CN104558036A - Tenofovir alafenamide hemi-fumarate crystal form and preparation method thereof - Google Patents
Tenofovir alafenamide hemi-fumarate crystal form and preparation method thereof Download PDFInfo
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- CN104558036A CN104558036A CN201410763742.XA CN201410763742A CN104558036A CN 104558036 A CN104558036 A CN 104558036A CN 201410763742 A CN201410763742 A CN 201410763742A CN 104558036 A CN104558036 A CN 104558036A
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Abstract
The invention discloses a tenofovir alafenamide hemi-fumarate crystal form and a preparation method thereof. Subjected to Cu-K alpha radiation, the tenofovir alafenamide hemi-fumarate crystal form is has the characteristic peaks at 2 theta angles in X-ray powder diffraction: 7.4+/-0.2 degrees, 8.6+/-0.2 degrees, 11.2+/-0.2 degrees, 19.5+/-0.2 degrees, and 21.3+/-0.2 degrees. The novel tenofovir alafenamide hemi-fumarate crystal form is simple to prepare, stable, and suitable for industrial production.
Description
Technical field
The invention belongs to medicine crystal technical field, be specifically related to a kind of tynofovir Chinese mugwort and draw phenol amine half fumarate crystal formation and preparation method.
Background technology
Polymorph in pharmaceuticals typically refers to the different arrangement modes of chemicals molecule, generally shows as medicine material existence form in the solid state.Identical molecule may form different crystal because of different spread patterns.Described polymorphic has different crystalline structure and physical properties, as solubleness, stability, thermal properties, mechanical properties etc.One or more analyzing and testing modes can be used for the different crystal forms distinguishing same compound, as X-ray diffraction, thermal analyses detection, infrared absorption spectrum, Raman spectrum and solid-state nmr etc.
The crystal formation that discovery active constituents of medicine is new can provide (comprising anhydride, hydrate, solvate) material of the working properties of advantage, find that new anhydrous crystal forms and solvate can provide the material with better physicochemical property, such as better bioavailability, stable storing, easily processing treatment, the easy intermediate crystal form of purifying or being converted into other crystal formations as promotion.The new crystal of the compound of pharmaceutically useful also can help improve the performance of medicine.It expands formulation science man to optimize the kenel of preparation performance and available raw material, such as, improve dissolution rate, improve shelf life, more easily process.
Chemical name is: L-Alanine,
N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-,1-methylethyl ester,(2E)-2-butenedioate(2:1)
Chemical formula is: C
21h
29n
6o
5p. (C
4h
4o
4)
0.5;
Molecular weight is: 534.50;
Chemical structural formula is as follows:
Gained tynofovir Chinese mugwort of preparing according to Chinese patent CN1291994C (Gilead Sciences Inc) embodiment 4 draws the fusing point of phenol amine fumarate to be 119.7-121.1 DEG C, has no other relevant crystal formation related datas.
US Patent No. 8754065 and Chinese patent application CN103732594A of the same clan describe tynofovir Chinese mugwort and draw phenol amine half fumarate salt form, and report a kind of crystal formation that tynofovir Chinese mugwort draws phenol amine half fumarate, fusing point is 131 ± 1 DEG C
The present inventor finds to be different from the new crystal that US Patent No. 8754065 tynofovir Chinese mugwort draws phenol amine half fumarate salt form in research process.
Summary of the invention
The object of this invention is to provide a kind of tynofovir Chinese mugwort and draw new crystal of half fumarate salt form of phenol amine (tenofovir alafenamide, chemistry 9-by name [(R)-2-[[(S)-[[(S)-1-(butyloxycarbonyl) ethyl] is amino] phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4) and preparation method thereof.
For achieving the above object, the present invention adopts following technical scheme:
The invention provides a kind of tynofovir Chinese mugwort and draw phenol amine half fumarate crystal formation, use Cu-K α radiation, the X-ray powder diffraction of described crystal formation has characteristic peak in following 2 θ angle positions: 7.4 ± 0.2 °, 8.6 ± 0.2 °, 11.2 ± 0.2 °, 19.5 ± 0.2 ° and 21.3 ± 0.2 °.
Further, described crystal formation also has characteristic peak in following 2 θ angle positions: 12.0 ± 0.2 °, 12.9 ± 0.2 °, 14.3 ± 0.2 °, 14.9 ± 0.2 °, 15.4 ± 0.2 °, 17.6 ± 0.2 °, 18.3 ± 0.2 °, 18.9 ± 0.2 °, 22.4 ± 0.2 °, 24.5 ± 0.2 ° and 25.5 ± 0.2 °.
