CN108148094A - A kind of tenofovir Chinese mugwort draws phenol amine fumarate crystal form C and its preparation method and application - Google Patents
A kind of tenofovir Chinese mugwort draws phenol amine fumarate crystal form C and its preparation method and application Download PDFInfo
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- CN108148094A CN108148094A CN201810126578.XA CN201810126578A CN108148094A CN 108148094 A CN108148094 A CN 108148094A CN 201810126578 A CN201810126578 A CN 201810126578A CN 108148094 A CN108148094 A CN 108148094A
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- phenol amine
- tenofovir
- crystal form
- chinese mugwort
- draws
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- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title claims abstract description 257
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims abstract description 192
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- ZCIGNRJZKPOIKD-CQXVEOKZSA-N cobicistat Chemical compound S1C(C(C)C)=NC(CN(C)C(=O)N[C@@H](CCN2CCOCC2)C(=O)N[C@H](CC[C@H](CC=2C=CC=CC=2)NC(=O)OCC=2SC=NC=2)CC=2C=CC=CC=2)=C1 ZCIGNRJZKPOIKD-CQXVEOKZSA-N 0.000 description 1
- 229960002402 cobicistat Drugs 0.000 description 1
- 229940117546 cobicistat / darunavir Drugs 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000000205 computational method Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical compound OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
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- 229960002179 ephedrine Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
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- 230000006872 improvement Effects 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229920003087 methylethyl cellulose Polymers 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
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- 229940080313 sodium starch Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
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- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960004946 tenofovir alafenamide Drugs 0.000 description 1
- 229960001355 tenofovir disoproxil Drugs 0.000 description 1
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
It ends the present invention relates to tenofovir and draws phenol amine fumarate crystal form C and preparation method thereof, include the pharmaceutical composition of the new solid-state form, and the new solid-state form is used to prepare prevention and/or treatment virus infects, the purposes in the drug of special hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) infection.
Description
The application is application number 201410633514.0, on November 2014 applying date 12, " tenofovir ends denomination of invention
The divisional application of drawing phenol amine fumarate novel crystal forms and its preparation method and application ".
Technical field
The present invention relates to organic chemistry fileds and pharmaceutical field, and in particular to tenofovir Chinese mugwort draws the new of phenol amine fumarate
Crystal form and preparation method thereof is used to prepare prevention comprising the pharmaceutical composition of these novel crystal forms and these novel crystal forms and/or controls
It treats virus to infect, the purposes in the drug of special hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) infection.
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]-l-Alanine -1- Methylethyl esters；CAS
Accession number is：379270-37-8；Molecular structural formula is as shown in formula I：
Tenofovir Chinese mugwort draws the ester prodrug thereof that phenol amine is tenofovir, is that a kind of acyclic nucleotide reverse transcriptase inhibits
Agent has broad-spectrum disease resistance toxic action, can inhibit the reverse transcriptase of HIV-1, HIV-2 and HBV polymerases, so as to inhibit virus multiple
System.Tenofovir Chinese mugwort draws phenol amine to be hydrolyzed to tenofovir after taking orally, and tenofovir by the chemical conversion of cell kinase phosphoric acid there is pharmacology to live
Property metabolite tenofovir diphosphonic acid, the latter and 5'- deoxyadenosine triphosphates acid competes, and participates in the synthesis of viral DNA, into
DNA is caused to extend and is obstructed due to lacking 3'- hydroxyls after entering viral DNA, so as to inhibit the duplication of virus.It is similar with what is listed
Drug tenofovir dipivoxil (Tenofovir disoproxil) is compared, and the antiviral activity of tenofovir Chinese mugwort drawing phenol amine is
Its 10 times, stability in blood plasma is its 200 times, half-life period compared with which raises 220 times, at peripheral blood mononuclear cells (PBMC)
Interior accumulation is compared with which raises nearly 10 times, therefore tenofovir Chinese mugwort draws phenol amine to exempt from for hepatitis type B virus (HBV) and the mankind
The prevention or/and treatment of epidemic disease defective virus (HIV/AIDS) infection have the effect of more preferable, higher safety and lower resistance to
Pharmacological property.At present, tenofovir Chinese mugwort draws phenol amine single preparations of ephedrine, and tenofovir Chinese mugwort draws phenol amine/emtricitabine/Cobicistat/ angstroms to replace
Draw Wei compound preparation and tenofovir Chinese mugwort that phenol amine/emtricitabine/Cobicistat/ darunavir compound preparations foreign countries is drawn to face
In bed research.
Tenofovir Chinese mugwort draws phenol amine, and since its solid-state fusing point is relatively low, solubility is smaller in water, is unfavorable for the system of pharmaceutical preparation
The standby and dissolution in pharmaceutical preparation, therefore the form that tenofovir Chinese mugwort draws phenol amine to be developed to salt is used for preparation.
Patent document CN1443189A[1]、CN1706855A[2]Etc. the fumarate for disclosing tenofovir Chinese mugwort drawing phenol amine
(formula II) and preparation method, the preparation method are：Tenofovir, which is ended, draws phenol amine and fumaric acid to be added in acetonitrile, and heating makes
Solid dissolves, and filters while hot, is cooled to 5 DEG C and is kept for 16 hours, filters to isolate product, dry product.Though these documents
It so discloses tenofovir Chinese mugwort and draws the preparation method of phenol amine fumarate, but its crystal form is not disclosed；Research shows that according to these
Disclosed preparation method prepares tenofovir Chinese mugwort and draws phenol amine fumarate, draws impurity content in phenol amine different when tenofovir ends
When, different crystal forms can be made.Draw phenol amine fumarate relatively free in water-soluble, physical behavior etc. because tenofovir ends
Alkali has larger improvement, it is therefore necessary to which its crystal form is further studied.Ending at us to tenofovir draws phenol amine fumarate brilliant
In the research process of type, surprisingly it is found that tenofovir Chinese mugwort draws a variety of novel crystal forms of phenol amine fumarate, it has apparent powder
Last X-ray diffracting spectrum feature, and preparation method is simple, and chemical stability is excellent, suitable for several formulations.
Invention content
End novel crystal forms for drawing phenol amine fumarate and preparation method thereof one of the objects of the present invention is to provide tenofovir.
Another object of the present invention is to provide to end containing tenofovir to draw the pharmaceutical composition of phenol amine fumarate novel crystal forms
Object.
Another object of the present invention is to provide tenofovir Chinese mugwort draw phenol amine fumarate novel crystal forms prepare prevention and/or
Treat the purposes in the drug of hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV/AIDS) infection.
In order to achieve the above-mentioned object of the invention, present invention firstly provides the tenofovir Chinese mugworts shown in a kind of formula II of crystalline state
Draw phenol amine fumarate.
Further, it ends the present invention provides crystalline state tenofovir and draws crystal form A, crystal form B, the crystal form of phenol amine fumarate
C, crystal form D.
Further, it ends the present invention provides above-mentioned tenofovir and draws the preparation method of phenol amine fumarate crystal form.
Further, the present invention provides end to draw the mixture of phenol amine fumarate crystal form containing above-mentioned tenofovir.
Further, the present invention provides end to draw the pharmaceutical composition of phenol amine fumarate crystal form containing above-mentioned tenofovir
Object.
Further, the present invention provides above-mentioned tenofovir end draw phenol amine fumarate crystal form prepare prevention and/
Or the purposes in the drug infected with treatment hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV/AIDS).
Tenofovir Chinese mugwort draws phenol amine fumarate crystal form A
Tenofovir Chinese mugwort provided by the invention draws the feature of the powder x-ray diffraction collection of illustrative plates of phenol amine fumarate crystal form A
For：It is 5.1 ° ± 0.2 °, 10.2 ° ± 0.2 °, 10.8 ° ± 0.2 °, 19.4 ° ± 0.2 °, 26.4 ° ± 0.2 ° etc. correspondence in 2 θ values
There is characteristic diffraction peak.
In one embodiment, tenofovir provided by the invention Chinese mugwort draw the powder X-ray of phenol amine fumarate crystal form A-
The feature of x ray diffraction collection of illustrative plates is：2 θ values for 5.1 ° ± 0.2 °, 10.2 ° ± 0.2 °, 10.8 ° ± 0.2 °, 12.0 ° ± 0.2 °,
14.1°±0.2°、14.7°±0.2°、15.4°±0.2°、16.5°±0.2°、17.5°±0.2°、18.4°±0.2°、18.7°
±0.2°、19.4°±0.2°、20.9°±0.2°、21.7°±0.2°、22.4°±0.2°、23.4°±0.2°、24.5°±
0.2 °, 26.4 ° ± 0.2 °, 26.9 ° ± 0.2 °, 27.6 ° ± 0.2 °, 31.8 ° ± 0.2 ° etc. is corresponding with characteristic diffraction peak.
