CN107793451A - Tenofovir Chinese mugwort draws phenol amine hemifumarate compound and its pharmaceutical composition - Google Patents
Tenofovir Chinese mugwort draws phenol amine hemifumarate compound and its pharmaceutical composition Download PDFInfo
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- CN107793451A CN107793451A CN201610778546.9A CN201610778546A CN107793451A CN 107793451 A CN107793451 A CN 107793451A CN 201610778546 A CN201610778546 A CN 201610778546A CN 107793451 A CN107793451 A CN 107793451A
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- phenol amine
- chinese mugwort
- tenofovir chinese
- amine hemifumarate
- tenofovir
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
Ended the invention provides tenofovir and draw a variety of crystal formations of phenol amine hemifumarate compound, especially crystal formation I, there is good stability, be adapted to preparation of preparation.The crystal formation I uses Cu target emanations, there is characteristic peak at about 5.28 ± 0.2,6.88 ± 0.2,10.95 ± 0.2,16.19 ± 0.2,19.55 ± 0.2,20.67 ± 0.2,21.27 ± 0.2,26.59 ± 0.2 degree with the X ray powder diffractions that 2 θ angles represent, and the preparation method of the crystal formation is simple to operate, it is adapted to industrialized production and application.
Description
Technical field
The invention belongs to field of medicaments, and in particular to tenofovir Chinese mugwort draw phenol amine hemifumarate compound novel crystal forms and
Its preparation method, and ended containing the tenofovir and draw the pharmaceutical composition of phenol amine hemifumarate compound.
Background technology
Tenofovir Chinese mugwort draws phenol amine (tenofovir alafenamide, structural formula are as follows), entitled 9- [(the R) -2- of chemistry
[[(S) -1- (isopropoxy carbonyl) ethyl] amino-benzene oxygen phosphinyl] methoxyl group] propyl group] adenine], it is by the U.S.
A kind of novel nucleoside acids RTI of Gilead Sciences companies research and development.List within 2015, be used in the U.S.
Treatment adult's HIV.The medicine also be used to treat hepatitis B, be currently in III phases clinic.Rapidly transformed into after this product is oral
Tenofovir, tenofovir diphosphate is phosphorylated in the presence of cell kinase, by competitively with natural deoxidation
Ribose substrate, which is combined, to be suppressed varial polymerases and is inserted into after viral DNA to cause DNA to extend to terminate, so as to suppress HIV and
HBV activity.
CN103732594A discloses a kind of crystal form that tenofovir Chinese mugwort draws phenol amine hemifumarate, this specification mark
For A crystal formations.CN104558036A discloses a kind of crystal form that tenofovir Chinese mugwort draws phenol amine hemifumarate, and we study hair
Now the crystal formation is that tenofovir Chinese mugwort draws phenol amine free alkali N crystal form and the mixed crystal of its hemifumarate A crystal formations.At present still without other
Ended for tenofovir and draw crystal formation and the correlative study of stability of phenol amine hemifumarate.Because the different crystal forms of compound can
So that there is difference in stability, physical property etc., the stability and bioavilability of bulk drug and preparation are directly influenced,
Therefore crystal formation of the exploitation with stability and applicability is significant.
The content of the invention
Ended it is an object of the invention to provide the tenofovir shown in a kind of formula (I) and draw the crystal formation of phenol amine hemifumarate,
The crystal formation has good stability, meets medicinal requirements, and preparation method is simple, is adapted to industrialized production.
To achieve these goals, the present invention provides following technical scheme:
The present invention provides a kind of tenofovir Chinese mugwort as shown in formula (I) and draws phenol amine hemifumarate compound, and its feature exists
In it is I crystal that the tenofovir Chinese mugwort, which draws phenol amine hemifumarate compound, and it uses Cu target emanations, is represented with 2 θ angles
X-ray powder diffraction collection is about 5.28 ± 0.2,6.88 ± 0.2,10.95 ± 0.2,16.19 ± 0.2,19.55 ± 0.2,
There is characteristic peak at 20.67 ± 0.2,21.27 ± 0.2,26.59 ± 0.2 degree, the wherein maximum peak of relative intensity is 26.59 ± 0.2
The characteristic peak of degree.
