CN105085571A

CN105085571A - Tenofovir alafenamide compound, preparation method and purpose thereof

Info

Publication number: CN105085571A
Application number: CN201410213317.3A
Authority: CN
Inventors: 赵雄; 袁道义; 程睿; 罗杰; 向志祥
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2014-05-20
Filing date: 2014-05-20
Publication date: 2015-11-25
Also published as: CN106414466B; CN106414466A; WO2015176602A1; CN111205325A

Abstract

The invention relates to a tenofovir alafenamide compound shown in a formula II. The invention also provides a preparation method of the tenofovir alafenamide compound, a pharmaceutical composition containing the tenofovir alafenamide compound, and an application of the tenofovir alafenamide compound in preparation of medicines for preventing and/or treating virus infection, especially hepatitis b virus (HBV) and/or human immunodeficiency virus (HIV) infection.

Description

Tenofovir alafenamide compound and preparation method and application thereof

Technical Field

The invention relates to the field of organic chemistry and pharmacy, in particular to a compound of tenofovir alafenamide serving as a medicament for preventing or/and treating virus infection, a preparation method thereof, application of the compound in preparing medicaments for preventing and/or treating virus infection, particularly Hepatitis B Virus (HBV) infection and/or Human Immunodeficiency Virus (HIV) infection, and a pharmaceutical composition containing the compound.

Background

Tenofovir alafenamide (Tenofoviralafenamide), chemical name is: n- [ (S) - [ [ (1R) -2- (6-amino-9H-purin-9-yl) -1-methylethoxy ] methyl ] phenoxyphosphono ] -L-alanine-1-methylethyl ester; CAS accession numbers are: 379270-37-8; the molecular structural formula is shown as formula I:

the tenofovir alafenamide is an ester prodrug of tenofovir, is an acyclic nucleotide reverse transcriptase inhibitor, has broad-spectrum antiviral effect, and can inhibit reverse transcriptase of HIV-1 and HIV-2 and HBV polymerase, thereby inhibiting virus replication. Tenofovir alafenamide is hydrolyzed into tenofovir after being orally taken, the tenofovir is phosphorylated into a metabolite tenofovir diphosphate with pharmacological activity by cell kinase, the tenofovir diphosphate competes with 5 '-triphosphate deoxyadenosine monophosphate to participate in the synthesis of virus DNA, and after entering the virus DNA, the DNA elongation is blocked due to the lack of 3' -hydroxyl, so that the replication of the virus is inhibited. Compared with the similar medicine tenofovir disoproxil (Tenofovirdisoproxil) on the market, the antiviral activity of tenofovir alafenamide is 10 times, the stability in blood plasma is 200 times, the half life is 220 times higher, and the accumulation in Peripheral Blood Mononuclear Cells (PBMC) is nearly 10 times higher, so that the tenofovir alafenamide is used for preventing or/and treating Hepatitis B Virus (HBV) and human immunodeficiency virus (HIV/AIDS) infection, and has better curative effect, higher safety and lower drug resistance. Currently, a single formulation of tenofovir alafenamide, a compound formulation of tenofovir alafenamide/emtricitabine/Cobicistat/ezetivir and a compound formulation of tenofovir alafenamide/emtricitabine/Cobicistat/darunavir are in clinical study abroad.

Because the tenofovir alafenamide has lower solid melting point and lower solubility in water, the preparation of a pharmaceutical preparation and the dissolution in the pharmaceutical preparation are not facilitated, and thus the tenofovir alafenamide is developed into a salt form for the preparation. For example, patent documents CN1443189A and CN1706855A disclose fumarate salts of tenofovir alafenamide, which are much improved in water solubility, physical properties, and the like compared with the free base, but have poor chemical stability and thermodynamic stability. Patent document CN103732594A discloses a hemifumarate of tenofovir alafenamide, wherein it is shown that tenofovir alafenamide hemifumarate is superior to tenofovir alafenamide fumarate in removing diastereoisomer impurities, chemical stability, thermodynamic stability, and is a more excellent salt of tenofovir alafenamide; however, the preparation process of tenofovir alafenamide hemifumarate is complicated, for example, a tenofovir alafenamide hemifumarate seed crystal needs to be added in the preparation process, and the seed crystal does not disclose the preparation method and is not easy to obtain.

Therefore, in order to overcome the defects in the prior art, it is necessary to develop a new solid form of tenofovir alafenamide, so as to further improve the special properties, chemical stability, process operability or preparation adaptability and the like of tenofovir alafenamide, further enhance the safety and effectiveness of the product, and provide better drug selection for patients.

Disclosure of Invention

It is an object of the present invention to provide novel complexes of tenofovir alafenamide. The compound is superior to the prior art in physical properties, chemical stability, process operability, preparation adaptability and the like.

Another object of the present invention is to provide a method for preparing the above tenofovir alafenamide complex.

It is still another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of the above tenofovir alafenamide complex.

The invention also aims to provide application of the tenofovir alafenamide compound in preparing a medicament for preventing and/or treating virus infection.

According to the purpose of the invention, the invention provides a tenofovir alafenamide compound shown as a formula II,

wherein n is 1, 2 or 3, and X is selected from: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, dodecylsulfuric acid, glycerophosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, taurine, camphorsulfonic acid, cyclamic acid, sulfamic acid, ethanedisulfonic acid, butanedisulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-hydroxyphenylsulfonic acid, o-hydroxybenzenesulfonic acid, 2, 5-dihydroxybenzenesulfonic acid, sulfanilic acid, saccharin, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, formic acid, acetic acid, glycolic acid, 2-dichloroacetic acid, propionic acid, L-lactic acid, D-lactic acid, racemic lactic acid (also known as DL-lactic acid), cyclopentanepropionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, nonanoic acid, capric acid, undecylenic acid, lauric acid, palmitic, Stearic acid, oleic acid, oxalic acid, malonic acid, succinic acid, L-malic acid, D-malic acid, racemic malic acid (also known as 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, sebacic acid, citric acid, benzoic acid, p-methoxybenzoic acid, 4-acetamidobenzoic acid, salicylic acid, acetylsalicylic acid, gentisic acid, 4-aminosalicylic acid, phenylacetic acid, L-mandelic acid, D-mandelic acid, racemic mandelic acid (also known as DL-mandelic acid), 3-phenylpropionic acid, cinnamic acid, caffeic acid, phenylbutyric acid, picric acid, nicotinic acid, orotic acid, quinic acid, ascorbic acid, tartaric, Glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, lactobionic acid, camphoric acid, galactaric acid (also known as mucic acid), tannic acid (also known as tannic acid), alginic acid, hydroxynaphthoic acid (also known as 3-hydroxy-2-naphthoic acid), pamoic acid (also known as 4,4' -methylenebis (3-hydroxy-2-naphthoic acid) or prussic acid), amino acids or acylated amino acids (such as acetoacetic acid, hippuric acid, aspartic acid, glutamic acid, pyroglutamic acid, glutamine, asparagine, etc.).

In the formula ii, the "complex" refers to a compound in which tenofovir alafenamide and a corresponding acid coexist by binding with each other by a non-covalent bond such as a hydrogen bond or an ionic bond, and includes a salt, a co-crystal, and the like. The composite further includes its polymorphic forms, solvates, solvate polymorphs, hydrates, hydrate polymorphs, and the like.

The "salts" are well known to those skilled in the art and refer to compounds formed by the action of cations and anions through ionic bonds. "tenofovir alafenamide salt" means that in a solid composed of tenofovir alafenamide and an acid, protons in the acid are transferred to the tenofovir alafenamide, and the protonated positive tenofovir alafenamide ions and negative acid ions are combined with each other through ionic bonding.

The "co-crystal" refers to a solid formed by tenofovir alafenamide and an acid in a co-crystal form. "eutectic" (Co-Crystals) refers to a multi-component crystal of fixed stoichiometric proportions in which the components coexist at the molecular level, bonded by hydrogen bonding or other non-covalent, non-ionic bonding. In pharmaceutical Co-crystals, typically comprising a pharmaceutical active ingredient and another Co-crystal former or formers (Co-crystallimers), such as the "tenofovir alafenamide Co-crystal", tenofovir alafenamide is the pharmaceutical active ingredient and the acid is the Co-crystal former. When the pure co-crystal former alone is present in a liquid state at room temperature, the co-crystal is also referred to as a "solvate", wherein the solvent is water, is referred to as a "hydrate", such as a co-crystal of tenofovir alafenamide with acetic acid, which may be referred to as an acetic acid solvate of tenofovir alafenamide.

The "co-crystals" also include multi-component crystals having a fixed stoichiometric ratio in which the pharmaceutically active ingredient is bound to the other components, in part by hydrogen bonding or other non-covalent bonding, and in part by ionic bonding or by forces between hydrogen bonding and ionic bonding.

The "tenofovir alafenamide co-crystal or salt" also includes solvates, hydrates and the like of the tenofovir alafenamide co-crystal or salt. When the tenofovir alafenamide eutectic is prepared, slurried or crystallized in a certain solvent, the solvent possibly enters the tenofovir alafenamide eutectic or salt crystals to form a solvate; when the solvent is water, hydrates may be formed.

The "tenofovir alafenamide eutectic crystal or salt" also includes a polycrystal of tenofovir alafenamide eutectic crystal or salt, a polycrystal of tenofovir alafenamide eutectic crystal or salt solvate, a polycrystal of tenofovir alafenamide eutectic crystal or salt hydrate, and the like.

Methods for determining "co-crystals" or "salts" are well known to those skilled in the art, such as by single crystal X-ray diffraction analysis and the like.

In the formula II, 1/n refers to the approximate molar composition ratio of tenofovir alafenamide to the corresponding acid in the structure of the compound, and can be determined by¹H-NMR, elemental analysis, HPLC, X-ray diffraction (e.g., single crystal X-ray diffraction), and the like. The "approximate" range is generally. + -. 0.15, preferably. + -. 0.1.

In the above formula II, the "tenofovir alafenamide complex" can be expressed as "X tenofovir alafenamide (1: n)" according to the stoichiometric number of tenofovir alafenamide and acid X in the structure, wherein X and n are defined as in the formula II, and "1: n" is the approximate molar composition ratio of acid X and tenofovir alafenamide in the tenofovir alafenamide complex, and can be determined by¹H-NMR, elemental analysis, HPLC, single crystal X-ray diffraction, etc.

In one embodiment, in formula ii, n ═ 3, X is selected from: phosphoric acid, citric acid, tannic acid (also known as tannic acid) or alginic acid.