Further, tenofovir Chinese mugwort of the present invention draws the powder that phenol amine fumarate crystal form A is represented with 2 θ angles
X-ray diffracting spectrum has characteristic diffraction peak and relative intensity in following position：
In one embodiment, tenofovir Chinese mugwort provided by the invention draws phenol amine fumarate crystal form A to have such as Fig. 1
Feature representated by shown powder x-ray diffraction collection of illustrative plates.
In one embodiment, the tenofovir Chinese mugwort of preparation provided by the invention is drawn in phenol amine fumarate mixture
Tenofovir Chinese mugwort draws phenol amine fumarate crystal form A contents (mass content) to be generally higher than 70%, preferably greater than 80%, most preferably greatly
In 90%.
It will be appreciated by persons skilled in the art that tenofovir Chinese mugwort of the present invention draws phenol amine fumarate mixture
It refers to drawing replacing for the phenol other crystal forms of amine fumarate containing impurity or tenofovir Chinese mugwort with what chemical synthesis process was synthetically prepared
Nuo Fuweiaila phenol amine fumarates.
It ends the present invention provides a kind of tenofovir and draws the preparation method of phenol amine fumarate crystal form A, this method includes：
(1), tenofovir ends draws phenol amine and fumaric acid to be dissolved in acetonitrile, tetrahydrofuran or 2- methyltetrahydrofurans,
Wherein tenofovir Chinese mugwort draw shown in phenol amine Chinese style III diastereoisomer N- [(R)-[[(1R) -2- (6- amino -9H- purine -
9- yls) -1- methyl ethoxies] methyl] phenoxy group phosphono]-l-Alanine -1- Methylethyls ester relative to tenofovir end draw
The content of phenol amine is less than or equal to 0.5%；
(2), solid is precipitated；
(3), solid be precipitated is detached；
(4), it is optional, the solid of separation is dried.
In above-mentioned preparation method step (1), described " tenofovir Chinese mugwort draws the diastereoisomer N- shown in phenol amine Chinese style III
[(R)-[[(1R) -2- (6- amino -9H- purine -9- bases) -1- methyl ethoxies] methyl] phenoxy group phosphono]-l-Alanine -
1- Methylethyls ester ends relative to tenofovir draws the content of phenol amine " it can be measured with the method for the art such as HPLC routine.
In one embodiment, the diastereoisomer shown in formula III ends relative to tenofovir draws the content HPLC areas of phenol amine to return
One, which changes method, measures, i.e., in HPLC chromatogram, phenol is drawn with the diastereoisomer peak area shown in formula III divided by tenofovir Chinese mugwort
The peak area of amine.
In above-mentioned preparation method step (1), the selected solvent dosage as unit of ml ends with the tenofovir as unit of g
The ratio of phenol amine dosage is drawn to be generally 5:1 to 30:1；The mode that heating can be used is dissolved.
In above-mentioned preparation method step (1), the mode of " dissolving ", which includes ending tenofovir, draws phenol amine and fumaric acid
It is dissolved in solvent simultaneously；Or tenofovir ends, phenol amine and fumaric acid is drawn to be dissolved in solvent respectively, it remixes.
In above-mentioned preparation method step (1), tenofovir Chinese mugwort draws the molar ratio of phenol amine and fumaric acid to be generally 0.8:1
To 1.3:1, preferred molar ratio 0.9:1 to 1.2:1.
In above-mentioned preparation method step (2), the method for " solid is precipitated " includes cooling and solid is precipitated, adds in poor solvent analysis
Go out solid, concentrate out partial solvent after solid is precipitated, adds in crystal seed solid etc. be precipitated, these methods can be used alone can also
It is applied in combination, can be carried out under static conditions, can also be carried out under agitation." poor solvent " refers in room temperature
Under draw phenol amine fumarate dissolubility bad the tenofovir Chinese mugwort formed and phenol amine and richness can be drawn with dissolving tenofovir Chinese mugwort
The miscible solvent of the solvent of horse acid, such as methyl tertiary butyl ether(MTBE), ether, isopropyl ether, n-hexane, hexamethylene, petroleum ether.
In above-mentioned preparation method step (3), " separation " method includes filtering or centrifugation etc..
In above-mentioned preparation method step (4), the temperature of " drying " is generally 30~100 DEG C, preferably 35~80 DEG C, Ke Yichang
Press dry it is dry, be dried under reduced pressure or combination thereof application.
Tenofovir Chinese mugwort draws phenol amine fumarate crystal form B
Tenofovir Chinese mugwort provided by the invention draws the feature of the powder x-ray diffraction collection of illustrative plates of phenol amine fumarate crystal form B
For：In 2 θ values feature diffraction is corresponding with for 4.6 ° ± 0.2 °, 10.1 ° ± 0.2 °, 10.6 ° ± 0.2 °, 20.4 ° ± 0.2 ° etc.
Peak.
In one embodiment, tenofovir provided by the invention Chinese mugwort draw the powder X-ray of phenol amine fumarate crystal form B-
The feature of x ray diffraction collection of illustrative plates is：2 θ values for 4.6 ° ± 0.2 °, 10.1 ° ± 0.2 °, 10.6 ° ± 0.2 °, 17.4 ° ± 0.2 °,
20.4 ° ± 0.2 °, 23.5 ° ± 0.2 °, 24.2 ° ± 0.2 °, 26.7 ° ± 0.2 ° etc. is corresponding with characteristic diffraction peak.
Further, tenofovir Chinese mugwort of the present invention draws the powder that phenol amine fumarate crystal form B is represented with 2 θ angles
X-ray diffracting spectrum has characteristic diffraction peak and relative intensity in following position：
In one embodiment, tenofovir Chinese mugwort provided by the invention draws phenol amine fumarate crystal form B to have such as Fig. 2
Feature representated by shown powder x-ray diffraction collection of illustrative plates.
In one embodiment, the tenofovir Chinese mugwort of preparation provided by the invention is drawn in phenol amine fumarate mixture
Tenofovir Chinese mugwort draws phenol amine fumarate crystal form B content (mass content) to be generally higher than 70%, preferably greater than 80%, most preferably greatly
In 90%.
It will be appreciated by persons skilled in the art that tenofovir Chinese mugwort of the present invention draws phenol amine fumarate mixture
It refers to drawing replacing for the phenol other crystal forms of amine fumarate containing impurity or tenofovir Chinese mugwort with what chemical synthesis process was synthetically prepared
Nuo Fuweiaila phenol amine fumarates.
It ends the present invention provides a kind of tenofovir and draws the preparation method of phenol amine fumarate crystal form B, this method includes：
(1), tenofovir ends draws phenol amine and fumaric acid to be dissolved in acetonitrile, and wherein tenofovir Chinese mugwort draws phenol amine Chinese style III
Shown diastereoisomer N- [(R)-[[(1R) -2- (6- amino -9H- purine -9- bases) -1- methyl ethoxies] methyl] benzene
Oxygroup phosphono]-l-Alanine -1- Methylethyls ester relative to tenofovir end draw phenol amine content be more than 0.5%；
(2), solid is precipitated；
(3), solid be precipitated is detached；
(4), it is optional, the solid of separation is dried.
In above-mentioned preparation method step (1), described " tenofovir Chinese mugwort draws the diastereoisomer N- shown in phenol amine Chinese style III
[(R)-[[(1R) -2- (6- amino -9H- purine -9- bases) -1- methyl ethoxies] methyl] phenoxy group phosphono]-l-Alanine -
1- Methylethyls ester ends relative to tenofovir draws the content of phenol amine " it can be measured with the method for the art such as HPLC routine.
In one embodiment, the diastereoisomer shown in formula III ends relative to tenofovir draws the content HPLC areas of phenol amine to return
One, which changes method, measures, i.e., in HPLC chromatogram, phenol is drawn with the diastereoisomer peak area shown in formula III divided by tenofovir Chinese mugwort
The peak area of amine.
In above-mentioned preparation method step (1), the selected solvent dosage as unit of ml ends with the tenofovir as unit of g
The ratio of phenol amine dosage is drawn to be generally 5:1 to 30:1；The mode that heating can be used is dissolved.
In above-mentioned preparation method step (1), the mode of " dissolving ", which includes ending tenofovir, draws phenol amine and fumaric acid
It is dissolved in acetonitrile simultaneously；Or tenofovir ends, phenol amine and fumaric acid is drawn to be dissolved in acetonitrile respectively, it remixes.Form the temperature of solution
Generally 0 DEG C to solvent boiling point.
In above-mentioned preparation method step (1), tenofovir Chinese mugwort draws the molar ratio of phenol amine and fumaric acid to be generally 0.8:1
To 1.3:1, preferred molar ratio 0.9:1 to 1.2:1.
