WO2017028766A1 - 用于制备水溶性紫杉烷类衍生物的方法及中间体 - Google Patents
用于制备水溶性紫杉烷类衍生物的方法及中间体 Download PDFInfo
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- WO2017028766A1 WO2017028766A1 PCT/CN2016/095278 CN2016095278W WO2017028766A1 WO 2017028766 A1 WO2017028766 A1 WO 2017028766A1 CN 2016095278 W CN2016095278 W CN 2016095278W WO 2017028766 A1 WO2017028766 A1 WO 2017028766A1
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- Prior art keywords
- acid
- compound
- formula
- benzyloxycarbonyl
- group
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- 238000000034 method Methods 0.000 title claims abstract description 61
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 130
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 82
- -1 3-chlorobenzyloxycarbonyl Chemical group 0.000 claims description 42
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 40
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- 239000003153 chemical reaction reagent Substances 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 27
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 26
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 16
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 14
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 11
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 235000011054 acetic acid Nutrition 0.000 claims description 10
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 10
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 150000001718 carbodiimides Chemical group 0.000 claims description 9
- 125000001309 chloro group Chemical class Cl* 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 239000007858 starting material Substances 0.000 claims description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 8
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 8
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 8
- 235000017168 chlorine Nutrition 0.000 claims description 8
- 235000019260 propionic acid Nutrition 0.000 claims description 8
- 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 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 7
- RYKLZUPYJFFNRR-UHFFFAOYSA-N 3-hydroxypiperidin-2-one Chemical compound OC1CCCNC1=O RYKLZUPYJFFNRR-UHFFFAOYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 5
- 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 5
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 claims description 5
- 239000005711 Benzoic acid Substances 0.000 claims description 5
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 5
- 235000010233 benzoic acid Nutrition 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- WOWBFOBYOAGEEA-UHFFFAOYSA-N diafenthiuron Chemical compound CC(C)C1=C(NC(=S)NC(C)(C)C)C(C(C)C)=CC(OC=2C=CC=CC=2)=C1 WOWBFOBYOAGEEA-UHFFFAOYSA-N 0.000 claims description 5
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical compound OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 claims description 5
- VFNGKCDDZUSWLR-UHFFFAOYSA-N disulfuric acid Chemical compound OS(=O)(=O)OS(O)(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 5
- 229940071870 hydroiodic acid Drugs 0.000 claims description 5
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 5
- 229910017604 nitric acid Inorganic materials 0.000 claims description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- ABNOKJAUAHDRQI-UHFFFAOYSA-N (3-chlorophenyl)methyl carbonochloridate Chemical compound ClC(=O)OCC1=CC=CC(Cl)=C1 ABNOKJAUAHDRQI-UHFFFAOYSA-N 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 3
- 235000015165 citric acid Nutrition 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 235000011087 fumaric acid Nutrition 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- 239000001630 malic acid Substances 0.000 claims description 3
- 235000011090 malic acid Nutrition 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- IJWMYYIUFNJDKN-UHFFFAOYSA-N (4-chlorophenyl)methyl carbonochloridate Chemical compound ClC(=O)OCC1=CC=C(Cl)C=C1 IJWMYYIUFNJDKN-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 2
- 125000000746 allylic group Chemical group 0.000 claims 2
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims 2
- 150000001721 carbon Chemical group 0.000 claims 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- ZOFJBHYCGASUQK-UHFFFAOYSA-N sodium;trimethylsilylazanide Chemical compound [Na+].C[Si](C)(C)[NH-] ZOFJBHYCGASUQK-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- 238000002360 preparation method Methods 0.000 description 52
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 51
- 229960003668 docetaxel Drugs 0.000 description 51
- 229930012538 Paclitaxel Natural products 0.000 description 47
- 229960001592 paclitaxel Drugs 0.000 description 47
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 239000003960 organic solvent Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- 238000006467 substitution reaction Methods 0.000 description 12
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 6
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 229940123237 Taxane Drugs 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
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- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 150000004579 taxol derivatives Chemical class 0.000 description 1
- CZTZICYNMYGUNU-JQXSQYPDSA-N tert-butyl (3r,4s)-3-(1-ethoxyethoxy)-2-oxo-4-phenylazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C(=O)[C@H](OC(C)OCC)[C@@H]1C1=CC=CC=C1 CZTZICYNMYGUNU-JQXSQYPDSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/91—Polymers modified by chemical after-treatment
Definitions
- the invention belongs to the field of medicine and relates to a method and an intermediate for preparing a water-soluble taxane derivative.
- Taxanes are excellent anti-tumor drugs, mainly used for the treatment of advanced breast cancer, ovarian cancer, non-small cell lung cancer and prostate cancer, etc., for head and neck cancer, stomach cancer, pancreatic cancer. And melanoma and so on have a certain effect.
- taxanes have good anticancer activity, they have poor water solubility and low bioavailability for oral administration, and thus can only be administered by injection in clinical practice.
- a nonionic surfactant such as polyethoxylated castor oil or Tween-80 to prepare an injection.
- a water-soluble taxane-type prodrug having the structure of the following formula 2 is reported in the International Patent Application No. PCT/CN2015/073178 filed by the applicant of the present application. These prodrugs have good water solubility and anti-tumor activity consistent with the original drug, thereby eliminating the side effects caused by the co-solvent in the original taxane injection:
- R 1 is t-butoxy or phenyl
- R 2 is H or acetyl
- X is H, C 1-6 alkyl or F
- Y is F or C 1-6 alkane substituted by one or more F Base
- n is 1, 2, 3, 4, 5 or 6
- W is NR 5 R 6 ⁇
- a or R 5 and R 6 are each independently H, C 1-6 alkyl or C 3-6 cycloalkyl optionally substituted by phenyl
- m is 0, 1, 2 or 3
- A is pharmaceutically acceptable acid.
- the compound of formula 2 is prepared by reacting docetaxel or paclitaxel with amino acid chloride under the catalysis of triethylamine, pyridine or 4-N,N-dimethylaminopyridine (DMAP);
- a compound having a carbodiimide structure such as dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-B), which is based on docetaxel or paclitaxel.
- a carbodiimide hydrochloride (EDCI) or the like an organic base such as DMAP, triethylamine or pyridine is used as a catalyst to react with an amino acid to prepare a compound of the formula 2.
- R 1 is a tert-butoxy group or a phenyl group
- R 2 is H or acetyl
- X is H, C 1-6 alkyl or F
- Y is F or a C 1-6 alkyl group substituted by one or more F;
- n 1, 2, 3, 4, 5 or 6;
- W is NR 5 R 6 ⁇ A or
- R 5 and R 6 are each independently H, C 1-6 alkyl optionally substituted by phenyl, or C 3-6 cycloalkyl;
- n 0, 1, 2 or 3;
- A is a pharmaceutically acceptable acid
- the method comprises preparing the compound of formula 2 from a compound of formula 1:
- R 1 , X, Y, n are as defined above for the compound of formula 2;
- R 3 is acetyl, benzyloxycarbonyl optionally substituted by one or more halogens, or allyloxycarbonyl;
- R 4 is benzyloxycarbonyl, or allyloxycarbonyl optionally substituted with one or more halogens;
- W 1 is NR 5 R 6 ⁇ B or
- R 5 , R 6 , m are as defined above for the compound of formula 2;
- the method provided by the present invention produces very little (or even no production at all) caused by substitution at the 7 position and/or at the 10 position. Impurities and disubstituted impurities resulting from simultaneous substitution of the 2' and 7 positions and/or simultaneous substitution of the 2' and 10 positions have higher yields and product purity.
- R 1 is a tert-butoxy group or a phenyl group
- R 3 is acetyl, benzyloxycarbonyl optionally substituted by one or more halogens, or allyloxycarbonyl;
- R 4 is benzyloxycarbonyl, or allyloxycarbonyl optionally substituted with one or more halogens;
- X is H, C 1-6 alkyl or F
- Y is F or a C 1-6 alkyl group substituted by one or more F;
- n 1, 2, 3, 4, 5 or 6;
- W 1 is NR 5 R 6 ⁇ B or
- R 5 and R 6 are each independently H, a C 1-6 alkyl group optionally substituted by a phenyl group, or a C 3-6 cycloalkyl group;
- n 0, 1, 2 or 3;
- Figure 1 is an HPLC chromatogram of 2'-O-[4-N,N-dimethylamino-2(R)-fluorobutyryl] docetaxel hydrochloride prepared according to the method of Example 16 of the present invention. .
- Figure 2 is a 2'-O-[4-N,N-dimethylamino-2(R)-fluorobutyryl] docetaxel prepared according to the method described in International Patent Application No. PCT/CN2015/073178 HPLC chromatogram of the hydrochloride.
- Figure 3 is an HPLC chromatogram of 2'-O-[4-N,N-dimethylamino-2(R)-fluorobutyryl] paclitaxel hydrochloride prepared according to the method of Example 33 of the present invention.
- Figure 4 is a 2'-O-[4-N,N-dimethylamino-2(R)-fluorobutyryl] paclitaxel hydrochloride prepared according to the method described in International Patent Application No. PCT/CN2015/073178 HPLC profile.
- halogen as used herein means fluoro, chloro, bromo or iodo, preferably chloro or bromo.
- C 1-6 alkyl refers to a saturated straight or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, etc., preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl More preferably, it is a methyl group, an ethyl group, a propyl group or an isopropyl group.
- C 3-6 cycloalkyl refers to a saturated monocyclic hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
- benzyloxycarbonyl refers to a benzyloxy group attached to the remainder of the molecule through a carbonyl linkage.
- allyloxycarbonyl refers to an allyloxy group attached to the remainder of the molecule through a carbonyl linkage.
- the term "acid which can form a salt with an amine” as used herein means an inorganic or organic acid which is commonly used in the field of organic chemistry to form a salt with an amine.
