CN102239163A - Sunitinib and salts thereof and their polymorphs - Google Patents
Sunitinib and salts thereof and their polymorphs Download PDFInfo
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- CN102239163A CN102239163A CN2009801381205A CN200980138120A CN102239163A CN 102239163 A CN102239163 A CN 102239163A CN 2009801381205 A CN2009801381205 A CN 2009801381205A CN 200980138120 A CN200980138120 A CN 200980138120A CN 102239163 A CN102239163 A CN 102239163A
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- sutent
- acetate
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- 239000002147 L01XE04 - Sunitinib Substances 0.000 title claims abstract description 361
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 title claims abstract description 150
- 229960001796 sunitinib Drugs 0.000 title claims abstract description 149
- 150000003839 salts Chemical class 0.000 title description 17
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical group OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 claims abstract description 212
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims abstract description 139
- 229940034785 sutent Drugs 0.000 claims description 212
- 239000000203 mixture Substances 0.000 claims description 191
- 239000003513 alkali Substances 0.000 claims description 145
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 138
- 239000002253 acid Substances 0.000 claims description 137
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 127
- 238000000034 method Methods 0.000 claims description 74
- 229940116298 l- malic acid Drugs 0.000 claims description 73
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 69
- 238000002360 preparation method Methods 0.000 claims description 61
- 239000007787 solid Substances 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 39
- 239000000725 suspension Substances 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 38
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 26
- 238000001556 precipitation Methods 0.000 claims description 26
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 238000002425 crystallisation Methods 0.000 claims description 14
- 230000008025 crystallization Effects 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 239000012296 anti-solvent Substances 0.000 claims description 8
- 238000006073 displacement reaction Methods 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 238000001757 thermogravimetry curve Methods 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
- 229940043232 butyl acetate Drugs 0.000 claims description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 5
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 73
- 238000003756 stirring Methods 0.000 description 41
- 229960004756 ethanol Drugs 0.000 description 30
- 238000001291 vacuum drying Methods 0.000 description 25
- 239000000843 powder Substances 0.000 description 24
- 238000005406 washing Methods 0.000 description 23
- 238000001035 drying Methods 0.000 description 21
- 238000001914 filtration Methods 0.000 description 21
- 238000010438 heat treatment Methods 0.000 description 13
- -1 sunitinib salt Chemical class 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 229960000935 dehydrated alcohol Drugs 0.000 description 9
- 238000011084 recovery Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000005303 weighing Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000004570 mortar (masonry) Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 238000005004 MAS NMR spectroscopy Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 229960003685 imatinib mesylate Drugs 0.000 description 2
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000000247 postprecipitation Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000001622 two pulse phase modulation pulse sequence Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 0 C*(C)C(CC(O)=O)(N)N Chemical compound C*(C)C(CC(O)=O)(N)N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 238000012565 NMR experiment Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
- 229920003080 Povidone K 25 Polymers 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000001875 carbon-13 cross-polarisation magic angle spinning nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000006059 cover glass Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 238000005388 cross polarization Methods 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- ZICQBHNGXDOVJF-UHFFFAOYSA-N diamantane Chemical compound C1C2C3CC(C4)CC2C2C4C3CC1C2 ZICQBHNGXDOVJF-UHFFFAOYSA-N 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000007887 hard shell capsule Substances 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- XEBWQGVWTUSTLN-UHFFFAOYSA-M phenylmercury acetate Chemical compound CC(=O)O[Hg]C1=CC=CC=C1 XEBWQGVWTUSTLN-UHFFFAOYSA-M 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229920000774 poly(2-methoxyaniline-5-sulfonic acid) polymer Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229960002812 sunitinib malate Drugs 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Polymorphs of sunitinib acetate and sunitinib base and sunitinib malate form 1 have been prepared and described.
Description
The cross reference of related application
The sequence number 61/137 that the application submitted on July 24th, 1; 005; the sequence number 61/086 that on August 6th, 2008 submitted to; 589; the sequence number 61/087 that on August 11st, 2008 submitted to; 859; the sequence number 61/088 that on August 14th, 2008 submitted to; 961; the sequence number 61/088 that on August 14th, 2008 submitted to; 998; the sequence number 61/094 that on September 4th, 2008 submitted to; 341; the sequence number 61/097 that on September 17th, 2008 submitted to; 592; the sequence number 61/105 that on October 14th, 2008 submitted to; 154; the sequence number 61/108 that on October 24th, 2008 submitted to; 078; the sequence number 61/113 that on November 10th, 2008 submitted to; 044; the sequence number 61/141 that on December 30th, 2008 submitted to; 385; the sequence number 61/164 that on March 30th, 2009 submitted to; the sequence number 61/177 that on May 13rd, 542 and 2009 submitted to; the rights and interests of 717 U.S. Provisional Patent Application, above-mentioned application is incorporated herein by reference.
Invention field
The present invention relates to acetate Sutent (sunitinib acetate) polymorph and sunitinib alkali (sunitinib base), their preparation method and the method that is used to prepare oxysuccinic acid Sutent (sunitinib malate) crystalline form 1.
Background of invention
The sunitinib alkali of following formula, N-[2-(diethylamino) ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo--3H-indoles-3-subunit) methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide:
Can be used as for example intermediate of the oxysuccinic acid Sutent of following formula of preparation Sutent salt (sunitinib salt):
The oxysuccinic acid Sutent is the many kinase inhibitor in U.S.'s listing, and (Pfizer Inc) produces, and commodity are called SUTENT by Pfizer for it
SUTENT
Ratify to be used for the treatment of or do not tolerate matter cancer and treatment renal cell carcinoma in late period between imatinib mesylate (imatinib mesylate) gi tract afterwards by FDA at disease progression.SUTENT
Hard-shell capsule for the oxysuccinic acid Sutent that contains following amount: described amount is equivalent to the Sutent of 12.5mg, 25mg or 50mg.Capsule comprises the oxysuccinic acid Sutent, and non-active ingredient N.F,USP MANNITOL, croscarmellose sodium, Povidone (K-25) and Magnesium Stearate.
U.S. Patent number 6,573,293 (" 293 patents ") relate to the preparation of sunitinib alkali and salt thereof and the purposes of these salt.' 293 patent relate to by in the presence of tetramethyleneimine in ethanol condensation 5-formyl radical-2,4-1H-pyrroles-3-carboxylic acid (2-diethylamino ethyl) acid amides and 5-fluoro-1, the 3-dihydro-indol-2-one synthesizes sunitinib alkali.Referring to ' 293 patent, col.204, ll.33-50 (embodiment 80, alternative synthesis method).Separate from reaction mixture by filtering the sunitinib alkali that will prepare thus, use washing with alcohol, pulp in ethanol separates by filtering from slurry, uses washing with alcohol, and vacuum-drying obtains orange solids then.Referring to existing together.
U.S. Patent number 7,119,209 (" ' 209 patents ") also relate to the preparation of sunitinib alkali.' 209 patent relates to by making 4-(1H-imidazoles-1-base carbonyl)-3, and 5-dimethyl-1H-pyrrole-2-aldehyde, N, N-diethyl ethylenediamine and 5-fluorine oxindole react in acetonitrile in the presence of triethylamine and prepare sunitinib alkali.Referring to ' 209 patent, col.15, ll.1-36.Separate from reaction mixture by filtering the sunitinib alkali that will prepare thus, with the acetonitrile washing, and vacuum-drying.
U.S. Patent Publication No. 2003/0069298 and U.S. Patent Publication No. 2007/0191458 relate to by making sunitinib alkali, L MALIC ACID and solvent reaction prepare the L MALIC ACID Sutent.In addition, above-mentioned patent also discloses its crystalline form I (this paper is also referred to as " crystalline form 1 ") and II.
Oxysuccinic acid Sutent crystalline form I is characterised in that the diffraction peak at about 13.2 and 24.2 degree 2 θ places, more preferably in the diffraction peak at about 13.2,19.4,24.2 and 25.5 degree 2 θ places, most preferably as in table 1 to the diffraction peak in the listed x-ray diffractogram of powder of crystalline form I.
The invention provides: a kind of new salt of Sutent, i.e. acetate Sutent, it can be used as the useful intermediates of preparation oxysuccinic acid Sutent; The preparation method of above-mentioned salt and the method that is translated into oxysuccinic acid Sutent crystalline form 1.In addition, the invention provides other method of preparation oxysuccinic acid Sutent crystalline form 1.
Summary of the invention
In one embodiment, oxysuccinic acid Sutent crystalline form 1 can be by following method preparation, and this method comprises reacts sunitinib alkali, weak acid and L MALIC ACID in the mixture of alcohol or water and alcohol, and precipitates described oxysuccinic acid Sutent crystalline form 1.
In another embodiment, the present invention includes the acetate Sutent.
In yet another embodiment, the present invention includes to be selected from the acetate Sutent crystalline form that following data are feature: the PXRD figure that the peak is arranged at about 5.1,9.6,10.2,12.8 and 16.9 ± 0.2 degree 2 θ places; PXRD figure shown in Figure 12; About 165.2,134.5,130.4,118.7,115.7,112.5 and 110.9 ± 0.2ppm place the solid-state of signal arranged
13C NMR spectrum; In the chemical shift range of 100-180ppm, presenting and having about 63.6,32.9,28.8,17.1,14.1,10.8 and the chemical shift difference of 9.2 ± 0.1ppm solid-state between the signal that minimizes displacement study and another signal
13C NMR spectrum; Shown in Figure 20 is solid-state
13C NMR spectrum and their combination.
In one embodiment, the present invention includes to be selected from the acetate Sutent crystalline form that following data are feature: the PXRD figure that the peak is arranged at about 6.1,11.0,15.8,16.4 and 20.2 ± 0.2 degree 2 θ places; PXRD figure shown in Figure 17; About 166.1,133.0,119.0,114.5,109.9 and 108.6 ± 0.2ppm place the solid-state of signal arranged
13C NMR spectrum; In the chemical shift range of 100-180ppm, presenting and having about 65.0,31.9,17.9,13.4,8.8 and the chemical shift difference of 7.5 ± 0.1ppm solid-state between the signal that minimizes displacement study and another signal
13C NMR spectrum; Shown in Figure 21 is solid-state
13C NMR spectrum and their combination.
