WO2017211325A1 - 富马酸替诺福韦艾拉酚胺盐的新晶型、制备方法及其用途 - Google Patents

富马酸替诺福韦艾拉酚胺盐的新晶型、制备方法及其用途 Download PDF

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WO2017211325A1
WO2017211325A1 PCT/CN2017/088538 CN2017088538W WO2017211325A1 WO 2017211325 A1 WO2017211325 A1 WO 2017211325A1 CN 2017088538 W CN2017088538 W CN 2017088538W WO 2017211325 A1 WO2017211325 A1 WO 2017211325A1
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ethyl
propyl
amino
isopropoxycarbonyl
phenoxyphosphinyl
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PCT/CN2017/088538
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French (fr)
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孟晓明
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上海诚妙医药科技有限公司
孟晓明
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Priority to CN201780035421.XA priority Critical patent/CN109476689B/zh
Publication of WO2017211325A1 publication Critical patent/WO2017211325A1/zh
Priority to US16/208,721 priority patent/US10479810B2/en

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    • 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 System
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • 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

Definitions

  • the present invention relates to 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl Novel crystals of adenine fumarate and preparation method and use thereof.
  • Compound 1 tenofovir alafenamide (TAF or GS-7340) is one of the main ingredients in the FDA-approved anti-AIDS drug Genvoya. The drug was developed by Gilead. Tenofovir iramol is a nucleic acid reverse transcriptase inhibitor and a potential drug for tenofovir.
  • tenofovir alafenamide is C 21 H 29 N 6 O 5 P, which has a molecular weight of 467.5.
  • the chemical structural formula of tenofovir alafenamide is as follows:
  • Chemical raw materials must be prepared into a preparation, which must have good purity, stability, physical and chemical properties and operability. And these properties are related to the crystalline form of the drug, and different crystal forms have Different physical and chemical properties.
  • the stability of drug preservation and the purpose of improving the efficacy of the drug require a state in which the drug is made into a crystal.
  • the physicochemical properties of the pharmaceutically active substance can be improved by selecting the form of its appropriate salt: such as solubility, dissolution rate, stability, purity, and the like. These physical and chemical properties further influence the quality and bioavailability of the drug.
  • the choice of ion pairs used for salt formation and the formation of salts are not always straightforward, as the physical and chemical properties of different pairs of ions forming salts with the same compounds can vary widely, and some salts can improve physical and chemical properties.
  • the salt can not be improved, and even the physical and chemical properties are more detrimental to pharmaceutical development. Therefore, finding and manufacturing a salt for pharmaceutically developable and improving the physical properties of a drug is a practical creation work.
  • a drug and a salt thereof may exist in a plurality of crystalline form states, and different crystal forms of the same drug and its salt may have different dissolution and absorption in the body, thereby affecting dissolution and release of the preparation.
  • the research on the polymorphic form of the drug and its salt can find the dominant crystalline form of the drug which is beneficial to the action of the drug, and at the same time, determine the formulation process according to the characteristics of the crystalline form, and effectively ensure the equivalence of the batch drug in the production.
  • Tenofovir alafenamide hemifumarate is one of the main components of the anti-AIDS drug Genvoya.
  • the combination of Genovya also contains other drugs such as Elvitegravir, cobicistat, emtricitabine.
  • TAF hemifumarate crystal form I WO2013025788A1
  • the chemical stability of TAF is affected, and degradation products are easily generated, thereby affecting the quality and efficacy of the mixed preparation, in order to solve
  • we have unexpectedly discovered that the new crystalline form II, monofumarate (form A) and sesquifusinate (form B) of TAF hemi-fumarate can significantly improve TAF.
  • the chemical stability associated with emtricitabine makes this compound more stable and improves quality and shelf life.
  • the ruthenium fumarate crystal form II is characterized in that it has a characteristic peak at least at 2 ⁇ values of 26.6 ⁇ 0.2, 21.3 ⁇ 0.2, 27.1 ⁇ 0.2, 19.6 ⁇ 0.2, and 18.7 ⁇ 0.2 in the X-ray powder diffraction pattern.
