WO2015176602A1 - Tenofovir alafenamide complex, preparation method therefor and use thereof - Google Patents

Tenofovir alafenamide complex, preparation method therefor and use thereof Download PDF

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WO2015176602A1
WO2015176602A1 PCT/CN2015/078188 CN2015078188W WO2015176602A1 WO 2015176602 A1 WO2015176602 A1 WO 2015176602A1 CN 2015078188 W CN2015078188 W CN 2015078188W WO 2015176602 A1 WO2015176602 A1 WO 2015176602A1
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Prior art keywords
acid
tenofovir alafenamide
tenofovir
alafenamide
ray powder
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PCT/CN2015/078188
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French (fr)
Chinese (zh)
Inventor
赵雄
袁道义
杜全胜
林志忠
高炳坤
李学超
李方群
罗杰
向志祥
孙鹏
钱春霞
徐同利
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四川海思科制药有限公司
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Priority to CN201580024952.XA priority Critical patent/CN106414466B/en
Publication of WO2015176602A1 publication Critical patent/WO2015176602A1/en

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    • 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
    • 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

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  • the present invention relates to the field of organic chemistry and the field of pharmacy, in particular to a complex for preventing and/or treating a viral infection drug tenofovir alafenamide, a preparation method thereof and a preparation thereof for preventing and/or treating a viral infection, in particular It is a use in a drug infected with hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV), and a pharmaceutical composition containing the same.
  • HBV hepatitis B virus
  • HAV human immunodeficiency virus
  • Tenofovir alafenamide chemical name: N-[(S)-[[(1R)-2-(6-amino-9H- ⁇ -9-yl)-1-methyl) Ethoxy]methyl]phenoxyphosphonyl]-L-alanine-1-methylethyl ester; CAS accession number: 379270-37-8; molecular formula is as shown in formula I:
  • Tenofovir alafenamide is an ester prodrug of tenofovir, an acyclic nucleotide reverse transcriptase inhibitor with broad-spectrum antiviral activity that inhibits HIV-1, HIV- 2 reverse transcriptase and HBV polymerase, thereby inhibiting viral replication.
  • Tenofovir alafluamine is orally hydrolyzed to tenofovir, and tenofovir is phosphorylated by cellular kinases into a pharmacologically active metabolite, tenofovir diphosphate, which is depleted with 5'-triphosphate deoxyadenosine.
  • Tenofovir alafenamide is not suitable for the preparation of pharmaceutical preparations due to its low solid-state melting point and low solubility in water. Dissolution in the pharmaceutical preparation, thus tenofovir alafenamide was developed into the form of a salt for use in the formulation.
  • CN1443189A, CN1706855A, etc. disclose the fumarate of tenofovir alafenamide. Although tenofovir alafenamide fumarate has a greater improvement in water solubility and physical properties than free base, However, its chemical stability and thermodynamic stability are not good.
  • CN103732594A discloses a hemi-fumarate salt of tenofovir alafenamide, wherein tenofovir alafenamide hemifumarate is compared to tenofovir alafenamide fumarate It has an advantage in removing diastereomer impurities, chemical stability and thermodynamic stability, and is a better salt of tenofovir alafenamide; but tenofovir alafenamide hemifumarate The preparation process is cumbersome, for example, it is necessary to add tenofovir alafenamide hemifumarate seed crystal during the preparation process.
  • the composite is superior to the prior art in at least one aspect of physical properties, chemical stability, process operability, formulation suitability, and the like.
  • Another object of the present invention is to provide a process for the preparation of the above tenofovir alafenamide complex.
  • It is a further object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of the above tenofovir alafenamide complex.
  • the present invention provides a tenofovir alafenamide complex of the formula II,
  • X is selected from the group consisting of: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, lauryl sulfate, glycerophosphoric acid, methanesulfonate Acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, taurine, camphorsulfonic acid, cyclohexylsulfonic acid, sulfamic acid, ethanedisulfonic acid, succinic acid, benzenesulfonic acid, p-toluenesulfonic acid, P-hydroxybenzenesulfonate Acid, o-hydroxybenzenesulfonic acid, 2,5-dihydroxybenzenesulfonic acid, p-aminobenzenesulfonic acid, naphthalene-2-
  • the "complex” means a compound in which tenofovir alafenamide and a corresponding acid are bonded by a non-covalent bond such as a hydrogen bond or an ionic bond, and includes a salt, a eutectic or the like.
  • the composite further includes its polymorph, solvate, solvate polycrystal, hydrate, hydrate polycrystal, and the like.
  • salts are well known to those skilled in the art and refer to compounds formed by the action of ionic bonds by cations and anions.
  • Teenofoviral acetatamine salt means that in the solid consisting of tenofovir alafenamide and acid, protons in the acid are transferred to tenofovir alafenamide, protonated teno The fuwei acetaminophen cation and the acid anion are bonded to each other by ionic bonding.
  • the “eutectic” refers to a solid formed in the form of a eutectic form of tenofovir alafenamide with an acid.
  • “Co-Crystals” means a multi-component crystal having a fixed stoichiometric ratio in which the components are at the molecular level, by hydrogen bonding or other non-covalent bonds, non-ionic bonds. The combination of roles and coexistence.
  • drug eutectic it generally includes a pharmaceutically active ingredient and another co-crystal former (Co-crystal former), such as "tenofovir acetamide eutectic", tenofovira
  • Co-crystal former such as "tenofovir acetamide eutectic", tenofovira
  • the phenolamine is a pharmaceutically active ingredient and the acid is a eutectic former.
  • the eutectic When a single pure eutectic former is present in a liquid state at room temperature, the eutectic is also referred to as a "solvate", wherein when the solvent is water, it is referred to as a "hydrate”, such as tenofovir acetamide.
  • solvate wherein when the solvent is water, it is referred to as a "hydrate”, such as tenofovir acetamide.
  • the eutectic formed by the amine and acetic acid may be referred to as the acetic acid solvate of tenofovir alafenamide.
  • the above “eutectic” also includes such multi-component crystals having a fixed stoichiometric ratio in which a part of the pharmaceutically active ingredient and the other components are partially hydrogen-bonded or other non-covalently bonded, and the other part is passed through the ion. The bond or bond between the hydrogen bond and the ionic bond is combined.
  • tenofovir alafenamide co-crystal or salt also includes a form of a solvate, a hydrate or the like of a tenofovir alafenamide co-crystal or a salt.
  • the solvent may enter the tenofovir alafenamide eutectic or salt crystals to form a solvate;
  • the solvent is water, it is possible to form a hydrate.
  • tenofovir alafenamide eutectic or salt also includes polymorph of tenofovir alafluamine co-crystal or salt, tenofovir alafenamide eutectic or salt solvate Crystalline, tenofovir eugenol eutectic or polymorphic form of salt hydrate.
  • 1/n means the approximate molar composition ratio of tenofovir alafenamide to the corresponding acid in the complex structure, which can be obtained by 1 H-NMR, elemental analysis, HPLC, X-ray diffraction (for example) Characterized by single crystal X-ray diffraction).
  • the "approximation" range is generally ⁇ 0.15, preferably ⁇ 0.1.
  • tenofovir alafenamide complex can be expressed as "X tenofovir alafenamide according to the stoichiometric number of tenofovir alafenamide and acid X in the structure. 1:n)", where X and n are as defined in formula II, "1:n” is the approximation of acid X and tenofovir alafenamide in the tenofovir alafenamide complex
  • the molar composition ratio can be obtained by 1 H-NMR, elemental analysis, HPLC, single crystal X-ray diffraction or the like.
  • X is selected from the group consisting of: phosphoric acid, citric acid, tannic acid (aka: tannic acid) or alginic acid.
  • X is selected from the group consisting of: sulfuric acid, persulfuric acid, thiocyanic acid, phosphoric acid, carbonic acid, glycerol phosphate, ethanedisulfonic acid, succinic acid, naphthalene-1,5- Disulfonic acid, oxalic acid, malonic acid, succinic acid, L-malic acid, D-malic acid, racemic malic acid (aka: DL-malic acid), L-tartaric acid, D-tartaric acid, racemic tartaric acid ( Also known as: DL-tartaric acid), meso-tartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, 2-oxoglutaric acid, adipic acid, azelaic acid, citric acid, camphoric acid, galactose Diacid (aka: mucic acid), tannic acid (aka: tannic acid), alginic acid
  • X is selected from the group consisting of: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, lauryl sulfate, glycerin Phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, taurine, camphorsulfonic acid, cyclohexylsulfonic acid, sulfamic acid, ethanedisulfonic acid, succinic acid, benzenesulfonic acid, Toluenesulfonic acid, p-hydroxybenzenesulfonic acid, o-hydroxybenzenesulfonic acid, 2,5-dihydroxybenzenesulfonic acid, p-aminobenzenesulfonic acid, saccharin, na
  • the tenofovir alafenamide complex of Formula II is selected from the group consisting of: l-norofovir lysamine (1:2), D-tenofovir, D-tartrate Lauramine (1:1), DL-tenofovir iracrolimum tartrate (1:1), tenofovir alafenamide (1:2), tenofovir citrate Iratonamine (1:1), tenofovir iramol succinate (1:1), tenofovir oxalatine oxalate (1:1), tenofovir alafenol phosphate (1:1) or tenofovir alafenamide (1:1).
  • the present invention provides a process for the preparation of a tenofovir alafenamide complex of formula II, the method comprising:
  • the isolated solid is dried or further purified and then dried.
  • tenofovir alafenamide can be obtained by the method disclosed in the patent documents CN1443189A and CN1706855A or WO2013052094A. These documents are incorporated herein by reference. Tenofovir alafenamide can be present in any form, including crystalline forms, amorphous forms, or a mixture thereof.
  • the "suitable solvent” means a solvent which has a certain solubility to tenofovir alafenamide and an acid, and at which a tenofovir alafenamide complex can be formed.
  • suitable solvents are selected from the group consisting of acetonitrile, ethanol, methanol, propanol, isopropanol, butanol, ethylene glycol, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, diethyl ether, isopropyl Ether, n-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, tert-butyl methyl ether, tetrahydrofuran, petroleum ether, dichloromethane, chloroform, n-hexane, cyclohexane, acetone, methyl ethyl ketone,
  • the "acid X" is selected from the acid represented by X in the formula II.
  • the tenofovir alafluramide and acid X charge molar ratio is generally 4:1 to 0.5:1, when preparing the "X tenofovir alafenamide (1:3)" complex, tenofovir
  • the molar ratio of levamide to acid X is generally from 2.7:1 to 3.5:1; when preparing the "X tenofovir alafenamide (1:2)" complex,
  • the molar ratio of tenofovir alafluramine to acid X is generally from 1.7:1 to 2.5:1; when preparing the "X tenofovir alafenamide (1:1)” complex, tenofovir
  • the molar ratio of levamide to acid X is generally from 0.5:1 to 1.5:1.
  • the method of "precipitating solid” is a conventional method in the art, such as cooling, adding an anti-solvent, concentrating a part of a solvent, adding a seed crystal, or the like, alone or in combination.
  • the "separation" method includes filtration or centrifugation or the like.
  • the collected solids can be washed with a suitable solvent.
  • the "drying” method includes atmospheric drying, reduced pressure drying or a combination thereof.
  • Methods for "further purification” include recrystallization, slurrying, washing, and the like.
  • n is selected to be 2
  • X is selected as L-tartaric acid, that is, a complex formed by the ratio of tenofovir alafenamide to L-tartaric acid in a ratio of 2:1 mole is provided.
  • L-tartaric acid that is, a complex formed by the ratio of tenofovir alafenamide to L-tartaric acid in a ratio of 2:1 mole is provided.
  • the invention provides a method of preparing tenofovir alafenide L-tartaric acid, the method comprising:
  • the isolated solid is dried or further purified and then dried.
  • the "suitable solvent” is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile, Ethanol, isopropanol or a mixture thereof.
  • the weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
  • the molar ratio of tenofovir alafenamide to L-tartaric acid is generally from 1.7:1 to 2.5:1, preferably from 1.9:1 to 2.3:1.
  • the method of "precipitating solid” is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination.
  • the solids precipitation process can be either standing or agitated.
  • the "separation" may employ a conventional method in the art such as filtration.
  • the collected solids may be washed with a suitable solvent in step (1).
  • the "drying” method includes atmospheric drying, reduced pressure drying or a combination thereof.
  • Methods for "further purification” include recrystallization, slurrying, washing, and the like.
  • the temperature of "drying" in the above step (4) is generally 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure. It can also be dried under reduced pressure.
  • Tenofovir alafenamide (1:2) of L-tartrate prepared in this embodiment is a crystal.
  • the present invention provides a crystalline form of tenofovir alafenamide (1:2) of L-tartrate (for convenience of expression, the crystal form is referred to as "L-tanofosyl alafenide" (1:2) Form A").
  • the X-ray powder diffraction pattern of the crystal form (using Cu-K ⁇ radiation) is characterized by a value of 8.2 ° ⁇ 0.2 °, 9.4 ° ⁇ 0.2 °, 10.8 ° ⁇ 0.2 °, 14.4 ° ⁇ 0.2 °, 17.9. Characteristic diffraction peaks correspond to ° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.7° ⁇ 0.2°, 21.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the tenofovir alafenamide (1:2) crystal form A of L-tartrate of the present invention is characterized by a value of 7.5 ° ⁇ 0.2 at 2 ⁇ .
  • the X-ray powder diffraction pattern of the tenofovir lysamine (1:2) crystal form A of L-tartrate of the present invention at a 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
  • the present invention provides tenofovir alafenamide (1:2) Form A of L-tartrate having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
  • the present invention provides a mixture of tenofovir alafenamide (1:2) of L-tartrate and tenofovir alafenamide (1:2) crystal form A
  • the content is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • mixture of tenofovir alafenamide (1:2) of L-tartrate of the present invention refers to L containing other impurities or crystal forms directly synthesized by chemical synthesis.
  • Tenofovir alafenamide (1:2) refers to L containing other impurities or crystal forms directly synthesized by chemical synthesis.
  • the method for preparing tenofovir alafenamide (1:2) Form A of L-tartrate of the present invention comprises:
  • the collected solid may be washed with the solvent used in the step (1);
  • the isolated solid is dried or further purified and then dried.
  • the drying temperature is usually 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
  • n is selected to be 1
  • X is selected as D-tartaric acid, that is, a complex formed by tenofovir alafenamide and D-tartaric acid in a 1:1 molar composition ratio is provided.
  • D-tenofovir alafenamide (1:1) is selected as D-tartaric acid
  • the present invention provides a method of preparing tenofovir alafenide, which comprises:
  • the isolated solid is dried or further purified and then dried.
  • the "suitable solvent” is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile, Isopropyl alcohol or a mixture thereof.
  • the weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
  • the molar ratio of tenofovir alafenamide to D-tartaric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
  • the method of "precipitating solid” is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination.
  • the solids precipitation process can be either standing or agitated.
  • the "separation" may employ a conventional method in the art such as filtration.
  • the collected solids may be washed with a suitable solvent in step (1).
  • the "drying” method includes atmospheric drying, reduced pressure drying or a combination thereof.
  • Methods for "further purification” include recrystallization, slurrying, washing, and the like.
  • the temperature of "drying" in the above step (4) is generally 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure. It can also be dried under reduced pressure.
  • Tenofovir alafenamide (1:1) of D-tartrate prepared in this embodiment is a crystal.
  • the present invention provides a crystalline form of tenofovir alafenamide (1:1) of D-tartrate (for convenience of presentation, the crystalline form is referred to as "D-tenofovir alafenide tartrate" (1:1) Form A").
  • the X-ray powder diffraction pattern of the crystal form (using Cu-K ⁇ radiation) is characterized by a value of 7.8° ⁇ 0.2°, 9.5° ⁇ 0.2°, 12.5° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.9. Characteristic diffraction peaks correspond to ° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.7° ⁇ 0.2°, 19.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of tenofovir alafenamide (1:1) Form A of D-tartrate of the present invention is characterized by a value of 4.4 ° ⁇ 0.2 at 2 ⁇ . °, 7.8 ° ⁇ 0.2 °, 9.0 ° ⁇ 0.2 °, 9.5 ° ⁇ 0.2 °, 12.5 ° ⁇ 0.2 °, 13.0 ° ⁇ 0.2 °, 15.1 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 17.0 ° ⁇ 0.2 °, 17.7° ⁇ 0.2°, 19.5° ⁇ 0.2°, 19.9° ⁇ 0.2°, 21.4° ⁇ 0.2°, 22.7° ⁇ 0.2°, 25.9° ⁇ 0.2° correspond to characteristic diffraction peaks.
  • the X-ray powder diffraction pattern represented by the present invention for tenofovir alafenamide (1:1) crystal form A in the 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
  • the present invention provides tenofovir alafenamide (1:1) Form A of D-tartrate having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
  • the present invention provides a mixture of ten-five valproate (1:1) of D-tartrate, tenofovir iramate (1:1) crystal form A
  • the content is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • mixture of tenofovir alafenamide (1:1) of D-tartrate of the present invention refers to D containing other impurities or crystal forms directly synthesized by chemical synthesis.
  • Tenofovir alafenamide (1:1) refers to D containing other impurities or crystal forms directly synthesized by chemical synthesis.
  • the preparation of the D-tartrolate acetamide (1:1) Form A of D-tartrate of the present invention includes:
  • the collected solid may be washed with the solvent in the step (1).
  • the isolated solid is dried or further purified and then dried.
  • the drying temperature is usually 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
  • n is selected to be 1
  • X is selected as DL-tartaric acid, that is, a complex formed by the ratio of tenofovir alafenamide to DL-tartaric acid in a ratio of 1:1 mole is provided.
  • DL-tenofovir levamide (1:1) is selected as DL-tartaric acid
  • the invention provides a method of preparing DL-tenofovir alafenamide (1:1), the method comprising:
  • the isolated solid is dried or further purified and then dried.
  • the "DL-tartaric acid” means racemic tartaric acid having a ratio of L-tartaric acid and D-tartaric acid.
  • the "suitable solvent” is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, and the like, or mixtures thereof, preferably acetonitrile.
  • the weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
  • the molar ratio of tenofovir alafenamide to DL-tartaric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
  • the method of "precipitating solid” is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination.
  • the solids precipitation process can be either standing or agitated.
  • the "separation" may employ a conventional method in the art such as filtration.
  • the collected solids may be washed with a suitable solvent in step (1).
  • the "drying” method includes atmospheric drying, reduced pressure drying or a combination thereof.
  • Methods for "further purification” include recrystallization, slurrying, washing, and the like.
  • the temperature of "drying" in the above step (4) is generally 20 to 120 ° C, preferably 30 to 80 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
  • Tenofovir alafenamide (1:1) of DL-tartrate prepared in this embodiment is a crystal.
  • the present invention provides a crystalline form of DL-tenofovir alafenamide (1:1) (for convenience of presentation, the crystal form is referred to as "DL-tenofovir alafenide tartrate” (1:1) Form A").
  • the X-ray powder diffraction pattern of the crystal form (using Cu-K ⁇ radiation) is characterized by a value of 2 ⁇ of 6.8° ⁇ 0.2°, 8.0° ⁇ 0.2°, 9.7° ⁇ 0.2°, 16.0° ⁇ 0.2°, 16.9. Characteristic diffraction peaks correspond to ° ⁇ 0.2°, 18.2° ⁇ 0.2°, 18.9° ⁇ 0.2°, 20.2° ⁇ 0.2°, 21.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of DL-tenofovir alafenamide (1:1) Form A of the present invention is characterized by a 2 ⁇ value of 6.8° ⁇ 0.2. °, 8.0 ° ⁇ 0.2 °, 9.7 ° ⁇ 0.2 °, 10.6 ° ⁇ 0.2 °, 12.6 ° ⁇ 0.2 °, 13.7 ° ⁇ 0.2 °, 14.9 ° ⁇ 0.2 °, 16.0 ° ⁇ 0.2 °, 16.9 ° ⁇ 0.2 °, 18.2° ⁇ 0.2°, 18.9° ⁇ 0.2°, 20.2° ⁇ 0.2°, 21.1° ⁇ 0.2°, 22.8° ⁇ 0.2° correspond to characteristic diffraction peaks.
  • the X-ray powder diffraction pattern of the DL-tenofovir alafenamide (1:1) crystal form A of the present invention at a 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
  • the DL-tenofovir alafenamide (1:1) Form A of the present invention has the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
  • the present invention provides a mixture of DL-tenofovir alafenamide (1:1) in a mixture of DL-tenofovir alafenamide (1:1) Form A
  • the content is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • the DL-tenofovir alafenamide (1:1) mixture of the present invention refers to a DL containing other impurities or crystal forms directly synthesized by chemical synthesis.
  • the method for preparing DL-tenofovir alafenamide (1:1) Form A of the present invention comprises:
  • Tenofovir alafenamide and DL-tartaric acid are dissolved in acetonitrile; the weight ratio of the solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
  • the molar ratio of tenofovir alafenamide to DL-tartaric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
  • the collected solid may be washed with acetonitrile.
  • the isolated solid is dried or further purified and then dried.
  • the drying temperature is usually 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
  • n is selected to be 2
  • X is selected as L-malic acid, that is, a complex formed by the ratio of tenofovir alafenamide to L-malic acid in a ratio of 2:1 mole is provided. It is called "L-malofovir alafenamide (1:2)".
  • the present invention provides a method of preparing tenofovir alafenamide of L-malic acid, the method comprising:
  • the isolated solid is dried or further purified and then dried.
  • the "suitable solvent” is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably isopropyl. alcohol.
  • the weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
  • the molar ratio of tenofovir alafenamide to L-malic acid is generally 1.7:1 to 2.5:1, preferably 1.9:1 to 2.3:1.
  • the method of "precipitating solid” is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination.
  • the solids precipitation process can be either standing or agitated.
  • the "separation" may employ a conventional method in the art such as filtration.
  • the collected solids may be washed with a suitable solvent in step (1).
  • the "drying” method includes atmospheric drying, reduced pressure drying or a combination thereof.
  • Methods for "further purification” include recrystallization, slurrying, washing, and the like.
  • the temperature of "drying” is generally 20 to 80 ° C, preferably 30 to 60 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
  • the tenofovir alafenamide (1:2) of L-malate prepared in this embodiment is a crystal.
  • the present invention provides a crystalline form of tenofovir alafenamide (1:2) of L-malate (for convenience of presentation, the crystal form is referred to as "L-malic acid tenofovira Phenolic amine (1:2) crystal form A").
  • the X-ray powder diffraction pattern of the crystal form (using Cu-K ⁇ radiation) is characterized by a 2 ⁇ value of 10.0° ⁇ 0.2°, 13.4° ⁇ 0.2°, 13.9° ⁇ 0.2°, 15.3° ⁇ 0.2°, 16.6. Characteristic diffraction peaks correspond to ° ⁇ 0.2°, 21.3° ⁇ 0.2°, 26.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the tenofovir alafenamide (1:2) crystal form A of the L-malic acid of the present invention is characterized by a value of 5.4 ° ⁇ 2 ⁇ . 0.2°, 10.0° ⁇ 0.2°, 11.9° ⁇ 0.2°, 13.4° ⁇ 0.2°, 13.9° ⁇ 0.2°, 15.3° ⁇ 0.2°, 16.6° ⁇ 0.2°, 20.3° ⁇ 0.2°, 21.3° ⁇ 0.2° There are characteristic diffraction peaks at 22.2° ⁇ 0.2° and 26.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle of the tenofovir alafenamide (1:2) crystal form A of the present invention has characteristic diffraction peaks and relative intensities at the following positions:
  • the present invention provides tenofovir alafenamide (1:2) Form A of L-malate having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
  • the present invention provides a mixture of tenofovir alafenamide (1:2) L-malate and tenofovir alafenamide (1:2) crystals.
  • the type A content is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • mixture of tenofovir alafenamide (1:2) of L-malate according to the present invention refers to a mixture of other impurities or crystal forms prepared by direct synthesis by chemical synthesis.
  • Tenofovir alafenamide (1:2) refers to a mixture of other impurities or crystal forms prepared by direct synthesis by chemical synthesis.
  • the method for preparing the crystalline form A of tenofovir alafenamide (1:2) of L-malate provided by the present invention comprises:
  • the weight ratio is generally 5:1 to 80:1.
  • the molar ratio of tenofovir alafenamide to L-malic acid is generally from 1.7:1 to 2.5:1, preferably from 1.9:1 to 2.3:1.
  • the collected solid may be washed with isopropyl alcohol.
  • the isolated solid is dried or further purified and then dried.
  • the drying temperature is usually 20 to 80 ° C, preferably 30 to 60 ° C; it can be dried at normal pressure or dried under reduced pressure.
  • n is selected to be 1
  • X is selected to be citric acid, that is, a complex formed by tenofovir alafenamide and citric acid in a 1:1 molar composition ratio, Tenofovir eugenol citrate (1:1)".
  • the present invention provides a process for the preparation of tenofovir alafenol citrate, the method comprising:
  • the isolated solid is dried or further purified and then dried.
  • the "suitable solvent” is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile, Methanol, ethanol, tetrahydrofuran or a mixture thereof.
  • the weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
  • the molar ratio of tenofovir alafenamide to citric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
  • the method of "precipitating solid” is a conventional method in the art, such as cooling, adding an anti-solvent, and the "anti-solvent” is selected from the group consisting of diethyl ether, ethyl acetate and methyl acetate. Ethyl formate, n-heptane, ethylene glycol dimethyl ether, diisopropyl ether, methyl tert-butyl ether, isooctane, anisole, etc. or a mixture thereof.
  • the method of concentrating a part of the solvent body, seeding, etc. may be used alone or in combination.
  • the solids precipitation process can be either standing or agitated.
  • the "separation" may employ a conventional method in the art such as filtration.
  • the collected solids may be washed with a suitable solvent in step (1).
  • the "drying” method includes atmospheric drying, reduced pressure drying or a combination thereof.
  • Methods for "further purification” include recrystallization, slurrying, washing, and the like.
  • the temperature of "drying” is generally 20 to 120 ° C, preferably 30 to 80 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
  • the tenofovir alafenamide (1:1) prepared by this embodiment is a crystal.
  • the present invention provides a crystalline form of tenofovir alafenamide (1:1) citrate (for convenience of presentation, the crystalline form is referred to as "tenofovir acetamide citrate (1) :1) Form A").
  • the X-ray powder diffraction pattern of the crystal form (using Cu-K ⁇ radiation) is characterized by a value of 2 ⁇ of 6.0° ⁇ 0.2°, 8.1° ⁇ 0.2°, 11.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.9. Characteristic diffraction peaks correspond to ° ⁇ 0.2°, 21.7° ⁇ 0.2°, 23.4° ⁇ 0.2°, and 26.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of tenofovir alafenamide (1:1) crystal form A of the present invention is characterized by a 2 ⁇ value of 6.0° ⁇ 0.2°. 8.1° ⁇ 0.2°, 11.7° ⁇ 0.2°, 12.6° ⁇ 0.2°, 15.4° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.5° ⁇ 0.2°, 17.9° ⁇ 0.2°, 20.1° ⁇ 0.2°, 20.6 ° ⁇ 0.2°, 21.4° ⁇ 0.2°, 21.7° ⁇ 0.2°, 23.4° ⁇ 0.2°, 26.9° ⁇ 0.2°, 29.3° ⁇ 0.2°, 31.9° ⁇ 0.2°, 32.7° ⁇ 0.2°, etc. Characteristic diffraction peaks.
  • the X-ray powder diffraction pattern of the tenofovir iramolamine (1:1) crystal form A of the present invention represented by the 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
  • the present invention provides tenofovir alafenamide (1:1) Form A having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
  • the present invention provides a tenofovir acetamide (1:1) crystalline form
  • a content in a mixture of tenofovir alafenamide (1:1) prepared by citrate is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • the tenofovir ylideamine (1:1) mixture of the present invention refers to a citric acid containing other impurities or crystal forms directly synthesized by chemical synthesis.
  • Tenofovir alafenamide (1:1) refers to a citric acid containing other impurities or crystal forms directly synthesized by chemical synthesis.
  • the method for preparing tenofovir alafenamide (1:1) crystal form A of the present invention comprises:
  • the molar ratio of tenofovir alafenamide to citric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
  • the collected solid may be washed with the solvent in the step (1).
  • the isolated solid is dried or further purified and then dried.
  • the drying temperature is usually 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
  • n is selected to be 1
  • X is selected to be succinic acid, that is, a complex formed by the ratio of tenofovir alafenamide to succinic acid in a molar ratio of 1:1 is referred to as "a compound”.
  • Tenofovir alafenamide succinate (1:1) is selected to be
  • the invention provides a method of preparing tenofovir alafenamide succinate, the method comprising:
  • the isolated solid is dried or further purified and then dried.
  • the "suitable solvent” is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile.
  • the weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
  • the molar ratio of tenofovir alafenamide to succinic acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
  • the method of "precipitating solid” is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination.
  • the solids precipitation process can be either standing or agitated.
  • the "separation" may employ a conventional method in the art such as filtration.
  • the collected solids may be washed with a suitable solvent in step (1).
  • the "drying” method includes atmospheric drying, reduced pressure drying or a combination thereof.
  • Methods for "further purification” include recrystallization, slurrying, washing, and the like.
  • the temperature of "drying” is generally 20 to 100 ° C, preferably 30 to 80 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
  • Tenofovir alafenamide (1:1) prepared in this embodiment is a crystal.
  • the present invention provides a crystalline form of tenofovir alafenamide (1:1) succinate (for convenience of presentation, the crystalline form is referred to as "tenofovir alafenol succinate (1) :1) Form A").
  • the X-ray powder diffraction pattern of the crystal form (using Cu-K ⁇ radiation) is characterized by a 2 ⁇ value of 10.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, 17.2° ⁇ 0.2°, 21.4° ⁇ 0.2°, 21.8. Characteristic diffraction peaks correspond to ° ⁇ 0.2°, 22.4° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of tenofovir alafenamide (1:1) Form A of the present invention is characterized by a 2 ⁇ value of 5.7° ⁇ 0.2°. 9.6° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.7° ⁇ 0.2°, 11.7° ⁇ 0.2°, 13.5° ⁇ 0.2°, 14.3° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.8° ⁇ 0.2°, 19.3 Characteristic diffraction peaks correspond to ° ⁇ 0.2°, 19.7° ⁇ 0.2°, 21.4° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.8° ⁇ 0.2°, 27.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the tenofovir alafenamide (1:1) crystalline form A of the present invention represented by the 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
  • the present invention provides tenofovir alafenamide (1:1) A having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
  • the present invention provides tenofovir alafenamide (1:1) crystalline form A in a mixture of tenofovir alafenamide (1:1) succinate (
  • the mass content) is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • the tenofovir alafenamide (1:1) mixture of the present invention refers to a succinic acid containing other impurities or crystal forms directly synthesized by chemical synthesis.
  • Tenofovir alafenamide (1:1) refers to a succinic acid containing other impurities or crystal forms directly synthesized by chemical synthesis.
  • the method for preparing tenofovir alafenamide (1:1) Form A of the present invention comprises:
  • the collected solid may be washed with acetonitrile.
  • the isolated solid is dried or further purified and then dried.
  • the drying temperature is usually 20 to 100 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
  • n is selected to be 1
  • X is selected as oxalic acid, that is, a complex formed by the ratio of tenofovir alafenamide to oxalic acid in a molar ratio of 1:1 is referred to as "oxalic acid”.
  • Norfoslavamide (1:1) is selected as oxalic acid.
  • the invention provides a method of preparing tenofovir alafenamide oxalate, the method comprising:
  • the isolated solid is dried or further purified and then dried.
  • the "suitable solvent” is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile.
  • the weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
  • the molar ratio of tenofovir alafenamide to oxalic acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
  • the method of "precipitating solid” is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination.
  • the solids precipitation process can be either standing or agitated.
  • the "separation" may employ a conventional method in the art such as filtration.
  • the collected solids may be washed with a suitable solvent in step (1).
  • the "drying” method includes atmospheric drying, reduced pressure drying or a combination thereof.
  • Methods for "further purification” include recrystallization, slurrying, washing, and the like.
  • the temperature of "drying” is generally 20 to 120 ° C, preferably 30 to 80 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
  • the tenofovir oxalatamide oxalate (1:1) prepared in this embodiment is a crystal.
  • the present invention provides a crystalline form of tenofovir alafenamide (1:1) (for convenience of presentation, the crystal form It is called "tenofovir oxalatine oxalate (1:1) crystal form A").
  • the X-ray powder diffraction pattern of the crystal form (using Cu-K ⁇ radiation) is characterized by a value of 2 ⁇ of 7.7° ⁇ 0.2°, 9.6° ⁇ 0.2°, 16.2° ⁇ 0.2°, 18.2° ⁇ 0.2°, 20.5. Characteristic diffraction peaks correspond to ° ⁇ 0.2°, 24.7° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of tenofovir alafenamide (1:1) crystalline form A of the present invention is characterized by a value of 7.7° ⁇ 0.2° at a 2 ⁇ value, 8.4° ⁇ 0.2°, 9.6° ⁇ 0.2°, 12.6° ⁇ 0.2°, 16.2° ⁇ 0.2°, 18.2° ⁇ 0.2°, 20.5° ⁇ 0.2°, 22.6° ⁇ 0.2°, 24.7° ⁇ 0.2°, 27.8° Characteristic diffraction peaks correspond to ⁇ 0.2°, 29.0° ⁇ 0.2°, and the like.
  • the X-ray powder diffraction pattern of the tenofovir oxalatine (1:1) crystalline form A of the present invention represented by the 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
  • the present invention provides tenofovir alafenamide (1:1) Form A having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
  • the present invention provides a preparation of tenofovir alafenamide (1:1) crystalline form A (mass content) in a mixture of tenofovir alafenamide (1:1). Generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • the tenofovir oxalatamide (1:1) mixture of the present invention refers to a oxalic acid oxalic acid containing other impurities or crystal forms directly synthesized by chemical synthesis. Fuviralolamine (1:1).
  • the method for preparing tenofovir oxalatine (1:1) crystalline form A of the present invention comprises:
  • Tenofovir alafenamide and oxalic acid are dissolved in acetonitrile; the weight ratio of the solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
  • the molar ratio of tenofovir alafenamide to oxalic acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
  • the collected solid may be washed with acetonitrile.
  • the isolated solid is dried or further purified and then dried.
  • the drying temperature is usually 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
  • n is selected to be 1
  • X is selected as phosphoric acid, that is, a complex formed by the ratio of tenofovir alafenamide to phosphoric acid in a molar ratio of 1:1 is referred to as "phosphoric acid”.
  • Norfoslavamide (1:1) is selected as phosphoric acid.
  • the invention provides a method of preparing tenofovir alafenol phosphate, the method comprising:
  • the isolated solid is dried or further purified and then dried.
  • the "suitable solvent” is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile.
  • the weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
  • the molar ratio of tenofovir alafenamide to phosphoric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
  • the method of "precipitating solid” is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination.
  • the solids precipitation process can be either standing or agitated.
  • the "separation" may employ a conventional method in the art such as filtration.
  • the collected solids may be washed with a suitable solvent in step (1).
  • the "drying” method includes atmospheric drying, reduced pressure drying or a combination thereof.
  • Methods for "further purification” include recrystallization, slurrying, washing, and the like.
  • the temperature of "drying” is generally 20 to 120 ° C, preferably 30 to 80 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
  • Tenofovir enalap phosphate (1:1) prepared in this embodiment is a crystal.
  • the present invention provides a crystalline form of tenofovir alafenamide (1:1) (for convenience of presentation, the crystal form is referred to as "tenofovir alafenol phosphate (1:1) ) Crystal form A").
  • the X-ray powder diffraction pattern of the crystal form (using Cu-K ⁇ radiation) is characterized by a value of 2 ⁇ of 8.0° ⁇ 0.2°, 9.4° ⁇ 0.2°, 10.6° ⁇ 0.2°, 14.5° ⁇ 0.2°, 19.3. Characteristic diffraction peaks correspond to ° ⁇ 0.2°, 21.1° ⁇ 0.2°, 23.4° ⁇ 0.2°, etc.
  • the X-ray powder of tenofovir alafenamide (1:1) crystal form A of the present invention is claimed.
  • the diffraction pattern is characterized by: 2 ⁇ values of 8.0° ⁇ 0.2°, 9.4° ⁇ 0.2°, 10.6° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.6° ⁇ 0.2 Characteristic diffraction peaks are corresponding to °, 18.6 ° ⁇ 0.2 °, 19.3 ° ⁇ 0.2 °, 21.1 ° ⁇ 0.2 °, 23.4 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the tenofovir alafenamide (1:1) crystal form A of the present invention represented by the 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
  • the present invention provides tenofovir alafenamide (1:1) Form A having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
  • the present invention provides a tenofovir 137 (1:1) crystal form A content (mass content) of a mixture of tenofovir alafenamide (1:1). Generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • the tenofovir enalapraphosphate (1:1) mixture of the present invention refers to a phosphonium tetrachloride containing other impurities or crystal forms which is directly synthesized by chemical synthesis. Fuviralolamine (1:1).
  • the method for preparing tenofovir alafenamide (1:1) crystal form A of the present invention comprises:
  • Tenofovir alafenamide and phosphoric acid are dissolved in acetonitrile; the weight ratio of the solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
  • the molar ratio of tenofovir alafenamide to phosphoric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
  • the collected solid may be washed with acetonitrile.
  • the isolated solid is dried or further purified and then dried.
  • the drying temperature is usually 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
  • n is selected to be 1
  • X is selected as sulfuric acid, that is, a complex formed by the ratio of tenofovir alafenamide to sulfuric acid in a molar ratio of 1:1 is referred to as "sulfuric acid”.
  • Norfoslavamide (1:1) is selected as sulfuric acid.
  • the invention provides a method of preparing tenofovir alafenol sulfate, the method comprising:
  • the isolated solid is dried or further purified and then dried.
  • the "suitable solvent” is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile.
  • the weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
  • the molar ratio of tenofovir alafenamide to sulfuric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
  • the method of "precipitating solid” is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination.
  • the solids precipitation process can be either standing or agitated.
  • the "separation" may employ a conventional method in the art such as filtration.
  • the collected solids may be washed with a suitable solvent in step (1).
  • the "drying” method includes atmospheric drying, reduced pressure drying or a combination thereof.
  • Methods for "further purification” include recrystallization, slurrying, washing, and the like.
  • the temperature of "drying” is generally 20 to 120 ° C, preferably 30 to 80 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
  • Tenofovir lysamine sulfate (1:1) prepared in this embodiment is a crystal.
  • the present invention provides a crystalline form of tenofovir alafenamide (1:1) (for convenience of description, the crystal form is referred to as "tenofovir alafenol sulfate (1:1) ) Crystal form A").
  • the X-ray powder diffraction pattern of the crystal form (using Cu-K ⁇ radiation) is characterized by a value of 2 ⁇ of 9.2° ⁇ 0.2°, 10.7° ⁇ 0.2°, 11.1° ⁇ 0.2°, 18.4° ⁇ 0.2°, 19.8. Characteristic diffraction peaks correspond to ° ⁇ 0.2°, 22.3° ⁇ 0.2°, and 24.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of tenofovir alafenamide (1:1) crystal form A of the present invention is characterized by a value of 9.2 ° ⁇ 0.2 ° at a 2 ⁇ value, 10.7° ⁇ 0.2°, 11.1° ⁇ 0.2°, 16.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, 19.2° ⁇ 0.2°, 19.8° ⁇ 0.2°, 21.7° ⁇ 0.2°, 22.3° ⁇ 0.2°, 23.1° Characteristic diffraction peaks correspond to ⁇ 0.2°, 24.3° ⁇ 0.2°, 28.1° ⁇ 0.2°, 31.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the tenofovir alafenamide (1:1) crystal form A of the present invention represented by the 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
  • the present invention provides tenofovir alafenamide (1:1) Form A having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
  • the tenofovir alafenamide (1:1) crystalline form A content (mass content) of the prepared tenofovir alafenamide (1:1) mixture provided by the present invention ) generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • the tenofovir enalapramate (1:1) mixture of the present invention refers to a thiosulfate containing other impurities or crystal forms directly synthesized by chemical synthesis. Fuviralolamine (1:1).
  • the method for preparing tenofovir alafenamide (1:1) Form A of the present invention comprises:
  • Tenofovir alafenamide and sulfuric acid are dissolved in acetonitrile; the weight ratio of the solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
  • the molar ratio of tenofovir alafenamide to sulfuric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
  • the collected solid may be washed with acetonitrile.
  • the isolated solid is dried or further purified and then dried.
  • the drying temperature is usually 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
  • the present invention provides a tenofovir alafenamide complex comprising a therapeutically effective amount of the tenofovir alafenamide complex of Formula II or the method of preparation, and a pharmaceutical A pharmaceutical composition or formulation of an excipient.
  • the above pharmaceutical composition or formulation may further comprise another or more antiviral agents or antiviral auxiliary agents including, but not limited to, emtricitabine, lamivudine, and abacavir (Abacavir).
  • Abacavir emtricitabine, lamivudine, and abacavir
  • the pharmaceutical composition of the invention is selected from one of the following:
  • composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, emtricitabine, Cobicistat, and eritavir; or
  • composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, emtricitabine, Cobicistat, and darunavir; or
  • composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II and emtricitabine; or
  • a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, emtricitabine and efavirenz; or
  • composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, emtricitabine and pirimivir hydrochloride; or
  • a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, lamivudine; or
  • a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, lamivudine and efavirenz; or
  • composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, lamivudine, Cobicistat, and ertivir; or
  • a pharmaceutical composition comprising a therapeutically effective amount of tenofovir alafenamide complex of formula II, lamivudine, Cobicistat, and darunavir.
  • the invention provides a therapeutically effective amount of tenofovir lysamine L-tartrate (1:2), ten-tenofovir lysamine D-tartaric acid (1:1) , DL-tenofovir iracrolimum tartrate (1:1), L-malofovir idolavir (1:2), tenofovir iramate citrate (1:1 ), tenofovir alafenamide succinate (1:1), tenofovir oxalatine oxalate (1:1), tenofovir enalapenoate (1:1), sulfate Norfoslavamide (1:1), L- Tenofovir lysamine tartrate (1:2) Form A, D-tenofovir iramol tartrate (1:1) Form A, DL-tenofovir alafenamide 1:1) Form A, L-Tanofovir alafenamide (1:2) Form A, Tenofovir iramol citrate (1:1) Form
  • compositions or preparations can be administered orally or parenterally.
  • tablets, capsules, pills, granules, solutions, syrups, suspensions, powders, sustained release preparations or controlled release preparations can be prepared by conventional formulation techniques.
  • it When it is not administered orally, it can be made into a transdermal preparation, an injection, an infusion solution or a suppository by a conventional formulation technique.
  • tenofovir alafenamide compound of formula II such as L-tenofovir lysamine L-tartaric acid (1:2), D-tenofovir lysine D-tartaric acid
  • the above pharmaceutical composition or preparation is preferably an oral dosage form including a tablet, a capsule, a pill, a granule, a solution, a syrup, a dry suspension, a suspension, a powder, a sustained release preparation or a controlled release preparation.
  • solid oral preparations such as tablets, capsules, granules, dry suspensions, and sustained release preparations or controlled release preparations are preferred, and tablets and capsules are more preferred.
  • the preferred pharmaceutical compositions or formulations of the present invention can be prepared according to any of the conventional methods employed in the preparation of solid oral formulations.
  • any form of coating can be carried out according to need, such as tablets can be made into any release form (such as immediate release, enteric and controlled release, etc.); capsules can be used It can be prepared by wet granulation capsule preparation, etc., and the capsule contents can be prepared into any release form (such as immediate release preparation, enteric preparation and controlled release preparation, etc.).
  • the present invention provides a tenofovir alafenamide complex of Formula II (such as L-tenofovir lysamine (1:2), D-tartrate D-tartaric acid Vesalamine (1:1), DL-tenofovir iracrolimum tartrate (1:1), tenofovir ialafen L-malate (1:2), citric acid titanoate Fuviralilamine (1:1), tenofovir iramol succinate (1:1), tenofovir oxalatine oxalate (1:1), tenofoviraine phosphate Phenolamine (1:1), tenofovir sulfate Iratonamine (1:1), Tenofovir alafenamide (1:2) Form A, D-tenofovir iramolamine (1:1) Form A, DL-tenofovir iracrolimide tartrate (1:1) crystal form A, L-tanofovir alafenamide (1:2)
  • compositions conventional in the art in oral dosage forms include fillers, disintegrants, binders, dispersants, lubricants or retention aids, as well as various types of coating materials and the like.
  • the filler generally comprises pregelatinized starch, starch, lactose, dextrin, calcium hydrogen phosphate, calcium carbonate, mannitol, microcrystalline cellulose, sorbitol, glucose, etc., which may be used singly or in combination, and preferably Pregelatinized starch, lactose, microcrystalline cellulose, mannitol.
  • the disintegrant generally comprises croscarmellose sodium, sodium carboxymethylcellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and the like. They may be used singly or in combination, and among them, croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, microcrystalline cellulose, and low-substituted hydroxypropylcellulose are preferable.
  • the binder generally comprises microcrystalline cellulose, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropylcellulose, povidone, starch syrup, gum arabic, polyethylene glycol 4000, polyvinyl alcohol Alginate, water, various concentrations of ethanol solution, which may be used singly or in combination, of which hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, and starch syrup are preferred.
  • the lubricant generally comprises magnesium stearate, stearic acid, calcium stearate, sodium stearate, sodium stearate, palmitic acid, micronized silica gel, stearic acid amide, talc, solid.
  • sweeteners such as aspartame, stevioside, etc.
  • coloring agents such as various medicinal or food colors such as tartrazine and iron oxide
  • Stabilizers such as calcium carbonate, calcium bicarbonate, sodium bicarbonate, sodium carbonate, calcium phosphate, calcium hydrogen phosphate, glycine, etc.
  • surfactants such as Tween 80, sodium lauryl sulfate, etc.
  • coating materials eg Opadry, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acrylic resin copolymers, etc.