In another embodiment, the present invention includes above-mentioned acetate Sutent and crystalline form thereof the purposes in preparation oxysuccinic acid Sutent.
In yet another embodiment, the present invention includes the method for preparing the oxysuccinic acid Sutent, this method comprises according to method of the present invention and prepares crystallization acetate Sutent and convert it into the oxysuccinic acid Sutent.
In one embodiment, the present invention includes preparation is the method for the mold cavity tartaric acid Sutent of feature with about 13.2 and 24.2 diffraction peaks of spending 2 θ places, and this method comprises provides the mixture that comprises the oxysuccinic acid Sutent and be selected from following solvent: pyridine, two
The mixture of mixture, Virahol, NMP and the n-propyl alcohol of the mixture of the mixture of alkane, butylacetate, ethyl acetate, dimethyl formamide, N,N-DIMETHYLACETAMIDE and n-propyl alcohol, N-methyl-pyrrolidone (" NMP ") and toluene, dimethyl sulfoxide (DMSO) (" DMSO "), DMSO and ethyl acetate, mixture, water, ethanol and the acetone three's of first alcohol and water mixture, NMP, 2-methyltetrahydrofuran, water, ethanol, methyl alcohol and their mixture.
In another embodiment, the present invention includes preparation is the method for the mold cavity tartaric acid Sutent of feature with about 13.2 and 24.2 diffraction peaks of spending 2 θ places, it is included in to suspend in methyl alcohol, ethanol or the water and is selected from the following composition that comprises sunitinib alkali and L MALIC ACID: to be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD at the peak of the position that is selected from 6.0,7.7,9.1,10.1,12.0,14.5,23.4 and 27.1 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 3; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 4 at the peak of the position that is selected from 6.2,7.7,9.3,12.4,14.5,23.2 and 27.4 ± 0.2 degree, 2 θ; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 5 at the peak of the position that is selected from 6.0,7.8,9.0,12.0,14.8,18.0,22.5 and 27.1 ± 0.2 degree, 2 θ; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD figure and the figure of PXRD as shown in Figure 5 at the peak of the position that is selected from 6.0,7.8,9.0,12.0,14.8,18.0,22.5 and 27.1 ± 0.2 degree, 2 θ; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 6 at the peak of the position that is selected from 6.0,7.7,9.2,12.2,14.5,22.9 and 27.3 ± 0.2 degree, 2 θ; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 7 at the peak of the position that is selected from 11.4,14.4,23.4,24.1 and 27.0 ± 0.2 degree, 2 θ; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 8 at the peak of the position that is selected from 5.9,8.9,11.8,20.6,22.6 and 27.3 ± 0.2 degree, 2 θ; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 10 at the peak of the position that is selected from 6.0,7.4,8.9,11.9,23.4 and 27.7 ± 0.2 degree, 2 θ; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 11 at the peak of the position that is selected from 6.1,7.9,9.2,12.1,15.2,22.9 and 27.7 ± 0.2 degree, 2 θ; And their mixture, wherein, when solvent is methyl alcohol or ethanol, described composition is selected from: to be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD at the peak of the position that is selected from 6.0,7.7,9.1,10.1,12.0,14.5,23.4 and 27.1 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 3; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 4 at the peak of the position that is selected from 6.2,7.7,9.3,12.4,14.5,23.2 and 27.4 ± 0.2 degree, 2 θ; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 5 at the peak of the position that is selected from 6.0,7.8,9.0,12.0,14.8,18.0,22.5 and 27.1 ± 0.2 degree, 2 θ; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 6 at the peak of the position that is selected from 6.0,7.7,9.2,12.2,14.5,22.9 and 27.3 ± 0.2 degree, 2 θ; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 7 at the peak of the position that is selected from 11.4,14.4,23.4,24.1 and 27.0 ± 0.2 degree, 2 θ; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 8 at the peak of the position that is selected from 5.9,8.9,11.8,20.6,22.6 and 27.3 ± 0.2 degree, 2 θ; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 10 at the peak of the position that is selected from 6.0,7.4,8.9,11.9,23.4 and 27.7 ± 0.2 degree, 2 θ; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 11 at the peak of the position that is selected from 6.1,7.9,9.2,12.1,15.2,22.9 and 27.7 ± 0.2 degree, 2 θ; And their mixture, and when solvent is water, described composition is selected from: to be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD at the peak of the position that is selected from 6.0,7.8,9.0,12.0,14.8,18.0,22.5 and 27.1 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 5; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 6 at the peak of the position that is selected from 6.0,7.7,9.2,12.2,14.5,22.9 and 27.3 ± 0.2 degree, 2 θ; To be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD and scheme and PXRD figure shown in Figure 7 at the peak of the position that is selected from 11.4,14.4,23.4,24.1 and 27.0 ± 0.2 degree, 2 θ; And their mixture.
The accompanying drawing summary
Fig. 1 shows the x-ray diffractogram of powder of the composition L that comprises sunitinib alkali and L MALIC ACID.
Fig. 2 shows the powder X-ray RD figure of sunitinib alkali crystalline form VIII.
Fig. 3 shows the x-ray diffractogram of powder of the composition F that comprises sunitinib alkali and L MALIC ACID.
Fig. 4 shows the x-ray diffractogram of powder of the composition G that comprises sunitinib alkali and L MALIC ACID.
Fig. 5 shows the x-ray diffractogram of powder of the composition H that comprises sunitinib alkali and L MALIC ACID.
Fig. 6 shows the x-ray diffractogram of powder of the composition I that comprises sunitinib alkali and L MALIC ACID.
Fig. 7 shows the x-ray diffractogram of powder of the composition K that comprises sunitinib alkali and L MALIC ACID.
Fig. 8 shows the x-ray diffractogram of powder of the composition Q that comprises sunitinib alkali and L MALIC ACID.
Fig. 9 shows the x-ray diffractogram of powder of oxysuccinic acid Sutent crystalline form 1.
Figure 10 shows the x-ray diffractogram of powder of the composition O that comprises sunitinib alkali and L MALIC ACID.
Figure 11 shows the x-ray diffractogram of powder of the composition P that comprises sunitinib alkali and L MALIC ACID.
Figure 12 shows the x-ray diffractogram of powder of acetate Sutent crystalline form α.
Figure 13 shows the DSC thermogram of acetate Sutent crystalline form α.
Figure 14 shows the TGA thermogram of acetate Sutent crystalline form α.
Figure 15 shows that the whole width of acetate Sutent crystalline form α is solid-state
13C NMR spectrum.
Figure 16 shows that acetate Sutent crystalline form α's is solid-state in detail
13C NMR spectrum.
Figure 17 shows the x-ray diffractogram of powder of acetate Sutent crystalline form β.
Figure 18 shows the DSC thermogram of acetate Sutent crystalline form β.
Figure 19 shows the TGA thermogram of acetate Sutent crystalline form β.
Figure 20 shows that the whole width of acetate Sutent crystalline form β is solid-state
13C NMR spectrum.
Figure 21 shows that acetate Sutent crystalline form β's is solid-state in detail
13C NMR spectrum.
Figure 22 shows the x-ray diffractogram of powder of sunitinib alkali crystalline form XX.
Figure 23 shows the x-ray diffractogram of powder of sunitinib alkali crystalline form XXI.
Figure 24 shows the x-ray diffractogram of powder of sunitinib alkali crystalline form XXII.
Detailed Description Of The Invention
Term used herein " oxysuccinic acid Sutent crystalline form 1 " is meant that with about 13.2 and 24.2 degree 2 θ places more preferably the diffraction peak with about 13.2,19.4,24.2 and 25.5 degree 2 θ places is the crystalline form of feature.
Term used herein " composition L " is meant to be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 in the PXRD figure at the peak of the position that is selected from 6.2,7.6,9.3,12.4,14.6,22.9 and 27.4 ± 0.2 degree, 2 θ, PXRD figure and their combination shown in Figure 1.
Term used herein " sunitinib alkali crystalline form VIII " is meant to be selected from the crystallization sunitinib alkali that following data are feature: have any 5 PXRD at the peak of the position that is selected from 3.8,7.6,8.5,9.5,10.4,11.4,16.5,17.8,20.6 and 27.0 degree ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 2.
Term used herein " composition F " is meant to be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD at the peak of the position that is selected from 6.0,7.7,9.1,10.1,12.0,14.5,23.4 and 27.1 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 3.
Term used herein " composition G " is meant to be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD at the peak of the position that is selected from 6.2,7.7,9.3,12.4,14.5,23.2 and 27.4 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 4.
Term used herein " composition H " is meant to be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD at the peak of the position that is selected from 6.0,7.8,9.0,12.0,14.8,18.0,22.5 and 27.1 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 5.
Term used herein " composition I " is meant to be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD at the peak of the position that is selected from 6.0,7.7,9.2,12.2,14.5,22.9 and 27.3 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 6.
Term used herein " composition K " is meant to be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD at the peak of the position that is selected from 11.4,14.4,23.4,24.1 and 27.0 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 7.
Term used herein " composition Q " is meant to be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD at the peak of the position that is selected from 5.9,8.9,11.8,20.6,22.6 and 27.3 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 8.
Term used herein " composition O " is meant to be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD at the peak of the position that is selected from 6.0,7.4,8.9,11.9,23.4 and 27.7 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 10.
Term used herein " composition P " is meant to be selected from the composition that comprises sunitinib alkali and L MALIC ACID that following data are feature: have any 5 PXRD at the peak of the position that is selected from 6.1,7.9,9.2,12.1,15.2,22.9 and 27.7 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 11.
Term used herein " room temperature " or " envrionment temperature " be meant about 15 ℃ to about 30 ℃ temperature, more preferably refer to about 20 ℃ to about 25 ℃ temperature.