  • the characteristic peaks are also present at 2 ⁇ values of 32.1 ⁇ 0.2, 21.9 ⁇ 0.2, 5.4 ⁇ 0.2, 22.4 ⁇ 0.2, 11.1 ⁇ 0.2, and 17.8 ⁇ 0.2.
  • characteristic peaks at 2 ⁇ values of 15.9 ⁇ 0.2, 24.5 ⁇ 0.2, 24.9 ⁇ 0.2, 19.0 ⁇ 0.2, 23.6 ⁇ 0.2, and 30.0 ⁇ 0.2.
  • the characteristic peaks are also present at 2 ⁇ values of 32.4 ⁇ 0.2, 37.5 ⁇ 0.2, 10.5 ⁇ 0.2, 14.5 ⁇ 0.2, 16.7 ⁇ 0.2, and 40.3 ⁇ 0.2. More preferably, it has a characteristic peak at 2 ⁇ values of 23.9 ⁇ 0.2, 12.3 ⁇ 0.2, 38.6 ⁇ 0.2, 43.0 ⁇ 0.2, 27.8 ⁇ 0.2, 35.8 ⁇ 0.2.
  • the ruthenium fumarate crystal form A is characterized in that it has a characteristic peak at least at 2 ⁇ values of 23.8 ⁇ 0.2, 10.5 ⁇ 0.2, 28.5 ⁇ 0.2, 21.2 ⁇ 0.2, and 19.5 ⁇ 0.2 in the X-ray powder diffraction pattern.
  • characteristic peaks at 2 ⁇ values of 15.1 ⁇ 0.2, 23.2 ⁇ 0.2, 17.0 ⁇ 0.2, 9.8 ⁇ 0.2, 20.8 ⁇ 0.2, and 17.6 ⁇ 0.2.
  • the characteristic peaks are also present at 2 ⁇ values of 15.7 ⁇ 0.2, 27.1 ⁇ 0.2, 25.2 ⁇ 0.2, 33.5 ⁇ 0.2, 22.4 ⁇ 0.2, and 19.0 ⁇ 0.2.
  • the characteristic peaks are also present at 2 ⁇ values of 14.0 ⁇ 0.2, 30.2 ⁇ 0.2, 8.5 ⁇ 0.2, 31.3 ⁇ 0.2, 21.9 ⁇ 0.2, and 12.5 ⁇ 0.2.
  • the ruthenium fumarate crystal form B is characterized in that it has a characteristic peak at least at 2 ⁇ values of 10.5 ⁇ 0.2, 21.0 ⁇ 0.2, 10.9 ⁇ 0.2, 27.2 ⁇ 0.2, and 22.5 ⁇ 0.2 in the X-ray powder diffraction pattern.
  • the 2 ⁇ values are also 28.9 ⁇ 0.2, 27.7 ⁇ 0.2, 24.1 ⁇ 0.2, 18.7 ⁇ 0.2, 13.5 ⁇ 0.2, 20.6 ⁇ 0.2. There are characteristic peaks.
  • the characteristic peaks are also present at 2 ⁇ values of 4.9 ⁇ 0.2, 14.1 ⁇ 0.2, 11.2 ⁇ 0.2, 16.4 ⁇ 0.2, 23.2 ⁇ 0.2, and 19.6 ⁇ 0.2.
  • the characteristic peaks are also present at 2 ⁇ values of 14.8 ⁇ 0.2, 15.1 ⁇ 0.2, 12.3 ⁇ 0.2, 38.0 ⁇ 0.2, 17.3 ⁇ 0.2, and 15.7 ⁇ 0.2. More preferably, it has a characteristic peak at a 2 ⁇ value of 18.1 ⁇ 0.2, 21.8 ⁇ 0.2, 31.8 ⁇ 0.2, 35.0 ⁇ 0.2, 41.7 ⁇ 0.2, and 40.0 ⁇ 0.2.