  • the invention provides a single composition or formulation wherein the active ingredient is selected from a therapeutically effective amount of a tenofovir alafenamide complex of formula II (eg, L-tartrate tinoate) Fouevirapide (1:2), D-tenofovir idylamine tartrate (1:1), DL-tenofovir idylamine tartrate (1:1), L-malic acid Tenofowe Lauramine (1:2), tenofovir eugenol citrate (1:1), tenofovir iramol succinate (1:1), tenofovir alafenamide (1:1), Tenofovir iramolamine phosphate (1:1), tenofovir alafenamide (1:1), and ten-tenofovir alafenamide (1: 2) Form A, D- tenofovir iraline tartrate (1:1) Form A, DL-tenofovir iraline tartrate (1
  • composition or formulation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are usually present in an amount of from 1 mg to 200 mg, preferably from 5 mg to 100 mg, for example, tenofovir alafenamide
  • the weight content is about 10 mg, about 12.5 mg, about 25 mg or about 50 mg, wherein "about” refers to a range of ⁇ 10%, preferably ⁇ 5%.
  • the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II.
  • the composition or formulation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, each is usually present in an amount of from 1 mg to 500 mg, preferably from 5 mg to 300 mg, for example, containing about 10 mg of the above first active ingredient. Or about 25 mg (based on tenofovir alaflurane), about 200 mg of the second active ingredient (entecitabine), about 150 mg of the third active ingredient (Cobicistat), and about the fourth active ingredient (etiravir). 150 mg, wherein "about” refers to a range of ⁇ 10%, preferably ⁇ 5%.
  • the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II.
  • the composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, each of them is usually present in an amount of from 1 mg to 1000 mg, preferably from 5 mg to 900 mg, for example, containing about 10 mg of the above-mentioned first active ingredient. Or about 25 mg (based on tenofovir alafenamide), about 200 mg of the second active ingredient (encindabine), about 150 mg of the third active ingredient (Cobicistat), and about the fourth active ingredient (darinavir). 800 mg, wherein "about” means a range of ⁇ 10%, preferably ⁇ 5%.
  • the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II.
  • the composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, each is usually present in an amount of from 1 mg to 500 mg, preferably from 5 mg to 300 mg, for example, about 10 mg of the above-mentioned first active ingredient. Or about 25 mg (based on tenofovir alafenamide) and a second active ingredient (enstattine) of about 200 mg, wherein "about” refers to a range of ⁇ 10%, preferably ⁇ 5%.
  • the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II.
  • the composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, each is usually present in an amount of from 1 mg to 800 g, preferably from 5 mg to 700 mg, for example, containing about 10 mg of the above first active ingredient. Or about 25 mg (based on tenofovir alafenamide), about 200 mg of the second active ingredient (enstattine) and about 600 mg of the third active ingredient (efavirenz), wherein "about” means ⁇ 10% The range is preferably in the range of ⁇ 5%.
  • the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II.
  • the composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, each is usually present in an amount of from 1 mg to 500 mg, preferably from 5 mg to 300 mg, for example, about 10 mg of the above-mentioned first active ingredient. Or about 25 mg (based on tenofovir alafenamide), about 200 mg of the second active ingredient (emtricitabine) and about 25 mg of the third active ingredient (rivivirine hydrochloride) (in terms of pirimivir) "About" means a range of ⁇ 10%, preferably ⁇ 5%.
  • the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II.
  • the composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; In the unit composition or formulation, they are each usually present in an amount of from 1 mg to 500 mg, preferably from 5 mg to 400 mg, for example, containing about 10 mg or about 25 mg of the above first active ingredient (based on tenofovir alafenamide) and The second active ingredient (lamivudine) is about 300 mg, wherein "about” means a range of ⁇ 10%, preferably ⁇ 5%.
  • the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II.
  • the composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, each is usually present in an amount of from 1 mg to 800 mg, preferably from 5 mg to 700 mg, for example, about 10 mg of the above-mentioned first active ingredient. Or 25 mg (based on tenofovir alafenamide), about 300 mg of the second active ingredient (lamivudine) and about 600 mg of the third active ingredient (efavirenz), wherein "about” means ⁇ 10% of the range Preferably, the range is ⁇ 5%.
  • the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II.
  • the composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, each is usually present in an amount of from 1 mg to 500 mg, preferably from 5 mg to 400 mg, for example, containing about 10 mg of the above first active ingredient. Or about 25 mg (based on tenofovir alafenamide), second active ingredient (Ramit Approximately 300 mg, a third active ingredient (Cobicistat) of about 150 mg and a fourth active ingredient (etilavir) of about 150 mg, wherein "about” means a range of ⁇ 10%, preferably ⁇ 5%.
  • the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II.
  • the composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, each of them is usually present in an amount of from 1 mg to 1000 mg, preferably from 5 mg to 900 mg, for example, containing about 10 mg of the above-mentioned first active ingredient. Or about 25 mg (based on tenofovir alafenamide), about 200 mg of the second active ingredient (lamivudine), about 150 mg of the third active ingredient (Cobicistat), and about the fourth active ingredient (darinavir). 800 mg, wherein "about” means a range of ⁇ 10%, preferably ⁇ 5%.
  • compositions are not only chemically stable, but also have synergistic effects and/or can reduce side effects and drug resistance of the individual active ingredients; and may increase patient compliance.
  • the present invention provides a method of preparing the above pharmaceutical compositions or formulations.
  • the method generally comprises mixing or contacting a therapeutically effective amount of the tenofovir alafenamide complex of Formula II with one or more pharmaceutical excipients.
  • the method will generally be a therapeutically effective amount of a tenofovir alafenamide complex of formula II, a second active ingredient (eg, emtricitabine, lamivudine, etc.) Mix or contact with one or more pharmaceutical excipients.
  • the method will generally be a therapeutically effective amount of a tenofovir alafenamide complex of formula II, a second active ingredient (eg, emtricitabine, lamiv) Mixing or contacting with another pharmaceutical active ingredient or other active ingredient.
  • a second active ingredient eg, emtricitabine, lamiv
  • the pharmaceutical composition or formulation can be prepared in a manner well known in the art.
  • the pharmaceutical excipients may be conventional pharmaceutical excipients in the art, including fillers, disintegrants, binders, lubricants and the like.
  • the present invention provides a tenofovir alafenamide complex of the formula II or the tenofovir alafenamide complex prepared by the preparation method for preparing a prophylactic and/or therapeutic virus Application in infected drugs.
  • the present invention provides a tenofovir alafenamide complex of the formula II for the preparation of a prophylactic and/or therapeutic hepatitis B.
  • a tenofovir alafenamide complex of the formula II for the preparation of a prophylactic and/or therapeutic hepatitis B.
  • the present invention provides a tenofovir alafenamide complex of Formula II for the preparation of a prophylactic and/or therapeutic hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV). Application in infected drugs.
  • HBV hepatitis B virus
  • HAV human immunodeficiency virus
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II and a pharmaceutically acceptable adjuvant for the preparation of a prophylactic and/or therapeutic hepatitis B virus (HBV) and/or use in drugs for human immunodeficiency virus (HIV) infection.
  • HBV hepatitis B virus
  • HAV human immunodeficiency virus
  • the invention provides a therapeutically effective amount of a tenofovir levamide complex of formula II, another or more antiviral or antiviral adjuvants, and a pharmaceutically acceptable adjuvant Use of a pharmaceutical composition for the manufacture of a medicament for the prevention and/or treatment of hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) infection.
  • HBV hepatitis B virus
  • HAV human immunodeficiency virus
  • the present invention provides tenofovir alafenamide compound represented by formula II, such as L-tenofovir lysamine (1:2) of L-tartrate, and tenofovira D-tartaric acid.
  • the X-ray powder diffraction analysis of the present invention is a CuK ⁇ source of the X.Pert PRO type X-ray powder diffractometer of the Netherlands PANaco at ambient temperature and ambient humidity ( The measurement is completed.
  • the "ambient temperature” is generally 0 to 40 ° C; the “ambient humidity” is generally 30% to 80% relative humidity.
  • Representative X-ray powder diffraction patterns provided by the present invention are listed in the accompanying drawings.
  • "Representative X-ray powder diffraction pattern” means that the X-ray powder diffraction characteristics of the crystal form conform to the overall morphology of the map, and it is understood that during the test, due to various factors (such as test samples) The effect of the particle size, sample processing method, instrument, test parameters, test operation, etc., the peak position or peak intensity of the X-ray powder diffraction pattern measured by the same crystal form may be different. In general, the experimental error of the diffraction peak 2 ⁇ value in the X-ray powder diffraction pattern may be ⁇ 0.2°.
  • Figure 1 X-ray powder diffraction pattern of L-norofovir lysamine (1:2) Form A of L-tartrate;
  • Figure 8 X-ray powder diffraction pattern of tenofovir alafenamide (1:1) crystal form A;
  • the 1 H NMR test in the following examples was carried out using deuterated dimethyl sulfoxide as a test solvent, tetramethylsilane as an internal standard, and a Bruke AV-II 400 MHz nuclear magnetic resonance spectrometer at room temperature.
  • the X-ray powder diffraction analysis in the following examples is a CuK ⁇ source from the Dutch PANalytical X'Pert PRO X-ray powder diffractometer at ambient temperature and ambient humidity ( The measurement is completed.
  • the "ambient temperature” is generally 0 to 40 ° C; the “ambient humidity” is generally 30% to 80% relative humidity.
  • Elemental analysis in the following examples was performed by an Italian CARLO ERBA 1106 elemental analyzer.
  • the melting range in the following examples was measured by a YRT-3 type drug melting point apparatus.
  • the concentrate was dissolved in a toluene/acetonitrile mixed solvent (volume ratio 4/1) at 25 L at 20 to 25 ° C, and tenofovir alafenamide seed crystal (prepared according to the method disclosed in CN1443189A) was added to 50 mg, and then continued. After stirring for 2 hours, suction filtration, the filter cake was washed with toluene/acetonitrile (volume ratio 4/1), and then dried under reduced pressure at 40 to 45 ° C to obtain tenofovir alafenamide.
  • Methyl H from the integrated area ratio of the two sets of signal peaks, it can be judged that the molar composition ratio of tenofovir alafluamine and L-tartaric acid in the sample is 2:1 (the 1 H NMR spectrum is shown in Fig. 11).
  • the measured X-ray powder diffraction pattern is shown in Fig. 1.
  • the measured values are as follows (measured by the diffraction peak corresponding to a relative intensity of 3% or more, and the measured value is rounded off to take three decimal places).
  • the signal peaks at chemical shifts of ⁇ 8.15 (s, 1H) and 8.11 (s, 1H) were assigned to 2 H, ⁇ 4 on tenofovir alafenamide adenine, respectively.
  • the signal peak at 32-4.26 (m, 3H) is compared with the 1 H NMR of tenofovir alafenamide free base in Example 1, and it can be judged that 2 of the H are classified as D-tartaric acid.
  • the molar composition ratio of tenofovir alafenamide to D-tartaric acid in the sample was judged to be 1:1 (see Figure 12 for the 1 H NMR spectrum).
  • the measured X-ray powder diffraction pattern is shown in Fig. 2, and the measured values are as follows (measured by the diffraction peak corresponding to the relative intensity of 3% or more, and the measured value is rounded off to take three decimal places).
  • the signal peaks at chemical shifts of ⁇ 8.14 (s, 1H) and 8.11 (s, 1H) were assigned to 2 H, ⁇ 4 on tenofovir alafenamide adenine, respectively.
  • the signal peak at 31-4.26 (m, 3H) was compared with the 1 H NMR of tenofovir alafenol free base in Example 1, and it was judged that 2 of the H were classified as DL-tartaric acid. Based on the integral area ratio of the two sets of signal peaks, the molar composition ratio of tenofovir alafenamide to DL-tartaric acid in the sample was determined to be 1:1 (see Figure 13 for the 1 H NMR spectrum).
  • the measured X-ray powder diffraction pattern is shown in Fig. 3, and the measured values are as follows (measured by the diffraction peak corresponding to the relative intensity of 3% or more, and the measured value is rounded off to take three decimal places).
  • the signal peaks at chemical shifts of ⁇ 8.15 (s, 1H) and 8.11 (s, 1H) were assigned to 2 H, ⁇ 2 on tenofovir alafenamide adenine, respectively.
  • the signal peak at 65-2.43 (m, 1H) is assigned to 2 H on the L-malic acid methylene group. From the integrated area ratio of the two sets of signal peaks, the tenofovir alafenamide in the sample can be judged.
  • the molar composition ratio of L-malic acid was 2:1 (see Figure 14 for the 1 H NMR spectrum).
  • the measured X-ray powder diffraction pattern is shown in Fig. 4.
  • the measured values are as follows (measured by the diffraction peak corresponding to the relative intensity of 3% or more, and the measured value is rounded off to take three decimal places).
  • the signal peaks at chemical shifts of ⁇ 8.14 (s, 1H) and 8.11 (s, 1H) were assigned to two H, ⁇ 2 on tenofovir alafenamide adenine, respectively.
  • the signal peaks at 78-2.74(d,2H) and 2.67-2.64(d,2H) are assigned to 4 Hs of 2 methylene groups on citric acid.
  • the integrated area ratio of the two sets of signal peaks can be judged in the sample.
  • the molar composition ratio of tenofovir alafenamide to citric acid was 1:1 (see Figure 15 for the 1 H NMR spectrum).
  • the measured X-ray powder diffraction pattern is shown in Fig. 5.
  • the measured values are as follows (measured by the diffraction peak corresponding to a relative intensity of 3% or more, and the measured value is rounded off to take three decimal places).
  • the signal peaks at chemical shifts of ⁇ 8.15 (s, 1H) and 8.11 (s, 1H) were assigned to 2 H, ⁇ 2 on tenofovir alafenamide adenine, respectively.
  • the signal peak at 43(s, 4H) is assigned to 4 H of 2 symmetrical methylene groups on succinic acid.
  • the integral area ratio of the two sets of signal peaks can be used to determine tenofovir alafenamide and amber in the sample.
  • the molar composition ratio of the acid was 1:1 (see Figure 16 for the 1 H NMR spectrum).
  • the measured X-ray powder diffraction pattern is shown in Fig. 6.
  • the measured values are as follows (measured by the diffraction peak corresponding to the relative intensity of 3% or more, and the measured value is rounded to three decimal places).
  • the measured X-ray powder diffraction pattern is shown in Fig. 7.
  • the measured values are shown in the following table (measured by the diffraction peak corresponding to a relative intensity of 3% or more, and the measured value is rounded off to take three decimal places).
  • the measured X-ray powder diffraction pattern is shown in Fig. 8.
  • the measured values are shown in the following table (measured corresponding to the diffraction peaks with a relative intensity of 3% or more, and the measured values are rounded off to take three decimal places).
  • the X-ray powder diffraction pattern measured is shown in Fig. 9.
  • the measured values are shown in the following table (measured corresponding to the diffraction peaks with a relative intensity of 3% or more, and the measured values are rounded off to take three decimal places).
  • the crystalline form of tenofovir alafenamide (1:2) of L-tartrate prepared according to the method of Example 2 was prepared according to the following solvent and manner.
  • the X-ray powder diffraction pattern was examined to examine the crystal form, and the results are as follows (TAF in the table below represents tenofovir alafenamide):
  • the tenofovir 137 (1:1) crystal form A prepared by the method of Example 2 was added to an appropriate amount of the solvent listed in the following table, heated and stirred, suction filtered, and the filter cake was dried under reduced pressure. .
  • the X-ray powder diffraction pattern was examined to examine the crystal form, and the results are as follows (TAF in the table below represents tenofovir alafenamide):
  • Tenofovir alafenamide fumarate (1:1) (prepared according to the method disclosed in patent document CN1443189A), tenofovir fumarate fumarate (1:2) (according to patent document CN103732594A) Prepared by the method disclosed), tenofofovir olamine tartrate (1:2) (prepared according to the method of Example 2), DL-tenofovir iramol tartrate (1:1) ( Prepared according to the method of Example 6 and tenofovir alafenamide (1:1) (prepared according to the method of Example 8), and tested under high temperature and high humidity for 20 days, respectively, the results are as follows (below TAF in the table stands for tenofovir alafenol):
  • the present invention provides tenofovir alafenamide (1:2), DL-tenofovir idylamine tartrate (1:1) and tenofovira citric acid.
  • the stability of phenolamine (1:1) under high temperature and high humidity conditions is better than tenofovir fumarate fumarate (1:1) and tenofovir fumarate fumarate (1:2) ) quite or better.
  • Tenofovir alafenamide fumarate (1:1) (prepared according to the method disclosed in patent document CN1443189A), tenofovir fumarate fumarate (1:1) (according to patent document CN103732594A) Prepared by the method disclosed), Tenofovir alafenamide (1:1) (prepared according to the method of Example 2), DL-tenofovir alafenamide (1:1) ( Prepared according to the method of Example 6 and tenofovir alafenamide (1:1) (prepared according to the method of Example 8), and tested their solubility in different media at 25 ° C, respectively.
  • TAF in the table below represents tenofovir alafenamide
  • the above studies show that the present invention provides tenofovir alafenamide (1:2), DL-tenofovir idylamine tartrate (1:1) and tenofovira citric acid.
  • the solubility of phenolamine (1:1) is comparable to or better than tenofovir lysamine fumarate (1:1) and tenofovir fumarate (1:2).
  • Tenofovir alafenamide (1:2) of L-tartrate with a relatively crystal size was prepared by sieving with a ⁇ m sieve [abbreviation: L-tartaric acid TAF (1:2), test drug 1], citric acid Tenofovir alafenamide (1:1) [abbreviation: citric acid TAF (1:1), test drug 2] and tenofovir alafenamide (1:2) [abbreviation: Fumaric acid TAF (1:2), reference drug].
  • Blood was collected from the jugular vein before administration and at 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration, about 200 ⁇ L each time, 3500 rpm, and centrifuged. After 10 minutes, the upper plasma was taken and the concentration of tenofovir in plasma was quantitatively analyzed by LC-MS/MS.
  • the paired t-test was used to compare the pharmacokinetic parameters of tenofovir after administration of the test drug and the reference drug. Tmax was tested by nonparametric test, and other parameters were tested after logarithmic transformation.
  • the main pharmacokinetic parameters and t test results are as follows:
  • Chip core L-tenofovir alafenamide (1:2) 28.9 Lactose monohydrate 100.0 Microcrystalline cellulose 60.0 Croscarmellose sodium 15.0 Magnesium stearate 3.0 Film coating material: Opadi II 10.0
  • the sodium carboxymethyl starch was first mixed with the microcrystalline cellulose, then the lactose monohydrate was added, and then the ten-five valeramine (1:2) was added.
  • Add purified water to the appropriate amount of wet granulation; dry; granules; add magnesium stearate to mix, fill with hypromellose capsules, that is.
  • Chip core D-tenofovir alafenamide tartrate (1:1) 32.9 Lactose monohydrate 100.0 Microcrystalline cellulose 60.0 Croscarmellose sodium 15.0 Magnesium stearate 3.0 Film coating material: Opadi II 10.0
  • Chip core DL-tenofovir alafenamide (1:1) 32.9 Lactose monohydrate 100.0 Microcrystalline cellulose 60.0 Croscarmellose sodium 15.0 Magnesium stearate 3.0 Film coating material: Opadi II 10.0
  • Chip core L-malofovir alafenamide (1:2) 28.5 Lactose monohydrate 100.0 Microcrystalline cellulose 60.0 Croscarmellose sodium 15.0 Magnesium stearate 3.0 Film coating material: Opadi II 10.0
  • Chip core Tenofovir eugenol citrate (1:1) 35.1 Lactose monohydrate 100.0 Microcrystalline cellulose 60.0 Croscarmellose sodium 15.0 Magnesium stearate 3.0 Film coating material: Opadi II 10.0
  • Chip core Tenofovir alafenamide succinate (1:1) 31.2 Lactose monohydrate 100.0 Microcrystalline cellulose 60.0 Croscarmellose sodium 15.0 Magnesium stearate 3.0 Film coating material: Opadi II 10.0
  • Chip core Tenofovir alafenamide (1:1) 29.7 Lactose monohydrate 100.0 Microcrystalline cellulose 60.0 Croscarmellose sodium 15.0 Magnesium stearate 3.0 Film coating material: Opadi II 10.0
  • the microcrystalline cellulose is mixed with croscarmellose sodium, then added with lactose monohydrate, and then mixed with tenofovir alafenamide (1:1); Adding purified water to the appropriate amount of wet granulation; drying; granulating; adding magnesium stearate to mix, tableting; then coating the coating material with 75% ethanol to form a suspension, that is, obtained.
  • Chip core Tenofovir alafenamide (1:1) 30.1 Lactose monohydrate 100.0 Microcrystalline cellulose 60.0 Croscarmellose sodium 15.0 Magnesium stearate 3.0 Film coating material: Opadi II 10.0
  • the microcrystalline cellulose was mixed with croscarmellose sodium, then added with lactose monohydrate, and then mixed with tenofovir alafenamide (1:1); Adding purified water to the appropriate amount of wet granulation; drying; granulating; adding magnesium stearate to mix, tableting; then coating the coating material with 75% ethanol to form a suspension, that is, obtained.
  • Chip core Tenofovir alafenamide (1:1) 30.1 Lactose monohydrate 100.0 Microcrystalline cellulose 60.0 Croscarmellose sodium 15.0 Magnesium stearate 3.0 Film coating material: Opadi II 10.0
  • Preparation of granule-I According to the raw materials in the above table, the pre-gelatinized side powder is mixed with croscarmellose sodium, then the lactose monohydrate and microcrystalline cellulose are mixed, and then added. L-tanofosyl alafenamide (1:2) is mixed, and finally added to emtricitabine; add purified water to prepare wet granulation; dry; granule; add magnesium stearate to mix, that is.
  • Chip core L-tenofovir alafenamide (1:2) 28.9 Emtricitabine 200.0 Microcrystalline cellulose 300.0 Lactose monohydrate 120.0 Pregelatinized starch 40.0 Croscarmellose sodium 15.0 Magnesium stearate 6.0 Film coating material: Opadi II 20.0
  • Chip core Tenofovir alafenamide (1:1) 30.1 Emtricitabine 200.0 Microcrystalline cellulose 300.0 Lactose monohydrate 120.0 Pregelatinized starch 40.0 Croscarmellose sodium 15.0 Magnesium stearate 6.0 Film coating material: Opadi II 20.0
  • Chip core Grain-I: D-tenofovir alafenamide tartrate (1:1) 13.1 Emtricitabine 200.0 Microcrystalline cellulose 200.0 Croscarmellose sodium 20.0 Magnesium stearate 7.0 Granule-II: Ephel 600.0 Microcrystalline cellulose 130.0 Hydroxypropyl cellulose 20.0 Croscarmellose sodium 20.0 Sodium lauryl sulfate 10.0 Magnesium stearate 10.0 Film coating material Opadi II 30.0
  • the core particle-I and the core particle-II are tableted by a double laminating machine; the coating material is coated with a 75% ethanol solution to obtain a suspension.
  • Chip core Grain-I: L-malofovir alafenamide (1:2) 11.4 Emtricitabine 200.0 Microcrystalline cellulose 200.0 Croscarmellose sodium 20.0 Magnesium stearate 7.0 Granule-II: Ephel 600.0 Microcrystalline cellulose 130.0 Hydroxypropyl cellulose 20.0 Croscarmellose sodium 20.0 Sodium lauryl sulfate 10.0 Magnesium stearate 10.0 Film coating material Opadi II 30.0
  • Chip core Grain-I: Tenofovir eugenol citrate (1:1) 14.0 Emtricitabine 200.0 Microcrystalline cellulose 200.0 Lactose monohydrate 150.0 Pregelatinized powder 40.0 Croscarmellose sodium 20.0 Magnesium stearate 7.0
  • Granule-II Lipiride hydrochloride 27.5 Lactose monohydrate 200.0 Microcrystalline cellulose 60.0 Croscarmellose sodium 15.0 Povidone K 30 3.0 Magnesium stearate 3.0 Polysorbate 20 0.5 Film coating material Opadi II 25.0
  • Preparation of granule-I According to the raw materials in the above table, the pre-gelatinized side powder is mixed with croscarmellose sodium, then the lactose monohydrate and microcrystalline cellulose are mixed, and then added. Mix tenofovir eugenol citrate (1:1), and finally add emtricitabine; add purified water to prepare wet granulation; dry; granule; add magnesium stearate to mix, that is.
  • the core particle-I and the core particle-II are tableted by a double laminating machine; the coating material is coated with a 75% ethanol solution to obtain a suspension.
  • Chip core Within the grain: Tenofovir alafenamide succinate (1:1) 12.5 Lamivudine 300.0 Microcrystalline cellulose 300.0 Croscarmellose sodium 15.0 Extragranular: Microcrystalline cellulose 140.0 Croscarmellose sodium 15.0 Magnesium stearate 10.0 Film coating material: Opadi II 25.0
  • the croscarmellose sodium and the microcrystalline cellulose are mixed uniformly by the equal amount, then the tenofovir alafenamide succinate (1:1) is added. Mixing, then adding lamivudine mixture; adding purified water to the appropriate amount of wet granulation; drying; granulating; adding croscarmellose sodium and microcrystalline cellulose mixed evenly, then adding magnesium stearate to mix, tableting
  • the coating material is coated with 75% ethanol to form a suspension, which is obtained.
  • Chip core Grain-I: Tenofovir alafenamide (1:1) 11.9 Lamivudine 300.0
  • the core particle-I and the core particle-II are tableted by a double laminating machine; the coating material is coated with a 75% ethanol solution to obtain a suspension.

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Abstract

The present invention relates to tenofovir alafenamide complex represented by formula II. The present invention also relates to a preparation method for said tenofovir alafenamide complex, pharmaceutical compositions containing the tenofovir alafenamide complex, and uses of the tenofovir alafenamide complex in preparing medicines for preventing and/or treating virus infection, especially Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection.

Description

替诺福韦艾拉酚胺复合物及其制备方法和用途Tenofovir levamide compound and preparation method and use thereof 技术领域Technical field
本发明涉及有机化学领域和药学领域，具体涉及预防和/或治疗病毒感染药物替诺福韦艾拉酚胺的复合物及其制备方法和该复合物在制备预防和/或治疗病毒感染，特别是乙型肝炎病毒(HBV)和/或人类免疫缺陷病毒(HIV)感染的药物中的用途，以及含有该复合物的药物组合物。The present invention relates to the field of organic chemistry and the field of pharmacy, in particular to a complex for preventing and/or treating a viral infection drug tenofovir alafenamide, a preparation method thereof and a preparation thereof for preventing and/or treating a viral infection, in particular It is a use in a drug infected with hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV), and a pharmaceutical composition containing the same.
背景技术Background technique
替诺福韦艾拉酚胺(Tenofovir alafenamide)，化学名为：N-[(S)-[[(1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基膦酰基]-L-丙氨酸-1-甲基乙基酯；CAS登录号为：379270-37-8；分子结构式如式I所示：Tenofovir alafenamide, chemical name: N-[(S)-[[(1R)-2-(6-amino-9H-嘌呤-9-yl)-1-methyl) Ethoxy]methyl]phenoxyphosphonyl]-L-alanine-1-methylethyl ester; CAS accession number: 379270-37-8; molecular formula is as shown in formula I:
Figure PCTCN2015078188-appb-000001
Figure PCTCN2015078188-appb-000001
替诺福韦艾拉酚胺是替诺福韦的酯类前体药物，是一种无环类核苷酸逆转录酶抑制剂，具有广谱抗病毒作用，可抑制HIV-1、HIV-2的逆转录酶及HBV聚合酶，从而抑制病毒复制。替诺福韦艾拉酚胺口服后水解为替诺福韦，替诺福韦被细胞激酶磷酸化成具有药理活性的代谢产物替诺福韦二磷酸，后者与5'-三磷酸脱氧腺苷酸竞争，参与病毒DNA的合成，进入病毒DNA后由于缺乏3'-羟基而导致DNA延长受阻，从而抑制病毒的复制。与已上市的类似药物替诺福韦二吡呋酯(Tenofovir disoproxil)相比，替诺福韦艾拉酚胺的抗病毒活性为其10倍，在血浆中的稳定性为其200倍，半衰期较其提高了220倍，在外周血单核细胞(PBMC)内的蓄积量较其提高了近10倍，因此替诺福韦艾拉酚胺用于乙型肝炎病毒(HBV)和人类免疫缺陷病毒(HIV/AIDS)感染的预防和/或治疗，具有更好的疗效、更高的安全性和更低的耐药性。目前，替诺福韦艾拉酚胺单方制剂，替诺福韦艾拉酚胺/恩曲他滨/Cobicistat/埃替拉韦复方制剂和替诺福韦艾拉酚胺/恩曲他滨/Cobicistat/地瑞那韦复方制剂国外正在临床研究中。Tenofovir alafenamide is an ester prodrug of tenofovir, an acyclic nucleotide reverse transcriptase inhibitor with broad-spectrum antiviral activity that inhibits HIV-1, HIV- 2 reverse transcriptase and HBV polymerase, thereby inhibiting viral replication. Tenofovir alafluamine is orally hydrolyzed to tenofovir, and tenofovir is phosphorylated by cellular kinases into a pharmacologically active metabolite, tenofovir diphosphate, which is depleted with 5'-triphosphate deoxyadenosine. Acid competition, involved in the synthesis of viral DNA, into the viral DNA, due to the lack of 3'-hydroxyl, resulting in DNA elongation is blocked, thereby inhibiting viral replication. Compared with the similar drug Tenofovir disoproxil, tenofovir levamide has 10-fold antiviral activity and 200-fold stability in plasma, half-life. Compared with it, it increased by 220 times, and its accumulation in peripheral blood mononuclear cells (PBMC) was nearly 10 times higher. Therefore, tenofovir alafenamide was used for hepatitis B virus (HBV) and human immunodeficiency. The prevention and/or treatment of viral (HIV/AIDS) infections has better efficacy, higher safety and lower drug resistance. Currently, tenofovir alafenamide monotherapy, tenofovir alafenamide / emtricitabine / Cobicistat / ethiravir combination and tenofovir alafenamide / emtricitabine / Cobicistat/Darenavir combination preparations are currently under clinical study.
替诺福韦艾拉酚胺由于其固态熔点较低，水中溶解度较小，不利于药物制剂的制备和 在药物制剂中的溶出，因此替诺福韦艾拉酚胺被开发成盐的形式用于制剂。比如CN1443189A、CN1706855A等公开了替诺福韦艾拉酚胺的富马酸盐，替诺福韦艾拉酚胺富马酸盐虽然在水溶性、物理性状等方面较游离碱有较大改善，但其化学稳定性、热力学稳定性欠佳。CN103732594A公开了替诺福韦艾拉酚胺的半富马酸盐，其中表明替诺福韦艾拉酚胺半富马酸盐与替诺福韦艾拉酚胺富马酸盐相比，在去除非对映异构体杂质、化学稳定性、热力学稳定性方面具有优势，是替诺福韦艾拉酚胺更优的一种盐；但替诺福韦艾拉酚胺半富马酸盐的制备工艺较繁琐，比如在制备过程中需要加入替诺福韦艾拉酚胺半富马酸盐晶种。Tenofovir alafenamide is not suitable for the preparation of pharmaceutical preparations due to its low solid-state melting point and low solubility in water. Dissolution in the pharmaceutical preparation, thus tenofovir alafenamide was developed into the form of a salt for use in the formulation. For example, CN1443189A, CN1706855A, etc. disclose the fumarate of tenofovir alafenamide. Although tenofovir alafenamide fumarate has a greater improvement in water solubility and physical properties than free base, However, its chemical stability and thermodynamic stability are not good. CN103732594A discloses a hemi-fumarate salt of tenofovir alafenamide, wherein tenofovir alafenamide hemifumarate is compared to tenofovir alafenamide fumarate It has an advantage in removing diastereomer impurities, chemical stability and thermodynamic stability, and is a better salt of tenofovir alafenamide; but tenofovir alafenamide hemifumarate The preparation process is cumbersome, for example, it is necessary to add tenofovir alafenamide hemifumarate seed crystal during the preparation process.
因此，为了克服上述现有技术中的不足，有必要开发替诺福韦艾拉酚胺的新固体形式，以期能进一步改善替诺福韦艾拉酚胺的物理性状、化学稳定性、工艺操作性或制剂适应性等，进而加强产品的安全有效性，为广大患者提供更好的药品选择。Therefore, in order to overcome the deficiencies in the prior art mentioned above, it is necessary to develop a new solid form of tenofovir alafenamide in order to further improve the physical properties, chemical stability, and process operation of tenofovir alafenamide. Adaptability of the sex or the preparation, etc., thereby enhancing the safety and effectiveness of the product and providing better drug selection for the majority of patients.
发明内容Summary of the invention
本发明一个目的在于提供替诺福韦艾拉酚胺的新的复合物。该复合物在物理性状、化学稳定性、工艺操作性、制剂适应性等至少一方面优于现有技术。It is an object of the present invention to provide novel complexes of tenofovir alafenamide. The composite is superior to the prior art in at least one aspect of physical properties, chemical stability, process operability, formulation suitability, and the like.
本发明的另一目的在于提供上述替诺福韦艾拉酚胺复合物的制备方法。Another object of the present invention is to provide a process for the preparation of the above tenofovir alafenamide complex.
本发明的又一目的在于提供上述替诺福韦艾拉酚胺复合物的晶型及其制备方法。It is still another object of the present invention to provide a crystalline form of the above tenofovir alafenamide complex and a process for the preparation thereof.
本发明的又一目的在于提供包含治疗有效量的上述替诺福韦艾拉酚胺复合物的药物组合物。It is a further object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of the above tenofovir alafenamide complex.
本发明的又一目的在于提供上述替诺福韦艾拉酚胺复合物在制备预防和/或治疗病毒感染的药物中的应用。It is still another object of the present invention to provide the use of the above tenofovir alafenamide complex for the preparation of a medicament for preventing and/or treating a viral infection.
根据本发明的目的，本发明提供了一种式Ⅱ所示的替诺福韦艾拉酚胺复合物，According to an object of the present invention, the present invention provides a tenofovir alafenamide complex of the formula II,
Figure PCTCN2015078188-appb-000002
Figure PCTCN2015078188-appb-000002
其中，n＝1、2或3，X选自：盐酸、硫酸、过硫酸、硫氰酸、氢溴酸、氢碘酸、磷酸、硝酸、碳酸、十二烷基硫酸、甘油磷酸、甲磺酸、乙磺酸、2-羟基乙磺酸、牛磺酸、樟脑磺酸、环己氨磺酸、氨基磺酸、乙二磺酸、丁二磺酸、苯磺酸、对甲苯磺酸、对羟基苯磺 酸、邻羟基苯磺酸、2,5-二羟基苯磺酸、对氨基苯磺酸、萘-2-磺酸、萘-1,5-二磺酸、甲酸、乙酸、羟乙酸、2,2-二氯乙酸、丙酸、L-乳酸、D-乳酸、消旋乳酸(又名：DL-乳酸)、环戊烷丙酸、丁酸、戊酸、己酸、庚酸、辛酸、壬酸、癸酸、十一烯酸、月桂酸、棕榈酸、硬脂酸、油酸、草酸、丙二酸、琥珀酸、L-苹果酸、D-苹果酸、消旋苹果酸(又名：DL-苹果酸)、L-酒石酸、D-酒石酸、外消旋酒石酸(又名：DL-酒石酸)、内消旋酒石酸、马来酸、羟基马来酸、戊二酸、2-氧代戊二酸、己二酸、癸二酸、柠檬酸、苯甲酸、对甲氧基苯甲酸、4-乙酰氨基苯甲酸、水杨酸、乙酰水杨酸、龙胆酸、4-氨基水杨酸、苯乙酸、L-扁桃酸、D-扁桃酸、消旋扁桃酸(又名：DL-扁桃酸)、3-苯基丙酸、肉桂酸、咖啡酸、苯丁酸、苦味酸、烟酸、乳清酸、奎尼酸、抗坏血酸、葡萄糖醛酸、葡萄糖酸、半乳糖醛酸、葡庚糖酸、乳糖酸、樟脑酸、半乳糖二酸(又名：粘酸)、单宁酸(又名：鞣酸)、海藻酸、羟萘酸(又名：3-羟基-2-萘甲酸)、双羟萘酸(又名：4,4'-亚甲基二(3-羟基-2-萘甲酸)或朴酸)、氨基酸或酰化氨基酸(如乙酰氨乙酸、马尿酸、天门冬氨酸、谷氨酸、焦谷氨酸、谷氨酰胺、天门冬酰胺等)。Wherein n = 1, 2 or 3, X is selected from the group consisting of: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, lauryl sulfate, glycerophosphoric acid, methanesulfonate Acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, taurine, camphorsulfonic acid, cyclohexylsulfonic acid, sulfamic acid, ethanedisulfonic acid, succinic acid, benzenesulfonic acid, p-toluenesulfonic acid, P-hydroxybenzenesulfonate Acid, o-hydroxybenzenesulfonic acid, 2,5-dihydroxybenzenesulfonic acid, p-aminobenzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, formic acid, acetic acid, glycolic acid, 2, 2-Dichloroacetic acid, propionic acid, L-lactic acid, D-lactic acid, racemic lactic acid (aka: DL-lactic acid), cyclopentanepropionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, octanoic acid, hydrazine Acid, tannic acid, undecylenic acid, lauric acid, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, succinic acid, L-malic acid, D-malic acid, racemic malic acid (aka: DL-malic acid), L-tartaric acid, D-tartaric acid, racemic tartaric acid (aka: DL-tartaric acid), meso-tartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, 2-oxopentane Diacid, adipic acid, sebacic acid, citric acid, benzoic acid, p-methoxybenzoic acid, 4-acetamidobenzoic acid, salicylic acid, acetylsalicylic acid, gentisic acid, 4-aminosalicylic acid , phenylacetic acid, L-mandelic acid, D-mandelic acid, racemic mandelic acid (aka: DL-mandelic acid), 3-phenylpropionic acid, cinnamic acid, caffeic acid, phenylbutyric acid, picric acid, niacin , orotic acid, quinic acid, ascorbic acid, glucuronic acid, grapes Acid, galacturonic acid, glucoheptonic acid, lactobionic acid, camphoric acid, galactosuccinic acid (aka: mucic acid), tannic acid (aka: tannic acid), alginic acid, hydroxynaphthoic acid (aka aka : 3-hydroxy-2-naphthoic acid), pamoic acid (also known as: 4,4'-methylenebis(3-hydroxy-2-naphthoic acid) or physic acid), amino acid or acylated amino acid (eg Acetaminoacetic acid, hippuric acid, aspartic acid, glutamic acid, pyroglutamic acid, glutamine, asparagine, etc.).
上述式Ⅱ中，“复合物”是指替诺福韦艾拉酚胺与相应的酸通过氢键、离子键等非共价键的作用结合而共存的化合物，包括盐、共晶等。该复合物还进一步包括它的多晶、溶剂合物、溶剂合物多晶、水合物、水合物多晶等形式。In the above formula II, the "complex" means a compound in which tenofovir alafenamide and a corresponding acid are bonded by a non-covalent bond such as a hydrogen bond or an ionic bond, and includes a salt, a eutectic or the like. The composite further includes its polymorph, solvate, solvate polycrystal, hydrate, hydrate polycrystal, and the like.
所述“盐”是本技术领域技术人员熟知的，是指由阳离子和阴离子通过离子键的作用而形成的化合物。“替诺福韦艾拉酚胺盐”即指在替诺福韦艾拉酚胺与酸组成的固体中，酸中的质子转移到了替诺福韦艾拉酚胺上，质子化的替诺福韦艾拉酚胺正离子与酸根负离子通过离子键作用而相互结合。The "salts" are well known to those skilled in the art and refer to compounds formed by the action of ionic bonds by cations and anions. "Tenofoviral acetatamine salt" means that in the solid consisting of tenofovir alafenamide and acid, protons in the acid are transferred to tenofovir alafenamide, protonated teno The fuwei acetaminophen cation and the acid anion are bonded to each other by ionic bonding.
所述“共晶”是指替诺福韦艾拉酚胺与酸以共晶形式形成的固体。“共晶”(Co-Crystals)是指一种具有固定化学计量比的多组分晶体，在该晶体中各组分是以分子水平，通过氢键或其他非共价键、非离子键的作用结合而共存。在药物共晶中，一般包括药物活性成分和另一种或多种共晶形成体(Co-crystal former)，如“替诺福韦艾拉酚胺共晶”中，替诺福韦艾拉酚胺为药物活性成分，酸为共晶形成体。当单独的纯共晶形成体在室温下以液态存在时，该共晶也被称为“溶剂合物”，其中溶剂为水时被称为“水合物”，如替诺福韦艾拉酚胺与乙酸形成的共晶，可以称为替诺福韦艾拉酚胺的乙酸溶剂合物。The "eutectic" refers to a solid formed in the form of a eutectic form of tenofovir alafenamide with an acid. "Co-Crystals" means a multi-component crystal having a fixed stoichiometric ratio in which the components are at the molecular level, by hydrogen bonding or other non-covalent bonds, non-ionic bonds. The combination of roles and coexistence. In drug eutectic, it generally includes a pharmaceutically active ingredient and another co-crystal former (Co-crystal former), such as "tenofovir acetamide eutectic", tenofovira The phenolamine is a pharmaceutically active ingredient and the acid is a eutectic former. When a single pure eutectic former is present in a liquid state at room temperature, the eutectic is also referred to as a "solvate", wherein when the solvent is water, it is referred to as a "hydrate", such as tenofovir acetamide. The eutectic formed by the amine and acetic acid may be referred to as the acetic acid solvate of tenofovir alafenamide.
上述“共晶”还包括这样一些具有固定化学计量比的多组分晶体，在这些晶体中药物活性成分与其他组分之间，一部分通过氢键或其他非共价键作用，另一部分通过离子键或介于氢键与离子键之间的作用力而结合。 The above "eutectic" also includes such multi-component crystals having a fixed stoichiometric ratio in which a part of the pharmaceutically active ingredient and the other components are partially hydrogen-bonded or other non-covalently bonded, and the other part is passed through the ion. The bond or bond between the hydrogen bond and the ionic bond is combined.
上述“替诺福韦艾拉酚胺共晶或盐”还包括替诺福韦艾拉酚胺共晶或盐的溶剂合物、水合物等形式。当替诺福韦艾拉酚胺共晶在某种溶剂中制备、浆化或结晶时，该溶剂有可能进入到替诺福韦艾拉酚胺共晶或盐晶体中，形成溶剂合物；当该溶剂为水时，即有可能形成水合物。The above "tenofovir alafenamide co-crystal or salt" also includes a form of a solvate, a hydrate or the like of a tenofovir alafenamide co-crystal or a salt. When the tenofovir alafenamide cocrystal is prepared, slurried or crystallized in a solvent, the solvent may enter the tenofovir alafenamide eutectic or salt crystals to form a solvate; When the solvent is water, it is possible to form a hydrate.
上述“替诺福韦艾拉酚胺共晶或盐”还包括替诺福韦艾拉酚胺共晶或盐的多晶、替诺福韦艾拉酚胺共晶或盐溶剂合物的多晶、替诺福韦艾拉酚胺共晶或盐水合物的多晶等形式。The above "tenofovir alafenamide eutectic or salt" also includes polymorph of tenofovir alafluamine co-crystal or salt, tenofovir alafenamide eutectic or salt solvate Crystalline, tenofovir eugenol eutectic or polymorphic form of salt hydrate.
确定“共晶”或“盐”的方法是本技术领域技术人员熟知的，如用单晶X-射线衍射分析等。Methods for determining "eutectic" or "salt" are well known to those skilled in the art, such as by single crystal X-ray diffraction analysis and the like.
上述式Ⅱ中，1/n是指该复合物结构中替诺福韦艾拉酚胺与相应酸的近似摩尔组成比，可以通过1H-NMR、元素分析、HPLC、X-射线衍射(例如单晶X-射线衍射)等方式表征。该“近似”的范围一般为±0.15，优选±0.1。In the above formula II, 1/n means the approximate molar composition ratio of tenofovir alafenamide to the corresponding acid in the complex structure, which can be obtained by 1 H-NMR, elemental analysis, HPLC, X-ray diffraction (for example) Characterized by single crystal X-ray diffraction). The "approximation" range is generally ± 0.15, preferably ± 0.1.
上述式Ⅱ中，“替诺福韦艾拉酚胺复合物”根据结构中替诺福韦艾拉酚胺和酸X的化学计量数，可表述为“X替诺福韦艾拉酚胺(1:n)”，其中X和n的定义如式Ⅱ中所述，“1:n”即为替诺福韦艾拉酚胺复合物中酸X与替诺福韦艾拉酚胺的近似摩尔组成比，可通过1H-NMR、元素分析、HPLC、单晶X-射线衍射等方式获得。In the above formula II, "tenofovir alafenamide complex" can be expressed as "X tenofovir alafenamide according to the stoichiometric number of tenofovir alafenamide and acid X in the structure. 1:n)", where X and n are as defined in formula II, "1:n" is the approximation of acid X and tenofovir alafenamide in the tenofovir alafenamide complex The molar composition ratio can be obtained by 1 H-NMR, elemental analysis, HPLC, single crystal X-ray diffraction or the like.
在一实施方案中，式Ⅱ中，n＝3，X选自：磷酸、柠檬酸、单宁酸(又名：鞣酸)或海藻酸。In one embodiment, in Formula II, n = 3, X is selected from the group consisting of: phosphoric acid, citric acid, tannic acid (aka: tannic acid) or alginic acid.
在一实施方案中，式Ⅱ中，n＝2，X选自：硫酸、过硫酸、硫氰酸、磷酸、碳酸、甘油磷酸、乙二磺酸、丁二磺酸、萘-1,5-二磺酸、草酸、丙二酸、琥珀酸、L-苹果酸、D-苹果酸、消旋苹果酸(又名：DL-苹果酸)、L-酒石酸、D-酒石酸、外消旋酒石酸(又名：DL-酒石酸)、内消旋酒石酸、马来酸、羟基马来酸、戊二酸、2-氧代戊二酸、己二酸、癸二酸、柠檬酸、樟脑酸、半乳糖二酸(又名：粘酸)、单宁酸(又名：鞣酸)、海藻酸、双羟萘酸(又名：4,4'-亚甲基二(3-羟基-2-萘甲酸)或朴酸)、天门冬氨酸、谷氨酸。In one embodiment, in Formula II, n=2, X is selected from the group consisting of: sulfuric acid, persulfuric acid, thiocyanic acid, phosphoric acid, carbonic acid, glycerol phosphate, ethanedisulfonic acid, succinic acid, naphthalene-1,5- Disulfonic acid, oxalic acid, malonic acid, succinic acid, L-malic acid, D-malic acid, racemic malic acid (aka: DL-malic acid), L-tartaric acid, D-tartaric acid, racemic tartaric acid ( Also known as: DL-tartaric acid), meso-tartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, 2-oxoglutaric acid, adipic acid, azelaic acid, citric acid, camphoric acid, galactose Diacid (aka: mucic acid), tannic acid (aka: tannic acid), alginic acid, pamoic acid (aka: 4,4'-methylenebis(3-hydroxy-2-naphthoic acid) ) or physic acid, aspartic acid, glutamic acid.
