WO2018214676A1 - 布格呋喃原料药及其制备方法和应用 - Google Patents

布格呋喃原料药及其制备方法和应用 Download PDF

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WO2018214676A1
WO2018214676A1 PCT/CN2018/083526 CN2018083526W WO2018214676A1 WO 2018214676 A1 WO2018214676 A1 WO 2018214676A1 CN 2018083526 W CN2018083526 W CN 2018083526W WO 2018214676 A1 WO2018214676 A1 WO 2018214676A1
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impurity
drug
compound
reaction
bulk drug
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PCT/CN2018/083526
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宋波
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北京元气知药科技有限公司
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Priority to US16/344,026 priority Critical patent/US10927090B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a bogfuran bulk medicine and a preparation method and application thereof.
  • Bugfuran is a derivative of the active ingredient ⁇ -Agarwood furan isolated from agarwood by researchers at the Institute of Materia Medica of the Chinese Academy of Medical Sciences. It has been proven to have anti-anxiety, anti-depression and sleep-relieving effects. Toxicity is a class 1.1 candidate new drug with independent intellectual property rights in China (Chinese Patent No. ZL98122447.4, US Patent No. US6486201B1, European Patent No. EP1132383B1, Japanese Patent No. JP No. 4321967). The applicant of the present invention has obtained the transfer of the patent rights and clinical research approval of the research institute of Bugarfuran, and is carrying out the phase II clinical research work (drug clinical trial approval number: 2014L00180, 2014L0018).
  • the existing reported preparation methods of bufffuran mainly include the following strategies:
  • burd furan is obtained by a total of 6 steps of oxidation, cyclization, dehydration, alkylation, reduction and cyclization.
  • a cyclized by-product is produced in the third step of the dehydration reaction in this route.
  • a water/n-hexane or water/petroleum ether two-phase system is required for the reaction, and the target intermediate is utilized.
  • the difference in polarity between compound 5 and cyclized by-product 6 is such that both are present in the two phases in the reaction system.
  • the compound 5 and the cyclized by-product 6 can be structurally converted to each other, and when the mixed solution is directly subjected to the butylation reaction to prepare the compound 7, the dibutylated impurity 8 is obtained (Yin Dali et al., Chinese Journal of Medicinal Chemistry) , Vol. 13, No. 4, pp. 187-193; Li Chun et al., China Chemical Letters, Vol. 14, No. 9, pp. 881-882.
  • the optimum ratio of the target compound 7 is only 69.8%, and still contains 15% of the dibutyl compound impurity 8 (Wu Xianghong et al., Chemical Research, Vol. 16, No. 4, pp. 10-12).
  • APIs must be of sufficient purity to meet the effectiveness and safety requirements of clinical applications.
  • the existing preparation methods are laboratory-level small-scale tests, and the column chromatography method is required to perform intermediate purification several times in the step, which is difficult to meet the needs of mass production, and there is a high content of impurities.
  • bugfuran has a special physical and chemical property and is in the form of an oil at room temperature, which makes it difficult to remove impurities.
  • the object of the present invention is to obtain a method suitable for large-scale production of a bulk pharmaceutical bulk drug, by which a high-purity bugfuran bulk drug can be obtained and used in a subsequent research process.
  • the present invention provides a bulk drug of bogfuran wherein the structure of the active form of the furfuran is as follows:
  • the present invention provides a bulk drug of bogfuran which, in addition to being active in the form of a glucofuran, also contains impurities of the following structure:
  • the content of the active-forming glucofuran in the raw material drug is higher than 97.5%, and the total content of the impurity A and the impurity B is less than 0.04%.
  • a certain amount of solvent remains in the buguefuran bulk drug, and the solvent remaining is preferably ethanol.
  • the bupuffuffan drug substance also has a certain residue of the enantiomer of bugfuran, which is derived from a small amount of enantiomer impurities present in the synthesis starting material, preferably The content of the enantiomeric impurities of the buffuran is not more than 0.02% in the drug substance.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the boehmfuran bulk drug of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier comprises polyvinylpyrrolidone. More preferably, the polyvinylpyrrolidone is PVP-K30.
