CN107445994A - Tenofovir Chinese mugwort draws phenol amine hemifumarate novel crystal forms - Google Patents
Tenofovir Chinese mugwort draws phenol amine hemifumarate novel crystal forms Download PDFInfo
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- CN107445994A CN107445994A CN201710710348.3A CN201710710348A CN107445994A CN 107445994 A CN107445994 A CN 107445994A CN 201710710348 A CN201710710348 A CN 201710710348A CN 107445994 A CN107445994 A CN 107445994A
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- Prior art keywords
- crystal formation
- phenol amine
- bases
- tenofovir
- amine hemifumarate
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- 239000013078 crystal Substances 0.000 title claims abstract description 78
- -1 phenol amine Chemical class 0.000 title claims abstract description 35
- 229960004556 tenofovir Drugs 0.000 title claims abstract description 29
- 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 29
- 235000010894 Artemisia argyi Nutrition 0.000 title claims abstract description 13
- 244000030166 artemisia Species 0.000 title claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 60
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 11
- 150000002118 epoxides Chemical class 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 239000001294 propane Substances 0.000 claims abstract description 10
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 6
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 6
- 238000005755 formation reaction Methods 0.000 claims description 58
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 9
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims 1
- 235000004279 alanine Nutrition 0.000 claims 1
- YAVVGPBYBUYPSR-UHFFFAOYSA-N benzene;oxygen Chemical compound [O].C1=CC=CC=C1 YAVVGPBYBUYPSR-UHFFFAOYSA-N 0.000 claims 1
- BZCGWAXQDLXLQM-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O.ClP(Cl)(Cl)=O BZCGWAXQDLXLQM-UHFFFAOYSA-N 0.000 claims 1
- 238000010992 reflux Methods 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- QDQVXVRZVCTVHE-YFKPBYRVSA-N propan-2-yl (2s)-2-aminopropanoate Chemical compound CC(C)OC(=O)[C@H](C)N QDQVXVRZVCTVHE-YFKPBYRVSA-N 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000002585 base Substances 0.000 description 14
- 239000000523 sample Substances 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 238000000113 differential scanning calorimetry Methods 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 6
- 238000009396 hybridization Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 241000272525 Anas platyrhynchos Species 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- 238000002411 thermogravimetry Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 208000002672 hepatitis B Diseases 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241000725618 Duck hepatitis B virus Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 238000007707 calorimetry Methods 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 239000003298 DNA probe Substances 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 231100000288 TD50 Toxicity 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 208000016350 chronic hepatitis B virus infection Diseases 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 1
- SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
Classifications
-
- 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 Table
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Tenofovir Chinese mugwort draws phenol amine hemifumarate novel crystal forms; ended the present invention relates to a kind of tenofovir and draw phenol amine hemifumarate; chemical name is the novel crystal forms (crystal formation B) of ((S) (((base of (R) 1 (base of 6 amino 9H purine 9) propane 2) epoxide) methyl) (phenoxy group) phosphono) L alanine isopropyl ester hemifumarates; pharmaceutical preparation, their therapeutical uses and preparation method thereof comprising this crystal formation；The novel crystal forms are stable under the conditions of high temperature, high humidity etc., are easy to prepare with scale, have preferable application prospect.
Description
Technical field
The present invention relates to ((S)-((((R) -1- (6- amino -9H- purine -9- bases) propane -2- bases) epoxide) methyl) (benzene
Epoxide) phosphono)-ALANINE isopropyl ester hemifumarate novel crystal forms, the pharmaceutical preparation comprising this crystal formation, their treatment
Purposes and preparation method thereof.
Background technology
It is to be used to suppress B-mode liver by one kind of Ji Leadd B.V of U.S. research and development that tenofovir Chinese mugwort, which draws phenol amine hemifumarate,
Scorching virus drugs, U.S. FDA approval listing, trade name Vemlidy, for treating with compensatory liver are obtained in November, 2017
The patient of the chronic hepatitis B infections of disease, as a kind of efabirenz, it is the prodrug of tenofovir, and for promise
Good fortune Wei dipivoxil is compared, and is had stronger antiviral activity, can be efficiently entering lymphoid tissue.