Further, described crystal formation also has characteristic peak in following 2 θ angle positions: 9.7 ± 0.2 °, 17.3 ± 0.2 °, 18.0 ± 0.2 °, 20.5 ± 0.2 °, 21.9 ± 0.2 °, 22.9 ± 0.2 °, 23.8 ± 0.2 °, 25.0 ± 0.2 °, 26.0 ± 0.2 °, 26.7 ± 0.2 °, 26.9 ± 0.2 °, 27.3 ± 0.2 °, 28.2 ± 0.2 °, 28.9 ± 0.2 °, 29.5 ± 0.2 °, 30.0 ± 0.2 °, 31.1 ± 0.2 °, 31.9 ± 0.2 °, 33.0 ± 0.2 °, 34.6 ± 0.2 °, 35.0 ± 0.2 °, 35.7 ± 0.2 °, 36.6 ± 0.2 °, 37.0 ± 0.2 ° and 37.9 ± 0.2 °.
Further, the DSC endothermic transition of described crystal formation is at 113 ± 1 DEG C.
Present invention also offers following four kinds and prepare the method that described tynofovir Chinese mugwort draws phenol amine half fumarate crystal formation:
Method 1:
At room temperature, draw phenol amine half fumarate to add in solvent system A the tynofovir prepared according to CN103732594A Chinese mugwort and form suspension, stirring and crystallizing 1 ~ 10 day, then by the crystal separation of precipitation, drying, obtain described crystal formation; Described solvent system A is selected from following one: (1) ether; (2) mixture of ether and organic solvent C; Described organic solvent C can be miscible with ether, is preferably one or more the mixture in C1 ~ C4 alcohol, C4 ~ C5 ester, C3 ~ C4 ketone, C5 ~ C8 alkane or naphthenic hydrocarbon, tetrahydrofuran (THF), Nitromethane 99Min., acetonitrile.
Further, described C1 ~ C4 alcohol particular methanol, propyl carbinol or sec-butyl alcohol; Described C4 ~ C5 ester ethyl acetate or isopropyl acetate; The preferred acetone of described C3 ~ C4 ketone or butanone; Described C5 ~ C8 alkane or the preferred hexanaphthene of naphthenic hydrocarbon, methylcyclohexane, normal hexane.
Further, in described suspension, tynofovir Chinese mugwort draws the consumption of phenol amine half fumarate (CN103732594A) to be 1 ~ 20 times of its solubleness in described solvent system A under room temperature, is preferably 1.5 ~ 10 times, is more preferably 2 ~ 5 times.
Method 2:
In room temperature, the dioxane of phenol amine half fumarate or aqueous isopropanol is drawn to be placed in be full of the closed atmosphere of diffusion solvent to carry out crystallization 1 week ~ 3 weeks the tynofovir prepared according to CN103732594A Chinese mugwort, then by the crystal separation of precipitation, drying, described crystal formation is obtained; Described diffusion solvent is volatile ethers.
Further, described diffusion solvent is preferably ether or isopropyl ether.
Further, described tynofovir Chinese mugwort draws the dioxane of phenol amine half fumarate or the concentration of aqueous isopropanol to be 0.1 ~ 5mg/mL, is preferably 0.1 ~ 3mg/mL.
Method 3:
In room temperature, to the tynofovir prepared according to CN103732594A end draw phenol amine half fumarate to be formed in organic solvent C solution in add ethers reagent, stirring and crystallizing 3 ~ 10 days, then by the crystal separation of precipitation, drying, obtain described tynofovir Chinese mugwort and draw phenol amine half fumarate crystal formation.The definition of organic solvent C is the same.
Further, in described solution, known tynofovir Chinese mugwort draws the consumption of phenol amine half fumarate (CN103732594A) to be 0.1 ~ 1 times of its solubleness in described organic solvent C under room temperature, is preferably 0.5 ~ 1 times, is more preferably 0.8 ~ 1 times.
Further, the volume ratio of described ethers and described organic solvent C is 0.1 ~ 100:1, is preferably 0.5 ~ 50:1, is more preferably 0.5 ~ 5:1.
