2 hours, add 500ml ethyl acetate, dissolve and clarify, and then let it stand. Layer, discard the water phase and keep the organic phase;
  • Step 4 The organic phase obtained in step 4 was distilled under reduced pressure to remove part of the solvent, fresh ethyl acetate was added and 5 g of anhydrous magnesium sulfate was added, stirred at 35°C for 2 hours, filtered, and the filtrate was slowly cooled to 0°C, stirred and crystallized 2 After ⁇ 4 hours, filter and vacuum dry to obtain refined valsartan product.
  • Product yield is 77%
  • HPLC purity is 99.9%
  • NDMA content ⁇ 30ppb.
  • Step 1 Add 50g of valsartan to be refined (NDMA content is 108ppm) into the reaction flasks A to E; then add different kinds of first organic solvents and purified water:
  • Group A Add 350ml methyl tert-butyl ether and 350ml purified water;
  • Group B add 350ml chloroform and 350ml purified water
  • Group C Add 350ml 2-methyltetrahydrofuran and 350ml purified water;
  • Group D add 350ml ethyl acetate and 350ml purified water
  • Group E add 350ml isopropyl acetate and 350ml purified water;
  • step 1 of groups A to E Add 500ml of purified water to the organic phase obtained in step 1 of groups A to E, add 30% sodium hydroxide aqueous solution dropwise, adjust the pH of the water phase to 9-12, stand still for layering, discard the organic phase, and keep the water phase;
  • step 4 The organic phase obtained in step 4 was distilled under reduced pressure to remove part of the solvent, fresh ethyl acetate was added, and 5 g of anhydrous magnesium sulfate was added, stirred at 35°C for 2 hours, filtered, and the filtrate was slowly cooled to 0°C, stirred and crystallized for 2 to 4 hours , Filtered and dried in vacuum to obtain valsartan refined products.
  • HPLC purity A ⁇ E: 99.9%, 99.9%, 99.9%, 99.9%, 99.9%, 99.9%;
  • NDMA content A ⁇ E: ⁇ 30ppb.
  • step 1
  • Group A Add 500ml ethyl acetate
  • Group C add 500ml methyl tert-butyl ether
  • Group D Add 500ml tert-butyl acetate
  • step 4 The organic phase obtained in step 4 was distilled under reduced pressure to remove part of the solvent, and an appropriate amount of fresh solvent was added respectively:
  • Group D add fresh tert-butyl acetate
  • HPLC purity A to D: 99.9%, 99.9%, 99.9%, 99.9%, 99.9%, 99.9%;
  • NDMA content A ⁇ D: ⁇ 30ppb.
  • the second organic solvent in step 3 can obtain a relatively high yield by using ethyl acetate. Since the crystal form of the final product is directly related to the final crystallization solvent, the amorphous crystal form specified by the CEP Pharmacopoeia standard in the European market and the USDMF Pharmacopoeia standard in the US market is crystallized from ethyl acetate according to the report in the patent document WO2004/083192 The amorphous valsartan can be directly obtained. If another second organic solvent is used, ethyl acetate can be used as the solvent for recrystallization to obtain the amorphous crystal form.