- the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, and the like.
- the organic acid includes, but is not limited to, formic acid, B Acid, propionic acid, butyric acid, pivalic acid, trifluoroacetic acid, difluoroacetic acid, fluoroacetic acid, acetoacetic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluene Acid, naphthalenesulfonic acid, camphorsulfonic acid, and the like.
- pharmaceutically acceptable acid means a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, acetic acid, propionic acid, methanesulfonic acid, lactic acid, benzenesulfonic acid, p-toluenesulfonic acid. Acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid or malic acid.
- the compounds of the invention may exist in crystalline or polymorphic form, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
- the compounds of the invention may exist in the form of their solvates, especially hydrates, wherein the compounds of the invention comprise a polar solvent as a structural element of the crystal lattice of the compound, such as water, ethanol, isopropanol, ethyl acetate or acetone.
- a polar solvent as a structural element of the crystal lattice of the compound, such as water, ethanol, isopropanol, ethyl acetate or acetone.
- the amount of polar solvent, particularly water may be present in stoichiometric or non-stoichiometric ratios.
- An object of the present invention is to provide a process for producing a taxane derivative represented by Formula 2:
- R 1 is a tert-butoxy group or a phenyl group
- R 2 is H or acetyl
- X is H, C 1-6 alkyl or F
- Y is F or a C 1-6 alkyl group substituted by one or more F;
- n 1, 2, 3, 4, 5 or 6;
- W is NR 5 R 6 ⁇ A or
- R 5 and R 6 are each independently H, C 1-6 alkyl optionally substituted by phenyl, or C 3-6 cycloalkyl;
- n 0, 1, 2 or 3;
- A is a pharmaceutically acceptable acid
- the method comprises preparing the compound of formula 2 from a compound of formula 1:
- R 1 , X, Y, n are as defined above for the compound of formula 2;
- R 3 is acetyl, benzyloxycarbonyl optionally substituted by one or more halogens, or allyloxycarbonyl;
- R 4 is benzyloxycarbonyl, or allyloxycarbonyl optionally substituted with one or more halogens;
- W 1 is NR 5 R 6 ⁇ B or
- R 5 , R 6 , m are as defined above for the compound of formula 2;
- X is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or F.
- X is H, methyl or F.
- Y is F or methyl, ethyl, propyl, isopropyl, butyl or isobutyl substituted by one or more F.
- Y is F, CF 3 , CH 2 F or CHF 2 .
- n 1, 2 or 3.
- R 5 and R 6 are each independently H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexyl.
- R 5 and R 6 are each independently H, methyl, ethyl or isopropyl.
- m is 2 or 3.
- A is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, Acetic acid, propionic acid, methanesulfonic acid, ethanesulfonic acid, lactic acid, benzenesulfonic acid, p-toluenesulfonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid or malic acid.
- R 3 is acetyl, benzyloxycarbonyl optionally substituted by one or more chlorines, or allyloxycarbonyl.
- R 3 is acetyl, benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl or allyloxycarbonyl. More preferably, R 3 is acetyl, benzyloxycarbonyl or 3-chlorobenzyloxycarbonyl.
- R 3 is benzyloxycarbonyl, or allyloxycarbonyl, optionally substituted by one or more halogens, preferably optionally with one or more chlorines a substituted benzyloxycarbonyl group or an allyloxycarbonyl group, more preferably a benzyloxycarbonyl group, a 3-chlorobenzyloxycarbonyl group, a 4-chlorobenzyloxycarbonyl group or an allyloxycarbonyl group; when R 2 is an acetyl group, R 3 is an acetyl group. base.
- R 4 is benzyloxycarbonyl, or allyloxycarbonyl, optionally substituted by one or more chlorines.
- R 4 is benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl or allyloxycarbonyl. More preferably, R 4 is benzyloxycarbonyl or 3-chlorobenzyloxycarbonyl.
- B is hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, trifluoroacetic acid, difluoroacetic acid , fluoroacetic acid, acetoacetic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid or camphorsulfonic acid.
- B is hydrochloric acid.
- the carbon atoms that are simultaneously attached to X and Y are a single R configuration, a single S configuration, or a mixture of R and S configurations.
- the method comprises: preparing the compound of the formula 2 via the following Reaction Scheme 1 using the compound of the formula 1 as a starting material:
- R 1 , R 2 , R 3 , R 4 , X, Y, n, W 1 and W are as defined above.
- step e comprises hydrogenolyzing a compound of formula 1 to provide a compound of formula 7.
- the hydrogenolysis is carried out in the presence of a Pd reagent.
- step e comprises:
- the Pd reagent is added to the organic solvent containing the compound of the formula 1 at a suitable temperature, hydrogen gas is introduced into the reaction solution, and after completion of the reaction, the compound of the formula 7 is obtained by post-treatment.
- the temperature is from -30 to 50 ° C, preferably from 10 to 35 ° C.
- the organic solvent is tetrahydrofuran, 1,4-dioxane, ethyl acetate, butyl acetate or a combination thereof, more preferably tetrahydrofuran or ethyl acetate.
- the Pd reagent is Pd/C, PdCl 2 , Pd(PPh 3 ) 4 or a combination thereof, more preferably Pd/C, more preferably Pd/C having a Pd content of 5-30%, most preferably It is a Pd/C containing 5-10% of Pd.
- the amount of the Pd reagent is from 5 to 60%, preferably from 10 to 30%, based on the amount of the compound of Formula 1.
- the pressure of the introduced hydrogen is 1-5 atm, preferably 1-2 atm.
- Step f
- step f comprises reacting a compound of formula 7 with a salt of said pharmaceutically acceptable acid A to provide a compound of formula 2.
- the salt of the acid A is preferably silver methanesulfonate.
- step f comprises:
- the organic solvent is an aprotic organic solvent which can dissolve the compound of the formula 7, such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, acetonitrile or the like.
- the temperature is from -10 to 30 ° C, preferably from 0 to 15 ° C.
- step f when acid A is methanesulfonic acid, step f comprises:
- a suitable solution of the compound of the formula 2 is obtained by adding a solution of silver methanesulfonate in acetonitrile to an organic solvent containing the compound of the formula 7 at an appropriate temperature in the dark, and after the completion of the reaction.
- the organic solvent is an aprotic organic solvent which can dissolve the compound of the formula 7, such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, acetonitrile or the like.
- the temperature is -30-50 ° C, preferably -10-30 ° C.
- the molar ratio of the compound of formula 7 to silver methanesulfonate is 1: (0.8-1.1).
- the compound of formula 1 can be prepared via the following Scheme 2:
- R 1 , R 2 , R 3 , R 4 , X, Y, n and W 1 are as defined above;
- G is a hydroxyl group or a halogen.
- G is hydroxy, Cl or Br.
- step a comprises reacting a compound of formula 3 with an acylating reagent to provide a compound of formula 4.
- the acylating agent is benzyl chloroformate, 3-chlorobenzyl chloroformate, 4-chlorobenzyl chloroformate or allyl chloroformate.
- Step b
- step b comprises reacting a compound of formula 4 with a compound of formula 8 to produce a compound of formula 5.
- step b the reaction of step b is carried out in the presence of an alkaline reagent.
- the reaction of step b can be carried out by referring to the method disclosed in Japanese Patent No. 5,336,785 or Xu Shaojie, "Docetaxel Synthetic Process", Science and Technology Review 2010 (28) 13: 82-86.
- step b comprises:
- the compound of the formula 4 is reacted with a compound of the formula 8 in an organic solvent in the presence of an alkaline reagent at a suitable temperature to prepare a compound of the formula 5.
- the temperature is from -40 to 40 ° C, preferably from -20 to 10 ° C.
- the organic solvent is tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-diethylformamide or a combination thereof.
- the alkaline agent is sodium hydride, sodium bis(trimethylsilyl)amide, n-butyllithium, lithium diisopropylamide or a combination thereof, more preferably sodium hydride.
- step c comprises removing the protecting group at the 2' position of the compound of formula 5 under acidic conditions to provide a compound of formula 6.
- step c is carried out at a reaction temperature of from -10 to 60 ° C, preferably from 20 to 35 ° C.
- the acidic condition is a mixture of an acid and water, such as a mixture of acetic acid and water.
- step d comprises reacting a compound of formula 6 with a compound of formula 9 in a nitrogen-containing basic organic reagent or a mixed reagent consisting of a nitrogen-containing basic organic reagent and a compound having a carbodiimide structure. There is a reaction in the presence.
- the nitrogen-containing basic organic reagent is an organic base such as triethylamine, pyridine, 4-N,N-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine (4-PPY) or combination.
- organic base such as triethylamine, pyridine, 4-N,N-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine (4-PPY) or combination.
- the compound having a carbodiimide structure is dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) ) or a combination thereof.
- DCC dicyclohexylcarbodiimide
- EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
- the molar ratio of the former to the latter is 1: (1-5).
- step d is carried out in the presence of a nitrogen-containing basic organic reagent.
- a halogen e.g., Cl or Br
- step d comprises:
- the compound of the formula 1 is reacted with a compound of the formula 9 in an organic solvent in the presence of a nitrogen-containing basic organic reagent at a suitable temperature to prepare a compound of the formula 1.
- the temperature is from -100 to 40 ° C, preferably from -60 to 0 ° C, more preferably from -30 to 0 ° C.
- the molar ratio of the compound of the formula 6, the compound of the formula 9 to the nitrogen-containing basic organic reagent is 1: (1-12.0): (1-15.0), preferably 1: (1-4.0): (1-8.0) ).
- the organic solvent is dichloromethane, chloroform, 1,2-dichloroethane or a combination thereof.
- Step d is carried out in the presence of a mixed reagent comprising a nitrogen-containing basic organic reagent and a compound having a carbodiimide structure.
