CN105085571A

CN105085571A - Tenofovir alafenamide compound, preparation method and purpose thereof

Info

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

Abstract

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

Description

Tynofovir Chinese mugwort draws phenol amine compound and its production and use

Technical field

The present invention relates to organic chemistry filed and pharmaceutical field, be specifically related to prevention or/and treatment virus infective medicament tynofovir Chinese mugwort draws mixture of phenol amine and preparation method thereof to prevent and/or treat virus infection with this mixture in preparation, purposes in the medicine that special hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) infect, and the pharmaceutical composition containing this mixture.

Background technology

Tynofovir Chinese mugwort draws phenol amine (Tenofoviralafenamide), and chemistry is by name: N-[(S)-[[(1R)-2-(6-amino-9H-purine-9-base)-1-methyl ethoxy] methyl] phenoxy group phosphono]-ALANINE-1-methylethyl ester; CAS accession number is: 379270-37-8; Molecular structural formula is such as formula shown in I:

Tynofovir Chinese mugwort draws phenol amine to be the ester prodrug thereof of tynofovir, is a kind of acyclic class nucleotide reverse transcriptase inhibitors, has broad-spectrum disease resistance toxic action, can suppress reversed transcriptive enzyme and the HBV polysaccharase of HIV-1, HIV-2, thus suppresses virus replication.Tynofovir is hydrolyzed to after tynofovir Chinese mugwort draws phenol amine oral, tynofovir is changed into the meta-bolites tynofovir bisphosphate with pharmacologically active by cell kinase phosphoric acid, the latter and the acid of 5'-Deoxy-ATP are competed, participate in the synthesis of viral DNA, cause owing to lacking 3'-hydroxyl DNA to extend after entering viral DNA to be obstructed, thus suppress copying of virus.Compared with similar medicine tynofovir two pyrrole furan ester (Tenofovirdisoproxil) gone on the market, tynofovir Chinese mugwort draws the antiviral activity of phenol amine to be its 10 times, stability in blood plasma is its 200 times, transformation period comparatively which raises 220 times, accumulation in peripheral blood lymphocytes (PBMC) comparatively which raises nearly 10 times, therefore tynofovir Chinese mugwort draw phenol amine to infect for hepatitis B virus (HBV) and human immunodeficiency virus (HIV/AIDS) prevention or/and treat, there is better curative effect, higher security and lower resistance.At present, tynofovir Chinese mugwort draws phenol amine single preparations of ephedrine, and tynofovir Chinese mugwort draws phenol amine/emtricitabine/Cobicistat/ dust to draw phenol amine/emtricitabine/Cobicistat/ DRV compound preparation external just in clinical studies for drawing Wei compound preparation and tynofovir Chinese mugwort.

Tynofovir Chinese mugwort draw phenol amine due to its solid-state fusing point lower, in water, solubleness is less, is unfavorable for the preparation of pharmaceutical preparation and the stripping in pharmaceutical preparation, therefore tynofovir Chinese mugwort draw phenol amine to be developed the form of salify for preparation.Such as patent documentation CN1443189A, CN1706855A etc. disclose the fumarate that tynofovir Chinese mugwort draws phenol amine, although tynofovir Chinese mugwort draw phenol amine fumarate in water-soluble, physical behavior etc. comparatively free alkali have larger improvement, its chemical stability, thermodynamic stability are not good enough.Patent documentation CN103732594A discloses the hemifumarate that tynofovir Chinese mugwort draws phenol amine, wherein show that tynofovir Chinese mugwort is drawn phenol amine hemifumarate and tynofovir to end and draws compared with phenol amine fumarate, in removal diastereomer impurity, chemical stability, thermodynamic stability, have advantage, be that tynofovir ends a kind of salt drawing phenol amine more excellent; But tynofovir Chinese mugwort draws the preparation technology of phenol amine hemifumarate more loaded down with trivial details, in preparation process, such as need to add tynofovir Chinese mugwort draw phenol amine hemifumarate crystal seed, and this crystal seed in this patent and unexposed its preparation method and being not easy to obtain.

Therefore, in order to overcome above-mentioned deficiency of the prior art, be necessary to develop the new solid forms that tynofovir Chinese mugwort draws phenol amine, the special rationality shape of phenol amine, chemical stability, process operability or preparation adaptability etc. are drawn to tynofovir Chinese mugwort can be improved further, and then strengthen the safety and effectiveness of product, for extensive patients provides better medicine to select.

Summary of the invention

The present invention's object is that providing tynofovir to end draws the new mixture of phenol amine.This mixture is better than prior art in physical behavior, chemical stability, process operability, preparation adaptability etc.

Another object of the present invention is to provide above-mentioned tynofovir to end and draw the preparation method of phenol amine compound.

Another object of the present invention is that providing package contains the pharmaceutical composition that the above-mentioned tynofovir Chinese mugwort treating significant quantity draws phenol amine compound.

Another object of the present invention is to provide above-mentioned tynofovir to end and draws phenol amine compound preparing the application prevented and/or treated in the medicine of virus infection.

According to object of the present invention, the invention provides the tynofovir Chinese mugwort shown in a kind of formula II and draw phenol amine compound,

Wherein, n=1, 2 or 3, X be selected from: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, nitric acid, carbonic acid, dodecyl sulphate, Phosphoric acid glycerol esters, methylsulfonic acid, ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, taurine, camphorsulfonic acid, cyclamic acid, thionamic acid, ethionic acid, fourth disulfonic acid, Phenylsulfonic acid, tosic acid, p-hydroxybenzenyl sulfonate, o hydroxybenzenesulfonic acid, 2,5-dihydroxy benzenes sulfonic acid, Sulphanilic Acid, asccharin, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, formic acid, acetic acid, hydroxyethanoic acid, 2,2-dichloro acetic acid, propionic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, racemic lactic acid (having another name called: DL-LACTIC ACID), pentamethylene propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, sad, n-nonanoic acid, capric acid, undecylenic acid, lauric acid, palmitinic acid, stearic acid, oleic acid, oxalic acid, propanedioic acid, succsinic acid, L MALIC ACID, D-malic acid, racemization oxysuccinic acid (having another name called: DL-oxysuccinic acid), L-TARTARIC ACID, D-tartrate, racemic tartaric acid (having another name called: DL-tartrate), mesotartaric acid, toxilic acid, hydroxymaleic acid, pentanedioic acid, 2-oxopentanedioic acid, hexanodioic acid, sebacic acid, citric acid, phenylformic acid, anisic acid, 4-acetylamino benzoic acid, Whitfield's ointment, acetylsalicylic acid, gentisinic acid, 4-ASA, toluylic acid, L-amygdalic acid, D-amygdalic acid, racemic mandelic acid (having another name called: DL-amygdalic acid), 3-phenylpropionic acid, styracin, coffic acid, benzenebutanoic acid, picric acid, nicotinic acid, vitamin B13, quinic acid, xitix, glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, lactobionic acid, dextrocamphoric acid, tetrahydroxyadipic acid (having another name called: glactaric acid), Weibull (having another name called: tannic acid), Lalgine, hydroxyl naphthoic acid (having another name called: 3-hydroxy-2-naphthoic acid), pamoic acid (having another name called: 4,4'-methylene radical two (3-hydroxy-2-naphthoic acid) or Piao's acid), amino acid or acylated amino are (as acetylgiycine, urobenzoic acid, aspartic acid, L-glutamic acid, Pyrrolidonecarboxylic acid, glutamine, asparagine etc.).

In above-mentioned formula II, " mixture " refers to that tynofovir Chinese mugwort draws phenol amine to be combined by the effect of the non covalent bond such as hydrogen bond, ionic linkage with corresponding acid and the compound that coexists, comprises salt, eutectic etc.This mixture also comprises its form such as polycrystalline, solvate, solvate polycrystalline, hydrate, hydrate polycrystalline further.

Described " salt " is well known to those skilled in the art of the present technique, refers to the compound formed by the effect of ionic linkage by positively charged ion and negatively charged ion." tynofovir Chinese mugwort draws phenol amine salt " namely refers in the solid drawing phenol amine and acid to form tynofovir Chinese mugwort, prototropy in acid has arrived tynofovir Chinese mugwort and has drawn on phenol amine, and protonated tynofovir Chinese mugwort draws phenol amine positive ion and acid radical anion to be combined with each other by ionic linkage effect.

Described " eutectic " refers to the solid that tynofovir Chinese mugwort draws phenol amine to be formed with eutectic form with acid." eutectic " (Co-Crystals) refers to a kind of polycomponent crystal with fixing stoichiometric ratio, and in this crystal, each component is with molecular level, is combined and coexist by the effect of hydrogen bond or other non covalent bonds, nonionic key.In pharmaceutical co-crystals, generally comprise active constituents of medicine and another kind of or multiple eutectic organizer (Co-crystalformer), as in " tynofovir Chinese mugwort draws phenol amine eutectic ", tynofovir Chinese mugwort draws phenol amine to be active constituents of medicine, and acid is eutectic organizer.When independent pure eutectic organizer at room temperature exists with liquid state, this eutectic is also referred to as " solvate ", be called as " hydrate " when wherein solvent is water, as tynofovir ends the eutectic drawing phenol amine and acetic acid to be formed, can be called that tynofovir Chinese mugwort draws the acetic acid solvate of phenol amine.

Above-mentioned " eutectic " also comprises like this that some have the polycomponent crystal of fixing stoichiometric ratio, between these crystal pharmaceutical active composition and other components, a part is by hydrogen bond or other non covalent bond effects, and another part is combined by ionic linkage or the reactive force between hydrogen bond and ionic linkage.

Above-mentioned " tynofovir Chinese mugwort draws phenol amine eutectic or salt " also comprises the form such as solvate, hydrate that tynofovir Chinese mugwort draws phenol amine eutectic or salt.When tynofovir Chinese mugwort draw that phenol amine eutectic prepare in certain solvent, pulp or crystallization time, this solvent likely enters into tynofovir Chinese mugwort and draws phenol amine eutectic or salt crystal, formation solvate; When this solvent is water, namely likely form hydrate.

Above-mentioned " tynofovir Chinese mugwort draws phenol amine eutectic or salt " also comprises tynofovir Chinese mugwort and draws the polycrystalline of phenol amine eutectic or salt, tynofovir Chinese mugwort to draw the polycrystalline of phenol amine eutectic or salt solvent compound, tynofovir Chinese mugwort to draw the forms such as the polycrystalline of phenol amine eutectic or salt hydrate.

Determine that the method for " eutectic " or " salt " is well known to those skilled in the art of the present technique, as with Advances in crystal X-ray diffraction analysis etc.

In above-mentioned formula II, 1/n refers to that in this composite structure, tynofovir Chinese mugwort draws the approx. molar ratio of components of phenol amine and respective acids, can pass through ¹the modes such as H-NMR, ultimate analysis, HPLC, X-ray diffraction (such as Advances in crystal X-ray diffraction) characterize.Should the scope of " be similar to " be generally ± 0.15, preferred ± 0.1.

In above-mentioned formula II, " tynofovir Chinese mugwort draws phenol amine compound " draws the stoichiometric number of phenol amine and sour X according to tynofovir Chinese mugwort in structure, can be expressed as " X tynofovir Chinese mugwort draws phenol amine (1:n) ", wherein the definition of X and n is such as formula described in II, " 1:n " is tynofovir Chinese mugwort and draws sour X and tynofovir in phenol amine compound to end to draw the approx. molar ratio of components of phenol amine, by ¹the modes such as H-NMR, ultimate analysis, HPLC, Advances in crystal X-ray diffraction obtain.

In one embodiment, in formula II, n=3, X are selected from: phosphoric acid, citric acid, Weibull (having another name called: tannic acid) or Lalgine.

