CN114736210A - Preparation method of a crystal form of morphinan derivative - Google Patents

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a crystal form of a morphinan derivative, which particularly relates to the preparation of high-purity and stable 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4, 5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride, obtains a crystal form I, and provides crystals comprising the crystal form I and amorphous 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4, 5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride and a method for preparing the crystals.

Description

Translated fromChinese

吗啡喃衍生物的一种晶型的制备方法Preparation method of a crystal form of morphinan derivative

技术领域technical field

本发明涉及药物合成领域，具体为吗啡喃衍生物的一种晶型的制备方法。The invention relates to the field of pharmaceutical synthesis, in particular to a method for preparing a crystal form of a morphinan derivative.

背景技术Background technique

尿毒性瘙痒症是许多需要血液透析的慢性肾功能衰竭患者的常见症状，其传统治疗方法包含口服抗组胺药及抗过敏药物，局部使用皮质类固醇药物，光疗以及皮肤护理。但一些患者对于上述常规治疗无反应，其生活质量急剧下降。Urticic pruritus is a common symptom in many patients with chronic renal failure requiring hemodialysis, and traditional treatments include oral antihistamines and antiallergic drugs, topical corticosteroids, phototherapy, and skin care. However, some patients do not respond to the above conventional treatments, and their quality of life declines sharply.

盐酸纳呋拉啡由日本东丽株式会社(Toray Industries,Inc.)开发，是一种含有吗啡骨架的κ-阿片受体激动剂，可明显改善现有治疗手段无效的血液透析患者，慢性肝病患者瘙痒症症状，无成瘾性和戒断症状。Nafuraphine hydrochloride was developed by Toray Industries, Inc., Japan. It is a κ-opioid receptor agonist containing a morphine skeleton, which can significantly improve hemodialysis patients who are ineffective in existing treatments, and chronic liver disease. The patient had symptoms of pruritus, but no addiction and withdrawal symptoms.

盐酸纳呋拉啡，化学名17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反式-3-(3-呋喃基)-丙烯酰胺基]吗啡喃盐酸盐，其化学结构式如下：Nafuraphine hydrochloride, chemical name 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)- Acrylamido] morphinan hydrochloride, its chemical structure is as follows:

药物合成领域中，药物的多晶型是影响药物安全性和有效性的重要因素，尤其是体现在固体制剂和非真溶液的制剂当中。因此，药物多晶型研究越来越受到医药研发与国家药监监管领域的关注与重视。In the field of drug synthesis, the polymorphism of drugs is an important factor affecting the safety and efficacy of drugs, especially in solid preparations and preparations that are not true solutions. Therefore, the research of drug polymorphism has attracted more and more attention and attention in the fields of pharmaceutical research and development and national drug administration.

目前有文献WO2006109671报道了盐酸纳呋拉啡的3种晶型及其制备方法，其公布了A型、B型及C型盐酸纳呋拉啡的制备方法，其A型的制备方法需要添加晶种来辅助析晶，而且析晶时间较长，达到16h至5天，收率70％～80％， B型需要在冰箱或黑暗条件下放置3天至8天时间来完成析晶，收率28％～77％，C型也需要添加晶种来辅助析晶或黑暗条件下放置4天至12天，收率80％～ 90％，生产时间长，析晶效率低下，难以在工业生产上实现。At present, the document WO2006109671 has reported three crystal forms of nalvuraphine hydrochloride and their preparation methods. It has published the preparation methods of A-type, B-type and C-type nalvuraphine hydrochloride. The preparation method of its A-type requires adding crystals. Seed to assist crystallization, and the crystallization time is longer, reaching 16h to 5 days, and the yield is 70% to 80%. Type B needs to be placed in a refrigerator or dark conditions for 3 to 8 days to complete the crystallization, and theyield 28% to 77%, the C type also needs to add seeds to assist crystallization or place it in the dark for 4 to 12 days, the yield is 80% to 90%, the production time is long, the crystallization efficiency is low, and it is difficult to be used in industrial production. accomplish.

发明内容SUMMARY OF THE INVENTION

本发明目的在于提供高纯度稳定的17-环丙基甲基-3,14β-二羟基-4,5α-环氧 -6β-[N-甲基-反式-3-(3-呋喃基)-丙烯酰胺基]吗啡喃盐酸盐的制备，提供了包括Ⅰ型及无定型17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反式-3-(3-呋喃基)-丙烯酰胺基]吗啡喃盐酸盐的晶体以及其制备它们的方法，所述晶型用于制备利尿、止疼和止痒作用的药物活性成分。The object of the present invention is to provide high-purity and stable 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl) - Preparation of acrylamido] morphinan hydrochloride, including type I and amorphous 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl -Crystals of trans-3-(3-furyl)-acrylamido]morphinan hydrochloride and methods for their preparation, said crystalline forms for the preparation of active pharmaceutical ingredients with diuretic, analgesic and antipruritic effects .