在一实施方案中，式Ⅱ中，n＝1，X选自：盐酸、硫酸、过硫酸、硫氰酸、氢溴酸、氢碘酸、磷酸、硝酸、碳酸、十二烷基硫酸、甘油磷酸、甲磺酸、乙磺酸、2-羟基乙磺酸、牛磺酸、樟脑磺酸、环己氨磺酸、氨基磺酸、乙二磺酸、丁二磺酸、苯磺酸、对甲苯磺酸、对羟基苯磺酸、邻羟基苯磺酸、2,5-二羟基苯磺酸、对氨基苯磺酸、糖精、萘-2-磺酸、萘-1,5-二磺酸、甲酸、乙酸、羟乙酸、2,2-二氯乙酸、丙酸、L-乳酸、D-乳酸、消旋乳酸(又名：DL-乳酸)、环戊烷丙酸、丁酸、戊酸、己酸、庚酸、辛酸、壬酸、癸酸、十一烯酸、月桂酸、棕榈酸、硬脂酸、油酸、草酸、丙二酸、琥珀酸、L-苹果酸、D-苹果酸、消旋苹果酸(又名：DL-苹果酸)、L-酒石酸、D-酒石酸、外消旋酒石酸(又名：DL-酒石酸)、内消 旋酒石酸、马来酸、羟基马来酸、戊二酸、2-氧代戊二酸、己二酸、癸二酸、柠檬酸、苯甲酸、对甲氧基苯甲酸、4-乙酰氨基苯甲酸、水杨酸、乙酰水杨酸、龙胆酸、4-氨基水杨酸、苯乙酸、L-扁桃酸、D-扁桃酸、消旋扁桃酸(又名：DL-扁桃酸)、3-苯基丙酸、肉桂酸、咖啡酸、苯丁酸、苦味酸、烟酸、乳清酸、奎尼酸、抗坏血酸、葡萄糖醛酸、葡萄糖酸、半乳糖醛酸、葡庚糖酸、乳糖酸、樟脑酸、半乳糖二酸(又名：粘酸)、单宁酸(又名：鞣酸)、海藻酸、羟萘酸(又名：3-羟基-2-萘甲酸)、双羟萘酸(又名：4,4'-亚甲基二(3-羟基-2-萘甲酸)或朴酸)、乙酰氨乙酸、马尿酸、天门冬氨酸、谷氨酸、焦谷氨酸、谷氨酰胺、天门冬酰胺。In one embodiment, in Formula II, n=1, X is selected from the group consisting of: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, lauryl sulfate, glycerin Phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, taurine, camphorsulfonic acid, cyclohexylsulfonic acid, sulfamic acid, ethanedisulfonic acid, succinic acid, benzenesulfonic acid, Toluenesulfonic acid, p-hydroxybenzenesulfonic acid, o-hydroxybenzenesulfonic acid, 2,5-dihydroxybenzenesulfonic acid, p-aminobenzenesulfonic acid, saccharin, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid , formic acid, acetic acid, glycolic acid, 2,2-dichloroacetic acid, propionic acid, L-lactic acid, D-lactic acid, racemic lactic acid (aka: DL-lactic acid), cyclopentanepropionic acid, butyric acid, valeric acid , hexanoic acid, heptanoic acid, caprylic acid, citric acid, citric acid, undecylenic acid, lauric acid, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, succinic acid, L-malic acid, D-apple Acid, racemic malic acid (aka: DL-malic acid), L-tartaric acid, D-tartaric acid, racemic tartaric acid (aka: DL-tartaric acid), internal elimination Tartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, 2-oxoglutaric acid, adipic acid, azelaic acid, citric acid, benzoic acid, p-methoxybenzoic acid, 4-acetamidobenzene Formic acid, salicylic acid, acetylsalicylic acid, gentisic acid, 4-aminosalicylic acid, phenylacetic acid, L-mandelic acid, D-mandelic acid, racemic mandelic acid (aka: DL-mandelic acid), 3 -Phenylpropionic acid, cinnamic acid, caffeic acid, phenylbutyric acid, picric acid, nicotinic acid, orotic acid, quinic acid, ascorbic acid, glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, lactose Acid, camphoric acid, galactosuccinic acid (aka: mucic acid), tannic acid (aka: tannic acid), alginic acid, hydroxynaphthoic acid (aka: 3-hydroxy-2-naphthoic acid), bishydroxy Naphthoic acid (aka: 4,4'-methylenebis(3-hydroxy-2-naphthoic acid) or physic acid), acetoacetic acid, hippuric acid, aspartic acid, glutamic acid, pyroglutamic acid , glutamine, asparagine.
在一具体实施方案中，式Ⅱ所示的替诺福韦艾拉酚胺复合物选自：L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)或硫酸替诺福韦艾拉酚胺(1:1)。In a specific embodiment, the tenofovir alafenamide complex of Formula II is selected from the group consisting of: l-norofovir lysamine (1:2), D-tenofovir, D-tartrate Lauramine (1:1), DL-tenofovir iracrolimum tartrate (1:1), tenofovir alafenamide (1:2), tenofovir citrate Iratonamine (1:1), tenofovir iramol succinate (1:1), tenofovir oxalatine oxalate (1:1), tenofovir alafenol phosphate (1:1) or tenofovir alafenamide (1:1).
根据本发明的目的，本发明提供了式Ⅱ所示替诺福韦艾拉酚胺复合物的制备方法，该方法包括：In accordance with the purpose of the present invention, the present invention provides a process for the preparation of a tenofovir alafenamide complex of formula II, the method comprising:
(1)在适宜溶剂中，形成一种包含替诺福韦艾拉酚胺和酸X的溶液；(1) forming a solution comprising tenofovir alafenamide and acid X in a suitable solvent;
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；(3) separating the precipitated solid;
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried.
上述方法步骤(1)中，替诺福韦艾拉酚胺可以按照专利文献CN1443189A和CN1706855A或WO2013052094A等中公开的方法制得。这些文献通过引用的方式并入到本发明中。替诺福韦艾拉酚胺可以任何形态存在，如包括晶型、无定形或它们的混合形式。In the above method step (1), tenofovir alafenamide can be obtained by the method disclosed in the patent documents CN1443189A and CN1706855A or WO2013052094A. These documents are incorporated herein by reference. Tenofovir alafenamide can be present in any form, including crystalline forms, amorphous forms, or a mixture thereof.
上述方法步骤(1)中，所述“适宜溶剂”是指对替诺福韦艾拉酚胺和酸有一定溶解度，同时能在其中形成替诺福韦艾拉酚胺复合物的溶剂。这些适宜溶剂选自乙腈、乙醇、甲醇、丙醇、异丙醇、丁醇、乙二醇、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸丁酯、乙醚、异丙醚、正丁醚、乙二醇单甲醚、乙二醇二甲醚、叔丁基甲基醚、四氢呋喃、石油醚、二氯甲烷、三氯甲烷、正己烷、环己烷、丙酮、丁酮、戊酮、环己酮、甲苯、二甲苯等或它们的混合物。所述适宜溶剂与替诺福韦艾拉酚胺的重量比一般为3:1～100:1。In the above method step (1), the "suitable solvent" means a solvent which has a certain solubility to tenofovir alafenamide and an acid, and at which a tenofovir alafenamide complex can be formed. These suitable solvents are selected from the group consisting of acetonitrile, ethanol, methanol, propanol, isopropanol, butanol, ethylene glycol, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, diethyl ether, isopropyl Ether, n-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, tert-butyl methyl ether, tetrahydrofuran, petroleum ether, dichloromethane, chloroform, n-hexane, cyclohexane, acetone, methyl ethyl ketone, Pentanone, cyclohexanone, toluene, xylene, etc. or a mixture thereof. The weight ratio of the suitable solvent to tenofovir alafenamide is generally from 3:1 to 100:1.
上述方法步骤(1)中，所述“酸X”选自式Ⅱ中X所代表的酸。替诺福韦艾拉酚胺与酸X投料摩尔比一般为4:1～0.5:1，当制备“X替诺福韦艾拉酚胺(1:3)”复合物时，替诺福韦艾拉酚胺与酸X投料摩尔比一般为2.7:1～3.5:1；当制备“X替诺福韦艾拉酚胺(1:2)”复合物时， 替诺福韦艾拉酚胺与酸X投料摩尔比一般为1.7:1～2.5:1；当制备“X替诺福韦艾拉酚胺(1:1)”复合物时，替诺福韦艾拉酚胺与酸X投料摩尔比一般为0.5:1～1.5:1。In the above method step (1), the "acid X" is selected from the acid represented by X in the formula II. The tenofovir alafluramide and acid X charge molar ratio is generally 4:1 to 0.5:1, when preparing the "X tenofovir alafenamide (1:3)" complex, tenofovir The molar ratio of levamide to acid X is generally from 2.7:1 to 3.5:1; when preparing the "X tenofovir alafenamide (1:2)" complex, The molar ratio of tenofovir alafluramine to acid X is generally from 1.7:1 to 2.5:1; when preparing the "X tenofovir alafenamide (1:1)" complex, tenofovir The molar ratio of levamide to acid X is generally from 0.5:1 to 1.5:1.
上述方法步骤(2)中，所述“析出固体”的方法为本技术领域内常规的方法，如冷却，加入反溶剂，浓缩出部分溶剂、加晶种等方法的单用或联用。In the above method step (2), the method of "precipitating solid" is a conventional method in the art, such as cooling, adding an anti-solvent, concentrating a part of a solvent, adding a seed crystal, or the like, alone or in combination.
上述方法步骤(3)中，所述“分离”方法包括过滤或离心等。可选地，可以用适宜溶剂对所收集固体进行洗涤。In the above method step (3), the "separation" method includes filtration or centrifugation or the like. Alternatively, the collected solids can be washed with a suitable solvent.
上述方法步骤(4)中，所述“干燥”方式包括常压干燥、减压干燥或它们的组合应用。“进一步纯化”的方法包括重结晶、浆化、洗涤等形式。In the above method step (4), the "drying" method includes atmospheric drying, reduced pressure drying or a combination thereof. Methods for "further purification" include recrystallization, slurrying, washing, and the like.
L-酒石酸替诺福韦艾拉酚胺(1:2)L-tenofovir alafenamide (1:2)
在一实施方案中，式Ⅱ中，n选为2，X选为L-酒石酸，即提供了替诺福韦艾拉酚胺与L-酒石酸以2:1摩尔组成比形成的复合物，称为“L-酒石酸替诺福韦艾拉酚胺(1:2)”。In one embodiment, in Formula II, n is selected to be 2, and X is selected as L-tartaric acid, that is, a complex formed by the ratio of tenofovir alafenamide to L-tartaric acid in a ratio of 2:1 mole is provided. For "L-tanofosyl alafenamide (1:2)".
在一实施方案中，本发明提供了一种L-酒石酸替诺福韦艾拉酚胺的制备方法，该方法包括：In one embodiment, the invention provides a method of preparing tenofovir alafenide L-tartaric acid, the method comprising:
(1)将替诺福韦艾拉酚胺和L-酒石酸溶解在适宜溶剂中；(1) dissolving tenofovir alafenamide and L-tartaric acid in a suitable solvent;
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；(3) separating the precipitated solid;
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried.
上述制备方法步骤(1)中，所述“适宜溶剂”选自乙腈、甲醇、乙醇、异丙醇、四氢呋喃、丙酮、二氯甲烷、三氯甲烷、甲苯等或它们的混合物，优选为乙腈、乙醇、异丙醇或它们的混合物。所述适宜溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1。In the above preparation method step (1), the "suitable solvent" is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile, Ethanol, isopropanol or a mixture thereof. The weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
上述制备方法步骤(1)中，替诺福韦艾拉酚胺与L-酒石酸的投料摩尔比一般1.7:1～2.5:1，优选1.9:1～2.3:1。In the above preparation method step (1), the molar ratio of tenofovir alafenamide to L-tartaric acid is generally from 1.7:1 to 2.5:1, preferably from 1.9:1 to 2.3:1.
上述制备方法步骤(2)中，所述“析出固体”的方法为本技术领域内常规的方法，如冷却，加入反溶剂，浓缩出部分溶剂体、加晶种等方法的单用或联用。析出固体过程可以是静置的，也可是搅拌的。In the above preparation method step (2), the method of "precipitating solid" is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination. . The solids precipitation process can be either standing or agitated.
上述制备方法步骤(3)中，所述“分离”可以采用过滤等本技术领域内的常规方法。可选地，可以用步骤(1)中的适宜溶剂对所收集的固体进行洗涤。In the above production method step (3), the "separation" may employ a conventional method in the art such as filtration. Alternatively, the collected solids may be washed with a suitable solvent in step (1).
上述制备方法步骤(4)中，所述“干燥”方式包括常压干燥、减压干燥或它们的组合应用。“进一步纯化”的方法包括重结晶、浆化、洗涤等形式。In the above preparation method step (4), the "drying" method includes atmospheric drying, reduced pressure drying or a combination thereof. Methods for "further purification" include recrystallization, slurrying, washing, and the like.
上述方法步骤(4)中“干燥”的温度一般为20～120℃，优选30～80℃；可以常压干燥， 也可以减压干燥。The temperature of "drying" in the above step (4) is generally 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure. It can also be dried under reduced pressure.
该实施方案所制备的L-酒石酸替诺福韦艾拉酚胺(1:2)是一种晶体。Tenofovir alafenamide (1:2) of L-tartrate prepared in this embodiment is a crystal.
因此，本发明提供了一种L-酒石酸替诺福韦艾拉酚胺(1:2)的晶型(为了表述方便，将该晶型称为“L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A”)。该晶型的X-射线粉末衍射图谱(使用Cu-Kα辐射)的特征为：在2θ值为8.2°±0.2°、9.4°±0.2°、10.8°±0.2°、14.4°±0.2°、17.9°±0.2°、18.9°±0.2°、19.7°±0.2°、21.6°±0.2°等处对应有特征衍射峰。Accordingly, the present invention provides a crystalline form of tenofovir alafenamide (1:2) of L-tartrate (for convenience of expression, the crystal form is referred to as "L-tanofosyl alafenide" (1:2) Form A"). The X-ray powder diffraction pattern of the crystal form (using Cu-Kα radiation) is characterized by a value of 8.2 ° ± 0.2 °, 9.4 ° ± 0.2 °, 10.8 ° ± 0.2 °, 14.4 ° ± 0.2 °, 17.9. Characteristic diffraction peaks correspond to °±0.2°, 18.9°±0.2°, 19.7°±0.2°, 21.6°±0.2°.
在一具体实施方案中，本发明所诉的L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A的X-射线粉末衍射图谱的特征为：在2θ值为7.5°±0.2°、8.2°±0.2°、9.4°±0.2°、10.8°±0.2°、12.4°±0.2°、14.4°±0.2°、16.0°±0.2°、16.3°±0.2°、17.1°±0.2°、17.9°±0.2°、18.9°±0.2°、19.7°±0.2°、20.4°±0.2°、21.6°±0.2°、23.0°±0.2°等处对应有特征衍射峰。In a specific embodiment, the X-ray powder diffraction pattern of the tenofovir alafenamide (1:2) crystal form A of L-tartrate of the present invention is characterized by a value of 7.5 ° ± 0.2 at 2θ. °, 8.2 ° ± 0.2 °, 9.4 ° ± 0.2 °, 10.8 ° ± 0.2 °, 12.4 ° ± 0.2 °, 14.4 ° ± 0.2 °, 16.0 ° ± 0.2 °, 16.3 ° ± 0.2 °, 17.1 ° ± 0.2 °, 17.9°±0.2°, 18.9°±0.2°, 19.7°±0.2°, 20.4°±0.2°, 21.6°±0.2°, 23.0°±0.2° correspond to characteristic diffraction peaks.
进一步地，本发明所述的L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征衍射峰及相对强度：Further, the X-ray powder diffraction pattern of the tenofovir lysamine (1:2) crystal form A of L-tartrate of the present invention at a 2θ angle has characteristic diffraction peaks and relative intensities at the following positions:
2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
7.5°±0.2°7.5°±0.2° 1010 21.0°±0.2°21.0°±0.2° 1717
8.2°±0.2°8.2°±0.2° 1010 21.6°±0.2°21.6°±0.2° 22twenty two
9.4°±0.2°9.4°±0.2° 9797 23.0°±0.2°23.0°±0.2° 22twenty two
10.8°±0.2°10.8°±0.2° 1616 23.5°±0.2°23.5°±0.2° 1818
12.4°±0.2°12.4°±0.2° 1313 24.3°±0.2°24.3°±0.2° 1212
14.4°±0.2°14.4°±0.2° 1616 24.6°±0.2°24.6 ° ± 0.2 ° 1010
16.0°±0.2°16.0°±0.2° 1616 25.7°±0.2°25.7°±0.2° 1111
16.3°±0.2°16.3°±0.2° 1818 26.7°±0.2°26.7°±0.2° 1111
17.1°±0.2°17.1°±0.2° 21twenty one 27.4°±0.2°27.4°±0.2° 99
17.9°±0.2°17.9°±0.2° 3434 28.4°±0.2°28.4° ± 0.2° 99
18.9°±0.2°18.9°±0.2° 3737 28.9°±0.2°28.9° ± 0.2° 88
19.7°±0.2°19.7°±0.2° 100100 30.4°±0.2°30.4°±0.2° 88
20.4°±0.2°20.4°±0.2° 2828    
在一具体实施方案中，本发明提供的L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A具有如图1所示的X-射线粉末衍射图谱所代表的特征。In a specific embodiment, the present invention provides tenofovir alafenamide (1:2) Form A of L-tartrate having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
在一具体实施方案中，本发明提供的制备的L-酒石酸替诺福韦艾拉酚胺(1:2)混合物中L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A含量(质量含量)一般大于70％，优选大于80％，最优选大于90％。In a specific embodiment, the present invention provides a mixture of tenofovir alafenamide (1:2) of L-tartrate and tenofovir alafenamide (1:2) crystal form A The content (mass content) is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本领域技术人员可以理解的是，本发明所述的L-酒石酸替诺福韦艾拉酚胺(1:2)混合物指的是用化学合成方法直接合成制备的含有其他杂质或晶型的L-酒石酸替诺福韦艾拉酚胺(1:2)。It will be understood by those skilled in the art that the mixture of tenofovir alafenamide (1:2) of L-tartrate of the present invention refers to L containing other impurities or crystal forms directly synthesized by chemical synthesis. - Tenofovir alafenamide (1:2).
在一具体实施方案中，本发明的L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A的制备方法包括： In a specific embodiment, the method for preparing tenofovir alafenamide (1:2) Form A of L-tartrate of the present invention comprises:
(1)将替诺福韦艾拉酚胺和L-酒石酸溶解在乙腈、乙醇、异丙醇或它们的混合物中；所述溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1；替诺福韦艾拉酚胺与L-酒石酸的投料摩尔比一般1.7:1～2.5:1，优选1.9:1～2.3:1(1) Dissolving tenofovir alafenamide and L-tartaric acid in acetonitrile, ethanol, isopropanol or a mixture thereof; the weight ratio of the solvent to tenofovir alafenamide is generally 5: 1 to 80:1; the molar ratio of tenofovir alafenamide to L-tartaric acid is generally 1.7:1 to 2.5:1, preferably 1.9:1 to 2.3:1.
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；可选地，可以用步骤(1)中使用的溶剂对所收集的固体进行洗涤；(3) separating the precipitated solid; alternatively, the collected solid may be washed with the solvent used in the step (1);
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。干燥温度一般为20～120℃，优选30～80℃；可以常压干燥，也可以减压干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried. The drying temperature is usually 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
D-酒石酸替诺福韦艾拉酚胺(1:1)D-tenofovir alafenamide tartrate (1:1)
在一实施方案中，式Ⅱ中，n选为1，X选为D-酒石酸，即提供了替诺福韦艾拉酚胺与D-酒石酸以1:1摩尔组成比形成的复合物，称为“D-酒石酸替诺福韦艾拉酚胺(1:1)”。In one embodiment, in Formula II, n is selected to be 1, and X is selected as D-tartaric acid, that is, a complex formed by tenofovir alafenamide and D-tartaric acid in a 1:1 molar composition ratio is provided. For "D-tenofovir alafenamide (1:1)".
在一实施方案中，本发明提供了一种D-酒石酸替诺福韦艾拉酚胺的制备方法，该方法包括：In one embodiment, the present invention provides a method of preparing tenofovir alafenide, which comprises:
(1)将替诺福韦艾拉酚胺和D-酒石酸溶解在适宜溶剂中；(1) dissolving tenofovir alafenamide and D-tartaric acid in a suitable solvent;
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；(3) separating the precipitated solid;
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried.
上述制备方法步骤(1)中，所述“适宜溶剂”选自乙腈、甲醇、乙醇、异丙醇、四氢呋喃、丙酮、二氯甲烷、三氯甲烷、甲苯等或它们的混合物，优选为乙腈、异丙醇或它们的混合物。所述适宜溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1。In the above preparation method step (1), the "suitable solvent" is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile, Isopropyl alcohol or a mixture thereof. The weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
上述制备方法步骤(1)中，替诺福韦艾拉酚胺与D-酒石酸的投料摩尔比一般0.5:1～1.5:1，优选0.8:1～1.2:1。In the above preparation method step (1), the molar ratio of tenofovir alafenamide to D-tartaric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
上述制备方法步骤(2)中，所述“析出固体”的方法为本技术领域内常规的方法，如冷却，加入反溶剂，浓缩出部分溶剂体、加晶种等方法的单用或联用。析出固体过程可以是静置的，也可是搅拌的。In the above preparation method step (2), the method of "precipitating solid" is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination. . The solids precipitation process can be either standing or agitated.
上述制备方法步骤(3)中，所述“分离”可以采用过滤等本技术领域内的常规方法。可选地，可以用步骤(1)中的适宜溶剂对所收集的固体进行洗涤。In the above production method step (3), the "separation" may employ a conventional method in the art such as filtration. Alternatively, the collected solids may be washed with a suitable solvent in step (1).
上述制备方法步骤(4)中，所述“干燥”方式包括常压干燥、减压干燥或它们的组合应用。“进一步纯化”的方法包括重结晶、浆化、洗涤等形式。In the above preparation method step (4), the "drying" method includes atmospheric drying, reduced pressure drying or a combination thereof. Methods for "further purification" include recrystallization, slurrying, washing, and the like.
上述方法步骤(4)中“干燥”的温度一般为20～120℃，优选30～80℃；可以常压干燥， 也可以减压干燥。The temperature of "drying" in the above step (4) is generally 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure. It can also be dried under reduced pressure.
该实施方案所制备的D-酒石酸替诺福韦艾拉酚胺(1:1)是一种晶体。Tenofovir alafenamide (1:1) of D-tartrate prepared in this embodiment is a crystal.
因此，本发明提供了一种D-酒石酸替诺福韦艾拉酚胺(1:1)的晶型(为了表述方便，将该晶型称为“D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A”)。该晶型的X-射线粉末衍射图谱(使用Cu-Kα辐射)的特征为：在2θ值为7.8°±0.2°、9.5°±0.2°、12.5°±0.2°、15.1°±0.2°、15.9°±0.2°、17.0°±0.2°、17.7°±0.2°、19.5°±0.2°等处对应有特征衍射峰。Accordingly, the present invention provides a crystalline form of tenofovir alafenamide (1:1) of D-tartrate (for convenience of presentation, the crystalline form is referred to as "D-tenofovir alafenide tartrate" (1:1) Form A"). The X-ray powder diffraction pattern of the crystal form (using Cu-Kα radiation) is characterized by a value of 7.8°±0.2°, 9.5°±0.2°, 12.5°±0.2°, 15.1°±0.2°, 15.9. Characteristic diffraction peaks correspond to °±0.2°, 17.0°±0.2°, 17.7°±0.2°, 19.5°±0.2°.
在一具体实施方案中，本发明所诉的D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱的特征为：在2θ值为4.4°±0.2°、7.8°±0.2°、9.0°±0.2°、9.5°±0.2°、12.5°±0.2°、13.0°±0.2°、15.1°±0.2°、15.9°±0.2°、17.0°±0.2°、17.7°±0.2°、19.5°±0.2°、19.9°±0.2°、21.4°±0.2°、22.7°±0.2°、25.9°±0.2°等处对应有特征衍射峰。In a specific embodiment, the X-ray powder diffraction pattern of tenofovir alafenamide (1:1) Form A of D-tartrate of the present invention is characterized by a value of 4.4 ° ± 0.2 at 2θ. °, 7.8 ° ± 0.2 °, 9.0 ° ± 0.2 °, 9.5 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.0 ° ± 0.2 °, 15.1 ° ± 0.2 °, 15.9 ° ± 0.2 °, 17.0 ° ± 0.2 °, 17.7°±0.2°, 19.5°±0.2°, 19.9°±0.2°, 21.4°±0.2°, 22.7°±0.2°, 25.9°±0.2° correspond to characteristic diffraction peaks.
进一步地，本发明所述的D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征衍射峰及相对强度：Further, the X-ray powder diffraction pattern represented by the present invention for tenofovir alafenamide (1:1) crystal form A in the 2θ angle has characteristic diffraction peaks and relative intensities at the following positions:
2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
4.4°±0.2°4.4°±0.2° 8686 19.5°±0.2°19.5°±0.2° 4444
7.8°±0.2°7.8°±0.2° 3939 19.9°±0.2°19.9°±0.2° 3838
8.6°±0.2°8.6°±0.2° 3939 20.8°±0.2°20.8°±0.2° 3030
9.0°±0.2°9.0°±0.2° 6262 21.4°±0.2°21.4°±0.2° 3434
9.5°±0.2°9.5°±0.2° 100100 22.0°±0.2°22.0°±0.2° 1717
10.8°±0.2°10.8°±0.2° 1616 22.7°±0.2°22.7° ± 0.2° 2929
12.5°±0.2°12.5°±0.2° 2828 23.5°±0.2°23.5°±0.2° 24twenty four
13.0°±0.2°13.0 ° ± 0.2 ° 1919 24.1°±0.2°24.1°±0.2° 2020
13.3°±0.2°13.3°±0.2° 1414 24.6°±0.2°24.6 ° ± 0.2 ° 1515
15.1°±0.2°15.1°±0.2° 2020 25.2°±0.2°25.2°±0.2° 22twenty two
15.9°±0.2°15.9°±0.2° 2727 25.9°±0.2°25.9°±0.2° 3030
17.0°±0.2°17.0°±0.2° 7272 27.3°±0.2°27.3°±0.2° 1111
17.7°±0.2°17.7°±0.2° 4242 28.3°±0.2°28.3°±0.2° 1010
18.9°±0.2°18.9°±0.2° 2929    
在一具体实施方案中，本发明提供的D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A具有如图2所示的X-射线粉末衍射图谱所代表的特征。In a specific embodiment, the present invention provides tenofovir alafenamide (1:1) Form A of D-tartrate having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
在一具体实施方案中，本发明提供的制备的D-酒石酸替诺福韦艾拉酚胺(1:1)混合物中D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A含量(质量含量)一般大于70％，优选大于80％，最优选大于90％。In a specific embodiment, the present invention provides a mixture of ten-five valproate (1:1) of D-tartrate, tenofovir iramate (1:1) crystal form A The content (mass content) is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本领域技术人员可以理解的是，本发明所述的D-酒石酸替诺福韦艾拉酚胺(1:1)混合物指的是用化学合成方法直接合成制备的含有其他杂质或晶型的D-酒石酸替诺福韦艾拉酚胺(1:1)。It will be understood by those skilled in the art that the mixture of tenofovir alafenamide (1:1) of D-tartrate of the present invention refers to D containing other impurities or crystal forms directly synthesized by chemical synthesis. - Tenofovir alafenamide (1:1).
在一具体实施方案中，本发明的D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A的制备方 法包括：In a specific embodiment, the preparation of the D-tartrolate acetamide (1:1) Form A of D-tartrate of the present invention The law includes:
(1)将替诺福韦艾拉酚胺和D-酒石酸溶解在乙腈、异丙醇或它们的混合物中；所述溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1；替诺福韦艾拉酚胺与D-酒石酸的投料摩尔比一般0.5:1～1.5:1，优选0.8:1～1.2:1。(1) Dissolving tenofovir alafenamide and D-tartaric acid in acetonitrile, isopropanol or a mixture thereof; the weight ratio of the solvent to tenofovir alafenamide is generally 5:1~ 80:1; the molar ratio of tenofovir alafenamide to D-tartaric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；可选地，可以用步骤(1)中的溶剂对所收集的固体进行洗涤。(3) Separating the precipitated solid; alternatively, the collected solid may be washed with the solvent in the step (1).
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。干燥的温度一般为20～120℃，优选30～80℃；可以常压干燥，也可以减压干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried. The drying temperature is usually 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
DL-酒石酸替诺福韦艾拉酚胺(1:1)DL-tenofovir alafenamide (1:1)
在一实施方案中，式Ⅱ中，n选为1，X选为DL-酒石酸，即提供了替诺福韦艾拉酚胺与DL-酒石酸以1:1摩尔组成比形成的复合物，称为“DL-酒石酸替诺福韦艾拉酚胺(1:1)”。In one embodiment, in Formula II, n is selected to be 1, and X is selected as DL-tartaric acid, that is, a complex formed by the ratio of tenofovir alafenamide to DL-tartaric acid in a ratio of 1:1 mole is provided. For "DL-tenofovir levamide (1:1)".
在一实施方案中，本发明提供了一种DL-酒石酸替诺福韦艾拉酚胺(1:1)的制备方法，该方法包括：In one embodiment, the invention provides a method of preparing DL-tenofovir alafenamide (1:1), the method comprising:
(1)将替诺福韦艾拉酚胺和DL-酒石酸溶解在适宜溶剂中；(1) dissolving tenofovir alafenamide and DL-tartaric acid in a suitable solvent;
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；(3) separating the precipitated solid;
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried.
上述制备方法步骤(1)中，所述“DL-酒石酸”是指L-酒石酸与D-酒石酸等比例组成的外消旋酒石酸。所述“适宜溶剂”选自乙腈、甲醇、乙醇、异丙醇、四氢呋喃、丙酮、二氯甲烷、三氯甲烷、甲苯等或它们的混合物，优选为乙腈。所述适宜溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1。In the above preparation method step (1), the "DL-tartaric acid" means racemic tartaric acid having a ratio of L-tartaric acid and D-tartaric acid. The "suitable solvent" is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, and the like, or mixtures thereof, preferably acetonitrile. The weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
上述制备方法步骤(1)中，替诺福韦艾拉酚胺与DL-酒石酸的投料摩尔比一般0.5:1～1.5:1，优选0.8:1～1.2:1。In the above preparation method step (1), the molar ratio of tenofovir alafenamide to DL-tartaric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
上述制备方法步骤(2)中，所述“析出固体”的方法为本技术领域内常规的方法，如冷却，加入反溶剂，浓缩出部分溶剂体、加晶种等方法的单用或联用。析出固体过程可以是静置的，也可是搅拌的。In the above preparation method step (2), the method of "precipitating solid" is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination. . The solids precipitation process can be either standing or agitated.
上述制备方法步骤(3)中，所述“分离”可以采用过滤等本技术领域内的常规方法。可选地，可以用步骤(1)中的适宜溶剂对所收集的固体进行洗涤。In the above production method step (3), the "separation" may employ a conventional method in the art such as filtration. Alternatively, the collected solids may be washed with a suitable solvent in step (1).
上述制备方法步骤(4)中，所述“干燥”方式包括常压干燥、减压干燥或它们的组合应用。“进一步纯化”的方法包括重结晶、浆化、洗涤等形式。 In the above preparation method step (4), the "drying" method includes atmospheric drying, reduced pressure drying or a combination thereof. Methods for "further purification" include recrystallization, slurrying, washing, and the like.
上述方法步骤(4)中“干燥”的温度一般为20～120℃，优选30～80℃；可以常压干燥，也可以减压干燥。The temperature of "drying" in the above step (4) is generally 20 to 120 ° C, preferably 30 to 80 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
该实施方案所制备的DL-酒石酸替诺福韦艾拉酚胺(1:1)是一种晶体。Tenofovir alafenamide (1:1) of DL-tartrate prepared in this embodiment is a crystal.
因此，本发明提供了一种DL-酒石酸替诺福韦艾拉酚胺(1:1)的晶型(为了表述方便，将该晶型称为“DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A”)。该晶型的X-射线粉末衍射图谱(使用Cu-Kα辐射)的特征为：在2θ值为6.8°±0.2°、8.0°±0.2°、9.7°±0.2°、16.0°±0.2°、16.9°±0.2°、18.2°±0.2°、18.9°±0.2°、20.2°±0.2°、21.1°±0.2°等处对应有特征衍射峰。Accordingly, the present invention provides a crystalline form of DL-tenofovir alafenamide (1:1) (for convenience of presentation, the crystal form is referred to as "DL-tenofovir alafenide tartrate" (1:1) Form A"). The X-ray powder diffraction pattern of the crystal form (using Cu-Kα radiation) is characterized by a value of 2θ of 6.8°±0.2°, 8.0°±0.2°, 9.7°±0.2°, 16.0°±0.2°, 16.9. Characteristic diffraction peaks correspond to °±0.2°, 18.2°±0.2°, 18.9°±0.2°, 20.2°±0.2°, 21.1°±0.2°.
在一具体实施方案中，本发明所诉的DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱的特征为：在2θ值为6.8°±0.2°、8.0°±0.2°、9.7°±0.2°、10.6°±0.2°、12.6°±0.2°、13.7°±0.2°、14.9°±0.2°、16.0°±0.2°、16.9°±0.2°、18.2°±0.2°、18.9°±0.2°、20.2°±0.2°、21.1°±0.2°、22.8°±0.2°等处对应有特征衍射峰。In a specific embodiment, the X-ray powder diffraction pattern of DL-tenofovir alafenamide (1:1) Form A of the present invention is characterized by a 2θ value of 6.8°±0.2. °, 8.0 ° ± 0.2 °, 9.7 ° ± 0.2 °, 10.6 ° ± 0.2 °, 12.6 ° ± 0.2 °, 13.7 ° ± 0.2 °, 14.9 ° ± 0.2 °, 16.0 ° ± 0.2 °, 16.9 ° ± 0.2 °, 18.2°±0.2°, 18.9°±0.2°, 20.2°±0.2°, 21.1°±0.2°, 22.8°±0.2° correspond to characteristic diffraction peaks.
进一步地，本发明所述的DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征衍射峰及相对强度：Further, the X-ray powder diffraction pattern of the DL-tenofovir alafenamide (1:1) crystal form A of the present invention at a 2θ angle has characteristic diffraction peaks and relative intensities at the following positions:
2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
6.8°±0.2°6.8°±0.2° 3939 19.6°±0.2°19.6°±0.2° 1919
8.0°±0.2°8.0°±0.2° 8585 20.2°±0.2°20.2°±0.2° 5252
9.7°±0.2°9.7°±0.2° 9494 21.1°±0.2°21.1°±0.2° 5353
10.6°±0.2°10.6°±0.2° 1010 22.8°±0.2°22.8°±0.2° 1616
12.6°±0.2°12.6°±0.2° 1717 24.4°±0.2°24.4°±0.2° 1111
13.7°±0.2°13.7°±0.2° 1616 25.9°±0.2°25.9°±0.2° 1717
14.9°±0.2°14.9°±0.2° 1515 26.7°±0.2°26.7°±0.2° 1010
16.0°±0.2°16.0°±0.2° 4141 29.4°±0.2°29.4°±0.2° 2020
16.9°±0.2°16.9°±0.2° 4646 32.5°±0.2°32.5°±0.2° 1010
18.2°±0.2°18.2°±0.2° 100100 35.8°±0.2°35.8°±0.2° 1717
18.9°±0.2°18.9°±0.2° 6060    
在一具体实施方案中，本发明提供的DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A具有如图3所示的X-射线粉末衍射图谱所代表的特征。In a specific embodiment, the DL-tenofovir alafenamide (1:1) Form A of the present invention has the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
在一具体实施方案中，本发明提供的制备的DL-酒石酸替诺福韦艾拉酚胺(1:1)混合物中DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A含量(质量含量)一般大于70％，优选大于80％，最优选大于90％。In a specific embodiment, the present invention provides a mixture of DL-tenofovir alafenamide (1:1) in a mixture of DL-tenofovir alafenamide (1:1) Form A The content (mass content) is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本领域技术人员可以理解的是，本发明所述的DL-酒石酸替诺福韦艾拉酚胺(1:1)混合物指的是用化学合成方法直接合成制备的含有其他杂质或晶型的DL-酒石酸替诺福韦艾拉酚胺(1:1)。It will be understood by those skilled in the art that the DL-tenofovir alafenamide (1:1) mixture of the present invention refers to a DL containing other impurities or crystal forms directly synthesized by chemical synthesis. - Tenofovir alafenamide (1:1).
在一具体实施方案中，本发明的DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A的制备方法包括： In a specific embodiment, the method for preparing DL-tenofovir alafenamide (1:1) Form A of the present invention comprises:
(1)将替诺福韦艾拉酚胺和DL-酒石酸溶解在乙腈中；所述溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1。替诺福韦艾拉酚胺与DL-酒石酸的投料摩尔比一般为0.5:1～1.5:1，优选0.8:1～1.2:1。(1) Tenofovir alafenamide and DL-tartaric acid are dissolved in acetonitrile; the weight ratio of the solvent to tenofovir alafenamide is generally from 5:1 to 80:1. The molar ratio of tenofovir alafenamide to DL-tartaric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；可选地，可以用乙腈对所收集的固体进行洗涤。(3) Separating the precipitated solid; alternatively, the collected solid may be washed with acetonitrile.
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。干燥温度一般为20～120℃，优选30～80℃；可以常压干燥，也可以减压干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried. The drying temperature is usually 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
L-苹果酸替诺福韦艾拉酚胺(1:2)L-malofovir alafenamide (1:2)
在一实施方案中，式Ⅱ中，n选为2，X选为L-苹果酸，即提供了替诺福韦艾拉酚胺与L-苹果酸以2:1摩尔组成比形成的复合物，称为“L-苹果酸替诺福韦艾拉酚胺(1:2)”。In one embodiment, in Formula II, n is selected to be 2, and X is selected as L-malic acid, that is, a complex formed by the ratio of tenofovir alafenamide to L-malic acid in a ratio of 2:1 mole is provided. It is called "L-malofovir alafenamide (1:2)".
在一实施方案中，本发明提供了一种L-苹果酸替诺福韦艾拉酚胺的制备方法，该方法包括：In one embodiment, the present invention provides a method of preparing tenofovir alafenamide of L-malic acid, the method comprising:
(1)将替诺福韦艾拉酚胺和L-苹果酸溶解在适宜溶剂中；(1) dissolving tenofovir alafenamide and L-malic acid in a suitable solvent;
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；(3) separating the precipitated solid;
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried.
上述制备方法步骤(1)中，所述“适宜溶剂”选自乙腈、甲醇、乙醇、异丙醇、四氢呋喃、丙酮、二氯甲烷、三氯甲烷、甲苯等或它们的混合物，优选为异丙醇。所述适宜溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1。In the above preparation method step (1), the "suitable solvent" is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably isopropyl. alcohol. The weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
上述制备方法步骤(1)中，替诺福韦艾拉酚胺与L-苹果酸的投料摩尔比一般1.7:1～2.5:1，优选1.9:1～2.3:1。In the above preparation method step (1), the molar ratio of tenofovir alafenamide to L-malic acid is generally 1.7:1 to 2.5:1, preferably 1.9:1 to 2.3:1.
上述制备方法步骤(2)中，所述“析出固体”的方法为本技术领域内常规的方法，如冷却，加入反溶剂，浓缩出部分溶剂体、加晶种等方法的单用或联用。析出固体过程可以是静置的，也可是搅拌的。In the above preparation method step (2), the method of "precipitating solid" is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination. . The solids precipitation process can be either standing or agitated.
上述制备方法步骤(3)中，所述“分离”可以采用过滤等本技术领域内的常规方法。可选地，可以用步骤(1)中的适宜溶剂对所收集的固体进行洗涤。In the above production method step (3), the "separation" may employ a conventional method in the art such as filtration. Alternatively, the collected solids may be washed with a suitable solvent in step (1).
上述制备方法步骤(4)中，所述“干燥”方式包括常压干燥、减压干燥或它们的组合应用。“进一步纯化”的方法包括重结晶、浆化、洗涤等形式。In the above preparation method step (4), the "drying" method includes atmospheric drying, reduced pressure drying or a combination thereof. Methods for "further purification" include recrystallization, slurrying, washing, and the like.
上述方法步骤(4)中，“干燥”的温度一般为20～80℃，优选30～60℃；可以常压干燥，也可以减压干燥。 In the above step (4), the temperature of "drying" is generally 20 to 80 ° C, preferably 30 to 60 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
该实施方案所制备的L-苹果酸替诺福韦艾拉酚胺(1:2)是一种晶体。The tenofovir alafenamide (1:2) of L-malate prepared in this embodiment is a crystal.
因此，本发明提供了一种L-苹果酸替诺福韦艾拉酚胺(1:2)的晶型(为了表述方便，将该晶型称为“L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A”)。该晶型的X-射线粉末衍射图谱(使用Cu-Kα辐射)的特征为：在2θ值为10.0°±0.2°、13.4°±0.2°、13.9°±0.2°、15.3°±0.2°、16.6°±0.2°、21.3°±0.2°、26.3°±0.2°等处对应有特征衍射峰。Accordingly, the present invention provides a crystalline form of tenofovir alafenamide (1:2) of L-malate (for convenience of presentation, the crystal form is referred to as "L-malic acid tenofovira Phenolic amine (1:2) crystal form A"). The X-ray powder diffraction pattern of the crystal form (using Cu-Kα radiation) is characterized by a 2θ value of 10.0°±0.2°, 13.4°±0.2°, 13.9°±0.2°, 15.3°±0.2°, 16.6. Characteristic diffraction peaks correspond to °±0.2°, 21.3°±0.2°, 26.3°±0.2°.
在一具体实施方案中，本发明所诉的L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A的X-射线粉末衍射图谱的特征为：在2θ值为5.4°±0.2°、10.0°±0.2°、11.9°±0.2°、13.4°±0.2°、13.9°±0.2°、15.3°±0.2°、16.6°±0.2°、20.3°±0.2°、21.3°±0.2°、22.2°±0.2°、26.3°±0.2°等处对应有特征衍射峰。In a specific embodiment, the X-ray powder diffraction pattern of the tenofovir alafenamide (1:2) crystal form A of the L-malic acid of the present invention is characterized by a value of 5.4 ° ± 2θ. 0.2°, 10.0°±0.2°, 11.9°±0.2°, 13.4°±0.2°, 13.9°±0.2°, 15.3°±0.2°, 16.6°±0.2°, 20.3°±0.2°, 21.3°±0.2° There are characteristic diffraction peaks at 22.2°±0.2° and 26.3°±0.2°.
进一步地，本发明所述的L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征衍射峰及相对强度：Further, the X-ray powder diffraction pattern represented by the 2θ angle of the tenofovir alafenamide (1:2) crystal form A of the present invention has characteristic diffraction peaks and relative intensities at the following positions:
2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
5.4°±0.2°5.4°±0.2° 1414 17.9°±0.2°17.9°±0.2° 88
9.7°±0.2°9.7°±0.2° 1919 19.4°±0.2°19.4°±0.2° 88
10.0°±0.2°10.0°±0.2° 6969 20.1°±0.2°20.1 ° ± 0.2 ° 1010
10.3°±0.2°10.3°±0.2° 1212 20.3°±0.2°20.3°±0.2° 1616
11.9°±0.2°11.9°±0.2° 2020 21.3°±0.2°21.3°±0.2° 100100
13.2°±0.2°13.2°±0.2° 1919 21.9°±0.2°21.9°±0.2° 1818
13.4°±0.2°13.4°±0.2° 3535 22.2°±0.2°22.2°±0.2° 1919
13.9°±0.2°13.9°±0.2° 6161 23.2°±0.2°23.2°±0.2° 1414
14.1°±0.2°14.1°±0.2° 3333 24.2°±0.2°24.2°±0.2° 99
15.3°±0.2°15.3°±0.2° 5555 25.3°±0.2°25.3°±0.2° 88
16.6°±0.2°16.6°±0.2° 5151 26.3°±0.2°26.3°±0.2° 3131
17.0°±0.2°17.0°±0.2° 88 29.3°±0.2°29.3°±0.2° 88
在一具体实施方案中，本发明提供的L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A具有如图4所示的X-射线粉末衍射图谱所代表的特征。In a specific embodiment, the present invention provides tenofovir alafenamide (1:2) Form A of L-malate having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
在一具体实施方案中，本发明提供的制备的L-苹果酸替诺福韦艾拉酚胺(1:2)混合物中L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A含量(质量含量)一般大于70％，优选大于80％，最优选大于90％。In a specific embodiment, the present invention provides a mixture of tenofovir alafenamide (1:2) L-malate and tenofovir alafenamide (1:2) crystals. The type A content (mass content) is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本领域技术人员可以理解的是，本发明所述的L-苹果酸替诺福韦艾拉酚胺(1:2)混合物指的是用化学合成方法直接合成制备的含有其他杂质或晶型的L-苹果酸替诺福韦艾拉酚胺(1:2)。It will be understood by those skilled in the art that the mixture of tenofovir alafenamide (1:2) of L-malate according to the present invention refers to a mixture of other impurities or crystal forms prepared by direct synthesis by chemical synthesis. Tenofovir alafenamide (1:2).
在一具体实施方案中，本发明提供的L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A的制备方法包括：In a specific embodiment, the method for preparing the crystalline form A of tenofovir alafenamide (1:2) of L-malate provided by the present invention comprises:
(1)将替诺福韦艾拉酚胺和L-苹果酸溶解在异丙醇中；所述溶剂与替诺福韦艾拉酚胺 的重量比一般为5:1～80:1。替诺福韦艾拉酚胺与L-苹果酸的投料摩尔比一般1.7:1～2.5:1，优选1.9:1～2.3:1。(1) dissolving tenofovir alafenamide and L-malic acid in isopropanol; the solvent and tenofovir alafenamide The weight ratio is generally 5:1 to 80:1. The molar ratio of tenofovir alafenamide to L-malic acid is generally from 1.7:1 to 2.5:1, preferably from 1.9:1 to 2.3:1.
