CN103626803A

CN103626803A - Solid of tenofovir disoproxil, and preparation method and application thereof

Info

Publication number: CN103626803A
Application number: CN201310346710.5A
Authority: CN
Inventors: 潘旭松; 肖宁; 王勇; 向志祥; 陆崇玉; 贾晓曼; 罗杰; 郑伟
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2012-08-23
Filing date: 2013-08-09
Publication date: 2014-03-12
Anticipated expiration: 2033-08-09
Also published as: CN103626803B

Abstract

The invention relates to a solid of tenofovir disoproxil. The solid is (1) a tenofovir disoproxil compound represented by a formula IV or (2) a tenofovir disoproxil cocrystal or salt represented by a formula V. The invention further relates to a preparation method for the solid of tenofovir disoproxil, a pharmaceutical composition containing the solid and application of the solid in preparation of drugs used for preventing and/or treating virus infection, especially hepatitis b virus (HBV) and/or human immunodeficiency virus (HIV) infection.

Description

Solid of tynofovir two pyrrole furan esters and its production and use

Technical field

The present invention relates to prevention or/and solid for the treatment of virus infective medicament tynofovir two pyrrole furan esters and preparation method thereof prevents and/or treats virus infection with these solids in preparation, purposes in the medicine that special hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) infect, and the pharmaceutical composition that contains these solids.

Background technology

Tynofovir two pyrrole furan esters (Tenofovir disoproxil), chemistry is by name: 9-[2-(R)-[[two [[(isopropoxy carbonyl) oxygen base] methoxyl group] phosphono] methoxyl group] propyl group] VITAMIN B4, its molecular structural formula is suc as formula shown in I:

Tynofovir two pyrrole furan esters are ester class prodrugs of tynofovir, are a kind of acyclic class nucleotide reverse transcriptase inhibitors, have broad-spectrum disease resistance toxic action, can suppress reversed transcriptive enzyme and the HBV polysaccharase of HIV-1, HIV-2, thereby suppress virus replication.After tynofovir two pyrrole furan esters are oral, be hydrolyzed to tynofovir, tynofovir is changed into the meta-bolites tynofovir bisphosphate with pharmacologically active by cell kinase phosphoric acid, the latter and 5'-Deoxy-ATP acid competition, participate in the synthetic of viral DNA, after entering viral DNA, owing to lacking 3'-hydroxyl, cause DNA prolongation to be obstructed, thereby suppress copying of virus.Compare with similar drugs, tynofovir two pyrrole furan esters are used for the prevention of hepatitis B virus (HBV) and human immunodeficiency virus (HIV/AIDS) infection or/and treatment has higher security and lower resistance.At present, the single preparations of ephedrine of tynofovir two pyrrole furan ester fumarates (Tenofovir disoproxil fumarate) at home and abroad goes on the market.

Alone nucleoside medicine carries out antiviral prevention or/and treatment often easily causes resistance and replys not good, one of Critical policies addressing this problem is drug combination treatment, therefore, develop safer and more effective, the anti-hepatitis b of low resistance, anti-Chinese mugwort compound medicine will become following developing direction.At present, the existing multiple compound preparation that comprises tynofovir two pyrrole furan ester fumarates is in the different development phases, such as: tynofovir two pyrrole furan ester fumarate/emtricitabines (Emtricitabine), tynofovir two pyrrole furan ester fumarate/emtricitabine/efavirenzs (Efavirenz), tynofovir two pyrrole furan ester fumarate/emtricitabine/hydrochloric acid rilpivirines (Rilpivrine HCl), tynofovir two pyrrole furan ester fumarate/emtricitabine/dusts are for drawing Wei (Elvitegravir)/compound preparation Yi U.S. such as Cobicistat, European Union, Canada, the listings such as Australia, the compounds such as tynofovir two pyrrole furan ester fumarate/lamivudines (Lamivudine), tynofovir two pyrrole furan ester fumarate/lamivudine/efavirenzs are in registration or registration last stage abroad.

In above-mentioned compound, except tynofovir two pyrrole furan esters, emtricitabine or lamivudine are another important activity compositions.Lamivudine and emtricitabine are analog (replaced and be emtricitabine by fluorine on pyrimidine ring 5-position in lamivudine structure), also be efabirenz, HIV-1, HIV-2, HBV are all had to antiviral activity, and they at home and abroad all go on the market.They can prepare according to disclosed method in patent documentation CN1132073A, CN1563002A, CN1149871A, CN1563003A etc.Lamivudine and emtricitabine structural formula are shown in respectively formula II and formula III:

Tynofovir two pyrrole furan esters are because its solid-state fusing point is lower, and in water, solubleness is less, is unfavorable for the preparation of pharmaceutical preparation and the stripping in pharmaceutical preparation, so the form that tynofovir two pyrrole furan esters are developed to fumarate is for single preparations of ephedrine and compound preparation.Although tynofovir two pyrrole furan ester fumarates are water-soluble, there is larger improvement the aspects such as physical behavior compared with tynofovir two pyrrole furan esters, but tynofovir two pyrrole furan ester fumarates have complicated heteromorphism, as patent documentation CN101066980A, CN101781335A, CN101948485A, WO2007013086, WO2008140302, the multiple crystal formation (comprising amorphous) of tynofovir two pyrrole furan ester fumarates is disclosed in WO2009064174 etc., such as showing in CN101778855A, analyze some commercially available tynofovir two pyrrole furan ester fumarates, find that these products are the mixture of different crystal forms, this may cause tynofovir two pyrrole furan ester fumarates in preparation, in storage, there is crystal formation conversion, and then cause quality, drug effect is unstable.

In addition, when tynofovir two pyrrole furan ester fumarates are used for compound preparation, the impact that is subject to other activeconstituentss or auxiliary material that its chemical stability is larger, such as, in WO2006135932, tynofovir two pyrrole furan ester fumarates, emtricitabine, efavirenz and other auxiliary materials are mixed, cause the rapid degraded of tynofovir two pyrrole furan ester fumarates.

Therefore, in order to overcome above-mentioned deficiency of the prior art, be necessary to develop the new solid forms (comprising eutectic, salt or mixture) of tynofovir two pyrrole furan esters, to further improving tynofovir two pyrrole furan esters or containing the chemical stability of tynofovir two pyrrole furan ester formulations, process controllability etc., and then the safety and effectiveness of reinforcement product, for providing better medicine, extensive patients selects.

Summary of the invention

Object of the present invention is to provide the new solid of tynofovir two pyrrole furan esters.This solid is better than prior art at aspects such as physical behavior, process controllability.

Another object of the present invention is to provide the preparation method of the solid of above-mentioned tynofovir two pyrrole furan esters.

Another object of the present invention is to provide the pharmaceutical composition of the solid that comprises the above-mentioned tynofovir two pyrrole furan esters for the treatment of significant quantity.

The solid that another object of the present invention is to provide above-mentioned tynofovir two pyrrole furan esters prevents and/or treats the application in the medicine of virus infection in preparation.

According to object of the present invention, the solid of tynofovir two pyrrole furan esters provided by the invention, it is:

(1) the two pyrrole furan ester complexes of the tynofovir shown in formula IV,

Wherein, m value is 0.5～1; X is selected from: DL-tartrate, D-tartrate, L-TARTARIC ACID, DL-oxysuccinic acid or D-malic acid;

Or,

(2) two pyrrole furan ester eutectic or the salt of the tynofovir shown in formula V;

Wherein, n=1, 2 or 3, B 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 (has 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 (has another name called: DL-oxysuccinic acid), L-TARTARIC ACID, D-tartrate, racemic tartaric acid (has another name called: DL-tartrate), mesotartaric acid, fumaric 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 (has 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 (has another name called: glactaric acid), Weibull (has another name called: tannic acid), Lalgine, hydroxyl naphthoic acid (has 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 IV, " mixture " refers to that tynofovir two pyrrole furan esters and corresponding acid is combined by the effect of the non covalent bonds such as hydrogen bond, ionic linkage the compound coexisting, and comprises salt well known in the art, eutectic or their mixed form etc.This mixture also further comprises the forms such as its polycrystalline, solvate, solvate polycrystalline, hydrate, hydrate polycrystalline.

In above-mentioned formula IV, m value is 0.5～1, and as m gets 0.5,0.75 or 1, wherein m preferably 0.5 or 1, refers to mole ratio of components of tynofovir two pyrrole furan esters and respective acids in above-mentioned composite structure, can pass through ¹the modes such as H-NMR, ultimate analysis, HPLC, X-ray diffraction (such as Advances in crystal X-ray diffraction) characterize.

In one embodiment, in formula IV: m is that 1, X is DL-tartrate, be DL-tartrate tynofovir two pyrrole furan esters; Or m is that 1, X is D-tartrate, be D-tartrate tynofovir two pyrrole furan esters; Or m is that 1, X is DL-oxysuccinic acid, be DL-oxysuccinic acid tynofovir two pyrrole furan esters; Or m is that 1, X is D-malic acid, be D-malic acid tynofovir two pyrrole furan esters; Or m is that 1, X is L-TARTARIC ACID, be L-TARTARIC ACID tynofovir two pyrrole furan esters.

In above-mentioned formula V, described " tynofovir two pyrrole furan ester eutectics " refer to the solid that tynofovir two pyrrole furan esters and acid form with eutectic form." eutectic " (Co-Crystals) refers to a kind of fixedly polycomponent crystal of stoichiometric ratio that has, and in this crystal, each component is with molecular level, and the effect by hydrogen bond or other non covalent bonds, nonionic key is in conjunction with coexisting.In pharmaceutical co-crystals, generally comprise active constituents of medicine and another kind of or multiple eutectic organizer (Co-crystal former), in " tynofovir two pyrrole furan ester eutectics ", tynofovir two pyrrole furan esters are active constituents of medicine, acid is eutectic organizer.When independent pure eutectic organizer at room temperature exists with liquid state, this eutectic is also referred to as " solvate ", when wherein solvent is water, be called as in " hydrate ", as the eutectic of tynofovir two pyrrole furan esters and acetic acid formation, can be called the acetic acid solvent compound of tynofovir two pyrrole furan esters.

Above-mentioned " pharmaceutical co-crystals " also comprises that some have the fixedly polycomponent crystal of stoichiometric ratio like this, between these crystal Chinese traditional medicine activeconstituentss and other components, a part is by hydrogen bond or other non covalent bond effects, another part combination by ionic linkage or the reactive force between hydrogen bond and ionic linkage.Such as, the mixture that tynofovir two pyrrole furan esters and a di-carboxylic acid form, wherein a carboxyl in this carboxylic acid is combined with tynofovir two pyrrole furan esters with ionic linkage, another carboxyl is combined with tynofovir two pyrrole furan esters with hydrogen bond, also depending on tynofovir two pyrrole furan esters and this dicarboxylic acid, has formed eutectic in this case.

In above-mentioned formula V, in " tynofovir two pyrrole furan ester salt ", the definition of " salt " is well known to those skilled in the art of the present technique, refers to the compound that the effect by ionic linkage forms by positively charged ion and negatively charged ion.In the solid that " tynofovir two pyrrole furan ester salt " refer to form in tynofovir two pyrrole furan esters and acid, prototropy in acid has arrived on tynofovir two pyrrole furan esters, and protonated tynofovir two pyrrole furan ester positive ions and acid radical anion mutually combine by ionic linkage effect.

In above-mentioned formula V, " tynofovir two pyrrole furan ester eutectic or salt " also comprise the forms such as the solvate, hydrate of tynofovir two pyrrole furan ester eutectics or salt.When tynofovir two pyrrole furan ester eutectic preparations in certain solvent, pulp or crystallization, this solvent likely enters into tynofovir two pyrrole furan ester eutectic or salt crystal, forms solvate; When this solvent is water, likely form hydrate.

The method of determining " eutectic " or " salt " is well known to those skilled in the art of the present technique, as used X-ray diffraction (such as monocrystalline or X-ray powder diffraction) analysis etc.

In above-mentioned formula V, " tynofovir two pyrrole furan ester eutectic or salt " are according to the stoichiometric number of the two pyrrole furan esters of tynofovir in structure and sour B and its solid form, general expression is " tynofovir two pyrrole furan ester B (n:1) eutectics " or " tynofovir two pyrrole furan ester B (n:1) salt ", and wherein the definition of B and n is suc as formula described in V.Be understandable that, " n:1 " is mole ratio of components of tynofovir two pyrrole furan esters and sour B in tynofovir two pyrrole furan ester eutectics or salt, can pass through ¹the modes such as H-NMR, ultimate analysis, HPLC, X-ray diffraction (such as monocrystalline or X-ray powder diffraction) obtain.

In one embodiment, in formula V, n=3, tannic acid) or Lalgine B is selected from: phosphoric acid, citric acid, Weibull (have another name called:.In the present embodiment, " tynofovir two pyrrole furan ester eutectics " are preferably tynofovir two pyrrole furan ester phosphoric acid (3:1) eutectics, tynofovir two pyrrole furan ester citric acid (3:1) eutectics.

In one embodiment, in formula V, n=2, B 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 (has another name called: DL-oxysuccinic acid), L-TARTARIC ACID, D-tartrate, racemic tartaric acid (has another name called: DL-tartrate), mesotartaric acid, fumaric acid, toxilic acid, hydroxymaleic acid, pentanedioic acid, 2-oxopentanedioic acid, hexanodioic acid, sebacic acid, citric acid, dextrocamphoric acid, tetrahydroxyadipic acid (has another name called: glactaric acid), Weibull (has 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 the present embodiment, " tynofovir two pyrrole furan ester eutectics " are preferably tynofovir two pyrrole furan ester phosphoric acid (2:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (2:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (2:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (2:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (2:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (2:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (2:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (2:1) eutectics, tynofovir two pyrrole furan ester (2:1) citric acid eutectics, tynofovir two pyrrole furan ester pamoic acid (2:1) eutectics.In the present embodiment, " tynofovir two pyrrole furan ester salt " are preferably tynofovir two pyrrole furan ester sulfuric acid (2:1) salt, tynofovir two pyrrole furan ester ethionic acid (2:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (2:1) salt, tynofovir two pyrrole furan ester naphthalene-1,5-disulfonic acid (2:1) salt.

In one embodiment, in formula V, n=1, B is 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 (has 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 (has another name called: DL-oxysuccinic acid), L-TARTARIC ACID, D-tartrate, racemic tartaric acid (has another name called: DL-tartrate), mesotartaric acid, fumaric 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 (has 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 (has another name called: glactaric acid), Weibull (has another name called: tannic acid), Lalgine, hydroxyl naphthoic acid (has 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 the present embodiment, " tynofovir two pyrrole furan ester eutectics " are preferably tynofovir two pyrrole furan ester phosphoric acid (1:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (1:1) eutectics, tynofovir two pyrrole furan ester acetic acid (1:1) eutectics, tynofovir two pyrrole furan ester (1:1) propionic acid eutectics, tynofovir two pyrrole furan ester Pfansteihl (1:1) eutectics, tynofovir two pyrrole furan ester D-ALPHA-Hydroxypropionic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic lactic acid (1:1) eutectics, tynofovir two pyrrole furan ester palmitinic acid (1:1) eutectics, tynofovir two pyrrole furan ester stearic acid (1:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (1:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (1:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (1:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (1:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (1:1) eutectics, tynofovir two pyrrole furan ester citric acid (1:1) eutectics, tynofovir two pyrrole furan ester phenylformic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester D-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic mandelic acid (1:1) eutectics, tynofovir two pyrrole furan ester nicotinic acid (1:1) eutectics, tynofovir two pyrrole furan ester hydroxyl naphthoic acid (1:1) eutectics, tynofovir two pyrrole furan ester pamoic acid (1:1) eutectics, tynofovir two pyrrole furan ester urobenzoic acid (1:1) eutectics.In the present embodiment, " tynofovir two pyrrole furan ester salt " are preferably tynofovir two pyrrole furan ester hydrochloride (1:1) salt, tynofovir two pyrrole furan ester sulfuric acid (1:1) salt, tynofovir two pyrrole furan ester thiocyanic acid (1:1) salt, tynofovir two pyrrole furan ester Hydrogen bromide (1:1) salt, tynofovir two pyrrole furan ester nitric acid (1:1) salt, tynofovir two pyrrole furan ester methylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester taurine (1:1) salt, tynofovir two pyrrole furan ester ethionic acid (1:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (1:1) salt, tynofovir two pyrrole furan ester Phenylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester tosic acid (1:1) salt, tynofovir two pyrrole furan esters 2, 5-dihydroxy benzenes sulfonic acid (1:1) salt, tynofovir two pyrrole furan ester naphthalene-2-sulfonic acid (1:1) salt.

According to object of the present invention, the invention provides the preparation method of the solid of described tynofovir two pyrrole furan esters, described preparation method is selected from following methods:

Method one: the preparation method of the two pyrrole furan ester complexes of tynofovir shown in formula IV, the method comprises:

(1) tynofovir two pyrrole furan esters and DL-tartrate, D-tartrate, L-TARTARIC ACID, DL-oxysuccinic acid or D-malic acid are dissolved in solvent;

(2) separate out solid;

(3) separated solid of separating out;

(4) alternatively, separated solid is dried, or dry again after separated solid is further purified;

Or,

Method two: the preparation method of the two pyrrole furan ester eutectics of tynofovir shown in formula V or salt, the method comprises:

(1), in solvent, form a kind of tynofovir two pyrrole furan esters and sour solution of comprising;

(2) crystallization;

(3) separated solid of separating out;

(4) alternatively, separated solid is dried, or dry again after separated solid is further purified.

In above-mentioned preparation method's one step (1), described tynofovir two pyrrole furan esters can make according to disclosed method in patent documentation CN1264387A, WO2008007392, CN101574356A etc.These documents mode is by reference incorporated in the application.Described tynofovir two pyrrole furan esters can be any form exist, as comprise crystal formation, amorphous or their mixed form." DL-tartrate " refers to the racemic tartaric acid that L-TARTARIC ACID and D-tartrate equal proportion form; " DL-oxysuccinic acid " refers to the racemize oxysuccinic acid that L MALIC ACID and D-malic acid equal proportion form.

In the step of aforesaid method one (1), described " solvent " refers to has certain solubility to tynofovir two pyrrole furan esters and acid, can form therein the solvent of above-mentioned tynofovir two pyrrole furan ester complexes simultaneously.These solvents are selected from methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), acetonitrile, methylene dichloride, trichloromethane, acetone, N,N-DIMETHYLACETAMIDE, dimethyl formamide, methyl-sulphoxide etc. or their mixture.The weight ratio of described solvent and tynofovir two pyrrole furan esters is generally 3:1～100:1.

In the step of aforesaid method one (1), the molar ratio of tynofovir two pyrrole furan esters and DL-tartrate, D-tartrate, L-TARTARIC ACID, DL-oxysuccinic acid or D-malic acid is generally 0.5:1～2:1.

In the step of aforesaid method one (2), the method for described " separating out solid ", for conventional in the art method, as cooling, adds anti-solvent, concentrates out partial solvent, adds the alone or coupling of the methods such as crystal seed.Described " anti-solvent " refers to and solvent that can with dissolve tynofovir two pyrrole furan esters and sour solvent miscible bad to formed tynofovir two pyrrole furan ester complexes solvabilities at normal temperatures, as normal hexane, hexanaphthene, sherwood oil, ether, ethyl acetate, normal heptane, glycol dimethyl ether, isopropyl ether, methyl tertiary butyl ether etc. or their mixture.Described anti-solvent is generally 0.2:1～5:1 with the volume ratio of dissolving tynofovir two pyrrole furan esters and sour solvent.

In the step of aforesaid method one (3), described " separation " can adopt and filter the ordinary method waiting in the art, and alternatively, the solvent in available step (1) washs separated solid.