In one embodiment, in formula II, n=2, X is selected from: sulfuric acid, persulfuric acid, thiocyanic acid, phosphoric acid, carbonic acid, Phosphoric acid glycerol esters, ethionic acid, fourth disulfonic acid, naphthalene-1, 5-disulfonic acid, oxalic acid, propanedioic acid, succsinic acid, L MALIC ACID, D-malic acid, racemization oxysuccinic acid (having another name called: DL-oxysuccinic acid), L-TARTARIC ACID, D-tartrate, racemic tartaric acid (having another name called: DL-tartrate), mesotartaric acid, toxilic acid, hydroxymaleic acid, pentanedioic acid, 2-oxopentanedioic acid, hexanodioic acid, sebacic acid, citric acid, dextrocamphoric acid, tetrahydroxyadipic acid (having another name called: glactaric acid), Weibull (having another name called: tannic acid), Lalgine, pamoic acid (has another name called: 4, 4'-methylene radical two (3-hydroxy-2-naphthoic acid) or Piao's acid), aspartic acid, L-glutamic acid.

In one embodiment, in formula II, n=1, X are selected from: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, nitric acid, carbonic acid, dodecyl sulphate, Phosphoric acid glycerol esters, methylsulfonic acid, ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, taurine, camphorsulfonic acid, cyclamic acid, thionamic acid, ethionic acid, fourth disulfonic acid, Phenylsulfonic acid, tosic acid, p-hydroxybenzenyl sulfonate, o hydroxybenzenesulfonic acid, 2,5-dihydroxy benzenes sulfonic acid, Sulphanilic Acid, asccharin, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, formic acid, acetic acid, hydroxyethanoic acid, 2,2-dichloro acetic acid, propionic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, racemic lactic acid (having another name called: DL-LACTIC ACID), pentamethylene propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, sad, n-nonanoic acid, capric acid, undecylenic acid, lauric acid, palmitinic acid, stearic acid, oleic acid, oxalic acid, propanedioic acid, succsinic acid, L MALIC ACID, D-malic acid, racemization oxysuccinic acid (having another name called: DL-oxysuccinic acid), L-TARTARIC ACID, D-tartrate, racemic tartaric acid (having another name called: DL-tartrate), mesotartaric acid, toxilic acid, hydroxymaleic acid, pentanedioic acid, 2-oxopentanedioic acid, hexanodioic acid, sebacic acid, citric acid, phenylformic acid, anisic acid, 4-acetylamino benzoic acid, Whitfield's ointment, acetylsalicylic acid, gentisinic acid, 4-ASA, toluylic acid, L-amygdalic acid, D-amygdalic acid, racemic mandelic acid (having another name called: DL-amygdalic acid), 3-phenylpropionic acid, styracin, coffic acid, benzenebutanoic acid, picric acid, nicotinic acid, vitamin B13, quinic acid, xitix, glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, lactobionic acid, dextrocamphoric acid, tetrahydroxyadipic acid (having another name called: glactaric acid), Weibull (having another name called: tannic acid), Lalgine, hydroxyl naphthoic acid (having another name called: 3-hydroxy-2-naphthoic acid), pamoic acid (having another name called: 4,4'-methylene radical two (3-hydroxy-2-naphthoic acid) or Piao's acid), acetylgiycine, urobenzoic acid, aspartic acid, L-glutamic acid, Pyrrolidonecarboxylic acid, glutamine, asparagine.

In one embodiment, tynofovir Chinese mugwort shown in formula II draws phenol amine compound to be selected from: L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw phenol amine (1:1).

According to object of the present invention, the invention provides the preparation method that the Chinese mugwort of tynofovir shown in formula II draws phenol amine compound, the method comprises:

(1) in suitable solvent, formed and a kind ofly comprise tynofovir Chinese mugwort and draw the solution of phenol amine and sour X;

(2) solid is separated out;

(3) solid of separating out is separated;

(4) alternatively, the solid of separation is carried out drying, or dry again after being further purified.

In aforesaid method step (1), tynofovir Chinese mugwort draws phenol amine can obtain according to method disclosed in patent documentation CN1443189A and CN1706855A or WO2013052094A etc.These documents are incorporated in the application by way of reference.Tynofovir Chinese mugwort draws phenol amine any form to exist, as comprised crystal formation, amorphous or their mixed form.

In aforesaid method step (1), described " suitable solvent " refers to and draws phenol amine and acid to have certain solubility to tynofovir Chinese mugwort, can form the solvent that tynofovir Chinese mugwort draws phenol amine compound wherein simultaneously.These suitable solvent are selected from acetonitrile, ethanol, methyl alcohol, propyl alcohol, Virahol, butanols, ethylene glycol, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, tetrahydrofuran (THF), sherwood oil, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene etc. or their mixture.Described suitable solvent and tynofovir end and draw the weight ratio of phenol amine to be generally 3:1 ~ 100:1.

In aforesaid method step (1), described " sour X " is selected from the acid representated by X in formula II.Tynofovir Chinese mugwort draws phenol amine and sour X molar ratio to be generally 4:1 ~ 0.5:1, and when preparing " X tynofovir Chinese mugwort draws phenol amine (1:3) " mixture, tynofovir Chinese mugwort draws phenol amine and sour X molar ratio to be generally 2.7:1 ~ 3.5:1; When preparing " X tynofovir Chinese mugwort draws phenol amine (1:2) " mixture, tynofovir Chinese mugwort draws phenol amine and sour X molar ratio to be generally 1.7:1 ~ 2.5:1; When preparing " X tynofovir Chinese mugwort draws phenol amine (1:1) " mixture, tynofovir Chinese mugwort draws phenol amine and sour X molar ratio to be generally 0.5:1 ~ 1.5:1.

In aforesaid method step (2), the method for described " precipitation solid " is method conventional in the art, as cooling, adds anti-solvent, concentrates out partial solvent, adds the alone of the methods such as crystal seed or coupling.

In aforesaid method step (3), described " separation " method comprises filters or centrifugal etc.Alternatively, can wash collected solid by suitable solvent.

In aforesaid method step (4), described " drying " mode comprises constant pressure and dry, drying under reduced pressure or their Combination application.The method " be further purified " comprises the forms such as recrystallization, pulp, washing.

l-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2)

In another embodiment, in formula II, n elects 2, X as and elects L-TARTARIC ACID as, namely provides tynofovir and to end the mixture drawing phenol amine and L-TARTARIC ACID to be formed with 2:1 molar composition ratio, is called " L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2) ".

In one embodiment, the invention provides the preparation method that a kind of L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine, the method comprises:

(1) phenol amine and L-TARTARIC ACID is drawn to be dissolved in suitable solvent tynofovir Chinese mugwort;

(2) solid is separated out;

(3) solid of separating out is separated;

In above-mentioned preparation method's step (1), described " suitable solvent " is selected from acetonitrile, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), acetone, methylene dichloride, trichloromethane, toluene etc. or their mixture, is preferably acetonitrile.Described suitable solvent and tynofovir end and draw the weight ratio of phenol amine to be generally 5:1 ~ 80:1.

In above-mentioned preparation method's step (1), tynofovir Chinese mugwort draws the general 1.7:1 ~ 2.5:1 of the molar ratio of phenol amine and L-TARTARIC ACID, preferred 1.9:1 ~ 2.3:1.

In above-mentioned preparation method's step (2), the method for described " precipitation solid " is method conventional in the art, as cooling, adds anti-solvent, concentrates out partial solvent body, adds the alone of the methods such as crystal seed or coupling.To separate out solid process can be standing, may also be stirring.

In above-mentioned preparation method's step (3), described " separation " can adopt the ordinary method of filtering and waiting in the art.Alternatively, by the suitable solvent in step (1), collected solid can be washed.

In above-mentioned preparation method's step (4), described " drying " mode comprises constant pressure and dry, drying under reduced pressure or their Combination application.The method " be further purified " comprises the forms such as recrystallization, pulp, washing.

d-tartrate tynofovir Chinese mugwort draws phenol amine (1:1)

In one embodiment, in formula II, n elects 1, X as and elects D-tartrate as, namely provides tynofovir and to end the mixture drawing phenol amine and D-tartrate to be formed with 1:1 molar composition ratio, is called " D-tartrate tynofovir Chinese mugwort draws phenol amine ".

In one embodiment, the invention provides the preparation method that a kind of D-tartrate tynofovir Chinese mugwort draws phenol amine, the method comprises:

(1) phenol amine and D-tartrate is drawn to be dissolved in suitable solvent tynofovir Chinese mugwort;

(2) solid is separated out;

(3) solid of separating out is separated;

In above-mentioned preparation method's step (1), described " suitable solvent " is selected from acetonitrile, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), acetone, methylene dichloride, trichloromethane, toluene etc. or their mixture, is preferably acetonitrile, Virahol or their mixture.Described suitable solvent and tynofovir end and draw the weight ratio of phenol amine to be generally 5:1 ~ 80:1.

In above-mentioned preparation method's step (1), tynofovir Chinese mugwort draws phenol amine and the general 0.5:1 ~ 1.5:1 of the tartaric molar ratio of D-, preferred 0.8:1 ~ 1.2:1.

dL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1)

In one embodiment, in formula II, n elects 1, X as and elects DL-tartrate as, namely provides tynofovir and to end the mixture drawing phenol amine and DL-tartrate to be formed with 1:1 molar composition ratio, is called " DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1) ".

In one embodiment, the invention provides the preparation method that a kind of DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), the method comprises:

(1) phenol amine and DL-tartrate is drawn to be dissolved in suitable solvent tynofovir Chinese mugwort;

(2) solid is separated out;

(3) solid of separating out is separated;

In above-mentioned preparation method's step (1), described " DL-tartrate " refers to the racemic tartaric acid that L-TARTARIC ACID and D-tartrate equal proportion form.Described " suitable solvent " is selected from acetonitrile, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), acetone, methylene dichloride, trichloromethane, toluene etc. or their mixture, is preferably acetonitrile.Described suitable solvent and tynofovir end and draw the weight ratio of phenol amine to be generally 5:1 ~ 80:1.

In above-mentioned preparation method's step (1), tynofovir Chinese mugwort draws phenol amine and the general 0.5:1 ~ 1.5:1 of the tartaric molar ratio of DL-, preferred 0.8:1 ~ 1.2:1.

l MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2)

In another embodiment, in formula II, n elects 2, X as and elects L MALIC ACID as, namely provides tynofovir and to end the mixture drawing phenol amine and L MALIC ACID to be formed with 2:1 molar composition ratio, is called " L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2) ".

In one embodiment, the invention provides the preparation method that a kind of L MALIC ACID tynofovir Chinese mugwort draws phenol amine, the method comprises:

(1) phenol amine and L MALIC ACID is drawn to be dissolved in suitable solvent tynofovir Chinese mugwort;

(2) solid is separated out;

(3) solid of separating out is separated;

In above-mentioned preparation method's step (1), described " suitable solvent " is selected from acetonitrile, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), acetone, methylene dichloride, trichloromethane toluene etc. or their mixture, is preferably Virahol.Described suitable solvent and tynofovir end and draw the weight ratio of phenol amine to be generally 5:1 ~ 80:1.

In above-mentioned preparation method's step (1), tynofovir Chinese mugwort draws the general 1.7:1 ~ 2.5:1 of the molar ratio of phenol amine and L MALIC ACID, preferred 1.9:1 ~ 2.3:1.

citric acid tynofovir Chinese mugwort draws phenol amine (1:1)

In another embodiment, in formula II, n elects 1, X as and elects citric acid as, namely provides tynofovir and to end the mixture drawing phenol amine and citric acid to be formed with 1:1 molar composition ratio, is called " citric acid tynofovir Chinese mugwort draws phenol amine (1:1) ".