  • the pharmaceutical composition is in the form of an oral preparation, and more preferably, the oral preparation is a capsule.
  • the present invention provides a method of preparing a bogfuran bulk drug of the present invention comprising the steps of:
  • step a is to add compound 4 to potassium hydroxide aqueous solution, heat and stir, and then cool down after the reaction, add concentrated hydrochloric acid to adjust pH to near neutrality, extract, dry, filter, and concentrate the filtrate;
  • step b is to dissolve compound 5 in uncle Butanol, added to the potassium hydroxide aqueous solution, heated and stirred, added bromobutane, adjust the pH to near neutral, filtered, the filtrate is concentrated, the concentrate is dissolved in methanol, sodium borohydride is added, stirred, and then n-hexane is added. With water, the pH of the system was adjusted to be acidic, and the n-hexane layer was separated and concentrated to obtain crude burboffuran.
  • the separated n-hexane layer contains impurities A and impurities B in addition to the crude bupropfuran:
  • the total content of the impurities A and B in the crude bupuffine is not more than 3.5%.
  • the compound 4 is prepared by the following method:
  • step i is a reduction reaction
  • step ii is an oxidation reaction
  • step iii is a ring-closing reaction of compound 3 with methyl vinyl ketone.
  • the reduction reaction of step i uses zinc powder as a catalyst
  • the oxidation reaction of step ii uses concentrated sulfuric acid as an oxidizing agent
  • the cyclization reaction of step iii contains an alkaline reagent potassium hydroxide.
  • the present invention provides a method for purifying a bogfuran bulk drug according to the present invention, comprising the steps of: dissolving crude bupuffine in ethanol, filtering, and cooling the filtrate to -10 ° C to -20 ° C, After suction filtration, the wetted product of bugfuran is obtained, and dried to obtain a buckfuran bulk drug.
  • the present invention provides the use of the bogerofan bulk drug of the present invention as a standard in pharmaceutical research of bupropfuran.
  • the present invention provides the use of Impurity A in the quality control of bupropfuran, wherein said impurity A is used as a reference for the detection of bugfuran impurities.
  • the present invention provides the use of impurity B in the quality control of bupropfuran, wherein said impurity B is used as a control for the detection of bugfuran impurities.
  • the present invention provides the use of impurities A and B in the quality control of bupropfuran drugs wherein the impurities A and B are used as controls for the detection of bugfuran impurities.
  • the present invention provides the use of the bogfuran bulk drug for the preparation of a medicament for treating a psychotic disorder, wherein the disorder is anxiety, depression or sleep disorder.
  • Figure 1 Entrusted the manufacturer to provide the quality inspection report of the bulk of the drug
  • Figure 2 Quality inspection report for the bulk of Bugfuran APIs supplied by the manufacturer
  • the preparation process in the invention is entrusted to Zhejiang Warner Pharmaceutical Co., Ltd. to complete the product quality inspection according to the GMP management standard. Unless otherwise stated, the starting materials and reagents used in the present invention are both chemically pure and of the above purity.
  • a mixture of the isopropyl ether of the compound 3 obtained in the previous step was added under stirring. After the addition, the mixture was further stirred and cooled to 0 to 10 ° C, and a pre-formed potassium hydroxide/ethanol solution (1.9 kg of potassium hydroxide + 5.7 kg of ethanol) was slowly added to the system, and the stirring was continued. The mixture was cooled to about -10 ° C, and a mixed solution of methyl vinyl ketone / isopropyl ether (6.7 kg of methyl vinyl ketone + 16.5 kg of isopropyl ether) was added dropwise.