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；可选地，可以用异丙醇对所收集的固体进行洗涤。(3) Separating the precipitated solid; alternatively, the collected solid may be washed with isopropyl alcohol.
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。干燥温度一般为20～80℃，优选30～60℃；可以常压干燥，也可以减压干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried. The drying temperature is usually 20 to 80 ° C, preferably 30 to 60 ° C; it can be dried at normal pressure or dried under reduced pressure.
柠檬酸替诺福韦艾拉酚胺(1:1)Tenofovir eugenol citrate (1:1)
在一实施方案中，式Ⅱ中，n选为1，X选为柠檬酸，即提供了替诺福韦艾拉酚胺与柠檬酸以1:1摩尔组成比形成的复合物，称为“柠檬酸替诺福韦艾拉酚胺(1:1)”。In one embodiment, in Formula II, n is selected to be 1, and X is selected to be citric acid, that is, a complex formed by tenofovir alafenamide and citric acid in a 1:1 molar composition ratio, Tenofovir eugenol citrate (1:1)".
在一实施方案中，本发明提供了一种柠檬酸替诺福韦艾拉酚胺的制备方法，该方法包括：In one embodiment, the present invention provides a process for the preparation of tenofovir alafenol citrate, the method comprising:
(1)将替诺福韦艾拉酚胺和柠檬酸溶解在适宜溶剂中；(1) dissolving tenofovir alafenamide and citric acid in a suitable solvent;
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；(3) separating the precipitated solid;
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried.
上述制备方法步骤(1)中，所述“适宜溶剂”选自乙腈、甲醇、乙醇、异丙醇、四氢呋喃、丙酮、二氯甲烷、三氯甲烷、甲苯等或它们的混合物，优选为乙腈、甲醇、乙醇、四氢呋喃或它们的混合物。所述适宜溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1。In the above preparation method step (1), the "suitable solvent" is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile, Methanol, ethanol, tetrahydrofuran or a mixture thereof. The weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
上述制备方法步骤(1)中，替诺福韦艾拉酚胺与柠檬酸的投料摩尔比一般0.5:1～1.5:1，优选0.8:1～1.2:1。In the above preparation method step (1), the molar ratio of tenofovir alafenamide to citric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
上述制备方法步骤(2)中，所述“析出固体”的方法为本技术领域内常规的方法，如冷却，加入反溶剂，所述“反溶剂”选自乙醚、乙酸乙酯、乙酸甲酯、甲酸乙酯、正庚烷、乙二醇二甲醚、异丙醚、甲基叔丁基醚、异辛烷、苯甲醚等或它们的混合物。浓缩出部分溶剂体、加晶种等方法的单用或联用。析出固体过程可以是静置的，也可是搅拌的。In the above preparation method step (2), the method of "precipitating solid" is a conventional method in the art, such as cooling, adding an anti-solvent, and the "anti-solvent" is selected from the group consisting of diethyl ether, ethyl acetate and methyl acetate. Ethyl formate, n-heptane, ethylene glycol dimethyl ether, diisopropyl ether, methyl tert-butyl ether, isooctane, anisole, etc. or a mixture thereof. The method of concentrating a part of the solvent body, seeding, etc. may be used alone or in combination. The solids precipitation process can be either standing or agitated.
上述制备方法步骤(3)中，所述“分离”可以采用过滤等本技术领域内的常规方法。可选地，可以用步骤(1)中的适宜溶剂对所收集的固体进行洗涤。In the above production method step (3), the "separation" may employ a conventional method in the art such as filtration. Alternatively, the collected solids may be washed with a suitable solvent in step (1).
上述制备方法步骤(4)中，所述“干燥”方式包括常压干燥、减压干燥或它们的组合应用。“进一步纯化”的方法包括重结晶、浆化、洗涤等形式。In the above preparation method step (4), the "drying" method includes atmospheric drying, reduced pressure drying or a combination thereof. Methods for "further purification" include recrystallization, slurrying, washing, and the like.
上述方法步骤(4)中，“干燥”的温度一般为20～120℃，优选30～80℃；可以常压干燥，也可以减压干燥。 In the above step (4), the temperature of "drying" is generally 20 to 120 ° C, preferably 30 to 80 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
该实施方案所制备的柠檬酸替诺福韦艾拉酚胺(1:1)是一种晶体。The tenofovir alafenamide (1:1) prepared by this embodiment is a crystal.
因此，本发明提供了一种柠檬酸替诺福韦艾拉酚胺(1:1)的晶型(为了表述方便，将该晶型称为“柠檬酸替诺福韦艾拉酚胺(1:1)晶型A”)。该晶型的X-射线粉末衍射图谱(使用Cu-Kα辐射)的特征为：在2θ值为6.0°±0.2°、8.1°±0.2°、11.7°±0.2°、15.9°±0.2°、17.9°±0.2°、21.7°±0.2°、23.4°±0.2°、26.9°±0.2°等处对应有特征衍射峰。Accordingly, the present invention provides a crystalline form of tenofovir alafenamide (1:1) citrate (for convenience of presentation, the crystalline form is referred to as "tenofovir acetamide citrate (1) :1) Form A"). The X-ray powder diffraction pattern of the crystal form (using Cu-Kα radiation) is characterized by a value of 2θ of 6.0°±0.2°, 8.1°±0.2°, 11.7°±0.2°, 15.9°±0.2°, 17.9. Characteristic diffraction peaks correspond to °±0.2°, 21.7°±0.2°, 23.4°±0.2°, and 26.9°±0.2°.
在一具体实施方案中，本发明所诉的柠檬酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱的特征为：在2θ值为6.0°±0.2°、8.1°±0.2°、11.7°±0.2°、12.6°±0.2°、15.4°±0.2°、15.9°±0.2°、17.5°±0.2°、17.9°±0.2°、20.1°±0.2°、20.6°±0.2°、21.4°±0.2°、21.7°±0.2°、23.4°±0.2°、26.9°±0.2°、29.3°±0.2°、31.9°±0.2°、32.7°±0.2°等处对应有特征衍射峰。In a specific embodiment, the X-ray powder diffraction pattern of tenofovir alafenamide (1:1) crystal form A of the present invention is characterized by a 2θ value of 6.0°±0.2°. 8.1°±0.2°, 11.7°±0.2°, 12.6°±0.2°, 15.4°±0.2°, 15.9°±0.2°, 17.5°±0.2°, 17.9°±0.2°, 20.1°±0.2°, 20.6 °±0.2°, 21.4°±0.2°, 21.7°±0.2°, 23.4°±0.2°, 26.9°±0.2°, 29.3°±0.2°, 31.9°±0.2°, 32.7°±0.2°, etc. Characteristic diffraction peaks.
进一步地，本发明所述的柠檬酸替诺福韦艾拉酚胺(1:1)晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征衍射峰及相对强度：Further, the X-ray powder diffraction pattern of the tenofovir iramolamine (1:1) crystal form A of the present invention represented by the 2θ angle has characteristic diffraction peaks and relative intensities at the following positions:
2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
6.0°±0.2°6.0°±0.2° 100100 20.1°±0.2°20.1 ° ± 0.2 ° 1616
8.1°±0.2°8.1°±0.2° 4747 20.6°±0.2°20.6°±0.2° 1212
8.5°±0.2°8.5°±0.2° 99 21.4°±0.2°21.4°±0.2° 2929
10.3°±0.2°10.3°±0.2° 77 21.7°±0.2°21.7°±0.2° 3232
11.7°±0.2°11.7°±0.2° 3939 22.1°±0.2°22.1°±0.2° 77
12.2°±0.2°12.2°±0.2° 88 22.5°±0.2°22.5°±0.2° 1212
12.6°±0.2°12.6°±0.2° 21twenty one 23.1°±0.2°23.1°±0.2° 1111
14.6°±0.2°14.6°±0.2° 1313 23.4°±0.2°23.4°±0.2° 3737
15.4°±0.2°15.4°±0.2° 23twenty three 26.0°±0.2°26.0°±0.2° 77
15.9°±0.2°15.9°±0.2° 3636 26.9°±0.2°26.9 ° ± 0.2 ° 3939
16.3°±0.2°16.3°±0.2° 77 29.2°±0.2°29.2°±0.2° 1010
17.5°±0.2°17.5° ± 0.2° 1616 29.3°±0.2°29.3°±0.2° 1414
17.9°±0.2°17.9°±0.2° 3232 31.9°±0.2°31.9°±0.2° 1111
19.9°±0.2°19.9°±0.2° 1010 32.7°±0.2°32.7°±0.2° 1212
在一具体实施方案中，本发明提供的柠檬酸替诺福韦艾拉酚胺(1:1)晶型A具有如图5所示的X-射线粉末衍射图谱所代表的特征。In a specific embodiment, the present invention provides tenofovir alafenamide (1:1) Form A having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
在一具体实施方案中，本发明提供的制备的柠檬酸替诺福韦艾拉酚胺(1:1)混合物中柠檬酸替诺福韦艾拉酚胺(1:1)晶型A含量(质量含量)一般大于70％，优选大于80％，最优选大于90％。In a specific embodiment, the present invention provides a tenofovir acetamide (1:1) crystalline form A content in a mixture of tenofovir alafenamide (1:1) prepared by citrate ( The mass content) is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本领域技术人员可以理解的是，本发明所述的柠檬酸替诺福韦艾拉酚胺(1:1)混合物指的是用化学合成方法直接合成制备的含有其他杂质或晶型的柠檬酸替诺福韦艾拉酚胺(1:1)。It will be understood by those skilled in the art that the tenofovir ylideamine (1:1) mixture of the present invention refers to a citric acid containing other impurities or crystal forms directly synthesized by chemical synthesis. Tenofovir alafenamide (1:1).
在一具体实施方案中，本发明的柠檬酸替诺福韦艾拉酚胺(1:1)晶型A的制备方法包括： In a specific embodiment, the method for preparing tenofovir alafenamide (1:1) crystal form A of the present invention comprises:
(1)将替诺福韦艾拉酚胺和柠檬酸溶解在乙腈、甲醇、乙醇、四氢呋喃或它们的混合物中；所述适宜溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1。替诺福韦艾拉酚胺与柠檬酸的投料摩尔比一般0.5:1～1.5:1，优选0.8:1～1.2:1。(1) Dissolving tenofovir alafenamide and citric acid in acetonitrile, methanol, ethanol, tetrahydrofuran or a mixture thereof; the weight ratio of the suitable solvent to tenofovir alafenamide is generally 5: 1 to 80:1. The molar ratio of tenofovir alafenamide to citric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；可选地，可以用步骤(1)中的溶剂对所收集的固体进行洗涤。(3) Separating the precipitated solid; alternatively, the collected solid may be washed with the solvent in the step (1).
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。干燥温度一般为20～120℃，优选30～80℃；可以常压干燥，也可以减压干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried. The drying temperature is usually 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
琥珀酸替诺福韦艾拉酚胺(1:1)Tenofovir alafenamide succinate (1:1)
在一实施方案中，式Ⅱ中，n选为1，X选为琥珀酸，即提供了替诺福韦艾拉酚胺与琥珀酸以1:1摩尔组成比形成的复合物，称为“琥珀酸替诺福韦艾拉酚胺(1:1)”。In one embodiment, in Formula II, n is selected to be 1, and X is selected to be succinic acid, that is, a complex formed by the ratio of tenofovir alafenamide to succinic acid in a molar ratio of 1:1 is referred to as "a compound". Tenofovir alafenamide succinate (1:1)".
在一实施方案中，本发明提供了一种琥珀酸替诺福韦艾拉酚胺的制备方法，该方法包括：In one embodiment, the invention provides a method of preparing tenofovir alafenamide succinate, the method comprising:
(1)将替诺福韦艾拉酚胺和琥珀酸溶解在适宜溶剂中；(1) dissolving tenofovir alafenamide and succinic acid in a suitable solvent;
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；(3) separating the precipitated solid;
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried.
上述制备方法步骤(1)中，所述“适宜溶剂”选自乙腈、甲醇、乙醇、异丙醇、四氢呋喃、丙酮、二氯甲烷、三氯甲烷、甲苯等或它们的混合物，优选为乙腈。所述适宜溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1。In the above production method step (1), the "suitable solvent" is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile. The weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
上述制备方法步骤(1)中，替诺福韦艾拉酚胺与琥珀酸的投料摩尔比一般0.5:1～1.5:1，优选0.8:1～1.2:1。In the above preparation method step (1), the molar ratio of tenofovir alafenamide to succinic acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
上述制备方法步骤(2)中，所述“析出固体”的方法为本技术领域内常规的方法，如冷却，加入反溶剂，浓缩出部分溶剂体、加晶种等方法的单用或联用。析出固体过程可以是静置的，也可是搅拌的。In the above preparation method step (2), the method of "precipitating solid" is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination. . The solids precipitation process can be either standing or agitated.
上述制备方法步骤(3)中，所述“分离”可以采用过滤等本技术领域内的常规方法。可选地，可以用步骤(1)中的适宜溶剂对所收集的固体进行洗涤。In the above production method step (3), the "separation" may employ a conventional method in the art such as filtration. Alternatively, the collected solids may be washed with a suitable solvent in step (1).
上述制备方法步骤(4)中，所述“干燥”方式包括常压干燥、减压干燥或它们的组合应用。“进一步纯化”的方法包括重结晶、浆化、洗涤等形式。In the above preparation method step (4), the "drying" method includes atmospheric drying, reduced pressure drying or a combination thereof. Methods for "further purification" include recrystallization, slurrying, washing, and the like.
上述方法步骤(4)中，“干燥”的温度一般为20～100℃，优选30～80℃；可以常压干燥，也可以减压干燥。 In the above step (4), the temperature of "drying" is generally 20 to 100 ° C, preferably 30 to 80 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
该实施方案所制备的琥珀酸替诺福韦艾拉酚胺(1:1)是一种晶体。Tenofovir alafenamide (1:1) prepared in this embodiment is a crystal.
因此，本发明提供了一种琥珀酸替诺福韦艾拉酚胺(1:1)的晶型(为了表述方便，将该晶型称为“琥珀酸替诺福韦艾拉酚胺(1:1)晶型A”)。该晶型的X-射线粉末衍射图谱(使用Cu-Kα辐射)的特征为：在2θ值为10.7°±0.2°、14.3°±0.2°、17.2°±0.2°、21.4°±0.2°、21.8°±0.2°、22.4°±0.2°等处对应有特征衍射峰。Accordingly, the present invention provides a crystalline form of tenofovir alafenamide (1:1) succinate (for convenience of presentation, the crystalline form is referred to as "tenofovir alafenol succinate (1) :1) Form A"). The X-ray powder diffraction pattern of the crystal form (using Cu-Kα radiation) is characterized by a 2θ value of 10.7°±0.2°, 14.3°±0.2°, 17.2°±0.2°, 21.4°±0.2°, 21.8. Characteristic diffraction peaks correspond to °±0.2°, 22.4°±0.2°, etc.
在一具体实施方案中，本发明所诉的琥珀酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱的特征为：在2θ值为5.7°±0.2°、9.6°±0.2°、10.0°±0.2°、10.7°±0.2°、11.7°±0.2°、13.5°±0.2°、14.3°±0.2°、17.2°±0.2°、17.8°±0.2°、19.3°±0.2°、19.7°±0.2°、21.4°±0.2°、21.8°±0.2°、22.4°±0.2°、23.8°±0.2°、27.9°±0.2°等处对应有特征衍射峰。In a specific embodiment, the X-ray powder diffraction pattern of tenofovir alafenamide (1:1) Form A of the present invention is characterized by a 2θ value of 5.7°±0.2°. 9.6°±0.2°, 10.0°±0.2°, 10.7°±0.2°, 11.7°±0.2°, 13.5°±0.2°, 14.3°±0.2°, 17.2°±0.2°, 17.8°±0.2°, 19.3 Characteristic diffraction peaks correspond to °±0.2°, 19.7°±0.2°, 21.4°±0.2°, 21.8°±0.2°, 22.4°±0.2°, 23.8°±0.2°, 27.9°±0.2°.
进一步地，本发明所述的琥珀酸替诺福韦艾拉酚胺(1:1)晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征衍射峰及相对强度：Further, the X-ray powder diffraction pattern of the tenofovir alafenamide (1:1) crystalline form A of the present invention represented by the 2θ angle has characteristic diffraction peaks and relative intensities at the following positions:
2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
5.7°±0.2°5.7°±0.2° 3434 19.7°±0.2°19.7°±0.2° 4747
9.6°±0.2°9.6°±0.2° 4949 21.1°±0.2°21.1°±0.2° 4242
10.0°±0.2°10.0°±0.2° 5151 21.4°±0.2°21.4°±0.2° 7979
10.4°±0.2°10.4°±0.2° 3030 21.8°±0.2°21.8°±0.2° 7979
10.7°±0.2°10.7°±0.2° 100100 22.4°±0.2°22.4°±0.2° 8282
11.2°±0.2°11.2°±0.2° 1313 23.8°±0.2°23.8°±0.2° 2626
11.7°±0.2°11.7°±0.2° 2828 24.7°±0.2°24.7° ± 0.2° 1818
12.7°±0.2°12.7°±0.2° 1515 26.1°±0.2°26.1°±0.2° 1313
13.5°±0.2°13.5°±0.2° 3333 27.0°±0.2°27.0°±0.2° 1818
14.3°±0.2°14.3°±0.2° 6969 27.9°±0.2°27.9°±0.2° 2020
14.7°±0.2°14.7° ± 0.2° 2020 28.7°±0.2°28.7°±0.2° 1111
17.2°±0.2°17.2°±0.2° 8383 30.6°±0.2°30.6°±0.2° 1616
17.8°±0.2°17.8°±0.2° 6060 33.6°±0.2°33.6 ° ± 0.2 ° 1010
18.9°±0.2°18.9°±0.2° 3232 34.1°±0.2°34.1°±0.2° 1111
19.3°±0.2°19.3°±0.2° 4646    
在一具体实施方案中，本发明提供的琥珀酸替诺福韦艾拉酚胺(1:1)A具有如图6所示的X-射线粉末衍射图谱所代表的特征。In a specific embodiment, the present invention provides tenofovir alafenamide (1:1) A having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
在一具体实施方案中，本发明提供的制备的琥珀酸替诺福韦艾拉酚胺(1:1)混合物中琥珀酸替诺福韦艾拉酚胺(1:1)晶型A含量(质量含量)一般大于70％，优选大于80％，最优选大于90％。In a specific embodiment, the present invention provides tenofovir alafenamide (1:1) crystalline form A in a mixture of tenofovir alafenamide (1:1) succinate ( The mass content) is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本领域技术人员可以理解的是，本发明所述的琥珀酸替诺福韦艾拉酚胺(1:1)混合物指的是用化学合成方法直接合成制备的含有其他杂质或晶型的琥珀酸替诺福韦艾拉酚胺(1:1)。It will be understood by those skilled in the art that the tenofovir alafenamide (1:1) mixture of the present invention refers to a succinic acid containing other impurities or crystal forms directly synthesized by chemical synthesis. Tenofovir alafenamide (1:1).
在一具体实施方案中，本发明的琥珀酸替诺福韦艾拉酚胺(1:1)晶型A的制备方法包括：In a specific embodiment, the method for preparing tenofovir alafenamide (1:1) Form A of the present invention comprises:
(1)将替诺福韦艾拉酚胺和琥珀酸溶解在乙腈中；所述溶剂与替诺福韦艾拉酚胺的重 量比一般为5:1～80:1。替诺福韦艾拉酚胺与琥珀酸的投料摩尔比一般0.5:1～1.5:1，优选0.8:1～1.2:1。(1) Dissolving tenofovir alafenamide and succinic acid in acetonitrile; the weight of the solvent and tenofovir alafenamide The ratio is generally 5:1 to 80:1. The molar ratio of tenofovir alafenamide to succinic acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；可选地，可以用乙腈对所收集的固体进行洗涤。(3) Separating the precipitated solid; alternatively, the collected solid may be washed with acetonitrile.
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。干燥温度一般为20～100℃，优选30～80℃；可以常压干燥，也可以减压干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried. The drying temperature is usually 20 to 100 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
草酸替诺福韦艾拉酚胺(1:1)Tenofovir alafenamide (1:1)
在一实施方案中，式Ⅱ中，n选为1，X选为草酸，即提供了替诺福韦艾拉酚胺与草酸以1:1摩尔组成比形成的复合物，称为“草酸替诺福韦艾拉酚胺(1:1)”。In one embodiment, in Formula II, n is selected to be 1, and X is selected as oxalic acid, that is, a complex formed by the ratio of tenofovir alafenamide to oxalic acid in a molar ratio of 1:1 is referred to as "oxalic acid". Norfoslavamide (1:1)".
在一实施方案中，本发明提供了一种草酸替诺福韦艾拉酚胺的制备方法，该方法包括：In one embodiment, the invention provides a method of preparing tenofovir alafenamide oxalate, the method comprising:
(1)将替诺福韦艾拉酚胺和草酸溶解在适宜溶剂中；(1) dissolving tenofovir alafenamide and oxalic acid in a suitable solvent;
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；(3) separating the precipitated solid;
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried.
上述制备方法步骤(1)中，所述“适宜溶剂”选自乙腈、甲醇、乙醇、异丙醇、四氢呋喃、丙酮、二氯甲烷、三氯甲烷、甲苯等或它们的混合物，优选为乙腈。所述适宜溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1。In the above production method step (1), the "suitable solvent" is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile. The weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
上述制备方法步骤(1)中，替诺福韦艾拉酚胺与草酸的投料摩尔比一般0.5:1～1.5:1，优选0.8:1～1.2:1。In the above preparation method step (1), the molar ratio of tenofovir alafenamide to oxalic acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
上述制备方法步骤(2)中，所述“析出固体”的方法为本技术领域内常规的方法，如冷却，加入反溶剂，浓缩出部分溶剂体、加晶种等方法的单用或联用。析出固体过程可以是静置的，也可是搅拌的。In the above preparation method step (2), the method of "precipitating solid" is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination. . The solids precipitation process can be either standing or agitated.
上述制备方法步骤(3)中，所述“分离”可以采用过滤等本技术领域内的常规方法。可选地，可以用步骤(1)中的适宜溶剂对所收集的固体进行洗涤。In the above production method step (3), the "separation" may employ a conventional method in the art such as filtration. Alternatively, the collected solids may be washed with a suitable solvent in step (1).
上述制备方法步骤(4)中，所述“干燥”方式包括常压干燥、减压干燥或它们的组合应用。“进一步纯化”的方法包括重结晶、浆化、洗涤等形式。In the above preparation method step (4), the "drying" method includes atmospheric drying, reduced pressure drying or a combination thereof. Methods for "further purification" include recrystallization, slurrying, washing, and the like.
上述方法步骤(4)中，“干燥”的温度一般为20～120℃，优选30～80℃；可以常压干燥，也可以减压干燥。In the above step (4), the temperature of "drying" is generally 20 to 120 ° C, preferably 30 to 80 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
该实施方案所制备的草酸替诺福韦艾拉酚胺(1:1)是一种晶体。The tenofovir oxalatamide oxalate (1:1) prepared in this embodiment is a crystal.
因此，本发明提供了一种草酸替诺福韦艾拉酚胺(1:1)的晶型(为了表述方便，将该晶型 称为“草酸替诺福韦艾拉酚胺(1:1)晶型A”)。该晶型的X-射线粉末衍射图谱(使用Cu-Kα辐射)的特征为：在2θ值为7.7°±0.2°、9.6°±0.2°、16.2°±0.2°、18.2°±0.2°、20.5°±0.2°、24.7°±0.2°等处对应有特征衍射峰。Accordingly, the present invention provides a crystalline form of tenofovir alafenamide (1:1) (for convenience of presentation, the crystal form It is called "tenofovir oxalatine oxalate (1:1) crystal form A"). The X-ray powder diffraction pattern of the crystal form (using Cu-Kα radiation) is characterized by a value of 2θ of 7.7°±0.2°, 9.6°±0.2°, 16.2°±0.2°, 18.2°±0.2°, 20.5. Characteristic diffraction peaks correspond to °±0.2°, 24.7°±0.2°, etc.
在一具体实施方案中，本发明所诉的草酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱的特征为：在2θ值为7.7°±0.2°、8.4°±0.2°、9.6°±0.2°、12.6°±0.2°、16.2°±0.2°、18.2°±0.2°、20.5°±0.2°、22.6°±0.2°、24.7°±0.2°、27.8°±0.2°、29.0°±0.2°等处对应有特征衍射峰。In a specific embodiment, the X-ray powder diffraction pattern of tenofovir alafenamide (1:1) crystalline form A of the present invention is characterized by a value of 7.7°±0.2° at a 2θ value, 8.4°±0.2°, 9.6°±0.2°, 12.6°±0.2°, 16.2°±0.2°, 18.2°±0.2°, 20.5°±0.2°, 22.6°±0.2°, 24.7°±0.2°, 27.8° Characteristic diffraction peaks correspond to ±0.2°, 29.0°±0.2°, and the like.
进一步地，本发明所述的草酸替诺福韦艾拉酚胺(1:1)晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征衍射峰及相对强度：Further, the X-ray powder diffraction pattern of the tenofovir oxalatine (1:1) crystalline form A of the present invention represented by the 2θ angle has characteristic diffraction peaks and relative intensities at the following positions:
2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
7.7°±0.2°7.7°±0.2° 3535 19.6°±0.2°19.6°±0.2° 1919
8.4°±0.2°8.4°±0.2° 22twenty two 20.5°±0.2°20.5°±0.2° 9292
9.6°±0.2°9.6°±0.2° 100100 21.9°±0.2°21.9°±0.2° 1616
11.0°±0.2°11.0°±0.2° 1010 22.6°±0.2°22.6°±0.2° 2626
12.2°±0.2°12.2°±0.2° 1313 23.8°±0.2°23.8°±0.2° 3030
12.6°±0.2°12.6°±0.2° 22twenty two 24.3°±0.2°24.3°±0.2° 2525
14.8°±0.2°14.8°±0.2° 1212 24.7°±0.2°24.7° ± 0.2° 5555
14.9°±0.2°14.9°±0.2° 1212 25.4°±0.2°25.4°±0.2° 22twenty two
16.2°±0.2°16.2°±0.2° 4747 25.8°±0.2°25.8°±0.2° 1717
16.6°±0.2°16.6°±0.2° 2626 26.2°±0.2°26.2°±0.2° 1010
16.9°±0.2°16.9°±0.2° 2727 27.8°±0.2°27.8°±0.2° 1818
18.2°±0.2°18.2°±0.2° 3434 29.0°±0.2°29.0°±0.2° 1919
19.1°±0.2°19.1°±0.2° 1515    
在一具体实施方案中，本发明提供的草酸替诺福韦艾拉酚胺(1:1)晶型A具有如图7所示的X-射线粉末衍射图谱所代表的特征。In a specific embodiment, the present invention provides tenofovir alafenamide (1:1) Form A having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
在一具体实施方案中，本发明提供的制备草酸替诺福韦艾拉酚胺(1:1)混合物中草酸替诺福韦艾拉酚胺(1:1)晶型A含量(质量含量)一般大于70％，优选大于80％，最优选大于90％。In a specific embodiment, the present invention provides a preparation of tenofovir alafenamide (1:1) crystalline form A (mass content) in a mixture of tenofovir alafenamide (1:1). Generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本领域技术人员可以理解的是，本发明所述的草酸替诺福韦艾拉酚胺(1:1)混合物指的是用化学合成方法直接合成制备的含有其他杂质或晶型的草酸替诺福韦艾拉酚胺(1:1)。It will be understood by those skilled in the art that the tenofovir oxalatamide (1:1) mixture of the present invention refers to a oxalic acid oxalic acid containing other impurities or crystal forms directly synthesized by chemical synthesis. Fuviralolamine (1:1).
在一具体实施方案中，本发明的草酸替诺福韦艾拉酚胺(1:1)晶型A的制备方法包括：In a specific embodiment, the method for preparing tenofovir oxalatine (1:1) crystalline form A of the present invention comprises:
(1)将替诺福韦艾拉酚胺和草酸溶解在乙腈中；所述溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1。替诺福韦艾拉酚胺与草酸的投料摩尔比一般0.5:1～1.5:1，优选0.8:1～1.2:1。(1) Tenofovir alafenamide and oxalic acid are dissolved in acetonitrile; the weight ratio of the solvent to tenofovir alafenamide is generally from 5:1 to 80:1. The molar ratio of tenofovir alafenamide to oxalic acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；可选地，可以用乙腈对所收集的固体进行洗涤。 (3) Separating the precipitated solid; alternatively, the collected solid may be washed with acetonitrile.
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。干燥温度一般为20～120℃，优选30～80℃；可以常压干燥，也可以减压干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried. The drying temperature is usually 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
磷酸替诺福韦艾拉酚胺(1:1)Tenofovir alafenamide (1:1)
在一实施方案中，式Ⅱ中，n选为1，X选为磷酸，即提供了替诺福韦艾拉酚胺与磷酸以1:1摩尔组成比形成的复合物，称为“磷酸替诺福韦艾拉酚胺(1:1)”。In one embodiment, in Formula II, n is selected to be 1, and X is selected as phosphoric acid, that is, a complex formed by the ratio of tenofovir alafenamide to phosphoric acid in a molar ratio of 1:1 is referred to as "phosphoric acid". Norfoslavamide (1:1)".
在一实施方案中，本发明提供了一种磷酸替诺福韦艾拉酚胺的制备方法，该方法包括：In one embodiment, the invention provides a method of preparing tenofovir alafenol phosphate, the method comprising:
(1)将替诺福韦艾拉酚胺和磷酸溶解在适宜溶剂中；(1) dissolving tenofovir alafenamide and phosphoric acid in a suitable solvent;
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；(3) separating the precipitated solid;
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried.
上述制备方法步骤(1)中，所述“适宜溶剂”选自乙腈、甲醇、乙醇、异丙醇、四氢呋喃、丙酮、二氯甲烷、三氯甲烷、甲苯等或它们的混合物，优选为乙腈。所述适宜溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1。In the above production method step (1), the "suitable solvent" is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile. The weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
上述制备方法步骤(1)中，替诺福韦艾拉酚胺与磷酸的投料摩尔比一般0.5:1～1.5:1，优选0.8:1～1.2:1。In the above preparation method step (1), the molar ratio of tenofovir alafenamide to phosphoric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
上述制备方法步骤(2)中，所述“析出固体”的方法为本技术领域内常规的方法，如冷却，加入反溶剂，浓缩出部分溶剂体、加晶种等方法的单用或联用。析出固体过程可以是静置的，也可是搅拌的。In the above preparation method step (2), the method of "precipitating solid" is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination. . The solids precipitation process can be either standing or agitated.
上述制备方法步骤(3)中，所述“分离”可以采用过滤等本技术领域内的常规方法。可选地，可以用步骤(1)中的适宜溶剂对所收集的固体进行洗涤。In the above production method step (3), the "separation" may employ a conventional method in the art such as filtration. Alternatively, the collected solids may be washed with a suitable solvent in step (1).
上述制备方法步骤(4)中，所述“干燥”方式包括常压干燥、减压干燥或它们的组合应用。“进一步纯化”的方法包括重结晶、浆化、洗涤等形式。In the above preparation method step (4), the "drying" method includes atmospheric drying, reduced pressure drying or a combination thereof. Methods for "further purification" include recrystallization, slurrying, washing, and the like.
上述方法步骤(4)中，“干燥”的温度一般为20～120℃，优选30～80℃；可以常压干燥，也可以减压干燥。In the above step (4), the temperature of "drying" is generally 20 to 120 ° C, preferably 30 to 80 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
该实施方案所制备的磷酸替诺福韦艾拉酚胺(1:1)是一种晶体。Tenofovir enalap phosphate (1:1) prepared in this embodiment is a crystal.
因此，本发明提供了一种磷酸替诺福韦艾拉酚胺(1:1)的晶型(为了表述方便，将该晶型称为“磷酸替诺福韦艾拉酚胺(1:1)晶型A”)。该晶型的X-射线粉末衍射图谱(使用Cu-Kα辐射)的特征为：在2θ值为8.0°±0.2°、9.4°±0.2°、10.6°±0.2°、14.5°±0.2°、19.3°±0.2°、21.1°±0.2°、23.4°±0.2°等处对应有特征衍射峰。Accordingly, the present invention provides a crystalline form of tenofovir alafenamide (1:1) (for convenience of presentation, the crystal form is referred to as "tenofovir alafenol phosphate (1:1) ) Crystal form A"). The X-ray powder diffraction pattern of the crystal form (using Cu-Kα radiation) is characterized by a value of 2θ of 8.0°±0.2°, 9.4°±0.2°, 10.6°±0.2°, 14.5°±0.2°, 19.3. Characteristic diffraction peaks correspond to °±0.2°, 21.1°±0.2°, 23.4°±0.2°, etc.
在一具体实施方案中，本发明所诉的磷酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末 衍射图谱的特征为：在2θ值为8.0°±0.2°、9.4°±0.2°、10.6°±0.2°、14.5°±0.2°、15.9°±0.2°、17.0°±0.2°、17.6°±0.2°、18.6°±0.2°、19.3°±0.2°、21.1°±0.2°、23.4°±0.2°等处对应有特征衍射峰。In a specific embodiment, the X-ray powder of tenofovir alafenamide (1:1) crystal form A of the present invention is claimed. The diffraction pattern is characterized by: 2θ values of 8.0°±0.2°, 9.4°±0.2°, 10.6°±0.2°, 14.5°±0.2°, 15.9°±0.2°, 17.0°±0.2°, 17.6°±0.2 Characteristic diffraction peaks are corresponding to °, 18.6 ° ± 0.2 °, 19.3 ° ± 0.2 °, 21.1 ° ± 0.2 °, 23.4 ° ± 0.2 °.
进一步地，本发明所述的磷酸替诺福韦艾拉酚胺(1:1)晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征衍射峰及相对强度：Further, the X-ray powder diffraction pattern of the tenofovir alafenamide (1:1) crystal form A of the present invention represented by the 2θ angle has characteristic diffraction peaks and relative intensities at the following positions:
2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
7.0°±0.2°7.0°±0.2° 77 18.6°±0.2°18.6°±0.2° 2828
8.0°±0.2°8.0°±0.2° 7575 19.3°±0.2°19.3°±0.2° 3939
9.4°±0.2°9.4°±0.2° 6565 19.8°±0.2°19.8°±0.2° 88
10.6°±0.2°10.6°±0.2° 3636 21.1°±0.2°21.1°±0.2° 4343
11.8°±0.2°11.8°±0.2° 77 22.9°±0.2°22.9°±0.2° 1111
14.5°±0.2°14.5°±0.2° 100100 23.4°±0.2°23.4°±0.2° 4040
15.5°±0.2°15.5°±0.2° 99 23.9°±0.2°23.9°±0.2° 1313
15.9°±0.2°15.9°±0.2° 2727 25.5°±0.2°25.5°±0.2° 88
17.0°±0.2°17.0°±0.2° 22twenty two 26.3°±0.2°26.3°±0.2° 1111
17.6°±0.2°17.6°±0.2° 3232    
在一具体实施方案中，本发明提供的磷酸替诺福韦艾拉酚胺(1:1)晶型A具有如图8所示的X-射线粉末衍射图谱所代表的特征。In a specific embodiment, the present invention provides tenofovir alafenamide (1:1) Form A having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
在一具体实施方案中，本发明提供的制备磷酸替诺福韦艾拉酚胺(1:1)混合物中磷酸替诺福韦艾拉酚胺(1:1)晶型A含量(质量含量)一般大于70％，优选大于80％，最优选大于90％。In a specific embodiment, the present invention provides a tenofovir 137 (1:1) crystal form A content (mass content) of a mixture of tenofovir alafenamide (1:1). Generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本领域技术人员可以理解的是，本发明所述的磷酸替诺福韦艾拉酚胺(1:1)混合物指的是用化学合成方法直接合成制备的含有其他杂质或晶型的磷酸替诺福韦艾拉酚胺(1:1)。It will be understood by those skilled in the art that the tenofovir enalapraphosphate (1:1) mixture of the present invention refers to a phosphonium tetrachloride containing other impurities or crystal forms which is directly synthesized by chemical synthesis. Fuviralolamine (1:1).
在一具体实施方案中，本发明的磷酸替诺福韦艾拉酚胺(1:1)晶型A的制备方法包括：In a specific embodiment, the method for preparing tenofovir alafenamide (1:1) crystal form A of the present invention comprises:
(1)将替诺福韦艾拉酚胺和磷酸溶解在乙腈中；所述溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1。替诺福韦艾拉酚胺与磷酸的投料摩尔比一般0.5:1～1.5:1，优选0.8:1～1.2:1。(1) Tenofovir alafenamide and phosphoric acid are dissolved in acetonitrile; the weight ratio of the solvent to tenofovir alafenamide is generally from 5:1 to 80:1. The molar ratio of tenofovir alafenamide to phosphoric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；可选地，可以用乙腈对所收集的固体进行洗涤。(3) Separating the precipitated solid; alternatively, the collected solid may be washed with acetonitrile.
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。干燥温度一般为20～120℃，优选30～80℃；可以常压干燥，也可以减压干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried. The drying temperature is usually 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
硫酸替诺福韦艾拉酚胺(1:1)Tenofovir alafenamide (1:1)
在一实施方案中，式Ⅱ中，n选为1，X选为硫酸，即提供了替诺福韦艾拉酚胺与硫酸以1:1摩尔组成比形成的复合物，称为“硫酸替诺福韦艾拉酚胺(1:1)”。 In one embodiment, in Formula II, n is selected to be 1, and X is selected as sulfuric acid, that is, a complex formed by the ratio of tenofovir alafenamide to sulfuric acid in a molar ratio of 1:1 is referred to as "sulfuric acid". Norfoslavamide (1:1)".
在一实施方案中，本发明提供了一种硫酸替诺福韦艾拉酚胺的制备方法，该方法包括：In one embodiment, the invention provides a method of preparing tenofovir alafenol sulfate, the method comprising:
(1)将替诺福韦艾拉酚胺和硫酸溶解在适宜溶剂中；(1) dissolving tenofovir alafenamide and sulfuric acid in a suitable solvent;
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；(3) separating the precipitated solid;
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried.
上述制备方法步骤(1)中，所述“适宜溶剂”选自乙腈、甲醇、乙醇、异丙醇、四氢呋喃、丙酮、二氯甲烷、三氯甲烷、甲苯等或它们的混合物，优选为乙腈。所述适宜溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1。In the above production method step (1), the "suitable solvent" is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile. The weight ratio of the suitable solvent to tenofovir alafenamide is generally from 5:1 to 80:1.
上述制备方法步骤(1)中，替诺福韦艾拉酚胺与硫酸的投料摩尔比一般0.5:1～1.5:1，优选0.8:1～1.2:1。In the above preparation method step (1), the molar ratio of tenofovir alafenamide to sulfuric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
上述制备方法步骤(2)中，所述“析出固体”的方法为本技术领域内常规的方法，如冷却，加入反溶剂，浓缩出部分溶剂体、加晶种等方法的单用或联用。析出固体过程可以是静置的，也可是搅拌的。In the above preparation method step (2), the method of "precipitating solid" is a conventional method in the technical field, such as cooling, adding an anti-solvent, concentrating a part of a solvent body, adding a seed crystal, etc., alone or in combination. . The solids precipitation process can be either standing or agitated.
上述制备方法步骤(3)中，所述“分离”可以采用过滤等本技术领域内的常规方法。可选地，可以用步骤(1)中的适宜溶剂对所收集的固体进行洗涤。In the above production method step (3), the "separation" may employ a conventional method in the art such as filtration. Alternatively, the collected solids may be washed with a suitable solvent in step (1).
上述制备方法步骤(4)中，所述“干燥”方式包括常压干燥、减压干燥或它们的组合应用。“进一步纯化”的方法包括重结晶、浆化、洗涤等形式。In the above preparation method step (4), the "drying" method includes atmospheric drying, reduced pressure drying or a combination thereof. Methods for "further purification" include recrystallization, slurrying, washing, and the like.
上述方法步骤(4)中，“干燥”的温度一般为20～120℃，优选30～80℃；可以常压干燥，也可以减压干燥。In the above step (4), the temperature of "drying" is generally 20 to 120 ° C, preferably 30 to 80 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
该实施方案所制备的硫酸替诺福韦艾拉酚胺(1:1)是一种晶体。Tenofovir lysamine sulfate (1:1) prepared in this embodiment is a crystal.
因此，本发明提供了一种硫酸替诺福韦艾拉酚胺(1:1)的晶型(为了表述方便，将该晶型称为“硫酸替诺福韦艾拉酚胺(1:1)晶型A”)。该晶型的X-射线粉末衍射图谱(使用Cu-Kα辐射)的特征为：在2θ值为9.2°±0.2°、10.7°±0.2°、11.1°±0.2°、18.4°±0.2°、19.8°±0.2°、22.3°±0.2°、24.3°±0.2°等处对应有特征衍射峰。Accordingly, the present invention provides a crystalline form of tenofovir alafenamide (1:1) (for convenience of description, the crystal form is referred to as "tenofovir alafenol sulfate (1:1) ) Crystal form A"). The X-ray powder diffraction pattern of the crystal form (using Cu-Kα radiation) is characterized by a value of 2θ of 9.2°±0.2°, 10.7°±0.2°, 11.1°±0.2°, 18.4°±0.2°, 19.8. Characteristic diffraction peaks correspond to °±0.2°, 22.3°±0.2°, and 24.3°±0.2°.
在一具体实施方案中，本发明所诉的硫酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱的特征为：在2θ值为9.2°±0.2°、10.7°±0.2°、11.1°±0.2°、16.9°±0.2°、18.4°±0.2°、19.2°±0.2°、19.8°±0.2°、21.7°±0.2°、22.3°±0.2°、23.1°±0.2°、24.3°±0.2°、28.1°±0.2°、31.1°±0.2°等处对应有特征衍射峰。In a specific embodiment, the X-ray powder diffraction pattern of tenofovir alafenamide (1:1) crystal form A of the present invention is characterized by a value of 9.2 ° ± 0.2 ° at a 2θ value, 10.7°±0.2°, 11.1°±0.2°, 16.9°±0.2°, 18.4°±0.2°, 19.2°±0.2°, 19.8°±0.2°, 21.7°±0.2°, 22.3°±0.2°, 23.1° Characteristic diffraction peaks correspond to ±0.2°, 24.3°±0.2°, 28.1°±0.2°, 31.1°±0.2°.
进一步地，本发明所述的硫酸替诺福韦艾拉酚胺(1:1)晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征衍射峰及相对强度： Further, the X-ray powder diffraction pattern of the tenofovir alafenamide (1:1) crystal form A of the present invention represented by the 2θ angle has characteristic diffraction peaks and relative intensities at the following positions:
2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
9.2°±0.2°9.2°±0.2° 5959 21.5°±0.2°21.5°±0.2° 1414
10.7°±0.2°10.7°±0.2° 4141 21.7°±0.2°21.7°±0.2° 1717
11.1°±0.2°11.1°±0.2° 4545 22.3°±0.2°22.3°±0.2° 5050
16.6°±0.2°16.6°±0.2° 2020 23.1°±0.2°23.1°±0.2° 3232
16.9°±0.2°16.9°±0.2° 2020 24.3°±0.2°24.3°±0.2° 5151
17.2°±0.2°17.2°±0.2° 1212 25.1°±0.2°25.1°±0.2° 1111
17.9°±0.2°17.9°±0.2° 22twenty two 25.7°±0.2°25.7°±0.2° 99
18.4°±0.2°18.4°±0.2° 100100 27.4°±0.2°27.4°±0.2° 99
19.2°±0.2°19.2°±0.2° 2525 28.1°±0.2°28.1°±0.2° 23twenty three
19.8°±0.2°19.8°±0.2° 5454 29.3°±0.2°29.3°±0.2° 1010
20.0°±0.2°20.0°±0.2° 21twenty one 31.1°±0.2°31.1°±0.2° 22twenty two
在一具体实施方案中，本发明提供的硫酸替诺福韦艾拉酚胺(1:1)晶型A具有如图9所示的X-射线粉末衍射图谱所代表的特征。In a specific embodiment, the present invention provides tenofovir alafenamide (1:1) Form A having the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
在一具体实施方案中，本发明提供的制备的硫酸替诺福韦艾拉酚胺(1:1)混合物中硫酸替诺福韦艾拉酚胺(1:1)晶型A含量(质量含量)一般大于70％，优选大于80％，最优选大于90％。In a specific embodiment, the tenofovir alafenamide (1:1) crystalline form A content (mass content) of the prepared tenofovir alafenamide (1:1) mixture provided by the present invention ) generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本领域技术人员可以理解的是，本发明所述的硫酸替诺福韦艾拉酚胺(1:1)混合物指的是用化学合成方法直接合成制备的含有其他杂质或晶型的硫酸替诺福韦艾拉酚胺(1:1)。It will be understood by those skilled in the art that the tenofovir enalapramate (1:1) mixture of the present invention refers to a thiosulfate containing other impurities or crystal forms directly synthesized by chemical synthesis. Fuviralolamine (1:1).
在一具体实施方案中，本发明的硫酸替诺福韦艾拉酚胺(1:1)晶型A的制备方法包括：In a specific embodiment, the method for preparing tenofovir alafenamide (1:1) Form A of the present invention comprises:
(1)将替诺福韦艾拉酚胺和硫酸溶解在乙腈中；所述溶剂与替诺福韦艾拉酚胺的重量比一般为5:1～80:1。替诺福韦艾拉酚胺与硫酸的投料摩尔比一般0.5:1～1.5:1，优选0.8:1～1.2:1。(1) Tenofovir alafenamide and sulfuric acid are dissolved in acetonitrile; the weight ratio of the solvent to tenofovir alafenamide is generally from 5:1 to 80:1. The molar ratio of tenofovir alafenamide to sulfuric acid is generally from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1.
(2)析出固体；(2) precipitation of solids;
(3)分离所析出的固体；可选地，可以用乙腈对所收集的固体进行洗涤。(3) Separating the precipitated solid; alternatively, the collected solid may be washed with acetonitrile.
(4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。干燥温度一般为20～120℃，优选30～80℃；可以常压干燥，也可以减压干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried. The drying temperature is usually 20 to 120 ° C, preferably 30 to 80 ° C; it can be dried at normal pressure or dried under reduced pressure.