In the step of aforesaid method one (4), described " being dried " mode comprises constant pressure and dry, drying under reduced pressure or their applied in any combination.The method " being further purified " comprises the forms such as recrystallization, pulp, washing.

In the step of aforesaid method two (1), tynofovir two pyrrole furan esters can make according to disclosed method in patent documentation CN1264387A, WO2008007392, CN101574356A etc.These documents mode is by reference incorporated in the application.Tynofovir two pyrrole furan esters can be any form exist, as comprise crystal formation, amorphous or their mixed form.

In the step of aforesaid method two (1), described " solvent " refers to has certain solubility to tynofovir two pyrrole furan esters and acid, can form therein the solvent of tynofovir two pyrrole furan ester eutectics or salt simultaneously.These solvents are selected from water, 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, acetonitrile, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene, N,N-DIMETHYLACETAMIDE, dimethyl formamide etc. or their mixture.The weight ratio of described solvent and tynofovir two pyrrole furan esters is generally 3:1～100:1.

In the step of aforesaid method two (1), described " acid " is selected from the acid of B representative in formula V.Tynofovir two pyrrole furan esters and sour molar ratio are generally 4:1～0.5:1, and when preparing tynofovir two pyrrole furan ester acid (3:1) eutectics or salt, tynofovir two pyrrole furan esters and sour molar ratio are generally 3.5:1～2.7:1; When preparing tynofovir two pyrrole furan ester acid (2:1) eutectics or salt, tynofovir two pyrrole furan esters and sour molar ratio are generally 2.5:1～1.7:1; When preparing tynofovir two pyrrole furan ester acid (1:1) eutectics or salt, tynofovir two pyrrole furan esters and sour molar ratio are generally 1.5:1～0.5:1.

In the step of aforesaid method two (2), described " crystallization " method comprises cooling crystallization, adds anti-solvent crystallization, concentrates out crystallization after partial solvent, adds crystal seed crystallization etc., and these methods can be used separately also and can be used in combination.Described " anti-solvent " refers at normal temperatures to formed tynofovir two pyrrole furan ester eutectics or salt solvability solvent bad and can be miscible with dissolving tynofovir two pyrrole furan esters and sour suitable solvent, as normal hexane, hexanaphthene, sherwood oil etc.Described anti-solvent is generally 0.2:1～5:1 with the volume ratio of dissolving tynofovir two pyrrole furan esters and sour suitable solvent.

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

In the step of aforesaid method two (4), described " being dried " mode comprises constant pressure and dry, drying under reduced pressure or their applied in any combination.The method " being further purified " comprises the forms such as recrystallization, pulp, washing.

dL-tartrate tynofovir two pyrrole furan esters

In one embodiment, in formula IV, m elects 1, X as and elects DL-tartrate as, and the mixture that provides tynofovir two pyrrole furan esters and DL-tartrate to form with 1:1 mole of ratio of components, is called " DL-tartrate tynofovir two pyrrole furan esters ".

In one embodiment, the invention provides a kind of preparation method of DL-tartrate tynofovir two pyrrole furan esters, the method comprises:

(1) tynofovir two pyrrole furan esters and DL-tartrate are dissolved in suitable solvent;

(2) separate out solid;

(3) separated solid of separating out;

(4) alternatively, separated solid is dried, or dry again after being further purified.

In above-mentioned preparation method's step (1), described " suitable solvent " is selected from methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), acetone, acetonitrile, methylene dichloride, trichloromethane, N,N-DIMETHYLACETAMIDE, dimethyl formamide, methyl-sulphoxide etc. or their mixture, is preferably methyl alcohol, ethanol, Virahol or their mixture.The weight ratio of described suitable solvent and tynofovir two pyrrole furan esters is generally 7:1～80:1.

In above-mentioned preparation method's step (1), the temperature of described dissolving is generally 20 ℃ to solvent boiling point, is preferably 35～50 ℃.

In above-mentioned preparation method's step (1), tynofovir two pyrrole furan esters and the general 0.5:1～1.5:1 of the tartaric molar ratio of DL-, preferably 0.8:1～1.2:1.

In above-mentioned preparation method's step (2), the method for described " separating out solid ", for conventional in the art method, as cooling, adds anti-solvent, concentrates out partial solvent body, adds the alone or coupling of the methods such as crystal seed.Described " anti-solvent " is selected from ether, ethyl acetate, normal heptane, glycol dimethyl ether, isopropyl ether, methyl tertiary butyl ether etc. or their mixture, is preferably isopropyl ether.Described anti-solvent is generally 0.3:1～3:1 with the volume ratio of dissolving tynofovir two pyrrole furan esters and the tartaric suitable solvent of DL-.It can be standing separating out solid process, also stirs.

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

In above-mentioned preparation method's step (4), the temperature of described " being dried " is generally 20～60 ℃, is preferably 25～40 ℃; Can constant pressure and dry, also can drying under reduced pressure.The method " being further purified " comprises the forms such as recrystallization, pulp, washing.

The prepared DL-tartrate tynofovir two pyrrole furan esters of this embodiment are a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, this crystal formation being called to " DL-tartrate tynofovir two pyrrole furan ester crystal form As ") of DL-tartrate tynofovir two pyrrole furan esters.Being characterized as of the X-ray powder diffraction of this crystal formation (use Cu-K α radiation): be that the position correspondences such as 7.7 ° ± 0.2 °, 10.1 ° ± 0.2 °, 10.8 ° ± 0.2 °, 13.4 ° ± 0.2 °, 16.8 ° ± 0.2 °, 17.6 ° ± 0.2 °, 19.2 ° ± 0.2 °, 20.6 ° ± 0.2 °, 21.4 ° ± 0.2 °, 22.5 ± 0.2 ° and 23.6 ° ± 0.2 ° have characteristic diffraction peak in 2 θ values.

In one embodiment, being characterized as of the X-ray powder diffraction of DL-tartrate tynofovir two pyrrole furan ester crystal form As of the present invention (using Cu-K α radiation): be 7.7 ° ± 0.2 ° in 2 θ values, 10.1 ° ± 0.2 °, 10.8 ° ± 0.2 °, 13.4 ° ± 0.2 °, 16.3 ° ± 0.2 °, 16.8 ° ± 0.2 °, 17.6 ° ± 0.2 °, 17.9 ° ± 0.2 °, 19.2 ° ± 0.2 °, 20.6 ° ± 0.2 °, 21.4 ° ± 0.2 °, 22.5 ° ± 0.2 °, 23.6 ° ± 0.2 °, 26.1 ° ± 0.2 °, the position correspondences such as 29.1 ° ± 0.2 ° and 30.5 ° ± 0.2 ° have characteristic diffraction peak.

Further, the X-ray powder diffraction of described DL-tartrate tynofovir two pyrrole furan ester crystal form As has following characteristic diffraction peak and relative intensity thereof:

2θ(°)	Relative intensity (%)
		7.7±0.2°	9
10.1±0.2°	100
		10.8±0.2°	9
13.4±0.2°	14
		16.3±0.2°	8
16.8±0.2°	18

17.6±0.2°	16
		17.9±0.2°	5
19.2±0.2°	10
		20.6±0.2°	7
21.4±0.2°	9
		22.5±0.2°	10
23.6±0.2°	17
		26.1±0.2°	5
29.1±0.2°	7
		30.5±0.2°	7

In one embodiment, being characterized as of the X-ray powder diffraction of DL-tartrate tynofovir two pyrrole furan ester crystal form As of the present invention (using Cu-K α radiation): be 6.7 ° ± 0.2 ° in 2 θ values, 7.7 ° ± 0.2 °, 8.0 ° ± 0.2 °, 10.1 ° ± 0.2 °, 10.8 ° ± 0.2 °, 11.9 ° ± 0.2 °, 13.4 ° ± 0.2 °, 14.7 ° ± 0.2 °, 15.3 ° ± 0.2 °, 16.3 ° ± 0.2 °, 16.8 ° ± 0.2 °, 17.6 ° ± 0.2 °, 17.9 ° ± 0.2 °, 19.2 ° ± 0.2 °, 20.0 ° ± 0.2 °, 20.6 ° ± 0.2 °, 21.4 ° ± 0.2 °, 22.1 ° ± 0.2 °, 22.5 ° ± 0.2 °, 22.9 ° ± 0.2 °, 23.6 ° ± 0.2 °, 26.1 ° ± 0.2 °, 26.9 ° ± 0.2 °, 27.8 ° ± 0.2 °, 29.1 ° ± 0.2 °, 29.8 ° ± 0.2 °, 30.5 ° ± 0.2 °, the position correspondences such as 32.1 ° ± 0.2 ° and 33.9 ° ± 0.2 ° have characteristic diffraction peak.

2θ(°)	Relative intensity (%)
		6.7±0.2°	4
7.7±0.2°	9
		8.0±0.2°	3
10.1±0.2°	100

10.8±0.2°	9
		11.9±0.2°	3
13.4±0.2°	14
		14.7±0.2°	4
15.3±0.2°	3
		16.3±0.2°	8
16.8±0.2°	18
		17.6±0.2°	16
17.9±0.2°	5
		19.2±0.2°	10
20.0±0.2°	4
		20.6±0.2°	7
21.4±0.2°	9
		22.1±0.2°	4
22.5±0.2°	10
		22.9±0.2°	3
23.6±0.2°	17
		26.1±0.2°	5
26.9±0.2°	4
		27.8±0.2°	4
29.1±0.2°	7
		29.8±0.2°	3

30.5±0.2°	7
		32.1±0.2°	3
33.9±0.2°	3

In one embodiment, DL-tartrate tynofovir two pyrrole furan ester crystal form As provided by the invention have the feature of X-ray powder diffraction representative as shown in Figure 1.

In one embodiment, being characterized as of means of differential scanning calorimetry (DSC) collection of illustrative plates (temperature rise rate: 10 ℃/minute) of DL-tartrate tynofovir two pyrrole furan ester crystal form As provided by the invention: endotherm(ic)peak peak temperature at 131 ℃ within the scope of 141 ℃.

In one embodiment, DL-tartrate tynofovir two pyrrole furan ester crystal form As provided by the invention have the feature of DSC collection of illustrative plates representative as shown in Figure 6.

In one embodiment, the crystal formation purity of DL-tartrate tynofovir two pyrrole furan ester crystal form As provided by the invention (being to contain the quality percentage composition of crystal form A in DL-tartrate tynofovir two pyrrole furan esters) is generally greater than 70%, be preferably greater than 80%, be most preferably greater than 90%.This content can record by x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc.

d-tartrate tynofovir two pyrrole furan esters

In one embodiment, in formula IV, m elects 1, X as and elects D-tartrate as, and the mixture that provides tynofovir two pyrrole furan esters and D-tartrate to form with 1:1 mole of ratio of components, is called " D-tartrate tynofovir two pyrrole furan esters ".

In one embodiment, the invention provides a kind of preparation method of D-tartrate tynofovir two pyrrole furan esters, the method comprises:

(1) tynofovir two pyrrole furan esters and D-tartrate are dissolved in suitable solvent;

(2) separate out solid;

(3) separated solid of separating out;

In above-mentioned preparation method's step (1), described " suitable solvent " is selected from Virahol, tetrahydrofuran (THF), acetone etc. or their mixture, is preferably Virahol.The weight ratio of described suitable solvent and tynofovir two pyrrole furan esters is generally 10:1～30:1.

In above-mentioned preparation method's step (1), tynofovir two pyrrole furan esters and the general 0.5:1～1.5:1 of the tartaric molar ratio of D-, be preferably 0.8:1～1.2:1.

In above-mentioned preparation method's step (2), the method for described " separating out solid ", for conventional in the art method, as cooling, adds anti-solvent, concentrates out partial solvent body, adds the alone or coupling of the methods such as crystal seed.Described " anti-solvent " is selected from ether, ethyl acetate, normal heptane, glycol dimethyl ether, isopropyl ether, methyl tertiary butyl ether etc. or their mixture, is preferably isopropyl ether.Described anti-solvent is generally 0.2:1～3:1 with the volume ratio of dissolving tynofovir two pyrrole furan esters and the tartaric suitable solvent of D-.It can be standing separating out solid process, also stirs.

The prepared D-tartrate tynofovir two pyrrole furan esters of this embodiment are a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, this crystal formation being called to " D-tartrate tynofovir two pyrrole furan ester crystal form As ") of D-tartrate tynofovir two pyrrole furan esters.Being characterized as of the X-ray powder diffraction of this crystal formation (use Cu-K α radiation): be that the position correspondences such as 4.7 ° ± 0.2 °, 10.4 ° ± 0.2 °, 16.5 ° ± 0.2 °, 17.1 ° ± 0.2 °, 20.5 ° ± 0.2 °, 24.7 ° ± 0.2 ° and 28.1 ° ± 0.2 ° have characteristic diffraction peak in 2 θ values.

In one embodiment, being characterized as of the X-ray powder diffraction of D-tartrate tynofovir two pyrrole furan ester crystal form As of the present invention (use Cu-K α radiation): be that the position correspondences such as 4.7 ° ± 0.2 °, 10.4 ° ± 0.2 °, 11.8 ° ± 0.2 °, 14.4 ° ± 0.2 °, 16.5 ° ± 0.2 °, 17.1 ° ± 0.2 °, 17.7 ° ± 0.2 °, 18.9 ° ± 0.2 °, 20.5 ° ± 0.2 °, 20.9 ° ± 0.2 °, 21.7 ° ± 0.2 °, 24.7 ° ± 0.2 ° and 28.1 ° ± 0.2 ° have characteristic diffraction peak in 2 θ values.

Further, the X-ray powder diffraction of described D-tartrate tynofovir two pyrrole furan ester crystal form As has following characteristic diffraction peak and relative intensity thereof:

2θ(°)	Relative intensity (%)
		4.7±0.2°	100
10.4±0.2°	7
		11.8±0.2°	5

14.4±0.2°	5
		16.5±0.2°	24
17.1±0.2°	12
		17.7±0.2°	8
18.9±0.2°	6
		20.5±0.2°	39
20.9±0.2°	9
		21.7±0.2°	7
24.7±0.2°	17
		28.1±0.2°	7

In one embodiment, being characterized as of the X-ray powder diffraction of D-tartrate tynofovir two pyrrole furan ester crystal form As of the present invention (using Cu-K α radiation): be 4.7 ° ± 0.2 ° in 2 θ values, 10.4 ° ± 0.2 °, 11.0 ° ± 0.2 °, 11.8 ° ± 0.2 °, 13.3 ° ± 0.2 °, 14.4 ° ± 0.2 °, 14.6 ° ± 0.2 °, 15.3 ° ± 0.2 °, 16.5 ° ± 0.2 °, 17.1 ° ± 0.2 °, 17.7 ° ± 0.2 °, 18.9 ° ± 0.2 °, 20.5 ° ± 0.2 °, 20.9 ° ± 0.2 °, 21.7 ° ± 0.2 °, 24.7 ° ± 0.2 °, 28.1 ° ± 0.2 °, the position correspondences such as 29.1 ° ± 0.2 ° and 33.5 ° ± 0.2 ° have characteristic diffraction peak.

2θ(°)	Relative intensity (%)
		4.7±0.2°	100
10.4±0.2°	7
		11.0±0.2°	3
11.8±0.2°	5
		13.3±0.2°	3

14.4±0.2°	5
		14.6±0.2°	4
15.3±0.2°	2
		16.5±0.2°	24
17.1±0.2°	12
		17.7±0.2°	8
18.9±0.2°	6
		20.5±0.2°	39
20.9±0.2°	9
		21.7±0.2°	7
24.7±0.2°	17
		28.1±0.2°	7
29.1±0.2°	2
		33.5±0.2°	2

In one embodiment, D-tartrate tynofovir two pyrrole furan ester crystal form As provided by the invention have the feature of X-ray powder diffraction representative as shown in Figure 2.

In one embodiment, the crystal formation purity of D-tartrate tynofovir two pyrrole furan ester crystal form As provided by the invention (being to contain the quality percentage composition of crystal form A in D-tartrate tynofovir two pyrrole furan esters) is generally greater than 70%, be preferably greater than 80%, be most preferably greater than 90%.This content can record by x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc.

dL-oxysuccinic acid tynofovir two pyrrole furan esters

In one embodiment, in formula IV, m elects 1, X as and elects DL-oxysuccinic acid as, and the mixture that provides tynofovir two pyrrole furan esters and DL-oxysuccinic acid to form with 1:1 mole of ratio of components, is called " DL-oxysuccinic acid tynofovir two pyrrole furan esters ".

In one embodiment, the invention provides a kind of preparation method of DL-oxysuccinic acid tynofovir two pyrrole furan esters, the method comprises:

(1) tynofovir two pyrrole furan esters and DL-oxysuccinic acid are dissolved in suitable solvent;

(2) separate out solid;

(3) separated solid of separating out;

In above-mentioned preparation method's step (1), described " suitable solvent " is selected from Virahol, tetrahydrofuran (THF), acetone, acetonitrile etc. or their mixture, is preferably Virahol.The weight ratio of described suitable solvent and tynofovir two pyrrole furan esters is generally 3:1～10:1.

In above-mentioned preparation method's step (1), the temperature of described dissolving is generally 20 ℃ to solvent boiling point, preferably 35～50 ℃.

In above-mentioned preparation method's step (1), the general 0.5:1～1.5:1 of molar ratio of tynofovir two pyrrole furan esters and DL-oxysuccinic acid, preferably 0.8:1～1.2:1.

In above-mentioned preparation method's step (2), the method for described " separating out solid ", for conventional in the art method, as cooling, adds anti-solvent, concentrates out partial solvent body, adds the alone or coupling of the methods such as crystal seed.Described " anti-solvent " is selected from ether, ethyl acetate, normal heptane, glycol dimethyl ether, isopropyl ether, methyl tertiary butyl ether etc. or their mixture, is preferably isopropyl ether, methyl tertiary butyl ether etc. or their mixture.Described anti-solvent is generally 0.5:1～5:1 with the volume ratio of dissolving the suitable solvent of tynofovir two pyrrole furan esters and DL-oxysuccinic acid.It can be standing separating out solid process, also stirs.

The prepared DL-oxysuccinic acid tynofovir two pyrrole furan esters of this embodiment are a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, this crystal formation being called to " DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As ") of DL-oxysuccinic acid tynofovir two pyrrole furan esters.Being characterized as of the X-ray powder diffraction of this crystal formation (use Cu-K α radiation): be that the position correspondences such as 5.0 ° ± 0.2 °, 8.1 ° ± 0.2 °, 10.1 ° ± 0.2 °, 13.1 ° ± 0.2 °, 13.8 ° ± 0.2 °, 17.2 ° ± 0.2 °, 19.4 ° ± 0.2 °, 20.1 ° ± 0.2 ° and 25.2 ° ± 0.2 ° have characteristic diffraction peak in 2 θ values.

In one embodiment, being characterized as of the X-ray powder diffraction of DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As of the present invention (using Cu-K α radiation): be 5.0 ° ± 0.2 ° in 2 θ values, 5.9 ° ± 0.2 °, 7.4 ° ± 0.2 °, 8.1 ° ± 0.2 °, 9.1 ° ± 0.2 °, 10.1 ° ± 0.2 °, 10.8 ° ± 0.2 °, 11.6 ° ± 0.2 °, 12.6 ° ± 0.2 °, 13.1 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.5 ° ± 0.2 °, 14.8 ° ± 0.2 °, 16.1 ° ± 0.2 °, 17.2 ° ± 0.2 °, 18.4 ° ± 0.2 °, 19.4 ° ± 0.2 °, 20.1 ° ± 0.2 °, 21.3 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.9 ° ± 0.2 °, 23.4 ° ± 0.2 °, 24.4 ° ± 0.2 °, 25.2 ° ± 0.2 °, 26.2 ° ± 0.2 °, the position correspondences such as 27.7 ° ± 0.2 ° and 30.4 ° ± 0.2 ° have characteristic diffraction peak.