Method 4:
The solution that draws phenol amine half fumarate to be formed under the boiling temperature of 40 DEG C ~ solvent system B in solvent system B of being ended by the tynofovir prepared according to CN103732594A is cooled to 0 ~ 30 DEG C and stirring and crystallizing 3 ~ 10 days, then by the crystal separation of precipitation, drying, obtain described tynofovir Chinese mugwort and draw phenol amine half fumarate crystal formation; Described solvent system B be selected from following any one: (1) acetonitrile; (2) mixture of acetonitrile and organic solvent D; Described organic solvent D can be miscible with acetonitrile, is preferably one or more the mixture in C1 ~ C4 alcohol, C4 ~ C5 ester, C3 ~ C4 ketone, C5 ~ C8 alkane or naphthenic hydrocarbon, tetrahydrofuran (THF), Nitromethane 99Min..
Further, described solution is preferably 50 ~ 80 DEG C of formation.
Further, preferably described solution is cooled to room temperature.
Further, in described solution, known tynofovir Chinese mugwort draws the consumption of phenol amine half fumarate (CN103732594A) to be 0.1 ~ 10 times of its solubleness in described solvent system B at the temperature forming solution, is preferably 0.5 ~ 10 times, is more preferably 0.8 ~ 10 times.
In the present invention, described stirring, concrete operations are: the magnetic agitation of carrying out with 50 ~ 1800 revs/min, preferably 300 ~ 900 revs/min of magnetic agitation of carrying out.
In the present invention, described separation, is undertaken by centrifugal usually.Described centrifugal concrete operations are: the sample for being separated being placed in 2mL centrifuge tube, carrying out centrifugal, treat that solid is all sink to bottom centrifuge tube with 6000 revs/min of speed.
In the present invention, described drying, can reduce pressure or not reduce pressure, and be preferably pressure and be less than 0.09MPa, carry out in 30 ~ 50 DEG C, the time is 10 ~ 72 hours, is preferably 10 ~ 48 hours, is more preferably 10 ~ 24 hours.
In the present invention, being operating as of described closed atmosphere: uncovered for the 20mL vial preparing solution being placed in is added with 10 ~ 30mL and spreads in the closed glass jar in the 100mL space of solvent, to treat in diffusion solvent diffusion 1 ~ 3 thoughtful 20mL vial and to separate out solid.
In some embodiments, new crystal of the present invention is pure, single, does not substantially mix any other crystal formation.In the present invention, " substantially do not have " to refer to that when being used to refer to new crystal this crystal formation contains other crystal formations being less than 20% (weight), especially be less than other crystal formations of 10% (weight), more refer to other crystal formations being less than 5% (weight), more refer to other crystal formations being less than 1% (weight).In other embodiments, described crystal formation contains 1% ~ 20% (weight), or 5% ~ 20% (weight), or other crystal formations of 5% ~ 10% (weight).
In the present invention, " crystal " or " crystal formation " refer to by shown X-ray diffractogram characterize confirm.It will be appreciated by those skilled in the art that physico-chemical property discussed herein can be characterized, experimental error wherein depends on the purity of the condition of instrument, the preparation of sample and sample.Particularly, as well known to those skilled in the art, X-ray diffractogram can change along with the condition of instrument usually to some extent.Special needs to be pointed out is, the relative intensity of X-ray diffractogram also may change along with the change of experiment condition, so the order of peak intensity can not as unique or deciding factor.In addition, the experimental error of peak angle is usually 5% or less, and the error of these angles also should be considered into, usually allows ± the error of 0.2.In addition, due to the impact of the empirical factors such as height of specimen, the overall offset of peak angle can be caused, usually allow certain skew.Thus, it will be appreciated by persons skilled in the art that the X-ray diffractogram of a crystal formation in the present invention need not be completely the same with the X-ray diffractogram in the example of indication here.Any have all belong within category of the present invention with the crystal formation of the same or analogous figure of the characteristic peak in these collection of illustrative plates.The collection of illustrative plates of collection of illustrative plates listed by the present invention with a unknown crystal formation can be compared by those skilled in the art, is identical or different crystal formations with what confirm the reflection of this two picture group spectrum.
" crystal formation " and " polymorphic " and other relative words refer to solid chemical compound in the present invention to be existed with specific crystal form state in crystalline structure.The difference of polymorphic physico-chemical property can be embodied in the aspects such as stability in storage, compressibility, density, dissolution rate.In extreme situations, the difference of solubleness or dissolution rate can cause medicine poor efficiency, even toxicity.