Abstract

本申请涉及一种缬沙坦的精制方法，主要去除缬沙坦中的亚硝胺类杂质，具体方法是：首先，将缬沙坦溶于有机溶剂，并用酸性水溶液洗涤，分离除去水相；其次，在有机溶剂-水的二元溶剂体系中使缬沙坦成盐而转溶于水中，分离除去有机相；然后，酸化水相重新生成缬沙坦，并加入有机溶剂溶解游离出的缬沙坦，分离除去水相；最后，分离出的有机相经过干燥后进行结晶即可得到精制缬沙坦。本申请提供的方法能够高效率的消除缬沙坦中的亚硝胺类杂质，使其残留水平降至30ppb以下。

Description

一种缬沙坦化合物的精制方法 技术领域
本申请属于医药技术领域，特别涉及一种缬沙坦精制方法。
背景技术
缬沙坦(Valsartan)，化学名称为N-(1-戊酰基)-N-[[2’-(1H-四氮唑-5-基)[1,1’-联苯基]-4-基]甲基]-L-缬氨酸，结构式如下：
Figure PCTCN2019091743-appb-000001
缬沙坦由诺华公司(Novatis)开发，1996年7月1日首先在德国获准上市，是第二个获准用于临床治疗高血压的非肽类血管紧张素II(A-TII)I型受体拮抗剂。缬沙坦可以通过阻断血管紧张素II在许多组织(如血管平滑肌和肾小球)中与AT1受体的结合而影响血管收缩和醛固酮的升血压作用。缬沙坦用于各种类型高血压，并对心脑肾有较好的保护作用，同时不影响心律，不影响高血压患者的总胆固醇、甘油三酯、血糖和尿酸水平，副作用小，有良好的应用和市场前景。
目前文献报道的关于缬沙坦的合成方法主要采用以下路线：
专利文献WO2005021535A2以L-缬氨酸甲酯盐酸盐和四氮唑被保护过的2’-四氮唑基-4-溴甲基联苯作为起始原料，经过缩合、戊酰化、皂化、酸化、脱保护基等操作，得到缬沙坦。
专利文献US5399578以L-缬氨酸甲酯盐酸盐和4-甲酰基-2’-氰基联苯作为起始原料，经过还原胺化反应、正戊酰化反应、上四氮唑反应，再经过皂化、酸化生成缬沙坦。
专利文献WO2004026847A1以L-缬氨酸苄酯对甲磺酸盐和4-溴甲基-2’-氰基联苯作为起始原料，经过缩合、戊酰化、上四氮唑和氢化还原，得到缬 沙坦。
以上所述的合成路线中均涉及四氮唑环的合成，反应原理为催化剂作用下的有机腈和叠氮化钠的环合反应。由于环合反应需要较高的反应温度和较长的反应时间，因此常使用高沸点的非质子极性溶剂DMF(N,N-二甲基甲酰胺)作为溶剂以提高反应效率。但在高温下，反应体系中的DMF存在分解成二甲胺的风险，且后处理步骤中常使用亚硝酸钠对过量的叠氮化钠进行淬灭，而亚硝酸钠与DMF的分解产物二甲胺在路易斯酸类催化剂(如氯化锌等)的酸性条件下会生成微量副产物N-二甲基亚硝胺(分子式C 2H 6N 2O，结构简式(CH 3) 2NNO，分子量74.08，缩写为NDMA)。相关的反应机理如下：
Figure PCTCN2019091743-appb-000002
NDMA为典型的亚硝胺类化合物，对已试验的啮齿类等7种动物经不同染毒途径(包括经口和吸入)均显示出致癌作用，已确定为动物致癌物，靶器官主要为肝和肾。美国政府工业卫生学家协会(ACGIH)已将NDMA列为人类可疑化学致癌物。
欧洲药典委员会(EDQM)目前按照ICH-M7的要求将亚硝胺类化合物定义为具有警示结构的基因毒性杂质，其中NDMA的可接受限度指标暂定为0.3ppm，且要求在一定期限内过渡为最终的0.03ppm。