  • step (ii) adding fumaric acid greater than the free base equivalent to the solution obtained in step (i) to precipitate the compound from the solution.
  • the disease is selected from the group consisting of: hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) infection.
  • HBV hepatitis B virus
  • HAV human immunodeficiency virus
  • the Rigaku Ultima IV powder diffractometer was used, which was irradiated with Cu-K ⁇ (40 kV, 40 mA) at room temperature using a D/tex Ultra detector.
  • the scanning range is from 3° to 45° in the 2 ⁇ range, and the scanning speed is 20°/min.
  • Measurement differences associated with such X-ray powder diffraction analysis results are produced by a variety of factors including: (a) errors in sample preparation (eg, sample height), (b) instrument error, (c) calibration differences, ( d) operator error (including errors that occur when determining peak position), and (e) properties of the substance (eg, preferred orientation error). Calibration errors and sample height errors often result in displacement of all peaks in the same direction. When a flat stent is used, a small difference in sample height will result in a large displacement of the XRPD peak position. Systematic studies have shown that a 1 mm sample height difference can result in a 2[Theta] peak shift of up to 1[deg.].
  • displacements can be identified from the X-ray diffraction pattern and can be eliminated by compensating for the displacement (using a system calibration factor for all peak position values) or recalibrating the instrument. As described above, measurement errors from different instruments can be corrected by applying a system calibration factor to make the peak positions consistent.
  • DSC Differential scanning calorimetry
  • thermogravimetric (TGA) analysis of the crystal form in the examples was carried out, and the operation and analysis steps were as follows.
  • a TA Q500 thermogravimetric analyzer was used, and an N 2 atmosphere was used, and the heating rate was 10 ° C/min.
  • the alcoholic organic solvent may be selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-octanol, 2,2,2-trifluoroethanol.
  • DSC Differential scanning calorimetry
  • TGA Thermogravimetric
  • the chlorinated alkane organic solvent may be selected from the group consisting of dichloromethane, chloroform, and 1,2-dichloroethane.
  • the ester organic solvent may be selected from the group consisting of ethyl formate, ethyl acetate, isopropyl acetate, butyl acetate, and dimethyl carbonate.
  • the ketone organic solvent may be selected from the group consisting of acetone, 2-butanone, 3-pentanone, and 4-methyl-2-pentanone.
  • the aromatic hydrocarbon organic solvent may be selected from the group consisting of toluene, cumene, p-xylene, mesitylene, and chlorobenzene.
  • the ether organic solvent may be selected from the group consisting of diethyl ether, diisopropyl ether, methyl tert-butyl ether, and methylcyclopentyl ether.
  • the alkane organic solvent may be selected from the group consisting of n-hexane, cyclohexane, and n-heptane.
  • TAF fumarate crystal form I prepared according to the method of WO2013025788A1
  • TAF fumarate crystal form II TAF fumarate crystal form A
  • TAF fumarate form B TAF fumarate form B
  • emtricitabine emtricitabine
  • the mixture was mixed at a weight ratio of about 1:15, placed at 40 ° C and a relative humidity of 75%, and placed open for 21 days.
