WO2021223398A1 - Crystal form for treating liver disease and use thereof - Google Patents

Crystal form for treating liver disease and use thereof Download PDF

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WO2021223398A1
WO2021223398A1 PCT/CN2020/130060 CN2020130060W WO2021223398A1 WO 2021223398 A1 WO2021223398 A1 WO 2021223398A1 CN 2020130060 W CN2020130060 W CN 2020130060W WO 2021223398 A1 WO2021223398 A1 WO 2021223398A1
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crystal
crystal form
crystals
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ray powder
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高中强
郭维博
何凯敏
田丹
张登科
金伟丽
张海峰
孙江凯
张艳侠
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西安新通药物研究股份有限公司
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Priority claimed from CN202010376833.3A external-priority patent/CN112010905B/en
Priority claimed from CN202010376938.9A external-priority patent/CN112028940B/en
Priority claimed from CN202010391424.0A external-priority patent/CN112047990B/en
Application filed by 西安新通药物研究股份有限公司 filed Critical 西安新通药物研究股份有限公司
Publication of WO2021223398A1 publication Critical patent/WO2021223398A1/en
Priority to AU2022100062A priority Critical patent/AU2022100062A4/en
Priority to ZA2022/06666A priority patent/ZA202206666B/en

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Abstract

Provided in the present invention is a crystal form for treating a liver disease of tenofovir phosphate(9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinane-2-methoxy]propyl]adenine fumarate), paladovir mesylate((+)-cis-9-{2-[4-[(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinane-2-methylene]-1-ethyl}adenine mesylate), cytarabine prodrug(4-amino-1-[5-O-(2R,4S)-2-oxy-4-(4-pyridine)-1,3,2-dioxaphosphorinane-2]-β-D-arabinofuranosyl-2(1H)-pyrimidinone; MB07133), etc. Further provided in the present invention are a pharmaceutical composition comprising the crystal form and a use thereof in the preparation of medicines.

Description

治疗肝病的晶型及其应用Crystal Forms for Treatment of Liver Diseases and Their Applications
在先申请First application
本申请要求中国专利申请202010376833.3(申请日：2020年5月7日)、202010376938.9(申请日：2020年5月7日)及202010391424.0(申请日：2020年5月11日)的优先权。This application claims the priority of Chinese patent applications 202010376833.3 (application date: May 7, 2020), 202010376938.9 (application date: May 7, 2020) and 202010391424.0 (application date: May 11, 2020).
技术领域Technical field
本发明属于药物化学领域，具体而言，本发明涉及替诺福韦磷酸酯(9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐)、甲磺酸帕拉德福韦((+)-顺-9-{2-[4-[(S)-(3-氯苯基)-2-氧-1,3,2–二氧磷杂六环-2-亚甲基]-1-乙基}腺嘌呤甲磺酸盐)和阿糖胞苷前药(4-氨基-1-[5-O-(2R,4S)-2-氧基-4-(4-吡啶)-1,3,2-二氧磷杂环己烷-2]-β-D-阿拉伯呋喃糖基-2(1H)-嘧啶酮)等治疗肝病的化合物晶型及其应用等。The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to tenofovir phosphate (9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo -1,3,2-Dioxaphosphine-2-methoxy]propyl)adenine fumarate), paradefovir mesylate ((+)-cis-9-{2 -[4-[(S)-(3-Chlorophenyl)-2-oxo-1,3,2-dioxaphosphate-2-methylene]-1-ethyl}adenine methanesulfonate Acid salt) and cytarabine prodrug (4-amino-1-[5-O-(2R,4S)-2-oxy-4-(4-pyridine)-1,3,2-dioxan Heterocyclohexane-2]-β-D-arabinofuranosyl-2(1H)-pyrimidinone) and other compound crystal forms and applications for the treatment of liver diseases.
背景技术Background technique
9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐(本发明中也称为替诺福韦磷酸酯)的结构如式(I)所示：9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-methoxy]propane The structure of adenine fumarate (also called tenofovir phosphate in the present invention) is shown in formula (I):
Figure PCTCN2020130060-appb-000001
Figure PCTCN2020130060-appb-000001
该化合物是中国专利第200580018611.8号公开的前药化合物中的替诺福韦的前药化合物(HTS)，可以用于治疗或预防肝脏疾病或代谢性疾病，包括乙型肝炎等。中国专利第201310283713.9号公开了替诺福韦前药(HTS)的一种晶体，具体描述了一种替诺福韦前药的琥珀酸盐(9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤琥珀酸盐)的晶体-I型 晶体的制备方法。The compound is a prodrug compound (HTS) of tenofovir among the prodrug compounds disclosed in Chinese Patent No. 200580018611.8, which can be used to treat or prevent liver diseases or metabolic diseases, including hepatitis B and the like. Chinese Patent No. 201310283713.9 discloses a crystal of tenofovir prodrug (HTS), specifically describing a succinate (9-[(2R)-2-[(2R, 4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphinothane-2-methoxy)propyl)adenine succinate) crystal type I Crystal preparation method.
甲磺酸帕拉德福韦(Pradefovir Mesylate)的化学名称为(+)-顺-9-{2-[4-[(S)-(3-氯苯基)-2-氧-1,3,2–二氧磷杂六环-2-亚甲基]-1-乙基}腺嘌呤甲磺酸盐，其结构如式(I)所示：The chemical name of Pradefovir Mesylate is (+)-cis-9-{2-[4-[(S)-(3-chlorophenyl)-2-oxo-1,3 ,2-Dioxaphosphacyclo-2-methylene]-1-ethyl}adenine methanesulfonate, its structure is shown in formula (I):
Figure PCTCN2020130060-appb-000002
Figure PCTCN2020130060-appb-000002
该化合物是中国专利CN1964967A号公开的PMEA肝靶向前药，在肝脏CYP3A4酶的催化下转化为有药物活性的PMEA，适用于治疗乙型肝炎病毒活动复制，并伴有血清氨基酸转移酶持续升高或肝组织学活动性病变的肝功能代偿的成年慢性乙型肝炎患者。可以显著抑制乙型肝炎病毒的复制，疗效显著。对拉米夫定耐药的变异株也有明显的抑制作用，解决了抗乙肝病毒药物的耐药性问题；与阿德福韦酯相比，其肝靶向性避免了药物代谢造成的肾毒性。中国专利CN102827206A报道了两种晶型，晶型Ⅰ和晶型Ⅱ；晶型Ⅰ是在含水的乙腈中结晶所得；晶型Ⅱ是在含水的甲醇中所得。此后没有新的甲磺酸帕拉德福韦晶型被报道。This compound is a liver-targeted prodrug of PMEA disclosed in Chinese Patent No. CN1964967A. It is converted into PMEA with pharmacological activity under the catalysis of liver CYP3A4 enzyme. Adult chronic hepatitis B patients with compensated liver function with high or active liver histological lesions. It can significantly inhibit the replication of hepatitis B virus, and the effect is remarkable. Variant strains resistant to lamivudine also have a significant inhibitory effect, solving the problem of drug resistance against hepatitis B virus; compared with adefovir dipivoxil, its liver targeting avoids nephrotoxicity caused by drug metabolism . Chinese patent CN102827206A reported two crystal forms, crystal form I and crystal form II; crystal form I was obtained by crystallization in water-containing acetonitrile; crystal form II was obtained in water-containing methanol. No new crystal form of paradefovir mesylate has been reported since then.
MB07133，即4-氨基-1-[5-O-(2R,4S)-2-氧基-4-(4-吡啶)-1,3,2-二氧磷杂环己烷-2]-β-D-阿拉伯呋喃糖基-2(1H)-嘧啶酮，又称阿糖胞苷前药，其结构如式(I)所示：MB07133, namely 4-amino-1-[5-O-(2R,4S)-2-oxy-4-(4-pyridine)-1,3,2-dioxaphosphorane-2]- β-D-arabinofuranosyl-2(1H)-pyrimidinone, also known as cytarabine prodrug, its structure is shown in formula (I):
Figure PCTCN2020130060-appb-000003
Figure PCTCN2020130060-appb-000003
该化合物是中国专利CN1711278A公开的前药化合物中的阿糖胞苷hepdirect前药的化合物，可以用于治疗或预防肝脏疾病或代谢性疾病，特别是用于治疗晚期肝癌。然而，该专利没有公开或启示要对该化合物的晶体学进行研究。The compound is a compound of the cytarabine hepdirect prodrug in the prodrug compound disclosed in Chinese Patent CN1711278A, and can be used to treat or prevent liver diseases or metabolic diseases, especially for the treatment of advanced liver cancer. However, the patent does not disclose or suggest that the crystallography of the compound should be studied.
本发明人高效地制备出了9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐，在替诺福韦前药的富马酸盐是否能形成新的(单)晶型尚无法预期的情况下，同样，在甲磺酸帕拉德福韦是否进一步存在新的(单)晶型尚无法预期的情况下，在MB07133是否存在新的(单)晶型也无法预期的情况下，可用于结晶的现有溶剂及混合溶剂更是天文数字般多，然而，本发明人没有畏缩，进行了长期艰苦的研究，发现对9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐、甲磺酸帕拉德福韦和MB07133分别进行结晶，晶体分布复杂，常结晶出多晶，不容易获得单晶，但是本发明人最终令人预料不到地有效结晶获得了一系列晶体，并从中分别优选出5种、5种和6种不同的单晶。这些晶体在稳定性方面带来了优势，从而便于生产、储运和/或提高肝靶向治疗的安全性。The present inventors efficiently prepared 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine -2-Methoxy]propyl]adenine fumarate, in the case that whether the fumarate of tenofovir prodrug can form a new (single) crystal form is still unpredictable, in the same way, Whether there is a new (single) crystal form of paradefovir sulfonate is still unpredictable, and whether there is a new (single) crystal form of MB07133 is also unpredictable, the existing solvents that can be used for crystallization and There are astronomical number of mixed solvents. However, the inventor did not flinch and conducted long-term and arduous research and found that 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl )-2-oxo-1,3,2-phosphorane-2-methoxy]propyl]adenine fumarate, paradefovir mesylate and MB07133 were crystallized separately. The distribution is complicated, and polycrystals are often crystallized, and it is not easy to obtain single crystals. However, the inventors finally obtained a series of crystals by crystallization, unexpectedly and effectively, and selected 5, 5 and 6 different single crystals respectively. crystal. These crystals bring advantages in terms of stability, thereby facilitating production, storage and transportation, and/or improving the safety of liver targeted therapy.
发明内容Summary of the invention
本发明要解决的技术问题在于提供治疗肝病的化合物的新晶型，包括9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐、甲磺酸帕拉德福韦或MB07133的新晶型。另外，本发明还提供了该晶型的制备方法、包含该晶型的药物以及治疗方面的应用和检测方法等。The technical problem to be solved by the present invention is to provide new crystal forms of compounds for treating liver disease, including 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1 ,3,2-Dioxaphosphine-2-methoxy]propyl]adenine fumarate, paradefovir mesylate or a new crystal form of MB07133. In addition, the present invention also provides a preparation method of the crystal form, a medicine containing the crystal form, and therapeutic applications and detection methods.
具体而言，在第一方面，本发明提供了治疗肝病的化合物的晶体，其为9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐的晶体、甲磺酸帕拉德福韦的晶体、或MB07133晶体。Specifically, in the first aspect, the present invention provides a crystal of a compound for treating liver disease, which is 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2- Oxy-1,3,2-dioxaphosphine-2-methoxy]propyl]adenine fumarate crystals, paradefovir mesylate, or MB07133 crystals.
在本发明第一方面的晶体中，9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐的晶体选自a晶型、b晶型、c晶型、d晶型和e晶型之一：In the crystal of the first aspect of the present invention, 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxphosphine The crystal of hexacyclic-2-methoxy]propyl]adenine fumarate is selected from one of crystal form a, crystal form b, crystal form c, crystal form d and crystal form e:
a晶型具有基本上如图1-1所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，a晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：5.9°，12.1°，24.8°，31.2°处有衍射峰；另外，a型晶体的差热分析曲线在151.7℃有一尖吸热峰；The crystal form a has an X-ray powder diffraction pattern as shown in Fig. 1-1. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form a has diffraction peaks at 2θ (°, ±0.2): 5.9°, 12.1°, 24.8°, and 31.2°; in addition, the crystal form a has diffraction peaks The differential thermal analysis curve has a sharp endothermic peak at 151.7℃;
b晶型具有基本上如图1-2所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，b晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：：9.8°，10.4°，11.6°，12.5°，13.3°，15.2°，15.5°，16.9°，17.3°，19.5°，22.1°，23.3°，24.9°， 31.2°有衍射峰；另外，b型晶体的差热分析曲线在152.3℃有一尖吸热峰；The crystal form b has an X-ray powder diffraction pattern as shown in Figure 1-2. In a specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form b is at 2θ(°, ±0.2): 9.8°, 10.4°, 11.6°, 12.5°, 13.3°, 15.2°, 15.5°, 16.9°, 17.3°, 19.5°, 22.1°, 23.3°, 24.9°, 31.2° have diffraction peaks; in addition, the differential thermal analysis curve of type b crystal has a sharp endothermic peak at 152.3°C;
c晶型具有基本上如图1-3所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，c晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：9.7°，10.4°，11.6°，12.5°，13.3°，15.2°，16.8°，17.2°，19.5°，21.5°，22.1°，23.2°，24.8°，26.0°，31.1°有衍射峰；另外，c型晶体的差热分析曲线在152.6℃有一尖吸热峰；The crystal form c has an X-ray powder diffraction pattern substantially as shown in Figs. 1-3. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form c is at 2θ (°, ±0.2): 9.7°, 10.4°, 11.6°, 12.5°, 13.3°, 15.2°, 16.8°, 17.2 °, 19.5°, 21.5°, 22.1°, 23.2°, 24.8°, 26.0°, 31.1° have diffraction peaks; in addition, the differential thermal analysis curve of type c crystal has a sharp endothermic peak at 152.6°C;
d晶型具有基本上如图1-4所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，d晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：9.9°，10.4°，12.6°，13.4°，13.8°，17.2°，18.3°，19.5°，20.2°，20.9°，22.0°，23.3°，25.1°有衍射峰；另外，d型晶体的差热分析曲线在149.2℃有一尖吸热峰；The crystal form d has an X-ray powder diffraction pattern as shown in Figs. 1-4. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form d is at 2θ (°, ±0.2): 9.9°, 10.4°, 12.6°, 13.4°, 13.8°, 17.2°, 18.3°, 19.5 °, 20.2°, 20.9°, 22.0°, 23.3°, 25.1° have diffraction peaks; in addition, the differential thermal analysis curve of d-type crystal has a sharp endothermic peak at 149.2°C;
e晶型具有基本上如图1-5所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，e晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：9.8°，10.5°，11.6°，12.6°，13.4°，13.9°，15.3°，17.4°，19.6°，21.0°，22.1°，23.4°，25.0°，26.2°有衍射峰；另外，e型晶体的差热分析曲线在151.4℃有一尖吸热峰。The crystal form e has an X-ray powder diffraction pattern basically as shown in Figs. 1-5. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form e is at 2θ (°, ±0.2): 9.8°, 10.5°, 11.6°, 12.6°, 13.4°, 13.9°, 15.3°, 17.4 °, 19.6°, 21.0°, 22.1°, 23.4°, 25.0°, 26.2° have diffraction peaks; in addition, the differential thermal analysis curve of the e-type crystal has a sharp endothermic peak at 151.4°C.
在本发明第一方面的晶体中，甲磺酸帕拉德福韦的晶体选自A晶型、B晶型、C晶型、D晶型和E晶型之一：In the crystal of the first aspect of the present invention, the crystal of paradefovir mesylate is selected from one of crystal form A, crystal form B, crystal form C, crystal form D, and crystal form E:
A型晶体具有基本上如图2-1所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，A晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：11.0°，12.0°，13.0°，16.5°，17.6°，19.7°，20.5°，22.0°，24.2°，26.4°，27.5°，27.9°，28.4°，33.6°，41.5°，45.6°处有衍射峰；另外，A型晶体的差热分析曲线在196.9℃有一尖吸热峰；The type A crystal has an X-ray powder diffraction pattern basically as shown in Fig. 2-1. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A is at 2θ (°, ±0.2): 11.0°, 12.0°, 13.0°, 16.5°, 17.6°, 19.7°, 20.5°, 22.0 °, 24.2°, 26.4°, 27.5°, 27.9°, 28.4°, 33.6°, 41.5°, 45.6°, there are diffraction peaks; in addition, the differential thermal analysis curve of type A crystal has a sharp endothermic peak at 196.9°C;
B型晶体具有基本上如图2-3所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，B晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：11.8°，12.8°，16.3°，17.4°，19.7°，20.2°，21.9°，24.0°，25.3°，26.1°，26.9°，27.2°，27.7°，28.1°处有衍射峰；另外，B型晶体的差热分析曲线在191.8℃有一尖吸热峰；Type B crystals have an X-ray powder diffraction pattern basically as shown in Figs. 2-3. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form B is at 2θ (°, ±0.2): 11.8°, 12.8°, 16.3°, 17.4°, 19.7°, 20.2°, 21.9°, 24.0 °, 25.3°, 26.1°, 26.9°, 27.2°, 27.7°, 28.1°, there are diffraction peaks; in addition, the differential thermal analysis curve of type B crystal has a sharp endothermic peak at 191.8°C;
C型晶体具有基本上如图2-5所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，C晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：13.0°，16.6°，17.6°，19.7°，22.2°，24.2°，26.4°，28.3°处有衍射峰；另外，C型晶体的差热分析曲线在193.4℃有一尖吸热峰；Type C crystals have an X-ray powder diffraction pattern as shown in Fig. 2-5. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form C is at 2θ (°, ±0.2): 13.0°, 16.6°, 17.6°, 19.7°, 22.2°, 24.2°, 26.4°, 28.3 ° There is a diffraction peak; in addition, the differential thermal analysis curve of the C-type crystal has a sharp endothermic peak at 193.4°C;
D型晶体具有基本上如图2-7所示的X-射线粉末衍射图谱。在本发明的具体 实施方式中，D晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：15.5°，17.2°，17.6°，21.9°，26.1°处有衍射峰；另外，D型晶体的差热分析曲线在192.6℃有一尖吸热峰；The D-type crystal has an X-ray powder diffraction pattern basically as shown in Figs. 2-7. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form D has diffraction peaks at 2θ(°, ±0.2): 15.5°, 17.2°, 17.6°, 21.9°, 26.1°; in addition, D The differential thermal analysis curve of the type crystal has a sharp endothermic peak at 192.6℃;
E型晶体具有基本上如图2-9所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，D晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：12.9°，16.4°，17.4°，19.5°，22.0°，26.2°，28.2°处有衍射峰；另外，D型晶体的差热分析曲线在193.2℃有一尖吸热峰。The E-type crystal has an X-ray powder diffraction pattern substantially as shown in Figs. 2-9. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form D has 2θ(°,±0.2): 12.9°, 16.4°, 17.4°, 19.5°, 22.0°, 26.2°, 28.2° Diffraction peak; In addition, the differential thermal analysis curve of type D crystal has a sharp endothermic peak at 193.2°C.