Compound I and pharmaceutically acceptable salt and preparation method thereof are set forth in United States Patent (USP) WO2013115916A1,
Compounds process for production thereof is also set forth in United States Patent (USP) WO2016178162A1.It is with piece that tenofovir Chinese mugwort, which draws phenol amine hemifumarate,
Dosage form formula is administered orally, and for tablet, stability of crystal form and dissolubility have considerable influence to bioavilability.Pharmaceutically may be used
One requirement of the active component of receiving is that it has suitable solubility curve, this bioavilability for medicinal compound
It is an important influence factor, there are many approach to go to improve the bioavilability of medicine for those skilled in the art, than
Such as various forms of salt using the compound or the crystal formation with suitable dissolution curve.Therefore, it is possible to provide more stabilizations
Novel crystal forms be necessary and favourable.
The content of the invention
The present invention provides ((S)-((((R) -1- (6- amino -9H- purine -9- bases) propane -2- bases) oxygen represented such as Formulas I
Base) methyl) (phenoxy group) phosphono) and-ALANINE isopropyl ester hemifumarate crystal formation B.
The first aspect of the invention, there is provided tenofovir Chinese mugwort draws phenol amine hemifumarate crystal formation B, and it, which has, is included in
Characteristic XRPD peaks at 5.478 ± 0.2,21.395 ± 0.2,26.791 ± 0.2.
The first aspect of the invention, there is provided tenofovir Chinese mugwort draws phenol amine hemifumarate crystal formation B, and it, which has, is included in
5.478 ± 0.2,11.157 ± 0.2,16.042 ± 0.2,16.784 ± 0.2,17.908 ± 0.2,18.844 ± 0.2,19.70
Characteristic at ± 0.2,21.395 ± 0.2,21.949 ± 0.2,26.791 ± 0.2,27.264 ± 0.2,32.238 ± 0.2
XRPD peaks.
The first aspect of the invention, additionally provide tenofovir Chinese mugwort and draw phenol amine hemifumarate crystal formation B, it is substantially wrapped
Include the characteristic XRPD peaks shown in table 1.
Table 1
| Peak number | The angle of diffraction (2 θ) | Relative intensity | Peak number | The angle of diffraction (2 θ) | Relative intensity |
| 1 | 5.478 | 60.3 | 7 | 19.780 | 28.9 |
| 2 | 11.157 | 14.4 | 8 | 21.395 | 68.1 |
| 3 | 16.042 | 14.0 | 9 | 21.949 | 12.4 |
| 4 | 16.784 | 11.5 | 10 | 26.791 | 100 |
| 5 | 17.908 | 19.1 | 11 | 27.264 | 25.5 |
| 6 | 18.844 | 27.9 | 12 | 32.238 | 15.1 |
Crystal formation B of the present invention, it is characterised in that：The crystal formation B has DSC collection of illustrative plates and the TGA described in specification
Collection of illustrative plates.
Crystal formation B of the present invention, it is characterised in that fusing point is about 124 DEG C
The present invention provides a kind of crystal formation B methods prepared described in claim, its step：By ((S)-((((R) -1- (6-
Amino -9H- purine -9- bases) propane -2- bases) epoxide) methyl) (phenoxy group) phosphono)-ALANINE isopropyl ester (free alkali)
Its hemifumarate is obtained into salt in acetonitrile with fumaric acid, hemifumarate is then turned to crystalline substance in ethanol obtains novel crystal forms B.
Characterized in that, (1) free alkali and fumaric acid into salt ratio (mol ratio) be 2:1, solvent is acetonitrile.(2) it is second to turn brilliant solvent
Alcohol, its dosage draw 5-10 times of volume of phenol amine hemifumarate, preferably 5 times of volumes for tenofovir Chinese mugwort.
The present invention provides a kind of composition, and it includes above-mentioned crystal formation B.
The present invention is provided to prepare the method for the pharmaceutical composition for including compound of formula I, methods described is included in dissolving
State crystal formation B.
