CN111205325A - Tenofovir alafenamide compound and preparation method and application thereof - Google Patents

Tenofovir alafenamide compound and preparation method and application thereof Download PDF

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CN111205325A
CN111205325A CN201910565745.5A CN201910565745A CN111205325A CN 111205325 A CN111205325 A CN 111205325A CN 201910565745 A CN201910565745 A CN 201910565745A CN 111205325 A CN111205325 A CN 111205325A
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tenofovir alafenamide
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tartrate
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高炳坤
李方群
罗杰
向志祥
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Sichuan Haisco Pharmaceutical Co Ltd
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    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

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Abstract

The invention relates to a tenofovir alafenamide compound shown in a formula II. The invention also relates to a preparation method of the tenofovir alafenamide compound, a pharmaceutical composition containing the tenofovir alafenamide compound, and application of the tenofovir alafenamide compound in preparation of medicines for preventing and/or treating virus infection, in particular Hepatitis B Virus (HBV) and/or humanUse in the treatment of immunodeficiency virus (HIV) infection.
Figure DDA0002109532610000011

Description

Tenofovir alafenamide compound and preparation method and application thereof
The application is a divisional application with the application number of 201580024952.X, the application date of 2015, 05 and 04, and the name of the invention being tenofovir alafenamide compound and a 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 and/or 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) and/or Human Immunodeficiency Virus (HIV) infection, and a pharmaceutical composition containing the compound.
Background
Tenofovir alafenamide (Tenofovir alafenamide), 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:
Figure BDA0002109532590000011
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 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 and/or 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, CN1443189A, CN1706855A and the like disclose fumarate salts of tenofovir alafenamide, which are greatly improved in water solubility, physical properties and the like compared with free base, but have poor chemical stability and thermodynamic stability. CN103732594A discloses a hemifumarate of tenofovir alafenamide, wherein it is shown that tenofovir alafenamide hemifumarate has advantages in removing diastereoisomer impurities, chemical stability, thermodynamic stability compared with tenofovir alafenamide fumarate, 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.
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 physical 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 at least one aspect of 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.
The invention further aims to provide a crystal form of the tenofovir alafenamide compound and a preparation method thereof.
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,
Figure BDA0002109532590000031
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, cyclohexylsulfamic acid, sulfamic acid, ethanedisulfonic acid, butanedisulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-hydroxybenzenesulfonic acid, o-hydroxybenzenesulfonic acid, 2, 5-dihydroxybenzenesulfonic acid, sulfanilic acid, 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, octanoic acid, nonanoic acid, decanoic acid, undecylenic acid, lauric acid, palmitic 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, glucuronic acid, tartaric 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 pruronic 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-crystal former), 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 invention. 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 one 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 ratio complex of tenofovir alafenamide to L-tartaric acid 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;
(4) optionally, the isolated solid is dried, or further purified and then dried.
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, ethanol, 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 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.
The drying temperature in the step (4) of the method is generally 20-120 ℃, and preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
This embodiment produces tenofovir alafenamide L-tartrate (1:2) as a crystal.
Therefore, the invention provides a crystal form of L-tenofovir alafenamide tartrate (1:2) (for the convenience of expression, the crystal form is called as 'tenofovir alafenamide tartrate (1:2) crystal form A'), an X-ray powder diffraction pattern (irradiated by Cu-K α) of the crystal form is characterized in that characteristic diffraction peaks are correspondingly arranged at 2 theta values of 8.2 degrees +/-0.2 degrees, 9.4 degrees +/-0.2 degrees, 10.8 degrees +/-0.2 degrees, 14.4 degrees +/-0.2 degrees, 17.9 degrees +/-0.2 degrees, 18.9 degrees +/-0.2 degrees, 19.7 degrees +/-0.2 degrees, 21.6 degrees +/-0.2 degrees and the like.
In a specific embodiment, the crystalline form a of tenofovir alafenamide L-tartrate (1:2) as claimed in the present invention has an X-ray powder diffraction pattern characterized by: characteristic diffraction peaks are correspondingly arranged at the positions of 7.5 degrees +/-0.2 degrees, 8.2 degrees +/-0.2 degrees, 9.4 degrees +/-0.2 degrees, 10.8 degrees +/-0.2 degrees, 12.4 degrees +/-0.2 degrees, 14.4 degrees +/-0.2 degrees, 16.0 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 17.1 degrees +/-0.2 degrees, 17.9 degrees +/-0.2 degrees, 18.9 degrees +/-0.2 degrees, 19.7 degrees +/-0.2 degrees, 20.4 degrees +/-0.2 degrees, 21.6 degrees +/-0.2 degrees, 23.0 degrees +/-0.2 degrees and the like of the 2 theta value.
Further, the X-ray powder diffraction pattern of the L-tenofovir alafenamide tartrate crystal form A (1:2) expressed by the angle of 2 theta has characteristic diffraction peaks and relative intensities at the following positions:
2 theta angle (°) Relative Strength (%) 2 theta angle (°) Relative Strength (%)
7.5°±0.2° 10 21.0°±0.2° 17
8.2°±0.2° 10 21.6°±0.2° 22
9.4°±0.2° 97 23.0°±0.2° 22
10.8°±0.2° 16 23.5°±0.2° 18
12.4°±0.2° 13 24.3°±0.2° 12
14.4°±0.2° 16 24.6°±0.2° 10
16.0°±0.2° 16 25.7°±0.2° 11
16.3°±0.2° 18 26.7°±0.2° 11
17.1°±0.2° 21 27.4°±0.2° 9
17.9°±0.2° 34 28.4°±0.2° 9
18.9°±0.2° 37 28.9°±0.2° 8
19.7°±0.2° 100 30.4°±0.2° 8
20.4°±0.2° 28
In a specific embodiment, the invention provides tenofovir alafenamide L-tartrate form a (1:2) having the characteristics represented by the X-ray powder diffraction pattern shown in fig. 1.
In a specific embodiment, the prepared tenofovir alafenamide L tartrate (1:2) mixture provided by the present invention generally has a crystalline form a content (by mass) of tenofovir alafenamide L tartrate (1:2) of greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
It will be understood by those skilled in the art that the tenofovir alafenamide L-tartrate (1:2) mixture of the present invention refers to tenofovir alafenamide L-tartrate (1:2) containing other impurities or crystal forms prepared by direct synthesis using chemical synthesis methods.
In a specific embodiment, the preparation method of the crystalline form a of tenofovir alafenamide L-tartrate (1:2) comprises the following steps:
(1) dissolving tenofovir alafenamide and L-tartaric acid in acetonitrile, ethanol, isopropanol or a mixture thereof; the weight ratio of the solvent to the tenofovir alafenamide is generally 5: 1-80: 1; the feeding molar ratio of tenofovir alafenamide to L-tartaric acid is generally 1.7: 1-2.5: 1, preferably 1.9: 1-2.3: 1
(2) Separating out solids;
(3) separating the precipitated solid; optionally, the collected solid may be washed with the solvent used in step (1);
(4) optionally, the isolated solid is dried, or further purified and then dried. The drying temperature is generally 20-120 ℃, and preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
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 (1: 1)".
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;
(4) optionally, the isolated solid is dried, or further purified and then dried.
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.
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.
The drying temperature in the step (4) of the method is generally 20-120 ℃, and preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
This embodiment produces tenofovir alafenamide D-tartrate (1:1) as a crystal.
Therefore, the invention provides a crystal form of D-tenofovir alafenamide tartrate (1:1) (for the convenience of expression, the crystal form is called as 'the D-tenofovir alafenamide tartrate (1:1) crystal form A'), an X-ray powder diffraction pattern (irradiated by Cu-K α) of the crystal form is characterized in that characteristic diffraction peaks are correspondingly arranged at positions with 2 theta values of 7.8 degrees +/-0.2 degrees, 9.5 degrees +/-0.2 degrees, 12.5 degrees +/-0.2 degrees, 15.1 degrees +/-0.2 degrees, 15.9 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 17.7 degrees +/-0.2 degrees, 19.5 degrees +/-0.2 degrees and the like.
In a specific embodiment, the X-ray powder diffraction pattern of crystalline form a of tenofovir alafenamide D-tartrate (1:1) as claimed in the present invention is characterized by: characteristic diffraction peaks are correspondingly arranged at the positions of 4.4 degrees +/-0.2 degrees, 7.8 degrees +/-0.2 degrees, 9.0 degrees +/-0.2 degrees, 9.5 degrees +/-0.2 degrees, 12.5 degrees +/-0.2 degrees, 13.0 degrees +/-0.2 degrees, 15.1 degrees +/-0.2 degrees, 15.9 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 17.7 degrees +/-0.2 degrees, 19.5 degrees +/-0.2 degrees, 19.9 degrees +/-0.2 degrees, 21.4 degrees +/-0.2 degrees, 22.7 degrees +/-0.2 degrees, 25.9 degrees +/-0.2 degrees and the like of the 2 theta value.
Further, the X-ray powder diffraction pattern of the D-tenofovir alafenamide tartrate crystal form A (1:1) expressed by the angle of 2 theta has characteristic diffraction peaks and relative intensities at the following positions:
Figure BDA0002109532590000101
Figure BDA0002109532590000111
in a specific embodiment, the invention provides crystalline form a of tenofovir alafenamide D-tartrate (1:1) having the characteristics represented by the X-ray powder diffraction pattern shown in fig. 2.
In a specific embodiment, the prepared mixture of tenofovir alafenamide D-tartrate (1:1) provided by the present invention generally has a crystalline form a content (by mass) of tenofovir alafenamide D-tartrate (1:1) of greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
It will be understood by those skilled in the art that the tenofovir alafenamide D-tartrate (1:1) mixture according to the present invention refers to tenofovir alafenamide D-tartrate (1:1) containing other impurities or crystal forms prepared by direct synthesis using chemical synthesis methods.
In a specific embodiment, the preparation method of the crystalline form a of the D-tenofovir alafenamide tartrate (1:1) comprises the following steps:
(1) dissolving tenofovir alafenamide and D-tartaric acid in acetonitrile, isopropanol or a mixture thereof; the weight ratio of the solvent to the tenofovir alafenamide is generally 5: 1-80: 1; the feeding molar ratio of tenofovir alafenamide to D-tartaric acid is generally 0.5: 1-1.5: 1, preferably 0.8: 1-1.2: 1.
