CN108948083A - 一种富马酸替诺福韦二吡呋酯新晶型及其制备方法 - Google Patents
一种富马酸替诺福韦二吡呋酯新晶型及其制备方法 Download PDFInfo
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- CN108948083A CN108948083A CN201710346394.XA CN201710346394A CN108948083A CN 108948083 A CN108948083 A CN 108948083A CN 201710346394 A CN201710346394 A CN 201710346394A CN 108948083 A CN108948083 A CN 108948083A
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- tenofovir disoproxil
- disoproxil fumarate
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- 239000013078 crystal Substances 0.000 title claims abstract description 32
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title claims abstract description 32
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title abstract description 3
- 239000000843 powder Substances 0.000 claims description 5
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 3
- 230000000149 penetrating effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 4
- 238000001514 detection method Methods 0.000 abstract description 3
- 238000000634 powder X-ray diffraction Methods 0.000 abstract description 3
- 229910017488 Cu K Inorganic materials 0.000 abstract description 2
- 229910017541 Cu-K Inorganic materials 0.000 abstract description 2
- 230000005855 radiation Effects 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 7
- 239000001530 fumaric acid Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 4
- 229960004556 tenofovir Drugs 0.000 description 4
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 3
- -1 fumaric acid tenofovir Furan ester Chemical class 0.000 description 3
- 208000002672 hepatitis B Diseases 0.000 description 3
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 2
- 229930024421 Adenine Natural products 0.000 description 2
- 229960000643 adenine Drugs 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229940126656 GS-4224 Drugs 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种新的富马酸替诺福韦二吡呋酯晶型以及其制备方法。所述的富马酸替诺福韦二吡呋酯新晶型命名为晶型1，使用Cu‑Kα辐射检测的X射线粉末衍射图谱中在约4.9，5.4，10.3，10.7，14.7，18.6，19.5，24.6，29.6，34.7(±0.2)度处有特征峰。本发明还提供一种制备富马酸替诺福韦二吡呋酯晶型1的方法，简便、重现性好，所得富马酸替诺福韦二吡呋酯晶型1纯度高、稳定性好，适于工业化生产。
Description
技术领域
本发明涉及富马酸替诺福韦二吡呋酯新的可药用晶型(即9-[(R)-2-[[双[[(异丙氧基羰基)氧基]甲氧基]氧膦基]甲氧基]-丙基]腺嘌呤富马酸盐)。
技术背景
富马酸替诺福韦二吡呋酯(Tenofovir Disoproxil Fumarate)化学名为 9-[(R)-2-[[双[[(异丙氧基羰基)氧基]甲氧基]氧膦基]甲氧基]-丙基]腺嘌呤富马酸盐，其结构式如下式所示：
富马酸替诺福韦二吡呋酯是美国吉利德公司(Gilead Sciences)公司研制的核苷酸逆转录酶抑制剂，具有抗人类免疫缺陷病毒(HIV)和慢性乙型肝炎(CHB) 的活性，最初于2001年FDA批准用于HIV感染的治疗，然后于2008年4月和 8月，欧盟委员会和美国FDA分别于批准用于治疗CHB。
专利文献报道了富马酸替诺福韦二吡呋酯多种晶型，分别为：FormⅠ、Form A、FormB。专利CN100383148C公开了富马酸替诺福韦二吡呋酯(FormⅠ)晶型。Crystal Growth&Design(Characterization of Tenofovir Disoproxil Fumarate and Its Behaviorunder Heating)期刊公布了富马酸替诺福韦二吡呋酯Form A、Form B 等多种晶型。