In one embodiment, in formula ii, n ═ 2, X is selected from: sulfuric acid, persulfuric acid, thiocyanic acid, phosphoric acid, carbonic acid, glycerophosphoric acid, ethanedisulfonic acid, butanedisulfonic acid, naphthalene-1, 5-disulfonic acid, oxalic acid, malonic acid, succinic acid, L-malic acid, D-malic acid, racemic malic acid (also known as 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, sebacic acid, citric acid, camphoric acid, galactaric acid (also known as mucic acid), tannic acid (also known as tannic acid), alginic acid, pamoic acid (also known as 4,4' -methylenebis (3-hydroxy-2-naphthoic acid) or prussic acid), aspartic acid, glutamic acid.

In one embodiment, in formula ii, n ═ 1, X is selected from: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, dodecylsulfuric acid, glycerophosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, taurine, camphorsulfonic acid, cyclamic acid, sulfamic acid, ethanedisulfonic acid, butanedisulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-hydroxyphenylsulfonic acid, o-hydroxybenzenesulfonic acid, 2, 5-dihydroxybenzenesulfonic acid, sulfanilic acid, saccharin, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, formic acid, acetic acid, glycolic acid, 2-dichloroacetic acid, propionic acid, L-lactic acid, D-lactic acid, racemic lactic acid (also known as DL-lactic acid), cyclopentanepropionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, nonanoic acid, capric acid, undecylenic acid, lauric acid, palmitic, Stearic acid, oleic acid, oxalic acid, malonic acid, succinic acid, L-malic acid, D-malic acid, racemic malic acid (also known as 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, sebacic acid, citric acid, benzoic acid, p-methoxybenzoic acid, 4-acetamidobenzoic acid, salicylic acid, acetylsalicylic acid, gentisic acid, 4-aminosalicylic acid, phenylacetic acid, L-mandelic acid, D-mandelic acid, racemic mandelic acid (also known as DL-mandelic acid), 3-phenylpropionic acid, cinnamic acid, caffeic acid, phenylbutyric acid, picric acid, nicotinic acid, orotic acid, quinic acid, ascorbic acid, tartaric, Glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, lactobionic acid, camphoric acid, galactaric acid (aka mucic acid), tannic acid (aka tannic acid), alginic acid, hydroxynaphthoic acid (aka 3-hydroxy-2-naphthoic acid), pamoic acid (aka 4,4' -methylenebis (3-hydroxy-2-naphthoic acid) or prussic acid), acetamidoacetic acid, hippuric acid, aspartic acid, glutamic acid, pyroglutamic acid, glutamine, asparagine.

In one embodiment, the tenofovir alafenamide complex of formula ii is selected from the group consisting of: l-tenofovir alafenamide tartrate (1:2), D-tenofovir alafenamide tartrate (1:1), DL-tenofovir alafenamide tartrate (1:1), tenofovir alafenamide L malate (1:2), tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1) or tenofovir alafenamide sulfate (1: 1).

According to an object of the present invention, there is provided a process for preparing a tenofovir alafenamide complex represented by formula ii, which comprises:

(1) forming a solution comprising tenofovir alafenamide and acid X in a suitable solvent;

(2) separating out solids;

(3) separating the precipitated solid;

(4) optionally, the isolated solid is dried, or further purified and then dried.

In the above process step (1), tenofovir alafenamide may be prepared according to the methods disclosed in patent documents CN1443189A and CN1706855A or WO2013052094A and the like. These documents are incorporated by reference into the present application. The tenofovir alafenamide may be present in any form, including crystalline forms, amorphous forms, or mixtures thereof.

In step (1) of the above process, the "suitable solvent" refers to a solvent having a certain solubility for tenofovir alafenamide and acid, and capable of forming a tenofovir alafenamide complex therein. These suitable solvents are selected from 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, t-butyl methyl ether, tetrahydrofuran, petroleum ether, dichloromethane, chloroform, n-hexane, cyclohexane, acetone, butanone, pentanone, cyclohexanone, toluene, xylene, and the like, or mixtures thereof. The weight ratio of the suitable solvent to the tenofovir alafenamide is generally 3: 1-100: 1.

In step (1) of the above process, the "acid X" is selected from the acids represented by X in the formula II. The feeding molar ratio of the tenofovir alafenamide to the acid X is generally 4: 1-0.5: 1, and when a compound 'X tenofovir alafenamide (1: 3)' is prepared, the feeding molar ratio of the tenofovir alafenamide to the acid X is generally 2.7: 1-3.5: 1; when preparing the compound 'X tenofovir alafenamide (1: 2)', the feeding molar ratio of the tenofovir alafenamide to the acid X is generally 1.7: 1-2.5: 1; when preparing the compound 'X tenofovir alafenamide (1: 1)', the feeding molar ratio of the tenofovir alafenamide to the acid X is generally 0.5: 1-1.5: 1.

In step (2), the "solid precipitation" method is a method conventional in the art, such as cooling, adding an anti-solvent, concentrating a part of the solvent, adding a seed crystal, and the like.

In the above step (3), the "separation" method includes filtration, centrifugation or the like. Optionally, the collected solid may be washed with a suitable solvent.

In step (4), the drying method includes drying under normal pressure, drying under reduced pressure or a combination thereof. Methods of "further purification" include recrystallization, slurrying, washing, and the like.

L-Tenofovir alafenamide tartrate (1:2)

In another embodiment, in formula II, n is selected to be 2 and X is selected to be L-tartaric acid, i.e., a 2:1 molar composition ratio of tenofovir alafenamide to L-tartaric acid complex is provided, referred to as "tenofovir alafenamide L-tartrate (1: 2)".

In one embodiment, the present invention provides a method for preparing tenofovir alafenamide L-tartrate, the method comprising:

(1) dissolving tenofovir alafenamide and L-tartaric acid in a suitable solvent;

(2) separating out solids;

(3) separating the precipitated solid;

In step (1) of the above production process, the "suitable solvent" is selected from acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene and the like or a mixture thereof, and preferably acetonitrile. The weight ratio of the suitable solvent to the tenofovir alafenamide is generally 5: 1-80: 1.

In the step (1) of the preparation method, the feeding molar ratio of tenofovir alafenamide to L-tartaric acid is generally 1.7: 1-2.5: 1, and preferably 1.9: 1-2.3: 1.

In the step (2) of the preparation method, the method of "precipitating a solid" is a method which is conventional in the art, and the method includes cooling, adding an anti-solvent, concentrating a part of the solvent body, adding a seed crystal and the like, and is used singly or in combination. The solid precipitation process can be static or stirring.

In the step (3) of the preparation method, the separation may be performed by a conventional method in the art such as filtration. Optionally, the collected solid may be washed with a suitable solvent in step (1).

In the step (4) of the preparation method, the drying manner includes drying under normal pressure, drying under reduced pressure or a combination thereof. Methods of "further purification" include recrystallization, slurrying, washing, and the like.

D-Tenofovir alafenamide tartrate (1:1)

In one embodiment, in formula II, n is selected to be 1 and X is selected to be D-tartaric acid, i.e., a complex of tenofovir alafenamide and D-tartaric acid in a 1:1 molar ratio is provided, referred to as "tenofovir alafenamide D-tartrate".

In one embodiment, the present invention provides a method for preparing tenofovir alafenamide D-tartrate, the method comprising:

(1) dissolving tenofovir alafenamide and D-tartaric acid in a suitable solvent;

(2) separating out solids;

(3) separating the precipitated solid;

In step (1) of the above preparation process, the "suitable solvent" is selected from acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or a mixture thereof, preferably acetonitrile, isopropanol or a mixture thereof. The weight ratio of the suitable solvent to the tenofovir alafenamide is generally 5: 1-80: 1.

In the step (1) of the preparation method, the feeding molar ratio of tenofovir alafenamide to D-tartaric acid is generally 0.5: 1-1.5: 1, and preferably 0.8: 1-1.2: 1.

DL-Tenofovir alafenamide tartrate (1:1)

In one embodiment, in formula II, n is selected to be 1 and X is selected to be DL-tartaric acid, i.e., a complex of tenofovir alafenamide and DL-tartaric acid in a 1:1 molar ratio is provided, referred to as "DL-tartaric acid tenofovir alafenamide (1: 1)".

In one embodiment, the present invention provides a process for the preparation of DL-tenofovir alafenamide tartrate (1:1), the process comprising:

(1) dissolving tenofovir alafenamide and DL-tartaric acid in a suitable solvent;

(2) separating out solids;

(3) separating the precipitated solid;

In the step (1) of the preparation method, the DL-tartaric acid refers to racemic tartaric acid consisting of L-tartaric acid and D-tartaric acid in equal proportion. The "suitable solvent" is selected from acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene, etc. or mixtures thereof, preferably acetonitrile. The weight ratio of the suitable solvent to the tenofovir alafenamide is generally 5: 1-80: 1.

In the step (1) of the preparation method, the feeding molar ratio of tenofovir alafenamide to DL-tartaric acid is generally 0.5: 1-1.5: 1, preferably 0.8: 1-1.2: 1.

L-malic acid tenofovir alafenamide (1:2)

In another embodiment, in formula II, n is selected to be 2 and X is selected to be L-malic acid, i.e., a complex of tenofovir alafenamide and L-malic acid in a 2:1 molar ratio is provided, referred to as "tenofovir alafenamide L-malate (1: 2)".

In one embodiment, the present invention provides a method for preparing tenofovir alafenamide L-malate, comprising:

(1) dissolving tenofovir alafenamide and L-malic acid in a suitable solvent;

(2) separating out solids;

(3) separating the precipitated solid;

In step (1) of the above production process, the "suitable solvent" is selected from acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene and the like or a mixture thereof, and preferably is isopropanol. The weight ratio of the suitable solvent to the tenofovir alafenamide is generally 5: 1-80: 1.

In the step (1) of the preparation method, the feeding molar ratio of tenofovir alafenamide to L-malic acid is generally 1.7: 1-2.5: 1, and preferably 1.9: 1-2.3: 1.

Tenofovir alafenamide citrate (1:1)

In another embodiment, where n is selected to be 1 and X is selected to be citric acid, i.e. a complex of tenofovir alafenamide and citric acid in a 1:1 molar composition ratio is provided, referred to as "tenofovir alafenamide citrate (1: 1)".

In one embodiment, the present invention provides a method for preparing tenofovir alafenamide citrate, comprising:

(1) dissolving tenofovir alafenamide and citric acid in a suitable solvent;

(2) separating out solids;

(3) separating the precipitated solid;

In the step (1) of the preparation method, the feeding molar ratio of tenofovir alafenamide to citric acid is generally 0.5: 1-1.5: 1, and preferably 0.8: 1-1.2: 1.

Tenofovir alafenamide succinate (1:1)

In another embodiment, in formula ii, n is selected to be 1 and X is selected to be succinic acid, i.e. a complex of tenofovir alafenamide and succinic acid in a 1:1 molar composition ratio is provided, referred to as "tenofovir alafenamide succinate (1: 1)".