Those skilled in the art, which know and understand equipment therefor, humidity, temperature, powder crystal are orientated and are related to acquisition X- penetrates
The other parameters of line powder diffraction (XRPD) figure can cause some variabilities of outward appearance, intensity and line position in diffraction pattern.With this
The XRPD figures that text provides figure (for example, Fig. 1) " substantially consistent " are that those skilled in the art will consider to represent and provide this
The XRPD that the compound of XRPD figures (for example, Fig. 1) has mutually isomorphous compound schemes.That is, the XRPD figures can be with the figure (example
Such as, Fig. 1) it is identical or can more likely have a little difference.Such a XRPD figures can may not show each bar of diffraction pattern illustrated herein
Line, and/or outward appearance, the trickle change of intensity or the displacement of the line can be shown, it is attributed to the condition for being related to and obtaining the data
Difference.Those skilled in the art by compare XRPD figures can determine that crystalline compounds sample whether with crystal formation disclosed herein have
There is identical or different crystal formation.For example, those skilled in the art, which can end tenofovir, draws phenol amine hemifumarate sample
XRPD figures are overlapping with Fig. 1 and easily determine that whether the XRPD of the sample is schemed with Fig. 1 and replacing using this area professional skill and knowledge
Nuo Fuweiaila phenol amine hemifumarate crystal formations B XRPD figures are substantially consistent.If the XRPD figure substantially with Fig. 1 phases one
Cause, then can easily and the precise Identification sample crystal formation has and tenofovir Chinese mugwort draws phenol amine hemifumarate crystal formation B identicals crystalline substance
Type.Similarly, those skilled in the art can determine that by an XRPD figure obtain the given angle of diffraction (being represented with ° 2 θ) whether with this paper
Shown value is substantially in same position.
Brief description of the drawings
Fig. 1：Ended according to tenofovir provided by the invention and draw phenol amine hemifumarate crystal formation A (original grinds crystal formation) X ray
Powder diffraction (XRPD) figure.
Fig. 2：Being ended according to tenofovir provided by the invention draws phenol amine hemifumarate crystal formation A (original grinds crystal formation) differential to sweep
Retouch calorimetry (DSC) figure
Fig. 3：Ended according to (10 grams of batches) tenofovir provided by the invention and draw phenol amine hemifumarate crystal formation B X ray
Powder diffraction (XRPD) figure.
Fig. 4：Being ended according to (10 grams of batches) tenofovir provided by the invention draws phenol amine hemifumarate crystal formation B differential to sweep
Retouch calorimetry (DSC).
Fig. 5：Ended according to (10 grams of batches) tenofovir provided by the invention and draw phenol amine hemifumarate crystal formation B DTG
(TGA)。
Fig. 6：Ended according to (100 grams of batches) tenofovir provided by the invention and draw phenol amine hemifumarate crystal formation B X ray
Powder diffraction (XRPD) figure.
Fig. 7：Ended according to (100 grams of batches) tenofovir provided by the invention and draw phenol amine hemifumarate crystal formation B differential
Scanning calorimetry (DSC).
Fig. 8：Ended according to (500 grams of batches) tenofovir provided by the invention and draw phenol amine hemifumarate crystal formation B X ray
Powder diffraction (XRPD) figure.
Fig. 9：Ended according to (500 grams of batches) tenofovir provided by the invention and draw phenol amine hemifumarate crystal formation B differential
Scanning calorimetry (DSC).
Embodiment
The following example will be further illustrated the present invention crystal formation B preparation but do not limit as it is defined herein or under
The scope of literary the present invention for required protection, unless listing in addition outer, otherwise all temperature are degree Celsius to enumerate and all percentages
Number is all remembered with weight.
Embodiment 1：Compound I crystal A (original grinds crystal formation) preparation
1, anhydrous tenofovir (100.0g, 0.35mol) forms dirty solution with pyridine (1000mL) stirring at room temperature, adds
Triphenyl phosphite (324.0g, 1.05mol), 115 DEG C of reaction 4h of backflow are heated to, precipitation is a large amount of solid after during which first becoming clarification
Body, is cooled to 0 DEG C, adds acetone (1000mL), stirs 1.5h, filtering, and filter cake is washed with acetone (100mL), filter cake 60~
70 DEG C of dry 5h, obtain white solid ((((R) -1- (6- amino -9H- purine -9- bases) propane -2- bases) epoxide) methyl) phosphoric acid one
Phenyl ester 101.3g, yield 80.1%.