  • Impurity B 1 H-NMR (500MHz, CDCl 3 , ⁇ ): 0.93 (t, 3H), 1.04 (s, 3H), 1.30 (s, 3H), 1.43 (s, 3H), 1.98 (d, 1H) , 2.76 (d, 1H), 5.91 (br.s, 1H); EI MS (m/z) 276 (M + ).
  • Ethanol was added to the crude bugfuran, stirred at room temperature, dissolved, and filtered. Cool the liquid to -20 ⁇ -10 ° C, stir for 30 minutes, suction filtration, and obtain the wet product of bugfuran.
  • the vacuum is ⁇ -0.090Mpa and the drying temperature is 20 ⁇ 30°C. Between, the yield was 87.2%.
  • the purity of bugfuran in the refined product was ⁇ 97.5%, and the content of impurity A and impurity B was ⁇ 0.04%.
  • the bugfuran bulk drug preparation has a certain amount of ethanol residue and no more than 0.02% of the bugfuran enantiomer impurity.
  • the invention relates to a process for preparing a bulk drug of buguefuran.
  • the purpose of the invention is to obtain a sample of a high-purity raw material of bogfuran, to clarify the structure of the impurity, and to control the content of the impurity, so that the sample of the drug substance is applied to clinical research and pharmacy.
  • New drug development processes such as research and quality control research.
  • the present invention is an improvement on the basis of the existing small-scale process to obtain a pilot process for preparing a sample of buffuran of a kilogram or more.
  • (1) an improved method for the solvent conditions of the dehydration reaction in the existing small-scale test process, and a simplification and improvement of the subsequent process steps, including a one-pot method for alkylation, reduction, and cyclization, and a three-step reaction are found. Optimize the reaction conditions and post-treatment modes to avoid column chromatography operations and achieve pilot scale-up of the process.
  • the inventors have unexpectedly discovered during the process of the process that when the compound 5 is produced by the dehydration reaction, the existing reported water/n-hexane or water/petroleum ether two-phase system is not used for the reaction, but only a single system using the aqueous phase is carried out.
  • the content of the dibutyl-substituted by-product 8 in the system can be monitored to be only 4.6%, which is disclosed in the prior art best practice.
  • the impurity content of % is greatly reduced; and the by-product impurity A obtained by the dibutyl by-product 8 undergoing the subsequent one-pot reaction step is found to be only 1.9% in the crude material of the buffalo raw material; (2) It was found that when the reaction step of adding the hydrochloric acid to carry out the final ring-synthesis bridged ring, the formation of the impurity B due to the acidity of hydrochloric acid was an oxide of burbfuran, and the yield was 1.3%.
  • Impurity A and impurity B are related substances in the preparation process of bupropfuran by the method of the present invention, and can be used as a reference for impurity detection in the quality control study of buffuran.
  • the present invention systematically studied the purification method of bugfuran, and found that the optimal purification solvent is ethanol, and the solution liquid cooling temperature is between -20 and -10 ° C (Table 1), and the cloth obtained at the temperature is obtained. Satisfactory results have been obtained in the yield and purity of ge furan, and the total content of impurity A and impurity B after purification can be controlled to less than 0.04%, which is a refining method that combines efficiency and economy.
  • the total yield of the obtained bupropfuran bulk drug was 24.3 ⁇ 5.8%, which was significantly improved compared with the original reported yield of about 10.2%.
  • the bogfuran bulk drug obtained by the method of the invention has a purity of ⁇ 97.5%, which meets the quality requirements of the raw material medicine developed by the new drug, and can also be used as a standard for pharmaceutical research of bugfuran.