(2) Separating out solids;
(3) separating the precipitated solid; optionally, the collected solid may be washed with the solvent in step (1).
(4) Optionally, the isolated solid is dried, or further purified and then dried. The drying temperature is generally 20-120 ℃, and preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
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;
(4) optionally, the isolated solid is dried, or further purified and then dried.
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.
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.
The drying temperature in the step (4) of the method is generally 20-120 ℃, and preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
This embodiment produces a crystalline form of DL-tenofovir alafenamide tartrate (1: 1).
Therefore, the invention provides a crystal form of DL-tenofovir alafenamide tartrate (1:1) (for the convenience of expression, the crystal form is called as 'the DL-tenofovir alafenamide tartrate (1:1) crystal form A'), an X-ray powder diffraction pattern (irradiated by Cu-K α) of the crystal form is characterized in that characteristic diffraction peaks are correspondingly arranged at 2 theta values of 6.8 degrees +/-0.2 degrees, 8.0 degrees +/-0.2 degrees, 9.7 degrees +/-0.2 degrees, 16.0 degrees +/-0.2 degrees, 16.9 degrees +/-0.2 degrees, 18.2 degrees +/-0.2 degrees, 18.9 degrees +/-0.2 degrees, 20.2 degrees +/-0.2 degrees, 21.1 degrees +/-0.2 degrees and the like.
In a specific embodiment, the X-ray powder diffraction pattern of crystalline form a of DL-tenofovir alafenamide tartrate (1:1) as claimed in the present invention is characterized by: characteristic diffraction peaks are correspondingly arranged at the positions of 6.8 degrees +/-0.2 degrees, 8.0 degrees +/-0.2 degrees, 9.7 degrees +/-0.2 degrees, 10.6 degrees +/-0.2 degrees, 12.6 degrees +/-0.2 degrees, 13.7 degrees +/-0.2 degrees, 14.9 degrees +/-0.2 degrees, 16.0 degrees +/-0.2 degrees, 16.9 degrees +/-0.2 degrees, 18.2 degrees +/-0.2 degrees, 18.9 degrees +/-0.2 degrees, 20.2 degrees +/-0.2 degrees, 21.1 degrees +/-0.2 degrees, 22.8 degrees +/-0.2 degrees and the like of the 2 theta value.
Further, the DL-tenofovir alafenamide tartrate (1:1) crystal form A has characteristic diffraction peaks and relative intensities at the following positions in an X-ray powder diffraction pattern expressed by 2 theta angles:
Figure BDA0002109532590000121
Figure BDA0002109532590000131
in a specific embodiment, the invention provides a crystalline form a of DL-tenofovir alafenamide tartrate (1:1) having the characteristics represented by the X-ray powder diffraction pattern shown in fig. 3.
In a specific embodiment, the prepared mixture of DL-tenofovir alafenamide tartrate (1:1) provided by the present invention generally has a content (mass content) of crystalline form a of DL-tenofovir alafenamide tartrate (1:1) of more than 70%, preferably more than 80%, and most preferably more than 90%.
It will be understood by those skilled in the art that the DL-tenofovir alafenamide tartrate (1:1) mixture of the present invention refers to DL-tenofovir alafenamide tartrate (1:1) containing other impurities or crystal forms prepared by direct synthesis using a chemical synthesis method.
In a specific embodiment, the preparation method of the crystalline form a of DL-tenofovir alafenamide tartrate (1:1) comprises the following steps:
(1) dissolving tenofovir alafenamide and DL-tartaric acid in acetonitrile; the weight ratio of the solvent to the tenofovir alafenamide is generally 5: 1-80: 1. The feeding molar ratio of the tenofovir alafenamide to the DL-tartaric acid is generally 0.5: 1-1.5: 1, and preferably 0.8: 1-1.2: 1.
(2) Separating out solids;
(3) separating the precipitated solid; alternatively, the collected solid may be washed with acetonitrile.
(4) Optionally, the isolated solid is dried, or further purified and then dried. The drying temperature is generally 20-120 ℃, and preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
L-malic acid tenofovir alafenamide (1:2)
In one 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;
(4) optionally, the isolated solid is dried, or further purified and then dried.
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 is preferably 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.
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.
In the step (4), the drying temperature is generally 20-80 ℃, preferably 30-60 ℃; drying under normal pressure or reduced pressure is also possible.
This embodiment produces tenofovir alafenamide L-malate (1:2) as a crystal.
Therefore, the invention provides a crystal form of tenofovir alafenamide L-malate (1:2) (for convenience of expression, the crystal form is called as 'tenofovir alafenamide L-malate (1:2) crystal form A'), an X-ray powder diffraction pattern (irradiated by Cu-K α) of the crystal form is characterized in that characteristic diffraction peaks are correspondingly arranged at 2 theta values of 10.0 degrees +/-0.2 degrees, 13.4 degrees +/-0.2 degrees, 13.9 degrees +/-0.2 degrees, 15.3 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 21.3 degrees +/-0.2 degrees, 26.3 degrees +/-0.2 degrees and the like.
In a specific embodiment, the crystalline form a of tenofovir alafenamide L-malate (1:2) according to the invention is characterized by an X-ray powder diffraction pattern: characteristic diffraction peaks are correspondingly arranged at positions with 2 theta values of 5.4 degrees +/-0.2 degrees, 10.0 degrees +/-0.2 degrees, 11.9 degrees +/-0.2 degrees, 13.4 degrees +/-0.2 degrees, 13.9 degrees +/-0.2 degrees, 15.3 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 20.3 degrees +/-0.2 degrees, 21.3 degrees +/-0.2 degrees, 22.2 degrees +/-0.2 degrees, 26.3 degrees +/-0.2 degrees and the like.
Further, the crystalline form a of tenofovir alafenamide L-malate (1:2) of the invention has an X-ray powder diffraction pattern expressed by 2 theta angles, and has characteristic diffraction peaks and relative intensities at the following positions:
2 theta angle (°) Relative Strength (%) 2 theta angle (°) Relative Strength (%)
5.4°±0.2° 14 17.9°±0.2° 8
9.7°±0.2° 19 19.4°±0.2° 8
10.0°±0.2° 69 20.1°±0.2° 10
10.3°±0.2° 12 20.3°±0.2° 16
11.9°±0.2° 20 21.3°±0.2° 100
13.2°±0.2° 19 21.9°±0.2° 18
13.4°±0.2° 35 22.2°±0.2° 19
13.9°±0.2° 61 23.2°±0.2° 14
14.1°±0.2° 33 24.2°±0.2° 9
15.3°±0.2° 55 25.3°±0.2° 8
16.6°±0.2° 51 26.3°±0.2° 31
17.0°±0.2° 8 29.3°±0.2° 8
In a specific embodiment, the invention provides tenofovir alafenamide L-malate (1:2) form a having the characteristics represented by the X-ray powder diffraction pattern shown in fig. 4.
In a specific embodiment, the prepared tenofovir alafenamide L malate (1:2) mixture provided by the present invention generally has a content (mass content) of tenofovir alafenamide L malate (1:2) form a of more than 70%, preferably more than 80%, and most preferably more than 90%.
It is understood by those skilled in the art that the tenofovir alafenamide L-malate (1:2) mixture of the present invention refers to tenofovir alafenamide L-malate (1:2) containing other impurities or crystal forms, which is prepared by direct synthesis using a chemical synthesis method.
In a specific embodiment, the preparation method of the tenofovir alafenamide L-malate (1:2) crystal form A provided by the invention comprises the following steps:
(1) dissolving tenofovir alafenamide and L-malic acid in isopropanol; the weight ratio of the solvent to the tenofovir alafenamide is generally 5: 1-80: 1. 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.
(2) Separating out solids;
(3) separating the precipitated solid; alternatively, the collected solid may be washed with isopropanol.
(4) Optionally, the isolated solid is dried, or further purified and then dried. The drying temperature is generally 20-80 ℃, preferably 30-60 ℃; drying under normal pressure or reduced pressure is also possible.
Tenofovir alafenamide citrate (1:1)
In one embodiment, where n is selected to be 1 and X is selected to be citric acid, a 1:1 molar ratio complex of tenofovir alafenamide and citric acid 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;
(4) optionally, the isolated solid is dried, or further purified and then dried.
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, methanol, ethanol, tetrahydrofuran 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 citric acid is generally 0.5: 1-1.5: 1, and preferably 0.8: 1-1.2: 1.
In step (2), the "precipitated solid" is prepared by conventional methods in the art, such as cooling, and adding an anti-solvent, wherein the "anti-solvent" is selected from diethyl ether, ethyl acetate, methyl acetate, ethyl formate, n-heptane, ethylene glycol dimethyl ether, isopropyl ether, methyl tert-butyl ether, isooctane, anisole, etc. or their mixture. Concentrating partial solvent, and adding seed crystal. 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.
In the step (4), the drying temperature is generally 20-120 ℃, preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
The tenofovir alafenamide citrate (1:1) prepared by this embodiment is a crystal.
Accordingly, the present invention provides a crystalline form of tenofovir alafenamide citrate (1:1) (for convenience of description, the crystalline form is referred to as "tenofovir alafenamide citrate (1:1) crystalline form a"). the X-ray powder diffraction pattern of the crystalline form (irradiated with Cu-K α) is characterized by characteristic diffraction peaks corresponding to 2 θ values of 6.0 ° ± 0.2 °, 8.1 ° ± 0.2 °, 11.7 ° ± 0.2 °, 15.9 ° ± 0.2 °, 17.9 ° ± 0.2 °, 21.7 ° ± 0.2 °, 23.4 ° ± 0.2 °, 26.9 ° ± 0.2 ° and the like.