Further, the X-ray powder diffraction of described DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As has following characteristic diffraction peak and relative intensity thereof:

2θ(°)	Relative intensity (%)
		5.0±0.2°	100
5.9±0.2°	34
		7.4±0.2°	31
8.1±0.2°	48
		9.1±0.2°	39
10.1±0.2°	96
		10.8±0.2°	26
11.6±0.2°	28
		12.6±0.2°	24
13.1±0.2°	40
		13.8±0.2°	55
14.5±0.2°	23
		14.8±0.2°	20
16.1±0.2°	28
		17.2±0.2°	98

18.4±0.2°	33
		19.4±0.2°	48
20.1±0.2°	82
		21.3±0.2°	36
21.7±0.2°	21
		22.9±0.2°	27
23.4±0.2°	31
		24.4±0.2°	31
25.2±0.2°	86
		26.2±0.2°	14
27.7±0.2°	15
		30.4±0.2°	22

In one embodiment, DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As provided by the invention have the feature of X-ray powder diffraction representative as shown in Figure 3.

In one embodiment, being characterized as of means of differential scanning calorimetry (DSC) collection of illustrative plates (temperature rise rate: 10 ℃/minute) of DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As provided by the invention: endotherm(ic)peak peak temperature at 69 ℃ within the scope of 79 ℃.

In one embodiment, DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As provided by the invention have the feature of DSC collection of illustrative plates representative as shown in Figure 7.

In one embodiment, the crystal formation purity of DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As provided by the invention ((being to contain the quality percentage composition of crystal form A in DL-oxysuccinic acid tynofovir two pyrrole furan esters)) is generally greater than 70%, be preferably greater than 80%, be most preferably greater than 90%.This content can record by x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc.

d-malic acid tynofovir two pyrrole furan esters

In one embodiment, in formula IV, m elects 1, X as and elects D-malic acid as, and the mixture that provides tynofovir two pyrrole furan esters and D-malic acid to form with 1:1 mole of ratio of components, is called " D-malic acid tynofovir two pyrrole furan esters ".

In one embodiment, the invention provides a kind of preparation method of D-malic acid tynofovir two pyrrole furan esters, the method comprises:

(1) tynofovir two pyrrole furan esters and D-malic acid are dissolved in suitable solvent;

(2) separate out solid;

(3) separated solid of separating out;

In above-mentioned preparation method's step (1), the general 0.5:1～1.5:1 of molar ratio of tynofovir two pyrrole furan esters and D-malic acid, is preferably 0.8:1～1.2:1.

In above-mentioned preparation method's step (2), the method for described " separating out solid ", for conventional in the art method, as cooling, adds anti-solvent, concentrates out partial solvent body, adds the alone or coupling of the methods such as crystal seed.Described " anti-solvent " is selected from ether, ethyl acetate, normal heptane, glycol dimethyl ether, isopropyl ether, methyl tertiary butyl ether etc. or their mixture, is preferably isopropyl ether.Described anti-solvent is generally 0.5:1～3:1 with the volume ratio of dissolving the suitable solvent of tynofovir two pyrrole furan esters and D-malic acid.It can be standing separating out solid process, also stirs.

The prepared D-malic acid tynofovir two pyrrole furan esters of this embodiment are a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, this crystal formation being called to " D-malic acid tynofovir two pyrrole furan ester crystal form As ") of D-malic acid tynofovir two pyrrole furan esters.Being characterized as of the X-ray powder diffraction of this crystal formation (use Cu-K α radiation): be that the position correspondences such as 7.8 ° ± 0.2 °, 8.1 ° ± 0.2 °, 11.8 ° ± 0.2 °, 14.1 ° ± 0.2 °, 16.6 ° ± 0.2 °, 18.9 ° ± 0.2 °, 21.0 ° ± 0.2 °, 22.6 ° ± 0.2 ° and 24.1 ° ± 0.2 ° have characteristic diffraction peak in 2 θ values.

In one embodiment, being characterized as of the X-ray powder diffraction of D-malic acid tynofovir two pyrrole furan ester crystal form As of the present invention (using Cu-K α radiation): be 7.8 ° ± 0.2 ° in 2 θ values, 8.1 ° ± 0.2 °, 9.9 ° ± 0.2 °, 11.8 ° ± 0.2 °, 12.0 ° ± 0.2 °, 12.4 ° ± 0.2 °, 13.6 ° ± 0.2 °, 14.1 ° ± 0.2 °, 16.1 ° ± 0.2 °, 16.6 ° ± 0.2 °, 16.8 ° ± 0.2 °, 18.1 ° ± 0.2 °, 18.9 ° ± 0.2 °, 19.5 ° ± 0.2 °, 20.3 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.6 ° ± 0.2 °, 24.1 ° ± 0.2 °, the position correspondences such as 25.0 ° ± 0.2 ° and 25.5 ° ± 0.2 ° have characteristic diffraction peak.

Further, the X-ray powder diffraction of described D-malic acid tynofovir two pyrrole furan ester crystal form As has following characteristic diffraction peak and relative intensity thereof:

2θ(°)	Relative intensity (%)
		7.8±0.2°	73
8.1±0.2°	69
		9.9±0.2°	12
11.8±0.2°	69
		12.0±0.2°	41
12.4±0.2°	10
		13.6±0.2°	25
14.1±0.2°	47
		16.1±0.2°	30
16.6±0.2°	81
		16.8±0.2°	26
18.1±0.2°	15
		18.9±0.2°	47
19.5±0.2°	14

20.3±0.2°	22
		21.0±0.2°	80
21.4±0.2°	44
		21.6±0.2°	16
22.6±0.2°	100
		24.1±0.2°	66
25.0±0.2°	34
		25.5±0.2°	28

In one embodiment, being characterized as of the X-ray powder diffraction of D-malic acid tynofovir two pyrrole furan ester crystal form As of the present invention (using Cu-K α radiation): be 7.8 ° ± 0.2 ° in 2 θ values, 8.1 ° ± 0.2 °, 9.9 ° ± 0.2 °, 10.5 ° ± 0.2 °, 11.2 ° ± 0.2 °, 11.8 ° ± 0.2 °, 12.0 ° ± 0.2 °, 12.4 ° ± 0.2 °, 13.6 ° ± 0.2 °, 14.1 ° ± 0.2 °, 14.7 ° ± 0.2 °, 16.1 ° ± 0.2 °, 16.6 ° ± 0.2 °, 16.8 ° ± 0.2 °, 18.1 ° ± 0.2 °, 18.9 ° ± 0.2 °, 19.5 ° ± 0.2 °, 20.3 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.6 ° ± 0.2 °, 24.1 ° ± 0.2 °, 24.3 ° ± 0.2 °, 25.0 ° ± 0.2 °, 25.5 ° ± 0.2 °, 26.1 ° ± 0.2 °, 27.4 ° ± 0.2 °, 28.7 ° ± 0.2 °, the position correspondences such as 32.5 ° ± 0.2 ° and 33.5 ° ± 0.2 ° have characteristic diffraction peak.

2θ(°)	Relative intensity (%)
		7.8±0.2°	73
8.1±0.2°	69
		9.9±0.2°	12
10.5±0.2°	9
		11.2±0.2°	8
11.8±0.2°	69

12.0±0.2°	41
		12.4±0.2°	10
13.6±0.2°	25
		14.1±0.2°	47
14.7±0.2°	9
		16.1±0.2°	30
16.6±0.2°	81
		16.8±0.2°	26
18.1±0.2°	15
		18.9±0.2°	47
19.5±0.2°	14
		20.3±0.2°	22
21.0±0.2°	80
		21.4±0.2°	44
21.6±0.2°	16
		22.6±0.2°	100
24.1±0.2°	66
		24.3±0.2°	8
25.0±0.2°	34
		25.5±0.2°	28
26.1±0.2°	5
		27.4±0.2°	8

28.7±0.2°	7
		32.5±0.2°	8
33.5±0.2°	6

In one embodiment, D-malic acid tynofovir two pyrrole furan ester crystal form As provided by the invention have the feature of X-ray powder diffraction representative as shown in Figure 4.

In one embodiment, being characterized as of means of differential scanning calorimetry (DSC) collection of illustrative plates (temperature rise rate: 10 ℃/minute) of D-malic acid tynofovir two pyrrole furan ester crystal form As provided by the invention: endotherm(ic)peak peak temperature at 80 ℃ within the scope of 90 ℃.

In one embodiment, D-malic acid tynofovir two pyrrole furan ester crystal form As provided by the invention have the feature of DSC collection of illustrative plates representative as shown in Figure 8.

In one embodiment, the crystal formation purity of D-malic acid tynofovir two pyrrole furan ester crystal form As provided by the invention (being to contain the quality percentage composition of crystal form A in D-malic acid tynofovir two pyrrole furan esters) is generally greater than 70%, be preferably greater than 80%, be most preferably greater than 90%.This content can record by x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc.

l-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As

In one embodiment, in formula IV, m elects 1, X as and elects L-TARTARIC ACID as, and the mixture that provides tynofovir two pyrrole furan esters and L-TARTARIC ACID to form with 1:1 mole of ratio of components, is called " L-TARTARIC ACID tynofovir two pyrrole furan esters ".

The prepared L-TARTARIC ACID tynofovir two pyrrole furan esters of this embodiment are a kind of crystal.

Therefore, the invention provides a kind of crystal formation (in order to express easily, this crystal formation being called to " L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As ") of L-TARTARIC ACID tynofovir two pyrrole furan esters.Being characterized as of the X-ray powder diffraction of these L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As (use Cu-K α radiation): be that the position correspondences such as 4.0 ° ± 0.2 °, 6.9 ° ± 0.2 °, 7.5 ° ± 0.2 °, 8.4 ° ± 0.2 °, 17.1 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.7 ° ± 0.2 ° and 22.5 ° ± 0.2 ° have characteristic diffraction peak in 2 θ values.

In one embodiment, being characterized as of the X-ray powder diffraction of L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As of the present invention (using Cu-K α radiation): be 4.0 ° ± 0.2 ° in 2 θ values, 6.3 ° ± 0.2 °, 6.5 ° ± 0.2 °, 6.9 ° ± 0.2 °, 7.5 ° ± 0.2 °, 8.4 ° ± 0.2 °, 9.2 ° ± 0.2 °, 10.3 ° ± 0.2 °, 11.4 ° ± 0.2 °, 12.2 ° ± 0.2 °, 13.0 ° ± 0.2 °, 13.8 ° ± 0.2 °, 15.0 ° ± 0.2 °, 16.0 ° ± 0.2 °, 17.1 ° ± 0.2 °, 18.0 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.3 ° ± 0.2 °, 20.7 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.5 ° ± 0.2 °, 23.3 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.4 ° ± 0.2 °, 24.9 ° ± 0.2 °, 25.3 ° ± 0.2 °, 26.0 ° ± 0.2 °, the position correspondences such as 27.5 ° ± 0.2 ° and 28.2 ° ± 0.2 ° have characteristic diffraction peak.

Further, the X-ray powder diffraction of described L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As has following characteristic diffraction peak and relative intensity thereof:

2θ(°)	Relative intensity (%)
		4.0±0.2°	100
6.3±0.2°	31
		6.5±0.2°	38
6.9±0.2°	45
		7.5±0.2°	37
8.4±0.2°	64
		9.2±0.2°	27
10.3±0.2°	23
		11.4±0.2°	18
12.2±0.2°	26
		13.0±0.2°	23
13.8±0.2°	19
		15.0±0.2°	15
16.0±0.2°	28
		17.1±0.2°	68
18.0±0.2°	25
		18.7±0.2°	53
19.7±0.2°	50

20.3±0.2°	32
		20.7±0.2°	30
21.0±0.2°	32
		21.6±0.2°	16
22.5±0.2°	52
		23.3±0.2°	18
23.8±0.2°	12
		24.4±0.2°	15
24.9±0.2°	20
		25.3±0.2°	24
26.0±0.2°	18
		27.5±0.2°	12
28.2±0.2°	11

In one embodiment, being characterized as of the X-ray powder diffraction of L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As of the present invention (using Cu-K α radiation): be 4.0 ° ± 0.2 ° in 2 θ values, 6.3 ° ± 0.2 °, 6.5 ° ± 0.2 °, 6.9 ° ± 0.2 °, 7.5 ° ± 0.2 °, 8.4 ° ± 0.2 °, 9.2 ° ± 0.2 °, 10.3 ° ± 0.2 °, 11.4 ° ± 0.2 °, 12.2 ° ± 0.2 °, 13.0 ° ± 0.2 °, 13.8 ° ± 0.2 °, 15.0 ° ± 0.2 °, 16.0 ° ± 0.2 °, 17.1 ° ± 0.2 °, 18.0 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.3 ° ± 0.2 °, 20.7 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.5 ° ± 0.2 °, 23.3 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.4 ° ± 0.2 °, 24.9 ° ± 0.2 °, 25.3 ° ± 0.2 °, 26.0 ° ± 0.2 °, 27.5 ° ± 0.2 °, the position correspondences such as 28.2 ° ± 0.2 ° and 28.9 ° ± 0.2 ° have characteristic diffraction peak.

2θ(°)	Relative intensity (%)
		4.0±0.2°	100

6.3±0.2°	31
		6.5±0.2°	38
6.9±0.2°	45
		7.5±0.2°	37
8.4±0.2°	64
		9.2±0.2°	27
10.3±0.2°	23
		11.4±0.2°	18
12.2±0.2°	26
		13.0±0.2°	23
13.8±0.2°	19
		15.0±0.2°	15
16.0±0.2°	28
		17.1±0.2°	68
18.0±0.2°	25
		18.7±0.2°	53
19.7±0.2°	50
		20.3±0.2°	32
20.7±0.2°	30
		21.0±0.2°	32
21.6±0.2°	16
		22.5±0.2°	52

23.3±0.2°	18
		23.8±0.2°	12
24.4±0.2°	15
		24.9±0.2°	20
25.3±0.2°	24
		26.0±0.2°	18
27.5±0.2°	12
		28.2±0.2°	11
28.9±0.2°	7

In one embodiment, L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As provided by the invention have the feature of X-ray powder diffraction representative as shown in Figure 5.

In one embodiment, being characterized as of means of differential scanning calorimetry (DSC) collection of illustrative plates (temperature rise rate: 10 ℃/minute) of L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As provided by the invention: endotherm(ic)peak peak temperature at 114 ℃ within the scope of 124 ℃.

In one embodiment, L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As provided by the invention have the feature of DSC collection of illustrative plates representative as shown in Figure 9.

In one embodiment, the crystal formation purity of L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As provided by the invention (being to contain the quality percentage composition of crystal form A in L-TARTARIC ACID tynofovir two pyrrole furan esters) is generally greater than 70%, be preferably greater than 80%, be most preferably greater than 90%.This content can record by x-ray powder diffraction, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc.

The preparation method who the invention provides a kind of L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As, the method comprises:

(1) tynofovir two pyrrole furan esters and L-TARTARIC ACID are dissolved in methyl alcohol or ethanol;

(2) separate out solid;

(3) separated solid of separating out;

In above-mentioned preparation method's step (1), the general 0.5:1～1.5:1 of molar ratio of tynofovir two pyrrole furan esters and L-TARTARIC ACID, preferably 0.8:1～1.2:1.

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

In above-mentioned preparation method's step (4), the temperature of described " being dried " is generally 20～60 ℃, preferably 25～40 ℃; Can constant pressure and dry, also can drying under reduced pressure.The method " being further purified " comprises the forms such as recrystallization, pulp, washing.

According to object of the present invention, the invention provides the solid that comprises the described tynofovir two pyrrole furan esters for the treatment of significant quantity or the solid of the tynofovir two pyrrole furan esters that described preparation method makes and the pharmaceutical composition of 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 Cobicistat, efavirenz, dust is for drawing Wei, hydrochloric acid rilpivirine.

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

The solid that comprises the described tynofovir two pyrrole furan esters for the treatment of significant quantity and the pharmaceutical composition of emtricitabine; Or,

The pharmaceutical composition of solid, emtricitabine and the efavirenz that comprises the described tynofovir two pyrrole furan esters for the treatment of significant quantity; Or,

The pharmaceutical composition of the vertical Wei Lin of solid, emtricitabine and hydrochloric acid that comprises the described tynofovir two pyrrole furan esters for the treatment of significant quantity; Or,

The solid that comprises the described tynofovir two pyrrole furan esters for the treatment of significant quantity, emtricitabine, dust replace the pharmaceutical composition of La Wei and Cobicistat; Or,

The solid that comprises the described tynofovir two pyrrole furan esters for the treatment of significant quantity and the pharmaceutical composition of lamivudine; Or,

The pharmaceutical composition of solid, lamivudine and the efavirenz that comprises the described tynofovir two pyrrole furan esters for the treatment of significant quantity.

In one embodiment, the invention provides and a kind ofly comprise the tynofovir two pyrrole furan ester complexes shown in the formula IV that treats significant quantity and (comprise DL-tartrate tynofovir two pyrrole furan esters, L-TARTARIC ACID tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters, DL-oxysuccinic acid tynofovir two pyrrole furan esters, D-malic acid tynofovir two pyrrole furan esters, DL-tartrate tynofovir two pyrrole furan ester crystal form As, L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As, D-tartrate tynofovir two pyrrole furan ester crystal form As, DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As or D-malic acid tynofovir two pyrrole furan ester crystal form As) and pharmaceutical composition or the preparation of pharmaceutical excipient.

Aforementioned pharmaceutical compositions or preparation can per os or oral administration not.During oral administration administration, can adopt conventional preparation technique to make tablet, capsule, pill, granule, solution, syrup, suspensoid, powder, sustained release preparation or controlled release preparation etc.During non-oral administration administration, can adopt conventional preparation technique 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 according to the ordinary method preparation of pharmaceutical field.For example, by the tynofovir two pyrrole furan ester complexes shown in the formula IV for the treatment of significant quantity, DL-tartrate tynofovir two pyrrole furan esters, L-TARTARIC ACID tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters, DL-oxysuccinic acid tynofovir two pyrrole furan esters, D-malic acid tynofovir two pyrrole furan esters, DL-tartrate tynofovir two pyrrole furan ester crystal form As, L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As, D-tartrate tynofovir two pyrrole furan ester crystal form As, DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As or D-malic acid tynofovir two pyrrole furan ester crystal form As, alternatively with the activeconstituents of another kind of or multiple treatment significant quantity, mix or contact with one or more pharmaceutical excipients, then be made into required formulation.

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.The solid orally ingestible such as preferred tablet, capsule, granule, dry suspensoid and sustained release preparation or controlled release preparation wherein, wherein more preferably Tablet and Capsula agent.Can prepare the preferred pharmaceutical composition of the present invention or preparation according to preparing any ordinary method that solid orally ingestible adopts.As tablet can adopt the modes such as wet granule compression tablet, prepare, can carry out as required the dressing of arbitrary form, as tablet can be made any releasing pattern (as quick-release, the gentle controlled release of enteric etc.); Capsule can adopt the modes such as encapsulated dose of wet granulation to prepare, and Capsule content can be made any releasing pattern (as quick releasing formulation, enteric coated preparation and sustained-release preparation etc.).