在本发明第一方面的晶体中，MB07133的晶体选自晶型A、晶型B、晶型C、晶型D、晶型E或晶型F之一：In the crystal of the first aspect of the present invention, the crystal of MB07133 is selected from one of crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, or crystal form F:
晶型A晶体具有基本上如图3-1所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，A晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：10.6°、12.5°、13.7°、16.0、16.3°、17.2°、17.4°、18.6°、20.3°、21.8°、22.2°、23.1°、23.4°、24.9°、25.6°、26.0°、28.7°、29.4°、30.1°、31.0°、32.9°、37.8°处有衍射峰；另外，A型晶体的差热分析曲线在239.81℃有一尖吸热峰；The crystal form A has an X-ray powder diffraction pattern basically as shown in Fig. 3-1. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A is at 2θ (°, ±0.2): 10.6°, 12.5°, 13.7°, 16.0, 16.3°, 17.2°, 17.4°, 18.6° There are diffraction peaks at, 20.3°, 21.8°, 22.2°, 23.1°, 23.4°, 24.9°, 25.6°, 26.0°, 28.7°, 29.4°, 30.1°, 31.0°, 32.9°, 37.8°; in addition, A The differential thermal analysis curve of the type crystal has a sharp endothermic peak at 239.81℃;
晶型B晶体具有基本上如图3-2所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，B晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：10.4°、12.1°、15.8°、16.1°、17.3°、18.6°、20.2°、21.6°、22.1°、22.9°、23.2°、24.8°、25.4°、25.8°、30.8°处有衍射峰；另外，B型晶体的差热分析曲线在253.21℃有一尖吸热峰；The crystal form B has an X-ray powder diffraction pattern substantially as shown in Fig. 3-2. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form B is at 2θ (°, ±0.2): 10.4°, 12.1°, 15.8°, 16.1°, 17.3°, 18.6°, 20.2°, 21.6 °, 22.1°, 22.9°, 23.2°, 24.8°, 25.4°, 25.8°, 30.8°, there are diffraction peaks; in addition, the differential thermal analysis curve of type B crystal has a sharp endothermic peak at 253.21°C;
晶型C晶体具有基本上如图3-3所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，C晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：10.5°、12.4°、13.5°、15.8°、16.3°、17.4°、18.6°、20.2°、21.6°、22.1°、23.0°、23.3°、24.8°、25.5°、28.6°、29.3°、31.0°处有衍射峰；另外，C型晶体的差热分析曲线在247.95℃有一尖吸热峰；The crystal form C has an X-ray powder diffraction pattern substantially as shown in Fig. 3-3. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form C is at 2θ (°, ±0.2): 10.5°, 12.4°, 13.5°, 15.8°, 16.3°, 17.4°, 18.6°, 20.2 °, 21.6°, 22.1°, 23.0°, 23.3°, 24.8°, 25.5°, 28.6°, 29.3°, 31.0°, there are diffraction peaks; in addition, the differential thermal analysis curve of type C crystal has a sharp endotherm at 247.95°C peak;
晶型D晶体具有基本上如图3-4所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，D晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：12.5°、15.5°、15.9°、16.3°、18.2°、18.6°、19.6°、20.3°、21.2°、23.1°、23.4°、24.2°、24.4°、24.8°、27.4°处有衍射峰；另外，D型晶体的差热分析曲线在251.10℃有一尖吸热峰；The crystal form D has an X-ray powder diffraction pattern substantially as shown in Figs. 3-4. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form D is at 2θ (°, ±0.2): 12.5°, 15.5°, 15.9°, 16.3°, 18.2°, 18.6°, 19.6°, 20.3 °, 21.2°, 23.1°, 23.4°, 24.2°, 24.4°, 24.8°, 27.4°, there are diffraction peaks; in addition, the differential thermal analysis curve of type D crystal has a sharp endothermic peak at 251.10°C;
晶型E晶体具有基本上如图3-5所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，E晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：10.6°、12.5°、13.7°、15.5°、16.0°、16.5°、17.2°、17.5°、18.2°、18.7°、20.4°、21.7°、22.2°、23.1°、23.4°、24.3°、24.9°、25.6°、26.0°、27.2°、29.4°、31.0°、41.5°处有衍射峰；另外，E型晶体的差热分析曲线在246.59℃有一尖吸热峰；The crystal form E has an X-ray powder diffraction pattern substantially as shown in Figs. 3-5. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form E is at 2θ (°, ±0.2): 10.6°, 12.5°, 13.7°, 15.5°, 16.0°, 16.5°, 17.2°, 17.5 °、18.2°、18.7°、20.4°、21.7°、22.2°、23.1°、23.4°、24.3°、24.9°、25.6°、26.0°、27.2°、29.4°、31.0°、41.5°There are diffraction peaks at ; In addition, the differential thermal analysis curve of the E-type crystal has a sharp endothermic peak at 246.59℃;
晶型F晶体具有基本上如图3-6所示的X-射线粉末衍射图谱。在本发明的具体实施方式中，F晶型的X-射线粉末衍射图谱在2θ(°,±0.2)：10.6°、12.3°、12.5°、13.7°、16.0°、16.5°、17.2°、17.5°、17.7°、18.7°、20.4°、21.8°、22.2°、23.1°、23.4°、24.9°、25.6°、28.7°、29.4°、30.1°、31.0°处有衍射峰；另外，E型晶体的差热分析曲线在249.26℃有一尖吸热峰。The crystal form F has an X-ray powder diffraction pattern as shown in Figs. 3-6. In the specific embodiment of the present invention, the X-ray powder diffraction pattern of crystal form F is at 2θ (°, ±0.2): 10.6°, 12.3°, 12.5°, 13.7°, 16.0°, 16.5°, 17.2°, 17.5 °, 17.7°, 18.7°, 20.4°, 21.8°, 22.2°, 23.1°, 23.4°, 24.9°, 25.6°, 28.7°, 29.4°, 30.1°, 31.0°, there are diffraction peaks; in addition, E-type crystal The differential thermal analysis curve has a sharp endothermic peak at 249.26℃.
在本文中，如无相反的指示，术语“晶体”和“晶型”可以互换使用，指的是内部质点在三维空间呈周期性重复排列的固体；术语(某化合物的)“(某)晶型”、“晶型(某)”、“晶型(某)晶体”和“(某)型晶体”可以互换使用，指的是(该化合物的)具体所指代的(某)一种晶体。优选本发明第一方面的晶体是单晶。In this article, if there is no indication to the contrary, the terms "crystal" and "crystal form" can be used interchangeably, referring to a solid whose internal particles are periodically and repeatedly arranged in a three-dimensional space; the term (of a compound) "(some) "Crystal form", "crystal form (certain)", "crystal form (certain) crystal" and "(certain) crystal" can be used interchangeably, referring to the (certain) one (of the compound) specifically referred to Kind of crystals. Preferably, the crystal of the first aspect of the present invention is a single crystal.
现有技术中能用于结晶的溶剂种类繁多，而不同种类和比例的溶剂组成的混合溶剂更是无法计数，而结晶实践基本上还留于经验，一般无法根据结晶条件预测出结晶出的晶型。而本发明人通过对9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐、甲磺酸帕拉德福韦和MB07133长期而艰苦的研究，并且凭借了一些运气，终于发现了能用于结晶9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐、甲磺酸帕拉德福韦和MB07133的溶剂及其制备方法。因此在第二方面，本发明提供了本发明第一方面的晶体的制备方法。In the prior art, there are many kinds of solvents that can be used for crystallization, and mixed solvents composed of solvents of different types and proportions cannot be counted. The crystallization practice is basically left to experience, and it is generally impossible to predict the crystals that will be crystallized based on the crystallization conditions. type. And the present inventors passed the analysis of 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2 -Methoxy]propyl]adenine fumarate, paradefovir mesylate and MB07133 have been studied for a long time and arduously, and with some luck, finally found that it can be used for crystallization 9-[(2R) -2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxphosphahexacyclo-2-methoxy]propyl]adenine fumar Solvents of salt, paradefovir mesylate and MB07133 and preparation methods thereof. Therefore, in the second aspect, the present invention provides a method for preparing the crystal of the first aspect of the present invention.
对于替诺福韦磷酸酯a晶型，其制备方法包括：将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐与甲醇混合加热至60-70℃，溶解后冷却至20～25℃，收集晶体并干燥。其中，9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐可以是无定型的，也可以是b晶型、c晶型、d晶型或e晶型。For tenofovir phosphate a crystal form, the preparation method includes: 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3 ,2-Dioxophosphinothane-2-methoxy]propyl]adenine fumarate is mixed with methanol and heated to 60-70°C, dissolved and cooled to 20-25°C, the crystals are collected and dried. Among them, 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy ] Propyl] adenine fumarate can be amorphous, or it can be crystal form b, crystal form c, crystal form d or crystal form e.
对于替诺福韦磷酸酯b晶型，其制备方法包括：将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐同水与乙 腈混合加热至65℃，溶解后冷却至20～25℃，收集晶体并干燥。其中，9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐可以是无定型的，也可以是a晶型或c晶型。For tenofovir phosphate b crystal form, the preparation method includes: 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3 ,2-Dioxaphosphinothane-2-methoxy]propyl]adenine fumarate is mixed with water and acetonitrile and heated to 65°C, dissolved and cooled to 20-25°C, the crystals are collected and dried. Among them, 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy ] Propyl] adenine fumarate can be amorphous, or it can be a crystal form or c crystal form.
对于替诺福韦磷酸酯c晶型，其制备方法包括：将(9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐与四氢呋喃混合加热至65℃，溶解后冷却至20～25℃，收集晶体并干燥。其中，9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐可以是无定型的，也可以是a晶型或e晶型。For tenofovir phosphate c crystal form, the preparation method includes: (9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1, 3,2-Dioxaphosphine-2-methoxy]propyl]adenine fumarate is mixed with tetrahydrofuran and heated to 65°C, dissolved and cooled to 20-25°C, the crystals are collected and dried. 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-methoxy]propane The base] adenine fumarate can be amorphous, or it can be a crystal form or e crystal form.
对于替诺福韦磷酸酯d晶型，其制备方法包括：将(9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐与水混合加热至80℃，溶解后冷却至20～25℃，收集晶体并干燥。其中，9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐可以是无定型的，也可以是a晶型。For tenofovir phosphate d crystal form, the preparation method includes: (9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1, 3,2-Dioxphosphinothane-2-methoxy]propyl]adenine fumarate is mixed with water and heated to 80°C, dissolved and cooled to 20-25°C, the crystals are collected and dried. 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-methoxy]propane The base] adenine fumarate can be amorphous or a crystal form.
对于替诺福韦磷酸酯e晶型，其制备方法包括：将(9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐与异丙醇混合加热至70℃，收集晶体并干燥。其中，9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐可以是无定型的，也可以是a晶型或c晶型。For tenofovir phosphate e crystal form, the preparation method includes: (9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1, 3,2-Dioxaphosphine-2-methoxy]propyl]adenine fumarate was mixed with isopropanol and heated to 70°C, the crystals were collected and dried. Among them, 9-[(2R)- 2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorane-2-methoxy]propyl]adenine fumaric acid The salt can be amorphous, or crystal a or crystal c.
对于甲磺酸帕拉德福韦A晶型，其制备方法包括：将甲磺酸帕拉德福韦溶解于水或甲醇，搅拌下滴加丙酮、甲基叔丁基醚或乙酸乙酯，然后于10～30℃搅拌，再降温至0～10℃搅拌，收集晶体并干燥。其中，甲磺酸帕拉德福韦可以是无定型的，也可以是CN102827206A报道的晶型I或晶型II，还可以是B晶型、C晶型、D晶型或E晶型。For paradefovir mesylate A crystal form, the preparation method includes: dissolving paradefovir mesylate in water or methanol, adding acetone, methyl tert-butyl ether or ethyl acetate dropwise under stirring, Then stir at 10-30°C, then lower the temperature to 0-10°C and stir, collect the crystals and dry. Among them, paradefovir mesylate can be amorphous, it can also be crystal form I or crystal form II reported in CN102827206A, and it can also be crystal form B, crystal form C, crystal form D or crystal form E.
对于甲磺酸帕拉德福韦B晶型，其制备方法包括：将甲磺酸帕拉德福韦溶解于1,4-二氧六环，于10～30℃搅拌，收集晶体并干燥。其中，甲磺酸帕拉德福韦可以是无定型的，也可以是CN102827206A报道的晶型I或晶型II，还可以是A晶型、C晶型、D晶型或E晶型。For paradefovir mesylate B crystal form, the preparation method includes: dissolving paradefovir mesylate in 1,4-dioxane, stirring at 10-30°C, collecting crystals and drying. Among them, paradefovir mesylate can be amorphous, it can also be crystal form I or crystal form II reported in CN102827206A, and it can also be crystal form A, crystal form C, crystal form D or crystal form E.
对于甲磺酸帕拉德福韦C晶型，其制备方法包括：将甲磺酸帕拉德福韦溶解于DMF，搅拌下滴加MTBE，然后于10～30℃搅拌，收集晶体并干燥。其中， 甲磺酸帕拉德福韦可以是无定型的，也可以是CN102827206A报道的晶型I或晶型II，还可以是A晶型、B晶型、D晶型或E晶型。For paradefovir mesylate C crystal form, the preparation method includes: dissolving paradefovir mesylate in DMF, adding MTBE dropwise under stirring, and then stirring at 10-30°C, collecting the crystals and drying. Among them, paradefovir mesylate can be amorphous, it can also be crystal form I or crystal form II reported in CN102827206A, and it can also be crystal form A, crystal form B, crystal form D, or crystal form E.
对于甲磺酸帕拉德福韦D晶型，其制备方法包括：将甲磺酸帕拉德福韦加热溶解于含有水的THF溶液，降温至10～30℃搅拌，收集晶体并干燥。其中，甲磺酸帕拉德福韦可以是无定型的，也可以是CN102827206A报道的晶型I或晶型II，还可以是A晶型、B晶型、D晶型或E晶型。For the paradefovir mesylate crystal form D, the preparation method includes heating and dissolving paradefovir mesylate in a THF solution containing water, cooling to 10-30° C. and stirring, collecting the crystals and drying. Among them, paradefovir mesylate can be amorphous, it can also be crystal form I or crystal form II reported in CN102827206A, and it can also be crystal form A, crystal form B, crystal form D, or crystal form E.
对于甲磺酸帕拉德福韦E晶型，其制备方法包括：将甲磺酸帕拉德福韦与乙腈混合，加热回流溶解，降温至10～30℃搅拌，收集晶体并干燥。其中，甲磺酸帕拉德福韦可以是无定型的，也可以是CN102827206A报道的晶型I或晶型II，还可以是A晶型、B晶型、D晶型或E晶型。For the paradefovir mesylate E crystal form, the preparation method includes: mixing paradefovir mesylate and acetonitrile, heating and refluxing to dissolve, cooling to 10-30°C and stirring, collecting the crystals and drying. Among them, paradefovir mesylate can be amorphous, it can also be crystal form I or crystal form II reported in CN102827206A, and it can also be crystal form A, crystal form B, crystal form D, or crystal form E.
对于MB07133晶型A晶体，其制备方法包括：将MB07133溶解于硫酸溶液中，于15～25℃搅拌后，加入磷酸二氢钠，再缓慢加入氢氧化钠溶液，调节pH值至5.0-8.0，于10～20℃搅拌，收集晶体并干燥。其中，MB07133可以是无定型的，也可以是晶型B、晶型C、晶型D、晶型E或晶型F。For MB07133 crystalline form A crystals, the preparation method includes: dissolving MB07133 in sulfuric acid solution, stirring at 15-25°C, adding sodium dihydrogen phosphate, and then slowly adding sodium hydroxide solution to adjust the pH to 5.0-8.0, Stir at 10-20°C, collect crystals and dry. Among them, MB07133 can be amorphous, or crystal form B, crystal form C, crystal form D, crystal form E, or crystal form F.
对于MB07133晶型B晶体，其制备方法包括：MB07133在二甲基亚砜中加热搅拌至溶解，滴加甲苯后冷却至0～10℃，搅拌，收集晶体并干燥。其中，MB07133可以是无定型的，也可以是晶型A、晶型C、晶型D、晶型E或晶型F。For MB07133 crystal form B crystals, the preparation method includes: heating and stirring MB07133 in dimethyl sulfoxide to dissolve, adding toluene dropwise and cooling to 0-10°C, stirring, collecting the crystals and drying. Among them, MB07133 can be amorphous, or crystal form A, crystal form C, crystal form D, crystal form E, or crystal form F.
对于MB07133晶型C晶体，其制备方法包括：MB07133在二甲基亚砜中加热搅拌至溶解，滴加丙酮后冷却至0～10℃，搅拌，收集晶体并干燥。其中，MB07133可以是无定型的，也可以是晶型A、晶型B、晶型D、晶型E或晶型F。For MB07133 crystal form C, the preparation method includes: heating and stirring MB07133 in dimethyl sulfoxide to dissolve, adding acetone dropwise and cooling to 0-10°C, stirring, collecting the crystals and drying. Among them, MB07133 can be amorphous, or crystal form A, crystal form B, crystal form D, crystal form E, or crystal form F.
对于MB07133晶型D晶体，其制备方法包括：MB07133在N，N-二甲基甲酰胺中加热搅拌至溶解，滴加乙酸乙酯后冷却至0～10℃，搅拌，收集晶体并干燥。其中，MB07133可以是无定型的，也可以是晶型A、晶型B、晶型C、晶型E或晶型F。For MB07133 crystal form D, the preparation method includes: heating and stirring MB07133 in N,N-dimethylformamide to dissolve, adding ethyl acetate dropwise and cooling to 0-10°C, stirring, collecting the crystals and drying. Among them, MB07133 can be amorphous, or crystal form A, crystal form B, crystal form C, crystal form E, or crystal form F.
对于MB07133晶型E晶体，其制备方法包括：MB07133在N-甲基吡咯烷酮和水中加热搅拌至溶解，滴加丙酮后冷却至0～10℃，搅拌，收集晶体并干燥。其中，MB07133可以是无定型的，也可以是晶型A、晶型B、晶型C、晶型D 或晶型F。For the MB07133 crystal form E, the preparation method includes: heating and stirring MB07133 in N-methylpyrrolidone and water to dissolve, adding acetone dropwise and cooling to 0-10°C, stirring, collecting the crystals and drying. Among them, MB07133 can be amorphous, or crystal form A, crystal form B, crystal form C, crystal form D, or crystal form F.
对于MB07133晶型F晶体，其制备方法包括：MB07133在二甲基亚砜和水中加热搅拌至溶解，滴加异丙醇后冷却至0～10℃，搅拌，收集晶体并干燥。其中，MB07133可以是无定型的，也可以是晶型A、晶型B、晶型C、晶型D或晶型E。For MB07133 crystal form F, the preparation method includes: heating and stirring MB07133 in dimethyl sulfoxide and water to dissolve, adding isopropanol dropwise and cooling to 0-10°C, stirring, collecting the crystals and drying. Among them, MB07133 can be amorphous, or crystal form A, crystal form B, crystal form C, crystal form D, or crystal form E.
在第三方面，本发明提供了用于治疗或预防肝脏疾病或代谢性疾病的药物组合物，其包括本发明第一方面的晶体和药学上可接受的辅料，优选其由本发明第一方面的晶体和药学上可接受的辅料组成。在本文中，药学上可接受的辅料指无毒的填充剂、稳定剂、稀释剂、佐剂或其他制剂辅料。例如，稀释剂、赋形剂，如水、生理盐水、微晶纤维素等；填充剂，如淀粉、蔗糖等；粘合剂，如淀粉、纤维素衍生物、藻酸盐、明胶和/或聚乙烯吡咯烷酮；湿润剂，如甘油；崩解剂，如琼脂、碳酸钙和/或碳酸氢钠；吸收促进剂，如季铵化合物；表面活性剂，如十六烷醇；吸附载体，如高岭土和/或皂粘土；润滑剂，如滑石粉、硬脂酸钙/镁、聚乙二醇等。另外，本发明的药物组合物还可以进一步含有其它辅料，如香味剂、甜味剂等。本发明第三方面的药物组合物还可以进一步包括其他用于治疗或预防肝脏疾病或代谢性疾病的活性成分。In the third aspect, the present invention provides a pharmaceutical composition for the treatment or prevention of liver disease or metabolic disease, which comprises the crystal of the first aspect of the present invention and pharmaceutically acceptable excipients, preferably composed of the first aspect of the present invention It consists of crystals and pharmaceutically acceptable excipients. In this article, pharmaceutically acceptable excipients refer to non-toxic fillers, stabilizers, diluents, adjuvants or other preparation excipients. For example, diluents, excipients, such as water, physiological saline, microcrystalline cellulose, etc.; fillers, such as starch, sucrose, etc.; binders, such as starch, cellulose derivatives, alginate, gelatin and/or poly Vinylpyrrolidone; wetting agents such as glycerin; disintegrating agents such as agar, calcium carbonate and/or sodium bicarbonate; absorption promoters such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and / Or soap clay; lubricants, such as talc, calcium/magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition of the present invention may further contain other auxiliary materials, such as flavors, sweeteners, and the like. The pharmaceutical composition of the third aspect of the present invention may further include other active ingredients for treating or preventing liver diseases or metabolic diseases.
优选在本发明第三方面的药物组合物中，药学上可接受的辅料包括甘露醇、预胶化淀粉、硬脂酸镁和/或二氧化硅。Preferably, in the pharmaceutical composition of the third aspect of the present invention, the pharmaceutically acceptable excipients include mannitol, pregelatinized starch, magnesium stearate and/or silicon dioxide.
本发明第三方面的药物组合物优选用于治疗或预防乙型肝炎，也优选用于降低患者中乙型肝炎病毒水平。当本发明第三方面的药物组合物包括MB07133晶体时，它优选用于治疗晚期肝癌，更优选用于靶向治疗晚期肝癌。The pharmaceutical composition of the third aspect of the present invention is preferably used to treat or prevent hepatitis B, and is also preferably used to reduce the level of hepatitis B virus in patients. When the pharmaceutical composition of the third aspect of the present invention includes MB07133 crystals, it is preferably used for the treatment of advanced liver cancer, and more preferably for the targeted treatment of advanced liver cancer.