四氮唑环的合成是缬沙坦合成工艺中必不可少的关键步骤，而叠氮化物作为必不可少的环合试剂，由于其易爆炸的特殊性质，反应结束后必须对其进行淬灭；作为应用最广泛的淬灭剂，亚硝酸钠在酸性环境下可将叠氮钠氧化为安全无害的氮气，同时终止反应。因此，在缬沙坦的合成工艺中除非不使用DMF或换用其它淬灭剂，否则必然存在产生NDMA的风险。而DMF作为环合反应的溶剂能够极大的提高反应效率；其它的淬灭剂淬灭效果较差(如大量的次氯酸钠溶液才能淬灭完全)，因此需要设计一种能够有效去除亚硝胺类杂质的后处理方法，以消除对生产工艺的限制，提高缬沙坦原料药的质量安全性。
专利文献EP443983中关于缬沙坦的后处理描述是从乙酸乙酯或异丙醚 中重结晶；专利文献WO2005049586中关于后处理的描述是在乙酸乙酯或乙酸乙酯和异丙醚的混合溶剂中重结晶；专利文献WO20055049588中关于后处理的描述是将缬沙坦在乙酸乙酯中结晶后，加入正戊烷搅拌，过滤后烘干；专利文献CN200810212026.7中关于后处理的描述是将缬沙坦在醇的水溶液中洗涤，过滤后烘干。
上述专利文献中所记载的精制方法主要为重结晶或打浆，申请人通过大量筛选实验，发现需要多次重复操作才能有效降低杂质含量，收率损失较多，而且混合溶剂重结晶或打浆可能会改变晶型，产品结晶形态的改变又会导致意想不到的问题；因此，上述方法并不适用于工业化生产。有鉴于此，找到一种简单实用、成本低廉、效果明显的精制方法，是亟待解决的技术问题。
发明内容
本申请的目的是提供一种新的缬沙坦精制方法，主要用于去除缬沙坦中的亚硝胺类杂质。
为实现上述目的，本申请采用如下技术方案：
1、一种缬沙坦的精制方法，其可以包括以下步骤：
步骤1：将待精制的缬沙坦溶于第一有机溶剂中，加入水和第一酸，或者加入预先配制好的第一酸的水溶液进行萃取，分离除去水相，保留有机相；
步骤2：向步骤1获得的有机相中加入水和碱性试剂，或者加入预先配制好的碱性试剂的水溶液，使缬沙坦成盐而转溶于水相，分离除去有机相，保留水相；
步骤3：向步骤2获得的水相中加入第二酸，进行酸化反应，使缬沙坦重新酸化析出，再加入第二有机溶剂，使析出的缬沙坦溶解于第二有机溶剂中，分离除去水相，保留有机相；
步骤4：将步骤3获得的有机相干燥处理后冷却结晶，过滤、真空干燥得到缬沙坦精制品。
本申请的技术方案，其对亚硝胺类杂质进行了三次萃取，然后通过结晶 获得缬沙坦精制品；具体地，
(1)在步骤1中进行第一次杂质萃取(水洗涤)：首先用一种良溶剂(第一有机溶剂)溶解缬沙坦，然后加入缬沙坦的不良溶剂(酸性水溶液)，萃取除去大部分亚硝胺类杂质。但是发明人发现，经过步骤1萃取后的有机相中难以避免的会残留少量亚硝胺类杂质。发明人尝试重复萃取过程以增加除杂效果，但是实验结果表明连续的酸性水溶液萃取对于亚硝胺类杂质的去除几乎没有叠加效果，例如以NDMA残留为108ppm的待精制缬沙坦为测试原料，采用酸性水溶液萃取3次的结果如下：
Figure PCTCN2019091743-appb-000003
(2)在步骤2中进行第二次杂质萃取(有机溶剂洗涤)：向步骤1获得的有机相中加入水与碱性试剂，或者直接加入预先配制好的碱性试剂的水溶液，通过成盐反应使有机相中溶解的缬沙坦分子变为缬沙坦盐而转溶于水相。发明人发现非酸性条件下亚硝胺类杂质在有机相中的分配比例较大，此时原有机相变为萃取溶剂，对残留的少量亚硝胺类杂质起到良好的萃取去除效果，部分实验结果如下：
萃取前NDMA残留/ppm 萃取后NDMA残留/ppm
检测样品：步骤1萃取后有机相浓缩物 检测样品：步骤2萃取后水相浓缩物