Further, the X-ray powder diffraction collection about 5.28 ± 0.2,6.88 ± 0.2,8.52 ± 0.2,
10.40±0.2、10.95±0.2、11.26±0.2、15.85±0.2、16.19±0.2、17.56±0.2、17.76±0.2、
18.27±0.2、18.70±0.2、19.55±0.2、20.67±0.2、21.27±0.2、21.95±0.2、22.41±0.2、
There is characteristic peak at 26.59 ± 0.2 degree.
Further, the tenofovir Chinese mugwort draws the I crystal of phenol amine hemifumarate to have substantially as shown in Figure 10
XRD.Wherein described 2 θ angles allow the error for having ± 0.2 degree.
The tenofovir Chinese mugwort draws the I crystal of phenol amine hemifumarate that there is DSC substantially as shown in figure 11 to scheme.
The tenofovir Chinese mugwort draws the I crystal of phenol amine hemifumarate that there is TGA substantially as shown in figure 12 to scheme.
The present invention also provides a kind of method that tenofovir Chinese mugwort as shown in formula (I) draws the I crystal of phenol amine hemifumarate,
Draw phenol amine hemifumarate to be dissolved in methanol including tenofovir is ended, add isopropyl ether, be concentrated to dryness or cooling crystallization, produce.
In methods described, it is 1g that tenofovir Chinese mugwort, which draws the ratio of phenol amine hemifumarate and methanol,:5~40ml.Methanol with
The volume ratio of isopropyl ether is 1:0.5~5.Preferably, it is 1g that tenofovir Chinese mugwort, which draws the ratio of phenol amine hemifumarate and methanol,:10
~30ml.The volume ratio of methanol and isopropyl ether is 1:1~3.Concentration can be rotary evaporation.Concentration can be in 30 DEG C of progress.
The present invention also provides the C crystal form that a kind of tenofovir Chinese mugwort as shown in formula (I) draws phenol amine hemifumarate compound,
It uses Cu target emanations, substantially as shown in Figure 1 with the X-ray powder diffraction collection that 2 θ angles represent.
The present invention also provides the crystal form E that a kind of tenofovir Chinese mugwort as shown in formula (I) draws phenol amine hemifumarate compound,
It uses Cu target emanations, substantially as shown in Figure 4 with the X-ray powder diffraction collection that 2 θ angles represent.
The present invention also provides the H crystal form that a kind of tenofovir Chinese mugwort as shown in formula (I) draws phenol amine hemifumarate compound,
It uses Cu target emanations, substantially as shown in Figure 7 with the X-ray powder diffraction collection that 2 θ angles represent.
The present invention also provides the K crystal formations that a kind of tenofovir Chinese mugwort as shown in formula (I) draws phenol amine hemifumarate compound,
It uses Cu target emanations, substantially as shown in figure 14 with the X-ray powder diffraction collection that 2 θ angles represent.
The present invention also provides the L crystal formations that a kind of tenofovir Chinese mugwort as shown in formula (I) draws phenol amine hemifumarate compound,
It uses Cu target emanations, substantially as shown in figure 17 with the X-ray powder diffraction collection that 2 θ angles represent.
The present invention also provides a kind of pharmaceutical composition, and its tenofovir Chinese mugwort for containing above-mentioned crystal form draws half rich horse of phenol amine
Phosphate compounds and pharmaceutically acceptable carrier.Any formulation, preferably oral formulations can be made in described pharmaceutical composition,
Such as tablet, capsule etc..
The present invention also provides above-mentioned tenofovir Chinese mugwort and draws phenol amine hemifumarate compound or its pharmaceutical composition preparing
Purposes in nucleotide reverse transcriptase inhibitor medicaments.
