CN106414466A

CN106414466A - Tenofovir alafenamide complex, preparation method therefor and use thereof

Info

Publication number: CN106414466A
Application number: CN201580024952.XA
Authority: CN
Inventors: 赵雄; 袁道义; 杜全胜; 林志忠; 高炳坤; 李学超; 李方群; 罗杰; 向志祥; 孙鹏; 钱春霞; 徐同利
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Haisike Pharmaceutical (Meishan) Co.,Ltd.
Priority date: 2014-05-20
Filing date: 2015-05-04
Publication date: 2017-02-15
Anticipated expiration: 2035-05-04
Also published as: CN105085571A; CN111205325A; CN106414466B; WO2015176602A1

Abstract

The present invention relates to tenofovir alafenamide complex represented by formula II. The present invention also relates to a preparation method for said tenofovir alafenamide complex, pharmaceutical compositions containing the tenofovir alafenamide complex, and uses of the tenofovir alafenamide complex in preparing medicines for preventing and/or treating virus infection, especially Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection.

Description

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

Technical field

The present invention relates to organic chemistry filed and pharmaceutical field, specifically related to prevent and/or treat virus infective medicament tenofovir Chinese mugwort to draw compound of phenol amine and preparation method thereof and the compound preparing prevention and/or treatment virus infection, purposes particularly in the medicine of hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) infection, and the pharmaceutical composition containing the compound.

Background technology

Tenofovir Chinese mugwort draws phenol amine (Tenofovir alafenamide), and chemistry is entitled：N- [(S)-[[(1R) -2- (6- amino -9H- purine -9- bases) -1- methyl ethoxies] methyl] phenoxy group phosphono]-ALANINE -1- Methylethyl esters；CAS accession number is：379270-37-8；Molecular structural formula is shown in formula I：

Tenofovir Chinese mugwort draws the ester prodrug thereof that phenol amine is tenofovir, is a kind of acyclic class nucleotide reverse transcriptase inhibitors, with broad-spectrum disease resistance toxic action, can suppress HIV-1, HIV-2 reverse transcriptase and HBV polymerases, so that suppressing virus replication.Tenofovir Chinese mugwort is hydrolyzed to tenofovir after drawing phenol amine oral, tenofovir is melted into the metabolite tenofovir diphosphonic acid with pharmacological activity by cell kinase phosphoric acid, the latter competes with 5'- deoxyadenosine triphosphates acid, participate in the synthesis of viral DNA, DNA extensions are caused to be obstructed due to lacking 3'- hydroxyls after into viral DNA, so as to suppress the duplication of virus.Compared with the similar medicine tenofovir dipivoxil (Tenofovir disoproxil) listed, tenofovir Chinese mugwort draws the antiviral activity of phenol amine to be its 10 times, stability in blood plasma is its 200 times, half-life period is compared with which raises 220 times, accumulation in PMBC (PBMC) is compared with which raises nearly 10 times, therefore tenofovir Chinese mugwort draws phenol amine to be used for the prevention and/or treatment that hepatitis type B virus (HBV) and human immunodeficiency virus (HIV/AIDS) infect, with more preferable curative effect, higher security and lower drug resistance.At present, tenofovir Chinese mugwort draws phenol amine single preparations of ephedrine, and tenofovir Chinese mugwort draws phenol amine/emtricitabine/Cobicistat/ angstroms to draw Wei compound preparation and tenofovir Chinese mugwort to draw phenol amine/emtricitabine/Cobicistat/ DRVs compound preparation external just in clinical studies.

Tenofovir Chinese mugwort draw phenol amine due to its solid-state fusing point it is relatively low, solubility is smaller in water, be unfavorable for pharmaceutical preparation preparation and Dissolution in pharmaceutical preparation, therefore the form that tenofovir Chinese mugwort draws phenol amine to be developed to salt is used for preparation.Such as CN1443189A, CN1706855A etc. disclose the fumarate that tenofovir Chinese mugwort draws phenol amine, although tenofovir Chinese mugwort draws phenol amine fumarate to have larger improvement compared with free alkali in terms of water-soluble, physical behavior, its chemical stability, thermodynamic stability be not good enough.CN103732594A discloses the hemifumarate that tenofovir Chinese mugwort draws phenol amine, wherein show that tenofovir Chinese mugwort draws phenol amine hemifumarate compared with tenofovir Chinese mugwort draws phenol amine fumarate, there is advantage in terms of diastereoisomer impurity, chemical stability, thermodynamic stability is removed, be that tenofovir Chinese mugwort draws a kind of more excellent salt of phenol amine；But tenofovir Chinese mugwort draws the preparation technology of phenol amine hemifumarate cumbersome, such as need to add tenofovir Chinese mugwort drawing phenol amine hemifumarate crystal seed in preparation process.

Therefore, in order to overcome above-mentioned deficiency of the prior art, it is necessary to develop the new solid forms that tenofovir Chinese mugwort draws phenol amine, physical behavior, chemical stability, process operability or preparation adaptability to can further improve tenofovir Chinese mugwort drawing phenol amine etc., and then strengthen the safety and effectiveness of product, provide more preferable medicine selection for many patients.

The content of the invention

A purpose of the invention is to provide the new compound that tenofovir Chinese mugwort draws phenol amine.The compound is better than prior art at least one aspects such as physical behavior, chemical stability, process operability, preparation adaptability.

The preparation method of phenol amine compound is drawn another object of the present invention is to provide above-mentioned tenofovir Chinese mugwort.

A further object of the present invention is that providing above-mentioned tenofovir Chinese mugwort draws crystal formation of phenol amine compound and preparation method thereof.

A further object of the present invention is to provide the pharmaceutical composition that the above-mentioned tenofovir Chinese mugwort comprising therapeutically effective amount draws phenol amine compound.

A further object of the present invention is that providing above-mentioned tenofovir Chinese mugwort draws application of the phenol amine compound in the medicine for preparing prevention and/or treatment virus infection.

According to the purpose of the present invention, phenol amine compound is drawn the invention provides a kind of Chinese mugwort of the tenofovir shown in formula II,

Wherein, n=1,2 or 3, X are selected from：Hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, dodecyl sulphate, phosphoglycerol, methanesulfonic acid, ethyl sulfonic acid, 2- ethylenehydrinsulfonic acids, taurine, camphorsulfonic acid, cyclamic acid, sulfamic acid, ethionic acid, fourth disulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, para hydroxybenzene sulphur Acid, o hydroxybenzenesulfonic acid, 2,5- dihydroxy benzenes sulfonic acids, p-aminobenzene sulfonic acid, naphthalene-2-sulfonic acid, naphthalene -1,5- disulfonic acid, formic acid, acetic acid, glycolic, 2,2- dichloroacetic acid, propionic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, racemic lactic acid (also known as：DL-LACTIC ACID), pentamethylene propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, octanoic acid, n-nonanoic acid, capric acid, undecenoic acid, laurate, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, butanedioic acid, L MALIC ACID, D-malic acid, racemization malic acid (also known as：DL-malic acid), L-TARTARIC ACID, D- tartaric acid, racemic tartaric acid (also known as：DL- tartaric acid), mesotartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, a-KG, adipic acid, decanedioic acid, citric acid, benzoic acid, P-methoxybenzoic acid, 4- acetaminobenzoic acids, salicylic acid, acetylsalicylic acid, gentianic acid, 4-ASA, phenylacetic acid, L- mandelic acids, D- mandelic acids, racemic mandelic acid (also known as：DL- mandelic acids), 3- phenylpropionic acids, cinnamic acid, caffeic acid, benzenebutanoic acid, picric acid, nicotinic acid, orotic acid, chinic acid, ascorbic acid, glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, lactobionic acid, camphoric acid, galactosaccharic acid (also known as：Glactaric acid), tannic acid (also known as：Tannic acid), alginic acid, hydroxyl naphthoic acid (also known as：3- hydroxy-2-naphthoic acids), pamoic acid (also known as：4,4'- methylene two (3- hydroxy-2-naphthoic acids) or Piao's acid), amino acid or acylated amino (such as acetylgiycine, hippuric acid, asparatate, glutamic acid, pyroglutamic acid, glutamine, asparagine).

In above-mentioned formula II, " compound " refers to the compound that tenofovir Chinese mugwort draws phenol amine to combine and coexist by the effect of the non-covalent bonds such as hydrogen bond, ionic bond with corresponding acid, including salt, eutectic etc..The compound still further comprises the forms such as its polycrystalline, solvate, solvate polycrystalline, hydrate, hydrate polycrystalline.

" salt " is well known to those skilled in the art of the present technique, refers to the compound as formed by cation and anion by the effect of ionic bond." tenofovir Chinese mugwort draws phenol amine salt " is to refer in tenofovir ends solid of the drawing phenol amine with acid composition, proton translocation in acid has arrived tenofovir Chinese mugwort and drawn on phenol amine, and the tenofovir Chinese mugwort of protonation draws phenol amine cation to act on and be combined with each other by ionic bond with acid radical anion.

" eutectic " refers to that tenofovir Chinese mugwort draws phenol amine with acid with the solid of eutectic form formation." eutectic " (Co-Crystals) refers to a kind of multicomponent crystal for having and fixing stoichiometric proportion, and each component is, with molecular level, to be combined and coexisted by hydrogen bond or other non-covalent bonds, the effect of nonionic key in the crystal.In pharmaceutical co-crystals, generally comprise active constituents of medicine and another or a variety of eutectic forming bodies (Co-crystal former), in " tenofovir Chinese mugwort draws phenol amine eutectic ", tenofovir Chinese mugwort draws phenol amine to be active constituents of medicine, and acid is eutectic forming body.When single pure eutectic forming body at room temperature with liquid in the presence of, the eutectic is also referred to as " solvate ", it is referred to as " hydrate " when wherein solvent is water, such as tenofovir, which ends, draws phenol amine and the eutectic of acetic acid formation, is properly termed as the acetic acid solvate that tenofovir Chinese mugwort draws phenol amine.

Above-mentioned " eutectic " also includes so some multicomponent crystal with fixed stoichiometric proportion, between these crystal pharmaceutical active compositions and other components, a part by hydrogen bond or other non-covalent bond effects, active force of the another part by ionic bond or between hydrogen bond and ionic bond and combine.

Above-mentioned " tenofovir Chinese mugwort draws phenol amine eutectic or salt " also includes tenofovir Chinese mugwort and draws the forms such as solvate, the hydrate of phenol amine eutectic or salt.Draw phenol amine eutectic to be prepared in certain solvent when tenofovir Chinese mugwort, pulp or during crystallization, the solvent is likely to enter tenofovir Chinese mugwort and drawn in phenol amine eutectic or salt crystal, formation solvate；When the solvent is water, that is, it is likely to form hydrate.

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

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

In above-mentioned formula II, 1/n refers to the approx. molar ratio of components of tenofovir Chinese mugwort drawing phenol amine and respective acids in the composite structure, can pass through¹Mode H-NMR, elementary analysis, HPLC, X-ray diffraction (such as Advances in crystal X-ray diffraction) is characterized.The scope for being somebody's turn to do " approximate " is generally ± 0.15, and preferably ± 0.1.

In above-mentioned formula II, " tenofovir Chinese mugwort drawing phenol amine compound " draws phenol amine and acid X stoichiometric number according to tenofovir Chinese mugwort in structure, can be expressed as " X tenofovirs Chinese mugwort drawing phenol amine (1:N) ", wherein X and n definition is as described in formula II, and " 1:N " is the approx. molar ratio of components that tenofovir Chinese mugwort draws acid X and tenofovir Chinese mugwort drawing phenol amine in phenol amine compound, can be passed through¹The modes such as H-NMR, elementary analysis, HPLC, Advances in crystal X-ray diffraction are obtained.

In one embodiment, in formula II, n=3, X is selected from：Phosphoric acid, citric acid, tannic acid (also known as：Tannic acid) or alginic acid.

In one embodiment, in formula II, n=2, X is selected from：Sulfuric acid, persulfuric acid, thiocyanic acid, phosphoric acid, carbonic acid, phosphoglycerol, ethionic acid, fourth disulfonic acid, naphthalene -1,5- disulfonic acid, oxalic acid, malonic acid, butanedioic acid, L MALIC ACID, D-malic acid, racemization malic acid (also known as：DL-malic acid), L-TARTARIC ACID, D- tartaric acid, racemic tartaric acid (also known as：DL- tartaric acid), mesotartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, a-KG, adipic acid, decanedioic acid, citric acid, camphoric acid, galactosaccharic acid (also known as：Glactaric acid), tannic acid (also known as：Tannic acid), alginic acid, pamoic acid (also known as：4,4'- methylene two (3- hydroxy-2-naphthoic acids) or Piao acid), asparatate, glutamic acid.

In one embodiment, in formula II, n=1, X is selected from：Hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, dodecyl sulphate, phosphoglycerol, methanesulfonic acid, ethyl sulfonic acid, 2- ethylenehydrinsulfonic acids, taurine, camphorsulfonic acid, cyclamic acid, sulfamic acid, ethionic acid, fourth disulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, p-hydroxybenzenyl sulfonate, o hydroxybenzenesulfonic acid, 2, 5- dihydroxy benzenes sulfonic acids, p-aminobenzene sulfonic acid, saccharin, naphthalene-2-sulfonic acid, naphthalene -1, 5- disulfonic acid, formic acid, acetic acid, glycolic, 2, 2- dichloroacetic acid, propionic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, racemic lactic acid (also known as：DL-LACTIC ACID), pentamethylene propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, octanoic acid, n-nonanoic acid, capric acid, undecenoic acid, laurate, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, butanedioic acid, L MALIC ACID, D-malic acid, racemization malic acid (also known as：DL-malic acid), L-TARTARIC ACID, D- tartaric acid, racemic tartaric acid (also known as：DL- tartaric acid), interior disappear Revolve tartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, a-KG, adipic acid, decanedioic acid, citric acid, benzoic acid, P-methoxybenzoic acid, 4- acetaminobenzoic acids, salicylic acid, acetylsalicylic acid, gentianic acid, 4-ASA, phenylacetic acid, L- mandelic acids, D- mandelic acids, racemic mandelic acid (also known as：DL- mandelic acids), 3- phenylpropionic acids, cinnamic acid, caffeic acid, benzenebutanoic acid, picric acid, nicotinic acid, orotic acid, chinic acid, ascorbic acid, glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, lactobionic acid, camphoric acid, galactosaccharic acid (also known as：Glactaric acid), tannic acid (also known as：Tannic acid), alginic acid, hydroxyl naphthoic acid (also known as：3- hydroxy-2-naphthoic acids), pamoic acid (also known as：4,4'- methylene two (3- hydroxy-2-naphthoic acids) or Piao acid), acetylgiycine, hippuric acid, asparatate, glutamic acid, pyroglutamic acid, glutamine, asparagine.

In one embodiment, the tenofovir Chinese mugwort shown in formula II draws phenol amine compound to be selected from：L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:Or sulfuric acid tenofovir Chinese mugwort draws phenol amine (1 1):1).

According to the purpose of the present invention, the invention provides the preparation method that the Chinese mugwort of tenofovir shown in formula II draws phenol amine compound, this method includes：

(1) in suitable solvent, form a kind of ended comprising tenofovir and draw the solution of phenol amine and acid X；

(2) solid is separated out；

(3) separated out solid is separated；

(4) alternatively, the solid of separation is dried, or rear re-dry is further purified.

In above method step (1), tenofovir Chinese mugwort draws phenol amine to be made according to the method disclosed in patent document CN1443189A and CN1706855A or WO2013052094A etc..These documents are incorporated into the present invention by reference.Tenofovir Chinese mugwort draws phenol amine to exist with any form, such as includes crystal formation, amorphous or their mixed form.

In above method step (1), " suitable solvent " refers to draw phenol amine and acid to have certain solubility tenofovir Chinese mugwort, while the solvent that tenofovir Chinese mugwort draws phenol amine compound can be formed wherein.These suitable solvents are selected from acetonitrile, ethanol, methanol, propyl alcohol, isopropanol, butanol, ethylene glycol, Ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ether, isopropyl ether, n-butyl ether, glycol monoethyl ether, glycol dimethyl ether, t-butyl methyl ether, tetrahydrofuran, petroleum ether, dichloromethane, chloroform, n-hexane, hexamethylene, acetone, butanone, pentanone, cyclohexanone, toluene, dimethylbenzene etc. or their mixture.The suitable solvent ends with tenofovir and draws the weight ratio generally 3 of phenol amine:1~100:1.

In above method step (1), described " sour X " is selected from the acid representated by X in formula II.Tenofovir Chinese mugwort draws phenol amine to be generally 4 with acid X molar ratios:1~0.5:1, when preparing, " X tenofovirs Chinese mugwort draws phenol amine (1:3) " during compound, tenofovir Chinese mugwort draws phenol amine to be generally 2.7 with acid X molar ratios:1~3.5:1；When preparing, " X tenofovirs Chinese mugwort draws phenol amine (1:2) " during compound, Tenofovir Chinese mugwort draws phenol amine to be generally 1.7 with acid X molar ratios:1~2.5:1；When preparing, " X tenofovirs Chinese mugwort draws phenol amine (1:1) " during compound, tenofovir Chinese mugwort draws phenol amine to be generally 0.5 with acid X molar ratios:1~1.5:1.

In above method step (2), the method for " the precipitation solid " is method conventional in the art, such as cools down, adds anti-solvent, concentrates out the alone of the methods such as partial solvent plus crystal seed or combination.

In above method step (3), " separation " method includes filtering or centrifugation etc..It is alternatively possible to be washed with suitable solvent to collected solid.

In above method step (4), " drying " mode includes constant pressure and dry, is dried under reduced pressure or combinations thereof application.The method of " being further purified " includes the forms such as recrystallization, pulp, washing.

L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2)

In one embodiment, in formula II, n elects 2, X as and elects L-TARTARIC ACID as, i.e., draw phenol amine with L-TARTARIC ACID with 2 there is provided tenofovir Chinese mugwort:The compound of 1 molar composition ratio formation, is referred to as " L-TARTARIC ACID tenofovir Chinese mugwort drawing phenol amine (1:2)”.

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

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

(2) solid is separated out；

(3) separated out solid is separated；

In above-mentioned preparation method step (1), " suitable solvent " is selected from acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene etc. or their mixture, preferably acetonitrile, ethanol, isopropanol or their mixture.The suitable solvent ends with tenofovir and draws the weight ratio generally 5 of phenol amine:1~80:1.

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

In above-mentioned preparation method step (2), the method for " the precipitation solid " is method conventional in the art, such as cools down, adds anti-solvent, concentrates out the alone of the methods such as partial solvent body plus crystal seed or combination.It can stand or stirring to separate out solid process.

In above-mentioned preparation method step (3), the conventional method that " separation " can be using filtering etc. in the art.It is alternatively possible to be washed with the suitable solvent in step (1) to collected solid.

In above-mentioned preparation method step (4), " drying " mode includes constant pressure and dry, is dried under reduced pressure or combinations thereof application.The method of " being further purified " includes the forms such as recrystallization, pulp, washing.

The temperature of " drying " is generally 20~120 DEG C, preferably 30~80 DEG C in above method step (4)；Can with constant pressure and dry, It can also be dried under reduced pressure.

L-TARTARIC ACID tenofovir Chinese mugwort prepared by the embodiment draws phenol amine (1:2) it is a kind of crystal.