The polymorphic of medicine can by including but not limited to that following method obtains: melting recrystallization, melting cooling, solvent recrystallization, mistake solvent, volatilization fast, fast cooling, at a slow speed cooling, vapor diffusion and distillation.Polymorphic can pass through X-ray powder diffraction (XRPD), differential scanning calorimetric analysis (DSC), thermogravimetric analysis (TGA), light microscope technique, water absorbability etc. and detect, finds and sort out.
Experimental technique can room temperature or close to the condition of room temperature under operate.Here refer to test is carry out under the condition identical or close with the temperature in room or stink cupboard.Usually this temperature is from 15 DEG C ~ 25 DEG C, or 17 DEG C, or 22 DEG C.
Experimental technique or step can operate when " spending the night ".Here refer to that this step crosses over the time in evening, there is no positive ground observation experiment phenomenon in period of spending the night.Can be 8 ~ 22 hours during this period of time, or 10 ~ 18 hours, normally 16 hours.
Unless stated otherwise, the crystal formation described in the present invention can through drying step.Drying can be carried out in room temperature or higher temperature.Crystal-form substances can be dry the temperature of 20 DEG C ~ about 60 DEG C, or to 40 DEG C, or to 50 DEG C.Time of drying can be 2 ~ 48 hours, or spends the night.Drying can be carried out in stink cupboard, convection oven or vacuum drying oven.
The crystallization mode adopted in the present invention comprises the method for room temperature volatilization, slowly volatilization, magma, cooling recrystallization and solvent resistant recrystallization.
Room temperature volatilization is such as be placed on by sample settled solution in uncovered 7mL vial, (is generally room temperature) and volatilizees under specific temperature conditions.The method that nitrogen can be used to blow or directly room temperature volatilization.
Slow volatilization (aperture volatilization) is such as be placed in the 7mL vial of punching by sample settled solution, is placed in air and slowly volatilizees.
Magma is such as stirred in different solvents system by the supersaturated solution of sample (having undissolved solid to exist), normally 2 hours ~ 2 time-of-weeks.
Cooling recrystallization be such as under specific hot conditions by sample dissolution in appropriate solvent, be placed in 7mL vial, be placed in water-bath, lower the temperature successively according to certain rate of temperature fall, stirred overnight at room temperature.The temperature of experiment can be 75 ~ 0 DEG C, preferably 50 ~ 15 DEG C.In each specific temperature, sample solution is incubated 1 little of 2 days.
Solvent resistant recrystallization is such as be dissolved in by sample in the good solvent of solvability, then adds appropriate solvent resistant, stirring at room temperature.
The tynofovir Chinese mugwort that the present invention obtains draws phenol amine half fumarate crystal formation, for the preparation of the medicine for the treatment of HIV.
Compared with prior art, beneficial effect of the present invention is: the present invention has obtained a kind of new tynofovir Chinese mugwort and drawn phenol amine half fumarate crystal formation, and preparation is simple, stable crystal form, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1: embodiment 1 gained tynofovir Chinese mugwort draws the XRD figure of phenol amine half fumarate crystal formation.
Fig. 2: embodiment 2 gained tynofovir Chinese mugwort draws the XRD figure of phenol amine half fumarate crystal formation.
Fig. 3: embodiment 2 gained tynofovir Chinese mugwort draws the DSC of phenol amine half fumarate crystal formation to scheme.
Embodiment
The present invention limits with further reference to following examples, and described embodiment describes the preparation and application of crystal formation of the present invention in detail.It will be apparent for a person skilled in the art that the many changes for both materials and methods can be implemented without departing from the present invention.
The instrument that image data is used and method:
The instrument that X-ray powder diffraction (XPRD) uses is Bruker D8Advance diffractometer, copper target wavelength is adopted to be the Ka X-ray of 1.54nm, under the operational condition of 40kV and 40mA, θ-2 θ goniometer, Mo monochromator, Lynxeye detector.Instrument is before use with standard substance (the being generally corundum) calibration that instrument carries.Acquisition software is Diffrac Plus XRD Commander, and analysis software is MDI Jade 5.0.Sample is tested at ambient temperature, is placed on organic slide needing the sample detected.Detailed testing conditions is as follows: angular range: 3 ~ 40 ° of 2 θ; Step-length: 0.02 ° of 2 θ; Speed: 0.2s/ walks.Unless stated otherwise, sample is before detection without grinding.