The invention provides: a kind of new salt of Sutent, i.e. acetate Sutent, it can be used as the useful intermediates of preparation oxysuccinic acid Sutent; The preparation method of above-mentioned salt; And the method that above-mentioned salt is converted into oxysuccinic acid Sutent crystalline form 1.
The applicant has found that it is favourable preparing the oxysuccinic acid Sutent by the acetate Sutent, because the acetate Sutent is solvable, but and even need not to make it change into the oxysuccinic acid Sutent with regard to original position under the isolating situation.In addition, also the acetate Sutent can be separated as crystalline solid, this is favourable, because this helps purifying, separation and processing usually.
First method provided by the invention by other additive salt for example the acetate Sutent carry out producing the oxysuccinic acid Sutent under the isolating situation of these salt need not.
In one embodiment, oxysuccinic acid Sutent crystalline form 1 can be by following method preparation, and this method comprises makes sunitinib alkali, weak acid and L MALIC ACID react and precipitate described oxysuccinic acid Sutent crystalline form 1 in the mixture of alcohol or water and alcohol.
Term used herein " weak acid " be meant the pKa value for about 3.40 to about 9.50, be preferably about 3.40 to about 6.00, about 3.40 acid more preferably.
Usually, the reaction between sunitinib alkali and the weak acid obtains the acid salt (acid addition salt) of Sutent.Preferably, mix the mixture of sunitinib alkali, weak acid and alcohol or water and alcohol,, preferably heat this first solution to obtain first solution.
Preferably be heated to about 40 ℃ to about 60 ℃ temperature.
Preferred weak acid is selected from: acetate, formic acid, xitix, phenylformic acid, succsinic acid, butanic acid, propionic acid (proionic acid) and boric acid.More preferably weak acid is acetate or formic acid.Most preferably weak acid is acetate.
The acid salt of preferred Sutent is acetate Sutent or formic acid Sutent (sunitinib formate).
Preferred described alcohol is selected from methyl alcohol, ethanol and Virahol, more preferably ethanol.
Usually, this acid salt is soluble in above-mentioned solvent, and also dissolves in other solvent that those of ordinary skills can expect.If needed, can from solution, reclaim this acid salt, for example by precipitation and filtration.With isolated acid salt with before L MALIC ACID mixes, it can be dissolved in the above-mentioned solvent.
Further, then preferably first solution is mixed with L MALIC ACID, to obtain second solution.
Preferably obtain this second solution, or obtain in opposite mode by first solution is added in the alcoholic solution that contains L MALIC ACID.
Preferably about 40 ℃ to about 70 ℃ temperature, more preferably from about 55 ℃ to about 65 ℃ temperature, most preferably from about finishes adding under 60 ℃ the temperature.
Can by keep the about 10-of described solution about 30 minutes, more preferably from about 10-precipitated in about 15 minutes.Preferably, solution is maintained at about under 60 ℃ the temperature.Usually, precipitation forms suspension.
Preferably after precipitation, can further cool off gained suspension to about 10 ℃ to about 0 ℃ temperature, more preferably arrive about 5 ℃ of about 0 ℃ temperature extremely, optimum is chosen about 0 ℃ temperature.
Preferably about 1 hour to about 6 hours, more preferably about 1.5 hours to about 2.5 hours, most preferably within about 2 hours, finish cooling.
In addition, before reclaiming described crystalline form, also can under such temperature, continue to keep through refrigerative suspension.The preferred maintenance about 0.5 hour to about 5 hours, more preferably from about 1 hour to about 3 hours, most preferably from about 1 hour.
The method for preparing described oxysuccinic acid Sutent crystalline form 1 can further comprise from the described crystalline form of suspension recovery.Can for example reclaim by filtering suspension liquid, washing precipitation and drying.
Preferably use washing with alcohol.Usually, preferably about 45 ℃ to about 80 ℃, more preferably carry out drying in the vacuum drying oven to about 50 ℃ of temperature.The preferred dry time length is about 1 hour to about 24 hours, more preferably about 16 to about 18 hours, most preferably is about 18 hours.A kind of new salt of Sutent also is provided as previously mentioned.
In one embodiment, the present invention includes the acetate Sutent.
In a preferred embodiment, provide the acetate Sutent with unpack format.The acetate Sutent of preferable separation is a solid, and more preferably it is crystallization.The term " isolating " of mentioning the acetate Sutent used herein is corresponding to the acetate Sutent that separates physically with the reaction mixture that forms it.
This paper has reported two kinds of crystalline forms of acetate Sutent.
First kind of crystalline form of acetate Sutent is feature to be selected from following data: have at about 5.1,9.6,10.2,12.8 and 16.9 ± 0.2 degree 2 θ places the PXRD figure at peak, PXRD shown in Figure 12 scheme, about 165.2,134.5,130.4,118.7,115.7,112.5 and 110.9 ± 0.2ppm place the solid-state of signal arranged
13C NMR spectrum, in the chemical shift range of 100-180ppm, presenting and have about 63.6,32.9,28.8,17.1,14.1,10.8 and the chemical shift difference of 9.2 ± 0.1ppm solid-state between the signal that minimizes displacement study and another signal
13C NMR spectrum, shown in Figure 20 solid-state
13C NMR spectrum, and their combination.This crystalline form can be described as crystalline form α.
Usually, presenting the signal that minimizes displacement study in the chemical shift range of 100-180ppm is at about 101.6 ± 1.0ppm place.
Acetate Sutent crystalline form α can be a feature to be selected from following data further: have at about 17.4,17.7,23.1,26.0 and 27.0 ± 0.2 degree 2 θ places that the PXRD at peak schemes, DSC thermogram shown in Figure 13 and a TGA thermogram shown in Figure 14.
Acetate Sutent crystalline form α is the acetic acid solvent thing of acetate Sutent.Preferably the amount of the acetate of being measured by TGA is about 20% to about 26% weight, and more preferably about 22% to 24% weight most preferably is about 23% weight.
Second kind of crystalline form of acetate Sutent is feature to be selected from following data: have at about 6.1,11.0,15.8,16.4 and 20.2 ± 0.2 degree 2 θ places the PXRD figure at peak, PXRD shown in Figure 17 scheme, about 166.1,133.0,119.0,114.5,109.9 and 108.6 ± 0.2ppm place the solid-state of signal arranged
13C NMR spectrum, in the chemical shift range of 100-180ppm, presenting and have about 65.0,31.9,17.9,13.4,8.8 and the chemical shift difference of 7.5 ± 0.1ppm solid-state between the signal that minimizes displacement study and another signal
13C NMR spectrum, shown in Figure 21 solid-state
13C MR spectrum and their combination.This crystalline form can be called crystalline form β.
Usually, presenting the signal that minimizes displacement study in the chemical shift range of 100-180ppm is at about 101.1 ± 1.0ppm place.
The acetate Sutent that is called crystalline form β can be a feature to be selected from following data further: have at about 9.1,18.2,24.4,25.0 and 29.3 ± 0.2 degree 2 θ places that the PXRD at peak schemes, DSC thermogram shown in Figure 180 and a TGA thermogram shown in Figure 19.
Acetate Sutent crystalline form β is anhydrous.
Preferably the amount of acetate is about 11% to about 15% weight among the acetate Sutent crystalline form β that is measured by TGA, and more preferably about 12% to 14% weight most preferably is about 13% weight.
The above-mentioned crystalline form of acetate Sutent can be by following method preparation, this method comprises provides the mixture that comprises sunitinib alkali, acetate and solvent, wherein crystallization acetate Sutent is precipitated out from this mixture, when the acetate that uses more than about 5 molar equivalents of the sunitinib alkali of every molar equivalent, obtain crystalline form α, and when the acetate of about 2 molar equivalents of about 1-of the sunitinib alkali that uses every molar equivalent, obtain crystalline form β.
Usually, by sunitinib alkali and the acetate solution in solvent is provided, is settled out described crystalline form then and obtains described mixture.
Solution can prepare by being dissolved into isolating sunitinib alkali in the solvent and mixing with acetate, or mixes with acetate by the reaction mixture that will form sunitinib alkali and to prepare; Preferred described mixture also comprises solvent.This mixture can preferably provide by making the reaction of Sutent chloride derivative and 2-diethylamino ethamine produce sunitinib alkali.
Preferred solvent is selected from the mixture of mixture, propyl carbinol and MTBE of mixture, ethanol and MTBE of propyl carbinol, diisopropyl ether and methyl tertiary butyl ether (" MTBE ") and their combination.
Preferably when the about 14 molar equivalent acetate of the about 5-that uses every molar equivalent sunitinib alkali, obtain crystalline form α.
Chose wantonly before causing precipitation, solution can be heated to about 45 ℃ to about 65 ℃, 60 ℃ of about 50 ℃ temperature extremely more preferably from about.
Can by keep described solution or add anti-solvent (anti solvent) to described solution for example among the MTBE or add anti-solvent then cooling cause precipitation.
The preferred maintenance is to finish by stirring about 60 minutes time of described solution, is settled out crystalline form during this period.
Preferably be cooled to temperature for making an appointment with-15 ℃ to about 5 ℃, more preferably extremely making an appointment with-10 ℃.
Preferably at post precipitation, can further cool off described solution to-15 ℃ to about 5 ℃ approximately, more preferably to the temperature of-10 ℃ of pacts.
The method of the crystalline form of preparation acetate Sutent can further comprise from the described crystalline form of suspension recovery.Suspension, washing and drying that recovery can be for example comprises acetate Sutent crystalline form α by filtration are finished.Preferably use methyl tertiary butyl ether (" MTBE ") to wash.Preferably carry out air-dry.Preferred drying be about 20 ℃ to about 25 ℃, more preferably from about carry out under 20 ℃ the temperature.The preferred dry time length is about 1 to 12 hour, more preferably about 1 to about 3 hours.
Can be further with the crystalline form α that obtains and β in MTBE pulp with the described crystalline form of purifying.
Acetate Sutent and crystalline form thereof can be used for preparing the oxysuccinic acid Sutent, and preferred preparation oxysuccinic acid Sutent crystalline form 1 is for example shown below.