Therefore, phenol amine (1 is drawn the invention provides a kind of L-TARTARIC ACID tenofovir Chinese mugwort:2) crystal formation (in order to express easily, is referred to as " L-TARTARIC ACID tenofovir Chinese mugwort drawing phenol amine (1 by crystal formation:2) crystal formation A ").The feature of the X-ray powder diffraction collection (being radiated using Cu-K α) of the crystal formation is：2 θ values be 8.2 ° ± 0.2 °, 9.4 ° ± 0.2 °, 10.8 ° ± 0.2 °, 14.4 ° ± 0.2 °, 17.9 ° ± 0.2 °, 18.9 ° ± 0.2 °, 19.7 ° ± 0.2 °, 21.6 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

In one embodiment, the L-TARTARIC ACID tenofovir Chinese mugwort that the present invention is told draws phenol amine (1:2) feature of crystal formation A X-ray powder diffraction collection is：2 θ values be 7.5 ° ± 0.2 °, 8.2 ° ± 0.2 °, 9.4 ° ± 0.2 °, 10.8 ° ± 0.2 °, 12.4 ° ± 0.2 °, 14.4 ° ± 0.2 °, 16.0 ° ± 0.2 °, 16.3 ° ± 0.2 °, 17.1 ° ± 0.2 °, 17.9 ° ± 0.2 °, 18.9 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.4 ° ± 0.2 °, 21.6 ° ± 0.2 °, 23.0 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

Further, L-TARTARIC ACID tenofovir Chinese mugwort of the present invention draws phenol amine (1:2) X-ray powder diffraction collection that crystal formation A is represented with 2 θ angles has characteristic diffraction peak and relative intensity in following position：

2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)
2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)	7.5°±0.2°	10	21.0°±0.2°	17
8.2°±0.2°	10	21.6°±0.2°	22	7.5°±0.2°	10	21.0°±0.2°	17
8.2°±0.2°	10	21.6°±0.2°	22	9.4°±0.2°	97	23.0°±0.2°	22
10.8°±0.2°	16	23.5°±0.2°	18	9.4°±0.2°	97	23.0°±0.2°	22
10.8°±0.2°	16	23.5°±0.2°	18	12.4°±0.2°	13	24.3°±0.2°	12
14.4°±0.2°	16	24.6°±0.2°	10	12.4°±0.2°	13	24.3°±0.2°	12
14.4°±0.2°	16	24.6°±0.2°	10	16.0°±0.2°	16	25.7°±0.2°	11
16.3°±0.2°	18	26.7°±0.2°	11	16.0°±0.2°	16	25.7°±0.2°	11
16.3°±0.2°	18	26.7°±0.2°	11	17.1°±0.2°	21	27.4°±0.2°	9
17.9°±0.2°	34	28.4°±0.2°	9	17.1°±0.2°	21	27.4°±0.2°	9
17.9°±0.2°	34	28.4°±0.2°	9	18.9°±0.2°	37	28.9°±0.2°	8
19.7°±0.2°	100	30.4°±0.2°	8	18.9°±0.2°	37	28.9°±0.2°	8
19.7°±0.2°	100	30.4°±0.2°	8	20.4°±0.2°	28

In one embodiment, the L-TARTARIC ACID tenofovir Chinese mugwort that the present invention is provided draws phenol amine (1:2) crystal formation A has the feature representated by X-ray powder diffraction collection as shown in Figure 1.

In one embodiment, the L-TARTARIC ACID tenofovir Chinese mugwort for the preparation that the present invention is provided draws phenol amine (1:2) L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1 in mixture:2) crystal formation A contents (mass content) are generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.

It will be appreciated by persons skilled in the art that L-TARTARIC ACID tenofovir Chinese mugwort of the present invention draws phenol amine (1:2) mixture refers to drawing phenol amine (1 with the directly synthetically prepared L-TARTARIC ACID tenofovir Chinese mugwort containing other impurities or crystal formation of chemical synthesis process:2).

In one embodiment, L-TARTARIC ACID tenofovir of the invention Chinese mugwort draws phenol amine (1:2) crystal formation A preparation method includes：

(1) phenol amine and L-TARTARIC ACID is drawn to be dissolved in acetonitrile, ethanol, isopropanol or their mixture tenofovir Chinese mugwort；The solvent ends with tenofovir and draws the weight ratio generally 5 of phenol amine:1~80:1；Tenofovir Chinese mugwort draws the molar ratio general 1.7 of phenol amine and L-TARTARIC ACID:1~2.5:1, preferably 1.9:1~2.3:1

(2) solid is separated out；

(3) separated out solid is separated；It is alternatively possible to be washed with the solvent used in step (1) to collected solid；

(4) alternatively, the solid of separation is dried, or rear re-dry is further purified.Drying temperature is generally 20~120 DEG C, preferably 30~80 DEG C；It is able to can also be dried under reduced pressure with constant pressure and dry.

D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1)

In one embodiment, in formula II, n elects 1, X as and elects D- tartaric acid as, i.e., draw phenol amine with D- tartaric acid with 1 there is provided tenofovir Chinese mugwort:The compound of 1 molar composition ratio formation, is referred to as " D- tartaric acid tenofovir Chinese mugwort drawing phenol amine (1:1)”.

In one embodiment, the invention provides the preparation method that a kind of D- tartaric acid tenofovir Chinese mugwort draws phenol amine, this method includes：

(1) phenol amine and D- tartaric acid is drawn to be dissolved in suitable solvent tenofovir Chinese mugwort；

(2) solid is separated out；

(3) separated out solid is separated；

In above-mentioned preparation method step (1), " suitable solvent " is selected from acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene etc. or their mixture, preferably acetonitrile, isopropanol or their mixture.The suitable solvent ends with tenofovir and draws the weight ratio generally 5 of phenol amine:1~80:1.

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

D- tartaric acid tenofovir Chinese mugwort prepared by the embodiment draws phenol amine (1:1) it is a kind of crystal.

Therefore, phenol amine (1 is drawn the invention provides a kind of D- tartaric acid tenofovir Chinese mugwort:1) crystal formation (in order to express easily, is referred to as " D- tartaric acid tenofovir Chinese mugwort drawing phenol amine (1 by crystal formation:1) crystal formation A ").The feature of the X-ray powder diffraction collection (being radiated using Cu-K α) of the crystal formation is：2 θ values be 7.8 ° ± 0.2 °, 9.5 ° ± 0.2 °, 12.5 ° ± 0.2 °, 15.1 ° ± 0.2 °, 15.9 ° ± 0.2 °, 17.0 ° ± 0.2 °, 17.7 ° ± 0.2 °, 19.5 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

In one embodiment, the D- tartaric acid tenofovir Chinese mugwort that the present invention is told draws phenol amine (1:1) feature of crystal formation A X-ray powder diffraction collection is：2 θ values be 4.4 ° ± 0.2 °, 7.8 ° ± 0.2 °, 9.0 ° ± 0.2 °, 9.5 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.0 ° ± 0.2 °, 15.1 ° ± 0.2 °, 15.9 ° ± 0.2 °, 17.0 ° ± 0.2 °, 17.7 ° ± 0.2 °, 19.5 ° ± 0.2 °, 19.9 ° ± 0.2 °, 21.4 ° ± 0.2 °, 22.7 ° ± 0.2 °, 25.9 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

Further, D- tartaric acid tenofovir Chinese mugwort of the present invention draws phenol amine (1:1) X-ray powder diffraction collection that crystal formation A is represented with 2 θ angles has characteristic diffraction peak and relative intensity in following position：

2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)
2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)	4.4°±0.2°	86	19.5°±0.2°	44
7.8°±0.2°	39	19.9°±0.2°	38	4.4°±0.2°	86	19.5°±0.2°	44
7.8°±0.2°	39	19.9°±0.2°	38	8.6°±0.2°	39	20.8°±0.2°	30
9.0°±0.2°	62	21.4°±0.2°	34	8.6°±0.2°	39	20.8°±0.2°	30
9.0°±0.2°	62	21.4°±0.2°	34	9.5°±0.2°	100	22.0°±0.2°	17
10.8°±0.2°	16	22.7°±0.2°	29	9.5°±0.2°	100	22.0°±0.2°	17
10.8°±0.2°	16	22.7°±0.2°	29	12.5°±0.2°	28	23.5°±0.2°	24
13.0°±0.2°	19	24.1°±0.2°	20	12.5°±0.2°	28	23.5°±0.2°	24
13.0°±0.2°	19	24.1°±0.2°	20	13.3°±0.2°	14	24.6°±0.2°	15
15.1°±0.2°	20	25.2°±0.2°	22	13.3°±0.2°	14	24.6°±0.2°	15
15.1°±0.2°	20	25.2°±0.2°	22	15.9°±0.2°	27	25.9°±0.2°	30
17.0°±0.2°	72	27.3°±0.2°	11	15.9°±0.2°	27	25.9°±0.2°	30
17.0°±0.2°	72	27.3°±0.2°	11	17.7°±0.2°	42	28.3°±0.2°	10
18.9°±0.2°	29			17.7°±0.2°	42	28.3°±0.2°	10

In one embodiment, the D- tartaric acid tenofovir Chinese mugwort that the present invention is provided draws phenol amine (1:1) crystal formation A has the feature representated by X-ray powder diffraction collection as shown in Figure 2.

In one embodiment, the D- tartaric acid tenofovir Chinese mugwort for the preparation that the present invention is provided draws phenol amine (1:1) D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1 in mixture:1) crystal formation A contents (mass content) are generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.

It will be appreciated by persons skilled in the art that D- tartaric acid tenofovir Chinese mugwort of the present invention draws phenol amine (1:1) mixture refers to drawing phenol amine (1 with the directly synthetically prepared D- tartaric acid tenofovir Chinese mugwort containing other impurities or crystal formation of chemical synthesis process:1).

In one embodiment, D- tartaric acid tenofovir of the invention Chinese mugwort draws phenol amine (1:1) crystal formation A preparation side Method includes：

(1) phenol amine and D- tartaric acid is drawn to be dissolved in acetonitrile, isopropanol or their mixture tenofovir Chinese mugwort；The solvent ends with tenofovir and draws the weight ratio generally 5 of phenol amine:1~80:1；Tenofovir Chinese mugwort draws the molar ratio general 0.5 of phenol amine and D- tartaric acid:1~1.5:1, preferably 0.8:1~1.2:1.

(2) solid is separated out；

(3) separated out solid is separated；It is alternatively possible to be washed with the solvent in step (1) to collected solid.

(4) alternatively, the solid of separation is dried, or rear re-dry is further purified.Dry temperature is generally 20~120 DEG C, preferably 30~80 DEG C；It is able to can also be dried under reduced pressure with constant pressure and dry.

DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1)

In one embodiment, in formula II, n elects 1, X as and elects DL- tartaric acid as, i.e., draw phenol amine with DL- tartaric acid with 1 there is provided tenofovir Chinese mugwort:The compound of 1 molar composition ratio formation, is referred to as " DL- tartaric acid tenofovir Chinese mugwort drawing phenol amine (1:1)”.

In one embodiment, phenol amine (1 is drawn the invention provides a kind of DL- tartaric acid tenofovir Chinese mugwort:1) preparation method, this method includes：

(1) phenol amine and DL- tartaric acid is drawn to be dissolved in suitable solvent tenofovir Chinese mugwort；

(2) solid is separated out；

(3) separated out solid is separated；

In above-mentioned preparation method step (1), " the DL- tartaric acid " refers to the racemic tartaric acid that L-TARTARIC ACID is constituted with D- tartaric acid equal proportion." suitable solvent " is selected from acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene etc. or their mixture, preferably acetonitrile.The suitable solvent ends with tenofovir and draws the weight ratio generally 5 of phenol amine:1~80:1.

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

The temperature of " drying " is generally 20~120 DEG C, preferably 30~80 DEG C in above method step (4)；It is able to can also be dried under reduced pressure with constant pressure and dry.

DL- tartaric acid tenofovir Chinese mugwort prepared by the embodiment draws phenol amine (1:1) it is a kind of crystal.

Therefore, phenol amine (1 is drawn the invention provides a kind of DL- tartaric acid tenofovir Chinese mugwort:1) crystal formation (in order to express easily, is referred to as " DL- tartaric acid tenofovir Chinese mugwort drawing phenol amine (1 by crystal formation:1) crystal formation A ").The feature of the X-ray powder diffraction collection (being radiated using Cu-K α) of the crystal formation is：2 θ values be 6.8 ° ± 0.2 °, 8.0 ° ± 0.2 °, 9.7 ° ± 0.2 °, 16.0 ° ± 0.2 °, 16.9 ° ± 0.2 °, 18.2 ° ± 0.2 °, 18.9 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.1 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

In one embodiment, the DL- tartaric acid tenofovir Chinese mugwort that the present invention is told draws phenol amine (1:1) feature of crystal formation A X-ray powder diffraction collection is：2 θ values be 6.8 ° ± 0.2 °, 8.0 ° ± 0.2 °, 9.7 ° ± 0.2 °, 10.6 ° ± 0.2 °, 12.6 ° ± 0.2 °, 13.7 ° ± 0.2 °, 14.9 ° ± 0.2 °, 16.0 ° ± 0.2 °, 16.9 ° ± 0.2 °, 18.2 ° ± 0.2 °, 18.9 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.1 ° ± 0.2 °, 22.8 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

Further, DL- tartaric acid tenofovir Chinese mugwort of the present invention draws phenol amine (1:1) X-ray powder diffraction collection that crystal formation A is represented with 2 θ angles has characteristic diffraction peak and relative intensity in following position：

2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)
2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)	6.8°±0.2°	39	19.6°±0.2°	19
8.0°±0.2°	85	20.2°±0.2°	52	6.8°±0.2°	39	19.6°±0.2°	19
8.0°±0.2°	85	20.2°±0.2°	52	9.7°±0.2°	94	21.1°±0.2°	53
10.6°±0.2°	10	22.8°±0.2°	16	9.7°±0.2°	94	21.1°±0.2°	53
10.6°±0.2°	10	22.8°±0.2°	16	12.6°±0.2°	17	24.4°±0.2°	11
13.7°±0.2°	16	25.9°±0.2°	17	12.6°±0.2°	17	24.4°±0.2°	11
13.7°±0.2°	16	25.9°±0.2°	17	14.9°±0.2°	15	26.7°±0.2°	10
16.0°±0.2°	41	29.4°±0.2°	20	14.9°±0.2°	15	26.7°±0.2°	10
16.0°±0.2°	41	29.4°±0.2°	20	16.9°±0.2°	46	32.5°±0.2°	10
18.2°±0.2°	100	35.8°±0.2°	17	16.9°±0.2°	46	32.5°±0.2°	10
18.2°±0.2°	100	35.8°±0.2°	17	18.9°±0.2°	60

In one embodiment, the DL- tartaric acid tenofovir Chinese mugwort that the present invention is provided draws phenol amine (1:1) crystal formation A has the feature representated by X-ray powder diffraction collection as shown in Figure 3.

In one embodiment, the DL- tartaric acid tenofovir Chinese mugwort for the preparation that the present invention is provided draws phenol amine (1:1) DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1 in mixture:1) crystal formation A contents (mass content) are generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.

It will be appreciated by persons skilled in the art that DL- tartaric acid tenofovir Chinese mugwort of the present invention draws phenol amine (1:1) mixture refers to drawing phenol amine (1 with the directly synthetically prepared DL- tartaric acid tenofovir Chinese mugwort containing other impurities or crystal formation of chemical synthesis process:1).

In one embodiment, DL- tartaric acid tenofovir of the invention Chinese mugwort draws phenol amine (1:1) crystal formation A preparation method includes：

(1) phenol amine and DL- tartaric acid is drawn to be dissolved in acetonitrile tenofovir Chinese mugwort；The solvent ends with tenofovir and draws the weight ratio generally 5 of phenol amine:1~80:1.Tenofovir Chinese mugwort draws the molar ratio of phenol amine and DL- tartaric acid to be generally 0.5:1~1.5:1, preferably 0.8:1~1.2:1.

(2) solid is separated out；

(3) separated out solid is separated；It is alternatively possible to be washed with acetonitrile to collected solid.

L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2)

In one embodiment, in formula II, n elects 2, X as and elects L MALIC ACID as, i.e., draw phenol amine with L MALIC ACID with 2 there is provided tenofovir Chinese mugwort:The compound of 1 molar composition ratio formation, is referred to as " L MALIC ACID tenofovir Chinese mugwort drawing phenol amine (1:2)”.

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

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

(2) solid is separated out；

(3) separated out solid is separated；

In above-mentioned preparation method step (1), " suitable solvent " is selected from acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene etc. or their mixture, preferably isopropanol.The suitable solvent ends with tenofovir and draws the weight ratio generally 5 of phenol amine:1~80:1.

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

In above method step (4), the temperature of " drying " is generally 20~80 DEG C, preferably 30~60 DEG C；It is able to can also be dried under reduced pressure with constant pressure and dry.

L MALIC ACID tenofovir Chinese mugwort prepared by the embodiment draws phenol amine (1:2) it is a kind of crystal.

Therefore, phenol amine (1 is drawn the invention provides a kind of L MALIC ACID tenofovir Chinese mugwort:2) crystal formation (in order to express easily, is referred to as " L MALIC ACID tenofovir Chinese mugwort drawing phenol amine (1 by crystal formation:2) crystal formation A ").The feature of the X-ray powder diffraction collection (being radiated using Cu-K α) of the crystal formation is：2 θ values be 10.0 ° ± 0.2 °, 13.4 ° ± 0.2 °, 13.9 ° ± 0.2 °, 15.3 ° ± 0.2 °, 16.6 ° ± 0.2 °, 21.3 ° ± 0.2 °, 26.3 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

In one embodiment, the L MALIC ACID tenofovir Chinese mugwort that the present invention is told draws phenol amine (1:2) feature of crystal formation A X-ray powder diffraction collection is：2 θ values be 5.4 ° ± 0.2 °, 10.0 ° ± 0.2 °, 11.9 ° ± 0.2 °, 13.4 ° ± 0.2 °, 13.9 ° ± 0.2 °, 15.3 ° ± 0.2 °, 16.6 ° ± 0.2 °, 20.3 ° ± 0.2 °, 21.3 ° ± 0.2 °, 22.2 ° ± 0.2 °, 26.3 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

Further, L MALIC ACID tenofovir Chinese mugwort of the present invention draws phenol amine (1:2) X-ray powder diffraction collection that crystal formation A is represented with 2 θ angles has characteristic diffraction peak and relative intensity in following position：

2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)
2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)	5.4°±0.2°	14	17.9°±0.2°	8
9.7°±0.2°	19	19.4°±0.2°	8	5.4°±0.2°	14	17.9°±0.2°	8
9.7°±0.2°	19	19.4°±0.2°	8	10.0°±0.2°	69	20.1°±0.2°	10
10.3°±0.2°	12	20.3°±0.2°	16	10.0°±0.2°	69	20.1°±0.2°	10
10.3°±0.2°	12	20.3°±0.2°	16	11.9°±0.2°	20	21.3°±0.2°	100
13.2°±0.2°	19	21.9°±0.2°	18	11.9°±0.2°	20	21.3°±0.2°	100
13.2°±0.2°	19	21.9°±0.2°	18	13.4°±0.2°	35	22.2°±0.2°	19
13.9°±0.2°	61	23.2°±0.2°	14	13.4°±0.2°	35	22.2°±0.2°	19
13.9°±0.2°	61	23.2°±0.2°	14	14.1°±0.2°	33	24.2°±0.2°	9
15.3°±0.2°	55	25.3°±0.2°	8	14.1°±0.2°	33	24.2°±0.2°	9
15.3°±0.2°	55	25.3°±0.2°	8	16.6°±0.2°	51	26.3°±0.2°	31
17.0°±0.2°	8	29.3°±0.2°	8	16.6°±0.2°	51	26.3°±0.2°	31

In one embodiment, the L MALIC ACID tenofovir Chinese mugwort that the present invention is provided draws phenol amine (1:2) crystal formation A has the feature representated by X-ray powder diffraction collection as shown in Figure 4.

In one embodiment, the L MALIC ACID tenofovir Chinese mugwort for the preparation that the present invention is provided draws phenol amine (1:2) L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1 in mixture:2) crystal formation A contents (mass content) are generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.