Differential thermal analysis (DSC) data acquisition is certainly in TA Instruments Q200MDSC, and instrument control software is Thermal Advantage, and analysis software is Universal Analysis.Usually the sample getting 1 ~ 10 milligram is positioned over does not add a cover in the aluminium crucible of (unless stated otherwise); under the protection of the dry N2 of 50mL/min, sample is risen to 250 DEG C from room temperature with the heat-up rate of 10 DEG C/min, simultaneously the thermal change of TA software records sample in temperature-rise period.In the present invention, fusing point is reported by starting temperature.
Embodiment 1: the preparation of known crystal formation (CN103732594A): the method preparation described with reference to embodiment 3 in patent documentation CN103732594.
9-[(R)-2-[[(S)-[[(S)-1-(butyloxycarbonyl) ethyl] is amino] phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (1g), FUMARIC ACID TECH GRADE (0.122g) and ACN (10mL) is added to being equipped with in the jacketed reactor of overhead type stirrer.Mixture is heated to 70 DEG C-75 DEG C with dissolved solids.Any undissolved particle is removed by filtering via core strainer.Filtered solution is cooled to 60 DEG C-65 DEG C, and draws phenol amine half fumarate to carry out adding crystal seed with 1% (by weight) tynofovir Chinese mugwort.Make slurry aging 30 minutes, and be cooled to 0 DEG C-5 DEG C through 2 hours.Holding temperature 1-18 hour, and filter gained slurry and wash with the ACN (0 DEG C-5 DEG C) that 0.2mL is cold.Under vacuo in 50 DEG C of drying solids, obtain tynofovir Chinese mugwort and draw the bright diacid salt form of half of phenol amine anti-fourth.
X-ray powder diffraction pattern as shown in Figure 1.The X-ray powder diffraction pattern of the crystal formation prepared with embodiment in patent CN103732594A 3 is substantially identical.
Embodiment 2
Take the known crystal formation 30mg that obtained by embodiment 1 in 20ml reaction flask, add 10ml ether, stirring at room temperature 48h, solid-liquid is by centrifugation, and gained solid spends the night in 40 DEG C of forced air dryings, obtains 27mg white solid (yield 90%), XRD is shown in Fig. 2, and DSC is shown in Fig. 3.
XRD data list
Embodiment 3
Take the known crystal formation 30mg that obtained by embodiment 1 in 20ml reaction flask, add 8ml ether and 2ml ethyl acetate, stirring at room temperature 48h, solid-liquid passes through centrifugation, gained solid spends the night in 40 DEG C of forced air dryings, obtains 28mg white solid (yield 93.3%).XRD figure and DSC scheme similar with Fig. 2, Fig. 3 respectively.
Embodiment 4
Take the known crystal formation 15mg that obtained by embodiment 1 in 20ml reaction flask, add 5ml Virahol, stirring and dissolving, system is placed in the 100ml wide-necked bottle containing 20ml ether, leave standstill 2 weeks, have solid to be formed, solid-liquid passes through centrifugation, gained solid spends the night in 40 DEG C of forced air dryings, obtains 12mg white solid (yield 80.0%).XRD figure and DSC scheme similar with Fig. 2, Fig. 3 respectively.
Embodiment 5
Take the known crystal formation 30mg that obtained by embodiment 1 in 20ml reaction flask, add 0.6ml secondary alcohol, stirring and dissolving, add 6ml ether, stirring at room temperature 3 days, have solid to be formed, solid-liquid passes through centrifugation, gained solid spends the night in 40 DEG C of forced air dryings, obtains 22mg white solid (yield 73.3%).XRD figure and DSC scheme similar with Fig. 2, Fig. 3 respectively.
Embodiment 6
Take the known crystal formation 30mg that obtained by embodiment 1 in 20ml reaction flask, add 0.5ml acetonitrile, reflux stirring and dissolving, be cooled to 20 DEG C of crystallizatioies, stir 3 days, solid-liquid is by centrifugation, and gained solid spends the night in 40 DEG C of forced air dryings, obtains 18mg white solid (yield 60.0%).XRD figure and DSC scheme similar with Fig. 2, Fig. 3 respectively.
Claims (8)
1. a tynofovir Chinese mugwort draws phenol amine half fumarate crystal formation, use Cu-K α radiation, the X-ray powder diffraction of described crystal formation has characteristic peak in following 2 θ angle positions: 7.4 ± 0.2 °, 8.6 ± 0.2 °, 11.2 ± 0.2 °, 19.5 ± 0.2 ° and 21.3 ± 0.2 °.