In one embodiment, the present invention provides a method for preparing tenofovir alafenamide succinate, comprising:

(1) dissolving tenofovir alafenamide and succinic acid in a suitable solvent;

(2) separating out solids;

(3) separating the precipitated solid;

In the step (1) of the preparation method, the feeding molar ratio of tenofovir alafenamide to succinic acid is generally 0.5: 1-1.5: 1, and preferably 0.8: 1-1.2: 1.

In the step (2) of the preparation method, the method of "precipitating a solid" is a method which is conventional in the art, and the method includes cooling, adding an anti-solvent, concentrating a part of the solvent body, adding a seed crystal and the like, and is used singly or in combination. . The solid precipitation process can be static or stirring.

Oxalic acid tenofovir alafenamide (1:1)

In another embodiment, in formula ii, n is selected to be 1 and X is selected to be oxalic acid, i.e. a complex of tenofovir alafenamide and oxalic acid in a 1:1 molar composition ratio is provided, referred to as "tenofovir alafenamide oxalate (1: 1)".

In one embodiment, the present invention provides a method for preparing tenofovir alafenamide oxalate, comprising:

(1) dissolving tenofovir alafenamide and oxalic acid in a suitable solvent;

(2) separating out solids;

(3) separating the precipitated solid;

In the step (1) of the preparation method, the feeding molar ratio of tenofovir alafenamide to oxalic acid is generally 0.5: 1-1.5: 1, and preferably 0.8: 1-1.2: 1.

Tenofovir alafenamide phosphate (1:1)

In another embodiment, n is selected to be 1 and X is selected to be phosphoric acid, i.e., in formula IITenofovir alafenamide and its preparation method are providedPhosphoric acidThe complex formed in a 1:1 molar composition ratio was referred to as "tenofovir alafenamide phosphate (1: 1)".

In one embodiment, the present invention provides a method for preparing tenofovir alafenamide phosphate, the method comprising:

(1) dissolving tenofovir alafenamide and phosphoric acid in a suitable solvent;

(2) separating out solids;

(3) separating the precipitated solid;

In the step (1) of the preparation method, the feeding molar ratio of tenofovir alafenamide to phosphoric acid is generally 0.5: 1-1.5: 1, and preferably 0.8: 1-1.2: 1.

Tenofovir alafenamide sulfate (1:1)

In another embodiment, where n is selected to be 1 and X is selected to be sulfuric acid in formula II, tenofovir alafenamide and tenofovir alafenamide are providedSulfuric acidThe complex formed in a 1:1 molar composition ratio was referred to as "tenofovir alafenamide sulfate (1: 1)".

In one embodiment, the present invention provides a method for preparing tenofovir alafenamide sulfate, comprising:

(1) dissolving tenofovir alafenamide and sulfuric acid in a suitable solvent;

(2) separating out solids;

(3) separating the precipitated solid;

In the step (1) of the preparation method, the feeding molar ratio of tenofovir alafenamide to sulfuric acid is generally 0.5: 1-1.5: 1, and preferably 0.8: 1-1.2: 1.

According to the purpose of the invention, the invention provides a pharmaceutical composition containing a therapeutically effective amount of tenofovir alafenamide compound shown in formula II or the tenofovir alafenamide compound shown in formula II prepared by the preparation method and a pharmaceutical excipient.

Optionally, the pharmaceutical composition or formulation may further comprise one or more antiviral agents or antiviral auxiliary agents, including, but not limited to, emtricitabine, lamivudine, Abacavir (Abacavir), Acemannan (Acemannan), Amprenavir (Ainprenavir), Amprenavir (Amprenavir), Atazanavir (Atazanavir), Clevudine (Clevudine), Cobicistat, Dapivirine (Dapivirine), Darunavir (Darunavir), Delavirdine (Delavirdine), Didanosine (Didanosine), deluvir (Dolutegravir), efavir (Efavirenz), efavir (Elvitegravir), envirtide (enfurvintide), Entecavir (entavir), Efavirenz (etravirucine), valviravirenz (Efavirenz), neviravir (neviravir), neviravir (fosalviravir), Nevirapine (valavir), Nevirapine (e), Nevirapine (Nevirapine), Nevirapine (e), Nevirapine (Nevirapine, Nevirapine, Penciclovir (Penticlovir), Pentamidine (Pentamidine), Phosphazid, propagum (Propagermanium), Rettgravir (Raltegravir), Ribavirin (Ribavirin), rilpivirine (Rilpivrine), Ritonavir (Ritonavir), Saquinavir (Saquinavir), Stavudine (Stavudine), Telbivudine (Telbivudine), Tipranavir (Tipranavir), Vorinostat (Vorinostat), Zalcitabine (Zalcitabine), Zidovudine (Zidovudine), and the like, or pharmaceutically acceptable salts thereof, with preference given to emtricitabine, lamivudine, Cobicistat, darunavir, Efavirenz, Etiravir, rilpivirin hydrochloride.

Preferably, the pharmaceutical composition of the invention is selected from one of the following:

a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, emtricitabine, Cobicistat and eltiravir; or,

a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, emtricitabine, Cobicistat and darunavir; or,

a pharmaceutical 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,

a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, emtricitabine, and ropinirovir hydrochloride; or,

a pharmaceutical composition comprising a therapeutically effective amount of 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,

a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, lamivudine, Cobicistat and eltoprevir; or,

a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, lamivudine, Cobicistat and darunavir.

In one embodiment, the present invention provides a pharmaceutical composition or formulation comprising a therapeutically effective amount of tenofovir alafenamide L tartrate (1:2), tenofovir alafenamide D tartrate (1:1), tenofovir alafenamide DL tartrate (1:1), tenofovir alafenamide L malate (1:2), tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1) or tenofovir alafenamide sulfate (1:1) and a pharmaceutically acceptable excipient.

The above pharmaceutical composition or preparation can be administered orally or parenterally. When the preparation is orally taken, the preparation can be prepared into tablets, capsules, pills, granules, solutions, syrups, suspensions, powders, sustained-release preparations or controlled-release preparations and the like by adopting the conventional preparation technology. When the preparation is administered parenterally, it can be made into transdermal preparation, injection, infusion solution or suppository by conventional preparation technology.

The various dosage forms of the above pharmaceutical composition can be prepared according to conventional methods in the pharmaceutical field. For example, a therapeutically effective amount of tenofovir alafenamide complex of formula ii, L-tenofovir alafenamide tartrate (1:2), D-tenofovir alafenamide tartrate (1:1), DL-tenofovir alafenamide tartrate (1:1), tenofovir alafenamide L malate (1:2), tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1), or tenofovir alafenamide sulfate (1:1), optionally mixed or contacted with another therapeutically effective amount of the active ingredient(s), with one or more pharmaceutical excipients, and then formulated into the desired dosage form.

The pharmaceutical composition or preparation is preferably an oral dosage form, including tablets, capsules, pills, granules, solutions, syrups, dry suspensions, powders, sustained-release preparations or controlled-release preparations and the like. Among them, solid oral preparations such as tablets, capsules, granules, dry suspensions, sustained-release preparations or controlled-release preparations are preferable, and among them, tablets and capsules are more preferable. Preferred pharmaceutical compositions or formulations of the present invention may be prepared according to any of the conventional methods employed for preparing solid oral formulations. For example, the tablet can be prepared by wet granulation, tabletting and the like, and can be coated in any form according to the needs, for example, the tablet can be prepared into any release form (such as quick release, enteric coating, sustained and controlled release and the like); the capsule can be prepared by wet granulation and capsule filling, and the capsule content can be prepared into any release form (such as quick release preparation, enteric preparation and sustained and controlled release preparation).

In one embodiment, the particle size distribution of the tenofovir alafenamide complex represented by formula II, L-tenofovir alafenamide tartrate (1:2), D-tenofovir alafenamide tartrate (1:1), DL-tenofovir alafenamide tartrate (1:1), tenofovir alafenamide L-malate (1:2), tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1), or tenofovir alafenamide sulfate (1:1) is controlled to be 95% less than 200 μm, preferably less than 180 μm, more preferably less than 150 μm, and still more preferably less than 100 μm. Pharmaceutical excipients which are conventional in the art in oral dosage forms include fillers, disintegrants, binders, dispersants, lubricants or retention aids, and various types of coating materials, and the like.

The filler generally includes pregelatinized starch, lactose, dextrin, calcium hydrogen phosphate, calcium carbonate, mannitol, microcrystalline cellulose, sorbitol, glucose, etc., which may be used alone or in combination, among which pregelatinized starch, lactose, microcrystalline cellulose, mannitol are preferred.

The disintegrant generally includes croscarmellose sodium, carboxymethylcellulose sodium, sodium carboxymethyl starch, crospovidone, starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and the like, which may be used alone or in combination, and among them, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose are preferred.

The binder generally comprises microcrystalline cellulose, pre-crosslinked starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, starch slurry, acacia, polyethylene glycol 4000, polyvinyl alcohol, alginate, water, and various concentrations of ethanol solution, which can be used alone or in combination, wherein hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and starch slurry are preferred.

Such lubricants generally include magnesium stearate, stearic acid, calcium stearate, sodium stearate fumarate, potassium stearate fumarate, palmitic acid, microsilica, stearamide, talc, solid polyethylene glycols, glyceryl triacetate, and the like. These may be used alone or in combination, and magnesium stearate, stearic acid, talc, microsilica, and glyceryl triacetate are preferable among them.

If necessary, other adjuvants such as sweetener (such as aspartame, steviosin, etc.), colorant (such as lemon yellow, iron oxide, etc., medicinal or edible pigment), stabilizer (such as calcium carbonate, calcium bicarbonate, sodium carbonate, calcium phosphate, calcium hydrogen phosphate, glycine, etc.), surfactant (such as Tween 80, sodium dodecyl sulfate, etc.), and coating material (such as Opadry, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acrylic resin copolymer, etc.) can be added into the composition or preparation.

In a specific embodiment, the present invention provides a single composition or formulation wherein the active ingredient is selected from the group consisting of a therapeutically effective amount of tenofovir alafenamide complex of formula ii, tenofovir alafenamide L tartrate (1:2), tenofovir alafenamide D tartrate (1:1), tenofovir alafenamide DL tartrate (1:1), tenofovir alafenamide L malate (1:2), tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1), and tenofovir alafenamide sulfate (1: 1). The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; they are generally present in a unit composition or formulation in an amount of from 1mg to 200mg, preferably 5mg to 100mg, for example about 10mg, about 12.5mg, about 25mg or about 50mg, calculated as tenofovir alafenamide, wherein "about" refers to the range of ± 10%, preferably the range of ± 5%.

