WO2015176602A1 - Complexe de ténofovir alafénamide, son procédé de préparation et utilisation - Google Patents

Complexe de ténofovir alafénamide, son procédé de préparation et utilisation 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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acid
tenofovir alafenamide
tenofovir
alafenamide
ray powder
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PCT/CN2015/078188
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English (en)
Chinese (zh)
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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/zh
Publication of WO2015176602A1 publication Critical patent/WO2015176602A1/fr

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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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  • Chemical & Material Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

Cette invention concerne le complexe de ténofovir alafénamide représenté par la formule II. Un procédé de préparation dudit complexe de ténofovir alafénamide, des compositions pharmaceutiques le contenant, et ses utilisations pour préparer des médicaments destinés à prévenir et/ou à traiter l'infection virale, notamment l'infection par le virus de l'hépatite B (VHB) et/ou par le virus de l'immunodéficience humaine (VIH) sont en outre décrits.
PCT/CN2015/078188 2014-05-20 2015-05-04 Complexe de ténofovir alafénamide, son procédé de préparation et utilisation WO2015176602A1 (fr)

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WO2016192692A1 (fr) * 2015-06-05 2016-12-08 Zentiva K.S. Formes solides d'alafénamide de ténofovir
WO2016205141A1 (fr) * 2015-06-17 2016-12-22 Gilead Sciences, Inc. Co-cristaux, sels et formes solides de ténofovir alafénamide
WO2018115046A1 (fr) 2016-12-23 2018-06-28 Sandoz Ag Formes solides cristallines de ténofovir alafénamide
CN108341841A (zh) * 2017-01-22 2018-07-31 成都倍特药业有限公司 一种替诺福韦艾拉酚胺与门冬氨酸的盐
US10287307B2 (en) 2017-01-31 2019-05-14 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
CN111686082A (zh) * 2019-03-11 2020-09-22 苏州特瑞药业有限公司 一种富马酸磷丙替诺福韦制剂及其制备方法
WO2020213794A1 (fr) * 2019-04-19 2020-10-22 유니셀랩 주식회사 Nouvelle forme cristalline d'agent antiviral et procédé de préparation correspondant
WO2021165995A1 (fr) 2020-02-20 2021-08-26 Cipla Limited Nouveaux sels et/ou co-cristaux de ténofovir alafénamide
US11667656B2 (en) 2021-01-27 2023-06-06 Apotex Inc. Crystalline forms of Tenofovir alafenamide

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CN105237571B (zh) * 2014-11-28 2018-03-09 成都苑东生物制药股份有限公司 9‑[(r)‑2‑[[(s)‑[[(s)‑1‑(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤的盐
CN104926872B (zh) * 2015-05-12 2017-08-04 杭州和泽医药科技有限公司 替诺福韦艾拉酚胺半酒石酸盐
CN106977548A (zh) * 2016-01-19 2017-07-25 四川海思科制药有限公司 倍司福韦复合物及其制备方法和用途
WO2017211325A1 (fr) * 2016-06-05 2017-12-14 上海诚妙医药科技有限公司 Nouvelle forme cristalline de sel de ténofovir alafénamide, procédé de préparation et utilisation correspondante
CN106380484A (zh) * 2016-08-29 2017-02-08 杭州百诚医药科技股份有限公司 一种替诺福韦艾拉酚胺的新晶型及其制备方法
CN108117570A (zh) * 2016-11-28 2018-06-05 正大天晴药业集团股份有限公司 一种替诺福韦艾拉酚胺半富马酸盐的结晶及其制备方法
CN107266499B (zh) * 2017-06-05 2019-07-02 珠海优润医药科技有限公司 一种抗病毒化合物及其制备方法
CN107865874A (zh) * 2017-10-23 2018-04-03 上海博悦生物科技有限公司 一种替诺福韦艾拉酚胺的药物组合物及其制备方法
KR102054104B1 (ko) * 2019-04-30 2019-12-09 유니셀랩 주식회사 신규한 테노포비어 알라펜아미드 염 및 이의 제조방법
CN112137981A (zh) * 2020-11-02 2020-12-29 成都晶富医药科技有限公司 富马酸丙酚替诺福韦片及其制备工艺

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WO2015040640A2 (fr) * 2013-09-20 2015-03-26 Laurus Labs Private Limited Procédé amélioré pour la préparation de ténofovir alafénamide ou de sels pharmaceutiquement acceptables de celui-ci

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CN103626803A (zh) * 2012-08-23 2014-03-12 四川海思科制药有限公司 替诺福韦二吡呋酯的固体及其制备方法和用途

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016192692A1 (fr) * 2015-06-05 2016-12-08 Zentiva K.S. Formes solides d'alafénamide de ténofovir
WO2016205141A1 (fr) * 2015-06-17 2016-12-22 Gilead Sciences, Inc. Co-cristaux, sels et formes solides de ténofovir alafénamide
US9777028B2 (en) 2015-06-17 2017-10-03 Gilead Sciences, Inc. Co-crystals, salts and solid forms of tenofovir alafenamide
US10155781B2 (en) 2015-06-17 2018-12-18 Gilead Sciences, Inc. Co-crystals, salts and solid forms of tenofovir alafenamide
EP4092037A1 (fr) * 2015-06-17 2022-11-23 Gilead Sciences, Inc. Co-cristaux, sels et formes solides de ténofovir alafenamide
AU2016277859B2 (en) * 2015-06-17 2019-08-01 Gilead Sciences, Inc. Co-crystals, salts and solid forms of tenofovir alafenamide
WO2018115046A1 (fr) 2016-12-23 2018-06-28 Sandoz Ag Formes solides cristallines de ténofovir alafénamide
CN108341841B (zh) * 2017-01-22 2020-07-17 成都倍特药业股份有限公司 一种替诺福韦艾拉酚胺与门冬氨酸的盐
CN108341841A (zh) * 2017-01-22 2018-07-31 成都倍特药业有限公司 一种替诺福韦艾拉酚胺与门冬氨酸的盐
CN110234655A (zh) * 2017-01-31 2019-09-13 吉利德科学公司 替诺福韦艾拉酚胺的结晶形式
US11440928B2 (en) 2017-01-31 2022-09-13 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
US10287307B2 (en) 2017-01-31 2019-05-14 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
US20230091736A1 (en) * 2017-01-31 2023-03-23 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
CN111686082A (zh) * 2019-03-11 2020-09-22 苏州特瑞药业有限公司 一种富马酸磷丙替诺福韦制剂及其制备方法
WO2020213794A1 (fr) * 2019-04-19 2020-10-22 유니셀랩 주식회사 Nouvelle forme cristalline d'agent antiviral et procédé de préparation correspondant
WO2021165995A1 (fr) 2020-02-20 2021-08-26 Cipla Limited Nouveaux sels et/ou co-cristaux de ténofovir alafénamide
US11667656B2 (en) 2021-01-27 2023-06-06 Apotex Inc. Crystalline forms of Tenofovir alafenamide

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