It will be appreciated by persons skilled in the art that L MALIC ACID tenofovir Chinese mugwort of the present invention draws phenol amine (1:2) mixture refers to drawing phenol amine (1 with the directly synthetically prepared L MALIC ACID tenofovir Chinese mugwort containing other impurities or crystal formation of chemical synthesis process:2).

In one embodiment, the L MALIC ACID tenofovir Chinese mugwort that the present invention is provided draws phenol amine (1:2) crystal formation A preparation method includes：

(1) phenol amine and L MALIC ACID is drawn to be dissolved in isopropanol tenofovir Chinese mugwort；The solvent draws phenol amine with tenofovir Chinese mugwort Weight ratio generally 5:1~80:1.Tenofovir Chinese mugwort draws the molar ratio general 1.7 of phenol amine and L MALIC ACID:1~2.5:1, preferably 1.9:1~2.3:1.

(2) solid is separated out；

(3) separated out solid is separated；It is alternatively possible to be washed with isopropanol to collected solid.

(4) alternatively, the solid of separation is dried, or rear re-dry is further purified.Drying temperature is generally 20~80 DEG C, preferably 30~60 DEG C；It is able to can also be dried under reduced pressure with constant pressure and dry.

Citric acid tenofovir Chinese mugwort draws phenol amine (1:1)

In one embodiment, in formula II, n elects 1, X as and elects citric acid as, i.e., draw phenol amine with citric acid with 1 there is provided tenofovir Chinese mugwort:The compound of 1 molar composition ratio formation, is referred to as " citric acid tenofovir Chinese mugwort drawing phenol amine (1:1)”.

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

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

(2) solid is separated out；

(3) separated out solid is separated；

In above-mentioned preparation method step (1), " suitable solvent " is selected from acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene etc. or their mixture, preferably acetonitrile, methanol, ethanol, tetrahydrofuran or their mixture.The suitable solvent ends with tenofovir and draws the weight ratio generally 5 of phenol amine:1~80:1.

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

In above-mentioned preparation method step (2), the method of " the precipitation solid " is method conventional in the art, as cooled down, anti-solvent is added, " anti-solvent " is selected from ether, ethyl acetate, methyl acetate, Ethyl formate, normal heptane, glycol dimethyl ether, isopropyl ether, methyl tertiary butyl ether(MTBE), isooctane, methyl phenyl ethers anisole etc. or their mixture.Concentrate out the alone of the methods such as partial solvent body plus crystal seed or combination.It can stand or stirring to separate out solid process.

In above method step (4), the temperature of " drying " is generally 20~120 DEG C, preferably 30~80 DEG C；It is able to can also be dried under reduced pressure with constant pressure and dry.

Citric acid tenofovir Chinese mugwort prepared by the embodiment draws phenol amine (1:1) it is a kind of crystal.

Therefore, phenol amine (1 is drawn the invention provides a kind of citric acid tenofovir Chinese mugwort:1) crystal formation (in order to express easily, is referred to as " citric acid tenofovir Chinese mugwort drawing phenol amine (1 by crystal formation:1) crystal formation A ").The feature of the X-ray powder diffraction collection (being radiated using Cu-K α) of the crystal formation is：2 θ values be 6.0 ° ± 0.2 °, 8.1 ° ± 0.2 °, 11.7 ° ± 0.2 °, 15.9 ° ± 0.2 °, 17.9 ° ± 0.2 °, 21.7 ° ± 0.2 °, 23.4 ° ± 0.2 °, 26.9 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

In one embodiment, the citric acid tenofovir Chinese mugwort that the present invention is told draws phenol amine (1:1) feature of crystal formation A X-ray powder diffraction collection is：2 θ values be 6.0 ° ± 0.2 °, 8.1 ° ± 0.2 °, 11.7 ° ± 0.2 °, 12.6 ° ± 0.2 °, 15.4 ° ± 0.2 °, 15.9 ° ± 0.2 °, 17.5 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.1 ° ± 0.2 °, 20.6 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.7 ° ± 0.2 °, 23.4 ° ± 0.2 °, 26.9 ° ± 0.2 °, 29.3 ° ± 0.2 °, 31.9 ° ± 0.2 °, 32.7 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

Further, citric acid tenofovir Chinese mugwort of the present invention draws phenol amine (1:1) X-ray powder diffraction collection that crystal formation A is represented with 2 θ angles has characteristic diffraction peak and relative intensity in following position：

2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)
2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)	6.0°±0.2°	100	20.1°±0.2°	16
8.1°±0.2°	47	20.6°±0.2°	12	6.0°±0.2°	100	20.1°±0.2°	16
8.1°±0.2°	47	20.6°±0.2°	12	8.5°±0.2°	9	21.4°±0.2°	29
10.3°±0.2°	7	21.7°±0.2°	32	8.5°±0.2°	9	21.4°±0.2°	29
10.3°±0.2°	7	21.7°±0.2°	32	11.7°±0.2°	39	22.1°±0.2°	7
12.2°±0.2°	8	22.5°±0.2°	12	11.7°±0.2°	39	22.1°±0.2°	7
12.2°±0.2°	8	22.5°±0.2°	12	12.6°±0.2°	21	23.1°±0.2°	11
14.6°±0.2°	13	23.4°±0.2°	37	12.6°±0.2°	21	23.1°±0.2°	11
14.6°±0.2°	13	23.4°±0.2°	37	15.4°±0.2°	23	26.0°±0.2°	7
15.9°±0.2°	36	26.9°±0.2°	39	15.4°±0.2°	23	26.0°±0.2°	7
15.9°±0.2°	36	26.9°±0.2°	39	16.3°±0.2°	7	29.2°±0.2°	10
17.5°±0.2°	16	29.3°±0.2°	14	16.3°±0.2°	7	29.2°±0.2°	10
17.5°±0.2°	16	29.3°±0.2°	14	17.9°±0.2°	32	31.9°±0.2°	11
19.9°±0.2°	10	32.7°±0.2°	12	17.9°±0.2°	32	31.9°±0.2°	11

In one embodiment, the citric acid tenofovir Chinese mugwort that the present invention is provided draws phenol amine (1:1) crystal formation A has the feature representated by X-ray powder diffraction collection as shown in Figure 5.

In one embodiment, the citric acid tenofovir Chinese mugwort for the preparation that the present invention is provided draws phenol amine (1:1) citric acid tenofovir Chinese mugwort draws phenol amine (1 in mixture:1) crystal formation A contents (mass content) are generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.

It will be appreciated by persons skilled in the art that citric acid tenofovir Chinese mugwort of the present invention draws phenol amine (1:1) mixture refers to drawing phenol amine (1 with the directly synthetically prepared citric acid tenofovir Chinese mugwort containing other impurities or crystal formation of chemical synthesis process:1).

In one embodiment, citric acid tenofovir of the invention Chinese mugwort draws phenol amine (1:1) crystal formation A preparation method includes：

(1) phenol amine and citric acid is drawn to be dissolved in acetonitrile, methanol, ethanol, tetrahydrofuran or their mixture tenofovir Chinese mugwort；The suitable solvent ends with tenofovir and draws the weight ratio generally 5 of phenol amine:1~80:1.Tenofovir Chinese mugwort draws the molar ratio general 0.5 of phenol amine and citric acid:1~1.5:1, preferably 0.8:1~1.2:1.

(2) solid is separated out；

Butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1)

In one embodiment, in formula II, n elects 1, X as and elects butanedioic acid as, i.e., draw phenol amine with butanedioic acid with 1 there is provided tenofovir Chinese mugwort:The compound of 1 molar composition ratio formation, is referred to as " butanedioic acid tenofovir Chinese mugwort drawing phenol amine (1:1)”.

In one embodiment, the invention provides the preparation method that a kind of butanedioic acid tenofovir Chinese mugwort draws phenol amine, this method includes：

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

(2) solid is separated out；

(3) separated out solid is separated；

In above-mentioned preparation method step (1), " suitable solvent " is selected from acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene etc. or their mixture, preferably acetonitrile.The suitable solvent ends with tenofovir and draws the weight ratio generally 5 of phenol amine:1~80:1.

In above-mentioned preparation method step (1), tenofovir Chinese mugwort draws the molar ratio general 0.5 of phenol amine and butanedioic acid:1~1.5:1, preferably 0.8:1~1.2:1.

In above method step (4), the temperature of " drying " is generally 20~100 DEG C, preferably 30~80 DEG C；It is able to can also be dried under reduced pressure with constant pressure and dry.

Butanedioic acid tenofovir Chinese mugwort prepared by the embodiment draws phenol amine (1:1) it is a kind of crystal.

Therefore, phenol amine (1 is drawn the invention provides a kind of butanedioic acid tenofovir Chinese mugwort:1) crystal formation (in order to express easily, is referred to as " butanedioic acid tenofovir Chinese mugwort drawing phenol amine (1 by crystal formation:1) crystal formation A ").The feature of the X-ray powder diffraction collection (being radiated using Cu-K α) of the crystal formation is：2 θ values be 10.7 ° ± 0.2 °, 14.3 ° ± 0.2 °, 17.2 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.4 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

In one embodiment, the butanedioic acid tenofovir Chinese mugwort that the present invention is told draws phenol amine (1:1) feature of crystal formation A X-ray powder diffraction collection is：2 θ values be 5.7 ° ± 0.2 °, 9.6 ° ± 0.2 °, 10.0 ° ± 0.2 °, 10.7 ° ± 0.2 °, 11.7 ° ± 0.2 °, 13.5 ° ± 0.2 °, 14.3 ° ± 0.2 °, 17.2 ° ± 0.2 °, 17.8 ° ± 0.2 °, 19.3 ° ± 0.2 °, 19.7 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.4 ° ± 0.2 °, 23.8 ° ± 0.2 °, 27.9 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

Further, butanedioic acid tenofovir Chinese mugwort of the present invention draws phenol amine (1:1) X-ray powder diffraction collection that crystal formation A is represented with 2 θ angles has characteristic diffraction peak and relative intensity in following position：

2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)
2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)	5.7°±0.2°	34	19.7°±0.2°	47
9.6°±0.2°	49	21.1°±0.2°	42	5.7°±0.2°	34	19.7°±0.2°	47
9.6°±0.2°	49	21.1°±0.2°	42	10.0°±0.2°	51	21.4°±0.2°	79
10.4°±0.2°	30	21.8°±0.2°	79	10.0°±0.2°	51	21.4°±0.2°	79
10.4°±0.2°	30	21.8°±0.2°	79	10.7°±0.2°	100	22.4°±0.2°	82
11.2°±0.2°	13	23.8°±0.2°	26	10.7°±0.2°	100	22.4°±0.2°	82
11.2°±0.2°	13	23.8°±0.2°	26	11.7°±0.2°	28	24.7°±0.2°	18
12.7°±0.2°	15	26.1°±0.2°	13	11.7°±0.2°	28	24.7°±0.2°	18
12.7°±0.2°	15	26.1°±0.2°	13	13.5°±0.2°	33	27.0°±0.2°	18
14.3°±0.2°	69	27.9°±0.2°	20	13.5°±0.2°	33	27.0°±0.2°	18
14.3°±0.2°	69	27.9°±0.2°	20	14.7°±0.2°	20	28.7°±0.2°	11
17.2°±0.2°	83	30.6°±0.2°	16	14.7°±0.2°	20	28.7°±0.2°	11
17.2°±0.2°	83	30.6°±0.2°	16	17.8°±0.2°	60	33.6°±0.2°	10
18.9°±0.2°	32	34.1°±0.2°	11	17.8°±0.2°	60	33.6°±0.2°	10
18.9°±0.2°	32	34.1°±0.2°	11	19.3°±0.2°	46

In one embodiment, the butanedioic acid tenofovir Chinese mugwort that the present invention is provided draws phenol amine (1:1) A has the feature representated by X-ray powder diffraction collection as shown in Figure 6.

In one embodiment, the butanedioic acid tenofovir Chinese mugwort for the preparation that the present invention is provided draws phenol amine (1:1) butanedioic acid tenofovir Chinese mugwort draws phenol amine (1 in mixture:1) crystal formation A contents (mass content) are generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.

It will be appreciated by persons skilled in the art that butanedioic acid tenofovir Chinese mugwort of the present invention draws phenol amine (1:1) mixture refers to drawing phenol amine (1 with the directly synthetically prepared butanedioic acid tenofovir Chinese mugwort containing other impurities or crystal formation of chemical synthesis process:1).

In one embodiment, butanedioic acid tenofovir of the invention Chinese mugwort draws phenol amine (1:1) crystal formation A preparation method includes：

(1) phenol amine and butanedioic acid is drawn to be dissolved in acetonitrile tenofovir Chinese mugwort；The solvent ends with tenofovir and draws the weight of phenol amine Measure ratio generally 5:1~80:1.Tenofovir Chinese mugwort draws the molar ratio general 0.5 of phenol amine and butanedioic acid:1~1.5:1, preferably 0.8:1~1.2:1.

(2) solid is separated out；

(4) alternatively, the solid of separation is dried, or rear re-dry is further purified.Drying temperature is generally 20~100 DEG C, preferably 30~80 DEG C；It is able to can also be dried under reduced pressure with constant pressure and dry.

Oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1)

In one embodiment, in formula II, n elects 1, X as and elects oxalic acid as, i.e., draw phenol amine with oxalic acid with 1 there is provided tenofovir Chinese mugwort:The compound of 1 molar composition ratio formation, is referred to as " oxalic acid tenofovir Chinese mugwort drawing phenol amine (1:1)”.

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

(1) tenofovir Chinese mugwort is drawn into phenol amine and dissolving oxalic acid in suitable solvent；

(2) solid is separated out；

(3) separated out solid is separated；

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

Oxalic acid tenofovir Chinese mugwort prepared by the embodiment draws phenol amine (1:1) it is a kind of crystal.

Therefore, phenol amine (1 is drawn the invention provides a kind of oxalic acid tenofovir Chinese mugwort:1) crystal formation is (in order to express easily, by the crystal formation Referred to as " oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A ").The feature of the X-ray powder diffraction collection (being radiated using Cu-K α) of the crystal formation is：2 θ values be 7.7 ° ± 0.2 °, 9.6 ° ± 0.2 °, 16.2 ° ± 0.2 °, 18.2 ° ± 0.2 °, 20.5 ° ± 0.2 °, 24.7 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

In one embodiment, the oxalic acid tenofovir Chinese mugwort that the present invention is told draws phenol amine (1:1) feature of crystal formation A X-ray powder diffraction collection is：2 θ values be 7.7 ° ± 0.2 °, 8.4 ° ± 0.2 °, 9.6 ° ± 0.2 °, 12.6 ° ± 0.2 °, 16.2 ° ± 0.2 °, 18.2 ° ± 0.2 °, 20.5 ° ± 0.2 °, 22.6 ° ± 0.2 °, 24.7 ° ± 0.2 °, 27.8 ° ± 0.2 °, 29.0 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

Further, oxalic acid tenofovir Chinese mugwort of the present invention draws phenol amine (1:1) X-ray powder diffraction collection that crystal formation A is represented with 2 θ angles has characteristic diffraction peak and relative intensity in following position：

2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)
2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)	7.7°±0.2°	35	19.6°±0.2°	19
8.4°±0.2°	22	20.5°±0.2°	92	7.7°±0.2°	35	19.6°±0.2°	19
8.4°±0.2°	22	20.5°±0.2°	92	9.6°±0.2°	100	21.9°±0.2°	16
11.0°±0.2°	10	22.6°±0.2°	26	9.6°±0.2°	100	21.9°±0.2°	16
11.0°±0.2°	10	22.6°±0.2°	26	12.2°±0.2°	13	23.8°±0.2°	30
12.6°±0.2°	22	24.3°±0.2°	25	12.2°±0.2°	13	23.8°±0.2°	30
12.6°±0.2°	22	24.3°±0.2°	25	14.8°±0.2°	12	24.7°±0.2°	55
14.9°±0.2°	12	25.4°±0.2°	22	14.8°±0.2°	12	24.7°±0.2°	55
14.9°±0.2°	12	25.4°±0.2°	22	16.2°±0.2°	47	25.8°±0.2°	17
16.6°±0.2°	26	26.2°±0.2°	10	16.2°±0.2°	47	25.8°±0.2°	17
16.6°±0.2°	26	26.2°±0.2°	10	16.9°±0.2°	27	27.8°±0.2°	18
18.2°±0.2°	34	29.0°±0.2°	19	16.9°±0.2°	27	27.8°±0.2°	18
18.2°±0.2°	34	29.0°±0.2°	19	19.1°±0.2°	15

In one embodiment, the oxalic acid tenofovir Chinese mugwort that the present invention is provided draws phenol amine (1:1) crystal formation A has the feature representated by X-ray powder diffraction collection as shown in Figure 7.

In one embodiment, what the present invention was provided prepares oxalic acid tenofovir Chinese mugwort drawing phenol amine (1:1) mixture mesoxalic acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A contents (mass content) are generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.

It will be appreciated by persons skilled in the art that oxalic acid tenofovir Chinese mugwort of the present invention draws phenol amine (1:1) mixture refers to drawing phenol amine (1 with the directly synthetically prepared oxalic acid tenofovir Chinese mugwort containing other impurities or crystal formation of chemical synthesis process:1).

In one embodiment, oxalic acid tenofovir of the invention Chinese mugwort draws phenol amine (1:1) crystal formation A preparation method includes：

(1) tenofovir Chinese mugwort is drawn into phenol amine and dissolving oxalic acid in acetonitrile；The solvent ends with tenofovir and draws the weight ratio generally 5 of phenol amine:1~80:1.Tenofovir Chinese mugwort draws the molar ratio general 0.5 of phenol amine and oxalic acid:1~1.5:1, preferably 0.8:1~1.2:1.

(2) solid is separated out；

Phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1)

In one embodiment, in formula II, n elects 1, X as and elects phosphoric acid as, i.e., there is provided tenofovir Chinese mugwort draw phenol amine withPhosphoric acidWith 1:The compound of 1 molar composition ratio formation, is referred to as " phosphoric acid tenofovir Chinese mugwort drawing phenol amine (1:1)”.

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

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

(2) solid is separated out；

(3) separated out solid is separated；

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

Phosphoric acid tenofovir Chinese mugwort prepared by the embodiment draws phenol amine (1:1) it is a kind of crystal.

Therefore, phenol amine (1 is drawn the invention provides a kind of phosphoric acid tenofovir Chinese mugwort:1) crystal formation (in order to express easily, is referred to as " phosphoric acid tenofovir Chinese mugwort drawing phenol amine (1 by crystal formation:1) crystal formation A ").The feature of the X-ray powder diffraction collection (being radiated using Cu-K α) of the crystal formation is：2 θ values be 8.0 ° ± 0.2 °, 9.4 ° ± 0.2 °, 10.6 ° ± 0.2 °, 14.5 ° ± 0.2 °, 19.3 ° ± 0.2 °, 21.1 ° ± 0.2 °, 23.4 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

In one embodiment, the phosphoric acid tenofovir Chinese mugwort that the present invention is told draws phenol amine (1:1) crystal formation A X-ray powder The feature of diffracting spectrum is：2 θ values be 8.0 ° ± 0.2 °, 9.4 ° ± 0.2 °, 10.6 ° ± 0.2 °, 14.5 ° ± 0.2 °, 15.9 ° ± 0.2 °, 17.0 ° ± 0.2 °, 17.6 ° ± 0.2 °, 18.6 ° ± 0.2 °, 19.3 ° ± 0.2 °, 21.1 ° ± 0.2 °, 23.4 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

Further, phosphoric acid tenofovir Chinese mugwort of the present invention draws phenol amine (1:1) X-ray powder diffraction collection that crystal formation A is represented with 2 θ angles has characteristic diffraction peak and relative intensity in following position：

2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)
2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)	7.0°±0.2°	7	18.6°±0.2°	28
8.0°±0.2°	75	19.3°±0.2°	39	7.0°±0.2°	7	18.6°±0.2°	28
8.0°±0.2°	75	19.3°±0.2°	39	9.4°±0.2°	65	19.8°±0.2°	8
10.6°±0.2°	36	21.1°±0.2°	43	9.4°±0.2°	65	19.8°±0.2°	8
10.6°±0.2°	36	21.1°±0.2°	43	11.8°±0.2°	7	22.9°±0.2°	11
14.5°±0.2°	100	23.4°±0.2°	40	11.8°±0.2°	7	22.9°±0.2°	11
14.5°±0.2°	100	23.4°±0.2°	40	15.5°±0.2°	9	23.9°±0.2°	13
15.9°±0.2°	27	25.5°±0.2°	8	15.5°±0.2°	9	23.9°±0.2°	13
15.9°±0.2°	27	25.5°±0.2°	8	17.0°±0.2°	22	26.3°±0.2°	11
17.6°±0.2°	32			17.0°±0.2°	22	26.3°±0.2°	11

In one embodiment, the phosphoric acid tenofovir Chinese mugwort that the present invention is provided draws phenol amine (1:1) crystal formation A has the feature representated by X-ray powder diffraction collection as shown in Figure 8.