  • the degradation of TAF was analyzed by HPLC at 0 days and 21 days. The results are shown in the following table. Shown as follows:

Abstract

本发明公开了9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新多晶型II、晶型A和晶型B其制备方法和药用用途。晶型II为半富马酸盐；晶型A为一富马酸盐；晶型B为倍半富马酸盐与现有晶型相比，新晶型在溶解度、稳定性和制备工艺方面具有明显优势。

Description

富马酸替诺福韦艾拉酚胺盐的新晶型、制备方法及其用途 技术领域
本发明涉及9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新型晶体及其制备方法和用途。
背景技术
化合物式1，替诺福韦艾拉酚胺(tenofovir alafenamide，TAF或GS-7340)是美国FDA已经批准的抗艾滋病药物Genvoya中的主要成份之一。该药物由Gilead公司开发。替诺福韦艾拉酚胺是一种核酸逆转录酶抑制剂，也是替诺福韦的潜药。
替诺福韦艾拉酚胺的分子式为C21H29N6O5P，其分子量为467.5。替诺福韦艾拉酚胺的化学结构式如下所示：
Figure PCTCN2017088538-appb-000001
化学原料药要成制剂，必须具备良好的纯度、稳定性、理化性质以及可操作性。而这些性质都与药物的结晶形态相关，不同晶型具有 不同的理化性质。药物保存的稳定性和提高药物疗效的目的，需要将药物制成晶体的状态。
药学活性物质的理化性质可通过选择其适当的盐的形式得以改善：如溶解度、溶出速率、稳定性、纯度等。这些理化性质又进一步的影响了药物的质量和生物利用度。然而，成盐所用的离子对的选择和盐的形成不总是简单易行的，因为不同对离子与相同的化合物形成盐的理化性质可有很大不同，有的盐可以改善理化性质，有的盐则不能改善，甚至理化性质更加不利于药学开发。因此寻找和制造出用于可药学开发并改善药物理化性质的盐是一种具有实用性的创造工作。
一种药物及其盐可以有多种晶型物质状态存在，同一种药物及其盐的不同晶型，在体内的溶解和吸收可能不同，从而会对制剂的溶出和释放产生影响。
对药物多晶型及其盐的研究，可发现有利于发挥药物作用的药物优势晶型，同时根据晶型的特点确定制剂工艺，有效保证生产的批间药物等效性等。
替诺福韦艾拉酚胺半富马酸盐是抗艾滋病药物Genvoya中的主要成份之一,Genovya这个复方制剂中还包含了其它药物如Elvitegravir,cobicistat,emtricitabine。而当前技术中，TAF半富马酸盐晶型I(WO2013025788A1)与emtricitabine混合制成片剂时，TAF化学稳定性会受到影响，易于产生降解产物，从而影响混合制剂的质量和疗效，为了解决这一难题，我们意外发现TAF半富马酸盐的新晶型II、一富马酸盐(晶型A)以及倍半富马酸盐(晶型B)可以显著提高TAF 与emtricitabine配伍的化学稳定性，从而使得这一复方制剂能够更加稳定和提高质量和保质期。
发明内容
9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II，其特征在于，其X射线粉末衍射图中至少在2θ值为26.6±0.2、21.3±0.2、27.1±0.2、19.6±0.2、18.7±0.2处具有特征峰。优选的，还可以在2θ值为32.1±0.2、21.9±0.2、5.4±0.2、22.4±0.2、11.1±0.2、17.8±0.2处具有特征峰。优选的，还可以在2θ值为15.9±0.2、24.5±0.2、24.9±0.2、19.0±0.2、23.6±0.2、30.0±0.2处具有特征峰。优选的，还可以在2θ值为32.4±0.2、37.5±0.2、10.5±0.2、14.5±0.2、16.7±0.2、40.3±0.2处具有特征峰。更优选的，还可以在2θ值为23.9±0.2、12.3±0.2、38.6±0.2、43.0±0.2、27.8±0.2、35.8±0.2处具有特征峰。
9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II的峰值熔点为106.6±2。
制备9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II的方法，其特征在于，
(i)将9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤游离碱解于有机溶液中。
(ii)向步骤(i)中得到的溶液中加入一定量的富马酸，使化合物从溶液中析出。
(iii)固液分离后得到9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II。