In a specific embodiment, the crystalline form a of tenofovir alafenamide citrate (1:1) of the present invention has an X-ray powder diffraction pattern characterized by: characteristic diffraction peaks are correspondingly arranged at the positions of 6.0 degrees +/-0.2 degrees, 8.1 degrees +/-0.2 degrees, 11.7 degrees +/-0.2 degrees, 12.6 degrees +/-0.2 degrees, 15.4 degrees +/-0.2 degrees, 15.9 degrees +/-0.2 degrees, 17.5 degrees +/-0.2 degrees, 17.9 degrees +/-0.2 degrees, 20.1 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees, 21.4 degrees +/-0.2 degrees, 21.7 degrees +/-0.2 degrees, 23.4 degrees +/-0.2 degrees, 26.9 degrees +/-0.2 degrees, 29.3 degrees +/-0.2 degrees, 31.9 degrees +/-0.2 degrees, 32.7 degrees +/-0.2 degrees and the like of the 2 theta value.
Further, the tenofovir alafenamide citrate (1:1) crystal form a has an X-ray powder diffraction pattern expressed by 2 theta angles, and has characteristic diffraction peaks and relative intensities at the following positions:
2 theta angle (°) Relative Strength (%) 2 theta angle (°) Relative Strength (%)
6.0°±0.2° 100 20.1°±0.2° 16
8.1°±0.2° 47 20.6°±0.2° 12
8.5°±0.2° 9 21.4°±0.2° 29
10.3°±0.2° 7 21.7°±0.2° 32
11.7°±0.2° 39 22.1°±0.2° 7
12.2°±0.2° 8 22.5°±0.2° 12
12.6°±0.2° 21 23.1°±0.2° 11
14.6°±0.2° 13 23.4°±0.2° 37
15.4°±0.2° 23 26.0°±0.2° 7
15.9°±0.2° 36 26.9°±0.2° 39
16.3°±0.2° 7 29.2°±0.2° 10
17.5°±0.2° 16 29.3°±0.2° 14
17.9°±0.2° 32 31.9°±0.2° 11
19.9°±0.2° 10 32.7°±0.2° 12
In a specific embodiment, the tenofovir alafenamide citrate (1:1) crystalline form a provided by the present invention has the characteristics represented by the X-ray powder diffraction pattern shown in fig. 5.
In a specific embodiment, the prepared tenofovir alafenamide citrate (1:1) mixture provided by the present invention generally has a tenofovir alafenamide citrate (1:1) crystalline form a content (by mass) of greater than 70%, preferably greater than 80%, most preferably greater than 90%.
It will be understood by those skilled in the art that the tenofovir alafenamide citrate (1:1) mixture according to the present invention refers to tenofovir alafenamide citrate (1:1) containing other impurities or crystal forms prepared by direct synthesis using chemical synthesis methods.
In a specific embodiment, the preparation method of tenofovir alafenamide citrate (1:1) crystal form a comprises the following steps:
(1) dissolving tenofovir alafenamide and citric acid in acetonitrile, methanol, ethanol, tetrahydrofuran or a mixture thereof; the weight ratio of the suitable solvent to the tenofovir alafenamide is generally 5: 1-80: 1. 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.
(2) Separating out solids;
(3) separating the precipitated solid; optionally, the collected solid may be washed with the solvent in step (1).
(4) Optionally, the isolated solid is dried, or further purified and then dried. The drying temperature is generally 20-120 ℃, and preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
Tenofovir alafenamide succinate (1:1)
In one 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;
(4) optionally, the isolated solid is dried, or further purified and then dried.
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 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.
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.
In the step (4), the drying temperature is generally 20-100 ℃, preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
The tenofovir alafenamide succinate (1:1) prepared by this embodiment is a crystal.
Accordingly, the present invention provides a crystalline form of tenofovir alafenamide succinate (1:1) (for convenience of presentation, this crystalline form is referred to as "tenofovir alafenamide succinate (1:1) form a"). the X-ray powder diffraction pattern of this crystalline form (irradiated with Cu-K α) is characterized by characteristic diffraction peaks corresponding to 2 θ values of 10.7 ° ± 0.2 °, 14.3 ° ± 0.2 °, 17.2 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.4 ° ± 0.2 °, and the like.
In a specific embodiment, the tenofovir alafenamide succinate (1:1) form a of the present invention has an X-ray powder diffraction pattern characterized by: characteristic diffraction peaks are correspondingly arranged at positions with 2 theta values of 5.7 degrees +/-0.2 degrees, 9.6 degrees +/-0.2 degrees, 10.0 degrees +/-0.2 degrees, 10.7 degrees +/-0.2 degrees, 11.7 degrees +/-0.2 degrees, 13.5 degrees +/-0.2 degrees, 14.3 degrees +/-0.2 degrees, 17.2 degrees +/-0.2 degrees, 17.8 degrees +/-0.2 degrees, 19.3 degrees +/-0.2 degrees, 19.7 degrees +/-0.2 degrees, 21.4 degrees +/-0.2 degrees, 21.8 degrees +/-0.2 degrees, 22.4 degrees +/-0.2 degrees, 23.8 degrees +/-0.2 degrees, 27.9 degrees +/-0.2 degrees and the like.
Further, the tenofovir alafenamide succinate (1:1) crystal form a has an X-ray powder diffraction pattern expressed by 2 theta angles, and has characteristic diffraction peaks and relative intensities at the following positions:
Figure BDA0002109532590000191
Figure BDA0002109532590000201
in a specific embodiment, the tenofovir alafenamide succinate (1:1) a provided by the present invention has the characteristics represented by the X-ray powder diffraction pattern shown in fig. 6.
In a specific embodiment, the prepared tenofovir alafenamide succinate (1:1) mixture provided by the present invention generally has a tenofovir alafenamide succinate (1:1) crystalline form a content (by mass) of greater than 70%, preferably greater than 80%, most preferably greater than 90%.
It will be understood by those skilled in the art that the tenofovir alafenamide succinate (1:1) mixture of the present invention refers to tenofovir alafenamide succinate (1:1) containing other impurities or crystal forms prepared by direct synthesis using chemical synthesis methods.
In a specific embodiment, the preparation method of tenofovir alafenamide succinate (1:1) crystalline form a of the present invention comprises:
(1) dissolving tenofovir alafenamide and succinic acid in acetonitrile; the weight ratio of the solvent to the tenofovir alafenamide is generally 5: 1-80: 1. 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.
(2) Separating out solids;
(3) separating the precipitated solid; alternatively, the collected solid may be washed with acetonitrile.
(4) Optionally, the isolated solid is dried, or further purified and then dried. The drying temperature is generally 20-100 ℃, preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
Oxalic acid tenofovir alafenamide (1:1)
In one 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;
(4) optionally, the isolated solid is dried, or further purified and then dried.
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 oxalic 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.
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.
In the step (4), the drying temperature is generally 20-120 ℃, preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
The tenofovir alafenamide oxalate (1:1) prepared by this embodiment is a crystal.
Accordingly, the present invention provides a crystalline form of tenofovir alafenamide oxalate (1:1) (for convenience of presentation, the crystalline form is referred to as "tenofovir alafenamide oxalate (1:1) crystalline form a"). the X-ray powder diffraction pattern of the crystalline form (irradiated with Cu-K α) is characterized by characteristic diffraction peaks corresponding to 2 θ values of 7.7 ° ± 0.2 °, 9.6 ° ± 0.2 °, 16.2 ° ± 0.2 °, 18.2 ° ± 0.2 °, 20.5 ° ± 0.2 °, 24.7 ° ± 0.2 °, and the like.
In a specific embodiment, the crystalline form a of tenofovir alafenamide oxalate (1:1) according to the present invention has an X-ray powder diffraction pattern characterized by: characteristic diffraction peaks are correspondingly arranged at the positions of 7.7 degrees +/-0.2 degrees, 8.4 degrees +/-0.2 degrees, 9.6 degrees +/-0.2 degrees, 12.6 degrees +/-0.2 degrees, 16.2 degrees +/-0.2 degrees, 18.2 degrees +/-0.2 degrees, 20.5 degrees +/-0.2 degrees, 22.6 degrees +/-0.2 degrees, 24.7 degrees +/-0.2 degrees, 27.8 degrees +/-0.2 degrees, 29.0 degrees +/-0.2 degrees and the like of the 2 theta value.
Further, the tenofovir alafenamide oxalate (1:1) crystal form a has an X-ray powder diffraction pattern expressed by 2 theta angles, and has characteristic diffraction peaks and relative intensities at the following positions:
2 theta angle (°) Relative Strength (%) 2 theta angle (°) Relative Strength (%)
7.7°±0.2° 35 19.6°±0.2° 19
8.4°±0.2° 22 20.5°±0.2° 92
9.6°±0.2° 100 21.9°±0.2° 16
11.0°±0.2° 10 22.6°±0.2° 26
12.2°±0.2° 13 23.8°±0.2° 30
12.6°±0.2° 22 24.3°±0.2° 25
14.8°±0.2° 12 24.7°±0.2° 55
14.9°±0.2° 12 25.4°±0.2° 22
16.2°±0.2° 47 25.8°±0.2° 17
16.6°±0.2° 26 26.2°±0.2° 10
16.9°±0.2° 27 27.8°±0.2° 18
18.2°±0.2° 34 29.0°±0.2° 19
19.1°±0.2° 15
In a specific embodiment, the tenofovir alafenamide oxalate (1:1) crystalline form a provided by the present invention has the characteristics represented by the X-ray powder diffraction pattern shown in fig. 7.
In a specific embodiment, the present invention provides a process for the preparation of tenofovir alafenamide oxalate (1:1) mixtures wherein the content (by mass) of crystalline form a of tenofovir alafenamide oxalate (1:1) is generally greater than 70%, preferably greater than 80%, most preferably greater than 90%.
It is understood by those skilled in the art that the tenofovir alafenamide oxalate (1:1) mixture of the present invention refers to tenofovir alafenamide oxalate (1:1) containing other impurities or crystal forms, which is prepared by direct synthesis by a chemical synthesis method.
In a specific embodiment, the preparation method of tenofovir alafenamide oxalate (1:1) crystal form a of the invention comprises the following steps:
(1) dissolving tenofovir alafenamide and oxalic acid in acetonitrile; the weight ratio of the solvent to the tenofovir alafenamide is generally 5: 1-80: 1. 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.
(2) Separating out solids;
(3) separating the precipitated solid; alternatively, the collected solid may be washed with acetonitrile.