In one embodiment, the invention provides the preparation method that a kind of citric acid tynofovir Chinese mugwort draws phenol amine, the method comprises:

(1) phenol amine and citric acid is drawn to be dissolved in suitable solvent tynofovir Chinese mugwort;

(2) solid is separated out;

(3) solid of separating out is separated;

In above-mentioned preparation method's step (1), tynofovir Chinese mugwort draws the general 0.5:1 ~ 1.5:1 of the molar ratio of phenol amine and citric acid, preferred 0.8:1 ~ 1.2:1.

succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1)

In another embodiment, in formula II, n elects 1, X as and elects succsinic acid as, namely provides tynofovir and to end the mixture drawing phenol amine and succsinic acid to be formed with 1:1 molar composition ratio, is called " succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1) ".

In one embodiment, the invention provides the preparation method that a kind of succsinic acid tynofovir Chinese mugwort draws phenol amine, the method comprises:

(1) phenol amine and succsinic acid is drawn to be dissolved in suitable solvent tynofovir Chinese mugwort;

(2) solid is separated out;

(3) solid of separating out is separated;

In above-mentioned preparation method's step (1), tynofovir Chinese mugwort draws the general 0.5:1 ~ 1.5:1 of the molar ratio of phenol amine and succsinic acid, preferred 0.8:1 ~ 1.2:1.

In above-mentioned preparation method's step (2), the method for described " precipitation solid " is method conventional in the art, as cooling, adds anti-solvent, concentrates out partial solvent body, adds the alone of the methods such as crystal seed or coupling.。To separate out solid process can be standing, may also be stirring.

oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1)

In another embodiment, in formula II, n elects 1, X as and elects oxalic acid as, namely provides tynofovir and to end the mixture drawing phenol amine and oxalic acid to be formed with 1:1 molar composition ratio, is called " oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1) ".

In one embodiment, the invention provides the preparation method that a kind of oxalic acid tynofovir Chinese mugwort draws phenol amine, the method comprises:

(1) draw phenol amine and dissolving oxalic acid in suitable solvent tynofovir Chinese mugwort;

(2) solid is separated out;

(3) solid of separating out is separated;

In above-mentioned preparation method's step (1), tynofovir Chinese mugwort draws the general 0.5:1 ~ 1.5:1 of the molar ratio of phenol amine and oxalic acid, preferred 0.8:1 ~ 1.2:1.

phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1)

In another embodiment, in formula II, n elects 1, X as and elects phosphoric acid as, namely provide tynofovir Chinese mugwort draw phenol amine with phosphoric acidwith the mixture that 1:1 molar composition ratio is formed, be called " phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) ".

In one embodiment, the invention provides the preparation method that a kind of phosphoric acid tynofovir Chinese mugwort draws phenol amine, the method comprises:

(1) phenol amine and phosphoric acid is drawn to be dissolved in suitable solvent tynofovir Chinese mugwort;

(2) solid is separated out;

(3) solid of separating out is separated;

In above-mentioned preparation method's step (1), tynofovir Chinese mugwort draws the general 0.5:1 ~ 1.5:1 of the molar ratio of phenol amine and phosphoric acid, preferred 0.8:1 ~ 1.2:1.

sulfuric acid tynofovir Chinese mugwort draws phenol amine (1:1)

In another embodiment, in formula II, n elects 1, X as and elects sulfuric acid as, namely provide tynofovir Chinese mugwort draw phenol amine with sulfuric acidwith the mixture that 1:1 molar composition ratio is formed, be called " sulfuric acid tynofovir Chinese mugwort draws phenol amine (1:1) ".

In one embodiment, the invention provides the preparation method that a kind of sulfuric acid tynofovir Chinese mugwort draws phenol amine, the method comprises:

(1) draw phenol amine and sulfuric acid dissolution in suitable solvent tynofovir Chinese mugwort;

(2) solid is separated out;

(3) solid of separating out is separated;

In above-mentioned preparation method's step (1), tynofovir Chinese mugwort draws the general 0.5:1 ~ 1.5:1 of the molar ratio of phenol amine and sulfuric acid, preferred 0.8:1 ~ 1.2:1.

According to object of the present invention, the invention provides comprise treatment significant quantity formula II shown in tynofovir end draw phenol amine compound or described preparation method to obtain formula II shown in tynofovir end and draw the pharmaceutical composition of phenol amine compound and pharmaceutical excipient.

Alternatively, aforementioned pharmaceutical compositions or preparation can further include another kind of or multiple antiviral agent or antiviral auxiliary reagent, include but not limited to emtricitabine, lamivudine, Abacavir (Abacavir), acemannan (Acemannan), amprenavir (Ainprenavir), amprenavir (Amprenavir), Reyataz R (Atazanavir), Clevudine (Clevudine), Cobicistat, reach a Wei Lin (Dapivirine), DRV (Darunavir), Delavirdine (Delavirdine), didanosine (Didanosine), De Luogewei (Dolutegravir), efavirenz (Efavirenz), dust is for drawing Wei (Elvitegravir), enfuirtide (Enfuvirtide), Entecavir (Entecavir), etravirine (Etravirine), Famciclovir (Famciclovir), fosamprenavir (Fosamprenavir), gsh (Glutathione), Indinavir (Indidnavir), LEVAMISOLE HCL (Levamisole), rltonavir (Lopinavir), Maraviroc (Maraviroc), viracept see nelfinaivr (Nelfinavir), nevirapine (Nevirapine), Penciclovir (Penciclovir), pentamidine (Pentamidine), Phosphazid, propagermanium (Propagermanium), Merck (Raltegravir), ribavirin (Ribavirin), rilpivirine (Rilpivrine), ritonavir (Ritonavir), Saquinavir (Saquinavir), stavudine (Stavudine), Telbivudine (Telbivudine), tipranavir (Tipranavir), Vorinostat (Vorinostat), zalcitabine (Zalcitabine), zidovudine (Zidovudine) etc. or their pharmaceutical salts, wherein preferred emtricitabine, lamivudine, Cobicistat, DRV, efavirenz, dust is for drawing Wei, hydrochloric acid rilpivirine.

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

Comprise treatment significant quantity formula II shown in tynofovir Chinese mugwort draw phenol amine compound, emtricitabine, Cobicistat and dust for the pharmaceutical composition drawing Wei; Or,

Shown in the formula II comprising treatment significant quantity, tynofovir Chinese mugwort draws the pharmaceutical composition of phenol amine compound, emtricitabine, Cobicistat and DRV; Or,

Shown in the formula II comprising treatment significant quantity, tynofovir Chinese mugwort draws the pharmaceutical composition of phenol amine compound and emtricitabine; Or,

Shown in the formula II comprising treatment significant quantity, tynofovir Chinese mugwort draws the pharmaceutical composition of phenol amine compound, emtricitabine and efavirenz; Or,

Comprise treatment significant quantity formula II shown in tynofovir Chinese mugwort draw phenol amine compound, emtricitabine and hydrochloric acid to found the pharmaceutical composition of a Wei Lin; Or,

Shown in the formula II comprising treatment significant quantity, tynofovir Chinese mugwort draws the pharmaceutical composition of phenol amine compound, lamivudine; Or,

Shown in the formula II comprising treatment significant quantity, tynofovir Chinese mugwort draws the pharmaceutical composition of phenol amine compound, lamivudine and efavirenz; Or,

Comprise treatment significant quantity formula II shown in tynofovir Chinese mugwort draw phenol amine compound, lamivudine, Cobicistat and dust for the pharmaceutical composition drawing Wei; Or,

Shown in the formula II comprising treatment significant quantity, tynofovir Chinese mugwort draws the pharmaceutical composition of phenol amine compound, lamivudine, Cobicistat and DRV.

In one embodiment, the invention provides a kind of L-TARTARIC ACID tynofovir Chinese mugwort comprising treatment significant quantity and draw phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw pharmaceutical composition or the preparation of phenol amine (1:1) and pharmaceutical excipient.

Aforementioned pharmaceutical compositions or preparation can per os or not oral administrations.During oral administration administration, conventional preparation technique can be adopted to make tablet, capsule, pill, granule, solution, syrup, suspensoid, powder, sustained release preparation or controlled release preparation etc.During non-oral administration administration, conventional preparation technique can be adopted to be made into preparation capable of permeating skin, injection liquid, infusion solution or suppository etc.

The various formulations of aforementioned pharmaceutical compositions can be prepared according to the ordinary method of pharmaceutical field.Such as the tynofovir Chinese mugwort shown in the formula II for the treatment of significant quantity is drawn phenol amine compound, L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw phenol amine (1:1), alternatively with activeconstituents that is another kind of or multiple treatment significant quantity, mix with one or more pharmaceutical excipients or contact, then required formulation is made into.

Aforementioned pharmaceutical compositions or preparation preferred oral formulation, comprise tablet, capsule, pill, granule, solution, syrup, dry suspensoid, suspensoid, powder, sustained release preparation or controlled release preparation etc.Wherein preferred tablet, capsule, granule, dry suspensoid and the solid orally ingestible such as sustained release preparation or controlled release preparation, wherein more preferably Tablet and Capsula agent.Can according to preparing any one ordinary method that solid orally ingestible adopts to prepare the preferred pharmaceutical composition of the present invention or preparation.As tablet can adopt the modes such as wet granule compression tablet to prepare, the dressing of arbitrary form can be carried out as required, as tablet can make any releasing pattern (as quick-release, enteric ease up controlled release etc.); Capsule can adopt the modes such as encapsulated dose of wet granulation to prepare, and Capsule content can make any releasing pattern (as quick releasing formulation, enteric coated preparation and sustained-release preparation etc.).

In one embodiment, tynofovir Chinese mugwort shown in formula II provided by the invention draws phenol amine compound, L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw the size distribution of phenol amine (1:1) to control to be less than 200 μm 95%, preferably be less than 180 μm, preferably be less than 150 μm again, be more preferably less than 100 μm.The pharmaceutical excipient of this area routine in oral dosage form, comprises weighting agent, disintegrating agent, tackiness agent, dispersion agent, lubricant or retention aid and all types of coating materials etc.

Described weighting agent generally comprises pregelatinized Starch, starch, lactose, dextrin, secondary calcium phosphate, calcium carbonate, N.F,USP MANNITOL, Microcrystalline Cellulose, sorbyl alcohol, glucose etc., they can be used alone also can be used in combination, wherein preferred pregelatinized Starch, lactose, Microcrystalline Cellulose, N.F,USP MANNITOL.

Described disintegrating agent generally comprises cross-linked carboxymethyl cellulose sodium, Xylo-Mucine, sodium starch glycolate, cross-linked polyvinylpyrrolidone, starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose etc., they can be used alone also can be used in combination, is wherein preferably cross-linked carboxymethyl cellulose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose.

Described tackiness agent generally comprises the ethanolic soln of Microcrystalline Cellulose, pre-paying starch, Vltra tears, hydroxypropylcellulose, polyvidone, starch slurry, gum arabic, Macrogol 4000, polyvinyl alcohol, alginate, water, various concentration, they can be used alone also can be used in combination, wherein preferred Vltra tears, hydroxypropylcellulose, polyvidone, starch slurry.

Described lubricant generally comprises Magnesium Stearate, stearic acid, calcium stearate, sodium stearyl fumarate, stearic acid Potassium fumarate, palmitinic acid, differential silica gel, stearylamide, talcum powder, solid polyethylene glycol, vanay etc.They can be used alone also can be used in combination, wherein preferred Magnesium Stearate, stearic acid, talcum powder, differential silica gel, vanay.

If needed, other auxiliary materials can also be added in above-mentioned composition or preparation, as sweeting agent (as aspartame, Steviosin etc.), tinting material (medicinal or food dye as various in lemon yellow, ferric oxide etc.), stablizer (as calcium carbonate, Calcium hydrogen carbonate, sodium bicarbonate, sodium carbonate, calcium phosphate, secondary calcium phosphate, glycine etc.), tensio-active agent (as tween 80, sodium lauryl sulphate etc.) coating material (as Opadry, Vltra tears, hydroxypropylcellulose, acrylic resin multipolymer etc.