Ended the invention provides tenofovir and draw a variety of crystal formations of phenol amine hemifumarate, especially I crystal, shown excellent
Good stability, suitable for preparing pharmaceutical preparation.The preparation method of the crystal formation is simple, is adapted to industrialized production.
Brief description of the drawings
Fig. 1~3 are XRD, DSC, TGA figure that tenofovir Chinese mugwort draws phenol amine hemifumarate C crystal form respectively.
Fig. 4~6 are XRD, DSC, TGA figure that tenofovir Chinese mugwort draws phenol amine hemifumarate crystal form E respectively.
Fig. 7~9 are XRD, DSC, TGA figure that tenofovir Chinese mugwort draws phenol amine hemifumarate H crystal form respectively.
Figure 10~13 are XRD, DSC, TGA, DVS figure that tenofovir Chinese mugwort draws phenol amine hemifumarate I crystal respectively.
Figure 14~16 are XRD, DSC, TGA figure that tenofovir Chinese mugwort draws phenol amine hemifumarate K crystal formations respectively.
Figure 17~19 are XRD, DSC, TGA figure that tenofovir Chinese mugwort draws phenol amine hemifumarate L crystal formations respectively.
Figure 20 is the XRD that tenofovir Chinese mugwort draws phenol amine free alkali N crystal form.
Embodiment
The present invention is described in detail below by way of specific embodiment, it will be appreciated by those skilled in the art that following implementations
Example is only purpose of explanation, without the scope limiting the invention in any way.Tenofovir Chinese mugwort draws the fumaric acid of phenol amine half
Salt is prepared according to the method for CN103732594A examples 3, and obtained solid is labeled as A crystal formations.Unless otherwise instructed, in embodiment
Operating procedure be routine operation, the crystallization time can be 3 hours to 3 days.
Method of testing:
XRD is tested:INSTRUMENT MODEL:Bruker D8Advance diffractometer, target:Cu targets (40kV, 40mA),
Scanning range:3 ° -40 ° (2 θ values), step-length:0.02 ° of 2 θ, speed:0.2s.step-1;Unless otherwise indicated, Cu targets X in the present invention
Ray uses Kα1。
DSC is tested:INSTRUMENT MODEL:TA Instruments Q200DSC, temperature range:20-200 DEG C, sweep speed:10
DEG C/min, nitrogen flow rate:40ml/min
TGA is tested:INSTRUMENT MODEL:TA Instruments Q500TGA, temperature range:5-250 DEG C, sweep speed:10
DEG C/min, nitrogen flow rate:40ml/min
DVS is tested:INSTRUMENT MODEL:TA Instruments Q5000TGA, nitrogen flow rate:40ml/min,
Equilibrate at25℃;Humidity 0%;Isothermal for 180min;Abort next iso if
Weight (%)<0.0100for 15.00min
Embodiment 1:Tenofovir Chinese mugwort draws the preparation of the C crystal form of phenol amine hemifumarate
Take 500mg tenofovirs Chinese mugwort to draw phenol amine hemifumarate, add 25mL acetone and be heated to 50 DEG C of dissolved clarifications, room temperature nitrogen blows
Dry solvent, is produced.
XRD spectrum is as shown in Figure 1.DSC collection of illustrative plates shows that sample fusing point is about 105 DEG C, melts and turns crystalline substance with heat release, after turning brilliant
Sample fusing point is about 130 DEG C (Fig. 2).TGA collection of illustrative plates is shown in weightlessness 0.8% before 120 DEG C, and sample is anhydride, decomposition temperature
About 178 DEG C (Fig. 3).
Embodiment 2:Tenofovir Chinese mugwort draws the preparation of the crystal form E of phenol amine hemifumarate
Take 100mg tenofovirs Chinese mugwort to draw phenol amine hemifumarate, it is small to be placed in diffusion 4 in trifluoroethanol solvent atmosphere at room temperature
When obtain.