In above-mentioned preparation method step (2), the method for " solid is precipitated " includes cooling and solid is precipitated, adds in poor solvent analysis
Go out solid, concentrate out partial solvent after solid is precipitated, adds in crystal seed solid etc. be precipitated, these methods can be used alone can also
It is applied in combination, can be carried out under static conditions, can also be carried out under agitation." poor solvent " refers in room temperature
Under draw phenol amine fumarate dissolubility bad the tenofovir Chinese mugwort formed and phenol amine and richness can be drawn with dissolving tenofovir Chinese mugwort
The miscible solvent of the solvent of horse acid, such as methyl tertiary butyl ether(MTBE), ether, isopropyl ether, n-hexane, hexamethylene, petroleum ether.
In above-mentioned preparation method step (3), " separation " method includes filtering or centrifugation etc..
In above-mentioned preparation method step (4), the temperature of " drying " is generally 30~100 DEG C, preferably 35~80 DEG C, Ke Yichang
Press dry it is dry, be dried under reduced pressure or combination thereof application.
Tenofovir Chinese mugwort draws phenol amine fumaric acid crystal form C
Tenofovir Chinese mugwort provided by the invention draws the feature of the powder x-ray diffraction collection of illustrative plates of phenol amine fumarate crystal form C
For：4.6 ° ± 0.2 ° of 2 θ values, 6.6 ° ± 0.2 °, 10.4 ° ± 0.2 °, 13.3 ° ± 0.2 °, 14.9 ° ± 0.2 °, 17.1 ° ±
0.2°、18.8°±0.2°、19.0°±0.2°、19.6°±0.2°、21.2°±0.2°、21.4°±0.2°、23.8°±0.2°、
29.2 ° ± 0.2 ° etc. is corresponding with characteristic diffraction peak.
In one embodiment, tenofovir provided by the invention Chinese mugwort draw the powder X-ray of phenol amine fumarate crystal form C-
The feature of x ray diffraction collection of illustrative plates is：2 θ values for 4.6 ° ± 0.2 °, 6.6 ° ± 0.2 °, 9.4 ° ± 0.2 °, 10.4 ° ± 0.2 °,
12.4°±0.2°、13.3°±0.2°、14.9°±0.2°、15.7°±0.2°、17.1°±0.2°、18.4°±0.2°、18.8°
±0.2°、19.0°±0.2°、19.6°±0.2°、20.7°±0.2°、21.2°±0.2°、21.4°±0.2°、22.3°±
0.2°、23.2°±0.2°、23.8°±0.2°、24.4°±0.2°、25.1°±0.2°、26.7°±0.2°、27.0°±0.2°、
28.8 ° ± 0.2 °, 29.2 ° ± 0.2 °, 33.7 ° ± 0.2 ° etc. is corresponding with characteristic diffraction peak.
Further, tenofovir Chinese mugwort of the present invention draws the powder that phenol amine fumarate crystal form C is represented with 2 θ angles
X-ray diffracting spectrum has characteristic diffraction peak and relative intensity in following position：
In one embodiment, tenofovir Chinese mugwort provided by the invention draws phenol amine fumarate crystal form C to have such as Fig. 3
Feature representated by shown powder x-ray diffraction collection of illustrative plates.
In one embodiment, the tenofovir Chinese mugwort of preparation provided by the invention is drawn in phenol amine fumarate mixture
Tenofovir Chinese mugwort draws phenol amine fumarate crystal form C content (mass content) to be generally higher than 70%, preferably greater than 80%, most preferably greatly
In 90%.
It will be appreciated by persons skilled in the art that tenofovir Chinese mugwort of the present invention draws phenol amine fumarate mixture
It refers to drawing replacing for the phenol other crystal forms of amine fumarate containing impurity or tenofovir Chinese mugwort with what chemical synthesis process was synthetically prepared
Nuo Fuweiaila phenol amine fumarates.
It ends the present invention provides a kind of tenofovir and draws the preparation method of phenol amine fumarate crystal form C, this method includes：
(1), tenofovir ends draws phenol amine and fumaric acid to be dissolved in isobutanol；
(2), solid is precipitated；
(3), solid be precipitated is detached；
(4), it is optional, the solid of separation is dried.
In above-mentioned preparation method step (1), the selected solvent dosage as unit of ml ends with the tenofovir as unit of g
The ratio of phenol amine dosage is drawn to be generally 5:1 to 15:1；The mode that heating can be used is dissolved.
In above-mentioned preparation method step (1), the mode of " dissolving ", which includes ending tenofovir, draws phenol amine and fumaric acid
It is dissolved in isobutanol simultaneously；Or tenofovir ends, phenol amine and fumaric acid is drawn to be dissolved in isobutanol respectively, it remixes.
In above-mentioned preparation method step (1), tenofovir Chinese mugwort draws the molar ratio of phenol amine and fumaric acid to be generally 0.8:1
To 1.3:1, preferred molar ratio 0.9:1 to 1.2:1.
In above-mentioned preparation method step (2), the method for " solid is precipitated " includes cooling and solid is precipitated, adds in poor solvent analysis
Go out solid, concentrate out partial solvent after solid is precipitated, adds in crystal seed solid etc. be precipitated, these methods can be used alone can also
It is applied in combination, can be carried out under static conditions, can also be carried out under agitation." poor solvent " refers in room temperature
Under draw phenol amine fumarate dissolubility bad the tenofovir Chinese mugwort formed and phenol amine and richness can be drawn with dissolving tenofovir Chinese mugwort
The miscible solvent of the solvent of horse acid, such as methyl tertiary butyl ether(MTBE), ether, isopropyl ether, n-hexane, hexamethylene, petroleum ether.
In above-mentioned preparation method step (3), " separation " method includes filtering or centrifugation etc..
In above-mentioned preparation method step (4), the temperature of " drying " is generally 30~100 DEG C, preferably 35~80 DEG C, Ke Yichang
Press dry it is dry, be dried under reduced pressure or combination thereof application.
Tenofovir Chinese mugwort draws phenol amine fumaric acid crystal form D
Tenofovir Chinese mugwort provided by the invention draws the feature of the powder x-ray diffraction collection of illustrative plates of phenol amine fumarate crystal form D
For：2 θ values for 4.4 ° ± 0.2 °, 6.8 ° ± 0.2 °, 8.8 ° ± 0.2 °, 10.2 ° ± 0.2 °, 13.9 ° ± 0.2 °, 14.8 ° ±
0.2 °, 18.8 ° ± 0.2 °, 22.5 ° ± 0.2 °, 23.6 ° ± 0.2 °, 28.5 ° ± 0.2 ° etc. is corresponding with characteristic diffraction peak.
In one embodiment, tenofovir provided by the invention Chinese mugwort draw the powder X-ray of phenol amine fumarate crystal form D-
The feature of x ray diffraction collection of illustrative plates is：2 θ values for 4.4 ° ± 0.2 °, 6.8 ° ± 0.2 °, 8.8 ° ± 0.2 °, 10.2 ° ± 0.2 °,
13.9°±0.2°、14.8°±0.2°、17.8°±0.2°、18.8°±0.2°、22.5°±0.2°、23.6°±0.2°、27.1°
± 0.2 °, 28.5 ° ± 0.2 ° etc. is corresponding with characteristic diffraction peak.
Further, tenofovir Chinese mugwort of the present invention draws the powder that phenol amine fumarate crystal form D is represented with 2 θ angles
X-ray diffracting spectrum has characteristic diffraction peak and relative intensity in following position：
In one embodiment, tenofovir Chinese mugwort provided by the invention draws phenol amine fumarate crystal form D to have such as Fig. 4
Feature representated by shown powder x-ray diffraction collection of illustrative plates.
In one embodiment, the tenofovir Chinese mugwort of preparation provided by the invention is drawn in phenol amine fumarate mixture
Tenofovir Chinese mugwort draws phenol amine fumarate crystal form D contents (mass content) to be generally higher than 70%, preferably greater than 80%, most preferably greatly
In 90%.
It will be appreciated by persons skilled in the art that tenofovir Chinese mugwort of the present invention draws phenol amine fumarate mixture
It refers to drawing replacing for the phenol other crystal forms of amine fumarate containing impurity or tenofovir Chinese mugwort with what chemical synthesis process was synthetically prepared
Nuo Fuweiaila phenol amine fumarates.
It ends the present invention provides a kind of tenofovir and draws the preparation method of phenol amine fumarate crystal form D, this method includes：
(1), tenofovir ends draws the solution of phenol amine and fumaric acid to dissolve in methylene chloride；
(2), solid is precipitated；
(3), solid be precipitated is detached；
(4), it is optional, the solid of separation is dried.
In above-mentioned preparation method step (1), the selected solvent dosage as unit of ml ends with the tenofovir as unit of g
The ratio of phenol amine dosage is drawn to be generally 5:1 to 15:1；The mode that heating can be used is dissolved.