为达成上述目的，本发明提出如下技术方案：吗啡喃衍生物的一种晶型的制备方法，包括如下步骤：In order to achieve the above object, the present invention proposes the following technical scheme: a method for preparing a crystal form of a morphinan derivative, comprising the following steps:

第一步：将盐酸纳曲酮用碳酸氢钠游离后，与苯甲酸、N-甲基苄胺、一水合对甲苯磺酸、苯混合均匀，加热至回流分水16h，氮气保护，降温至25℃后加入4A分子筛、乙醇和氰基硼氢化钠，25℃反应2h，反应液经过浓缩，二氯甲烷萃取，浓缩得到NAHY-1粗品，进行第二步反应；The first step: after dissociating naltrexone hydrochloride with sodium bicarbonate, it is mixed with benzoic acid, N-methylbenzylamine, p-toluenesulfonic acid monohydrate, and benzene, heated to reflux for 16h, nitrogen protection, and cooled to After 25°C, 4A molecular sieve, ethanol and sodium cyanoborohydride were added, and the reaction was carried out at 25°C for 2 h. The reaction solution was concentrated, extracted with dichloromethane, and concentrated to obtain the crude product of NAHY-1, and the second step was carried out;

第二步：将NAHY-1溶解于甲醇中，25℃搅拌下加入10％Pd/C，置换氢气， 25℃反应4h，过滤，二氯甲烷萃取得NAHY-2产品；The second step: dissolve NAHY-1 in methanol, add 10% Pd/C under stirring at 25°C, replace hydrogen, react at 25°C for 4 h, filter, and extract with dichloromethane to obtain NAHY-2 product;

第三步：将SM-2溶解于二氯甲烷中，25℃搅拌下加入催化量的N,N-二甲基甲酰胺，滴加氯化亚砜，25℃搅拌反应2h，反应液直接浓缩得NAHY-3产品，用于后续反应；Step 3: Dissolve SM-2 in dichloromethane, add a catalytic amount of N,N-dimethylformamide under stirring at 25 °C, add thionyl chloride dropwise, stir at 25 °C for 2 hours, and concentrate the reaction solution directly Obtain NAHY-3 product for subsequent reaction;

第四步：将NAHY-2溶解于四氢呋喃和水中，25℃搅拌下加入碳酸钠，将 NAHY-3溶解于四氢呋喃中，滴入反应体系，滴加完毕后25℃搅拌30min后，再加入甲醇及3M氢氧化钠水溶液，保持25℃继续搅拌1h后，用乙酸乙酯萃取，浓缩得NAHY-4粗品，乙酸乙酯打浆得到NAHY-4精制品；The fourth step: dissolve NAHY-2 in tetrahydrofuran and water, add sodium carbonate under stirring at 25°C, dissolve NAHY-3 in tetrahydrofuran, dropwise into the reaction system, and stir at 25°C for 30min after the dropwise addition, then add methanol and 3M aqueous sodium hydroxide solution, kept stirring at 25°C for 1 h, extracted with ethyl acetate, concentrated to obtain crude NAHY-4, and beaten with ethyl acetate to obtain refined NAHY-4;

第五步：将17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反式-3-(3-呋喃基)-丙烯酰胺基]吗啡喃(NAHY-4)与氯化氢溶于良性溶剂中，然后加入不良性溶剂搅拌反应，获得17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反式-3-(3-呋喃基)-丙烯酰胺基]吗啡喃盐酸盐的无定型晶体，向该无定型晶体中加入醇类溶剂或纯化水，加热至40℃-80℃，搅拌反应后，反应时间为30分钟至2 小时，然后冷却降温，过滤得到晶型Ⅰ。The fifth step: 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)-acrylamido [ Amorphous crystal of N-methyl-trans-3-(3-furyl)-acrylamido]morphinan hydrochloride, add alcohol solvent or purified water to the amorphous crystal, heat to 40℃- After stirring the reaction at 80°C, the reaction time is 30 minutes to 2 hours, and then the temperature is cooled down, and the crystal form I is obtained by filtration.