XRD spectrum is as shown in Figure 4.DSC collection of illustrative plates shows, there is small and wide endothermic peak at 60~90 DEG C, sample after desolventizing
Fusing point is 130 DEG C, and crystal phenomenon (Fig. 5) occurs.Weightlessness 7.1% before TGA collection of illustrative plates is shown in 120 DEG C, close to half of trifluoro second
Alcohol molecule (theoretical weight ratio is 8.6%), sample is half trifluoroethanol solvate, and decomposition temperature is about 181 DEG C (Fig. 6).
Embodiment 3:Tenofovir Chinese mugwort draws the preparation of the H crystal form of phenol amine hemifumarate
Take 100mg tenofovirs Chinese mugwort draw phenol amine hemifumarate, at room temperature add Isosorbide-5-Nitrae-dioxane, be heated to 45 DEG C it is molten
Filtered after clear, 4 DEG C of sub-cooled crystallizations separate out a small amount of sample, and nitrogen dries up to obtain.
XRD spectrum is as shown in Figure 7.DSC collection of illustrative plates shows desolventizing along with melting, and initial temperature is about 121 DEG C (Fig. 8).
TGA collection of illustrative plates is shown in weightlessness 6.9% before 120 DEG C, and close to half of Isosorbide-5-Nitrae-dioxane molecule, (theoretical weight ratio is
7.6%), sample is half Isosorbide-5-Nitrae-dioxane solvent compound, and decomposition temperature is about 180 DEG C (Fig. 9).
Embodiment 4:Tenofovir Chinese mugwort draws the preparation of the I crystal of phenol amine hemifumarate
Method 1:Take 500mg tenofovirs Chinese mugwort to draw phenol amine hemifumarate, add 10mL methanol at room temperature, add 20mL
Isopropyl ether, filter after ultrasonic dissolved clarification, 30 DEG C are spin-dried for, and produce.
Method 2:Take 1.0g tenofovirs Chinese mugwort to draw phenol amine hemifumarate, add 20mL methanol at room temperature, add 50mL
Isopropyl ether, 4 DEG C of sub-cooled crystallizations, filter, vacuum drying, produce.
XRD spectrum is as shown in Figure 10, and spectrum data is listed in the table below 1.DSC collection of illustrative plates shows that the fusing point of the I crystal is about 102
DEG C, then melting turns crystalline substance, and fusing point is about 131 DEG C (Figure 11).TGA collection of illustrative plates shows I crystal weightlessness 0.6% before 120 DEG C, is
Anhydride, decomposition temperature are about 181 DEG C (Figure 12).DVS/ isothermal adsorption figures show, weight change in the range of 0%RH to 80%RH
About 0.5% (Figure 13).
The tenofovir of table 1. Chinese mugwort draws the crystal formation I of phenol amine hemifumarate XRD modal data
Embodiment 5:Tenofovir Chinese mugwort draws the preparation of the K crystal formations of phenol amine hemifumarate
Take 100mg tenofovirs Chinese mugwort to draw phenol amine hemifumarate, add 0.6mL tetrahydrofurans at room temperature, be stirred at room temperature 1
My god, centrifugal drying obtains.
XRD spectrum is as shown in figure 14.DSC collection of illustrative plates shows that sample fusing point is about 131 DEG C, and single endothermic peak is presented, it is possible to
Sample has sloughed solvent (Figure 15) in detection.Weightlessness 2.3% before TGA collection of illustrative plates is shown in 120 DEG C, is roughly equal to 1/4 tetrahydrochysene furan
Mutter molecule (hemifumarate theoretical weight ratio be 3.2%), decomposition temperature is about 185 DEG C (Figure 16).
Embodiment 6:Tenofovir Chinese mugwort draws the preparation of the L crystal formations of phenol amine hemifumarate
Take 100mg tenofovirs Chinese mugwort to draw phenol amine hemifumarate, add 1.0mL chloroforms, low temperature magma centrifuges after 3 days
Arrive.