In a specific embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from the group consisting of a therapeutically effective amount of tenofovir alafenamide complex of formula ii, tenofovir alafenamide L-tartrate (1:2), tenofovir alafenamide D-tartrate (1:1), tenofovir alafenamide DL-tartrate (1:1), tenofovir alafenamide L-malate (1:2), tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1), or tenofovir alafenamide sulfate (1:1), the second active ingredient is a therapeutically effective amount of emtricitabine, and the third active ingredient is a therapeutically effective amount of cobistat, the fourth active ingredient is an effective amount of eltamivir. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 500mg, preferably from 5mg to 300mg, for example containing about 10mg or about 25mg of the first active ingredient described above (calculated as tenofovir alafenamide), about 200mg of the second active ingredient (emtricitabine), about 150mg of the third active ingredient (Cobicistat) and about 150mg of the fourth active ingredient (entecavir), where "about" means a range of ± 10%, preferably a range of ± 5%.

In a specific embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from the group consisting of a therapeutically effective amount of tenofovir alafenamide complex of formula ii, tenofovir alafenamide L-tartrate (1:2), tenofovir alafenamide D-tartrate (1:1), tenofovir alafenamide DL-tartrate (1:1), tenofovir alafenamide L-malate (1:2), tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1), or tenofovir alafenamide sulfate (1:1), the second active ingredient is a therapeutically effective amount of emtricitabine, and the third active ingredient is a therapeutically effective amount of cobistat, the fourth active ingredient is darunavir with effective treatment amount. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 1000mg, preferably from 5mg to 900mg, for example containing about 10mg or about 25mg of the first active ingredient (calculated as tenofovir alafenamide), about 200mg of the second active ingredient (emtricitabine), about 150mg of the third active ingredient (Cobicistat) and about 800mg of the fourth active ingredient (darunavir), where "about" means a range of ± 10%, preferably a range of ± 5%.

In a specific embodiment, the present invention provides a combination composition or formulation, wherein the first active ingredient is selected from the group consisting of a therapeutically effective amount of tenofovir alafenamide complex of formula ii, tenofovir alafenamide L-tartrate (1:2), tenofovir alafenamide D-tartrate (1:1), tenofovir alafenamide DL-tartrate (1:1), tenofovir alafenamide L-malate (1:2), tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1), and tenofovir alafenamide sulfate (1:1), and the second active ingredient is a therapeutically effective amount of emtricitabine. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 500mg, preferably from 5mg to 300mg, for example containing about 10mg or about 25mg (calculated as tenofovir alafenamide) of the first active ingredient described above and about 200mg of the second active ingredient (emtricitabine), where "about" refers to the range of ± 10%, preferably the range of ± 5%.

In a specific embodiment, the present invention provides a combination composition or formulation, wherein the first active ingredient is selected from the group consisting of a therapeutically effective amount of tenofovir alafenamide complex of formula ii, tenofovir alafenamide L-tartrate (1:2), tenofovir alafenamide D-tartrate (1:1), tenofovir alafenamide DL-tartrate (1:1), tenofovir alafenamide L-malate (1:2), the composition comprises tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1) or tenofovir alafenamide sulfate (1:1), a second active ingredient is emtricitabine with a therapeutically effective amount, and a third active ingredient is efavirenz with a therapeutically effective amount. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 800g, preferably from 5mg to 700mg, for example containing about 10mg or about 25mg of the first active ingredient described above (calculated as tenofovir alafenamide), about 200mg of the second active ingredient (emtricitabine) and about 600mg of the third active ingredient (efavirenz), where "about" refers to the range of ± 10%, preferably the range of ± 5%.

In a specific embodiment, the present invention provides a combination composition or formulation, wherein the first active ingredient is selected from the group consisting of a therapeutically effective amount of tenofovir alafenamide complex of formula ii, tenofovir alafenamide L-tartrate (1:2), tenofovir alafenamide D-tartrate (1:1), tenofovir alafenamide DL-tartrate (1:1), tenofovir alafenamide L-malate (1:2), the composition comprises tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1) or tenofovir alafenamide sulfate (1:1), a second active ingredient is emtricitabine with a therapeutically effective amount, and a third active ingredient is rilpivirine hydrochloride with a therapeutically effective amount. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, the respective weight content is typically from 1mg to 500mg, preferably from 5mg to 300mg, for example containing about 10mg or about 25mg of the first active ingredient described above (calculated as tenofovir alafenamide), about 200mg of the second active ingredient (emtricitabine) and about 25mg of the third active ingredient (rilpivirine hydrochloride) (calculated as rilpivirine), "about" means a range of ± 10%, preferably a range of ± 5%.

In a specific embodiment, the present invention provides a combination composition or formulation, wherein the first active ingredient is selected from the group consisting of a therapeutically effective amount of tenofovir alafenamide complex of formula ii, tenofovir alafenamide L-tartrate (1:2), tenofovir alafenamide D-tartrate (1:1), tenofovir alafenamide DL-tartrate (1:1), tenofovir alafenamide L-malate (1:2), tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1), and tenofovir alafenamide sulfate (1:1), and the second active ingredient is a therapeutically effective amount of lamivudine. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 500mg, preferably from 5mg to 400mg, for example containing about 10mg or about 25mg (calculated as tenofovir alafenamide) of the first active ingredient described above and about 300mg of the second active ingredient (lamivudine), where "about" refers to the range of ± 10%, preferably the range of ± 5%.

In a specific embodiment, the present invention provides a combination composition or formulation, wherein the first active ingredient is selected from the group consisting of a therapeutically effective amount of tenofovir alafenamide complex of formula ii, tenofovir alafenamide L-tartrate (1:2), tenofovir alafenamide D-tartrate (1:1), tenofovir alafenamide DL-tartrate (1:1), tenofovir alafenamide L-malate (1:2), tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1) or tenofovir alafenamide sulfate (1:1), a second active ingredient is lamivudine with a therapeutically effective amount, and a third active ingredient is efavirenz with a therapeutically effective amount. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 800mg, preferably from 5mg to 700mg, for example containing about 10mg or 25mg of the first active ingredient (calculated as tenofovir alafenamide), about 300mg of the second active ingredient (lamivudine) and about 600mg of the third active ingredient (efavirenz) as described above, where "about" refers to the range of ± 10%, preferably the range of ± 5%.

In a specific embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from the group consisting of a therapeutically effective amount of tenofovir alafenamide complex of formula ii, tenofovir alafenamide L-tartrate (1:2), tenofovir alafenamide D-tartrate (1:1), tenofovir alafenamide DL-tartrate (1:1), tenofovir alafenamide L-malate (1:2), tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1), or tenofovir alafenamide sulfate (1:1), the second active ingredient is a therapeutically effective amount of lamivudine, and the third active ingredient is a therapeutically effective amount of cobistat, the fourth active ingredient is an effective amount of eltamivir. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 500mg, preferably from 5mg to 400mg, for example containing about 10mg or about 25mg of the first active ingredient (calculated as tenofovir alafenamide), about 300mg of the second active ingredient (lamivudine), about 150mg of the third active ingredient (Cobicistat) and about 150mg of the fourth active ingredient (ezetimibe), where "about" means a range of ± 10%, preferably a range of ± 5%.

In a specific embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from the group consisting of a therapeutically effective amount of tenofovir alafenamide complex of formula ii, tenofovir alafenamide L-tartrate (1:2), tenofovir alafenamide D-tartrate (1:1), tenofovir alafenamide DL-tartrate (1:1), tenofovir alafenamide L-malate (1:2), tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1), or tenofovir alafenamide sulfate (1:1), the second active ingredient is a therapeutically effective amount of lamivudine, and the third active ingredient is a therapeutically effective amount of cobistat, the fourth active ingredient is darunavir with effective treatment amount. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 1000mg, preferably from 5mg to 900mg, for example containing about 10mg or about 25mg of the first active ingredient (calculated as tenofovir alafenamide), about 200mg of the second active ingredient (lamivudine), about 150mg of the third active ingredient (Cobicistat) and about 800mg of the fourth active ingredient (darunavir), where "about" means a range of ± 10%, preferably a range of ± 5%.

The above compositions are not only chemically stable, but also have a synergistic effect and/or can reduce the side effects and resistance of the individual active ingredients; while possibly increasing patient compliance.

The invention provides a method for preparing the medicinal composition or the preparation. For single compositions or formulations, the method generally involves mixing or contacting a therapeutically effective amount of the tenofovir alafenamide complex of formula ii with one or more pharmaceutical excipients. For a combination composition or formulation, the method generally comprises mixing or contacting a therapeutically effective amount of the tenofovir alafenamide complex of formula II, a second active ingredient (e.g., emtricitabine, lamivudine, etc.), and one or more pharmaceutical excipients. For a tri-or multi-compound composition or formulation, the method generally comprises mixing or contacting a therapeutically effective amount of the tenofovir alafenamide complex of formula ii, a second active ingredient (e.g., emtricitabine, lamivudine, etc.), and one or more additional active ingredients with a pharmaceutically acceptable excipient. The pharmaceutical compositions or formulations are prepared in a manner well known in the art. The pharmaceutic adjuvant is a conventional pharmaceutic adjuvant in the field and comprises a filler, a disintegrant, an adhesive, a lubricant and the like.

The filler generally includes pregelatinized starch, lactose, mannitol, microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, etc., which may be used alone or in combination, among which pregelatinized starch, lactose, mannitol, microcrystalline cellulose are preferred.

The disintegrating agent generally includes croscarmellose sodium, sodium carboxymethylcellulose, sodium carboxymethyl starch, crospovidone, starch, polyvinylpyrrolidone, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and the like, and they may be used alone or in combination, and among them, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, and crospovidone are preferable.

The binder generally comprises microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, starch slurry, polyethylene glycol 4000, polyvinyl alcohol, alginate, water, and ethanol solution with various concentrations, which can be used alone or in combination, wherein hydroxypropyl methylcellulose, hydroxypropyl cellulose, and povidone are preferred.

Such lubricants typically include magnesium stearate, stearic acid, calcium stearate, palmitic acid, silicon dioxide, stearamide, talc, solid polyethylene glycols and the like. These may be used alone or in combination, and magnesium stearate, silicon dioxide, stearic acid, and talc are preferred.

The pharmaceutical composition or preparation is preferably an oral dosage form comprising: tablets, capsules, pills, granules, solutions, syrups, suspensions, powders, sustained-release preparations or controlled-release preparations, and the like. Among them, solid oral preparations such as tablets, capsules, granules, drinkable suspensions and the like are preferable, and among them, tablets and capsules are more preferable. Preferred pharmaceutical compositions or formulations of the present invention may be prepared according to any of the conventional methods employed for preparing solid oral formulations. For example, the tablet can be prepared by wet granulation and tabletting and the like, and can be coated as required; the capsule can be prepared by wet granulation and capsule filling.

According to the purpose of the invention, the invention provides application of a tenofovir alafenamide compound shown in formula II or a tenofovir alafenamide compound shown in formula II prepared by the preparation method in preparation of a medicament for preventing and/or treating virus infection.