- step d comprises:
- the compound of the formula 6 is reacted with the compound of the formula 9 in an organic solvent in the presence of a mixed reagent of a nitrogen-containing basic organic reagent and a compound having a carbodiimide structure at a suitable temperature to prepare a formula.
- a mixed reagent of a nitrogen-containing basic organic reagent and a compound having a carbodiimide structure at a suitable temperature to prepare a formula.
- the temperature is -60-40 ° C, preferably -30-30 ° C, more preferably -30-0 ° C.
- the molar ratio of the compound of the formula 6, the compound of the formula 9 to the mixed reagent of the nitrogen-containing basic organic reagent and the compound having a carbodiimide structure is 1: (1-12.0): (1-15.0), Preferably 1: (1-4.0): (1-8.0).
- the organic solvent is dichloromethane, chloroform, 1,2-dichloroethane or a combination thereof.
- the compound of formula 9 wherein G is a halogen may be obtained by reacting a corresponding compound wherein G is a hydroxyl group with a halogenating agent (e.g., dichlorosulfoxide, phosphorus trichloride, five The phosphorus chloride, phosphorus tribromide, etc. are obtained by halogenation reaction.
- a halogenating agent e.g., dichlorosulfoxide, phosphorus trichloride, five The phosphorus chloride, phosphorus tribromide, etc. are obtained by halogenation reaction.
- the method of the present invention has the following advantages over the two methods disclosed in International Patent Application No. PCT/CN2015/073178:
- the method of the present invention overcomes the impurities present in the original route which result from the substitution of the 7-position and/or the 10-position, the simultaneous substitution by the 2'-position and the 7-position, and/or the simultaneous substitution of the 2'-position and the 10-position. Defects of disubstituted impurities and even more substituted impurities.
- the compounds of formula 2 obtained by the process of the invention have higher yields and product purity.
- Another object of the present invention is to provide an intermediate compound, or a polymorph, solvate or hydrate thereof, for use in the preparation of a compound of Formula 2, which has the following Formula 1:
- R 1 is a tert-butoxy group or a phenyl group
- R 3 is acetyl, benzyloxycarbonyl optionally substituted by one or more halogens, or allyloxycarbonyl;
- R 4 is benzyloxycarbonyl, or allyloxycarbonyl optionally substituted with one or more halogens;
- X is H, C 1-6 alkyl or F
- Y is F or a C 1-6 alkyl group substituted by one or more F;
- n 1, 2, 3, 4, 5 or 6;
- W 1 is NR 5 R 6 ⁇ B or
- R 5 and R 6 are each independently H, C 1-6 alkyl optionally substituted by phenyl, or C 3-6 cycloalkyl;
- n 0, 1, 2 or 3;
- R 3 is acetyl, benzyloxycarbonyl, or allyloxycarbonyl, optionally substituted by one or more chloro groups.
- R 3 is acetyl, benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl or allyloxycarbonyl. More preferably, R 3 is acetyl, benzyloxycarbonyl or 3-chlorobenzyloxycarbonyl.
- R 4 is benzyloxycarbonyl, or allyloxycarbonyl, optionally substituted by one or more chlorines.
- R 4 is benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl or allyloxycarbonyl. More preferably, R 4 is benzyloxycarbonyl or 3-chlorobenzyloxycarbonyl.
- X is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or F.
- X is H, methyl or F.
- Y is F or methyl, ethyl, propyl, isopropyl, butyl or isobutyl substituted by one or more F.
- Y is F, CF 3 , CH 2 F or CHF 2 .
- n 1, 2 or 3.
- R 5 and R 6 are each independently H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexyl.
- R 5 and R 6 are each independently H, methyl, ethyl or isopropyl.
- m is 2 or 3.
- B is an acid which can form a salt with an amine, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, butyric acid, and pentylene.
- an amine such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, butyric acid, and pentylene.
- Acid trifluoroacetic acid, difluoroacetic acid, fluoroacetic acid, acetoacetic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid or camphorsulfonic acid.
- B is hydrochloric acid.
- R 3 is acetyl, benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl or allyloxycarbonyl;
- R 4 is benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl , 4-chlorobenzyloxycarbonyl or allyloxycarbonyl;
- X is H, methyl or F;
- Y is F, CF 3 , CH 2 F or CHF 2 ;
- n is 1, 2 or 3; each of R 5 and R 6 Independently H, methyl, ethyl or isopropyl;
- m is 2 or 3; and
- B is hydrochloric acid.
- the carbon atoms that are simultaneously attached to X and Y are a single R configuration, a single S configuration, or a mixture of R and S configurations.
- the compound of formula 1 of the invention is selected from the group consisting of
- 7,10-O-Dibenzyloxycarbonyl-10-deacetylbaccatin III (8.2 g, 10 mmol) was dissolved in anhydrous tetrahydrofuran (90 ml), the solution was cooled to -20 ° C, and 60 wt% sodium hydride (600 mg) was added.