XRD spectrum is as shown in figure 17.DSC collection of illustrative plates shows multiple endothermic peaks, and endothermic peak is Form L desolventizings at 81 DEG C
Caused, heat release turn crystalline substance after desolventizing, sample has a small endothermic peak at 115 DEG C after turning brilliant, and sample fusing point is 130 DEG C afterwards
(Figure 18).TGA collection of illustrative plates be shown in there are about before 90 DEG C 4.4% step it is weightless, have 1.8% weightlessness between 90-140 DEG C, always
Meter weightlessness 6.2%, it is roughly equal to 2 hydrones (theoretical weight ratio is 6.3%), may is dihydrate, decomposition temperature is about 179
DEG C (Figure 19).
Embodiment 7:Tenofovir Chinese mugwort draws the polymorphous study on the stability of phenol amine hemifumarate
Tenofovir Chinese mugwort prepared by above-described embodiment draws the different crystal forms of phenol amine hemifumarate to be placed under different condition,
Sampling detection crystal formation change.It the results are shown in Table 2.
The tenofovir of table 2. Chinese mugwort draws the polymorphous study on the stability of phenol amine hemifumarate
Crystal formation | Testing result |
A | Placed 10 days under the conditions of hot and humid, crystal formation and fusing point are constant |
C | Room temperature places 1 day mixed crystal that can switch to A crystal formations and free alkali N crystal form, and high temperature drying, which is placed, is changed into A crystal formations |
E | Heating desolventizing is changed into amorphous article |
H | Heating desolventizing is changed into A crystal formations |
I | Placed 10 days under the conditions of hot and humid, crystal formation and fusing point are constant |
K | Room temperature, which is placed 10 days, is changed into A crystal formations |
L | Heating desolventizing is changed into C crystal form |
Note:Room temperature condition:About 25 DEG C;High temperature drying:60 DEG C of freeze-day with constant temperature;It is hot and humid:60 DEG C, RH 75 ± 5%.
Test result indicates that in hot environment, crystal formation C, E, H, K, L are not sufficiently stable;Crystal formation A and crystal formation I is nothing
Crystal type, under the conditions of hot and humid, the stability of the two is fine.Crystal formation I is the tenofovir Chinese mugwort that the present inventor has found first
The new stable crystal form of phenol amine hemifumarate is drawn, DVS investigates result and shown, crystal formation I hygroscopicity very little, is adapted to prepare and replaces promise
The pharmaceutical composition and preparation of Fu Weiaila phenol amine hemifumarates, especially solid pharmaceutical preparation, the stability of effective guarantee product
And security.
Claims (10)
1. a kind of tenofovir Chinese mugwort as shown in formula (I) draws phenol amine hemifumarate compound,
Characterized in that, it is I crystal that the tenofovir Chinese mugwort, which draws phenol amine hemifumarate compound, it uses Cu target emanations, with 2
The X-ray powder diffraction collection that θ angles represent is 5.28 ± 0.2,6.88 ± 0.2,10.95 ± 0.2,16.19 ± 0.2,
There is characteristic peak at 19.55 ± 0.2,20.67 ± 0.2,21.27 ± 0.2,26.59 ± 0.2 degree.
2. tenofovir Chinese mugwort as claimed in claim 1 draws phenol amine hemifumarate compound, it is characterised in that the X-ray
Powder diffraction spectrum is 5.28 ± 0.2,6.88 ± 0.2,8.52 ± 0.2,10.40 ± 0.2,10.95 ± 0.2,11.26 ± 0.2,
15.85±0.2、16.19±0.2、17.56±0.2、17.76±0.2、18.27±0.2、18.70±0.2、19.55±0.2、
There is characteristic peak at 20.67 ± 0.2,21.27 ± 0.2,21.95 ± 0.2,22.41 ± 0.2,26.59 ± 0.2 degree.
3. tenofovir Chinese mugwort as claimed in claim 1 draws phenol amine hemifumarate compound, it is characterised in that described to replace promise good fortune
The I crystal of Wei Aila phenol amine hemifumarates has XRD substantially as shown in Figure 10.