2. tynofovir Chinese mugwort as claimed in claim 1 draws phenol amine half fumarate crystal formation, it is characterized in that described crystal formation also has characteristic peak in following 2 θ angle positions: 12.0 ± 0.2 °, 12.9 ± 0.2 °, 14.3 ± 0.2 °, 14.9 ± 0.2 °, 15.4 ± 0.2 °, 17.6 ± 0.2 °, 18.3 ± 0.2 °, 18.9 ± 0.2 °, 22.4 ± 0.2 °, 24.5 ± 0.2 ° and 25.5 ± 0.2 °.
3. tynofovir Chinese mugwort as claimed in claim 2 draws phenol amine half fumarate crystal formation, it is characterized in that described crystal formation also has characteristic peak in following 2 θ angle positions: 9.7 ± 0.2 °, 17.3 ± 0.2 °, 18.0 ± 0.2 °, 20.5 ± 0.2 °, 21.9 ± 0.2 °, 22.9 ± 0.2 °, 23.8 ± 0.2 °, 25.0 ± 0.2 °, 26.0 ± 0.2 °, 26.7 ± 0.2 °, 26.9 ± 0.2 °, 27.3 ± 0.2 °, 28.2 ± 0.2 °, 28.9 ± 0.2 °, 29.5 ± 0.2 °, 30.0 ± 0.2 °, 31.1 ± 0.2 °, 31.9 ± 0.2 °, 33.0 ± 0.2 °, 34.6 ± 0.2 °, 35.0 ± 0.2 °, 35.7 ± 0.2 °, 36.6 ± 0.2 °, 37.0 ± 0.2 ° and 37.9 ± 0.2 °.
4. the tynofovir Chinese mugwort as described in one of claims 1 to 3 draws phenol amine half fumarate crystal formation, it is characterized in that the DSC endothermic transition of described crystal formation is at 113 ± 1 DEG C.
5. prepare the method that the Chinese mugwort of tynofovir as claimed in claim 1 draws phenol amine half fumarate crystal formation for one kind, comprise: at room temperature, draw phenol amine half fumarate to add in solvent system A the tynofovir prepared according to CN103732594A Chinese mugwort and form suspension, stirring and crystallizing 1 ~ 10 day, then by the crystal separation of precipitation, drying, obtain described tynofovir Chinese mugwort and draw phenol amine half fumarate crystal formation; Described solvent system A is selected from following one: (1) ether; (2) mixture of ether and organic solvent C; Described organic solvent C can be miscible with ether, is selected from one or more the mixture in C1 ~ C4 alcohol, C4 ~ C5 ester, C3 ~ C4 ketone, C5 ~ C8 alkane or naphthenic hydrocarbon, tetrahydrofuran (THF), Nitromethane 99Min., acetonitrile.
6. prepare the method that the Chinese mugwort of tynofovir as claimed in claim 1 draws phenol amine half fumarate crystal formation for one kind, comprise: in room temperature, the dioxane of phenol amine half fumarate or aqueous isopropanol is drawn to be placed in be full of the closed atmosphere of diffusion solvent to carry out crystallization 1 week ~ 3 weeks the tynofovir prepared according to CN103732594A Chinese mugwort, then by the crystal separation of precipitation, drying, obtain described tynofovir Chinese mugwort and draw phenol amine half fumarate crystal formation; Described diffusion solvent is volatile ethers.
7. prepare the method that the Chinese mugwort of tynofovir as claimed in claim 1 draws phenol amine half fumarate crystal formation for one kind, comprise: in room temperature, to the tynofovir prepared according to CN103732594A end draw phenol amine half fumarate to be formed in organic solvent C solution in add ethers reagent, stirring and crystallizing 3 ~ 10 days, then by the crystal separation of precipitation, drying, obtain described tynofovir Chinese mugwort and draw phenol amine half fumarate crystal formation; Described organic solvent C can be miscible with ether, is selected from one or more the mixture in C1 ~ C4 alcohol, C4 ~ C5 ester, C3 ~ C4 ketone, C5 ~ C8 alkane or naphthenic hydrocarbon, tetrahydrofuran (THF), Nitromethane 99Min., acetonitrile.
