技术领域technical field
本发明涉及一种吡唑衍生物的制备方法，属于制药技术领域。The invention relates to a preparation method of pyrazole derivatives, which belongs to the technical field of pharmacy.
背景技术Background technique
依鲁替尼(Ibrutinib)，化学名为1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮；是一种不可逆的布鲁顿酪氨酸激酶(BTK，Bruton's tyrosine kinase)抑制剂，能够抑制恶性B细胞的增殖、生存，可用于治疗慢性淋巴细胞白血病(CLL)和套细胞淋巴瘤(MCL)等疾病。Ibrutinib, chemical name 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine -1-yl]-1-piperidinyl]-2-propen-1-one; is an irreversible Bruton's tyrosine kinase (BTK, Bruton's tyrosine kinase) inhibitor that can inhibit the proliferation of malignant B cells , survival, and can be used to treat diseases such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).
在制备依鲁替尼的过程中，需要先制备中间体化合物3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺，其结构如式(02)所示：In the process of preparing ibrutinib, the intermediate compound 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine needs to be prepared first, and its structure is as follows: As shown in (02):
现有技术中，通常采用在高温180℃长时间反应以制备化合物(02)；此方法反应温度高，反应时间长，造成反应成本高，并且因为长时间高温反应，易产生较多杂质，使得获得的产物纯化难纯度低，收率低；并且带来较大安全隐患，不适于工业化生产。In the prior art, compound (02) is usually prepared by reacting at a high temperature of 180°C for a long time; this method has a high reaction temperature and a long reaction time, resulting in high reaction cost, and because of the long-term high-temperature reaction, it is easy to produce more impurities, which makes The obtained product is difficult to purify, has low purity, and low yield; and it brings relatively large safety hazards, and is not suitable for industrial production.
发明内容Contents of the invention
发明概述Summary of the invention
本发明提供了一种化合物(02)的制备方法，其解决了现有技术中的高温长时间反应的问题，并且产物纯度高、收率高，方法操作简便，成本低，适于工业化生产。The invention provides a preparation method of compound (02), which solves the problem of high-temperature and long-time reaction in the prior art, and has high product purity and high yield. The method is easy to operate and low in cost, and is suitable for industrial production.
发明详述Detailed description of the invention
本发明提供了一种制备化合物(02)的方法，其包括：化合物(01)与甲脒的盐在有机溶剂中，在一定温度反应，反应完毕后，降温，收集析出的固体，得到化合物(02)，如下式所示：The present invention provides a method for preparing compound (02), which comprises: compound (01) reacts with a salt of formamidine in an organic solvent at a certain temperature, after the reaction is completed, the temperature is lowered, and the precipitated solid is collected to obtain compound ( 02), as shown in the following formula:
发明人发现，化合物(01)与甲脒的盐在有机溶剂中反应，有利于降低反应温度，减少杂质产生。The inventors found that the reaction between compound (01) and the salt of formamidine in an organic solvent is beneficial to reduce the reaction temperature and reduce the generation of impurities.
所述甲脒的盐包括醋酸甲脒，盐酸甲脒。在一些实施方式中，化合物(01)与醋酸甲脒反应，而制得化合物(02)。The salts of formamidine include formamidine acetate and formamidine hydrochloride. In some embodiments, compound (01) is reacted with formamidine acetate to prepare compound (02).
所述甲脒的盐与化合物(01)的投料摩尔比为1.2:1-4.5:1。在一些实施方式中，所述醋酸甲脒与化合物(01)的投料摩尔比为2.5:1-4.5:1。在一些实施方式中，所述醋酸甲脒与化合物(01)的投料摩尔比为3:1-4:1。在一些实施方式中，所述醋酸甲脒与化合物(01)的投料摩尔比为3:1-3.5:1。The molar ratio of the formamidine salt to the compound (01) is 1.2:1-4.5:1. In some embodiments, the molar ratio of formamidine acetate to compound (01) is 2.5:1-4.5:1. In some embodiments, the molar ratio of formamidine acetate to compound (01) is 3:1-4:1. In some embodiments, the molar ratio of formamidine acetate to compound (01) is 3:1-3.5:1.