发明内容
本发明公开了一种新的纯度高、稳定性好的富马酸替诺福韦二吡呋酯的晶型。
本发明所述富马酸替诺福韦二吡呋酯新晶型称为晶型1，使用Cu-Kα辐射检测其X射线粉末衍射图谱中，具有以下特征峰，其2θ角度值及相对强度如下表所示：
本发明所述的富马酸替诺福韦二吡呋酯晶型1具有如附图1所示的X粉末衍射图谱。
本发明所述的富马酸替诺福韦二吡呋酯晶型1具有如附图2所示的差示扫描量热法分析图谱。
本发明同时提供一种制备富马酸替诺福韦二吡呋酯晶型1的方法：将富马酸替诺福韦二吡呋酯溶于异丙醇中，配置成150-300g/L混悬液，加热到50-70℃使溶液完全溶解，将溶液预冷至-5～10℃，过夜，抽滤、真空干燥富马酸替诺福韦二吡呋酯至恒重。
附图说明
附图1根据本发明实施例1得到的富马酸替诺福韦二吡呋酯晶型1的X射线粉末衍射(XRPD)图谱。
附图2根据本发明实施例1得到的富马酸替诺福韦二吡呋酯晶型1的差示扫描量热法分析图谱(DSC)。
具体实施方式
以下的实施例在于详细说明本发明，而非限制本发明
本发明的分析检测条件如下：
1、X-射线粉末衍射数据是使用德国布鲁克公司的BRUKER D8 Advance测定的，电压电流：40kV,40mA；测角仪：立式测角仪，半径280mm；狭缝： DS＝2°,SS＝1/2°,mask＝15mm,RS＝5.0mm；探测器：LYNXEYE检测器；扫描模式：连续扫描；扫描范围：3°-40°；每步计数时间：0.2s；扫描总时间：390s。
2、DSC是由德国NETZSCH公司的DSC 200 F3测定，测试条件为N2流速 50ml/min,升温速度10℃/min。
实施例1
将1g富马酸替诺福韦二吡呋酯溶于5ml异丙醇形成悬浊液，搅拌下加热至 60℃使其完全溶解，搅拌下冷却至0℃搅拌1小时。抽滤、真空40℃干燥.得到富马酸替诺福韦二吡呋酯晶型1。
实施例2
将5g富马酸替诺福韦二吡呋酯溶于25ml异丙醇形成悬浊液，搅拌下加热至60℃使其完全溶解，搅拌下冷却至0℃搅拌2小时。抽滤、真空40℃干燥.得到富马酸替诺福韦二吡呋酯晶型1
实施例3
将10g富马酸替诺福韦二吡呋酯溶于50ml异丙醇形成悬浊液，搅拌下加热至60℃使其完全溶解，搅拌下冷却至0℃搅拌2小时。抽滤、真空40℃干燥.得到富马酸替诺福韦二吡呋酯晶型1
实施例4
将100g富马酸替诺福韦二吡呋酯溶于500ml异丙醇形成悬浊液，搅拌下加热至60℃使其完全溶解，搅拌下冷却至0℃搅拌2小时。抽滤、真空40℃干燥.得到富马酸替诺福韦二吡呋酯晶型1。
Claims (5)
1.一种富马酸替诺福韦二吡呋酯(式1)的晶型1，其特征在于所述晶型1的X射线粉末衍射图谱中包括以下2θ角所示的特征峰：4.9，5.4，10.3，10.7，14.7，18.6，19.5，24.6，29.6，34.7(±0.2)。
2.如权利要求1所述的富马酸替诺福韦二吡呋酯的晶型1，其特征在于其具有如附图1所示的X粉末衍射图谱。
3.如权利要求1所述的富马酸替诺福韦二吡呋酯的晶型1，其特征在于所述晶型1通过差示扫描量热法分析显示在约99-107℃处有吸热峰。
4.如权利要求1所述的富马酸替诺福韦二吡呋酯的晶型1，其特征在于所述晶型1通过差示扫描量热法分析显示在约115-122℃处有吸热峰。
5.如权利要求1所述的富马酸替诺福韦二吡呋酯的晶型1，其特征在于其具有如附图2所示的DSC图谱。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109942634A (zh) * | 2019-01-24 | 2019-06-28 | 深圳科兴药业有限公司 | 一种富马酸替诺福韦二吡呋酯的晶型i及制备方法和应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101948485A (zh) * | 2010-08-30 | 2011-01-19 | 杭州和素化学技术有限公司 | 富马酸替诺福韦酯α晶型及其制备方法和应用 |
| US20110112292A1 (en) * | 2008-04-25 | 2011-05-12 | Cipla Limited | Crystalline Form of Tenofovir Disoproxil and a Process for Its Preparation |
| CN103641858A (zh) * | 2013-12-31 | 2014-03-19 | 湖南千金湘江药业股份有限公司 | 一种富马酸替诺福韦二吡呋酯及其制备方法 |
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- 2017-05-17 CN CN201710346394.XA patent/CN108948083A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110112292A1 (en) * | 2008-04-25 | 2011-05-12 | Cipla Limited | Crystalline Form of Tenofovir Disoproxil and a Process for Its Preparation |
| CN101948485A (zh) * | 2010-08-30 | 2011-01-19 | 杭州和素化学技术有限公司 | 富马酸替诺福韦酯α晶型及其制备方法和应用 |
| CN103641858A (zh) * | 2013-12-31 | 2014-03-19 | 湖南千金湘江药业股份有限公司 | 一种富马酸替诺福韦二吡呋酯及其制备方法 |
Non-Patent Citations (1)
| Title |
|---|
| 吕扬 等: "《晶型药物》", 31 October 2009, 人民卫生出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109942634A (zh) * | 2019-01-24 | 2019-06-28 | 深圳科兴药业有限公司 | 一种富马酸替诺福韦二吡呋酯的晶型i及制备方法和应用 |
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