9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型A，其特征在于，其X射线粉末衍射图中至少在2θ值为23.8±0.2、10.5±0.2、28.5±0.2、21.2±0.2、19.5±0.2处具有特征峰。优选的，还可以在2θ值为15.1±0.2、23.2±0.2、17.0±0.2、9.8±0.2、20.8±0.2、17.6±0.2处具有特征峰。优选的，还可以在2θ值为15.7±0.2、27.1±0.2、25.2±0.2、33.5±0.2、22.4±0.2、19.0±0.2处具有特征峰。优选的，还可以在2θ值为13.3±0.2、4.8±0.2、9.6±0.2、26.7±0.2、5.3±0.2、11.4±0.2处具有特征峰。更优选的，优选的，还可以在2θ值为14.0±0.2、30.2±0.2、8.5±0.2、31.3±0.2、21.9±0.2、12.5±0.2处具有特征峰。
制备9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型A的方法，其特征在于，
(i)将9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤游离碱解于有机溶液中。
(ii)向步骤(i)中得到的溶液中加入不少于等当量游离碱的富马酸，使化合物从溶液中析出。
(iii)固液分离后得到9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型A。
9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型B，其特征在于，其X射线粉末衍射图中至少在2θ值为10.5±0.2、21.0±0.2、10.9±0.2、27.2±0.2、22.5±0.2处具有特征峰。优选的，还可以在2θ值为28.9±0.2、27.7±0.2、24.1±0.2、18.7±0.2、13.5±0.2、20.6±0.2 处具有特征峰。优选的，还可以在2θ值为4.9±0.2、14.1±0.2、11.2±0.2、16.4±0.2、23.2±0.2、19.6±0.2处具有特征峰。优选的，还可以在2θ值为14.8±0.2、15.1±0.2、12.3±0.2、38.0±0.2、17.3±0.2、15.7±0.2处具有特征峰。更优选的，还可以在2θ值为18.1±0.2、21.8±0.2、31.8±0.2、35.0±0.2、41.7±0.2、40.0±0.2处具有特征峰。
制备9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型B的方法，其特征在于，
(i)将9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤游离碱解于有机溶液中。
(ii)向步骤(i)中得到的溶液中加入大于游离碱当量的富马酸，使化合物从溶液中析出。
(iii)固液分离后得到9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型B。
医药组合物，其含作为9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II、晶型A或晶型B有效成分。
任一9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的晶型II、晶型A或晶型B及其医药组合物的用途，用于治疗病毒相关疾病的用途。
用于治疗病毒相关疾病，疾病选自：乙型肝炎病毒(HBV)和/或人类免疫缺陷病毒(HIV)感染。
附图说明
错误！未找到引用源。为9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的晶型II的X射线粉末衍射图，横坐标为角度2θ(°)，纵坐标为强度。
错误！未找到引用源。为9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的晶型II的DSC图。
错误！未找到引用源。为9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的晶型II的TGA图。
错误！未找到引用源。为9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的晶型A的X射线粉末衍射图，横坐标为角度2θ(°)，纵坐标为强度。
错误！未找到引用源。为9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的晶型B的X射线粉末衍射图，横坐标为角度2θ(°)，纵坐标为强度。
具体实施方式
下面结合附图和实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但并不用来限制本发明的范围。本专利中X射线粉末衍射，操作和分析步骤如下：
采用Rigaku Ultima IV粉末衍射仪，该仪器采用Cu-Kα照射(40kV，40mA)，于室温下使用D/tex Ultra检测器进行。扫描范围在2θ区间自3°至45°，扫描速度为20°/分钟