10.1 2.6
(3)在步骤3中进行第三次杂质萃取(水洗涤)：通过水和有机溶剂的两次洗涤，绝大部分亚硝胺类杂质已经被除去。向步骤2获得的水相中再次加入酸，使缬沙坦盐与酸反应重新生成缬沙坦，再加入良溶剂(第二有机溶剂)溶解生成的缬沙坦沉淀，此时原水相又变为萃取溶剂，在酸性条件下对有机相中残留的微量亚硝胺类杂质再次进行良好的萃取去除。部分实验结果如下：
萃取前NDMA残留/ppm 萃取后NDMA残留/ppm
检测样品：步骤2萃取后水相浓缩物 检测样品：步骤3萃取后有机相浓缩物
2.6 ＜0.3
(4)结晶：经过水、有机溶剂、水的三次交替洗涤，亚硝胺类杂质残留已经处于极低的水平，步骤3获得的有机相干燥处理后经过结晶即可得到提纯后的缬沙坦。由于结晶母液对有机相中残留的痕量亚硝胺类杂质仍有溶解和去除效果，因此最终所得缬沙坦精制品中亚硝胺类杂质的残留水平小于30ppb，符合EDQM最新发布的关于沙坦类药物中该类杂质残留水平的最终要求(≤30ppb)。部分实验结果如下：
结晶前NDMA残留/ppm 结晶后NDMA残留/ppm
检测样品：步骤3萃取后有机相浓缩物 检测样品：步骤4结晶干燥后缬沙坦
﹤0.3 ﹤0.03
在本申请的一些实施方式中，步骤1中所用的第一有机溶剂为具有极性且与水不互溶的有机溶剂；优选地，所述第一有机溶剂选自：乙醚、异丙醚、甲基叔丁基醚、2-甲基四氢呋喃、二氯甲烷、氯仿、四氯化碳、乙酸乙酯、乙酸丁酯、醋酸异丙酯、叔丁基醋酸酯中的一种或至少两种；更优选地，所述第一有机溶剂选自甲基叔丁基醚或氯仿。
在本申请的一些实施方式中，步骤1中所用第一有机溶剂的体积与待精制缬沙坦质量的比为(1～30)mL/g；优选为(3～10)mL/g。
在本申请的一些实施方式中，步骤1中所用第一酸选自无机酸和/或有机酸；优选地，所述无机酸选自盐酸、硫酸、磷酸中的一种或至少两种；所述有机酸选自甲酸、乙酸、丙酸、草酸、柠檬酸中的一种或至少两种；更优选地，所述第一酸为无机酸，进一步优选为盐酸。
在本申请的一些实施方式中，步骤1中水相的pH范围为pH≤5，优选为pH＝1～3。
在本申请的一些实施方式中，步骤1中所用水的体积与待精制缬沙坦质量的比为(1～50)mL/g；优选为(5～10)mL/g。
在本申请的一些实施方式中，步骤2中所用水的体积与待精制缬沙坦质量的比为(1～30)mL/g；优选为(5～10)mL/g。
在本申请的一些实施方式中，步骤2中的碱性试剂选自无机碱、有机碱、强碱弱酸盐中的一种或至少两种；优选地，所述无机碱选自碱金属的氢氧化物和/或氨水；所述有机碱选自苯乙胺、三乙胺、二乙胺、异丙胺中的一种或至少两种；所述强碱弱酸盐选自碳酸钠、碳酸钾、碳酸钙、碳酸氢钠、碳酸氢钾中的一种或至少两种；更优选地，所述碱金属的氢氧化物选自氢氧化钠、氢氧化钾、氢氧化钙中的一种或至少两种。
在本申请的一些实施方式中，步骤2中的碱性试剂选自碱金属的氢氧化物，优选为氢氧化钠和氢氧化钾。
在本申请的一些实施方式中，步骤2中水相的pH值为pH≥8，优选为pH值8～12。
在本申请的一些实施方式中，步骤3中的第二酸选自无机酸和/或有机酸；优选地，所述无机酸选自盐酸、硫酸、磷酸中的一种或至少两种；所述有机酸选自甲酸、乙酸、丙酸、草酸、柠檬酸中的一种或至少两种。
在本申请的一些实施方式中，步骤3中的第二酸为无机酸，进一步优选为盐酸。
在本申请的一些实施方式中，步骤3中所述酸化反应的终点pH值为pH≤3；优选为pH值0.5～2。