根据本领域的公知技术，可以根据治疗目的、给药途径的需要将药物组合物制成各种剂型，优选该组合物为单位给药剂量形式，如冻干剂、片剂、胶囊、粉剂、乳液剂、水针剂或喷雾剂，更优选该药物组合物为注射剂型(如，冻干粉针剂)或口服剂型，更优选是口服剂型(如，片剂或胶囊)。药物可以通过常规途径施用，特别是肠内，例如口服，例如以片剂或胶囊剂形式，进行施用；或非肠道施用，例如以可注射溶液剂或混悬剂形式，进行施用；或鼻部使用。在本发明的具体实施方式中，示例性的包括替诺福韦磷酸酯的晶体的药物组合物是口服剂型，如片剂；示例性的包括替诺福韦磷酸酯的晶体的药物组合物是注射剂，如冻 干粉针剂。According to the well-known technology in the art, the pharmaceutical composition can be made into various dosage forms according to the needs of the treatment purpose and the route of administration. Emulsion, water injection or spray, more preferably, the pharmaceutical composition is in the form of injection (e.g., freeze-dried powder injection) or oral dosage form, and more preferably in the form of oral dosage (e.g., tablet or capsule). The drug can be administered by conventional routes, especially enteral, for example, oral administration, for example, in the form of tablets or capsules; or parenteral administration, for example, in the form of injectable solutions or suspensions; or nasal Department use. In a specific embodiment of the present invention, an exemplary pharmaceutical composition including crystals of tenofovir phosphate is an oral dosage form, such as a tablet; an exemplary pharmaceutical composition including crystals of tenofovir phosphate is Injections, such as freeze-dried powder injections.
在第四方面，本发明提供了本发明第一方面的晶体在制备用于治疗或预防肝脏疾病或代谢性疾病的药物中的应用。相应地，在第五方面，本发明提供了治疗或预防肝脏疾病或代谢性疾病的方法，其包括向有需要的患者给药有效剂量的本发明第一方面的晶体。In the fourth aspect, the present invention provides the use of the crystal of the first aspect of the present invention in the preparation of a medicament for the treatment or prevention of liver diseases or metabolic diseases. Accordingly, in the fifth aspect, the present invention provides a method for treating or preventing liver disease or metabolic disease, which comprises administering an effective dose of the crystal of the first aspect of the present invention to a patient in need.
本发明的药物以有效剂量施用，其中有效剂量通常是以本发明第一方面的晶体的量计的。有效剂量可以是单位给药剂量形式(如，一片、一针、一丸或一剂)的药物中的含量，也可以是所需治疗/预防的患者的单位剂量(如，单位体重剂量)。药物制造商能够很容易地通过所需治疗/预防的患者群体的平均体重将所需治疗/预防的患者的单位体重剂量换算成单位给药剂量形式的药物中的含量，例如，成人患者的平均体重可以是60kg，因此通过平均体重乘以成人的单位体重剂量，即可得到用于成人的单位给药剂量形式的药物中的含量。在本文中，患者可以是哺乳动物，如人、兔、狗或鼠，优选是人。根据本领域普通技术人员所公知的实验动物与人的等效剂量换算关系(通常可参见FDA、SFDA等药品管理机构的指导意见，也可参见“黄继汉等.药理试验中动物间和动物与人体间的等效剂量换算.中国临床药理学与治疗学,2004，9(9):1069-1072”)可从实验动物的剂量推导出人的单位体重剂量。例如，对于常用的实验动物小鼠而言，根据上述文献，其与成人的换算关系约为12：1；对于常用的实验动物大鼠而言，根据上述文献，其与成人的换算关系约为6：1。例如，MB07133晶体的给药量为300～1200mg/m 2/d，连续7天静脉滴注，停用三周后重复给药。通过计算，患者平均每日给药量约为500～2000mg。剂量递增按以下的剂量水平进行：300、600、1200、1800、2400和3000mg/m 2/d，直到出现明确的剂量限制性毒性(DLT)并确定最大耐受剂量(MTD)。 The medicament of the present invention is administered in an effective dose, wherein the effective dose is usually based on the amount of the crystal of the first aspect of the present invention. The effective dose can be the content of the drug in a unit dosage form (e.g., a tablet, an injection, a pill, or a dose), or it can be a unit dose (e.g., a unit weight dose) of the patient to be treated/prevented. The drug manufacturer can easily convert the unit weight dose of the patient to be treated/prevented into the content of the drug in the unit dose form by the average weight of the patient population to be treated/prevented, for example, the average of adult patients The body weight can be 60 kg, so by multiplying the average body weight by the adult's unit weight dose, the content of the drug in the unit dosage form for adult can be obtained. In this context, the patient may be a mammal, such as a human, rabbit, dog or mouse, preferably a human. According to the equivalent dose conversion relationship between experimental animals and humans known to those of ordinary skill in the art (usually refer to the guidance of the FDA, SFDA and other drug regulatory agencies, and also refer to "Huang Jihan et al. Animals and Animals and Humans in Pharmacological Tests" The equivalent dose conversion between the two. Chinese Clinical Pharmacology and Therapeutics, 2004, 9(9): 1069-1072”) can deduce the human dose per unit body weight from the dose of experimental animals. For example, for commonly used experimental animal mice, according to the above-mentioned literature, its conversion relationship with adults is about 12:1; for commonly used laboratory animal rats, according to the above-mentioned literature, its conversion relationship with adults is about 6:1. For example, the dosage of MB07133 crystals is 300-1200 mg/m 2 /d, intravenous infusion for 7 consecutive days, and repeated administration after three weeks of discontinuation. By calculation, the average daily dose of patients is about 500-2000mg. The dose escalation is carried out at the following dose levels: 300, 600, 1200, 1800, 2400, and 3000 mg/m 2 /d until a clear dose-limiting toxicity (DLT) appears and the maximum tolerated dose (MTD) is determined.
优选本发明第四方面的应用是在制备用于治疗或预防乙型肝炎的药物中的应用，相应地，本发明第五方面的方法优选是治疗或预防乙型肝炎的方法。也优选本发明第四方面的应用是在制备用于降低患者中乙型肝炎病毒水平的药物中的应用，相应地，本发明第五方面的方法优选是降低患者中乙型肝炎病毒水平的方法。另外，对于MB07133晶体，也优选本发明第四方面的应用是在制备用于治疗晚期肝癌的药物中的应用，相应地，本发明第五方面的方法也优选是治疗晚 期肝癌的方法。Preferably, the application of the fourth aspect of the present invention is an application in the preparation of a medicine for treating or preventing hepatitis B. Accordingly, the method of the fifth aspect of the present invention is preferably a method for treating or preventing hepatitis B. It is also preferred that the application of the fourth aspect of the present invention is an application in the preparation of a medicine for reducing the level of hepatitis B virus in a patient. Accordingly, the method of the fifth aspect of the present invention is preferably a method of reducing the level of hepatitis B virus in a patient. . In addition, for MB07133 crystals, it is also preferable that the application of the fourth aspect of the present invention is an application in the preparation of drugs for treating advanced liver cancer. Accordingly, the method of the fifth aspect of the present invention is also preferably a method of treating advanced liver cancer.
在第六方面，本发明提供了检测本发明第一方面的晶体的方法，其特征在于，对疑似晶体进行X-射线粉末衍射检测，将所得到的X-射线粉末衍射图谱与如图图1-1或1-2或1-3或1-4或1-5或2-1或2-3或2-5或2-7或2-9或3-1或3-2或3-3或3-4或3-5或3-6所示的X-射线粉末衍射图谱进行比对。根据图谱的谱线位置(通常以Bragg’s 2θ角的度数表示)、谱线高度、相对丰度和/或晶面间距离d(通常以
Figure PCTCN2020130060-appb-000004
表示)等参数，本领域技术人员能够比对出疑似晶体是否就是本发明第一方面的晶体。 In the sixth aspect, the present invention provides a method for detecting the crystal of the first aspect of the present invention, characterized in that the suspected crystal is subjected to X-ray powder diffraction detection, and the obtained X-ray powder diffraction pattern is compared with that shown in Figure 1. -1 or 1-2 or 1-3 or 1-4 or 1-5 or 2-1 or 2-3 or 2-5 or 2-7 or 2-9 or 3-1 or 3-2 or 3-3 Or compare the X-ray powder diffraction patterns shown in 3-4 or 3-5 or 3-6. According to the spectral line position of the spectrum (usually expressed in degrees of Bragg's 2θ angle), spectral line height, relative abundance and/or distance between crystal planes d (usually expressed in degrees of Bragg's 2θ angle),
Figure PCTCN2020130060-appb-000004
Representation) and other parameters, those skilled in the art can compare whether the suspected crystal is the crystal of the first aspect of the present invention.
本发明的有益效果在于，获得了9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐的性质优异的晶体，其具有良好的温度和湿度稳定性，且纯度高，不含溶剂和水分，更加方便了制剂工艺过程的适应性，也便于长期储存；获得了甲磺酸帕拉德福韦的性质优异的晶体，其具有良好的温度和湿度稳定性，且纯度高，更加方便了制剂工艺过程的适应性，也便于长期储存；获得了MB07133性质优异的晶体，其具有良好稳定性，且纯度高，不含溶剂和水分，更加方便了制剂工艺过程的适应性，也便于储存。The beneficial effect of the present invention is to obtain 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine Cyclo-2-methoxy]propyl]adenine fumarate is a crystal with excellent properties. It has good temperature and humidity stability, high purity, and does not contain solvents and moisture, which is more convenient for the preparation process Adaptability and easy long-term storage; crystals with excellent properties of paradefovir mesylate are obtained, which have good temperature and humidity stability, and are high in purity, which facilitates the adaptability of the preparation process and is also convenient Long-term storage; MB07133 crystals with excellent properties are obtained, which has good stability, high purity, and does not contain solvents and moisture, which facilitates the adaptability of the preparation process and is also convenient for storage.
为了便于理解，本发明引用了公开文献，这些文献是为了更清楚地描述本发明，其全文内容均纳入本文进行参考，就好像它们全文在本文中完整记载过一遍了。In order to facilitate understanding, the present invention quotes published documents, which are used to describe the present invention more clearly, and their full content is incorporated herein by reference, as if they were fully described in this article.
以下将通过具体的实施例和附图对本发明进行详细地描述。需要特别指出的是，这些描述仅仅是示例性的描述，并不构成对本发明范围的限制。依据本说明书的论述，本发明的许多变化、改变对所属领域技术人员来说都是显而易见了。Hereinafter, the present invention will be described in detail through specific embodiments and drawings. It should be particularly pointed out that these descriptions are merely exemplary descriptions and do not constitute a limitation on the scope of the present invention. Based on the description of this specification, many changes and modifications of the present invention are obvious to those skilled in the art.
附图说明Description of the drawings
图1-1：替诺福韦磷酸酯a晶型的X-射线粉末衍射图谱。Figure 1-1: X-ray powder diffraction pattern of tenofovir phosphate a crystal form.
图1-2：替诺福韦磷酸酯b晶型的X-射线粉末衍射图谱。Figure 1-2: X-ray powder diffraction pattern of tenofovir phosphate b crystal form.
图1-3：替诺福韦磷酸酯c晶型的X-射线粉末衍射图谱。Figure 1-3: X-ray powder diffraction pattern of Tenofovir Phosphate Form c.
图1-4：替诺福韦磷酸酯d晶型的X-射线粉末衍射图谱。Figure 1-4: X-ray powder diffraction pattern of tenofovir phosphate d crystal form.
图1-5：替诺福韦磷酸酯e晶型的X-射线粉末衍射图谱。Figure 1-5: X-ray powder diffraction pattern of Tenofovir Phosphate E crystal form.
图1-6：替诺福韦磷酸酯a晶型的DSC图谱。Figure 1-6: DSC spectrum of tenofovir phosphate a crystal form.
图1-7：替诺福韦磷酸酯b晶型的DSC图谱。Figure 1-7: DSC spectrum of Tenofovir Phosphate b crystalline form.
图1-8：替诺福韦磷酸酯c晶型的DSC图谱。Figure 1-8: DSC spectrum of Tenofovir Phosphate Form c.
图1-9：替诺福韦磷酸酯d晶型的DSC图谱。Figure 1-9: DSC spectrum of tenofovir phosphate d crystal form.
图1-10：替诺福韦磷酸酯e晶型的DSC图谱。Figure 1-10: DSC spectrum of Tenofovir Phosphate E crystal form.
图2-1：A晶型甲磺酸帕拉德福韦的X-射线粉末衍射图谱。Figure 2-1: X-ray powder diffraction pattern of crystal form A paradefovir mesylate.
图2-2：A晶型甲磺酸帕拉德福韦的DSC图谱。Figure 2-2: DSC spectrum of paradefovir mesylate of crystal form A.
图2-3：B晶型甲磺酸帕拉德福韦的X-射线粉末衍射图谱。Figure 2-3: X-ray powder diffraction pattern of paradefovir mesylate of crystal form B.
图2-4：B晶型甲磺酸帕拉德福韦的DSC图谱。Figure 2-4: DSC spectrum of paradefovir mesylate of crystal form B.
图2-5：C晶型甲磺酸帕拉德福韦的X-射线粉末衍射图谱。Figure 2-5: X-ray powder diffraction pattern of crystal form C paradefovir mesylate.
图2-6：C晶型甲磺酸帕拉德福韦的DSC图谱。Figure 2-6: DSC spectrum of paradefovir mesylate of crystal form C.
图2-7：D晶型甲磺酸帕拉德福韦的X-射线粉末衍射图谱。Figure 2-7: X-ray powder diffraction pattern of crystal form D paradefovir mesylate.
图2-8：D晶型甲磺酸帕拉德福韦的DSC图谱。Figure 2-8: DSC spectrum of paradefovir mesylate of crystal form D.
图2-9：E晶型甲磺酸帕拉德福韦的X-射线粉末衍射图谱。Figure 2-9: X-ray powder diffraction pattern of crystal form E paradefovir mesylate.
图2-10：E晶型甲磺酸帕拉德福韦的DSC图谱。Figure 2-10: DSC spectrum of paradefovir mesylate of crystal form E.
图3-1：MB07133晶型A的X-射线粉末衍射图谱。Figure 3-1: X-ray powder diffraction pattern of MB07133 crystal form A.
图3-2：MB07133晶型B的X-射线粉末衍射图谱。Figure 3-2: X-ray powder diffraction pattern of MB07133 crystal form B.
图3-3：MB07133晶型C的X-射线粉末衍射图谱。Figure 3-3: X-ray powder diffraction pattern of MB07133 crystal form C.
图3-4：MB07133晶型D的X-射线粉末衍射图谱。Figure 3-4: X-ray powder diffraction pattern of MB07133 crystal form D.
图3-5：MB07133晶型E的X-射线粉末衍射图谱。Figure 3-5: X-ray powder diffraction pattern of MB07133 crystal form E.
图3-6：MB07133晶型F的X-射线粉末衍射图谱。Figure 3-6: X-ray powder diffraction pattern of MB07133 crystal form F.
图3-7：MB07133晶型A的差热分析曲线图谱。Figure 3-7: Differential thermal analysis curve chart of MB07133 crystal form A.
图3-8：MB07133晶型B的差热分析曲线图谱。Figure 3-8: Differential thermal analysis curve chart of MB07133 crystal form B.
图3-9：MB07133晶型C的差热分析曲线图谱。Figure 3-9: Differential thermal analysis curve chart of MB07133 crystal form C.
图3-10：MB07133晶型D的差热分析曲线图谱。Figure 3-10: Differential thermal analysis curve chart of MB07133 crystal form D.
图3-11：MB07133晶型E的差热分析曲线图谱。Figure 3-11: Differential thermal analysis curve chart of MB07133 crystal form E.
图3-12：MB07133晶型F的差热分析曲线图谱。Figure 3-12: Differential thermal analysis curve chart of MB07133 crystal form F.
具体实施方式Detailed ways
以下将结合实例详细的解释本发明，本发明的实施例仅用于说明本发明技术 方案，但是本发明的保护范围并非限定于此。The present invention will be explained in detail below in conjunction with examples. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, but the protection scope of the present invention is not limited thereto.
实施例1 替诺福韦磷酸酯的晶体Example 1 Crystals of Tenofovir Phosphate
实验所用的测试仪器Test equipment used in the experiment
1、X-射线粉末衍射图谱1. X-ray powder diffraction pattern
仪器：PHI-5400型X-射线光电子分析仪(可购自美国PE公司)Instrument: PHI-5400 X-ray photoelectron analyzer (available from PE company in the United States)
测试参数为：电压：46kv，电流：40mA，铜kα辐射，λ：
Figure PCTCN2020130060-appb-000005
The test parameters are: voltage: 46kv, current: 40mA, copper kα radiation, λ:
Figure PCTCN2020130060-appb-000005
2、热差分析图谱(DSC)2. Thermal Differential Analysis Chart (DSC)
仪器：SII Nano，EXSTAR，DSC6220Instruments: SII Nano, EXSTAR, DSC6220
升温速度：10℃/minHeating rate: 10℃/min
温度范围：50～250℃Temperature range: 50～250℃
载气：高纯氮气Carrier gas: high purity nitrogen
实施例1-1Example 1-1
9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐的制备9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-methoxy]propane Preparation of Adenine Fumarate
具体步骤如下：Specific steps are as follows:
Figure PCTCN2020130060-appb-000006
Figure PCTCN2020130060-appb-000006
RegentRegent MW.MW. 投料量Feeding amount molmol 摩尔比The molar ratio of 备注Remark
替诺福韦Tenofovir 287287 28.7g28.7g 0.10.1 11  To
二醇Glycol 186186 18.6g18.6g 0.10.1 11  To
草酰氯Oxalyl Chloride 127127 50.8g50.8g 0.40.4 44  To
DEFDEF 101101 10.9g10.9g 0.110.11 1.081.08  To
四氯化钛Titanium tetrachloride 189.7189.7 19.0g19.0g 0.10.1 11  To
三乙胺 Triethylamine 100100 42.0g42.0g 0.420.42 4.24.2  To
二氯甲烷1 Dichloromethane 1 // 900mL900mL // //  To
甲醇Methanol // 1000mL1000mL // //  To
水water // 370mL370mL // //  To
丙酮acetone // 200mL200mL // //  To
甲基叔丁基醚Methyl tert-butyl ether // 510mL510mL // //  To
琥珀酸Succinic acid 118.1118.1 11.8g11.8g 0.10.1 11  To
富马酸Fumaric acid 116.1116.1 11.6g11.6g 0.10.1 11  To
向干燥洁净的250mL反应瓶中加入二醇18.6g、二氯甲烷90mL，搅拌降温至0～5℃开始向反应体系中滴加四氯化钛19.0g，再向反应液中滴加三乙胺42.0g滴加完毕，记作反应液A。Add 18.6g of diol and 90mL of dichloromethane to a dry and clean 250mL reaction flask, stir and cool to 0～5℃, start adding 19.0g of titanium tetrachloride to the reaction system, and then add triethylamine to the reaction solution. After 42.0 g was added dropwise, it was recorded as reaction solution A.
常温下向1.0L反应瓶中加入二氯甲烷370mL，开启搅拌并加入替诺福韦28.7g、DEF 50.8g，10～25℃滴加草酰氯10.9g，滴加完毕，开启加热至回流；回流反应2～3h，停止加热，降温至10℃以下滴加反应液A至1.0L反应体系；滴加完毕，搅拌反应1h。Add 370mL of dichloromethane to the 1.0L reaction flask at room temperature, start stirring and add 28.7g of Tenofovir, 50.8g of DEF, and 10.9g of oxalyl chloride at 10～25℃. After the addition is complete, turn on and heat to reflux; After reacting for 2 to 3 hours, stop heating, and drop the reaction solution A to 1.0L reaction system when the temperature is lowered to 10°C; after the addition is completed, the reaction is stirred for 1 hour.
向反应体系加入甲醇和水，搅拌5min，分液，水相用二氯甲烷萃取4次，合并有机相，用饱和食盐水洗涤，分液，有机相用无水硫酸镁干燥；过滤，滤饼用二氯甲烷洗涤，滤液减压浓缩至无馏分；将浓缩液加入乙醇溶解，转移至500mL反应瓶，并加入乙酸32mL加热回流5-6h。60-70℃减压浓缩至基本无馏分，加入甲醇和琥珀酸，搅拌反应1h；搅拌降温析晶，过滤，滤饼55～65℃鼓风烘料5h，得30g琥珀酸盐。Add methanol and water to the reaction system, stir for 5 min, separate the liquids, extract the aqueous phase 4 times with dichloromethane, combine the organic phases, wash with saturated brine, separate the liquids, dry the organic phase over anhydrous magnesium sulfate; filter, filter cake Wash with dichloromethane, and concentrate the filtrate under reduced pressure to no fraction; add ethanol to dissolve the concentrate, transfer to a 500mL reaction flask, and add 32mL of acetic acid to reflux for 5-6h. Concentrate under reduced pressure at 60-70°C until there is almost no fraction, add methanol and succinic acid, stir and react for 1h; stir to cool down and crystallize, filter, and dry the filter cake at 55-65°C with air blowing for 5h to obtain 30g succinate.