In one embodiment, the invention provides a kind of folk prescription composition or preparation, wherein activeconstituents is selected from the Chinese mugwort of the tynofovir shown in formula II treating significant quantity and draws phenol amine compound, L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw phenol amine (1:1).Said composition or preparation preferred oral preparation, more preferably Tablet and Capsula agent; In unit composition or preparation, their weight content is generally 1mg to 200mg, preferred 5mg to 100mg, such as draw phenol amine in tynofovir Chinese mugwort, weight content is about 10mg, about 12.5mg, about 25mg or about 50mg, and wherein " about " refers to ± scope of 10%, the scope of preferably ± 5%.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the Chinese mugwort of the tynofovir shown in formula II treating significant quantity and draws phenol amine compound, L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw phenol amine (1:1), second activeconstituents is the emtricitabine for the treatment of significant quantity, 3rd activeconstituents is the Cobicistat for the treatment of significant quantity, 4th activeconstituents is that the dust for the treatment of significant quantity is for drawing Wei.Said composition or preparation preferred oral preparation, more preferably Tablet and Capsula agent; In unit composition or preparation, their respective weight contents are generally 1mg to 500mg, preferred 5mg to 300mg, such as be about 10mg or about 25mg (drawing phenol amine in tynofovir Chinese mugwort), the second activeconstituents (emtricitabine) about 200mg, the 3rd activeconstituents (Cobicistat) about 150mg and the 4th activeconstituents (dust is for drawing Wei) about 150mg containing above-mentioned first activeconstituents, wherein " about " refers to ± scope of 10%, the scope of preferably ± 5%.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the Chinese mugwort of the tynofovir shown in formula II treating significant quantity and draws phenol amine compound, L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw phenol amine (1:1), second activeconstituents is the emtricitabine for the treatment of significant quantity, 3rd activeconstituents is the Cobicistat for the treatment of significant quantity, 4th activeconstituents is the DRV for the treatment of significant quantity.Said composition or preparation preferred oral preparation, more preferably Tablet and Capsula agent; In unit composition or preparation, their respective weight contents are generally 1mg to 1000mg, preferred 5mg to 900mg, such as be about 10mg or about 25mg (drawing phenol amine in tynofovir Chinese mugwort), the second activeconstituents (emtricitabine) about 200mg, the 3rd activeconstituents (Cobicistat) about 150mg and the 4th activeconstituents (DRV) about 800mg containing above-mentioned first activeconstituents, wherein " about " refers to ± scope of 10%, the scope of preferably ± 5%.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the Chinese mugwort of the tynofovir shown in formula II treating significant quantity and draws phenol amine compound, L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw phenol amine (1:1), second activeconstituents is the emtricitabine for the treatment of significant quantity.Said composition or preparation preferred oral preparation, more preferably Tablet and Capsula agent; In unit composition or preparation, their respective weight contents are generally 1mg to 500mg, preferred 5mg to 300mg, such as be about 10mg or about 25mg (drawing phenol amine in tynofovir Chinese mugwort) and the second activeconstituents (emtricitabine) about 200mg containing above-mentioned first activeconstituents, wherein " about " refers to ± scope of 10%, the scope of preferably ± 5%.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the Chinese mugwort of the tynofovir shown in formula II treating significant quantity and draws phenol amine compound, L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw phenol amine (1:1), second activeconstituents is the emtricitabine for the treatment of significant quantity, 3rd activeconstituents is the efavirenz for the treatment of significant quantity.Said composition or preparation preferred oral preparation, more preferably Tablet and Capsula agent; In unit composition or preparation, their respective weight contents are generally 1mg to 800g, preferred 5mg to 700mg, such as be about 10mg or about 25mg (drawing phenol amine in tynofovir Chinese mugwort), the second activeconstituents (emtricitabine) about 200mg and the 3rd activeconstituents (efavirenz) about 600mg containing above-mentioned first activeconstituents, wherein " about " refers to ± scope of 10%, the scope of preferably ± 5%.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the Chinese mugwort of the tynofovir shown in formula II treating significant quantity and draws phenol amine compound, L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw phenol amine (1:1), second activeconstituents is the emtricitabine for the treatment of significant quantity, 3rd activeconstituents is the hydrochloric acid rilpivirine for the treatment of significant quantity.Said composition or preparation preferred oral preparation, more preferably Tablet and Capsula agent; In unit composition or preparation, their respective weight contents are generally 1mg to 500mg, preferred 5mg to 300mg, such as be about 10mg or about 25mg (drawing phenol amine in tynofovir Chinese mugwort), the second activeconstituents (emtricitabine) about 200mg and the 3rd activeconstituents (hydrochloric acid rilpivirine) about 25mg (in rilpivirine) containing above-mentioned first activeconstituents, " about " ± the scope of 10% is referred to, the scope of preferably ± 5%.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the Chinese mugwort of the tynofovir shown in formula II treating significant quantity and draws phenol amine compound, L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw phenol amine (1:1), second activeconstituents is the lamivudine for the treatment of significant quantity.Said composition or preparation preferred oral preparation, more preferably Tablet and Capsula agent; In unit composition or preparation, their respective weight contents are generally 1mg to 500mg, preferred 5mg to 400mg, such as be about 10mg or about 25mg (drawing phenol amine in tynofovir Chinese mugwort) and the second activeconstituents (lamivudine) about 300mg containing above-mentioned first activeconstituents, wherein " about " refers to ± scope of 10%, the scope of preferably ± 5%.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the Chinese mugwort of the tynofovir shown in formula II treating significant quantity and draws phenol amine compound, L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw phenol amine (1:1), second activeconstituents is the lamivudine for the treatment of significant quantity, 3rd activeconstituents is the efavirenz for the treatment of significant quantity.Said composition or preparation preferred oral preparation, more preferably Tablet and Capsula agent; In unit composition or preparation, their respective weight contents are generally 1mg to 800mg, preferred 5mg to 700mg, such as be about 10mg or 25mg (drawing phenol amine in tynofovir Chinese mugwort), the second activeconstituents (lamivudine) about 300mg and the 3rd activeconstituents (efavirenz) about 600mg containing above-mentioned first activeconstituents, wherein " about " refers to ± scope of 10%, the scope of preferably ± 5%.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the Chinese mugwort of the tynofovir shown in formula II treating significant quantity and draws phenol amine compound, L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw phenol amine (1:1), second activeconstituents is the lamivudine for the treatment of significant quantity, 3rd activeconstituents is the Cobicistat for the treatment of significant quantity, 4th activeconstituents is that the dust for the treatment of significant quantity is for drawing Wei.Said composition or preparation preferred oral preparation, more preferably Tablet and Capsula agent; In unit composition or preparation, their respective weight contents are generally 1mg to 500mg, preferred 5mg to 400mg, such as be about 10mg or about 25mg (drawing phenol amine in tynofovir Chinese mugwort), the second activeconstituents (lamivudine) about 300mg, the 3rd activeconstituents (Cobicistat) about 150mg and the 4th activeconstituents (dust is for drawing Wei) about 150mg containing above-mentioned first activeconstituents, wherein " about " refers to ± scope of 10%, the scope of preferably ± 5%.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the Chinese mugwort of the tynofovir shown in formula II treating significant quantity and draws phenol amine compound, L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw phenol amine (1:1), second activeconstituents is the lamivudine for the treatment of significant quantity, 3rd activeconstituents is the Cobicistat for the treatment of significant quantity, 4th activeconstituents is the DRV for the treatment of significant quantity.Said composition or preparation preferred oral preparation, more preferably Tablet and Capsula agent; In unit composition or preparation, their respective weight contents are generally 1mg to 1000mg, preferred 5mg to 900mg, such as be about 10mg or about 25mg (drawing phenol amine in tynofovir Chinese mugwort), the second activeconstituents (lamivudine) about 200mg, the 3rd activeconstituents (Cobicistat) about 150mg and the 4th activeconstituents (DRV) about 800mg containing above-mentioned first activeconstituents, wherein " about " refers to ± scope of 10%, the scope of preferably ± 5%.

Above-mentioned composition is being not only chemically stable, and has the side effect and the resistance that act synergistically and/or can reduce independent activeconstituents; The compliance of patient may be increased simultaneously.

The invention provides the method for the above-mentioned medicinal compositions of preparation or preparation.For folk prescription composition or preparation, the method is generally drawn by the tynofovir Chinese mugwort shown in the formula II for the treatment of significant quantity phenol amine compound mix with one or more pharmaceutical excipients or contact.For two compounds or preparation, the method is generally drawn by the tynofovir Chinese mugwort shown in the formula II for the treatment of significant quantity phenol amine compound, the second activeconstituents (as emtricitabine, lamivudine etc.) mix with one or more pharmaceutical excipients or contact.For three compounds or many compounds or preparation, the method is generally drawn by the tynofovir Chinese mugwort shown in the formula II for the treatment of significant quantity phenol amine compound, the second activeconstituents (as emtricitabine, lamivudine etc.) and another kind or various active composition mix with pharmaceutical excipient or contact.This pharmaceutical composition or preparation adopt mode well known in the art to be prepared.Described pharmaceutical excipient is all pharmaceutical excipients of this area routine, comprises weighting agent, disintegrating agent, tackiness agent, lubricant etc.

Described weighting agent generally comprises pregelatinized Starch, starch, lactose, N.F,USP MANNITOL, Microcrystalline Cellulose, secondary calcium phosphate, calcium carbonate etc., they can be used alone also can be used in combination, wherein preferred pregelatinized Starch, lactose, N.F,USP MANNITOL, Microcrystalline Cellulose.

Described disintegrating agent generally comprises cross-linked carboxymethyl cellulose sodium, Xylo-Mucine, sodium starch glycolate, cross-linked polyvinylpyrrolidone, starch, polyvinylpyrrolidone, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose etc., they can be used alone also can be used in combination, is wherein preferably cross-linked carboxymethyl cellulose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose, cross-linked polyvinylpyrrolidone.

Described tackiness agent generally comprises the ethanolic soln of Microcrystalline Cellulose, Vltra tears, hydroxypropylcellulose, polyvidone, starch slurry, Macrogol 4000, polyvinyl alcohol, alginate, water, various concentration, they can be used alone also can be used in combination, wherein preferred Vltra tears, hydroxypropylcellulose, polyvidone.

Described lubricant generally comprises Magnesium Stearate, stearic acid, calcium stearate, palmitinic acid, silicon-dioxide, stearylamide, talcum powder, solid polyethylene glycol etc.They can be used alone also can be used in combination, wherein preferred Magnesium Stearate, silicon-dioxide, stearic acid, talcum powder.

Aforementioned pharmaceutical compositions or preparation preferred oral formulation, comprising: tablet, capsule, pill, granule, solution, syrup, suspensoid, powder, sustained release preparation or controlled release preparation etc.The wherein solid orally ingestible such as preferred tablet, capsule, granule, drinkable suspensoid, wherein more preferably Tablet and Capsula agent.Can according to preparing any one ordinary method that solid orally ingestible adopts to prepare the preferred pharmaceutical composition of the present invention or preparation.As tablet can adopt the modes such as wet granule compression tablet to prepare, dressing can be carried out as required; Capsule can adopt the modes such as encapsulated dose of wet granulation to prepare.

According to object of the present invention, the invention provides tynofovir shown in formula II end draw phenol amine compound or described preparation method to obtain formula II shown in tynofovir Chinese mugwort draw phenol amine compound preparing the application that prevents and/or treats in the medicine of virus infection.