Abstract

本发明提供了一种适合于大规模生产布格呋喃原料药的方法，通过该方法可制备高纯度的布格呋喃原料药，应用于临床研究、药学研究和质量控制研究等新药开发过程。

Description

布格呋喃原料药及其制备方法和应用 技术领域
本发明属于医药技术领域，具体涉及一种布格呋喃原料药及其制备方法和应用。
背景技术
布格呋喃是中国医学科学院药物研究所的研究人员从沉香中分离得到的活性成分α-沉香呋喃的衍生物，已被证明具有抗焦虑、抗抑郁和缓解睡眠障碍的药效，具有较低的毒性，为我国具有自主知识产权的1.1类候选新药(中国专利号ZL98122447.4，美国专利号US6486201B1，欧洲专利号EP1132383B1，日本专利号JP特许第4321967号)。本发明申请人已获得该研究所的布格呋喃专利权利和临床研究批件转让，正在开展II期临床研究工作(药物临床试验批件号：2014L00180，2014L0018)。
现有报道的布格呋喃的制备方法主要包括如下几种策略：
路线一：
Figure PCTCN2018083526-appb-000001
以左旋香芹酮为原料，经过还原、Robinson环合、脱水、烷基化、环氧化、还原、环合共7步反应制得布格呋喃(刘倩等，《中国药物化学杂志》，第13卷，第3期，第125-130页)。但是，申请人在重现该制备工艺时发现，第五步双键进行环氧化过程中末端甲基容易发生脱去，在中试生产时很难避免末端甲基脱除的副产物，导致最终产物中含有桥环上少一个甲基的副产物，该副产物与布格呋喃的性质极为近似，难以除去，降低了布格呋喃原料药的品质；另外，环氧基的还原反应使用了昂贵的LiAlH 4，带来不期望的成本提升。
路线二：
Figure PCTCN2018083526-appb-000002
以左旋二氢香芹酮为原料，经氧化、环合、脱水、烷基化、还原、环合共6步反应制得 布格呋喃。但是，该路线中的第3步脱水反应中会产生一个环合的副产物，对此，上述文献中报道了需使用水/正己烷或水/石油醚两相体系进行反应，利用目标中间体化合物5与环合副产物6的极性差异，使两者在反应体系中分别存在于两相中。但是，化合物5与环合副产物6可以相互进行结构转化，将其混合溶液直接进行丁基化反应制备化合物7时，会得到双丁基化杂质8(尹大力等，《中国药物化学杂志》，第13卷，第4期，第187-193页；李春等，《中国化学快报》，第14卷，第9期，第881-882页)。随后通过优化丁基化过程中的碱性条件和丁基化剂的用量，最优方案的目标化合物7的收率仅69.8％，仍含有15％的双丁基化合物杂质8(吴向宏等，《化学研究》，第16卷，第4期，第10-12页)。
Figure PCTCN2018083526-appb-000003
众所周知，原料药必须具备足够高的纯度才能满足临床应用的有效性和安全性要求。而且，从临床研究到今后生产上市过程中，需要制备足够量的样品，并完成其相关的药学研究工作。但是，现有的制备方法均为实验室级别的小试研究，步骤中需要多次进行柱层析方法进行中间体纯化，难以满足大批量生产的需要，且存在较高含量的杂质。而布格呋喃具有特殊的理化性质，在室温下为油状物形式，导致杂质的除去困难。因此，有必要对于大规模制备布格呋喃原料药的方法进行研究，获得高纯度的布格呋喃原料药样品，明确杂质的结构，控制杂质的含量，以便该原料药样品被应用于临床研究、药学研究和质量控制研究等新药开发过程。
发明内容
本发明的目的在于获得一种适合于大规模生产布格呋喃原料药的方法，通过该方法可获得高纯度的布格呋喃原料药，应用于后续研究过程。
具体来说，本发明提供了一种布格呋喃的原料药，其中活性成分布格呋喃的结构如下：