(4) Optionally, the isolated solid is dried, or further purified and then dried. The drying temperature is generally 20-120 ℃, and preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
Tenofovir alafenamide phosphate (1:1)
In one embodiment, where n is selected to be 1 and X is selected to be phosphoric acid in formula II, tenofovir alafenamide and tenofovir alafenamide are providedPhosphoric acidComposite formed with 1:1 molar composition ratioThis was called "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;
(4) optionally, the isolated solid is dried, or further purified and then dried.
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 phosphoric 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.
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.
In the step (4), the drying temperature is generally 20-120 ℃, preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
The tenofovir alafenamide phosphate (1:1) prepared in this embodiment is a crystal.
Accordingly, the present invention provides a crystalline form of tenofovir alafenamide phosphate (1:1) (for convenience of description, the crystalline form is referred to as "tenofovir alafenamide phosphate (1:1) crystalline form a"). the X-ray powder diffraction pattern of the crystalline form (irradiated with Cu-K α) is characterized by characteristic diffraction peaks corresponding to 2 θ values of 8.0 ° ± 0.2 °, 9.4 ° ± 0.2 °, 10.6 ° ± 0.2 °, 14.5 ° ± 0.2 °, 19.3 ° ± 0.2 °, 21.1 ° ± 0.2 °, 23.4 ° ± 0.2 ° and the like.
In a specific embodiment, the crystalline form a of tenofovir alafenamide phosphate (1:1) according to the present invention has an X-ray powder diffraction pattern characterized by: characteristic diffraction peaks are correspondingly arranged at the positions of 8.0 degrees +/-0.2 degrees, 9.4 degrees +/-0.2 degrees, 10.6 degrees +/-0.2 degrees, 14.5 degrees +/-0.2 degrees, 15.9 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 17.6 degrees +/-0.2 degrees, 18.6 degrees +/-0.2 degrees, 19.3 degrees +/-0.2 degrees, 21.1 degrees +/-0.2 degrees, 23.4 degrees +/-0.2 degrees and the like of the 2 theta value.
Further, the tenofovir alafenamide phosphate (1:1) crystal form a has an X-ray powder diffraction pattern expressed by 2 theta angles, and has characteristic diffraction peaks and relative intensities at the following positions:
2 theta angle (°) Relative Strength (%) 2 theta angle (°) Relative Strength (%)
7.0°±0.2° 7 18.6°±0.2° 28
8.0°±0.2° 75 19.3°±0.2° 39
9.4°±0.2° 65 19.8°±0.2° 8
10.6°±0.2° 36 21.1°±0.2° 43
11.8°±0.2° 7 22.9°±0.2° 11
14.5°±0.2° 100 23.4°±0.2° 40
15.5°±0.2° 9 23.9°±0.2° 13
15.9°±0.2° 27 25.5°±0.2° 8
17.0°±0.2° 22 26.3°±0.2° 11
17.6°±0.2° 32
In a specific embodiment, the tenofovir alafenamide phosphate (1:1) crystalline form a provided by the present invention has the characteristics represented by the X-ray powder diffraction pattern shown in fig. 8.
In a specific embodiment, the tenofovir alafenamide phosphate (1:1) crystal form a content (by mass) in the preparation of a tenofovir alafenamide phosphate (1:1) mixture provided by the present invention is generally greater than 70%, preferably greater than 80%, most preferably greater than 90%.
It will be understood by those skilled in the art that the tenofovir alafenamide phosphate (1:1) mixture according to the present invention refers to tenofovir alafenamide phosphate (1:1) containing other impurities or crystal forms prepared by direct synthesis using chemical synthesis methods.
In a specific embodiment, the preparation method of tenofovir alafenamide phosphate (1:1) crystal form a of the present invention comprises:
(1) dissolving tenofovir alafenamide and phosphoric acid in acetonitrile; the weight ratio of the solvent to the tenofovir alafenamide is generally 5: 1-80: 1. 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.
(2) Separating out solids;
(3) separating the precipitated solid; alternatively, the collected solid may be washed with acetonitrile.
(4) Optionally, the isolated solid is dried, or further purified and then dried. The drying temperature is generally 20-120 ℃, and preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
Tenofovir alafenamide sulfate (1:1)
In one 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;
(4) optionally, the isolated solid is dried, or further purified and then dried.
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 sulfuric 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.
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.
In the step (4), the drying temperature is generally 20-120 ℃, preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
The tenofovir alafenamide sulfate (1:1) prepared in this embodiment is a crystal.
Accordingly, the present invention provides a crystalline form of tenofovir alafenamide sulfate (1:1) (for convenience of description, the crystalline form is referred to as "tenofovir alafenamide sulfate (1:1) form a"). the X-ray powder diffraction pattern of the crystalline form (irradiated with Cu-K α) is characterized by characteristic diffraction peaks corresponding to 2 θ values of 9.2 ° ± 0.2 °, 10.7 ° ± 0.2 °, 11.1 ° ± 0.2 °, 18.4 ° ± 0.2 °, 19.8 ° ± 0.2 °, 22.3 ° ± 0.2 °, 24.3 ° ± 0.2 °, and the like.
In a specific embodiment, the crystalline form a of tenofovir alafenamide sulfate (1:1) of the present invention has an X-ray powder diffraction pattern characterized by: characteristic diffraction peaks are correspondingly arranged at the positions of 9.2 degrees +/-0.2 degrees, 10.7 degrees +/-0.2 degrees, 11.1 degrees +/-0.2 degrees, 16.9 degrees +/-0.2 degrees, 18.4 degrees +/-0.2 degrees, 19.2 degrees +/-0.2 degrees, 19.8 degrees +/-0.2 degrees, 21.7 degrees +/-0.2 degrees, 22.3 degrees +/-0.2 degrees, 23.1 degrees +/-0.2 degrees, 24.3 degrees +/-0.2 degrees, 28.1 degrees +/-0.2 degrees, 31.1 degrees +/-0.2 degrees and the like of the 2 theta value.
Further, the tenofovir alafenamide sulfate (1:1) crystal form a has characteristic diffraction peaks and relative intensities at the following positions in an X-ray powder diffraction pattern expressed by 2 theta angles:
2 theta angle (°) Relative Strength (%) 2 theta angle (°) Relative Strength (%)
9.2°±0.2° 59 21.5°±0.2° 14
10.7°±0.2° 41 21.7°±0.2° 17
11.1°±0.2° 45 22.3°±0.2° 50
16.6°±0.2° 20 23.1°±0.2° 32
16.9°±0.2° 20 24.3°±0.2° 51
17.2°±0.2° 12 25.1°±0.2° 11
17.9°±0.2° 22 25.7°±0.2° 9
18.4°±0.2° 100 27.4°±0.2° 9
19.2°±0.2° 25 28.1°±0.2° 23
19.8°±0.2° 54 29.3°±0.2° 10
20.0°±0.2° 21 31.1°±0.2° 22
In a specific embodiment, the tenofovir alafenamide sulfate (1:1) crystalline form a provided by the present invention has the characteristics represented by the X-ray powder diffraction pattern shown in fig. 9.
In a specific embodiment, the prepared tenofovir alafenamide sulfate (1:1) mixture provided by the present invention generally has a tenofovir alafenamide sulfate (1:1) crystalline form a content (by mass) of greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
It is understood by those skilled in the art that the tenofovir alafenamide sulfate (1:1) mixture according to the present invention refers to tenofovir alafenamide sulfate (1:1) containing other impurities or crystal forms, which is prepared by direct synthesis using a chemical synthesis method.
In a specific embodiment, the preparation method of tenofovir alafenamide sulfate (1:1) crystal form a of the present invention comprises:
(1) dissolving tenofovir alafenamide and sulfuric acid in acetonitrile; the weight ratio of the solvent to the tenofovir alafenamide is generally 5: 1-80: 1. 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.
(2) Separating out solids;
(3) separating the precipitated solid; alternatively, the collected solid may be washed with acetonitrile.
(4) Optionally, the isolated solid is dried, or further purified and then dried. The drying temperature is generally 20-120 ℃, and preferably 30-80 ℃; drying under normal pressure or reduced pressure is also possible.
According to the purpose of the invention, the invention provides a pharmaceutical composition or preparation containing a therapeutically effective amount of tenofovir alafenamide compound shown in formula II or the tenofovir alafenamide compound 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; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, emtricitabine, Cobicistat and darunavir; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii and emtricitabine; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, emtricitabine, and efavirenz; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, emtricitabine, and ropinirovir hydrochloride; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of tenofovir alafenamide complex of formula ii, lamivudine; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, lamivudine and efavirenz; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, lamivudine, Cobicistat and eltoprevir; alternatively, the first and second electrodes may be,
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 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), tenofovir alafenamide sulfate (1:1), tenofovir alafenamide L-tartrate (1:2) crystalline form A, D-tenofovir alafenamide tartrate (1:1) crystalline form A, DL-tenofovir alafenamide tartrate (1:1) crystalline form A, A pharmaceutical composition or a preparation of the L-tenofovir alafenamide malate (1:2) crystal form A, the tenofovir alafenamide citrate (1:1) crystal form A, the tenofovir alafenamide succinate (1:1) crystal form A, the tenofovir alafenamide oxalate (1:1) crystal form A, the tenofovir alafenamide phosphate (1:1) crystal form A or the tenofovir alafenamide sulfate (1:1) crystal form A and a pharmaceutical 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 a tenofovir alafenamide complex of formula II (e.g., 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), tenofovir alafenamide sulfate (1:1), tenofovir alafenamide L-tartrate (1:2) crystalline form A, D-tenofovir alafenamide tartrate (1:1) crystalline form A, DL-tenofovir alafenamide tartrate (1:1) crystalline form A, L-tenofovir alafenamide malate (1:2) crystal form a, tenofovir alafenamide citrate (1:1) crystal form a, tenofovir alafenamide succinate (1:1) crystal form a, tenofovir alafenamide oxalate (1:1) crystal form a, tenofovir alafenamide phosphate (1:1) crystal form a or tenofovir alafenamide sulfate (1:1) crystal form a), optionally with another therapeutically effective amount of active ingredient(s), mixed or contacted with one or more pharmaceutical excipients, and then made 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 invention provides a tenofovir alafenamide complex of formula ii (e.g., 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), tenofovir alafenamide sulfate (1:1), tenofovir alafenamide L-tartrate (1:2) crystal form A, D-tenofovir alafenamide tartrate (1:1) crystal form A, DL-tenofovir alafenamide tartrate (1:1) crystal form a, The particle size distribution of the L-tenofovir alafenamide malate (1:2) crystal form A, the tenofovir alafenamide citrate (1:1) crystal form A, the tenofovir alafenamide succinate (1:1) crystal form A, the tenofovir alafenamide oxalate (1:1) crystal form A, the tenofovir alafenamide phosphate (1:1) crystal form A or the tenofovir alafenamide sulfate (1:1) crystal form A) is controlled to be 95% less than 200 mu m, preferably less than 180 mu m, further preferably less than 150 mu m, and more preferably less than 100 mu m.