优选的，醇类溶剂为单一醇类溶剂或两种醇类溶剂或三种醇类溶剂的混合，醇类溶剂包括：甲醇、乙醇、异丙醇或正丁醇。Preferably, the alcohol solvent is a single alcohol solvent or a mixture of two alcohol solvents or three alcohol solvents, and the alcohol solvent includes methanol, ethanol, isopropanol or n-butanol.

优选的，醇类溶剂为甲醇和异丙醇的混合溶剂，比例为1:1。Preferably, the alcohol solvent is a mixed solvent of methanol and isopropanol, and the ratio is 1:1.

优选的，所述第五步中，良性溶剂为甲醇、乙醇、水或异丙醇，其中甲醇体积为无定形晶体质量的5～15倍，乙醇或异丙醇体积10～20倍。Preferably, in the fifth step, the benign solvent is methanol, ethanol, water or isopropanol, wherein the volume of methanol is 5-15 times the mass of the amorphous crystal, and the volume of ethanol or isopropanol is 10-20 times.

优选的，其中甲醇体积为无定形晶体质量10倍，乙醇或异丙醇体积为无定形晶体质量15倍。Preferably, the volume of methanol is 10 times the mass of the amorphous crystal, and the volume of ethanol or isopropanol is 15 times the mass of the amorphous crystal.

优选的，所述第一步中，不良性溶剂为乙酸乙酯、乙酸异丙酯、乙酸异丁酯或丙酮。Preferably, in the first step, the poor solvent is ethyl acetate, isopropyl acetate, isobutyl acetate or acetone.

优选的，不良性溶剂为乙酸乙酯和丙酮，体积为良性溶剂的3倍-10倍。Preferably, the poor solvent is ethyl acetate and acetone, and the volume is 3 to 10 times that of the benign solvent.

优选的，晶型Ⅰ在其X-粉末衍射图中10.4°、10.9°、11.4°、12°、19°、20.5°、 21.6°的2θ角位置具高强度衍射峰。Preferably, Form I has high-intensity diffraction peaks at 2θ angular positions of 10.4°, 10.9°, 11.4°, 12°, 19°, 20.5°, and 21.6° in its X-powder diffraction pattern.

有益效果，本申请的技术方案具备如下技术效果：Beneficial effects, the technical scheme of the present application has the following technical effects:

本发明人详细研究了盐酸纳呋拉啡的结构特征，以及在不同溶剂中的溶解度，本发明在原研的基础上对转晶方案做了优化，不需要添加晶种辅助析晶，且析晶时间仅需要4h以内，避免了长时间在暗处或冰箱的析晶操作，即可以得到与原研一致的A晶型，收率相当，能达到75％～90％，产品质量一致，所有单杂均可达到0.10％以内，产品pH值稳定，与原研一致，适用于工业化生产，是对原研A晶型制备方法的有效优化。The inventor has studied in detail the structural characteristics of nalvuraphine hydrochloride and its solubility in different solvents. The present invention optimizes the crystallization scheme on the basis of the original research. It does not need to add seeds to assist crystallization, and the crystallization The time only takes less than 4 hours, avoiding the long-term crystallization operation in the dark or the refrigerator, that is, the A crystal form consistent with the original research can be obtained, the yield is equivalent, can reach 75% to 90%, the product quality is consistent, and all single impurities All can reach within 0.10%, the pH value of the product is stable, consistent with the original research, it is suitable for industrial production, and it is an effective optimization of the preparation method of the original research A crystal form.

应当理解，前述构思以及在下面更加详细地描述的额外构思的所有组合只要在这样的构思不相互矛盾的情况下都可以被视为本公开的发明主题的一部分。It is to be understood that all combinations of the foregoing concepts, as well as additional concepts described in greater detail below, are considered to be part of the inventive subject matter of the present disclosure to the extent that such concepts are not contradictory.

结合附图从下面的描述中可以更加全面地理解本发明教导的前述和其他方面、实施例和特征。本发明的其他附加方面例如示例性实施方式的特征和/或有益效果将在下面的描述中显见，或通过根据本发明教导的具体实施方式的实践中得知。The foregoing and other aspects, embodiments and features of the present teachings can be more fully understood from the following description when taken in conjunction with the accompanying drawings. Other additional aspects of the invention, such as features and/or benefits of the exemplary embodiments, will be apparent from the description below, or learned by practice of specific embodiments in accordance with the teachings of this invention.