4. a kind of method that tenofovir Chinese mugwort prepared described in claim 1 draws phenol amine hemifumarate compound, its feature exist
In tenofovir is ended and draws phenol amine hemifumarate to be dissolved in methanol, adds isopropyl ether, is concentrated to dryness or cooling crystallization, is produced.
It is 1g that 5. method as claimed in claim 4, wherein tenofovir Chinese mugwort, which draw the ratio of phenol amine hemifumarate and methanol,:5
~40ml;The volume ratio of methanol and isopropyl ether is 1:0.5~5.
It is 1g that 6. method as claimed in claim 5, wherein tenofovir Chinese mugwort, which draw the ratio of phenol amine hemifumarate and methanol,:10
~30ml;The volume ratio of methanol and isopropyl ether is 1:1~3.
7. a kind of pharmaceutical composition, its tenofovir Chinese mugwort for containing described in any one of claims 1 to 3 of effective dose draws phenol amine half
Fumarate compound, and pharmaceutically acceptable carrier.
8. pharmaceutical composition as claimed in claim 7, wherein described pharmaceutical composition can be prepared into oral formulations.
9. the tenofovir Chinese mugwort described in claim 1 draws phenol amine hemifumarate compound preparing nucleotide reverse transcriptase suppression
Purposes in preparation medicine.
10. purposes of the pharmaceutical composition in nucleotide reverse transcriptase inhibitor medicaments are prepared described in claim 7 or 8.
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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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 |
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 |
CN110526942A (en) * | 2019-06-18 | 2019-12-03 | 株洲千金药业股份有限公司 | A kind of unformed fumaric acid tenofovir Chinese mugwort draws phenol amine and preparation method thereof |
CN111989335A (en) * | 2018-06-12 | 2020-11-24 | 四川科伦博泰生物医药股份有限公司 | Phosphonamide ester compounds and salts and related crystal forms, preparation methods and uses thereof |
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CN105237571A (en) * | 2014-11-28 | 2016-01-13 | 成都苑东药业有限公司 | Salt of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl) ethyl] amino] phenoxy-phosphinyl] methoxyl] propyl] adenine |
CN105646584A (en) * | 2014-11-12 | 2016-06-08 | 四川海思科制药有限公司 | Novel crystal forms of Tenofovir alafenamide fumarate, preparation methods therefor and use of novel crystal forms of Tenofovir alafenamide fumarate |
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CN103732594A (en) * | 2011-08-16 | 2014-04-16 | 吉联亚科学公司 | Tenofovir alafenamide hemifumarate |
WO2015040640A2 (en) * | 2013-09-20 | 2015-03-26 | Laurus Labs Private Limited | An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof |
CN105646584A (en) * | 2014-11-12 | 2016-06-08 | 四川海思科制药有限公司 | Novel crystal forms of Tenofovir alafenamide fumarate, preparation methods therefor and use of novel crystal forms of Tenofovir alafenamide fumarate |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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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 |
CN111989335A (en) * | 2018-06-12 | 2020-11-24 | 四川科伦博泰生物医药股份有限公司 | Phosphonamide ester compounds and salts and related crystal forms, preparation methods and uses thereof |
CN111989335B (en) * | 2018-06-12 | 2023-06-13 | 四川科伦博泰生物医药股份有限公司 | Phosphonamide ester compounds and salts thereof and related crystalline forms, methods of preparation and uses |
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 |
CN110526942A (en) * | 2019-06-18 | 2019-12-03 | 株洲千金药业股份有限公司 | A kind of unformed fumaric acid tenofovir Chinese mugwort draws phenol amine and preparation method thereof |
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Address after: 211112 Kejian Road, Jiangning Science Park, Nanjing City, Jiangsu Province, 699 Applicant after: Jiangsu Aosaikang Pharmaceutical Co., Ltd. Address before: 211112 Kejian Road, Jiangning Science Park, Nanjing City, Jiangsu Province, 699 Applicant before: Jiangsu Aosaikang Pharmaceutical Co., Ltd. |
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Application publication date: 20180313 |