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, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, starch slurry, acacia, 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, povidone, and starch slurry are preferred.
Such lubricants typically include magnesium stearate, stearic acid, calcium stearate, sodium stearate fumarate, potassium stearate fumarate, palmitic acid, aerosil, stearamide, talc, solid polyethylene glycols, glyceryl triacetate, and the like. These may be used alone or in combination, and among them, magnesium stearate, stearic acid, talc, colloidal silica, and glyceryl triacetate are preferable.
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 a tenofovir alafenamide complex of formula ii (e.g., 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), tenofovir alafenamide sulfate (1:1), tenofovir alafenamide L-tartrate (1:2) crystal form A, D-tenofovir alafenamide tartrate (1:1) crystal form a, DL-tenofovir alafenamide tartrate (1:1) crystal form A, L-tenofovir alafenamide malate (1:2) crystal form a, tenofovir alafenamide citrate (1:1) crystal form a, tenofovir alafenamide succinate (1:1) crystal form a, tenofovir alafenamide oxalate (1:1) crystal form a, tenofovir alafenamide phosphate (1:1) crystal form a, or tenofovir alafenamide sulfate (1:1) crystal form a). 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 a tenofovir alafenamide complex of formula ii (e.g., 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), tenofovir alafenamide sulfate (1:1), tenofovir alafenamide L-tartrate (1:2) crystal form A, D-tenofovir alafenamide tartrate (1:1) crystal form a, DL-Tenofovir alafenamide tartrate (1:1) crystal form A, L-Tenofovir alafenamide malate (1:2) crystal form A, Tenofovir alafenamide citrate (1:1) crystal form A, Tenofovir alafenamide succinate (1:1) crystal form A, Tenofovir alafenamide oxalate (1:1) crystal form A, Tenofovir alafenamide phosphate (1:1) crystal form A or Tenofovir alafenamide sulfate (1:1) crystal form A), a second active ingredient is Entricitabine with a treatment effective amount, a third active ingredient is Cobicistat with a treatment effective amount, and a fourth active ingredient is Etorivir with a treatment 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 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 a tenofovir alafenamide complex of formula ii (e.g., 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), tenofovir alafenamide sulfate (1:1), tenofovir alafenamide L-tartrate (1:2) crystal form A, D-tenofovir alafenamide tartrate (1:1) crystal form a, DL-tenofovir alafenamide tartrate (1:1) crystal form A, L-tenofovir alafenamide malate (1:2) crystal form A, tenofovir alafenamide citrate (1:1) crystal form A, tenofovir alafenamide succinate (1:1) crystal form A, tenofovir alafenamide oxalate (1:1) crystal form A, tenofovir alafenamide phosphate (1:1) crystal form A or tenofovir alafenamide sulfate (1:1) crystal form A), a second active ingredient is therapeutically effective amount of emtricitabine, a third active ingredient is therapeutically effective amount of Cobicistat, and a fourth active ingredient is therapeutically effective amount of darunavir. 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 a tenofovir alafenamide complex of formula ii (e.g., 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), tenofovir alafenamide sulfate (1:1), tenofovir alafenamide L-tartrate (1:2) crystal form A, D-tenofovir alafenamide tartrate (1:1) crystal form a, DL-tenofovir alafenamide tartrate (1:1) crystal form A, L-tenofovir alafenamide malate (1:2) crystal form A, tenofovir alafenamide citrate (1:1) crystal form A, tenofovir alafenamide succinate (1:1) crystal form A, tenofovir alafenamide oxalate (1:1) crystal form A, tenofovir alafenamide phosphate (1:1) crystal form A or tenofovir alafenamide sulfate (1:1) crystal form A), and the second active ingredient is 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 a tenofovir alafenamide complex of formula ii (e.g., 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), tenofovir alafenamide sulfate (1:1), tenofovir alafenamide L-tartrate (1:2) crystal form A, D-tenofovir alafenamide tartrate (1:1) crystal form a, DL-Tenofovir alafenamide tartrate (1:1) crystal form A, L-Tenofovir alafenamide malate (1:2) crystal form A, Tenofovir alafenamide citrate (1:1) crystal form A, Tenofovir alafenamide succinate (1:1) crystal form A, Tenofovir alafenamide oxalate (1:1) crystal form A, Tenofovir alafenamide phosphate (1:1) crystal form A or Tenofovir alafenamide sulfate (1:1) crystal form A), a second active ingredient is therapeutically effective amount of emtricitabine, and a third active ingredient is therapeutically effective amount of efavirenz. 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 a tenofovir alafenamide complex of formula ii (e.g., 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), tenofovir alafenamide sulfate (1:1), tenofovir alafenamide L-tartrate (1:2) crystal form A, D-tenofovir alafenamide tartrate (1:1) crystal form a, DL-tenofovir alafenamide tartrate (1:1) crystal form A, L-tenofovir alafenamide malate (1:2) crystal form A, tenofovir alafenamide citrate (1:1) crystal form A, tenofovir alafenamide succinate (1:1) crystal form A, tenofovir alafenamide oxalate (1:1) crystal form A, tenofovir alafenamide phosphate (1:1) crystal form A or tenofovir alafenamide sulfate (1:1) crystal form A), a second active ingredient is therapeutically effective amount of emtricitabine, and a third active ingredient is therapeutically effective amount of rilpivirine hydrochloride. 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 a tenofovir alafenamide complex of formula ii (e.g., 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), tenofovir alafenamide sulfate (1:1), tenofovir alafenamide L-tartrate (1:2) crystal form A, D-tenofovir alafenamide tartrate (1:1) crystal form a, DL-Tenofovir alafenamide tartrate (1:1) crystal form A, L-Tenofovir alafenamide malate (1:2) crystal form A, Tenofovir alafenamide citrate (1:1) crystal form A, Tenofovir alafenamide succinate (1:1) crystal form A, Tenofovir alafenamide oxalate (1:1) crystal form A, Tenofovir alafenamide phosphate (1:1) crystal form A or Tenofovir alafenamide sulfate (1:1) crystal form A), and the second active ingredient is lamivudine 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 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 a tenofovir alafenamide complex of formula ii (e.g., 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), tenofovir alafenamide sulfate (1:1), tenofovir alafenamide L-tartrate (1:2) crystal form A, D-tenofovir alafenamide tartrate (1:1) crystal form a, DL-Tenofovir alafenamide tartrate (1:1) crystal form A, L-Tenofovir alafenamide malate (1:2) crystal form A, Tenofovir alafenamide citrate (1:1) crystal form A, Tenofovir alafenamide succinate (1:1) crystal form A, Tenofovir alafenamide oxalate (1:1) crystal form A, Tenofovir alafenamide phosphate (1:1) crystal form A or Tenofovir alafenamide sulfate (1:1) crystal form A), 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 a tenofovir alafenamide complex of formula ii (e.g., 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), tenofovir alafenamide sulfate (1:1), tenofovir alafenamide L-tartrate (1:2) crystal form A, D-tenofovir alafenamide tartrate (1:1) crystal form a, DL-Tenofovir alafenamide tartrate (1:1) crystal form A, L-Tenofovir alafenamide malate (1:2) crystal form A, Tenofovir alafenamide citrate (1:1) crystal form A, Tenofovir alafenamide succinate (1:1) crystal form A, Tenofovir alafenamide oxalate (1:1) crystal form A, Tenofovir alafenamide phosphate (1:1) crystal form A or Tenofovir alafenamide sulfate (1:1) crystal form A), a second active ingredient is lamivudine with a therapeutically effective amount, a third active ingredient is Cobicistat with a therapeutically effective amount, and a fourth active ingredient is Televivir 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 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 a tenofovir alafenamide complex of formula ii (e.g., 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), tenofovir alafenamide sulfate (1:1), tenofovir alafenamide L-tartrate (1:2) crystal form A, D-tenofovir alafenamide tartrate (1:1) crystal form a, DL-Tenofovir alafenamide tartrate (1:1) crystal form A, L-Tenofovir alafenamide malate (1:2) crystal form A, Tenofovir alafenamide citrate (1:1) crystal form A, Tenofovir alafenamide succinate (1:1) crystal form A, Tenofovir alafenamide oxalate (1:1) crystal form A, Tenofovir alafenamide phosphate (1:1) crystal form A or Tenofovir alafenamide sulfate (1:1) crystal form A), a second active ingredient is lamivudine with a therapeutically effective amount, a third active ingredient is Cobicistat with a therapeutically effective amount, and a fourth active ingredient is Darunavir 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 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 may be prepared in a manner well known in the art. The pharmaceutic adjuvant can be conventional pharmaceutic adjuvants in the field, and comprises a filler, a disintegrant, an adhesive, a lubricant and the like.
According to the purpose of the invention, the invention provides application of a tenofovir alafenamide compound shown in a formula II or the tenofovir alafenamide compound prepared by the preparation method in preparing 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 as a formula II, such as a tenofovir alafenamide L-tartrate crystal form A (1:2), tenofovir alafenamide D-tartrate crystal form 1:1, tenofovir alafenamide DL-tartrate crystal form 1:1, tenofovir alafenamide L-malate crystal form 1:2, tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1), tenofovir alafenamide sulfate (1:1), tenofovir alafenamide L-tartrate crystal form 1:2) crystal form A, D-tenofovir alafenamide tartrate (1:1) crystal form A, DL-tenofovir alafenamide tartrate crystal form A (1:1), The crystal form A of the L-malic acid tenofovir alafenamide (1:2), the crystal form A of the citric acid tenofovir alafenamide (1:1), the crystal form A of the succinic acid tenofovir alafenamide (1:1), the crystal form A of the oxalic acid tenofovir alafenamide (1:1), the crystal form A of the phosphoric acid tenofovir alafenamide (1:1), the crystal form A of the sulfuric acid tenofovir alafenamide (1:1), and the like.