将300L水加入到反应瓶，加入30gHTS琥珀酸盐，丙酮200mL，升温至30～40℃溶解后，用甲基叔丁基醚萃取。弃去有机相，水相用饱和碳酸氢钠溶液调Ph至8～9；水相用二氯甲烷萃取。合并有机相，并用饱和氯化钠洗1次，有机相加入无水硫酸镁干燥，过滤，滤饼用二氯甲烷洗涤。滤液30～40℃减压浓缩至无馏分。得到油状物约18g，加入甲醇溶解后加入反应瓶，搅拌下加入富马酸约11.6g，30℃以下搅拌反应30min。搅拌降温析晶，过滤，滤饼55～65℃鼓风烘料10h以上。得到约15g白色粉末。Add 300L of water to the reaction flask, add 30g of HTS succinate, 200mL of acetone, heat up to 30-40°C to dissolve, and extract with methyl tert-butyl ether. The organic phase was discarded, the aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate solution; the aqueous phase was extracted with dichloromethane. The organic phases were combined and washed with saturated sodium chloride once, the organic phase was added with anhydrous magnesium sulfate and dried, filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure at 30-40°C to no fraction. Approximately 18 g of an oily substance is obtained, which is added to the reaction flask after being dissolved in methanol, and about 11.6 g of fumaric acid is added under stirring, and the reaction is stirred for 30 minutes below 30°C. Stir and cool to crystallize, filter, and bake the filter cake at 55～65℃ with air blowing for more than 10h. Approximately 15 g of white powder was obtained.
该化合物核磁数据如下：The NMR data of the compound are as follows:
1H NMR(600MHz,DMSO):δ13.1～13.2(2H,s)，δ8.145(1H,s),δ8.082(1H,s),7.45(2H,m),7.395-7.403(2H,m),7.259(2H,s)7.216-7.233(1H,m),6.647(2H,s),5.633-5.648(1H,d),4.488-4.513(1H,m),4.29-4.297(1H,m),4.213-4.247(1H,m),4.042-4.062(1H,t),3.942-3.999(2H,m),2.051-2.055(2H,d),1.117-1.127(3H,d)。 1 H NMR (600MHz, DMSO): δ 13.1～13.2 (2H, s), δ 8.145 (1H, s), δ 8.082 (1H, s), 7.45 (2H, m), 7.395-7.403 (2H) ,m),7.259(2H,s)7.216-7.233(1H,m),6.647(2H,s),5.633-5.648(1H,d),4.488-4.513(1H,m),4.29-4.297(1H, m), 4.213-4.247 (1H, m), 4.042-4.062 (1H, t), 3.942-3.999 (2H, m), 2.051-2.055 (2H, d), 1.117-1.127 (3H, d).
实施例1-2 替诺福韦磷酸酯a型晶体的制备和鉴定Example 1-2 Preparation and identification of tenofovir phosphate type a crystals
取实施例1-1所得的白色粉末5g加入25ml甲醇中，加热至60-70℃的同时搅拌，至完全溶解，然后冷却至20～25℃，发现有晶体析出，抽滤，保留晶体， 然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为a型单晶，如图1和6所示。Take 5g of the white powder obtained in Example 1-1 and add it to 25ml of methanol, heat to 60-70°C while stirring until it is completely dissolved, and then cool to 20-25°C. It is found that crystals are precipitated. Filter by suction to retain the crystals. Dry directly in an oven at 55°C. X-ray powder diffraction and DSC detection showed a type a single crystal, as shown in Figures 1 and 6.
实施例1-3 替诺福韦磷酸酯a型晶体的制备和鉴定Example 1-3 Preparation and identification of tenofovir phosphate type a crystals
将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐b型晶体3g加入18ml甲醇中，加热至60-70℃的同时搅拌，至完全溶解，然后冷却至20～25℃，发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为a型单晶。Add 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy] Add 3g of propyl]adenine fumarate type b crystals to 18ml of methanol, heat to 60-70℃ and stir until completely dissolved, then cool to 20～25℃, find crystals precipitated, filter with suction to keep the crystals , And then directly dried in an oven at 55°C. X-ray powder diffraction and DSC inspection showed that it was a-type single crystal.
实施例1-4 替诺福韦磷酸酯a型晶体的制备和鉴定Example 1-4 Preparation and identification of tenofovir phosphate type a crystals
将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐c型晶体2g加入11ml甲醇中，加热至60-70℃的同时搅拌，至完全溶解，然后冷却至20～25℃，发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为a型单晶。Add 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy] Add 2g of propyl]adenine fumarate type c crystals to 11ml of methanol, stir while heating to 60-70°C until completely dissolved, then cool to 20-25°C, find crystals precipitated, filter with suction to keep the crystals , And then directly dried in an oven at 55°C. X-ray powder diffraction and DSC inspection showed that it was a-type single crystal.
实施例1-5 替诺福韦磷酸酯a型晶体的制备和鉴定Example 1-5 Preparation and identification of tenofovir phosphate type a crystals
将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐d型晶体2g加入11ml甲醇中，加热至60-70℃的同时搅拌，至完全溶解，然后冷却至20～25℃，发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为a型单晶。Add 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy] Add 2g of propyl]adenine fumarate type d crystals to 11ml of methanol, heat to 60-70°C while stirring until completely dissolved, then cool to 20-25°C, find crystals precipitated, filter with suction to keep the crystals , And then directly dried in an oven at 55°C. X-ray powder diffraction and DSC inspection showed that it was a-type single crystal.
实施例1-6 替诺福韦磷酸酯a型晶体的制备和鉴定Example 1-6 Preparation and identification of tenofovir phosphate type a crystals
将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐e型晶体2g加入10ml甲醇中，加热至60-70℃的同时搅拌，至完全溶解，然后冷却至20～25℃，发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为a型单晶。Add 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy] Add 2g of propyl]adenine fumarate type e crystals to 10ml of methanol, heat to 60-70℃ while stirring until completely dissolved, then cool to 20～25℃, find crystals precipitated, filter with suction to keep the crystals , And then directly dried in an oven at 55°C. X-ray powder diffraction and DSC inspection showed that it was a-type single crystal.
实施例1-7 替诺福韦磷酸酯b型晶体的制备和鉴定Example 1-7 Preparation and identification of tenofovir phosphate type b crystals
取实施例1-1所得的白色粉末6g加入5ml水，乙腈60ml，加热至65℃溶解，降温至20～25℃发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为b型单晶，如图2和7所示。Take 6g of the white powder obtained in Example 1-1, add 5ml of water, 60ml of acetonitrile, heat to 65°C to dissolve, and cool to 20-25°C to find crystals precipitated, filter with suction to retain the crystals, and then directly dry it in an oven at 55°C. X-ray powder diffraction and DSC inspection showed a type b single crystal, as shown in Figures 2 and 7.
实施例1-8 替诺福韦磷酸酯b型晶体的制备和鉴定Example 1-8 Preparation and identification of tenofovir phosphate type b crystals
将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐a型晶体3g加入2ml水，乙腈30ml，加热至65℃溶解， 降温至20～25℃发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为b型单晶。Add 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy] Add 3g of propyl]adenine fumarate type a crystals to 2ml of water, 30ml of acetonitrile, heat to 65°C to dissolve, cool to 20～25°C to find crystals precipitated, filter with suction to retain the crystals, and then directly oven at 55°C Dry. X-ray powder diffraction and DSC inspection showed a type b single crystal.
实施例1-9 替诺福韦磷酸酯b型晶体的制备和鉴定Example 1-9 Preparation and identification of tenofovir phosphate type b crystals
将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐c型晶体3g加入2ml水，乙腈30ml，加热至65℃溶解，降温至20～25℃发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为b型单晶。Add 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy] Add 3g of propyl]adenine fumarate type c crystals to 2ml of water, 30ml of acetonitrile, heat to 65°C to dissolve, cool to 20～25°C to find crystals precipitated, filter with suction to retain the crystals, and then directly oven at 55°C Dry. X-ray powder diffraction and DSC inspection showed a type b single crystal.
实施例1-10 替诺福韦磷酸酯c型晶体的制备和鉴定Example 1-10 Preparation and identification of tenofovir phosphate type c crystals
取实施例1-1所得的白色粉末3g加入四氢呋喃35ml，加热至65℃溶剂，降温至20～25℃发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为c型单晶，如图3和8所示。Take 3g of the white powder obtained in Example 1-1, add 35ml of tetrahydrofuran, heat to 65°C solvent, cool to 20-25°C and find crystals precipitated, filter with suction to retain the crystals, and then directly oven dry at 55°C. X-ray powder diffraction and DSC inspection showed a type c single crystal, as shown in Figs. 3 and 8.
实施例1-11 替诺福韦磷酸酯c型晶体的制备和鉴定Example 1-11 Preparation and identification of tenofovir phosphate type c crystals
将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐a型晶体3g加入四氢呋喃30ml，加热至65℃溶剂，降温至20～25℃发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为c型单晶。Add 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy] Add 3g of propyl]adenine fumarate type a crystals, add 30ml of tetrahydrofuran, heat to 65°C solvent, cool to 20-25°C and find crystals precipitated, filter with suction to retain the crystals, and then directly dry in 55°C oven. X-ray powder diffraction and DSC inspection showed that it was a c-type single crystal.
实施例1-12 替诺福韦磷酸酯c型晶体的制备和鉴定Example 1-12 Preparation and identification of tenofovir phosphate type c crystals
将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐b型晶体2g加入四氢呋喃22ml，加热至65℃溶剂，降温至20～25℃发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为c型单晶。Add 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy] Add 2g of propyl]adenine fumarate type b crystals, add 22ml of tetrahydrofuran, heat to 65°C solvent, cool down to 20-25°C and find crystals precipitated, filter with suction to retain the crystals, and then directly dry in an oven at 55°C. X-ray powder diffraction and DSC inspection showed that it was a c-type single crystal.
实施例1-13 替诺福韦磷酸酯c型晶体的制备和鉴定Example 1-13 Preparation and identification of tenofovir phosphate type c crystals
将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐d型晶体2g加入四氢呋喃18ml，加热至65℃溶剂，降温至20～25℃发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为c型单晶。Add 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy] Add 2g of propyl]adenine fumarate type d crystals to 18ml of tetrahydrofuran, heat to 65°C solvent, and cool to 20-25°C to find crystals precipitated, filter with suction to retain the crystals, and then directly dry in an oven at 55°C. X-ray powder diffraction and DSC inspection showed that it was a c-type single crystal.
实施例1-14 替诺福韦磷酸酯d型晶体的制备和鉴定Example 1-14 Preparation and identification of tenofovir phosphate d-type crystals
取实施例1-1所得的白色粉末3g加入水30ml，加热至80℃溶解，降温至 20～25℃发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为d型单晶，如图4和9所示。Add 3g of the white powder obtained in Example 1-1 to 30ml of water, heat to 80°C to dissolve, and cool to 20-25°C to find crystals precipitated, filter with suction to retain the crystals, and then directly dry in an oven at 55°C. X-ray powder diffraction and DSC inspection showed a d-type single crystal, as shown in Figures 4 and 9.
实施例1-15 替诺福韦磷酸酯d型晶体的制备和鉴定Example 1-15 Preparation and identification of tenofovir phosphate d-type crystals
将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐a型晶体5g加入水40ml，加热至80℃溶解，降温至20～25℃发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为d型单晶。Add 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy] Add 5g of propyl]adenine fumarate type a crystals to 40ml of water, heat to 80°C to dissolve, and cool to 20-25°C to find crystals precipitated, filter with suction to retain the crystals, and then directly dry in an oven at 55°C. X-ray powder diffraction and DSC inspection showed a d-type single crystal.
实施例1-16 替诺福韦磷酸酯d型晶体的制备和鉴定Example 1-16 Preparation and identification of tenofovir phosphate d-type crystals
将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐b型晶2g加入水22ml，加热至80℃溶解，降温至20～25℃发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为d型单晶。Add 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy] 2g of propyl]adenine fumarate type b crystals were added to 22ml of water, heated to 80°C to dissolve, and cooled to 20-25°C to find crystals precipitated, filtered with suction to retain the crystals, and then directly dried in an oven at 55°C. X-ray powder diffraction and DSC inspection showed a d-type single crystal.
实施例1-17 替诺福韦磷酸酯e型晶体的制备和鉴定Example 1-17 Preparation and Identification of Tenofovir Phosphate E-type Crystal
取实施例1-1所得的白色粉末3g加入异丙醇30ml，加热至70℃溶剂，降温至20～25℃发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为e型单晶，如图5和10所示。Take 3g of the white powder obtained in Example 1-1 and add 30ml of isopropanol, heat to 70°C solvent, and lower the temperature to 20-25°C to find crystals precipitated, filter with suction to retain the crystals, and then directly oven dry at 55°C. X-ray powder diffraction and DSC inspection showed an e-type single crystal, as shown in Figures 5 and 10.
实施例1-18 替诺福韦磷酸酯e型晶体的制备和鉴定Example 1-18 Preparation and Identification of Tenofovir Phosphate E-type Crystal
将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐a型晶5g加入异丙醇45ml，加热至70℃溶剂，降温至20～25℃发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为e型单晶。Add 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy] Add 5g of propyl]adenine fumarate type a crystals to 45ml of isopropanol, heat to 70°C solvent, cool to 20～25°C and find crystals precipitated, filter with suction to retain the crystals, and then directly oven dry at 55°C . X-ray powder diffraction and DSC inspection showed an e-type single crystal.
实施例1-19 替诺福韦磷酸酯e型晶体的制备和鉴定Example 1-19 Preparation and Identification of Tenofovir Phosphate E-type Crystals
将9-[(2R)-2-[(2R,4S)-4-(3-氯苯基)-2-氧-1,3,2-二氧膦杂六环-2-甲氧基]丙基]腺嘌呤富马酸盐c型晶3g加入异丙醇35ml，加热至70℃溶剂，降温至20～25℃发现有晶体析出，抽滤，保留晶体，然后直接于55℃烘箱烘干。X-射线粉末衍射和DSC检测显示为e型单晶。Add 9-[(2R)-2-[(2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphine-2-methoxy] 3g of propyl]adenine fumarate type c crystals were added to 35ml of isopropanol, heated to 70°C solvent, cooled to 20～25°C to find crystals precipitated, filtered with suction to retain the crystals, and then directly dried in an oven at 55°C . X-ray powder diffraction and DSC inspection showed an e-type single crystal.
实施例1-20 替诺福韦磷酸酯a型晶体的稳定性Example 1-20 Stability of Tenofovir Phosphate Type A Crystals
本实施例描述了晶体a型晶体的稳定性实验。This example describes the stability experiment of the crystal a-type crystal.
在高温、高湿、光照三种条件下进行a型晶体的稳定性测试，结果如下表(表 1-1)所示,这表明该晶体在高温、高湿、光照条件下是稳定的。The stability test of a-type crystal was carried out under the three conditions of high temperature, high humidity and light. The results are shown in the following table (Table 1-1), which shows that the crystal is stable under the conditions of high temperature, high humidity and light.
表1-1 a型晶体(高温、高湿、光照)稳定性实验结果Table 1-1 Stability test results of type a crystal (high temperature, high humidity, light)
Figure PCTCN2020130060-appb-000007
Figure PCTCN2020130060-appb-000007
在40℃下进行经6月稳定性测试，结果如下表(表1-2)所示，这表明该晶体稳定性良好，适合长期保存。The stability test was carried out at 40°C for 6 months, and the results are shown in the following table (Table 1-2), which indicates that the crystal has good stability and is suitable for long-term storage.
表1-2 40℃下进行经6月稳定性测试Table 1-2 Stability test for 6 months at 40℃
样品1 Sample 1 总杂质Total impurities 杂质AImpurity A 杂质BImpurity B 杂质CImpurity C 杂质DImpurity D
0月0 month 1.821.82 0.710.71 0.450.45 0.290.29 0.110.11
3月March 1.891.89 0.700.70 0.440.44 0.280.28 0.130.13
6月June 1.981.98 0.740.74 0.420.42 0.270.27 0.100.10
实施例1-21 替诺福韦磷酸酯b型晶体的稳定性Example 1-21 The stability of tenofovir phosphate type b crystals
本实施例描述了晶体b型晶体的稳定性实验。This example describes the stability experiment of the crystal b-type crystal.
在高温、高湿、光照三种条件下进行b型晶体的稳定性测试，结果如下表(表1-3)所示,这表明该晶体在高温、高湿、光照条件下是稳定的。The stability test of the b-type crystal was carried out under the three conditions of high temperature, high humidity and light. The results are shown in the following table (Table 1-3), which shows that the crystal is stable under the conditions of high temperature, high humidity and light.
表1-3 b型晶体(高温、高湿、光照)稳定性实验结果Table 1-3 Stability test results of type b crystal (high temperature, high humidity, light)
Figure PCTCN2020130060-appb-000008
Figure PCTCN2020130060-appb-000008
Figure PCTCN2020130060-appb-000009
Figure PCTCN2020130060-appb-000009
在40℃下进行经6月稳定性测试，结果如下表(表1-4)所示，这表明该晶体稳定性良好，适合长期保存。The stability test was carried out at 40°C for 6 months, and the results are shown in the following table (Table 1-4), which indicates that the crystal has good stability and is suitable for long-term storage.
表1-4 40℃下进行经6月稳定性测试Table 1-4 Stability test for 6 months at 40℃
样品1 Sample 1 总杂质Total impurities 杂质AImpurity A 杂质BImpurity B 杂质CImpurity C 杂质DImpurity D
0月0 month 1.821.82 0.710.71 0.450.45 0.290.29 0.110.11
3月March 1.911.91 0.720.72 0.440.44 0.290.29 0.130.13
6月June 1.991.99 0.740.74 0.430.43 0.270.27 0.110.11
实施例1-22 替诺福韦磷酸酯c型晶体的稳定性Example 1-22 The stability of tenofovir phosphate type c crystals
本实施例描述了晶体c型晶体的稳定性实验。This example describes the stability experiment of the crystal c-type crystal.
在高温、高湿、光照三种条件下进行c型晶体的稳定性测试，结果如下表(表1-5)所示，这表明该晶体在高温、高湿、光照条件下是稳定的。The stability test of the c-type crystal was carried out under the three conditions of high temperature, high humidity and light. The results are shown in the following table (Table 1-5), which shows that the crystal is stable under the conditions of high temperature, high humidity and light.
表1-5 c型晶体(高温、高湿、光照)稳定性实验结果Table 1-5 Stability test results of type c crystal (high temperature, high humidity, light)
Figure PCTCN2020130060-appb-000010
Figure PCTCN2020130060-appb-000010
Figure PCTCN2020130060-appb-000011
Figure PCTCN2020130060-appb-000011
在40℃下进行经6月稳定性测试，结果如下表(表1-6)所示，这表明该晶体稳定性良好，适合长期保存。The stability test was carried out at 40°C for 6 months, and the results are shown in the following table (Table 1-6), which indicates that the crystal has good stability and is suitable for long-term storage.
表1-6 40℃下进行经6月稳定性测试Table 1-6 Stability test for 6 months at 40℃
样品1 Sample 1 总杂质Total impurities 杂质AImpurity A 杂质BImpurity B 杂质CImpurity C 杂质DImpurity D
0月0 month 1.821.82 0.710.71 0.450.45 0.290.29 0.110.11
3月March 1.911.91 0.730.73 0.440.44 0.290.29 0.120.12
6月June 1.991.99 0.740.74 0.450.45 0.300.30 0.110.11
实施例1-23 替诺福韦磷酸酯d型晶体的稳定性Example 1-23 The stability of tenofovir phosphate d-type crystals
本实施例描述了晶体d型晶体的稳定性实验。This example describes the stability experiment of the crystal d-type crystal.
在高温、高湿、光照三种条件下进行d型晶体的稳定性测试，结果如下表(表1-7)所示,这表明该晶体在高温、高湿、光照条件下是稳定的。The stability test of the d-type crystal was carried out under the three conditions of high temperature, high humidity and light. The results are shown in the following table (Table 1-7), which shows that the crystal is stable under the conditions of high temperature, high humidity and light.
表1-7 d型晶体(高温、高湿、光照)稳定性实验结果Table 1-7 Stability test results of type d crystal (high temperature, high humidity, light)
Figure PCTCN2020130060-appb-000012
Figure PCTCN2020130060-appb-000012
在40℃下进行经6月稳定性测试，结果如下表(表1-8)所示，这表明该晶体稳定性良好，适合长期保存。The stability test was conducted at 40°C for 6 months, and the results are shown in the following table (Table 1-8), which indicates that the crystal has good stability and is suitable for long-term storage.