Specifically, the invention provides an application of a tenofovir alafenamide compound shown in a formula II in preparing a medicament for preventing and/or treating Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection.

In a specific embodiment, the invention provides application of a tenofovir alafenamide compound shown in a formula II in preparing a medicament for preventing and/or treating Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection.

In a specific embodiment, the invention provides application of a pharmaceutical composition containing a therapeutically effective amount of tenofovir alafenamide complex shown in formula II and a pharmaceutical excipient in preparing a medicament for preventing and/or treating Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection.

In a specific embodiment, the invention provides the application of a pharmaceutical composition containing a therapeutically effective amount of tenofovir alafenamide complex shown in formula II, another antiviral agent or antiviral auxiliary agents and pharmaceutical excipients in preparing a medicament for preventing and/or treating Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection.

Experiments prove that the invention provides a tenofovir alafenamide compound shown in formula II, such as L-tenofovir alafenamide tartrate (1:2), D-tenofovir alafenamide tartrate (1:1), DL-tenofovir alafenamide tartrate (1:1), tenofovir alafenamide L-malate (1:2), tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), the preparation method is simple, convenient and controllable, and the physical properties, stability, solubility, preparation adaptability and the like are not lower than or better than those of the existing tenofovir alafenamide fumarate and hemifumarate, so that the preparation method has good industrial practicability.

Detailed Description

The present invention is described in further detail below with reference to specific embodiments of examples, but it should not be construed that the present invention is limited to the examples, and the present invention based on the above description is within the scope of the present invention.

In the following examples¹The HNMR test is carried out by taking deuterated dimethyl sulfoxide as a test solvent, taking tetramethylsilane as an internal standard and measuring at room temperature by using a BrukeAV-II 400MHz nuclear magnetic resonance instrument.

The melting range in the following examples was measured by a YRT-3 model drug melting point apparatus.

Example 1

Preparation of tenofovir alafenamide (I)

500.0g (1.38mol, 1.0eq) of monophenyl tenofovir (prepared by the method disclosed in CN 1443189A) was added to 3.0L of toluene at 20 to 25 ℃, the solid was completely dissolved with stirring, 150ml (2.05mol,1.5eq) of thionyl chloride was then added, and the resulting mixture was heated to about 70 ℃ and stirred for 96 hours. Concentrating the mixture at 40-45 ℃ under reduced pressure to dryness, adding 2.5L of toluene into the concentrate, dropwise adding 813.5g (6.21mol,4.5eq) of L-isopropyl alaninate (commercially available) dissolved in 4.0L of dichloromethane at-10 ℃, stirring the mixture at-10 ℃ for 30 minutes, raising the temperature to room temperature, washing the mixture with 2.5L x 2 of 10% sodium dihydrogen phosphate aqueous solution, separating out an organic phase, washing the organic phase with 1.0L x 2 of 15% potassium bicarbonate aqueous solution, washing the organic phase with 2.5L of purified water, drying the obtained organic phase with anhydrous sodium sulfate, filtering the organic phase, and concentrating the filtrate under reduced pressure to dryness. Dissolving the concentrate with 2.5L of a toluene/acetonitrile mixed solvent (in a volume ratio of 4/1) at 20-25 ℃, adding 50mg of tenofovir alafenamide seed crystal (prepared according to the method disclosed in CN 1443189A), continuously stirring for 2 hours, performing suction filtration, washing a filter cake with toluene/acetonitrile (in a volume ratio of 4/1), and then performing reduced pressure drying at 40-45 ℃ to obtain tenofovir alafenamide.

¹HNMR(400MHz，DMSO-d₆):8.15(s，1H)，8.11(s，1H)，7.32-7.28(t，2H)，7.21(s，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.65-5.59(m，1H)，4.90-4.81(m，1H)，4.31-4.26(m，1H)，4.18-4.13(m，1H)，3.98-3.91(m，1H)，3.90-3.81(m，2H)，3.80-3.75(m，1H)，1.16-1.14(m，9H)，1.09-1.07(d，3H)。

Example 2

Preparation of Tenofovir alafenamide L-tartrate (1:2)

Dissolving 4.76g (10.0mmol) of tenofovir alafenamide and 0.75g (5.0mmol) of L-tartaric acid in 100ml of acetonitrile at 70-75 ℃, stirring and cooling to 15-20 ℃ after complete dissolution, and then continuing stirring and crystallizing; and (3) carrying out suction filtration, washing a filter cake by using an appropriate amount of acetonitrile, and drying under reduced pressure at 40-45 ℃ to obtain the L-tenofovir alafenamide tartrate (1: 2).

¹HNMR(400MHz，DMSO-d₆):8.14(s，1H)，8.10(s，1H)，7.31-7.27(t，2H)，7.19(s，2H)，7.15-7.11(m，1H)，7.07-7.04(m，2H)，5.64-5.58(m，1H)，4.90-4.80(m，1H)，4.30-4.25(m，2H)，4.18-4.12(m，1H)，3.98-3.91(m，1H)，3.89-3.81(m，2H)，3.80-3.74(m，1H)，1.16-1.13(t，9H)，1.08-1.06(d，3H)。

Melting range: 158-.

As described above¹In HNMR results, the signal peaks at chemical shifts of 8.14(s, 1H) and 8.10(s, 1H) were assigned to 2H on the adenine ring of tenofovir alafenamide, and the signal peaks at 4.30-4.25(m, 2H) were assigned to the free base of tenofovir alafenamide in example 1, respectively¹HNMR control, can judge that 1H is assigned to 2 methine H of L-tartaric acid, can judge from the integral area ratio of two groups of signal peaks that the molar composition ratio of tenofovir alafenamide and L-tartaric acid in the sample is 2: 1.

Example 3

Preparation of Tenofovir alafenamide D-tartrate (1:1)

Dissolving 4.76g (10.0mmol) of tenofovir alafenamide and 1.50g (10.0mmol) of D-tartaric acid in 100ml of acetonitrile at 70-75 ℃, stirring and cooling to 15-20 ℃ after complete dissolution, and continuing stirring and crystallizing; and (3) carrying out suction filtration, washing a filter cake by using an appropriate amount of acetonitrile, and drying under reduced pressure at 40-45 ℃ to obtain the D-tenofovir alafenamide tartrate (1: 1).

¹HNMR(400MHz，DMSO-d₆):8.15(s，1H)，8.11(s，1H)，7.31-7.28(t，2H)，7.22(s，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.63-5.58(m，1H)，4.90-4.81(m，1H)，4.32-4.26(m，3H)，4.18-4.13(m，1H)，4.00-3.92(m，1H)，3.90-3.81(m，2H)，3.80-3.74(m，1H)，1.16-1.13(t，9H)，1.09-1.07(d，3H)。

Melting range: 135 ℃ and 138 ℃.

As described above¹In HNMR results, the signal peaks at chemical shifts of 8.15(s, 1H) and 8.11(s, 1H) were assigned to 2H on the adenine of tenofovir alafenamide, and the signal peaks at 4.32-4.26(m, 3H) and the free base of tenofovir alafenamide in example 1, respectively¹HNMR control, can judge 2H assign to 2 methine H of D-tartaric acid among them, can judge from the integral area ratio of two groups of signal peaks that tenofovir alafenamide and D-tartaric acid in this sample are in molar composition than 1: 1.

Example 4

Preparation of DL-tenofovir alafenamide tartrate (1:1)

Dissolving 4.76g (10.0mmol) of tenofovir alafenamide and 1.50g (10.0mmol) of DL-tartaric acid in 100ml of acetonitrile at 70-75 ℃, stirring and cooling to 15-20 ℃ after complete dissolution, and continuing stirring and crystallizing; and (3) carrying out suction filtration, washing a filter cake by using an appropriate amount of acetonitrile, and drying under reduced pressure at 40-45 ℃ to obtain DL-tenofovir alafenamide tartrate (1: 1).

¹HNMR(400MHz，DMSO-d₆):8.14(s，1H)，8.11(s，1H)，7.31-7.27(t，2H)，7.20(s，2H)，7.15-7.11(m，1H)，7.07-7.04(m，2H)，5.63-5.58(m，1H)，4.90-4.80(m，1H)，4.31-4.26(m，3H)，4.18-4.13(m，1H)，4.00-3.91(m，1H)，3.90-3.81(m，2H)，3.80-3.74(m，1H)，1.16-1.13(t，9H)，1.08-1.07(d，3H)。

Melting range: 175 ℃ and 178 ℃.

As described above¹In HNMR results, the signal peaks at chemical shifts of 8.14(s, 1H) and 8.11(s, 1H) were assigned to 2H on the adenine of tenofovir alafenamide, and the signal peaks at 4.31-4.26(m, 3H) and the free base of tenofovir alafenamide in example 1, respectively¹HNMR control, can judge 2H assign as DL-2 methine H of tartaric acid among them, can judge from the integral area ratio of two groups of signal peaks that Tenofovir alafenamide and DL-tartaric acid in this sample are in molar composition ratio of 1: 1.

Example 5

Preparation of tenofovir alafenamide L-malate (1:2)

Dissolving 4.76g (10.0mmol) of tenofovir alafenamide and 0.67g (5.0mmol) of L-malic acid in 50ml of isopropanol at 70-75 ℃, stirring and cooling to 15-20 ℃ after complete dissolution, and continuing stirring and crystallizing; and (3) carrying out suction filtration, washing a filter cake by using a proper amount of isopropanol, and drying under reduced pressure at 40-45 ℃ to obtain the tenofovir alafenamide L-malate (1: 2).

¹HNMR(400MHz，DMSO-d₆):8.15(s，1H)，8.11(s，1H)，7.32-7.28(m，2H)，7.22(s，2H)，7.15-7.12(t,1H),7.07-7.05(m，2H)，5.65-5.59(m，1H)，4.90-4.81(m，1H)，4.31-4.26(m，2H)，4.19-4.13(m，1H)，4.00-3.92(m，1H)，3.90-3.83(m，2H)，3.80-3.74(m，1H)，2.65-2.43(m，1H)，1.16-1.14(m，9H)，1.09-1.07(d，3H)。

As described above¹In the HNMR results, the signal peaks at chemical shifts of 8.15(s, 1H) and 8.11(s, 1H) are respectively assigned to 2H on the adenine of tenofovir alafenamide, the signal peaks at 2.65-2.43(m, 1H) are assigned to 2H on the methylene of L-malic acid, and the molar composition ratio of the tenofovir alafenamide and the L-malic acid in the sample can be judged to be 2:1 from the integral area ratio of the two groups of signal peaks.

Example 6

Preparation of tenofovir alafenamide citrate (1:1)

Dissolving 4.76g (10.0mmol) of tenofovir alafenamide and 1.92g (10.0mmol) of citric acid in 100ml of acetonitrile at 70-75 ℃, stirring and cooling to 15-20 ℃ after complete dissolution, and continuing stirring and crystallizing; and (3) carrying out suction filtration, washing a filter cake by using an appropriate amount of acetonitrile, and drying under reduced pressure at 40-45 ℃ to obtain the tenofovir alafenamide citrate (1: 1).