The X-ray powder diffraction analysis of the invention is CuK α source passing through an X' PertPRO type X-ray powder diffractometer of Parnacidae, the Netherlands under the environment temperature and the environment humidity
Figure BDA0002109532590000371
The assay was complete. The "ambient temperature" is generally 0 to 40 ℃; "ambient humidity" is typically 30% to 80% relative humidity.
Representative X-ray powder diffraction patterns provided by the present invention are shown in the accompanying drawings. The 'representative X-ray powder diffraction pattern' refers to that the X-ray powder diffraction characteristics of the crystal form accord with the overall appearance displayed by the pattern, and it can be understood that in the test process, the peak-appearing positions or peak intensities of the X-ray powder diffraction patterns measured by the same crystal form have certain differences due to the influence of various factors (such as the granularity of a test sample, a sample processing method, an instrument, test parameters, test operation and the like in the test process). In general, the experimental error of the diffraction peak 2 θ value in the X-ray powder diffraction pattern may be. + -. 0.2 °.
Drawings
FIG. 1X-ray powder diffraction pattern of crystalline form A of Tenofovir alafenamide tartrate (1: 2);
FIG. 2X-ray powder diffraction pattern of crystalline form A of Tenofovir alafenamide tartrate (1: 1);
FIG. 3X-ray powder diffraction pattern of DL-tenofovir alafenamide tartrate (1:1) form A;
figure 4X-ray powder diffraction pattern of tenofovir alafenamide malate (1:2) form a;
FIG. 5X-ray powder diffraction pattern of tenofovir alafenamide citrate (1:1) form A;
FIG. 6X-ray powder diffraction pattern of tenofovir alafenamide succinate (1:1) form A;
FIG. 7X-ray powder diffraction pattern of tenofovir alafenamide oxalate (1:1) form A;
FIG. 8X-ray powder diffraction pattern of tenofovir alafenamide phosphate (1:1) form A;
FIG. 9X-ray powder diffraction pattern of tenofovir alafenamide sulfate (1:1) form A;
FIG. 10 Tenofovir alafenamide1H NMR spectrum;
FIG. 11L-Tenofovir alafenamide tartrate (1:2)1H NMR spectrum;
FIG. 12D-Tenofovir alafenamide tartrate (1:1)1H NMR spectrum;
FIG. 13 DL-Tenofovir alafenamide tartrate (1:1)1H NMR spectrum;
FIG. 14L-tenofovir alafenamide malate (1:2)1H NMR spectrum;
FIG. 15 Tenofovir alafenamide citrate (1:1)1H NMR spectrum;
FIG. 16 Tenofovir alafenamide succinate (1:1)1H NMR spectrum;
FIG. 17 Tenofovir alafenamide oxalate (1:1)1H NMR spectrum;
FIG. 18 Tenofovir alafenamide phosphate (1:1)1H NMR spectrum;
FIG. 19 Tenofovir alafenamide sulfate (1:1)1H NMR spectrum.
Detailed Description
The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.
In the following examples1The H NMR 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 Bruke AV-II 400MHz nuclear magnetic resonance instrument.
The X-ray powder diffraction analysis in the following examples is CuK α source by X' Pert PRO type X-ray powder diffractometer of Parnacidae, Netherlands under ambient temperature and humidity
Figure BDA0002109532590000381
The assay was complete. The "ambient temperature" is generally 0 to 40 ℃; "ambient humidity" is typically 30% to 80% relative humidity.
The elemental analysis in the following examples was determined by the CARLO ERBA 1106 elemental analyzer, Italy.
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.
1H NMR(400MHz，DMSO-d6)δ:8.15(s，1H)，8.11(s，1H)，7.32-7.28(t，2H)，7.21(s，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.65-5.59(m，1H)，4.90-4.81(m，1H)，4.31-4.26(m，1H)，4.18-4.13(m，1H)，3.98-3.91(m，1H)，3.90-3.81(m，2H)，3.80-3.75(m，1H)，1.16-1.14(m，9H)，1.09-1.07(d，3H)(1The H NMR spectrum is shown in figure 10).
Example 2
Preparation of L-tenofovir alafenamide tartrate (1:2) and crystal form A thereof
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).
1H NMR(400MHz，DMSO-d6)δ:8.14(s，1H)，8.10(s，1H)，7.31-7.27(t，2H)，7.19(s，2H)，7.15-7.11(m，1H)，7.07-7.04(m，2H)，5.64-5.58(m，1H)，4.90-4.80(m，1H)，4.30-4.25(m，2H)，4.18-4.12(m，1H)，3.98-3.91(m，1H)，3.89-3.81(m，2H)，3.80-3.74(m，1H)，1.16-1.13(t，9H)，1.08-1.06(d，3H)。
Melting range: 158-.
As described above1In the H NMR results, the signal peaks at δ 8.14(s, 1H) and 8.10(s, 1H) in the chemical shifts were assigned to 2H on the adenine ring of tenofovir alafenamide, respectively, and the signal peaks at δ 4.30 to 4.25(m, 2H) were assigned to the free base of tenofovir alafenamide in example 11H NMR contrast can judge that 1H is assigned to 2 methine H of L-tartaric acid, and the molar composition ratio of tenofovir alafenamide and L-tartaric acid in the sample can be judged to be 2:1 (by the integral area ratio of two groups of signal peaks)1The H NMR spectrum is shown in FIG. 11).
The X-ray powder diffraction pattern thus measured is shown in FIG. 1, and the measured values are shown in the following table (three decimal places are rounded off from the measured values corresponding to diffraction peaks having a relative intensity of 3% or more).
Figure BDA0002109532590000401
The obtained crystal form is named as a crystal form A of the L-tartaric acid tenofovir alafenamide (1: 2).
Example 3
Preparation of L-tenofovir alafenamide tartrate (1:2) and crystal form A thereof
Dissolving 4.76g (10.0mmol) of tenofovir alafenamide and 0.78g (5.2mmol) of L-tartaric acid in 40ml of isopropanol 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 a proper amount of isopropanol, and drying under reduced pressure at the temperature of 30-35 ℃ to obtain the L-tenofovir alafenamide tartrate crystal form A (1: 2).
Example 4
Preparation of L-tenofovir alafenamide tartrate (1:2) and crystal form A thereof
Dissolving 4.76g (10.0mmol) of tenofovir alafenamide and 0.65g (4.3mmol) of L-tartaric acid in 200ml of ethanol 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 a proper amount of ethanol, and drying under reduced pressure at 55-60 ℃ to obtain the L-tenofovir alafenamide tartrate crystal form A (1: 2).
Example 5
Preparation of D-tenofovir alafenamide tartrate (1:1) and crystal form A thereof
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).
1H NMR(400MHz，DMSO-d6)δ:8.15(s，1H)，8.11(s，1H)，7.31-7.28(t，2H)，7.22(s，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.63-5.58(m，1H)，4.90-4.81(m，1H)，4.32-4.26(m，3H)，4.18-4.13(m，1H)，4.00-3.92(m，1H)，3.90-3.81(m，2H)，3.80-3.74(m，1H)，1.16-1.13(t，9H)，1.09-1.07(d，3H)。
Melting range: 135 ℃ and 138 ℃.
As described above1In the H NMR results, the signal peaks at δ 8.15(s, 1H) and 8.11(s, 1H) in the chemical shifts were assigned to 2H on the adefovir dipivoxil adenine, and the signal peaks at δ 4.32 to 4.26(m, 3H) and the free base of the tenofovir alafenamide in example 1, respectively1H NMR contrast, 2 methine H in which 2H are assigned to D-tartaric acid can be judged, and the molar composition ratio of tenofovir alafenamide to D-tartaric acid in the sample can be judged to be 1:1 (from the integral area ratio of two groups of signal peaks)1The H NMR spectrum is shown in figure 12).
The X-ray powder diffraction pattern thus measured is shown in FIG. 2, and the measured values are shown in the following table (three decimal places are rounded off from the measured values corresponding to diffraction peaks having a relative intensity of 3% or more).
Figure BDA0002109532590000411
The obtained crystal form is named as the crystal form A of the D-tenofovir alafenamide tartrate (1: 1).
Example 6
Preparation of DL-tenofovir alafenamide tartrate (1:1) and crystal form A thereof
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).
1H NMR(400MHz，DMSO-d6)δ:8.14(s，1H)，8.11(s，1H)，7.31-7.27(t，2H)，7.20(s，2H)，7.15-7.11(m，1H)，7.07-7.04(m，2H)，5.63-5.58(m，1H)，4.90-4.80(m，1H)，4.31-4.26(m，3H)，4.18-4.13(m，1H)，4.00-3.91(m，1H)，3.90-3.81(m，2H)，3.80-3.74(m，1H)，1.16-1.13(t，9H)，1.08-1.07(d，3H)。
Melting range: 175 ℃ and 178 ℃.
As described above1In the H NMR results, the signal peaks at δ 8.14(s, 1H) and 8.11(s, 1H) in the chemical shifts were assigned to 2H on the adefovir dipivoxil adenine, and the signal peaks at δ 4.31 to 4.26(m, 3H) and the free base of the tenofovir alafenamide in example 1, respectively1H NMR contrast, 2 methine H in which 2H are assigned to DL-tartaric acid can be judged, and the molar composition ratio of tenofovir alafenamide to DL-tartaric acid in the sample can be judged to be 1:1 (from the integrated area ratio of two groups of signal peaks)1The H NMR spectrum is shown in figure 13).
The X-ray powder diffraction pattern thus measured is shown in FIG. 3, and the measured values are shown in the following table (three decimal places are rounded off from the measured values corresponding to diffraction peaks having a relative intensity of 3% or more).
Figure BDA0002109532590000421
The obtained crystal form is named as a DL-tenofovir alafenamide tartrate (1:1) crystal form A.