In above-mentioned preparation method step (1), the mode of " dissolving ", which includes ending tenofovir, draws phenol amine and fumaric acid
It is dissolved in dichloromethane simultaneously；Or tenofovir ends, phenol amine and fumaric acid is drawn to be dissolved in dichloromethane respectively, it remixes.
In above-mentioned preparation method step (1), tenofovir Chinese mugwort draws the molar ratio of phenol amine and fumaric acid to be generally 0.8:1
To 1.3:1, preferred molar ratio 0.9:1 to 1.2:1.
In above-mentioned preparation method step (2), the method for " solid is precipitated " includes cooling and solid is precipitated, adds in poor solvent analysis
Go out solid, concentrate out partial solvent after solid is precipitated, adds in crystal seed solid etc. be precipitated, these methods can be used alone can also
It is applied in combination, can be carried out under static conditions, can also be carried out under agitation." poor solvent " refers in room temperature
Under draw phenol amine fumarate dissolubility bad the tenofovir Chinese mugwort formed and phenol amine and richness can be drawn with dissolving tenofovir Chinese mugwort
The miscible solvent of the solvent of horse acid, such as methyl tertiary butyl ether(MTBE), ether, isopropyl ether, n-hexane, hexamethylene, petroleum ether.
In above-mentioned preparation method step (3), " separation " method includes filtering or centrifugation etc..
In above-mentioned preparation method step (4), the temperature of " drying " is generally 30~100 DEG C, preferably 35~80 DEG C, Ke Yichang
Press dry it is dry, be dried under reduced pressure or combination thereof application.
On the other hand, it ends the present invention provides tenofovir and draws a variety of solid-state forms of phenol amine, is i.e. tenofovir Chinese mugwort draws phenol
Crystal form a and tenofovir Chinese mugwort draw phenol amine amorphous.
Tenofovir Chinese mugwort draws phenol amine crystal form a
Tenofovir provided by the invention Chinese mugwort draws the feature of the powder x-ray diffraction collection of illustrative plates of phenol amine crystal form a to be：In 2 θ values
For 7.3 ° ± 0.2 °, 11.1 ° ± 0.2 °, 12.8 ° ± 0.2 °, 15.3 ° ± 0.2 °, 19.4 ° ± 0.2 °, 21.2 ° ± 0.2 °,
22.1 ° ± 0.2 °, 22.3 ° ± 0.2 ° etc. is corresponding with characteristic diffraction peak.
In one embodiment, tenofovir Chinese mugwort provided by the invention draws the powder x-ray diffraction of phenol amine crystal form a
The feature of collection of illustrative plates is：2 θ values for 7.3 ° ± 0.2 °, 9.6 ° ± 0.2 °, 11.1 ° ± 0.2 °, 11.8 ° ± 0.2 °, 12.8 ° ±
0.2°、14.2°±0.2°、15.3±0.2°、17.5°±0.2°、18.1°±0.2°、18.8°±0.2°、19.4°±0.2°、
21.2°±0.2°、22.1°±0.2°、22.3°±0.2°、22.8°±0.2°、24.4°±0.2°、25.3°±0.2°、26.7°
± 0.2 ° etc. is corresponding with characteristic diffraction peak.
Further, tenofovir Chinese mugwort of the present invention draws phenol amine crystal form a to spread out with the powder X-ray that 2 θ angles represent
Penetrate collection of illustrative plates has characteristic diffraction peak and relative intensity in following position：
In one embodiment, tenofovir Chinese mugwort provided by the invention draws phenol amine crystal form a to have powder as shown in Figure 5
Feature representated by last X-ray diffracting spectrum.
In one embodiment, the tenofovir Chinese mugwort of preparation provided by the invention draws tenofovir in phenol amine blends
Chinese mugwort draws phenol amine crystal form a contents (mass content) to be generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.
It will be appreciated by persons skilled in the art that tenofovir Chinese mugwort of the present invention draws phenol amine blends to refer to using
What chemical synthesis process was synthetically prepared draws the tenofovir Chinese mugwort of the other crystal forms of phenol amine to draw phenol containing other impurities or tenofovir Chinese mugwort
Amine.
It ends the present invention provides a kind of tenofovir and draws the preparation method of phenol amine crystal form a, this method includes：
(1), tenofovir ends draws phenol amine to be dissolved in ethyl acetate, isopropanol or acetone；
(2), solid is precipitated；
(3), solid be precipitated is detached；
(4), it is optional, the solid of separation is dried.
In above-mentioned preparation method step (1), the selected solvent dosage as unit of ml ends with the tenofovir as unit of g
The ratio of phenol amine dosage is drawn to be generally 5:1 to 20:1；The mode that heating can be used is dissolved.
In above-mentioned preparation method step (2), the method for " solid is precipitated " includes cooling and solid is precipitated, adds in poor solvent analysis
Go out solid, concentrate out partial solvent after solid is precipitated, adds in crystal seed solid etc. be precipitated, these methods can be used alone can also
It is applied in combination, can be carried out under static conditions, can also be carried out under agitation." poor solvent " refers in room temperature
Under end to tenofovir miscible molten of suitable solvent drawn phenol amine solvent bad and phenol amine can be drawn with dissolving tenofovir Chinese mugwort
Agent, such as toluene, methyl tertiary butyl ether(MTBE), ether, isopropyl ether, n-hexane, hexamethylene, petroleum ether etc..
In above-mentioned preparation method step (3), " separation " method includes filtering or centrifugation etc..It optionally, can be with suitable
Solvent washs collected solid.
In above-mentioned preparation method step (4), the temperature of " drying " is generally 30~100 DEG C, preferably 35~80 DEG C, Ke Yichang
Press dry it is dry, be dried under reduced pressure or combination thereof application.
Tenofovir Chinese mugwort draws phenol amine amorphous
Tenofovir Chinese mugwort provided by the invention draws phenol amine is amorphous to have powder x-ray diffraction collection of illustrative plates institute as shown in Figure 6
The feature of representative.
In one embodiment, the tenofovir Chinese mugwort of preparation provided by the invention draws tenofovir in phenol amine blends
Chinese mugwort draws phenol amine amorphous content (mass content) to be generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.
It will be appreciated by persons skilled in the art that tenofovir Chinese mugwort of the present invention draws phenol amine blends to refer to using
What chemical synthesis process was synthetically prepared draws the tenofovir Chinese mugwort of the other crystal forms of phenol amine to draw phenol containing other impurities or tenofovir Chinese mugwort
Amine.
It ends the present invention provides a kind of tenofovir and draws the unbodied preparation method of phenol amine, this method includes：
(1), tenofovir ends draws phenol amine to be dissolved in suitable solvent；
(2), solvent concentration is obtained into solid to dry；
(3), it is optional, obtained solid is dried.
In above-mentioned preparation method step (1), the suitable solvent includes dichloromethane, acetonitrile, ethyl acetate etc..It can be used
The mode of heating is dissolved.
In above-mentioned preparation method step (2), " concentration " temperature is generally 30 DEG C to solvent boiling point, can be concentrated under reduced pressure,
It can be concentrated with normal pressure.
In above-mentioned preparation method step (3), the temperature of " drying " is generally 30~100 DEG C, preferably 35~80 DEG C, Ke Yichang
Press dry it is dry, be dried under reduced pressure or combination thereof application.
Above-mentioned powder x-ray diffraction analysis is under environment temperature and ambient humidity, through Dutch Panaco X`Pert PRO
The CuK α sources of type Powder X-ray DiffractometerMeasure what is completed." environment temperature " is usually 0~40 DEG C；" ring
Border humidity " is usually 30%~80% relative humidity.
Tenofovir Chinese mugwort provided by the invention draws the representative powder X-ray of phenol amine fumarate crystal form A, B, C, D to spread out
Collection of illustrative plates is penetrated to be listed in attached drawing 1~4；Tenofovir Chinese mugwort provided by the invention draws phenol amine crystal form a and unbodied representative powder
X-ray diffracting spectrum is listed in attached Figures 5 and 6." representative powder x-ray diffraction collection of illustrative plates " refers to this crystal form or unbodied
Powder x-ray diffraction feature meet this collection of illustrative plates display whole pattern, it is to be appreciated that during the test, due to by
The shadow of many factors (processing method of sample, instrument, test parameter, test operation when the granularity of such as test sample, test)
Ring, powder x-ray diffraction collection of illustrative plates measured by same crystal form go out peak position or peak intensity has certain difference.Generally
In the case of, the experimental error of 2 θ values of diffraction maximum can be ± 0.2 ° in X-ray powder diffraction collection.
Above-mentioned tenofovir Chinese mugwort draws phenol amine can be by the method system disclosed in patent CN1291994C or WO2013052094A2
.The tenofovir Chinese mugwort that different purity can be recrystallized to give by acetonitrile, ethyl acetate, acetone equal solvent draws phenol amine.