表1-8 40℃下进行经6月稳定性测试Table 1-8 Stability test for 6 months at 40℃
样品1 Sample 1 总杂质Total impurities 杂质AImpurity A 杂质BImpurity B 杂质CImpurity C 杂质DImpurity D
0月0 month 1.821.82 0.710.71 0.450.45 0.290.29 0.110.11
3月March 1.891.89 0.720.72 0.440.44 0.290.29 0.120.12
6月June 1.981.98 0.730.73 0.430.43 0.280.28 0.100.10
实施例1-24 替诺福韦磷酸酯e型晶体的稳定性Example 1-24 Stability of Tenofovir Phosphate E-type Crystal
本实施例描述了晶体e型晶体的稳定性实验。This example describes the stability experiment of the crystal e-type crystal.
在高温、高湿、光照三种条件下进行e型晶体的稳定性测试，结果如下表(表1-9)所示,这表明该晶体在高温、高湿、光照条件下是稳定的。The stability test of the e-type crystal was carried out under the three conditions of high temperature, high humidity and light. The results are shown in the following table (Table 1-9), which shows that the crystal is stable under the conditions of high temperature, high humidity and light.
表1-9 e型晶体(高温、高湿、光照)稳定性实验结果Table 1-9 E-type crystal (high temperature, high humidity, light) stability test results
Figure PCTCN2020130060-appb-000013
Figure PCTCN2020130060-appb-000013
在40℃下进行经6月稳定性测试，结果如下表(表1-10)所示，这表明该晶体稳定性良好，适合长期保存。The stability test was conducted at 40°C for 6 months, and the results are shown in the following table (Table 1-10), which indicates that the crystal has good stability and is suitable for long-term storage.
表1-10 40℃下进行经6月稳定性测试Table 1-10 Stability test for 6 months at 40℃
样品1 Sample 1 总杂质Total impurities 杂质AImpurity A 杂质BImpurity B 杂质CImpurity C 杂质DImpurity D
0月0 month 1.821.82 0.710.71 0.450.45 0.290.29 0.110.11
3月March 1.901.90 0.720.72 0.470.47 0.320.32 0.110.11
6月June 1.991.99 0.720.72 0.460.46 0.340.34 0.100.10
实施例1-25 包含替诺福韦磷酸酯a型晶体的药物组合物Example 1-25 Pharmaceutical composition containing tenofovir phosphate type A crystals
根据表1-11的配方，取替诺福韦磷酸酯a型晶体与二氧化硅混合过筛，然后加入甘露醇和预胶化淀粉混和均匀，然后加入硬脂酸镁，压片、包衣即制得片 剂。According to the formula in Table 1-11, take tenofovir phosphate type a crystals and silicon dioxide, mix and sieve, then add mannitol and pregelatinized starch to mix evenly, then add magnesium stearate, press the tablet, and coat it. Prepare tablets.
表1-11 a型晶体片剂配方Table 1-11 Formulation of type a crystal tablet
Figure PCTCN2020130060-appb-000014
Figure PCTCN2020130060-appb-000014
实施例1-26 包含替诺福韦磷酸酯b型晶体的药物组合物Example 1-26 Pharmaceutical composition containing tenofovir phosphate type b crystals
根据表1-12的配方，取替诺福韦磷酸酯b型晶体与二氧化硅混合过筛，然后加入甘露醇和预胶化淀粉混和均匀，然后加入硬脂酸镁，压片、包衣即制得片剂。According to the formula in Table 1-12, take tenofovir phosphate type b crystals and silicon dioxide, mix and sieve, then add mannitol and pregelatinized starch to mix evenly, then add magnesium stearate, press the tablet, and coat it. Prepare tablets.
表1-12 b型晶体片剂配方Table 1-12 Formulation of type b crystal tablet
Figure PCTCN2020130060-appb-000015
Figure PCTCN2020130060-appb-000015
实施例1-27 包含替诺福韦磷酸酯c型晶体的药物组合物Example 1-27 Pharmaceutical composition containing tenofovir phosphate type c crystals
根据表1-13的配方，取替诺福韦磷酸酯c型晶体与二氧化硅混合过筛，然后加入甘露醇和预胶化淀粉混和均匀，然后加入硬脂酸镁，压片、包衣即制得片剂。According to the formula in Table 1-13, take tenofovir phosphate type c crystals and silicon dioxide, mix and sieve, then add mannitol and pregelatinized starch to mix evenly, then add magnesium stearate, press and coat it. Prepare tablets.
表1-13 c型晶体片剂配方Table 1-13 Formulation of c-type crystal tablet
Figure PCTCN2020130060-appb-000016
Figure PCTCN2020130060-appb-000016
Figure PCTCN2020130060-appb-000017
Figure PCTCN2020130060-appb-000017
实施例1-28 包含替诺福韦磷酸酯d型晶体的药物组合物Example 1-28 Pharmaceutical composition containing tenofovir phosphate d-type crystals
根据表1-14的配方，取替诺福韦磷酸酯d型晶体与二氧化硅混合过筛，然后加入甘露醇和预胶化淀粉混和均匀，然后加入硬脂酸镁，压片、包衣即制得片剂。According to the formula in Table 1-14, take tenofovir phosphate d-type crystals and silicon dioxide, mix and sieve, then add mannitol and pregelatinized starch to mix evenly, then add magnesium stearate, press the tablet, and coat it. Prepare tablets.
表1-14 d型晶体片剂配方Table 1-14 Formulation of type d crystal tablet
Figure PCTCN2020130060-appb-000018
Figure PCTCN2020130060-appb-000018
实施例29 包含替诺福韦磷酸酯e型晶体的药物组合物Example 29 Pharmaceutical composition containing tenofovir phosphate E-type crystals
根据表1-15的配方，取替诺福韦磷酸酯e型晶体与二氧化硅混合过筛，然后加入甘露醇和预胶化淀粉混和均匀，然后加入硬脂酸镁，压片、包衣即制得片剂。According to the formula in Table 1-15, take Tenofovir Phosphate E-type crystals and silicon dioxide, mix and sieve, then add mannitol and pregelatinized starch to mix evenly, then add magnesium stearate, press the tablet, and coat it. Prepare tablets.
表1-15 e型晶体片剂配方Table 1-15 E-type crystal tablet formula
Figure PCTCN2020130060-appb-000019
Figure PCTCN2020130060-appb-000019
实施例2 甲磺酸帕拉德福韦的晶体Example 2 Crystals of paradefovir mesylate
实验所用的测试仪器Test equipment used in the experiment
1、X-射线粉末衍射图谱1. X-ray powder diffraction pattern
仪器：PHI-5400型X-射线光电子分析仪(可购自美国PE公司)Instrument: PHI-5400 X-ray photoelectron analyzer (available from PE company in the United States)
测试参数为：电压：46kv，电流：40mA，铜kα辐射，λ：
Figure PCTCN2020130060-appb-000020
The test parameters are: voltage: 46kv, current: 40mA, copper kα radiation, λ:
Figure PCTCN2020130060-appb-000020
2、热差分析图谱(DSC)2. Thermal Differential Analysis Chart (DSC)
仪器：SII Nano，EXSTAR，DSC6220Instruments: SII Nano, EXSTAR, DSC6220
升温速度：10℃/minHeating rate: 10℃/min
温度范围：50～250℃Temperature range: 50～250℃
载气：高纯氮气Carrier gas: high purity nitrogen
3、物料来源：甲磺酸帕拉德福韦晶型I，其为按照中国专利CN102827206A实施例1制备得到的晶型I。3. Material source: Paradefovir mesylate crystal form I, which is crystal form I prepared according to Example 1 of Chinese patent CN102827206A.
实施例2-1 甲磺酸帕拉德福韦A型晶体Example 2-1 Paradefovir mesylate type A crystals
取甲磺酸帕拉德福韦晶型I 10g加入纯化水8ml，搅拌溶解，搅拌下滴加入丙酮92ml。滴加完毕，10～30℃搅拌2h。降温至0～10℃搅拌2h。过滤，13ml丙酮洗涤滤饼，55～65℃鼓风烘干18h以上，得到7.9g白色固体。经检测属于A晶型(如图1和2所示)。Take 10g of paradefovir mesylate crystal form I and add 8ml of purified water, stir to dissolve, and add 92ml of acetone dropwise under stirring. After the addition is complete, stir at 10-30°C for 2h. Cool to 0～10℃ and stir for 2h. Filter, wash the filter cake with 13ml of acetone, and blast dry at 55-65°C for more than 18 hours to obtain 7.9g of white solid. After testing, it belongs to crystal form A (as shown in Figures 1 and 2).
实施例2-2 甲磺酸帕拉德福韦A型晶体Example 2-2 Paradefovir mesylate type A crystals
取甲磺酸帕拉德福韦B晶型10g加入纯化水20ml，搅拌溶解，搅拌下滴加入丙酮300ml。滴加完毕，10～30℃搅拌2h。降温至0～10℃搅拌2h。过滤，20ml丙酮洗涤滤饼，55～65℃鼓风烘干18h以上，得到7.2g白色固体。经检测属于A晶型。Take 10g of paradefovir mesylate B crystal form and add 20ml of purified water, stir to dissolve, and add 300ml of acetone dropwise under stirring. After the addition is complete, stir at 10-30°C for 2h. Cool to 0～10℃ and stir for 2h. Filter, wash the filter cake with 20ml of acetone, and blast dry at 55-65°C for more than 18 hours to obtain 7.2g of white solid. It belongs to crystal form A after testing.
实施例2-3 甲磺酸帕拉德福韦A型晶体Example 2-3 Paradefovir mesylate type A crystals
取甲磺酸帕拉德福韦C晶型10g加入纯化水30ml，搅拌溶解，搅拌下滴加入丙酮400ml。滴加完毕，10～30℃搅拌2h。降温至0～10℃搅拌2h。过滤，13ml丙酮洗涤滤饼，55～65℃鼓风烘干18h以上，得到7.0g白色固体。经检测属于A晶型。Take 10g of paradefovir mesylate C crystal form and add 30ml of purified water, stir to dissolve, and add 400ml of acetone dropwise under stirring. After the addition is complete, stir at 10-30°C for 2h. Cool to 0～10℃ and stir for 2h. Filter, wash the filter cake with 13ml of acetone, and blast dry at 55-65°C for more than 18 hours to obtain 7.0g of white solid. It belongs to crystal form A after testing.
实施例2-4 甲磺酸帕拉德福韦A型晶体Example 2-4 Paradefovir mesylate type A crystals
取甲磺酸帕拉德福韦D晶型10g加入甲醇170ml，搅拌溶解，搅拌下滴加入甲基叔丁基醚250ml。滴加完毕，10～30℃搅拌2h。降温至0～10℃搅拌2h。过滤，20ml甲基叔丁基醚洗涤滤饼，55～65℃鼓风烘干18h以上，得到6.5g白色固体。经检测属于A晶型。Take 10g of paradefovir mesylate D crystal form and add 170ml of methanol, stir to dissolve, add 250ml of methyl tert-butyl ether dropwise with stirring. After the addition is complete, stir at 10-30°C for 2h. Cool to 0～10℃ and stir for 2h. After filtering, washing the filter cake with 20 ml of methyl tert-butyl ether, drying at 55-65° C. for more than 18 hours by blowing air to obtain 6.5 g of white solid. It belongs to crystal form A after testing.
实施例2-5 甲磺酸帕拉德福韦A型晶体Example 2-5 Paradefovir mesylate type A crystals
取甲磺酸帕拉德福韦E晶型10g加入甲醇200ml，搅拌溶解，搅拌下滴加入乙酸乙酯300ml。滴加完毕，10～30℃搅拌2h。降温至0～10℃搅拌2h。过滤，20ml乙酸乙酯洗涤滤饼，55～65℃鼓风烘干18h以上，得到7.1g白色固体。经检测属于A晶型。Take 10 g of paradefovir mesylate E crystal form and add 200 ml of methanol, stir to dissolve, and add 300 ml of ethyl acetate dropwise with stirring. After the addition is complete, stir at 10-30°C for 2h. Cool to 0～10℃ and stir for 2h. After filtration, the filter cake was washed with 20 ml of ethyl acetate, and dried at 55-65° C. for more than 18 hours to obtain 7.1 g of white solid. It belongs to crystal form A after testing.
实施例2-6 甲磺酸帕拉德福韦B型晶体Example 2-6 Paradefovir mesylate Type B crystals
取甲磺酸帕拉德福韦晶型I 5g加入1.4-二氧六环350ml，搅拌溶解，10～30℃搅拌2h。过滤、洗涤，55～65℃鼓风烘干18h以上，得到2.5g白色固体。经检测属于B晶型(如图3和4所示)。Take 5g of paradefovir mesylate crystal form I, add 350ml of 1.4-dioxane, stir to dissolve, and stir for 2h at 10-30°C. Filter, wash, and blow dry at 55-65°C for more than 18 hours to obtain 2.5 g of white solid. After testing, it belongs to the B crystal form (as shown in Figures 3 and 4).
实施例2-7 甲磺酸帕拉德福韦B型晶体Example 2-7 Paradefovir mesylate Type B crystals
取甲磺酸帕拉德福韦A晶型5g加入1.4-二氧六环500ml，搅拌溶解，10～30℃搅拌2h。过滤、洗涤，55～65℃鼓风烘干18h以上，得到2.3g白色固体。经检测属于B晶型。Take 5g of paradefovir mesylate A crystal form and add 500ml of 1.4-dioxane, stir to dissolve, stir at 10～30℃ for 2h. Filter, wash, and blow dry at 55-65°C for more than 18 hours to obtain 2.3 g of white solid. It belongs to crystal form B after testing.
实施例2-8 甲磺酸帕拉德福韦C型晶体Example 2-8 Paradefovir mesylate Type C crystals
取甲磺酸帕拉德福韦晶型I 10g加入DMF50ml，搅拌溶解，搅拌下滴加入MTBE50ml。滴加完毕，10～30℃搅拌2h。过滤，10mlMTBE洗涤滤饼，55～65℃鼓风烘干18h以上，得到8.4g白色固体。经检测属于C晶型(如图5和6所示)。Take 10g of paradefovir mesylate crystalline form I and add 50ml of DMF, stir to dissolve, and add 50ml of MTBE dropwise with stirring. After the addition is complete, stir at 10-30°C for 2h. Filter, wash the filter cake with 10ml MTBE, and blast dry at 55-65°C for more than 18 hours to obtain 8.4g of white solid. After testing, it belongs to crystal form C (as shown in Figures 5 and 6).
实施例2-9 甲磺酸帕拉德福韦C型晶体Example 2-9 Paradefovir mesylate Type C crystals
取甲磺酸帕拉德福韦A晶型10g加入DMF60ml，搅拌溶解，搅拌下滴加入MTBE100ml。滴加完毕，10～30℃搅拌2h。过滤，10mlMTBE洗涤滤饼，55～65℃鼓风烘干18h以上，得到8.6g白色固体。经检测属于C晶型。Take 10g of paradefovir mesylate A crystal form and add 60ml of DMF, stir to dissolve, and add 100ml of MTBE dropwise under stirring. After the addition is complete, stir at 10-30°C for 2h. Filter, wash the filter cake with 10ml MTBE, and blow dry at 55-65°C for more than 18 hours to obtain 8.6g of white solid. It belongs to crystal form C after testing.
实施例2-10 甲磺酸帕拉德福韦D型晶体Example 2-10 Paradefovir mesylate Type D crystals
取甲磺酸帕拉德福韦晶型I 10g加入含有2.5％水的THF溶液40ml，加热至55℃搅拌溶解。10～30℃搅拌2h。过滤，5mlTHF洗涤滤饼，55～65℃鼓风烘干18h以上，得到7.1g白色固体。经检测属于D晶型(如图7和8所示)。Take 10g of paradefovir mesylate crystal form I, add 40ml of THF solution containing 2.5% water, and heat to 55°C and stir to dissolve. Stir at 10～30℃ for 2h. Filter, wash the filter cake with 5ml THF, and blow dry at 55-65°C for more than 18 hours to obtain 7.1g of white solid. It was found to belong to the D crystal form (as shown in Figures 7 and 8).
实施例2-11 甲磺酸帕拉德福韦D型晶体Example 2-11 Paradefovir mesylate Type D crystals
取甲磺酸帕拉德福韦A晶型10g加入含有2％水的THF溶液60ml，加热至55℃搅拌溶解。10～30℃搅拌2h。过滤，5mlTHF洗涤滤饼，55～65℃鼓风烘干18h以上，得到6.8g白色固体。经检测属于D晶型。Take 10g of paradefovir mesylate A crystal form and add 60ml of THF solution containing 2% water, and heat to 55°C and stir to dissolve. Stir at 10～30℃ for 2h. After filtering, washing the filter cake with 5ml THF, drying at 55-65°C with air blowing for more than 18 hours to obtain 6.8g white solid. It belongs to crystal form D after testing.
实施例2-12 甲磺酸帕拉德福韦E型晶体Example 2-12 Paradefovir mesylate type E crystals
取甲磺酸帕拉德福韦晶型I 2g加入乙腈200ml，加热回流搅拌溶解，10～30℃搅拌2h。过滤，10ml乙腈洗涤滤饼，55～65℃鼓风烘干18h以上，得到1.5g白色固体。经检测属于E晶型(如图9和10所示)。Take 2g of paradefovir mesylate crystal form I and add 200ml of acetonitrile, heat to reflux and stir to dissolve, and stir at 10-30°C for 2h. Filter, wash the filter cake with 10ml of acetonitrile, and blast dry at 55-65°C for more than 18 hours to obtain 1.5g of white solid. It was found to belong to the E crystal form (as shown in Figures 9 and 10).
实施例2-13 甲磺酸帕拉德福韦E型晶体Example 2-13 Paradefovir mesylate type E crystals
取甲磺酸帕拉德福韦A晶型5g加入乙腈600ml，加热回流搅拌溶解，10～30℃搅拌2h。过滤，10ml乙腈洗涤滤饼，55～65℃鼓风烘干18h以上，得到4.3g白色固体。经检测属于E晶型。Take 5g of paradefovir mesylate A crystal form and add 600ml of acetonitrile, heat to reflux and stir to dissolve, and stir for 2h at 10-30°C. Filter, wash the filter cake with 10ml of acetonitrile, and blast dry at 55-65°C for more than 18 hours to obtain 4.3g of white solid. It belongs to crystal form E after testing.
实施例2-14 甲磺酸帕拉德福韦A晶型的稳定性研究实验Example 2-14 Stability research experiment of paradefovir mesylate A crystal form
甲磺酸帕拉德福韦A晶型的稳定性实验数据。Stability experimental data of paradefovir mesylate A crystal form.
在高温、高湿、光照三种条件下进行稳定性测试，结果如下表(表2-1)所示，这表明该晶体具有长期高温、高湿、光照稳定性。The stability test was carried out under the three conditions of high temperature, high humidity and light. The results are shown in the following table (Table 2-1), which shows that the crystal has long-term high temperature, high humidity and light stability.
表2-1 高温、高湿、光照下进行稳定性测试Table 2-1 Stability test under high temperature, high humidity and light
Figure PCTCN2020130060-appb-000021
Figure PCTCN2020130060-appb-000021
在长期高湿稳定性测试，结果如下表(表2-2)所示，各杂质随时间未见明显增大，这表明该晶体具有长期高湿稳定性。In the long-term high-humidity stability test, the results are shown in the following table (Table 2-2). The impurities did not increase significantly over time, which indicates that the crystal has long-term high-humidity stability.
表2-2 甲磺酸帕拉德福韦A型晶体长期稳定性测试Table 2-2 Long-term stability test of paradefovir mesylate type A crystals
Figure PCTCN2020130060-appb-000022
Figure PCTCN2020130060-appb-000022
Figure PCTCN2020130060-appb-000023
Figure PCTCN2020130060-appb-000023
实施例2-15 甲磺酸帕拉德福韦B晶型的稳定性研究实验Example 2-15 Stability research experiment of paradefovir mesylate B crystal form
甲磺酸帕拉德福韦B晶型的稳定性实验数据。Stability experimental data of paradefovir mesylate B crystal form.
在高温、高湿、光照三种条件下进行稳定性测试，结果如下表(表2-3)所示，这表明该晶体具有长期高温、高湿、光照稳定性。The stability test was carried out under three conditions of high temperature, high humidity and light. The results are shown in the following table (Table 2-3), which shows that the crystal has long-term high temperature, high humidity and light stability.
表2-3 高温、高湿、光照下进行稳定性测试Table 2-3 Stability test under high temperature, high humidity and light
Figure PCTCN2020130060-appb-000024
Figure PCTCN2020130060-appb-000024
在长期高湿稳定性测试，结果如下表(表2-4)所示，各杂质随时间未见明显增大，这表明该晶体具有长期高湿稳定性。In the long-term high-humidity stability test, the results are shown in the following table (Table 2-4). The impurities did not increase significantly over time, which indicates that the crystal has long-term high-humidity stability.