在本申请的一些实施方式中，步骤3中所用第二有机溶剂为具有极性且与水不互溶的有机溶剂；优选地，所述第二有机溶剂选自：乙醚、异丙醚、甲基叔丁基醚、2-甲基四氢呋喃、二氯甲烷、氯仿、四氯化碳、乙酸乙酯、乙酸丁酯、醋酸异丙酯、叔丁基醋酸酯中的一种或至少两种；更优选地，所用第二有机溶剂的体积与待精制缬沙坦质量的比为(3～30)mL/g。
在本申请的一些实施方式中，步骤3中所用第二有机溶剂为乙酸乙酯；优选地，乙酸乙酯的体积与待精制缬沙坦质量的比为(5～10)mL/g。
在本申请的一些实施方式中，所用的水可以是纯化水，例如去离子水、 蒸馏水或双蒸水。
在本申请的一些实施方式中，步骤4中的干燥方式可以选自干燥剂干燥或者蒸馏干燥。
本申请根据缬沙坦和亚硝胺类杂质的理化性质，将萃取技术和结晶技术相结合，利用酸碱转换的方法，通过水和有机溶剂两类溶剂的多次交替洗涤，简单有效的实现了缬沙坦的精制。实验证明本申请提供的方法能够高效率的消除缬沙坦中的亚硝胺类杂质，使其残留水平降至10ppb以下；而且该方法具有简单高效的特点，为工业化生产、提高药物质量和药物安全性提供了一种新的方法。
具体实施方式
为了使本申请所解决的技术问题、技术方案及有益效果更加清楚明白，以下结合具体实施例，对本申请作进一步的说明。下述实施例中，除非另有说明，所述的试验方法具体条件通常按照常规条件或制造厂商建议的条件实施；原料、试剂均通过市售获得或者使用公开信息制备。
下述各实施例中，步骤1所用缬沙坦均为浙江华海药业因缬沙坦原料药生产工艺优化评估过程中检测和鉴定出NDMA杂质，在国内外主动发起召回后退回和隔离的NDMA超标批次缬沙坦。
下述各实施例中，NDMA采用GC-MS(指气相色谱-质谱联用仪)检测，具检测条件如下：
Figure PCTCN2019091743-appb-000004
Figure PCTCN2019091743-appb-000005
实施例1：
步骤1：向反应瓶中加入50g待精制缬沙坦(NDMA含量为108ppm)、250ml甲基叔丁基醚、250ml体积分数为5％的稀盐酸水溶液(pH值为1)，搅拌至溶解澄清后静置分层，弃去水相，保留有机相；
步骤2：向步骤1获得的有机相中加入250ml纯化水，搅拌下滴加质量分数为30％的氢氧化钠水溶液，调水相pH值至pH＝10～12，静置分层，弃去有机相，保留水相；
步骤3：向步骤2获得的水相中滴加6mol/L盐酸溶液，调节pH值为0.5～2，析出不溶物，搅拌析晶1～2小时，加入250ml乙酸乙酯，溶解澄清后静置分层，弃去水相，保留有机相；
步骤4：向步骤3获得的有机相中加入5g无水硫酸镁，搅拌1～2小时，过滤，滤液缓慢冷却至0-10℃，搅拌析晶1～2小时，过滤，真空干燥得缬沙坦精制品。产品收率90％，HPLC纯度99.9％，NDMA含量：＜30ppb。
实施例2：
步骤1：向反应瓶中加入50g待精制缬沙坦(NDMA含量为108ppm)、500ml氯仿、500ml体积分数为10％的磷酸水溶液(pH值为1)，搅拌溶解澄清后静置分层，弃去水相，保留有机相；
步骤2：向步骤1获得的有机相中加入500ml纯化水，搅拌下滴加饱和碳酸钠水溶液，调水相pH值至pH＝8，静置分层，弃去有机相，保留水相；
步骤3：向步骤2获得的水相中滴加体积分数为50％的冰乙酸水溶液， 调节pH值为2，析出不溶物，搅拌析晶2小时，加入500ml醋酸异丙酯，溶解澄清后静置分层，弃去水相，保留有机相；