附图说明Description of drawings

附图不意在按比例绘制。在附图中，在各个图中示出的每个相同或近似相同的组成部分可以用相同的标号表示。为了清晰起见，在每个图中，并非每个组成部分均被标记。现在，将通过例子并参考附图来描述本发明的各个方面的实施例，其中：The drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by the same reference numeral. For clarity, not every component is labeled in every figure. Embodiments of various aspects of the present invention will now be described by way of example and with reference to the accompanying drawings, wherein:

图1为本发明的17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反式 -3-(3-呋喃基)-丙烯酰胺基]吗啡喃盐酸盐的晶型Ⅰ的X-射线粉末衍射图。Fig. 1 is 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)-acrylamide of the present invention X-ray powder diffraction pattern of crystalline form I of [methyl]morphinan hydrochloride.

图2为本发明的17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反式 -3-(3-呋喃基)-丙烯酰胺基]吗啡喃盐酸盐的晶型Ⅰ的XPRD图，包括2θ角具体数据。Figure 2 is 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)-acrylamide of the present invention XPRD pattern of Form I of the hydrochloride salt of [

图3为本发明的17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反式 -3-(3-呋喃基)-丙烯酰胺基]吗啡喃盐酸盐的无定型晶体的X-射线粉末衍射图。Figure 3 is 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)-acrylamide of the present invention X-ray powder diffraction pattern of amorphous crystals of [

图4为本发明实施例5液相色谱检测图。FIG. 4 is a liquid chromatography detection diagram of Example 5 of the present invention.

图5为本发明实施例7液相色谱检测图。FIG. 5 is a liquid chromatography detection diagram of Example 7 of the present invention.

图6为本发明实施例8液相色谱检测图。FIG. 6 is a liquid chromatography detection diagram of Example 8 of the present invention.

具体实施方式Detailed ways

为了更了解本发明的技术内容，特举具体实施例并配合所附图式说明如下。在本公开中参照附图来描述本发明的各方面，附图中示出了许多说明的实施例。本公开的实施例不必定义在包括本发明的所有方面。应当理解，上面介绍的多种构思和实施例，以及下面更加详细地描述的那些构思和实施方式可以以很多方式中任意一种来实施，这是因为本发明所公开的构思和实施例并不限于任何实施方式。另外，本发明公开的一些方面可以单独使用，或者与本发明公开的其他方面的任何适当组合来使用。In order to better understand the technical content of the present invention, specific embodiments are given and described below in conjunction with the accompanying drawings. Aspects of the invention are described in this disclosure with reference to the accompanying drawings, in which a number of illustrative embodiments are shown. Embodiments of the present disclosure are not necessarily defined to include all aspects of the invention. It should be understood that the various concepts and embodiments described above, as well as those described in greater detail below, can be implemented in any of a variety of ways, as the concepts and embodiments disclosed herein do not limited to any implementation. Additionally, some aspects of the present disclosure may be used alone or in any suitable combination with other aspects of the present disclosure.

实施例的路线如下：The route of the embodiment is as follows:

实施例1：Example 1:

将SM-1(550g)混悬于5.5L DCM中，25℃搅拌下加入5.5L饱和NaHCO₃水溶液，保持25℃搅拌15min后静置分层，水层再用2L DCM萃取；有机层合并，外温40℃浓缩得游离态原料共计约470g，将该游离态原料混悬于苯(15 L)中，加入苯甲酸-1(178g)，N-甲基苄胺(264g)，25℃搅拌至溶清，再依次加入苯甲酸-2(267g)、一水合对甲苯磺酸(14g)，体系逐渐浑浊，有固体析出，外温升至110℃，内温79℃回流反应16h，体系逐渐变为黄色澄清溶液，氮气保护，降温至内温25℃，加入4A分子筛(200g)，乙醇(15L)，一次性加入氰基硼氢化钠(137g)，无明显放热现象，搅拌反应2h，反应完全，向体系中加入甲醇10L，25℃搅拌至固体基本溶清，45℃浓缩得半固体，向此残留物中加DCM(10L)，饱和NaHCO₃水溶液(7.5L)，25℃搅拌至基本溶清，过滤除分子筛和少量粘性固体，滤液分层，水层再用DCM(5L)反萃，有机层合并浓缩得产品，为类白色发泡固体，共计471.2g，收率64％。SM-1 (550g) was suspended in 5.5L DCM, 5.5L saturated aqueous NaHCO₃ solution was added under stirring at 25°C, kept at 25°C for 15 min, then left to stand for separation, and the aqueous layer was extracted with 2L DCM; the organic layers were combined, Concentrated at an external temperature of 40°C to obtain a total of about 470 g of free raw materials. The free raw materials were suspended in benzene (15 L), benzoic acid-1 (178 g) and N-methylbenzylamine (264 g) were added, and the mixture was stirred at 25 °C until dissolved. Then add benzoic acid-2 (267g) and p-toluenesulfonic acid monohydrate (14g) in turn, the system is gradually turbid, and solids are precipitated. Yellow clear solution, nitrogen protection, cooling to the internal temperature of 25 ℃, adding 4A molecular sieve (200g), ethanol (15L), adding sodium cyanoborohydride (137g) at one time, no obvious exothermic phenomenon, stirring reaction for 2h, the reaction is complete , add methanol 10L to the system, stir at 25°C until the solid is almost dissolved, concentrate at 45°C to obtain a semi-solid, add DCM (10L) to the residue, saturated aqueous NaHCO (7.5L), stir at₂₅ °C until almost dissolved Clear, filtered to remove molecular sieves and a small amount of sticky solids, the filtrate was layered, the aqueous layer was back extracted with DCM (5L), the organic layers were combined and concentrated to obtain a product, which was an off-white foaming solid, totaling 471.2 g, yield 64%.