- N-dimethylamino-2(R)-fluorobutyrate is an acylating agent based on 7,10-O-bis(3-chlorobenzyloxycarbonyl) docetaxel
- ESI-MS[M+H] + 1275.39
- HPLC purity of the product prepared in Example 16 was 99.2%, and its HPLC profile is shown in Figure 1.
- HPLC purity of the product prepared in Example 33 was 97.99%, and its HPLC profile is shown in Figure 3.
- the HPLC prepared by the product of Comparative Example 2 had a purity of 95.52%, and its HPLC spectrum is shown in Fig. 4.
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Abstract
一种制备式2的紫杉烷类衍生物的方法，以及用作制备式2的紫杉烷类衍生物的原料或中间体的式1的化合物。
Description
相关申请的交叉引用
本申请要求2015年8月14日提交的中国专利申请第201510502909.1号的优先权，所述申请的公开内容援引加入本文。
本发明属于医药领域，涉及用于制备水溶性紫杉烷类衍生物的方法及中间体。
紫杉烷类药物(例如紫杉醇和多西他赛)是优良的抗肿瘤药物，主要用于治疗晚期乳腺癌、卵巢癌、非小细胞肺癌及前列腺癌等，对头颈部癌、胃癌、胰腺癌和黑色素瘤等也具有一定疗效。然而，虽然紫杉烷类药物的抗癌活性好，但它们的水溶性差、口服给药生物利用度低，因而在临床上只能通过注射给药。这类化合物在用于临床时，常加入非离子表面活性剂如聚乙氧基蓖麻油或吐温-80等助溶，以配制成注射剂。令人遗憾的是，这类表面活性剂具有血管舒张、血压降低、肝脏毒性及严重的过敏反应等副作用，使得紫杉烷类药物在临床应用中受到很大的限制。鉴于此，世界上许多药物学家力图通过剂型改进和结构改造来改变这种状态。
在本发明的申请人于2015年2月提交的第PCT/CN2015/073178号国际专利申请中，报道了具有以下式2的结构的水溶性紫杉烷类前药。这类前药具有良好的水溶性以及与原药一致的抗肿瘤活性，从而消除了原有紫杉烷类注射剂中因助溶剂而带来的毒副作用：
其中R1为叔丁氧基或苯基；R2为H或乙酰基；X为H、C1-6烷基或F；Y为F或者被一个或多个F取代的C1-6烷基；n为1、2、3、4、5或6；W为NR5R6·A或
R5、R6各自独立地为H、任选地被苯基取代的C1-6烷基或C3-6环烷基；m为0、1、2或3；A为药学可接受的酸。
在上述专利申请中描述了以下两种制备的方法：
其一，以多西他赛或紫杉醇为原料，在三乙胺、吡啶或4-N,N-二甲基氨基吡啶(DMAP)的催化下与氨基酸酰氯反应，从而制备式2的化合物；
其二，以多西他赛或紫杉醇为原料，在具有碳二亚胺结构的化合物(如二环己基碳二亚胺(DCC)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)等)的存在下，以DMAP、三乙胺或吡啶等有机碱作为催化剂与氨基酸反应，从而制备式2的化合物。
这两种方法虽然都能够制得式2化合物，但由于多西他赛和紫杉醇的结构中除了2’位的羟基外，在7位和/或10位也存在羟基，因而在制备过程中会生成7位取代和/或10位取代的产物以及2’位和7位同时取代和/或2’位和10位同时取代的二取代产物，甚至更多位点的取代产物，使得不仅降低了终产物的收率，还产生了大量影响产品质量的杂质。
发明内容
根据本发明的第一方面，本发明提供了一种制备由式2表示的紫杉烷类衍生物的方法：
其中：
R1为叔丁氧基或苯基；
R2为H或乙酰基；
X为H、C1-6烷基或F；
Y为F或者被一个或多个F取代的C1-6烷基；
n为1、2、3、4、5或6；
W为NR5R6·A或
R5、R6各自独立地为H、任选地被苯基取代的C1-6烷基、或C3-6环烷基；
m为0、1、2或3；且
A为药学可接受的酸，
所述方法包括：以式1的化合物为原料制备所述式2的化合物：
其中：
R1、X、Y、n如上文中对式2的化合物所定义；
R3为乙酰基、任选地被一个或多个卤素取代的苄氧羰基、或烯丙氧羰基；
R4为任选地被一个或多个卤素取代的苄氧羰基、或烯丙氧羰基；
W1为NR5R6·B或
R5、R6、m如上文中对式2的化合物所定义；且
B为酸。
与第PCT/CN2015/073178号国际专利申请中所公开的两种方法相比，本发明所提供的方法产生极少的(甚至完全不产生)由7位取代和/或10位取代而导致的杂质以及由2’位和7位同时取代和/或由2’位和10位同时取代而导致的二取代杂质，具有更高的收率和产品纯度。
根据本发明的第二方面，本发明提供了一种用于制备式2的化合物的中间体化合物或其多晶型物、溶剂合物或水合物，所述中间体化合物具有以下通式1：
其中，
R1为叔丁氧基或苯基；
R3为乙酰基、任选地被一个或多个卤素取代的苄氧羰基、或烯丙氧羰基；
R4为任选地被一个或多个卤素取代的苄氧羰基、或烯丙氧羰基；
X为H、C1-6烷基或F；
Y为F或者被一个或多个F取代的C1-6烷基；
n为1、2、3、4、5或6；
W1为NR5R6·B或
R5、R6各自独立地为H、任选地被苯基取代的C1-6烷基、或C3-6环烷
基；
m为0、1、2或3；
B为酸。
图1为按照本发明实施例16的方法制备的2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]多西他赛盐酸盐的HPLC图谱。
图2为按照第PCT/CN2015/073178号国际专利申请所描述方法制备的2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]多西他赛盐酸盐的HPLC图谱。
图3为按照本发明实施例33的方法制备的2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]紫杉醇盐酸盐的HPLC图谱。
图4为按照第PCT/CN2015/073178号国际专利申请所描述方法制备的2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]紫杉醇盐酸盐的HPLC图谱。
定义
本文所用的术语“卤素”是指氟、氯、溴或碘，优选为氯或溴。
本文所用的术语“C1-6烷基”是指具有1-6个碳原子的饱和的直链或支链烃基，例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基等，优选甲基、乙基、丙基、异丙基、丁基或异丁基，更优选甲基、乙基、丙基或异丙基。
本文所用的术语“C3-6环烷基”是指具有3-6个碳原子的饱和的单环烃基，例如环丙基、环丁基、环戊基或环己基。
本文所用的术语“苄氧羰基”是指通过羰基键与分子的其余部分相连的苄氧基。
本文所用的术语“烯丙氧羰基”是指通过羰基键与分子的其余部分相连的烯丙氧基。
本文所用的术语“可与胺成盐的酸”是指有机化学领域常用的可与胺反应形成盐的无机酸或有机酸。所述无机酸包括但不限于盐酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、硝酸等。所述有机酸包括但不限于甲酸、乙
酸、丙酸、丁酸、特戊酸、三氟乙酸、二氟乙酸、氟乙酸、乙酰乙酸、苯甲酸、甲磺酸、乙磺酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、樟脑磺酸等。
本文所用的术语“药学可接受的酸”是指可药用的酸，例如盐酸、氢溴酸、硫酸、磷酸、碳酸、乙酸、丙酸、甲磺酸、乳酸、苯磺酸、对甲苯磺酸、丁二酸、马来酸、富马酸、酒石酸、枸橼酸或苹果酸。
本发明的化合物可以结晶形式或多晶型物形式存在，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
本发明的化合物可以其溶剂合物特别是水合物的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，例如水、乙醇、异丙醇、乙酸乙酯或丙酮。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
制备方法
本发明的一个目的在于提供一种制备由式2表示的紫杉烷类衍生物的方法：
其中：
R1为叔丁氧基或苯基；
R2为H或乙酰基；
X为H、C1-6烷基或F；
Y为F或者被一个或多个F取代的C1-6烷基；
n为1、2、3、4、5或6；
W为NR5R6·A或
R5、R6各自独立地为H、任选地被苯基取代的C1-6烷基、或C3-6环烷基；
m为0、1、2或3；且
A为药学可接受的酸，
所述方法包括：以式1的化合物为原料制备所述式2的化合物：
其中：
R1、X、Y、n如上文中对式2的化合物所定义；
R3为乙酰基、任选地被一个或多个卤素取代的苄氧羰基、或烯丙氧羰基；
R4为任选地被一个或多个卤素取代的苄氧羰基、或烯丙氧羰基；
W1为NR5R6·B或
R5、R6、m如上文中对式2的化合物所定义；且
B为酸。
根据本发明的一个实施方案，X为H、甲基、乙基、丙基、异丙基、丁基、异丁基或F。优选地，X为H、甲基或F。
根据本发明的一个实施方案，Y为F或者被一个或多个F取代的甲基、乙基、丙基、异丙基、丁基或异丁基。优选地，Y为F、CF3、CH2F或CHF2。
根据本发明的一个实施方案，n为1、2或3。
根据本发明的一个实施方案，R5、R6各自独立地为H、甲基、乙基、丙基、异丙基、丁基、异丁基、苄基、环丙基、环丁基、环戊基或环己基。优选地，R5、R6各自独立地为H、甲基、乙基或异丙基。
根据本发明的一个实施方案，m为2或3。
根据本发明的一个实施方案，A为盐酸、氢溴酸、硫酸、磷酸、碳酸、
乙酸、丙酸、甲磺酸、乙磺酸、乳酸、苯磺酸、对甲苯磺酸、丁二酸、马来酸、富马酸、酒石酸、枸橼酸或苹果酸。
根据本发明的一个实施方案，R3为乙酰基、任选地被一个或多个氯取代的苄氧羰基、或烯丙氧羰基。优选地，R3为乙酰基、苄氧羰基、3-氯苄氧羰基、4-氯苄氧羰基或烯丙氧羰基。更优选地，R3为乙酰基、苄氧羰基或3-氯苄氧羰基。
根据本发明的一个实施方案，当R2为H时，R3为任选地被一个或多个卤素取代的苄氧羰基、或烯丙氧羰基，优选为任选地被一个或多个氯取代的苄氧羰基、或烯丙氧羰基，更优选为苄氧羰基、3-氯苄氧羰基、4-氯苄氧羰基或烯丙氧羰基；当R2为乙酰基时，R3为乙酰基。
根据本发明的一个实施方案，R4为任选地被一个或多个氯取代的苄氧羰基、或烯丙氧羰基。优选地，R4为苄氧羰基、3-氯苄氧羰基、4-氯苄氧羰基或烯丙氧羰基。更优选地，R4为苄氧羰基或3-氯苄氧羰基。
根据本发明的一个实施方案，B为盐酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、硝酸、甲酸、乙酸、丙酸、丁酸、特戊酸、三氟乙酸、二氟乙酸、氟乙酸、乙酰乙酸、苯甲酸、甲磺酸、乙磺酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸或樟脑磺酸。优选地，B为盐酸。
根据本发明的一个实施方案，当X与Y不同时，同时与X和Y连接的碳原子为单一的R构型、单一的S构型，或R与S构型的混合物。
根据本发明的一个实施方案，所述方法包括：以所述式1的化合物为原料经由以下反应路线1制备所述式2的化合物：
反应路线1