所述有机溶剂为N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、乙二醇单甲醚、乙二醇单乙醚、乙二醇二甲醚(DME)、正丁醇、异丁醇、正戊醇和异戊醇中的一种或多种。在一些实施方式中，所述有机溶剂为乙二醇单甲醚、乙二醇单乙醚和正丁醇中的一种或多种。在一些实施方式中，所述有机溶剂为乙二醇单甲醚、正丁醇、或其组合。在一些实施方式中，所述有机溶剂为正丁醇。在一些实施方式中，所述有机溶剂为乙二醇单甲醚。The organic solvent is N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether One or more of (DME), n-butanol, isobutanol, n-amyl alcohol and isoamyl alcohol. In some embodiments, the organic solvent is one or more of ethylene glycol monomethyl ether, ethylene glycol monoethyl ether and n-butanol. In some embodiments, the organic solvent is ethylene glycol monomethyl ether, n-butanol, or a combination thereof. In some embodiments, the organic solvent is n-butanol. In some embodiments, the organic solvent is ethylene glycol monomethyl ether.
所述有机溶剂用量，按照化合物(01)的质量计算，每一克化合物(01)，有机溶剂用量为3毫升-20毫升。在一些实施方式中，每一克化合物(01)，有机溶剂用量为5毫升-15毫升。在一些实施方式中，每一克化合物(01)，有机溶剂用量为7毫升-13毫升。The amount of the organic solvent is calculated according to the mass of the compound (01), and the amount of the organic solvent is 3 milliliters to 20 milliliters per gram of the compound (01). In some embodiments, for every gram of compound (01), the amount of organic solvent used is 5ml-15ml. In some embodiments, for every gram of compound (01), the amount of organic solvent used is 7ml-13ml.
所述化合物(01)与甲脒的盐反应的反应温度为60℃-130℃。在一些实施方式中，所述化合物(01)与甲脒的盐的反应温度为80℃-130℃。在一些实施方式中，所述化合物(01)与甲脒的盐的反应温度为100℃-120℃。The reaction temperature of the reaction between the compound (01) and the salt of formamidine is 60°C-130°C. In some embodiments, the reaction temperature of the compound (01) and the salt of formamidine is 80°C-130°C. In some embodiments, the reaction temperature of the compound (01) and the salt of formamidine is 100°C-120°C.
所述化合物(01)与甲脒的盐反应的反应时间为8小时-24小时。在一些实施方式中，所述化合物(01)与甲脒的盐反应的反应时间为10小时-20小时。在一些实施方式中，所述化合物(01)与甲脒的盐反应的反应时间为12小时-16小时。The reaction time of the compound (01) reacting with the salt of formamidine is 8 hours to 24 hours. In some embodiments, the reaction time of the compound (01) reacting with the salt of formamidine is 10 hours to 20 hours. In some embodiments, the reaction time of the compound (01) reacting with the salt of formamidine is 12 hours to 16 hours.
化合物(01)与甲脒的盐反应，在反应完毕后，将反应混合液降温至-5℃-35℃，然后经过固液分离，得到产物。在一些实施方式中，在反应完毕后，将反应混合液降温至0℃-35℃。在一些实施方式中，在反应完毕后，将反应混合液降温至10℃-30℃。在一些实施方式中，在反应完毕后，将反应混合液降温至15℃-30℃。在一些实施方式中，在反应完毕后，将反应混合液降温至15℃-25℃。在一些实施方式中，在反应完毕后，将反应混合液降温至0℃-5℃。The compound (01) is reacted with the salt of formamidine, and after the reaction is completed, the temperature of the reaction mixture is lowered to -5°C-35°C, followed by solid-liquid separation to obtain the product. In some embodiments, after the reaction is completed, the temperature of the reaction mixture is lowered to 0°C-35°C. In some embodiments, after the reaction is completed, the temperature of the reaction mixture is lowered to 10°C-30°C. In some embodiments, after the reaction is completed, the temperature of the reaction mixture is lowered to 15°C-30°C. In some embodiments, after the reaction is completed, the temperature of the reaction mixture is lowered to 15°C-25°C. In some embodiments, after the reaction is completed, the temperature of the reaction mixture is lowered to 0°C-5°C.
在固液分离后，所得固体粗品可经过洗涤、打浆、纯化、结晶等操作以进一步提高其纯度质量。After solid-liquid separation, the obtained solid crude product can be subjected to operations such as washing, beating, purification, and crystallization to further improve its purity and quality.
所得固体产物可经过干燥以除去溶剂，可以采用的干燥方法有真空干燥，鼓风干燥等常规干燥方法。在一些实施方式中，所得固体在40℃-100℃真空干燥。在一些实施方式中，所得固体在50℃-80℃真空干燥。The obtained solid product can be dried to remove the solvent, and the drying methods that can be used include conventional drying methods such as vacuum drying and blast drying. In some embodiments, the resulting solid is dried under vacuum at 40°C to 100°C. In some embodiments, the resulting solid is dried under vacuum at 50°C to 80°C.