In one embodiment, what the present invention was provided prepares phosphoric acid tenofovir Chinese mugwort drawing phenol amine (1:1) phosphoric acid tenofovir Chinese mugwort draws phenol amine (1 in mixture:1) crystal formation A contents (mass content) are generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.

It will be appreciated by persons skilled in the art that phosphoric acid tenofovir Chinese mugwort of the present invention draws phenol amine (1:1) mixture refers to drawing phenol amine (1 with the directly synthetically prepared phosphoric acid tenofovir Chinese mugwort containing other impurities or crystal formation of chemical synthesis process:1).

In one embodiment, phosphoric acid tenofovir of the invention Chinese mugwort draws phenol amine (1:1) crystal formation A preparation method includes：

(1) phenol amine and phosphoric acid is drawn to be dissolved in acetonitrile tenofovir Chinese mugwort；The solvent ends with tenofovir and draws the weight ratio generally 5 of phenol amine:1~80:1.Tenofovir Chinese mugwort draws the molar ratio general 0.5 of phenol amine and phosphoric acid:1~1.5:1, preferably 0.8:1~1.2:1.

(2) solid is separated out；

Sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1)

In one embodiment, in formula II, n elects 1, X as and elects sulfuric acid as, i.e., there is provided tenofovir Chinese mugwort draw phenol amine withSulfuric acidWith 1:The compound of 1 molar composition ratio formation, is referred to as " sulfuric acid tenofovir Chinese mugwort drawing phenol amine (1:1)”.

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

(1) tenofovir Chinese mugwort is drawn into phenol amine and sulfuric acid dissolution in suitable solvent；

(2) solid is separated out；

(3) separated out solid is separated；

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

Sulfuric acid tenofovir Chinese mugwort prepared by the embodiment draws phenol amine (1:1) it is a kind of crystal.

Therefore, phenol amine (1 is drawn the invention provides a kind of sulfuric acid tenofovir Chinese mugwort:1) crystal formation (in order to express easily, is referred to as " sulfuric acid tenofovir Chinese mugwort drawing phenol amine (1 by crystal formation:1) crystal formation A ").The feature of the X-ray powder diffraction collection (being radiated using Cu-K α) of the crystal formation is：2 θ values be 9.2 ° ± 0.2 °, 10.7 ° ± 0.2 °, 11.1 ° ± 0.2 °, 18.4 ° ± 0.2 °, 19.8 ° ± 0.2 °, 22.3 ° ± 0.2 °, 24.3 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

In one embodiment, the sulfuric acid tenofovir Chinese mugwort that the present invention is told draws phenol amine (1:1) feature of crystal formation A X-ray powder diffraction collection is：2 θ values be 9.2 ° ± 0.2 °, 10.7 ° ± 0.2 °, 11.1 ° ± 0.2 °, 16.9 ° ± 0.2 °, 18.4 ° ± 0.2 °, 19.2 ° ± 0.2 °, 19.8 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.3 ° ± 0.2 °, 23.1 ° ± 0.2 °, 24.3 ° ± 0.2 °, 28.1 ° ± 0.2 °, 31.1 ° ± 0.2 ° etc. to that should have characteristic diffraction peak.

Further, sulfuric acid tenofovir Chinese mugwort of the present invention draws phenol amine (1:1) X-ray powder diffraction collection that crystal formation A is represented with 2 θ angles has characteristic diffraction peak and relative intensity in following position：

2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)
2 θ angles (°)	Relative intensity (%)	2 θ angles (°)	Relative intensity (%)	9.2°±0.2°	59	21.5°±0.2°	14
10.7°±0.2°	41	21.7°±0.2°	17	9.2°±0.2°	59	21.5°±0.2°	14
10.7°±0.2°	41	21.7°±0.2°	17	11.1°±0.2°	45	22.3°±0.2°	50
16.6°±0.2°	20	23.1°±0.2°	32	11.1°±0.2°	45	22.3°±0.2°	50
16.6°±0.2°	20	23.1°±0.2°	32	16.9°±0.2°	20	24.3°±0.2°	51
17.2°±0.2°	12	25.1°±0.2°	11	16.9°±0.2°	20	24.3°±0.2°	51
17.2°±0.2°	12	25.1°±0.2°	11	17.9°±0.2°	22	25.7°±0.2°	9
18.4°±0.2°	100	27.4°±0.2°	9	17.9°±0.2°	22	25.7°±0.2°	9
18.4°±0.2°	100	27.4°±0.2°	9	19.2°±0.2°	25	28.1°±0.2°	23
19.8°±0.2°	54	29.3°±0.2°	10	19.2°±0.2°	25	28.1°±0.2°	23
19.8°±0.2°	54	29.3°±0.2°	10	20.0°±0.2°	21	31.1°±0.2°	22

In one embodiment, the sulfuric acid tenofovir Chinese mugwort that the present invention is provided draws phenol amine (1:1) crystal formation A has the feature representated by X-ray powder diffraction collection as shown in Figure 9.

In one embodiment, the sulfuric acid tenofovir Chinese mugwort for the preparation that the present invention is provided draws phenol amine (1:1) sulfuric acid tenofovir Chinese mugwort draws phenol amine (1 in mixture:1) crystal formation A contents (mass content) are generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.

It will be appreciated by persons skilled in the art that sulfuric acid tenofovir Chinese mugwort of the present invention draws phenol amine (1:1) mixture refers to drawing phenol amine (1 with the directly synthetically prepared sulfuric acid tenofovir Chinese mugwort containing other impurities or crystal formation of chemical synthesis process:1).

In one embodiment, sulfuric acid tenofovir of the invention Chinese mugwort draws phenol amine (1:1) crystal formation A preparation method includes：

(1) tenofovir Chinese mugwort is drawn into phenol amine and sulfuric acid dissolution in acetonitrile；The solvent ends with tenofovir and draws the weight ratio generally 5 of phenol amine:1~80:1.Tenofovir Chinese mugwort draws the molar ratio general 0.5 of phenol amine and sulfuric acid:1~1.5:1, preferably 0.8:1~1.2:1.

(2) solid is separated out；

According to the purpose of the present invention, the invention provides the pharmaceutical composition or preparation that the Chinese mugwort of tenofovir shown in the formula II comprising therapeutically effective amount draws tenofovir Chinese mugwort drawing phenol amine compound and pharmaceutic adjuvant made from phenol amine compound or the preparation method.

Alternatively, aforementioned pharmaceutical compositions or preparation can further include another or a variety of antivirotics or antiviral auxiliary reagent, including but not limited to emtricitabine, Lamivudine, Abacavir (Abacavir), Acemannan (Acemannan), VX-478 (Ainprenavir), VX-478 (Amprenavir), atazanavir (Atazanavir), Clevudine (Clevudine), Cobicistat, up to a Wei Lin (Dapivirine), DRV (Darunavir), Delavirdine (Delavirdine), Didanosine (Didanosine), De Luogewei (Dolutegravir), efavirenz (Efavirenz), angstrom for draw Wei (Elvitegravir), enfuirtide (Enfuvirtide), Entecavir (Entecavir), etravirine (Etravirine), FCV (Famciclovir), good fortune Sha Nawei (Fosamprenavir), glutathione (Glutathione), indinavir (Indidnavir), levamisol (Levamisole), Lopinavir (Lopinavir), Maraviroc (Maraviroc), Nai Feinawei (Nelfinavir), NVP (Nevirapine), Penciclovir (Penciclovir), pentamidine (Pentamidine), Phosphazid, Propagermanium (Propagermanium), Merck (Raltegravir), Ribavirin (Ribavirin), rilpivirine (Rilpivrine), Ritonavir (Ritonavir), inverase (Saquinavir), stavudine (Stavudine), Sebivo (Telbivudine), tipranavir (Tipranavir), Vorinostat (Vorinostat), zalcitabine (Zalcitabine), Zidovudine (Zidovudine) etc. or their pharmaceutical salts, wherein it is preferred that emtricitabine, Lamivudine, Cobicistat, DRV, efavirenz, angstrom for draw Wei, hydrochloric acid rilpivirine.

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

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws phenol amine compound, emtricitabine, Cobicistat and angstrom for the pharmaceutical composition for drawing Wei；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws the pharmaceutical composition of phenol amine compound, emtricitabine, Cobicistat and DRV；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws the pharmaceutical composition of phenol amine compound and emtricitabine；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws the pharmaceutical composition of phenol amine compound, emtricitabine and efavirenz；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws the vertical Wei Lin of phenol amine compound, emtricitabine and hydrochloric acid pharmaceutical composition；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws phenol amine compound, the pharmaceutical composition of Lamivudine；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws the pharmaceutical composition of phenol amine compound, Lamivudine and efavirenz；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws phenol amine compound, Lamivudine, Cobicistat and angstrom for the pharmaceutical composition for drawing Wei；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws the pharmaceutical composition of phenol amine compound, Lamivudine, Cobicistat and DRV.

In one embodiment, phenol amine (1 is drawn the invention provides a kind of L-TARTARIC ACID tenofovir Chinese mugwort comprising therapeutically effective amount:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1)、L- Tartaric acid tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, L MALIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) crystal formation A, citric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, butanedioic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, oxalic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, phosphoric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A or sulfuric acid tenofovir Chinese mugwort draw phenol amine (1:1) pharmaceutical composition or preparation of crystal formation A and pharmaceutic adjuvant.

Aforementioned pharmaceutical compositions or preparation can orally or not oral administrations.During oral administration, tablet, capsule, pill, granule, solution, syrup, supensoid agent, powder, sustained release preparation or controlled release preparation etc. can be made using conventional preparation technique.During non-oral administration, preparation capable of permeating skin, parenteral solution, infusion solution or suppository etc. can be made into using conventional preparation technique.

The various formulations of aforementioned pharmaceutical compositions can be prepared according to the conventional method of pharmaceutical field.The tenofovir Chinese mugwort shown in the formula II of therapeutically effective amount for example is drawn into phenol amine compound, and (such as L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1), L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, L MALIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) crystal formation A, citric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, butanedioic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, oxalic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, phosphoric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A or sulfuric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A), alternatively with the active component of another or a variety of therapeutically effective amounts, mix or contact with one or more pharmaceutic adjuvants, be then made into required formulation.

Aforementioned pharmaceutical compositions or the preferred peroral dosage form of preparation, including tablet, capsule, pill, granule, solution, syrup, dry suspensoid agent, supensoid agent, powder, sustained release preparation or controlled release preparation etc..The wherein solid orally ingestible such as preferred tablet, capsule, granule, dry suspensoid agent and sustained release preparation or controlled release preparation, wherein more preferably tablet and capsule.Currently preferred pharmaceutical composition or preparation can be prepared according to any conventional method that solid orally ingestible used is prepared.Such as tablet can be prepared using wet granule compression tablet mode, can carry out any form of coating as needed, and any releasing pattern (such as quick-release, enteric ease up controlled release) can be made in such as tablet；Capsule can be prepared using modes such as encapsulated dose of wet granulations, and any releasing pattern (such as quick releasing formulation, enteric coated preparations and sustained-release preparation) can be made in Capsule content.

In one embodiment, the tenofovir Chinese mugwort shown in the formula II that the present invention is provided draws phenol amine compound, and (such as L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1), L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, L MALIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) crystal formation A, citric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, butanedioic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, oxalic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, phosphoric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A or sulfuric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A) particle diameter distribution control 95% be less than 200 μm, preferably smaller than 180 μm, more preferably less than 150 μm, more preferably less than 100 μm.

The conventional pharmaceutic adjuvant in this area in peroral dosage form, including filler, disintegrant, adhesive, dispersant, lubricant or retention agent and all types of coating materials etc..

The filler generally comprises pregelatinized starch, starch, lactose, dextrin, calcium monohydrogen phosphate, calcium carbonate, mannitol, microcrystalline cellulose, sorbierite, glucose etc., they, which can be used alone, to be used in mixed way, wherein it is preferred that pregelatinized starch, lactose, microcrystalline cellulose, mannitol.

The disintegrant generally comprises cross-linked carboxymethyl cellulose sodium, sodium carboxymethylcellulose, sodium carboxymethyl starch, PVPP, starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose etc., they, which can be used alone, to be used in mixed way, wherein preferably cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, PVPP, microcrystalline cellulose, low-substituted hydroxypropyl cellulose.

Described adhesive generally comprises microcrystalline cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, PVP, starch slurry, Arabic gum, Macrogol 4000, polyvinyl alcohol, alginates, water, the ethanol solution of various concentration, they, which can be used alone, to be used in mixed way, wherein it is preferred that hydroxypropyl methyl cellulose, hydroxypropylcellulose, PVP, starch slurry.

The lubricant generally comprises magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, stearic acid Potassium fumarate, palmitic acid, superfine silica gel powder, stearmide, talcum powder, solid polyethylene glycol, glyceryl triacetate etc..They, which can be used alone, to be used in mixed way, wherein it is preferred that magnesium stearate, stearic acid, talcum powder, superfine silica gel powder, glyceryl triacetate.

If desired, other auxiliary materials can also be added into above-mentioned composition or preparation, such as sweetener (such as aspartame, Steviosin), colouring agent (such as lemon yellow, iron oxide various medicinal or food coloring), stabilizer (such as calcium carbonate, calcium bicarbonate, sodium acid carbonate, sodium carbonate, calcium phosphate, calcium monohydrogen phosphate, glycine), surfactant (such as Tween 80, lauryl sodium sulfate) coating material (such as Opadry, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, acrylic resin copolymer etc..

In one embodiment, the invention provides a kind of folk prescription composition or preparation, the tenofovir Chinese mugwort that wherein active component is selected from shown in the formula II of therapeutically effective amount draws phenol amine compound, and (such as L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir ends Draw phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1), L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, L MALIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) crystal formation A, citric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, butanedioic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, oxalic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, phosphoric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A or sulfuric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A).Said composition or the preferred oral formulations of preparation, more preferably tablet or capsule；In unit composition or preparation, their weight content is generally 1mg to 200mg, preferably 5mg to 100mg, for example in terms of tenofovir Chinese mugwort drawing phenol amine, weight content is about 10mg, about 12.5mg, about 25mg or about 50mg, wherein " about " refers to the scope of ± 10% scope, preferably ± 5%.

In one embodiment, the invention provides a kind of compound or preparation, wherein the tenofovir Chinese mugwort that the first active component is selected from shown in the formula II of therapeutically effective amount draws phenol amine compound, (such as L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1), L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, L MALIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) crystal formation A, citric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, butanedioic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, oxalic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, phosphoric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A or sulfuric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A), the second active component be therapeutically effective amount emtricitabine, the 3rd active component be therapeutically effective amount Cobicistat, the 4th active component for therapeutically effective amount angstrom for draw Wei.Said composition or the preferred oral formulations of preparation, more preferably tablet or capsule；In unit composition or preparation, their own weight content is generally 1mg to 500mg, it is preferred that 5mg to 300mg, for example containing above-mentioned first active component about 10mg or about 25mg (in terms of drawing phenol amine by tenofovir Chinese mugwort), the second active component (emtricitabine) about 200mg, the 3rd active component (Cobicistat) about 150mg and the 4th active component (angstrom for draw Wei) about 150mg, wherein " about " refer to ± 10% scope, preferably ± 5% scope.

In one embodiment, the invention provides a kind of compound or preparation, wherein the tenofovir Chinese mugwort that the first active component is selected from shown in the formula II of therapeutically effective amount draws phenol amine compound, (such as L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1), L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, DL- winestones Sour tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, L MALIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) crystal formation A, citric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, butanedioic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, oxalic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, phosphoric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A or sulfuric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A), the second active component is the emtricitabine of therapeutically effective amount, and the 3rd active component is the Cobicistat of therapeutically effective amount, and the 4th active component is the DRV of therapeutically effective amount.Said composition or the preferred oral formulations of preparation, more preferably tablet and capsule；In unit composition or preparation, their own weight content is generally 1mg to 1000mg, it is preferred that 5mg to 900mg, for example containing above-mentioned first active component about 10mg or about 25mg (in terms of tenofovir Chinese mugwort drawing phenol amine), the second active component (emtricitabine) about 200mg, the 3rd active component (Cobicistat) about 150mg and the 4th active component (DRV) about 800mg, wherein " about " refer to ± 10% scope, preferably ± 5% scope.

In one embodiment, the invention provides a kind of compound or preparation, wherein the tenofovir Chinese mugwort that the first active component is selected from shown in the formula II of therapeutically effective amount draws phenol amine compound, (such as L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1), L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, L MALIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) crystal formation A, citric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, butanedioic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, oxalic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, phosphoric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A or sulfuric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A), the second active component is the emtricitabine of therapeutically effective amount.Said composition or the preferred oral formulations of preparation, more preferably tablet and capsule；In unit composition or preparation, their own weight content is generally 1mg to 500mg, it is preferred that 5mg to 300mg, for example containing above-mentioned first active component about 10mg or about 25mg (in terms of tenofovir Chinese mugwort drawing phenol amine) and the second active component (emtricitabine) about 200mg, wherein " about " refer to ± 10% scope, preferably ± 5% scope.

In one embodiment, the invention provides a kind of compound or preparation, wherein the tenofovir Chinese mugwort that the first active component is selected from shown in the formula II of therapeutically effective amount draws phenol amine compound, (such as L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1), L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, L MALIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) crystal formation A, citric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, butanedioic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, oxalic acid tenofovir Chinese mugwort draw phenol amine (1:1) Crystal formation A, phosphoric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A or sulfuric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A), the second active component is the emtricitabine of therapeutically effective amount, and the 3rd active component is the efavirenz of therapeutically effective amount.Said composition or the preferred oral formulations of preparation, more preferably tablet and capsule；In unit composition or preparation, their own weight content is generally 1mg to 800g, it is preferred that 5mg to 700mg, for example containing above-mentioned first active component about 10mg or about 25mg (in terms of tenofovir Chinese mugwort drawing phenol amine), the second active component (emtricitabine) about 200mg and the 3rd active component (efavirenz) about 600mg, wherein " about " refer to ± 10% scope, preferably ± 5% scope.

In one embodiment, the invention provides a kind of compound or preparation, wherein the tenofovir Chinese mugwort that the first active component is selected from shown in the formula II of therapeutically effective amount draws phenol amine compound, (such as L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1), L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, L MALIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) crystal formation A, citric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, butanedioic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, oxalic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, phosphoric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A or sulfuric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A), the second active component is the emtricitabine of therapeutically effective amount, and the 3rd active component is the hydrochloric acid rilpivirine of therapeutically effective amount.Said composition or the preferred oral formulations of preparation, more preferably tablet and capsule；In unit composition or preparation, their own weight content is generally 1mg to 500mg, it is preferred that 5mg to 300mg, for example containing above-mentioned first active component about 10mg or about 25mg (in terms of tenofovir Chinese mugwort drawing phenol amine), the second active component (emtricitabine) about 200mg and the 3rd active component (hydrochloric acid rilpivirine) about 25mg (in terms of rilpivirine), " about " scope of ± 10% scope, preferably ± 5% is referred to.