¹HNMR(400MHz，DMSO-d₆):8.14(s，1H)，8.11(s，1H)，7.31-7.27(m，2H)，7.22(s，2H)，7.15-7.11(m，1H)，7.07-7.04(m，2H)，5.63-5.58(m，1H)，4.90-4.80(m，1H)，4.30-4.26(m，1H)，4.18-4.13(m，1H)，4.00-3.91(m，1H)，3.89-3.81(m，2H)，3.79-3.74(m，1H)，2.78-2.74(d，2H)，2.67-2.64(d，2H)，1.16-1.13(t，9H)，1.08-1.06(d，3H)。

Melting range: 144 ℃ and 147 ℃.

As described above¹In the HNMR results, the signal peaks at chemical shifts of 8.14(s, 1H) and 8.11(s, 1H) were assigned to 2H on tenofovir alafenamide adenine, 2.78-2.74(d, 2H) and 2.67-2.64(d, 2H), respectively, to 4H of 2 methylene groups on citric acid, and the molar composition ratio of tenofovir alafenamide to citric acid in the sample was judged to be 1:1 from the integrated area ratio of the two sets of signal peaks.

Example 7

Preparation of tenofovir alafenamide succinate (1:1)

Dissolving 4.76g (10.0mmol) of tenofovir alafenamide and 1.18g (10.0mmol) of succinic acid in 50ml of acetonitrile at 70-75 ℃, stirring and cooling to 15-20 ℃ after complete dissolution, and continuing stirring and crystallizing; and (3) carrying out suction filtration, washing a filter cake by using an appropriate amount of acetonitrile, and drying under reduced pressure at 40-45 ℃ to obtain tenofovir alafenamide succinate (1: 1).

¹HNMR(400MHz，DMSO-d₆):12.13(s，2H)，8.15(s，1H)，8.11(s，1H)，7.31-7.27(t，2H)，7.21(s，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.64-5.59(m，1H)，4.90-4.81(m，1H)，4.30-4.26(m，1H)，4.18-4.13(m，1H)，4.00-3.92(m，1H)，3.90-3.81(m，2H)，3.80-3.74(m，1H)，2.43(s，4H)，1.16-1.13(t，9H)，1.08-1.07(d，3H)。

As described above¹In the HNMR results, the signal peaks at chemical shifts of 8.15(s, 1H) and 8.11(s, 1H) were assigned to 2H on tenofovir alafenamide adenine and the signal peak at 2.43(s, 4H) was assigned to 4H on 2 symmetric methylene groups on succinic acid, respectively, and the molar composition ratio of tenofovir alafenamide to succinic acid in this sample was judged to be 1:1 from the integrated area ratio of the two sets of signal peaks.

Example 8

Preparation of tenofovir alafenamide oxalate (1:1)

Dissolving 4.76g (10.0mmol) of tenofovir alafenamide and 1.26g (10.0mmol) of oxalic acid dihydrate in 100ml of acetonitrile at 70-75 ℃, stirring and cooling to 15-20 ℃ after complete dissolution, and continuing stirring and crystallizing; and (3) carrying out suction filtration, washing a filter cake by using an appropriate amount of acetonitrile, and drying under reduced pressure at 40-45 ℃ to obtain tenofovir alafenamide oxalate (1: 1).

¹HNMR(400MHz，DMSO-d₆):8.19(s，1H)，8.15(s，1H)，7.49(s，2H)，7.32-7.28(m，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.64-5.58(m，1H)，4.90-4.80(m，1H)，4.32-4.28(m，1H)，4.19-4.14(m，1H)，4.00-3.91(m，1H)，3.90-3.83(m，2H)，3.80-3.75(m，1H)，1.16-1.13(m，9H)，1.09-1.08(d，3H)。

Melting range: 182 ℃ and 185 ℃.

Example 9

Preparation of tenofovir alafenamide phosphate (1:1)

Dissolving 4.76g (10.0mmol) of tenofovir alafenamide and 1.20g (10.0mmol) of phosphoric acid (85% aqueous solution) in 50ml of acetonitrile at 20-25 ℃, and then stirring for crystallization at 20-25 ℃; and (3) carrying out suction filtration, washing a filter cake by using an appropriate amount of acetonitrile, and drying under reduced pressure at 40-45 ℃ to obtain tenofovir alafenamide phosphate (1: 1).

¹HNMR(400MHz，DMSO-d₆):8.15(s，1H)，8.11(s，1H)，7.31-7.27(m，2H)，7.25(s，2H)，7.15-7.11(t,1H),7.07-7.05(m，2H)，5.64-5.59(m，1H)，4.90-4.80(m，1H)，4.30-4.26(m，1H)，4.18-4.13(m，1H)，3.98-3.91(m，1H)，3.90-3.83(m，2H)，3.81-3.74(m，1H)，1.16-1.13(m，9H)，1.08-1.07(d，3H)。

Melting range: 165 ℃ and 168 ℃.

Example 10

Preparation of tenofovir alafenamide sulfate (1:1)

Dissolving 4.76g (10.0mmol) of tenofovir alafenamide and 1.00g (10.0mmol) of 98% sulfuric acid in 50ml of acetonitrile at the temperature of 20-25 ℃, and then stirring for crystallization at the temperature of 20-25 ℃; and (3) carrying out suction filtration, washing a filter cake by using an appropriate amount of acetonitrile, and drying under reduced pressure at 40-45 ℃ to obtain tenofovir alafenamide sulfate (1: 1).

¹HNMR(400MHz，DMSO-d₆):9.46(brs，1H)，8.74(brs，1H)，8.48(s，1H)，8.46(s，1H)，7.34-7.30(t，2H)，7.17-7.13(t,1H),7.08-7.06(d，2H)，5.63-5.57(m，1H)，4.88-4.79(m，1H)，4.44-4.39(m，1H)，4.28-4.23(m，1H)，4.05-3.98(m，1H)，3.93-3.88(m，2H)，3.85-3.78(m，1H)，1.15-1.11(m，12H)。

Melting range: 146 ℃ and 149 ℃.

Example 11

L-Tenofovir alafenamide tartrate (1:2) film coated tablet and preparation method thereof

Components	Content (mg/tablet)
		Tablet core:
L-Tenofovir alafenamide tartrate (1:2)	28.9

Lactose monohydrate	100.0
		Microcrystalline cellulose	60.0
Croscarmellose sodium	15.0
		Magnesium stearate	3.0
Film coating material:
		opadry II	10.0

The method comprises the following specific operations:

weighing the raw materials and auxiliary materials in the table above, mixing microcrystalline cellulose and croscarmellose sodium, then adding lactose monohydrate, mixing, adding tenofovir alafenamide L-tartrate (1:2), and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, mixing, and tabletting; then preparing the coating material into suspension with 75% ethanol for coating.

Example 12

L-tenofovir alafenamide tartrate (1:2) capsule and preparation method thereof

Components	Content (mg/tablet)
		L-Tenofovir alafenamide tartrate (1:2)	28.9
Lactose monohydrate	100.0
		Microcrystalline cellulose	100.0
Sodium carboxymethyl starch	15.0
		Magnesium stearate	1.5

The method comprises the following specific operations:

weighing the raw materials and auxiliary materials in the table, firstly mixing sodium carboxymethyl starch with microcrystalline cellulose, then adding lactose monohydrate for mixing, and then adding tenofovir alafenamide L-tartrate (1: 2); adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, mixing, and filling into hypromellose capsule.

Example 13

D-tenofovir alafenamide tartrate (1:1) film coated tablet and preparation method thereof

Components

Content (mg/tablet)

Tablet 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:
		opadry II	10.0

The method comprises the following specific operations:

weighing the raw materials and auxiliary materials in the table above, mixing microcrystalline cellulose and croscarmellose sodium, then adding lactose monohydrate, mixing, adding tenofovir alafenamide D-tartrate (1:1), and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, mixing, and tabletting; then preparing the coating material into suspension with 75% ethanol for coating.

Example 14

DL-Tenofovir alafenamide tartrate (1:1) film coated tablet and preparation thereof

Components	Content (mg/tablet)
		Tablet core:
DL-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:
opadry II	10.0

The method comprises the following specific operations:

weighing the raw materials and auxiliary materials in the table above, mixing microcrystalline cellulose and croscarmellose sodium, then adding lactose monohydrate, mixing, adding DL-tenofovir alafenamide tartrate (1:1), and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, mixing, and tabletting; then preparing the coating material into suspension with 75% ethanol for coating.

Example 15

Tenofovir alafenamide L-malate (1:2) film coated tablet and preparation thereof

Components	Content (mg/tablet)
		Tablet core:
l-malic acid tenofovir alafenamide (1:2)	28.5
		Lactose monohydrate	100.0
Microcrystalline cellulose	60.0
		Croscarmellose sodium	15.0
Magnesium stearate	3.0
		Film coating material:
opadry II	10.0

The method comprises the following specific operations:

weighing the raw materials and auxiliary materials in the table above, mixing microcrystalline cellulose and croscarmellose sodium, then adding lactose monohydrate, mixing, adding tenofovir alafenamide L-malate (1:2), and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, mixing, and tabletting; then preparing the coating material into suspension with 75% ethanol for coating.

Example 16

Tenofovir alafenamide citrate (1:1) film-coated tablet and preparation method thereof

Components	Content (mg/tablet)
		Tablet core:
tenofovir alafenamide citrate (1:1)	35.1
		Lactose monohydrate	100.0

Microcrystalline cellulose	60.0
		Croscarmellose sodium	15.0
Magnesium stearate	3.0
		Film coating material:
opadry II	10.0

The method comprises the following specific operations:

weighing the raw materials and auxiliary materials in the table above, mixing microcrystalline cellulose and croscarmellose sodium, then adding lactose monohydrate, mixing, adding tenofovir alafenamide citrate (1:1), and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, mixing, and tabletting; then preparing the coating material into suspension with 75% ethanol for coating.

Example 17

Tenofovir alafenamide succinate (1:1) film-coated tablet and preparation thereof

Components	Content (mg/tablet)
		Tablet 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:
opadry II	10.0

The method comprises the following specific operations:

weighing the raw materials and auxiliary materials in the table above, mixing microcrystalline cellulose and croscarmellose sodium, then adding lactose monohydrate, mixing, adding tenofovir alafenamide succinate (1:1), and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, mixing, and tabletting; then preparing the coating material into suspension with 75% ethanol for coating.