In one embodiment, tynofovir two pyrrole furan ester complexes shown in formula IV provided by the invention, DL-tartrate tynofovir two pyrrole furan esters, L-TARTARIC ACID tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters, DL-oxysuccinic acid tynofovir two pyrrole furan esters, D-malic acid tynofovir two pyrrole furan esters, DL-tartrate tynofovir two pyrrole furan ester crystal form As, L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As, D-tartrate tynofovir two pyrrole furan ester crystal form As, the size distribution of DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As or D-malic acid tynofovir two pyrrole furan ester crystal form As is controlled at 95% and is less than 200 μ m, preferably be less than 180 μ m, preferably be less than again 150 μ m, be more preferably less than 100 μ m.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 material 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 use separately also can mix use, 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 use separately also can mix use, 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 use separately also can mix use, 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 use separately also can mix use, wherein preferred Magnesium Stearate, stearic acid, talcum powder, differential silica gel, vanay.

If needed, can also in above-mentioned composition or preparation, add other auxiliary materials, 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 DL-tartrate tynofovir two pyrrole furan esters for the treatment of significant quantity, L-TARTARIC ACID tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters, DL-oxysuccinic acid tynofovir two pyrrole furan esters, D-malic acid tynofovir two pyrrole furan esters, DL-tartrate tynofovir two pyrrole furan ester crystal form As, L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As, D-tartrate tynofovir two pyrrole furan ester crystal form As, DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As or D-malic acid tynofovir two pyrrole furan ester crystal form As.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 1g, preferred 100mg to 400mg, about 245mg (in tynofovir two pyrrole furan esters) for example, wherein " approximately " refer to ± scope of 5%.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the DL-tartrate tynofovir two pyrrole furan esters for the treatment of significant quantity, L-TARTARIC ACID tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters, DL-oxysuccinic acid tynofovir two pyrrole furan esters, D-malic acid tynofovir two pyrrole furan esters, DL-tartrate tynofovir two pyrrole furan ester crystal form As, L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As, D-tartrate tynofovir two pyrrole furan ester crystal form As, DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As or D-malic acid tynofovir two pyrrole furan ester crystal form As, the 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 weight contents are separately generally 1mg to 1g, preferred 100mg to 400mg, for example, containing the about 245mg of above-mentioned the first activeconstituents (in tynofovir two pyrrole furan esters) and the about 200mg of the second activeconstituents (emtricitabine), " approximately " refer to ± scope of 5% wherein.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the DL-tartrate tynofovir two pyrrole furan esters for the treatment of significant quantity, L-TARTARIC ACID tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters, DL-oxysuccinic acid tynofovir two pyrrole furan esters, D-malic acid tynofovir two pyrrole furan esters, DL-tartrate tynofovir two pyrrole furan ester crystal form As, L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As, D-tartrate tynofovir two pyrrole furan ester crystal form As, DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As or D-malic acid tynofovir two pyrrole furan ester crystal form As, the second activeconstituents is the emtricitabine for the treatment of significant quantity, the 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 weight contents are separately generally 1mg to 1g, preferred 100mg to 700mg, for example, containing the about 245mg of above-mentioned the first activeconstituents (in tynofovir two pyrrole furan esters), the about 200mg of the second activeconstituents (emtricitabine) and the about 600mg of the 3rd activeconstituents (efavirenz), " approximately " refer to ± scope of 5% wherein.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the DL-tartrate tynofovir two pyrrole furan esters for the treatment of significant quantity, L-TARTARIC ACID tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters, DL-oxysuccinic acid tynofovir two pyrrole furan esters, D-malic acid tynofovir two pyrrole furan esters, DL-tartrate tynofovir two pyrrole furan ester crystal form As, L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As, D-tartrate tynofovir two pyrrole furan ester crystal form As, DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As or D-malic acid tynofovir two pyrrole furan ester crystal form As, the second activeconstituents is the emtricitabine for the treatment of significant quantity, the 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 weight contents are separately generally 1mg to 1g, preferred 100mg to 400mg, for example, containing the about 245mg of above-mentioned the first activeconstituents (in tynofovir two pyrrole furan esters), the about 200mg of the second activeconstituents (emtricitabine) and the 3rd activeconstituents (hydrochloric acid rilpivirine) about 25mg (in rilpivirine), " approximately " refer to ± scope of 5% wherein.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the DL-tartrate tynofovir two pyrrole furan esters for the treatment of significant quantity, L-TARTARIC ACID tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters, DL-oxysuccinic acid tynofovir two pyrrole furan esters, D-malic acid tynofovir two pyrrole furan esters, DL-tartrate tynofovir two pyrrole furan ester crystal form As, L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As, D-tartrate tynofovir two pyrrole furan ester crystal form As, DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As or D-malic acid tynofovir two pyrrole furan ester crystal form As, the second activeconstituents is the emtricitabine for the treatment of significant quantity, the dust that the 3rd activeconstituents is treatment significant quantity is for drawing Wei, the 4th activeconstituents is the Cobicistat 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 weight contents are separately generally 1mg to 1g, preferred 100mg to 400mg, for example, containing the about 245mg of above-mentioned the first activeconstituents (in tynofovir two pyrrole furan esters), the about 200mg of the second activeconstituents (emtricitabine), the 3rd activeconstituents (dust is for drawing Wei) about 150mg and the about 150mg of the 4th activeconstituents (Cobicistat), " approximately " refer to ± scope of 5% wherein.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the DL-tartrate tynofovir two pyrrole furan esters for the treatment of significant quantity, L-TARTARIC ACID tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters, DL-oxysuccinic acid tynofovir two pyrrole furan esters, D-malic acid tynofovir two pyrrole furan esters, DL-tartrate tynofovir two pyrrole furan ester crystal form As, L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As, D-tartrate tynofovir two pyrrole furan ester crystal form As, DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As or D-malic acid tynofovir two pyrrole furan ester crystal form As, the 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 weight contents are separately generally 1mg to 1g, preferred 100mg to 400mg, for example, containing the about 245mg of above-mentioned the first activeconstituents (in tynofovir two pyrrole furan esters) and the about 300mg of the second activeconstituents (lamivudine), " approximately " refer to ± scope of 5% wherein.

In one embodiment, the invention provides a kind of compound or preparation, wherein the first activeconstituents is selected from the DL-tartrate tynofovir two pyrrole furan esters for the treatment of significant quantity, L-TARTARIC ACID tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters, DL-oxysuccinic acid tynofovir two pyrrole furan esters, D-malic acid tynofovir two pyrrole furan esters, DL-tartrate tynofovir two pyrrole furan ester crystal form As, L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As, D-tartrate tynofovir two pyrrole furan ester crystal form As, DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As or D-malic acid tynofovir two pyrrole furan ester crystal form As, the second activeconstituents is the lamivudine for the treatment of significant quantity, the 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 weight contents are separately generally 1mg to 1g, preferred 100mg to 700mg, for example, containing the about 245mg of above-mentioned the first activeconstituents (in tynofovir two pyrrole furan esters), the about 300mg of the second activeconstituents (lamivudine) and the about 600mg of the 3rd activeconstituents (efavirenz), " approximately " refer to ± scope of 5% wherein.

Aforementioned pharmaceutical compositions or preparation can be according to the conventional production method preparations of pharmaceutical field, for example one or more of DL-tartrate tynofovir two pyrrole furan ester crystal form As, L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As, D-tartrate tynofovir two pyrrole furan ester crystal form As, DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As or D-malic acid tynofovir two pyrrole furan ester crystal form As are mixed with one or more carriers, be then made into required formulation.

Above-mentioned composition is being not only chemically stable, and has side effect and the resistance that acts synergistically and/or can reduce independent tynofovir two pyrrole furan esters, emtricitabine or lamivudine or another activeconstituents; May increase patient's compliance simultaneously.

In sum, DL-tartrate tynofovir two pyrrole furan esters provided by the invention, L-TARTARIC ACID tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters, DL-oxysuccinic acid tynofovir two pyrrole furan esters, D-malic acid tynofovir two pyrrole furan esters are obviously different from the existing solid of tynofovir two pyrrole furan ester, are the new mixture solids of tynofovir two pyrrole furan ester.These new mixture solid preparation methods are easy to be controlled for tynofovir two pyrrole furan esters, physical behavior, stability, solvability, preparation adaptability etc. are not less than or are better than former other salt that grind tenofovir disoproxil fumarate or tynofovir two pyrrole furan esters, have good industrialization practicality.

In one embodiment, the invention provides a kind of tynofovir two pyrrole furan ester eutectics shown in the formula V that treats significant quantity or pharmaceutical composition or preparation of salt and pharmaceutical excipient of comprising.

In one embodiment, the invention provides a kind of tynofovir two pyrrole furan ester eutectics shown in the formula V that treats significant quantity or pharmaceutical composition or preparation of salt and emtricitabine or lamivudine of comprising.

Alternatively, aforementioned pharmaceutical compositions can further include another kind of or multiple antiviral agent or antiviral auxiliary reagent, includes but not limited to 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 Cobicistat, efavirenz, dust is for drawing Wei, hydrochloric acid rilpivirine.

Aforementioned pharmaceutical compositions or preparation are preferred: two pyrrole furan ester eutectic or the salt/emtricitabines of tynofovir shown in formula V, two pyrrole furan ester eutectic or the salt/emtricitabine/efavirenzs of tynofovir shown in formula V, the two pyrrole furan ester eutectics of tynofovir shown in formula V or salt/emtricitabine/hydrochloric acid rilpivirine, two pyrrole furan ester eutectic or the salt/lamivudines of tynofovir shown in formula V, two pyrrole furan ester eutectic or the salt/lamivudine/efavirenzs of tynofovir shown in formula V, the two pyrrole furan ester eutectics of tynofovir shown in formula V or salt/emtricitabine/dust are for drawing Wei/Cobicistat.

Aforementioned pharmaceutical compositions can be made the administration in a variety of forms of multiple formulation with pharmaceutical excipient, and wherein preferred oral formulation, comprises tablet, capsule, pill, granule, solution, syrup, suspensoid, powder, sustained release preparation or controlled release preparation etc.The preferred solid orally ingestible such as capsule, tablet, granule, suspensoid wherein, wherein more preferably Tablet and Capsula agent.

In aforementioned pharmaceutical compositions or preparation, activeconstituents comprises tynofovir two pyrrole furan ester eutectics or salt, emtricitabine or lamivudine, another kind of or multiple antiviral agent or antiviral auxiliary reagent alternatively, in unit composition or preparation, their weight contents are separately generally 1mg to 1g, preferably 10mg to 700mg.

In one embodiment, the invention provides and treat the tynofovir two pyrrole furan ester eutectics of significant quantity or composition or the preparation of salt and emtricitabine a kind of comprising, or treat the tynofovir two pyrrole furan ester eutectics of significant quantity or pharmaceutical composition or the preparation of salt and lamivudine a kind of comprising.

Alternatively, the composition that the present embodiment provides can further include efavirenz (Efavirenz), rilpivirine (Rilpivrine), Cobicistat, dust for drawing Wei (Elvitegravir) or their pharmaceutical salts isoreactivity composition.

Preferably, the present embodiment provides following composition or preparation:

Pharmaceutical composition or a preparation, the first active ingredient comprising is tynofovir two pyrrole furan ester phosphoric acid (3:1) eutectics, tynofovir two pyrrole furan ester citric acid (3:1) eutectics, tynofovir two pyrrole furan ester phosphoric acid (2:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (2:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (2:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (2:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (2:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (2:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (2:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (2:1) eutectics, tynofovir two pyrrole furan ester (2:1) citric acid eutectics, tynofovir two pyrrole furan ester pamoic acid (2:1) eutectics, tynofovir two pyrrole furan ester sulfuric acid (2:1) salt, tynofovir two pyrrole furan ester ethionic acid (2:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (2:1) salt, tynofovir two pyrrole furan ester naphthalene-1,5-disulfonic acid (2:1) salt, tynofovir two pyrrole furan ester phosphoric acid (1:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (1:1) eutectics, tynofovir two pyrrole furan ester acetic acid (1:1) eutectics, tynofovir two pyrrole furan ester (1:1) propionic acid eutectics, tynofovir two pyrrole furan ester Pfansteihl (1:1) eutectics, tynofovir two pyrrole furan ester D-ALPHA-Hydroxypropionic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic lactic acid (1:1) eutectics, tynofovir two pyrrole furan ester palmitinic acid (1:1) eutectics, tynofovir two pyrrole furan ester stearic acid (1:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (1:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (1:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (1:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (1:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (1:1) eutectics, tynofovir two pyrrole furan ester citric acid (1:1) eutectics, tynofovir two pyrrole furan ester phenylformic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester D-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic mandelic acid (1:1) eutectics, tynofovir two pyrrole furan ester nicotinic acid (1:1) eutectics, tynofovir two pyrrole furan ester hydroxyl naphthoic acid (1:1) eutectics, tynofovir two pyrrole furan ester pamoic acid (1:1) eutectics, tynofovir two pyrrole furan ester urobenzoic acid (1:1) eutectics, tynofovir two pyrrole furan ester hydrochloride (1:1) salt, tynofovir two pyrrole furan ester sulfuric acid (1:1) salt, tynofovir two pyrrole furan ester thiocyanic acid (1:1) salt, tynofovir two pyrrole furan ester Hydrogen bromide (1:1) salt, tynofovir two pyrrole furan ester nitric acid (1:1) salt, tynofovir two pyrrole furan ester methylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester taurine (1:1) salt, tynofovir two pyrrole furan ester ethionic acid (1:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (1:1) salt, tynofovir two pyrrole furan ester Phenylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester tosic acid (1:1) salt, tynofovir two pyrrole furan esters 2, a kind of in 5-dihydroxy benzenes sulfonic acid (1:1) salt or tynofovir two pyrrole furan ester naphthalene-2-sulfonic acid (1:1) salt, the second active ingredient is emtricitabine, preferred oral preparation, more preferably Tablet and Capsula agent, in unit composition or preparation, their weight contents are separately generally 1mg to 1g, preferred 100mg to 400mg, for example, containing the above-mentioned tynofovir two about 245mg of pyrrole furan ester eutectic (in free alkali) and the about 200mg of emtricitabine, " approximately " refer to ± scope of 5% wherein.

Pharmaceutical composition or a preparation, the first active ingredient comprising is tynofovir two pyrrole furan ester phosphoric acid (3:1) eutectics, tynofovir two pyrrole furan ester citric acids (3:1), tynofovir two pyrrole furan ester phosphoric acid (2:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (2:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (2:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (2:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (2:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (2:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (2:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (2:1) eutectics, tynofovir two pyrrole furan ester (2:1) citric acid eutectics, tynofovir two pyrrole furan ester pamoic acid (2:1) eutectics, tynofovir two pyrrole furan ester sulfuric acid (2:1) salt, tynofovir two pyrrole furan ester ethionic acid (2:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (2:1) salt, tynofovir two pyrrole furan ester naphthalene-1,5-disulfonic acid (2:1) salt, tynofovir two pyrrole furan ester phosphoric acid (1:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (1:1) eutectics, tynofovir two pyrrole furan ester acetic acid (1:1) eutectics, tynofovir two pyrrole furan ester (1:1) propionic acid eutectics, tynofovir two pyrrole furan ester Pfansteihl (1:1) eutectics, tynofovir two pyrrole furan ester D-ALPHA-Hydroxypropionic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic lactic acid (1:1) eutectics, tynofovir two pyrrole furan ester palmitinic acid (1:1) eutectics, tynofovir two pyrrole furan ester stearic acid (1:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (1:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (1:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (1:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (1:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (1:1) eutectics, tynofovir two pyrrole furan ester citric acid (1:1) eutectics, tynofovir two pyrrole furan ester phenylformic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester D-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic mandelic acid (1:1) eutectics, tynofovir two pyrrole furan ester nicotinic acid (1:1) eutectics, tynofovir two pyrrole furan ester hydroxyl naphthoic acid (1:1) eutectics, tynofovir two pyrrole furan ester pamoic acid (1:1) eutectics, tynofovir two pyrrole furan ester urobenzoic acid (1:1) eutectics, tynofovir two pyrrole furan ester hydrochloride (1:1) salt, tynofovir two pyrrole furan ester sulfuric acid (1:1) salt, tynofovir two pyrrole furan ester thiocyanic acid (1:1) salt, tynofovir two pyrrole furan ester Hydrogen bromide (1:1) salt, tynofovir two pyrrole furan ester nitric acid (1:1) salt, tynofovir two pyrrole furan ester methylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester taurine (1:1) salt, tynofovir two pyrrole furan ester ethionic acid (1:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (1:1) salt, tynofovir two pyrrole furan ester Phenylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester tosic acid (1:1) salt, tynofovir two pyrrole furan esters 2, a kind of in 5-dihydroxy benzenes sulfonic acid (1:1) salt or tynofovir two pyrrole furan ester naphthalene-2-sulfonic acid (1:1) salt, the second active ingredient is emtricitabine, the 3rd active ingredient is efavirenz, preferred oral preparation, more preferably Tablet and Capsula, in unit composition or preparation, their weight contents are separately generally 1mg to 1g, preferred 100mg to 700mg, for example, containing the tynofovir two about 245mg of pyrrole furan ester eutectic (in free alkali), the about 200mg of emtricitabine and the about 600mg of efavirenz in this first active ingredient, " approximately " refer to ± scope of 5% wherein.

Pharmaceutical composition or a preparation, the first active ingredient comprising is tynofovir two pyrrole furan ester phosphoric acid (3:1) eutectics, tynofovir two pyrrole furan ester citric acid (3:1) eutectics, tynofovir two pyrrole furan ester phosphoric acid (2:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (2:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (2:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (2:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (2:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (2:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (2:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (2:1) eutectics, tynofovir two pyrrole furan ester (2:1) citric acid eutectics, tynofovir two pyrrole furan ester pamoic acid (2:1) eutectics, tynofovir two pyrrole furan ester sulfuric acid (2:1) salt, tynofovir two pyrrole furan ester ethionic acid (2:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (2:1) salt or tynofovir two pyrrole furan ester naphthalene-1,5-disulfonic acid (2:1) salt, tynofovir two pyrrole furan ester phosphoric acid (1:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (1:1) eutectics, tynofovir two pyrrole furan ester acetic acid (1:1) eutectics, tynofovir two pyrrole furan ester (1:1) propionic acid eutectics, tynofovir two pyrrole furan ester Pfansteihl (1:1) eutectics, tynofovir two pyrrole furan ester D-ALPHA-Hydroxypropionic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic lactic acid (1:1) eutectics, tynofovir two pyrrole furan ester palmitinic acid (1:1) eutectics, tynofovir two pyrrole furan ester stearic acid (1:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (1:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (1:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (1:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (1:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (1:1) eutectics, tynofovir two pyrrole furan ester citric acid (1:1) eutectics, tynofovir two pyrrole furan ester phenylformic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester D-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic mandelic acid (1:1) eutectics, tynofovir two pyrrole furan ester nicotinic acid (1:1) eutectics, tynofovir two pyrrole furan ester hydroxyl naphthoic acid (1:1) eutectics, tynofovir two pyrrole furan ester pamoic acid (1:1) eutectics, tynofovir two pyrrole furan ester urobenzoic acid (1:1) eutectics, tynofovir two pyrrole furan ester hydrochloride (1:1) salt, tynofovir two pyrrole furan ester sulfuric acid (1:1) salt, tynofovir two pyrrole furan ester thiocyanic acid (1:1) salt, tynofovir two pyrrole furan ester Hydrogen bromide (1:1) salt, tynofovir two pyrrole furan ester nitric acid (1:1) salt, tynofovir two pyrrole furan ester methylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester taurine (1:1) salt, tynofovir two pyrrole furan ester ethionic acid (1:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (1:1) salt, tynofovir two pyrrole furan ester Phenylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester tosic acid (1:1) salt, tynofovir two pyrrole furan esters 2, a kind of in 5-dihydroxy benzenes sulfonic acid (1:1) salt or tynofovir two pyrrole furan ester naphthalene-2-sulfonic acid (1:1) salt, the second active ingredient is emtricitabine, the 3rd active ingredient is the vertical Wei Lin of hydrochloric acid, preferred oral preparation, more preferably Tablet and Capsula agent, in unit composition or preparation, their weight contents are separately generally 1mg to 1g, preferred 10mg to 400mg, for example, containing the tynofovir two about 245mg of pyrrole furan ester eutectic (in free alkali), the about 200mg of emtricitabine in this first active ingredient and the vertical about 25mg of a Wei Lin (in free alkali) of hydrochloric acid, " approximately " refer to ± scope of 5% wherein.