In another embodiment, the present invention includes the method for preparing the oxysuccinic acid Sutent, this method comprises that foundation method of the present invention prepares acetate Sutent and crystalline form thereof, and they are changed into the oxysuccinic acid Sutent, and example is as mentioned above.Preferred acetate Sutent and crystalline form thereof are that any embodiment according to the inventive method prepares.
The oxysuccinic acid Sutent that obtains is feature (" crystalline form 1 ") with the diffraction peak at about 13.2 and 24.2 degree 2 θ places.
In addition, crystalline form 1 can be by another kind of method preparation, and this method comprises provides the mixture that comprises the oxysuccinic acid Sutent and be selected from following solvent: pyridine, two
The mixture of mixture, Virahol, NMP and the n-propyl alcohol of the mixture of the mixture of alkane, butylacetate, ethyl acetate, dimethyl formamide, N,N-DIMETHYLACETAMIDE and n-propyl alcohol, N-methyl-pyrrolidone (" NMP ") and toluene, dimethyl sulfoxide (DMSO) (" DMSO "), DMSO and ethyl acetate, mixture, water, ethanol and the acetone three's of first alcohol and water mixture, NMP, 2-methyltetrahydrofuran, water, ethanol, methyl alcohol and their mixture.
In a preferred embodiment, be selected from when solvent: two
When alkane, butylacetate, ethyl acetate or their mixture, described mixture is preferably suspension, and it is provided by following method, and this method is included in the described suspension that sunitinib alkali and oxysuccinic acid is reacted obtain to comprise described crystalline form.
At first, sunitinib alkali, oxysuccinic acid and solvent mentioned above are produced suspension.Add hot suspension then to obtain to comprise the described mixture of oxysuccinic acid Sutent crystalline form 1.Preferably being heated to temperature is about 60 ℃ to about 120 ℃.
Chose wantonly before reclaiming oxysuccinic acid Sutent crystalline form 1, cool off described mixture.Preferably be cooled to about 25 ℃ to about 20 ℃ temperature.
In another preferred embodiment, when solvent was pyridine, described mixture was a solution, and it makes the method for sunitinib alkali and oxysuccinic acid reaction provide by being included in pyridine.
Preferably before reacting, sunitinib alkali is dissolved in the pyridine with oxysuccinic acid.
The preferred dissolving of sunitinib alkali in pyridine is to carry out under about 95 ℃ to 105 ℃ temperature.More preferably dissolving is to carry out under about 100 ℃ temperature.
Then solution is mixed with oxysuccinic acid, preferably mix with L MALIC ACID so that second solution to be provided.From the solution that produces described mixture, be settled out crystalline form 1 then, reclaim crystalline form 1 from described mixture.
Preferably by keeping second solution to come induced precipitation.Preferably under about 20 ℃ temperature, keep solution, preferably the time that continues to spend the night approximately.
In another preferred embodiment, when solvent was the mixture of first alcohol and water, described mixture was preferably suspension, and it makes the method for sunitinib alkali and oxysuccinic acid reaction provide by being included in described solvent.
At first, sunitinib alkali is suspended in the methyl alcohol, then suspension is mixed producing second suspension with oxysuccinic acid, from this second suspension recovery crystalline form 1.Preferably the form with the aqueous solution adds oxysuccinic acid.
Reaction between preferred sunitinib alkali and the oxysuccinic acid is at room temperature finished.
In another embodiment, when solvent is selected from: when the mixture of the mixture of N,N-DIMETHYLACETAMIDE and n-propyl alcohol, N-methyl-pyrrolidone (" NMP ") and toluene and the mixture of N-methyl-pyrrolidone (" NMP ") and n-propyl alcohol, described mixture makes sunitinib alkali and oxysuccinic acid reaction provide with the method that produces the oxysuccinic acid Sutent by being included in the described solvent, by described solution and the anti-solvent that is selected from n-propyl alcohol, toluene, ethyl acetate and their mixture are settled out the oxysuccinic acid Sutent.
The preferred crystalline form 1 that is settled out that reclaims subsequently.
Preferably sunitinib alkali, solvent and oxysuccinic acid are mixed obtaining mixture, optional this mixture of postheating, thus obtain described solution.Preferably be heated to about 35 ℃ to about 60 ℃ temperature.More preferably be heated to about 40 ℃ temperature.
Further, anti-solvent is added in the solution to obtain described mixture as suspension.Preferably about 35 ℃ to about 40 ℃ temperature, more preferably to about 40 ℃ temperature, add anti-solvent at about 20 ℃.
Choose wantonly under uniform temp and to keep about 30 minutes of suspension to about 3 hours time.The time that more preferably keeps about 1-1.5 hour.Most preferably keep about 1 hour time.
Then, before reclaiming described crystalline form, described suspension is cooled to about 10 ℃ to about 0 ℃, more preferably arrives about 0 ℃ temperature.
In another preferred embodiment, when solvent is the combination of water, ethanol and acetone, as the described mixture of suspension by comprising from oxysuccinic acid Sutent crystalline method being provided as the water of solvent and the mixture as the ethanol of anti-solvent and acetone mixture.
At first, the oxysuccinic acid Sutent is dissolved into produces solution in the water.Then add ethanol and acetone and in solution, produce second solution, the crystalline form 1 of oxysuccinic acid Sutent is come out from this second solution precipitation, it can be reclaimed subsequently.
Can keep second solution to be precipitated out to allow oxysuccinic acid Sutent crystalline form 1.Preferably under about 40 ℃ temperature, keep described solution, the preferably time that continues to spend the night approximately.
In another preferred embodiment, when solvent is N-methyl-pyrrolidone (" NMP "), by comprising oxysuccinic acid Sutent crystalline method is provided as the described mixture of suspension.
At first, the oxysuccinic acid Sutent is dissolved into generation solution in N-methyl-pyrrolidone (" NMP ").Preferably finish dissolving by being heated to about 100 ℃ temperature.
The solution cooling that preferably will heat is precipitated out with the crystalline form 1 that allows the oxysuccinic acid Sutent.
The time that preferred precipitation continues to spend the night approximately.
The aforesaid method for preparing described oxysuccinic acid Sutent crystalline form 1 can further comprise from described mixture recovery oxysuccinic acid Sutent crystalline form 1.Recovery can for example be finished by filtering mixt and drying.Preferably to about 70 ℃ temperature, carry out drying, preferably continue about 16 hours to about 20 hours time at about 40 ℃.
In another preferred embodiment, when solvent is selected from: when water, methyl alcohol, ethanol and their mixture, described mixture is by comprising that the method with comprising composition L pulp in described solvent of sunitinib alkali and L MALIC ACID provides.
Preferably before reclaiming crystalline form, slurries are kept about 3 days time.The preferred slurry that keeps desolvates up to removing fully.
In another preferred embodiment, when solvent is methyl alcohol, described mixture also can be provided by following method: described method comprise mix powdery crystallization sunitinib alkali crystalline form VIII and powdery crystallization L MALIC ACID with the mixture that obtains two kinds of powder and with described mixed powder and methanol mixed with acquisition oxysuccinic acid Sutent crystalline form 1.
Preferably before mixing them, grind two kinds of powder respectively.Preferably after mixing, form the homogenizing powder.Preferably in mortar, grind by pestle.Preferably finish homogenizing by vibration.
Subsequently, with described powder and methanol mixed, and keep about 3 days time to obtain oxysuccinic acid Sutent crystalline form 1 mixture.
Oxysuccinic acid Sutent crystalline form 1 also can prepare by being included in the method for compositions that comprises sunitinib alkali and L MALIC ACID that suspends in methyl alcohol, ethanol or the water, described composition is selected from composition F, G, H, I, K, O, P, Q and their mixture, wherein, when solvent is methyl alcohol or ethanol, described composition is selected from composition F, G, H, I, K, O, P, Q and their mixture, and when solvent was water, described composition was selected from composition H, I, K and their mixture.
Preferably before the oxysuccinic acid Sutent crystalline form 1 that recovery obtains, keep suspension.Preferably suspension is kept about 3 days time.Preferably under the temperature of about room temperature, keep suspension.More preferably to about 30 ℃ temperature, keep suspension at about 20 ℃.
Composition F, G, H, I, K, O, P and Q can for example prepare according to WO patent publication No. 20090067686 disclosed methods, by reference this patent disclosure are attached to herein.
In one embodiment, the present invention includes to be selected from the crystalline form that following data are the sunitinib alkali of feature: the PXRD figure at peak and PXRD figure shown in Figure 22 are arranged at about 6.2,9.0,13.0,19.3 and 22.4 ± 0.2 degree 2 θ places.This crystalline form can be described as crystalline form XX.
It is feature that sunitinib alkali crystalline form XX can also be selected from following data: the PXRD figure that the peak is arranged at about 11.9,18.1,23.8 and 25.4 ± 0.2 degree 2 θ places.
Preferably as passing through solution
1H NMR surveys, no more than 0.5% (w/w) of the amount of acetate among the sunitinib alkali crystalline form XX.
The above-mentioned crystalline form of sunitinib alkali crystalline form XX can be prepared by the method that is included in dry acetate Sutent crystalline form α under about 120 ℃ temperature.
The above-mentioned crystalline form of sunitinib alkali crystalline form XX also can prepare by the following method: described method comprises makes the crystallization of acetate Sutent and dry resulting crystalline forms under about 75 ℃ temperature from the mixture of MTBE or ethanol and MTBE.
Preferably carry out vacuum-drying.
Usually, evaporation of acetic acid in current method, thus produce the crystallization sunitinib alkali that comprises no more than 0.5% (w/w) acetate.
In one embodiment, the present invention includes to be selected from the crystalline form that following data are the sunitinib alkali of feature: the PXRD figure at peak and PXRD figure shown in Figure 23 are arranged at about 6.2,10.9,12.4,15.9 and 26.2 ± 0.2 degree 2 θ places.This crystalline form can be described as crystalline form XXI.