由包括以下的多种因素产生与这类X射线粉末衍射分析结果相关的测量差异：(a)样品制备物(例如样品高度)中的误差，(b)仪器误差，(c)校准差异，(d)操作人员误差(包括在测定峰位置时出现的误差)，和(e)物质的性质(例如优选的定向误差)。校准误差和样品高度误差经常导致所有峰在相同方向中的位移。当使用平的支架时，样品高度的小差异将导致XRPD峰位置的大位移。系统研究显示1mm的样品高度差异可以导致高至1°的2θ的峰位移。可以从X射线衍射图鉴定这些位移，并且可以通过针对所述位移进行补偿(将系统校准因子用于所有峰位置值)或再校准仪器消除所述位移。如上所述，通过应用系统校准因子使峰位置一致，可校正来自不同仪器的测量误差。
对实施例中的晶型做差示扫描量热(DSC)分析，操作和分析步骤如下，采用TA Q2000差示扫描量热仪，采用N2气氛，升温速度为10℃/min。
对实施例中的晶型做热重(TGA)分析，操作和分析步骤如下，采用TA Q500热重分析仪，采用N2气氛，升温速度为10℃/min。
实施例1
将50mg替诺福韦艾拉酚胺游离碱溶解或悬浮于1mL醇类有机溶剂中，加入0.5～1当量的富马酸，产生沉淀，悬浮搅拌24小时，得9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II。
醇类有机溶剂可以选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、正辛醇、2,2,2-三氟乙醇。
本发明制备的9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的晶型II，其X射线粉末衍射图如图1所示，晶型II的XRPD图的衍射峰列于下表：
Figure PCTCN2017088538-appb-000002
Figure PCTCN2017088538-appb-000003
对实施例1中的晶型II做差示扫描量热(DSC)分析，操作和分析步骤如下，采用TA Q2000差示扫描量热仪，采用N2气氛，升温速度为10℃/min。对实施例1中的晶型II做热重(TGA)分析。采用TA Q500热重分析仪，采用N2气氛，升温速度为10℃/min。
晶型II的DSC图如错误！未找到引用源。所示，晶型II的TGA图如错误！未找到引用源。所示。图2显示晶型II的峰值熔点为106.56℃。图3显示在加热至160℃之前，未见明显失重，显示晶型II为无水物。
实施例2
将50mg替诺福韦艾拉酚胺游离碱溶解或悬浮于1mL氯代烷烃 类有机溶剂中，加入0.5～1当量的富马酸，产生沉淀，悬浮搅拌24小时，得9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II。所得富马酸盐晶型II的XRPD图与图1一致。
氯代烷烃类有机溶剂可以选自二氯甲烷、氯仿、1,2-二氯乙烷。
实施例3
将50mg替诺福韦艾拉酚胺游离碱溶解或悬浮于1mL酯类有机溶剂中，加入0.5～1当量的富马酸，产生沉淀，悬浮搅拌24小时，得9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II。所得富马酸盐晶型II的XRPD图与图1一致。
酯类有机溶剂可以选自甲酸乙酯、乙酸乙酯、乙酸异丙酯、乙酸丁酯、碳酸二甲酯。
实施例4
将50mg替诺福韦艾拉酚胺游离碱溶解或悬浮于1ml酮类有机溶剂中，加入0.5～1当量的富马酸，产生沉淀，悬浮搅拌24小时，得9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II。所得富马酸盐晶型II的XRPD图与图1一致。
酮类有机溶剂可以选自丙酮、2-丁酮、3-戊酮、4-甲基-2-戊酮。
实施例5
将50mg替诺福韦艾拉酚胺游离碱溶解或悬浮于1mL芳香烃类 有机溶剂中，加入0.5～1当量的富马酸，产生沉淀，悬浮搅拌24小时，得9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II。所得富马酸盐晶型II的XRPD图与图1一致。
芳香烃类有机溶剂可以选自甲苯、异丙苯、对二甲苯、均三甲苯、氯苯。
实施例6
将50mg替诺福韦艾拉酚胺游离碱溶解或悬浮于1mL醚类有机溶剂中，加入0.5～1当量的富马酸，产生沉淀，悬浮搅拌24小时，得9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II。所得富马酸盐晶型II的XRPD图与图1一致。
醚类有机溶剂可以选自乙醚、异丙醚、甲基叔丁基醚、甲基环戊基醚。
实施例7
将50mg替诺福韦艾拉酚胺游离碱悬浮于1mL烷烃类有机溶剂中，加入0.5～1当量的富马酸，产生沉淀，悬浮搅拌24小时，得9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II。所得富马酸盐晶型II的XRPD图与图1一致。
烷烃类有机溶剂可以选自正己烷、环己烷、正庚烷。
实施例8
将50mg替诺福韦艾拉酚胺游离碱悬浮于1mL乙腈，加入0.5～1当量的富马酸，产生沉淀，悬浮搅拌24小时，得9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II。所得富马酸盐晶型II的XRPD图与图1一致。
实施例9