其中R1、R2、R3、R4、X、Y、n、W1和W如上文中所定义。
步骤e：
根据本发明的一个实施方案，步骤e包括将式1的化合物氢解，从而得到式7的化合物。
优选地，所述氢解是在Pd试剂的存在下进行的。
根据本发明的一个实施方案，步骤e包括：
在适当的温度下，向含有式1化合物的有机溶剂中加入Pd试剂，向反应溶液中通入氢气，反应完毕后经后处理制得式7的化合物。
优选地，所述温度为-30-50℃，优选10-35℃。
优选地，所述有机溶剂为四氢呋喃、1,4-二氧六环、乙酸乙酯、乙酸丁酯或其组合，更优选为四氢呋喃或乙酸乙酯。
优选地，所述Pd试剂为Pd/C、PdCl2、Pd(PPh3)4或其组合，更优选为Pd/C，更优选为含Pd量为5-30％的Pd/C，最优选为含Pd量为5-10％的Pd/C。
优选地，所述Pd试剂的量为式1的化合物的量的5-60％，优选10-30％。
优选地，所通入的氢气的压力为1-5atm，优选1-2atm。
步骤f：
根据本发明的一个实施方案，步骤f包括使式7的化合物与所述药学可接受的酸A的盐反应，从而得到式2的化合物。
根据本发明的一个实施方案，当酸A为甲磺酸时，所述酸A的盐优选为甲磺酸银。
根据本发明的一个实施方案，步骤f包括：
在适当的温度下，将步骤e中所得的式7的化合物在有机溶剂中溶解后，用酸A的盐的水溶液(用酸A将pH调节至pH 5以下)洗涤，从而得到式2的化合物。所述有机溶剂为可溶解式7的化合物的非质子有机溶剂，例如二氯甲烷、氯仿、1,2-二氯乙烷、氯苯、乙腈等。
优选地，所述温度为-10-30℃，优选0-15℃。
根据本发明的另一个实施方案，当酸A为甲磺酸时，步骤f包括：
在适当的温度下，向含有式7的化合物的有机溶剂中加入甲磺酸银的乙腈溶液，避光搅拌，反应完成后经后处理得到相应的式2的化合物。所述有机溶剂为可溶解式7的化合物的非质子有机溶剂，例如二氯甲烷、氯仿、1,2-二氯乙烷、氯苯、乙腈等。
优选地，所述温度为-30-50℃，优选-10-30℃。
优选地，式7的化合物与甲磺酸银的摩尔比为1:(0.8-1.1)。
根据本发明的一个实施方案，式1的化合物可经由以下反应路线2制得：
反应路线2
其中R1、R2、R3、R4、X、Y、n和W1如上文中所定义；且
G为羟基或卤素。
根据本发明的一个实施方案，G为羟基、Cl或Br。
步骤a：
根据本发明的一个实施方案，步骤a包括使式3的化合物与酰化试剂反应，从而得到式4的化合物。
根据本发明的一个实施方案，所述酰化试剂为氯甲酸苄酯、3-氯苄基氯甲酸酯、4-氯苄基氯甲酸酯或氯甲酸烯丙酯。
根据本发明的一个实施方案，可以参照第US6307071号专利或徐少杰，
《多西他赛合成工艺》，科技导报2010(28)13:82-86中报道的方法进行步骤a的反应。
步骤b：
根据本发明的一个实施方案，步骤b包括使式4的化合物与式8的化合物反应，从而制得式5的化合物。
优选地，步骤b的反应是在碱性试剂的存在下进行的。
根据本发明的一个实施方案，可以参照第US5336785号专利或徐少杰，《多西他赛合成工艺》，科技导报2010(28)13:82-86中报道的方法进行步骤b的反应。
根据本发明的一个实施方案，步骤b包括：
在适当的温度下，使式4的化合物与式8的化合物在碱性试剂的存在下，在有机溶剂中反应，从而制得式5的化合物。
优选地，所述温度为-40-40℃，优选-20-10℃。
优选地，所述有机溶剂为四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二乙基甲酰胺或其组合。
优选地，所述碱性试剂为氢化钠、双(三甲基硅烷基)氨基钠、正丁基锂、二异丙基氨基锂或其组合，更优选为氢化钠。
步骤c：
根据本发明的一个实施方案，步骤c包括在酸性条件下使式5的化合物脱去2’位的保护基，从而得到式6的化合物。
优选地，步骤c在-10-60℃，优选20-35℃的反应温度下进行。
优选地，所述酸性条件为酸与水的混合物，例如乙酸与水的混合物。
步骤d：
根据本发明的一个实施方案，步骤d包括使式6的化合物与式9的化合物在含氮碱性有机试剂或者由含氮碱性有机试剂与具有碳二亚胺结构的化合物组成的混合试剂的存在下反应。
优选地，所述含氮碱性有机试剂为有机碱，例如三乙胺、吡啶、4-N,N-二甲基氨基吡啶(DMAP)、4-吡咯烷基吡啶(4-PPY)或其组合。
优选地，所述具有碳二亚胺结构的化合物为二环己基碳二亚胺(DCC)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)或其组合。
优选地，在由含氮碱性有机试剂与具有碳二亚胺结构的化合物组成的混合试剂中，前者与后者的摩尔比为1:(1-5)。
根据本发明的一个实施方案，当式9的化合物中的G为卤素(例如Cl或Br)时，步骤d在含氮碱性有机试剂的存在下进行。
根据本发明的一个实施方案，当式9的化合物中的G为卤素(例如Cl或Br)时，步骤d包括：
在适当的温度下，在含氮碱性有机试剂的存在下，使式6的化合物与式9的化合物在有机溶剂中反应，从而制得式1的化合物。
优选地，所述温度为-100-40℃，优选-60-0℃，更优选-30-0℃。
优选地，式6的化合物、式9的化合物与含氮碱性有机试剂的摩尔比为1:(1-12.0):(1-15.0)，优选1:(1-4.0):(1-8.0)。
优选地，所述有机溶剂为二氯甲烷、氯仿、1,2-二氯乙烷或其组合。
根据本发明的一个实施方案，当式9的化合物中的G为羟基时，步骤d在含氮碱性有机试剂与具有碳二亚胺结构的化合物组成的混合试剂的存在下进行
根据本发明的一个实施方案，当式9的化合物中的G为羟基时，步骤d包括：
在适当的温度下，在含氮碱性有机试剂与具有碳二亚胺结构的化合物组成的混合试剂的存在下，使式6的化合物与式9的化合物在有机溶剂中反应，从而制得式1的化合物。
优选地，所述温度为-60-40℃，优选-30-30℃，更优选-30-0℃。
优选地，式6的化合物、式9的化合物与含氮碱性有机试剂与具有碳二亚胺结构的化合物组成的混合试剂的摩尔比为1:(1-12.0):(1-15.0)，优选1:(1-4.0):(1-8.0)。
优选地，所述有机溶剂为二氯甲烷、氯仿、1,2-二氯乙烷或其组合。
根据本发明的一个实施方案，其中G为卤素(例如Cl或Br)的式9的化合物可以通过使其中G为羟基的相应化合物与卤代试剂(例如二氯亚砜、三氯化磷、五氯化磷、三溴化磷等)进行卤代反应而得到。
与第PCT/CN2015/073178号国际专利申请中所公开的两种方法相比，本发明的方法具有以下优点：
本发明方法克服了原有路线中存在的产生由7位取代和/或10位取代而导致的杂质、由2’位和7位同时取代和/或由2’位和10位同时取代而导致的二取代杂质以及甚至更多取代的杂质的缺陷。采用本发明的方法制得的式2的化合物具有更高的收率和产品纯度。
中间体化合物
本发明的另一目的在于提供一种用于制备式2的化合物的中间体化合物或其多晶型物、溶剂合物或水合物，所述中间体化合物具有以下通式1：
其中，
R1为叔丁氧基或苯基；
R3为乙酰基、任选地被一个或多个卤素取代的苄氧羰基、或烯丙氧羰基；
R4为任选地被一个或多个卤素取代的苄氧羰基、或烯丙氧羰基；
X为H、C1-6烷基或F；
Y为F或者被一个或多个F取代的C1-6烷基；
n为1、2、3、4、5或6；
W1为NR5R6·B或
R5、R6各自独立地为H、任选地被苯基取代的C1-6烷基、或C3-6环烷基；
m为0、1、2或3；
B为酸。
根据本发明的一个实施方案，R3为乙酰基、任选地被一个或多个氯取
代的苄氧羰基、或烯丙氧羰基。优选地，R3为乙酰基、苄氧羰基、3-氯苄氧羰基、4-氯苄氧羰基或烯丙氧羰基。更优选地，R3为乙酰基、苄氧羰基或3-氯苄氧羰基。
根据本发明的一个实施方案，R4为任选地被一个或多个氯取代的苄氧羰基、或烯丙氧羰基。优选地，R4为苄氧羰基、3-氯苄氧羰基、4-氯苄氧羰基或烯丙氧羰基。更优选地，R4为苄氧羰基或3-氯苄氧羰基。
根据本发明的一个实施方案，X为H、甲基、乙基、丙基、异丙基、丁基、异丁基或F。优选地，X为H、甲基或F。
根据本发明的一个实施方案，Y为F或者被一个或多个F取代的甲基、乙基、丙基、异丙基、丁基或异丁基。优选地，Y为F、CF3、CH2F或CHF2。
根据本发明的一个实施方案，n为1、2或3。
根据本发明的一个实施方案，R5、R6各自独立地为H、甲基、乙基、丙基、异丙基、丁基、异丁基、苄基、环丙基、环丁基、环戊基或环己基。优选地，R5、R6各自独立地为H、甲基、乙基或异丙基。
根据本发明的一个实施方案，m为2或3。
根据本发明的一个实施方案，B为可与胺成盐的酸，例如盐酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、硝酸、甲酸、乙酸、丙酸、丁酸、特戊酸、三氟乙酸、二氟乙酸、氟乙酸、乙酰乙酸、苯甲酸、甲磺酸、乙磺酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸或樟脑磺酸。优选地，B为盐酸。
根据本发明的一个实施方案，R3为乙酰基、苄氧羰基、3-氯苄氧羰基、4-氯苄氧羰基或烯丙氧羰基；R4为苄氧羰基、3-氯苄氧羰基、4-氯苄氧羰基或烯丙氧羰基；X为H、甲基或F；Y为F、CF3、CH2F或CHF2；n为1、2或3；R5、R6各自独立地为H、甲基、乙基或异丙基；m为2或3；且B为盐酸。
根据本发明的一个实施方案，当X与Y不同时，同时与X和Y连接的碳原子为单一的R构型、单一的S构型，或R与S构型的混合物。
根据本发明的一个实施方案，本发明的式1的化合物选自：
实施例
为了使本发明的目的和技术方案更加清楚，下面对本发明的优选实施例进行详细的描述。要说明的是：以下实施例只用于对本发明进行进一步的说明，而不能理解为对本发明保护范围的限制。本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。本领域普通技术人员能够根据实际情况确定干燥剂的用量与结晶溶剂的的用量。
多西他赛水溶性衍生物及中间体的制备
实施例1
7,10-O-二苄氧羰基-10-脱乙酰巴卡丁III的制备
室温下，将10-脱乙酰巴卡丁III(13.0g，23.9mmol)溶于无水四氢呋喃(180ml)，加入DMAP(29.1g，0.239mol)，缓慢加热至40-50℃。滴加含有氯甲酸苄酯(40.7g，0.239mol)的无水四氢呋喃溶液(80ml)，经HPLC监测反应。反应完毕后，过滤，将滤液减压浓缩以除去溶剂，将残余物用乙酸乙酯(300ml)溶解，用饱和氯化铵(50ml×2)洗涤有机层，再用饱和食盐水(50ml)洗涤，无水硫酸镁干燥，过滤，将滤液减压浓缩以除去溶剂，将残余物用乙酸乙酯和石油醚结晶，得到白色固体18.6g，收率96％。ESI-MS[M]+＝812.24；13C-NMR(600MHz，CDCl3)δ：10.61，15.37，20.09，22.56，25.62，26.57，33.44，38.36，42.69，47.43，56.30，67.96，67.98，69.87，70.05，74.31，75.61，76.36，78.71，78.95，80.60，83.94，128.26，128.32，128.36，128.44，128.49，128.60，128.65，129.29，130.10，131.46，133.70，135.24，135.33，145.64，154.18，154.20，166.97，170.73，201.96。
实施例2
7,10-O-二(3-氯苄氧羰基)-10-脱乙酰巴卡丁III的制备
以10-脱乙酰巴卡丁III为原料，3-氯苄基氯甲酸酯为羟基保护剂，按照实施例1的操作制得标题化合物。ESI-MS[M]+＝880.21
实施例3
7,10-O-二烯丙氧羰基-10-脱乙酰巴卡丁III的制备