It is feature that sunitinib alkali crystalline form XXI can also be selected from following data: the PXRD figure that the peak is arranged at about 3.7,17.3,18.2 and 19.0 ± 0.2 degree 2 θ places.
Preferably according to solution
1H NMR surveys, the no more than 0.5%w/w of amount of acetate among the sunitinib alkali crystalline form XXI.
The above-mentioned crystalline form of sunitinib alkali crystalline form XXI can prepare by the following method: described method comprises makes the crystallization of acetate Sutent and dry resulting crystalline forms under about 75 ℃ temperature from the mixture that comprises ethanol and diisopropyl ether.
Preferably carry out vacuum-drying.
In one embodiment, the present invention includes to be selected from the crystalline form that following data are the sunitinib alkali of feature: the PXRD figure at peak and PXRD figure shown in Figure 24 are arranged at about 3.8,7.7,11.5,18.0 and 26.7 ± 0.2 degree 2 θ places.This crystalline form is called crystalline form XXII.
It is feature that sunitinib alkali crystalline form XXII can also be selected from following data: the PXRD figure that the peak is arranged at about 9.6,10.3,15.8 and 16.9 ± 0.2 degree 2 θ places.
Preferably according to solution
1H NMR surveys, the no more than 0.5%w/w of amount of acetate among the sunitinib alkali crystalline form XXII.
The above-mentioned crystalline form of sunitinib alkali crystalline form XXII can prepare by the method that comprises dry acetate Sutent crystalline form β.
Preferably carry out drying by heating acetate Sutent crystalline form β under about 120 ℃ temperature.Preferably carry out vacuum-drying.
Embodiment
PXRD
The XRD diffraction carries out on x-ray powder diffraction instrument: Philips X ' pert Pro powder diffractometer, and CuK α radiation,
X ' Celerator detector useful length (2 θ)=2.122mm, laboratory temperature is 22-25 ℃.Use zero background specimen holder.Before the analysis, utilize mortar and pestle ground sample lightly, so that obtain fine powder.The sample that ground is adjusted in the cavity of specimen holder, and utilized cover glass that sample surfaces is flattened.
Measuring parameter:
Sweep limit: 4-40 ° of 2 θ at least;
Scan pattern: continuously;
Step-length: 0.0167 °;
The time in per step: 21s;
Sample spin: 16rpm;
Specimen holder: quartz plate.
DSC
Dsc measurement carries out on Differential Scanning Calorimeter DSC823e (Mettle Toledo).The 40 μ l alumina crucibles of band PIN are used for specimen preparation.The common weight of sample is 1.5-3.5mg.Program: temperature range is from 40 ℃ at least 300 ℃ at the most, and heating rate is 10 ℃/min, nitrogen gas stream 50ml/min.
TGA
TGA measures and carries out on thermogravimetric analyzer TGA851e (Mettler Toledo).70 μ l alumina crucibles are used for specimen preparation.The common weight of sample is 7-13mg.Program: temperature range is from 40 ℃ at least 300 ℃ at the most, and heating rate is 10 ℃/min, 50 ℃/min of nitrogen gas stream.
Solid-state
13C NMR
All
13C CP/MAS NMR spectrum utilizes the Bruker Avance 500WB/US NMR spectrometer (Karlsruhe, Germany, 2003) of magic angle spinning (MAS) frequency 11kHz to measure down in 125MHz.In all cases, the sample with finely powdered places 4mm ZrO
2In the rotor, and use standard C PMAS pulse protocol.In data-generating process, utilizing high power dipole decoupling zero TPPM (the two pulse phase modulation).The phase modulation angle is 15 °, and upset pulse (flip-pulse) length is 4.8 μ s.The B that uses
1(
1H) nutation frequency is 89.3kHz.B during the cross polarization
1(
13C) field and B
1(
1H) Chang nutation frequency is 62.5kHz, and duplicate delays is 4s.Number of scans is 3600, and therefore total experimental period is about 4 hours.Utilize as outer target glycine (low carbonyl signal of 176.03ppm-) calibration
13The C scale.
Thoroughly calibrate the NMR spectrometer, and before research, optimize all experiment parameters meticulously.In the criteria optimization step, utilize KBr to set magic-angle, utilize the diamantane sample to optimize magnetic field homogeneity (half height Δ v
1/2The gained line width at place is less than 3.5Hz when acquisition time 250ms).Consider the frictional heat of sample in the fast rotational process, (carrying out the precise dose calibration) carried out in all NMR experiments under 305K.
Solution
1H NMR
Instrument: Bruker Avance III (
1H:400.13MHz,
13C:100.61MHz, DMSO-d
6, 30 ℃).(1ppm, 6H) (1.9ppm, 3H) assign to measure for signal and ethanoyl by the upper area quadrature of signal appearance by record proton wave spectrum with to ethyl for the ratio of acetate/Sutent.
Embodiment 1: the preparation of oxysuccinic acid Sutent crystalline form 1
Under 100 ℃, sunitinib alkali (600mg) is dissolved in pyridine (5ml), adds L MALIC ACID (230mg) then in hot solution.Heating obtains clear solution a little.Under 20 ℃, spend the night and form the oxysuccinic acid Sutent.
Embodiment 2: the preparation of oxysuccinic acid Sutent crystalline form 1
With two
Alkane (10ml) joins in sunitinib alkali (300mg) and the L MALIC ACID (101mg), and slurries are heated 10min to reflux temperature, so that the formation of oxysuccinic acid Sutent crystalline form 1 (374mg).
Embodiment 3: the preparation of oxysuccinic acid Sutent crystalline form 1
Sunitinib alkali (300mg), L MALIC ACID (101mg) and butylacetate (10ml) are heated to backflow 10min.Make suspension be cooled to RT, filter, wash also air-dry with normal hexane.
Embodiment 4: the preparation of oxysuccinic acid Sutent crystalline form 1
L MALIC ACID (101mg) and AcOEt (10ml) are added in the sunitinib alkali (300mg), and with mixture heating up to 77 ℃ lasting 10min, post precipitation is with the gained solid filtering, and is air-dry.
Embodiment 5: the preparation of oxysuccinic acid Sutent crystalline form 1
The 1g sunitinib alkali is dissolved in the 3ml N-Methyl pyrrolidone, under RT, adds 0.336g oxysuccinic acid (as solid): solution is heated to 40 ℃, adds 15ml toluene afterwards and observe precipitation.Suspension was kept 1 hour at 40 ℃, be cooled to 0 ℃ afterwards, filter, and use toluene wash.At 60 ℃ of following vacuum-drying 16h.
Embodiment 6: the preparation of oxysuccinic acid Sutent crystalline form 1
Under RT, under stirring, the 2g sunitinib alkali is suspended among the 6ml NMP.In mixture, add the 0.673g oxysuccinic acid, temperature is set in 40 ℃ then.The 40ml n-propyl alcohol that drips in 30 minutes is cooled to 0 ℃ with suspension, filters, and washs with the 10ml n-propyl alcohol.At 70 ℃ of following vacuum-drying 16h.
Embodiment 7: the preparation of oxysuccinic acid Sutent crystalline form 1
Under RT, under stirring, the 2g sunitinib alkali is suspended among the 6ml DMA.In mixture, add the 0.673g oxysuccinic acid, temperature is set in 40 ℃ then.The 40ml n-propyl alcohol that drips in 30 minutes is cooled to 0 ℃ with suspension, filters, and washs with the 10ml n-propyl alcohol.At 70 ℃ of following vacuum-drying 16h.
Embodiment 8: the preparation of oxysuccinic acid Sutent crystalline form 1
The 5g sunitinib alkali is suspended in the 100ml methyl alcohol.Under RT, add the 1.684g oxysuccinic acid that is dissolved in the 15ml water.Observe mixture and be partly dissolved, have precipitation to form after 5 minutes.Filtering suspension liquid, and use the 50ml methanol wash.At 50 ℃ of following vacuum-drying 16h.
Embodiment 9: the preparation of oxysuccinic acid Sutent crystalline form 1
The 1g sunitinib alkali is suspended in the 20ml methyl alcohol.Under RT, add the 0.332g oxysuccinic acid that is dissolved in the 3ml water.Observe mixture and be partly dissolved, have precipitation to form after 5 minutes.Filtering suspension liquid, and use the 10ml methanol wash.At 50 ℃ of following vacuum-drying 16h.
Embodiment 10: the preparation of oxysuccinic acid Sutent crystalline form 1
Under 80 ℃, 0.5g oxysuccinic acid Sutent is dissolved in the 3.5g water, uses 3.5g ethanol and 7g acetone diluted again, under RT, leave standstill crystallization and spend the night, filter, and use washing with acetone.40 ℃ of following vacuum-dryings 20 hours.
Embodiment 11: the preparation of oxysuccinic acid Sutent crystalline form 1
Under 100 ℃, 0.5g oxysuccinic acid Sutent is dissolved among the 3.5g NMP, under RT, leaves standstill afterwards and spend the night with slow crystallization.Filter crystal and use hexane wash.40 ℃ of following vacuum-dryings 20 hours.
Embodiment 12: the preparation of oxysuccinic acid Sutent crystalline form 1
Take by weighing comprise sunitinib alkali and L MALIC ACID composition L (10mg) in bottle, then add 10 μ L water, and by the vibration bottle blend is mixed.With little bottle closure, and leave standstill 3 days at ambient temperature, obtain crystalline form 1 up to drying.
Embodiment 13: the preparation of oxysuccinic acid Sutent crystalline form 1
Take by weighing comprise sunitinib alkali and L MALIC ACID composition L (10mg) in bottle, then add 10 μ L methyl alcohol, and by the vibration bottle blend is mixed.With little bottle closure, and leave standstill 3 days at ambient temperature, obtain crystalline form 1 up to drying.
Embodiment 14: the preparation of oxysuccinic acid Sutent crystalline form 1
Take by weighing comprise sunitinib alkali and L MALIC ACID composition L (10mg) in bottle, then add 10 μ L ethanol, and by the vibration bottle blend is mixed.With little bottle closure, and leave standstill 3 days at ambient temperature, obtain crystalline form 1 up to drying.