将50mg替诺福韦艾拉酚胺游离碱悬浮于1mL硝基甲烷，加入0.5～1当量的富马酸，产生沉淀，悬浮搅拌24小时，得9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II。所得富马酸盐晶型II的XRPD图与图1一致。
实施例10
将50mg替诺福韦艾拉酚胺游离碱悬浮于1mL 1,4-二氧六环，加入0.5～1当量的富马酸，产生沉淀，悬浮搅拌24小时，得9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II。所得富马酸盐晶型II的XRPD图与图1一致。
实施例11
将50mg替诺福韦艾拉酚胺游离碱悬浮于1mL 3-甲基-1-丁醇，加入不小于等当量的富马酸，产生沉淀，悬浮搅拌24小时，得9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型A。所得富马酸盐晶型A的XRPD 图与图4一致。
本发明制备的9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的晶型A的XRPD图与图4一致。
晶型A的XRPD图的衍射峰列于下表：
Figure PCTCN2017088538-appb-000004
Figure PCTCN2017088538-appb-000005
实施例12
将50mg替诺福韦艾拉酚胺游离碱悬浮于1mL四氢呋喃，加入不小于等当量的富马酸，产生沉淀，悬浮搅拌24小时，得9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型B。所得富马酸盐晶型B的XRPD图与图5一致。
晶型B的XRPD图的衍射峰列于下表：
Figure PCTCN2017088538-appb-000006
Figure PCTCN2017088538-appb-000007
实施例13
不同晶型的TAF富马酸盐与emtricitabine配伍稳定性的研究。本专利中比较了TAF富马酸盐晶型I(按WO2013025788A1中方法制备得到)，TAF富马酸盐晶型II、TAF富马酸盐晶型A与TAF富马酸盐晶型B与emtricitabine按重量比约(1:15)混合，置于40摄氏度相对湿度75％的条件下，敞口放置21天，在一开始0天和第21天时用HPLC分析TAF的降解情况，分析结果如下表所示：
Figure PCTCN2017088538-appb-000008
结果可见，当TAF富马酸盐晶型I单独放置时，降解比例较小，当与emtricitabine混合时，降解比例明显升高，显示emtricitabine明显加速了TAF富马酸盐晶型I降解。而与富马酸盐晶型II、晶型A和晶型B配伍时，emtricitabine对这些晶型的降解加速作用明显减弱，显示富马酸盐晶型II、晶型A和晶型B具有更加优越的化学稳定性。有利于配方制剂的开发和应用，从而提高复方制剂的稳定性和有效期。

Claims (10)

  1. 9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型A，其特征在于，其X射线粉末衍射图中至少在2θ值为23.8±0.2、10.5±0.2、28.5±0.2、21.2±0.2、19.5±0.2处具有特征峰。优选的，还可以在2θ值为15.1±0.2、23.2±0.2、17.0±0.2、9.8±0.2、20.8±0.2、17.6±0.2处具有特征峰。优选的，还可以在2θ值为15.7±0.2、27.1±0.2、25.2±0.2、33.5±0.2、22.4±0.2、19.0±0.2处具有特征峰。优选的，还可以在2θ值为13.3±0.2、4.8±0.2、9.6±0.2、26.7±0.2、5.3±0.2、11.4±0.2处具有特征峰。更优选的，优选的，还可以在2θ值为14.0±0.2、30.2±0.2、8.5±0.2、31.3±0.2、21.9±0.2、12.5±0.2处具有特征峰。
  2. 制备权利要求1所述的9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型A的方法，其特征在于，
    (i)将9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤游离碱解于有机溶液中。
    (ii)向步骤(i)中得到的溶液中加入不少于游离碱当量的富马酸，使化合物从溶液中析出。
    (iii)固液分离后得到9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型A。
  3. 9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型B，其特征在于，其X射线粉末衍射图中至少在2θ值为10.5±0.2、21.0±0.2、10.9±0.2、27.2±0.2、22.5±0.2处具有特征峰。优选的，还可以 在2θ值为28.9±0.2、27.7±0.2、24.1±0.2、18.7±0.2、13.5±0.2、20.6±0.2处具有特征峰。优选的，还可以在2θ值为4.9±0.2、14.1±0.2、11.2±0.2、16.4±0.2、23.3±0.2、19.6±0.2处具有特征峰。优选的，还可以在2θ值为14.8±0.2、15.1±0.2、12.3±0.2、38.0±0.2、17.3±0.2、15.7±0.2处具有特征峰。更优选的，还可以在2θ值为18.1±0.2、21.8±0.2、31.8±0.2、35.0±0.2、41.7±0.2、40.0±0.2处具有特征峰。