步骤4：将步骤3获得的有机相减压蒸馏除去部分溶剂，补加新鲜醋酸异丙酯后再次蒸馏除去部分溶剂，补加新鲜醋酸异丙酯并溶解澄清后过滤，滤液缓慢冷却至10℃，搅拌析晶1～2小时，过滤，真空干燥得缬沙坦精制品。产品收率88％，HPLC纯度99.9％，NDMA含量：＜30ppb。
实施例3：
步骤1：向反应瓶中加入50g待精制缬沙坦(NDMA含量为108ppm)、200ml醋酸异丙酯、500ml体积分数为10％的乙酸水溶液(pH值为2)，搅拌溶解澄清后静置分层，弃去水相，保留有机相；
步骤2：向步骤1获得的有机相中加入300ml纯化水，搅拌下滴加浓氨水溶液，调水相pH值至pH＝12，静置分层，弃去有机相，保留水相；
步骤3：向步骤2获得的水相中滴加40％柠檬酸水溶液，调节pH值为2，析出不溶物，搅拌析晶1小时，加入500ml醋酸异丙酯，溶解澄清后静置分层，弃去水相，保留有机相；
步骤4：将步骤3获得的有机相减压蒸馏除去部分溶剂，补加新鲜叔丁基醋酸酯后再次蒸馏除去部分溶剂，补加新鲜醋酸异丙酯并溶解澄清后过滤，滤液缓慢冷却至5℃，搅拌析晶2小时，过滤，真空干燥得缬沙坦精制品。产品收率81％，HPLC纯度99.9％，NDMA含量：＜30ppb。
实施例4：
步骤1：向反应瓶中加入50g待精制缬沙坦(NDMA含量为108ppm)、500ml 2-甲基四氢呋喃、500ml纯化水，滴加浓盐酸调pH值为1，搅拌溶解澄清后静置分层，弃去水相，保留有机相；
步骤2：向步骤1获得的有机相中加入500ml纯化水，搅拌下滴加三乙胺，调水相pH值至pH＝9，静置分层，弃去有机相，保留水相；
步骤3：向步骤2获得的水相中滴加体积分数为5％的硫酸水溶液，调节pH值为3，析出不溶物，搅拌析晶2小时，加入500ml乙酸乙酯，溶解澄清后静置分层，弃去水相，保留有机相；
步骤4：将步骤4获得的有机相减压蒸馏除去部分溶剂，补加新鲜乙酸乙酯后加入5g无水硫酸镁，35℃搅拌2小时，过滤，滤液缓慢冷却至0℃，搅拌析晶2～4小时，过滤，真空干燥得缬沙坦精制品。产品收率77％，HPLC纯度99.9％，NDMA含量：＜30ppb。
实施例5：
步骤1：向反应瓶A～E分别加入50g待精制缬沙坦(NDMA含量均为108ppm)；然后分别加入不同种类的第一有机溶剂与纯化水：
A组：加入350ml甲基叔丁基醚、350ml纯化水；
B组：加入350ml氯仿、350ml纯化水；
C组：加入350ml 2-甲基四氢呋喃、350ml纯化水；
D组：加入350ml乙酸乙酯、350ml纯化水；
E组：加入350ml醋酸异丙酯、350ml纯化水；
分别向A～E组滴加盐酸调pH值为1，搅拌溶清后静置分层，弃去水相，保留有机相；
步骤2：
向A～E组由步骤1获得的有机相中分别加入500ml纯化水，滴加30％氢氧化钠水溶液，调水相pH值至9～12，静置分层，弃去有机相，保留水相；
步骤3：
向A～E组由步骤2获得的水相中分别滴加盐酸，调节pH值为1～3，析出不溶物，搅拌析晶2小时，分别加入500ml乙酸乙酯，溶清后静置分层，弃去水相，保留有机相；
步骤4：
将步骤4获得的有机相减压蒸馏除去部分溶剂，补加新鲜乙酸乙酯后加入5g无水硫酸镁，35℃搅拌2小时，过滤，滤液缓慢冷却至0℃，搅拌析晶2～4小时，过滤，真空干燥得缬沙坦精制品。
产品收率：A～E：91％，90％，79％，74％，82％；
HPLC纯度：A～E：99.9％，99.9％，99.9％，99.9％，99.9％；
NDMA含量：A～E：＜30ppb.