表2-4 甲磺酸帕拉德福韦B型晶体长期稳定性测试Table 2-4 Long-term stability test of paradefovir mesylate type B crystal
Figure PCTCN2020130060-appb-000025
Figure PCTCN2020130060-appb-000025
实施例2-16Example 2-16
甲磺酸帕拉德福韦C晶型的稳定性研究实验Study on the stability of paradefovir mesylate C crystal form
甲磺酸帕拉德福韦C晶型的稳定性实验数据。Stability experimental data of paradefovir mesylate C crystal form.
在高温、高湿、光照三种条件下进行稳定性测试，结果如下表(表2-5)所示，这表明该晶体具有长期高温、高湿、光照稳定性。The stability test was carried out under three conditions of high temperature, high humidity and light. The results are shown in the following table (Table 2-5), which shows that the crystal has long-term high temperature, high humidity and light stability.
表2-5 高温、高湿、光照下进行稳定性测试Table 2-5 Stability test under high temperature, high humidity and light
Figure PCTCN2020130060-appb-000026
Figure PCTCN2020130060-appb-000026
在长期高湿稳定性测试，结果如下表(表2-6)所示，各杂质随时间未见明显增大，这表明该晶体具有长期高湿稳定性。In the long-term high-humidity stability test, the results are shown in the following table (Table 2-6). The impurities did not increase significantly over time, which indicates that the crystal has long-term high-humidity stability.
表2-6 甲磺酸帕拉德福韦C型晶体长期稳定性测试Table 2-6 Long-term stability test of paradefovir mesylate type C crystals
Figure PCTCN2020130060-appb-000027
Figure PCTCN2020130060-appb-000027
实施例2-17 甲磺酸帕拉德福韦D晶型的稳定性研究实验Example 2-17 Stability research experiment of paradefovir mesylate D crystal form
甲磺酸帕拉德福韦D晶型的稳定性实验数据。Experimental data on stability of paradefovir mesylate crystal form D.
在高温、高湿、光照三种条件下进行稳定性测试，结果如下表(表2-7)所示，这表明该晶体具有长期高温、高湿、光照稳定性。The stability test was carried out under the three conditions of high temperature, high humidity and light. The results are shown in the following table (Table 2-7), which shows that the crystal has long-term high temperature, high humidity and light stability.
表2-7 高温、高湿、光照下进行稳定性测试Table 2-7 Stability test under high temperature, high humidity and light
Figure PCTCN2020130060-appb-000028
Figure PCTCN2020130060-appb-000028
Figure PCTCN2020130060-appb-000029
Figure PCTCN2020130060-appb-000029
在长期高湿稳定性测试，结果如下表(表2-8)所示，各杂质随时间未见明显增大，这表明该晶体具有长期高湿稳定性。In the long-term high-humidity stability test, the results are shown in the following table (Table 2-8). The impurities did not increase significantly over time, which indicates that the crystal has long-term high-humidity stability.
表2-8 甲磺酸帕拉德福韦D型晶体长期稳定性测试Table 2-8 Long-term stability test of paradefovir mesylate type D crystal
Figure PCTCN2020130060-appb-000030
Figure PCTCN2020130060-appb-000030
实施例2-18 甲磺酸帕拉德福韦E晶型的稳定性研究实验Example 2-18 Stability research experiment of paradefovir mesylate E crystal form
甲磺酸帕拉德福韦E晶型的稳定性实验数据。Stability experimental data of paradefovir mesylate E crystal form.
在高温、高湿、光照三种条件下进行稳定性测试，结果如下表(表2-9)所示，这表明该晶体具有长期高温、高湿、光照稳定性。The stability test was carried out under three conditions of high temperature, high humidity and light. The results are shown in the following table (Table 2-9), which shows that the crystal has long-term high temperature, high humidity and light stability.
表2-9 高温、高湿、光照下进行稳定性测试Table 2-9 Stability test under high temperature, high humidity and light
Figure PCTCN2020130060-appb-000031
Figure PCTCN2020130060-appb-000031
Figure PCTCN2020130060-appb-000032
Figure PCTCN2020130060-appb-000032
在长期高湿稳定性测试，结果如下表(表2-10)所示，各杂质随时间未见明显增大，这表明该晶体具有长期高湿稳定性。In the long-term high-humidity stability test, the results are shown in the following table (Table 2-10). The impurities did not increase significantly over time, which indicates that the crystal has long-term high-humidity stability.
表2-10 甲磺酸帕拉德福韦E型晶体长期稳定性测试Table 2-10 Long-term stability test of paradefovir mesylate E crystal
Figure PCTCN2020130060-appb-000033
Figure PCTCN2020130060-appb-000033
实施例3 MB07133晶体Example 3 MB07133 crystal
实验所用的测试仪器Test equipment used in the experiment
1、X-射线粉末衍射图谱1. X-ray powder diffraction pattern
仪器：PHI-5400型X-射线光电子分析仪(可购自美国PE公司)Instrument: PHI-5400 X-ray photoelectron analyzer (available from PE company in the United States)
测试参数为：电压：46kv，电流：40mA，铜kα辐射，λ：
Figure PCTCN2020130060-appb-000034
The test parameters are: voltage: 46kv, current: 40mA, copper kα radiation, λ:
Figure PCTCN2020130060-appb-000034
2、热差分析图谱(DSC)2. Thermal Differential Analysis Chart (DSC)
仪器：SII Nano，EXSTAR，DSC6220Instruments: SII Nano, EXSTAR, DSC6220
升温速度：10℃/minHeating rate: 10℃/min
温度范围：50～250℃Temperature range: 50～250℃
载气：高纯氮气Carrier gas: high purity nitrogen
3、物料来源：3. Material source:
MB07133化合物合成参照中国专利CN1711278A的制备方法制备。具体如下：The synthesis of MB07133 compound was prepared with reference to the preparation method of Chinese patent CN1711278A. details as follows:
氮气保护下，向反应釜中加入2,3-二O-TBS-阿糖胞苷-N,N-二甲基甲脒(250g，0.47moL)和四氢呋喃(2.5L)，冷却至4℃，控温不超过8℃滴加氯化叔丁基镁溶液(617mL，0.62moL)，加毕反应1.25h。一次性加入磷酸酯试剂(262g，0.78moL)，室温下搅拌反应16h。滴加氯化铵溶液(20％，2.5L)，并加入乙酸乙 酯(2.5L)搅拌分液，再用乙酸乙酯(1.1L)萃取水相，合并有机相，氯化钠溶液(15％，1.6L)反洗分液，硫酸镁(260g)干燥，过滤浓缩至干，得526g深橙色浆状物。Under the protection of nitrogen, add 2,3-DiO-TBS-cytarabine-N,N-dimethylformamidine (250g, 0.47moL) and tetrahydrofuran (2.5L) into the reaction kettle, and cool to 4℃, Control the temperature not to exceed 8°C and add tert-butylmagnesium chloride solution (617mL, 0.62moL) dropwise, and complete the reaction for 1.25h. Phosphate reagent (262g, 0.78moL) was added all at once, and the reaction was stirred at room temperature for 16h. Add ammonium chloride solution (20%, 2.5L) dropwise, add ethyl acetate (2.5L) and stir to separate the liquids, then extract the aqueous phase with ethyl acetate (1.1L), combine the organic phases, and sodium chloride solution (15 %, 1.6L) was backwashed and separated, dried over magnesium sulfate (260g), filtered and concentrated to dryness to obtain 526g of dark orange slurry.
用甲醇(2.5L)和HCl-二恶烷溶液(790mL,3.16moL)，在50～55℃溶解上述深橙色浆状物，并在50～55℃下反应16h，减压浓缩，得到粘稠橙色焦油。用水(800mL)和乙酸乙酯(800mL)进行分配上述焦油，缓慢加入碳酸氢钠固体，直至水pH值为7，分液，乙酸乙酯(800mL)再次萃取，水相过滤减压浓缩，并用乙醇带水至干，得到445g油状物。加入乙醇(700mL)，常温搅拌2h，过滤干燥得到199g固体，再用水(650mL)打浆，并加入盐酸(20mL),搅拌反应，再加入碳酸氢钠固体(36g)调节值为6-7，过滤，烘干，得到MB07133固体160g。Use methanol (2.5L) and HCl-dioxane solution (790mL, 3.16moL) to dissolve the dark orange slurry at 50～55℃, and react at 50～55℃ for 16h, and concentrate under reduced pressure to obtain viscous Orange tar. The above tar was partitioned with water (800mL) and ethyl acetate (800mL), sodium bicarbonate solid was slowly added until the pH of the water was 7, the liquids were separated, the ethyl acetate (800mL) was extracted again, and the aqueous phase was filtered and concentrated under reduced pressure. The ethanol was brought to dryness with water to obtain 445 g of oil. Add ethanol (700mL), stir at room temperature for 2h, filter and dry to obtain 199g of solid, then beaten with water (650mL), add hydrochloric acid (20mL), stir the reaction, then add sodium bicarbonate solid (36g) to adjust the value to 6-7, filter And dry to obtain 160g of MB07133 solid.
MB07133化合物的 1H NMR(600MHz,DMSO):δ:8.61(2H,dd)，7.54(1H,d),7.43(2H,dd),7.07-7.14(2H,s),6.12(1H,d),5.75-5.78(1H,m),5.63-5.64(2H,d),5.60(1H,d),4.41-4.59(2H,m),4.25-4.33(2H,m),4.00(1H,m),3.95-3.97(1H,m),3.92(1H,s),2.13-2.28(2H,m)。 1 H NMR (600MHz, DMSO) of MB07133 compound: δ: 8.61 (2H, dd), 7.54 (1H, d), 7.43 (2H, dd), 7.07-7.14 (2H, s), 6.12 (1H, d) ,5.75-5.78(1H,m),5.63-5.64(2H,d),5.60(1H,d),4.41-4.59(2H,m),4.25-4.33(2H,m), 4.00(1H,m) , 3.95-3.97 (1H, m), 3.92 (1H, s), 2.13-2.28 (2H, m).
实施例3-1 MB07133晶型A晶体的制备和鉴定Example 3-1 Preparation and identification of MB07133 crystal form A crystal
向100mL三口瓶中，加入纯化水30mL，加入前述获得MB07133白色粉末10g，搅拌下滴加3mol/L的硫酸水溶液，调节pH值为2.0-5.0。控制温度15～25℃搅拌1h，加入磷酸二氢钠0.14g，向反应体系中缓慢滴加14％的氢氧化钠水溶液，调节pH值为5.0-8.0。调节pH值后，控制温度10～20℃，搅拌3小时，离心，收集滤饼，保留晶体，然后直接于50℃烘干。X-射线粉末衍射和DSC检测显示为晶型A晶体，如图1和7所示，表明用该方法能够获得稳定的晶型A晶体。To a 100 mL three-necked flask, add 30 mL of purified water, add 10 g of the white powder of MB07133 obtained as described above, and add 3 mol/L sulfuric acid aqueous solution dropwise with stirring to adjust the pH to 2.0-5.0. Control the temperature at 15-25°C and stir for 1 hour, add 0.14 g of sodium dihydrogen phosphate, slowly drop a 14% sodium hydroxide aqueous solution into the reaction system, and adjust the pH to 5.0-8.0. After adjusting the pH value, control the temperature at 10-20°C, stir for 3 hours, centrifuge, collect the filter cake, retain the crystals, and then directly dry it at 50°C. X-ray powder diffraction and DSC detection showed that it was crystal form A, as shown in Figures 1 and 7, indicating that stable crystal form A can be obtained by this method.
实施例3-2 MB07133晶型A晶体的制备和鉴定Example 3-2 Preparation and identification of MB07133 crystal form A crystal
向100mL三口瓶中，加入纯化水24mL，MB07133晶型B晶体8g，搅拌下滴加3mol/L的硫酸水溶液，调节pH值为2.0-5.0。控制温度15～25℃搅拌1h，加入磷酸二氢钠1.2g，向反应体系中缓慢滴加14％的氢氧化钠水溶液，调节pH值为5.0-8.0。调节pH值后，控制温度10～20℃，搅拌3小时，离心，收集滤饼，保留晶体，然后直接于50℃烘干。X-射线粉末衍射和DSC检测显示为晶型A晶体。Into a 100 mL three-necked flask, add 24 mL of purified water and 8 g of MB07133 crystal form B crystals, and add 3 mol/L sulfuric acid aqueous solution dropwise with stirring to adjust the pH to 2.0-5.0. Control the temperature at 15-25°C and stir for 1 hour, add 1.2 g of sodium dihydrogen phosphate, slowly drop a 14% sodium hydroxide aqueous solution into the reaction system, and adjust the pH to 5.0-8.0. After adjusting the pH value, control the temperature at 10-20°C, stir for 3 hours, centrifuge, collect the filter cake, retain the crystals, and then directly dry it at 50°C. X-ray powder diffraction and DSC detection showed that it was a crystal of form A.
实施例3-3 MB07133晶型A晶体的制备和鉴定Example 3-3 Preparation and identification of MB07133 crystal form A
向100mL三口瓶中，加入纯化水24mL，MB07133晶型C晶体8g，搅拌下滴加3mol/L的硫酸水溶液，调节pH值为2.0-5.0。控制温度15～25℃搅拌1h，加入磷酸二氢钠1.2g，向反应体系中缓慢滴加14％的氢氧化钠水溶液，调节pH值为5.0-8.0。调节pH值后，控制温度10～20℃，搅拌3小时，离心，收集滤饼，保留晶体，然后直接于50℃烘干。X-射线粉末衍射和DSC检测显示为晶型A晶体。To a 100 mL three-necked flask, add 24 mL of purified water and 8 g of MB07133 crystal form C, and add 3 mol/L sulfuric acid aqueous solution dropwise with stirring to adjust the pH to 2.0-5.0. Control the temperature at 15-25°C and stir for 1 hour, add 1.2 g of sodium dihydrogen phosphate, slowly drop a 14% sodium hydroxide aqueous solution into the reaction system, and adjust the pH to 5.0-8.0. After adjusting the pH value, control the temperature at 10-20°C, stir for 3 hours, centrifuge, collect the filter cake, retain the crystals, and then directly dry it at 50°C. X-ray powder diffraction and DSC detection showed that it was a crystal of form A.
实施例3-4 MB07133晶型A晶体的制备和鉴定Example 3-4 Preparation and identification of MB07133 crystal form A crystal
向100mL三口瓶中，加入纯化水30mL，MB07133晶型D晶体10g，搅拌下滴加3mol/L的硫酸水溶液，调节pH值为2.0-5.0。控制温度15～25℃搅拌1h，加入磷酸二氢钠1.2g，向反应体系中缓慢滴加14％的氢氧化钠水溶液，调节pH值为5.0-8.0。调节pH值后，控制温度10～20℃，搅拌3小时，离心，收集滤饼，保留晶体，然后直接于50℃烘干。X-射线粉末衍射和DSC检测显示为晶型A晶体。Into a 100 mL three-necked flask, add 30 mL of purified water and 10 g of MB07133 crystal form D crystals, and add 3 mol/L sulfuric acid aqueous solution dropwise with stirring to adjust the pH to 2.0-5.0. Control the temperature at 15-25°C and stir for 1 hour, add 1.2 g of sodium dihydrogen phosphate, slowly drop a 14% sodium hydroxide aqueous solution into the reaction system, and adjust the pH to 5.0-8.0. After adjusting the pH value, control the temperature at 10-20°C, stir for 3 hours, centrifuge, collect the filter cake, retain the crystals, and then directly dry it at 50°C. X-ray powder diffraction and DSC detection showed that it was a crystal of form A.
实施例3-5 MB07133晶型A晶体的制备和鉴定Example 3-5 Preparation and identification of MB07133 crystal form A crystal
向100mL三口瓶中，加入纯化水24mL，MB07133晶型E晶体8g，搅拌下滴加3mol/L的硫酸水溶液，调节pH值为2.0-5.0。控制温度15～25℃搅拌1h，加入磷酸二氢钠1.2g，向反应体系中缓慢滴加14％的氢氧化钠水溶液，调节pH值为5.0-8.0。调节pH值后，控制温度10～20℃，搅拌3小时，离心，收集滤饼，保留晶体，然后直接于50℃烘干。X-射线粉末衍射和DSC检测显示为晶型A晶体。Into a 100 mL three-necked flask, add 24 mL of purified water and 8 g of MB07133 crystal form E crystals, and add 3 mol/L sulfuric acid aqueous solution dropwise with stirring to adjust the pH to 2.0-5.0. Control the temperature at 15-25°C and stir for 1 hour, add 1.2 g of sodium dihydrogen phosphate, slowly drop a 14% sodium hydroxide aqueous solution into the reaction system, and adjust the pH to 5.0-8.0. After adjusting the pH value, control the temperature at 10-20°C, stir for 3 hours, centrifuge, collect the filter cake, retain the crystals, and then directly dry it at 50°C. X-ray powder diffraction and DSC detection showed that it was a crystal of form A.
实施例3-6 MB07133晶型A晶体的制备和鉴定Example 3-6 Preparation and identification of MB07133 crystal form A
向100mL三口瓶中，加入纯化水30mL，MB07133晶型F晶体10g，搅拌下滴加3mol/L的硫酸水溶液，调节pH值为2.0-5.0。控制温度15～25℃搅拌1h，加入磷酸二氢钠1.2g，向反应体系中缓慢滴加14％的氢氧化钠水溶液，调节pH值为5.0-8.0。调节pH值后，控制温度10～20℃，搅拌3小时，离心，收集滤饼，保留晶体，然后直接于50℃烘干。X-射线粉末衍射和DSC检测显示为晶型A晶体。Into a 100 mL three-necked flask, add 30 mL of purified water and 10 g of MB07133 crystal form F crystals, and add 3 mol/L sulfuric acid aqueous solution dropwise with stirring to adjust the pH to 2.0-5.0. Control the temperature at 15-25°C and stir for 1 hour, add 1.2 g of sodium dihydrogen phosphate, slowly drop a 14% sodium hydroxide aqueous solution into the reaction system, and adjust the pH to 5.0-8.0. After adjusting the pH value, control the temperature at 10-20°C, stir for 3 hours, centrifuge, collect the filter cake, retain the crystals, and then directly dry it at 50°C. X-ray powder diffraction and DSC detection showed that it was a crystal of form A.
实施例3-7 MB07133晶型B晶体的制备和鉴定Example 3-7 Preparation and identification of MB07133 crystal form B crystal
向500mL三口瓶中，加入100mL二甲基亚砜，加入前述获得MB07133白 色粉末10g，搅拌加热至130℃，使固体完全溶解，然后滴加100mL甲苯，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型B晶体，如图2和8所示，表明用该方法能够获得稳定的晶型B晶体。Into a 500mL three-necked flask, add 100mL dimethyl sulfoxide, add 10g of the MB07133 white powder obtained above, stir and heat to 130°C to dissolve the solid completely, then add 100mL toluene dropwise, after the addition, cool to 0～10°C, and Keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC detection showed crystal form B crystals, as shown in Figures 2 and 8, indicating that stable crystal form B crystals can be obtained by this method.
实施例3-8 MB07133晶型B晶体的制备和鉴定Example 3-8 Preparation and identification of MB07133 crystal form B crystal
向500mL三口瓶中，加入100mL二甲基亚砜，加入MB07133晶型A晶体10g，搅拌加热至125℃，使固体完全溶解，然后滴加100mL甲苯，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型B晶体。Into a 500mL three-necked flask, add 100mL dimethyl sulfoxide, add 10g of MB07133 crystal form A crystal, stir and heat to 125°C to completely dissolve the solid, then add 100mL of toluene dropwise, after the addition, cool to 0～10°C, and Keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was crystal form B.
实施例3-9 MB07133晶型B晶体的制备和鉴定Example 3-9 Preparation and identification of MB07133 crystal form B crystal
向500mL三口瓶中，加入100mL二甲基亚砜，加入MB07133晶型C晶体10g，搅拌加热至130℃，使固体完全溶解，然后滴加100mL甲苯，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型B晶体。Into a 500mL three-neck flask, add 100mL dimethyl sulfoxide, add 10g of MB07133 crystal form C, stir and heat to 130°C to completely dissolve the solid, then add 100mL of toluene dropwise, after the addition, cool to 0～10°C, and Keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was crystal form B.
实施例3-10 MB07133晶型B晶体的制备和鉴定Example 3-10 Preparation and identification of MB07133 crystal form B crystal
向500mL三口瓶中，加入100mL二甲基亚砜，加入MB07133晶型D晶体10g，搅拌加热至128℃，使固体完全溶解，然后滴加100mL甲苯，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型B晶体。Into a 500mL three-necked flask, add 100mL dimethyl sulfoxide, add 10g of MB07133 crystal form D crystal, stir and heat to 128℃ to dissolve the solid completely, then add 100mL toluene dropwise, after the addition, cool to 0～10℃, and Keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was crystal form B.