In one embodiment, the invention provides a kind of compound or preparation, wherein the tenofovir Chinese mugwort that the first active component is selected from shown in the formula II of therapeutically effective amount draws phenol amine compound, (such as L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1), L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, L MALIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) crystal formation A, citric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, butanedioic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, oxalic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, phosphoric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A or sulfuric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A), the second active component is the Lamivudine of therapeutically effective amount.Said composition or the preferred oral formulations of preparation, more preferably tablet and capsule； In unit composition or preparation, their own weight content is generally 1mg to 500mg, it is preferred that 5mg to 400mg, for example containing above-mentioned first active component about 10mg or about 25mg (in terms of tenofovir Chinese mugwort drawing phenol amine) and the second active component (Lamivudine) about 300mg, wherein " about " refer to ± 10% scope, preferably ± 5% scope.

In one embodiment, the invention provides a kind of compound or preparation, wherein the tenofovir Chinese mugwort that the first active component is selected from shown in the formula II of therapeutically effective amount draws phenol amine compound, (such as L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1), L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, L MALIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) crystal formation A, citric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, butanedioic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, oxalic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, phosphoric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A or sulfuric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A), the second active component is the Lamivudine of therapeutically effective amount, and the 3rd active component is the efavirenz of therapeutically effective amount.Said composition or the preferred oral formulations of preparation, more preferably tablet and capsule；In unit composition or preparation, their own weight content is generally 1mg to 800mg, it is preferred that 5mg to 700mg, for example containing above-mentioned first active component about 10mg or 25mg (in terms of tenofovir Chinese mugwort drawing phenol amine), the second active component (Lamivudine) about 300mg and the 3rd active component (efavirenz) about 600mg, wherein " about " refer to ± 10% scope, preferably ± 5% scope.

In one embodiment, the invention provides a kind of compound or preparation, wherein the tenofovir Chinese mugwort that the first active component is selected from shown in the formula II of therapeutically effective amount draws phenol amine compound, (such as L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1), L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, L MALIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) crystal formation A, citric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, butanedioic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, oxalic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, phosphoric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A or sulfuric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A), the second active component be therapeutically effective amount Lamivudine, the 3rd active component be therapeutically effective amount Cobicistat, the 4th active component for therapeutically effective amount angstrom for draw Wei.Said composition or the preferred oral formulations of preparation, more preferably tablet and capsule；In unit composition or preparation, their own weight content is generally 1mg to 500mg, it is preferred that 5mg to 400mg, such as containing above-mentioned first active component about 10mg or about 25mg (in terms of tenofovir Chinese mugwort drawing phenol amine), the second active component (rummy husband It is fixed) about 300mg, the 3rd active component (Cobicistat) about 150mg and the 4th active component (angstrom for draw Wei) about 150mg, wherein " about " refers to the scope of ± 10% scope, preferably ± 5%.

In one embodiment, the invention provides a kind of compound or preparation, wherein the tenofovir Chinese mugwort that the first active component is selected from shown in the formula II of therapeutically effective amount draws phenol amine compound, (such as L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1), L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, L MALIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) crystal formation A, citric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, butanedioic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, oxalic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, phosphoric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A or sulfuric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A), the second active component is the Lamivudine of therapeutically effective amount, and the 3rd active component is the Cobicistat of therapeutically effective amount, and the 4th active component is the DRV of therapeutically effective amount.Said composition or the preferred oral formulations of preparation, more preferably tablet and capsule；In unit composition or preparation, their own weight content is generally 1mg to 1000mg, it is preferred that 5mg to 900mg, for example containing above-mentioned first active component about 10mg or about 25mg (in terms of tenofovir Chinese mugwort drawing phenol amine), the second active component (Lamivudine) about 200mg, the 3rd active component (Cobicistat) about 150mg and the 4th active component (DRV) about 800mg, wherein " about " refer to ± 10% scope, preferably ± 5% scope.

Above-mentioned composition is not only stable in chemistry, and also has synergy and/or can reduce side effect and the drug resistance of independent active component；The compliance of patient may be increased simultaneously.

The invention provides the method for preparing above-mentioned Pharmaceutical composition or preparation.For folk prescription composition or preparation, this method is usually to draw phenol amine compound to mix or contact with one or more pharmaceutic adjuvants the tenofovir Chinese mugwort shown in the formula II of therapeutically effective amount.For two compounds or preparation, this method is usually to draw phenol amine compound, the second active component (such as emtricitabine, Lamivudine) to mix or contact with one or more pharmaceutic adjuvants the tenofovir Chinese mugwort shown in the formula II of therapeutically effective amount.For three compounds or many compounds or preparation, this method is usually to draw phenol amine compound, the second active component (such as emtricitabine, Lamivudine) and another or various active composition to mix or contact with pharmaceutic adjuvant the tenofovir Chinese mugwort shown in the formula II of therapeutically effective amount.The pharmaceutical composition or preparation can be prepared by the way of well known in the art.Described pharmaceutic adjuvant can be the conventional pharmaceutic adjuvant in this area, including filler, disintegrant, adhesive, lubricant etc..

According to the purpose of the present invention, tenofovir Chinese mugwort made from phenol amine compound or the preparation method is drawn to draw application of the phenol amine compound in the medicine for preparing prevention and/or treatment virus infection the invention provides the Chinese mugwort of tenofovir shown in formula II.

Specifically, phenol amine compound is drawn to prepare prevention and/or treating B-mode liver the invention provides the Chinese mugwort of tenofovir shown in formula II Application in the medicine of scorching virus (HBV) and/or human immunodeficiency virus (HIV) infection.

In one embodiment, application of the phenol amine compound in the medicine for preparing prevention and/or treatment hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) infection is drawn the invention provides the Chinese mugwort of the tenofovir shown in formula II.

In one embodiment, application of the pharmaceutical composition of phenol amine compound and pharmaceutic adjuvant in the medicine for preparing prevention and/or treatment hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) infection is drawn the invention provides the Chinese mugwort of the tenofovir shown in the formula II comprising therapeutically effective amount.

In one embodiment, application of the pharmaceutical composition of phenol amine compound, another or a variety of antivirotics or antiviral auxiliary reagent and pharmaceutic adjuvant in the medicine for preparing prevention and/or treatment hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) infection is drawn the invention provides the Chinese mugwort of the tenofovir shown in the formula II comprising therapeutically effective amount.

It the experiment proved that, the tenofovir Chinese mugwort shown in offer formula II of the present invention draws phenol amine compound, such as L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1), sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1), L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, L MALIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) crystal formation A, citric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, butanedioic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, oxalic acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, phosphoric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A, sulfuric acid tenofovir Chinese mugwort draw phenol amine (1:1) crystal formation A etc., preparation method simplicity is controllable, and physical behavior, stability, dissolubility, preparation adaptability etc. are not less than or draw phenol amine fumarate and hemifumarate better than existing tenofovir Chinese mugwort, with good industrialization practicality.

The X-ray powder diffraction analysis of the present invention be under environment temperature and ambient humidity, CuK α sources through Dutch PANalytical X`Pert PRO type X-ray powder diffraction instrument () determine what is completed." environment temperature " is usually 0~40 DEG C；" ambient humidity " is usually 30%~80% relative humidity.

The representational X-ray powder diffraction collection that the present invention is provided is listed in accompanying drawing." representational X-ray powder diffraction collection " refers to that the X-ray powder diffraction feature of this crystal formation meets the overall pattern of this collection of illustrative plates display, it is appreciated that in test process, due to being influenceed by many factors (processing method of sample, instrument, test parameter, test operation when the granularity of such as test sample, test), the X-ray powder diffraction collection measured by same crystal formation go out peak position or peak intensity has certain difference.Generally, the experimental error of the θ values of diffraction maximum 2 can be ± 0.2 ° in X-ray powder diffraction collection.

Brief description of the drawings

Fig. 1 L-TARTARIC ACIDs tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A X-ray powder diffraction collection；

Fig. 2 D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A X-ray powder diffraction collection；

Fig. 3 DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A X-ray powder diffraction collection；

Fig. 4 L MALIC ACIDs tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A X-ray powder diffraction collection；

Fig. 5 citric acids tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A X-ray powder diffraction collection；

Fig. 6 butanedioic acids tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A X-ray powder diffraction collection；

Fig. 7 oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A X-ray powder diffraction collection；

Fig. 8 phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A X-ray powder diffraction collection；

Fig. 9 sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A X-ray powder diffraction collection；

Figure 10 tenofovirs Chinese mugwort draws phenol amine¹H NMR spectras；

Figure 11 L-TARTARIC ACIDs tenofovir Chinese mugwort draws phenol amine (1:2)¹H NMR spectras；

Figure 12 D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1)¹H NMR spectras；

Figure 13 DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1)¹H NMR spectras；

Figure 14 L MALIC ACIDs tenofovir Chinese mugwort draws phenol amine (1:2)¹H NMR spectras；

Figure 15 citric acids tenofovir Chinese mugwort draws phenol amine (1:1)¹H NMR spectras；

Figure 16 butanedioic acids tenofovir Chinese mugwort draws phenol amine (1:1)¹H NMR spectras；

Figure 17 oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1)¹H NMR spectras；

Figure 18 phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1)¹H NMR spectras；

Figure 19 sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1)¹H NMR spectras.

Embodiment

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

In following examples¹H NMR tests are, using deuterated dimethyl sulfoxide as test solvent, internal standard to be made with tetramethylsilane, are determined at room temperature with the 400MHz NMRs of Bruke AV- II.

X-ray powder diffraction analysis in following examples be under environment temperature and ambient humidity, CuK α sources through Dutch PANalytical X`Pert PRO type X-ray powder diffraction instrument () determine what is completed." environment temperature " is usually 0~40 DEG C；" ambient humidity " is usually 30%~80% relative humidity.

Elementary analysis in following examples is determined through the Italian elemental analysers of CARLO ERBA 1106.

Melting range is determined through YRT-3 type drug melting points instrument in following examples.

Embodiment 1

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

At 20~25 DEG C, one phenyl tenofovir (is prepared into) 500.0g (1.38mol by the method disclosed in CN1443189A, 1.0eq) it is added in toluene 3.0L, solid is completely dissolved under stirring, then thionyl chloride 150ml (2.05mol are added, 1.5eq), gained mixed liquor is heated to about stirring 96 hours at 70 DEG C.40~45 DEG C be concentrated under reduced pressure it is dry, toluene 2.5L is added in concentrate, ALANINE isopropyl ester (commercially viable to buy) 813.5g (6.21mol are added dropwise at -10 DEG C~10 DEG C, 4.5eq) it is dissolved in dichloromethane 4.0L solution, then it is warmed to room temperature after being stirred 30 minutes at -10 DEG C -10 DEG C, washed with 10% biphosphate sodium water solution 2.5L × 2, separate organic phase, washed with 15% potassium bicarbonate aqueous solution 1.0L × 2, then washed with purified water 2.5L, obtained organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression concentration is dry.At 20~25 DEG C, concentrate toluene/acetonitrile mixed solvent (volume ratio 4/1) 2.5L dissolves, adding tenofovir Chinese mugwort draws phenol amine crystal seed (to prepare) 50mg by the method disclosed in CN1443189A, then proceed to stirring 2 hours, suction filtration, filter cake is washed with toluene/acetonitrile (volume ratio 4/1), is then dried under reduced pressure at 40~45 DEG C and is obtained tenofovir Chinese mugwort drawing phenol amine.

¹H NMR (400MHz, DMSO-d₆)δ:8.15 (s, 1H), 8.11 (s, 1H), 7.32-7.28 (t, 2H), 7.21 (s, 2H), 7.15-7.12 (m, 1H), 7.07-7.05 (m, 2H), 5.65-5.59 (m, 1H), 4.90-4.81 (m, 1H), 4.31-4.26 (m, 1H), 4.18-4.13 (m, 1H), 3.98-3.91 (m, 1H), 3.90-3.81 (m, 2H), 3.80-3.75 (m, 1H), 1.16-1.14 (m, 9H), 1.09-1.07 (d, 3H) (¹H NMR spectras are shown in accompanying drawing 10).

Embodiment 2

L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) and its crystal formation A preparation

At 70~75 DEG C, phenol amine 4.76g (10.0mmol) and L-TARTARIC ACID 0.75g (5.0mmol) is drawn to be dissolved in acetonitrile 100ml tenofovir Chinese mugwort, stirring is cooled to 15~20 DEG C after dissolving completely, then proceedes to stirring and crystallizing；Suction filtration, filter cake is washed through appropriate acetonitrile, is dried under reduced pressure at 40~45 DEG C, is obtained L-TARTARIC ACID tenofovir Chinese mugwort and is drawn phenol amine (1:2).

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

Melting range：158-161℃.

It is above-mentioned¹In H NMR results, chemical shift is in (the s of δ 8.14,1H) with 8.10 (s, 1H) signal peak at place is attributed to 2 H on tenofovir Chinese mugwort drawing phenol amine adenine ring respectively, the signal peak at δ 4.30-4.25 (m, 2H) place draws phenol amine free alkali with the tenofovir Chinese mugwort in embodiment 1¹H NMR are compareed, it can be determined that wherein 1 H is attributed to 2 methine H of L-TARTARIC ACID, from the integral area ratio of two groups of signal peaks can determine whether the sample in tenofovir Chinese mugwort draw rubbing for phenol amine and L-TARTARIC ACID Your ratio of components is 2:1(¹H NMR spectras are shown in Figure 11).

The X-ray powder diffraction collection surveyed is shown in Fig. 1, measured value such as following table (the corresponding measured value of diffraction maximum for taking relative intensity to be more than or equal to 3%, measured value round off takes three decimals).

The above-mentioned crystal formation of gained is named as L-TARTARIC ACID tenofovir Chinese mugwort and draws phenol amine (1:2) crystal formation A.

Embodiment 3

At 70~75 DEG C, phenol amine 4.76g (10.0mmol) and L-TARTARIC ACID 0.78g (5.2mmol) is drawn to be dissolved in isopropanol 40ml tenofovir Chinese mugwort, stirring is cooled to 15~20 DEG C after dissolving completely, then proceedes to stirring and crystallizing；Suction filtration, filter cake is washed through appropriate isopropanol, is dried under reduced pressure at 30~35 DEG C, is obtained L-TARTARIC ACID tenofovir Chinese mugwort and is drawn phenol amine (1:2) crystal formation A.

Embodiment 4

At 70~75 DEG C, phenol amine 4.76g (10.0mmol) and L-TARTARIC ACID 0.65g (4.3mmol) is drawn to be dissolved in ethanol 200ml tenofovir Chinese mugwort, stirring is cooled to 15~20 DEG C after dissolving completely, then proceedes to stirring and crystallizing；Suction filtration, filter cake is washed through ethanol in proper amount, is dried under reduced pressure at 55~60 DEG C, is obtained L-TARTARIC ACID tenofovir Chinese mugwort and is drawn phenol amine (1:2) crystal formation A.

Embodiment 5

D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) and its crystal formation A preparation

At 70~75 DEG C, phenol amine 4.76g (10.0mmol) and D- tartaric acid 1.50g (10.0mmol) is drawn to be dissolved in acetonitrile 100ml tenofovir Chinese mugwort, stirring is cooled to 15~20 DEG C after dissolving completely, continues stirring and crystallizing；Suction filtration, filter cake is washed through appropriate acetonitrile, is dried under reduced pressure at 40~45 DEG C, is obtained D- tartaric acid tenofovir Chinese mugwort and is drawn phenol amine (1:1).

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

Melting range：135-138℃.

It is above-mentioned¹In H NMR results, chemical shift is in (the s of δ 8.15,1H) with 8.11 (s, 1H) signal peak at place is attributed to 2 H on tenofovir Chinese mugwort drawing phenol amine adenine respectively, the signal peak at δ 4.32-4.26 (m, 3H) place draws phenol amine free alkali with the tenofovir Chinese mugwort in embodiment 1¹H NMR are compareed, it can be determined that wherein 2 H are attributed to 2 methine H of D- tartaric acid, from the integral area ratio of two groups of signal peaks can determine whether the sample in tenofovir Chinese mugwort draw the molar composition ratio of phenol amine and D- tartaric acid to be 1:1(¹H NMR spectras are shown in accompanying drawing 12).

The X-ray powder diffraction collection surveyed is shown in Fig. 2, measured value such as following table (the corresponding measured value of diffraction maximum for taking relative intensity to be more than or equal to 3%, measured value round off takes three decimals).

The above-mentioned crystal formation of gained is named as D- tartaric acid tenofovir Chinese mugwort and draws phenol amine (1:1) crystal formation A.

Embodiment 6

DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) and its crystal formation A preparation

At 70~75 DEG C, phenol amine 4.76g (10.0mmol) and DL- tartaric acid 1.50g (10.0mmol) is drawn to be dissolved in acetonitrile 100ml tenofovir Chinese mugwort, stirring is cooled to 15~20 DEG C after dissolving completely, continues stirring and crystallizing；Suction filtration, filter cake is washed through appropriate acetonitrile, is dried under reduced pressure at 40~45 DEG C, is obtained DL- tartaric acid tenofovir Chinese mugwort and is drawn phenol amine (1:1).

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

Melting range：175-178℃.

It is above-mentioned¹In H NMR results, chemical shift is in (the s of δ 8.14,1H) with 8.11 (s, 1H) signal peak at place is attributed to 2 H on tenofovir Chinese mugwort drawing phenol amine adenine respectively, the signal peak at δ 4.31-4.26 (m, 3H) place draws phenol amine free alkali with the tenofovir Chinese mugwort in embodiment 1¹H NMR are compareed, it can be determined that wherein 2 H are attributed to 2 methine H of DL- tartaric acid, from the integral area ratio of two groups of signal peaks can determine whether the sample in tenofovir Chinese mugwort draw the molar composition ratio of phenol amine and DL- tartaric acid to be 1:1(¹H NMR spectras are shown in accompanying drawing 13).

The X-ray powder diffraction collection surveyed is shown in Fig. 3, measured value such as following table (the corresponding measured value of diffraction maximum for taking relative intensity to be more than or equal to 3%, measured value round off takes three decimals).

The above-mentioned crystal formation of gained is named as DL- tartaric acid tenofovir Chinese mugwort and draws phenol amine (1:1) crystal formation A.

Embodiment 7

L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) and its crystal formation A preparation

At 70~75 DEG C, phenol amine 4.76g (10.0mmol) and L MALIC ACID 0.67g (5.0mmol) is drawn to be dissolved in isopropanol 50ml tenofovir Chinese mugwort, stirring is cooled to 15~20 DEG C after dissolving completely, continues stirring and crystallizing；Suction filtration, filter cake is washed through appropriate isopropanol, is dried under reduced pressure at 40~45 DEG C, is obtained L MALIC ACID tenofovir Chinese mugwort and is drawn phenol amine (1:2).

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

It is above-mentioned¹In H NMR results, chemical shift is attributed to 2 H on tenofovir Chinese mugwort drawing phenol amine adenine respectively in the signal peak at δ 8.15 (s, 1H) and 8.11 (s, 1H) places, the signal peak at δ 2.65-2.43 (m, 1H) place is attributed to L MALIC ACID 2 H on methylene, from the integral area ratio of two groups of signal peaks can determine whether the sample in tenofovir Chinese mugwort draw the molar composition ratio of phenol amine and L MALIC ACID to be 2:1(¹H NMR spectras are shown in accompanying drawing 14).