Pharmaceutical composition or a preparation, the first active ingredient comprising is tynofovir two pyrrole furan ester phosphoric acid (3:1) eutectics, tynofovir two pyrrole furan ester citric acid (3:1) eutectics, tynofovir two pyrrole furan ester phosphoric acid (2:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (2:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (2:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (2:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (2:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (2:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (2:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (2:1) eutectics, tynofovir two pyrrole furan ester (2:1) citric acid eutectics, tynofovir two pyrrole furan ester pamoic acid (2:1) eutectics, tynofovir two pyrrole furan ester sulfuric acid (2:1) salt, tynofovir two pyrrole furan ester ethionic acid (2:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (2:1) salt or tynofovir two pyrrole furan ester naphthalene-1,5-disulfonic acid (2:1) salt, tynofovir two pyrrole furan ester phosphoric acid (1:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (1:1) eutectics, tynofovir two pyrrole furan ester acetic acid (1:1) eutectics, tynofovir two pyrrole furan ester (1:1) propionic acid eutectics, tynofovir two pyrrole furan ester Pfansteihl (1:1) eutectics, tynofovir two pyrrole furan ester D-ALPHA-Hydroxypropionic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic lactic acid (1:1) eutectics, tynofovir two pyrrole furan ester palmitinic acid (1:1) eutectics, tynofovir two pyrrole furan ester stearic acid (1:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (1:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (1:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (1:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (1:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (1:1) eutectics, tynofovir two pyrrole furan ester citric acid (1:1) eutectics, tynofovir two pyrrole furan ester phenylformic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester D-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic mandelic acid (1:1) eutectics, tynofovir two pyrrole furan ester nicotinic acid (1:1) eutectics, tynofovir two pyrrole furan ester hydroxyl naphthoic acid (1:1) eutectics, tynofovir two pyrrole furan ester pamoic acid (1:1) eutectics, tynofovir two pyrrole furan ester urobenzoic acid (1:1) eutectics, tynofovir two pyrrole furan ester hydrochloride (1:1) salt, tynofovir two pyrrole furan ester sulfuric acid (1:1) salt, tynofovir two pyrrole furan ester thiocyanic acid (1:1) salt, tynofovir two pyrrole furan ester Hydrogen bromide (1:1) salt, tynofovir two pyrrole furan ester nitric acid (1:1) salt, tynofovir two pyrrole furan ester methylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester taurine (1:1) salt, tynofovir two pyrrole furan ester ethionic acid (1:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (1:1) salt, tynofovir two pyrrole furan ester Phenylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester tosic acid (1:1) salt, tynofovir two pyrrole furan esters 2, a kind of in 5-dihydroxy benzenes sulfonic acid (1:1) salt or tynofovir two pyrrole furan ester naphthalene-2-sulfonic acid (1:1) salt, the second active ingredient is emtricitabine, and the 3rd active ingredient is that dust replaces and draws Wei, and the 4th active ingredient is Cobicistat, preferred oral preparation, more preferably Tablet and Capsula agent, in unit composition or preparation, their weight contents are separately generally 1mg to 1000mg, preferred 10mg to 400mg, for example containing the tynofovir two about 245mg of pyrrole furan ester eutectic (in free alkali), the about 200mg of emtricitabine, dust in this first active ingredient for drawing the about 150mg of Wei and the about 150mg of Cobicistat, " approximately " refer to ± scope of 5% wherein.

Pharmaceutical composition or a preparation, the first active ingredient comprising is tynofovir two pyrrole furan ester phosphoric acid (3:1) eutectics, tynofovir two pyrrole furan ester citric acid (3:1) eutectics, tynofovir two pyrrole furan ester phosphoric acid (2:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (2:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (2:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (2:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (2:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (2:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (2:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (2:1) eutectics, tynofovir two pyrrole furan ester (2:1) citric acid eutectics, tynofovir two pyrrole furan ester pamoic acid (2:1) eutectics, tynofovir two pyrrole furan ester sulfuric acid (2:1) salt, tynofovir two pyrrole furan ester ethionic acid (2:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (2:1) salt, tynofovir two pyrrole furan ester naphthalene-1,5-disulfonic acid (2:1) salt, tynofovir two pyrrole furan ester phosphoric acid (1:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (1:1) eutectics, tynofovir two pyrrole furan ester acetic acid (1:1) eutectics, tynofovir two pyrrole furan ester (1:1) propionic acid eutectics, tynofovir two pyrrole furan ester Pfansteihl (1:1) eutectics, tynofovir two pyrrole furan ester D-ALPHA-Hydroxypropionic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic lactic acid (1:1) eutectics, tynofovir two pyrrole furan ester palmitinic acid (1:1) eutectics, tynofovir two pyrrole furan ester stearic acid (1:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (1:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (1:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (1:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (1:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (1:1) eutectics, tynofovir two pyrrole furan ester citric acid (1:1) eutectics, tynofovir two pyrrole furan ester phenylformic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester D-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic mandelic acid (1:1) eutectics, tynofovir two pyrrole furan ester nicotinic acid (1:1) eutectics, tynofovir two pyrrole furan ester hydroxyl naphthoic acid (1:1) eutectics, tynofovir two pyrrole furan ester pamoic acid (1:1) eutectics, tynofovir two pyrrole furan ester urobenzoic acid (1:1) eutectics, tynofovir two pyrrole furan ester hydrochloride (1:1) salt, tynofovir two pyrrole furan ester sulfuric acid (1:1) salt, tynofovir two pyrrole furan ester thiocyanic acid (1:1) salt, tynofovir two pyrrole furan ester Hydrogen bromide (1:1) salt, tynofovir two pyrrole furan ester nitric acid (1:1) salt, tynofovir two pyrrole furan ester methylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester taurine (1:1) salt, tynofovir two pyrrole furan ester ethionic acid (1:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (1:1) salt, tynofovir two pyrrole furan ester Phenylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester tosic acid (1:1) salt, tynofovir two pyrrole furan esters 2, a kind of in 5-dihydroxy benzenes sulfonic acid (1:1) salt or tynofovir two pyrrole furan ester naphthalene-2-sulfonic acid (1:1) salt, the second active ingredient is lamivudine, preferred oral preparation, more preferably Tablet and Capsula agent, in unit composition or preparation, their weight contents are separately generally 1mg to 1000mg, preferred 100mg to 400mg, for example, containing the tynofovir two about 245mg of pyrrole furan ester eutectic (in free alkali) and the about 300mg of lamivudine in this first active ingredient, " approximately " refer to ± scope of 5% wherein.

Pharmaceutical composition or a preparation, the first active ingredient comprising is tynofovir two pyrrole furan ester phosphoric acid (3:1) eutectics, tynofovir two pyrrole furan ester citric acid (3:1) eutectics, tynofovir two pyrrole furan ester phosphoric acid (2:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (2:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (2:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (2:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (2:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (2:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (2:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (2:1) eutectics, tynofovir two pyrrole furan ester (2:1) citric acid eutectics, tynofovir two pyrrole furan ester pamoic acid (2:1) eutectics, tynofovir two pyrrole furan ester sulfuric acid (2:1) salt, tynofovir two pyrrole furan ester ethionic acid (2:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (2:1) salt, tynofovir two pyrrole furan ester naphthalene-1,5-disulfonic acid (2:1) salt, tynofovir two pyrrole furan ester phosphoric acid (1:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (1:1) eutectics, tynofovir two pyrrole furan ester acetic acid (1:1) eutectics, tynofovir two pyrrole furan ester (1:1) propionic acid eutectics, tynofovir two pyrrole furan ester Pfansteihl (1:1) eutectics, tynofovir two pyrrole furan ester D-ALPHA-Hydroxypropionic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic lactic acid (1:1) eutectics, tynofovir two pyrrole furan ester palmitinic acid (1:1) eutectics, tynofovir two pyrrole furan ester stearic acid (1:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (1:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (1:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (1:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (1:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (1:1) eutectics, tynofovir two pyrrole furan ester citric acid (1:1) eutectics, tynofovir two pyrrole furan ester phenylformic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester D-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic mandelic acid (1:1) eutectics, tynofovir two pyrrole furan ester nicotinic acid (1:1) eutectics, tynofovir two pyrrole furan ester hydroxyl naphthoic acid (1:1) eutectics, tynofovir two pyrrole furan ester pamoic acid (1:1) eutectics, tynofovir two pyrrole furan ester urobenzoic acid (1:1) eutectics, tynofovir two pyrrole furan ester hydrochloride (1:1) salt, tynofovir two pyrrole furan ester sulfuric acid (1:1) salt, tynofovir two pyrrole furan ester thiocyanic acid (1:1) salt, tynofovir two pyrrole furan ester Hydrogen bromide (1:1) salt, tynofovir two pyrrole furan ester nitric acid (1:1) salt, tynofovir two pyrrole furan ester methylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester taurine (1:1) salt, tynofovir two pyrrole furan ester ethionic acid (1:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (1:1) salt, tynofovir two pyrrole furan ester Phenylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester tosic acid (1:1) salt, tynofovir two pyrrole furan esters 2, a kind of in 5-dihydroxy benzenes sulfonic acid (1:1) salt or tynofovir two pyrrole furan ester naphthalene-2-sulfonic acid (1:1) salt, the second active ingredient is lamivudine, the 3rd active ingredient is efavirenz, preferred oral preparation, more preferably Tablet and Capsula agent, in unit composition or preparation, their weight contents are separately generally 1mg to 1000mg, preferred 100mg to 700mg, for example, containing the tynofovir two about 245mg of pyrrole furan ester eutectic (in free alkali), the about 300mg of lamivudine and the about 600mg of efavirenz in this first active ingredient, " approximately " refer to ± scope of 5% wherein.

Aforementioned pharmaceutical compositions is being not only chemically stable, and has side effect and the resistance that acts synergistically and/or can reduce independent tynofovir two pyrrole furan ester eutectics or salt, emtricitabine or lamivudine or another activeconstituents; May increase patient's compliance simultaneously.

In addition 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 with one or more pharmaceutical excipients mixing or contact by the tynofovir two pyrrole furan ester complexes shown in the formula IV for the treatment of significant quantity or the tynofovir two pyrrole furan ester eutectics shown in formula V or salt.For two compounds or preparation, the method be generally by the tynofovir two pyrrole furan ester complexes shown in the formula IV for the treatment of significant quantity or the tynofovir two pyrrole furan ester eutectics shown in formula V or salt, emtricitabine (or lamivudine) is with one or more pharmaceutical excipients mixing or contact.For three compounds or many compounds or preparation, the method is generally with pharmaceutical excipient mixing or contact by the tynofovir two pyrrole furan ester complexes shown in the formula IV for the treatment of significant quantity or the tynofovir two pyrrole furan ester eutectics shown in formula V or salt, emtricitabine (or lamivudine) and another kind or various active composition.This pharmaceutical composition or preparation are to 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 use separately also can mix use, 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 use separately also can mix use, 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 use separately also can mix use, 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 use separately also can mix use, 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 solid orally ingestible such as preferred tablet, capsule, granule, drinkable suspensoid wherein, wherein more preferably Tablet and Capsula agent.Can prepare the preferred pharmaceutical composition of the present invention or preparation according to preparing any ordinary method that solid orally ingestible adopts.As tablet can adopt the modes such as wet granule compression tablet, prepare, can carry out as required dressing; Capsule can adopt the modes such as encapsulated dose of wet granulation to prepare.

According to object of the present invention, the solid that the invention provides the solid of above-mentioned tynofovir two pyrrole furan esters or the tynofovir two pyrrole furan esters that described preparation method makes prevents and/or treats the application in the medicine of virus infection in preparation.

Particularly, the solid that the invention provides above-mentioned tynofovir two pyrrole furan esters prevents and/or treats 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 two pyrrole furan ester complexes shown in formula IV and 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 pharmaceutical composition that the invention provides the tynofovir two pyrrole furan ester complexes that comprise shown in the formula IV that treats significant quantity and pharmaceutical excipient prevents and/or treats the application in the medicine that hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) infect in preparation.

In one embodiment, the pharmaceutical composition that the invention provides the tynofovir two pyrrole furan ester complexes, another kind or multiple antiviral agent or antiviral auxiliary reagent and the pharmaceutical excipient that comprise shown in the formula IV that treats significant quantity prevents and/or treats 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 two pyrrole furan ester eutectics shown in formula V or salt and 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 pharmaceutical composition that the invention provides the tynofovir two pyrrole furan ester eutectics that comprise shown in the formula V that treats significant quantity or salt and pharmaceutical excipient prevents and/or treats the application in the medicine that hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) infect in preparation.

In one embodiment, the pharmaceutical composition that the invention provides the tynofovir two pyrrole furan ester eutectics that comprise shown in the formula V that treats significant quantity or salt, another kind or multiple antiviral agent or antiviral auxiliary reagent and pharmaceutical excipient prevents and/or treats the application in the medicine that hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) infect in preparation.

The experiment proved that, DL-tartrate tynofovir two pyrrole furan esters provided by the invention, L-TARTARIC ACID tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters, DL-oxysuccinic acid tynofovir two pyrrole furan esters or D-malic acid tynofovir two pyrrole furan esters have following advantage:

(1) preparation method is easy, and crystal formation is easy to control; Can make high purity, such as product more than HPLC area normalization method purity 98%, 99% or 99.5%.

(2) there is physical behavior, chemical stability or preparation adaptability good or that improve.Such as DL-tartrate tynofovir two pyrrole furan ester fusing points are higher than the former tenofovir disoproxil fumarate that grinds listing, be more conducive to preparation; And for example the solvability in different pH medium of DL-tartrate tynofovir two pyrrole furan esters, L-TARTARIC ACID tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters, DL-oxysuccinic acid tynofovir two pyrrole furan esters and D-malic acid tynofovir two pyrrole furan esters is all better than tenofovir disoproxil fumarate, is conducive to the stripping of preparation; DL-tartrate tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters, DL-oxysuccinic acid tynofovir two pyrrole furan esters or D-malic acid tynofovir two pyrrole furan esters are also better than the salt that tynofovir two pyrrole furan esters and hydrochloric acid, phosphoric acid, methylsulfonic acid, tosic acid, succsinic acid, oxalic acid, citric acid, phenylformic acid etc. form at aspects such as preparation technology's amplification, crystal formation controllability, solvability, chemical stability or preparation adaptability in addition.

(3) with former tenofovir disoproxil fumarate pharmacokinetics of grinding listing without significant difference, and that DL-tartrate, L-TARTARIC ACID, D-tartrate, DL-oxysuccinic acid and D-malic acid are is conventional, have for many years people with medicinal acid or the pharmaceutical excipient of history, so they have good safety and effectiveness with the mixture of tynofovir two pyrrole furan esters formation.

The X-ray powder diffraction analysis of above-mentioned crystal of the present invention is under envrionment temperature and ambient moisture, through the Cu-K α radiation of Dutch PANalytical X`Pert PRO type X-ray powder diffraction instrument

mensuration completes." envrionment temperature " is generally 0～40 ℃; " ambient moisture " is generally 30%～80% relative humidity.Be understandable that in test process, owing to being subject to the impact of many factors (as the treatment process of the granularity of specimen, when test sample, instrument, test parameter, test operation etc.), characteristic diffraction peak position or the intensity of the X-ray powder diffraction that same crystal formation is measured have certain difference.Generally, in X-ray powder diffraction the experimental error of characteristic diffraction peak 2 θ values can be ± 0.2 °.

The means of differential scanning calorimetry of above-mentioned crystal of the present invention (DSC) analysis is to carry out in the temperature range of 40 ℃～200 ℃, and temperature rise rate 10℃ /Fen，Jing U.S. TA DSC Q200 type differential scanning calorimeter has been measured.

Experiment shows, tynofovir two pyrrole furan ester eutectic or salt provided by the invention, and the composition that comprises they and emtricitabine or lamivudine or preparation have physical behavior, chemical stability, process controllability or safety and effectiveness good or that improve.

Accompanying drawing explanation

Fig. 1 is the X-ray powder diffraction of DL-tartrate tynofovir two pyrrole furan ester crystal form As.

Fig. 2 is the X-ray powder diffraction of D-tartrate tynofovir two pyrrole furan ester crystal form As.

Fig. 3 is the X-ray powder diffraction of DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As.

Fig. 4 is the X-ray powder diffraction of D-malic acid tynofovir two pyrrole furan ester crystal form As.

Fig. 5 is the X-ray powder diffraction of L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As.

Fig. 6 is the DSC collection of illustrative plates of DL-tartrate tynofovir two pyrrole furan ester crystal form As.

Fig. 7 is the DSC collection of illustrative plates of DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As.

Fig. 8 is the DSC collection of illustrative plates of D-malic acid tynofovir two pyrrole furan ester crystal form As.

Fig. 9 is the DSC collection of illustrative plates of L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As.

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 only limit to following examples, all inventions of making based on foregoing of the present invention all belong to scope of the present invention.

In following examples ¹h NMR test is to using deuterated dimethyl sulfoxide as test solvent, and mark in doing with tetramethylsilane, at room temperature measures by Bruke AV-II 300MHz nuclear magnetic resonance analyser.

In following examples, specific rotation is measured through Shanghai precision SGW-3 type polarimeter.

In following examples, X-ray powder diffraction is measured by Dutch PANalytical X`Pert PRO type X-ray powder diffraction instrument, and test condition is 4 °-50 ° for take θ-θ configuration, sweep limit, and step-length is 0.0130 °, continuous sweep.Testing light source is copper target K α radiation

pIXcel detector; Voltage and current is respectively 40kV and 40mA.Method for making sample is: under envrionment conditions, with spoon, get the groove that appropriate sample is placed in glass load sample sheet, with slide glass, suitably roll, sample is evenly distributed in load sample sheet groove, then with slide glass, sample surfaces is struck off.Test period sample does not rotate in himself plane.

Means of differential scanning calorimetry in following examples (DSC) analysis is what in the temperature range of 40 ℃ to 200 ℃, to be carried out, and temperature rise rate 10℃ /Fen，Jing U.S. TA DSC Q200 type differential scanning calorimeter is measured.

Embodiment 1

The preparation of tynofovir two pyrrole furan esters

At 20～25 ℃, one hydration tynofovir (can commercialization buy or by disclosed method preparation in CN1264387A) 41.4g is added in N-Methyl pyrrolidone 164g, under agitation add again triethylamine 40g, at 20～25 ℃, stir after 0.5 hour, add chloromethyl sec.-propyl carbonic ether 100g, be warming up to 55-65 ℃ of insulation reaction 5 hours; Stop heating, be cooled to 20～30 ℃, add ethyl acetate 320g, purified water 180g, separatory after stirring at 0～5 ℃, lower floor extracts at 0～5 ℃ with ethyl acetate 110g again, combined ethyl acetate layer, purifying washing secondary at 0～5 ℃, each 320g, concentrated ethyl acetate at 30～35 ℃; In enriched material, add hexanaphthene 150mL, stir after 10 hours at 20～25 ℃, filter, hexanaphthene 20mL drip washing, obtains tynofovir two pyrrole furan esters, white solid.