Embodiment 15: the preparation of oxysuccinic acid Sutent crystalline form 1
The mol ratio of preparation sunitinib alkali (crystalline form VIII) and L MALIC ACID is 1: 1 a mixture (280mg).With mortar and pestle aforementioned sunitinib alkali and L MALIC ACID are worn into powder respectively.Take by weighing powdery sunitinib alkali (210mg) in bottle, then in same bottle, add powdery L MALIC ACID (70mg).Afterwards, by making mixture even with hand vibration bottle.Take by weighing mixture (10mg) in bottle, add 10 μ L methyl alcohol again, and blend is mixed by the vibration bottle.With little bottle closure, and leave standstill 3 days at ambient temperature, obtain crystalline form 1 up to drying.
Embodiment 16: the preparation of oxysuccinic acid Sutent crystalline form 1
The 1g sunitinib alkali is suspended among the 4ml DMSO, under RT, adds 0.336g oxysuccinic acid (as solid) and obtain solution, then dropwise add the 20ml ethyl acetate, and observe precipitation.Suspension was kept 1 hour down at 20-25 ℃, filter then and wash with ethyl acetate.At 80 ℃ of following vacuum-drying 16-18h, obtain 1.03g oxysuccinic acid Sutent.
Embodiment 17: the preparation of oxysuccinic acid Sutent crystalline form 1
At room temperature, 0.672g (1 equivalent) L MALIC ACID is packed in the 250ml reactor, and be dissolved in the 40ml dehydrated alcohol.
With mixture heating up to 60 ℃.So prepare the solution of acetate Sutent in the following manner: 2g sunitinib alkali (1 equivalent) is suspended in the 10ml water, stirs adding 0.30g (1 equivalent) acetate afterwards, thereby obtain solution.Under 60 ℃, this drips of solution is added in the ethanolic soln of oxysuccinic acid.60 ℃ down keep 10 minutes after, in 2 hours, mixture is cooled to 0 ℃, and under this temperature other 1 hour of restir.On gooch P3, filter the gained solid, and with 3 * 5ml washing with alcohol.
Under 80 ℃, in vacuum drying oven, be dried 18 hours, obtain 2.21g oxysuccinic acid Sutent.
Embodiment 18 (a)-(h): the preparation of oxysuccinic acid Sutent crystalline form 1
Composition F, G, H, I, K, O, P or the Q (10mg) that will comprise sunitinib alkali and L MALIC ACID pour in the vial, and add about 10 μ l methyl alcohol.With little bottle closure, and leave standstill suspension 3 days at ambient temperature, obtain crystalline form 1 up to drying.
Embodiment 19 (a)-(h): the preparation of oxysuccinic acid Sutent crystalline form 1
Composition F, G, H, I, K, O, P or the Q (10mg) that will comprise sunitinib alkali and L MALIC ACID pour in the vial, and add about 10 μ l ethanol.With little bottle closure, and leave standstill suspension 3 days at ambient temperature, obtain crystalline form 1 up to drying.
Embodiment 20 (a)-(c): the preparation of oxysuccinic acid Sutent crystalline form 1
Composition H, I or the K (10mg) that will comprise sunitinib alkali and L MALIC ACID pour in the vial, and add about 10 μ l water.With little bottle closure, and leave standstill suspension 3 days at ambient temperature, obtain crystalline form 1 up to drying.
Embodiment 21: the preparation of oxysuccinic acid Sutent crystalline form 1
At room temperature 0.74g (1.1 equivalent) L MALIC ACID is packed in the 250ml reactor, and be dissolved in the 40ml dehydrated alcohol.
With mixture heating up to 60 ℃.So prepare the solution of formic acid Sutent in the following manner: 2g sunitinib alkali (1 equivalent) is suspended in the 10ml water, stirs adding 0.24g (1.05 equivalent) formic acid afterwards, thereby obtain solution.Under 60 ℃, this drips of solution is added in the ethanolic soln of oxysuccinic acid.60 ℃ down keep 10 minutes after, in 2 hours, mixture is cooled to 0 ℃, and under this temperature restir 1 hour.On gooch P3, filter the gained solid, and with 3 * 5ml washing with alcohol.
Under 80 ℃, in vacuum drying oven, be dried 18 hours, obtain 2.1g oxysuccinic acid Sutent.
Embodiment 22: the preparation of oxysuccinic acid Sutent crystalline form 1
The solution for preparing the acetate Sutent in the following manner: 10g sunitinib alkali (1 equivalent) is suspended in the 50ml water, and stirring afterwards adds 1.58g (1.05 equivalent) acetate and obtains solution.This solution is heated to 60 ℃.Then under this temperature, add 160ml ethanol.
At room temperature 3.7g (1.1 equivalent) L MALIC ACID is dissolved in the 40ml dehydrated alcohol.Down this solution is joined in the solution of acetate Sutent at 60 ℃.60 ℃ down keep 10 minutes after, in 2 hours, mixture is cooled to 0 ℃, and under this temperature restir 1 hour.On gooch P3, filter the gained solid, and with 3 * 50ml washing with alcohol.
Under 80 ℃, in vacuum drying oven, be dried 18 hours, obtain 12.4g oxysuccinic acid Sutent.
Embodiment 23: the preparation of oxysuccinic acid Sutent crystalline form 1
3g sunitinib alkali (1 equivalent) is suspended in 9ml (the 3 times of volumes) acetate, obtains solution.This solution is heated to 40 ℃.Then under this temperature, add 33ml (11 times of volumes) dehydrated alcohol, solution is heated to 60 ℃ then.
Under the room temperature 1.1g (1.1 equivalent) L MALIC ACID is dissolved in the 3ml dehydrated alcohol.Down this solution is joined in the solution of acetate Sutent at 60 ℃.
60 ℃ down keep 15 minutes after, in 3 hours, mixture is cooled to 0 ℃, and under this temperature restir 1 hour.On gooch P3, filter the gained solid, and with 3 * 6ml washing with alcohol.
Under 60 ℃, in vacuum drying oven, be dried 18 hours, obtain 3.37g oxysuccinic acid Sutent (yield 84%, HPLC record purity 99.85%).
Embodiment 24: the preparation of acetate Sutent crystalline form α
Sunitinib alkali (1.5g) is suspended in the propyl carbinol (7.5ml), and under 20 ℃ along with stirring disposable adding acetate (2.3ml).Add acetate and promoted sunitinib alkali dissolving fully in 2 minutes.With solution stirring 60 minutes, form orange precipitation during this period.By the filtered and recycled precipitation, usefulness t-butyl methyl ether (50ml) washing, and at 20 ℃ of following air-dry 12h (output 1.074g).
Embodiment 25: the preparation of acetate Sutent crystalline form α
Down sunitinib alkali (1.3g) is dissolved in acetate (10ml) at 20 ℃ by stirring 5 minutes.Then in 30 minutes, stir and add diisopropyl ether (20min).Then solution is filtered, and in 5 minutes, t-butyl methyl ether (50ml) is added in the solution that stirred.By the orange precipitation that filtered and recycled forms thus, wash with t-butyl methyl ether (50ml), and air-dry 12h (output 1.425g) under 20 ℃.
Embodiment 26: the preparation of acetate Sutent crystalline form α
Stir down at 20 ℃ and sunitinib alkali (3g) to be dissolved in acetate (6ml) and the dehydrated alcohol (6ml) in 10 minutes, and solution is heated to 50 ℃.Then in 30 minutes, stir adding methyl tertiary butyl ether (60ml), mixture is cooled to-10 ℃.After keeping 16h under-10 ℃, with solid filtering, with 2 * 20ml MTBE washing, drying is 1 hour on strainer, obtains red solid.
Embodiment 27: the preparation of acetate Sutent crystalline form α
Under 25 ℃, gained solid among the 1.5g embodiment 26 with 25ml MTBE pulp 30 minutes, is filtered on gooch P3 afterwards, and on strainer dry 1 hour.
Embodiment 28: the preparation of acetate Sutent crystalline form β
Under 20 ℃, sunitinib alkali (3g) is suspended in the propyl carbinol (15ml), then adds 1.05 equivalents (0.45ml) acetate, observe dissolving and 1-2 ' orange solids precipitation afterwards along with stirring.With mixture heating up to 60 ℃, add other 6ml propyl carbinol.Afterwards, in 10 minutes, stirring adding methyl tertiary butyl ether (60ml) under 60 ℃, in 2 hours mixture is cooled to-10 ℃.-10 ℃ down keep 1h after, with solid filtering, with 2 * 20ml MTBE washing, and on strainer drying 1 hour.
Embodiment 29: the preparation of acetate Sutent crystalline form β
Under 25 ℃, gained solid among the 1.5g embodiment 28 with 25ml MTBE pulp 30 minutes, is filtered on gooch P3 afterwards, and on strainer dry 1 hour.
Embodiment 30: the preparation of acetate Sutent crystalline form β
Under 20 ℃, along with stirring sunitinib alkali (3g) is suspended in the propyl carbinol (15ml), and with mixture heating up to 60 ℃.Then add 1.05 equivalents (0.45ml) acetate, observe dissolving and 1-2 ' orange solids precipitation afterwards.Then add other 6ml propyl carbinol and other 0.45ml acetate.Then, in 2 hours mixture is cooled to-10 ℃ in 10 minutes, stirring adding methyl tertiary butyl ether (60ml) under 60 ℃.After-10 ℃ down keep 16h, with solid filtering, with 2 * 20ml MTBE washing, and on strainer drying 1 hour.
Embodiment 31: the preparation of acetate Sutent crystalline form β
Under 20-25 ℃, sunitinib alkali (4g) is suspended in the propyl carbinol (12ml) along with stirring.Then add 1.05 equivalents (0.45ml) acetate, observe dissolving and 1-2 ' orange solids precipitation afterwards.Then, in 2 hours mixture is cooled to-10 ℃ in 10 minutes, stirring adding methyl tertiary butyl ether (80ml) under 20-25 ℃.After-10 ℃ down keep 16h, with solid filtering, with 2 * 20ml MTBE washing, and on strainer drying 1 hour, obtain 4g acetate Sutent.
