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
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- tenofovir disoproxil
- disoproxil fumarate
- crystal form
- preparation
- crystal forms
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 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
Landscapes
- 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。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710346394.XA CN108948083A (zh) | 2017-05-17 | 2017-05-17 | 一种富马酸替诺福韦二吡呋酯新晶型及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710346394.XA CN108948083A (zh) | 2017-05-17 | 2017-05-17 | 一种富马酸替诺福韦二吡呋酯新晶型及其制备方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN108948083A true CN108948083A (zh) | 2018-12-07 |
Family
ID=64461396
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710346394.XA Pending CN108948083A (zh) | 2017-05-17 | 2017-05-17 | 一种富马酸替诺福韦二吡呋酯新晶型及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108948083A (zh) |
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 |
-
2017
- 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 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN113527203B (zh) | 乐伐替尼甲磺酸盐的晶型及其制备方法和用途 | |
CN104302628B (zh) | 羧酸化合物 | |
WO2017025784A1 (en) | A carbon dioxide adduct of palbociclib | |
WO2016165650A1 (zh) | 奥拉帕尼与尿素的共晶及其制备方法 | |
SK285222B6 (sk) | Spôsob výroby 2,5-diamino-4,6-dihalogénpyrimidínu | |
CN108948083A (zh) | 一种富马酸替诺福韦二吡呋酯新晶型及其制备方法 | |
JP2018510914A (ja) | ジシクロプラチンの製造方法 | |
JP2014524476A5 (zh) | ||
US10435395B1 (en) | Crystal forms of lifitegrast | |
CN108290882B (zh) | 用于治疗呼吸道合胞病毒感染的4-喹唑啉胺衍生物的晶形 | |
CN104926872B (zh) | 替诺福韦艾拉酚胺半酒石酸盐 | |
WO2016001844A1 (en) | Amorphous form of afatinib dimaleate | |
US10196360B2 (en) | Crystal forms of bedaquiline fumarate and preparation methods therefor | |
JP2018030884A (ja) | テノホビルの固体形態 | |
CN111393318A (zh) | 一种新型粉背蕨酸酰胺衍生物的合成及其在抗肿瘤药物中的应用 | |
WO2016092442A1 (en) | Processes for the preparation of crystalline forms of palbociclib acetate | |
JP2024520704A (ja) | アミスルプリドの結晶形態を製造するための方法 | |
CN110627793B (zh) | 一种喷昔洛韦与3,5-二羟基苯甲酸共晶及其制备方法 | |
WO2011001383A1 (en) | Crystalline form of fosamprenavir calcium | |
CN108727381B (zh) | 一种alk酪氨酸激酶抑制剂的盐及其制备方法 | |
KR20230022882A (ko) | 라벡시모드의 결정성 형태를 제조하는 방법 | |
CN110606841A (zh) | 吡啶胺基嘧啶衍生物的晶型及其制备方法 | |
CN107344934A (zh) | 药物活性物质的固体形式 | |
CN109863149A (zh) | 一种依匹哌唑新晶型及其制备方法 | |
WO2018183686A1 (en) | 1-aminocyclopropane-1-carboxylic acid polymorphs |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20181207 |
|
RJ01 | Rejection of invention patent application after publication |