Particularly, the invention provides the Chinese mugwort of tynofovir shown in formula II draws phenol amine compound to prevent and/or treat the application in the medicine that hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) infect in preparation.

In one embodiment, the invention provides the tynofovir Chinese mugwort shown in formula II draws phenol amine compound to prevent and/or treat the application in the medicine that hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) infect in preparation.

In one embodiment, the invention provides the Chinese mugwort of the tynofovir shown in formula II comprising treatment significant quantity draws the pharmaceutical composition of phenol amine compound and pharmaceutical excipient to prevent and/or treat the application in the medicine that hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) infect in preparation.

In one embodiment, the invention provides that the Chinese mugwort of the tynofovir shown in formula II comprising treatment significant quantity draws phenol amine compound, the pharmaceutical composition of another kind or multiple antiviral agent or antiviral auxiliary reagent and pharmaceutical excipient prevents and/or treats application in the medicine that hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) infect in preparation.

The experiment proved that, the invention provides the tynofovir Chinese mugwort shown in formula II and draw phenol amine compound, such as L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tynofovir Chinese mugwort draws phenol amine (1:1) etc., preparation method is easy to be controlled, physical behavior, stability, solvability, preparation adaptability etc. is not less than or is better than existing tynofovir Chinese mugwort draws phenol amine fumarate and hemifumarate, there is good industrialization practicality.

Embodiment

The embodiment of form by the following examples, foregoing invention content of the present invention is described in further details, but should not be construed as summary of the invention of the present invention and be only limitted to following examples, all inventions made based on foregoing of the present invention all belong to scope of the present invention.

In following examples ¹hNMR test is using deuterated dimethyl sulfoxide as test solvent, and mark in doing with tetramethylsilane, at room temperature measures by BrukeAV-II 400MHz nuclear magnetic resonance analyser.

In following examples, melting range measures through YRT-3 type drug melting point instrument.

Embodiment 1

Tynofovir Chinese mugwort draws the preparation of phenol amine (I)

At 20 ~ 25 DEG C, by a phenyl tynofovir (by the preparation of method disclosed in CN1443189A) 500.0g (1.38mol, 1.0eq) join in toluene 3.0L, under stirring, solid is dissolved completely, then thionyl chloride 150ml (2.05mol is added, 1.5eq), stir 96 hours at gained mixed solution being heated to about 70 DEG C.40 ~ 45 DEG C of concentrating under reduced pressure are done, toluene 2.5L is added in enriched material, ALANINE isopropyl ester (can commercialization buy) 813.5g (6.21mol is dripped at-10 DEG C ~ 10 DEG C, 4.5eq) be dissolved in the solution of methylene dichloride 4.0L, then stir at-10 DEG C-10 DEG C after 30 minutes and rise to room temperature, with 10% biphosphate sodium water solution 2.5L × 2 washing, separate organic phase, with 15% potassium bicarbonate aqueous solution 1.0L × 2 washing, then with purified water 2.5L washing, the organic phase anhydrous sodium sulfate drying obtained, filters, and filtrate reduced in volume is done.At 20 ~ 25 DEG C, enriched material toluene/acetonitrile mixed solvent (volume ratio 4/1) 2.5L dissolves, add tynofovir Chinese mugwort and draw phenol amine crystal seed (by the preparation of method disclosed in CN1443189A) 50mg, then stirring 2 hours is continued, suction filtration, filter cake toluene/acetonitrile (volume ratio 4/1) washs, and then at 40 ~ 45 DEG C, drying under reduced pressure obtains tynofovir Chinese mugwort and draws phenol amine.

¹HNMR(400MHz，DMSO-d ₆)δ:8.15(s，1H)，8.11(s，1H)，7.32-7.28(t，2H)，7.21(s，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.65-5.59(m，1H)，4.90-4.81(m，1H)，4.31-4.26(m，1H)，4.18-4.13(m，1H)，3.98-3.91(m，1H)，3.90-3.81(m，2H)，3.80-3.75(m，1H)，1.16-1.14(m，9H)，1.09-1.07(d，3H)。

Embodiment 2

L-TARTARIC ACID tynofovir Chinese mugwort draws the preparation of phenol amine (1:2)

At 70 ~ 75 DEG C, draw phenol amine 4.76g (10.0mmol) and L-TARTARIC ACID 0.75g (5.0mmol) to be dissolved in acetonitrile 100ml tynofovir Chinese mugwort, dissolve stirring completely and be cooled to 15 ~ 20 DEG C, then continue stirring and crystallizing; Suction filtration, filter cake is through appropriate acetonitrile wash, and drying under reduced pressure at 40 ~ 45 DEG C, obtains L-TARTARIC ACID tynofovir Chinese mugwort and draw phenol amine (1:2).

¹HNMR(400MHz，DMSO-d ₆)δ:8.14(s，1H)，8.10(s，1H)，7.31-7.27(t，2H)，7.19(s，2H)，7.15-7.11(m，1H)，7.07-7.04(m，2H)，5.64-5.58(m，1H)，4.90-4.80(m，1H)，4.30-4.25(m，2H)，4.18-4.12(m，1H)，3.98-3.91(m，1H)，3.89-3.81(m，2H)，3.80-3.74(m，1H)，1.16-1.13(t，9H)，1.08-1.06(d，3H)。

Melting range: 158-161 DEG C.

Above-mentioned ¹in HNMR result, chemical shift is at δ 8.14 (s, 1H) He 8.10 (s, 1H) fignal center at place is attributed to tynofovir Chinese mugwort respectively and draws 2 H on phenol amine VITAMIN B4 ring, tynofovir in the fignal center at δ 4.30-4.25 (m, 2H) place and embodiment 1 ends and draws phenol amine free alkali ¹hNMR contrasts, and can judge that wherein 1 H is attributed to 2 methyne H of L-TARTARIC ACID, can judge that this sample, tynofovir Chinese mugwort draws the molar composition ratio of phenol amine and L-TARTARIC ACID to be 2:1 from the integral area ratio of two groups of fignal centers.

Embodiment 3

D-tartrate tynofovir Chinese mugwort draws the preparation of phenol amine (1:1)

At 70 ~ 75 DEG C, draw phenol amine 4.76g (10.0mmol) and D-tartrate 1.50g (10.0mmol) to be dissolved in acetonitrile 100ml tynofovir Chinese mugwort, dissolve stirring completely and be cooled to 15 ~ 20 DEG C, continue stirring and crystallizing; Suction filtration, filter cake is through appropriate acetonitrile wash, and drying under reduced pressure at 40 ~ 45 DEG C, obtains D-tartrate tynofovir Chinese mugwort and draw phenol amine (1:1).

¹HNMR(400MHz，DMSO-d ₆)δ:8.15(s，1H)，8.11(s，1H)，7.31-7.28(t，2H)，7.22(s，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.63-5.58(m，1H)，4.90-4.81(m，1H)，4.32-4.26(m，3H)，4.18-4.13(m，1H)，4.00-3.92(m，1H)，3.90-3.81(m，2H)，3.80-3.74(m，1H)，1.16-1.13(t，9H)，1.09-1.07(d，3H)。

Melting range: 135-138 DEG C.

Above-mentioned ¹in HNMR result, chemical shift is at δ 8.15 (s, 1H) He 8.11 (s, 1H) fignal center at place is attributed to tynofovir Chinese mugwort respectively and draws 2 H in phenol amine VITAMIN B4, tynofovir in the fignal center at δ 4.32-4.26 (m, 3H) place and embodiment 1 ends and draws phenol amine free alkali ¹hNMR contrasts, and can judge that wherein 2 H are attributed to tartaric 2 the methyne H of D-, can judge that this sample, tynofovir Chinese mugwort draws phenol amine and the tartaric molar composition ratio of D-to be 1:1 from the integral area ratio of two groups of fignal centers.

Embodiment 4

DL-tartrate tynofovir Chinese mugwort draws the preparation of phenol amine (1:1)

At 70 ~ 75 DEG C, draw phenol amine 4.76g (10.0mmol) and DL-tartrate 1.50g (10.0mmol) to be dissolved in acetonitrile 100ml tynofovir Chinese mugwort, dissolve stirring completely and be cooled to 15 ~ 20 DEG C, continue stirring and crystallizing; Suction filtration, filter cake is through appropriate acetonitrile wash, and drying under reduced pressure at 40 ~ 45 DEG C, obtains DL-tartrate tynofovir Chinese mugwort and draw phenol amine (1:1).

¹HNMR(400MHz，DMSO-d ₆)δ:8.14(s，1H)，8.11(s，1H)，7.31-7.27(t，2H)，7.20(s，2H)，7.15-7.11(m，1H)，7.07-7.04(m，2H)，5.63-5.58(m，1H)，4.90-4.80(m，1H)，4.31-4.26(m，3H)，4.18-4.13(m，1H)，4.00-3.91(m，1H)，3.90-3.81(m，2H)，3.80-3.74(m，1H)，1.16-1.13(t，9H)，1.08-1.07(d，3H)。

Melting range: 175-178 DEG C.

Above-mentioned ¹in HNMR result, chemical shift is at δ 8.14 (s, 1H) He 8.11 (s, 1H) fignal center at place is attributed to tynofovir Chinese mugwort respectively and draws 2 H in phenol amine VITAMIN B4, tynofovir in the fignal center at δ 4.31-4.26 (m, 3H) place and embodiment 1 ends and draws phenol amine free alkali ¹hNMR contrasts, and can judge that wherein 2 H are attributed to tartaric 2 the methyne H of DL-, can judge that this sample, tynofovir Chinese mugwort draws phenol amine and the tartaric molar composition ratio of DL-to be 1:1 from the integral area ratio of two groups of fignal centers.

Embodiment 5

L MALIC ACID tynofovir Chinese mugwort draws the preparation of phenol amine (1:2)

At 70 ~ 75 DEG C, draw phenol amine 4.76g (10.0mmol) and L MALIC ACID 0.67g (5.0mmol) to be dissolved in Virahol 50ml tynofovir Chinese mugwort, dissolve stirring completely and be cooled to 15 ~ 20 DEG C, continue stirring and crystallizing; Suction filtration, filter cake is through appropriate washed with isopropyl alcohol, and drying under reduced pressure at 40 ~ 45 DEG C, obtains L MALIC ACID tynofovir Chinese mugwort and draw phenol amine (1:2).

¹HNMR(400MHz，DMSO-d ₆)δ:8.15(s，1H)，8.11(s，1H)，7.32-7.28(m，2H)，7.22(s，2H)，7.15-7.12(t,1H),7.07-7.05(m，2H)，5.65-5.59(m，1H)，4.90-4.81(m，1H)，4.31-4.26(m，2H)，4.19-4.13(m，1H)，4.00-3.92(m，1H)，3.90-3.83(m，2H)，3.80-3.74(m，1H)，2.65-2.43(m，1H)，1.16-1.14(m，9H)，1.09-1.07(d，3H)。

Above-mentioned ¹in HNMR result, chemical shift is at δ 8.15 (s, 1H) He 8.11 (s, 1H) fignal center at place is attributed to tynofovir Chinese mugwort respectively and draws 2 H in phenol amine VITAMIN B4, δ 2.65-2.43 (m, 1H) fignal center at place is attributed to 2 H on L MALIC ACID methylene radical, can judge that this sample, tynofovir Chinese mugwort draws the molar composition ratio of phenol amine and L MALIC ACID to be 2:1 from the integral area ratio of two groups of fignal centers.

Embodiment 6

Citric acid tynofovir Chinese mugwort draws the preparation of phenol amine (1:1)

At 70 ~ 75 DEG C, draw phenol amine 4.76g (10.0mmol) and citric acid 1.92g (10.0mmol) to be dissolved in acetonitrile 100ml tynofovir Chinese mugwort, dissolve stirring completely and be cooled to 15 ~ 20 DEG C, continue stirring and crystallizing; Suction filtration, filter cake is through appropriate acetonitrile wash, and drying under reduced pressure at 40 ~ 45 DEG C, obtains citric acid tynofovir Chinese mugwort and draw phenol amine (1:1).