2, by the phenyl ester of ((((R) -1- (6- amino -9H- purine -9- bases) propane -2- bases) epoxide) methyl) phosphoric acid one
(80.0g, 220mmol) and toluene (500mL) mix, and add thionyl chloride (39.2g, 330mmol) 70 DEG C of reaction 24h afterwards.Subtract
Pressure adds toluene (400mL) dissolving after being concentrated to dryness, standby.To ALANINE isopropyl ester (129.6g, 990mmol) and DCM
Above-mentioned solution of acid chloride, temperature control -25~-20 DEG C, time for adding 45min are added dropwise in the solution of (500mL).Stirred below -20 DEG C
Mix at least 30min, reacting liquid temperature rise to after 19~25 DEG C once with 10% (w/w) sodium dihydrogen phosphate (2 × 400mL),
15% saleratus (2 × 200mL) and water (500mL) washing.Organic phase after anhydrous sodium sulfate drying, be concentrated under reduced pressure into it is dry,
Obtain amber grease.With toluene/acetonitrile (4:1) mixed solvent (500mL) dissolving, and addition crystal seed (10mg, 99:1 diastereomeric
Ratios of the isomers), 2h is stirred at room temperature.Filtering, filter cake toluene/acetonitrile (4:1) mixed solvent (100mL) washing, then 40 DEG C
16h is dried under reduced pressure, obtains white solid ((S)-((((R) -1- (6- amino -9H- purine -9- bases) propane -2- bases) epoxide) methyl)
(phenoxy group) phosphono)-ALANINE isopropyl ester 72.0g, yield 68.6%.
3, by ((S)-((((R) -1- (6- amino -9H- purine -9- bases) propane -2- bases) epoxide) methyl) (phenoxy group) phosphine
Acyl group)-ALANINE isopropyl ester (70.0g), acetonitrile (500mL) stirs and dissolves in 1000mL reaction bulbs.Add rich
Horse acid (8.5g), heating is opened, 75~78 DEG C is warming up to, system dissolved clarification, is cooled to 65~67 DEG C, add a small amount of crystal seed.Stirring
Heating is closed after 30min, Temperature fall, stirring and crystallizing 14h, system is cooled to -5 DEG C~0 DEG C stirring 1h, filtering, filter cake is used
A small amount of cold acetonitrile elution, drains filter cake, collects filter cake, and 40~50 DEG C are dried under reduced pressure and obtain 66.5g white solids to constant weight and replace promise good fortune
Wei Aila phenol amine hemifumarates (crystal formation A).Yield 84.8%, chemical purity 99.87%, isomers 0.04%.
Embodiment 2：Compound I crystal B preparation
1, compound I crystal B (10 grams of batches) preparation take crystal formation A tenofovir to end and draw phenol amine hemifumarate
(10.0g), ethanol (50mL) is added, stirring, being warming up to backflow (about 78 DEG C) makes it all dissolve, and is slowly dropped to room temperature crystallization 2-
3 hours, filter, 40~50 DEG C of solid is dried under reduced pressure to constant weight and obtains white solid 7.1g, yield 71.0%.
2, compound I crystal B (100 grams of batches) preparation take crystal formation A tenofovir to end and draw phenol amine hemifumarate
(100.0g), ethanol (500mL) is added, stirring, being warming up to backflow (about 78 DEG C) makes it all dissolve, and is slowly dropped to room temperature crystallization
2-3 hours, filter, 40~50 DEG C of solid is dried under reduced pressure to constant weight and obtains white solid 68.5g, yield 68.5%.
3, compound I crystal B (500 grams of batches) preparation take crystal formation A tenofovir to end and draw phenol amine hemifumarate
(500.0g), ethanol (2.5L) is added, stirring, being warming up to backflow (about 78 DEG C) makes it all dissolve, and is slowly dropped to room temperature crystallization
2-3 hours, filter, 40~50 DEG C of solid is dried under reduced pressure to constant weight and obtains white solid 351.0g, yield 70.2%.