  4. 制备权利要求3所述的9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型B的方法，其特征在于，
    (i)将9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤游离碱解于有机溶液中。
    (ii)向步骤(i)中得到的溶液中加入大于游离碱当量的富马酸，使化合物从溶液中析出。
    (iii)固液分离后得到9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型B。
  5. 9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II，其特征在于，其X射线粉末衍射图中至少在2θ值为26.6±0.2、21.3±0.2、27.1±0.2、19.6±0.2、18.7±0.2处具有特征峰。优选的，还可以在2θ值为32.1±0.2、21.9±0.2、5.4±0.2、22.4±0.2、11.1±0.2、17.8±0.2处具有特征峰。优选的，还可以在2θ值为15.9±0.2、24.5±0.2、24.9±0.2、19.0±0.2、23.6±0.2、30.0±0.2处具有特征峰。优选的，还可以在2θ值为32.4±0.2、37.5±0.2、10.5±0.2、14.5±0.2、16.7±0.2、40.3±0.2处具有特征峰。更优选的，还可 以在2θ值为23.9±0.2、12.3±0.2、38.6±0.2、43.0±0.2、27.8±0.2、35.8±0.2处具有特征峰。
  6. 制备权利要求5所述的9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II的熔点为106.6±2℃。
  7. 制备权利要求5所述的9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II的方法，其特征在于，
    (i)将9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤游离碱解于有机溶液中。
    (ii)向步骤(i)中得到的溶液中加入一定量的富马酸，使化合物从溶液中析出。
    (iii)固液分离后得到9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型II。
  8. 医药组合物，其含有权利要求1、4或6所述的晶体作为有效成分。
  9. 如权利要求1～7任一项所述的9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的晶型II、晶型A或晶型B及其医药组合物的用途：用于治疗病毒相关疾病的用途。
  10. 如权利要求9所述的用途，用于治疗病毒相关疾病。疾病选自：乙型肝炎病毒(HBV)和/或人类免疫缺陷病毒(HIV)感染。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1443189A (zh) * 2000-07-21 2003-09-17 吉里德科学公司 核苷酸膦酸酯类似物前药及其筛选和制备方法
CN103732594A (zh) * 2011-08-16 2014-04-16 吉联亚科学公司 替诺福韦艾拉酚胺(tenofovir alafenamide)半反丁烯二酸盐
CN104817593A (zh) * 2015-04-27 2015-08-05 广州同隽医药科技有限公司 半富马酸替诺福韦艾拉酚胺关键中间体的合成工艺
CN105085571A (zh) * 2014-05-20 2015-11-25 四川海思科制药有限公司 替诺福韦艾拉酚胺复合物及其制备方法和用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1443189A (zh) * 2000-07-21 2003-09-17 吉里德科学公司 核苷酸膦酸酯类似物前药及其筛选和制备方法
CN103732594A (zh) * 2011-08-16 2014-04-16 吉联亚科学公司 替诺福韦艾拉酚胺(tenofovir alafenamide)半反丁烯二酸盐
CN105085571A (zh) * 2014-05-20 2015-11-25 四川海思科制药有限公司 替诺福韦艾拉酚胺复合物及其制备方法和用途
CN104817593A (zh) * 2015-04-27 2015-08-05 广州同隽医药科技有限公司 半富马酸替诺福韦艾拉酚胺关键中间体的合成工艺

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