实施例2：Example 2:

将NAHY-1(430g)溶解于9L甲醇中，加入10％Pd/C(86g)，抽换三次氢气，保持25℃反应，4h后加硅藻土过滤，滤饼甲醇(4L)洗涤，滤液合并，外温40℃浓缩，残留物加4L饱和NaHCO₃水溶液，DCM萃取(4L*3)，有机层合并，外温40℃浓缩得产品，为淡黄色发泡固体，共计284g，收率80％。NAHY-1 (430g) was dissolved in 9L methanol, 10% Pd/C (86g) was added, the hydrogen was pumped three times, kept at 25°C for reaction, celite was added to filter after 4h, the filter cake was washed with methanol (4L), and the filtrate was Combined, concentrated at an external temperature of 40°C, added 4L saturated aqueous NaHCO₃ solution to the residue, extracted with DCM (4L*3), combined the organic layers, concentrated at an external temperature of 40°C to obtain the product, which was a pale yellow foaming solid, totaling 284g, yield 80 %.

实施例3：Example 3:

将SM-2(88g)混悬于DCM(1L)中，25℃搅拌均匀，加入N,N-二甲基甲酰胺(2g)，滴加二氯亚砜(113g)，滴加过程放气，保持25℃反应，2h 后，体系逐渐溶清，放气停止，反应液外温40℃浓缩得产品，为土黄色固体，共计110g，收率按100％计算，直接投下一步。SM-2 (88g) was suspended in DCM (1L), stirred at 25°C, N,N-dimethylformamide (2g) was added, thionyl chloride (113g) was added dropwise, and gas was released during the dropwise addition , keep the reaction at 25°C, after 2h, the system gradually dissolves and clears, the gassing stops, and the reaction solution is concentrated at an external temperature of 40°C to obtain the product, which is a khaki solid, a total of 110g, and the yield is calculated as 100%, which is directly put into the next step.

实施例4：Example 4:

将NAHY-2(206g)溶解于THF/水(1L/1L)中，加入碳酸钠(123g)，25℃搅拌均匀，将NAHY-3溶解于THF(1L)滴入反应体系，25℃反应0.5h，向反应体系中加入甲醇(6L)，3M NaOH水溶液(8L)，25℃反应1h，向反应体系中加入饱和NaHCO₃水溶液(3.5L)，5L乙酸乙酯，搅拌分层，水层再用5L乙酸乙酯萃取，有机相合并，饱和盐水(5L)洗涤，有机相无水硫酸钠干燥过滤浓缩得粗品，加入7L乙酸乙酯25℃打浆30min，过滤，滤饼1L EA漂洗，滤饼拉干得产品，共计244g，类白色固体，收率90％。Dissolve NAHY-2 (206g) in THF/water (1L/1L), add sodium carbonate (123g), stir evenly at 25°C, dissolve NAHY-3 in THF (1L) and drop into the reaction system, react at 25°C for 0.5 h, add methanol (6L), 3M NaOH aqueous solution (8L) to the reaction system, react at 25°C for 1 h, add saturated NaHCO₃ aqueous solution (3.5L), 5L ethyl acetate to the reaction system, stir and separate the layers, and the water layer is again Extract with 5L ethyl acetate, combine the organic phases, wash with saturated brine (5L), dry, filter and concentrate the organic phase over anhydrous sodium sulfate to obtain the crude product, add 7L ethyl acetate at 25°C for 30min beating, filter, rinse the filter cake with 1L EA, filter cake The product was obtained by pulling dry, a total of 244 g, an off-white solid, and a yield of 90%.