Another object of the present invention is to provide the tenofovir Chinese mugwort containing the above-mentioned arbitrary crystal form to draw phenol amine richness horse
Hydrochlorate mixture, the crystal form mass content are more than 70%, preferably greater than 80%, more preferably greater than 90%.
Wherein it should be understood that crystal form described here is single selected from crystal form A, B, C, D a kind of crystal form therein, and
The mixing of non-above-mentioned crystal form；That is, contain in the mixture selected from crystal form A, B, C, D a kind of crystal form therein
Mass content is more than 70%, preferably greater than 80%, more preferably greater than 90%.
Another object of the present invention is to provide to end containing tenofovir to draw the above-mentioned new solid-state form of phenol amine fumarate
Pharmaceutical composition and the purposes that the above-mentioned new solid-state form of phenol amine fumarate is drawn to be used to manufacture human medicine that tenofovir ends.
In order to realize the purpose, on the one hand the present invention provides a kind of tenofovir Chinese mugworts comprising effective therapeutic dose to draw phenol amine
Fumarate crystal form A, crystal form B, crystal form C, crystal form D and pharmaceutic adjuvant pharmaceutical composition or preparation.
On the other hand, it ends the present invention provides tenofovir and draws phenol amine fumarate crystal form A, crystal form B, crystal form C, crystal form D
Preparing prevention and/or treatment virus infection, special hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) sense
Purposes in the drug of dye.
On the other hand, the present invention provides a kind of tenofovir Chinese mugworts comprising effective therapeutic dose to draw phenol amine crystal form a and medicinal
The pharmaceutical composition or preparation of auxiliary material.Further, ending the present invention also provides tenofovir draws phenol amine crystal form a preparing prevention
And/or treatment is infected by virus, the drug of special hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) infection
In purposes.
Aforementioned pharmaceutical compositions or preparation can be prepared according to the conventional production process of pharmaceutical field, such as by tenofovir
Chinese mugwort draws phenol amine fumarate crystal form A, crystal form B, crystal form C, the one or more of crystal form D to be mixed with one or more carriers, then
It is made into required dosage form.In one embodiment, tenofovir Chinese mugwort draw phenol amine fumarate crystal form A, crystal form B, crystal form C,
The particle diameter distribution control of crystal form D is less than 100 μm 90%, preferably smaller than 50 μm, more preferably less than 10 μm.
The drug that aforementioned pharmaceutical compositions or preparation can be infected as prevention and/or treatment by virus, for treating by disease
Disease caused by poison infection, disease caused by special hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV).
Aforementioned pharmaceutical compositions or the dosage form of preparation include：Tablet, pill, granule, powder, aerosol, powder spray, spray
It is mist agent, suspension, solution, emulsion, syrup, tincture, suppository, injection, gelling agent, implantation system, film, cream, soft
Paste, paste, patch etc..They according to the characteristics of respective dosage form, administration route include oral, sublingual, injection, cavity, it is transpulmonary/
Tracheae is percutaneous etc..
The dosage of above-mentioned composition or preparation according to conditions of patients property and seriousness, administration route and patient age,
Weight etc. is adjusted, and general daily dose is in 1mg between 500mg, and preferably 5mg is between 200mg, more preferable 5mg to 100mg
Between；Daily can be with single administration, it can also multiple dosing.
In one embodiment, pharmaceutical composition provided by the invention be oral solid formulation, preferred tablet.This is oral solid
Body preparation also contains pharmaceutic adjuvant, the pharmaceutic adjuvant is in addition to active constituent tenofovir ends and draws phenol amine fumarate
The pharmaceutic adjuvant of this field routine, including filler, disintegrant, adhesive or wetting agent, lubricant, surfactant, solubilising
Agent or cosolvent etc..
The filler generally comprise lactose, microcrystalline cellulose, mannitol, pregelatinized starch, starch, sucrose, dextrin,
Sorbierite, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate, calcium bicarbonate, sodium bicarbonate, sodium carbonate, hydroxypropyl methyl cellulose, ethyl
Cellulose and aluminium hydroxide etc..They, which can be used alone, to be used in mixed way, wherein it is preferred that lactose, microcrystalline cellulose, sweet
Reveal alcohol, pregelatinized starch or calcium monohydrogen phosphate.
The disintegrant generally comprise starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch,
Croscarmellose sodium, Crospovidone, low-substituted hydroxypropyl cellulose and hydroxypropul starch etc..They can be used alone
It can also be used in mixed way, wherein it is preferred that Crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose or carboxymethyl
Sodium starch.
The adhesive or wetting agent generally comprise povidone (polyvinylpyrrolidone), hydroxypropyl methyl cellulose,
Microcrystalline cellulose, hydroxypropyl cellulose, ethyl cellulose, polyethylene glycol, starch slurry, Arabic gum, water and various concentration second
Alcoholic solution etc..They, which can be used alone, to be used in mixed way, wherein it is preferred that povidone (polyvinylpyrrolidone), crystallite are fine
Dimension element or hydroxypropyl cellulose.
The lubricant generally comprises zinc stearate, magnesium stearate, calcium stearate, sodium stearyl fumarate, talcum powder, fat
Fat acid sucrose ester, superfine silica gel powder (including light silicon dioxide, hydrated SiO 2 and colloidal silicon dioxide), stearic acid, palm
Acid, alumina silicate and solid polyethylene glycol etc..They, which can be used alone, to be used in mixed way, wherein it is preferred that magnesium stearate, micro-
Powder silica gel or talcum powder.
Surfactant, solubilizer or the cosolvent generally comprises lauryl sodium sulfate, Tween-80, Bo Luosha
Nurse, Sodium Laurylsulfate etc..They, which can be used alone, to be used in mixed way, wherein preferably sodium dodecyl sulfate or tween-
80。
If necessary, other auxiliary materials can also be added into above-mentioned composition or preparation, such as sweetener (such as A Sipa
Smooth, Steviosin etc.), colorant (such as yellow iron oxide, red iron oxide), stabilizer (such as citric acid, lactic acid, malic acid and
Glycine etc.), pH adjusting agent (such as calcium carbonate, sodium carbonate, sodium bicarbonate, tartaric acid, fumaric acid, citric acid).
If necessary, other suitable active constituents can also be included in above-mentioned composition or preparation.
The preparation of above-mentioned oral solid formulation can be according to the conventional method for preparing oral solid formulation in the art
It carries out, such as：Wet granule compression tablet, dry granulation tabletting, fluidized bed granulation tabletting, powder mixing direct tablet compressing may be used in tablet
Etc. modes prepare.When the oral solid formulation is tablet or pellet, it further can be coated as needed, film is made
Garment piece or pellet, sugar coating piece or pellet.Enteric coated or pellet and packet sustained release tablets or pellet.Wherein coating material includes
Cellulose family, crylic acid resin and carbohydrate, such as hydroxypropyl methyl cellulose and sucrose, wherein can also add plasticizer, resist
Stick and opacifier etc..
The experiment proved that tenofovir Chinese mugwort provided by the invention draws phenol amine fumarate crystal form A, crystal form B, crystal form C and crystalline substance
Type D and tenofovir Chinese mugwort draw phenol amine crystal form a to have easy preparation method；It can be reachable with high-purity, such as HPLC purity
99% or more than 99.5%；There is more good stability and preparation adaptability.These advantages are conducive to be made with them
Into corresponding preparation, for example their preparation is with good stability in preparation and storage and validity.
Specific embodiment with reference to embodiments is described in further detail the above of the present invention again.
But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.The above-mentioned thought feelings of the present invention are not being departed from
Under condition, the various replacements or change made according to ordinary skill knowledge and customary means should all be included in the present invention's
In the range of.
Description of the drawings
Fig. 1 tenofovirs Chinese mugwort draws phenol amine fumarate crystal form A powder x-ray diffraction collection of illustrative plates；
Fig. 2 tenofovirs Chinese mugwort draws phenol amine fumarate crystal form B powder x-ray diffraction collection of illustrative plates；
Fig. 3 tenofovirs Chinese mugwort draws phenol amine fumarate crystal form C powder x-ray diffraction collection of illustrative plates；
Fig. 4 tenofovirs Chinese mugwort draws phenol amine fumarate crystal form D powder x-ray diffraction collection of illustrative plates；
Fig. 5 tenofovirs Chinese mugwort draws phenol amine crystal form a powder x-ray diffraction collection of illustrative plates；
Fig. 6 tenofovirs Chinese mugwort draws phenol amine amorphous powder X-ray diffracting spectrum.
Specific embodiment
The technical solution that the present invention will be described in detail with reference to the accompanying drawings and embodiments, but protection scope of the present invention include but
It is not limited to this.