Figure PCTCN2018083526-appb-000004
另一方面，本发明提供了一种布格呋喃的原料药，除活性成分布格呋喃外，其还含有如下结构的杂质：
Figure PCTCN2018083526-appb-000005
其中，活性成分布格呋喃在原料药中的含量高于97.5％，杂质A和杂质B的合计含量低于0.04％。特别的，该布格呋喃原料药中还有一定量的溶剂残留，所残留的溶剂优选乙醇。特别的，该布格呋喃原料药中还有一定的布格呋喃对映异构体的残留，该对映异构体来源于合成起始原料中存在的少量对映异构体杂质，优选的，布格呋喃对映异构体杂质残留在原料药中的含量不高于0.02％。
另一方面，本发明提供了一种药物组合物，其含有本发明所述的布格呋喃原料药以及药学上可接受的的载体。优选的，所述药学上可接受的的载体包括聚乙烯吡咯烷酮。更优选的，所述的聚乙烯吡咯烷酮为PVP-K30。优选的，所述的药物组合物为口服制剂形式，更优选的，所述的口服制剂为胶囊。
另一方面，本发明提供了一种制备本发明所述的布格呋喃原料药的方法，包括如下步骤：
Figure PCTCN2018083526-appb-000006
其中，步骤a为在氢氧化钾水溶液中加入化合物4，加热搅拌，反应结束后降温，加入浓盐酸调节pH至近中性，萃取，干燥，过滤，滤液浓缩；步骤b为将化合物5溶于叔丁醇，再将其加入到氢氧化钾水溶液中，加热搅拌，加入溴丁烷，调节pH至近中性，过滤，滤液浓缩，浓缩物溶于甲醇，加入硼氢化钠，搅拌，随后加入正己烷和水，调节体系pH至酸性，分离出正己烷层，浓缩，得到布格呋喃粗品。
特别的，在所述的调节体系pH至酸性后，分离出的正己烷层中除布格呋喃粗品外，还含有杂质A和杂质B：
Figure PCTCN2018083526-appb-000007
优选的，所述杂质A和B在布格呋喃粗品中的合计含量不高于3.5％。
优选的，所述的化合物4通过如下方法制备：
Figure PCTCN2018083526-appb-000008
其中，步骤i为还原反应；步骤ii为氧化反应；步骤iii为化合物3与甲基乙烯基酮发生环合反应。优选的，步骤i的还原反应使用锌粉为催化剂；步骤ii的氧化反应使用浓硫酸为氧化剂；步骤iii的环合反应中含有碱性试剂氢氧化钾。
另一方面，本发明提供了一种本发明所述的布格呋喃原料药的精制方法，包括如下步骤：将布格呋喃粗品溶解于乙醇，过滤，滤液冷却至-10℃～-20℃，抽滤，得布格呋喃精制品湿品，干燥，即得布格呋喃原料药。
另一方面，本发明提供了本发明所述的布格呋喃原料药在布格呋喃的药学研究中作为标准品的用途。
另一方面，本发明提供了杂质A在布格呋喃药物质量控制中的应用，其中所述的杂质A作为布格呋喃杂质检测的对照品。
另一方面，本发明提供了杂质B在布格呋喃药物质量控制中的应用，其中所述的杂质B作为布格呋喃杂质检测的对照品。
另一方面，本发明提供了杂质A和B在布格呋喃药物质量控制中的应用，其中所述的杂质A和B作为布格呋喃杂质检测的对照品。
另一方面，本发明提供了所述的布格呋喃原料药在制备治疗精神类疾病药物中的用途，其中所述的疾病为焦虑症、抑郁症或睡眠障碍。
附图说明
图1委托生产企业提供的布格呋喃原料药的质量检验报告第一部分
图2委托生产企业提供的布格呋喃原料药的质量检验报告第二部分
具体实施方式
下面结合具体实施例对本发明作进一步的详细说明。以下实施例用于理解本发明的方法和核心思想，对于本领域的技术人员来说，在不脱离本发明构思的前提下，进行任何可能的变化或替换，均属于本发明的保护范围。