¹HNMR(400MHz，DMSO-d ₆)δ:8.14(s，1H)，8.11(s，1H)，7.31-7.27(m，2H)，7.22(s，2H)，7.15-7.11(m，1H)，7.07-7.04(m，2H)，5.63-5.58(m，1H)，4.90-4.80(m，1H)，4.30-4.26(m，1H)，4.18-4.13(m，1H)，4.00-3.91(m，1H)，3.89-3.81(m，2H)，3.79-3.74(m，1H)，2.78-2.74(d，2H)，2.67-2.64(d，2H)，1.16-1.13(t，9H)，1.08-1.06(d，3H)。

Melting range: 144-147 DEG C.

Above-mentioned ¹in HNMR result, chemical shift is at δ 8.14 (s, 1H) He 8.11 (s, 1H) fignal center at place is attributed to tynofovir Chinese mugwort respectively and draws 2 H in phenol amine VITAMIN B4, δ 2.78-2.74 (d, 2H) be attributed to 4 H of 2 methylene radical on citric acid with the fignal center at 2.67-2.64 (d, 2H) place, can judge that this sample, tynofovir Chinese mugwort draws the molar composition ratio of phenol amine and citric acid to be 1:1 from the integral area ratio of two groups of fignal centers.

Embodiment 7

Succsinic acid tynofovir Chinese mugwort draws the preparation of phenol amine (1:1)

At 70 ~ 75 DEG C, draw phenol amine 4.76g (10.0mmol) and succsinic acid 1.18g (10.0mmol) to be dissolved in acetonitrile 50ml tynofovir Chinese mugwort, dissolve stirring completely and be cooled to 15 ~ 20 DEG C, continue stirring and crystallizing; Suction filtration, filter cake is through appropriate acetonitrile wash, and drying under reduced pressure at 40 ~ 45 DEG C, obtains succsinic acid tynofovir Chinese mugwort and draw phenol amine (1:1).

¹HNMR(400MHz，DMSO-d ₆)δ:12.13(s，2H)，8.15(s，1H)，8.11(s，1H)，7.31-7.27(t，2H)，7.21(s，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.64-5.59(m，1H)，4.90-4.81(m，1H)，4.30-4.26(m，1H)，4.18-4.13(m，1H)，4.00-3.92(m，1H)，3.90-3.81(m，2H)，3.80-3.74(m，1H)，2.43(s，4H)，1.16-1.13(t，9H)，1.08-1.07(d，3H)。

Above-mentioned ¹in HNMR result, chemical shift is at δ 8.15 (s, 1H) He 8.11 (s, 1H) fignal center at place is attributed to tynofovir Chinese mugwort respectively and draws 2 H in phenol amine VITAMIN B4, δ 2.43 (s, 4H) fignal center at place is attributed to 4 H of 2 symmetrical methylene radical on succsinic acid, can judge that this sample, tynofovir Chinese mugwort draws the molar composition ratio of phenol amine and succsinic acid to be 1:1 from the integral area ratio of two groups of fignal centers.

Embodiment 8

Oxalic acid tynofovir Chinese mugwort draws the preparation of phenol amine (1:1)

At 70 ~ 75 DEG C, draw phenol amine 4.76g (10.0mmol) and oxalic acid dihydrate 1.26g (10.0mmol) to be dissolved in acetonitrile 100ml tynofovir Chinese mugwort, dissolve stirring completely and be cooled to 15 ~ 20 DEG C, continue stirring and crystallizing; Suction filtration, filter cake is through appropriate acetonitrile wash, and drying under reduced pressure at 40 ~ 45 DEG C, obtains oxalic acid tynofovir Chinese mugwort and draw phenol amine (1:1).

¹HNMR(400MHz，DMSO-d ₆)δ:8.19(s，1H)，8.15(s，1H)，7.49(s，2H)，7.32-7.28(m，2H)，7.15-7.12(m，1H)，7.07-7.05(m，2H)，5.64-5.58(m，1H)，4.90-4.80(m，1H)，4.32-4.28(m，1H)，4.19-4.14(m，1H)，4.00-3.91(m，1H)，3.90-3.83(m，2H)，3.80-3.75(m，1H)，1.16-1.13(m，9H)，1.09-1.08(d，3H)。

Melting range: 182-185 DEG C.

Embodiment 9

Phosphoric acid tynofovir Chinese mugwort draws the preparation of phenol amine (1:1)

At 20 ~ 25 DEG C, phenol amine 4.76g (10.0mmol) and phosphoric acid (85% aqueous solution) 1.20g (10.0mmol) is drawn to be dissolved in acetonitrile 50ml tynofovir Chinese mugwort, then stirring and crystallizing at 20 ~ 25 DEG C; Suction filtration, filter cake is through appropriate acetonitrile wash, and drying under reduced pressure at 40 ~ 45 DEG C, obtains phosphoric acid tynofovir Chinese mugwort and draw phenol amine (1:1).

¹HNMR(400MHz，DMSO-d ₆)δ:8.15(s，1H)，8.11(s，1H)，7.31-7.27(m，2H)，7.25(s，2H)，7.15-7.11(t,1H),7.07-7.05(m，2H)，5.64-5.59(m，1H)，4.90-4.80(m，1H)，4.30-4.26(m，1H)，4.18-4.13(m，1H)，3.98-3.91(m，1H)，3.90-3.83(m，2H)，3.81-3.74(m，1H)，1.16-1.13(m，9H)，1.08-1.07(d，3H)。

Melting range: 165-168 DEG C.

Embodiment 10

Sulfuric acid tynofovir Chinese mugwort draws the preparation of phenol amine (1:1)

At 20 ~ 25 DEG C, phenol amine 4.76g (10.0mmol) and 98% sulfuric acid 1.00g (10.0mmol) is drawn to be dissolved in acetonitrile 50ml tynofovir Chinese mugwort, then stirring and crystallizing at 20 ~ 25 DEG C; Suction filtration, filter cake is through appropriate acetonitrile wash, and drying under reduced pressure at 40 ~ 45 DEG C, obtains sulfuric acid tynofovir Chinese mugwort and draw phenol amine (1:1).

¹HNMR(400MHz，DMSO-d ₆)δ:9.46(brs，1H)，8.74(brs，1H)，8.48(s，1H)，8.46(s，1H)，7.34-7.30(t，2H)，7.17-7.13(t,1H),7.08-7.06(d，2H)，5.63-5.57(m，1H)，4.88-4.79(m，1H)，4.44-4.39(m，1H)，4.28-4.23(m，1H)，4.05-3.98(m，1H)，3.93-3.88(m，2H)，3.85-3.78(m，1H)，1.15-1.11(m，12H)。

Melting range: 146-149 DEG C.

Embodiment 11

L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2) thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:
L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2)	28.9

Zeparox	100.0
		Microcrystalline Cellulose	60.0
Cross-linked carboxymethyl cellulose sodium	15.0
		Magnesium Stearate	3.0
Thin film coating material:
		Opadry II	10.0

Concrete operations:

Weigh according to each supplementary material in upper table, Microcrystalline Cellulose mix with cross-linked carboxymethyl cellulose sodium, then add Zeparox and mix, then add L-TARTARIC ACID tynofovir and end and draw phenol amine (1:2) to mix; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, compressing tablet; Then coating material 75% ethanol is made into suspension dressing, obtains final product.

Embodiment 12

L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2) capsule and preparation thereof

Component	Content (mg/ sheet)
		L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2)	28.9
Zeparox	100.0
		Microcrystalline Cellulose	100.0
Sodium starch glycolate	15.0
		Magnesium Stearate	1.5

Concrete operations:

Weigh according to each supplementary material in upper table, first sodium starch glycolate mix with Microcrystalline Cellulose, then add Zeparox and mix, then add L-TARTARIC ACID tynofovir and end and draw phenol amine (1:2); Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, is packed into hypromellose cellulose capsule, obtains final product.

Embodiment 13

D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1) thin membrane coated tablet and preparation thereof

Component

Content (mg/ sheet)

Label:
		D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1)	32.9
Zeparox	100.0
		Microcrystalline Cellulose	60.0
Cross-linked carboxymethyl cellulose sodium	15.0
		Magnesium Stearate	3.0
Thin film coating material:
		Opadry II	10.0

Concrete operations:

Weigh according to each supplementary material in upper table, Microcrystalline Cellulose mix with cross-linked carboxymethyl cellulose sodium, then add Zeparox and mix, then add D-tartrate tynofovir and end and draw phenol amine (1:1) to mix; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, compressing tablet; Then coating material 75% ethanol is made into suspension dressing, obtains final product.

Embodiment 14

DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1) thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:
DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1)	32.9
		Zeparox	100.0
Microcrystalline Cellulose	60.0
		Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium Stearate	3.0
		Thin film coating material:
Opadry II	10.0

Concrete operations:

Weigh according to each supplementary material in upper table, Microcrystalline Cellulose mix with cross-linked carboxymethyl cellulose sodium, then add Zeparox and mix, then add DL-tartrate tynofovir and end and draw phenol amine (1:1) to mix; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, compressing tablet; Then coating material 75% ethanol is made into suspension dressing, obtains final product.

Embodiment 15

L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2) thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:
L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2)	28.5
		Zeparox	100.0
Microcrystalline Cellulose	60.0
		Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium Stearate	3.0
		Thin film coating material:
Opadry II	10.0

Concrete operations:

Weigh according to each supplementary material in upper table, Microcrystalline Cellulose mix with cross-linked carboxymethyl cellulose sodium, then add Zeparox and mix, then add L MALIC ACID tynofovir and end and draw phenol amine (1:2) to mix; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, compressing tablet; Then coating material 75% ethanol is made into suspension dressing, obtains final product.

Embodiment 16

Citric acid tynofovir Chinese mugwort draws phenol amine (1:1) thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:
Citric acid tynofovir Chinese mugwort draws phenol amine (1:1)	35.1
		Zeparox	100.0

Microcrystalline Cellulose	60.0
		Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium Stearate	3.0
		Thin film coating material:
Opadry II	10.0

Concrete operations:

Weigh according to each supplementary material in upper table, Microcrystalline Cellulose mix with cross-linked carboxymethyl cellulose sodium, then add Zeparox and mix, then add citric acid tynofovir and end and draw phenol amine (1:1) to mix; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, compressing tablet; Then coating material 75% ethanol is made into suspension dressing, obtains final product.

Embodiment 17

Succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1) thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:
Succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1)	31.2
		Zeparox	100.0
Microcrystalline Cellulose	60.0
		Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium Stearate	3.0
		Thin film coating material:
Opadry II	10.0

Concrete operations:

Weigh according to each supplementary material in upper table, Microcrystalline Cellulose mix with cross-linked carboxymethyl cellulose sodium, then add Zeparox and mix, then add succsinic acid tynofovir and end and draw phenol amine (1:1) to mix; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, compressing tablet; Then coating material 75% ethanol is made into suspension dressing, obtains final product.

Embodiment 18

Oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1) thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:
Oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1)	29.7
		Zeparox	100.0
Microcrystalline Cellulose	60.0
		Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium Stearate	3.0
		Thin film coating material:
Opadry II	10.0

Concrete operations:

Weigh according to each supplementary material in upper table, Microcrystalline Cellulose mix with cross-linked carboxymethyl cellulose sodium, then add Zeparox and mix, then add oxalic acid tynofovir and end and draw phenol amine (1:1) to mix; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, compressing tablet; Then coating material 75% ethanol is made into suspension dressing, obtains final product.