在一些实施方式中，一种制备化合物(02)的方法包括：化合物(01)与醋酸甲脒在正丁醇中，在80℃-120℃反应12小时-16小时，然后将反应混合液降温至-5℃-35℃，搅拌，过滤，所得固体用正丁醇洗涤后干燥，得到化合物(02)。In some embodiments, a method for preparing compound (02) comprises: reacting compound (01) with formamidine acetate in n-butanol at 80°C-120°C for 12 hours-16 hours, and then cooling the reaction mixture Temperature to -5°C-35°C, stirred, filtered, the obtained solid was washed with n-butanol and dried to obtain compound (02).
在一些实施方式中，一种制备化合物(02)的方法包括：化合物(01)与醋酸甲脒在正丁醇中，在100℃-120℃反应12小时-16小时，然后将反应混合液降温至-5℃-5℃，搅拌，过滤，所得固体用正丁醇洗涤后干燥，得到化合物(02)。In some embodiments, a method for preparing compound (02) comprises: reacting compound (01) with formamidine acetate in n-butanol at 100°C-120°C for 12 hours-16 hours, and then cooling the reaction mixture To -5°C-5°C, stirred, filtered, the obtained solid was washed with n-butanol and dried to obtain compound (02).
在一些实施方式中，一种制备化合物(02)的方法包括：化合物(01)与醋酸甲脒在正丁醇中，在80℃-120℃反应12小时-16小时，然后将反应混合液降温至15℃-30℃，搅拌，过滤，所得固体用正丁醇洗涤后在40℃-80℃真空干燥至干，得到化合物(02)。In some embodiments, a method for preparing compound (02) comprises: reacting compound (01) with formamidine acetate in n-butanol at 80°C-120°C for 12 hours-16 hours, and then cooling the reaction mixture to 15°C-30°C, stirred, filtered, and the obtained solid was washed with n-butanol and then vacuum-dried to dryness at 40°C-80°C to obtain compound (02).
在一些实施方式中，一种制备化合物(02)的方法包括：化合物(01)与醋酸甲脒在正丁醇中，在100℃-120℃反应12小时-16小时，然后将反应混合液降温至15℃-30℃，搅拌，过滤，所得固体用正丁醇洗涤后在40℃-80℃真空干燥至干，得到化合物(02)；其中，醋酸甲脒与化合物(01)的投料摩尔比为3:1-3.5:1，每一克化合物(01)，正丁醇的用量为3毫升-20毫升。In some embodiments, a method for preparing compound (02) comprises: reacting compound (01) with formamidine acetate in n-butanol at 100°C-120°C for 12 hours-16 hours, and then cooling the reaction mixture to 15°C-30°C, stirred, filtered, and the obtained solid was washed with n-butanol and then vacuum-dried to dryness at 40°C-80°C to obtain compound (02); wherein, the molar ratio of formamidine acetate to compound (01) was 3:1-3.5:1, the amount of n-butanol is 3ml-20ml for every gram of compound (01).
在一些实施方式中，一种制备化合物(02)的方法包括：化合物(01)与醋酸甲脒在正丁醇中，在100℃-120℃反应12小时-16小时，然后将反应混合液降温至-5℃-5℃，搅拌，过滤，所得固体用正丁醇洗涤后在40℃-80℃真空干燥至干，得到化合物(02)；其中，醋酸甲脒与化合物(01)的投料摩尔比为3:1-3.5:1，每一克化合物(01)，正丁醇的用量为5毫升-15毫升。In some embodiments, a method for preparing compound (02) comprises: reacting compound (01) with formamidine acetate in n-butanol at 100°C-120°C for 12 hours-16 hours, and then cooling the reaction mixture to -5°C-5°C, stirred, filtered, and the resulting solid was washed with n-butanol and then vacuum-dried to dryness at 40°C-80°C to obtain compound (02); wherein, the feeding mole of formamidine acetate and compound (01) The ratio is 3:1-3.5:1, and the amount of n-butanol is 5ml-15ml for every gram of compound (01).
本发明所述的方法，通过使用有机溶剂，特别是正丁醇，是反应温度降低，杂质较少，方法简便，可用于工业化生产。The method of the present invention uses an organic solvent, especially n-butanol, so that the reaction temperature is lowered, the impurities are less, the method is simple and convenient, and can be used in industrialized production.