根据本发明的目的，本发明提供了包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物或所述制备方法制得的替诺福韦艾拉酚胺复合物以及药用辅料的药物组合物或制剂。In accordance with the purpose of the present invention, the present invention provides a tenofovir alafenamide complex comprising a therapeutically effective amount of the tenofovir alafenamide complex of Formula II or the method of preparation, and a pharmaceutical A pharmaceutical composition or formulation of an excipient.
可选地，上述药物组合物或制剂还可以进一步包括另一种或多种抗病毒剂或抗病毒辅助试剂，包括但不限于恩曲他滨、拉米夫定、阿巴卡韦(Abacavir)、醋孟南(Acemannan)、安普那韦(Ainprenavir)、安普那韦(Amprenavir)、阿扎那韦(Atazanavir)、克拉夫定(Clevudine)、Cobicistat、达匹韦林(Dapivirine)、地瑞那韦(Darunavir)、地拉韦啶(Delavirdine)、去羟肌苷(Didanosine)、德罗格韦(Dolutegravir)、依法韦仑(Efavirenz)、埃替拉韦(Elvitegravir)、恩夫韦地(Enfuvirtide)、恩替卡韦(Entecavir)、依曲韦林(Etravirine)、泛昔洛韦(Famciclovir)、福 沙那韦(Fosamprenavir)、谷胱甘肽(Glutathione)、茚地那韦(Indidnavir)、左旋咪唑(Levamisole)、洛匹那韦(Lopinavir)、马拉维若(Maraviroc)、奈非那韦(Nelfinavir)、奈韦拉平(Nevirapine)、喷昔洛韦(Penciclovir)、喷他脒(Pentamidine)、Phosphazid、丙帕锗(Propagermanium)、雷特格韦(Raltegravir)、利巴韦林(Ribavirin)、利匹韦林(Rilpivrine)、利托那韦(Ritonavir)、沙奎那韦(Saquinavir)、司他夫定(Stavudine)、替比夫定(Telbivudine)、替拉那韦(Tipranavir)、伏立诺他(Vorinostat)、扎西他滨(Zalcitabine)、齐多夫定(Zidovudine)等或它们的药用盐，其中优选恩曲他滨、拉米夫定、Cobicistat、地瑞那韦、依法韦仑、埃替拉韦、盐酸利匹韦林。Alternatively, the above pharmaceutical composition or formulation may further comprise another or more antiviral agents or antiviral auxiliary agents including, but not limited to, emtricitabine, lamivudine, and abacavir (Abacavir). , Acemannan, Ainprenavir, Amprenavir, Atazanavir, Clevudine, Cobicistat, Dapivirine, Earth Darunavir, Delavirdine, Didanosine, Dolutegravir, Efavirenz, Elvitegravir, Enfuvirdi (Enfuvirtide), Entecavir, Etravirine, Famciclovir, Fu Fosamprenavir, Glutathione, Indidnavir, Levamisole, Lopinavir, Maraviroc, nelfinavir ( Nelfinavir), Nevirapine, Penciclovir, Pentamidine, Phosphazid, Propagermanium, Raltegravir, Ribavirin, Lippi Rilpivrine, Ritonavir, Saquinavir, Stavudine, Telbivudine, Tipranavir, Vorinostat (Vorinostat), Zalcitabine, Zidovudine, etc. or their pharmaceutically acceptable salts, preferably emtricitabine, lamivudine, Cobicistat, darunavir, efavirenz, Etiravir, lipiride hydrochloride.
优选地，本发明的药物组合物，其选自下列之一：Preferably, the pharmaceutical composition of the invention is selected from one of the following:
包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、恩曲他滨、Cobicistat和埃替拉韦的药物组合物；或者，a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, emtricitabine, Cobicistat, and eritavir; or
包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、恩曲他滨、Cobicistat和地瑞那韦的药物组合物；或者，a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, emtricitabine, Cobicistat, and darunavir; or
包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物和恩曲他滨的药物组合物；或者，a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II and emtricitabine; or
包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、恩曲他滨和依法韦仑的药物组合物；或者，A pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, emtricitabine and efavirenz; or
包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、恩曲他滨和盐酸立匹韦林的药物组合物；或者，a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, emtricitabine and pirimivir hydrochloride; or
包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、拉米夫定的药物组合物；或者，A pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, lamivudine; or
包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、拉米夫定和依法韦仑的药物组合物；或者，A pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, lamivudine and efavirenz; or
包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、拉米夫定、Cobicistat和埃替拉韦的药物组合物；或者，a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, lamivudine, Cobicistat, and ertivir; or
包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、拉米夫定、Cobicistat和地瑞那韦的药物组合物。A pharmaceutical composition comprising a therapeutically effective amount of tenofovir alafenamide complex of formula II, lamivudine, Cobicistat, and darunavir.
在一实施方案中，本发明提供了一种包含治疗有效量的L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)、硫酸替诺福韦艾拉酚胺(1:1)、L- 酒石酸替诺福韦艾拉酚胺(1:2)晶型A、D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A、柠檬酸替诺福韦艾拉酚胺(1:1)晶型A、琥珀酸替诺福韦艾拉酚胺(1:1)晶型A、草酸替诺福韦艾拉酚胺(1:1)晶型A、磷酸替诺福韦艾拉酚胺(1:1)晶型A或硫酸替诺福韦艾拉酚胺(1:1)晶型A和药用辅料的药物组合物或制剂。In one embodiment, the invention provides a therapeutically effective amount of tenofovir lysamine L-tartrate (1:2), ten-tenofovir lysamine D-tartaric acid (1:1) , DL-tenofovir iracrolimum tartrate (1:1), L-malofovir idolavir (1:2), tenofovir iramate citrate (1:1 ), tenofovir alafenamide succinate (1:1), tenofovir oxalatine oxalate (1:1), tenofovir enalapenoate (1:1), sulfate Norfoslavamide (1:1), L- Tenofovir lysamine tartrate (1:2) Form A, D-tenofovir iramol tartrate (1:1) Form A, DL-tenofovir alafenamide 1:1) Form A, L-Tanofovir alafenamide (1:2) Form A, Tenofovir iramol citrate (1:1) Form A, succinic acid Tenofovir alafenamide (1:1) Form A, tenofovir oxalatine oxalate (1:1) Form A, tenofovir ylide (1:1) crystal A pharmaceutical composition or formulation of Form A or tenofovir alafenamide (1:1) Form A and a pharmaceutical excipient.
上述药物组合物或制剂可经口或不经口给药。经口服给药时，可采用常规的制剂技术制成片剂、胶囊剂、丸剂、颗粒剂、溶液剂、糖浆剂、混悬剂、散剂、缓释制剂或控释制剂等。非经口服给药时，可采用常规的制剂技术将其制成透皮制剂、注射液、输液剂或栓剂等。The above pharmaceutical compositions or preparations can be administered orally or parenterally. When administered orally, tablets, capsules, pills, granules, solutions, syrups, suspensions, powders, sustained release preparations or controlled release preparations can be prepared by conventional formulation techniques. When it is not administered orally, it can be made into a transdermal preparation, an injection, an infusion solution or a suppository by a conventional formulation technique.
上述药物组合物的各种剂型可以按照药学领域的常规方法制备。例如将治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物(比如L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)、硫酸替诺福韦艾拉酚胺(1:1)、L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A、D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A、柠檬酸替诺福韦艾拉酚胺(1:1)晶型A、琥珀酸替诺福韦艾拉酚胺(1:1)晶型A、草酸替诺福韦艾拉酚胺(1:1)晶型A、磷酸替诺福韦艾拉酚胺(1:1)晶型A或硫酸替诺福韦艾拉酚胺(1:1)晶型A)，可选地与另一种或多种治疗有效量的活性成分，与一种或多种药用辅料混合或接触，然后将其制成所需的剂型。Various dosage forms of the above pharmaceutical compositions can be prepared according to conventional methods in the pharmaceutical field. For example, a therapeutically effective amount of tenofovir alafenamide compound of formula II (such as L-tenofovir lysamine L-tartaric acid (1:2), D-tenofovir lysine D-tartaric acid) Amine (1:1), DL-tenofovir idylamine tartrate (1:1), tenofovir ilafenamide (1:2), tenofovira citrate Phenolamine (1:1), tenofovir iramolamine succinate (1:1), tenofovir oxalatine oxalate (1:1), tenofovir alafenamide (1) :1), Tenofovir alafenamide (1:1), L-tanofosyl alafenamide (1:2) Form A, D-tenofovir alafenamide (1:1) Form A, DL- tenofovir iracrolimide tartrate (1:1) Form A, L-tanofovir alafenamide (1:2) Form A, L-malate Tenofovir iramol citrate (1:1) Form A, tenofovir iramol succinate (1:1) Form A, tenofovir alafenamide (1: 1) Form A, tenofovir alafenamide (1:1) Form A or tenofovir alafenamide (1:1) Form A), optionally with another Or a plurality of therapeutically effective amounts of the active ingredient, mixed or contacted with one or more pharmaceutical excipients, It is made into the desired formulation.
上述药物组合物或制剂优选口服剂型，包括片剂、胶囊剂、丸剂、颗粒剂、溶液剂、糖浆剂、干混悬剂、混悬剂、散剂、缓释制剂或控释制剂等。其中优选片剂、胶囊剂、颗粒剂、干混悬剂以及缓释制剂或控释制剂等固体口服制剂，其中更优选片剂和胶囊剂。可以按照制备固体口服制剂所采用的任何一种常规方法来制备本发明优选的药物组合物或制剂。如片剂可采用湿法制粒压片等方式制备，可根据需要进行任意形式的包衣，如片剂可以制成任意释放形式(如速释、肠溶和缓控释等)；胶囊剂可采用湿法制粒装胶囊剂等方式制备，胶囊剂内容物可以制成任意释放形式(如速释制剂、肠溶制剂和缓控释制剂等)。The above pharmaceutical composition or preparation is preferably an oral dosage form including a tablet, a capsule, a pill, a granule, a solution, a syrup, a dry suspension, a suspension, a powder, a sustained release preparation or a controlled release preparation. Among them, solid oral preparations such as tablets, capsules, granules, dry suspensions, and sustained release preparations or controlled release preparations are preferred, and tablets and capsules are more preferred. The preferred pharmaceutical compositions or formulations of the present invention can be prepared according to any of the conventional methods employed in the preparation of solid oral formulations. If the tablet can be prepared by wet granulation tableting, etc., any form of coating can be carried out according to need, such as tablets can be made into any release form (such as immediate release, enteric and controlled release, etc.); capsules can be used It can be prepared by wet granulation capsule preparation, etc., and the capsule contents can be prepared into any release form (such as immediate release preparation, enteric preparation and controlled release preparation, etc.).
在一实施方案中，本发明提供的式Ⅱ所示的替诺福韦艾拉酚胺复合物(比如L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)、硫酸替诺福韦 艾拉酚胺(1:1)、L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A、D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A、柠檬酸替诺福韦艾拉酚胺(1:1)晶型A、琥珀酸替诺福韦艾拉酚胺(1:1)晶型A、草酸替诺福韦艾拉酚胺(1:1)晶型A、磷酸替诺福韦艾拉酚胺(1:1)晶型A或硫酸替诺福韦艾拉酚胺(1:1)晶型A)的粒径分布控制在95％小于200μm,优选小于180μm，再优选小于150μm，更优选小于100μm。In one embodiment, the present invention provides a tenofovir alafenamide complex of Formula II (such as L-tenofovir lysamine (1:2), D-tartrate D-tartaric acid Vesalamine (1:1), DL-tenofovir iracrolimum tartrate (1:1), tenofovir ialafen L-malate (1:2), citric acid titanoate Fuviralilamine (1:1), tenofovir iramol succinate (1:1), tenofovir oxalatine oxalate (1:1), tenofoviraine phosphate Phenolamine (1:1), tenofovir sulfate Iratonamine (1:1), Tenofovir alafenamide (1:2) Form A, D-tenofovir iramolamine (1:1) Form A, DL-tenofovir iracrolimide tartrate (1:1) crystal form A, L-tanofovir alafenamide (1:2) crystal form A, tenofovir eugenol citrate Amine (1:1) Form A, tenofovir alafenamide (1:1) Form A, tenofovir oxalinamide (1:1) Form A, Phosphate Tino The particle size distribution of fosmein (1:1) Form A or tenofovir alafenamide (1:1) Form A) is controlled to be 95% less than 200 μm, preferably less than 180 μm, and further preferably It is less than 150 μm, more preferably less than 100 μm.
在口服剂型中本领域常规的药用辅料，包括填充剂、崩解剂、粘合剂、分散剂、润滑剂或助留剂以及各类型的包衣材料等。Pharmaceutical excipients conventional in the art in oral dosage forms include fillers, disintegrants, binders, dispersants, lubricants or retention aids, as well as various types of coating materials and the like.
所述填充剂一般包括预胶化淀粉、淀粉、乳糖、糊精、磷酸氢钙、碳酸钙、甘露醇、微晶纤维素、山梨醇、葡萄糖等，它们可以单独使用也可以混合使用，其中优选预胶化淀粉、乳糖、微晶纤维素、甘露醇。The filler generally comprises pregelatinized starch, starch, lactose, dextrin, calcium hydrogen phosphate, calcium carbonate, mannitol, microcrystalline cellulose, sorbitol, glucose, etc., which may be used singly or in combination, and preferably Pregelatinized starch, lactose, microcrystalline cellulose, mannitol.
所述崩解剂一般包括交联羧甲纤维素钠、羧甲基纤维素钠、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、淀粉、微晶纤维素、低取代羟丙基纤维素等，它们可以单独使用也可以混合使用，其中优选为交联羧甲纤维素钠、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、微晶纤维素、低取代羟丙基纤维素。The disintegrant generally comprises croscarmellose sodium, sodium carboxymethylcellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and the like. They may be used singly or in combination, and among them, croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, microcrystalline cellulose, and low-substituted hydroxypropylcellulose are preferable.
所述粘合剂一般包括微晶纤维素、预胶化淀粉、羟丙基甲基纤维素、羟丙基纤维素、聚维酮、淀粉浆、阿拉伯胶、聚乙二醇4000、聚乙烯醇、藻酸盐、水、各种浓度的乙醇溶液，它们可以单独使用也可以混合使用，其中优选羟丙基甲基纤维素、羟丙纤维素、聚维酮、淀粉浆。The binder generally comprises microcrystalline cellulose, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropylcellulose, povidone, starch syrup, gum arabic, polyethylene glycol 4000, polyvinyl alcohol Alginate, water, various concentrations of ethanol solution, which may be used singly or in combination, of which hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, and starch syrup are preferred.
所述润滑剂一般包括硬脂酸镁、硬脂酸、硬脂酸钙、硬脂酸富马酸钠、硬脂酸富马酸钾、棕榈酸、微粉硅胶、硬脂酰胺、滑石粉、固体聚乙二醇、三乙酸甘油酯等。它们可以单独使用也可以混合使用，其中优选硬脂酸镁、硬脂酸、滑石粉、微粉硅胶、三乙酸甘油酯。The lubricant generally comprises magnesium stearate, stearic acid, calcium stearate, sodium stearate, sodium stearate, palmitic acid, micronized silica gel, stearic acid amide, talc, solid. Polyethylene glycol, triacetin, and the like. They may be used singly or in combination, and among them, magnesium stearate, stearic acid, talc, micronized silica gel, and triacetin are preferable.
如果需要，还可以向上述组合物或制剂中添加其他辅料，如甜味剂(如阿司帕坦、甜菊素等)、着色剂(如柠檬黄、氧化铁等各种药用或食用色素)、稳定剂(如碳酸钙、碳酸氢钙、碳酸氢钠、碳酸钠、磷酸钙、磷酸氢钙、甘氨酸等)、表面活性剂(如吐温80、十二烷基硫酸钠等)包衣材料(如欧巴代，羟丙基甲基纤维素、羟丙基纤维素、丙烯酸树脂共聚物等。If necessary, other excipients such as sweeteners (such as aspartame, stevioside, etc.) and coloring agents (such as various medicinal or food colors such as tartrazine and iron oxide) may be added to the above composition or preparation. Stabilizers (such as calcium carbonate, calcium bicarbonate, sodium bicarbonate, sodium carbonate, calcium phosphate, calcium hydrogen phosphate, glycine, etc.), surfactants (such as Tween 80, sodium lauryl sulfate, etc.) coating materials (eg Opadry, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acrylic resin copolymers, etc.).
在一具体实施方案中，本发明提供了一种单方组合物或制剂，其中活性成分选自治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物(比如L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾 拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)、硫酸替诺福韦艾拉酚胺(1:1)、L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A、D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A、柠檬酸替诺福韦艾拉酚胺(1:1)晶型A、琥珀酸替诺福韦艾拉酚胺(1:1)晶型A、草酸替诺福韦艾拉酚胺(1:1)晶型A、磷酸替诺福韦艾拉酚胺(1:1)晶型A或硫酸替诺福韦艾拉酚胺(1:1)晶型A)。该组合物或制剂优选口服制剂，更优选片剂或胶囊剂；在单位组合物或制剂中，它们的重量含量一般为1mg至200mg，优选5mg至100mg，例如以替诺福韦艾拉酚胺计，重量含量为约10mg、约12.5mg、约25mg或约50mg，其中“约”指±10％的范围，优选±5％的范围。In a specific embodiment, the invention provides a single composition or formulation wherein the active ingredient is selected from a therapeutically effective amount of a tenofovir alafenamide complex of formula II (eg, L-tartrate tinoate) Fouevirapide (1:2), D-tenofovir idylamine tartrate (1:1), DL-tenofovir idylamine tartrate (1:1), L-malic acid Tenofowe Lauramine (1:2), tenofovir eugenol citrate (1:1), tenofovir iramol succinate (1:1), tenofovir alafenamide (1:1), Tenofovir iramolamine phosphate (1:1), tenofovir alafenamide (1:1), and ten-tenofovir alafenamide (1: 2) Form A, D- tenofovir iraline tartrate (1:1) Form A, DL-tenofovir iraline tartrate (1:1) Form A, L-malic acid Tenofovir alafenamide (1:2) Form A, tenofovir alafenamide (1:1) Form A, tenofovir alafenamide (1:1) Crystalline A, tenofovir oxalatine oxalate (1:1) Form A, tenofovir alafenamide (1:1) Form A or tenofovir alafenamide (1:1) Form A). The composition or formulation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are usually present in an amount of from 1 mg to 200 mg, preferably from 5 mg to 100 mg, for example, tenofovir alafenamide The weight content is about 10 mg, about 12.5 mg, about 25 mg or about 50 mg, wherein "about" refers to a range of ± 10%, preferably ± 5%.
在一具体实施方案中，本发明提供了一种复方组合物或制剂，其中第一活性成分选自治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物(比如L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)、硫酸替诺福韦艾拉酚胺(1:1)、L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A、D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A、柠檬酸替诺福韦艾拉酚胺(1:1)晶型A、琥珀酸替诺福韦艾拉酚胺(1:1)晶型A、草酸替诺福韦艾拉酚胺(1:1)晶型A、磷酸替诺福韦艾拉酚胺(1:1)晶型A或硫酸替诺福韦艾拉酚胺(1:1)晶型A)，第二活性成分为治疗有效量的恩曲他滨，第三活性成分为治疗有效量的Cobicistat，第四活性成分为治疗有效量的埃替拉韦。该组合物或制剂优选口服制剂，更优选片剂或胶囊剂；在单位组合物或制剂中，它们各自的重量含量一般为1mg至500mg，优选5mg至300mg，例如含上述第一活性成分约10mg或约25mg(以替诺福韦艾拉酚胺计)、第二活性成分(恩曲他滨)约200mg、第三活性成分(Cobicistat)约150mg和第四活性成分(埃替拉韦)约150mg，其中“约”指±10％的范围，优选±5％的范围。In a specific embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II. Tenofovir alafenamide (1:2), D-norofovir idylamine tartrate (1:1), DL-tenofovir idylamine tartrate (1:1), L- Tenofovir alafenamide (1:2), tenofovir iramol citrate (1:1), tenofovir alafenamide (1:1), oxalic acid Norfoslavamide (1:1), tenofovir iramol phosphate (1:1), tenofovir iramol sulfate (1:1), L-tenofovir t-tartrate ILa phenolamine (1:2) crystal form A, D- tenofovir iramate tartrate (1:1) crystal form A, DL-tenofovir iramate (1:1) crystal Type A, L-malofovir alafenamide (1:2) Form A, tenofovir iramol citrate (1:1) Form A, tenofovir succinate Lactophene (1:1) Form A, tenofovir oxalatine oxalate (1:1) Form A, tenofovir ylide (1:1) crystal form A or sulfate Norfoslavamide (1:1) crystal form A), second activity Into a therapeutically effective amount of emtricitabine, the third active ingredient is a therapeutically effective amount of Cobicistat, the fourth active ingredient is a therapeutically effective amount of elvitegravir. The composition or formulation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, each is usually present in an amount of from 1 mg to 500 mg, preferably from 5 mg to 300 mg, for example, containing about 10 mg of the above first active ingredient. Or about 25 mg (based on tenofovir alaflurane), about 200 mg of the second active ingredient (entecitabine), about 150 mg of the third active ingredient (Cobicistat), and about the fourth active ingredient (etiravir). 150 mg, wherein "about" refers to a range of ± 10%, preferably ± 5%.
在一具体实施方案中，本发明提供了一种复方组合物或制剂，其中第一活性成分选自治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物(比如L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)、硫酸替诺福韦艾拉酚胺(1:1)、L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A、D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、DL-酒石 酸替诺福韦艾拉酚胺(1:1)晶型A、L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A、柠檬酸替诺福韦艾拉酚胺(1:1)晶型A、琥珀酸替诺福韦艾拉酚胺(1:1)晶型A、草酸替诺福韦艾拉酚胺(1:1)晶型A、磷酸替诺福韦艾拉酚胺(1:1)晶型A或硫酸替诺福韦艾拉酚胺(1:1)晶型A)，第二活性成分为治疗有效量的恩曲他滨，第三活性成分为治疗有效量的Cobicistat，第四活性成分为治疗有效量的地瑞那韦。该组合物或制剂优选口服制剂，更优选片剂和胶囊剂；在单位组合物或制剂中，它们各自的重量含量一般为1mg至1000mg，优选5mg至900mg，例如含上述第一活性成分约10mg或约25mg(以替诺福韦艾拉酚胺计)、第二活性成分(恩曲他滨)约200mg、第三活性成分(Cobicistat)约150mg和第四活性成分(地瑞那韦)约800mg，其中“约”指±10％的范围，优选±5％的范围。In a specific embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II. Tenofovir alafenamide (1:2), D-norofovir idylamine tartrate (1:1), DL-tenofovir idylamine tartrate (1:1), L- Tenofovir alafenamide (1:2), tenofovir iramol citrate (1:1), tenofovir alafenamide (1:1), oxalic acid Norfoslavamide (1:1), tenofovir iramol phosphate (1:1), tenofovir iramol sulfate (1:1), L-tenofovir t-tartrate ILa phenolamine (1:2) crystal form A, D- tenofovir alafenamide (1:1) crystal form A, DL-tartar Acid tenofovir alafenamide (1:1) crystal form A, L-malofovir alafenamide (1:2) crystal form A, tenofovir eugenol citrate ( 1:1) Form A, tenofovir alafenamide (1:1) Form A, tenofovir oxalatine oxalate (1:1) Form A, tenofovir phosphate Iratonamine (1:1) Form A or tenofovir alafenamide (1:1) Form A), the second active ingredient is a therapeutically effective amount of emtricitabine, the third active ingredient For a therapeutically effective amount of Cobicistat, the fourth active ingredient is a therapeutically effective amount of darinavir. The composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, each of them is usually present in an amount of from 1 mg to 1000 mg, preferably from 5 mg to 900 mg, for example, containing about 10 mg of the above-mentioned first active ingredient. Or about 25 mg (based on tenofovir alafenamide), about 200 mg of the second active ingredient (encindabine), about 150 mg of the third active ingredient (Cobicistat), and about the fourth active ingredient (darinavir). 800 mg, wherein "about" means a range of ± 10%, preferably ± 5%.
在一具体实施方案中，本发明提供了一种复方组合物或制剂，其中第一活性成分选自治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物(比如L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)、硫酸替诺福韦艾拉酚胺(1:1)、L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A、D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A、柠檬酸替诺福韦艾拉酚胺(1:1)晶型A、琥珀酸替诺福韦艾拉酚胺(1:1)晶型A、草酸替诺福韦艾拉酚胺(1:1)晶型A、磷酸替诺福韦艾拉酚胺(1:1)晶型A或硫酸替诺福韦艾拉酚胺(1:1)晶型A)，第二活性成分为治疗有效量的恩曲他滨。该组合物或制剂优选口服制剂，更优选片剂和胶囊剂；在单位组合物或制剂中，它们各自的重量含量一般为1mg至500mg，优选5mg至300mg，例如含上述第一活性成分约10mg或约25mg(以替诺福韦艾拉酚胺计)和第二活性成分(恩曲他滨)约200mg，其中“约”指±10％的范围，优选±5％的范围。In a specific embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II. Tenofovir alafenamide (1:2), D-norofovir idylamine tartrate (1:1), DL-tenofovir idylamine tartrate (1:1), L- Tenofovir alafenamide (1:2), tenofovir iramol citrate (1:1), tenofovir alafenamide (1:1), oxalic acid Norfoslavamide (1:1), tenofovir iramol phosphate (1:1), tenofovir iramol sulfate (1:1), L-tenofovir t-tartrate ILa phenolamine (1:2) crystal form A, D- tenofovir iramate tartrate (1:1) crystal form A, DL-tenofovir iramate (1:1) crystal Type A, L-malofovir alafenamide (1:2) Form A, tenofovir iramol citrate (1:1) Form A, tenofovir succinate Lactophene (1:1) Form A, tenofovir oxalatine oxalate (1:1) Form A, tenofovir ylide (1:1) crystal form A or sulfate Norfoslavamide (1:1) crystal form A), second activity Into a therapeutically effective amount of emtricitabine. The composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, each is usually present in an amount of from 1 mg to 500 mg, preferably from 5 mg to 300 mg, for example, about 10 mg of the above-mentioned first active ingredient. Or about 25 mg (based on tenofovir alafenamide) and a second active ingredient (enstattine) of about 200 mg, wherein "about" refers to a range of ± 10%, preferably ± 5%.
在一具体实施方案中，本发明提供了一种复方组合物或制剂，其中第一活性成分选自治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物(比如L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)、硫酸替诺福韦艾拉酚胺(1:1)、L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A、D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A、柠檬酸替诺福韦艾拉酚胺(1:1)晶型A、琥珀酸替诺福韦艾拉酚胺(1:1)晶型A、草酸替诺福韦艾拉酚胺(1:1) 晶型A、磷酸替诺福韦艾拉酚胺(1:1)晶型A或硫酸替诺福韦艾拉酚胺(1:1)晶型A)，第二活性成分为治疗有效量的恩曲他滨，第三活性成分为治疗有效量的依法韦仑。该组合物或制剂优选口服制剂，更优选片剂和胶囊剂；在单位组合物或制剂中，它们各自的重量含量一般为1mg至800g，优选5mg至700mg，例如含上述第一活性成分约10mg或约25mg(以替诺福韦艾拉酚胺计)、第二活性成分(恩曲他滨)约200mg和第三活性成分(依法韦仑)约600mg，其中“约”指±10％的范围，优选±5％的范围。In a specific embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II. Tenofovir alafenamide (1:2), D-norofovir idylamine tartrate (1:1), DL-tenofovir idylamine tartrate (1:1), L- Tenofovir alafenamide (1:2), tenofovir iramol citrate (1:1), tenofovir alafenamide (1:1), oxalic acid Norfoslavamide (1:1), tenofovir iramol phosphate (1:1), tenofovir iramol sulfate (1:1), L-tenofovir t-tartrate ILa phenolamine (1:2) crystal form A, D- tenofovir iramate tartrate (1:1) crystal form A, DL-tenofovir iramate (1:1) crystal Type A, L-malofovir alafenamide (1:2) Form A, tenofovir iramol citrate (1:1) Form A, tenofovir succinate Lauramine (1:1) Form A, Tenofovir alafenamide (1:1) Form A, tenofovir alafenamide (1:1) Form A or tenofovir alafenamide (1:1) Form A), the second active ingredient is a therapeutically effective amount Emtricitabine, the third active ingredient is a therapeutically effective amount of efavirenz. The composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, each is usually present in an amount of from 1 mg to 800 g, preferably from 5 mg to 700 mg, for example, containing about 10 mg of the above first active ingredient. Or about 25 mg (based on tenofovir alafenamide), about 200 mg of the second active ingredient (enstattine) and about 600 mg of the third active ingredient (efavirenz), wherein "about" means ±10% The range is preferably in the range of ± 5%.
在一具体实施方案中，本发明提供了一种复方组合物或制剂，其中第一活性成分选自治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物(比如L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)、硫酸替诺福韦艾拉酚胺(1:1)、L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A、D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A、柠檬酸替诺福韦艾拉酚胺(1:1)晶型A、琥珀酸替诺福韦艾拉酚胺(1:1)晶型A、草酸替诺福韦艾拉酚胺(1:1)晶型A、磷酸替诺福韦艾拉酚胺(1:1)晶型A或硫酸替诺福韦艾拉酚胺(1:1)晶型A)，第二活性成分为治疗有效量的恩曲他滨，第三活性成分为治疗有效量的盐酸利匹韦林。该组合物或制剂优选口服制剂，更优选片剂和胶囊剂；在单位组合物或制剂中，它们各自的重量含量一般为1mg至500mg，优选5mg至300mg，例如含上述第一活性成分约10mg或约25mg(以替诺福韦艾拉酚胺计)、第二活性成分(恩曲他滨)约200mg和第三活性成分(盐酸利匹韦林)约25mg(以利匹韦林计)，“约”指±10％的范围，优选±5％的范围。In a specific embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II. Tenofovir alafenamide (1:2), D-norofovir idylamine tartrate (1:1), DL-tenofovir idylamine tartrate (1:1), L- Tenofovir alafenamide (1:2), tenofovir iramol citrate (1:1), tenofovir alafenamide (1:1), oxalic acid Norfoslavamide (1:1), tenofovir iramol phosphate (1:1), tenofovir iramol sulfate (1:1), L-tenofovir t-tartrate ILa phenolamine (1:2) crystal form A, D- tenofovir iramate tartrate (1:1) crystal form A, DL-tenofovir iramate (1:1) crystal Type A, L-malofovir alafenamide (1:2) Form A, tenofovir iramol citrate (1:1) Form A, tenofovir succinate Lactophene (1:1) Form A, tenofovir oxalatine oxalate (1:1) Form A, tenofovir ylide (1:1) crystal form A or sulfate Norfoslavamide (1:1) crystal form A), second activity Divided therapeutically effective amount of emtricitabine, the third active ingredient is a therapeutically effective amount of a hydrochloride horse Waring profit. The composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, each is usually present in an amount of from 1 mg to 500 mg, preferably from 5 mg to 300 mg, for example, about 10 mg of the above-mentioned first active ingredient. Or about 25 mg (based on tenofovir alafenamide), about 200 mg of the second active ingredient (emtricitabine) and about 25 mg of the third active ingredient (rivivirine hydrochloride) (in terms of pirimivir) "About" means a range of ±10%, preferably ±5%.
在一具体实施方案中，本发明提供了一种复方组合物或制剂，其中第一活性成分选自治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物(比如L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)、硫酸替诺福韦艾拉酚胺(1:1)、L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A、D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A、柠檬酸替诺福韦艾拉酚胺(1:1)晶型A、琥珀酸替诺福韦艾拉酚胺(1:1)晶型A、草酸替诺福韦艾拉酚胺(1:1)晶型A、磷酸替诺福韦艾拉酚胺(1:1)晶型A或硫酸替诺福韦艾拉酚胺(1:1)晶型A)，第二活性成分为治疗有效量的拉米夫定。该组合物或制剂优选口服制剂，更优选片剂和胶囊剂； 在单位组合物或制剂中，它们各自的重量含量一般为1mg至500mg，优选5mg至400mg，例如含上述第一活性成分约10mg或约25mg(以替诺福韦艾拉酚胺计)和第二活性成分(拉米夫定)约300mg，其中“约”指±10％的范围，优选±5％的范围。In a specific embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II. Tenofovir alafenamide (1:2), D-norofovir idylamine tartrate (1:1), DL-tenofovir idylamine tartrate (1:1), L- Tenofovir alafenamide (1:2), tenofovir iramol citrate (1:1), tenofovir alafenamide (1:1), oxalic acid Norfoslavamide (1:1), tenofovir iramol phosphate (1:1), tenofovir iramol sulfate (1:1), L-tenofovir t-tartrate ILa phenolamine (1:2) crystal form A, D- tenofovir iramate tartrate (1:1) crystal form A, DL-tenofovir iramate (1:1) crystal Type A, L-malofovir alafenamide (1:2) Form A, tenofovir iramol citrate (1:1) Form A, tenofovir succinate Lactophene (1:1) Form A, tenofovir oxalatine oxalate (1:1) Form A, tenofovir ylide (1:1) crystal form A or sulfate Norfoslavamide (1:1) crystal form A), second activity Into a therapeutically effective amount of lamivudine. The composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; In the unit composition or formulation, they are each usually present in an amount of from 1 mg to 500 mg, preferably from 5 mg to 400 mg, for example, containing about 10 mg or about 25 mg of the above first active ingredient (based on tenofovir alafenamide) and The second active ingredient (lamivudine) is about 300 mg, wherein "about" means a range of ±10%, preferably ±5%.
在一具体实施方案中，本发明提供了一种复方组合物或制剂，其中第一活性成分选自治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物(比如L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)、硫酸替诺福韦艾拉酚胺(1:1)、L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A、D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A、柠檬酸替诺福韦艾拉酚胺(1:1)晶型A、琥珀酸替诺福韦艾拉酚胺(1:1)晶型A、草酸替诺福韦艾拉酚胺(1:1)晶型A、磷酸替诺福韦艾拉酚胺(1:1)晶型A或硫酸替诺福韦艾拉酚胺(1:1)晶型A)，第二活性成分为治疗有效量的拉米夫定，第三活性成分为治疗有效量的依法韦仑。该组合物或制剂优选口服制剂，更优选片剂和胶囊剂；在单位组合物或制剂中，它们各自的重量含量一般为1mg至800mg，优选5mg至700mg，例如含上述第一活性成分约10mg或25mg(以替诺福韦艾拉酚胺计)、第二活性成分(拉米夫定)约300mg和第三活性成分(依法韦仑)约600mg，其中“约”指±10％的范围，优选±5％的范围。In a specific embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II. Tenofovir alafenamide (1:2), D-norofovir idylamine tartrate (1:1), DL-tenofovir idylamine tartrate (1:1), L- Tenofovir alafenamide (1:2), tenofovir iramol citrate (1:1), tenofovir alafenamide (1:1), oxalic acid Norfoslavamide (1:1), tenofovir iramol phosphate (1:1), tenofovir iramol sulfate (1:1), L-tenofovir t-tartrate ILa phenolamine (1:2) crystal form A, D- tenofovir iramate tartrate (1:1) crystal form A, DL-tenofovir iramate (1:1) crystal Type A, L-malofovir alafenamide (1:2) Form A, tenofovir iramol citrate (1:1) Form A, tenofovir succinate Lactophene (1:1) Form A, tenofovir oxalatine oxalate (1:1) Form A, tenofovir ylide (1:1) crystal form A or sulfate Norfoslavamide (1:1) crystal form A), second activity Into a therapeutically effective amount of lamivudine, a third active ingredient is a therapeutically effective amount of efavirenz. The composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, each is usually present in an amount of from 1 mg to 800 mg, preferably from 5 mg to 700 mg, for example, about 10 mg of the above-mentioned first active ingredient. Or 25 mg (based on tenofovir alafenamide), about 300 mg of the second active ingredient (lamivudine) and about 600 mg of the third active ingredient (efavirenz), wherein "about" means ±10% of the range Preferably, the range is ± 5%.
在一具体实施方案中，本发明提供了一种复方组合物或制剂，其中第一活性成分选自治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物(比如L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)、硫酸替诺福韦艾拉酚胺(1:1)、L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A、D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A、柠檬酸替诺福韦艾拉酚胺(1:1)晶型A、琥珀酸替诺福韦艾拉酚胺(1:1)晶型A、草酸替诺福韦艾拉酚胺(1:1)晶型A、磷酸替诺福韦艾拉酚胺(1:1)晶型A或硫酸替诺福韦艾拉酚胺(1:1)晶型A)，第二活性成分为治疗有效量的拉米夫定，第三活性成分为治疗有效量的Cobicistat，第四活性成分为治疗有效量的埃替拉韦。该组合物或制剂优选口服制剂，更优选片剂和胶囊剂；在单位组合物或制剂中，它们各自的重量含量一般为1mg至500mg，优选5mg至400mg，例如含上述第一活性成分约10mg或约25mg(以替诺福韦艾拉酚胺计)、第二活性成分(拉米夫 定)约300mg、第三活性成分(Cobicistat)约150mg和第四活性成分(埃替拉韦)约150mg，其中“约”指±10％的范围，优选±5％的范围。In a specific embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II. Tenofovir alafenamide (1:2), D-norofovir idylamine tartrate (1:1), DL-tenofovir idylamine tartrate (1:1), L- Tenofovir alafenamide (1:2), tenofovir iramol citrate (1:1), tenofovir alafenamide (1:1), oxalic acid Norfoslavamide (1:1), tenofovir iramol phosphate (1:1), tenofovir iramol sulfate (1:1), L-tenofovir t-tartrate ILa phenolamine (1:2) crystal form A, D- tenofovir iramate tartrate (1:1) crystal form A, DL-tenofovir iramate (1:1) crystal Type A, L-malofovir alafenamide (1:2) Form A, tenofovir iramol citrate (1:1) Form A, tenofovir succinate Lactophene (1:1) Form A, tenofovir oxalatine oxalate (1:1) Form A, tenofovir ylide (1:1) crystal form A or sulfate Norfoslavamide (1:1) crystal form A), second activity Into a therapeutically effective amount of lamivudine, third active ingredient a therapeutically effective amount of a cobicistat, the fourth active ingredient is a therapeutically effective amount of a elvitegravir. The composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, each is usually present in an amount of from 1 mg to 500 mg, preferably from 5 mg to 400 mg, for example, containing about 10 mg of the above first active ingredient. Or about 25 mg (based on tenofovir alafenamide), second active ingredient (Ramit Approximately 300 mg, a third active ingredient (Cobicistat) of about 150 mg and a fourth active ingredient (etilavir) of about 150 mg, wherein "about" means a range of ±10%, preferably ±5%.
在一具体实施方案中，本发明提供了一种复方组合物或制剂，其中第一活性成分选自治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物(比如L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)、硫酸替诺福韦艾拉酚胺(1:1)、L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A、D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A、柠檬酸替诺福韦艾拉酚胺(1:1)晶型A、琥珀酸替诺福韦艾拉酚胺(1:1)晶型A、草酸替诺福韦艾拉酚胺(1:1)晶型A、磷酸替诺福韦艾拉酚胺(1:1)晶型A或硫酸替诺福韦艾拉酚胺(1:1)晶型A)，第二活性成分为治疗有效量的拉米夫定，第三活性成分为治疗有效量的Cobicistat，第四活性成分为治疗有效量的地瑞那韦。该组合物或制剂优选口服制剂，更优选片剂和胶囊剂；在单位组合物或制剂中，它们各自的重量含量一般为1mg至1000mg，优选5mg至900mg，例如含上述第一活性成分约10mg或约25mg(以替诺福韦艾拉酚胺计)、第二活性成分(拉米夫定)约200mg、第三活性成分(Cobicistat)约150mg和第四活性成分(地瑞那韦)约800mg，其中“约”指±10％的范围，优选±5％的范围。In a specific embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from a therapeutically effective amount of tenofovir alafenamide complex (such as L-tartaric acid) of Formula II. Tenofovir alafenamide (1:2), D-norofovir idylamine tartrate (1:1), DL-tenofovir idylamine tartrate (1:1), L- Tenofovir alafenamide (1:2), tenofovir iramol citrate (1:1), tenofovir alafenamide (1:1), oxalic acid Norfoslavamide (1:1), tenofovir iramol phosphate (1:1), tenofovir iramol sulfate (1:1), L-tenofovir t-tartrate ILa phenolamine (1:2) crystal form A, D- tenofovir iramate tartrate (1:1) crystal form A, DL-tenofovir iramate (1:1) crystal Type A, L-malofovir alafenamide (1:2) Form A, tenofovir iramol citrate (1:1) Form A, tenofovir succinate Lactophene (1:1) Form A, tenofovir oxalatine oxalate (1:1) Form A, tenofovir ylide (1:1) crystal form A or sulfate Norfoslavamide (1:1) crystal form A), second activity Into a therapeutically effective amount of lamivudine, third active ingredient a therapeutically effective amount of a cobicistat, the fourth active ingredient is a therapeutically effective amount of darunavir. The composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, each of them is usually present in an amount of from 1 mg to 1000 mg, preferably from 5 mg to 900 mg, for example, containing about 10 mg of the above-mentioned first active ingredient. Or about 25 mg (based on tenofovir alafenamide), about 200 mg of the second active ingredient (lamivudine), about 150 mg of the third active ingredient (Cobicistat), and about the fourth active ingredient (darinavir). 800 mg, wherein "about" means a range of ± 10%, preferably ± 5%.
上述组合物不仅在化学上是稳定的，并且还具有协同作用和/或可以降低单独活性成分的副作用和耐药性；同时可能会增加患者的依从性。The above compositions are not only chemically stable, but also have synergistic effects and/or can reduce side effects and drug resistance of the individual active ingredients; and may increase patient compliance.
本发明提供了制备上述药用组合物或制剂的方法。对于单方组合物或制剂，该方法一般是将治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物与一种或多种药用辅料混合或接触。对于二复方组合物或制剂，该方法一般是将治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物、第二活性成分(如恩曲他滨、拉米夫定等)与一种或多种药用辅料混合或接触。对于三复方或多复方组合物或制剂，该方法一般是将治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物、第二活性成分(如恩曲他滨、拉米夫定等)和另一种或多种活性成分与药用辅料混合或接触。该药物组合物或制剂可以是采用本领域中熟知的方式进行制备的。所述的药用辅料均可是本领域常规的药用辅料，包括填充剂、崩解剂、粘合剂、润滑剂等。The present invention provides a method of preparing the above pharmaceutical compositions or formulations. For a single composition or formulation, the method generally comprises mixing or contacting a therapeutically effective amount of the tenofovir alafenamide complex of Formula II with one or more pharmaceutical excipients. For a two-composition composition or formulation, the method will generally be a therapeutically effective amount of a tenofovir alafenamide complex of formula II, a second active ingredient (eg, emtricitabine, lamivudine, etc.) Mix or contact with one or more pharmaceutical excipients. For a three- or multiple-combination composition or formulation, the method will generally be a therapeutically effective amount of a tenofovir alafenamide complex of formula II, a second active ingredient (eg, emtricitabine, lamiv) Mixing or contacting with another pharmaceutical active ingredient or other active ingredient. The pharmaceutical composition or formulation can be prepared in a manner well known in the art. The pharmaceutical excipients may be conventional pharmaceutical excipients in the art, including fillers, disintegrants, binders, lubricants and the like.
根据本发明的目的，本发明提供了式Ⅱ所示替诺福韦艾拉酚胺复合物或所述制备方法制得的替诺福韦艾拉酚胺复合物在制备预防和/或治疗病毒感染的药物中的应用。According to the object of the present invention, the present invention provides a tenofovir alafenamide complex of the formula II or the tenofovir alafenamide complex prepared by the preparation method for preparing a prophylactic and/or therapeutic virus Application in infected drugs.
具体地，本发明提供了式Ⅱ所示替诺福韦艾拉酚胺复合物在制备预防和/或治疗乙型肝 炎病毒(HBV)和/或人类免疫缺陷病毒(HIV)感染的药物中的应用。Specifically, the present invention provides a tenofovir alafenamide complex of the formula II for the preparation of a prophylactic and/or therapeutic hepatitis B. Use in inflammatory virus (HBV) and/or human immunodeficiency virus (HIV) infections.
在一具体实施方案中，本发明提供了式Ⅱ所示的替诺福韦艾拉酚胺复合物在制备预防和/或治疗乙型肝炎病毒(HBV)和/或人类免疫缺陷病毒(HIV)感染的药物中的应用。In a specific embodiment, the present invention provides a tenofovir alafenamide complex of Formula II for the preparation of a prophylactic and/or therapeutic hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV). Application in infected drugs.
在一具体实施方案中，本发明提供了包含治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物和药用辅料的药物组合物在制备预防和/或治疗乙型肝炎病毒(HBV)和/或人类免疫缺陷病毒(HIV)感染的药物中的应用。In a specific embodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II and a pharmaceutically acceptable adjuvant for the preparation of a prophylactic and/or therapeutic hepatitis B virus (HBV) and/or use in drugs for human immunodeficiency virus (HIV) infection.
在一具体实施方案中，本发明提供了包含治疗有效量的式Ⅱ所示的替诺福韦艾拉酚胺复合物、另一种或多种抗病毒剂或抗病毒辅助试剂和药用辅料的药物组合物在制备预防和/或治疗乙型肝炎病毒(HBV)和/或人类免疫缺陷病毒(HIV)感染的药物中的应用。In a specific embodiment, the invention provides a therapeutically effective amount of a tenofovir levamide complex of formula II, another or more antiviral or antiviral adjuvants, and a pharmaceutically acceptable adjuvant Use of a pharmaceutical composition for the manufacture of a medicament for the prevention and/or treatment of hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) infection.