以10-脱乙酰巴卡丁III为原料，氯甲酸烯丙酯为羟基保护剂，按照实施例1的操作制得标题化合物。ESI-MS[M]+＝712.23
实施例4
2’-O-(1-乙氧基乙基)-7,10-O-二苄氧羰基多西他赛的制备
将7,10-O-二苄氧羰基-10-脱乙酰巴卡丁III(8.2g，10mmol)溶于无水四氢呋喃(90ml)，将溶液冷却至-20℃，加入60wt％氢化钠(600mg，15mmol)，搅拌30min，滴加含有(3R,4S)-3-(1-乙氧基乙氧基)-2-氧代-4-苯基-氮杂环丁基羧酸叔丁酯(4.4g，13mmol)的无水四氢呋喃溶液(50ml)，滴加时反应容器内的温度不超过-15℃，滴加完毕后缓慢升温至0℃，经HPLC监测反应。
反应完毕后，向反应液中加入饱和氯化铵(5ml)，通过减压浓缩除去溶剂，将残余物用乙酸乙酯(100ml)溶解，将有机层依次用饱和氯化铵(30ml×2)，饱和食盐水(50ml)洗涤，用无水硫酸钠干燥，过滤，将滤液减压浓缩以除去溶剂，将残余物用乙酸乙酯-石油醚结晶，得到白色固体10.5g，收率91％。ESI-MS[M]+＝1147.32；13C-NMR(600MHz,CDCl3)δ：10.69，14.74，18.45，20.93，22.55，26.34，28.22，30.97，33.44，35.32，43.19，46.98，56.26，58.49，69.98，70.12，72.37，73.57，74.32，75.37，76.42，78.37，78.70，80.25，80.94，83.86，126.81，128.10，128.25，128.27，128.45，128.54，128.63，128.73，128.87，129.07，130.18，132.57，133.77，135.14，135.26，141.76，154.18，166.94，170.25，201.56。
实施例5
2’-O-(1-乙氧基乙基)-7,10-O-二(3-氯苄氧羰基)多西他赛的制备
以7,10-O-二(3-氯苄氧羰基)-10-脱乙酰巴卡丁III为原料，按照实施例4的操作制得标题化合物。ESI-MS[M]+＝1215.36
实施例6
2’-O-(1-乙氧基乙基)-7,10-O-二烯丙氧羰基多西他赛的制备
以7,10-O-二烯丙氧羰基-10-脱乙酰巴卡丁III为原料，按照实施例4的操作制得标题化合物。ESI-MS[M]+＝1047.41
实施例7
7,10-O-二苄氧羰基多西他赛的制备
室温下，将2’-O-(1-乙氧基乙基)-7,10-O-二苄氧羰基多西他赛(5g，4.4mmol)溶于乙酸(32ml)，缓慢滴加水(5ml)，滴加完毕后，在室温下反应，经HPLC监测反应。反应完毕后，继续向反应混合物中加入水(70ml)，有白色固体析出，过滤，将滤饼用冷水洗涤(30ml×2)后减压真空干燥，得白色固体4.5g，收率96％。ESI-MS[M]+＝1075.38；13C-NMR(600MHz,CDCl3)δ：10.65，14.69，20.90，22.51，26.30，28.18，29.66，30.89，33.39，35.28，43.14，46.93，56.20，69.93，70.08，72.28，73.54，74.27，75.33，76.33，78.32，78.63，80.19，80.87，83.81，126.76，128.04，128.20，128.32，128.41，128.58，128.67，128.81，129.02，130.13，132.49，133.72，135.08，135.20，138.33，141.67，154.09，154.12，155.32，166.83，170.21，172.69，201.51。
实施例8
7,10-O-二(3-氯苄氧羰基)多西他赛的制备
以2’-O-(1-乙氧基乙基)-7,10-O-二(3-氯苄氧羰基)多西他赛为原料，按照实施例7的操作制得标题化合物。ESI-MS[M]+＝1143.29
实施例9
7,10-O-二烯丙氧羰基多西他赛的制备
以2’-O-(1-乙氧基乙基)-7,10-O-二烯丙氧羰基多西他赛为原料，按照实施例7的操作制得标题化合物。ESI-MS[M]+＝975.33
实施例10
2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]-7,10-O-二苄氧羰基多西他赛盐酸盐的制备(化合物1)
1)4-N,N-二甲基氨基-2(R)-氟代丁酰氯盐酸盐的制备：于烧瓶中，将4-N,N-二甲基氨基-2(R)-氟代丁酸盐酸盐(1.67g，9mmol)加入到二氯亚砜(10ml)中，缓慢加热至40℃，反应4小时。通过减压蒸发除去二氯亚砜，加入无水二氯甲烷(25ml)，再通过减压蒸发除去溶剂，向残余物中加入无水二氯甲烷(60ml)，备用。
2)在-50℃下，在150ml无水二氯甲烷(DCM)中加入7,10-O-二苄氧羰基多西他赛(2.2g，2mmol)、4-N,N-二甲基氨基吡啶(1.4g，11.5mmol)，搅拌使之溶解。缓缓滴加1)中制得的4-N,N-二甲基氨基-2(R)-氟代丁酰氯盐酸盐的二氯甲烷溶液，经HPLC检测反应，反应完全后用饱和氯化钠水溶液(用盐酸调节pH约2.0)洗涤DCM层，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去DCM，将残余物用丙酮和甲基叔丁基醚结晶，得白色固体2.16g，收率85％。ESI-MS[M+H]+＝1207.53；13C-NMR(600MHz,DMSO)δ：10.83，14.62，21.52，22.88，26.57，27.27，28.56，31.13，33.34，34.62，40.41，42.69，43.26，46.65，52.34，55.34，55.84，69.83，69.93，71.73，74.31，75.56，75.99，77.05，78.32，79.14，80.13，83.17，85.84，87.05，127.83，128.8，128.84，128.96，129.02，129.16130.07，130.12，132.66，134.06，135.53，135.63，137.50，141.78，153.88，153.93，155.66，165.65，169.05，170.5，202.1。
实施例11
2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]-7,10-O-二(3-氯苄氧羰基)多西他赛盐酸盐的制备(化合物2)
以7,10-O-二(3-氯苄氧羰基)多西他赛为原料，4-N,N-二甲基氨基-2(R)-氟代丁酸盐酸盐为酰化剂，按照实施例10的操作制得标题化合物。ESI-MS[M+H]+＝1275.39
实施例12
2′-O-[4-N,N-二甲基氨基-2(S)-氟代丁酰基]-7,10-O-二苄氧羰基多西他赛盐酸盐的制备(化合物6)
以7,10-O-二苄氧羰基多西他赛为原料，4-N,N-二甲基氨基-2(S)-氟代丁酸盐酸盐为酰化剂，按照实施例10的操作制得标题化合物。ESI-MS[M+H]+＝1207.47
实施例13
2′-O-[4-N,N-二甲基氨基-2(S)-氟代丁酰基]-7,10-O-二烯丙氧羰基多西他赛盐酸盐的制备(化合物8)
以7,10-O-二烯丙氧羰基多西他赛为原料，4-N,N-二甲基氨基-2(S)-氟代丁酸盐酸盐为酰化剂，按照实施例10的操作制得标题化合物。ESI-MS[M+H]+＝1107.43
实施例14
2′-O-[4-N,N-二乙基氨基-2(R)-氟代丁酰基]-7,10-O-二苄氧羰基多西他赛盐酸盐的制备(化合物17)
以7,10-O-二苄氧羰基多西他赛为原料，4-N,N-二乙基氨基-2(R)-氟代丁酸盐酸盐为酰化剂，按照实施例10的操作制得标题化合物。ESI-MS[M+H]+＝1235.48.
实施例15
2′-O-[4-N,N-二甲基氨基-2(R)-三氟甲基丁酰基]-7,10-O-二(3-氯苄氧羰基)多西他赛盐酸盐的制备(化合物19)
以7,10-O-二(3-氯苄氧羰基)多西他赛为原料，4-N,N-二甲基氨基-2(R)-三氟甲基丁酸盐酸盐为酰化剂，按照实施例10的操作制得标题化合物。ESI-MS[M+H]+＝1325.37.
实施例16
2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]多西他赛盐酸盐的制备
室温下，将2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]-7,10-O-二苄氧羰基多西他赛盐酸盐(化合物1，1.25g，1mmol)溶于无水四氢呋喃(30ml)，加入10％Pd/C(120mg)，通入氢气，在室温下反应1.5小时。反应完全后，用无水四氢呋喃(20ml)稀释反应液，过滤，将滤饼通过减压浓缩除去溶剂，得到白色固体0.88g，收率90％。ESI-MS[M+H]+＝939.37；13C-NMR(600MHz,DMSO)δ:209.458，169.376，168.425，167.682，167.513，166.869，165.229，155.167，137.026，136.896，135.884，133.171，131.278，129.960，129.539，128.542，128.044，127.201，86.406，85.187，83.701，80.367，79.033，78.811，78.596，76.788，75.416，74.703，73.715，71.883，70.710，67.308，57.007，54.708，51.949，45.925，42.867，42.515，42.086，39.909，39.771，39.625，39.488，39.350，39.212，39.074，38.077，36.391，34.675，29.777，28.980，28.337，28.061，26.566，26.436，26.298，23.209，22.405，20.627，13.806，13.614，10.717，9.667。
实施例16所制备的产物的HPLC纯度为99.2％，其HPLC图谱参见图1。
比较例1
按照第PCT/CN2015/073178号国际专利申请所描述的方法制备2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]多西他赛盐酸盐
在-15℃下，在150ml二氯甲烷(DCM)中加入多西他赛(2.1g)、4-N,N-二甲基氨基吡啶(1.8g)，搅拌使之溶解，缓缓滴加4-N,N-二甲基氨基-2(R)-氟代丁酰氯盐酸盐(以4-N,N-二甲基氨基-2(R)-氟代丁酸盐酸盐为原料制得)的二氯甲烷溶液，经HPLC检测反应，反应完全后用饱和氯化钠水溶液(用盐酸调节pH约3.0)洗涤DCM层，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去DCM，将残余物用丙酮和甲基叔丁基醚结晶，得到白色固体，收率51％。
比较例1所制备的产物的HPLC纯度为96.5％，其HPLC图谱参见图2。
由以上数据可以看出按照本发明提供的制备方法制备得到的水溶性多西他赛衍生物的纯度高于按照第PCT/CN2015/073178号国际专利申请所描
述的方法制得的相应产物的纯度。
实施例17
2′-O-[4-N,N-二乙基氨基-2(R)-氟代丁酰基]多西他赛盐酸盐的制备
以2′-O-[4-N,N-二乙基氨基-2(R)-氟代丁酰基]-7,10-O-二苄氧羰基多西他赛盐酸盐(化合物17)为原料，按照实施例16的操作制得标题化合物，收率88％，HPLC纯度98.54％。ESI-MS[M+H]+＝967.41.