¹H?NMR(300MHz，DMSO-d ₆)δ:8.14(s，1H)，8.03(s，1H)，7.21(s，2H)，5.57-5.51(m，4H)，4.82-4.80(m，2H)，4.23-4.19(m，2H)，4.00-3.96(m，3H)，1.25-1.23(d，12H)，1.07-1.05(d，3H)。

Melting range: 102～105 ℃.

Embodiment 2

The preparation of DL-tartrate tynofovir two pyrrole furan esters and crystal form A thereof

At 40～45 ℃, tynofovir two pyrrole furan ester 50.0g (96.3mmol) and DL-tartrate 14.4g (95.9mmol) are dissolved in Virahol 4.5L, after dissolve complete, stir and be cooled to 15～20 ℃, continue stirring and crystallizing; Suction filtration; Filter cake is drying under reduced pressure at 30～35 ℃, obtains DL-tartrate tynofovir two pyrrole furan ester 57.0g, productive rate 88.5%.

Institute surveys ¹h NMR result is: ¹h NMR (300MHz, DMSO-d ₆) δ: 8.13 (s, 1H), 8.03 (s, 1H), 7.30 (s, 2H), 5.57-5.53 (m, 4H), 4.83-4.79 (m, 2H), 4.33-4.32 (d, 2H), 4.24-4.19 (m, 2H), 4.01-3.96 (m, 3H), 1.24-1.22 (d, 12H), 1.07-1.05 (d, 3H).

Above-mentioned ¹in H NMR result, chemical shift is at δ 8.13 (s, 1H) He 8.03 (s, the fignal center of 1H) locating is attributed to respectively two H in tynofovir two pyrrole furan ester VITAMIN B4, δ 4.33-4.32 (d, the fignal center of 2H) locating is attributed to the H of 2 methynes on DL-tartrate, from the integral area ratio of two groups of fignal centers, can judge this sample that tynofovir two pyrrole furan esters and tartaric mole of ratio of components of DL-are 1:1.

Specific rotation test: the tynofovir two pyrrole furan ester solutions of the volumetric molar concentrations such as preparation and DL-tartrate tynofovir two pyrrole furan ester solutions, parallel testing specific rotation, measured tynofovir two pyrrole furan ester solution specific rotatioies and DL-tartrate tynofovir two pyrrole furan ester solution specific rotatioies equate, when usining tynofovir two pyrrole furan ester solutions during as blank, the specific rotation of measured DL-tartrate tynofovir two pyrrole furan ester solutions is 0.

The X-ray powder diffraction of surveying is accompanying drawing 1.Observed value is as following table (get relative intensity and be more than or equal to 3% observed value corresponding to diffraction peak, three decimals are got in observed value round off).

Institute's error of measurement shows that scanning amount thermal map spectrum (DSC) is for accompanying drawing 6.

The above-mentioned crystal formation called after of gained DL-tartrate tynofovir two pyrrole furan ester crystal form As.

Test shows, DL-tartrate tynofovir two pyrrole furan esters and former tenofovir disoproxil fumarate pharmacokinetics of grinding listing are without significant difference.

Embodiment 3

At 45～50 ℃, tynofovir two pyrrole furan ester 50.0g (96.3mmol) and DL-tartrate 15.9g (105.9mmol) are dissolved in the mixed solvent of methanol/ethanol (volume ratio 1/1) 1L, after dissolve complete, in controlling, at warm 45～50 ℃, drip isopropyl ether 500mL, dropwise rear stirring and be cooled to 15～20 ℃, continue stirring and crystallizing; Suction filtration; Filter cake is drying under reduced pressure at 35～40 ℃, obtains DL-tartrate tynofovir two pyrrole furan ester crystal form A 53.0g, productive rate 82.3%.X-ray powder diffraction is similar to Fig. 1.

Embodiment 4

At 50～55 ℃, tynofovir two pyrrole furan ester 10.0g (19.2mmol) and DL-tartrate 2.9g (19.3mmol) are dissolved in ethanol 500mL, after dissolve complete, stir and be cooled to 15～20 ℃, continue stirring and crystallizing; Suction filtration; Filter cake is drying under reduced pressure at 30～35 ℃, obtains DL-tartrate tynofovir two pyrrole furan ester crystal form A 10.1g, productive rate 78.4%.X-ray powder diffraction is similar to Fig. 1.

Embodiment 5

At 40～45 ℃, tynofovir two pyrrole furan ester 5.0g (9.63mmol) and DL-tartrate 1.6g (10.6mmol) are dissolved in acetonitrile 300mL, after dissolve complete, stir and be cooled to 15～20 ℃, continue stirring and crystallizing; Suction filtration; Filter cake is drying under reduced pressure at 25～30 ℃, obtains DL-tartrate tynofovir two pyrrole furan ester crystal form A 4.9g, productive rate 76.1%.X-ray powder diffraction is similar to Fig. 1.

Embodiment 6

At 50～55 ℃, tynofovir two pyrrole furan ester 5.0g (9.63mmol) and DL-tartrate 1.6g (10.6mmol) are dissolved in the solvent of methyl alcohol 50mL, after dissolve complete, in controlling, at warm 45～50 ℃, drip methyl tertiary butyl ether 50mL, dropwise rear stirring and be cooled to 15～20 ℃, continue stirring and crystallizing; Suction filtration; Filter cake is drying under reduced pressure at 30～35 ℃, obtains DL-tartrate tynofovir two pyrrole furan ester crystal form A 5.4g, productive rate 83.9%.X-ray powder diffraction is similar to Fig. 1.

Embodiment 7

DL-tartrate tynofovir two pyrrole furan ester crystal form As and former pharmacokinetics comparative study of grinding listing tenofovir disoproxil fumarate

By using μ m sieve to sieve, preparation possesses suitable crystalline size formerly grinds listing tenofovir disoproxil fumarate crystal (preparing by disclosed method in patent documentation CN1264387A) and DL-tartrate tynofovir two pyrrole furan ester crystal form A crystal is multiple batches of.Select 12 of male SD rats, 240-270g, is divided into 2 groups at random, and gavage gives tenofovir disoproxil fumarate or DL-tartrate tynofovir two pyrrole furan ester A crystal formations respectively, and dosage is 10mg/kg (by tynofovir).Before administration He after administration, within 15 minutes, 30 minutes, 45 minutes, 1 hour, 3 hours, 6 hours, 8 hours, 12 hours, 24 hours and 28 hours, by jugular vein, take a blood sample, each approximately 200 μ L, 5500rpm centrifuging and taking upper plasma, frozen stand-by in-40 ℃ of preservations.

Further process plasma sample, to analyze tynofovir (active metabolite of tenofovir disoproxil fumarate) content wherein by LC-MS/MS.A certain amount of tynofovir is mixed to rat blank plasma and make typical curve, by the tynofovir concentration in LC-MS/MS quantitative assay plasma sample.After calculating pharmacokinetic parameters, carry out T check, result is as following table.

DL-tartrate tynofovir two pyrrole furan ester crystal form As and former main pharmacokinetic parameters of grinding listing tenofovir disoproxil fumarate crystal all do not have significant difference (P>0.05).

Embodiment 8

The recrystallization of DL-tartrate tynofovir two pyrrole furan ester crystal form As

Get the DL-tartrate tynofovir two pyrrole furan ester crystal form As of preparing by the method for embodiment 2, at 45～50 ℃, join in the listed solvent of appropriate following table and dissolve, cooling crystallization; Suction filtration; Filter cake drying under reduced pressure.Through surveying X-ray powder diffraction, investigate the crystal formation situation after its recrystallization, result is as follows:

Recrystallization solvent	Crystal formation
		Methyl alcohol	Crystal form A
Ethanol	Crystal form A
		Tetrahydrofuran (THF)	Crystal form A
Virahol	Crystal form A
		Acetonitrile	Crystal form A
Acetone	Crystal form A
		Virahol/isopropyl ether (volume ratio 7/1)	Crystal form A
Acetone/isopropyl ether (volume ratio 6/1)	Crystal form A
		Methanol/water/isopropyl ether (volume ratio 10/1/5)	Crystal form A
Ethanol/DMF/isopropyl ether (volume ratio 10/1/2.5)	Crystal form A

Above-mentioned research shows: DL-tartrate tynofovir two pyrrole furan ester crystal form As provided by the invention all can reappear under multiple recrystallization condition.

Embodiment 9

The preparation of D-tartrate tynofovir two pyrrole furan esters and crystal form A thereof

In 35～45 ℃, by tynofovir two pyrrole furan ester 10.0g (19.3mmol) and D-tartrate 3.1g (20.6mmol), be dissolved in Virahol 300mL, after dissolve complete, in controlling, at warm 35～45 ℃, drip isopropyl ether 100mL, dropwise rear stirring and be cooled to 15～20 ℃, continue stirring and crystallizing; Suction filtration; Filter cake is drying under reduced pressure at 20～30 ℃, obtains D-tartrate tynofovir two pyrrole furan ester 9.7g, productive rate 75.3%.

Institute surveys ¹h NMR result is: ¹h NMR (300MHz, DMSO-d ₆) δ: 8.16-8.15 (d, 1H), 8.05-8.04 (d, 1H), 7.33 (s, 2H), 5.57-5.53 (m, 4H), 4.81-4.79 (m, 2H), 4.35-4.33 (d, 2H), 4.25-4.19 (m, 2H), 3.96 (s, 3H), 1.21 (s, 12H), 1.05-1.01 (m, 3H).

Above-mentioned ¹in H NMR result, chemical shift is at δ 8.16-8.15 (d, 1H) and 8.05-8.04 (d, the fignal center of 1H) locating is attributed to respectively two H in tynofovir two pyrrole furan ester VITAMIN B4, δ 4.35-4.33 (d, the fignal center of 2H) locating is attributed to the H of 2 methynes on D-tartrate, from the integral area ratio of two groups of fignal centers, can judge this sample that tynofovir two pyrrole furan esters and tartaric mole of ratio of components of D-are about 1:1.

The X-ray powder diffraction of surveying is accompanying drawing 2.Observed value is as following table (get relative intensity and be more than or equal to 1% observed value corresponding to diffraction peak, three decimals are got in observed value round off).

The above-mentioned crystal formation called after of gained D-tartrate tynofovir two pyrrole furan ester crystal form As.

Embodiment 10

The preparation of DL-oxysuccinic acid tynofovir two pyrrole furan esters and new crystal A thereof

In 40～50 ℃, by tynofovir two pyrrole furan ester 50g (96.3mmol) and DL-oxysuccinic acid 12.9g (96.2mmol), be dissolved in Virahol 200mL, after dissolve complete, in controlling, at warm 40～50 ℃, drip isopropyl ether 300mL, dropwise rear stirring and be cooled to 15～20 ℃, continue stirring and crystallizing; Suction filtration; Filter cake after drying under reduced pressure, obtains DL-oxysuccinic acid tynofovir two pyrrole furan ester 53.5g, productive rate 85.0% at 25～30 ℃.

Institute surveys ¹h NMR result is: ¹h NMR (300MHz, DMSO-d ₆) δ: 8.16-8.14 (d, 1H), 8.05-8.04 (d, 1H), 7.29 (s, 2H), 5.58-5.50 (m, 4H), 4.83-4.79 (m, 2H), 4.29-4.28 (d, 1H), 4.27-4.15 (m, 2H), 3.99-3.97 (d, 3H), 2.59-2.67 (m, 1H), 2.49-2.41 (m, 1H), 1.25-1.22 (t, 12H), 1.08-1.05 (t, 3H).

Above-mentioned ¹in H NMR result, chemical shift is at δ 8.16-8.15 (d, 1H) and 8.05-8.04 (d, the fignal center of 1H) locating is attributed to respectively two H in tynofovir two pyrrole furan ester VITAMIN B4, δ 4.29-4.28 (d, the fignal center of 1H) locating is attributed to the H of methyne on DL-oxysuccinic acid, from the integral area ratio of two groups of fignal centers, can judge that this sample, a mole ratio of components for tynofovir two pyrrole furan esters and DL-oxysuccinic acid is about 1:1.

Specific rotation test: the tynofovir two pyrrole furan ester solutions of the volumetric molar concentrations such as preparation and DL-oxysuccinic acid tynofovir two pyrrole furan ester solutions, parallel testing specific rotation, measured tynofovir two pyrrole furan ester solution specific rotatioies and DL-oxysuccinic acid tynofovir two pyrrole furan ester solution specific rotatioies equate, when usining tynofovir two pyrrole furan ester solutions during as blank, the specific rotation of measured DL-oxysuccinic acid tynofovir two pyrrole furan ester solutions is 0.

The X-ray powder diffraction of surveying is accompanying drawing 3.Observed value is as following table (get relative intensity and be more than or equal to 10% observed value corresponding to diffraction peak, three decimals are got in observed value round off).

Institute's error of measurement shows that scanning amount thermal map spectrum (DSC) is for accompanying drawing 7.

The above-mentioned crystal formation called after of gained DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As.

Pharmacokinetics comparative study shows, DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As and the former main pharmacokinetic parameters there was no significant difference that grinds listing tenofovir disoproxil fumarate crystal.

Embodiment 11

The preparation of DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As

At 40～45 ℃, by tynofovir two pyrrole furan ester 5.0g (9.63mmol) and DL-oxysuccinic acid 1.1g (8.5mmol), be dissolved in Virahol 20mL, after dissolve complete, in controlling, at warm 40～45 ℃, drip methyl tertiary butyl ether 30mL, dropwise rear stirring and be cooled to 15～20 ℃, continue stirring and crystallizing; Suction filtration; Filter cake is drying under reduced pressure at 30～35 ℃, obtains DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form A 5.0g, productive rate 90.6%.X-ray powder diffraction is similar to Fig. 3.

Embodiment 12

The preparation of D-malic acid tynofovir two pyrrole furan esters and crystal form A thereof

At 40～50 ℃, by tynofovir two pyrrole furan ester 50g (96.3mmol) and D-malic acid 12.9g (96.2mmol), be dissolved in Virahol 250mL, after dissolve complete, in controlling, at warm 40～50 ℃, drip isopropyl ether 250mL, dropwise rear stirring and be cooled to 15～20 ℃, continue stirring and crystallizing; Suction filtration; Filter cake is drying under reduced pressure at 30～40 ℃, obtains D-malic acid tynofovir two pyrrole furan ester 48.2g, productive rate 76.6%.

Institute surveys ¹h NMR result is: ¹h NMR (300MHz, DMSO-d ₆) δ: 8.16-8.14 (d, 1H), 8.05-8.03 (d, 1H), 7.30 (s, 2H), 5.58-5.54 (m, 4H), 4.81-4.80 (m, 2H), 4.26-4.25 (d, 1H), 4.21-4.15 (m, 2H), 3.97 (s, 3H), 2.66-2.61 (m, 1H), 2.49-2.43 (m, 1H), 1.22 (s, 12H), 1.07-1.06 (d, 3H).

Above-mentioned ¹in H NMR result, chemical shift is at δ 8.16-8.14 (d, 1H) and 8.05-8.03 (d, the fignal center of 1H) locating is attributed to respectively two H in tynofovir two pyrrole furan ester VITAMIN B4, δ 4.26-4.25 (d, the fignal center of 1H) locating is attributed to the H of methyne on D-malic acid, from the integral area ratio of two groups of fignal centers, can judge that this sample, a mole ratio of components for tynofovir two pyrrole furan esters and D-malic acid is about 1:1.

The X-ray powder diffraction of surveying is accompanying drawing 4; Observed value is as following table (get relative intensity and be more than or equal to 3% observed value corresponding to diffraction peak, three decimals are got in observed value round off).

Institute's error of measurement shows that scanning amount thermal map spectrum (DSC) is for accompanying drawing 8.

The above-mentioned crystal formation called after of gained D-malic acid tynofovir two pyrrole furan ester crystal form As.

Embodiment 13

The preparation of L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As

At 40～50 ℃, by tynofovir two pyrrole furan ester 50.0g (96.3mmol) and L-TARTARIC ACID 14.4g (95.9mmol), be dissolved in the mixed solvent of methanol/ethanol (volume ratio 3:2) 500mL, after dissolve complete, stir and be cooled to 15～20 ℃, continue stirring and crystallizing; Suction filtration; Filter cake is drying under reduced pressure at 25～30 ℃, obtains L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form A 57.8g, productive rate 89.8%.

Institute surveys ¹h NMR result is: ¹h NMR (300MHz, DMSO-d ₆) δ: 8.19-8.15 (d, 1H), 8.08-8.04 (d, 1H), 7.29-7.25 (d, 2H), 5.61-5.55 (m, 4H), 4.86-4.84 (m, 2H), 4.36-4.33 (d, 2H), 4.29-4.24 (m, 2H), 4.01-3.98 (m, 3H), 1.29-1.23 (d, 12H), 1.11-1.06 (d, 3H).

Above-mentioned ¹in H NMR result, chemical shift is at δ 8.19-8.15 (d, 1H) and 8.08-8.04 (d, the fignal center of 1H) locating is attributed to respectively two H in tynofovir two pyrrole furan ester VITAMIN B4, δ 4.36-4.33 (d, the fignal center of 2H) locating is attributed to the H of 2 methynes on L-TARTARIC ACID, from the integral area ratio of two groups of fignal centers, can judge that this sample, a mole ratio of components for tynofovir two pyrrole furan esters and L-TARTARIC ACID is about 1:1.

The X-ray powder diffraction of surveying is accompanying drawing 5.Observed value is as following table (get relative intensity and be more than or equal to 1% observed value corresponding to diffraction peak, three decimals are got in observed value round off).

Institute's error of measurement shows that scanning amount thermal map spectrum (DSC) is for accompanying drawing 9.

Embodiment 14

Stability study

Get tenofovir disoproxil fumarate (the former listing salt type that grinds, by disclosed method preparation in patent documentation CN1264387A), DL-tartrate tynofovir two pyrrole furan esters (by the method preparation of embodiment 2) and DL-oxysuccinic acid tynofovir two pyrrole furan esters (preparing by the method for embodiment 10) test respectively under high temperature, high humidity, high light condition, after 10 days, detect, result as

Under:

Upper table moderate purity detects by HPLC method, and its testing conditions is:

Moving phase: acetonitrile: 0.1% triethylamine aqueous solution (phosphoric acid regulates pH=6.0)=45:55

Chromatographic column: Inertsil ODS-3,5 μ m, 4.6 * 250mm

Column temperature: 30 ℃

Wavelength: 262nm

Flow velocity: 1.0mL/min

Moving phase: according to the form below carries out gradient elution

Detection method: sample thief is appropriate, accurately weighed, add dissolve with methanol dilution make every 1mL approximately containing 0.5mg solution as need testing solution, precision measures 10 μ L, injection liquid chromatography, records color atlas, according to area normalization method, calculates its related substances.

Above-mentioned research shows: DL-tartrate tynofovir two pyrrole furan esters provided by the invention are suitable with stability and the tenofovir disoproxil fumarate of DL-oxysuccinic acid tynofovir two pyrrole furan esters under high temperature, high humidity, illumination condition.Further research shows, the stability of DL-tartrate tynofovir two pyrrole furan esters or DL-oxysuccinic acid tynofovir two pyrrole furan esters also has advantage compared with other mixtures or the salt of tynofovir two pyrrole furan esters.