实施例3-11 MB07133晶型B晶体的制备和鉴定Example 3-11 Preparation and identification of MB07133 crystal form B
向500mL三口瓶中，加入100mL二甲基亚砜，加入MB07133晶型E晶体10g，搅拌加热至125℃，使固体完全溶解，然后滴加100mL甲苯，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型B晶体。Into a 500mL three-neck flask, add 100mL dimethyl sulfoxide, add 10g of MB07133 crystal form E crystal, stir and heat to 125℃ to dissolve the solid completely, then add 100mL toluene dropwise, after the addition, cool to 0～10℃, and Keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was crystal form B.
实施例3-12 MB07133晶型B晶体的制备和鉴定Example 3-12 Preparation and identification of MB07133 crystal form B
向500mL三口瓶中，加入100mL二甲基亚砜，加入MB07133晶型F晶体10g，搅拌加热至128℃，使固体完全溶解，然后滴加100mL甲苯，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型B晶体。Into a 500mL three-neck flask, add 100mL dimethyl sulfoxide, add 10g of MB07133 crystal form F crystal, stir and heat to 128℃ to completely dissolve the solid, then add 100mL toluene dropwise, after the addition, cool to 0～10℃, and Keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was crystal form B.
实施例3-13 MB07133晶型C晶体的制备和鉴定Example 3-13 Preparation and identification of MB07133 crystal form C
向500mL三口瓶中，加入100mL二甲基亚砜，加入前述获得MB07133白色粉末10g，搅拌加热至115℃，使固体完全溶解，然后滴加150mL丙酮，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型B晶体，如图3和9所示，表明用该方法能够获得稳定的晶型B晶体。Into a 500mL three-necked flask, add 100mL dimethyl sulfoxide, add 10g of the MB07133 white powder obtained above, stir and heat to 115°C to completely dissolve the solid, then add 150mL acetone dropwise, after the addition, cool to 0～10°C, and Keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC detection showed crystal form B crystals, as shown in Figures 3 and 9, indicating that stable crystal form B crystals can be obtained by this method.
实施例3-14 MB07133晶型C晶体的制备和鉴定Example 3-14 Preparation and identification of MB07133 crystal form C
向500mL三口瓶中，加入100mL二甲基亚砜，加入MB07133晶型A晶体10g，搅拌加热至120℃，使固体完全溶解，然后滴加150mL丙酮，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型C晶体。Into a 500mL three-necked flask, add 100mL dimethyl sulfoxide, add 10g of MB07133 crystal form A crystal, stir and heat to 120℃ to dissolve the solid completely, then add 150mL acetone dropwise, after the addition, cool to 0～10℃, and Keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a form C crystal.
实施例3-15 MB07133晶型C晶体的制备和鉴定Example 3-15 Preparation and identification of MB07133 crystal form C
向500mL三口瓶中，加入100mL二甲基亚砜，加入MB07133晶型B晶体10g，搅拌加热至118℃，使固体完全溶解，然后滴加150mL丙酮，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型C晶体。Into a 500mL three-neck flask, add 100mL dimethyl sulfoxide, add 10g of MB07133 crystal form B crystal, stir and heat to 118°C to dissolve the solid completely, then add 150mL acetone dropwise, after the addition, cool to 0～10°C, and Keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a form C crystal.
实施例3-16 MB07133晶型C晶体的制备和鉴定Example 3-16 Preparation and identification of MB07133 crystal form C
向500mL三口瓶中，加入100mL二甲基亚砜，加入MB07133晶型D晶体10g，搅拌加热至118℃，使固体完全溶解，然后滴加150mL丙酮，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型C晶体。Into a 500mL three-neck flask, add 100mL dimethyl sulfoxide, add 10g MB07133 crystal form D crystal, stir and heat to 118°C to completely dissolve the solid, then add 150mL acetone dropwise, after the addition, cool to 0～10°C, and Keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a form C crystal.
实施例3-17 MB07133晶型C晶体的制备和鉴定Example 3-17 Preparation and identification of MB07133 crystal form C
向500mL三口瓶中，加入100mL二甲基亚砜，加入MB07133晶型E晶体10g，搅拌加热至115℃，使固体完全溶解，然后滴加150mL丙酮，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型C晶体。Into a 500mL three-necked flask, add 100mL dimethyl sulfoxide, add 10g of MB07133 crystal form E crystal, stir and heat to 115℃ to completely dissolve the solid, then add 150mL acetone dropwise, after the addition, cool to 0～10℃, and Keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a form C crystal.
实施例3-18 MB07133晶型C晶体的制备和鉴定Example 3-18 Preparation and identification of MB07133 crystal form C
向500mL三口瓶中，加入100mL二甲基亚砜，加入MB07133晶型F晶体10g，搅拌加热至120℃，使固体完全溶解，然后滴加150mL丙酮，加毕，冷却 至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型C晶体。Into a 500mL three-necked flask, add 100mL dimethyl sulfoxide, add 10g of MB07133 crystal form F crystal, stir and heat to 120℃ to dissolve the solid completely, then add 150mL acetone dropwise, after the addition, cool to 0～10℃, and Keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a form C crystal.
实施例3-19 MB07133晶型D晶体的制备和鉴定Example 3-19 Preparation and identification of MB07133 crystal form D
向500mL三口瓶中，加入100mLN，N-二甲基甲酰胺，加入前述获得MB07133白色粉末10g，搅拌加热至120℃，使固体完全溶解，然后降温滴加200mL乙酸乙酯，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型D晶体，如图4和10所示，表明用该方法能够获得稳定的晶型D晶体。Into a 500mL three-necked flask, add 100mL of N,N-dimethylformamide, add 10g of the MB07133 white powder obtained as described above, stir and heat to 120°C to completely dissolve the solid, then drop in 200mL of ethyl acetate after the addition is complete, and cool to 0～10℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC detection showed crystal form D, as shown in Figures 4 and 10, indicating that stable crystal form D can be obtained by this method.
实施例3-20 MB07133晶型D晶体的制备和鉴定Example 3-20 Preparation and identification of MB07133 crystal form D
向500mL三口瓶中，加入100mLN，N-二甲基甲酰胺，加入MB07133晶型A晶体10g，搅拌加热至125℃，使固体完全溶解，然后降温滴加200mL乙酸乙酯，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型D晶体。Into a 500mL three-necked flask, add 100mL of N,N-dimethylformamide, add 10g of MB07133 crystal form A, stir and heat to 125°C to completely dissolve the solid, then add 200mL of ethyl acetate dropwise to the flask. After the addition, cool to 0～10℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a form D crystal.
实施例3-21 MB07133晶型D晶体的制备和鉴定Example 3-21 Preparation and identification of MB07133 crystal form D
向500mL三口瓶中，加入100mLN，N-二甲基甲酰胺，加入MB07133晶型B晶体10g，搅拌加热至120℃，使固体完全溶解，然后降温滴加200mL乙酸乙酯，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型D晶体。Into a 500mL three-neck flask, add 100mL of N,N-dimethylformamide, add 10g of MB07133 crystal form B crystal, stir and heat to 120°C to completely dissolve the solid, then drop in 200mL of ethyl acetate after the addition is complete, and cool to 0～10℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a form D crystal.
实施例3-22 MB07133晶型D晶体的制备和鉴定Example 3-22 Preparation and identification of MB07133 crystal form D
向500mL三口瓶中，加入100mLN，N-二甲基甲酰胺，加入MB07133晶型C晶体10g，搅拌加热至118℃，使固体完全溶解，然后降温滴加200mL乙酸乙酯，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型D晶体。Into a 500mL three-neck flask, add 100mL of N,N-dimethylformamide, add 10g of MB07133 crystal form C, stir and heat to 118°C to completely dissolve the solid, then drop in 200mL of ethyl acetate after the addition is complete, and cool to 0～10℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a form D crystal.
实施例3-23 MB07133晶型D晶体的制备和鉴定Example 3-23 Preparation and identification of MB07133 crystal form D
向500mL三口瓶中，加入100mLN，N-二甲基甲酰胺，加入MB07133晶型E晶体10g，搅拌加热至116℃，使固体完全溶解，然后降温滴加200mL乙酸乙酯，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型D晶体。Into a 500mL three-necked flask, add 100mL of N,N-dimethylformamide, add 10g of MB07133 crystal form E, stir and heat to 116°C to dissolve the solid completely, then add 200mL of ethyl acetate dropwise to the flask, after the addition, cool to 0～10℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a form D crystal.
实施例3-24 MB07133晶型D晶体的制备和鉴定Example 3-24 Preparation and identification of MB07133 crystal form D
向500mL三口瓶中，加入100mLN，N-二甲基甲酰胺，加入MB07133晶型F晶体10g，搅拌加热至118℃，使固体完全溶解，然后降温滴加200mL乙酸乙酯，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型D晶体。Into a 500mL three-neck flask, add 100mL of N,N-dimethylformamide, add 10g of MB07133 crystal form F crystals, stir and heat to 118°C to completely dissolve the solid, then drop in 200mL of ethyl acetate after the addition is complete, and cool to 0～10℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a form D crystal.
实施例3-25 MB07133晶型E晶体的制备和鉴定Example 3-25 Preparation and identification of MB07133 crystal form E
向500mL三口瓶中，加入20mL N-甲基吡咯烷酮，加入20mL水，再加入前述获得MB07133白色粉末10g，搅拌加热至100℃，使固体完全溶解，然后降温滴加100mL丙酮，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型D晶体，如图5和11所示，表明用该方法能够获得稳定的晶型E晶体。Into a 500mL three-necked flask, add 20mL N-methylpyrrolidone, add 20mL water, and then add 10g of the MB07133 white powder obtained above, stir and heat to 100°C to dissolve the solid completely, then add 100mL acetone dropwise to the flask. After the addition, cool to 0～10℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC detection showed crystal form D, as shown in Figures 5 and 11, indicating that stable crystal form E can be obtained by this method.
实施例3-26 MB07133晶型E晶体的制备和鉴定Example 3-26 Preparation and identification of MB07133 crystal form E
向500mL三口瓶中，加入20mL N-甲基吡咯烷酮，加入20mL水，再加入MB07133晶型A晶体10g，搅拌加热至105℃，使固体完全溶解，然后滴加100mL丙酮，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型E晶体。To a 500mL three-necked flask, add 20mL N-methylpyrrolidone, add 20mL water, then add 10g MB07133 crystal form A crystal, stir and heat to 105°C to completely dissolve the solid, then add 100mL acetone dropwise, after the addition, cool to 0 ～10℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a crystal form E.
实施例3-27 MB07133晶型E晶体的制备和鉴定Example 3-27 Preparation and identification of MB07133 crystal form E
向500mL三口瓶中，加入20mL N-甲基吡咯烷酮，加入20mL水，再加入MB07133晶型B晶体10g，搅拌加热至110℃，使固体完全溶解，然后滴加100mL丙酮，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型E晶体。Into a 500mL three-necked flask, add 20mL N-methylpyrrolidone, add 20mL water, and then add 10g of MB07133 crystal form B crystal, stir and heat to 110°C to completely dissolve the solid, then add 100mL acetone dropwise, after the addition, cool to 0 ～10℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a crystal form E.
实施例3-28 MB07133晶型E晶体的制备和鉴定Example 3-28 Preparation and identification of MB07133 crystal form E
向500mL三口瓶中，加入20mL N-甲基吡咯烷酮，加入20mL水，再加入MB07133晶型C晶体10g，搅拌加热至110℃，使固体完全溶解，然后滴加100mL丙酮，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型E晶体。Into a 500mL three-necked flask, add 20mL N-methylpyrrolidone, add 20mL water, then add 10g of MB07133 crystal form C, stir and heat to 110°C to completely dissolve the solid, then add 100mL acetone dropwise, after the addition, cool to 0 ～10℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a crystal form E.
实施例3-29 MB07133晶型E晶体的制备和鉴定Example 3-29 Preparation and identification of MB07133 crystal form E
向500mL三口瓶中，加入20mL N-甲基吡咯烷酮，加入20mL水，再加入MB07133晶型D晶体10g，搅拌加热至107℃，使固体完全溶解，然后滴加100mL丙酮，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直 接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型E晶体。To a 500mL three-necked flask, add 20mL N-methylpyrrolidone, add 20mL of water, then add 10g of MB07133 crystal form D, stir and heat to 107°C to completely dissolve the solid, then add 100mL of acetone dropwise, after the addition, cool to 0 ～10℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a crystal form E.
实施例3-30 MB07133晶型E晶体的制备和鉴定Example 3-30 Preparation and identification of MB07133 crystal form E
向500mL三口瓶中，加入20mL N-甲基吡咯烷酮，加入20mL水，再加入MB07133晶型F晶体10g，搅拌加热至120℃，使固体完全溶解，然后滴加100mL丙酮，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型E晶体。To a 500mL three-necked flask, add 20mL N-methylpyrrolidone, add 20mL water, then add 10g of MB07133 crystal form F crystal, stir and heat to 120°C to completely dissolve the solid, then add 100mL acetone dropwise, after the addition, cool to 0 ～10℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a crystal form E.
实施例3-31 MB07133晶型F晶体的制备和鉴定Example 3-31 Preparation and identification of MB07133 crystal form F
向250mL三口瓶中，分别加入10mL纯化水，加入10mL DMSO，加入前述获得MB07133白色粉末5g，搅拌加热至100℃，至固体完全溶解，然后滴加150mL异丙醇，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型F晶体，如图6和12所示，表明用该方法能够获得稳定的晶型F晶体。Into a 250mL three-necked flask, add 10mL purified water, 10mL DMSO, add 5g of the MB07133 white powder obtained above, stir and heat to 100°C until the solid is completely dissolved, then add 150mL isopropanol dropwise, after the addition, cool to 0~ Stir at 10°C and keep it at 0～10°C for 3 hours, filter with suction to retain the crystals, and then directly blow dry at 50°C. X-ray powder diffraction and DSC detection showed crystal form F, as shown in Figures 6 and 12, indicating that stable crystal form F can be obtained by this method.
实施例3-32 MB07133晶型F晶体的制备和鉴定Example 3-32 Preparation and identification of MB07133 crystal form F crystal
向500mL三口瓶中，分别加入20mL纯化水，20mL DMSO，再加入MB07133晶型A晶体10g，搅拌加热至110℃，至固体完全溶解，然后滴加300mL异丙醇，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型F晶体。Into a 500mL three-necked flask, add 20mL purified water, 20mL DMSO, and then add 10g MB07133 crystal form A crystal, stir and heat to 110℃, until the solid is completely dissolved, then add 300mL isopropanol dropwise, after the addition, cool to 0～ Stir at 10°C and keep it at 0～10°C for 3 hours, filter with suction to retain the crystals, and then directly blow dry at 50°C. X-ray powder diffraction and DSC inspection showed that it was a crystalline form F crystal.
实施例3-33 MB07133晶型F晶体的制备和鉴定Example 3-33 Preparation and identification of MB07133 crystal form F
向250mL三口瓶中，分别加入20mL纯化水，20mLDMSO，再加入MB07133晶型B晶体10g，搅拌加热至120℃，至固体完全溶解，然后滴加300mL异丙醇，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型F晶体。Into a 250mL three-necked flask, add 20mL purified water, 20mL DMSO, and then add 10g of MB07133 crystal form B crystal, stir and heat to 120℃ until the solid is completely dissolved, then add 300mL isopropanol dropwise, and cool to 0～10 after the addition is complete. ℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a crystalline form F crystal.
实施例3-34 MB07133晶型F晶体的制备和鉴定Example 3-34 Preparation and identification of MB07133 crystal form F crystal
向250mL三口瓶中，分别加入20mL纯化水，20mLDMSO，再加入MB07133晶型C晶体10g，搅拌加热至110℃，至固体完全溶解，然后滴加300mL异丙醇，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型F晶体。Into a 250mL three-necked flask, add 20mL purified water, 20mL DMSO, and then add 10g of MB07133 crystal form C, stir and heat to 110℃, until the solid is completely dissolved, then add 300mL isopropanol dropwise, after the addition, cool to 0～10 ℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a crystalline form F crystal.
实施例3-35 MB07133晶型F晶体的制备和鉴定Example 3-35 Preparation and identification of MB07133 crystal form F
向250mL三口瓶中，分别加入20mL纯化水，20mLDMSO，再加入MB07133 晶型D晶体10g，搅拌加热至115℃，至固体完全溶解，然后滴加300mL异丙醇，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型F晶体。Into a 250mL three-necked flask, add 20mL purified water, 20mL DMSO, and then add 10g MB07133 crystal form D crystal, stir and heat to 115℃, until the solid is completely dissolved, then add 300mL isopropanol dropwise, after the addition, cool to 0～10 ℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a crystalline form F crystal.
实施例3-36 MB07133晶型F晶体的制备和鉴定Example 3-36 Preparation and identification of MB07133 crystal form F crystal
向250mL三口瓶中，分别加入20mL纯化水，20mLDMSO，再加入MB07133晶型E晶体10g，搅拌加热至112℃，至固体完全溶解，然后滴加300mL异丙醇，加毕，冷却至0～10℃，并保温0～10℃搅拌3h，抽滤，保留晶体，然后直接于50℃鼓风烘干。X-射线粉末衍射和DSC检测显示为晶型F晶体。Into a 250mL three-necked flask, add 20mL purified water, 20mL DMSO, and then add 10g of MB07133 crystal form E crystal, stir and heat to 112℃, until the solid is completely dissolved, then add 300mL isopropanol dropwise, after the addition, cool to 0～10 ℃, keep the temperature at 0～10℃, stir for 3h, filter with suction to retain the crystals, and then directly blow dry at 50℃. X-ray powder diffraction and DSC inspection showed that it was a crystalline form F crystal.
实施例3-37 MB07133晶型A晶体化合物的稳定性Example 3-37 The stability of MB07133 crystal form A crystal compound
本实施例描述了晶型A晶体化合物的稳定性实验。This example describes the stability experiment of the crystalline compound of Form A.
在高温、高湿、光照三种条件下晶型A晶体化合物的稳定性测试，结果如下表(表3-1)所示，高温(60℃)、高湿(90％±5％)、强光(4500Lx)条件下样品有关物质基本无变化，表明晶型A对高温60℃、高湿、光照稳定。The stability test of the crystal compound of Form A under the three conditions of high temperature, high humidity and light, the results are shown in the following table (Table 3-1), high temperature (60℃), high humidity (90%±5%), strong Under the condition of light (4500Lx), the related substances of the sample are basically unchanged, indicating that the crystal form A is stable to high temperature 60℃, high humidity and light.
表3-1 晶型A稳定性结果测定表Table 3-1 Determination of stability results of crystal form A
Figure PCTCN2020130060-appb-000035
Figure PCTCN2020130060-appb-000035
在40℃下进行经6月稳定性测试，结果如下表(表3-2)所示，这表明该晶体稳定性良好，适合长期保存。The stability test was carried out at 40°C for 6 months, and the results are shown in the following table (Table 3-2), which indicates that the crystal has good stability and is suitable for long-term storage.
表3-2 晶型A长期试验测定结果表Table 3-2 Long-term test results of crystal form A
Figure PCTCN2020130060-appb-000036
Figure PCTCN2020130060-appb-000036
实施例3-38 MB07133晶型B晶体化合物的稳定性Example 3-38 The stability of MB07133 crystal form B crystal compound
本实施例描述了晶型B晶体化合物的稳定性实验。This example describes the stability experiment of the crystalline compound of Form B.
在高温、高湿、光照三种条件下晶型B晶体化合物的稳定性测试，结果如下表(表3-3)所示，高温(60℃)、高湿(90％±5％)、强光(4500Lx)条件下 样品有关物质基本无变化，表明晶型B对高温60℃、高湿、光照稳定。The stability test of the crystal compound of Form B under the three conditions of high temperature, high humidity and light, the results are shown in the following table (Table 3-3), high temperature (60℃), high humidity (90%±5%), strong Under the condition of light (4500Lx), the related substances of the sample are basically unchanged, indicating that the crystal form B is stable to high temperature 60℃, high humidity and light.
表3-3 晶型B稳定性结果测定表Table 3-3 Determination of stability results of crystal form B
Figure PCTCN2020130060-appb-000037
Figure PCTCN2020130060-appb-000037
在40℃下进行经6月稳定性测试，结果如下表(表3-4)所示，这表明该晶体稳定性良好，适合长期保存。The stability test was carried out at 40°C for 6 months, and the results are shown in the following table (Table 3-4), which indicates that the crystal has good stability and is suitable for long-term storage.