实施例18
2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]多西他赛甲磺酸盐的制备
室温下，将2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]多西他赛盐酸盐(1.0g，10mmol)溶于干燥的二氯甲烷中，加入含有甲磺酸银(208mg，10mmol)的乙腈溶液(1ml)，避光搅拌，取样过滤，用AgNO3溶液监测滤液中是否还含有氯离子，反应完全后，过滤，将滤液通过减压浓缩除去有机溶剂，得白色固体1g，收率96％。
实施例19
2′-O-[4-N,N-二乙基氨基-2(S)-氟代丁酰基]多西他赛甲磺酸盐的制备
以2′-O-[4-N,N-二乙基氨基-2(S)-氟代丁酰基]多西他赛盐酸盐为原料，按照实施例18的操作制备标题化合物。
紫杉醇水溶性衍生物及中间体的制备
实施例20
7-O-苄氧羰基-巴卡丁III的制备
室温下，将巴卡丁III(15.0g，25.6mmol)溶于无水四氢呋喃(200ml)，加入DMAP(31.2g，0.256mol)，缓慢加热至40-50℃，滴加含有氯甲酸苄酯(43.6g，0.256mol)的无水四氢呋喃溶液(100ml)，经HPLC监测反应。反应完毕后，过滤，将滤液减压浓缩以除去溶剂，将残余物用乙酸乙酯(300ml)溶解，用饱和氯化铵(50ml×2)洗涤有机层，再用饱和食盐水(50ml)洗涤，用无水硫酸镁干燥，过滤，将滤液减压浓缩以除去溶剂，将残余物用乙酸乙酯和石油醚结晶，得白色固体17.5g，收率95％。ESI-MS[M]+＝720.19。
实施例21
7-O-(3-氯苄氧羰基)-巴卡丁III的制备
以巴卡丁III为原料，3-氯苄基氯甲酸酯为羟基保护剂，按照实施例20的操作制得标题化合物。ESI-MS[M]+＝754.21
实施例22
7-O-(4-氯苄氧羰基)-巴卡丁III的制备
以巴卡丁III为原料，4-氯苄基氯甲酸酯为羟基保护剂，按照实施例20的操作制得标题化合物。ESI-MS[M]+＝754.17
实施例23
2’-O-(1-乙氧基乙基)-7-O-苄氧羰基紫杉醇的制备
将7-O-苄氧羰基-巴卡丁III(7.2g，10mmol)溶于无水四氢呋喃(80ml)，冷却至-20℃，加入60％氢化钠(600mg，15mmol)，搅拌30min，滴加含有(3R,4S)-1-苯甲酰基-3-(1-乙氧基乙氧基)-4-苯基-2-氮杂环丁酮(4.41g，13mmol)的无水四氢呋喃溶液(50ml)，滴加时反应容器内的温度不超过-10℃，滴加完毕后缓慢升温至0℃，经HPLC监测反应。反应完毕后，向反应液中加入饱和氯化铵(5ml)，通过减压浓缩除去溶剂，将残余物用乙酸乙酯(100ml)溶解，将有机层依次用饱和氯化铵(30ml×2)，饱和食盐水(50ml)洗涤，用无水硫酸钠干燥，过滤，将滤液减压浓缩以除去溶剂，将残余物用乙酸乙酯-石油醚结晶，得到白色固体9.5g，收率90％。ESI-MS[M]+＝1059.38。
实施例24
2’-O-(1-乙氧基乙基)-7-O-(3-氯苄氧羰基)紫杉醇的制备
以7-O-(3-氯苄氧羰基)-巴卡丁III为原料，按照实施例23的操作制得标题化合物。ESI-MS[M]+＝1093.18
实施例25
2’-O-(1-乙氧基乙基)-7-O-烯丙氧羰基紫杉醇的制备
以7-O-烯丙氧羰基-巴卡丁III为原料，按照实施例23的操作制得标题化合物。ESI-MS[M]+＝1009.37
实施例26
7-O-苄氧羰基紫杉醇的制备
室温下，将2’-O-(1-乙氧基乙基)-7-O-苄氧羰基紫杉醇(3g，2.8mmol)溶于乙酸(15ml)中，缓慢滴加水(3ml)，滴加完毕后，经HPLC监测反应。
反应完毕后，向反应中加入水(50ml)，有白色固体析出，过滤，将滤饼用冷水洗涤(25ml×2)后，减压真空干燥，得白色固体2.74g，收率98％。ESI-MS[M]+＝987.34。
实施例27
7-O-(3-氯苄氧羰基)紫杉醇的制备
以2’-O-(1-乙氧基乙基)-7-O-(3-氯苄氧羰基)紫杉醇为原料，按照实施例26的操作制得标题化合物。ESI-MS[M]+＝1021.29。
实施例28
2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]-7-O-苄氧羰基紫杉醇盐酸盐的制备(化合物10)
1)4-N,N-二甲基氨基-2(R)-氟代丁酰氯盐酸盐的制备：于烧瓶中，将4-N,N-二甲基氨基-2(R)-氟代丁酸盐酸盐(1.67g，9mmol)加入二氯亚砜(10ml)中，缓慢加热至40℃，反应4小时。通过减压蒸发除去二氯亚砜，加入无水二氯甲烷(25ml)，再通过减压蒸发除去溶剂，向残余物中加入无水二氯甲烷(60ml)，备用。
2)在-50℃下，在150ml无水二氯甲烷(DCM)中加入7-O-苄氧羰基紫杉醇(2.2g，2.2mmol)、4-N,N-二甲基氨基吡啶(1.4g，11.5mmol)，搅拌使之溶解；缓缓滴加1)中制得的4-N,N-二甲基氨基-2(R)-氟代丁酰氯盐酸盐的二氯甲烷溶液，经HPLC检测反应。反应完全后用饱和氯化钠水溶液(用盐酸调节pH约2.0)洗涤DCM层，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去DCM，将残余物用丙酮和甲基叔丁基醚结晶，得白色固体2.05g，收率80％。ESI-MS[M+H]+＝1119.41。
实施例29
2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]-7-O-(4-氯苄氧羰基)紫杉醇盐酸盐的制备(化合物12)
以7-O-(4-氯苄氧羰基)紫杉醇为原料，4-N,N-二甲基氨基-2(R)-氟代丁酸盐酸盐为酰化剂，按照实施例28的操作制得标题化合物。ESI-MS[M+H]+＝1153.39。
实施例30
2′-O-[4-N,N-二乙基氨基-2(R)-氟代丁酰基]-7-O-苄氧羰基紫杉醇盐酸
盐的制备(化合物23)
以7-O-苄氧羰基紫杉醇为原料，4-N,N-二乙基氨基-2(R)-氟代丁酸盐酸盐为酰化剂，按照实施例28的操作制得标题化合物。ESI-MS[M+H]+＝1147.39。
实施例31
2′-O-[4-N,N-二甲基氨基-2(S)-氟代丁酰基]-7-O-(3-氯苄氧羰基)紫杉醇盐酸盐的制备(化合物14)
在室温下，在150ml乙腈中加入4-N,N-二甲基氨基-2(S)-氟代丁酸盐酸盐(2.0g，10.7mmol)、DMAP(1.8g，14.8mmol)、二环己基碳二亚胺(3.2g，15.3mmol)。加入7-O-(3-氯苄氧羰基)紫杉醇(1.6g，1.56mmol)，反应18小时。反应完全后通过减压蒸发除去溶剂，将残余物用二氯甲烷(100ml)溶解，用饱和氯化钠水溶液(盐酸调节pH约3.0)洗涤DCM层，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去DCM，将残余物用丙酮溶解，加入异丙醚析晶，得到白色固体1.58g，收率85％。ESI-MS[M+H]+＝1153.47。
实施例32
2′-O-[4-N,N-二乙基氨基-2(S)-氟代丁酰基]-7-O-苄氧羰基紫杉醇盐酸盐的制备(化合物28)
以7-O-苄氧羰基紫杉醇为原料，4-N,N-二乙基氨基-2(S)-氟代丁酸盐酸盐为酰化剂，按照实施例31的操作制得标题化合物。ESI-MS[M+H]+＝1147.39。
实施例33
2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]紫杉醇盐酸盐的制备
室温下，将2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]-7-O-苄氧羰基紫杉醇盐酸盐(1.30g，1.1mmol)溶于无水四氢呋喃(30ml)，加入10％Pd/C(130mg)，用氮气置换空气后，通入氢气，在室温下搅拌。反应完全后，用无水四氢呋喃(20ml)稀释反应液，过滤，将滤饼通过减压浓缩除去溶剂，得到白色固体1.05g，收率91％。
实施例33所制备的产品的HPLC纯度为97.99％，其HPLC图谱参见图3。
比较例2
按照第PCT/CN2015/073178号国际专利申请所描述的方法制备2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]紫杉醇盐酸盐
1)4-N,N-二甲基氨基-2(R)-氟代丁酰氯盐酸盐的制备：于烧瓶中，将4-N,N-二甲基氨基-2(R)-氟代丁酸盐酸盐(10mmol)加入二氯亚砜(10ml)中，缓慢加热至40℃，反应4小时。通过减压蒸发除去二氯亚砜，加入无水二氯甲烷15ml，再通过减压蒸发除去溶剂，在残余物中加入无水二氯甲烷(60ml)，备用。