8. prepare the method that the Chinese mugwort of tynofovir as claimed in claim 1 draws phenol amine half fumarate crystal formation for one kind, comprise: the solution that draws phenol amine half fumarate to be formed under the boiling temperature of 40 DEG C ~ solvent system B in solvent system B of being ended by the tynofovir prepared according to CN103732594A is cooled to 0 ~ 30 DEG C and stirring and crystallizing 3 ~ 10 days, then by the crystal separation of precipitation, drying, obtain described tynofovir Chinese mugwort and draw phenol amine half fumarate crystal formation; Described solvent system B be selected from following any one: (1) acetonitrile; (2) mixture of acetonitrile and organic solvent D; Described organic solvent D can be miscible with acetonitrile, is selected from one or more the mixture in C1 ~ C4 alcohol, C4 ~ C5 ester, C3 ~ C4 ketone, C5 ~ C8 alkane or naphthenic hydrocarbon, tetrahydrofuran (THF), Nitromethane 99Min..
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| WO2016205141A1 (en) * | 2015-06-17 | 2016-12-22 | Gilead Sciences, Inc. | Co-crystals, salts and solid forms of tenofovir alafenamide |
| WO2017134089A1 (en) * | 2016-02-02 | 2017-08-10 | Sandoz Ag | Crystalline forms of tenofovir alafenamide monofumarate |
| CN107226826A (en) * | 2016-03-25 | 2017-10-03 | 江苏奥赛康药业股份有限公司 | Tenofovir Chinese mugwort draws phenol amine fumarate compound and its pharmaceutical composition |
| 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 |
| CN107522743A (en) * | 2017-09-30 | 2017-12-29 | 深圳科兴生物工程有限公司 | A kind of half fumaric acid tenofovir Chinese mugwort draws phenol amine industrial continuous producing method |
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| CN108070003A (en) * | 2016-12-02 | 2018-05-25 | 上海博志研新药物技术有限公司 | Tenofovir Chinese mugwort draws half fumarate crystal form of phenol amine and preparation method and application |
| 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 |
| CN108440596A (en) * | 2018-03-22 | 2018-08-24 | 山东科兴生物制品有限公司 | A kind of half fumaric acid tenofovir Chinese mugwort draws the novel preparation process of phenol amine |
| 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 |
| US10287307B2 (en) | 2017-01-31 | 2019-05-14 | Gilead Sciences, Inc. | Crystalline forms of tenofovir alafenamide |
| CN110452268A (en) * | 2019-08-21 | 2019-11-15 | 天地恒一制药股份有限公司 | A kind of preparation method of third phenol tenofovir, half fumaric acid monocrystalline |
| CN115160367A (en) * | 2022-07-01 | 2022-10-11 | 浙江美诺华药物化学有限公司 | Method for preparing tenofovir alafenamide hemifumarate single crystal under low-temperature and low-concentration conditions |
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| WO2016205141A1 (en) * | 2015-06-17 | 2016-12-22 | Gilead Sciences, Inc. | Co-crystals, salts and solid forms of tenofovir alafenamide |
| JP2018524308A (en) * | 2015-06-17 | 2018-08-30 | ギリアード サイエンシーズ， インコーポレイテッド | Co-crystals, salts and crystalline forms of tenofovir arafenamide |
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| CN107226826A (en) * | 2016-03-25 | 2017-10-03 | 江苏奥赛康药业股份有限公司 | Tenofovir Chinese mugwort draws phenol amine fumarate compound and its pharmaceutical composition |
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| CN108070003A (en) * | 2016-12-02 | 2018-05-25 | 上海博志研新药物技术有限公司 | Tenofovir Chinese mugwort draws half fumarate crystal form of phenol amine and preparation method and application |
| US11440928B2 (en) | 2017-01-31 | 2022-09-13 | Gilead Sciences, Inc. | Crystalline forms of tenofovir alafenamide |
| US10287307B2 (en) | 2017-01-31 | 2019-05-14 | Gilead Sciences, Inc. | Crystalline forms of tenofovir alafenamide |
| 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 |
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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 |
| CN110452268A (en) * | 2019-08-21 | 2019-11-15 | 天地恒一制药股份有限公司 | A kind of preparation method of third phenol tenofovir, half fumaric acid monocrystalline |
| CN115160367A (en) * | 2022-07-01 | 2022-10-11 | 浙江美诺华药物化学有限公司 | Method for preparing tenofovir alafenamide hemifumarate single crystal under low-temperature and low-concentration conditions |
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