Embodiment and preparation example center magnetic tester are to use III HD 400MHz Nuclear Magnetic Resonance of BRUKER AVANCE, deuterated
Dimethyl sulfoxide (DMSO) (DMSO-d6) make test solvent, tetramethylsilane is made internal standard, is completed at room temperature.
1 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine fumarate crystal form A
At room temperature, tenofovir is ended and draws phenol amine (diastereoisomer N- [(R)-[[(1R) -2- wherein shown in formula III
(6- amino -9H- purine -9- bases) -1- methyl ethoxies] methyl] phenoxy group phosphono]-l-Alanine -1- Methylethyl ester phases
It ends for tenofovir and the content of phenol amine is drawn to be added in acetonitrile 48ml for 0.5%) 1.90g and fumaric acid 0.42g, heating makes solid
Dissolving, is filtered while hot, is cooled to 5 DEG C and is kept for 16 hours, filtering, filter cake is washed through acetonitrile 15ml, is depressurized at 35~45 DEG C
It is dry that tenofovir Chinese mugwort draws phenol amine fumaric acid crystal form A, HPLC purity：99.38%, chiral HPLC purity:99.73%.
1H NMR (400MHz, DMSO-d6) δ:13.10 (br, 2H), 8.14 (s, 1H), 8.10 (s, 1H), 7.29-7.28
(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), 3.81-
3.74 (m, 1H), 1.16-1.13 (m, 9H), 1.08-1.06 (d, 3H).
The powder x-ray diffraction collection of illustrative plates surveyed is shown in Fig. 1, the following (diffraction maximum that relative intensity is taken to be more than 5% of measured value
Corresponding measured value)：
Tenofovir Chinese mugwort draws phenol amine fumaric acid chirality HPLC method for detecting purity
| Chromatographic column | Chiralpak AD-H (4.6 × 250mm, 5 μm) |
| Mobile phase | N-hexane：Isopropanol (50:50) |
| Flow velocity | 0.7ml/min |
| Column temperature | 35℃ |
| Detection wavelength | 260nm |
| Sample introduction concentration | 1mg/ml |
| Computational methods | Area normalization method |
2 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine fumarate crystal form A
At room temperature, tenofovir is ended and draws phenol amine (diastereoisomer N- [(R)-[[(1R) -2- wherein shown in formula III
(6- amino -9H- purine -9- bases) -1- methyl ethoxies] methyl] phenoxy group phosphono]-l-Alanine -1- Methylethyl ester phases
It ends for tenofovir and the content of phenol amine is drawn to be added in acetonitrile 48ml for 0.3%) 1.90g and fumaric acid 0.42g, heating makes solid
Dissolving, is filtered while hot, is cooled to 5 DEG C and is kept for 16 hours, and filtering, filter cake is washed through acetonitrile 15ml, is obtained tenofovir Chinese mugwort and is drawn phenol
Amine fumarate crystal form A, HPLC purity：99.44%, chiral HPLC purity：99.87%.
3 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine fumarate crystal form A
At room temperature, tenofovir is ended and draws phenol amine (diastereoisomer N- [(R)-[[(1R) -2- wherein shown in formula III
(6- amino -9H- purine -9- bases) -1- methyl ethoxies] methyl] phenoxy group phosphono]-l-Alanine -1- Methylethyl ester phases
It ends for tenofovir and the content of phenol amine is drawn to be added in tetrahydrofuran 20ml for 0.2%) 1.90g and fumaric acid 0.46g, heating is molten
After clear, stop heating, be naturally cooling to 15~25 DEG C, at such a temperature stir about 2 hours, filter, filter cake is through at 70~80 DEG C
It is dry, it obtains tenofovir Chinese mugwort and draws phenol amine fumarate crystal form A.
4 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine fumarate crystal form A
At room temperature, tenofovir is ended and draws phenol amine (diastereoisomer N- [(R)-[[(1R) -2- wherein shown in formula III
(6- amino -9H- purine -9- bases) -1- methyl ethoxies] methyl] phenoxy group phosphono]-l-Alanine -1- Methylethyl ester phases
It ends for tenofovir and the content of phenol amine is drawn to be added in 2- methyltetrahydrofurans 15ml for 0.2%) 1.90g and fumaric acid 0.38g,
After the dissolved clarification that heats up, stop heating, be cooled to 0~5 DEG C, stir about 2 hours filters, and obtains tenofovir Chinese mugwort and draws phenol amine fumarate
Crystal form A.
5 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine fumarate crystal form B
At room temperature, tenofovir is ended and draws phenol amine (diastereoisomer N- [(R)-[[(1R) -2- wherein shown in formula III
(6- amino -9H- purine -9- bases) -1- methyl ethoxies] methyl] phenoxy group phosphono]-l-Alanine -1- Methylethyl ester phases
It ends for tenofovir and the content of phenol amine is drawn to be added in acetonitrile 48ml for 0.6%) 1.90g and fumaric acid 0.42g, heating makes solid
Dissolving, is filtered while hot, is cooled to 5 DEG C and is kept for 16 hours, and filtering, filter cake is washed through acetonitrile 15ml, dry in 35~45 DEG C of decompressions
It is dry that tenofovir Chinese mugwort draws phenol amine fumarate crystal form B, HPLC purity：99.10%, chiral HPLC purity：99.65%.
The powder x-ray diffraction collection of illustrative plates surveyed is shown in Fig. 2, the following (diffraction maximum that relative intensity is taken to be more than 1% of measured value
Corresponding measured value)：
6 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine fumarate crystal form B
At room temperature, tenofovir is ended and draws phenol amine (diastereoisomer N- [(R)-[[(1R) -2- wherein shown in formula III
(6- amino -9H- purine -9- bases) -1- methyl ethoxies] methyl] phenoxy group phosphono]-l-Alanine -1- Methylethyl ester phases
It ends for tenofovir and the content of phenol amine is drawn to be added in acetonitrile 48ml for 1.5%) 1.90g and fumaric acid 0.42g, heating makes solid
Dissolving, is filtered while hot, is cooled to 5 DEG C and is kept for 16 hours, and filtering, filter cake is washed through acetonitrile 15ml, is obtained tenofovir Chinese mugwort and is drawn phenol
Amine fumarate crystal form B, HPLC purity：99.01%, chiral HPLC purity：99.14%.
7 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine fumarate crystal form C
At room temperature, tenofovir is ended draws phenol amine 1.90g and fumaric acid 0.42g to add in isobutanol 20ml, and heat up dissolved clarification,
15~20 DEG C are cooled to, at such a temperature stir about 2 hours, filtered, filter cake is dried under reduced pressure at 35~45 DEG C, obtains tenofovir
Chinese mugwort draws phenol amine fumarate crystal form C, HPLC purity：99.52%, chiral HPLC purity：99.64%.
The powder x-ray diffraction collection of illustrative plates surveyed is shown in Fig. 3, the following (diffraction maximum that relative intensity is taken to be more than 5% of measured value
Corresponding measured value)：
8 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine fumarate crystal form C
At room temperature, tenofovir is ended draws phenol amine 1.90g and fumaric acid 0.46g to add in isobutanol 10ml, and heat up dissolved clarification,
5~10 DEG C are cooled to, at such a temperature stir about 2 hours, filtered, obtained tenofovir Chinese mugwort and draw phenol amine fumarate crystal form C.
9 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine fumarate crystal form C
At room temperature, tenofovir is ended draws phenol amine fumaric acid crystal form A 0.5g to add in isobutanol 5ml, is stirred at room temperature
Night filters, and filter cake is through dry that tenofovir Chinese mugwort draws phenol amine fumarate crystal form C at 70~80 DEG C.
10 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine fumarate crystal form D
At room temperature, tenofovir is ended draws phenol amine 1.90g and fumaric acid 0.42g to add in dichloromethane 20ml, and heating is molten
Clearly, 20~25 DEG C are cooled to, stir about 2 hours filters, and filter cake obtains tenofovir Chinese mugwort and draw phenol through being dried under reduced pressure at 35~45 DEG C
Amine fumarate crystal form D, HPLC purity：99.39%, chiral HPLC purity：99.61%.
The powder x-ray diffraction collection of illustrative plates surveyed is shown in Fig. 4, the following (diffraction maximum that relative intensity is taken to be more than 10% of measured value
Corresponding measured value)：
11 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine fumarate crystal form D
At room temperature, tenofovir is ended draws phenol amine 1.90g and fumaric acid 0.46g to add in dichloromethane 10ml, and heating is molten
After clear, 15~25 DEG C are cooled to, stir about 2 hours filters, and obtains tenofovir Chinese mugwort and draws phenol amine fumarate crystal form D.
12 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine fumarate crystal form D
At room temperature, tenofovir is ended draws phenol amine fumaric acid crystal form A 0.5g to add in dichloromethane 5ml, is stirred overnight,
It filters, filter cake obtains tenofovir Chinese mugwort and draw phenol amine fumarate crystal form D through being dried under reduced pressure at 35~45 DEG C.