实施例5：Example 5:

将160.0g 17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反式-3-(3-呋喃基)-丙烯酰胺基]吗啡喃混悬于0.65L乙醇中，25℃搅拌均匀后加入150ml HCl/MeOH溶液(4mol/L)，继续搅拌30分钟，然后加入8L丙酮，搅拌析晶 2小时，过滤，滤饼用少量丙酮淋洗，烘干后得到类白色固体，共计165.2g，收率95％。得到无定型态的17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基- 反式-3-(3-呋喃基)-丙烯酰胺基]吗啡喃盐酸盐。HPLC纯度98.9％。160.0 g of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)-acrylamido]morphine Suspended in 0.65L of ethanol, stirred evenly at 25°C, added 150ml of HCl/MeOH solution (4mol/L), continued to stir for 30 minutes, then added 8L of acetone, stirred and crystallized for 2 hours, filtered, and drenched the filter cake with a small amount of acetone After washing and drying, an off-white solid was obtained, totaling 165.2 g, and the yield was 95%. 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)-acrylamide was obtained in amorphous form base] morphinan hydrochloride. HPLC purity 98.9%.

实施例6：Example 6:

将100.0g 17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反式-3-(3-呋喃基)-丙烯酰胺基]吗啡喃混悬于0.5L甲醇中，25℃搅拌均匀后加入107ml HCl/MeOH溶液(4Mol/L)，继续搅拌30分钟，然后加入5L乙酸乙酯，搅拌析晶2小时，过滤，滤饼用少量乙酸乙酯淋洗，烘干后得到类白色固体，共计 96.4g，收率89.6％。得到无定型态的17-环丙基甲基-3,14β-二羟基-4,5α-环氧 -6β-[N-甲基-反式-3-(3-呋喃基)-丙烯酰胺基]吗啡喃盐酸盐。100.0 g of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)-acrylamido]morphine Suspended in 0.5L methanol, stirred evenly at 25°C, added 107ml HCl/MeOH solution (4Mol/L), continued stirring for 30 minutes, then added 5L ethyl acetate, stirred and crystallized for 2 hours, filtered, and used a small amount of filter cake. Rinse with ethyl acetate and dry to obtain an off-white solid, totaling 96.4 g, with a yield of 89.6%. 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)-acrylamide was obtained in amorphous form base] morphinan hydrochloride.

实施例7：Example 7:

将实施例1得到无定型17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反式-3-(3-呋喃基)-丙烯酰胺基]吗啡喃盐酸盐，取100g加入三口瓶中，加入 100ml甲醇和异丙醇(1:1)混合溶剂中，氮气保护下加热至40℃，搅拌2小时，过滤，滤饼干燥后得到白色结晶性粉末，收率：82.7g，收率82.7％。得到的为晶型Ⅰ。HPLC纯度为99.4％。Example 1 gave amorphous 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)-propene Amido] morphinan hydrochloride, add 100 g to a three-necked flask, add 100 ml of a mixed solvent of methanol and isopropanol (1:1), heat to 40°C under nitrogen protection, stir for 2 hours, filter, and dry the filter cake A white crystalline powder was obtained, yield: 82.7 g, yield 82.7%. The obtained form is Form I. HPLC purity was 99.4%.

实施例8：Example 8:

将实施例1得到无定型17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反式-3-(3-呋喃基)-丙烯酰胺基]吗啡喃盐酸盐，取100g加入三口瓶中，加入甲醇、乙醇和异丙醇(1:1:1)混合溶剂中，氮气保护下加热至50℃，搅拌2小时，过滤，滤饼干燥后得到白色结晶性粉末，收率：79.7g，收率79.7％。得到的为晶型Ⅰ。HPLC纯度为99.8％。Example 1 gave amorphous 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)-propene Amido] morphinan hydrochloride, add 100 g to a three-necked flask, add methanol, ethanol and isopropanol (1:1:1) mixed solvent, heat to 50°C under nitrogen protection, stir for 2 hours, filter, filter After the cake was dried, a white crystalline powder was obtained, yield: 79.7 g, yield 79.7%. The obtained form is Form I. HPLC purity was 99.8%.