Embodiment 19

Phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:
Phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1)	30.1
		Zeparox	100.0
Microcrystalline Cellulose	60.0
		Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium Stearate	3.0
		Thin film coating material:

Opadry II

10.0

Concrete operations:

Weigh according to each supplementary material in upper table, Microcrystalline Cellulose mix with cross-linked carboxymethyl cellulose sodium, then add Zeparox and mix, then add phosphoric acid tynofovir and end and draw phenol amine (1:1) to mix; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, compressing tablet; Then coating material 75% ethanol is made into suspension dressing, obtains final product.

Embodiment 20

Sulfuric acid tynofovir Chinese mugwort draws phenol amine (1:1) thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:
Sulfuric acid tynofovir Chinese mugwort draws phenol amine (1:1)	30.1
		Zeparox	100.0
Microcrystalline Cellulose	60.0
		Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium Stearate	3.0
		Thin film coating material:
Opadry II	10.0

Concrete operations:

Weigh according to each supplementary material in upper table, Microcrystalline Cellulose mix with cross-linked carboxymethyl cellulose sodium, then add Zeparox and mix, then add sulfuric acid tynofovir and end and draw phenol amine (1:1) to mix; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, compressing tablet; Then coating material 75% ethanol is made into suspension dressing, obtains final product.

Embodiment 21

L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), emtricitabine, Cobicistat, dust for drawing Wei double-layer tablets and preparation thereof

Component	Content (mg/ sheet)
		Grain-I:
L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2)	11.6

Emtricitabine	200.0
		Microcrystalline Cellulose	250.0
Zeparox	150.0
		Pregelatinated shore powder	50.0
Cross-linked carboxymethyl cellulose sodium	20.0
		Magnesium Stearate	10.0
Grain-II:
		Dust is for drawing Wei	150.0
Cobicistat	150.0
		Microcrystalline Cellulose	200.0
Zeparox	200.0
		Cross-linked carboxymethyl cellulose sodium	20.0
Hydroxypropylcellulose	15.0
		Magnesium Stearate	6.0

Concrete operations:

(1), prepared by grain-I: weigh according to supplementary material each in upper table, first pregelatinated shore powder is mixed with cross-linked carboxymethyl cellulose sodium, then Zeparox and Microcrystalline Cellulose mixing is added, adding L-TARTARIC ACID tynofovir Chinese mugwort again draws phenol amine (1:2) to mix, and finally adds emtricitabine mixing; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, to obtain final product.

(2), prepared by grain-II: weigh according to supplementary material each in upper table, first hydroxypropylcellulose, cross-linked carboxymethyl cellulose sodium and 20% Zeparox are mixed, then add the mixing of residue Zeparox, then add dust for La Wei and Cobicistat mixing, finally add Microcrystalline Cellulose mixing; Use Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, to obtain final product.

(3), core grain-I and core grain-II are adopted bi-layer tablet press compressing tablet; Then coating material 75% ethanol is made into suspension dressing, obtains final product.

Embodiment 22

DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), emtricitabine, Cobicistat, DRV double-layer tablets and preparation thereof

Component	Content (mg/ sheet)
		Grain-I:
DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1)	13.1
		Emtricitabine	200.0
Microcrystalline Cellulose	200.0
		Zeparox	150.0
Pregelatinated shore powder	40.0
		Cross-linked carboxymethyl cellulose sodium	20.0
Magnesium Stearate	6.0
		Grain-II:
DRV	800.0
		Cobicistat	150.0
Microcrystalline Cellulose	100.0
		Zeparox	100.0
Cross-linked carboxymethyl cellulose sodium	40.0
		Hydroxypropylcellulose	20.0
Sulfuric acid,monododecyl ester, sodium salt	10.0
		Magnesium Stearate	10.0

Concrete operations:

(1), prepared by grain-I: weigh according to supplementary material each in upper table, first pregelatinated shore powder and cross-linked carboxymethyl cellulose sodium are mixed together, then Zeparox and Microcrystalline Cellulose mixing is added, adding DL-tartrate tynofovir Chinese mugwort again draws phenol amine (1:1) to mix, and finally adds emtricitabine mixing; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, to obtain final product.

(2), prepared by grain-II: weigh according to supplementary material each in upper table, first Sulfuric acid,monododecyl ester, sodium salt, hydroxypropylcellulose, cross-linked carboxymethyl cellulose sodium and 20% Zeparox are mixed, then the mixing of residue Zeparox is added, add DRV and Cobicistat mixing again, finally add Microcrystalline Cellulose mixing; Use Purified Water q. s wet method; Dry; Whole grain; Additional Magnesium Stearate mixing, to obtain final product.

Embodiment 23

L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), emtricitabine thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:
L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2)	28.9
		Emtricitabine	200.0
Microcrystalline Cellulose	300.0
		Zeparox	120.0
Pregelatinized Starch	40.0
		Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium Stearate	6.0
		Thin film coating material:
Opadry II	20.0

Concrete operations:

Weigh according to supplementary material each in upper table, first pregelatinized Starch is mixed with cross-linked carboxymethyl cellulose sodium, then add Zeparox mixing, then add emtricitabine mixing, finally add L-TARTARIC ACID tynofovir Chinese mugwort and draw phenol amine (1:2) and Microcrystalline Cellulose mixing; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, compressing tablet; Coating material 75% ethanol is made into suspension dressing, obtains final product.

Embodiment 24

Phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1), emtricitabine thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:
Phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1)	30.1
		Emtricitabine	200.0
Microcrystalline Cellulose	300.0
		Zeparox	120.0
Pregelatinized Starch	40.0
		Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium Stearate	6.0
		Thin film coating material:
Opadry II	20.0

Concrete operations:

Weigh according to supplementary material each in upper table, first pregelatinized Starch is mixed with cross-linked carboxymethyl cellulose sodium, then add Zeparox mixing, then add emtricitabine mixing, finally add phosphoric acid tynofovir Chinese mugwort and draw phenol amine (1:1) and Microcrystalline Cellulose mixing; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, compressing tablet; Coating material 75% ethanol is made into suspension dressing, obtains final product.

Embodiment 25

D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), emtricitabine, efavirenz film coating double-layer tablets and preparation thereof

Component	Content (mg/ sheet)
		Label:
Grain-I:
		D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1)	13.1
Emtricitabine	200.0

Microcrystalline Cellulose	200.0
		Cross-linked carboxymethyl cellulose sodium	20.0
Magnesium Stearate	7.0
		Grain-II:
Efavirenz	600.0
		Microcrystalline Cellulose	130.0
Hydroxypropylcellulose	20.0
		Cross-linked carboxymethyl cellulose sodium	20.0
Sulfuric acid,monododecyl ester, sodium salt	10.0
		Magnesium Stearate	10.0
Thin film coating material
		Opadry II	30.0

Concrete operations:

(1), prepared by grain-I: weigh according to supplementary material each in upper table, first Microcrystalline Cellulose and cross-linked carboxymethyl cellulose sodium are mixed together, then add D-tartrate tynofovir Chinese mugwort and draw phenol amine (1:1) to mix, then add emtricitabine mixing; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, to obtain final product.

(2), prepared by grain-II: weigh according to supplementary material each in upper table, first Sulfuric acid,monododecyl ester, sodium salt, cross-linked carboxymethyl cellulose sodium and hydroxypropylcellulose are mixed, then add Microcrystalline Cellulose mixing, then add efavirenz mixing; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, to obtain final product.

(3), core grain-I and core grain-II are adopted bi-layer tablet press compressing tablet; Coating material 75% ethanol is made into suspension dressing, obtains final product.

Embodiment 26

L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), emtricitabine, efavirenz film coating double-layer tablets and preparation thereof

Component	Content (mg/ sheet)
		Label:

Grain-I:
		L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2)	11.4
Emtricitabine	200.0
		Microcrystalline Cellulose	200.0
Cross-linked carboxymethyl cellulose sodium	20.0
		Magnesium Stearate	7.0
Grain-II:
		Efavirenz	600.0
Microcrystalline Cellulose	130.0
		Hydroxypropylcellulose	20.0
Cross-linked carboxymethyl cellulose sodium	20.0
		Sulfuric acid,monododecyl ester, sodium salt	10.0
Magnesium Stearate	10.0
		Thin film coating material
Opadry II	30.0

Concrete operations:

(1), prepared by grain-I: weigh according to supplementary material each in upper table, first mixed with cross-linked carboxymethyl cellulose sodium by Microcrystalline Cellulose, then add L MALIC ACID tynofovir Chinese mugwort and draw phenol amine (1:2) to mix, then add emtricitabine mixing; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, to obtain final product.

Embodiment 27

Citric acid tynofovir Chinese mugwort draws phenol amine (1:1), emtricitabine, hydrochloric acid rilpivirine film coating double-layer tablets and preparation thereof

Component	Content (mg/ sheet)
		Label:
Grain-I:
		Citric acid tynofovir Chinese mugwort draws phenol amine (1:1)	14.0
Emtricitabine	200.0
		Microcrystalline Cellulose	200.0
Zeparox	150.0
		Pregelatinated shore powder	40.0
Cross-linked carboxymethyl cellulose sodium	20.0
		Magnesium Stearate	7.0
Grain-II:
		Hydrochloric acid rilpivirine	27.5
Zeparox	200.0
		Microcrystalline Cellulose	60.0
Cross-linked carboxymethyl cellulose sodium	15.0
		PVP K30	3.0
Magnesium Stearate	3.0
		Polysorbate20	0.5
Thin film coating material
		Opadry II	25.0

Concrete operations:

(1), prepared by grain-I: weigh according to supplementary material each in upper table, first pregelatinated shore powder is mixed with cross-linked carboxymethyl cellulose sodium, then Zeparox and Microcrystalline Cellulose mixing is added, adding citric acid tynofovir Chinese mugwort again draws phenol amine (1:1) to mix, and finally adds emtricitabine mixing; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, to obtain final product.

(2), prepared by grain-II: weigh according to supplementary material each in upper table, first by Microcrystalline Cellulose and cross-linked carboxymethyl cellulose sodium mixing, then add Zeparox mixing, then add the mixing of hydrochloric acid rilpivirine; With the aqueous solution wet granulation of PVP K30 and polysorbate20; Dry; Whole grain; Additional Magnesium Stearate mixing, to obtain final product.

Embodiment 28

Succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), lamivudine thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:
Intragranular:
		Succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1)	12.5
Lamivudine	300.0
		Microcrystalline Cellulose	300.0
Cross-linked carboxymethyl cellulose sodium	15.0
		Outside grain:
Microcrystalline Cellulose	140.0
		Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium Stearate	10.0
		Thin film coating material:
Opadry II	25.0

Concrete operations:

Weigh according to each supplementary material in upper table, first cross-linked carboxymethyl cellulose sodium and Microcrystalline Cellulose are adopted equivalent method of progressively increasing to mix, then add succsinic acid tynofovir and end and draw phenol amine (1:1) to mix, then add lamivudine and mix; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional cross-linked carboxymethyl cellulose sodium and Microcrystalline Cellulose mix, then add Magnesium Stearate mixing, compressing tablet; Coating material 75% ethanol is made into suspension dressing, obtains final product.

Embodiment 29

Oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), lamivudine, efavirenz film coating double-layer tablets and preparation thereof

Component	Content (mg/ sheet)
		Label:
Grain-I:
		Oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1)	11.9
Lamivudine	300.0
		Microcrystalline Cellulose	200.0
Cross-linked carboxymethyl cellulose sodium	35.0
		Magnesium Stearate	7.0
Grain-II:
		Efavirenz	600.0
Microcrystalline Cellulose	145.0
		Hydroxypropylcellulose	20.0
Cross-linked carboxymethyl cellulose sodium	20.0
		Sulfuric acid,monododecyl ester, sodium salt	10.0
Magnesium Stearate	10.0
		Thin film coating material:
Opadry II	35.0

Concrete operations:

(1), prepared by grain-I: weigh according to supplementary material each in upper table, first mixed with cross-linked carboxymethyl cellulose sodium by Microcrystalline Cellulose, then add oxalic acid tynofovir Chinese mugwort and draw phenol amine (1:1) to mix, then add lamivudine mixing; Add Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, to obtain final product.