Example 18

Tenofovir alafenamide oxalate (1:1) film coated tablet and preparation thereof

Components	Content (mg/tablet)
		Tablet core:
oxalic acid 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:
opadry II	10.0

The method comprises the following specific operations:

weighing the raw materials and auxiliary materials in the table above, mixing microcrystalline cellulose and croscarmellose sodium, then adding lactose monohydrate, mixing, adding tenofovir alafenamide oxalate (1:1), and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, mixing, and tabletting; then preparing the coating material into suspension with 75% ethanol for coating.

Example 19

Tenofovir alafenamide phosphate (1:1) film-coated tablet and preparation thereof

Components	Content (mg/tablet)
		Tablet core:
tenofovir alafenamide phosphate (1:1)	30.1
		Lactose monohydrate	100.0
Microcrystalline cellulose	60.0
		Croscarmellose sodium	15.0
Magnesium stearate	3.0
		Film coating material:

opadry II

10.0

The method comprises the following specific operations:

weighing the raw materials and auxiliary materials in the table above, mixing microcrystalline cellulose and croscarmellose sodium, then adding lactose monohydrate, mixing, adding tenofovir alafenamide phosphate (1:1), and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, mixing, and tabletting; then preparing the coating material into suspension with 75% ethanol for coating.

Example 20

Tenofovir alafenamide sulfate (1:1) film-coated tablet and preparation method thereof

Components	Content (mg/tablet)
		Tablet core:
tenofovir alafenamide sulfate (1:1)	30.1
		Lactose monohydrate	100.0
Microcrystalline cellulose	60.0
		Croscarmellose sodium	15.0
Magnesium stearate	3.0
		Film coating material:
opadry II	10.0

The method comprises the following specific operations:

weighing the raw materials and auxiliary materials in the table above, mixing microcrystalline cellulose and croscarmellose sodium, then adding lactose monohydrate, mixing, adding tenofovir alafenamide sulfate (1:1), and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, mixing, and tabletting; then preparing the coating material into suspension with 75% ethanol for coating.

Example 21

Tenofovir alafenamide L-tartrate (1:2), emtricitabine, Cobicistat and Ettelavavir double-layer tablets and preparation thereof

Components	Content (mg/tablet)
		granule-I:
L-Tenofovir alafenamide tartrate (1:2)	11.6

Emtricitabine	200.0
		Microcrystalline cellulose	250.0
Lactose monohydrate	150.0
		Pregelatinized shore powder	50.0
Croscarmellose sodium	20.0
		Magnesium stearate	10.0
Particle II:
		ettelavir	150.0
Cobicistat	150.0
		Microcrystalline cellulose	200.0
Lactose monohydrate	200.0
		Croscarmellose sodium	20.0
Hydroxypropyl cellulose	15.0
		Magnesium stearate	6.0

The method comprises the following specific operations:

(1) preparation of granule-I: weighing the raw materials and auxiliary materials in the table, mixing the pre-gelatinized capecitabine powder with the croscarmellose sodium, then adding the lactose monohydrate and the microcrystalline cellulose for mixing, then adding the tenofovir alafenamide L-tartrate (1:2) for mixing, and finally adding the emtricitabine for mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, and mixing.

(2) Preparation of granule-II: weighing the raw materials and auxiliary materials in the table, mixing hydroxypropyl cellulose, croscarmellose sodium and 20% lactose monohydrate, adding the rest lactose monohydrate, mixing, adding the ezetivir and the Cobicistat, mixing, and finally adding the microcrystalline cellulose, and mixing; wet granulating with purified water; drying; finishing the grains; adding magnesium stearate, and mixing.

(3) Tabletting the core particles-I and the core particles-II by adopting a double-layer tablet machine; then preparing the coating material into suspension with 75% ethanol for coating.

Example 22

DL-tenofovir alafenamide tartrate (1:1), emtricitabine, Cobicistat and darunavir double-layer tablet and preparation thereof

Components	Content (mg/tablet)
		granule-I:
DL-Tenofovir alafenamide tartrate (1:1)	13.1
		Emtricitabine	200.0
Microcrystalline cellulose	200.0
		Lactose monohydrate	150.0
Pregelatinized shore powder	40.0
		Croscarmellose sodium	20.0
Magnesium stearate	6.0
		Particle II:
darunavir	800.0
		Cobicistat	150.0
Microcrystalline cellulose	100.0
		Lactose monohydrate	100.0
Croscarmellose sodium	40.0
		Hydroxypropyl cellulose	20.0
Sodium lauryl sulfate	10.0
		Magnesium stearate	10.0

The method comprises the following specific operations:

(1) preparation of granule-I: weighing the raw materials and auxiliary materials in the table, mixing the pre-gelatinized capecitabine powder and the croscarmellose sodium, then adding the lactose monohydrate and the microcrystalline cellulose for mixing, then adding the DL-tenofovir alafenamide tartrate (1:1) for mixing, and finally adding the emtricitabine for mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, and mixing.

(2) Preparation of granule-II: weighing the raw and auxiliary materials in the table, mixing sodium lauryl sulfate, hydroxypropyl cellulose, croscarmellose sodium and 20% lactose monohydrate, adding the rest lactose monohydrate, mixing, adding darunavir and Cobicistat, mixing, and finally adding microcrystalline cellulose; wet treating with purified water; drying; finishing the grains; adding magnesium stearate, and mixing.

Example 23

L-tenofovir alafenamide tartrate (1:2), emtricitabine film-coated tablets and preparation thereof

Components	Content (mg/tablet)
		Tablet core:
L-Tenofovir alafenamide tartrate (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:
opadry II	20.0

The method comprises the following specific operations:

weighing the raw materials and auxiliary materials in the table, mixing pregelatinized starch with croscarmellose sodium, then adding lactose monohydrate, mixing, adding emtricitabine, mixing, and finally adding tenofovir alafenamide L-tartrate (1:2) and microcrystalline cellulose, and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, mixing, and tabletting; mixing the coating material with 75% ethanol to obtain suspension, and coating.

Example 24

Tenofovir alafenamide phosphate (1:1), emtricitabine film-coated tablets and preparation thereof

Components	Content (mg/tablet)
		Tablet core:
tenofovir alafenamide phosphate (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:
opadry II	20.0

The method comprises the following specific operations:

weighing the raw materials and auxiliary materials in the table, mixing pregelatinized starch with croscarmellose sodium, then adding lactose monohydrate, mixing, adding emtricitabine, mixing, and finally adding tenofovir alafenamide phosphate (1:1) and microcrystalline cellulose, and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, mixing, and tabletting; mixing the coating material with 75% ethanol to obtain suspension, and coating.

Example 25

Film-coated double-layer tablet of D-tenofovir alafenamide tartrate (1:1), emtricitabine and efavirenz and preparation thereof

Components	Content (mg/tablet)
		Tablet core:
granule-I:
		D-Tenofovir alafenamide tartrate (1:1)	13.1
Emtricitabine	200.0

Microcrystalline cellulose	200.0
		Croscarmellose sodium	20.0
Magnesium stearate	7.0
		Particle II:
efavirenz	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
		Opadry II	30.0

The method comprises the following specific operations:

(1) preparation of granule-I: weighing the raw materials and auxiliary materials in the table, mixing microcrystalline cellulose and croscarmellose sodium, adding tenofovir alafenamide D-tartrate (1:1), mixing, adding emtricitabine, and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, and mixing.

(2) Preparation of granule-II: weighing the raw materials and auxiliary materials in the table, mixing the sodium lauryl sulfate, the croscarmellose sodium and the hydroxypropyl cellulose, adding the microcrystalline cellulose, mixing, adding the efavirenz, and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, and mixing.

(3) Tabletting the core particles-I and the core particles-II by adopting a double-layer tablet machine; mixing the coating material with 75% ethanol to obtain suspension, and coating.

Example 26

Film-coated double-layer tablet of Tenofovir alafenamide L-malate (1:2), emtricitabine and efavirenz and preparation thereof

Components	Content (mg/tablet)
		Tablet core:

granule-I:
		l-malic acid tenofovir alafenamide (1:2)	11.4
Emtricitabine	200.0
		Microcrystalline cellulose	200.0
Croscarmellose sodium	20.0
		Magnesium stearate	7.0
Particle II:
		efavirenz	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
Opadry II	30.0

The method comprises the following specific operations:

(1) preparation of granule-I: weighing the raw materials and auxiliary materials in the table, mixing microcrystalline cellulose and croscarmellose sodium, adding tenofovir alafenamide L-malate (1:2), mixing, adding emtricitabine, and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, and mixing.

Example 27

Tenofovir alafenamide citrate (1:1), emtricitabine, rilpivirine hydrochloride film-coated double-layer tablet and preparation thereof

Components	Content (mg/tablet)
		Tablet core:
granule-I:
		tenofovir alafenamide citrate (1:1)	14.0
Emtricitabine	200.0
		Microcrystalline cellulose	200.0
Lactose monohydrate	150.0
		Pregelatinized shore powder	40.0
Croscarmellose sodium	20.0
		Magnesium stearate	7.0
Particle II:
		rilpivirine hydrochloride	27.5
Water emulsionCandy	200.0
		Microcrystalline cellulose	60.0
Croscarmellose sodium	15.0
		Povidone K30	3.0
Magnesium stearate	3.0
		Polysorbate 20	0.5
Film coating material
		Opadry II	25.0

The method comprises the following specific operations:

(1) preparation of granule-I: weighing the raw materials and auxiliary materials in the table, mixing the pre-gelatinized capecitabine powder with the croscarmellose sodium, then adding the lactose monohydrate and the microcrystalline cellulose for mixing, then adding the tenofovir alafenamide citrate (1:1) for mixing, and finally adding the emtricitabine for mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, and mixing.

(2) Preparation of granule-II: weighing the raw materials and auxiliary materials in the table, mixing microcrystalline cellulose and croscarmellose sodium, then adding lactose monohydrate for mixing, and then adding rilpivirine hydrochloride for mixing; wet granulation with povidone K30 and polysorbate 20 in water; drying; finishing the grains; adding magnesium stearate, and mixing.

Example 28

Tenofovir alafenamide succinate (1:1), lamivudine film coated tablets and preparation thereof

Components	Content (mg/tablet)
		Tablet core:
inside the granule:
		tenofovir alafenamide succinate (1:1)	12.5
Lamivudine	300.0
		Microcrystalline cellulose	300.0
Croscarmellose sodium	15.0
		Outside the particle:
microcrystalline cellulose	140.0
		Croscarmellose sodium	15.0
Magnesium stearate	10.0
		Film coating material:
opadry II	25.0

The method comprises the following specific operations:

weighing the raw and auxiliary materials in the table, uniformly mixing the croscarmellose sodium and the microcrystalline cellulose by an equivalent progressive method, adding the tenofovir alafenamide succinate (1:1), mixing, adding the lamivudine, and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding croscarmellose sodium and microcrystalline cellulose, mixing, adding magnesium stearate, mixing, and tabletting; mixing the coating material with 75% ethanol to obtain suspension, and coating.