本发明中的制备工艺操作均委托浙江华纳药业有限公司在GMP车间中完成，按照GMP 管理规范进行产品质量检测。除非特别说明，本发明中所用原料和试剂均为化学纯及以上纯度。
实施例1 布格呋喃原料药的制备
(1)化合物2的合成
在搅拌下依次加入40.8kg饮用水、16.3kg氢氧化钾直至溶清，再依次加入98.0kg甲醇，32.6kg锌粉。升温回流搅拌，缓慢滴加左旋香芹酮甲醇溶液。继续回流搅拌至反应完全。冷却，过滤，滤饼用水淋洗。控制温度不超过65℃，滤液减压浓缩除去甲醇。残余物冷却静置，分出油层。水层以正己烷萃取。将正己烷与油层合并，饮用水洗涤至近中性。干燥，过滤，减压蒸馏正己烷。剩余物料用高真空泵继续减压精馏60～70℃馏分(2～3mmHg的馏分)，得化合物2(bp 74℃/2mmHg，nd 1.470，收率：86.2％)。
(2)化合物3的合成
在搅拌下将31.6kg浓硫酸缓慢地加入37.0kg饮用水中，加入化合物2。继续搅拌至反应完全。正己烷萃取，洗涤，干燥，过滤，减压蒸馏，结束后继续泵入44.1kg异丙醚搅拌溶清得化合物3的异丙醚混合液。化合物3：EI MS(m/z)170(M +)。
(3)化合物4的合成
搅拌下加入上步所得的化合物3的异丙醚的混合液。加毕，继续搅拌降温至0～10℃，将预先配制好的氢氧化钾/乙醇溶液(1.9kg氢氧化钾+5.7kg乙醇配制的溶液)缓慢加入体系中，加毕、继续搅拌。降温至-10℃左右，滴加甲基乙烯基酮/异丙醚的混合溶液(6.7kg甲基乙烯基酮+16.5kg异丙醚)。滴加结束，反应液继续搅拌，缓慢加入3.3kg浓盐酸调节体系至近中性，抽滤，滤饼用异丙醚淋洗，室温真空干燥得化合物4(收率：83.3％)。
化合物4：[α] D 15＝+56.9°； 1HNMR(400MHz,CD 3OD,δ):2.83(d,1H),2.60(dt,1H),2.16-1.97(m,3H),1.83-1.68(m,2H),1.56-1.51(m,1H),1.47-1.42(m,1H),1.36-1.20(m,4H),1.13(s,3H),1.06(s,6H)； 13CNMR(100MHz,CD 3OD,δ):212.6(C＝O),76.3(C-OH),72.8(C-OH),54.3,44.3,38.4,37.7,36.8,35.8,32.8,27.3,27.2,22.6,22.1；EI MS(m/z):240(M +),222([M-H 2O] +),207,164,149,126。
(4)化合物5的合成
在搅拌下，依次加入41.8kg饮用水、2.2kg氢氧化钾。缓慢加入上步所得的化合物4。继续搅拌升温回流至反应完全。降温，加入浓盐酸调节体系至近中性。二氯甲烷萃取，干燥，过滤，减压蒸馏回收二氯甲烷。加入8.0Kg叔丁醇制备化合物5/叔丁醇混合液，待进行下步反应。
化合物5： 1H NMR(CDCl 3,δ)5.80(s,1H),1.09-2.65(m,11H),1.30(s,3H),1.18(s,3H), 1.15(s,3H)；EI MS(m/z)222(M +)。
(5)布格呋喃的合成
在搅拌下将2.8kg氢氧化钾溶入59.5kg叔丁醇中搅拌至溶清，加入上步所得的化合物5/叔丁醇溶液。加毕升温至回流状态。滴加溴丁烷/叔丁醇混合液(6.2kg溴丁烷+4.5kg叔丁醇中的混合液)，继续搅拌反应至完全。冷却，浓盐酸调节体系至近中性，过滤，滤液减压浓缩。残余粘稠物加入31.0kg甲醇溶清，加入2.7kg硼氢化钠继续反应至完全。加入10.0kg饮用水，继续搅拌。再加入39.0kg正己烷搅拌，以盐酸调节体系pH至3.0～4.0，继续搅拌反应至完全。静置分层，取正己烷层，水洗，干燥，过滤。滤液减压浓缩，硅胶柱层析，洗脱液为石油醚：乙酸乙酯＝40～80:1，得布格呋喃粗品，收率85.2％。柱层析过程中还可收集到杂质A和杂质B，杂质A产率1.9％；杂质B产率1.3％。