Embodiment 15

Solubility studies

Get tenofovir disoproxil fumarate (the former listing salt type that grinds, press disclosed method preparation in patent documentation CN1264387A), DL-tartrate tynofovir two pyrrole furan esters (pressing the method preparation of embodiment 2), DL-oxysuccinic acid tynofovir two pyrrole furan esters (pressing the method preparation of embodiment 10), L-TARTARIC ACID tynofovir two pyrrole furan esters (pressing the method preparation of embodiment 13), D-tartrate tynofovir two pyrrole furan esters (pressing the method preparation of embodiment 9) and D-malic acid tynofovir two pyrrole furan esters (by the method preparation of embodiment 12), at 25 ℃, measure respectively their solvabilities in different pH medium, result is as follows:

Above-mentioned research shows: the solvability of DL-tartrate tynofovir two pyrrole furan esters provided by the invention, DL-oxysuccinic acid tynofovir two pyrrole furan esters, L-TARTARIC ACID tynofovir two pyrrole furan esters, D-tartrate tynofovir two pyrrole furan esters and D-malic acid tynofovir two pyrrole furan esters and tenofovir disoproxil fumarate are quite or better.

Embodiment 16

Two pyrrole furan ester film coating tablet and the preparations thereof of DL-tartrate tynofovir

Component	Content (mg/ sheet)
		Label:	?
DL-tartrate tynofovir two pyrrole furan esters	316.0
		Microcrystalline Cellulose	300.0

Zeparox	120.0
		Pregelatinized Starch	50.0
Cross-linked carboxymethyl cellulose sodium	20.0
		Magnesium Stearate	10.0
Thin film coating material:	?
		Opadry II	20.0

Concrete operations:

According to each supplementary material in upper table, weigh, pregelatinized Starch and cross-linked carboxymethyl cellulose sodium are mixed together to 5 minutes, add Zeparox to mix 10 minutes, then add DL-tartrate tynofovir two pyrrole furan esters and Microcrystalline Cellulose to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, compressing tablet; Then coating material is stirred and is made into suspension with 75% ethanol, adopt Highefficentcoatingmachine, make sheet bed tempertaure carry out dressing 45 ℃ of left and right, obtain.

Embodiment 17

Two pyrrole furan ester gum wafer and the preparations thereof of DL-tartrate tynofovir

Component	Content (mg/ sheet)
		DL-tartrate tynofovir two pyrrole furan ester crystal form As	316.0
Microcrystalline Cellulose	70.0
		Zeparox	65.0
Sodium starch glycolate	15.0
		Magnesium Stearate	1.5

Concrete operations:

According to each supplementary material in upper table, weigh, sodium starch glycolate and Zeparox are mixed together to 5 minutes, add Microcrystalline Cellulose to mix 10 minutes, then add DL-tartrate tynofovir two pyrrole furan ester crystal form As to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, is packed into hypromellose capsule, obtains.

Embodiment 18

Two pyrrole furan ester film coating tablet and the preparations thereof of DL-oxysuccinic acid tynofovir

Component	Content (mg/ sheet)
		Label:	?
DL-oxysuccinic acid tynofovir two pyrrole furan esters	308.0
		Microcrystalline Cellulose	300.0
Zeparox	120.0
		Pregelatinized Starch	50.0
Cross-linked carboxymethyl cellulose sodium	20.0
		Magnesium Stearate	10.0
Thin film coating material:	?
		Opadry II	20.0

Concrete operations:

According to each supplementary material in upper table, weigh, pregelatinized Starch and cross-linked carboxymethyl cellulose sodium are mixed together to 5 minutes, add Zeparox to mix 10 minutes, then add DL-oxysuccinic acid tynofovir two pyrrole furan esters and Microcrystalline Cellulose to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 50 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, compressing tablet; Then coating material is stirred and is made into suspension with 75% ethanol, adopt Highefficentcoatingmachine, make sheet bed tempertaure carry out dressing 45 ℃ of left and right, obtain.

Embodiment 19

Two pyrrole furan ester gum wafer and the preparations thereof of D-malic acid tynofovir

Component	Content (mg/ sheet)
		D-malic acid tynofovir two pyrrole furan esters	308.0

Microcrystalline Cellulose	70.0
		Zeparox	65.0
Sodium starch glycolate	15.0
		Magnesium Stearate	1.5

Concrete operations:

According to each supplementary material in upper table, weigh, sodium starch glycolate and Zeparox are mixed together to 5 minutes, add Microcrystalline Cellulose to mix 10 minutes, then add D-malic acid tynofovir two pyrrole furan esters to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, be dried to moisture be less than 1.5% with fluidized-bed 50 ℃ of left and right, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, filled capsules obtains.

Embodiment 20

Component	Content (mg/ sheet)
		D-malic acid tynofovir two pyrrole furan esters	308.0
Microcrystalline Cellulose	70.0
		Zeparox	65.0
Polyvinylpolypyrrolidone	10.0
		Magnesium Stearate	1.5

Concrete operations:

Microcrystalline Cellulose, Zeparox and polyvinylpolypyrrolidone are dried to 10 hours 85 ℃ of left and right, according to each supplementary material in upper table, weigh, polyvinylpolypyrrolidone and Zeparox are mixed together to 5 minutes, add Microcrystalline Cellulose to mix 10 minutes, add again D-malic acid tynofovir two pyrrole furan esters to mix 10 minutes, finally add Magnesium Stearate to mix 10 minutes, filled capsules, obtains.

Embodiment 21

Two pyrrole furan ester film coating tablet and the preparations thereof of D-tartrate tynofovir

Component

Content (mg/ sheet)

Label:	?
		D-tartrate tynofovir two pyrrole furan esters	316.0
Microcrystalline Cellulose	300.0
		Zeparox	120.0
Pregelatinized Starch	50.0
		Cross-linked carboxymethyl cellulose sodium	20.0
Magnesium Stearate	10.0
		Thin film coating material:	?
Opadry II	20.0

Concrete operations:

According to each supplementary material in upper table, weigh, pregelatinized Starch and cross-linked carboxymethyl cellulose sodium are mixed together to 5 minutes, add Zeparox to mix 10 minutes, then add D-tartrate tynofovir two pyrrole furan esters and Microcrystalline Cellulose to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, compressing tablet; Then coating material is stirred and is made into suspension with 75% ethanol, adopt Highefficentcoatingmachine, make sheet bed tempertaure carry out dressing 45 ℃ of left and right, obtain.

Embodiment 22

Two pyrrole furan ester film coating tablet and the preparations thereof of L-TARTARIC ACID tynofovir

Component	Content (mg/ sheet)
		Label:	?
L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As	316.0
		Microcrystalline Cellulose	300.0
Zeparox	120.0
		Pregelatinized Starch	50.0
Cross-linked carboxymethyl cellulose sodium	20.0

Magnesium Stearate	10.0
		Thin film coating material:	?
Opadry II	20.0

Concrete operations:

According to each supplementary material in upper table, weigh, pregelatinized Starch and cross-linked carboxymethyl cellulose sodium are mixed together to 5 minutes, add Zeparox to mix 10 minutes, then add L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As and Microcrystalline Cellulose to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%,, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, compressing tablet; Then coating material is stirred and is made into suspension with 75% ethanol, adopt Highefficentcoatingmachine, make sheet bed tempertaure carry out dressing 45 ℃ of left and right, obtain.

Embodiment 23

DL-tartrate tynofovir two pyrrole furan esters, emtricitabine thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:	?
DL-tartrate tynofovir two pyrrole furan esters	316.0
		Emtricitabine	200.0
Microcrystalline Cellulose	300.0
		Zeparox	120.0
Pregelatinized Starch	50.0
		Cross-linked carboxymethyl cellulose sodium	20.0
Magnesium Stearate	10.0
		Thin film coating material:	?
Opadry II	20.0

Concrete operations:

According to each supplementary material in upper table, weigh, pregelatinized Starch and cross-linked carboxymethyl cellulose sodium are mixed together to 5 minutes, add Zeparox to mix 10 minutes, add DL-tartrate tynofovir two pyrrole furan esters to mix 10 minutes, then add emtricitabine and Microcrystalline Cellulose to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, compressing tablet; Then coating material is stirred and is made into suspension with 75% ethanol, adopt Highefficentcoatingmachine, make sheet bed tempertaure carry out dressing 45 ℃ of left and right, obtain.

Test shows, said preparation and former tenofovir disoproxil fumarate/emtricitabine composite tablet equivalence of grinding listing.

Embodiment 24

DL-oxysuccinic acid tynofovir two pyrrole furan esters, emtricitabine thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:	?
DL-oxysuccinic acid tynofovir two pyrrole furan esters	308.0
		Emtricitabine	200.0
Microcrystalline Cellulose	300.0
		Zeparox	120.0
Pregelatinized Starch	50.0
		Cross-linked carboxymethyl cellulose sodium	20.0
Magnesium Stearate	10.0
		Thin film coating material:	?
Opadry II	20.0

Concrete operations:

According to each supplementary material in upper table, weigh, pregelatinized Starch and cross-linked carboxymethyl cellulose sodium are mixed together to 5 minutes, add Zeparox to mix 10 minutes, add DL-oxysuccinic acid tynofovir two pyrrole furan esters to mix 10 minutes, then add emtricitabine and Microcrystalline Cellulose to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 50 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, compressing tablet; Then coating material is stirred and is made into suspension with 75% ethanol, adopt Highefficentcoatingmachine, make sheet bed tempertaure carry out dressing 45 ℃ of left and right, obtain.

Embodiment 25

DL-tartrate tynofovir two pyrrole furan esters, emtricitabine capsule and preparation thereof

Component	Content (mg/ sheet)
		DL-tartrate tynofovir two pyrrole furan ester crystal form As	316.0
Emtricitabine	200.0
		Microcrystalline Cellulose	145.0
Sodium starch glycolate	30.0
		Magnesium Stearate	2.0

Concrete operations:

Microcrystalline Cellulose, sodium starch glycolate are dried to 10 hours 85 ℃ of left and right, according to each supplementary material in upper table, weigh, sodium starch glycolate and Microcrystalline Cellulose are mixed together to 5 minutes, add emtricitabine to mix 10 minutes, add again DL-tartrate tynofovir two pyrrole furan ester crystal form As to mix 10 minutes, finally add Magnesium Stearate to mix 10 minutes, be packed into hypromellose capsule, obtain.

Embodiment 26

DL-oxysuccinic acid tynofovir two pyrrole furan esters, emtricitabine capsule and preparation thereof

Component	Content (mg/ sheet)
		DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As	308.0
Emtricitabine	200.0
		Microcrystalline Cellulose	145.0
Sodium starch glycolate	30.0
		Magnesium Stearate	2.0

Concrete operations:

Microcrystalline Cellulose, sodium starch glycolate are dried to 10 hours 85 ℃ of left and right, according to each supplementary material in upper table, weigh, sodium starch glycolate and Microcrystalline Cellulose are mixed together to 5 minutes, add emtricitabine to mix 10 minutes, add again DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As to mix 10 minutes, finally add Magnesium Stearate to mix 10 minutes, be packed into hypromellose capsule, obtain.

Embodiment 27

DL-tartrate tynofovir two pyrrole furan esters, emtricitabine, efavirenz film coating double-layer tablets and preparation thereof

Component	Content (mg/ sheet)
		Label:	?
Grain-I:	?
		DL-tartrate tynofovir two pyrrole furan esters	316.0
Emtricitabine	200.0
		Microcrystalline Cellulose	80.0
Cross-linked carboxymethyl cellulose sodium	20.0
		Magnesium Stearate	7.5
Grain-II:	?
		Efavirenz	600.0
Microcrystalline Cellulose	130.0
		Cross-linked carboxymethyl cellulose sodium	20.0
Sulfuric acid,monododecyl ester, sodium salt	10.0
		Hydroxypropylcellulose	20.0
Magnesium Stearate	10.0
		Thin film coating material	?

Opadry II

30.0

Concrete operations:

(1), grain-I preparation: weigh according to each supplementary material in upper table, Microcrystalline Cellulose and cross-linked carboxymethyl cellulose sodium are mixed together to 5 minutes, add emtricitabine to mix 10 minutes, add DL-tartrate tynofovir two pyrrole furan esters to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, obtains.

(1), grain-II preparation: weigh according to each supplementary material in upper table, Sulfuric acid,monododecyl ester, sodium salt, cross-linked carboxymethyl cellulose sodium and hydroxypropylcellulose are mixed together to 10 minutes, add Microcrystalline Cellulose to mix 10 minutes, then add efavirenz to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, obtains.

(3), core grain-I and core grain-II are adopted to bi-layer tablet press compressing tablet; Then coating material is stirred and is made into suspension with 75% ethanol, adopt Highefficentcoatingmachine, make sheet bed tempertaure carry out dressing 45 ℃ of left and right, obtain.

Embodiment 28

D-malic acid tynofovir two pyrrole furan esters, emtricitabine, efavirenz film coating double-layer tablets and preparation thereof

Component	Content (mg/ sheet)
		Label:	?
Grain-I:	?
		D-malic acid tynofovir two pyrrole furan esters	308.0
Emtricitabine	200.0
		Microcrystalline Cellulose	80.0
Cross-linked carboxymethyl cellulose sodium	20.0
		Magnesium Stearate	7.5
Grain-II:	?

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

Concrete operations:

(1), grain-I preparation: weigh according to each supplementary material in upper table, Microcrystalline Cellulose and cross-linked carboxymethyl cellulose sodium are mixed together to 5 minutes, add emtricitabine to mix 10 minutes, add D-malic acid tynofovir two pyrrole furan esters to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 50 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, obtains.

Embodiment 29

DL-tartrate tynofovir two pyrrole furan esters, emtricitabine, hydrochloric acid rilpivirine film coating double-layer tablets and preparation thereof

Component	Content (mg/ sheet)
		Label:	?

Grain-I:	?
		DL-tartrate tynofovir two pyrrole furan esters	316.0
Emtricitabine	200.0
		Microcrystalline Cellulose	180.0
Zeparox	80.0
		Pregelatinated shore powder	50.0
Cross-linked carboxymethyl cellulose sodium	20.0
		Magnesium Stearate	10.0
Grain-II:	?
		Hydrochloric acid rilpivirine	27.5
Microcrystalline Cellulose	60.0
		Zeparox	200.0
Cross-linked carboxymethyl cellulose sodium	15.0
		30 POVIDONE K 30 BP/USP ₃₀	3.0
Polysorbate20	0.5
		Magnesium Stearate	3.0
Thin film coating material	?
		Opadry II	25.0

Concrete operations:

(1), grain-I preparation: weigh according to each supplementary material in upper table, pregelatinated shore powder and cross-linked carboxymethyl cellulose sodium are mixed together to 5 minutes, add Zeparox and Microcrystalline Cellulose to mix 10 minutes, add emtricitabine to mix 10 minutes, then add DL-tartrate tynofovir two pyrrole furan esters to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, obtains.

(1), grain-II preparation: weigh according to each supplementary material in upper table, Microcrystalline Cellulose and cross-linked carboxymethyl cellulose sodium are mixed 10 minutes, add Zeparox to mix 10 minutes, then add hydrochloric acid rilpivirine to mix 10 minutes.Use 30 POVIDONE K 30 BP/USP ₃₀with the aqueous solution of polysorbate20, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, obtains.

Embodiment 30

L-TARTARIC ACID tynofovir two pyrrole furan esters, emtricitabine, hydrochloric acid rilpivirine film coating double-layer tablets and preparation thereof

Component	Content (mg/ sheet)
		Label:	?
Grain-I:	?
		L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As	316.0
Emtricitabine	200.0
		Microcrystalline Cellulose	180.0
Zeparox	80.0
		Pregelatinated shore powder	50.0
Cross-linked carboxymethyl cellulose sodium	20.0
		Magnesium Stearate	10.0
Grain-II:	?
		Hydrochloric acid rilpivirine	27.5
Microcrystalline Cellulose	60.0

Zeparox	200.0
		Cross-linked carboxymethyl cellulose sodium	15.0
30 POVIDONE K 30 BP/USP ₃₀	3.0
		Polysorbate20	0.5
Magnesium Stearate	3.0
		Thin film coating material	?
Opadry II	25.0

Concrete operations:

(1), grain-I preparation: weigh according to each supplementary material in upper table, pregelatinated shore powder and cross-linked carboxymethyl cellulose sodium are mixed together to 5 minutes, add Zeparox and Microcrystalline Cellulose to mix 10 minutes, add emtricitabine to mix 10 minutes, then add L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, obtains.

Embodiment 31

DL-tartrate tynofovir two pyrrole furan esters, emtricitabine, dust are for drawing Wei, Cobicistat double-layer tablets and preparation thereof

Component	Content (mg/ sheet)
		Grain-I:	?

DL-tartrate tynofovir two pyrrole furan esters	316.0
		Emtricitabine	200.0
Microcrystalline Cellulose	150.0
		Zeparox	120.0
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), grain-II preparation: weigh according to each supplementary material in upper table, hydroxypropylcellulose, cross-linked carboxymethyl cellulose sodium and 20% Zeparox are mixed 10 minutes, add residue Zeparox to mix 10 minutes, add again dust to replace La Wei and Cobicistat to mix 10 minutes, finally add Microcrystalline Cellulose to mix 10 minutes.Appropriate by purified water, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, obtains.

Embodiment 32

D-tartrate tynofovir two pyrrole furan esters, emtricitabine, dust are for drawing Wei, Cobicistat double-layer tablets and preparation thereof

Component	Content (mg/ sheet)
		Grain-I:	?
D-tartrate tynofovir two pyrrole furan esters	316.0
		Emtricitabine	200.0
Microcrystalline Cellulose	150.0
		Zeparox	120.0
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), grain-I preparation: weigh according to each supplementary material in upper table, pregelatinated shore powder and cross-linked carboxymethyl cellulose sodium are mixed together to 5 minutes, add Zeparox and Microcrystalline Cellulose to mix 10 minutes, add emtricitabine to mix 10 minutes, then add D-tartrate tynofovir two pyrrole furan esters to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, obtains.

Embodiment 33

DL-tartrate tynofovir two pyrrole furan esters, lamivudine thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:	?
Intragranular:	?
		DL-tartrate tynofovir two pyrrole furan esters	316.0
Lamivudine	300.0
		Microcrystalline Cellulose	220.0
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

According to each supplementary material in upper table, weigh, adopt the equivalent method of progressively increasing to be mixed together evenly cross-linked carboxymethyl cellulose sodium and Microcrystalline Cellulose, add lamivudine to mix 10 minutes, add emtricitabine to mix 10 minutes, then add DL-tartrate tynofovir two pyrrole furan esters to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens.Additional cross-linked carboxymethyl cellulose sodium and Microcrystalline Cellulose mix, and finally add Magnesium Stearate to mix 10 minutes, compressing tablet.Then coating material is stirred and is made into suspension with 75% ethanol, adopt Highefficentcoatingmachine, make sheet bed tempertaure carry out dressing 45 ℃ of left and right, obtain.

Embodiment 34

DL-tartrate tynofovir two pyrrole furan esters, lamivudine, efavirenz film coating double-layer tablets and preparation thereof

Component	Content (mg/ sheet)
		Label:	?
Grain-I:	?
		DL-tartrate tynofovir two pyrrole furan ester crystal form As	316.0
Lamivudine	300.0
		Microcrystalline Cellulose	60.0
Cross-linked carboxymethyl cellulose sodium	40.0
		Magnesium Stearate	7.5
Grain-II:	?

Efavirenz	600.0
		Microcrystalline Cellulose	145.0
Cross-linked carboxymethyl cellulose sodium	20.0
		Sulfuric acid,monododecyl ester, sodium salt	10.0
Hydroxypropylcellulose	20.0
		Magnesium Stearate	10.0
Thin film coating material:	?
		Opadry II	35.0

Concrete operations:

(1), grain-I preparation: weigh according to each supplementary material in upper table, Microcrystalline Cellulose and cross-linked carboxymethyl cellulose sodium are mixed together to 5 minutes, add lamivudine to mix 10 minutes, finally add DL-tartrate tynofovir two pyrrole furan ester crystal form As to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, obtains.