Example 29

Tenofovir alafenamide oxalate (1:1), lamivudine and efavirenz film-coated double-layer tablet and preparation thereof

Components	Content (mg/tablet)
		Tablet core:
granule-I:
		oxalic acid tenofovir alafenamide (1:1)	11.9
Lamivudine	300.0
		Microcrystalline cellulose	200.0
Croscarmellose sodium	35.0
		Magnesium stearate	7.0
Particle II:
		efavirenz	600.0
Microcrystalline cellulose	145.0
		Hydroxypropyl cellulose	20.0
Croscarmellose sodium	20.0
		Sodium lauryl sulfate	10.0
Magnesium stearate	10.0
		Film coating material:
opadry II	35.0

The method comprises the following specific operations:

(1) preparation of granule-I: weighing the raw materials and auxiliary materials in the table, mixing microcrystalline cellulose and croscarmellose sodium, adding tenofovir alafenamide oxalate (1:1), mixing, adding lamivudine, and mixing; adding a proper amount of purified water for wet granulation; drying; finishing the grains; adding magnesium stearate, and mixing.

(2) Preparation of granule-II: weighing the raw materials and auxiliary materials in the table, and mixing hydroxypropyl cellulose, sodium lauryl sulfate and croscarmellose sodium; then adding microcrystalline cellulose for mixing, and then adding efavirenz for mixing; wet granulating with purified water; drying; finishing the grains; adding magnesium stearate, and mixing.

The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be made by those skilled in the art without inventive work within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope defined by the claims.

Claims

1. A tenofovir alafenamide compound shown in a formula II,

Ⅱ

wherein n =1, 2 or 3, X is selected from: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, dodecylsulfuric acid, glycerophosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, taurine, camphorsulfonic acid, cyclamic acid, sulfamic acid, ethanedisulfonic acid, butanedisulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-hydroxyphenylsulfonic acid, o-hydroxybenzenesulfonic acid, 2, 5-dihydroxybenzenesulfonic acid, sulfanilic acid, saccharin, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, formic acid, acetic acid, glycolic acid, 2-dichloroacetic acid, propionic acid, L-lactic acid, D-lactic acid, racemic lactic acid, cyclopentanepropionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, nonanoic acid, capric acid, undecylenic acid, lauric acid, palmitic acid, stearic acid, oleic acid, oxalic acid, Succinic acid, L-malic acid, D-malic acid, racemic malic acid, L-tartaric acid, D-tartaric acid, racemic tartaric acid, meso-tartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, 2-oxoglutaric acid, adipic acid, sebacic acid, citric acid, benzoic acid, p-methoxybenzoic acid, 4-acetamidobenzoic acid, salicylic acid, acetylsalicylic acid, gentisic acid, 4-aminosalicylic acid, phenylacetic acid, L-mandelic acid, D-mandelic acid, racemic mandelic acid, 3-phenylpropionic acid, cinnamic acid, caffeic acid, phenylbutyric acid, picric acid, nicotinic acid, orotic acid, quinic acid, ascorbic acid, glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, lactobionic acid, camphoric acid, galactaric acid, tannic acid, alginic acid, hydroxynaphthoic acid, pamoic acid, Acetominoacetic acid, hippuric acid, aspartic acid, glutamic acid, pyroglutamic acid, glutamine, asparagine.

2. The tenofovir alafenamide complex of claim 1, wherein,

n =3, X is selected from: phosphoric acid, citric acid, tannic acid, or alginic acid; or,

n =2, X is selected from: sulfuric acid, persulfuric acid, thiocyanic acid, phosphoric acid, carbonic acid, glycerophosphoric acid, ethanedisulfonic acid, butanedisulfonic acid, naphthalene-1, 5-disulfonic acid, oxalic acid, malonic acid, succinic acid, L-malic acid, D-malic acid, racemic malic acid, L-tartaric acid, D-tartaric acid, racemic tartaric acid, meso-tartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, 2-oxoglutaric acid, adipic acid, sebacic acid, citric acid, camphoric acid, galactaric acid, tannic acid, alginic acid, pamoic acid, aspartic acid, glutamic acid; or,

n =1, X is selected from: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, dodecylsulfuric acid, glycerophosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, taurine, camphorsulfonic acid, cyclamic acid, sulfamic acid, ethanedisulfonic acid, butanedisulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-hydroxyphenylsulfonic acid, o-hydroxybenzenesulfonic acid, 2, 5-dihydroxybenzenesulfonic acid, sulfanilic acid, saccharin, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, formic acid, acetic acid, glycolic acid, 2-dichloroacetic acid, propionic acid, L-lactic acid, D-lactic acid, racemic lactic acid, cyclopentanepropionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, nonanoic acid, capric acid, undecylenic acid, lauric acid, palmitic acid, stearic acid, oleic acid, oxalic acid, Succinic acid, L-malic acid, D-malic acid, racemic malic acid (also known as DL-malic acid), L-tartaric acid, D-tartaric acid, racemic tartaric acid, meso-tartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, 2-oxoglutaric acid, adipic acid, sebacic acid, citric acid, benzoic acid, p-methoxybenzoic acid, 4-acetamidobenzoic acid, salicylic acid, acetylsalicylic acid, gentisic acid, 4-aminosalicylic acid, phenylacetic acid, L-mandelic acid, D-mandelic acid, racemic mandelic acid, 3-phenylpropionic acid, cinnamic acid, caffeic acid, phenylbutyric acid, picric acid, nicotinic acid, orotic acid, quinic acid, ascorbic acid, glucuronic acid, gluconic acid, galacturonic acid, heptonic acid, lactobionic acid, camphoric acid, galactaric acid, tannic acid, tartaric acid, malic acid, Alginic acid, hydroxynaphthoic acid, pamoic acid, acetamidoacetic acid, hippuric acid, aspartic acid, glutamic acid, pyroglutamic acid, glutamine, asparagine.

3. The tenofovir alafenamide complex of claim 2, selected from the group consisting of: l-tenofovir alafenamide tartrate (1:2), D-tenofovir alafenamide tartrate (1:1), DL-tenofovir alafenamide tartrate (1:1), tenofovir alafenamide L malate (1:2), tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1) or tenofovir alafenamide sulfate (1: 1).

4. A method for preparing the tenofovir alafenamide complex of claim 1 or 2, comprising:

(2) separating out solids;

(3) separating the precipitated solid;

5. The production method according to claim 4, wherein in step (1), the suitable solvent is selected from 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, t-butyl methyl ether, tetrahydrofuran, petroleum ether, dichloromethane, chloroform, n-hexane, cyclohexane, acetone, butanone, pentanone, cyclohexanone, toluene, xylene or a mixture thereof; the acid X is selected from the acid represented by X in the formula II; the feeding molar ratio of the tenofovir alafenamide to the acid X is 4: 1-0.5: 1, when an X tenofovir alafenamide (1:3) compound is prepared, the feeding molar ratio of the tenofovir alafenamide to the acid X is 2.7: 1-3.5: 1, when an X tenofovir alafenamide (1:2) compound is prepared, the feeding molar ratio of the tenofovir alafenamide to the acid X is 1.7: 1-2.5: 1, and when the X tenofovir alafenamide (1:1) compound is prepared, the feeding molar ratio of the tenofovir alafenamide to the acid X is 0.5: 1-1.5: 1.

6. A method for preparing the tenofovir alafenamide complex of claim 3, comprising:

(1) dissolving tenofovir alafenamide, L-tartaric acid, D-tartaric acid, DL-tartaric acid, L-malic acid, citric acid, succinic acid, oxalic acid, phosphoric acid or sulfuric acid in a proper solvent according to the following feeding molar ratio,

the ratio of tenofovir alafenamide to L-tartaric acid is 1.7: 1-2.5: 1, preferably 1.9: 1-2.3: 1, or,

the ratio of tenofovir alafenamide to D-tartaric acid is 0.5: 1-1.5: 1, preferably 0.8: 1-1.2: 1, or,

the ratio of the tenofovir alafenamide to the DL-tartaric acid is 0.5: 1-1.5: 1, preferably 0.8: 1-1.2: 1, or,

the ratio of tenofovir alafenamide to L-malic acid is 1.7: 1-2.5: 1, preferably 1.9: 1-2.3: 1, or,

the ratio of tenofovir alafenamide to citric acid is 0.5: 1-1.5: 1, preferably 0.8: 1-1.2: 1, or,

the ratio of tenofovir alafenamide to succinic acid is 0.5: 1-1.5: 1, preferably 0.8: 1-1.2: 1, or,

the ratio of tenofovir alafenamide to oxalic acid is 0.5: 1-1.5: 1, preferably 0.8: 1-1.2: 1, or,

the ratio of tenofovir alafenamide to phosphoric acid is 0.5: 1-1.5: 1, preferably 0.8: 1-1.2: 1, or,

the ratio of tenofovir alafenamide to sulfuric acid is 0.5: 1-1.5: 1, preferably 0.8: 1-1.2: 1, or,

(2) separating out solids;

(3) separating the precipitated solid;

7. The process according to claim 6, wherein the suitable solvent in step (1) is selected from acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene or a mixture thereof, preferably acetonitrile or isopropanol.

8. A pharmaceutical composition comprising a therapeutically effective amount of the tenofovir alafenamide complex of any one of claims 1 to 3 or the tenofovir alafenamide complex prepared by the preparation method of any one of claims 4 to 7, and a pharmaceutically acceptable excipient.

9. The pharmaceutical composition according to claim 8, further comprising another antiviral agent or antiviral co-agent selected from the group consisting of: emtricitabine, lamivudine, abacavir, acemenan, amprenavir, atazanavir, cladribine, Cobicistat, dapivirine, darunavir, delavirdine, didoglivir, efavirenz, emfuvirdine, entecavir, etravirine, famciclovir, fosamprenavir, glutathione, indinavir, levamisole, lopinavir, maraviroc, nelfinavir, nevirapine, penciclovir, pentamidine, Phosphazid, propiprogagage, raltegravir, ribavirin, rilpivirine, ritonavir, sanavir, stavudine, tipivudine, tipranavir, vorinostat, certavir, zivudine, zidovudine, or pharmaceutically acceptable salts thereof; preference is given to emtricitabine, lamivudine, Cobicistat, efavirenz, ezetivir or rilpivirine or their pharmaceutically acceptable salts.

10. The pharmaceutical composition according to claim 9, selected from the group consisting of:

11. Use of the tenofovir alafenamide complex according to any one of claims 1 to 3 or the tenofovir alafenamide complex prepared by the preparation method according to any one of claims 4 to 7 in the preparation of a medicament for preventing and/or treating viral infection.

12. The use according to claim 11, wherein the tenofovir alafenamide complex is used in the preparation of a medicament for the prevention and/or treatment of hepatitis b virus and/or human immunodeficiency virus infection.