布格呋喃：[α] D 20＝+22.5°(无水乙醇), 1H NMR(500MHz,CDCl 3,δ)0.92(s,3H),0.92(t,3H),1.05(dd,1H),1.19(dd,1H),1.24(s,3H),1.28～1.45(m,4H),1.36(s,3H),1.60～1.71(m,4H),1.75(dd,1H),1.80～2.05(m,5H),2.22(dd,1H),5.58(dd,1H)； 13C NMR(100MHz,CDCl 3,δ)85.27,136.37,125.91,22.48,32.91,36.92,34.47,24.41,44.10,80.74,32.60,30.77,22.83,31.27,14.06,21.89,22.83,30.34；EI MS(m/z)262(M +)。
杂质A： 1H NMR(500MHz,CDCl 3,δ):0.88(t,6H)；1.06(s,3H)；1.20-1.41(m,20H)；1.76-2.02(m,5H)；4.49(s,1H)；5.29(s,1H)；5.37(d,J＝5.3Hz,1H)；5.51(d,J＝5.3Hz,1H)；EI MS(m/z)318(M +)。
杂质B： 1H-NMR(500MHz,CDCl 3,δ):0.93(t,3H),1.04(s,3H),1.30(s,3H),1.43(s,3H),1.98(d,1H),2.76(d,1H),5.91(br.s,1H)；EI MS(m/z)276(M +)。
(6)布格呋喃的精制
在布格呋喃粗中加入乙醇，室温搅拌，溶解，过滤。冷却料液至-20～-10℃之间，保温搅拌30分钟，抽滤，收料得布格呋喃精制成品湿品，真空度≥-0.090Mpa条件下干燥，干燥温度在20～30℃之间，收率87.2％，经检测，精制品中布格呋喃纯度≥97.5％，杂质A和杂质B的含量≤0.04％。该布格呋喃原料药精制品中存在一定量的乙醇残留和不高于0.02％的布格呋喃对映体杂质。
总结：经由本实施例1所述步骤获得的布格呋喃原料药的总收率在24.3±5.8％。
实施例2 布格呋喃胶囊的制备
(1)处方(按制备1000粒投料计算)：
Figure PCTCN2018083526-appb-000009
(2)胶囊制备工艺
按处方量称取布格呋喃及PVP K-30置圆底烧瓶中，加入无水乙醇，搅拌使全部溶解后，于60℃减压条件下旋蒸，待干燥至完全固化后取出，粉碎，过40目筛，置真空干燥箱中于70℃干燥4小时，得固体分散体颗粒，装入硬胶囊，包装。
本发明的有益效果
本发明涉及大规模制备布格呋喃原料药的工艺，发明目的是获得高纯度的布格呋喃原料药样品，明确杂质的结构，控制杂质的含量，以便该原料药样品被应用于临床研究、药学研究和质量控制研究等新药研发过程。
本发明是在现有的小试规模的工艺基础上进行的改进，以获得一种制备公斤级以上布格呋喃样品的中试工艺。具体来说，(1)发现了现有小试工艺中脱水反应溶剂条件的改进方法，以及后续工艺步骤的简化和改进，包括使用一锅法进行烷基化、还原以及环合3步反应并对反应条件和后处理操作方式进行优化，避免柱层析操作，实现工艺的中试放大。发明人在工艺研究过程中出人意料地发现，在通过脱水反应制备化合物5时，不使用现有报道的水/正己烷或水/石油醚两相体系进行反应，而仅仅使用水相的单一体系进行脱水反应，在随后的一锅法进行丁基化、还原以及环合反应过程中，可监测到体系中双丁基取代副产物8的含量仅4.6％，与现有技术最优方法公开的15％的杂质含量相比大大降低；且发现了由双丁基副产物8经历后续的一锅法反应步骤所得到的副产物杂质A，其在布格呋喃原料药粗品中含量仅为1.9％；(2)发现了在加入盐酸进行最后的环合成桥环的反应步骤时，由于盐酸的酸性导致生成杂质B，为布格呋喃的氧化物，产率为1.3％。杂质A和杂质B是通过本发明方法的布格呋喃制备工艺中的有关物质，可在布格呋喃质量控制研究中作为杂质检测的对照品。