Example 7
Preparation of tenofovir alafenamide L-malate (1:2) and crystal form A thereof
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).
1H NMR(400MHz，DMSO-d6)δ:8.15(s，1H)，8.11(s，1H)，7.32-7.28(m，2H)，7.22(s，2H)，7.15-7.12(t,1H),7.07-7.05(m，2H)，5.65-5.59(m，1H)，4.90-4.81(m，1H)，4.31-4.26(m，2H)，4.19-4.13(m，1H)，4.00-3.92(m，1H)，3.90-3.83(m，2H)，3.80-3.74(m，1H)，2.65-2.43(m，1H)，1.16-1.14(m，9H)，1.09-1.07(d，3H)。
As described above1In the H NMR results, the signal peaks at the chemical shifts of delta 8.15(s, 1H) and 8.11(s, 1H) are respectively assigned to 2H on the tenofovir alafenamide adenine, the signal peaks at delta 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 (1) from the integral area ratio of the two groups of signal peaks1The H NMR spectrum is shown in figure 14).
The X-ray powder diffraction pattern thus measured is shown in FIG. 4, and the measured values are shown in the following table (three decimal places are rounded off from the measured values corresponding to diffraction peaks having a relative intensity of 3% or more).
Figure BDA0002109532590000431
The obtained crystal form is named as a tenofovir alafenamide L-malate (1:2) crystal form A.
Example 8
Preparation of tenofovir alafenamide citrate (1:1) and crystal form A thereof
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).
1H NMR(400MHz，DMSO-d6)δ:8.14(s，1H)，8.11(s，1H)，7.31-7.27(m，2H)，7.22(s，2H)，7.15-7.11(m，1H)，7.07-7.04(m，2H)，5.63-5.58(m，1H)，4.90-4.80(m，1H)，4.30-4.26(m，1H)，4.18-4.13(m，1H)，4.00-3.91(m，1H)，3.89-3.81(m，2H)，3.79-3.74(m，1H)，2.78-2.74(d，2H)，2.67-2.64(d，2H)，1.16-1.13(t，9H)，1.08-1.06(d，3H)。
Melting range: 144 ℃ and 147 ℃.
As described above1In the H NMR results, the signal peaks at δ 8.14(s, 1H) and 8.11(s, 1H) in the chemical shifts were assigned to tenofovir alafenamide, respectivelyThe signal peaks at 2H on the aniline adenine, delta 2.78-2.74(d, 2H) and 2.67-2.64(d, 2H) are assigned to 4H of 2 methylene on citric acid, and the molar composition ratio of tenofovir alafenamide and citric acid in the sample is judged to be 1:1 (from the integral area ratio of the two groups of signal peaks1The H NMR spectrum is shown in figure 15).
The X-ray powder diffraction pattern thus measured is shown in FIG. 5, and the measured values are shown in the following table (three decimal places are rounded off from the measured values corresponding to diffraction peaks having a relative intensity of 3% or more).
Figure BDA0002109532590000441
The obtained crystal form is named as tenofovir alafenamide citrate (1:1) crystal form A.
Example 9
Preparation of tenofovir alafenamide citrate (1:1) and crystal form A thereof
Dissolving 4.76g (10.0mmol) of tenofovir alafenamide and 2.40g (12.5mmol) of citric acid in 40ml of ethanol 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 ethanol, and drying under reduced pressure at the temperature of 30-35 ℃ to obtain the tenofovir alafenamide citrate (1:1) crystal form A.
Example 10
Preparation of tenofovir alafenamide citrate (1:1) and crystal form A thereof
Dissolving 4.76g (10.0mmol) of tenofovir alafenamide and 1.54g (8.0mmol) of citric acid in 200ml of methanol at the temperature of 60-64 ℃, 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 methanol, and drying under reduced pressure at 35-40 ℃ to obtain the tenofovir alafenamide citrate (1:1) crystal form A.
Example 11
Preparation of tenofovir alafenamide citrate (1:1) and crystal form A thereof
Dissolving 4.76g (10.0mmol) of tenofovir alafenamide and 1.92g (10.0mmol) of citric acid in 150ml of tetrahydrofuran at the temperature of 60-65 ℃, 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 tetrahydrofuran, and drying under reduced pressure at 40-45 ℃ to obtain the tenofovir alafenamide citrate (1:1) crystal form A.
Example 12
Preparation of tenofovir alafenamide succinate (1:1) and crystal form A thereof
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).
1H NMR(400MHz，DMSO-d6)δ:12.13(s，2H)，8.15(s，1H)，8.11(s，1H)，7.31-7.27(t，2H)，7.21(s，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.64-5.59(m，1H)，4.90-4.81(m，1H)，4.30-4.26(m，1H)，4.18-4.13(m，1H)，4.00-3.92(m，1H)，3.90-3.81(m，2H)，3.80-3.74(m，1H)，2.43(s，4H)，1.16-1.13(t，9H)，1.08-1.07(d，3H)。
As described above1In the H NMR results, the signal peaks at δ 8.15(s, 1H) and 8.11(s, 1H) in the chemical shift were assigned to 2H on tenofovir alafenamide adenine, the signal peak at δ 2.43(s, 4H) was assigned to 4H on 2 symmetric methylene groups on succinic acid, and the molar composition ratio of tenofovir alafenamide to succinic acid in the sample was determined to be 1: 1(s, 1H) from the integrated area ratio of the two sets of signal peaks1The H NMR spectrum is shown in figure 16).
The X-ray powder diffraction pattern thus measured is shown in FIG. 6, and the measured values are shown in the following table (three decimal places are rounded off from the measured values corresponding to diffraction peaks having a relative intensity of 3% or more).
Figure BDA0002109532590000461
The obtained crystal form is named as tenofovir alafenamide succinate (1:1) crystal form A.
Example 13
Preparation of tenofovir alafenamide oxalate (1:1) and crystal form A thereof
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).
1H NMR(400MHz，DMSO-d6)δ:8.19(s，1H)，8.15(s，1H)，7.49(s，2H)，7.32-7.28(m，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.64-5.58(m，1H)，4.90-4.80(m，1H)，4.32-4.28(m，1H)，4.19-4.14(m，1H)，4.00-3.91(m，1H)，3.90-3.83(m，2H)，3.80-3.75(m，1H)，1.16-1.13(m，9H)，1.09-1.08(d，3H)(1The H NMR spectrum is shown in figure 17).
Elemental analysis: c: 48.70 percent; h: 5.50 percent; n: 14.75 percent. From the elemental analysis results, it was determined that the ratio of oxalic acid to tenofovir alafenamide in the sample was about 1: 1.
Melting range: 182 ℃ and 185 ℃.
The X-ray powder diffraction pattern thus measured is shown in FIG. 7, and the measured values are shown in the following table (three decimal places are rounded off from the measured values corresponding to diffraction peaks having a relative intensity of 3% or more).
Figure BDA0002109532590000471
The obtained crystal form is named as tenofovir alafenamide oxalate (1:1) crystal form A.
Example 14
Preparation of tenofovir alafenamide phosphate (1:1) and crystal form A thereof
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).
1H NMR(400MHz，DMSO-d6)δ:8.15(s，1H)，8.11(s，1H)，7.31-7.27(m，2H)，7.25(s，2H)，7.15-7.11(t,1H),7.07-7.05(m，2H)，5.64-5.59(m，1H)，4.90-4.80(m，1H)，4.30-4.26(m，1H)，4.18-4.13(m，1H)，3.98-3.91(m，1H)，3.90-3.83(m，2H)，3.81-3.74(m，1H)，1.16-1.13(m，9H)，1.08-1.07(d，3H)(1The H NMR spectrum is shown in figure 18).
Elemental analysis: c: 43.72 percent; h: 5.64 percent; n: 14.56 percent. From the elemental analysis results, the ratio of phosphoric acid to tenofovir alafenamide in the sample was judged to be about 1: 1.
Melting range: 165 ℃ and 168 ℃.
The X-ray powder diffraction pattern thus measured is shown in FIG. 8, and the measured values are shown in the following table (three decimal places are rounded off from the measured values corresponding to diffraction peaks having a relative intensity of 3% or more).
Figure BDA0002109532590000472
Figure BDA0002109532590000481
The obtained crystal form is named as tenofovir alafenamide phosphate (1:1) crystal form A.
Example 15
Preparation of tenofovir alafenamide sulfate (1:1) and crystal form A thereof
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)δ:9.46(brs，1H)，8.74(brs，1H)，8.48(s，1H)，8.46(s，1H)，7.34-7.30(t，2H)，7.17-7.13(t,1H),7.08-7.06(d，2H)，5.63-5.57(m，1H)，4.88-4.79(m，1H)，4.44-4.39(m，1H)，4.28-4.23(m，1H)，4.05-3.98(m，1H)，3.93-3.88(m，2H)，3.85-3.78(m，1H)，1.15-1.11(m，12H)(1The H NMR spectrum is shown in figure 19).
Elemental analysis: c: 43.82%; h: 5.42 percent; n: 14.54 percent; s: 5.50 percent. From the elemental analysis results, the ratio of sulfuric acid to tenofovir alafenamide in the sample was judged to be about 1: 1.
Melting range: 146 ℃ and 149 ℃.
The X-ray powder diffraction pattern thus measured is shown in FIG. 9, and the measured values are shown in the following table (three decimal places are rounded off from the measured values corresponding to diffraction peaks having a relative intensity of 3% or more).
Figure BDA0002109532590000482
Figure BDA0002109532590000491
The obtained crystal form is named as tenofovir alafenamide sulfate (1:1) crystal form A.
Example 16
Polymorphism research of crystal form A of L-tenofovir alafenamide tartrate (1:2)
Taking the crystalline form a of tenofovir alafenamide L-tartrate (1:2) prepared according to the method of example 2, the crystalline form was prepared according to the following table of solvents and manners. The crystal form is examined by measuring an X-ray powder diffraction pattern, and the results are as follows (TAF stands for tenofovir alafenamide in the following table):
Figure BDA0002109532590000492
the research shows that the crystal form A of the L-tenofovir alafenamide tartrate (1:2) can be stably obtained under various crystallization conditions, and the polymorphism of the crystal form A of the L-tenofovir alafenamide tartrate (1:2) is not found, namely the controllability of the crystal form A of the L-tenofovir alafenamide tartrate (1:2) is strong.