The X-ray powder diffraction collection surveyed is shown in Fig. 4, measured value such as following table (the corresponding measured value of diffraction maximum for taking relative intensity to be more than or equal to 3%, measured value round off takes three decimals).

The above-mentioned crystal formation of gained is named as L MALIC ACID tenofovir Chinese mugwort and draws phenol amine (1:2) crystal formation A.

Embodiment 8

Citric acid tenofovir Chinese mugwort draws phenol amine (1:1) and its crystal formation A preparation

At 70~75 DEG C, phenol amine 4.76g (10.0mmol) and citric acid 1.92g (10.0mmol) is drawn to be dissolved in acetonitrile 100ml tenofovir Chinese mugwort, stirring is cooled to 15~20 DEG C after dissolving completely, continues stirring and crystallizing；Suction filtration, filter cake is washed through appropriate acetonitrile, is dried under reduced pressure at 40~45 DEG C, is obtained citric acid tenofovir Chinese mugwort and is drawn phenol amine (1:1).

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

Melting range：144-147℃.

It is above-mentioned¹In H NMR results, chemical shift is in (the s of δ 8.14,1H) with 8.11 (s, 1H) signal peak at place is attributed to 2 H on tenofovir Chinese mugwort drawing phenol amine adenine respectively, δ 2.78-2.74 (d, 2H) and the signal peak at 2.67-2.64 (d, 2H) place is attributed to 4 H of 2 methylene on citric acid, from the integral area ratio of two groups of signal peaks can determine whether the sample in replace promise good fortune The molar composition ratio of Wei Aila phenol amine and citric acid is 1:1(¹H NMR spectras are shown in accompanying drawing 15).

The X-ray powder diffraction collection surveyed is shown in Fig. 5, measured value such as following table (the corresponding measured value of diffraction maximum for taking relative intensity to be more than or equal to 3%, measured value round off takes three decimals).

The above-mentioned crystal formation of gained is named as citric acid tenofovir Chinese mugwort and draws phenol amine (1:1) crystal formation A.

Embodiment 9

At 70~75 DEG C, phenol amine 4.76g (10.0mmol) and citric acid 2.40g (12.5mmol) is drawn to be dissolved in ethanol 40ml tenofovir Chinese mugwort, stirring is cooled to 15~20 DEG C after dissolving completely, continues stirring and crystallizing；Suction filtration, filter cake is washed through ethanol in proper amount, is dried under reduced pressure at 30~35 DEG C, is obtained citric acid tenofovir Chinese mugwort and is drawn phenol amine (1:1) crystal formation A.

Embodiment 10

At 60~64 DEG C, phenol amine 4.76g (10.0mmol) and citric acid 1.54g (8.0mmol) is drawn to be dissolved in methanol 200ml tenofovir Chinese mugwort, stirring is cooled to 15~20 DEG C after dissolving completely, continues stirring and crystallizing；Suction filtration, filter cake is washed through proper amount of methanol, is dried under reduced pressure at 35~40 DEG C, is obtained citric acid tenofovir Chinese mugwort and is drawn phenol amine (1:1) crystal formation A.

Embodiment 11

At 60~65 DEG C, phenol amine 4.76g (10.0mmol) and citric acid 1.92g (10.0mmol) is drawn to be dissolved in tetrahydrofuran 150ml tenofovir Chinese mugwort, stirring is cooled to 15~20 DEG C after dissolving completely, continues stirring and crystallizing；Suction filtration, filter cake is through appropriate four Hydrogen furans is washed, and is dried under reduced pressure at 40~45 DEG C, is obtained citric acid tenofovir Chinese mugwort and is drawn phenol amine (1:1) crystal formation A.

Embodiment 12

Butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1) and its crystal formation A preparation

At 70~75 DEG C, phenol amine 4.76g (10.0mmol) and butanedioic acid 1.18g (10.0mmol) is drawn to be dissolved in acetonitrile 50ml tenofovir Chinese mugwort, stirring is cooled to 15~20 DEG C after dissolving completely, continues stirring and crystallizing；Suction filtration, filter cake is washed through appropriate acetonitrile, is dried under reduced pressure at 40~45 DEG C, is obtained butanedioic acid tenofovir Chinese mugwort and is drawn phenol amine (1:1).

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

It is above-mentioned¹In H NMR results, chemical shift is in (the s of δ 8.15,1H) with 8.11 (s, 1H) signal peak at place is attributed to 2 H on tenofovir Chinese mugwort drawing phenol amine adenine respectively, (the s of δ 2.43,4H) signal peak at place is attributed to 4 H of 2 symmetrical methylene on butanedioic acid, from the integral area ratio of two groups of signal peaks can determine whether the sample in tenofovir Chinese mugwort draw the molar composition ratio of phenol amine and butanedioic acid to be 1:1(¹H NMR spectras are shown in accompanying drawing 16).

The X-ray powder diffraction collection surveyed is shown in Fig. 6, measured value such as following table (the corresponding measured value of diffraction maximum for taking relative intensity to be more than or equal to 3%, measured value round off takes three decimals).

The above-mentioned crystal formation of gained is named as butanedioic acid tenofovir Chinese mugwort and draws phenol amine (1:1) crystal formation A.

Embodiment 13

Oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1) and its crystal formation A preparation

At 70~75 DEG C, phenol amine 4.76g (10.0mmol) and oxalic acid dihydrate 1.26g (10.0mmol) is drawn to be dissolved in acetonitrile 100ml tenofovir Chinese mugwort, stirring is cooled to 15~20 DEG C after dissolving completely, continues stirring and crystallizing；Suction filtration, filter cake is washed through appropriate acetonitrile, is dried under reduced pressure at 40~45 DEG C, is obtained oxalic acid tenofovir Chinese mugwort and is drawn phenol amine (1:1).

¹H NMR (400MHz, DMSO-d₆)δ:8.19 (s, 1H), 8.15 (s, 1H), 7.49 (s, 2H), 7.32-7.28 (m, 2H), 7.15-7.12 (m, 1H), 7.07-7.05 (m, 2H), 5.64-5.58 (m, 1H), 4.90-4.80 (m, 1H), 4.32-4.28 (m, 1H), 4.19-4.14 (m, 1H), 4.00-3.91 (m, 1H), 3.90-3.83 (m, 2H), 3.80-3.75 (m, 1H), 1.16-1.13 (m, 9H), 1.09-1.08 (d, 3H) (¹H NMR spectras are shown in accompanying drawing 17).

Elementary analysis：C：48.70%；H：5.50%；N：14.75%.It can determine whether that the sample mesoxalic acid and tenofovir Chinese mugwort draw the ratio of phenol amine to be about 1 from elementary analysis result:1.

Melting range：182-185℃.

The X-ray powder diffraction collection surveyed is shown in Fig. 7, measured value such as following table (the corresponding measured value of diffraction maximum for taking relative intensity to be more than or equal to 3%, measured value round off takes three decimals).

The above-mentioned crystal formation of gained is named as oxalic acid tenofovir Chinese mugwort and draws phenol amine (1:1) crystal formation A.

Embodiment 14

Phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1) and its crystal formation A preparation

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

¹H NMR (400MHz, DMSO-d₆)δ:8.15 (s, 1H), 8.11 (s, 1H), 7.31-7.27 (m, 2H), 7.25 (s, 2H), 7.15-7.11 (t, 1H), 7.07-7.05 (m, 2H), 5.64-5.59 (m, 1H), 4.90-4.80 (m, 1H), 4.30-4.26 (m, 1H), 4.18-4.13 (m, 1H), 3.98-3.91 (m, 1H), 3.90-3.83 (m, 2H), 3.81-3.74 (m, 1H), 1.16-1.13 (m, 9H), 1.08-1.07 (d, 3H) (¹H NMR spectras are shown in accompanying drawing 18).

Elementary analysis：C：43.72%；H：5.64%；N：14.56%.From elementary analysis result can determine whether the sample in phosphoric acid and tenofovir Chinese mugwort draw phenol amine ratio be about 1:1.

Melting range：165-168℃.

The X-ray powder diffraction collection surveyed is shown in Fig. 8, measured value such as following table (the corresponding measured value of diffraction maximum for taking relative intensity to be more than or equal to 3%, measured value round off takes three decimals).

The above-mentioned crystal formation of gained is named as phosphoric acid tenofovir Chinese mugwort and draws phenol amine (1:1) crystal formation A.

Embodiment 15

Sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1) and its crystal formation A preparation

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

¹H NMR (400MHz, DMSO-d₆)δ:9.46 (brs, 1H), 8.74 (brs, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 7.34-7.30 (t, 2H), 7.17-7.13 (t, 1H), 7.08-7.06 (d, 2H), 5.63-5.57 (m, 1H), 4.88-4.79 (m, 1H), 4.44-4.39 (m, 1H), 4.28-4.23 (m, 1H), 4.05-3.98 (m, 1H), 3.93-3.88 (m, 2H), 3.85-3.78 (m, 1H), 1.15-1.11 (m, 12H) (¹H NMR spectras are shown in accompanying drawing 19).

Elementary analysis：C：43.82%；H：5.42%；N：14.54%；S：5.50%.From elementary analysis result can determine whether the sample in sulfuric acid and tenofovir Chinese mugwort draw phenol amine ratio be about 1:1.

Melting range：146-149℃.

The X-ray powder diffraction collection surveyed is shown in Fig. 9, measured value such as following table (the corresponding measured value of diffraction maximum for taking relative intensity to be more than or equal to 3%, measured value round off takes three decimals).

The above-mentioned crystal formation of gained is named as sulfuric acid tenofovir Chinese mugwort and draws phenol amine (1:1) crystal formation A.

Embodiment 16

L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A polymorphic research

Take the L-TARTARIC ACID tenofovir prepared as described in Example 2 to end and draw phenol amine (1:2) crystal formation A, according to the form below solvent and mode prepare crystal formation.Through surveying X-ray powder diffraction collection, its crystal formation situation is investigated, as a result following (TAF represents tenofovir Chinese mugwort and draws phenol amine in following table)：

The studies above shows, L-TARTARIC ACID tenofovir Chinese mugwort can be stably obtained under a variety of crystallization conditions and draws phenol amine (1:2) it is brilliant Type A, does not have found that L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) there is polymorphism, i.e. L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A controllability is strong.

Embodiment 17

Citric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A polymorphic research

Take the citric acid tenofovir prepared as described in Example 2 to end and draw phenol amine (1:1) crystal formation A, is added to heating stirring in appropriate solvent listed in Table, and suction filtration, filter cake is dried under reduced pressure.Through surveying X-ray powder diffraction collection, its crystal formation situation is investigated, as a result following (TAF represents tenofovir Chinese mugwort and draws phenol amine in following table)：

The studies above shows, citric acid tenofovir Chinese mugwort can be stably obtained under a variety of crystallization conditions and draws phenol amine (1:1) crystal formation A, does not have found that citric acid tenofovir Chinese mugwort draws phenol amine (1:1) there is polymorphism, i.e. citric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A controllability is strong.

Embodiment 18

Stability study

Fumaric acid tenofovir Chinese mugwort is taken to draw phenol amine (1:1) (being prepared by the method disclosed in patent document CN1443189A), fumaric acid tenofovir Chinese mugwort draw phenol amine (1:2) (being prepared by the method disclosed in patent document CN103732594A), L-TARTARIC ACID tenofovir Chinese mugwort draw phenol amine (1:2) (preparing as described in Example 2), DL- tartaric acid tenofovir Chinese mugwort draw phenol amine (1:1) (prepare as described in Example 6) and citric acid tenofovir Chinese mugwort draws phenol amine (1:1) (prepare), detected respectively after 20 days under high temperature and high humidity as described in Example 8, as a result following (TAF represents tenofovir Chinese mugwort and draws phenol amine in following table)：

The studies above shows that the L-TARTARIC ACID tenofovir Chinese mugwort that the present invention is provided draws phenol amine (1:2), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) end with citric acid tenofovir and draw phenol amine (1:1) stability under high temperature, super-humid conditions draws phenol amine (1 compared with fumaric acid tenofovir Chinese mugwort:1), fumaric acid tenofovir Chinese mugwort draws phenol amine (1:2) it is quite or more preferable.

Embodiment 19

Solubility studies

Fumaric acid tenofovir Chinese mugwort is taken to draw phenol amine (1:1) (being prepared by the method disclosed in patent document CN1443189A), fumaric acid tenofovir Chinese mugwort draw phenol amine (1:1) (being prepared by the method disclosed in patent document CN103732594A), L-TARTARIC ACID tenofovir Chinese mugwort draw phenol amine (1:1) (preparing as described in Example 2), DL- tartaric acid tenofovir Chinese mugwort draw phenol amine (1:1) (prepare as described in Example 6) and citric acid tenofovir Chinese mugwort draws phenol amine (1:1) (prepare as described in Example 8), test their dissolubilities in different medium respectively at 25 DEG C, as a result following (TAF represents tenofovir Chinese mugwort and draws phenol amine in following table)：

The studies above shows that the L-TARTARIC ACID tenofovir Chinese mugwort that the present invention is provided draws phenol amine (1:2), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) end with citric acid tenofovir and draw phenol amine (1:1) dissolubility draws phenol amine (1 with fumaric acid tenofovir Chinese mugwort:1), fumaric acid tenofovir Chinese mugwort draws phenol amine (1:2) it is quite or more preferable.

Embodiment 20

Animal pharmacokinetics are tested

Sieve is sieved through by using μm, the L-TARTARIC ACID tenofovir Chinese mugwort for possessing suitable crystalline size is prepared and draws phenol amine (1:2) [referred to as：L-TARTARIC ACID TAF (1:2), test medicine 1], citric acid tenofovir Chinese mugwort draw phenol amine (1:1) [referred to as：Citric acid TAF (1:1), test medicine 2] and fumaric acid tenofovir Chinese mugwort drawing phenol amine (1:2) [referred to as：Fumaric acid TAF (1:2), reference agent].From SD rats 24, male and female half and half, body weight 200-270g is randomly divided into 3 groups, and gavage gives test medicine 1, test medicine 2 and reference agent respectively, and dosage is 10mg/kg (based on drawing phenol amine by tenofovir Chinese mugwort).Pass through jugular vein blood collection within 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours and 24 hours before being administered and after administration, each about 200 μ L, 3500 revs/min, centrifugation 10 minutes, upper plasma is taken, passes through tenofovir drug concentration in LC-MS/MS quantitative analysis blood plasma.

The main pharmacokinetic parameters of tenofovir after beasle dog administration are calculated using the non-chamber method of the softwares of WinNonlin 5.3：Peak time T_maxWith up to Cmax C_maxUsing measured value；Area AUC under plasma drug level-time graph_0-tUsing trapezoidal method calculated value；AUC_0-∞Calculated by following equation：AUC_0-∞=AUC_0-t+C_t/k_e, C_tFor the concentration of last detectable time point, k_eFor elimination rate constant；Plasma elimination half life t_1/2=0.693/k_e。

Using paired t-test, compare difference of the pharmacokinetic parameters of tenofovir after test medicine and reference agent is given, T_maxUsing non-parametric test, other specification is tested after Logarithm conversion.Main pharmacokinetic parameters and t assays such as following table：

The studies above shows, L-TARTARIC ACID TAF (1:2), citric acid TAF (1:1) with fumaric acid TAF (1:2) main pharmacokinetic parameters are without significant difference (P>0.05) L-TARTARIC ACID TAF (1, is shown:2), citric acid TAF (1:1) with fumaric acid TAF (1:2) in rat Internal pharmacokinetics property no difference of science of statistics, bioequivalence.

Embodiment 21

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

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2)	28.9	Label：
	28.9	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Thin film coating material：
Opadry II	10.0	Thin film coating material：

Concrete operations：

Weighed according to each supplementary material in upper table, microcrystalline cellulose is mixed with cross-linked carboxymethyl cellulose sodium, then add lactose monohydrate mixing, added L-TARTARIC ACID tenofovir Chinese mugwort and draw phenol amine (1:2) mix；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, tabletting；Then coating material is made into suspension with 75% ethanol to be coated, produced.

Embodiment 22

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

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A	28.9
Lactose monohydrate	100.0		28.9
Lactose monohydrate	100.0	Microcrystalline cellulose	100.0
Sodium carboxymethyl starch	15.0	Microcrystalline cellulose	100.0
Sodium carboxymethyl starch	15.0	Magnesium stearate	1.5

Concrete operations：

Weigh, first mix sodium carboxymethyl starch with microcrystalline cellulose according to each supplementary material in upper table, then add lactose monohydrate mixing, add L-TARTARIC ACID tenofovir Chinese mugwort and draw phenol amine (1:2)；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, and is packed into hypromellose cellulose capsule, is produced.

Embodiment 23

D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) thin membrane coated tablet and its preparation

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1)	32.9	Label：
	32.9	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Thin film coating material：
Opadry II	10.0	Thin film coating material：

Concrete operations：

Weighed according to each supplementary material in upper table, microcrystalline cellulose is mixed with cross-linked carboxymethyl cellulose sodium, then add lactose monohydrate mixing, added D- tartaric acid tenofovir Chinese mugwort and draw phenol amine (1:1) mix；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, tabletting；Then coating material is made into suspension with 75% ethanol to be coated, produced.

Embodiment 24

DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) thin membrane coated tablet and its preparation

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1)	32.9	Label：
	32.9	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Thin film coating material：
Opadry II	10.0	Thin film coating material：

Concrete operations：

Weighed according to each supplementary material in upper table, microcrystalline cellulose is mixed with cross-linked carboxymethyl cellulose sodium, then add lactose monohydrate mixing, added DL- tartaric acid tenofovir Chinese mugwort and draw phenol amine (1:1) mix；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, tabletting；Then coating material is made into suspension with 75% ethanol to be coated, produced.

Embodiment 25

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

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2)	28.5	Label：
	28.5	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Thin film coating material：
Opadry II	10.0	Thin film coating material：

Concrete operations：

Weighed according to each supplementary material in upper table, microcrystalline cellulose is mixed with cross-linked carboxymethyl cellulose sodium, then add lactose monohydrate mixing, added L MALIC ACID tenofovir Chinese mugwort and draw phenol amine (1:2) mix；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, tabletting；Then coating material is made into suspension with 75% ethanol to be coated, produced.

Embodiment 26

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

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
Citric acid tenofovir Chinese mugwort draws phenol amine (1:1)	35.1	Label：
	35.1	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Thin film coating material：
Opadry II	10.0	Thin film coating material：

Concrete operations：

Weighed according to each supplementary material in upper table, microcrystalline cellulose is mixed with cross-linked carboxymethyl cellulose sodium, then add lactose monohydrate mixing, added citric acid tenofovir Chinese mugwort and draw phenol amine (1:1) mix；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, tabletting；Then coating material is made into suspension with 75% ethanol to be coated, produced.

Embodiment 27

Butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1) thin membrane coated tablet and its preparation

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
Butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1)	31.2	Label：
	31.2	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Thin film coating material：
Opadry II	10.0	Thin film coating material：

Concrete operations：

Weighed according to each supplementary material in upper table, microcrystalline cellulose is mixed with cross-linked carboxymethyl cellulose sodium, then add lactose monohydrate mixing, added butanedioic acid tenofovir Chinese mugwort and draw phenol amine (1:1) mix；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, tabletting；Then coating material is made into suspension with 75% ethanol to be coated, produced.

Embodiment 28

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

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
Oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1)	29.7	Label：
	29.7	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Thin film coating material：
Opadry II	10.0	Thin film coating material：

Concrete operations：

Weighed according to each supplementary material in upper table, microcrystalline cellulose is mixed with cross-linked carboxymethyl cellulose sodium, then add lactose monohydrate mixing, added oxalic acid tenofovir Chinese mugwort and draw phenol amine (1:1) mix；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, tabletting；Then coating material is made into suspension with 75% ethanol to be coated, produced.