Embodiment 3：Compound I crystal formation B sign
Fig. 3 is compound I crystal formation B X-ray powder diffraction (XRPD) figure, and display has 5.478 ± 0.2,
Characteristic XRPD peaks at 21.395 ± 0.2,26.791 ± 0.2, compound I crystal formation B is further with differential scanning calorimetry
(DSC) characterized.Fig. 4 is compound I crystal formation B differential scanning calorimetry (DSC) heating track.Compound I crystal formation B
Sample be shown in about 110 DEG C and start to absorb heat, compound I crystal formation B is further characterized with thermogravimetry (TGA),
Compound I crystal formation B sample is shown about starts weightless decomposition at 156 DEG C, and compound I crystal formation is further with melting point data
Characterized, display fusing point is about 120 DEG C.
Embodiment 4：Compound I crystal formation B stability studies
Be derived from grind raw material accelerated test (40 DEG C ± 2 DEG C, RH75% ± 5%), keep sample for a long time (25 DEG C ± 2 DEG C, RH60% ±
5%) and bulk drug is ground, carries out X-ray powder diffraction test to sample after tabletting, the results detailed in Table：
Test result indicates that：This product medicine is ground, is tested after tabletting through X-ray powder diffraction, and main 2 θ angles do not occur
Significant changes, illustrate that this product will not change in production process, in addition, this product bulk drug is accelerating 6 months, keeping sample 12 for a long time
After individual month, significant changes do not occur for main 2 θ angles, illustrate that this crystal formation is stable in storing process.
Embodiment 5, biological activity determination
The measure of 5.1 effect on hepatitics B virus in vitro activity and cytotoxicity
By Hep G 2.2.15 cell culture in the DMEM nutrient solutions containing 10% calf serum, it is inoculated in 96 orifice plates,
Cell number 3 × 104/ hole, in 5%CO2It is incubated in culture, when cell density reaches 80%, abandons old nutrient solution, add containing difference
The new nutrient solution of medicine to be measured, 200 μ l/ holes, 3 parallel holes are set；Nutrient solution was changed every 2 days.The 10th day upon administration, take
100 μ l supernatants, HBV DNA content is determined with the method for quantitative PCR, calculates 50% inhibition concentration, as IC50Value.
In 96 orifice plates for taking 100 μ l supernatants, 7.5mg/ml MTT is added, 30 μ l/ holes, continues culture 3 hours, abandons
After supernatant, the acid isopropyl alcoholic solution containing 10% tween X-100,120 μ l/ holes, with the suction at enzyme-linked instrument measure 540nm are added
Receive, calculate LC50, as CC50Value.
Experimental result is shown in Table 1.
The external hepatitis B activity of table and cytotoxicity
Note：IC50For half amount of suppression, it is worth smaller then show and suppresses the active stronger of virus
CC50For median toxic dose, its value is bigger, and explanation Drug safety is stronger.
5.2nd, Anti-HBV activity serum pharmacological research
The foundation and administration of Duck hepatitis B model：1d age south China sheldrake, foot intravenous injection DHBV positive serums, every 0.2mL,
1W metapedes venous blood samplings, detection DHBV-DNA positives are tested.Duck is divided to 3 groups at random, model group, has listed sample sets
(25mg gavages), crystal formation B groups of the present invention (25mg gavages), daily gastric infusion 1 time.
The DNA of DHBV mono- are detected：Respectively before administration and administration after 5d, 10d, 3d after drug withdrawal, detected with spot hybridization
DHBV—DNA.(1) mark of probe：DHBV-DNA probe mark uses nick-translation, by promego medicine boxs specification slightly
Change is added to carry out.(2) dot hybridization：1. point sample：Nitrocellulose filter is respectively soaked with deionized water and 10xSSC solution
30min, room temperature put film, 40 μ l/ samples, vacuum filtration after drying；2. it is denatured：Film is respectively placed in the 10min of denaturing liquid I, denaturing liquid
II 10min, denaturing liquid III 10min, the film room temperature after denaturation is dried into and puts 2h in 80 DEG C of baking boxs, is dried；3. prehybridization：Will
Film is put in 3xSSC-0.1%SDS 10mL, 65 DEG C, 30min, changes in 10xDendhart-0.1%SDS 10mL .65 DEG C, 4h mistakes
Night；4. hybridize：Abandon prehybridization solution and add people's hybridization solution, 42 DEG C after sealing, 36h~48h in hybridization bag；5. film is washed, with medical x
Line film, it is development after -70 DEG C of photosensitive 5d, fixing.The light relatively for determining hybridising band on X-ray is scanned using image analysis system
Density value (OD values)
As a result：Duck hepatitis B model DHBV-DNA level after two kinds of sample treatments has different degrees of reduction.It is wherein brilliant
For type B groups after 10d is treated, DHBV-DNA OD values significantly reduce .P compared with model group<0.05, and its antiviral effect is better than on
City's sample sets.