经实验证明，本发明提供式Ⅱ所示的替诺福韦艾拉酚胺复合物，比如L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)、硫酸替诺福韦艾拉酚胺(1:1)、L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A、D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A、L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A、柠檬酸替诺福韦艾拉酚胺(1:1)晶型A、琥珀酸替诺福韦艾拉酚胺(1:1)晶型A、草酸替诺福韦艾拉酚胺(1:1)晶型A、磷酸替诺福韦艾拉酚胺(1:1)晶型A、硫酸替诺福韦艾拉酚胺(1:1)晶型A等，制备方法简便可控，物理性状、稳定性、溶解性、制剂适应性等不低于或优于现有的替诺福韦艾拉酚胺富马酸盐和半富马酸盐，具有良好的工业化实用性。It has been experimentally proved that the present invention provides tenofovir alafenamide compound represented by formula II, such as L-tenofovir lysamine (1:2) of L-tartrate, and tenofovira D-tartaric acid. Phenolic Amine (1:1), DL-Tenofovir Ilegolide Tartrate (1:1), Tenofovir Ilegolide L-malate (1:2), Tenofovir Acesulfate Lauramine (1:1), tenofovir alafenamide (1:1), tenofovir oxalatine oxalate (1:1), tenofovir alafenamide ( 1:1), Tenofovir alafenamide (1:1), L-tenofovir alafenamide (1:2) crystal form A, D-tenofovir eugenol tartrate Amine (1:1) Form A, DL-Tenofovir Ilegolide Tartrate (1:1) Form A, L-Tenofovir Eilafenamide (1:2) Form A , tenofovir eugenol citrate (1:1) crystal form A, tenofovir iramol succinate (1:1) crystal form A, tenofovir alafenamide oxalate (1 :1) crystal form A, tenofovir ilapramide phosphate (1:1) crystal form A, tenofovir iramol sulfate (1:1) crystal form A, etc., the preparation method is simple and controllable, Physical properties, stability, solubility, formulation suitability, etc. are not lower or better than the present Alternative alafenamide hemifumarate and fumarate, having a good industrial applicability.
本发明的X-射线粉末衍射分析是在环境温度及环境湿度下，经荷兰帕纳科X`Pert PRO型X-射线粉末衍射仪的CuKα源(
Figure PCTCN2015078188-appb-000003
)测定完成的。“环境温度”一般是0～40℃；“环境湿度”一般是30％～80％的相对湿度。The X-ray powder diffraction analysis of the present invention is a CuKα source of the X.Pert PRO type X-ray powder diffractometer of the Netherlands PANaco at ambient temperature and ambient humidity (
Figure PCTCN2015078188-appb-000003
The measurement is completed. The "ambient temperature" is generally 0 to 40 ° C; the "ambient humidity" is generally 30% to 80% relative humidity.
本发明提供的代表性的X-射线粉末衍射图谱列于附图中。“代表性的X-射线粉末衍射图谱”是指本晶型的X-射线粉末衍射特征符合本图谱显示的整体形貌，可以理解的是在测试过程中，由于受到多种因素(如测试样品的粒度、测试时样品的处理方法、仪器、测试参数、测试操作等)的影响，同一种晶型所测得的X-射线粉末衍射图谱的出峰位置或峰强度会有一定的差异。一般情况下，X-射线粉末衍射图谱中衍射峰2θ值的实验误差可为±0.2°。Representative X-ray powder diffraction patterns provided by the present invention are listed in the accompanying drawings. "Representative X-ray powder diffraction pattern" means that the X-ray powder diffraction characteristics of the crystal form conform to the overall morphology of the map, and it is understood that during the test, due to various factors (such as test samples) The effect of the particle size, sample processing method, instrument, test parameters, test operation, etc., the peak position or peak intensity of the X-ray powder diffraction pattern measured by the same crystal form may be different. In general, the experimental error of the diffraction peak 2θ value in the X-ray powder diffraction pattern may be ±0.2°.
附图说明DRAWINGS
图1 L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A的X-射线粉末衍射图谱； Figure 1 X-ray powder diffraction pattern of L-norofovir lysamine (1:2) Form A of L-tartrate;
图2 D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱；Figure 2 X-ray powder diffraction pattern of D-tenofovir alafenamide (1:1) Form A;
图3 DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱；Figure 3 X-ray powder diffraction pattern of DL-tenofovir alafenamide (1:1) Form A;
图4 L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A的X-射线粉末衍射图谱；Figure 4 X-ray powder diffraction pattern of L-furofovir alafenamide (1:2) Form A;
图5 柠檬酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱；Figure 5 X-ray powder diffraction pattern of tenofovir alafenamide (1:1) crystal form A;
图6 琥珀酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱；Figure 6 X-ray powder diffraction pattern of tenofovir alafenamide (1:1) Form A;
图7 草酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱；Figure 7 X-ray powder diffraction pattern of tenofovir alafenamide (1:1) crystalline form A;
图8 磷酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱；Figure 8 X-ray powder diffraction pattern of tenofovir alafenamide (1:1) crystal form A;
图9 硫酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱；Figure 9 X-ray powder diffraction pattern of tenofovir alafenamide (1:1) Form A;
图10 替诺福韦艾拉酚胺1H NMR图谱；Figure 10 Tenofovir alafenamide 1 H NMR spectrum;
图11 L-酒石酸替诺福韦艾拉酚胺(1:2)1H NMR图谱；Figure 11 1 - H NMR spectrum of tenofovir alafenamide (1:2);
图12 D-酒石酸替诺福韦艾拉酚胺(1:1)1H NMR图谱；Figure 12 D-tenofovir idylamine tartrate (1:1) 1 H NMR spectrum;
图13 DL-酒石酸替诺福韦艾拉酚胺(1:1)1H NMR图谱；Figure 13 DL-tenofovir alafenamide (1:1) 1 H NMR spectrum;
图14 L-苹果酸替诺福韦艾拉酚胺(1:2)1H NMR图谱；Figure 14 1 - H NMR spectrum of tenofovir alafenamide (1:2);
图15 柠檬酸替诺福韦艾拉酚胺(1:1)1H NMR图谱；Figure 15 Tenofovir iramol citrate (1:1) 1 H NMR spectrum;
图16 琥珀酸替诺福韦艾拉酚胺(1:1)1H NMR图谱；Figure 16 Tenofovir alafenamide (1:1) 1 H NMR spectrum;
图17 草酸替诺福韦艾拉酚胺(1:1)1H NMR图谱；Figure 17 Tenofovir oxalatine oxalate (1:1) 1 H NMR spectrum;
图18 磷酸替诺福韦艾拉酚胺(1:1)1H NMR图谱；Figure 18 Tenofovir alafenamide (1:1) 1 H NMR spectrum;
图19 硫酸替诺福韦艾拉酚胺(1:1)1H NMR图谱。Figure 19 Tenofovir alafenamide (1:1) 1 H NMR spectrum.
具体实施方式detailed description
以下通过实施例形式的具体实施方式，对本发明的上述发明内容做进一步详细说明，但不应理解为本发明的发明内容仅限于以下实施例，凡基于本发明上述内容所做出的发明均属于本发明的范围。The above summary of the present invention will be further described in detail by the embodiments of the present invention, but it should be understood that the invention of the present invention is limited to the following embodiments. The scope of the invention.
以下实施例中的1H NMR测试是以氘代二甲亚砜作为测试溶剂，以四甲基硅烷作内标，用Bruke AV-Ⅱ 400MHz核磁共振仪在室温下测定的。The 1 H NMR test in the following examples was carried out using deuterated dimethyl sulfoxide as a test solvent, tetramethylsilane as an internal standard, and a Bruke AV-II 400 MHz nuclear magnetic resonance spectrometer at room temperature.
以下实施例中的X-射线粉末衍射分析是在环境温度及环境湿度下，经荷兰帕纳科X`Pert PRO型X-射线粉末衍射仪的CuKα源(
Figure PCTCN2015078188-appb-000004
)测定完成的。“环境温度”一般是0～40℃；“环境湿度”一般是30％～80％的相对湿度。The X-ray powder diffraction analysis in the following examples is a CuKα source from the Dutch PANalytical X'Pert PRO X-ray powder diffractometer at ambient temperature and ambient humidity (
Figure PCTCN2015078188-appb-000004
The measurement is completed. The "ambient temperature" is generally 0 to 40 ° C; the "ambient humidity" is generally 30% to 80% relative humidity.
以下实施例中的元素分析是经意大利CARLO ERBA 1106元素分析仪测定的。Elemental analysis in the following examples was performed by an Italian CARLO ERBA 1106 elemental analyzer.
以下实施例中熔程是经YRT-3型药物熔点仪测定的。 The melting range in the following examples was measured by a YRT-3 type drug melting point apparatus.
实施例1Example 1
替诺福韦艾拉酚胺(I)的制备Preparation of tenofovir alafenamide (I)
在20～25℃下，将一苯基替诺福韦(按CN1443189A中公开的方法制备)500.0g(1.38mol，1.0eq)加入到甲苯3.0L中，搅拌下使固体完全溶解，然后加入二氯亚砜150ml(2.05mol,1.5eq)，将所得混合液加热至约70℃下搅拌96小时。40～45℃减压浓缩干，浓缩物中加入甲苯2.5L，在-10℃～10℃下滴加L-丙氨酸异丙酯(可商业化购得)813.5g(6.21mol,4.5eq)溶于二氯甲烷4.0L的溶液，然后在-10℃-10℃下搅拌30分钟后升至室温，用10％磷酸二氢钠水溶液2.5L×2洗涤，分出有机相，用15％碳酸氢钾水溶液1.0L×2洗涤，然后用纯化水2.5L洗涤，得到的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干。在20～25℃下，浓缩物用甲苯/乙腈混合溶剂(体积比4/1)2.5L溶解，加入替诺福韦艾拉酚胺晶种(按CN1443189A中公开的方法制备)50mg，然后继续搅拌2小时，抽滤，滤饼用甲苯/乙腈(体积比4/1)洗涤，然后在40～45℃下减压干燥得到替诺福韦艾拉酚胺。500.0 g (1.38 mol, 1.0 eq) of monophenyl tenofovir (prepared according to the method disclosed in CN1443189A) was added to 3.0 L of toluene at 20-25 ° C, and the solid was completely dissolved by stirring, then added two Chlorosulfoxide 150 ml (2.05 mol, 1.5 eq), and the resulting mixture was heated to about 70 ° C and stirred for 96 hours. The mixture was concentrated to dryness under reduced pressure at 40 to 45 ° C. Toluene (2.5 L) was added to the concentrate, and L-alanine isopropyl ester (commercially available) was added dropwise at -10 ° C to 10 ° C. 813.5 g (6.21 mol, 4.5 eq) ) dissolved in 4.0 L of dichloromethane, then stirred at -10 ° C -10 ° C for 30 minutes, then raised to room temperature, washed with 10% aqueous sodium dihydrogen phosphate solution 2.5L × 2, the organic phase was separated, with 15% The aqueous solution of potassium hydrogencarbonate was washed with 1.0 L × 2 and then washed with EtOAc EtOAc. The concentrate was dissolved in a toluene/acetonitrile mixed solvent (volume ratio 4/1) at 25 L at 20 to 25 ° C, and tenofovir alafenamide seed crystal (prepared according to the method disclosed in CN1443189A) was added to 50 mg, and then continued. After stirring for 2 hours, suction filtration, the filter cake was washed with toluene/acetonitrile (volume ratio 4/1), and then dried under reduced pressure at 40 to 45 ° C to obtain tenofovir alafenamide.
1H NMR(400MHz，DMSO-d6)δ:8.15(s，1H)，8.11(s，1H)，7.32-7.28(t，2H)，7.21(s，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.65-5.59(m，1H)，4.90-4.81(m，1H)，4.31-4.26(m，1H)，4.18-4.13(m，1H)，3.98-3.91(m，1H)，3.90-3.81(m，2H)，3.80-3.75(m，1H)，1.16-1.14(m，9H)，1.09-1.07(d，3H)(1H NMR谱图见附图10)。 1 H NMR (400MHz, DMSO- d 6) δ: 8.15 (s, 1H), 8.11 (s, 1H), 7.32-7.28 (t, 2H), 7.21 (s, 2H), 7.15-7.12 (m, 1H ), 7.07-7.05 (m, 2H), 5.65-5.59 (m, 1H), 4.90-4.81 (m, 1H), 4.31-4.26 (m, 1H), 4.18-4.13 (m, 1H), 3.98-3.91 (m, 1H), 3.90-3.81 (m, 2H), 3.80-3.75 (m, 1H), 1.16-1.14 (m, 9H), 1.09-1.07 (d, 3H) ( 1 H NMR spectrum see attached drawing 10).
实施例2Example 2
L-酒石酸替诺福韦艾拉酚胺(1:2)及其晶型A的制备Preparation of tenofovir alafenamide (1:2) and its crystal form A
在70～75℃下，将替诺福韦艾拉酚胺4.76g(10.0mmol)和L-酒石酸0.75g(5.0mmol)溶于乙腈100ml中，溶解完全后搅拌降温至15～20℃，然后继续搅拌析晶；抽滤，滤饼经适量乙腈洗涤，40～45℃下减压干燥，得L-酒石酸替诺福韦艾拉酚胺(1:2)。4.70g (10.0mmol) of tenofovir alafenamide and 0.75g (5.0mmol) of L-tartaric acid were dissolved in 100ml of acetonitrile at 70-75 ° C, dissolved completely and stirred to 15-20 ° C, then Stirring and crystallization were continued; the filter cake was washed with an appropriate amount of acetonitrile, and dried under reduced pressure at 40 to 45 ° C to obtain tenofovir alafenamide (1:2).
1H NMR(400MHz，DMSO-d6)δ:8.14(s，1H)，8.10(s，1H)，7.31-7.27(t，2H)，7.19(s，2H)，7.15-7.11(m，1H)，7.07-7.04(m，2H)，5.64-5.58(m，1H)，4.90-4.80(m，1H)，4.30-4.25(m，2H)，4.18-4.12(m，1H)，3.98-3.91(m，1H)，3.89-3.81(m，2H)，3.80-3.74(m，1H)，1.16-1.13(t，9H)，1.08-1.06(d，3H)。 1 H NMR (400MHz, DMSO- d 6) δ: 8.14 (s, 1H), 8.10 (s, 1H), 7.31-7.27 (t, 2H), 7.19 (s, 2H), 7.15-7.11 (m, 1H ), 7.07-7.04 (m, 2H), 5.64-5.58 (m, 1H), 4.90-4.80 (m, 1H), 4.30-4.25 (m, 2H), 4.18-4.12 (m, 1H), 3.98-3.91 (m, 1H), 3.89-3.81 (m, 2H), 3.80-3.74 (m, 1H), 1.16-1.13 (t, 9H), 1.08-1.06 (d, 3H).
熔程：158-161℃。Melting range: 158-161 ° C.
上述1H NMR结果中，化学位移在δ8.14(s，1H)和8.10(s，1H)处的信号峰分别归属为替诺福韦艾拉酚胺腺嘌呤环上的2个H，δ4.30-4.25(m，2H)处的信号峰与实施例1中的替诺福韦艾拉酚胺游离碱的1H NMR对照，可以判断其中1个H归属为L-酒石酸的2个次甲基H，从两组信号峰的积分面积比可判断该样品中替诺福韦艾拉酚胺和L-酒石酸的摩 尔组成比为2:1(1H NMR谱图见图11)。In the above 1 H NMR results, the signal peaks at chemical shifts at δ 8.14 (s, 1H) and 8.10 (s, 1H) were assigned to 2 H, δ 4 on the tenofovir alaline amine adenine ring, respectively. The signal peak at .30-4.25 (m, 2H) was compared with the 1 H NMR of tenofovir alafenamide free base in Example 1, and it was judged that one H was classified as L-tartaric acid twice. Methyl H, from the integrated area ratio of the two sets of signal peaks, it can be judged that the molar composition ratio of tenofovir alafluamine and L-tartaric acid in the sample is 2:1 (the 1 H NMR spectrum is shown in Fig. 11).
所测的X-射线粉末衍射图谱见图1，测量值如下表(取相对强度大于等于3％的衍射峰对应的测量值，测量值按四舍五入取三位小数)。The measured X-ray powder diffraction pattern is shown in Fig. 1. The measured values are as follows (measured by the diffraction peak corresponding to a relative intensity of 3% or more, and the measured value is rounded off to take three decimal places).
Figure PCTCN2015078188-appb-000005
Figure PCTCN2015078188-appb-000005
所得上述晶型命名为L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A。The above crystal form obtained was named L-norofovir lysamine (1:2) Form A of L-tartrate.
实施例3Example 3
L-酒石酸替诺福韦艾拉酚胺(1:2)及其晶型A的制备Preparation of tenofovir alafenamide (1:2) and its crystal form A
在70～75℃下，将替诺福韦艾拉酚胺4.76g(10.0mmol)和L-酒石酸0.78g(5.2mmol)溶于异丙醇40ml中，溶解完全后搅拌降温至15～20℃，然后继续搅拌析晶；抽滤，滤饼经适量异丙醇洗涤，30～35℃下减压干燥，得L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A。4.70g (10.0mmol) of tenofovir alafenamide and 0.78g (5.2mmol) of L-tartaric acid were dissolved in 40ml of isopropyl alcohol at 70-75 ° C, dissolved completely and stirred to 15-20 ° C. Then, the mixture is continuously stirred and crystallized; the filter cake is washed with an appropriate amount of isopropanol, and dried under reduced pressure at 30 to 35 ° C to obtain crystalline form A of tenofovir alafenamide (1:2).
实施例4Example 4
L-酒石酸替诺福韦艾拉酚胺(1:2)及其晶型A的制备Preparation of tenofovir alafenamide (1:2) and its crystal form A
在70～75℃下，将替诺福韦艾拉酚胺4.76g(10.0mmol)和L-酒石酸0.65g(4.3mmol)溶于乙醇200ml中，溶解完全后搅拌降温至15～20℃，然后继续搅拌析晶；抽滤，滤饼经适量乙醇洗涤，55～60℃下减压干燥，得L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A。4.70g (10.0mmol) of tenofovir alafenamide and 0.65g (4.3mmol) of L-tartaric acid were dissolved in 200ml of ethanol at 70-75 ° C, dissolved completely and stirred to 15-20 ° C, then Stirring was continued; the filter cake was washed with an appropriate amount of ethanol, and dried under reduced pressure at 55 to 60 ° C to obtain crystalline form A of tenofovir alafenamide (1:2).
实施例5Example 5
D-酒石酸替诺福韦艾拉酚胺(1:1)及其晶型A的制备Preparation of D-norofovir yoglycinamine (1:1) and its crystal form A
在70～75℃下，将替诺福韦艾拉酚胺4.76g(10.0mmol)和D-酒石酸1.50g(10.0mmol)溶于乙腈100ml中，溶解完全后搅拌降温至15～20℃，继续搅拌析晶；抽滤，滤饼经适量乙腈洗涤，40～45℃下减压干燥，得D-酒石酸替诺福韦艾拉酚胺(1:1)。 4.70g (10.0mmol) of tenofovir alafenamide and 1.50g (10.0mmol) of D-tartaric acid were dissolved in 100ml of acetonitrile at 70-75 ° C, dissolved completely and stirred to 15 ~ 20 ° C, continue The mixture was stirred and leached; the filter cake was washed with an appropriate amount of acetonitrile, and dried under reduced pressure at 40 to 45 ° C to obtain Dinofosyl lysamine (1:1).
1H NMR(400MHz，DMSO-d6)δ:8.15(s，1H)，8.11(s，1H)，7.31-7.28(t，2H)，7.22(s，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.63-5.58(m，1H)，4.90-4.81(m，1H)，4.32-4.26(m，3H)，4.18-4.13(m，1H)，4.00-3.92(m，1H)，3.90-3.81(m，2H)，3.80-3.74(m，1H)，1.16-1.13(t，9H)，1.09-1.07(d，3H)。 1 H NMR (400MHz, DMSO- d 6) δ: 8.15 (s, 1H), 8.11 (s, 1H), 7.31-7.28 (t, 2H), 7.22 (s, 2H), 7.15-7.12 (m, 1H ), 7.07-7.05 (m, 2H), 5.63-5.58 (m, 1H), 4.90-4.81 (m, 1H), 4.32-4.26 (m, 3H), 4.18-4.13 (m, 1H), 4.00-3.92 (m, 1H), 3.90-3.81 (m, 2H), 3.80-3.74 (m, 1H), 1.16-1.13 (t, 9H), 1.09-1.07 (d, 3H).
熔程：135-138℃。Melting range: 135-138 ° C.
上述1H NMR结果中，化学位移在δ8.15(s，1H)和8.11(s，1H)处的信号峰分别归属为替诺福韦艾拉酚胺腺嘌呤上的2个H，δ4.32-4.26(m，3H)处的信号峰与实施例1中的替诺福韦艾拉酚胺游离碱的1H NMR对照，可以判断其中2个H归属为D-酒石酸的2个次甲基H，从两组信号峰的积分面积比可判断该样品中替诺福韦艾拉酚胺和D-酒石酸的摩尔组成比为1:1(1H NMR谱图见附图12)。In the above 1 H NMR results, the signal peaks at chemical shifts of δ 8.15 (s, 1H) and 8.11 (s, 1H) were assigned to 2 H, δ 4 on tenofovir alafenamide adenine, respectively. The signal peak at 32-4.26 (m, 3H) is compared with the 1 H NMR of tenofovir alafenamide free base in Example 1, and it can be judged that 2 of the H are classified as D-tartaric acid. Based on the integral area ratio of the two sets of signal peaks, the molar composition ratio of tenofovir alafenamide to D-tartaric acid in the sample was judged to be 1:1 (see Figure 12 for the 1 H NMR spectrum).
所测的X-射线粉末衍射图谱见图2，测量值如下表(取相对强度大于等于3％的衍射峰对应的测量值，测量值按四舍五入取三位小数)。The measured X-ray powder diffraction pattern is shown in Fig. 2, and the measured values are as follows (measured by the diffraction peak corresponding to the relative intensity of 3% or more, and the measured value is rounded off to take three decimal places).
Figure PCTCN2015078188-appb-000006
Figure PCTCN2015078188-appb-000006
所得上述晶型命名为D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A。The above crystal form obtained was named D-norofovir ylide (1:1) Form A of D-tartrate.
实施例6Example 6
DL-酒石酸替诺福韦艾拉酚胺(1:1)及其晶型A的制备Preparation of DL-tenofovir alafenamide (1:1) and its crystal form A
在70～75℃下，将替诺福韦艾拉酚胺4.76g(10.0mmol)和DL-酒石酸1.50g(10.0mmol)溶于乙腈100ml中，溶解完全后搅拌降温至15～20℃，继续搅拌析晶；抽滤，滤饼经适量乙腈洗涤，40～45℃下减压干燥，得DL-酒石酸替诺福韦艾拉酚胺(1:1)。4.70g (10.0mmol) of tenofovir alafenamide and 1.50g (10.0mmol) of DL-tartaric acid were dissolved in 100ml of acetonitrile at 70-75 ° C, dissolved completely and stirred to 15 ~ 20 ° C, continue The mixture was stirred and filtered; the filter cake was washed with an appropriate amount of acetonitrile, and dried under reduced pressure at 40 to 45 ° C to obtain DL-tenofovir lysamine (1:1).
1H NMR(400MHz，DMSO-d6)δ:8.14(s，1H)，8.11(s，1H)，7.31-7.27(t，2H)，7.20(s，2H)，7.15-7.11(m，1H)，7.07-7.04(m，2H)，5.63-5.58(m，1H)，4.90-4.80(m，1H)，4.31-4.26 (m，3H)，4.18-4.13(m，1H)，4.00-3.91(m，1H)，3.90-3.81(m，2H)，3.80-3.74(m，1H)，1.16-1.13(t，9H)，1.08-1.07(d，3H)。 1 H NMR (400MHz, DMSO- d 6) δ: 8.14 (s, 1H), 8.11 (s, 1H), 7.31-7.27 (t, 2H), 7.20 (s, 2H), 7.15-7.11 (m, 1H ), 7.07-7.04 (m, 2H), 5.63-5.58 (m, 1H), 4.90-4.80 (m, 1H), 4.31-4.26 (m, 3H), 4.18-4.13 (m, 1H), 4.00-3.91 (m, 1H), 3.90-3.81 (m, 2H), 3.80-3.74 (m, 1H), 1.16-1.13 (t, 9H), 1.08-1.07 (d, 3H).
熔程：175-178℃。Melting range: 175-178 ° C.
上述1H NMR结果中，化学位移在δ8.14(s，1H)和8.11(s，1H)处的信号峰分别归属为替诺福韦艾拉酚胺腺嘌呤上的2个H，δ4.31-4.26(m，3H)处的信号峰与实施例1中的替诺福韦艾拉酚胺游离碱的1H NMR对照，可以判断其中2个H归属为DL-酒石酸的2个次甲基H，从两组信号峰的积分面积比可判断该样品中替诺福韦艾拉酚胺和DL-酒石酸的摩尔组成比为1:1(1H NMR谱图见附图13)。In the above 1 H NMR results, the signal peaks at chemical shifts of δ 8.14 (s, 1H) and 8.11 (s, 1H) were assigned to 2 H, δ 4 on tenofovir alafenamide adenine, respectively. The signal peak at 31-4.26 (m, 3H) was compared with the 1 H NMR of tenofovir alafenol free base in Example 1, and it was judged that 2 of the H were classified as DL-tartaric acid. Based on the integral area ratio of the two sets of signal peaks, the molar composition ratio of tenofovir alafenamide to DL-tartaric acid in the sample was determined to be 1:1 (see Figure 13 for the 1 H NMR spectrum).
所测的X-射线粉末衍射图谱见图3，，测量值如下表(取相对强度大于等于3％的衍射峰对应的测量值，测量值按四舍五入取三位小数)。The measured X-ray powder diffraction pattern is shown in Fig. 3, and the measured values are as follows (measured by the diffraction peak corresponding to the relative intensity of 3% or more, and the measured value is rounded off to take three decimal places).
Figure PCTCN2015078188-appb-000007
Figure PCTCN2015078188-appb-000007
所得上述晶型命名为DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A。The above crystal form obtained was named DL-tenofovir alafenamide (1:1) Form A.
实施例7Example 7
L-苹果酸替诺福韦艾拉酚胺(1:2)及其晶型A的制备Preparation of tenofovir alafenamide (1:2) and its crystal form A
在70～75℃下，将替诺福韦艾拉酚胺4.76g(10.0mmol)和L-苹果酸0.67g(5.0mmol)溶于异丙醇50ml中，溶解完全后搅拌降温至15～20℃，继续搅拌析晶；抽滤，滤饼经适量异丙醇洗涤，40～45℃下减压干燥，得L-苹果酸替诺福韦艾拉酚胺(1:2)。4.70g (10.0mmol) of tenofovir lysamine and 0.67g (5.0mmol) of L-malic acid were dissolved in 50ml of isopropanol at 70-75 ° C, dissolved completely and stirred to 15-20 °C, stirring and crystallization were continued; suction filtration, the filter cake was washed with an appropriate amount of isopropanol, and dried under reduced pressure at 40 to 45 ° C to obtain tenofovir alafenamide (1:2).
1H NMR(400MHz，DMSO-d6)δ:8.15(s，1H)，8.11(s，1H)，7.32-7.28(m，2H)，7.22(s，2H)，7.15-7.12(t,1H),7.07-7.05(m，2H)，5.65-5.59(m，1H)，4.90-4.81(m，1H)，4.31-4.26(m，2H)，4.19-4.13(m，1H)，4.00-3.92(m，1H)，3.90-3.83(m，2H)，3.80-3.74(m，1H)，2.65-2.43(m，1H)，1.16-1.14(m，9H)，1.09-1.07(d，3H)。 1 H NMR (400MHz, DMSO- d 6) δ: 8.15 (s, 1H), 8.11 (s, 1H), 7.32-7.28 (m, 2H), 7.22 (s, 2H), 7.15-7.12 (t, 1H ), 7.07-7.05 (m, 2H), 5.65-5.59 (m, 1H), 4.90-4.81 (m, 1H), 4.31-4.26 (m, 2H), 4.19-4.13 (m, 1H), 4.00-3.92 (m, 1H), 3.90-3.83 (m, 2H), 3.80-3.74 (m, 1H), 2.65-2.43 (m, 1H), 1.16-1.14 (m, 9H), 1.09-1.07 (d, 3H) .
上述1H NMR结果中，化学位移在δ8.15(s，1H)和8.11(s，1H)处的信号峰分别归属为替诺福韦艾拉酚胺腺嘌呤上的2个H，δ2.65-2.43(m，1H)处的信号峰归属为L-苹果酸 亚甲基上的2个H，从两组信号峰的积分面积比可判断该样品中替诺福韦艾拉酚胺和L-苹果酸的摩尔组成比为2:1(1H NMR谱图见附图14)。In the above 1 H NMR results, the signal peaks at chemical shifts of δ 8.15 (s, 1H) and 8.11 (s, 1H) were assigned to 2 H, δ 2 on tenofovir alafenamide adenine, respectively. The signal peak at 65-2.43 (m, 1H) is assigned to 2 H on the L-malic acid methylene group. From the integrated area ratio of the two sets of signal peaks, the tenofovir alafenamide in the sample can be judged. The molar composition ratio of L-malic acid was 2:1 (see Figure 14 for the 1 H NMR spectrum).
所测的X-射线粉末衍射图谱见图4，测量值如下表(取相对强度大于等于3％的衍射峰对应的测量值，测量值按四舍五入取三位小数)。The measured X-ray powder diffraction pattern is shown in Fig. 4. The measured values are as follows (measured by the diffraction peak corresponding to the relative intensity of 3% or more, and the measured value is rounded off to take three decimal places).
Figure PCTCN2015078188-appb-000008
Figure PCTCN2015078188-appb-000008
所得上述晶型命名为L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A。The above crystal form obtained was named as crystalline form A of tenofovir alafenamide (1:2).
实施例8Example 8
柠檬酸替诺福韦艾拉酚胺(1:1)及其晶型A的制备Preparation of tenofovir iramol citrate (1:1) and its crystal form A
在70～75℃下，将替诺福韦艾拉酚胺4.76g(10.0mmol)和柠檬酸1.92g(10.0mmol)溶于乙腈100ml中，溶解完全后搅拌降温至15～20℃，继续搅拌析晶；抽滤，滤饼经适量乙腈洗涤，40～45℃下减压干燥，得柠檬酸替诺福韦艾拉酚胺(1:1)。4.70g (10.0mmol) of tenofovir levamide and 1.92g (10.0mmol) of citric acid were dissolved in 100ml of acetonitrile at 70-75 ° C, dissolved completely and stirred to 15-20 ° C, stirring was continued. Crystallization; suction filtration, the filter cake was washed with an appropriate amount of acetonitrile, and dried under reduced pressure at 40 to 45 ° C to obtain tenofovir eric acid citrate (1:1).
1H NMR(400MHz，DMSO-d6)δ:8.14(s，1H)，8.11(s，1H)，7.31-7.27(m，2H)，7.22(s，2H)，7.15-7.11(m，1H)，7.07-7.04(m，2H)，5.63-5.58(m，1H)，4.90-4.80(m，1H)，4.30-4.26(m，1H)，4.18-4.13(m，1H)，4.00-3.91(m，1H)，3.89-3.81(m，2H)，3.79-3.74(m，1H)，2.78-2.74(d，2H)，2.67-2.64(d，2H)，1.16-1.13(t，9H)，1.08-1.06(d，3H)。 1 H NMR (400MHz, DMSO- d 6) δ: 8.14 (s, 1H), 8.11 (s, 1H), 7.31-7.27 (m, 2H), 7.22 (s, 2H), 7.15-7.11 (m, 1H ), 7.07-7.04 (m, 2H), 5.63-5.58 (m, 1H), 4.90-4.80 (m, 1H), 4.30-4.26 (m, 1H), 4.18-4.13 (m, 1H), 4.00-3.91 (m,1H), 3.89-3.81 (m, 2H), 3.79-3.74 (m, 1H), 2.78-2.74 (d, 2H), 2.67-2.64 (d, 2H), 1.16-1.13 (t, 9H) , 1.08-1.06 (d, 3H).
熔程：144-147℃。Melting range: 144-147 ° C.
上述1H NMR结果中，化学位移在δ8.14(s，1H)和8.11(s，1H)处的信号峰分别归属为替诺福韦艾拉酚胺腺嘌呤上的2个H，δ2.78-2.74(d，2H)和2.67-2.64(d，2H)处的信号峰归属为柠檬酸上2个亚甲基的4个H，从两组信号峰的积分面积比可判断该样品中替诺福 韦艾拉酚胺和柠檬酸的摩尔组成比为1:1(1H NMR谱图见附图15)。In the above 1 H NMR results, the signal peaks at chemical shifts of δ 8.14 (s, 1H) and 8.11 (s, 1H) were assigned to two H, δ 2 on tenofovir alafenamide adenine, respectively. The signal peaks at 78-2.74(d,2H) and 2.67-2.64(d,2H) are assigned to 4 Hs of 2 methylene groups on citric acid. The integrated area ratio of the two sets of signal peaks can be judged in the sample. The molar composition ratio of tenofovir alafenamide to citric acid was 1:1 (see Figure 15 for the 1 H NMR spectrum).
所测的X-射线粉末衍射图谱见图5，测量值如下表(取相对强度大于等于3％的衍射峰对应的测量值，测量值按四舍五入取三位小数)。The measured X-ray powder diffraction pattern is shown in Fig. 5. The measured values are as follows (measured by the diffraction peak corresponding to a relative intensity of 3% or more, and the measured value is rounded off to take three decimal places).
Figure PCTCN2015078188-appb-000009
Figure PCTCN2015078188-appb-000009
所得上述晶型命名为柠檬酸替诺福韦艾拉酚胺(1:1)晶型A。The above crystal form obtained was named as tenofovir alafenamide (1:1) crystal form A.
实施例9Example 9
柠檬酸替诺福韦艾拉酚胺(1:1)及其晶型A的制备Preparation of tenofovir iramol citrate (1:1) and its crystal form A
在70～75℃下，将替诺福韦艾拉酚胺4.76g(10.0mmol)和柠檬酸2.40g(12.5mmol)溶于乙醇40ml中，溶解完全后搅拌降温至15～20℃，继续搅拌析晶；抽滤，滤饼经适量乙醇洗涤，30～35℃下减压干燥，得柠檬酸替诺福韦艾拉酚胺(1:1)晶型A。4.70g (10.0mmol) of tenofovir alafenamide and 2.40g (12.5mmol) of citric acid were dissolved in 40ml of ethanol at 70-75 ° C, dissolved completely and stirred to 15-20 ° C, stirring was continued. Crystallization; suction filtration, the filter cake was washed with an appropriate amount of ethanol, and dried under reduced pressure at 30 to 35 ° C to obtain tenofovir acetamide (1:1) crystal form A.
实施例10Example 10
柠檬酸替诺福韦艾拉酚胺(1:1)及其晶型A的制备Preparation of tenofovir iramol citrate (1:1) and its crystal form A
在60～64℃下，将替诺福韦艾拉酚胺4.76g(10.0mmol)和柠檬酸1.54g(8.0mmol)溶于甲醇200ml中，溶解完全后搅拌降温至15～20℃，继续搅拌析晶；抽滤，滤饼经适量甲醇洗涤，35～40℃下减压干燥，得柠檬酸替诺福韦艾拉酚胺(1:1)晶型A。4.76g (10.0mmol) of tenofovir lysamine and 1.54g (8.0mmol) of citric acid were dissolved in 200ml of methanol at 60-64 ° C, dissolved completely, stirred and cooled to 15 ~ 20 ° C, continue to stir. Crystallization; suction filtration, the filter cake was washed with an appropriate amount of methanol, and dried under reduced pressure at 35 to 40 ° C to obtain tenofovir ylide (1:1) crystal form A.
实施例11Example 11
柠檬酸替诺福韦艾拉酚胺(1:1)及其晶型A的制备Preparation of tenofovir iramol citrate (1:1) and its crystal form A
在60～65℃下，将替诺福韦艾拉酚胺4.76g(10.0mmol)和柠檬酸1.92g(10.0mmol)溶于四氢呋喃150ml中，溶解完全后搅拌降温至15～20℃，继续搅拌析晶；抽滤，滤饼经适量四 氢呋喃洗涤，40～45℃下减压干燥，得柠檬酸替诺福韦艾拉酚胺(1:1)晶型A。4.76g (10.0mmol) of tenofovir alafenamide and 1.92g (10.0mmol) of citric acid were dissolved in 150ml of tetrahydrofuran at 60-65 ° C, dissolved completely and stirred to 15-20 ° C, stirring was continued. Crystallization; suction filtration, filter cake by appropriate amount of four The mixture was washed with hydrogen furan and dried under reduced pressure at 40 to 45 ° C to obtain tenofovir ylide (1:1) crystal form A.
实施例12Example 12
琥珀酸替诺福韦艾拉酚胺(1:1)及其晶型A的制备Preparation of tenofovir alafenamide succinate (1:1) and its crystal form A
在70～75℃下，将替诺福韦艾拉酚胺4.76g(10.0mmol)和琥珀酸1.18g(10.0mmol)溶于乙腈50ml中，溶解完全后搅拌降温至15～20℃，继续搅拌析晶；抽滤，滤饼经适量乙腈洗涤，40～45℃下减压干燥，得琥珀酸替诺福韦艾拉酚胺(1:1)。4.70g (10.0mmol) of tenofovir alafenamide and 1.18g (10.0mmol) of succinic acid were dissolved in 50ml of acetonitrile at 70-75 ° C, dissolved completely, stirred and cooled to 15-20 ° C, stirring was continued. Crystallization; suction filtration, the filter cake was washed with an appropriate amount of acetonitrile, and dried under reduced pressure at 40 to 45 ° C to obtain tenofovir alafenamide (1:1).
1H NMR(400MHz，DMSO-d6)δ:12.13(s，2H)，8.15(s，1H)，8.11(s，1H)，7.31-7.27(t，2H)，7.21(s，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.64-5.59(m，1H)，4.90-4.81(m，1H)，4.30-4.26(m，1H)，4.18-4.13(m，1H)，4.00-3.92(m，1H)，3.90-3.81(m，2H)，3.80-3.74(m，1H)，2.43(s，4H)，1.16-1.13(t，9H)，1.08-1.07(d，3H)。 1 H NMR (400MHz, DMSO- d 6) δ: 12.13 (s, 2H), 8.15 (s, 1H), 8.11 (s, 1H), 7.31-7.27 (t, 2H), 7.21 (s, 2H), 7.15-7.12(m,1H),7.07-7.05(m,2H),5.64-5.59(m,1H),4.90-4.81(m,1H), 4.30-4.26(m,1H),4.18-4.13(m , 1H), 4.00-3.92 (m, 1H), 3.90-3.81 (m, 2H), 3.80-3.74 (m, 1H), 2.43 (s, 4H), 1.16-1.13 (t, 9H), 1.08-1.07 (d, 3H).
上述1H NMR结果中，化学位移在δ8.15(s，1H)和8.11(s，1H)处的信号峰分别归属为替诺福韦艾拉酚胺腺嘌呤上的2个H，δ2.43(s，4H)处的信号峰归属为琥珀酸上2个对称亚甲基的4个H，从两组信号峰的积分面积比可判断该样品中替诺福韦艾拉酚胺和琥珀酸的摩尔组成比为1:1(1H NMR谱图见附图16)。In the above 1 H NMR results, the signal peaks at chemical shifts of δ 8.15 (s, 1H) and 8.11 (s, 1H) were assigned to 2 H, δ 2 on tenofovir alafenamide adenine, respectively. The signal peak at 43(s, 4H) is assigned to 4 H of 2 symmetrical methylene groups on succinic acid. The integral area ratio of the two sets of signal peaks can be used to determine tenofovir alafenamide and amber in the sample. The molar composition ratio of the acid was 1:1 (see Figure 16 for the 1 H NMR spectrum).
所测的X-射线粉末衍射图谱见图6，测量值如下表(取相对强度大于等于3％的衍射峰对应的测量值，测量值按四舍五入取三位小数)。The measured X-ray powder diffraction pattern is shown in Fig. 6. The measured values are as follows (measured by the diffraction peak corresponding to the relative intensity of 3% or more, and the measured value is rounded to three decimal places).
Figure PCTCN2015078188-appb-000010
Figure PCTCN2015078188-appb-000010
所得上述晶型命名为琥珀酸替诺福韦艾拉酚胺(1:1)晶型A。The above crystal form obtained was named as tenofovir alafenamide (1:1) Form A.
实施例13Example 13
草酸替诺福韦艾拉酚胺(1:1)及其晶型A的制备Preparation of tenofovir alafenamide (1:1) and its crystal form A
在70～75℃下，将替诺福韦艾拉酚胺4.76g(10.0mmol)和草酸二水合物1.26g(10.0mmol)溶于乙腈100ml中，溶解完全后搅拌降温至15～20℃，继续搅拌析晶；抽滤，滤饼经适量乙腈洗涤，40～45℃下减压干燥，得草酸替诺福韦艾拉酚胺(1:1)。4.70g (10.0mmol) of tenofovir alafenamide and 1.26g (10.0mmol) of oxalic acid dihydrate were dissolved in 100ml of acetonitrile at 70-75 ° C, dissolved completely and stirred to 15-20 ° C. Stirring and crystallization were continued; the filter cake was washed with an appropriate amount of acetonitrile, and dried under reduced pressure at 40 to 45 ° C to obtain tenofovir alafenamide (1:1).
1H NMR(400MHz，DMSO-d6)δ:8.19(s，1H)，8.15(s，1H)，7.49(s，2H)，7.32-7.28(m，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.64-5.58(m，1H)，4.90-4.80(m，1H)，4.32-4.28(m，1H)，4.19-4.14(m，1H)，4.00-3.91(m，1H)，3.90-3.83(m，2H)，3.80-3.75(m，1H)，1.16-1.13(m，9H)，1.09-1.08(d，3H)(1H NMR谱图见附图17)。 1 H NMR (400MHz, DMSO- d 6) δ: 8.19 (s, 1H), 8.15 (s, 1H), 7.49 (s, 2H), 7.32-7.28 (m, 2H), 7.15-7.12 (m, 1H ), 7.07-7.05 (m, 2H), 5.64-5.58 (m, 1H), 4.90-4.80 (m, 1H), 4.32-4.28 (m, 1H), 4.19-4.14 (m, 1H), 4.00-3.91 (m,1H), 3.90-3.83 (m, 2H), 3.80-3.75 (m, 1H), 1.16-1.13 (m, 9H), 1.09-1.08 (d, 3H) ( 1 H NMR spectrum see attached drawing 17).
元素分析：C：48.70％；H：5.50％；N：14.75％。从元素分析结果可判断该样品中草酸与替诺福韦艾拉酚胺的比例约为1:1。Elemental analysis: C: 48.70%; H: 5.50%; N: 14.75%. From the elemental analysis results, the ratio of oxalic acid to tenofovir alafenamide in the sample was determined to be about 1:1.
熔程：182-185℃。Melting range: 182-185 ° C.
所测的X-射线粉末衍射图谱见图7，测量值如下表(取相对强度大于等于3％的衍射峰对应的测量值，测量值按四舍五入取三位小数)。The measured X-ray powder diffraction pattern is shown in Fig. 7. The measured values are shown in the following table (measured by the diffraction peak corresponding to a relative intensity of 3% or more, and the measured value is rounded off to take three decimal places).
Figure PCTCN2015078188-appb-000011
Figure PCTCN2015078188-appb-000011
所得上述晶型命名为草酸替诺福韦艾拉酚胺(1:1)晶型A。The above crystal form obtained was named as tenofovir oxalatine oxalate (1:1) Form A.
实施例14Example 14
磷酸替诺福韦艾拉酚胺(1:1)及其晶型A的制备Preparation of tenofovir alafenamide (1:1) and its crystal form A
在20～25℃下，将替诺福韦艾拉酚胺4.76g(10.0mmol)和磷酸(85％水溶液)1.20g(10.0mmol)溶于乙腈50ml中，然后在20～25℃下搅拌析晶；抽滤，滤饼经适量乙腈洗 涤，40～45℃下减压干燥，得磷酸替诺福韦艾拉酚胺(1:1)。4.76g (10.0mmol) of tenofovir alafenamide and 1.20g (10.0mmol) of phosphoric acid (85% aqueous solution) were dissolved in 50ml of acetonitrile at 20～25°C, and then stirred at 20～25°C. Crystal; suction filtration, filter cake washed with appropriate amount of acetonitrile The polyester was dried under reduced pressure at 40 to 45 ° C to obtain tenofovir alafenol phosphate (1:1).
1H NMR(400MHz，DMSO-d6)δ:8.15(s，1H)，8.11(s，1H)，7.31-7.27(m，2H)，7.25(s，2H)，7.15-7.11(t,1H),7.07-7.05(m，2H)，5.64-5.59(m，1H)，4.90-4.80(m，1H)，4.30-4.26(m，1H)，4.18-4.13(m，1H)，3.98-3.91(m，1H)，3.90-3.83(m，2H)，3.81-3.74(m，1H)，1.16-1.13(m，9H)，1.08-1.07(d，3H)(1H NMR谱图见附图18)。 1 H NMR (400MHz, DMSO- d 6) δ: 8.15 (s, 1H), 8.11 (s, 1H), 7.31-7.27 (m, 2H), 7.25 (s, 2H), 7.15-7.11 (t, 1H ), 7.07-7.05 (m, 2H), 5.64-5.59 (m, 1H), 4.90-4.80 (m, 1H), 4.30-4.26 (m, 1H), 4.18-4.13 (m, 1H), 3.98-3.91 (m, 1H), 3.90-3.83 (m, 2H), 3.81-3.74 (m, 1H), 1.16-1.13 (m, 9H), 1.08-1.07 (d, 3H) ( 1 H NMR spectrum see attached drawing 18).
元素分析：C：43.72％；H：5.64％；N：14.56％。从元素分析结果可判断该样品中磷酸与替诺福韦艾拉酚胺的比例约为1:1。Elemental analysis: C: 43.72%; H: 5.64%; N: 14.56%. From the elemental analysis results, the ratio of phosphoric acid to tenofovir alafenamide in the sample was determined to be about 1:1.
熔程：165-168℃。Melting range: 165-168 ° C.
所测的X-射线粉末衍射图谱见图8，测量值如下表(取相对强度大于等于3％的衍射峰对应的测量值，测量值按四舍五入取三位小数)。The measured X-ray powder diffraction pattern is shown in Fig. 8. The measured values are shown in the following table (measured corresponding to the diffraction peaks with a relative intensity of 3% or more, and the measured values are rounded off to take three decimal places).
Figure PCTCN2015078188-appb-000012
Figure PCTCN2015078188-appb-000012
所得上述晶型命名为磷酸替诺福韦艾拉酚胺(1:1)晶型A。The above crystal form obtained was named as tenofovir alafenamide (1:1) crystal form A.