(1), grain-II preparation: weigh according to each supplementary material in upper table, hydroxypropylcellulose, Sulfuric acid,monododecyl ester, sodium salt and cross-linked carboxymethyl cellulose sodium are mixed 10 minutes, add Microcrystalline Cellulose to mix 10 minutes, then add efavirenz mixing 10 minutes.Appropriate by purified water, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens, additional Magnesium Stearate mixes 10 minutes, obtains.

Embodiment 35

The preparation of tynofovir two pyrrole furan ester succsinic acid (2:1) eutectics

Tynofovir two pyrrole furan ester 2.0g (3.84mmol) and succsinic acid 0.24g (2.12mmol) are dissolved in tetrahydrofuran (THF) 10ml, add normal hexane 5ml, stirring and crystallizing, filters, and dries, and obtains tynofovir two pyrrole furan ester succsinic acid (2:1) eutectics.

Embodiment 36～54

With reference to the operation of above-described embodiment 35, prepare eutectic or the salt of multiple tynofovir two pyrrole furan esters and medicinal acid:

Embodiment 55

Tynofovir two pyrrole furan ester succsinic acid (2:1) eutectics, emtricitabine thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:	?
Tynofovir two pyrrole furan ester succsinic acid (2:1) eutectics	273.0
		Emtricitabine	200.0
Microcrystalline Cellulose	300.0
		Zeparox	120.0
Pregelatinized Starch	50.0

Cross-linked carboxymethyl cellulose sodium	20.0
		Magnesium Stearate	10.0
Thin film coating material:	?
		Opadry II	20.0

According to each supplementary material in upper table, weigh, cross-linked carboxymethyl cellulose sodium, pregelatinized Starch and Zeparox are mixed together to 10 minutes, add Microcrystalline Cellulose to mix 10 minutes, add emtricitabine to mix 10 minutes, then add tynofovir two pyrrole furan ester succsinic acid (2:1) eutectics to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens.The additional Magnesium Stearate that adds mixes 10 minutes, compressing tablet.Then coating material is stirred and is made into suspension with 75% ethanol, adopt Highefficentcoatingmachine, make sheet bed tempertaure carry out dressing 45 ℃ of left and right, obtain.

Embodiment 56

Tynofovir two pyrrole furan ester fumaric acid (1:1) eutectics, emtricitabine thin membrane coated tablet and preparation thereof

Component	Content (mg/ sheet)
		Label:	?
Tynofovir two pyrrole furan ester fumaric acid (1:1) eutectics	300.0
		Emtricitabine	200.0
Microcrystalline Cellulose	300.0
		Zeparox	150.0
Pregelatinized Starch	50.0
		Cross-linked carboxymethyl cellulose sodium	20.0
Magnesium Stearate	10.0
		Thin film coating material	?
Opadry II	20.0

According to each supplementary material in upper table, weigh, cross-linked carboxymethyl cellulose sodium, pregelatinized Starch and Zeparox are mixed together to 10 minutes, add Microcrystalline Cellulose to mix 10 minutes, add emtricitabine to mix 10 minutes, then add tynofovir two pyrrole furan ester fumaric acid (1:1) eutectics to mix 10 minutes.Add purified water appropriate, adopt efficient wet nodulizer to granulate, with fluidized-bed, 60 ℃ of left and right, be dried to moisture and be less than 1.5%, then through the whole grain of 24 order perforated screens.The additional Magnesium Stearate that adds mixes 10 minutes, compressing tablet.Then coating material is stirred and is made into suspension with 75% ethanol, adopt Highefficentcoatingmachine, make sheet bed tempertaure carry out dressing 45 ℃ of left and right, obtain.

The above; it is only the specific embodiment of the present invention; but protection scope of the present invention is not limited to this; any those of ordinary skill in the art are in the disclosed technical scope of the present invention; the variation that can expect without creative work or replacement, within all should being encompassed in protection scope of the present invention.Therefore, protection scope of the present invention should be as the criterion with the protection domain that claims were limited.

Claims

1. the solid of tynofovir two pyrrole furan esters, it is:

(1) the two pyrrole furan ester complexes of the tynofovir shown in formula IV,

IV

Or,

(2) two pyrrole furan ester eutectic or the salt of the tynofovir shown in formula V,

V

Wherein, n=1, 2 or 3, B 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 2, fourth disulfonic acid 2, 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, fumaric 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 or asparagine.

2. the solid of tynofovir two pyrrole furan esters according to claim 1, wherein,

In formula IV:

M is that 1, X is DL-tartrate, is DL-tartrate tynofovir two pyrrole furan esters; Or,

M is that 1, X is D-tartrate, is D-tartrate tynofovir two pyrrole furan esters; Or,

M is that 1, X is DL-oxysuccinic acid, is DL-oxysuccinic acid tynofovir two pyrrole furan esters; Or,

M is that 1, X is D-malic acid, is D-malic acid tynofovir two pyrrole furan esters; Or,

M is that 1, X is L-TARTARIC ACID, is L-TARTARIC ACID tynofovir two pyrrole furan esters;

In formula V:

N=3, B is selected from: phosphoric acid, citric acid, Weibull or Lalgine; Or,

N=2, B 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, fumaric 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 or L-glutamic acid; Or,

N=1, B is 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, fumaric 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 or asparagine.

3. the solid of tynofovir two pyrrole furan esters according to claim 2, wherein,

Described DL-tartrate tynofovir two pyrrole furan esters are DL-tartrate tynofovir two pyrrole furan ester crystal form As, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 7.7 ° ± 0.2 °, 10.1 ° ± 0.2 °, 10.8 ° ± 0.2 °, 13.4 ° ± 0.2 °, 16.8 ° ± 0.2 °, 17.6 ° ± 0.2 °, 19.2 ° ± 0.2 °, 20.6 ° ± 0.2 °, 21.4 ° ± 0.2 °, 22.5 ± 0.2 ° and 23.6 ° ± 0.2 °;

Described D-tartrate tynofovir two pyrrole furan esters are D-tartrate tynofovir two pyrrole furan ester crystal form As, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 4.7 ° ± 0.2 °, 10.4 ° ± 0.2 °, 16.5 ° ± 0.2 °, 17.1 ° ± 0.2 °, 20.5 ° ± 0.2 °, 24.7 ° ± 0.2 ° and 28.1 ° ± 0.2 °;

Described DL-oxysuccinic acid tynofovir two pyrrole furan esters are DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 5.0 ° ± 0.2 °, 8.1 ° ± 0.2 °, 10.1 ° ± 0.2 °, 13.1 ° ± 0.2 °, 13.8 ° ± 0.2 °, 17.2 ° ± 0.2 °, 19.4 ° ± 0.2 °, 20.1 ° ± 0.2 ° and 25.2 ° ± 0.2 °;

Described D-malic acid tynofovir two pyrrole furan esters are D-malic acid tynofovir two pyrrole furan ester crystal form As, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 7.8 ° ± 0.2 °, 8.1 ° ± 0.2 °, 11.8 ° ± 0.2 °, 14.1 ° ± 0.2 °, 16.6 ° ± 0.2 °, 18.9 ° ± 0.2 °, 21.0 ° ± 0.2 °, 22.6 ° ± 0.2 ° and 24.1 ° ± 0.2 °;

Described L-TARTARIC ACID tynofovir two pyrrole furan esters are L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As, use Cu-K α radiation, its X-ray powder diffraction has characteristic diffraction peak in following 2 θ positions: 4.0 ° ± 0.2 °, 6.9 ° ± 0.2 °, 7.5 ° ± 0.2 °, 8.4 ° ± 0.2 °, 17.1 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.7 ° ± 0.2 ° and 22.5 ° ± 0.2 °;

Described tynofovir two pyrrole furan ester eutectics are tynofovir two pyrrole furan ester phosphoric acid (3:1) eutectics, tynofovir two pyrrole furan ester citric acid (3:1) eutectics, tynofovir two pyrrole furan ester phosphoric acid (2:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (2:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (2:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (2:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (2:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (2:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (2:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (2:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (2:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (2:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (2:1) eutectics, tynofovir two pyrrole furan ester (2:1) citric acid eutectics, tynofovir two pyrrole furan ester pamoic acid (2:1) eutectics, tynofovir two pyrrole furan ester phosphoric acid (1:1) eutectics, tynofovir two pyrrole furan ester carbonic acid (1:1) eutectics, tynofovir two pyrrole furan ester acetic acid (1:1) eutectics, tynofovir two pyrrole furan ester (1:1) propionic acid eutectics, tynofovir two pyrrole furan ester Pfansteihl (1:1) eutectics, tynofovir two pyrrole furan ester D-ALPHA-Hydroxypropionic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic lactic acid (1:1) eutectics, tynofovir two pyrrole furan ester palmitinic acid (1:1) eutectics, tynofovir two pyrrole furan ester stearic acid (1:1) eutectics, tynofovir two pyrrole furan ester oxalic acid (1:1) eutectics, tynofovir two pyrrole furan ester propanedioic acid (1:1) eutectics, tynofovir two pyrrole furan ester succsinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L MALIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-malic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemization oxysuccinic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-TARTARIC ACID (1:1) eutectics, tynofovir two pyrrole furan ester D-tartrate (1:1) eutectics, tynofovir two pyrrole furan ester racemic tartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester mesotartaric acid (1:1) eutectics, tynofovir two pyrrole furan ester fumaric acid (1:1) eutectics, tynofovir two pyrrole furan ester toxilic acid (1:1) eutectics, tynofovir two pyrrole furan ester citric acid (1:1) eutectics, tynofovir two pyrrole furan ester phenylformic acid (1:1) eutectics, tynofovir two pyrrole furan ester L-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester D-amygdalic acid (1:1) eutectics, tynofovir two pyrrole furan ester racemic mandelic acid (1:1) eutectics, tynofovir two pyrrole furan ester nicotinic acid (1:1) eutectics, tynofovir two pyrrole furan ester hydroxyl naphthoic acid (1:1) eutectics, tynofovir two pyrrole furan ester pamoic acid (1:1) eutectics or tynofovir two pyrrole furan ester urobenzoic acid (1:1) eutectics,

Described tynofovir two pyrrole furan ester salt are tynofovir two pyrrole furan ester sulfuric acid (2:1) salt, tynofovir two pyrrole furan ester ethionic acid (2:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (2:1) salt, tynofovir two pyrrole furan ester naphthalene-1, 5-disulfonic acid (2:1) salt, tynofovir two pyrrole furan ester hydrochloride (1:1) salt, tynofovir two pyrrole furan ester sulfuric acid (1:1) salt, tynofovir two pyrrole furan ester thiocyanic acid (1:1) salt, tynofovir two pyrrole furan ester Hydrogen bromide (1:1) salt, tynofovir two pyrrole furan ester nitric acid (1:1) salt, tynofovir two pyrrole furan ester methylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester taurine (1:1) salt, tynofovir two pyrrole furan ester ethionic acid (1:1) salt, tynofovir two pyrrole furan ester fourth disulfonic acid (1:1) salt, tynofovir two pyrrole furan ester Phenylsulfonic acid (1:1) salt, tynofovir two pyrrole furan ester tosic acid (1:1) salt, tynofovir two pyrrole furan esters 2, 5-dihydroxy benzenes sulfonic acid (1:1) salt or tynofovir two pyrrole furan ester naphthalene-2-sulfonic acid (1:1) salt.

4. the solid of tynofovir two pyrrole furan esters according to claim 3, wherein,

The X-ray powder diffraction of described DL-tartrate tynofovir two pyrrole furan ester crystal form As has characteristic diffraction peak in following 2 θ positions: 7.7 ° ± 0.2 °, 10.1 ° ± 0.2 °, 10.8 ° ± 0.2 °, 13.4 ° ± 0.2 °, 16.3 ° ± 0.2 °, 16.8 ° ± 0.2 °, 17.6 ° ± 0.2 °, 17.9 ° ± 0.2 °, 19.2 ° ± 0.2 °, 20.6 ° ± 0.2 °, 21.4 ° ± 0.2 °, 22.5 ° ± 0.2 °, 23.6 ° ± 0.2 °, 26.1 ° ± 0.2 °, 29.1 ° ± 0.2 ° and 30.5 ° ± 0.2 °,

The X-ray powder diffraction of described D-tartrate tynofovir two pyrrole furan ester crystal form As has characteristic diffraction peak in following 2 θ positions: 4.7 ° ± 0.2 °, 10.4 ° ± 0.2 °, 11.8 ° ± 0.2 °, 14.4 ° ± 0.2 °, 16.5 ° ± 0.2 °, 17.1 ° ± 0.2 °, 17.7 ° ± 0.2 °, 18.9 ° ± 0.2 °, 20.5 ° ± 0.2 °, 20.9 ° ± 0.2 °, 21.7 ° ± 0.2 °, 24.7 ° ± 0.2 ° and 28.1 ° ± 0.2 °;

The X-ray powder diffraction of described DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As has characteristic diffraction peak in following 2 θ positions: 5.0 ° ± 0.2 °, 5.9 ° ± 0.2 °, 7.4 ° ± 0.2 °, 8.1 ° ± 0.2 °, 9.1 ° ± 0.2 °, 10.1 ° ± 0.2 °, 10.8 ° ± 0.2 °, 11.6 ° ± 0.2 °, 12.6 ° ± 0.2 °, 13.1 ° ± 0.2 °, 13.8 ° ± 0.2 °, 14.5 ° ± 0.2 °, 14.8 ° ± 0.2 °, 16.1 ° ± 0.2 °, 17.2 ° ± 0.2 °, 18.4 ° ± 0.2 °, 19.4 ° ± 0.2 °, 20.1 ° ± 0.2 °, 21.3 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.9 ° ± 0.2 °, 23.4 ° ± 0.2 °, 24.4 ° ± 0.2 °, 25.2 ° ± 0.2 °, 26.2 ° ± 0.2 °, 27.7 ° ± 0.2 ° and 30.4 ° ± 0.2 °,

The X-ray powder diffraction of described D-malic acid tynofovir two pyrrole furan ester crystal form As has characteristic diffraction peak in following 2 θ positions: 7.8 ° ± 0.2 °, 8.1 ° ± 0.2 °, 9.9 ° ± 0.2 °, 11.8 ° ± 0.2 °, 12.0 ° ± 0.2 °, 12.4 ° ± 0.2 °, 13.6 ° ± 0.2 °, 14.1 ° ± 0.2 °, 16.1 ° ± 0.2 °, 16.6 ° ± 0.2 °, 16.8 ° ± 0.2 °, 18.1 ° ± 0.2 °, 18.9 ° ± 0.2 °, 19.5 ° ± 0.2 °, 20.3 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.6 ° ± 0.2 °, 24.1 ° ± 0.2 °, 25.0 ° ± 0.2 ° and 25.5 ° ± 0.2 °,

The X-ray powder diffraction of described L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As has characteristic diffraction peak in following 2 θ positions: 4.0 ° ± 0.2 °, 6.3 ° ± 0.2 °, 6.5 ° ± 0.2 °, 6.9 ° ± 0.2 °, 7.5 ° ± 0.2 °, 8.4 ° ± 0.2 °, 9.2 ° ± 0.2 °, 10.3 ° ± 0.2 °, 11.4 ° ± 0.2 °, 12.2 ° ± 0.2 °, 13.0 ° ± 0.2 °, 13.8 ° ± 0.2 °, 15.0 ° ± 0.2 °, 16.0 ° ± 0.2 °, 17.1 ° ± 0.2 °, 18.0 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.3 ° ± 0.2 °, 20.7 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.5 ° ± 0.2 °, 23.3 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.4 ° ± 0.2 °, 24.9 ° ± 0.2 °, 25.3 ° ± 0.2 °, 26.0 ° ± 0.2 °, 27.5 ° ± 0.2 ° and 28.2 ° ± 0.2 °.

5. the solid of tynofovir two pyrrole furan esters according to claim 4, wherein,

The X-ray powder diffraction of described DL-tartrate tynofovir two pyrrole furan ester crystal form As has following characteristic diffraction peak and relative intensity thereof:

Preferably, the X-ray powder diffraction of described DL-tartrate tynofovir two pyrrole furan ester crystal form As substantially as shown in Figure 1;

The X-ray powder diffraction of described D-tartrate tynofovir two pyrrole furan ester crystal form As has following characteristic diffraction peak and relative intensity thereof:

Preferably, the X-ray powder diffraction of described D-tartrate tynofovir two pyrrole furan ester crystal form As substantially as shown in Figure 2;

The X-ray powder diffraction of described DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As has following characteristic diffraction peak and relative intensity thereof:

Preferably, the X-ray powder diffraction of described DL-oxysuccinic acid tynofovir two pyrrole furan ester crystal form As substantially as shown in Figure 3;

The X-ray powder diffraction of described D-malic acid tynofovir two pyrrole furan ester crystal form As has following characteristic diffraction peak and relative intensity thereof:

Preferably, the X-ray powder diffraction of described D-malic acid tynofovir two pyrrole furan ester crystal form As substantially as shown in Figure 4;

The X-ray powder diffraction of described L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As has following characteristic diffraction peak and relative intensity thereof:

Preferably, the X-ray powder diffraction of described L-TARTARIC ACID tynofovir two pyrrole furan ester crystal form As substantially as shown in Figure 5.

6. the preparation method of the solid of the two pyrrole furan esters of the tynofovir described in any one in claim 1～5, described preparation method is selected from any one in following methods:

(2) separate out solid;

(3) separated solid of separating out;

(2) crystallization;

(3) separated solid of separating out;

7. the preparation method of the solid of tynofovir two pyrrole furan esters according to claim 6, wherein,

In the step of method one (1), described solvent is selected from methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), acetonitrile, methylene dichloride, trichloromethane, acetone, N,N-DIMETHYLACETAMIDE, dimethyl formamide, methyl-sulphoxide or their mixture; The mol ratio of tynofovir two pyrrole furan esters and DL-tartrate, D-tartrate, L-TARTARIC ACID, DL-oxysuccinic acid or D-malic acid is 0.5:1～2:1;

In the step of method two (1), described solvent is selected from water, 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, acetonitrile, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, pimelinketone, toluene, dimethylbenzene, N,N-DIMETHYLACETAMIDE, dimethyl formamide or their mixture; Described tynofovir two pyrrole furan esters and sour mol ratio are 4:1～0.5:1; Preferably, when preparing tynofovir two pyrrole furan ester acid (3:1) eutectics or salt, tynofovir two pyrrole furan esters and sour mol ratio are 3.5:1～2.7:1; When preparing tynofovir two pyrrole furan ester acid (2:1) eutectics or salt, tynofovir two pyrrole furan esters and sour mol ratio are 2.5:1～1.7:1; When preparing tynofovir two pyrrole furan ester acid (1:1) eutectics or salt, tynofovir two pyrrole furan esters and sour mol ratio are 1.5:1～0.5:1.

8. a pharmaceutical composition, the solid of the tynofovir two pyrrole furan esters that in the solid that it comprises the two pyrrole furan esters of the tynofovir described in any one in the claim 1～5 for the treatment of significant quantity or claim 6～7, any one preparation method makes, and pharmaceutical excipient.

9. pharmaceutical composition according to claim 8, it also comprises another kind or other multiple following antiviral agent or the antiviral auxiliary reagent of being selected from: 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, preferably 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 one of following:

The solid of the tynofovir two pyrrole furan esters that the preparation method in the solid of the tynofovir two pyrrole furan esters in 11. claims 1～5 described in any one or claim 6～7 described in any one makes prevents and/or treats the application in the medicine of virus infection in preparation.

12. application according to claim 11, is characterized in that, the solid of described tynofovir two pyrrole furan esters prevents and/or treats the application in the medicine of hepatitis B virus and/or HIV (human immunodeficiency virus) infection in preparation.