Embodiment 32: the preparation of acetate Sutent crystalline form β
Under 25 ℃, with gained solid among the 1.5g embodiment 30 and 25ml MTBE pulp 30 minutes, then on gooch P3, filter, and on strainer dry 1 hour.
Embodiment 33: the preparation of acetate Sutent
(10g 0.025mol) is suspended in the 1-butanols (70ml), then adds 1.05 equivalents (1.54ml) acetate, observes dissolving and the orange solids after about 5 minutes precipitation with sunitinib alkali along with stirring under 20 ℃.With mixture heating up to 60 ℃, stir in 40 minutes at 60 ℃ and to add methyl tertiary butyl ethers (200ml), in 2 hours, mixture is cooled to-10 ℃.After-10 ℃ down keep 16h, with solid filtering, with 2 * 20ml MTBE washing, and on strainer drying 1 hour.So obtained 10.8g acetate Sutent (yield 94%).
Embodiment 34: the acetate Sutent is to the conversion of oxysuccinic acid Sutent
Under 20 ℃, 10g acetate Sutent is dissolved in 50ml water, then adds 20ml ethanol.With mixture heating up to 60 ℃, add other 170ml ethanol and stir.Then stirring adds the 3.7g L MALIC ACID that is dissolved in the 10ml ethanol, so obtain solution.Stirred this solution 10-15 minute down at 60 ℃, in 2 hours, mixture is cooled to 0 ℃ afterwards, and under this temperature, stirred other 1 hour.On gooch P3, filter the gained solid, and with 2 * 30ml washing with alcohol.With solid under 50 ℃ in vacuum drying oven dry 18 hours, obtain 10.8 oxysuccinic acid Sutents (from sunitinib alkali calculated yield 87%, the HPLC method records purity 99.88%).
Embodiment 35: the acetate Sutent is to the conversion of oxysuccinic acid Sutent
Under 20 ℃, 10g acetate Sutent is dissolved in the 50ml water.With mixture heating up to 60 ℃, add 190ml ethanol and stir.Then stirring adds the 3.7g L MALIC ACID that is dissolved in the 10ml ethanol, so obtain solution.At 60 ℃ of following stirred solution 10-15 minutes, then in 2 hours, mixture is cooled to 0 ℃, and under this temperature, stirred other 1 hour.On gooch P3, filter the gained solid, and with 2 * 30ml washing with alcohol.With solid under 50 ℃ in vacuum drying oven dry 18 hours, obtain 10.8 oxysuccinic acid Sutents (from sunitinib alkali calculated yield 87%, the HPLC method records purity 99.88%).
Embodiment 36: in the formation that does not separate acetate Sutent under the alkali situation
6g Sutent chloride derivative (SAC) is packed in the reactor, reinstall 90ml 2-methyltetrahydrofuran and stir.Then reaction mixture is heated to 40 ℃, and in 5 minutes, drips 2.9ml 2-diethylamino ethamine at 40 ℃.Observe and be partly dissolved, occur the product precipitation afterwards.Afterreaction finished (being less than 2% up to the Sutent ester) in 1 hour: under 40 ℃ 90ml water and 2N HCl being joined in the suspension, is 2 up to the pH value.
Separate two-phase down at 40 ℃, and discard organic phase.Under 40 ℃,, wash water once more with 90ml 2-methyltetrahydrofuran along with stirring.Separate two-phase once more, and discard organic phase.
Afterwards, the ammonia soln with 5% alkalizes water to pH 9.0 under 40 ± 2 ℃.
Stir after 30 minutes, suspension is heated to 90 ℃, add the 100ml1-butanols, observe and dissolve fully and be separated.Separate two-phase down at 90 ℃, in the reactor of then organic phase being packed into once more, and in 70 ℃ of following vacuum concentration to residual 30ml (5 times of volumes), sunitinib alkali (SUN Base) begins precipitation.Then mixture is cooled to 25 ℃, and under this temperature, adds 1.1ml acetate, realize dissolving fully.Under this temperature, in about 30 minutes, drip 120ml MTBE, then in 2 hours, mixture is cooled to 0 ℃, stirred 16 hours down and on Gooch P3, filter at 0 ℃, with the MTBE washing, and the solid drying 4 hours on strainer that will wet.
Detect through the HPLC method, obtain the acetate Sutent (is 76% from the SAC calculated yield) of 6.4g purity 99.5%.
Under 25 ℃, 30ml water and 6g acetate Sutent packed in the reactor, and stir about 10 minutes.Solution is heated to 40 ℃, and by on the decalite pad, filtering so that its clarification.Solution is heated to 60 ℃, and in about 30 minutes, adds 114ml ethanol.Then in about 10 minutes, drip the 6ml ethanolic soln that contains the 1.94g L MALIC ACID, and stir.Add when finishing, in 2 hours, mixture is cooled to 35 ℃, then under uniform temp, stirred 3-4 hour.In about 5 hours suspension is cooled to 0 ℃, then stirring is no less than 10 hours under this temperature.On Gooch P3, filter the gained solid, and with 3 * 10ml washing with alcohol, the solid that will wet obtained 6.2g oxysuccinic acid Sutent (yield 90%, the HPLC method records purity 99.7%) at 80 ℃ of following vacuum-drying 16-18 hours.
Embodiment 37: form the oxysuccinic acid Sutent from acetate Sutent crystalline form α
Sunitinib alkali (3g) is dissolved in acetate (6ml) and the dehydrated alcohol (6ml) down at 20 ℃, solution is heated to 50 ℃ by stirring 10 minutes.Then in 30 minutes, stir adding methyl tertiary butyl ether (60ml), mixture is cooled to-10 ℃.After-10 ℃ kept 16h down, with solid filtering, with 2 * 20ml MTBE washing, drying was 1 hour on strainer, obtains red solid (3.1g, yield 90%).
Under 25 ℃, 15ml water and 3g acetate Sutent are packed in the reactor, and stir about 10 minutes.Solution is heated to 40 ℃, and by on the decalite pad, filtering so that its clarification.Solution is heated to 60 ℃, and in about 30 minutes, adds 57ml ethanol.Then in about 10 minutes, drip the 3ml ethanolic soln that contains the 0.97g L MALIC ACID, and stir.Add when finishing, in 2 hours, mixture is cooled to 35 ℃, under uniform temp, stirred 3-4 hour then.In about 5 hours suspension is cooled to 0 ℃, then stirring is no less than 10 hours under this temperature.On Gooch P3, filter the gained solid, and with 3 * 5ml washing with alcohol, the solid that will wet obtained 3.1g oxysuccinic acid Sutent (yield 90%, the HPLC method records purity 99.7%) at 80 ℃ of following vacuum-drying 16-18 hours.
Embodiment 38: the preparation of sunitinib alkali crystalline form XX
Under 120 ℃, 100Pa vacuum condition, acetate Sutent crystalline form α was heated 1 hour in the opening bottle.
Embodiment 39: the preparation of sunitinib alkali crystalline form XX
20 ℃ down by stir 5 minutes with sunitinib alkali (crystalline form D 5g) is dissolved in acetate (10ml) and the dehydrated alcohol (10ml), and solution is heated to 40 ℃.Then, in 30 minutes, stir adding methyl tertiary butyl ether (100ml), mixture is cooled to-10 ℃, precipitation occurs.After keeping 2 hours under-10 ℃,, and, obtain the 4.8g orange solids 75 ℃ of following vacuum-dryings 16 hours with solid filtering.
Embodiment 40: the preparation of sunitinib alkali crystalline form XX
20 ℃ down by stir 5 minutes with sunitinib alkali (crystalline form D 7g) is dissolved in acetate (17.5ml), and solution is heated to 45 ℃.In 30 minutes, stir adding methyl tertiary butyl ether (140ml) then, mixture is cooled to-10 ℃, precipitation occurs.After keeping 2 hours under-10 ℃,, and, obtain the 5.3g orange solids 75 ℃ of following vacuum-dryings 16 hours with solid filtering.
Embodiment 41: the preparation of sunitinib alkali crystalline form XXI
Under 20 ℃ of stirrings, acetate Sutent (1g) is suspended in the dehydrated alcohol (20ml), and with mixture heating up to 40 ℃.Then in 10 minutes, stir adding diisopropyl ether (40ml), in 2 hours, mixture is cooled to-10 ℃, after keeping 2 hours under-10 ℃,, and, obtain the 0.8g orange solids then 75 ℃ of following vacuum-dryings 16 hours with solid filtering.
Embodiment 42: the preparation of sunitinib alkali crystalline form XXII
Under 120 ℃, 100Pa vacuum condition, acetate Sutent crystalline form β was heated 1 hour in the opening bottle.
Claims (27)
1. a diffraction peak for preparing with about 13.2 and 24.2 degree 2 θ places is the method for the oxysuccinic acid Sutent crystalline form 1 of feature, described method comprises to be reacted sunitinib alkali, weak acid and L MALIC ACID and makes described oxysuccinic acid Sutent crystalline form 1 precipitation in the mixture of alcohol or water and alcohol.
2. the process of claim 1 wherein that the mixture with sunitinib alkali, described weak acid and alcohol or water and alcohol mixes to obtain first solution.
3. the process of claim 1 wherein that described weak acid is selected from acetate, formic acid, xitix, phenylformic acid, succsinic acid, butanic acid, propionic acid and boric acid.
4. the process of claim 1 wherein that described alcohol is selected from methyl alcohol, ethanol and Virahol.
5. the method for claim 1, it also comprises the crystalline form 1 that reclaims described oxysuccinic acid Sutent.
6. acetate Sutent.
7. the acetate Sutent of claim 6, wherein said acetate Sutent is isolating form.
8. the acetate Sutent of claim 6, wherein said acetate Sutent is solid form.