Embodiment 29

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

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
Phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1)	30.1	Label：
	30.1	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Thin film coating material：
Opadry II	10.0	Thin film coating material：

Concrete operations：

Weighed according to each supplementary material in upper table, microcrystalline cellulose is mixed with cross-linked carboxymethyl cellulose sodium, then add lactose monohydrate mixing, added phosphoric acid tenofovir Chinese mugwort and draw phenol amine (1:1) mix；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, tabletting；Then coating material is made into suspension with 75% ethanol to be coated, produced.

Embodiment 30

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

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
Sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1)	30.1	Label：
	30.1	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Lactose monohydrate	100.0
Microcrystalline cellulose	60.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	3.0	Thin film coating material：
Opadry II	10.0	Thin film coating material：

Concrete operations：

Weighed according to each supplementary material in upper table, microcrystalline cellulose is mixed with cross-linked carboxymethyl cellulose sodium, then add lactose monohydrate mixing, added sulfuric acid tenofovir Chinese mugwort and draw phenol amine (1:1) mix；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, tabletting；Then coating material is made into suspension with 75% ethanol to be coated, produced.

Embodiment 31

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

Concrete operations：

(1), prepared by grain-I：Weigh, first mix pregelatinated shore powder with cross-linked carboxymethyl cellulose sodium according to each supplementary material in upper table, then add lactose monohydrate and microcrystalline cellulose mixing, add L-TARTARIC ACID tenofovir Chinese mugwort and draw phenol amine (1:2) mix, be eventually adding emtricitabine mixing；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, and is produced.

(2), prepared by grain-II：Weigh, first mix hydroxypropylcellulose, cross-linked carboxymethyl cellulose sodium and 20% lactose monohydrate according to each supplementary material in upper table, then add remaining lactose monohydrate mixing, add and angstrom mixed for La Wei and Cobicistat, be eventually adding microcrystalline cellulose mixing；Use Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, and is produced.

(3) core particles-I and core particles-II, are used into bi-layer tablet press tabletting；Then coating material is made into suspension with 75% ethanol to be coated, produced.

Embodiment 32

DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), emtricitabine, Cobicistat, DRV double-layer tablets and its preparation

Concrete operations：

(1), prepared by grain-I：Weigh, be first mixed together pregelatinated shore powder and cross-linked carboxymethyl cellulose sodium according to each supplementary material in upper table, then add lactose monohydrate and microcrystalline cellulose mixing, add DL- tartaric acid tenofovir Chinese mugwort and draw phenol amine (1:1) mix, be eventually adding emtricitabine mixing；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, and is produced.

(2), prepared by grain-II：Weighed according to each supplementary material in upper table, first Sodium Laurylsulfate, hydroxypropylcellulose, cross-linked carboxymethyl cellulose sodium and 20% lactose monohydrate are mixed, then remaining lactose monohydrate mixing is added, DRV and Cobicistat mixing is added, microcrystalline cellulose mixing is eventually adding；Use Purified Water q. s wet method；Dry；Whole grain；Additional magnesium stearate is mixed, and is produced.

Embodiment 33

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

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2)	28.9	Label：
	28.9	Emtricitabine	200.0
Microcrystalline cellulose	300.0	Emtricitabine	200.0
Microcrystalline cellulose	300.0	Lactose monohydrate	120.0
Pregelatinized starch	40.0	Lactose monohydrate	120.0
Pregelatinized starch	40.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	6.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	6.0	Thin film coating material：
Opadry II	20.0	Thin film coating material：

Concrete operations：

Weigh, first mix pregelatinized starch with cross-linked carboxymethyl cellulose sodium according to each supplementary material in upper table, then add lactose monohydrate mixing, add emtricitabine mixing, be eventually adding L-TARTARIC ACID tenofovir Chinese mugwort and draw phenol amine (1:2) mixed with microcrystalline cellulose；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, tabletting；Coating material is made into suspension with 75% ethanol to be coated, produced.

Embodiment 34

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

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
Phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1)	30.1	Label：
	30.1	Emtricitabine	200.0
Microcrystalline cellulose	300.0	Emtricitabine	200.0
Microcrystalline cellulose	300.0	Lactose monohydrate	120.0
Pregelatinized starch	40.0	Lactose monohydrate	120.0
Pregelatinized starch	40.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	6.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	6.0	Thin film coating material：
Opadry II	20.0	Thin film coating material：

Concrete operations：

Weigh, first mix pregelatinized starch with cross-linked carboxymethyl cellulose sodium according to each supplementary material in upper table, then add lactose monohydrate mixing, add emtricitabine mixing, be eventually adding phosphoric acid tenofovir Chinese mugwort and draw phenol amine (1:1) mixed with microcrystalline cellulose；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, tabletting；Coating material is made into suspension with 75% ethanol to be coated, produced.

Embodiment 35

D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), emtricitabine, efavirenz film coating double-layer tablets and its preparation

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
Grain-I：		Label：
Grain-I：		D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1)	13.1
Emtricitabine	200.0		13.1
Emtricitabine	200.0	Microcrystalline cellulose	200.0
Cross-linked carboxymethyl cellulose sodium	20.0	Microcrystalline cellulose	200.0
Cross-linked carboxymethyl cellulose sodium	20.0	Magnesium stearate	7.0
Grain-II：		Magnesium stearate	7.0
Grain-II：		Efavirenz	600.0
Microcrystalline cellulose	130.0	Efavirenz	600.0
Microcrystalline cellulose	130.0	Hydroxypropylcellulose	20.0
Cross-linked carboxymethyl cellulose sodium	20.0	Hydroxypropylcellulose	20.0
Cross-linked carboxymethyl cellulose sodium	20.0	Sodium Laurylsulfate	10.0
Magnesium stearate	10.0	Sodium Laurylsulfate	10.0
Magnesium stearate	10.0	Thin film coating material
Opadry II	30.0	Thin film coating material

Concrete operations：

(1), prepared by grain-I：Weigh, be first mixed together microcrystalline cellulose with cross-linked carboxymethyl cellulose sodium according to each supplementary material in upper table, then add D- tartaric acid tenofovir Chinese mugwort and draw phenol amine (1:1) mix, add emtricitabine mixing；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, and is produced.

(2), prepared by grain-II：Weigh, first mix Sodium Laurylsulfate, cross-linked carboxymethyl cellulose sodium and hydroxypropylcellulose according to each supplementary material in upper table, then add microcrystalline cellulose mixing, add efavirenz mixing；Plus Purified Water q. s wet method system Grain；Dry；Whole grain；Additional magnesium stearate is mixed, and is produced.

(3) core particles-I and core particles-II, are used into bi-layer tablet press tabletting；Coating material is made into suspension with 75% ethanol to be coated, produced.

Embodiment 36

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

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
Grain-I：		Label：
Grain-I：		L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2)	11.4
Emtricitabine	200.0		11.4
Emtricitabine	200.0	Microcrystalline cellulose	200.0
Cross-linked carboxymethyl cellulose sodium	20.0	Microcrystalline cellulose	200.0
Cross-linked carboxymethyl cellulose sodium	20.0	Magnesium stearate	7.0
Grain-II：		Magnesium stearate	7.0
Grain-II：		Efavirenz	600.0
Microcrystalline cellulose	130.0	Efavirenz	600.0
Microcrystalline cellulose	130.0	Hydroxypropylcellulose	20.0
Cross-linked carboxymethyl cellulose sodium	20.0	Hydroxypropylcellulose	20.0
Cross-linked carboxymethyl cellulose sodium	20.0	Sodium Laurylsulfate	10.0
Magnesium stearate	10.0	Sodium Laurylsulfate	10.0
Magnesium stearate	10.0	Thin film coating material
Opadry II	30.0	Thin film coating material

Concrete operations：

(1), prepared by grain-I：Weigh, first mix microcrystalline cellulose with cross-linked carboxymethyl cellulose sodium according to each supplementary material in upper table, then add L MALIC ACID tenofovir Chinese mugwort and draw phenol amine (1:2) mix, add emtricitabine mixing；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, and is produced.

(2), prepared by grain-II：Weigh, first mix Sodium Laurylsulfate, cross-linked carboxymethyl cellulose sodium and hydroxypropylcellulose according to each supplementary material in upper table, then add microcrystalline cellulose mixing, add efavirenz mixing；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, and is produced.

(3) core particles-I and core particles-II, are used into bi-layer tablet press tabletting；Coating material is made into suspension bag with 75% ethanol Clothing, is produced.

Embodiment 37

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

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
Grain-I：		Label：
Grain-I：		Citric acid tenofovir Chinese mugwort draws phenol amine (1:1)	14.0
Emtricitabine	200.0		14.0
Emtricitabine	200.0	Microcrystalline cellulose	200.0
Lactose monohydrate	150.0	Microcrystalline cellulose	200.0
Lactose monohydrate	150.0	Pregelatinated shore powder	40.0
Cross-linked carboxymethyl cellulose sodium	20.0	Pregelatinated shore powder	40.0
Cross-linked carboxymethyl cellulose sodium	20.0	Magnesium stearate	7.0
Grain-II：		Magnesium stearate	7.0
Grain-II：		Hydrochloric acid rilpivirine	27.5
Lactose monohydrate	200.0	Hydrochloric acid rilpivirine	27.5
Lactose monohydrate	200.0	Microcrystalline cellulose	60.0
Cross-linked carboxymethyl cellulose sodium	15.0	Microcrystalline cellulose	60.0
Cross-linked carboxymethyl cellulose sodium	15.0	30 POVIDONE K 30 BP/USP₃₀	3.0
Magnesium stearate	3.0	30 POVIDONE K 30 BP/USP₃₀	3.0
Magnesium stearate	3.0	Polysorbate20	0.5
Thin film coating material		Polysorbate20	0.5
Thin film coating material		Opadry II	25.0

Concrete operations：

(1), prepared by grain-I：Weigh, first mix pregelatinated shore powder with cross-linked carboxymethyl cellulose sodium according to each supplementary material in upper table, then add lactose monohydrate and microcrystalline cellulose mixing, add citric acid tenofovir Chinese mugwort and draw phenol amine (1:1) mix, be eventually adding emtricitabine mixing；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, and is produced.

(2), prepared by grain-II：Weigh, first mix microcrystalline cellulose and cross-linked carboxymethyl cellulose sodium according to each supplementary material in upper table, then add lactose monohydrate mixing, add the mixing of hydrochloric acid rilpivirine；Use 30 POVIDONE K 30 BP/USP₃₀It is water-soluble with polysorbate20 Liquid wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, and is produced.

Embodiment 38

Butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), Lamivudine thin membrane coated tablet and its preparation

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
Intragranular：		Label：
Intragranular：		Butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1)	12.5
Lamivudine	300.0		12.5
Lamivudine	300.0	Microcrystalline cellulose	300.0
Cross-linked carboxymethyl cellulose sodium	15.0	Microcrystalline cellulose	300.0
Cross-linked carboxymethyl cellulose sodium	15.0	Grain is outer：
Microcrystalline cellulose	140.0	Grain is outer：
Microcrystalline cellulose	140.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	10.0	Cross-linked carboxymethyl cellulose sodium	15.0
Magnesium stearate	10.0	Thin film coating material：
Opadry II	25.0	Thin film coating material：

Concrete operations：

Weigh, be first well mixed cross-linked carboxymethyl cellulose sodium and microcrystalline cellulose using equivalent method of progressively increasing according to each supplementary material in upper table, then add butanedioic acid tenofovir and end drawing phenol amine (1:1) mix, add Lamivudine mixing；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional cross-linked carboxymethyl cellulose sodium and microcrystalline cellulose are well mixed, and add magnesium stearate mixing, tabletting；Coating material is made into suspension with 75% ethanol to be coated, produced.

Embodiment 39

Oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), Lamivudine, efavirenz film coating double-layer tablets and its preparation

Component	Content (mg/ pieces)
Component	Content (mg/ pieces)	Label：
Grain-I：		Label：
Grain-I：		Oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1)	11.9
Lamivudine	300.0		11.9

Microcrystalline cellulose	200.0
Microcrystalline cellulose	200.0	Cross-linked carboxymethyl cellulose sodium	35.0
Magnesium stearate	7.0	Cross-linked carboxymethyl cellulose sodium	35.0
Magnesium stearate	7.0	Grain-II：
Efavirenz	600.0	Grain-II：
Efavirenz	600.0	Microcrystalline cellulose	145.0
Hydroxypropylcellulose	20.0	Microcrystalline cellulose	145.0
Hydroxypropylcellulose	20.0	Cross-linked carboxymethyl cellulose sodium	20.0
Sodium Laurylsulfate	10.0	Cross-linked carboxymethyl cellulose sodium	20.0
Sodium Laurylsulfate	10.0	Magnesium stearate	10.0
Thin film coating material：		Magnesium stearate	10.0
Thin film coating material：		Opadry II	35.0

Concrete operations：

(1), prepared by grain-I：Weigh, first mix microcrystalline cellulose with cross-linked carboxymethyl cellulose sodium according to each supplementary material in upper table, then add oxalic acid tenofovir Chinese mugwort and draw phenol amine (1:1) mix, add Lamivudine mixing；Plus Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, and is produced.

(2), prepared by grain-II：Weigh, first mix hydroxypropylcellulose, Sodium Laurylsulfate and cross-linked carboxymethyl cellulose sodium according to each supplementary material in upper table；Then microcrystalline cellulose mixing is added, then adds efavirenz mixing；Use Purified Water q. s wet granulation；Dry；Whole grain；Additional magnesium stearate is mixed, and is produced.

It is described above; only embodiment of the invention; but protection scope of the present invention is not limited thereto; any those skilled in the art disclosed herein technical scope in; the change or replacement that can be expected without creative work, should all be included within the scope of the present invention.Therefore, protection scope of the present invention should be determined by the scope of protection defined in the claims.

Claims

Tenofovir Chinese mugwort shown in formula II draws phenol amine compound,

Wherein, n=1,2 or 3, X are selected from：Hydrochloric acid,Sulfuric acid,Persulfuric acid,Thiocyanic acid,Hydrobromic acid,Hydroiodic acid,Phosphoric acid,Nitric acid,Carbonic acid,Dodecyl sulphate,Phosphoglycerol,Methanesulfonic acid,Ethyl sulfonic acid,2- ethylenehydrinsulfonic acids,Taurine,Camphorsulfonic acid,Cyclamic acid,Sulfamic acid,Ethionic acid,Fourth disulfonic acid,Benzene sulfonic acid,P-methyl benzenesulfonic acid,P-hydroxybenzenyl sulfonate,O hydroxybenzenesulfonic acid,2,5- dihydroxy benzenes sulfonic acids,P-aminobenzene sulfonic acid,Naphthalene-2-sulfonic acid,Naphthalene -1,5- disulfonic acid,Formic acid,Acetic acid,Glycolic,2,2- dichloroacetic acid,Propionic acid,Pfansteihl,D-ALPHA-Hydroxypropionic acid,Racemic lactic acid,Pentamethylene propionic acid,Butyric acid,Valeric acid,Caproic acid,Enanthic acid,Octanoic acid,N-nonanoic acid,Capric acid,Undecenoic acid,Laurate,Palmitic acid,Stearic acid,Oleic acid,Oxalic acid,Malonic acid,Butanedioic acid,L MALIC ACID,D-malic acid,Racemization malic acid,L-TARTARIC ACID,D- tartaric acid,Racemic tartaric acid,Mesotartaric acid,Maleic acid,Hydroxymaleic acid,Glutaric acid,A-KG,Adipic acid,Decanedioic acid,Citric acid,Benzoic acid,P-methoxybenzoic acid,4- acetaminobenzoic acids,Salicylic acid,Acetylsalicylic acid,Gentianic acid,4-ASA,Phenylacetic acid,L- mandelic acids,D- mandelic acids,Racemic mandelic acid,3- phenylpropionic acids,Cinnamic acid,Caffeic acid,Benzenebutanoic acid,Picric acid,Nicotinic acid,Orotic acid,Chinic acid,Ascorbic acid,Glucuronic acid,Gluconic acid,Galacturonic acid,Glucoheptonic acid,Lactobionic acid,Camphoric acid,Galactosaccharic acid,Tannic acid,Alginic acid,Hydroxyl naphthoic acid,Pamoic acid,Acetylgiycine,Hippuric acid,Asparatate,Glutamic acid,Pyroglutamic acid,Glutamine,Asparagine.
Tenofovir Chinese mugwort according to claim 1 draws phenol amine compound, wherein,

N=3, X are selected from：Phosphoric acid, citric acid, tannic acid or alginic acid；Or,

N=2, X are selected from：Sulfuric acid, persulfuric acid, thiocyanic acid, phosphoric acid, carbonic acid, phosphoglycerol, ethionic acid, fourth disulfonic acid, naphthalene -1,5- disulfonic acid, oxalic acid, malonic acid, butanedioic acid, L MALIC ACID, D-malic acid, racemization malic acid, L-TARTARIC ACID, D- tartaric acid, racemic tartaric acid, mesotartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, a-KG, adipic acid, decanedioic acid, citric acid, camphoric acid, galactosaccharic acid, tannic acid, alginic acid, pamoic acid, asparatate, glutamic acid；Or,

N=1, X are selected from：Hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, dodecyl sulphate, phosphoglycerol, methanesulfonic acid, ethyl sulfonic acid, 2- ethylenehydrinsulfonic acids, taurine, camphorsulfonic acid, cyclamic acid, sulfamic acid, ethionic acid, fourth disulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, p-hydroxybenzenyl sulfonate, o-hydroxy Sulfonic acid, 2,5- dihydroxy benzenes sulfonic acids, p-aminobenzene sulfonic acid, saccharin, naphthalene-2-sulfonic acid, naphthalene -1,5- disulfonic acid, formic acid, acetic acid, glycolic, 2,2- dichloroacetic acid, propionic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, racemic lactic acid, pentamethylene propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, octanoic acid, n-nonanoic acid, capric acid, undecenoic acid, laurate, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, butanedioic acid, L MALIC ACID, D-malic acid, racemization malic acid (also known as：DL-malic acid), L-TARTARIC ACID, D- tartaric acid, racemic tartaric acid, mesotartaric acid, maleic acid, hydroxymaleic acid, glutaric acid, a-KG, adipic acid, decanedioic acid, citric acid, benzoic acid, P-methoxybenzoic acid, 4- acetaminobenzoic acids, salicylic acid, acetylsalicylic acid, gentianic acid, 4-ASA, phenylacetic acid, L- mandelic acids, D- mandelic acids, racemic mandelic acid, 3- phenylpropionic acids, cinnamic acid, caffeic acid, benzenebutanoic acid, picric acid, nicotinic acid, orotic acid, chinic acid, ascorbic acid, glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, lactobionic acid, camphoric acid, galactosaccharic acid, tannic acid, alginic acid, hydroxyl naphthoic acid, pamoic acid, acetylgiycine, hippuric acid, asparatate, glutamic acid, pyroglutamic acid, glutamine, asparagine.
Tenofovir Chinese mugwort according to claim 2 draws phenol amine compound, and it is selected from：L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1), L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2), citric acid tenofovir Chinese mugwort draws phenol amine (1:1), butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1), oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1), phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:Or sulfuric acid tenofovir Chinese mugwort draws phenol amine (1 1):1).
Tenofovir Chinese mugwort according to claim 3 draws phenol amine compound, wherein,

The L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) it is crystal；

The D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) it is crystal；

The DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) it is crystal；

The L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) it is crystal；

The citric acid tenofovir Chinese mugwort draws phenol amine (1:1) it is crystal；

The butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1) it is crystal；

The oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1) it is crystal；

The phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1) it is crystal；

The sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1) it is crystal.
Tenofovir Chinese mugwort according to claim 4 draws phenol amine compound, wherein,