实施例9：Example 9:

将实施例1得到无定型17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反式-3-(3-呋喃基)-丙烯酰胺基]吗啡喃盐酸盐，取100g加入三口瓶中，加入纯化水(550mL)，25℃搅拌至溶清，加热至内温55℃搅拌15min，开始降温，内温30℃过滤，滤饼干燥后得到白色结晶性粉末，收率：85.2g，收率85.2％。得到的为晶型Ⅰ。如图2，所示晶型Ⅰ在其X-粉末衍射图中10.4°、10.9°、11.4°、12°、19°、20.5°、21.6°的2θ角位置具高强度衍射峰。Example 1 gave amorphous 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)-propene Amido] morphinan hydrochloride, add 100g into a three-necked flask, add purified water (550mL), stir at 25°C until it dissolves, heat to an internal temperature of 55°C and stir for 15min, start to cool down, filter at an internal temperature of 30°C, filter the cake After drying, white crystalline powder was obtained, yield: 85.2 g, yield 85.2%. The obtained form is Form I. As shown in Fig. 2, Form I has high intensity diffraction peaks at 2θ angle positions of 10.4°, 10.9°, 11.4°, 12°, 19°, 20.5°, 21.6° in its X-powder diffraction pattern.

虽然本发明已以较佳实施例揭露如上，然其并非用以限定本发明。本发明所属技术领域中具有通常知识者，在不脱离本发明的精神和范围内，当可作各种的更动与润饰。因此，本发明的保护范围当视权利要求书所界定者为准。Although the present invention has been disclosed above with preferred embodiments, it is not intended to limit the present invention. Those skilled in the art to which the present invention pertains can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention should be determined according to the claims.

Claims (8)

Translated fromChinese

1.吗啡喃衍生物的一种晶型的制备方法，其特征在于：包括如下步骤：1. the preparation method of a kind of crystal form of morphinan derivative, is characterized in that: comprise the steps:

第一步：将盐酸纳曲酮用碳酸氢钠游离后，与苯甲酸、N-甲基苄胺、一水合对甲苯磺酸、苯混合均匀，加热至回流分水16h，氮气保护，降温至25℃后加入4A分子筛、乙醇和氰基硼氢化钠，25℃反应2h，反应液经过浓缩，二氯甲烷萃取，浓缩得到NAHY-1粗品，进行第二步反应；The first step: after dissociating naltrexone hydrochloride with sodium bicarbonate, it is mixed with benzoic acid, N-methylbenzylamine, p-toluenesulfonic acid monohydrate, and benzene, heated to reflux for 16h, nitrogen protection, and cooled to After 25°C, 4A molecular sieve, ethanol and sodium cyanoborohydride were added, and the reaction was carried out at 25°C for 2 h. The reaction solution was concentrated, extracted with dichloromethane, and concentrated to obtain the crude product of NAHY-1, and the second step was carried out;第二步：将NAHY-1溶解于甲醇中，25℃搅拌下加入10％Pd/C，置换氢气，25℃反应4h，过滤，二氯甲烷萃取得NAHY-2产品；The second step: dissolve NAHY-1 in methanol, add 10% Pd/C under stirring at 25°C, replace hydrogen, react at 25°C for 4 h, filter, and extract with dichloromethane to obtain NAHY-2 product;第三步：将SM-2溶解于二氯甲烷中，25℃搅拌下加入催化量的N,N-二甲基甲酰胺，滴加氯化亚砜，25℃搅拌反应2h，反应液直接浓缩得NAHY-3产品，用于后续反应；The third step: dissolve SM-2 in dichloromethane, add a catalytic amount of N,N-dimethylformamide under stirring at 25 °C, add thionyl chloride dropwise, stir at 25 °C for 2 hours, and concentrate the reaction solution directly Obtain NAHY-3 product for subsequent reaction;第四步：将NAHY-2溶解于四氢呋喃和水中，25℃搅拌下加入碳酸钠，将NAHY-3溶解于四氢呋喃中，滴入反应体系，滴加完毕后25℃搅拌30min后，再加入甲醇及3M氢氧化钠水溶液，保持25℃继续搅拌1h后，用乙酸乙酯萃取，浓缩得NAHY-4粗品，乙酸乙酯打浆得到NAHY-4精制品；The fourth step: dissolve NAHY-2 in tetrahydrofuran and water, add sodium carbonate under stirring at 25°C, dissolve NAHY-3 in tetrahydrofuran, dropwise into the reaction system, and stir at 25°C for 30min after the dropwise addition, then add methanol and 3M aqueous sodium hydroxide solution, kept stirring at 25°C for 1 h, extracted with ethyl acetate, concentrated to obtain crude NAHY-4, and beaten with ethyl acetate to obtain refined NAHY-4;第五步：将17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反式-3-(3-呋喃基)-丙烯酰胺基]吗啡喃(NAHY-4)与氯化氢溶于良性溶剂中，然后加入不良性溶剂搅拌反应，获得17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反式-3-(3-呋喃基)-丙烯酰胺基]吗啡喃盐酸盐的无定型晶体，向该无定型晶体中加入醇类溶剂或纯化水，加热至40℃-80℃，搅拌反应后，反应时间为30分钟至2小时，然后冷却降温，过滤得到晶型Ⅰ。The fifth step: 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)-acrylamido [ Amorphous crystal of N-methyl-trans-3-(3-furyl)-acrylamido]morphinan hydrochloride, add alcohol solvent or purified water to the amorphous crystal, heat to 40℃- After stirring the reaction at 80°C, the reaction time is 30 minutes to 2 hours, then cooling and cooling to obtain crystal form I by filtration.2.根据权利要求1所述的吗啡喃衍生物的一种晶型的制备方法，其特征在于：醇类溶剂为单一醇类溶剂或两种醇类溶剂或三种醇类溶剂的混合，醇类溶剂包括：甲醇、乙醇、异丙醇或正丁醇。2. the preparation method of a kind of crystal form of morphinan derivative according to claim 1, is characterized in that: alcoholic solvent is the mixing of single alcoholic solvent or two kinds of alcoholic solvents or three kinds of alcoholic solvents, alcohol Solvents include: methanol, ethanol, isopropanol, or n-butanol.3.根据权利要求2所述的吗啡喃衍生物的一种晶型的制备方法，其特征在于：醇类溶剂为甲醇和异丙醇的混合溶剂，比例为1:1。3. the preparation method of a kind of crystal form of morphinan derivative according to claim 2, is characterized in that: alcoholic solvent is the mixed solvent of methyl alcohol and isopropanol, and the ratio is 1:1.4.根据权利要求2所述的吗啡喃衍生物的一种晶型的制备方法，其特征在于：所述第五步中，良性溶剂为甲醇、乙醇、水或异丙醇，其中甲醇体积为无定形晶体质量的5～15倍，乙醇或异丙醇体积10～20倍。4. the preparation method of a kind of crystal form of morphinan derivative according to claim 2, is characterized in that: in described 5th step, benign solvent is methanol, ethanol, water or isopropanol, and wherein methanol volume is 5 to 15 times the mass of amorphous crystals, and 10 to 20 times the volume of ethanol or isopropanol.5.根据权利要求4所述的吗啡喃衍生物的一种晶型的制备方法，其特征在于：其中甲醇体积为无定形晶体质量10倍，乙醇或异丙醇体积为无定形晶体质量15倍。5. the preparation method of a kind of crystal form of morphinan derivative according to claim 4, is characterized in that: wherein methanol volume is 10 times of amorphous crystal quality, and ethanol or isopropanol volume is 15 times of amorphous crystal quality .6.根据权利要求5所述的吗啡喃衍生物的一种晶型的制备方法，其特征在于：所述第一步中，不良性溶剂为乙酸乙酯、乙酸异丙酯、乙酸异丁酯或丙酮。6. the preparation method of a kind of crystal form of morphinan derivative according to claim 5, is characterized in that: in described first step, poor solvent is ethyl acetate, isopropyl acetate, isobutyl acetate or acetone.7.根据权利要求6所述的吗啡喃衍生物的一种晶型的制备方法，其特征在于：不良性溶剂为乙酸乙酯和丙酮，体积为良性溶剂的3倍-10倍。7. The preparation method of a crystal form of morphinan derivative according to claim 6, wherein the poor solvent is ethyl acetate and acetone, and the volume is 3 times-10 times that of the benign solvent.8.根据权利要求1所述的吗啡喃衍生物的一种晶型的制备方法，其特征在于：晶型Ⅰ在其X-粉末衍射图中10.4°、10.9°、11.4°、12°、19°、20.5°、21.6°的2θ角位置具高强度衍射峰。8. the preparation method of a kind of crystal form of morphinan derivative according to claim 1 is characterized in that: crystal form I is 10.4°, 10.9°, 11.4°, 12°, 19° in its X-powder diffractogram The 2θ angular positions of °, 20.5°, and 21.6° have high-intensity diffraction peaks.

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