具体实施方式Detailed ways
为了使本领域的技术人员更好地理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.
本发明中，g表示克，mL表示毫升。In the present invention, g means gram, and mL means milliliter.
实施例1Example 1
反应器中，加入3-氨基-5-(4-苯氧基苯基)-4-氰基-1H-吡唑10.00g，，醋酸甲脒7.61g和正丁醇100mL，室温下搅拌均匀。加热升温至110℃，在110℃反应15小时。然后将反应混合液降温至20℃-30℃，过滤，滤饼用正丁醇20mL淋洗，所得固体在60℃真空干燥至干，得到固体10.21g，经过质谱和核磁氢谱确认，为3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺，纯度：99.43％。Into the reactor, add 10.00 g of 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, 7.61 g of formamidine acetate and 100 mL of n-butanol, and stir evenly at room temperature. Heat up to 110°C and react at 110°C for 15 hours. Then the reaction mixture was cooled to 20°C-30°C, filtered, and the filter cake was rinsed with 20mL of n-butanol, and the obtained solid was vacuum-dried to dryness at 60°C to obtain 10.21g of solid, which was confirmed by mass spectrometry and nuclear magnetic spectrum. -(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, purity: 99.43%.
质谱MS：304.90；Mass spectrum MS: 304.90;
核磁1H NMR(600MHz,DMSO)δ13.55(s,1H),8.22(s,1H),7.67(d,J＝8.5Hz,2H),7.44(t,J＝7.8Hz,2H),7.16(ddd,J＝21.5,13.8,7.7Hz,5H)。1 H NMR (600MHz, DMSO) δ13.55(s, 1H), 8.22(s, 1H), 7.67(d, J＝8.5Hz, 2H), 7.44(t, J＝7.8Hz, 2H), 7.16 (ddd, J=21.5, 13.8, 7.7Hz, 5H).
实施例2Example 2
反应器中，加入3-氨基-5-(4-苯氧基苯基)-4-氰基-1H-吡唑10.00g，醋酸甲脒6.74g和正丁醇80mL，室温下搅拌均匀。加热升温至100℃-110℃，在100℃-110℃反应16小时。然后将反应混合液降温至10℃-20℃，过滤，滤饼用20mL正丁醇淋洗，所得固体在70℃真空干燥至干，得到固体10.28g，纯度：99.21％，经过质谱确认为3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺。Into the reactor, add 10.00 g of 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, 6.74 g of formamidine acetate and 80 mL of n-butanol, and stir evenly at room temperature. Heat up to 100°C-110°C, and react at 100°C-110°C for 16 hours. Then the reaction mixture was cooled to 10°C-20°C, filtered, and the filter cake was rinsed with 20mL of n-butanol, and the obtained solid was vacuum-dried to dryness at 70°C to obtain 10.28g of solid, purity: 99.21%, confirmed by mass spectrometry as 3 -(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
实施例3Example 3
反应器中，加入3-氨基-5-(4-苯氧基苯基)-4-氰基-1H-吡唑10.00g，醋酸甲脒8.70g和正丁醇120mL，室温下搅拌均匀。加热升温至120℃，在120℃反应13小时。然后将反应混合液降温至25℃-35℃，过滤，滤饼用正丁醇20mL淋洗，所得固体在60℃真空干燥至干，得到固体10.24g，纯度：99.65％，经过质谱确认为3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺。Into the reactor, add 10.00 g of 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, 8.70 g of formamidine acetate and 120 mL of n-butanol, and stir evenly at room temperature. Heat up to 120°C and react at 120°C for 13 hours. Then the reaction mixture was cooled to 25°C-35°C, filtered, and the filter cake was rinsed with 20 mL of n-butanol, and the obtained solid was vacuum-dried to dryness at 60°C to obtain 10.24 g of solid, purity: 99.65%, confirmed by mass spectrometry as 3 -(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
实施例4Example 4
反应器中，加入3-氨基-5-(4-苯氧基苯基)-4-氰基-1H-吡唑10.00g，醋酸甲脒8.70g和正丁醇130mL，室温下搅拌均匀。加热升温至120℃，在110℃-120℃反应14小时。然后将反应混合液降温至0℃-5℃，过滤，滤饼用正丁醇20mL淋洗，所得固体在60℃真空干燥至干，得到固体10.24g，纯度：99.65％，经过质谱确认为3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺。Into the reactor, add 10.00 g of 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, 8.70 g of formamidine acetate and 130 mL of n-butanol, and stir evenly at room temperature. Heat up to 120°C, and react at 110°C-120°C for 14 hours. Then the reaction mixture was cooled to 0°C-5°C, filtered, and the filter cake was rinsed with 20 mL of n-butanol, and the obtained solid was vacuum-dried to dryness at 60°C to obtain 10.24 g of solid, purity: 99.65%, confirmed by mass spectrometry as 3 -(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
实施例5Example 5