实施例15Example 15
硫酸替诺福韦艾拉酚胺(1:1)及其晶型A的制备Preparation of tenofovir alafenamide (1:1) and its crystal form A
在20～25℃下，将替诺福韦艾拉酚胺4.76g(10.0mmol)和98％硫酸1.00g(10.0mmol)溶于乙腈50ml中，然后在20～25℃下搅拌析晶；抽滤，滤饼经适量乙腈洗涤，40～45℃下减压干燥，得硫酸替诺福韦艾拉酚胺(1:1)。4.76g (10.0mmol) of tenofovir alafenamide and 1.00g (10.0mmol) of 98% sulfuric acid were dissolved in 50ml of acetonitrile at 20-25 ° C, and then stirred and liquefied at 20-25 ° C; After filtration, the filter cake was washed with an appropriate amount of acetonitrile and dried under reduced pressure at 40 to 45 ° C to obtain tenofovir alafenamide (1:1).
1H NMR(400MHz，DMSO-d6)δ:9.46(brs，1H)，8.74(brs，1H)，8.48(s，1H)，8.46(s，1H)，7.34-7.30(t，2H)，7.17-7.13(t,1H),7.08-7.06(d，2H)，5.63-5.57(m，1H)，4.88-4.79(m，1H)，4.44-4.39(m，1H)，4.28-4.23(m，1H)，4.05-3.98(m，1H)，3.93-3.88(m，2H)，3.85-3.78(m，1H)，1.15-1.11(m，12H)(1H NMR谱图见附图19)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.46 (brs, 1H), 8.74 (brs, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 7.34-7.30 (t, 2H), 7.17-7.13(t,1H),7.08-7.06(d,2H),5.63-5.57(m,1H),4.88-4.79(m,1H),4.44-4.39(m,1H),4.28-4.23(m , 1H), 4.05-3.98 (m, 1H), 3.93-3.88 (m, 2H), 3.85-3.78 (m, 1H), 1.15-1.11 (m, 12H) (see Figure 19 for 1 H NMR spectrum) .
元素分析：C：43.82％；H：5.42％；N：14.54％；S：5.50％。从元素分析结果可判断该样品中硫酸与替诺福韦艾拉酚胺的比例约为1:1。 Elemental analysis: C: 43.82%; H: 5.42%; N: 14.54%; S: 5.50%. From the elemental analysis results, the ratio of sulfuric acid to tenofovir alafenamide in the sample was determined to be about 1:1.
熔程：146-149℃。Melting range: 146-149 ° C.
所测的X-射线粉末衍射图谱见图9，测量值如下表(取相对强度大于等于3％的衍射峰对应的测量值，测量值按四舍五入取三位小数)。The X-ray powder diffraction pattern measured is shown in Fig. 9. The measured values are shown in the following table (measured corresponding to the diffraction peaks with a relative intensity of 3% or more, and the measured values are rounded off to take three decimal places).
Figure PCTCN2015078188-appb-000013
Figure PCTCN2015078188-appb-000013
所得上述晶型命名为硫酸替诺福韦艾拉酚胺(1:1)晶型A。The above crystal form obtained was named as tenofovir alafenamide (1:1) crystal form A.
实施例16Example 16
L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A的多晶型研究Study on the polymorphism of crystallinity A of tenofovir alafenamide (1:2) L-tartrate
取按实施例2的方法制备的L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A，按下表溶剂及方式制备晶型。经测X-射线粉末衍射图谱，考察其晶型情况，结果如下(下表中TAF代表替诺福韦艾拉酚胺)：The crystalline form of tenofovir alafenamide (1:2) of L-tartrate prepared according to the method of Example 2 was prepared according to the following solvent and manner. The X-ray powder diffraction pattern was examined to examine the crystal form, and the results are as follows (TAF in the table below represents tenofovir alafenamide):
Figure PCTCN2015078188-appb-000014
Figure PCTCN2015078188-appb-000014
上述研究表明，在多种结晶条件下均能稳定的得到L-酒石酸替诺福韦艾拉酚胺(1:2)晶 型A，未发现L-酒石酸替诺福韦艾拉酚胺(1:2)具有多晶现象，即L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A的可控性强。The above studies show that the tenofovir alafenamide (1:2) crystal of L-tartrate can be stably obtained under various crystallization conditions. Type A, no polymorphism of tenofovir alafenamide (1:2) of L-tartrate, ie the controllability of tenofovir alafenamide (1:2) crystal form A Strong.
实施例17Example 17
柠檬酸替诺福韦艾拉酚胺(1:1)晶型A的多晶型研究Polymorphism of tenofovir alafenamide (1:1) crystal form A
取按实施例2的方法制备的柠檬酸替诺福韦艾拉酚胺(1:1)晶型A，加入到适量的下表所列的溶剂中加热搅拌，抽滤，滤饼减压干燥。经测X-射线粉末衍射图谱，考察其晶型情况，结果如下(下表中TAF代表替诺福韦艾拉酚胺)：The tenofovir 137 (1:1) crystal form A prepared by the method of Example 2 was added to an appropriate amount of the solvent listed in the following table, heated and stirred, suction filtered, and the filter cake was dried under reduced pressure. . The X-ray powder diffraction pattern was examined to examine the crystal form, and the results are as follows (TAF in the table below represents tenofovir alafenamide):
Figure PCTCN2015078188-appb-000015
Figure PCTCN2015078188-appb-000015
上述研究表明，在多种结晶条件下均能稳定的得到柠檬酸替诺福韦艾拉酚胺(1:1)晶型A，未发现柠檬酸替诺福韦艾拉酚胺(1:1)具有多晶现象，即柠檬酸替诺福韦艾拉酚胺(1:1)晶型A的可控性强。The above studies showed that tenofovir oxalatine citrate (1:1) crystal form A was stably obtained under various crystallization conditions, and tenofovir eric acid citrate was not found (1:1). It has a polymorphism, that is, the controllability of tenofovir alafenamide (1:1) crystal form A is strong.
实施例18Example 18
稳定性研究Stability study
取富马酸替诺福韦艾拉酚胺(1:1)(按专利文献CN1443189A中公开的方法制备)、富马酸替诺福韦艾拉酚胺(1:2)(按专利文献CN103732594A中公开的方法制备)、L-酒石酸替诺福韦艾拉酚胺(1:2)(按实施例2的方法制备)、DL-酒石酸替诺福韦艾拉酚胺(1:1)(按实施例6的方法制备)和柠檬酸替诺福韦艾拉酚胺(1:1)(按实施例8的方法制备)，在高温和高湿下分别20天后进行检测，结果如下(下表中TAF代表替诺福韦艾拉酚胺)：Tenofovir alafenamide fumarate (1:1) (prepared according to the method disclosed in patent document CN1443189A), tenofovir fumarate fumarate (1:2) (according to patent document CN103732594A) Prepared by the method disclosed), tenofofovir olamine tartrate (1:2) (prepared according to the method of Example 2), DL-tenofovir iramol tartrate (1:1) ( Prepared according to the method of Example 6 and tenofovir alafenamide (1:1) (prepared according to the method of Example 8), and tested under high temperature and high humidity for 20 days, respectively, the results are as follows (below TAF in the table stands for tenofovir alafenol):
Figure PCTCN2015078188-appb-000016
Figure PCTCN2015078188-appb-000016
上述研究表明，本发明提供的L-酒石酸替诺福韦艾拉酚胺(1:2)、DL-酒石酸替诺福韦艾拉酚胺(1:1)和柠檬酸替诺福韦艾拉酚胺(1:1)在高温、高湿条件下的稳定性较富马酸替诺福韦艾拉酚胺(1:1)、富马酸替诺福韦艾拉酚胺(1:2)相当或更好。The above studies show that the present invention provides tenofovir alafenamide (1:2), DL-tenofovir idylamine tartrate (1:1) and tenofovira citric acid. The stability of phenolamine (1:1) under high temperature and high humidity conditions is better than tenofovir fumarate fumarate (1:1) and tenofovir fumarate fumarate (1:2) ) quite or better.
实施例19Example 19
溶解度研究Solubility study
取富马酸替诺福韦艾拉酚胺(1:1)(按专利文献CN1443189A中公开的方法制备)、富马酸替诺福韦艾拉酚胺(1:1)(按专利文献CN103732594A中公开的方法制备)、L-酒石酸替诺福韦艾拉酚胺(1:1)(按实施例2的方法制备)、DL-酒石酸替诺福韦艾拉酚胺(1:1)(按实施例6的方法制备)和柠檬酸替诺福韦艾拉酚胺(1:1)(按实施例8的方法制备)，在25℃下分别测试它们在不同介质中的溶解性，结果如下(下表中TAF代表替诺福韦艾拉酚胺)： Tenofovir alafenamide fumarate (1:1) (prepared according to the method disclosed in patent document CN1443189A), tenofovir fumarate fumarate (1:1) (according to patent document CN103732594A) Prepared by the method disclosed), Tenofovir alafenamide (1:1) (prepared according to the method of Example 2), DL-tenofovir alafenamide (1:1) ( Prepared according to the method of Example 6 and tenofovir alafenamide (1:1) (prepared according to the method of Example 8), and tested their solubility in different media at 25 ° C, respectively. As follows (TAF in the table below represents tenofovir alafenamide):
Figure PCTCN2015078188-appb-000017
Figure PCTCN2015078188-appb-000017
上述研究表明，本发明提供的L-酒石酸替诺福韦艾拉酚胺(1:2)、DL-酒石酸替诺福韦艾拉酚胺(1:1)和柠檬酸替诺福韦艾拉酚胺(1:1)的溶解性与富马酸替诺福韦艾拉酚胺(1:1)、富马酸替诺福韦艾拉酚胺(1:2)相当或更好。The above studies show that the present invention provides tenofovir alafenamide (1:2), DL-tenofovir idylamine tartrate (1:1) and tenofovira citric acid. The solubility of phenolamine (1:1) is comparable to or better than tenofovir lysamine fumarate (1:1) and tenofovir fumarate (1:2).
实施例20Example 20
动物药代动力学实验Animal pharmacokinetics experiment
通过使用μm筛过筛，制备具备相当晶体尺寸的L-酒石酸替诺福韦艾拉酚胺(1:2)[简称：L-酒石酸TAF(1:2)，受试药物1]、柠檬酸替诺福韦艾拉酚胺(1:1)[简称：柠檬酸TAF(1:1)，受试药物2]和富马酸替诺福韦艾拉酚胺(1:2)[简称：富马酸TAF(1:2)，参比药物]。选用SD大鼠24只，雌雄各半，体重200-270g，随机分为3组，分别灌胃给予受试药物1、受试药物2及参比药物，剂量均为10mg/kg(按替诺福韦艾拉酚胺计)。于给药前和给药后15分钟、30分钟、1小时、2小时、3小时、4小时、8小时、12小时和24小时通过颈静脉采血，每次约200μL，3500转/分钟，离心10分钟，取上层血浆，通过LC-MS/MS定量分析血浆中替诺福韦药物浓度。Tenofovir alafenamide (1:2) of L-tartrate with a relatively crystal size was prepared by sieving with a μm sieve [abbreviation: L-tartaric acid TAF (1:2), test drug 1], citric acid Tenofovir alafenamide (1:1) [abbreviation: citric acid TAF (1:1), test drug 2] and tenofovir alafenamide (1:2) [abbreviation: Fumaric acid TAF (1:2), reference drug]. Twenty-four SD rats, male and female, weighing 200-270 g, were randomly divided into 3 groups. The test drugs, test drug 2 and reference drug were administered by gavage respectively. The doses were all 10 mg/kg. Fuwei ilaphenolamine meter). Blood was collected from the jugular vein before administration and at 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration, about 200 μL each time, 3500 rpm, and centrifuged. After 10 minutes, the upper plasma was taken and the concentration of tenofovir in plasma was quantitatively analyzed by LC-MS/MS.
采用WinNonlin 5.3软件非房室方法计算比格犬给药后替诺福韦的主要药动学参数：达峰时间Tmax和达峰浓度Cmax采用实测值；血浆药物浓度-时间曲线下面积AUC0-t采用梯形法计算值；AUC0-∞按下列公式计算：AUC0-∞＝AUC0-t+Ct/ke，Ct为最后一个可测定时间点的浓度，ke为消除速率常数；血浆消除半衰期t1/2＝0.693/ke。The main pharmacokinetic parameters of tenofovir after Beagle administration were calculated by WinNonlin 5.3 software non-compartmental method: peak time T max and peak concentration C max were measured; plasma drug concentration-time curve area AUC 0-t is calculated by the trapezoidal method; AUC 0-∞ is calculated according to the following formula: AUC 0-∞ =AUC 0-t +C t /k e , C t is the concentration of the last measurable time point, k e is the elimination Rate constant; plasma elimination half-life t 1/2 =0.693/k e .
采用配对t检验，比较替诺福韦的药动学参数在给予受试药物和参比药物后的差异， Tmax采用非参数检验，其他参数经对数转换后进行检验。主要药动学参数及t检验结果如下表：The paired t-test was used to compare the pharmacokinetic parameters of tenofovir after administration of the test drug and the reference drug. Tmax was tested by nonparametric test, and other parameters were tested after logarithmic transformation. The main pharmacokinetic parameters and t test results are as follows:
Figure PCTCN2015078188-appb-000018
Figure PCTCN2015078188-appb-000018
上述研究表明，L-酒石酸TAF(1:2)、柠檬酸TAF(1:1)与富马酸TAF(1:2)的主要药动学参数均没有统计学差异(P>0.05)，表明L-酒石酸TAF(1:2)、柠檬酸TAF(1:1)与富马酸TAF(1:2)在大鼠体内药动学性质无统计学差异，生物等效。The above studies showed that the main pharmacokinetic parameters of T-tartaric acid TAF (1:2), citric acid TAF (1:1) and fumaric acid TAF (1:2) were not statistically different (P>0.05), indicating The pharmacokinetic properties of L-tartaric acid TAF (1:2), citric acid TAF (1:1) and fumaric acid TAF (1:2) in rats were not statistically different and bioequivalent.
实施例21Example 21
L-酒石酸替诺福韦艾拉酚胺(1:2)薄膜包衣片及其制备L-norofovir alafenamide (1:2) film coated tablet of L-tartaric acid and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
L-酒石酸替诺福韦艾拉酚胺(1:2)L-tenofovir alafenamide (1:2) 28.928.9
一水乳糖Lactose monohydrate 100.0100.0
微晶纤维素Microcrystalline cellulose 60.060.0
交联羧甲纤维素钠Croscarmellose sodium 15.015.0
硬脂酸镁Magnesium stearate 3.03.0
薄膜包衣材料：Film coating material:  
欧巴代ⅡOpadi II 10.010.0
具体操作：Specific operations:
按照上表中各原辅料称量，将微晶纤维素与交联羧甲纤维素钠混合，然后加入一水乳糖混合，再加入L-酒石酸替诺福韦艾拉酚胺(1:2)混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，压片；然后将包衣材料用75％乙醇配成混悬液包衣，即得。Weigh the microcrystalline cellulose with croscarmellose sodium according to the raw materials in the above table, then add lactose monohydrate, then add tenofovir alafenamide (1:2). Mixing; adding purified water to the appropriate amount of wet granulation; drying; granulating; adding magnesium stearate to mix, tableting; and then coating the coating material with 75% ethanol to form a suspension, that is.
实施例22 Example 22
L-酒石酸替诺福韦艾拉酚胺(1:2)胶囊剂及其制备L-tenofovir levamide (1:2) capsule of L-tartaric acid and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
L-酒石酸替诺福韦艾拉酚胺(1:2)晶型AL-tenofovir alafenamide (1:2) crystal form A 28.928.9
一水乳糖Lactose monohydrate 100.0100.0
微晶纤维素Microcrystalline cellulose 100.0100.0
羧甲基淀粉钠Carboxymethyl starch sodium 15.015.0
硬脂酸镁Magnesium stearate 1.51.5
具体操作：Specific operations:
按照上表中各原辅料称量，先将羧甲基淀粉钠与微晶纤维素混合，然后加入一水乳糖混合，再加入L-酒石酸替诺福韦艾拉酚胺(1:2)；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，填充入羟丙甲纤维素胶囊，即得。According to the raw materials in the above table, the sodium carboxymethyl starch was first mixed with the microcrystalline cellulose, then the lactose monohydrate was added, and then the ten-five valeramine (1:2) was added. Add purified water to the appropriate amount of wet granulation; dry; granules; add magnesium stearate to mix, fill with hypromellose capsules, that is.
实施例23Example 23
D-酒石酸替诺福韦艾拉酚胺(1:1)薄膜包衣片及其制备D-tanofos acetamide (1:1) film coated tablet of D-tartaric acid and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
D-酒石酸替诺福韦艾拉酚胺(1:1)D-tenofovir alafenamide tartrate (1:1) 32.932.9
一水乳糖Lactose monohydrate 100.0100.0
微晶纤维素Microcrystalline cellulose 60.060.0
交联羧甲纤维素钠Croscarmellose sodium 15.015.0
硬脂酸镁Magnesium stearate 3.03.0
薄膜包衣材料：Film coating material:  
欧巴代ⅡOpadi II 10.010.0
具体操作：Specific operations:
按照上表中各原辅料称量，将微晶纤维素与交联羧甲纤维素钠混合，然后加入一水乳糖混合，再加入D-酒石酸替诺福韦艾拉酚胺(1:1)混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，压片；然后将包衣材料用75％乙醇配成混悬液包衣，即得。Weigh the microcrystalline cellulose with croscarmellose sodium according to the raw materials in the above table, then add lactose monohydrate, then add Dinofosyl alafenamide (1:1). Mixing; adding purified water to the appropriate amount of wet granulation; drying; granulating; adding magnesium stearate to mix, tableting; and then coating the coating material with 75% ethanol to form a suspension, that is.
实施例24Example 24
DL-酒石酸替诺福韦艾拉酚胺(1:1)薄膜包衣片及其制备 DL-tenofovir alafenamide (1:1) film coated tablet and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
DL-酒石酸替诺福韦艾拉酚胺(1:1)DL-tenofovir alafenamide (1:1) 32.932.9
一水乳糖Lactose monohydrate 100.0100.0
微晶纤维素Microcrystalline cellulose 60.060.0
交联羧甲纤维素钠Croscarmellose sodium 15.015.0
硬脂酸镁Magnesium stearate 3.03.0
薄膜包衣材料：Film coating material:  
欧巴代ⅡOpadi II 10.010.0
具体操作：Specific operations:
按照上表中各原辅料称量，将微晶纤维素与交联羧甲纤维素钠混合，然后加入一水乳糖混合，再加入DL-酒石酸替诺福韦艾拉酚胺(1:1)混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，压片；然后将包衣材料用75％乙醇配成混悬液包衣，即得。Weigh the microcrystalline cellulose and croscarmellose sodium according to the raw materials in the above table, then add the lactose monohydrate, then add DL-tenofovir alafenamide (1:1). Mixing; adding purified water to the appropriate amount of wet granulation; drying; granulating; adding magnesium stearate to mix, tableting; and then coating the coating material with 75% ethanol to form a suspension, that is.
实施例25Example 25
L-苹果酸替诺福韦艾拉酚胺(1:2)薄膜包衣片及其制备L-malofovir alafenamide (1:2) film coated tablet and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
L-苹果酸替诺福韦艾拉酚胺(1:2)L-malofovir alafenamide (1:2) 28.528.5
一水乳糖Lactose monohydrate 100.0100.0
微晶纤维素Microcrystalline cellulose 60.060.0
交联羧甲纤维素钠Croscarmellose sodium 15.015.0
硬脂酸镁Magnesium stearate 3.03.0
薄膜包衣材料：Film coating material:  
欧巴代ⅡOpadi II 10.010.0
具体操作：Specific operations:
按照上表中各原辅料称量，将微晶纤维素与交联羧甲纤维素钠混合，然后加入一水乳糖混合，再加入L-苹果酸替诺福韦艾拉酚胺(1:2)混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，压片；然后将包衣材料用75％乙醇配成混悬液包衣，即得。Weigh the microcrystalline cellulose and croscarmellose sodium according to the raw materials in the above table, then add lactose monohydrate, then add tenofovir alafenamide (1:2). Mixing; adding purified water to the appropriate amount of wet granulation; drying; granulating; adding magnesium stearate to mix, tableting; and then coating the coating material with 75% ethanol to form a suspension, that is.
实施例26 Example 26
柠檬酸替诺福韦艾拉酚胺(1:1)薄膜包衣片及其制备Tenofovir acetamide (1:1) film coated tablets and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
柠檬酸替诺福韦艾拉酚胺(1:1)Tenofovir eugenol citrate (1:1) 35.135.1
一水乳糖Lactose monohydrate 100.0100.0
微晶纤维素Microcrystalline cellulose 60.060.0
交联羧甲纤维素钠Croscarmellose sodium 15.015.0
硬脂酸镁Magnesium stearate 3.03.0
薄膜包衣材料：Film coating material:  
欧巴代ⅡOpadi II 10.010.0
具体操作：Specific operations:
按照上表中各原辅料称量，将微晶纤维素与交联羧甲纤维素钠混合，然后加入一水乳糖混合，再加入柠檬酸替诺福韦艾拉酚胺(1:1)混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，压片；然后将包衣材料用75％乙醇配成混悬液包衣，即得。Weigh the microcrystalline cellulose with croscarmellose sodium according to the raw materials in the above table, then add lactose monohydrate, then add tenofovir ylide (1:1). Adding purified water to the appropriate amount of wet granulation; drying; granulating; adding magnesium stearate to mix, tableting; and then coating the coating material with 75% ethanol to form a suspension, that is.
实施例27Example 27
琥珀酸替诺福韦艾拉酚胺(1:1)薄膜包衣片及其制备Tenofovir alafenamide (1:1) film coated tablets and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
琥珀酸替诺福韦艾拉酚胺(1:1)Tenofovir alafenamide succinate (1:1) 31.231.2
一水乳糖Lactose monohydrate 100.0100.0
微晶纤维素Microcrystalline cellulose 60.060.0
交联羧甲纤维素钠Croscarmellose sodium 15.015.0
硬脂酸镁Magnesium stearate 3.03.0
薄膜包衣材料：Film coating material:  
欧巴代ⅡOpadi II 10.010.0
具体操作：Specific operations:
按照上表中各原辅料称量，将微晶纤维素与交联羧甲纤维素钠混合，然后加入一水乳糖混合，再加入琥珀酸替诺福韦艾拉酚胺(1:1)混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，压片；然后将包衣材料用75％乙醇配成混悬液包衣，即得。Weigh the microcrystalline cellulose and croscarmellose sodium according to the raw materials in the above table, then add lactose monohydrate, then add tenofovir alafenamide (1:1). Adding purified water to the appropriate amount of wet granulation; drying; granulating; adding magnesium stearate to mix, tableting; and then coating the coating material with 75% ethanol to form a suspension, that is.
实施例28 Example 28
草酸替诺福韦艾拉酚胺(1:1)薄膜包衣片及其制备Tenofovir alafenamide (1:1) film coated tablets and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
草酸替诺福韦艾拉酚胺(1:1)Tenofovir alafenamide (1:1) 29.729.7
一水乳糖Lactose monohydrate 100.0100.0
微晶纤维素Microcrystalline cellulose 60.060.0
交联羧甲纤维素钠Croscarmellose sodium 15.015.0
硬脂酸镁Magnesium stearate 3.03.0
薄膜包衣材料：Film coating material:  
欧巴代ⅡOpadi II 10.010.0
具体操作：Specific operations:
按照上表中各原辅料称量，将微晶纤维素与交联羧甲纤维素钠混合，然后加入一水乳糖混合，再加入草酸替诺福韦艾拉酚胺(1:1)混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，压片；然后将包衣材料用75％乙醇配成混悬液包衣，即得。According to the raw materials in the above table, the microcrystalline cellulose is mixed with croscarmellose sodium, then added with lactose monohydrate, and then mixed with tenofovir alafenamide (1:1); Adding purified water to the appropriate amount of wet granulation; drying; granulating; adding magnesium stearate to mix, tableting; then coating the coating material with 75% ethanol to form a suspension, that is, obtained.
实施例29Example 29
磷酸替诺福韦艾拉酚胺(1:1)薄膜包衣片及其制备Tenofovir alafenamide (1:1) film coated tablets and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
磷酸替诺福韦艾拉酚胺(1:1)Tenofovir alafenamide (1:1) 30.130.1
一水乳糖Lactose monohydrate 100.0100.0
微晶纤维素Microcrystalline cellulose 60.060.0
交联羧甲纤维素钠Croscarmellose sodium 15.015.0
硬脂酸镁Magnesium stearate 3.03.0
薄膜包衣材料：Film coating material:  
欧巴代ⅡOpadi II 10.010.0
具体操作：Specific operations:
按照上表中各原辅料称量，将微晶纤维素与交联羧甲纤维素钠混合，然后加入一水乳糖混合，再加入磷酸替诺福韦艾拉酚胺(1:1)混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，压片；然后将包衣材料用75％乙醇配成混悬液包衣，即得。According to the raw materials in the above table, the microcrystalline cellulose was mixed with croscarmellose sodium, then added with lactose monohydrate, and then mixed with tenofovir alafenamide (1:1); Adding purified water to the appropriate amount of wet granulation; drying; granulating; adding magnesium stearate to mix, tableting; then coating the coating material with 75% ethanol to form a suspension, that is, obtained.
实施例30 Example 30
硫酸替诺福韦艾拉酚胺(1:1)薄膜包衣片及其制备Tenofovir alafenamide (1:1) film coated tablets and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
硫酸替诺福韦艾拉酚胺(1:1)Tenofovir alafenamide (1:1) 30.130.1
一水乳糖Lactose monohydrate 100.0100.0
微晶纤维素Microcrystalline cellulose 60.060.0
交联羧甲纤维素钠Croscarmellose sodium 15.015.0
硬脂酸镁Magnesium stearate 3.03.0
薄膜包衣材料：Film coating material:  
欧巴代ⅡOpadi II 10.010.0
具体操作：Specific operations:
按照上表中各原辅料称量，将微晶纤维素与交联羧甲纤维素钠混合，然后加入一水乳糖混合，再加入硫酸替诺福韦艾拉酚胺(1:1)混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，压片；然后将包衣材料用75％乙醇配成混悬液包衣，即得。Weigh the microcrystalline cellulose and croscarmellose sodium according to the raw materials in the above table, then add lactose monohydrate, and then add tenofovir alafenamide (1:1). Adding purified water to the appropriate amount of wet granulation; drying; granulating; adding magnesium stearate to mix, tableting; then coating the coating material with 75% ethanol to form a suspension, that is, obtained.
实施例31Example 31
L-酒石酸替诺福韦艾拉酚胺(1:2)、恩曲他滨、Cobicistat、埃替拉韦双层片及其制备Tenofovir ilafenamide (1:2), emtricitabine, Cobicistat, ethiravir double-layer tablets and preparation thereof
Figure PCTCN2015078188-appb-000019
Figure PCTCN2015078188-appb-000019
具体操作：Specific operations:
(1)、粒-I制备：按照上表中各原辅料称量，先将预胶化滨粉与交联羧甲纤维素钠混合，然后加入一水乳糖和微晶纤维素混合，再加入L-酒石酸替诺福韦艾拉酚胺(1:2)混合，最后加入恩曲他滨混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，即得。 (1) Preparation of granule-I: According to the raw materials in the above table, the pre-gelatinized side powder is mixed with croscarmellose sodium, then the lactose monohydrate and microcrystalline cellulose are mixed, and then added. L-tanofosyl alafenamide (1:2) is mixed, and finally added to emtricitabine; add purified water to prepare wet granulation; dry; granule; add magnesium stearate to mix, that is.
(2)、粒-II制备：按照上表中各原辅料称量，先将羟丙纤维素、交联羧甲纤维素钠和20％一水乳糖混合，然后加入剩余一水乳糖混合，再加入埃替拉韦和Cobicistat混合，最后加入微晶纤维素混合；用纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，即得。(2) Preparation of granule-II: According to the raw materials in the above table, first mix hydroxypropyl cellulose, croscarmellose sodium and 20% lactose monohydrate, then add the remaining lactose to mix, then Add ethivavir and Cobicistat to mix, finally add microcrystalline cellulose to mix; use appropriate amount of purified water to wet granulation; dry; granule; add magnesium stearate to mix, that is.
(3)、将芯粒-I和芯粒-Ⅱ采用双层压片机压片；然后将包衣材料用75％乙醇配成混悬液包衣，即得。(3) The core particle-I and the core particle-II are tableted by a double laminating machine; then the coating material is coated with 75% ethanol to form a suspension, which is obtained.
实施例32Example 32
DL-酒石酸替诺福韦艾拉酚胺(1:1)、恩曲他滨、Cobicistat、地瑞那韦双层片及其制备DL-tenofovir levamide (1:1), emtricitabine, Cobicistat, darunavir double-layer tablets and preparation thereof
Figure PCTCN2015078188-appb-000020
Figure PCTCN2015078188-appb-000020
具体操作：Specific operations:
(1)、粒-I制备：按照上表中各原辅料称量，先将预胶化滨粉与交联羧甲纤维素钠一起混合，然后加入一水乳糖和微晶纤维素混合，再加入DL-酒石酸替诺福韦艾拉酚胺(1:1)混合，最后加入恩曲他滨混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，即得。(1) Preparation of granule-I: According to the weighing of the raw materials in the above table, the pre-gelatinized side powder is mixed with croscarmellose sodium, and then lactose monohydrate and microcrystalline cellulose are mixed, and then Add DL-tenofovir alafenamide (1:1), and finally add emtricitabine; add purified water to wet granulation; dry; granule; add magnesium stearate to mix, that is .
(2)、粒-II制备：按照上表中各原辅料称量，先将月桂硫酸钠、羟丙纤维素、交联羧甲纤维素钠和20％一水乳糖混合，然后加入剩余一水乳糖混合，再加入地瑞那韦和Cobicistat混合，最后加入微晶纤维素混合；用纯化水适量湿法；干燥；整粒；外加硬脂酸镁混匀，即得。(2) Preparation of granule-II: According to the raw materials in the above table, first mix sodium lauryl sulfate, hydroxypropyl cellulose, croscarmellose sodium and 20% lactose monohydrate, then add the remaining water. Lactose is mixed, and then added darunavir and Cobicistat, and finally mixed with microcrystalline cellulose; wet water with purified water; dried; granules; added with magnesium stearate, which is obtained.
(3)、将芯粒-I和芯粒-Ⅱ采用双层压片机压片；然后将包衣材料用75％乙醇配成混悬液包衣，即得。(3) The core particle-I and the core particle-II are tableted by a double laminating machine; then the coating material is coated with 75% ethanol to form a suspension, which is obtained.
实施例33 Example 33
L-酒石酸替诺福韦艾拉酚胺(1:2)、恩曲他滨薄膜包衣片及其制备L-tenofovir lysamine (1:2), emtricitabine film coated tablets and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
L-酒石酸替诺福韦艾拉酚胺(1:2)L-tenofovir alafenamide (1:2) 28.928.9
恩曲他滨Emtricitabine 200.0200.0
微晶纤维素Microcrystalline cellulose 300.0300.0
一水乳糖Lactose monohydrate 120.0120.0
预胶化淀粉Pregelatinized starch 40.040.0
交联羧甲纤维素钠Croscarmellose sodium 15.015.0
硬脂酸镁Magnesium stearate 6.06.0
薄膜包衣材料：Film coating material:  
欧巴代ⅡOpadi II 20.020.0
具体操作：Specific operations:
按照上表中各原辅料称量，先将预胶化淀粉与交联羧甲纤维素钠混合，然后加入一水乳糖混合，再加入恩曲他滨混合，最后加入L-酒石酸替诺福韦艾拉酚胺(1:2)和微晶纤维素混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，压片；将包衣材料用75％乙醇配成混悬液包衣，即得。Weigh the pre-gelatinized starch with croscarmellose sodium according to the raw materials in the above table, then add lactose monohydrate, then add emtricitabine, and finally add l-folvavir L-tartrate. Mixing levamide (1:2) and microcrystalline cellulose; adding purified water to wet granulation; drying; granulating; adding magnesium stearate to mix, tableting; Suspension coating, that is.
实施例34Example 34
磷酸替诺福韦艾拉酚胺(1:1)、恩曲他滨薄膜包衣片及其制备Tenofovir iramol phosphate (1:1), emtricitabine film coated tablets and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
磷酸替诺福韦艾拉酚胺(1:1)Tenofovir alafenamide (1:1) 30.130.1
恩曲他滨Emtricitabine 200.0200.0
微晶纤维素Microcrystalline cellulose 300.0300.0
一水乳糖Lactose monohydrate 120.0120.0
预胶化淀粉Pregelatinized starch 40.040.0
交联羧甲纤维素钠Croscarmellose sodium 15.015.0
硬脂酸镁Magnesium stearate 6.06.0
薄膜包衣材料：Film coating material:  
欧巴代ⅡOpadi II 20.020.0
具体操作：Specific operations:
按照上表中各原辅料称量，先将预胶化淀粉与交联羧甲纤维素钠混合，然后加入一水乳糖混合，再加入恩曲他滨混合，最后加入磷酸替诺福韦艾拉酚胺(1:1)和微晶纤维素混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，压片；将包衣材料用75％乙醇配成混悬液包衣，即得。Weigh the pre-gelatinized starch with croscarmellose sodium according to the raw materials in the above table, then add lactose monohydrate, then add emtricitabine, and finally add tenofoviraine phosphate. Mixing phenolamine (1:1) with microcrystalline cellulose; adding appropriate amount of purified water to wet granulation; drying; granulating; adding magnesium stearate to mix and compress; compressing the coating material with 75% ethanol Liquid coating, that is.
实施例35Example 35
D-酒石酸替诺福韦艾拉酚胺(1:1)、恩曲他滨、依法韦仑薄膜包衣双层片及其制备D-tanofos levamide (1:1), emtricitabine, efavirenz film coated double-layer tablets and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
粒-I：Grain-I:  
D-酒石酸替诺福韦艾拉酚胺(1:1)D-tenofovir alafenamide tartrate (1:1) 13.113.1
恩曲他滨Emtricitabine 200.0200.0
微晶纤维素Microcrystalline cellulose 200.0200.0
交联羧甲纤维素钠Croscarmellose sodium 20.020.0
硬脂酸镁Magnesium stearate 7.07.0
粒-Ⅱ：Granule-II:  
依法韦仑Ephel 600.0600.0
微晶纤维素Microcrystalline cellulose 130.0130.0
羟丙纤维素Hydroxypropyl cellulose 20.020.0
交联羧甲纤维素钠Croscarmellose sodium 20.020.0
月桂硫酸钠Sodium lauryl sulfate 10.010.0
硬脂酸镁Magnesium stearate 10.010.0
薄膜包衣材料Film coating material  
欧巴代ⅡOpadi II 30.030.0
具体操作：Specific operations:
(1)、粒-I制备：按照上表中各原辅料称量，先将微晶纤维素与交联羧甲纤维素钠一起混合，然后加入D-酒石酸替诺福韦艾拉酚胺(1:1)混合，再加入恩曲他滨混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，即得。(1) Preparation of granule-I: According to the raw materials in the above table, the microcrystalline cellulose is mixed with croscarmellose sodium, and then D-norfosyl alafenide D (tartrate) is added. 1:1) mixing, then adding emtricitabine mixture; adding purified water to the appropriate amount of wet granulation; drying; granules; adding magnesium stearate to mix, that is.
(2)、粒-II制备：按照上表中各原辅料称量，先将月桂硫酸钠、交联羧甲纤维素钠以及羟丙纤维素混合，然后加入微晶纤维素混合，再加入依法韦仑混合；加纯化水适量湿法制 粒；干燥；整粒；外加硬脂酸镁混匀，即得。(2) Preparation of granule-II: According to the raw materials in the above table, the sodium lauryl sulfate, croscarmellose sodium and hydroxypropyl cellulose are mixed first, then the microcrystalline cellulose is mixed, and then added according to the law. Weilun mixture; adding purified water to the amount of wet method Granules; dry; whole granules; add magnesium stearate to mix, that is.
(3)、将芯粒-I和芯粒-Ⅱ采用双层压片机压片；将包衣材料用75％乙醇配成混悬液包衣，即得。(3) The core particle-I and the core particle-II are tableted by a double laminating machine; the coating material is coated with a 75% ethanol solution to obtain a suspension.
实施例36Example 36
L-苹果酸替诺福韦艾拉酚胺(1:2)、恩曲他滨、依法韦仑薄膜包衣双层片及其制备Tenofovir alafenamide (1:2), emtricitabine, efavirenz film coated double-layer tablets and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
粒-I：Grain-I:  
L-苹果酸替诺福韦艾拉酚胺(1:2)L-malofovir alafenamide (1:2) 11.411.4
恩曲他滨Emtricitabine 200.0200.0
微晶纤维素Microcrystalline cellulose 200.0200.0
交联羧甲纤维素钠Croscarmellose sodium 20.020.0
硬脂酸镁Magnesium stearate 7.07.0
粒-Ⅱ：Granule-II:  
依法韦仑Ephel 600.0600.0
微晶纤维素Microcrystalline cellulose 130.0130.0
羟丙纤维素Hydroxypropyl cellulose 20.020.0
交联羧甲纤维素钠Croscarmellose sodium 20.020.0
月桂硫酸钠Sodium lauryl sulfate 10.010.0
硬脂酸镁Magnesium stearate 10.010.0
薄膜包衣材料Film coating material  
欧巴代ⅡOpadi II 30.030.0
具体操作：Specific operations:
(1)、粒-I制备：按照上表中各原辅料称量，先将微晶纤维素与交联羧甲纤维素钠混合，然后加入L-苹果酸替诺福韦艾拉酚胺(1:2)混合，再加入恩曲他滨混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，即得。(1) Preparation of granule-I: According to the weighing of the raw materials in the above table, the microcrystalline cellulose is mixed with croscarmellose sodium, and then tenofovir alafenamide L-malate is added. 1:2) Mixing, then adding emtricitabine; adding purified water to the appropriate amount of wet granulation; drying; granulating; adding magnesium stearate to mix, that is.
(2)、粒-II制备：按照上表中各原辅料称量，先将月桂硫酸钠、交联羧甲纤维素钠以及羟丙纤维素混合，然后加入微晶纤维素混合，再加入依法韦仑混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，即得。(2) Preparation of granule-II: According to the raw materials in the above table, the sodium lauryl sulfate, croscarmellose sodium and hydroxypropyl cellulose are mixed first, then the microcrystalline cellulose is mixed, and then added according to the law. Welch mixture; add purified water to the appropriate amount of wet granulation; drying; granules; add magnesium stearate to mix, that is.
(3)、将芯粒-I和芯粒-Ⅱ采用双层压片机压片；将包衣材料用75％乙醇配成混悬液包 衣，即得。(3), the core particles -I and core particles - II using a double laminator tablet; the coating material with 75% ethanol into a suspension package Clothing, that is.
实施例37Example 37
柠檬酸替诺福韦艾拉酚胺(1:1)、恩曲他滨、盐酸利匹韦林薄膜包衣双层片及其制备Tenofovir acetamide citrate (1:1), emtricitabine, lipirone hydrochloride film coated double-layer tablets and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
粒-I：Grain-I:  
柠檬酸替诺福韦艾拉酚胺(1:1)Tenofovir eugenol citrate (1:1) 14.014.0
恩曲他滨Emtricitabine 200.0200.0
微晶纤维素Microcrystalline cellulose 200.0200.0
一水乳糖Lactose monohydrate 150.0150.0
预胶化滨粉Pregelatinized powder 40.040.0
交联羧甲纤维素钠Croscarmellose sodium 20.020.0
硬脂酸镁Magnesium stearate 7.07.0
粒-Ⅱ：Granule-II:  
盐酸利匹韦林Lipiride hydrochloride 27.527.5
一水乳糖Lactose monohydrate 200.0200.0
微晶纤维素Microcrystalline cellulose 60.060.0
交联羧甲纤维素钠Croscarmellose sodium 15.015.0
聚维酮K30 Povidone K 30 3.03.0
硬脂酸镁Magnesium stearate 3.03.0
聚山梨醇酯20Polysorbate 20 0.50.5
薄膜包衣材料Film coating material  
欧巴代ⅡOpadi II 25.025.0
具体操作：Specific operations:
(1)、粒-I制备：按照上表中各原辅料称量，先将预胶化滨粉与交联羧甲纤维素钠混合，然后加入一水乳糖和微晶纤维素混合，再加入柠檬酸替诺福韦艾拉酚胺(1:1)混合，最后加入恩曲他滨混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，即得。(1) Preparation of granule-I: According to the raw materials in the above table, the pre-gelatinized side powder is mixed with croscarmellose sodium, then the lactose monohydrate and microcrystalline cellulose are mixed, and then added. Mix tenofovir eugenol citrate (1:1), and finally add emtricitabine; add purified water to prepare wet granulation; dry; granule; add magnesium stearate to mix, that is.
(2)、粒-II制备：按照上表中各原辅料称量，先将微晶纤维素和交联羧甲纤维素钠混合，然后加入一水乳糖混合，再加入盐酸利匹韦林混合；用聚维酮K30和聚山梨醇酯20的水溶 液湿法制粒；干燥；整粒；外加硬脂酸镁混匀，即得。(2) Preparation of granule-II: According to the raw materials in the above table, the microcrystalline cellulose and the croscarmellose sodium are mixed first, then the lactose monohydrate is added, and then the lipirulin hydrochloride is mixed. Wet granulation with an aqueous solution of povidone K 30 and polysorbate 20; drying; granulating; adding magnesium stearate to mix, that is.
(3)、将芯粒-I和芯粒-Ⅱ采用双层压片机压片；将包衣材料用75％乙醇配成混悬液包衣，即得。(3) The core particle-I and the core particle-II are tableted by a double laminating machine; the coating material is coated with a 75% ethanol solution to obtain a suspension.
实施例38Example 38
琥珀酸替诺福韦艾拉酚胺(1:1)、拉米夫定薄膜包衣片及其制备Tenofovir alafenamide succinate (1:1), lamivudine film coated tablets and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
粒内：Within the grain:  
琥珀酸替诺福韦艾拉酚胺(1:1)Tenofovir alafenamide succinate (1:1) 12.512.5
拉米夫定Lamivudine 300.0300.0
微晶纤维素Microcrystalline cellulose 300.0300.0
交联羧甲纤维素钠Croscarmellose sodium 15.015.0
粒外：Extragranular:  
微晶纤维素Microcrystalline cellulose 140.0140.0
交联羧甲纤维素钠Croscarmellose sodium 15.015.0
硬脂酸镁Magnesium stearate 10.010.0
薄膜包衣材料：Film coating material:  
欧巴代ⅡOpadi II 25.025.0
具体操作：Specific operations:
按照上表中各原辅料称量，先将交联羧甲纤维素钠与微晶纤维素采用等量递加方法混合均匀，然后加入琥珀酸替诺福韦艾拉酚胺(1:1)混合，再加入拉米夫定混合；加纯化水适量湿法制粒；干燥；整粒；外加交联羧甲纤维素钠和微晶纤维素混合均匀，再加入硬脂酸镁混匀，压片；将包衣材料用75％乙醇配成混悬液包衣，即得。According to the weighing of the raw materials in the above table, the croscarmellose sodium and the microcrystalline cellulose are mixed uniformly by the equal amount, then the tenofovir alafenamide succinate (1:1) is added. Mixing, then adding lamivudine mixture; adding purified water to the appropriate amount of wet granulation; drying; granulating; adding croscarmellose sodium and microcrystalline cellulose mixed evenly, then adding magnesium stearate to mix, tableting The coating material is coated with 75% ethanol to form a suspension, which is obtained.
实施例39Example 39
草酸替诺福韦艾拉酚胺(1:1)、拉米夫定、依法韦仑薄膜包衣双层片及其制备Tenofovir alafenamide (1:1), lamivudine, efavirenz film coated double-layer tablets and preparation thereof
组分Component 含量(mg/片)Content (mg/tablet)
片芯：Chip core:  
粒-I：Grain-I:  
草酸替诺福韦艾拉酚胺(1:1)Tenofovir alafenamide (1:1) 11.911.9
拉米夫定Lamivudine 300.0300.0
微晶纤维素Microcrystalline cellulose 200.0200.0
交联羧甲纤维素钠Croscarmellose sodium 35.035.0
硬脂酸镁Magnesium stearate 7.07.0
粒-Ⅱ：Granule-II:  
依法韦仑Ephel 600.0600.0
微晶纤维素Microcrystalline cellulose 145.0145.0
羟丙纤维素Hydroxypropyl cellulose 20.020.0
交联羧甲纤维素钠Croscarmellose sodium 20.020.0
月桂硫酸钠Sodium lauryl sulfate 10.010.0
硬脂酸镁Magnesium stearate 10.010.0
薄膜包衣材料：Film coating material:  
欧巴代ⅡOpadi II 35.035.0
具体操作：Specific operations:
(1)、粒-I制备：按照上表中各原辅料称量，先将微晶纤维素与交联羧甲纤维素钠混合，然后加入草酸替诺福韦艾拉酚胺(1:1)混合，再加入拉米夫定混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，即得。(1) Preparation of granule-I: According to the raw materials in the above table, the microcrystalline cellulose was mixed with croscarmellose sodium, and then tenofovir alafenamide was added (1:1). Mixing, then adding lamivudine mixture; adding purified water to the appropriate amount of wet granulation; drying; granules; adding magnesium stearate to mix, that is.
(2)、粒-II制备：按照上表中各原辅料称量，先将羟丙纤维素、月桂硫酸钠以及交联羧甲纤维素钠混合；然后加入微晶纤维素混合，再加依法韦仑混合；用纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，即得。(2) Preparation of granule-II: According to the weighing of the raw materials in the above table, first mix hydroxypropyl cellulose, sodium lauryl sulfate and croscarmellose sodium; then add microcrystalline cellulose to mix, plus legal Welch mixture; use purified water to prepare granulation by wet method; dry; granule; add magnesium stearate to mix, that is.
(3)、将芯粒-I和芯粒-Ⅱ采用双层压片机压片；将包衣材料用75％乙醇配成混悬液包衣，即得。(3) The core particle-I and the core particle-II are tableted by a double laminating machine; the coating material is coated with a 75% ethanol solution to obtain a suspension.
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求书所限定的保护范围为准。 The above is only the specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can change without thinking of creative work within the technical scope of the present invention. Alternatives are intended to be covered by the scope of the present invention. Therefore, the scope of the invention should be determined by the scope of the invention as defined by the appended claims.