OD values compare (X ± S, λ=490nm) after the development of each group duck DHBV-DNA dot hybridizations
Claims (8)
1. ((S)-((((R) -1- (6- amino -9H- purine -9- bases) propane -2- bases) epoxide) methyl) (the benzene oxygen that Formulas I represents
Base) phosphono)-ALANINE isopropyl ester hemifumarate crystal formation B, it is characterised in that X-ray powder diffraction figure substantially with
Fig. 1 is consistent.
2. crystal formation B according to claim 1, it is characterised in that X-ray powder diffraction figure at least 5.478 ± 0.2,
There is characteristic diffraction peak at 21.395 ± 0.2,26.791 ± 0.2.
3. crystal formation B according to claim 1, it is characterised in that X-ray powder diffraction figure at least 5.478 ± 0.2,
11.157 ± 0.2,16.042 ± 0.2,16.784 ± 0.2,17.908 ± 0.2,18.844 ± 0.2,19.70 ± 0.2,21.395
There is characteristic diffraction peak at ± 0.2,21.949 ± 0.2,26.791 ± 0.2,27.264 ± 0.2,32.238 ± 0.2.
4. crystal formation B according to claim 1, it is characterised in that：The crystal formation B has the DSC collection of illustrative plates described in specification
With TGA collection of illustrative plates.
5. crystal formation B according to claim 1, it is characterised in that fusing point is about 124 DEG C.
6. a kind of crystal formation B methods prepared described in claim, its step include：1) tenofovir Chinese mugwort draws phenol amine hemifumarate
Crystal formation A preparation, first, tenofovir react to obtain ((((R) -1- (6- amino -9H- purine -9- bases) with triphenyl phosphite
Propane -2- bases) epoxide) methyl) one phenyl ester of phosphoric acid；Its phosphoryl chloride phosphorus oxychloride is prepared under thionyl chloride effect, it is then different with ALANINE
Propyl ester reacts to obtain ((S)-((((R) -1- (6- amino -9H- purine -9- bases) propane -2- bases) epoxide) methyl) (phenoxy group) phosphine
Acyl group)-ALANINE isopropyl ester, finally obtain tenofovir Chinese mugwort into salt with fumaric acid and draw phenol amine hemifumarate crystal formation A；2) replace
Nuo Fuweiaila phenol amine hemifumarate crystal formations B:Crystal formation A turns crystalline substance and obtains novel crystal forms B in ethanol；Characterized in that, (1) turns crystalline substance
Solvent is ethanol, and its dosage draws 5~10 times of volumes of phenol amine hemifumarate, preferably 5 times of volumes for tenofovir Chinese mugwort；(2) turn
Brilliant temperature is 40 DEG C~78 DEG C, preferably 78 DEG C of reflux temperature.
7. composition, it includes the crystal formation according to any one of claim 1-5.
8. the method for preparing the pharmaceutical composition comprising compound of formula I, methods described includes dissolving according to claim 1-6
The crystal formation of any one.
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| CN108409788A (en) * | 2018-03-12 | 2018-08-17 | 山东科兴生物制品有限公司 | A kind of fumaric acid tenofovir Chinese mugwort draws the preparation method 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 |
| WO2019130354A1 (en) * | 2017-12-30 | 2019-07-04 | Cipla Limited | Polymorphic forms of (9-[(r)-2-[[(s)-[[(s)-1- (isopropoxycarbonyl)ethyl]amino]phenoxy phosphinyl]methoxy]propyl] adenine and pharmaceutically acceptable salts thereof |
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