另外，本发明对于布格呋喃的精制方法进行了系统研究，发现最优的精制溶剂为乙醇，料液冷却温度为-20～-10℃之间(表1)，在该温度下获得的布格呋喃的收率和纯度均取得了满意的结果，且通过精制后杂质A和杂质B的合计含量可控制到低于0.04％，是一种兼顾效率和经济性的精制方法。
表1 布格呋喃精制条件筛选结果
Figure PCTCN2018083526-appb-000010
基于上述对于制备工艺条件、操作方式的改进，获得的布格呋喃原料药的总收率为24.3±5.8％，与原有报道的收率10.2％左右相比明显提高。由本发明方法获得的布格呋喃原料药，具有≥97.5％的纯度，符合新药研发的原料药质量要求，也可作为布格呋喃的药学研究的标准品。

Claims (10)

  1. 一种布格呋喃原料药，包含活性成分布格呋喃，其特征在于，还包含如下所示的杂质A和B，
    Figure PCTCN2018083526-appb-100001
    其中，活性成分布格呋喃在原料药中的含量高于97.5％，杂质A和杂质B的合计含量低于0.04％。
  2. 一种药物组合物，其特征在于，含有如权利要求1所述的布格呋喃原料药以及药学上可接受的载体。
  3. 根据权利要求2所述的药物组合物，其特征在于，所述药学上可接受的的载体包括聚乙烯吡咯烷酮。
  4. 一种制备如权利要求1所述的布格呋喃原料药的方法，其特征在于，包括如下步骤：
    Figure PCTCN2018083526-appb-100002
    其中，步骤a为在氢氧化钾水溶液中加入化合物4，加热搅拌，反应结束后降温，加入浓盐酸调节pH至近中性，萃取，干燥，过滤，滤液浓缩；步骤b为将化合物5溶于叔丁醇，再将其加入到氢氧化钾水溶液中，加热搅拌，加入溴丁烷，调节pH至近中性，过滤，滤液浓缩，浓缩物溶于甲醇，加入硼氢化钠，搅拌，随后加入正己烷和水，调节体系pH至酸性，分离出正己烷层，浓缩，得到布格呋喃粗品。
  5. 根据权利要求4所述的方法，其特征在于，所述的化合物4通过如下方法制备：
    Figure PCTCN2018083526-appb-100003
    其中，步骤i为还原反应；步骤ii为氧化反应；步骤iii为化合物3与甲基乙烯基酮发生环合反应。
  6. 一种如权利要求1所述的布格呋喃原料药的精制方法，其特征在于，包括如下步骤：将布 格呋喃粗品溶解于乙醇，过滤，滤液冷却至-10℃～-20℃，抽滤，得布格呋喃精制品湿品，干燥。
  7. 权利要求1所述的布格呋喃原料药在布格呋喃的药学研究中作为标准品的用途。
  8. 权利要求1所述的杂质A在布格呋喃药物质量控制中的应用，其特征在于，所述的杂质A作为布格呋喃杂质检测的对照品。
  9. 权利要求1所述的杂质B在布格呋喃药物质量控制中的应用，其特征在于，所述的杂质B杂质作为布格呋喃杂质检测的对照品。
  10. 权利要求1所述的布格呋喃原料药在制备治疗精神类疾病药物中的用途，其特征在于，所述的疾病为焦虑症、抑郁症或睡眠障碍。
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