由实验结果可知步骤1中所述第一有机溶剂使用甲基叔丁醚或氯仿可以获得相对较高的精制收率。
实施例6：
步骤1：
向反应瓶A～C分别加入50g待精制缬沙坦(NDMA含量均为108ppm)；然后分别加入300ml氯仿和300ml去离子水，滴加冰乙酸调pH至1～2，搅拌溶清后静置分层，弃去水相，保留有机相；
步骤2：
向A～D组由步骤1获得的有机相中分别加入500ml纯化水，滴加30％氢氧化钾水溶液，调水相pH值至9～12，静置分层，弃去有机相，保留水相；
步骤3：
向A～D组由步骤2获得的水相中分别滴加盐酸，调节pH值为1～3，析出不溶物，搅拌析晶2小时，分别加入不同种类的第二溶剂：
A组：加入500ml乙酸乙酯；
B组：加入500ml氯仿；
C组：加入500ml甲基叔丁基醚；
D组：加入500ml叔丁基醋酸酯；
溶清后静置分层，弃去水相，保留有机相；
步骤4：
将步骤4获得的有机相减压蒸馏除去部分溶剂，分别补加适量新鲜溶剂：
A组：补加新鲜乙酸乙酯；
B组：补加新鲜氯仿；
C组：补加新鲜甲基叔丁基醚；
D组：补加新鲜叔丁基醋酸酯；
然后于35℃搅拌2小时，过滤，滤液缓慢冷却至0℃，搅拌析晶2～4小时，过滤，真空干燥得缬沙坦精制品。
产品收率：A～D：90％，83％，79％，86％；
HPLC纯度：A～D：99.9％，99.9％，99.9％，99.9％，99.9％；
NDMA含量：A～D：＜30ppb.
由实验结果可知步骤3中所述第二有机溶剂使用乙酸乙酯可以获得相对较高的收率。由于终产品的晶型与最后结晶溶剂直接相关，对于欧洲市场的CEP药典标准和美国市场的USDMF药典标准所指定的无定型晶型，根据专利文献WO2004/083192的报道，从乙酸乙酯中结晶可以直接得到无定型缬沙坦，如用其它第二有机溶剂，则可以再次用乙酸乙酯作为溶剂进行重结晶以得到无定型晶型。
上述实施例的作用在于说明本申请的实质性内容，但并不以此限定本申请的保护范围。本领域的普通技术人员应当理解，可以对本申请的技术方案进行修改或者等同替换，而不脱离本申请技术方案的实质和保护范围。

Claims (15)

  1. 一种缬沙坦的精制方法，其特征在于，包括以下步骤：
    步骤1：将待精制缬沙坦溶于第一有机溶剂中，加入水和第一酸，或者加入预先配制好的第一酸的水溶液进行萃取，分离除去水相，保留有机相；
    步骤2：向步骤1获得的有机相中加入水和碱性试剂，或者加入预先配制好的碱性试剂的水溶液，使缬沙坦成盐而转溶于水相，分离除去有机相，保留水相；
    步骤3：向步骤2获得的水相中加入第二酸，进行酸化反应，使缬沙坦重新酸化析出，再加入第二有机溶剂，使析出的缬沙坦溶解于第二有机溶剂中，分离除去水相，保留有机相；
    步骤4：将步骤3获得的有机相干燥处理后冷却结晶，过滤、真空干燥得到缬沙坦精制品。
  2. 根据权利要求1所述的缬沙坦的精制方法，其特征在于，步骤1中所用的第一有机溶剂为具有极性且与水不互溶的有机溶剂；优选地，所述第一有机溶剂选自：乙醚、异丙醚、甲基叔丁基醚、2-甲基四氢呋喃、二氯甲烷、氯仿、四氯化碳、乙酸乙酯、乙酸丁酯、醋酸异丙酯、叔丁基醋酸酯中的一种或至少两种；更优选地，所述第一有机溶剂选自甲基叔丁基醚或氯仿。