Claims (18)

  1. 式Ⅱ所示的替诺福韦艾拉酚胺复合物，Tenofovir alafenamide compound of formula II,
    Figure PCTCN2015078188-appb-100001
    Figure PCTCN2015078188-appb-100001
    其中，n＝1、2或3，X选自：盐酸、硫酸、过硫酸、硫氰酸、氢溴酸、氢碘酸、磷酸、硝酸、碳酸、十二烷基硫酸、甘油磷酸、甲磺酸、乙磺酸、2-羟基乙磺酸、牛磺酸、樟脑磺酸、环己氨磺酸、氨基磺酸、乙二磺酸、丁二磺酸、苯磺酸、对甲苯磺酸、对羟基苯磺酸、邻羟基苯磺酸、2,5-二羟基苯磺酸、对氨基苯磺酸、萘-2-磺酸、萘-1,5-二磺酸、甲酸、乙酸、羟乙酸、2,2-二氯乙酸、丙酸、L-乳酸、D-乳酸、消旋乳酸、环戊烷丙酸、丁酸、戊酸、己酸、庚酸、辛酸、壬酸、癸酸、十一烯酸、月桂酸、棕榈酸、硬脂酸、油酸、草酸、丙二酸、琥珀酸、L-苹果酸、D-苹果酸、消旋苹果酸、L-酒石酸、D-酒石酸、外消旋酒石酸、内消旋酒石酸、马来酸、羟基马来酸、戊二酸、2-氧代戊二酸、己二酸、癸二酸、柠檬酸、苯甲酸、对甲氧基苯甲酸、4-乙酰氨基苯甲酸、水杨酸、乙酰水杨酸、龙胆酸、4-氨基水杨酸、苯乙酸、L-扁桃酸、D-扁桃酸、消旋扁桃酸、3-苯基丙酸、肉桂酸、咖啡酸、苯丁酸、苦味酸、烟酸、乳清酸、奎尼酸、抗坏血酸、葡萄糖醛酸、葡萄糖酸、半乳糖醛酸、葡庚糖酸、乳糖酸、樟脑酸、半乳糖二酸、单宁酸、海藻酸、羟萘酸、双羟萘酸、乙酰氨乙酸、马尿酸、天门冬氨酸、谷氨酸、焦谷氨酸、谷氨酰胺、天门冬酰胺。Wherein n = 1, 2 or 3, X is selected from the group consisting of: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, lauryl sulfate, glycerophosphoric acid, methanesulfonate Acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, taurine, camphorsulfonic acid, cyclohexylsulfonic acid, sulfamic acid, ethanedisulfonic acid, succinic acid, benzenesulfonic acid, p-toluenesulfonic acid, P-hydroxybenzenesulfonic acid, o-hydroxybenzenesulfonic acid, 2,5-dihydroxybenzenesulfonic acid, p-aminobenzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, formic acid, acetic acid, hydroxyl Acetic acid, 2,2-dichloroacetic acid, propionic acid, L-lactic acid, D-lactic acid, racemic lactic acid, cyclopentanepropionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, octanoic acid, citric acid, citric acid , undecylenic acid, lauric acid, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, succinic acid, L-malic acid, D-malic acid, racemic malic acid, L-tartaric acid, D-tartaric acid , racemic tartaric acid, meso-tartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, 2-oxoglutaric acid, adipic acid, azelaic acid, citric acid, benzoic acid, p-methoxy Benzoic acid, 4-acetamidobenzoic acid, water Acid, acetylsalicylic acid, gentisic acid, 4-aminosalicylic acid, phenylacetic acid, L-mandelic acid, D-mandelic acid, racemic mandelic acid, 3-phenylpropionic acid, cinnamic acid, caffeic acid, benzene Butyric acid, picric acid, nicotinic acid, orotic acid, quinic acid, ascorbic acid, glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, lactobionic acid, camphoric acid, galactosuccinic acid, tannic acid Alginic acid, hydroxynaphthoic acid, pamoic acid, acetoacetic acid, hippuric acid, aspartic acid, glutamic acid, pyroglutamic acid, glutamine, asparagine.
  2. 根据权利要求1所述的替诺福韦艾拉酚胺复合物，其中，The tenofovir alafenamide complex according to claim 1, wherein
    n＝3，X选自：磷酸、柠檬酸、单宁酸或海藻酸；或者，n=3, X is selected from: phosphoric acid, citric acid, tannic acid or alginic acid; or
    n＝2，X选自：硫酸、过硫酸、硫氰酸、磷酸、碳酸、甘油磷酸、乙二磺酸、丁二磺酸、萘-1,5-二磺酸、草酸、丙二酸、琥珀酸、L-苹果酸、D-苹果酸、消旋苹果酸、L-酒石酸、D-酒石酸、外消旋酒石酸、内消旋酒石酸、马来酸、羟基马来酸、戊二酸、2-氧代戊二酸、己二酸、癸二酸、柠檬酸、樟脑酸、半乳糖二酸、单宁酸、海藻酸、双羟萘酸、天门冬氨酸、谷氨酸；或者，n=2, X is selected from the group consisting of sulfuric acid, persulfuric acid, thiocyanic acid, phosphoric acid, carbonic acid, glycerol phosphate, ethanedisulfonic acid, succinic acid, naphthalene-1,5-disulfonic acid, oxalic acid, malonic acid, Succinic acid, L-malic acid, D-malic acid, racemic malic acid, L-tartaric acid, D-tartaric acid, racemic tartaric acid, meso-tartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, 2 - oxoglutaric acid, adipic acid, sebacic acid, citric acid, camphoric acid, galactonic acid, tannic acid, alginic acid, pamoic acid, aspartic acid, glutamic acid; or
    n＝1，X选自：盐酸、硫酸、过硫酸、硫氰酸、氢溴酸、氢碘酸、磷酸、硝酸、碳酸、十二烷基硫酸、甘油磷酸、甲磺酸、乙磺酸、2-羟基乙磺酸、牛磺酸、樟脑磺酸、环己氨磺酸、氨基磺酸、乙二磺酸、丁二磺酸、苯磺酸、对甲苯磺酸、对羟基苯磺酸、邻羟基苯 磺酸、2,5-二羟基苯磺酸、对氨基苯磺酸、糖精、萘-2-磺酸、萘-1,5-二磺酸、甲酸、乙酸、羟乙酸、2,2-二氯乙酸、丙酸、L-乳酸、D-乳酸、消旋乳酸、环戊烷丙酸、丁酸、戊酸、己酸、庚酸、辛酸、壬酸、癸酸、十一烯酸、月桂酸、棕榈酸、硬脂酸、油酸、草酸、丙二酸、琥珀酸、L-苹果酸、D-苹果酸、消旋苹果酸(又名：DL-苹果酸)、L-酒石酸、D-酒石酸、外消旋酒石酸、内消旋酒石酸、马来酸、羟基马来酸、戊二酸、2-氧代戊二酸、己二酸、癸二酸、柠檬酸、苯甲酸、对甲氧基苯甲酸、4-乙酰氨基苯甲酸、水杨酸、乙酰水杨酸、龙胆酸、4-氨基水杨酸、苯乙酸、L-扁桃酸、D-扁桃酸、消旋扁桃酸、3-苯基丙酸、肉桂酸、咖啡酸、苯丁酸、苦味酸、烟酸、乳清酸、奎尼酸、抗坏血酸、葡萄糖醛酸、葡萄糖酸、半乳糖醛酸、葡庚糖酸、乳糖酸、樟脑酸、半乳糖二酸、单宁酸、海藻酸、羟萘酸、双羟萘酸、乙酰氨乙酸、马尿酸、天门冬氨酸、谷氨酸、焦谷氨酸、谷氨酰胺、天门冬酰胺。n=1, X is selected from the group consisting of hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, dodecyl sulfuric acid, glycerophosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, taurine, camphorsulfonic acid, cyclohexylsulfonic acid, sulfamic acid, ethanedisulfonic acid, succinic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-hydroxybenzenesulfonic acid, O-hydroxybenzene Sulfonic acid, 2,5-dihydroxybenzenesulfonic acid, p-aminobenzenesulfonic acid, saccharin, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, formic acid, acetic acid, glycolic acid, 2,2-di Chloroacetic acid, propionic acid, L-lactic acid, D-lactic acid, racemic lactic acid, cyclopentanepropionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, capric acid, capric acid, undecylenic acid, laurel Acid, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, succinic acid, L-malic acid, D-malic acid, racemic malic acid (aka: DL-malic acid), L-tartaric acid, D -tartaric acid, racemic tartaric acid, meso-tartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, 2-oxoglutaric acid, adipic acid, azelaic acid, citric acid, benzoic acid, para Oxybenzoic acid, 4-acetamidobenzoic acid, salicylic acid, acetylsalicylic acid, gentisic acid, 4-aminosalicylic acid, phenylacetic acid, L-mandelic acid, D-mandelic acid, racemic mandelic acid, 3-phenylpropionic acid, cinnamic acid, caffeic acid, phenylbutyric acid, picric acid, nicotinic acid, orotic acid, quinic acid, ascorbic acid, glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, Lactose, camphoric acid, galactose Acid, tannic acid, alginic acid, hydroxynaphthoic acid, pamoic acid, acetylamino-acetic acid, hippuric acid, aspartic acid, glutamic acid, pyroglutamic acid, glutamine, asparagine.
  3. 根据权利要求2所述的替诺福韦艾拉酚胺复合物，其选自：L-酒石酸替诺福韦艾拉酚胺(1:2)、D-酒石酸替诺福韦艾拉酚胺(1:1)、DL-酒石酸替诺福韦艾拉酚胺(1:1)、L-苹果酸替诺福韦艾拉酚胺(1:2)、柠檬酸替诺福韦艾拉酚胺(1:1)、琥珀酸替诺福韦艾拉酚胺(1:1)、草酸替诺福韦艾拉酚胺(1:1)、磷酸替诺福韦艾拉酚胺(1:1)或硫酸替诺福韦艾拉酚胺(1:1)。The tenofovir alafenamide complex according to claim 2, which is selected from the group consisting of: L-norofovir lysamine (1:2) of L-tartrate, and tenofovir alafenamide of D-tartrate (1:1), DL-tenofovir iracrolimide tartrate (1:1), t-fibufur ylide (1:2), tenofovir eugenol Amine (1:1), tenofovir iramolamine succinate (1:1), tenofovir oxalatine oxalate (1:1), tenofovir enacil phosphate (1: 1) or tenofovir alafenamide (1:1).
  4. 根据权利要求3所述的替诺福韦艾拉酚胺复合物，其中，The tenofovir alafenamide complex according to claim 3, wherein
    所述L-酒石酸替诺福韦艾拉酚胺(1:2)为晶体；The tenofovir alafenamide (1:2) of L-tartrate is a crystal;
    所述D-酒石酸替诺福韦艾拉酚胺(1:1)为晶体；The D-tanofosyl alafenamide (1:1) of D-tartrate is a crystal;
    所述DL-酒石酸替诺福韦艾拉酚胺(1:1)为晶体；The DL-tenofovir alafenamide (1:1) is a crystal;
    所述L-苹果酸替诺福韦艾拉酚胺(1:2)为晶体；The tenofovir alafenamide (1:2) of L-malate is a crystal;
    所述柠檬酸替诺福韦艾拉酚胺(1:1)为晶体；The tenofovir iramol citrate (1:1) is a crystal;
    所述琥珀酸替诺福韦艾拉酚胺(1:1)为晶体；The tenofovir alafenamide succinate (1:1) is a crystal;
    所述草酸替诺福韦艾拉酚胺(1:1)为晶体；The tenofovir oxalatamide oxalate (1:1) is a crystal;
    所述磷酸替诺福韦艾拉酚胺(1:1)为晶体；The tenofovir ilapramide phosphate (1:1) is a crystal;
    所述硫酸替诺福韦艾拉酚胺(1:1)为晶体。The tenofovir alafenamide (1:1) is a crystal.
  5. 根据权利要求4所述的替诺福韦艾拉酚胺复合物，其中，The tenofovir alafenamide complex according to claim 4, wherein
    所述L-酒石酸替诺福韦艾拉酚胺(1:2)的晶型为晶型A，其使用Cu-Kα辐射的X-射线粉末衍射图谱的特征为：在2θ值为8.2°±0.2°、9.4°±0.2°、10.8°±0.2°、14.4°±0.2°、17.9°±0.2°、18.9°±0.2°、19.7°±0.2°、21.6°±0.2°处对应有特征衍射峰；The crystalline form of tenofovir alafenamide (1:2) of L-tartrate is crystalline form A, and its X-ray powder diffraction pattern using Cu-Kα radiation is characterized by a value of 8.2 ° ± 2θ. Characteristic diffraction peaks at 0.2°, 9.4°±0.2°, 10.8°±0.2°, 14.4°±0.2°, 17.9°±0.2°, 18.9°±0.2°, 19.7°±0.2°, 21.6°±0.2° ;
    所述D-酒石酸替诺福韦艾拉酚胺(1:1)的晶型为晶型A，其使用Cu-Kα辐射的X-射线粉末衍射图谱的特征为：在2θ值为7.8°±0.2°、9.5°±0.2°、12.5°±0.2°、15.1°±0.2°、15.9°±0.2°、 17.0°±0.2°、17.7°±0.2°、19.5°±0.2°处对应有特征衍射峰；The crystalline form of the ten-tenofovir alafenamide (1:1) of the D-tartrate is crystalline form A, and the X-ray powder diffraction pattern using Cu-Kα radiation is characterized by a value of 7.8° ± 2θ. 0.2°, 9.5°±0.2°, 12.5°±0.2°, 15.1°±0.2°, 15.9°±0.2°, Characteristic diffraction peaks corresponding to 17.0°±0.2°, 17.7°±0.2°, and 19.5°±0.2°;
    所述DL-酒石酸替诺福韦艾拉酚胺(1:1)的晶型为晶型A，其使用Cu-Kα辐射的X-射线粉末衍射图谱的特征为：在2θ值为6.8°±0.2°、8.0°±0.2°、9.7°±0.2°、16.0°±0.2°、16.9°±0.2°、18.2°±0.2°、18.9°±0.2°、20.2°±0.2°、21.1°±0.2°处对应有特征衍射峰；The crystalline form of the DL-tenofovir alafenamide (1:1) is crystalline form A, and the X-ray powder diffraction pattern using Cu-Kα radiation is characterized by a value of 6.8 ° ± 2θ. 0.2°, 8.0°±0.2°, 9.7°±0.2°, 16.0°±0.2°, 16.9°±0.2°, 18.2°±0.2°, 18.9°±0.2°, 20.2°±0.2°, 21.1°±0.2° Corresponding to characteristic diffraction peaks;
    所述L-苹果酸替诺福韦艾拉酚胺(1:2)的晶型为晶型A，其使用Cu-Kα辐射的X-射线粉末衍射图谱的特征为：在2θ值为10.0°±0.2°、13.4°±0.2°、13.9°±0.2°、15.3°±0.2°、16.6°±0.2°、21.3°±0.2°、26.3°±0.2°处对应有特征衍射峰；The crystalline form of tenofovir alafenamide (1:2) of L-malate is crystalline form A, and its X-ray powder diffraction pattern using Cu-Kα radiation is characterized by a 2θ value of 10.0°. Characteristic diffraction peaks corresponding to ±0.2°, 13.4°±0.2°, 13.9°±0.2°, 15.3°±0.2°, 16.6°±0.2°, 21.3°±0.2°, and 26.3°±0.2°;
    所述柠檬酸替诺福韦艾拉酚胺(1:1)的晶型为晶型A，其使用Cu-Kα辐射的X-射线粉末衍射图谱的特征为：在2θ值为6.0°±0.2°、8.1°±0.2°、11.7°±0.2°、15.9°±0.2°、17.9°±0.2°、21.7°±0.2°、23.4°±0.2°、26.9°±0.2°处对应有特征衍射峰；The crystalline form of tenofovir alafenamide (1:1) is crystalline form A, and the X-ray powder diffraction pattern using Cu-Kα radiation is characterized by a value of 6.0°±0.2 at 2θ. Characteristic diffraction peaks corresponding to °, 8.1 ° ± 0.2 °, 11.7 ° ± 0.2 °, 15.9 ° ± 0.2 °, 17.9 ° ± 0.2 °, 21.7 ° ± 0.2 °, 23.4 ° ± 0.2 °, 26.9 ° ± 0.2 °;
    所述琥珀酸替诺福韦艾拉酚胺(1:1)的晶型为晶型A，其使用Cu-Kα辐射的X-射线粉末衍射图谱的特征为：在2θ值为10.7°±0.2°、14.3°±0.2°、17.2°±0.2°、21.4°±0.2°、21.8°±0.2°、22.4°±0.2°处对应有特征衍射峰；The crystalline form of tenofovir alafenamide (1:1) of succinate is crystalline form A, and its X-ray powder diffraction pattern using Cu-Kα radiation is characterized by a 2θ value of 10.7 ° ± 0.2. Characteristic diffraction peaks corresponding to °, 14.3 ° ± 0.2 °, 17.2 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.4 ° ± 0.2 °;
    所述草酸替诺福韦艾拉酚胺(1:1)的晶型为晶型A，其使用Cu-Kα辐射的X-射线粉末衍射图谱的特征为：在2θ值为7.7°±0.2°、9.6°±0.2°、16.2°±0.2°、18.2°±0.2°、20.5°±0.2°、24.7°±0.2°处对应有特征衍射峰；The crystalline form of tenofovir alafenamide (1:1) is crystalline form A, and the X-ray powder diffraction pattern using Cu-Kα radiation is characterized by a value of 7.7°±0.2° at 2θ. 9.6°±0.2°, 16.2°±0.2°, 18.2°±0.2°, 20.5°±0.2°, 24.7°±0.2° corresponding to characteristic diffraction peaks;
    所述磷酸替诺福韦艾拉酚胺(1:1)的晶型为晶型A，其使用Cu-Kα辐射的X-射线粉末衍射图谱的特征为：在2θ值为8.0°±0.2°、9.4°±0.2°、10.6°±0.2°、14.5°±0.2°、19.3°±0.2°、21.1°±0.2°、23.4°±0.2°处对应有特征衍射峰；The crystalline form of tenofovir alafenamide (1:1) is crystalline form A, and the X-ray powder diffraction pattern using Cu-Kα radiation is characterized by a value of 8.0°±0.2° at 2θ. 9.4°±0.2°, 10.6°±0.2°, 14.5°±0.2°, 19.3°±0.2°, 21.1°±0.2°, 23.4°±0.2° corresponding to characteristic diffraction peaks;
    所述硫酸替诺福韦艾拉酚胺(1:1)的晶型为晶型A，其使用Cu-Kα辐射的X-射线粉末衍射图谱的特征为：在2θ值为9.2°±0.2°、10.7°±0.2°、11.1°±0.2°、18.4°±0.2°、19.8°±0.2°、22.3°±0.2°、24.3°±0.2°处对应有特征衍射峰。The crystalline form of tenofovir alafenamide (1:1) is crystalline form A, and the X-ray powder diffraction pattern using Cu-Kα radiation is characterized by a value of 9.2°±0.2° at 2θ. Characteristic diffraction peaks are corresponding to 10.7°±0.2°, 11.1°±0.2°, 18.4°±0.2°, 19.8°±0.2°, 22.3°±0.2°, and 24.3°±0.2°.
  6. 根据权利要求5所述的替诺福韦艾拉酚胺复合物，其中，The tenofovir alafenamide complex according to claim 5, wherein
    所述L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱的特征为：在2θ值为7.5°±0.2°、8.2°±0.2°、9.4°±0.2°、10.8°±0.2°、12.4°±0.2°、14.4°±0.2°、16.0°±0.2°、16.3°±0.2°、17.1°±0.2°、17.9°±0.2°、18.9°±0.2°、19.7°±0.2°、20.4°±0.2°、21.6°±0.2°、23.0°±0.2°处对应有特征衍射峰；The L-norofovir lysamine (1:2) crystal form A of L-tartrate uses Cu-Kα radiation, and its X-ray powder diffraction pattern is characterized by a value of 7.5°±0.2°, 8.2 in 2θ. °±0.2°, 9.4°±0.2°, 10.8°±0.2°, 12.4°±0.2°, 14.4°±0.2°, 16.0°±0.2°, 16.3°±0.2°, 17.1°±0.2°, 17.9°± Characteristic diffraction peaks corresponding to 0.2°, 18.9°±0.2°, 19.7°±0.2°, 20.4°±0.2°, 21.6°±0.2°, and 23.0°±0.2°;
    所述D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱的特征为：在2θ值为4.4°±0.2°、7.8°±0.2°、9.0°±0.2°、9.5°±0.2°、12.5°±0.2°、13.0°±0.2°、15.1°±0.2°、15.9°±0.2°、17.0°±0.2°、17.7°±0.2°、19.5°±0.2°、19.9°±0.2°、21.4°±0.2°、22.7°±0.2°、 25.9°±0.2°处对应有特征衍射峰；The D-norofovir alafenamide (1:1) Form A of D-tartrate uses Cu-Kα radiation, and its X-ray powder diffraction pattern is characterized by a value of 4.4°±0.2°, 7.8 at 2θ. °±0.2°, 9.0°±0.2°, 9.5°±0.2°, 12.5°±0.2°, 13.0°±0.2°, 15.1°±0.2°, 15.9°±0.2°, 17.0°±0.2°, 17.7°± 0.2°, 19.5°±0.2°, 19.9°±0.2°, 21.4°±0.2°, 22.7°±0.2°, There is a characteristic diffraction peak at 25.9 ° ± 0.2 °;
    所述DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱的特征为：在2θ值为6.8°±0.2°、8.0°±0.2°、9.7°±0.2°、10.6°±0.2°、12.6°±0.2°、13.7°±0.2°、14.9°±0.2°、16.0°±0.2°、16.9°±0.2°、18.2°±0.2°、18.9°±0.2°、20.2°±0.2°、21.1°±0.2°、22.8°±0.2°处对应有特征衍射峰；The DL-tenofovir alafenamide (1:1) crystal form A, using Cu-Kα radiation, has an X-ray powder diffraction pattern characterized by a value of 6.8°±0.2°, 8.0 at 2θ. °±0.2°, 9.7°±0.2°, 10.6°±0.2°, 12.6°±0.2°, 13.7°±0.2°, 14.9°±0.2°, 16.0°±0.2°, 16.9°±0.2°, 18.2°± Characteristic diffraction peaks corresponding to 0.2°, 18.9°±0.2°, 20.2°±0.2°, 21.1°±0.2°, and 22.8°±0.2°;
    所述L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱的特征为：在2θ值为5.4°±0.2°、10.0°±0.2°、11.9°±0.2°、13.4°±0.2°、13.9°±0.2°、15.3°±0.2°、16.6°±0.2°、20.3°±0.2°、21.3°±0.2°、22.2°±0.2°、26.3°±0.2°处对应有特征衍射峰；The L-malic acid tenofovir alafenamide (1:2) crystal form A, using Cu-Kα radiation, has an X-ray powder diffraction pattern characterized by a value of 5.4 ° ± 0.2 ° at 2θ, 10.0°±0.2°, 11.9°±0.2°, 13.4°±0.2°, 13.9°±0.2°, 15.3°±0.2°, 16.6°±0.2°, 20.3°±0.2°, 21.3°±0.2°, 22.2° Characteristic diffraction peaks corresponding to ±0.2° and 26.3°±0.2°;
    所述柠檬酸替诺福韦艾拉酚胺(1:1)晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱的特征为：在2θ值为6.0°±0.2°、8.1°±0.2°、11.7°±0.2°、12.6°±0.2°、15.4°±0.2°、15.9°±0.2°、17.5°±0.2°、17.9°±0.2°、20.1°±0.2°、20.6°±0.2°、21.4°±0.2°、21.7°±0.2°、23.4°±0.2°、26.9°±0.2°、29.3°±0.2°、31.9°±0.2°、32.7°±0.2°处对应有特征衍射峰；The tenofovir iramol citrate (1:1) crystal form A, using Cu-Kα radiation, has an X-ray powder diffraction pattern characterized by a 2θ value of 6.0°±0.2° and 8.1°. ±0.2°, 11.7°±0.2°, 12.6°±0.2°, 15.4°±0.2°, 15.9°±0.2°, 17.5°±0.2°, 17.9°±0.2°, 20.1°±0.2°, 20.6°±0.2 Characteristic diffraction peaks corresponding to °, 21.4 ° ± 0.2 °, 21.7 ° ± 0.2 °, 23.4 ° ± 0.2 °, 26.9 ° ± 0.2 °, 29.3 ° ± 0.2 °, 31.9 ° ± 0.2 °, 32.7 ° ± 0.2 °;
    所述琥珀酸替诺福韦艾拉酚胺(1:1)晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱的特征为：在2θ值为5.7°±0.2°、9.6°±0.2°、10.0°±0.2°、10.7°±0.2°、11.7°±0.2°、13.5°±0.2°、14.3°±0.2°、17.2°±0.2°、17.8°±0.2°、19.3°±0.2°、19.7°±0.2°、21.4°±0.2°、21.8°±0.2°、22.4°±0.2°、23.8°±0.2°、27.9°±0.2°处对应有特征衍射峰；The tenofovir alafenamide (1:1) crystalline form A of succinic acid, using Cu-Kα radiation, has an X-ray powder diffraction pattern characterized by a value of 5.7°±0.2° and 9.6° at 2θ. ±0.2°, 10.0°±0.2°, 10.7°±0.2°, 11.7°±0.2°, 13.5°±0.2°, 14.3°±0.2°, 17.2°±0.2°, 17.8°±0.2°, 19.3°±0.2 Characteristic diffraction peaks corresponding to °, 19.7 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.4 ° ± 0.2 °, 23.8 ° ± 0.2 °, 27.9 ° ± 0.2 °;
    所述草酸替诺福韦艾拉酚胺(1:1)晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱的特征为：在2θ值为7.7°±0.2°、8.4°±0.2°、9.6°±0.2°、12.6°±0.2°、16.2°±0.2°、18.2°±0.2°、20.5°±0.2°、22.6°±0.2°、24.7°±0.2°、27.8°±0.2°、29.0°±0.2°处对应有特征衍射峰；The tenofovir oxalatine oxalate (1:1) crystal form A, using Cu-Kα radiation, has an X-ray powder diffraction pattern characterized by a value of 7.7°±0.2° and 8.4°±2θ. 0.2°, 9.6°±0.2°, 12.6°±0.2°, 16.2°±0.2°, 18.2°±0.2°, 20.5°±0.2°, 22.6°±0.2°, 24.7°±0.2°, 27.8°±0.2° , at 29.0 ° ± 0.2 ° corresponding to characteristic diffraction peaks;
    所述磷酸替诺福韦艾拉酚胺(1:1)晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱的特征为：在2θ值为8.0°±0.2°、9.4°±0.2°、10.6°±0.2°、14.5°±0.2°、15.9°±0.2°、17.0°±0.2°、17.6°±0.2°、18.6°±0.2°、19.3°±0.2°、21.1°±0.2°、23.4°±0.2°处对应有特征衍射峰；The tenofovir enalapenoate (1:1) crystal form A, using Cu-Kα radiation, has an X-ray powder diffraction pattern characterized by a value of 8.0°±0.2° and 9.4°±2θ. 0.2°, 10.6°±0.2°, 14.5°±0.2°, 15.9°±0.2°, 17.0°±0.2°, 17.6°±0.2°, 18.6°±0.2°, 19.3°±0.2°, 21.1°±0.2° , at 23.4 ° ± 0.2 ° corresponding to characteristic diffraction peaks;
    所述硫酸替诺福韦艾拉酚胺(1:1)晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱的特征为：在2θ值为9.2°±0.2°、10.7°±0.2°、11.1°±0.2°、16.9°±0.2°、18.4°±0.2°、19.2°±0.2°、19.8°±0.2°、21.7°±0.2°、22.3°±0.2°、23.1°±0.2°、24.3°±0.2°、28.1°±0.2°、31.1°±0.2°处对应有特征衍射峰。The tenofovir alafenamide (1:1) crystal form A, using Cu-Kα radiation, has an X-ray powder diffraction pattern characterized by a value of 9.2°±0.2° and 10.7°±2θ. 0.2°, 11.1°±0.2°, 16.9°±0.2°, 18.4°±0.2°, 19.2°±0.2°, 19.8°±0.2°, 21.7°±0.2°, 22.3°±0.2°, 23.1°±0.2° Characteristic peaks are corresponding to 24.3°±0.2°, 28.1°±0.2°, and 31.1°±0.2°.
  7. 根据权利要求6所述的替诺福韦艾拉酚胺复合物，其中，The tenofovir alafenamide complex according to claim 6, wherein
    所述L-酒石酸替诺福韦艾拉酚胺(1:2)晶型A的X-射线粉末衍射图谱基本如图1所示；The X-ray powder diffraction pattern of the crystalline form A of tenofovir alafenamide (1:2) of L-tartrate is substantially as shown in FIG. 1;
    所述D-酒石酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱基本如图2所示； The X-ray powder diffraction pattern of the D-norofovir alafenamide (1:1) crystal form A of D-tartrate is basically as shown in FIG. 2;
    所述DL-酒石酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱基本如图3所示；The X-ray powder diffraction pattern of the DL-tenofovir alafenamide (1:1) crystal form A is substantially as shown in FIG. 3;
    所述L-苹果酸替诺福韦艾拉酚胺(1:2)晶型A的X-射线粉末衍射图谱基本如图4所示；The X-ray powder diffraction pattern of the crystalline form A of tenofovir alafenamide (1:2) of L-malate is substantially as shown in FIG. 4;
    所述柠檬酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱基本如图5所示；The X-ray powder diffraction pattern of the tenofovir alafenamide (1:1) crystal form A is substantially as shown in FIG. 5;
    所述琥珀酸替诺福韦艾拉酚胺(1:1)A的X-射线粉末衍射图谱基本如图6所示；The X-ray powder diffraction pattern of the tenofovir alafenamide (1:1) A succinate is substantially as shown in FIG. 6;
    所述草酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱基本如图7所示；The X-ray powder diffraction pattern of the tenofovir alafenamide (1:1) crystalline form A is substantially as shown in FIG. 7;
    所述磷酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱基本如图8所示；The X-ray powder diffraction pattern of the tenofovir alafenamide (1:1) crystal form A is substantially as shown in FIG. 8;
    所述硫酸替诺福韦艾拉酚胺(1:1)晶型A的X-射线粉末衍射图谱基本如图9所示。The X-ray powder diffraction pattern of the tenofovir alafenamide (1:1) crystal form A is substantially as shown in FIG.
  8. 一种替诺福韦艾拉酚胺复合物的制备方法，该方法包括：A method for preparing tenofovir alafenamide complex, the method comprising:
    (1)在适宜溶剂中，形成一种包含替诺福韦艾拉酚胺和酸X的溶液；(1) forming a solution comprising tenofovir alafenamide and acid X in a suitable solvent;
    (2)析出固体；(2) precipitation of solids;
    (3)分离所析出的固体；(3) separating the precipitated solid;
    (4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried.
  9. 根据权利要求8所述的制备方法，其中步骤(1)中，所述适宜溶剂选自乙腈、乙醇、甲醇、丙醇、异丙醇、丁醇、乙二醇、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸丁酯、乙醚、异丙醚、正丁醚、乙二醇单甲醚、乙二醇二甲醚、叔丁基甲基醚、四氢呋喃、石油醚、二氯甲烷、三氯甲烷、正己烷、环己烷、丙酮、丁酮、戊酮、环己酮、甲苯、二甲苯或它们的混合物；所述酸X选自式Ⅱ中X所代表的酸；所述替诺福韦艾拉酚胺与酸X的投料摩尔比为4:1～0.5:1，当制备X替诺福韦艾拉酚胺(1:3)复合物时，替诺福韦艾拉酚胺与酸X投料摩尔比为2.7:1～3.5:1，当制备X替诺福韦艾拉酚胺(1:2)复合物时，替诺福韦艾拉酚胺与酸X投料摩尔比为1.7:1～2.5:1，当制备X替诺福韦艾拉酚胺(1:1)复合物时，替诺福韦艾拉酚胺与酸X投料摩尔比为0.5:1～1.5:1。The preparation method according to claim 8, wherein in the step (1), the suitable solvent is selected from the group consisting of acetonitrile, ethanol, methanol, propanol, isopropanol, butanol, ethylene glycol, ethyl formate, and methyl acetate. Ethyl acetate, isopropyl acetate, butyl acetate, diethyl ether, diisopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, tert-butyl methyl ether, tetrahydrofuran, petroleum ether, dichloro Methane, chloroform, n-hexane, cyclohexane, acetone, methyl ethyl ketone, pentanone, cyclohexanone, toluene, xylene or a mixture thereof; the acid X is selected from the group consisting of the acid represented by X in the formula II; The molar ratio of tenofovir alafenamide to acid X is 4:1 to 0.5:1, and when preparing X tenofovir alafenamide (1:3) complex, tenofovir The molar ratio of phenolamine to acid X is 2.7:1 to 3.5:1. When preparing X tenofovir alafenamide (1:2) complex, tenofovir alafenamide and acid X are charged. The molar ratio is 1.7:1 to 2.5:1. When preparing the X tenofovir alafenamide (1:1) complex, the molar ratio of tenofovir alafenamide to acid X is 0.5:1~ 1.5:1.
  10. 一种权利要求8所述的替诺福韦艾拉酚胺复合物的制备方法，该方法包括：A method of preparing a tenofovir alafenamide complex according to claim 8, the method comprising:
    (1)将替诺福韦艾拉酚胺和L-酒石酸、D-酒石酸、DL-酒石酸、L-苹果酸、柠檬酸、琥珀酸、草酸、磷酸或硫酸按以下投料摩尔比溶解在适宜溶剂中，(1) Dissolving tenofovir alafenamide and L-tartaric acid, D-tartaric acid, DL-tartaric acid, L-malic acid, citric acid, succinic acid, oxalic acid, phosphoric acid or sulfuric acid in a suitable solvent in the following molar ratio in,
    替诺福韦艾拉酚胺:L-酒石酸为1.7:1～2.5:1，优选1.9:1～2.3:1，或者，Tenofovir alafenamide: L-tartaric acid is from 1.7:1 to 2.5:1, preferably from 1.9:1 to 2.3:1, or
    替诺福韦艾拉酚胺:D-酒石酸为0.5:1～1.5:1，优选0.8:1～1.2:1，或者，Tenofovir alafenamide: D-tartaric acid is from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1, or
    替诺福韦艾拉酚胺:DL-酒石酸为0.5:1～1.5:1，优选0.8:1～1.2:1，或者，Tenofovir alafenamide: DL-tartaric acid is from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1, or
    替诺福韦艾拉酚胺:L-苹果酸为1.7:1～2.5:1，优选1.9:1～2.3:1，或者，Tenofovir alafenamide: L-malic acid is from 1.7:1 to 2.5:1, preferably from 1.9:1 to 2.3:1, or
    替诺福韦艾拉酚胺:柠檬酸为0.5:1～1.5:1，优选0.8:1～1.2:1，或者，Tenofovir alafenamide: citric acid is from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1, or
    替诺福韦艾拉酚胺:琥珀酸为0.5:1～1.5:1，优选0.8:1～1.2:1，或者， Tenofovir alafenamide: succinic acid is from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1, or
    替诺福韦艾拉酚胺:草酸为0.5:1～1.5:1，优选0.8:1～1.2:1，或者，Tenofovir alafenamide: oxalic acid is from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1, or
    替诺福韦艾拉酚胺:磷酸为0.5:1～1.5:1，优选0.8:1～1.2:1，或者，Tenofovir alafenamide: phosphoric acid is from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1, or
    替诺福韦艾拉酚胺:硫酸为0.5:1～1.5:1，优选0.8:1～1.2:1，或者，Tenofovir alafenamide: sulfuric acid is from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1, or
    (2)析出固体；(2) precipitation of solids;
    (3)分离所析出的固体；(3) separating the precipitated solid;
    (4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。(4) Alternatively, the isolated solid is dried or further purified and then dried.
  11. 根据权利要求10所述的制备方法，其中步骤(1)中适宜溶剂选自乙腈、甲醇、乙醇、异丙醇、四氢呋喃、丙酮、二氯甲烷、三氯甲烷、甲苯或它们的混合物，优选为乙腈或异丙醇。The process according to claim 10, wherein the suitable solvent in the step (1) is selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene or a mixture thereof, preferably Acetonitrile or isopropanol.
  12. 一种替诺福韦艾拉酚胺复合物晶型的制备方法，该方法包括：A method for preparing a crystalline form of tenofovir alafenamide complex, the method comprising:
    (1)将替诺福韦艾拉酚胺和L-酒石酸溶解在乙腈、乙醇、异丙醇或它们的混合物中，替诺福韦艾拉酚胺与L-酒石酸的投料摩尔比为1.7:1～2.5:1，优选1.9:1～2.3:1，或者，(1) Dissolving tenofovir alafenamide and L-tartaric acid in acetonitrile, ethanol, isopropanol or a mixture thereof, and the molar ratio of tenofovir alafenamide to L-tartaric acid is 1.7: 1 to 2.5:1, preferably 1.9:1 to 2.3:1, or,
    将替诺福韦艾拉酚胺和D-酒石酸溶解在乙腈、异丙醇或它们的混合物中，替诺福韦艾拉酚胺与D-酒石酸的投料摩尔比为0.5:1～1.5:1，优选0.8:1～1.2:1，或者，The tenofovir alafenamide and D-tartaric acid are dissolved in acetonitrile, isopropanol or a mixture thereof, and the molar ratio of tenofovir alafenamide to D-tartaric acid is 0.5:1 to 1.5:1. , preferably 0.8:1 to 1.2:1, or,
    将替诺福韦艾拉酚胺和DL-酒石酸溶解在乙腈中，替诺福韦艾拉酚胺与DL-酒石酸的投料摩尔比为0.5:1～1.5:1，优选0.8:1～1.2:1，或者，The tenofovir alafenamide and DL-tartaric acid are dissolved in acetonitrile, and the molar ratio of tenofovir alafenamide to DL-tartaric acid is from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2: 1, or,
    将替诺福韦艾拉酚胺和L-苹果酸溶解在异丙醇中，替诺福韦艾拉酚胺与L-苹果酸的投料摩尔比为1.7:1～2.5:1，优选1.9:1～2.3:1，或者，The tenofovir alafenamide and L-malic acid are dissolved in isopropanol, and the molar ratio of tenofovir alafenamide to L-malic acid is 1.7:1 to 2.5:1, preferably 1.9: 1 to 2.3:1, or,
    将替诺福韦艾拉酚胺和柠檬酸溶解在乙腈、甲醇、乙醇、四氢呋喃或它们的混合物中，替诺福韦艾拉酚胺与柠檬酸的投料摩尔比为0.5:1～1.5:1，优选0.8:1～1.2:1，或者，The tenofovir alafenamide and citric acid are dissolved in acetonitrile, methanol, ethanol, tetrahydrofuran or a mixture thereof, and the molar ratio of tenofovir alafenamide to citric acid is 0.5:1 to 1.5:1. , preferably 0.8:1 to 1.2:1, or,
    将替诺福韦艾拉酚胺和琥珀酸溶解在乙腈中，替诺福韦艾拉酚胺与琥珀酸的投料摩尔比为0.5:1～1.5:1，优选0.8:1～1.2:1，或者，The tenofovir alafenamide and succinic acid are dissolved in acetonitrile, and the molar ratio of tenofovir alafenamide to succinic acid is from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1. or,
    将替诺福韦艾拉酚胺和草酸溶解在乙腈中，替诺福韦艾拉酚胺与草酸的投料摩尔比为0.5:1～1.5:1，优选0.8:1～1.2:1，或者，The tenofovir alafenamide and oxalic acid are dissolved in acetonitrile, and the molar ratio of tenofovir alafenamide to oxalic acid is 0.5:1 to 1.5:1, preferably 0.8:1 to 1.2:1, or
    将替诺福韦艾拉酚胺和磷酸溶解在乙腈中，替诺福韦艾拉酚胺与磷酸的投料摩尔比为0.5:1～1.5:1，优选0.8:1～1.2:1，或者，The tenofovir alafenamide and phosphoric acid are dissolved in acetonitrile, and the molar ratio of tenofovir alafenamide to phosphoric acid is 0.5:1 to 1.5:1, preferably 0.8:1 to 1.2:1, or
    将替诺福韦艾拉酚胺和硫酸溶解在乙腈中，替诺福韦艾拉酚胺与硫酸的投料摩尔比为0.5:1～1.5:1，优选0.8:1～1.2:1；Dissolving tenofovir alafenamide and sulfuric acid in acetonitrile, the molar ratio of tenofovir alafenamide to sulfuric acid is from 0.5:1 to 1.5:1, preferably from 0.8:1 to 1.2:1;
    (2)析出固体；(2) precipitation of solids;
    (3)分离所析出的固体；(3) separating the precipitated solid;
    (4)可选地，将分离的固体进行干燥，或进一步纯化后再干燥。 (4) Alternatively, the isolated solid is dried or further purified and then dried.
  13. 一种药物组合物，其包含治疗有效量的权利要求1～3中任一项所述的替诺福韦艾拉酚胺复合物或权利要求8～12中任一项制备方法制得的替诺福韦艾拉酚胺复合物或其晶型，以及药用辅料。A pharmaceutical composition comprising a therapeutically effective amount of the tenofovir alafenamide complex according to any one of claims 1 to 3 or a preparation method according to any one of claims 8 to 12. Norfovir levamide complex or its crystalline form, as well as pharmaceutical excipients.
  14. 根据权利要求13所述的药物组合物，其还包含另一种或多种选自以下的抗病毒剂或抗病毒辅助试剂：恩曲他滨、拉米夫定、阿巴卡韦、醋孟南、安普那韦、安普那韦、阿扎那韦、克拉夫定、Cobicistat、达匹韦林、地瑞那韦、地拉韦啶、去羟肌苷、德罗格韦、依法韦仑、埃替拉韦、恩夫韦地、恩替卡韦、依曲韦林、泛昔洛韦、福沙那韦、谷胱甘肽、茚地那韦、左旋咪唑、洛匹那韦、马拉维若、奈非那韦、奈韦拉平、喷昔洛韦、喷他脒、Phosphazid、丙帕锗、雷特格韦、利巴韦林、利匹韦林、利托那韦、沙奎那韦、司他夫定、替比夫定、替拉那韦、伏立诺他、扎西他滨、齐多夫定或它们的药用盐；优选恩曲他滨、拉米夫定、Cobicistat、依法韦仑、埃替拉韦或利匹韦林或它们的药用盐。The pharmaceutical composition according to claim 13, which further comprises another or more antiviral agents or antiviral auxiliary agents selected from the group consisting of emtricitabine, lamivudine, abacavir, vinegar South, amprenavir, amprenavir, atazanavir, clafidine, Cobicistat, dapivirine, darunavir, delavirdine, didanosine, delogvir, efavi Lun, ethiravir, enfuvirtide, entecavir, etravirine, famciclovir, fosanavir, glutathione, indinavir, levamisole, lopinavir, malawi, nai Fenavir, nevirapine, penciclovir, pentamidine, Phosphazid, propacetam, ritvavir, ribavirin, rivivirin, ritonavir, saquinavir, stavudine , telbivudine, telanavir, vorinostat, zalcitabine, zidovudine or their pharmaceutically acceptable salts; preferably emtricitabine, lamivudine, Cobicistat, efavirenz, ang Telavir or ripavirin or their pharmaceutically acceptable salts.
  15. 根据权利要求14所述的药物组合物，其选自：The pharmaceutical composition according to claim 14 which is selected from the group consisting of:
    包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、恩曲他滨、Cobicistat和埃替拉韦的药物组合物；或者，a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, emtricitabine, Cobicistat, and eritavir; or
    包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、恩曲他滨、Cobicistat和地瑞那韦的药物组合物；或者，a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, emtricitabine, Cobicistat, and darunavir; or
    包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物和恩曲他滨的药物组合物；或者，a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II and emtricitabine; or
    包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、恩曲他滨和依法韦仑的药物组合物；或者，A pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, emtricitabine and efavirenz; or
    包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、恩曲他滨和盐酸立匹韦林的药物组合物；或者，a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, emtricitabine and pirimivir hydrochloride; or
    包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、拉米夫定的药物组合物；或者，A pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, lamivudine; or
    包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、拉米夫定和依法韦仑的药物组合物；或者，A pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, lamivudine and efavirenz; or
    包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、拉米夫定、Cobicistat和埃替拉韦的药物组合物；或者，a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula II, lamivudine, Cobicistat, and ertivir; or
    包含治疗有效量的式Ⅱ所示替诺福韦艾拉酚胺复合物、拉米夫定、Cobicistat和地瑞那韦的药物组合物。A pharmaceutical composition comprising a therapeutically effective amount of tenofovir alafenamide complex of formula II, lamivudine, Cobicistat, and darunavir.
  16. 权利要求1～3中任一项所述的替诺福韦艾拉酚胺复合物、权利要求8～12中任一项所述的制备方法制得的替诺福韦艾拉酚胺复合物、或权利要求13～15的药物组合物在制备预防和/或治疗病毒感染的药物中的应用。 The tenofovir alafenamide complex according to any one of claims 1 to 3, and the tenofovir acetamide complex obtained by the production method according to any one of claims 8 to 12. Or the use of the pharmaceutical composition according to claims 13 to 15 for the preparation of a medicament for preventing and/or treating a viral infection.
  17. 根据权利要求16所述的应用，其中所述的替诺福韦艾拉酚胺复合物在制备预防和/或治疗乙型肝炎病毒和/或人类免疫缺陷病毒感染的药物中的应用。The use according to claim 16, wherein the tenofovir alafenamide complex is used in the preparation of a medicament for preventing and/or treating hepatitis B virus and/or human immunodeficiency virus infection.
  18. 一种预防和/或治疗病毒感染的方法，该方法包括给予个体有效量的权利要求1～3中任一项所述的替诺福韦艾拉酚胺复合物、权利要求8～12中任一项所述的制备方法制得的替诺福韦艾拉酚胺复合物、或权利要求13～15的药物组合物。 A method for preventing and/or treating a viral infection, which comprises administering to an individual an effective amount of the tenofovir alafenamide complex according to any one of claims 1 to 3, or any of claims 8 to 12. A tenofovir alafenamide complex prepared by the preparation method, or a pharmaceutical composition according to claims 13-15.
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US10287307B2 (en) 2017-01-31 2019-05-14 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
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WO2020213794A1 (en) * 2019-04-19 2020-10-22 유니셀랩 주식회사 Novel crystalline form of antiviral agent and preparation method therefor
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US11667656B2 (en) 2021-01-27 2023-06-06 Apotex Inc. Crystalline forms of Tenofovir alafenamide

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