(2), prepared by grain-II: weigh according to supplementary material each in upper table, first hydroxypropylcellulose, Sulfuric acid,monododecyl ester, sodium salt and cross-linked carboxymethyl cellulose sodium are mixed; Then add Microcrystalline Cellulose mixing, then add efavirenz mixing; Use Purified Water q. s wet granulation; Dry; Whole grain; Additional Magnesium Stearate mixing, to obtain final product.

The above; be only the specific embodiment of the present invention; but protection scope of the present invention is not limited thereto; any those of ordinary skill in the art are in the technical scope disclosed by the present invention; the change can expected without creative work or replacement, all should be encompassed within protection scope of the present invention.Therefore, the protection domain that protection scope of the present invention should limit with claims is as the criterion.

Claims

1. the tynofovir Chinese mugwort shown in formula II draws phenol amine compound,

Ⅱ

Wherein, n=1, 2 or 3, X be selected from: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, nitric acid, carbonic acid, dodecyl sulphate, Phosphoric acid glycerol esters, methylsulfonic acid, ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, taurine, camphorsulfonic acid, cyclamic acid, thionamic acid, ethionic acid, fourth disulfonic acid, Phenylsulfonic acid, tosic acid, p-hydroxybenzenyl sulfonate, o hydroxybenzenesulfonic acid, 2,5-dihydroxy benzenes sulfonic acid, Sulphanilic Acid, asccharin, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, formic acid, acetic acid, hydroxyethanoic acid, 2,2-dichloro acetic acid, propionic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, racemic lactic acid, pentamethylene propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, sad, n-nonanoic acid, capric acid, undecylenic acid, lauric acid, palmitinic acid, stearic acid, oleic acid, oxalic acid, propanedioic acid, succsinic acid, L MALIC ACID, D-malic acid, racemization oxysuccinic acid, L-TARTARIC ACID, D-tartrate, racemic tartaric acid, mesotartaric acid, toxilic acid, hydroxymaleic acid, pentanedioic acid, 2-oxopentanedioic acid, hexanodioic acid, sebacic acid, citric acid, phenylformic acid, anisic acid, 4-acetylamino benzoic acid, Whitfield's ointment, acetylsalicylic acid, gentisinic acid, 4-ASA, toluylic acid, L-amygdalic acid, D-amygdalic acid, racemic mandelic acid, 3-phenylpropionic acid, styracin, coffic acid, benzenebutanoic acid, picric acid, nicotinic acid, vitamin B13, quinic acid, xitix, glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, lactobionic acid, dextrocamphoric acid, tetrahydroxyadipic acid, Weibull, Lalgine, hydroxyl naphthoic acid, pamoic acid, acetylgiycine, urobenzoic acid, aspartic acid, L-glutamic acid, Pyrrolidonecarboxylic acid, glutamine, asparagine.

2. tynofovir Chinese mugwort according to claim 1 draws phenol amine compound, wherein,

N=3, X are selected from: phosphoric acid, citric acid, Weibull or Lalgine; Or,

N=2, X is selected from: sulfuric acid, persulfuric acid, thiocyanic acid, phosphoric acid, carbonic acid, Phosphoric acid glycerol esters, ethionic acid, fourth disulfonic acid, naphthalene-1,5-disulfonic acid, oxalic acid, propanedioic acid, succsinic acid, L MALIC ACID, D-malic acid, racemization oxysuccinic acid, L-TARTARIC ACID, D-tartrate, racemic tartaric acid, mesotartaric acid, toxilic acid, hydroxymaleic acid, pentanedioic acid, 2-oxopentanedioic acid, hexanodioic acid, sebacic acid, citric acid, dextrocamphoric acid, tetrahydroxyadipic acid, Weibull, Lalgine, pamoic acid, aspartic acid, L-glutamic acid; Or,

N=1, X are selected from: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, nitric acid, carbonic acid, dodecyl sulphate, Phosphoric acid glycerol esters, methylsulfonic acid, ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, taurine, camphorsulfonic acid, cyclamic acid, thionamic acid, ethionic acid, fourth disulfonic acid, Phenylsulfonic acid, tosic acid, p-hydroxybenzenyl sulfonate, o hydroxybenzenesulfonic acid, 2,5-dihydroxy benzenes sulfonic acid, Sulphanilic Acid, asccharin, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, formic acid, acetic acid, hydroxyethanoic acid, 2,2-dichloro acetic acid, propionic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, racemic lactic acid, pentamethylene propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, sad, n-nonanoic acid, capric acid, undecylenic acid, lauric acid, palmitinic acid, stearic acid, oleic acid, oxalic acid, propanedioic acid, succsinic acid, L MALIC ACID, D-malic acid, racemization oxysuccinic acid (having another name called: DL-oxysuccinic acid), L-TARTARIC ACID, D-tartrate, racemic tartaric acid, mesotartaric acid, toxilic acid, hydroxymaleic acid, pentanedioic acid, 2-oxopentanedioic acid, hexanodioic acid, sebacic acid, citric acid, phenylformic acid, anisic acid, 4-acetylamino benzoic acid, Whitfield's ointment, acetylsalicylic acid, gentisinic acid, 4-ASA, toluylic acid, L-amygdalic acid, D-amygdalic acid, racemic mandelic acid, 3-phenylpropionic acid, styracin, coffic acid, benzenebutanoic acid, picric acid, nicotinic acid, vitamin B13, quinic acid, xitix, glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, lactobionic acid, dextrocamphoric acid, tetrahydroxyadipic acid, Weibull, Lalgine, hydroxyl naphthoic acid, pamoic acid, acetylgiycine, urobenzoic acid, aspartic acid, L-glutamic acid, Pyrrolidonecarboxylic acid, glutamine, asparagine.

3. tynofovir Chinese mugwort according to claim 2 draws phenol amine compound, it is selected from: L-TARTARIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), D-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), DL-tartrate tynofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tynofovir Chinese mugwort draws phenol amine (1:2), citric acid tynofovir Chinese mugwort draws phenol amine (1:1), succsinic acid tynofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tynofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tynofovir Chinese mugwort draws phenol amine (1:1) or sulfuric acid tynofovir Chinese mugwort to draw phenol amine (1:1).

4. the tynofovir Chinese mugwort described in claim 1 or 2 draws a preparation method for phenol amine compound, and the method comprises:

(2) solid is separated out;

(3) solid of separating out is separated;

5. preparation method according to claim 4, wherein in step (1), described suitable solvent is selected from acetonitrile, ethanol, methyl alcohol, propyl alcohol, Virahol, butanols, ethylene glycol, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, tetrahydrofuran (THF), sherwood oil, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene or their mixture; Described sour X is selected from the acid in formula II representated by X; Described tynofovir Chinese mugwort draws the molar ratio of phenol amine and sour X to be 4:1 ~ 0.5:1, when preparing X tynofovir Chinese mugwort and drawing phenol amine (1:3) mixture, tynofovir Chinese mugwort draws phenol amine and sour X molar ratio to be 2.7:1 ~ 3.5:1, when preparing X tynofovir Chinese mugwort and drawing phenol amine (1:2) mixture, tynofovir Chinese mugwort draws phenol amine and sour X molar ratio to be 1.7:1 ~ 2.5:1, when preparing X tynofovir Chinese mugwort and drawing phenol amine (1:1) mixture, tynofovir Chinese mugwort draws phenol amine and sour X molar ratio to be 0.5:1 ~ 1.5:1.

6. tynofovir Chinese mugwort according to claim 3 draws a preparation method for phenol amine compound, and the method comprises:

(1) phenol amine and L-TARTARIC ACID, D-tartrate, DL-tartrate, L MALIC ACID, citric acid, succsinic acid, oxalic acid, phosphoric acid or sulfuric acid is drawn to be dissolved in suitable solvent by following molar ratio tynofovir Chinese mugwort,

Tynofovir Chinese mugwort draws phenol amine: L-TARTARIC ACID is 1.7:1 ~ 2.5:1, preferred 1.9:1 ~ 2.3:1, or,

Tynofovir Chinese mugwort draws phenol amine: D-tartrate is 0.5:1 ~ 1.5:1, preferred 0.8:1 ~ 1.2:1, or,

Tynofovir Chinese mugwort draws phenol amine: DL-tartrate is 0.5:1 ~ 1.5:1, preferred 0.8:1 ~ 1.2:1, or,

Tynofovir Chinese mugwort draws phenol amine: L MALIC ACID is 1.7:1 ~ 2.5:1, preferred 1.9:1 ~ 2.3:1, or,

Tynofovir Chinese mugwort draws phenol amine: citric acid is 0.5:1 ~ 1.5:1, preferred 0.8:1 ~ 1.2:1, or,

Tynofovir Chinese mugwort draws phenol amine: succsinic acid is 0.5:1 ~ 1.5:1, preferred 0.8:1 ~ 1.2:1, or,

Tynofovir Chinese mugwort draws phenol amine: oxalic acid is 0.5:1 ~ 1.5:1, preferred 0.8:1 ~ 1.2:1, or,

Tynofovir Chinese mugwort draws phenol amine: phosphoric acid is 0.5:1 ~ 1.5:1, preferred 0.8:1 ~ 1.2:1, or,

Tynofovir Chinese mugwort draws phenol amine: sulfuric acid is 0.5:1 ~ 1.5:1, preferred 0.8:1 ~ 1.2:1, or,

(2) solid is separated out;

(3) solid of separating out is separated;

7. preparation method according to claim 6, wherein in step (1), suitable solvent is selected from acetonitrile, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), acetone, methylene dichloride, trichloromethane, toluene or their mixture, is preferably acetonitrile or Virahol.

8. a pharmaceutical composition, its Chinese mugwort of the tynofovir according to any one of claim 1 ~ 3 comprising treatment significant quantity draws the tynofovir Chinese mugwort that any one of phenol amine compound or claim 4 ~ 7, preparation method obtains to draw phenol amine compound, and pharmaceutical excipient.

9. pharmaceutical composition according to claim 8, it also comprises and another kind of or is multiplely selected from following antiviral agent or antiviral auxiliary reagent: emtricitabine, lamivudine, Abacavir, acemannan, amprenavir, amprenavir, Reyataz R, Clevudine, Cobicistat, reach a Wei Lin, DRV, Delavirdine, didanosine, De Luogewei, efavirenz, dust is for drawing Wei, enfuirtide, Entecavir, etravirine, Famciclovir, fosamprenavir, gsh, Indinavir, LEVAMISOLE HCL, rltonavir, Maraviroc, viracept see nelfinaivr, nevirapine, Penciclovir, pentamidine, Phosphazid, propagermanium, Merck, ribavirin, rilpivirine, ritonavir, Saquinavir, stavudine, Telbivudine, tipranavir, Vorinostat, zalcitabine, zidovudine or their pharmaceutical salts, preferred emtricitabine, lamivudine, Cobicistat, efavirenz, dust are for La Wei or rilpivirine or their pharmaceutical salts.

10. pharmaceutical composition according to claim 9, it is selected from:

Tynofovir according to any one of the 11. claims 1 ~ 3 tynofovir Chinese mugwort drawing the preparation method according to any one of phenol amine compound or claim 4 ~ 7 to obtain that ends draws phenol amine compound preparing the application that prevents and/or treats in the medicine of virus infection.

12. application according to claim 11, wherein said tynofovir Chinese mugwort draws phenol amine compound preparing the application prevented and/or treated in the medicine of hepatitis B virus and/or HIV (human immunodeficiency virus) infection.