  3. 根据权利要求1或2所述的缬沙坦的精制方法，其特征在于，步骤1中所用第一有机溶剂的体积与待精制缬沙坦质量的比为(1～30)mL/g；优选为(3～10)mL/g。
  4. 根据权利要求1-3中任一项所述的缬沙坦的精制方法，其特征在于，步骤1中所用第一酸选自无机酸和/或有机酸；优选地，所述无机酸选自盐酸、硫酸、磷酸中的一种或至少两种；所述有机酸选自甲酸、乙酸、丙酸、草酸、柠檬酸中的一种或至少两种；更优选地，所述第一酸为无机酸，进一步优选为盐酸。
  5. 根据权利要求1-4中任一项所述的缬沙坦的精制方法，其特征在于，步骤1中水相的pH范围为pH≤5，优选为pH＝1～3。
  6. 根据权利要求1-5中任一项所述的缬沙坦的精制方法，其特征在于，步骤1中所用水的体积与待精制缬沙坦质量的比为(1～50)mL/g；优选为(5～10)mL/g。
  7. 根据权利要求1-6中任一项所述的缬沙坦的精制方法，其特征在于，步骤2中所用水的体积与待精制缬沙坦质量的比为(1～30)mL/g；优选为(5～10)mL/g。
  8. 根据权利要求1-7中任一项所述的缬沙坦的精制方法，其特征在于，步骤2中的碱性试剂选自无机碱、有机碱、强碱弱酸盐中的一种或至少两种；优选地，所述无机碱选自碱金属的氢氧化物和/或氨水；所述有机碱选自苯乙胺、三乙胺、二乙胺、异丙胺中的一种或至少两种；所述强碱弱酸盐选自碳酸钠、碳酸钾、碳酸钙、碳酸氢钠、碳酸氢钾中的一种或至少两种；更优选地，所述碱金属的氢氧化物选自氢氧化钠、氢氧化钾中的一种或至少两种。
  9. 根据权利要求1-8中任一项所述的缬沙坦的精制方法，其特征在于，步骤2中的碱性试剂选自碱金属的氢氧化物，优选为氢氧化钠和氢氧化钾。
  10. 根据权利要求1-9中任一项所述的纯缬沙坦的精制方法，其特征在于，步骤2中水相的pH值为pH≥8，优选为pH值8～12。
  11. 根据权利要求1-10中任一项所述的纯化缬沙坦的方法，其特征在于，步骤3中的第二酸选自无机酸和/或有机酸；优选地，所述无机酸选自盐酸、硫酸、磷酸中的一种或至少两种；所述有机酸选自甲酸、乙酸、丙酸、草酸、柠檬酸中的一种或至少两种。
  12. 根据权利要求1-11中任一项所述的纯化缬沙坦的方法，其特征在于，步骤3中的第二酸为无机酸，进一步优选为盐酸。
  13. 根据权利要求1-12中任一项所述的缬沙坦的精制方法，其特征在于，步骤3中所述酸化反应的终点pH值为pH≤3；优选为pH值0.5～2。
  14. 根据权利要求1-13中任一项所述的缬沙坦的精制方法，其特征在于，步骤3中所用第二有机溶剂为具有极性且与水不互溶的有机溶剂；优选地，所述第二有机溶剂选自：乙醚、异丙醚、甲基叔丁基醚、2-甲基四氢呋喃、二氯甲烷、氯仿、四氯化碳、乙酸乙酯、乙酸丁酯、醋酸异丙酯、叔丁基醋酸 酯中的一种或至少两种；更优选地，所用第二有机溶剂的体积与待精制缬沙坦质量的比为(3～30)mL/g。
  15. 根据权利要求1-14中任一项所述的缬沙坦的精制方法，其特征在于，步骤3中所用第二有机溶剂为乙酸乙酯；优选地，乙酸乙酯的体积与待精制缬沙坦质量的比为(5～10)mL/g。
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