13 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine crystal form a
At room temperature, tenofovir is ended draws phenol amine 100.0g to add in ethyl acetate 1000ml, after the dissolved clarification that heats up, is cooled to
It 15~25 DEG C, stirs 2 hours, filters, filter cake obtains tenofovir Chinese mugwort and draw phenol amine crystal form a, HPLC through being dried under reduced pressure at 35~45 DEG C
Purity：99.56%, chiral HPLC purity：99.51%.
The powder x-ray diffraction collection of illustrative plates surveyed is shown in Fig. 5, the following (diffraction maximum that relative intensity is taken to be more than 5% of measured value
Corresponding measured value)：
14 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine crystal form a
At room temperature, tenofovir is ended draws phenol amine 10.0g to add in isopropanol 50ml, after the dissolved clarification that heats up, is cooled to 5~15
DEG C, it stirs 2 hours, filters, filter cake obtains tenofovir Chinese mugwort and draw phenol amine crystal form a through being dried under reduced pressure at 35~45 DEG C.
15 tenofovir of embodiment Chinese mugwort draws the preparation of phenol amine crystal form a
At room temperature, tenofovir is ended draws phenol amine 10.0g to add in acetone 100ml, after the dissolved clarification that heats up, is cooled to 5~15
DEG C, it stirs 2 hours, filters, obtain tenofovir Chinese mugwort and draw phenol amine crystal form a.
16 tenofovir of embodiment Chinese mugwort draws the unbodied preparation of phenol amine
At room temperature, tenofovir is ended draws phenol amine 5.0g to add in dichloromethane 50ml, after the dissolved clarification that heats up, is concentrated to dryness,
Obtaining tenofovir Chinese mugwort draws phenol amine amorphous.
17 tenofovir of embodiment Chinese mugwort draws the unbodied preparation of phenol amine
At room temperature, tenofovir is ended draws phenol amine 5.0g to be dissolved in acetonitrile 100ml, after the dissolved clarification that heats up, is concentrated to dryness, obtains
Tenofovir Chinese mugwort draws phenol amine amorphous.
18 tenofovir of embodiment Chinese mugwort draws the unbodied preparation of phenol amine
At room temperature, tenofovir is ended draws phenol amine 5.0g to be dissolved in ethyl acetate 100ml, after the dissolved clarification that heats up, is concentrated into
It is dry, it obtains tenofovir Chinese mugwort and draws phenol amine amorphous.
19 tenofovir of embodiment Chinese mugwort draws phenol amine fumarate and tenofovir Chinese mugwort to draw phenol amine stable crystal form Journal of Sex Research
Tenofovir Chinese mugwort is taken to draw phenol amine fumarate crystal form A (being prepared by 1 method of embodiment) respectively, tenofovir Chinese mugwort draws phenol
Amine fumarate crystal form B (is prepared) by 5 method of embodiment, and tenofovir Chinese mugwort draws phenol amine fumarate crystal form C (to press 7 side of embodiment
It is prepared by method) and tenofovir Chinese mugwort drawing phenol amine fumarate crystal form D (by the preparation of 10 method of embodiment), tenofovir Chinese mugwort draws phenol amine a
(being prepared by 13 method of embodiment) places 10 days at 60 DEG C, and the testing result of purity is as follows：
20 tenofovir of embodiment Chinese mugwort draws phenol amine fumarate crystal form A thin membrane coated tablets and its preparation
| Component | Content (mg/ pieces) |
| Label： | |
| Tenofovir Chinese mugwort draws phenol amine fumarate crystal form A | 31.1 |
| Lactose monohydrate | 100.0 |
| Microcrystalline cellulose | 60.0 |
| Cross-linked carboxymethyl cellulose sodium | 15.0 |
| Magnesium stearate | 3.0 |
| Thin film coating material： | |
| Opadry II | 10.0 |
Concrete operations:
It is weighed according to supplementary material each in upper table, microcrystalline cellulose with cross-linked carboxymethyl cellulose sodium is mixed, then adds in one
Water and milk sugar mixes, and adds tenofovir Chinese mugwort and draws phenol amine fumarate crystal form A mixing；Add Purified Water q. s wet granulation；It is dry；
Whole grain；Additional magnesium stearate mixing, tabletting；Then by coating material with 75% ethyl alcohol be made into suspension coating to get.
21 tenofovir of embodiment Chinese mugwort draws phenol amine fumarate crystal form A capsules and its preparation
Concrete operations：
It is weighed according to supplementary material each in upper table, first sodium carboxymethyl starch with microcrystalline cellulose is mixed, then adds in a water
Lactose mixes, and adds tenofovir Chinese mugwort and draws phenol amine fumarate crystal form A；Add Purified Water q. s wet granulation；It is dry；Whole grain；
Additional magnesium stearate mixing, be packed into hypromellose cellulose capsule to get.
22 tenofovir of embodiment Chinese mugwort draws phenol amine fumarate crystal form A, emtricitabine thin membrane coated tablet and its preparation
| Component | Content (mg/ pieces) |
| Label： | |
| Tenofovir Chinese mugwort draws phenol amine fumarate crystal form A | 31.1 |
| Emtricitabine | 200.0 |
| Microcrystalline cellulose | 300.0 |
| Lactose monohydrate | 120.0 |
| Pregelatinized starch | 40.0 |
| Cross-linked carboxymethyl cellulose sodium | 15.0 |
| Magnesium stearate | 6.0 |
| Thin film coating material： | |
| Opadry II | 20.0 |
Concrete operations：
It is weighed according to supplementary material each in upper table, first pregelatinized starch with cross-linked carboxymethyl cellulose sodium is mixed, is then added in
Lactose monohydrate mixes, and adds emtricitabine mixing, is eventually adding tenofovir Chinese mugwort and draws phenol amine fumarate crystal form A and crystallite fine
Dimension element mixing；Add Purified Water q. s wet granulation；It is dry；Whole grain；Additional magnesium stearate mixing, tabletting；Coating material is used
75% ethyl alcohol be made into suspension coating to get.
23 tenofovir of embodiment Chinese mugwort draws phenol amine fumarate crystal form B thin membrane coated tablets and its preparation
| Component | Content (mg/ pieces) |
| Label： | |
| Tenofovir Chinese mugwort draws phenol amine fumarate crystal form B | 31.1 |
| Lactose monohydrate | 100.0 |
| Microcrystalline cellulose | 60.0 |
| Cross-linked carboxymethyl cellulose sodium | 15.0 |
| Magnesium stearate | 3.0 |
| Thin film coating material： | |
| Opadry II | 10.0 |
Concrete operations:
It is weighed according to supplementary material each in upper table, microcrystalline cellulose with cross-linked carboxymethyl cellulose sodium is mixed, then adds in one
Water and milk sugar mixes, and adds tenofovir Chinese mugwort and draws phenol amine fumarate crystal form B mixing；Add Purified Water q. s wet granulation；It is dry；
Whole grain；Additional magnesium stearate mixing, tabletting；Then by coating material with 75% ethyl alcohol be made into suspension coating to get.
24 tenofovir of embodiment Chinese mugwort draws phenol amine fumarate crystal form C capsules and its preparation
| Component | Content (mg/ pieces) |
| Tenofovir Chinese mugwort draws phenol amine fumarate crystal form C | 31.1 |
| Lactose monohydrate | 100.0 |
| Microcrystalline cellulose | 100.0 |
| Sodium carboxymethyl starch | 15.0 |
| Magnesium stearate | 1.5 |
Concrete operations：
It is weighed according to supplementary material each in upper table, first sodium carboxymethyl starch with microcrystalline cellulose is mixed, then adds in a water
Lactose mixes, and adds tenofovir Chinese mugwort and draws phenol amine fumarate crystal form C；Add Purified Water q. s wet granulation；It is dry；Whole grain；
Additional magnesium stearate mixing, be packed into hypromellose cellulose capsule to get.
25 tenofovir of embodiment Chinese mugwort draws phenol amine fumarate crystal form D thin membrane coated tablets and its preparation
| Component | Content (mg/ pieces) |
| Label： | |
| Tenofovir Chinese mugwort draws phenol amine fumarate crystal form D | 31.1 |
| Lactose monohydrate | 100.0 |
| Microcrystalline cellulose | 60.0 |
| Cross-linked carboxymethyl cellulose sodium | 15.0 |
| Magnesium stearate | 3.0 |
| Thin film coating material： | |
| Opadry II | 10.0 |
Concrete operations:
It is weighed according to supplementary material each in upper table, microcrystalline cellulose with cross-linked carboxymethyl cellulose sodium is mixed, then adds in one
Water and milk sugar mixes, and adds tenofovir Chinese mugwort and draws phenol amine fumarate crystal form D mixing；Add Purified Water q. s wet granulation；It is dry；
Whole grain；Additional magnesium stearate mixing, tabletting；Then by coating material with 75% ethyl alcohol be made into suspension coating to get.