Example 17
Polymorphism research of tenofovir alafenamide citrate (1:1) crystal form A
Taking tenofovir alafenamide citrate (1:1) crystal form A prepared by the method of example 2, adding the crystal form A into a proper amount of solvent listed in the following table, heating, stirring, filtering, and drying a filter cake under reduced pressure. The crystal form is examined by measuring an X-ray powder diffraction pattern, and the results are as follows (TAF stands for tenofovir alafenamide in the following table):
Figure BDA0002109532590000501
the research shows that the tenofovir alafenamide citrate (1:1) crystal form A can be stably obtained under various crystallization conditions, and the polymorphism of the tenofovir alafenamide citrate (1:1) is not found, namely the controllability of the tenofovir alafenamide citrate (1:1) crystal form A is strong.
Example 18
Stability study
Taking tenofovir alafenamide fumarate (1:1) (prepared as disclosed in patent document CN 1443189A), tenofovir alafenamide fumarate (1:2) (prepared as disclosed in patent document CN 103732594A), tenofovir alafenamide L-tartrate (1:2) (prepared as in example 2), tenofovir alafenamide DL-tartrate (1:1) (prepared as in example 6) and tenofovir alafenamide citrate (1:1) (prepared as in example 8), testing was performed after 20 days respectively at high temperature and high humidity, and the results were as follows (in the following table, TAF represents tenofovir alafenamide):
Figure BDA0002109532590000511
the above studies show that the stability of the L-tenofovir alafenamide tartrate (1:2), the DL-tenofovir alafenamide tartrate (1:1) and the tenofovir alafenamide citrate (1:1) provided by the invention is equivalent to or better than that of tenofovir alafenamide fumarate (1:1) and tenofovir alafenamide fumarate (1:2) under high-temperature and high-humidity conditions.
Example 19
Solubility study
Taking tenofovir alafenamide fumarate (1:1) (prepared as disclosed in patent document CN 1443189A), tenofovir alafenamide fumarate (1:1) (prepared as disclosed in patent document CN 103732594A), tenofovir alafenamide L-tartrate (1:1) (prepared as in example 2), tenofovir alafenamide DL-tartrate (1:1) (prepared as in example 6) and tenofovir alafenamide citrate (1:1) (prepared as in example 8), their solubility in different media was tested at 25 ℃ respectively, and the results were as follows (TAF in the following table represents tenofovir alafenamide):
Figure BDA0002109532590000512
Figure BDA0002109532590000521
the above studies indicate that the solubility of L-tenofovir alafenamide tartrate (1:2), DL-tenofovir alafenamide tartrate (1:1) and tenofovir alafenamide citrate (1:1) provided by the present invention is equivalent to or better than that of tenofovir alafenamide fumarate (1:1) and tenofovir alafenamide fumarate (1: 2).
Example 20
Animal pharmacokinetic experiments
Tenofovir alafenamide L-tartrate (1:2) [ abbreviation: l-tartaric acid TAF (1:2), test drug 1], tenofovir alafenamide citrate (1:1) [ abbreviation: TAF citrate (1:1), test drug 2] and tenofovir alafenamide fumarate (1:2) [ abbreviation: fumaric acid TAF (1:2), reference drug ]. 24 SD rats with half weight of 200-. Blood was collected by jugular vein at approximately 200 μ L each at 3500 rpm for 10 minutes, centrifuged at for 4 hours, 8 hours, 12 hours and 24 hours before and after administration, and the plasma was taken as an upper layer, and the concentration of tenofovir drug in the plasma was quantitatively analyzed by LC-MS/MS.
Non-compartmental prescription adopting WinNonlin 5.3 softwareThe main pharmacokinetic parameters of tenofovir after administration to beagle dogs were calculated: time to peak TmaxAnd peak concentration CmaxAdopting an actual measurement value; area under plasma drug concentration-time Curve AUC0-tCalculating a value by adopting a trapezoidal method; AUC0-∞Calculated according to the following formula: AUC0-∞＝AUC0-t+Ct/ke，CtConcentration, k, for the last measurable time pointeTo eliminate the rate constant; plasma elimination half-life t1/2＝0.693/ke。
Comparison of the pharmacokinetic parameters of Tenofovir with the differences after administration of test and reference drugs, T, Using paired T-testmaxNon-parameter test is adopted, and other parameters are tested after logarithmic conversion. The main pharmacokinetic parameters and the t-test results are as follows:
Figure BDA0002109532590000531
the above studies showed that there was no statistical difference in the main pharmacokinetic parameters of TAF (1:2) and TAF (1:1) citrate versus TAF (1:2) fumarate (P >0.05), indicating that TAF (1:2) and TAF (1:1) citrate are not statistically different from TAF (1:2) fumarate in vivo and are bioequivalent.
Example 21
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 22
L-tenofovir alafenamide tartrate (1:2) capsule and preparation method thereof
Figure BDA0002109532590000541
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 23
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 24
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 25
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 26
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 27
Tenofovir alafenamide succinate (1:1) film-coated tablet and preparation thereof
Figure BDA0002109532590000561
Figure BDA0002109532590000571
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 28
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 fibreVegetable extract 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 29
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 30
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 31
Tenofovir alafenamide L-tartrate (1:2), emtricitabine, Cobicistat and Ettelavavir double-layer tablets and preparation thereof
Figure BDA0002109532590000591
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 32
DL-tenofovir alafenamide tartrate (1:1), emtricitabine, Cobicistat and darunavir double-layer tablet and preparation thereof
Figure BDA0002109532590000601
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.
(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 33
L-tenofovir alafenamide tartrate (1:2), emtricitabine film-coated tablets and preparation thereof
Figure BDA0002109532590000602
Figure BDA0002109532590000611
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 34
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 35
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 36
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.
(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 37
Tenofovir alafenamide citrate (1:1), emtricitabine, rilpivirine hydrochloride film-coated double-layer tablet and preparation thereof
Figure BDA0002109532590000641
Figure BDA0002109532590000651
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, firstly, microcrystalline cellulose and croscarmellose sodiumMixing, adding lactose monohydrate, mixing, adding rilpivirine hydrochloride, and mixing; with povidone K30And aqueous polysorbate 20 solution 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 38
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 39
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.
(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.
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 (12)

1. A tenofovir alafenamide compound shown in a formula II,
Figure FDA0002109532580000011
wherein n is 2 and X is selected from: l-tartaric acid, i.e. the complex, was tenofovir alafenamide L-tartrate (1: 2).
2. The tenofovir alafenamide complex of claim 1, wherein,
the L-tenofovir alafenamide tartrate (1:2) is a crystal.
3. The tenofovir alafenamide complex of claim 2, wherein,
the crystal form of the L-tenofovir alafenamide tartrate (1:2) is a crystal form A, and an X-ray powder diffraction pattern radiated by Cu-K α is characterized in that characteristic diffraction peaks are correspondingly arranged at positions with 2 theta values of 8.2 degrees +/-0.2 degrees, 9.4 degrees +/-0.2 degrees, 10.8 degrees +/-0.2 degrees, 14.4 degrees +/-0.2 degrees, 17.9 degrees +/-0.2 degrees, 18.9 degrees +/-0.2 degrees, 19.7 degrees +/-0.2 degrees and 21.6 degrees +/-0.2 degrees.
4. The tenofovir alafenamide complex of claim 3, wherein,
the L-tenofovir alafenamide tartrate crystal form A (1:2) is radiated by using Cu-K α, and an X-ray powder diffraction pattern is characterized in that characteristic diffraction peaks are correspondingly arranged at positions with 2 theta values of 7.5 degrees +/-0.2 degrees, 8.2 degrees +/-0.2 degrees, 9.4 degrees +/-0.2 degrees, 10.8 degrees +/-0.2 degrees, 12.4 degrees +/-0.2 degrees, 14.4 degrees +/-0.2 degrees, 16.0 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 17.1 degrees +/-0.2 degrees, 17.9 degrees +/-0.2 degrees, 18.9 degrees +/-0.2 degrees, 19.7 degrees +/-0.2 degrees, 20.4 degrees +/-0.2 degrees, 21.6 degrees +/-0.2 degrees and 23.0 degrees +/-0.2 degrees.
5. A method for preparing a tenofovir alafenamide complex according to any one of claims 1 to 4, comprising:
(1) dissolving tenofovir alafenamide and L-tartaric 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,
(2) separating out solids;
(3) separating the precipitated solid;
(4) optionally, the isolated solid is dried, or further purified and then dried.
6. The process according to claim 5, 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.
7. A method for preparing a crystalline form of a tenofovir alafenamide complex, the method comprising:
(1) dissolving tenofovir alafenamide and L-tartaric acid in acetonitrile, ethanol, isopropanol or a mixture thereof, wherein the feeding molar ratio of the tenofovir alafenamide to the L-tartaric acid is 1.7: 1-2.5: 1, preferably 1.9: 1-2.3: 1;
(2) separating out solids;
(3) separating the precipitated solid;
(4) optionally, the isolated solid is dried, or further purified and then dried.
8. A pharmaceutical composition, which comprises a therapeutically effective amount of tenofovir alafenamide complex as claimed in any one of claims 1 to 4 or tenofovir alafenamide complex or crystal form thereof prepared by the preparation method as claimed in any one of claims 5 to 7, and a pharmaceutical 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:
a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, emtricitabine, Cobicistat and eltiravir; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, emtricitabine, Cobicistat and darunavir; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii and emtricitabine; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, emtricitabine, and efavirenz; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, emtricitabine, and ropinirovir hydrochloride; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of tenofovir alafenamide complex of formula ii, lamivudine; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, lamivudine and efavirenz; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, lamivudine, Cobicistat and eltoprevir; alternatively, the first and second electrodes may be,
a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir alafenamide complex of formula ii, lamivudine, Cobicistat and darunavir.
11. Use of the tenofovir alafenamide complex of any one of claims 1 to 4, the tenofovir alafenamide complex prepared by the preparation method of any one of claims 5 to 7, or the pharmaceutical composition of claims 8 to 10 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.
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