反应器中，加入3-氨基-5-(4-苯氧基苯基)-4-氰基-1H-吡唑10.00g，醋酸甲脒8.70g和乙二醇单甲醚130mL，室温下搅拌均匀。加热升温至130℃，在120℃-130℃反应14小时。然后将反应混合液降温至10℃-20℃，过滤，滤饼用乙二醇单甲醚20mL淋洗，所得固体在70℃真空干燥至干，得到固体10.30g，纯度：99.69％，经过质谱确认为3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺。In the reactor, add 10.00 g of 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, 8.70 g of formamidine acetate and 130 mL of ethylene glycol monomethyl ether, and stir at room temperature uniform. Heat up to 130°C and react at 120°C-130°C for 14 hours. Then the reaction mixture was cooled to 10°C-20°C, filtered, and the filter cake was rinsed with 20mL of ethylene glycol monomethyl ether, and the obtained solid was vacuum-dried to dryness at 70°C to obtain 10.30g of solid, purity: 99.69%, after mass spectrometry Confirmed as 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
实施例6Example 6
反应器中，加入3-氨基-5-(4-苯氧基苯基)-4-氰基-1H-吡唑10.00g，醋酸甲脒10.10g和乙二醇单乙醚130mL，室温下搅拌均匀。加热升温至130℃，在120℃-130℃反应14小时。然后将反应混合液降温至10℃-20℃，过滤，滤饼用乙二醇单乙醚30mL淋洗，所得固体在75℃真空干燥至干，得到固体10.27g，纯度：99.63％，经过质谱确认为3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺。In the reactor, add 10.00 g of 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, 10.10 g of formamidine acetate and 130 mL of ethylene glycol monoethyl ether, and stir evenly at room temperature . Heat up to 130°C and react at 120°C-130°C for 14 hours. Then the reaction mixture was cooled to 10°C-20°C, filtered, and the filter cake was rinsed with 30 mL of ethylene glycol monoethyl ether, and the obtained solid was vacuum-dried to dryness at 75°C to obtain 10.27 g of solid, purity: 99.63%, confirmed by mass spectrometry For 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。The method of the present invention has been described through preferred embodiments, and relevant persons can obviously make changes or appropriate changes and combinations to the methods and applications described herein within the content, spirit and scope of the present invention to realize and apply the technology of the present invention . Those skilled in the art can refer to the content of this article to appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.
| Application Number | Priority Date | Filing Date | Title |
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| CN201410714363.1ACN104447761A (en) | 2014-11-27 | 2014-11-27 | A kind of preparation method of pyrazole derivative |
| Application Number | Priority Date | Filing Date | Title |
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| CN201410714363.1ACN104447761A (en) | 2014-11-27 | 2014-11-27 | A kind of preparation method of pyrazole derivative |
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| CN104447761Atrue CN104447761A (en) | 2015-03-25 |
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| CN201410714363.1APendingCN104447761A (en) | 2014-11-27 | 2014-11-27 | A kind of preparation method of pyrazole derivative |
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| CN101610676A (en)* | 2006-09-22 | 2009-12-23 | 药品循环公司 | Inhibitors of Bruton's tyrosine kinase |
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| CN101610676A (en)* | 2006-09-22 | 2009-12-23 | 药品循环公司 | Inhibitors of Bruton's tyrosine kinase |
| WO2008054827A2 (en)* | 2006-11-03 | 2008-05-08 | Pharmacyclics, Inc. | Bruton's tyrosine kinase activity probe and method of using |
| CN103319488A (en)* | 2007-03-28 | 2013-09-25 | 环状药物公司 | Inhibitors of bruton's tyrosine kinase |
| WO2014139970A1 (en)* | 2013-03-15 | 2014-09-18 | Janssen Pharmaceutica Nv | Processes and intermediates for preparing a medicament |
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| WO2017029586A1 (en)* | 2015-08-19 | 2017-02-23 | Sun Pharmaceutical Industries Limited | Crystalline forms of ibrutinib |
| US11001585B2 (en) | 2015-08-19 | 2021-05-11 | Sun Pharmaceutical Industries Limited | Crystalline forms of ibrutinib |
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