26 tenofovir of embodiment Chinese mugwort draws phenol amine crystal form a thin membrane coated tablets and its preparation
Concrete operations:
It is weighed according to supplementary material each in upper table, microcrystalline cellulose with cross-linked carboxymethyl cellulose sodium is mixed, then adds in one
Water and milk sugar mixes, and adds tenofovir Chinese mugwort and draws phenol amine crystal form a mixing；Add Purified Water q. s wet granulation；It is dry；Whole grain；Outside
Stiffened fatty acid magnesium mixing, tabletting；Then by coating material with 75% ethyl alcohol be made into suspension coating to get.
Claims (7)
1. a kind of tenofovir Chinese mugwort draws phenol amine fumarate crystal form C, it is characterised in that its powder x-ray diffraction collection of illustrative plates is in 2 θ values
It is 4.6 ° ± 0.2 °, 6.6 ° ± 0.2 °, 10.4 ° ± 0.2 °, 13.3 ° ± 0.2 °, 14.9 ° ± 0.2 °, 17.1 ° ± 0.2 °, 18.8 °
±0.2°、19.0°±0.2°、19.6°±0.2°、21.2°±0.2°、21.4°±0.2°、23.8°±0.2°、29.2°±
Be corresponding at 0.2 ° characteristic diffraction peak or its powder x-ray diffraction collection of illustrative plates 2 θ values for 4.6 ° ± 0.2 °, 6.6 ° ± 0.2 °,
9.4°±0.2°、10.4°±0.2°、12.4°±0.2°、13.3°±0.2°、14.9°±0.2°、15.7°±0.2°、17.1°
±0.2°、18.4°±0.2°、18.8°±0.2°、19.0°±0.2°、19.6°±0.2°、20.7°±0.2°、21.2°±
0.2°、21.4°±0.2°、22.3°±0.2°、23.2°±0.2°、23.8°±0.2°、24.4°±0.2°、25.1°±0.2°、
Feature diffraction is corresponding at 26.7 ° ± 0.2 °, 27.0 ° ± 0.2 °, 28.8 ° ± 0.2 °, 29.2 ° ± 0.2 °, 33.7 ° ± 0.2 °
Peak or with the feature representated by powder x-ray diffraction collection of illustrative plates as shown in Figure 3.
2. tenofovir Chinese mugwort as described in claim 1 draws phenol amine fumarate crystal form, it is characterised in that crystal form content is more than
70%, preferably greater than 80%, most preferably greater than 90%.
3. tenofovir Chinese mugwort as claimed in claim 2 draws phenol amine fumarate crystal form, it is characterised in that crystal form content is more than
80%.
4. tenofovir Chinese mugwort as claimed in claim 3 draws phenol amine fumarate crystal form, it is characterised in that crystal form content is more than
90%.
5. a kind of tenofovir Chinese mugwort draws the preparation method of phenol amine fumarate crystal form C, it is characterised in that including：
(1), tenofovir ends draws phenol amine and fumaric acid to be dissolved in isobutanol；
(2), solid is precipitated；
(3), solid be precipitated is detached；
(4), it is optional, the solid of separation is dried.
6. a kind of pharmaceutical composition ends it includes the tenofovir described in any one of claim 1-4 of therapeutically effective amount and draws
Tenofovir Chinese mugwort draws phenol amine fumarate crystal form and medicinal made from phenol amine fumarate crystal form or claim 5 preparation method
Auxiliary material.
7. the tenofovir Chinese mugwort described in any one of claim 1-4 draws phenol amine fumarate crystal form or claim 5 side of preparation
Tenofovir Chinese mugwort made from method draws phenol amine fumarate crystal form preparing prevention and/or treatment hepatitis type B virus and/or the mankind
Purposes in the drug of immunodeficiency virus infection.
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| CN201410633514.0A CN105646584B (en) | 2014-11-12 | 2014-11-12 | Tenofovir Chinese mugwort draws phenol amine fumarate crystal form and its preparation method and application |
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| CN201410633514.0A Active CN105646584B (en) | 2014-11-12 | 2014-11-12 | Tenofovir Chinese mugwort draws phenol amine fumarate crystal form and its preparation method and application |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112294773A (en) * | 2020-10-27 | 2021-02-02 | 石药集团中奇制药技术（石家庄）有限公司 | Pharmaceutical composition of propane fumarate and tenofovir |
| CN112336695A (en) * | 2020-09-28 | 2021-02-09 | 华北制药华坤河北生物技术有限公司 | Propofol fumarate and tenofovir tablet, preparation method thereof and detection method of related substances |
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| CN107663217B (en) * | 2016-07-28 | 2021-03-02 | 苏州朗科生物技术股份有限公司 | Tenofovir alafenamide crystal compound and preparation method thereof |
| CN107793451A (en) * | 2016-08-30 | 2018-03-13 | 江苏奥赛康药业股份有限公司 | Tenofovir Chinese mugwort draws phenol amine hemifumarate compound and its pharmaceutical composition |
| CN106478725B (en) * | 2016-10-14 | 2018-11-09 | 上海礼泰医药科技有限公司 | The preparation method and applications of high-purity phosphine the third tenofovir intermediate |
| CN108117570A (en) * | 2016-11-28 | 2018-06-05 | 正大天晴药业集团股份有限公司 | A kind of tenofovir Chinese mugwort draws crystallization of phenol amine hemifumarate and preparation method thereof |
| CN108794530A (en) * | 2017-04-26 | 2018-11-13 | 上海医药工业研究院 | A kind of the third phenol of tenofovir amidic-salt crystal form and its preparation method and application |
| CN107445994A (en) * | 2017-05-31 | 2017-12-08 | 北京阜康仁生物制药科技有限公司 | Tenofovir Chinese mugwort draws phenol amine hemifumarate novel crystal forms |
| CN107865874A (en) * | 2017-10-23 | 2018-04-03 | 上海博悦生物科技有限公司 | A kind of tenofovir Chinese mugwort draws pharmaceutical composition of phenol amine and preparation method thereof |
| CN108440596B (en) * | 2018-03-22 | 2020-07-03 | 科兴生物制药股份有限公司 | Novel preparation process of tenofovir alafenamide hemifumarate |
| CN108299500A (en) * | 2018-04-04 | 2018-07-20 | 安徽安科恒益药业有限公司 | A kind of fumaric acid tenofovir Chinese mugwort draws phenol amine bulk pharmaceutical chemicals and its production technology |
| CN108546274A (en) * | 2018-06-29 | 2018-09-18 | 成都倍特药业有限公司 | A kind of tenofovir Chinese mugwort draws the preparation method of phenol amine hemifumarate |
| CN110407878A (en) * | 2019-07-16 | 2019-11-05 | 杭州和泽医药科技有限公司 | Tenofovir prodrug crystal form and preparation method and use thereof |
| CN114527199A (en) * | 2020-11-23 | 2022-05-24 | 广东东阳光药业有限公司 | Method for separating and detecting enantiomers of fosaprepifuvir fumarate |
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| WO2013052094A2 (en) * | 2011-10-07 | 2013-04-11 | Gilead Sciences, Inc. | Methods for preparing anti-viral nucleotide analogs |
| CN103732594A (en) * | 2011-08-16 | 2014-04-16 | 吉联亚科学公司 | Tenofovir alafenamide hemifumarate |
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2014
- 2014-11-12 CN CN201810126578.XA patent/CN108148094A/en not_active Withdrawn
- 2014-11-12 CN CN201410633514.0A patent/CN105646584B/en active Active
- 2014-11-12 CN CN201810116655.3A patent/CN108191913A/en not_active Withdrawn
Patent Citations (3)
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|---|---|---|---|---|
| CN1443189A (en) * | 2000-07-21 | 2003-09-17 | 吉里德科学公司 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
| CN103732594A (en) * | 2011-08-16 | 2014-04-16 | 吉联亚科学公司 | Tenofovir alafenamide hemifumarate |
| WO2013052094A2 (en) * | 2011-10-07 | 2013-04-11 | Gilead Sciences, Inc. | Methods for preparing anti-viral nucleotide analogs |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112336695A (en) * | 2020-09-28 | 2021-02-09 | 华北制药华坤河北生物技术有限公司 | Propofol fumarate and tenofovir tablet, preparation method thereof and detection method of related substances |
| CN112294773A (en) * | 2020-10-27 | 2021-02-02 | 石药集团中奇制药技术（石家庄）有限公司 | Pharmaceutical composition of propane fumarate and tenofovir |
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| CN105646584B (en) | 2018-09-28 |
| CN105646584A (en) | 2016-06-08 |
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