9. the acetate Sutent of claim 6, wherein said acetate Sutent is crystalline form.
10. one kind to be selected from the crystalline form that following data are the acetate Sutent of feature: have at about 5.1,9.6,10.2,12.8 and 16.9 ± 0.2 degree 2 θ places the PXRD figure at peak, PXRD shown in Figure 12 scheme, about 165.2,134.5,130.4,118.7,115.7,112.5 and 110.9 ± 0.2ppm place the solid-state of signal arranged
13C NMR spectrum, in the chemical shift range of 100-180ppm, presenting and have about 63.6,32.9,28.8,17.1,14.1,10.8 and the chemical shift difference of 9.2 ± 0.1ppm solid-state between the signal that minimizes displacement study and another signal
13C NMR spectrum, shown in Figure 20 solid-state
13C NMR spectrum and their combination.
11. the acetate Sutent crystalline form of claim 10 is a feature to be selected from following data also: have at about 17.4,17.7,23.1,26.0 and 27.0 ± 0.2 degree 2 θ places that the PXRD at peak schemes, DSC thermogram shown in Figure 13 and a TGA thermogram shown in Figure 14.
12. the acetate Sutent crystalline form of claim 10, wherein said crystalline form is the acetic acid solvent thing.
13. one kind to be selected from the crystalline form that following data are the acetate Sutent of feature: have at about 6.1,11.0,15.8,16.4 and 20.2 ± 0.2 degree 2 θ places the PXRD figure at peak, PXRD shown in Figure 17 scheme, about 166.1,133.0,119.0,114.5,109.9 and 108.6 ± 0.2ppm place the solid-state of signal arranged
13C NMR spectrum, in the chemical shift range of 100-180ppm, presenting and have about 65.0,31.9,17.9,134,8.8 and the chemical shift difference of 7.5 ± 0.1ppm solid-state between the signal that minimizes displacement study and another signal
13C NMR spectrum, shown in Figure 21 solid-state
13C NMR spectrum and their combination.
14. the acetate Sutent crystalline form of claim 13 is a feature to be selected from following data also: have at about 9.1,18.2,244,25.0 and 29.3 ± 0.2 degree 2 θ places that the PXRD at peak schemes, DSC thermogram shown in Figure 180 and a TGA thermogram shown in Figure 19.
15. the acetate Sutent crystalline form of claim 13, wherein said crystalline form is anhydrous.
16. a method for preparing the acetate Sutent, described method comprises
The mixture that comprises sunitinib alkali, acetate and solvent is provided, wherein crystallization acetate Sutent is precipitated out from this mixture, when use every molar equivalent sunitinib alkali more than about 5 molar equivalent acetate the time, obtain the acetate Sutent crystalline form of claim 10, and when the about 2 molar equivalent acetate of the about 1-that uses every molar equivalent sunitinib alkali, obtain the acetate Sutent crystalline form of claim 13.
17. the method for claim 16 wherein by sunitinib alkali and the acetate solution in solvent is provided, is settled out described crystalline form then and obtains described mixture.
18. the method for claim 17, wherein said solution can prepare by being dissolved into isolating sunitinib alkali in the solvent and mixing with acetate, or mixes with acetate by the reaction mixture that will form sunitinib alkali and to prepare.
19. the method for claim 16, wherein said solvent are selected from the mixture of mixture, propyl carbinol and MTBE of mixture, ethanol and MTBE of propyl carbinol, diisopropyl ether and methyl tertiary butyl ether (" MTBE ") and their combination.
20. the method for claim 17 is wherein by keeping described solution or adding anti-solvent and cause precipitation.
21. also comprising, the method for claim 17, wherein said method from suspension, reclaim described crystalline form.
22. the purposes of each crystallization acetate Sutent in preparation oxysuccinic acid Sutent among claim 10-12 and the 13-15.
23. the purposes of claim 22, wherein the oxysuccinic acid Sutent is a feature with the diffraction peak at about 13.2 and 24.2 degree 2 θ places.
24. a method for preparing the oxysuccinic acid Sutent, described method comprise according to claim 16 preparation crystallization acetate Sutent and convert it into the oxysuccinic acid Sutent.
25. the method for claim 24, wherein gained oxysuccinic acid Sutent is a feature with the diffraction peak at about 13.2 and 24.2 degree 2 θ places.
26. a diffraction peak for preparing with about 13.2 and 24.2 degree 2 θ places is the method for the mold cavity tartaric acid Sutent of feature, described method comprises provides the mixture that comprises the oxysuccinic acid Sutent and be selected from following solvent: pyridine, two
The mixture of mixture, Virahol, NMP and the n-propyl alcohol of the mixture of the mixture of alkane, butylacetate, ethyl acetate, dimethyl formamide, N,N-DIMETHYLACETAMIDE and n-propyl alcohol, n-methyl-2-pyrrolidone (" NMP ") and toluene, dimethyl sulfoxide (DMSO) (" DMSO "), DMSO and ethyl acetate, mixture, water, ethanol and the acetone three's of first alcohol and water mixture, NMP, 2-methyltetrahydrofuran, water, ethanol, methyl alcohol and their mixture.
27. a diffraction peak for preparing with about 13.2 and 24.2 degree 2 θ places is the method for the mold cavity tartaric acid Sutent of feature, described method comprises:
In methyl alcohol, ethanol or water, suspend and be selected from the following composition that comprises sunitinib alkali and L MALIC ACID:
To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.0,7.7,9.1,10.1,12.0,14.5,23.4 and 27.1 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 3; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.2,7.7,9.3,12.4,14.5,23.2 and 27.4 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 4; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.0,7.8,9.0,12.0,14.8,18.0,22.5 and 27.1 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 5; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.0,7.8,9.0,12.0,14.8,18.0,22.5 and 27.1 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 5; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.0,7.7,9.2,12.2,14.5,22.9 and 27.3 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 6; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 11.4,14.4,23.4,24.1 and 27.0 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 7; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 5.9,8.9,11.8,20.6,22.6 and 27.3 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 8; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.0,7.4,8.9,11.9,23.4 and 27.7 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 10; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.1,7.9,9.2,12.1,15.2,22.9 and 27.7 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 11; And their mixture;
Wherein, when solvent was methyl alcohol or ethanol, described composition was selected from: to be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.0,7.7,9.1,10.1,12.0,14.5,23.4 and 27.1 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 3; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.2,7.7,9.3,12.4,14.5,23.2 and 27.4 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 4; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.0,7.8,9.0,12.0,14.8,18.0,22.5 and 27.1 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 5; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.0,7.7,9.2,12.2,14.5,22.9 and 27.3 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 6; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 11.4,14.4,23.4,24.1 and 27.0 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 7; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 5.9,8.9,11.8,20.6,22.6 and 27.3 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 8; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.0,7.4,8.9,11.9,23.4 and 27.7 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 10; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.1,7.9,9.2,12.1,15.2,22.9 and 27.7 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 11; And their mixture; With
When solvent was water, described composition was selected from: to be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.0,7.8,9.0,12.0,14.8,18.0,22.5 and 27.1 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 5; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 6.0,7.7,9.2,12.2,14.5,22.9 and 27.3 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 6; To be selected from following data is the combination of features thing: have any 5 PXRD at the peak of the position that is selected from 11.4,14.4,23.4,24.1 and 27.0 ± 0.2 degree, 2 θ and scheme and PXRD figure shown in Figure 7; And their mixture.
Applications Claiming Priority (24)
| Application Number | Priority Date | Filing Date | Title |
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| US13700508P | 2008-07-24 | 2008-07-24 | |
| US61/137005 | 2008-07-24 | ||
| US8658908P | 2008-08-06 | 2008-08-06 | |
| US61/086589 | 2008-08-06 | ||
| US8785908P | 2008-08-11 | 2008-08-11 | |
| US61/087859 | 2008-08-11 | ||
| US8899808P | 2008-08-14 | 2008-08-14 | |
| US8896108P | 2008-08-14 | 2008-08-14 | |
| US61/088998 | 2008-08-14 | ||
| US61/088961 | 2008-08-14 | ||
| US9434108P | 2008-09-04 | 2008-09-04 | |
| US61/094341 | 2008-09-04 | ||
| US9759208P | 2008-09-17 | 2008-09-17 | |
| US61/097592 | 2008-09-17 | ||
| US10515408P | 2008-10-14 | 2008-10-14 | |
| US61/105154 | 2008-10-14 | ||
| US10807808P | 2008-10-24 | 2008-10-24 | |
| US61/108078 | 2008-10-24 | ||
| US11304408P | 2008-11-10 | 2008-11-10 | |
| US61/113044 | 2008-11-10 | ||
| US61/141385 | 2008-12-30 | ||
| US61/164542 | 2009-03-30 | ||
| US61/177717 | 2009-05-13 | ||
| PCT/US2009/051530 WO2010011834A2 (en) | 2008-07-24 | 2009-07-23 | Sunitinib and salts thereof and their polymorphs |
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| CN103833733A (en) * | 2012-11-21 | 2014-06-04 | 广东东阳光药业有限公司 | New crystal form of tini-type medicines |
| CN103896922B (en) * | 2012-12-25 | 2017-05-03 | 上海科胜药物研发有限公司 | Novel sunitinib salts and preparing method thereof |
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| WO2004075775A2 (en) * | 2003-02-24 | 2004-09-10 | Sugen, Inc. | Treatment of excessive osteolyisis with indolinone compounds |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004075775A2 (en) * | 2003-02-24 | 2004-09-10 | Sugen, Inc. | Treatment of excessive osteolyisis with indolinone compounds |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103833733A (en) * | 2012-11-21 | 2014-06-04 | 广东东阳光药业有限公司 | New crystal form of tini-type medicines |
| CN103833733B (en) * | 2012-11-21 | 2017-08-25 | 广东东阳光药业有限公司 | One kind replaces Buddhist nun's class medicine novel crystal forms |
| CN103896922B (en) * | 2012-12-25 | 2017-05-03 | 上海科胜药物研发有限公司 | Novel sunitinib salts and preparing method thereof |
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