表3-4 晶型B长期试验测定结果表Table 3-4 Long-term test results of crystal form B
Figure PCTCN2020130060-appb-000038
Figure PCTCN2020130060-appb-000038
实施例3-39 MB07133晶型C晶体化合物的稳定性Example 3-39 The stability of MB07133 crystal form C crystal compound
本实施例描述了晶型C晶体化合物的稳定性实验。This example describes the stability experiment of the crystalline compound of Form C.
在高温、高湿、光照三种条件下晶型C晶体化合物的稳定性测试，结果如下表(表3-5)所示，高温(60℃)、高湿(90％±5％)、强光(4500Lx)条件下样品有关物质基本无变化，表明晶型B对高温60℃、高湿、光照稳定。The stability test of the crystal compound of Form C under the three conditions of high temperature, high humidity and light, the results are shown in the following table (table 3-5), high temperature (60℃), high humidity (90%±5%), strong Under the condition of light (4500Lx), the related substances of the sample are basically unchanged, indicating that the crystal form B is stable to high temperature 60℃, high humidity and light.
表3-5 晶型C稳定性结果测定表Table 3-5 Determination of stability results of crystal form C
Figure PCTCN2020130060-appb-000039
Figure PCTCN2020130060-appb-000039
在40℃下进行经6月稳定性测试，结果如下表(表3-6)所示，这表明该晶体稳定性良好，适合长期保存。The stability test was carried out at 40°C for 6 months, and the results are shown in the following table (Table 3-6), which indicates that the crystal has good stability and is suitable for long-term storage.
表3-6 晶型C长期试验测定结果表Table 3-6 Long-term test results of crystal form C
Figure PCTCN2020130060-appb-000040
Figure PCTCN2020130060-appb-000040
Figure PCTCN2020130060-appb-000041
Figure PCTCN2020130060-appb-000041
实施例3-40 MB07133晶型D晶体化合物的稳定性Example 3-40 The stability of MB07133 crystal form D crystal compound
本实施例描述了晶型D晶体化合物的稳定性实验。This example describes the stability experiment of the crystalline compound of Form D.
在高温、高湿、光照三种条件下晶型D晶体化合物的稳定性测试，结果如下表(表3-7)所示，高温(60℃)、高湿(90％±5％)、强光(4500Lx)条件下样品有关物质基本无变化，表明晶型D对高温60℃、高湿、光照稳定。The stability test of the crystal compound of Form D under the three conditions of high temperature, high humidity and light, the results are shown in the following table (table 3-7), high temperature (60℃), high humidity (90%±5%), strong Under the condition of light (4500Lx), the related substances of the sample are basically unchanged, indicating that the crystal form D is stable to high temperature 60℃, high humidity and light.
表3-7 晶型D稳定性结果测定表Table 3-7 Determination of stability results of crystal form D
Figure PCTCN2020130060-appb-000042
Figure PCTCN2020130060-appb-000042
在40℃下进行经6月稳定性测试，结果如下表(表3-8)所示，这表明该晶体稳定性良好，适合长期保存。The stability test was carried out at 40°C for 6 months, and the results are shown in the following table (Table 3-8), which indicates that the crystal has good stability and is suitable for long-term storage.
表3-8 晶型D长期试验测定结果表Table 3-8 Long-term test results of crystal form D
Figure PCTCN2020130060-appb-000043
Figure PCTCN2020130060-appb-000043
实施例3-41 MB07133晶型E晶体化合物的稳定性Example 3-41 The stability of MB07133 crystal form E crystal compound
本实施例描述了晶型E晶体化合物的稳定性实验。This example describes the stability experiment of the crystalline compound of Form E.
在高温、高湿、光照三种条件下晶型E晶体化合物的稳定性测试，结果如下表(表3-9)所示，高温(60℃)、高湿(90％±5％)、强光(4500Lx)条件下样品有关物质基本无变化，表明晶型E对高温60℃、高湿、光照稳定。The stability test of the crystal compound of Form E under the three conditions of high temperature, high humidity and light, the results are shown in the following table (Table 3-9), high temperature (60℃), high humidity (90%±5%), strong Under the condition of light (4500Lx), the related substances of the sample are basically unchanged, indicating that the crystal form E is stable to high temperature 60℃, high humidity and light.
表3-9 晶型E稳定性结果测定表Table 3-9 Determination of stability results of crystal form E
Figure PCTCN2020130060-appb-000044
Figure PCTCN2020130060-appb-000044
在40℃下进行经6月稳定性测试，结果如下表(表3-10)所示，这表明该晶体稳定性良好，适合长期保存。The stability test was carried out at 40°C for 6 months, and the results are shown in the following table (Table 3-10), which indicates that the crystal has good stability and is suitable for long-term storage.
表3-10 晶型E长期试验测定结果表Table 3-10 Long-term test results of crystal form E
Figure PCTCN2020130060-appb-000045
Figure PCTCN2020130060-appb-000045
实施例3-42 MB07133晶型F晶体化合物的稳定性Example 3-42 The stability of MB07133 crystal form F crystal compound
本实施例描述了晶型F晶体化合物的稳定性实验。This example describes the stability experiment of the crystalline compound of crystalline form F.
在高温、高湿、光照三种条件下晶型F晶体化合物的稳定性测试，结果如下表(表3-11)所示，高温(60℃)、高湿(90％±5％)、强光(4500Lx)条件下样品有关物质基本无变化，表明晶型F对高温60℃、高湿、光照稳定。The stability test of the crystal compound of Form F under the three conditions of high temperature, high humidity and light, the results are shown in the following table (Table 3-11), high temperature (60℃), high humidity (90%±5%), strong Under the condition of light (4500Lx), the related substances of the sample are basically unchanged, indicating that the crystal form F is stable to high temperature 60℃, high humidity and light.
表3-11 晶型F稳定性结果测定表Table 3-11 Determination of stability results of crystal form F
Figure PCTCN2020130060-appb-000046
Figure PCTCN2020130060-appb-000046
在40℃下进行经6月稳定性测试，结果如下表(表3-12)所示，这表明该晶体稳定性良好，适合长期保存。The stability test was carried out at 40°C for 6 months, and the results are shown in the following table (Table 3-12), which indicates that the crystal has good stability and is suitable for long-term storage.
表3-12 晶型F长期试验测定结果表Table 3-12 Long-term test results of crystal form F
Figure PCTCN2020130060-appb-000047
Figure PCTCN2020130060-appb-000047
实施例3-43 包含MB07133晶型A晶体的药物组合物Example 3-43 Pharmaceutical composition containing MB07133 crystal form A crystals
按处方如下表(表3-13)称取或量取物料，将MB07133的晶型A晶体加入至温度为(2℃～8℃)的注射用水中，搅拌加入磷酸调节pH值至3.8～4.0，继续搅拌使溶液澄清。置于低温水浴中，使其温度保持在(2℃～8℃)，加入0.1％(w/v)的针用活性炭，搅拌30min，脱炭，经0.45μm滤膜初滤，再经0.22μm滤膜精滤，灌装和半加塞后，置入冷冻干燥机中，冷冻干燥，全压塞，轧盖。得到MB07133冻干粉针剂。Weigh or measure the materials according to the recipe in the following table (Table 3-13), add the crystal form A of MB07133 to the water for injection at a temperature of (2℃～8℃), stir and add phosphoric acid to adjust the pH to 3.8～4.0 , Continue to stir to make the solution clear. Put it in a low temperature water bath, keep the temperature at (2℃～8℃), add 0.1%(w/v) activated carbon for needles, stir for 30min, decarburize, filter through 0.45μm membrane, and then through 0.22μm After the filter membrane is finely filtered, filled and partially plugged, it is placed in a freeze dryer, freeze-dried, fully plugged, and capped. Obtain MB07133 freeze-dried powder injection.
表3-13 晶型A晶体的药物配方Table 3-13 Drug formula of crystal form A
Figure PCTCN2020130060-appb-000048
Figure PCTCN2020130060-appb-000048
实施例3-44 包含MB07133晶型B晶体的药物组合物Example 3-44 Pharmaceutical composition containing MB07133 crystal form B crystal
按处方如下表(表3-14)称取或量取物料，将MB07133的晶型B晶体加入至温度为(2℃～8℃)的注射用水中，搅拌加入磷酸调节pH值至3.8～4.0，继续搅拌使溶液澄清。置于低温水浴中，使其温度保持在(2℃～8℃)，加入0.1％(w/v)的针用活性炭，搅拌30min，脱炭，经0.45μm滤膜初滤，再经0.22μm滤膜精滤，灌装和半加塞后，置入冷冻干燥机中，冷冻干燥，全压塞，轧盖。得到MB07133冻干粉针剂。Weigh or measure the materials according to the following prescription (Table 3-14), add the crystal form B of MB07133 to the water for injection at the temperature (2℃～8℃), stir and add phosphoric acid to adjust the pH to 3.8～4.0 , Continue to stir to make the solution clear. Put it in a low temperature water bath, keep the temperature at (2℃～8℃), add 0.1%(w/v) activated carbon for needles, stir for 30min, decarburize, filter through 0.45μm membrane, and then through 0.22μm After the filter membrane is finely filtered, filled and partially plugged, it is placed in a freeze dryer, freeze-dried, fully plugged, and capped. Obtain MB07133 freeze-dried powder injection.
表3-14 晶型B晶体的药物配方Table 3-14 Drug formula of crystal form B
Figure PCTCN2020130060-appb-000049
Figure PCTCN2020130060-appb-000049
实施例3-45 包含MB07133晶型C晶体的药物组合物Example 3-45 Pharmaceutical composition containing MB07133 crystal form C crystal
按处方如下表(表3-15)称取或量取物料，将MB07133的晶型C晶体加入至温度为(2℃～8℃)的注射用水中，搅拌加入磷酸调节pH值至3.8～4.0，继续搅拌使溶液澄清。置于低温水浴中，使其温度保持在(2℃～8℃)，加入0.1％(w/v)的针用活性炭，搅拌30min，脱炭，经0.45μm滤膜初滤，再经0.22μm滤膜精滤，灌装和半加塞后，置入冷冻干燥机中，冷冻干燥，全压塞，轧盖。得到MB07133冻干粉针剂。Weigh or measure the materials in the following table (Table 3-15) according to the prescription, add the crystal form C of MB07133 to the water for injection at the temperature (2℃～8℃), stir and add phosphoric acid to adjust the pH to 3.8～4.0 , Continue to stir to make the solution clear. Put it in a low temperature water bath, keep the temperature at (2℃～8℃), add 0.1%(w/v) activated carbon for needles, stir for 30min, decarburize, filter through 0.45μm membrane, and then through 0.22μm After the filter membrane is finely filtered, filled and partially plugged, it is placed in a freeze dryer, freeze-dried, fully plugged, and capped. Obtain MB07133 freeze-dried powder injection.
表3-15 晶型C晶体的药物配方Table 3-15 Drug formula of crystal form C
Figure PCTCN2020130060-appb-000050
Figure PCTCN2020130060-appb-000050
实施例3-46 包含MB07133晶型D晶体的药物组合物Example 3-46 Pharmaceutical composition containing MB07133 crystal form D
按处方如下表(表3-16)称取或量取物料，将MB07133的晶型D晶体加入至温度为(2℃～8℃)的注射用水中，搅拌加入磷酸调节pH值至3.8～4.0，继续搅拌使溶液澄清。置于低温水浴中，使其温度保持在(2℃～8℃)，加入0.1％(w/v)的针用活性炭，搅拌30min，脱炭，经0.45μm滤膜初滤，再经0.22μm滤膜精滤，灌装和半加塞后，置入冷冻干燥机中，冷冻干燥，全压塞，轧盖。得到MB07133冻干粉针剂。Weigh or measure the materials according to the recipe in the following table (Table 3-16), add the crystal form D of MB07133 to the water for injection at the temperature (2℃～8℃), stir and add phosphoric acid to adjust the pH to 3.8～4.0 , Continue to stir to make the solution clear. Put it in a low temperature water bath, keep the temperature at (2℃～8℃), add 0.1%(w/v) activated carbon for needles, stir for 30min, decarburize, filter through 0.45μm membrane, and then through 0.22μm After the filter membrane is finely filtered, filled and partially plugged, it is placed in a freeze dryer, freeze-dried, fully plugged, and capped. Obtain MB07133 freeze-dried powder injection.
表3-16 晶型D晶体的药物配方Table 3-16 Drug formula of crystal form D
Figure PCTCN2020130060-appb-000051
Figure PCTCN2020130060-appb-000051
实施例3-47 包含MB07133晶型E晶体的药物组合物Example 3-47 Pharmaceutical composition containing MB07133 crystal form E crystal
按处方如下表(表3-17)称取或量取物料，将MB07133的晶型E晶体加入至温度为(2℃～8℃)的注射用水中，搅拌加入磷酸调节pH值至3.8～4.0，继续搅拌使溶液澄清。置于低温水浴中，使其温度保持在(2℃～8℃)，加入0.1％(w/v)的针用活性炭，搅拌30min，脱炭，经0.45μm滤膜初滤，再经0.22μm滤膜精滤，灌装和半加塞后，置入冷冻干燥机中，冷冻干燥，全压塞，轧盖。得到MB07133冻干粉针剂。Weigh or measure the materials according to the following prescription (Table 3-17), add the crystal form E of MB07133 to the water for injection at the temperature (2℃～8℃), stir and add phosphoric acid to adjust the pH to 3.8～4.0 , Continue to stir to make the solution clear. Put it in a low temperature water bath, keep the temperature at (2℃～8℃), add 0.1%(w/v) activated carbon for needles, stir for 30min, decarburize, filter through 0.45μm membrane, and then through 0.22μm After the filter membrane is finely filtered, filled and partially plugged, it is placed in a freeze dryer, freeze-dried, fully plugged, and capped. Obtain MB07133 freeze-dried powder injection.
表3-17 晶型E晶体的药物配方Table 3-17 Drug formula of crystal form E
Figure PCTCN2020130060-appb-000052
Figure PCTCN2020130060-appb-000052
Figure PCTCN2020130060-appb-000053
Figure PCTCN2020130060-appb-000053
实施例3-48 包含MB07133晶型F晶体的药物组合物Example 3-48 Pharmaceutical composition containing MB07133 crystal form F crystal
按处方如下表(表3-18)称取或量取物料，将MB07133的晶型F晶体加入至温度为(2℃～8℃)的注射用水中，搅拌加入磷酸调节pH值至3.8～4.0，继续搅拌使溶液澄清。置于低温水浴中，使其温度保持在(2℃～8℃)，加入0.1％(w/v)的针用活性炭，搅拌30min，脱炭，经0.45μm滤膜初滤，再经0.22μm滤膜精滤，灌装和半加塞后，置入冷冻干燥机中，冷冻干燥，全压塞，轧盖。得到MB07133冻干粉针剂。Weigh or measure the materials according to the recipe in the following table (Table 3-18), add the crystal form F of MB07133 to the water for injection at the temperature (2℃～8℃), stir and add phosphoric acid to adjust the pH to 3.8～4.0 , Continue to stir to make the solution clear. Put it in a low temperature water bath, keep the temperature at (2℃～8℃), add 0.1%(w/v) activated carbon for needles, stir for 30min, decarburize, filter through 0.45μm membrane, and then through 0.22μm After the filter membrane is finely filtered, filled and partially plugged, it is placed in a freeze dryer, freeze-dried, fully plugged, and capped. Obtain MB07133 freeze-dried powder injection.
表3-18 晶型F晶体的药物配方Table 3-18 Drug formula of crystal form F
Figure PCTCN2020130060-appb-000054
Figure PCTCN2020130060-appb-000054

Claims (12)

  1. 治疗肝病的晶体，其为替诺福韦磷酸酯的晶体、甲磺酸帕拉德福韦的晶体、或MB07133晶体，其中，替诺福韦磷酸酯的晶体具有基本上如图1-1、1-2、1-3、1-4或1-5所示的X-射线粉末衍射图谱，甲磺酸帕拉德福韦的晶体具有基本上如图2-1、2-3、2-5、2-7或2-9所示的X-射线粉末衍射图谱，MB07133晶体具有基本上如图3-1、3-2、3-3、3-4、3-5或3-6所示的X-射线粉末衍射图谱。The crystals for the treatment of liver disease are tenofovir phosphate crystals, paradefovir mesylate crystals, or MB07133 crystals. Among them, tenofovir phosphate crystals are basically shown in Figure 1-1, The X-ray powder diffraction patterns shown in 1-2, 1-3, 1-4 or 1-5, the crystals of paradefovir mesylate have basically shown in Figures 2-1, 2-3, 2- 5. X-ray powder diffraction pattern shown in 2-7 or 2-9, MB07133 crystal has basically shown in Figure 3-1, 3-2, 3-3, 3-4, 3-5 or 3-6 X-ray powder diffraction pattern shown.
  2. 权利要求1所述的晶体，其特征在于，替诺福韦磷酸酯的晶体的差热分析曲线在151.7℃、152.3℃、152.6℃、149.2℃或151.4℃有一尖吸热峰，甲磺酸帕拉德福韦的晶体的差热分析曲线在196.9℃、191.8℃、193.4℃、192.6℃或193.2℃有一尖吸热峰，或者，MB07133晶体的差热分析曲线在239.81℃、253.21℃、247.95℃、251.10℃、246.57℃或249.26℃有一尖吸热峰。The crystal of claim 1, wherein the differential thermal analysis curve of the crystal of tenofovir phosphate has a sharp endothermic peak at 151.7°C, 152.3°C, 152.6°C, 149.2°C or 151.4°C. The differential thermal analysis curve of the crystal of Radfovir has a sharp endothermic peak at 196.9℃, 191.8℃, 193.4℃, 192.6℃ or 193.2℃, or the differential thermal analysis curve of the MB07133 crystal is 239.81℃, 253.21℃, 247.95℃ There is a sharp endothermic peak at 251.10℃, 246.57℃ or 249.26℃.
  3. 权利要求1或2所述的晶体，其为单晶。The crystal of claim 1 or 2, which is a single crystal.
  4. 用于治疗或预防肝脏疾病或代谢性疾病的药物组合物，其包括权利要求1～3之任一所述的晶体和药学上可接受的辅料。A pharmaceutical composition for treating or preventing liver disease or metabolic disease, which comprises the crystal of any one of claims 1 to 3 and pharmaceutically acceptable excipients.
  5. 权利要求4所述的药物组合物，其为口服剂型，优选为片剂。The pharmaceutical composition of claim 4, which is an oral dosage form, preferably a tablet.
  6. 权利要求4所述的药物组合物，其为注射剂。The pharmaceutical composition of claim 4, which is an injection.
  7. 权利要求4所述的药物组合物，其中，药学上可接受的辅料包括甘露醇、预胶化淀粉、硬脂酸镁和/或二氧化硅。The pharmaceutical composition of claim 4, wherein the pharmaceutically acceptable excipients include mannitol, pregelatinized starch, magnesium stearate and/or silicon dioxide.
  8. 权利要求1-3之任一所述的晶体在制备用于治疗或预防肝脏疾病或代谢性疾病的药物中的应用。The use of the crystals of any one of claims 1 to 3 in the preparation of medicines for the treatment or prevention of liver diseases or metabolic diseases.
  9. 权利要求8所述的应用，其是在制备用于治疗或预防乙型肝炎的药物中的应用，或者是在制备用于降低患者中乙型肝炎病毒水平的药物中的应用。The application according to claim 8, which is an application in the preparation of a medicine for treating or preventing hepatitis B, or an application in the preparation of a medicine for reducing the level of hepatitis B virus in a patient.
  10. 权利要求8所述的应用，其是在制备用于治疗晚期肝癌的药物中的应用。The application according to claim 8, which is an application in the preparation of a medicament for the treatment of advanced liver cancer.
  11. 权利要求10所述的应用，其是MB07133晶体的应用。The application of claim 10, which is an application of MB07133 crystal.
  12. 检测权利要求1-3之任一所述的晶体的方法，其特征在于，对疑似晶体进行X-射线粉末衍射检测，将所得到的X-射线粉末衍射图谱与如图1-1、1-2、1-3、1-4、1-5、2-1、2-3、2-5、2-7、2-9、3-1、3-2、3-3、3-4、3-5和3-6之一所示的X-射线粉末衍射图谱进行比对。The method for detecting the crystal of any one of claims 1 to 3, characterized in that the suspected crystal is subjected to X-ray powder diffraction detection, and the obtained X-ray powder diffraction pattern is compared with that shown in Figs. 1-1, 1- 2. 1-3, 1-4, 1-5, 2-1, 2-3, 2-5, 2-7, 2-9, 3-1, 3-2, 3-3, 3-4, Compare the X-ray powder diffraction patterns shown in one of 3-5 and 3-6.
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CN1964967A (en) * 2004-06-08 2007-05-16 症变治疗公司 Lewis acid mediated synthesis of cyclic esters
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