The L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation is crystal formation A, and it is using the feature of the alpha-emitting X-ray powder diffraction collections of Cu-K：It is to that should have characteristic diffraction peak at 8.2 ° ± 0.2 °, 9.4 ° ± 0.2 °, 10.8 ° ± 0.2 °, 14.4 ° ± 0.2 °, 17.9 ° ± 0.2 °, 18.9 ° ± 0.2 °, 19.7 ° ± 0.2 °, 21.6 ° ± 0.2 ° in 2 θ values；

The D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation is crystal formation A, and it is using the feature of the alpha-emitting X-ray powder diffraction collections of Cu-K：2 θ values be 7.8 ° ± 0.2 °, 9.5 ° ± 0.2 °, 12.5 ° ± 0.2 °, 15.1 ° ± 0.2 °, 15.9 ° ± 0.2 °, To that should have characteristic diffraction peak at 17.0 ° ± 0.2 °, 17.7 ° ± 0.2 °, 19.5 ° ± 0.2 °；

The DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation is crystal formation A, and it is using the feature of the alpha-emitting X-ray powder diffraction collections of Cu-K：It is to that should have characteristic diffraction peak at 6.8 ° ± 0.2 °, 8.0 ° ± 0.2 °, 9.7 ° ± 0.2 °, 16.0 ° ± 0.2 °, 16.9 ° ± 0.2 °, 18.2 ° ± 0.2 °, 18.9 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.1 ° ± 0.2 ° in 2 θ values；

The L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation is crystal formation A, and it is using the feature of the alpha-emitting X-ray powder diffraction collections of Cu-K：It is to that should have characteristic diffraction peak at 10.0 ° ± 0.2 °, 13.4 ° ± 0.2 °, 13.9 ° ± 0.2 °, 15.3 ° ± 0.2 °, 16.6 ° ± 0.2 °, 21.3 ° ± 0.2 °, 26.3 ° ± 0.2 ° in 2 θ values；

The citric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation is crystal formation A, and it is using the feature of the alpha-emitting X-ray powder diffraction collections of Cu-K：It is to that should have characteristic diffraction peak at 6.0 ° ± 0.2 °, 8.1 ° ± 0.2 °, 11.7 ° ± 0.2 °, 15.9 ° ± 0.2 °, 17.9 ° ± 0.2 °, 21.7 ° ± 0.2 °, 23.4 ° ± 0.2 °, 26.9 ° ± 0.2 ° in 2 θ values；

The butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation is crystal formation A, and it is using the feature of the alpha-emitting X-ray powder diffraction collections of Cu-K：It is to that should have characteristic diffraction peak at 10.7 ° ± 0.2 °, 14.3 ° ± 0.2 °, 17.2 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.4 ° ± 0.2 ° in 2 θ values；

The oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation is crystal formation A, and it is using the feature of the alpha-emitting X-ray powder diffraction collections of Cu-K：It is to that should have characteristic diffraction peak at 7.7 ° ± 0.2 °, 9.6 ° ± 0.2 °, 16.2 ° ± 0.2 °, 18.2 ° ± 0.2 °, 20.5 ° ± 0.2 °, 24.7 ° ± 0.2 ° in 2 θ values；

The phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation is crystal formation A, and it is using the feature of the alpha-emitting X-ray powder diffraction collections of Cu-K：It is to that should have characteristic diffraction peak at 8.0 ° ± 0.2 °, 9.4 ° ± 0.2 °, 10.6 ° ± 0.2 °, 14.5 ° ± 0.2 °, 19.3 ° ± 0.2 °, 21.1 ° ± 0.2 °, 23.4 ° ± 0.2 ° in 2 θ values；

The sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation is crystal formation A, and it is using the feature of the alpha-emitting X-ray powder diffraction collections of Cu-K：It is to that should have characteristic diffraction peak at 9.2 ° ± 0.2 °, 10.7 ° ± 0.2 °, 11.1 ° ± 0.2 °, 18.4 ° ± 0.2 °, 19.8 ° ± 0.2 °, 22.3 ° ± 0.2 °, 24.3 ° ± 0.2 ° in 2 θ values.
Tenofovir Chinese mugwort according to claim 5 draws phenol amine compound, wherein,

The L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, is radiated using Cu-K α, and the feature of its X-ray powder diffraction collection is：It is to that should have characteristic diffraction peak at 7.5 ° ± 0.2 °, 8.2 ° ± 0.2 °, 9.4 ° ± 0.2 °, 10.8 ° ± 0.2 °, 12.4 ° ± 0.2 °, 14.4 ° ± 0.2 °, 16.0 ° ± 0.2 °, 16.3 ° ± 0.2 °, 17.1 ° ± 0.2 °, 17.9 ° ± 0.2 °, 18.9 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.4 ° ± 0.2 °, 21.6 ° ± 0.2 °, 23.0 ° ± 0.2 ° in 2 θ values；

The D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, is radiated using Cu-K α, and the feature of its X-ray powder diffraction collection is：2 θ values be 4.4 ° ± 0.2 °, 7.8 ° ± 0.2 °, 9.0 ° ± 0.2 °, 9.5 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.0 ° ± 0.2 °, 15.1 ° ± 0.2 °, 15.9 ° ± 0.2 °, 17.0 ° ± 0.2 °, 17.7 ° ± 0.2 °, 19.5 ° ± 0.2 °, 19.9 ° ± 0.2 °, 21.4 ° ± 0.2 °, 22.7 ° ± 0.2 °, To that should have characteristic diffraction peak at 25.9 ° ± 0.2 °；

The DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, is radiated using Cu-K α, and the feature of its X-ray powder diffraction collection is：It is to that should have characteristic diffraction peak at 6.8 ° ± 0.2 °, 8.0 ° ± 0.2 °, 9.7 ° ± 0.2 °, 10.6 ° ± 0.2 °, 12.6 ° ± 0.2 °, 13.7 ° ± 0.2 °, 14.9 ° ± 0.2 °, 16.0 ° ± 0.2 °, 16.9 ° ± 0.2 °, 18.2 ° ± 0.2 °, 18.9 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.1 ° ± 0.2 °, 22.8 ° ± 0.2 ° in 2 θ values；

The L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A, is radiated using Cu-K α, and the feature of its X-ray powder diffraction collection is：It is to that should have characteristic diffraction peak at 5.4 ° ± 0.2 °, 10.0 ° ± 0.2 °, 11.9 ° ± 0.2 °, 13.4 ° ± 0.2 °, 13.9 ° ± 0.2 °, 15.3 ° ± 0.2 °, 16.6 ° ± 0.2 °, 20.3 ° ± 0.2 °, 21.3 ° ± 0.2 °, 22.2 ° ± 0.2 °, 26.3 ° ± 0.2 ° in 2 θ values；

The citric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, is radiated using Cu-K α, and the feature of its X-ray powder diffraction collection is：It is to that should have characteristic diffraction peak at 6.0 ° ± 0.2 °, 8.1 ° ± 0.2 °, 11.7 ° ± 0.2 °, 12.6 ° ± 0.2 °, 15.4 ° ± 0.2 °, 15.9 ° ± 0.2 °, 17.5 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.1 ° ± 0.2 °, 20.6 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.7 ° ± 0.2 °, 23.4 ° ± 0.2 °, 26.9 ° ± 0.2 °, 29.3 ° ± 0.2 °, 31.9 ° ± 0.2 °, 32.7 ° ± 0.2 ° in 2 θ values；

The butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, is radiated using Cu-K α, and the feature of its X-ray powder diffraction collection is：It is to that should have characteristic diffraction peak at 5.7 ° ± 0.2 °, 9.6 ° ± 0.2 °, 10.0 ° ± 0.2 °, 10.7 ° ± 0.2 °, 11.7 ° ± 0.2 °, 13.5 ° ± 0.2 °, 14.3 ° ± 0.2 °, 17.2 ° ± 0.2 °, 17.8 ° ± 0.2 °, 19.3 ° ± 0.2 °, 19.7 ° ± 0.2 °, 21.4 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.4 ° ± 0.2 °, 23.8 ° ± 0.2 °, 27.9 ° ± 0.2 ° in 2 θ values；

The oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, is radiated using Cu-K α, and the feature of its X-ray powder diffraction collection is：It is to that should have characteristic diffraction peak at 7.7 ° ± 0.2 °, 8.4 ° ± 0.2 °, 9.6 ° ± 0.2 °, 12.6 ° ± 0.2 °, 16.2 ° ± 0.2 °, 18.2 ° ± 0.2 °, 20.5 ° ± 0.2 °, 22.6 ° ± 0.2 °, 24.7 ° ± 0.2 °, 27.8 ° ± 0.2 °, 29.0 ° ± 0.2 ° in 2 θ values；

The phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, is radiated using Cu-K α, and the feature of its X-ray powder diffraction collection is：It is to that should have characteristic diffraction peak at 8.0 ° ± 0.2 °, 9.4 ° ± 0.2 °, 10.6 ° ± 0.2 °, 14.5 ° ± 0.2 °, 15.9 ° ± 0.2 °, 17.0 ° ± 0.2 °, 17.6 ° ± 0.2 °, 18.6 ° ± 0.2 °, 19.3 ° ± 0.2 °, 21.1 ° ± 0.2 °, 23.4 ° ± 0.2 ° in 2 θ values；

The sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A, is radiated using Cu-K α, and the feature of its X-ray powder diffraction collection is：It is to that should have characteristic diffraction peak at 9.2 ° ± 0.2 °, 10.7 ° ± 0.2 °, 11.1 ° ± 0.2 °, 16.9 ° ± 0.2 °, 18.4 ° ± 0.2 °, 19.2 ° ± 0.2 °, 19.8 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.3 ° ± 0.2 °, 23.1 ° ± 0.2 °, 24.3 ° ± 0.2 °, 28.1 ° ± 0.2 °, 31.1 ° ± 0.2 ° in 2 θ values.
Tenofovir Chinese mugwort according to claim 6 draws phenol amine compound, wherein,

The L-TARTARIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A X-ray powder diffraction collection is substantially as shown in Figure 1；

The D- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A X-ray powder diffraction collection is substantially as shown in Figure 2；

The DL- tartaric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A X-ray powder diffraction collection is substantially as shown in Figure 3；

The L MALIC ACID tenofovir Chinese mugwort draws phenol amine (1:2) crystal formation A X-ray powder diffraction collection is substantially as shown in Figure 4；

The citric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A X-ray powder diffraction collection is substantially as shown in Figure 5；

The butanedioic acid tenofovir Chinese mugwort draws phenol amine (1:1) A X-ray powder diffraction collection is substantially as shown in Figure 6；

The oxalic acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A X-ray powder diffraction collection is substantially as shown in Figure 7；

The phosphoric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A X-ray powder diffraction collection is substantially as shown in Figure 8；

The sulfuric acid tenofovir Chinese mugwort draws phenol amine (1:1) crystal formation A X-ray powder diffraction collection is substantially as shown in Figure 9.
A kind of tenofovir Chinese mugwort draws the preparation method of phenol amine compound, and this method includes：

(1) in suitable solvent, form a kind of ended comprising tenofovir and draw the solution of phenol amine and acid X；

(2) solid is separated out；

(3) separated out solid is separated；

(4) alternatively, the solid of separation is dried, or rear re-dry is further purified.
Preparation method according to claim 8, wherein in step (1), the suitable solvent is selected from acetonitrile, ethanol, methanol, propyl alcohol, isopropanol, butanol, ethylene glycol, Ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ether, isopropyl ether, n-butyl ether, glycol monoethyl ether, glycol dimethyl ether, t-butyl methyl ether, tetrahydrofuran, petroleum ether, dichloromethane, chloroform, n-hexane, hexamethylene, acetone, butanone, pentanone, cyclohexanone, toluene, dimethylbenzene or their mixture；The sour X is selected from the acid representated by X in formula II；The tenofovir Chinese mugwort draws phenol amine and acid X molar ratio to be 4:1~0.5:1, draw phenol amine (1 when preparing X tenofovirs Chinese mugwort:3) during compound, tenofovir Chinese mugwort draws phenol amine to be 2.7 with acid X molar ratios:1~3.5:1, draw phenol amine (1 when preparing X tenofovirs Chinese mugwort:2) during compound, tenofovir Chinese mugwort draws phenol amine to be 1.7 with acid X molar ratios:1~2.5:1, draw phenol amine (1 when preparing X tenofovirs Chinese mugwort:1) during compound, tenofovir Chinese mugwort draws phenol amine to be 0.5 with acid X molar ratios:1~1.5:1.
A kind of tenofovir Chinese mugwort described in claim 8 draws the preparation method of phenol amine compound, and this method includes：

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

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

Tenofovir Chinese mugwort draws phenol amine:D- tartaric acid is 0.5:1~1.5:1, preferably 0.8:1~1.2:1, or,

Tenofovir Chinese mugwort draws phenol amine:DL- tartaric acid is 0.5:1~1.5:1, preferably 0.8:1~1.2:1, or,

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

Tenofovir Chinese mugwort draws phenol amine:Citric acid is 0.5:1~1.5:1, preferably 0.8:1~1.2:1, or,

Tenofovir Chinese mugwort draws phenol amine:Butanedioic acid is 0.5:1~1.5:1, preferably 0.8:1~1.2:1, or,

Tenofovir Chinese mugwort draws phenol amine:Oxalic acid is 0.5:1~1.5:1, preferably 0.8:1~1.2:1, or,

Tenofovir Chinese mugwort draws phenol amine:Phosphoric acid is 0.5:1~1.5:1, preferably 0.8:1~1.2:1, or,

Tenofovir Chinese mugwort draws phenol amine:Sulfuric acid is 0.5:1~1.5:1, preferably 0.8:1~1.2:1, or,

(2) solid is separated out；

(3) separated out solid is separated；

(4) alternatively, the solid of separation is dried, or rear re-dry is further purified.
Preparation method according to claim 10, suitable solvent is selected from acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dichloromethane, chloroform, toluene or their mixture, preferably acetonitrile or isopropanol wherein in step (1).
A kind of tenofovir Chinese mugwort draws the preparation method of phenol amine compound crystal formation, and this method includes：

(1) phenol amine and L-TARTARIC ACID is drawn to be dissolved in acetonitrile, ethanol, isopropanol or their mixture tenofovir Chinese mugwort, tenofovir Chinese mugwort draws the molar ratio of phenol amine and L-TARTARIC ACID to be 1.7:1~2.5:1, preferably 1.9:1~2.3:1, or,

Phenol amine and D- tartaric acid is drawn to be dissolved in acetonitrile, isopropanol or their mixture tenofovir Chinese mugwort, tenofovir Chinese mugwort draws the molar ratio of phenol amine and D- tartaric acid to be 0.5:1~1.5:1, preferably 0.8:1~1.2:1, or,

Phenol amine and DL- tartaric acid is drawn to be dissolved in acetonitrile tenofovir Chinese mugwort, tenofovir Chinese mugwort draws the molar ratio of phenol amine and DL- tartaric acid to be 0.5:1~1.5:1, preferably 0.8:1~1.2:1, or,

Phenol amine and L MALIC ACID is drawn to be dissolved in isopropanol tenofovir Chinese mugwort, tenofovir Chinese mugwort draws the molar ratio of phenol amine and L MALIC ACID to be 1.7:1~2.5:1, preferably 1.9:1~2.3:1, or,

Phenol amine and citric acid is drawn to be dissolved in acetonitrile, methanol, ethanol, tetrahydrofuran or their mixture tenofovir Chinese mugwort, tenofovir Chinese mugwort draws the molar ratio of phenol amine and citric acid to be 0.5:1~1.5:1, preferably 0.8:1~1.2:1, or,

Phenol amine and butanedioic acid is drawn to be dissolved in acetonitrile tenofovir Chinese mugwort, tenofovir Chinese mugwort draws the molar ratio of phenol amine and butanedioic acid to be 0.5:1~1.5:1, preferably 0.8:1~1.2:1, or,

Tenofovir Chinese mugwort is drawn into phenol amine and dissolving oxalic acid in acetonitrile, tenofovir Chinese mugwort draws the molar ratio of phenol amine and oxalic acid to be 0.5:1~1.5:1, preferably 0.8:1~1.2:1, or,

Phenol amine and phosphoric acid is drawn to be dissolved in acetonitrile tenofovir Chinese mugwort, tenofovir Chinese mugwort draws the molar ratio of phenol amine and phosphoric acid to be 0.5:1~1.5:1, preferably 0.8:1~1.2:1, or,

Tenofovir Chinese mugwort is drawn into phenol amine and sulfuric acid dissolution in acetonitrile, tenofovir Chinese mugwort draws the molar ratio of phenol amine and sulfuric acid to be 0.5:1~1.5:1, preferably 0.8:1~1.2:1；

(2) solid is separated out；

(3) separated out solid is separated；

(4) alternatively, the solid of separation is dried, or rear re-dry is further purified.
A kind of pharmaceutical composition, its tenofovir according to any one of claims 1 to 3 Chinese mugwort comprising therapeutically effective amount draws tenofovir Chinese mugwort made from any one of phenol amine compound or claim 8~12 preparation method to draw phenol amine compound or its crystal formation, and pharmaceutic adjuvant.
Pharmaceutical composition according to claim 13, it is also comprising another or a variety of selected from following antivirotic or antiviral auxiliary reagent：Emtricitabine, Lamivudine, Abacavir, Acemannan, VX-478, VX-478, atazanavir, Clevudine, Cobicistat, up to a Wei Lin, DRV, Delavirdine, Didanosine, De Luogewei, efavirenz, angstrom for draw Wei, enfuirtide, Entecavir, etravirine, FCV, fosamprenavir, glutathione, indinavir, levamisol, Lopinavir, Maraviroc, Nai Feinawei, NVP, Penciclovir, pentamidine, Phosphazid, Propagermanium, Merck, Ribavirin, rilpivirine, Ritonavir, inverase, stavudine, Sebivo, tipranavir, Vorinostat, zalcitabine, Zidovudine or their pharmaceutical salts；It is preferred that emtricitabine, Lamivudine, Cobicistat, efavirenz, angstrom replace La Wei or rilpivirine or their pharmaceutical salts.
Pharmaceutical composition according to claim 14, it is selected from：

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws phenol amine compound, emtricitabine, Cobicistat and angstrom for the pharmaceutical composition for drawing Wei；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws the pharmaceutical composition of phenol amine compound, emtricitabine, Cobicistat and DRV；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws the pharmaceutical composition of phenol amine compound and emtricitabine；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws the pharmaceutical composition of phenol amine compound, emtricitabine and efavirenz；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws the vertical Wei Lin of phenol amine compound, emtricitabine and hydrochloric acid pharmaceutical composition；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws phenol amine compound, the pharmaceutical composition of Lamivudine；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws the pharmaceutical composition of phenol amine compound, Lamivudine and efavirenz；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws phenol amine compound, Lamivudine, Cobicistat and angstrom for the pharmaceutical composition for drawing Wei；Or,

The Chinese mugwort of tenofovir shown in formula II comprising therapeutically effective amount draws the pharmaceutical composition of phenol amine compound, Lamivudine, Cobicistat and DRV.
Tenofovir Chinese mugwort made from preparation method any one of tenofovir Chinese mugwort drawing phenol amine compound according to any one of claims 1 to 3, claim 8~12 draws application of the pharmaceutical composition of phenol amine compound or claim 13~15 in preparing prevention and/or treating the medicine of virus infection.
Application according to claim 16, wherein described tenofovir Chinese mugwort draws application of the phenol amine compound in the medicine for preparing prevention and/or treatment hepatitis type B virus and/or HIV infection.
It is a kind of prevent and/or treatment virus infection method, the tenofovir according to any one of claims 1 to 3 Chinese mugwort that this method includes giving individual effective dose draws phenol amine compound, tenofovir Chinese mugwort made from the preparation method any one of claim 8~12 to draw the pharmaceutical composition of phenol amine compound or claim 13~15.