2)在-50℃下，在150ml二氯甲烷(DCM)中加入紫杉醇(1.6g)、4-N,N-二甲基氨基吡啶(1.4g)，搅拌溶使之解。缓缓滴加步骤1)中制得的4-N,N-二甲基氨基-2(R)-氟代丁酰氯盐酸盐的二氯甲烷溶液，经HPLC检测反应。反应完全后用饱和氯化钠水溶液(用盐酸调节pH约3.0)洗涤DCM层，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去DCM，将残余物用丙酮和甲基叔丁基醚结晶，得到白色固体，收率50％。
比较例2所制备的产品的HPLC为纯度95.52％，其HPLC图谱参见图4。
由以上数据可以看出按照本发明提供的制备方法制备得到的水溶性紫杉醇衍生物的纯度高于按照第PCT/CN2015/073178号国际专利申请所描述的方法制得的相应产物的纯度。
实施例34
2′-O-[4-N,N-二甲基氨基-2(S)-氟代丁酰基]紫杉醇盐酸盐的制备
以2′-O-[4-N,N-二甲基氨基-2(S)-氟代丁酰基]-7-O-(3-氯苄氧羰基)紫杉醇盐酸盐为原料，按照实施例33的操作制得标题化合物，收率90％，HPLC纯度97.52％。
实施例35
2′-O-[4-N,N-二乙基氨基-2(R)-氟代丁酰基]紫杉醇盐酸盐的制备
以2′-O-[4-N,N-二乙基氨基-2(R)-氟代丁酰基]-7-O-(4-氯苄氧羰基)紫杉醇盐酸盐为原料，按照实施例33的操作制得标题化合物，收率91％，HPLC纯度97.43％。ESI-MS[M+H]+＝1013.38。
实施例36
2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]紫杉醇甲磺酸盐的制备
室温下，将2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]紫杉醇盐酸盐(1.0g，1mmol)溶于干燥的二氯甲烷中，加入含有甲磺酸银(20.8mg，1mmol)的乙腈溶液(1ml)，避光搅拌，取样过滤，用AgNO3溶液监测滤液中是否还有氯离子，反应完全后，过滤，滤液通过减压浓缩除去有机溶剂，得白色固体1g，收率94％。
实施例37
2′-O-[4-N,N-二乙基氨基-2(R)-氟代丁酰基]紫杉醇甲磺酸盐的制备
以2′-O-[4-N,N-二乙基氨基-2(R)-氟代丁酰基]紫杉醇盐酸盐为原料，按照实施例36的操作制得标题化合物。
按照上面描述的方法，发明人还制备了以下化合物：
2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]-7,10-O-二(4-氯苄氧羰基)多西他赛盐酸盐(化合物3)
2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]-7,10-O-二烯丙氧羰基多西他赛盐酸盐(化合物4)
2′-O-[4-N,N-二甲基氨基-2(S)-氟代丁酰基]-7,10-O-二(4-氯苄氧羰基)多西他赛盐酸盐(化合物5)
2′-O-[4-N,N-二甲基氨基-2(S)-氟代丁酰基]-7,10-O-二(3-氯苄氧羰基)多西他赛盐酸盐(化合物7)
2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]-7-O-烯丙氧羰基紫杉醇盐酸盐(化合物9)
2′-O-[4-N,N-二甲基氨基-2(R)-氟代丁酰基]-7-O-(3-氯苄氧羰基)紫杉醇盐酸盐(化合物11)
2′-O-[4-N,N-二甲基氨基-2(S)-氟代丁酰基]-7-O-(4-氯苄氧羰基)紫杉醇盐酸盐(化合物13)
2′-O-[4-N,N-二甲基氨基-2(S)-氟代丁酰基]-7-O-苄氧羰基紫杉醇盐酸盐(化合物15)
2′-O-[4-N,N-二甲基氨基-2(S)-氟代丁酰基]-7-O-烯丙氧羰基紫杉醇盐酸盐(化合物16)
2′-O-[4-N-甲基-N-乙基-氨基-2(R)-氟代丁酰基]-7,10-O-二苄氧羰基多西他赛盐酸盐(化合物18)
2′-O-[4-N,N-二甲基氨基-2-氟甲基丁酰基]-7,10-O-二(3-氯苄氧羰基)多西他赛盐酸盐(化合物20)
2′-O-[4-N-甲基氨基-2(R)-氟代丁酰基]-7,10-O-二苄氧羰基多西他赛盐酸盐(化合物21)
2′-O-[4-N-(吡咯烷-1-基)-2-氟代丁酰基]-7,10-O-二苄氧羰基多西他赛盐酸盐(化合物22)
2′-O-[4-N-甲基-N-乙基-氨基-2(R)-氟代丁酰基]-7-O-(4-氯苄氧羰基)紫杉醇盐酸盐(化合物24)
2′-O-[4-N-(哌啶烷-1-基)-2(R)-氟代丁酰基]-7-O-(4-氯苄氧羰基)紫杉醇盐酸盐(化合物25)
2′-O-[4-N-甲基氨基-2-氟甲基丁酰基]-7-O-苄氧羰基紫杉醇盐酸盐(化合物26)
2′-O-[4-N,N-二乙基氨基-2(S)-氟代丁酰基]-7,10-O-二苄氧羰基多西他赛盐酸盐(化合物27)
2′-O-[4-氨基-2(R)-氟代丁酰基]-7,10-O-二苄氧羰基多西他赛盐酸盐(化合物29)
2′-O-[4-氨基-2(R)-氟代丁酰基]-7-O-苄氧羰基紫杉醇盐酸盐(化合物30)
2′-O-[4-N-异丙基氨基-2(R)-氟代丁酰基]-7,10-O-二苄氧羰基多西他赛盐酸盐(化合物31)
2′-O-[4-N-异丙基氨基-2(R)-氟代丁酰基]-7-O-苄氧羰基紫杉醇盐酸盐(化合物32)
2′-O-[3-N-二甲基氨基-2(R)-氟代丙酰基]-7,10-O-二苄氧羰基多西他赛盐酸盐(化合物33)
2′-O-[5-N,N-二甲基氨基-2-氟代戊酰基]-7-O-苄氧羰基紫杉醇盐酸盐(化合物34)
从以上提供的实施例以及附图1-4可以看出，与第PCT/CN2015/073178号国际专利申请中所公开的方法相比，本发明所提供的方法产生极少的(甚
至完全不产生)由7位取代和/或10位取代而导致的杂质以及由2’位和7位同时取代和/或由2’位和10位同时取代而导致的二取代杂质，具有更高的收率和产品纯度。
Claims (15)
- 制备式2的化合物的方法：
其中：R1为叔丁氧基或苯基；R2为H或乙酰基；X为H、C1-6烷基或F，优选为H、甲基、乙基、丙基、异丙基、丁基、异丁基或F，更优选为H、甲基或F；Y为F或者被一个或多个F取代的C1-6烷基，优选为F或者被一个或多个F取代的甲基、乙基、丙基、异丙基、丁基或异丁基，更优选为F、CF3、CH2F或CHF2；n为1、2、3、4、5或6，优选为1、2或3；W为NR5R6·A或
R5、R6各自独立地为H、任选地被苯基取代的C1-6烷基、或C3-6环烷基，优选地，R5、R6各自独立地为H、甲基、乙基、丙基、异丙基、丁基、异丁基、苄基、环丙基、环丁基、环戊基或环己基，更优选地，R5、R6各自独立地为H、甲基、乙基或异丙基；m为0、1、2或3，优选为2或3；且A为药学可接受的酸，优选为盐酸、氢溴酸、硫酸、磷酸、碳酸、乙酸、丙酸、甲磺酸、乙磺酸、乳酸、苯磺酸、对甲苯磺酸、丁二酸、马来酸、富马酸、酒石酸、枸橼酸或苹果酸，其特征在于：以式1的化合物为原料制备所述式2的化合物：
其中：R1、X、Y、n如对式2的化合物所定义；R3为乙酰基、任选地被一个或多个卤素取代的苄氧羰基、或烯丙氧羰基，优选为乙酰基、任选地被一个或多个氯取代的苄氧羰基、或烯丙氧羰基，更优选为乙酰基、苄氧羰基、3-氯苄氧羰基、4-氯苄氧羰基或烯丙氧羰基；R4为任选地被一个或多个卤素取代的苄氧羰基、或烯丙氧羰基，优选为任选地被一个或多个氯取代的苄氧羰基、或烯丙氧羰基，更优选为苄氧羰基、3-氯苄氧羰基、4-氯苄氧羰基或烯丙氧羰基；W1为NR5R6·B或
R5、R6、m如对式2的化合物所定义；且B为酸，优选为盐酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、硝酸、甲酸、乙酸、丙酸、丁酸、特戊酸、三氟乙酸、二氟乙酸、氟乙酸、乙酰乙酸、苯甲酸、甲磺酸、乙磺酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸或樟脑磺酸，更优选为盐酸。 - 如权利要求1所述的方法，其特征在于：当R2为H时，R3为任选地被一个或多个卤素取代的苄氧羰基、或烯丙氧羰基，优选为任选地被一个或多个氯取代的苄氧羰基、或烯丙氧羰基，更优选为苄氧羰基、3-氯苄氧羰基、4-氯苄氧羰基或烯丙氧羰基；当R2为乙酰基时，R3为乙酰基。
- 如权利要求1所述的方法，其特征在于：当X与Y不同时，同时与 X和Y连接的碳原子为单一的R构型、单一的S构型，或R与S构型的混合物。
- 如权利要求1-3中任一项所述的方法，其特征在于：以所述式1的化合物为原料经由以下反应路线1制备所述式2的化合物：
其中R1、R2、R3、R4、X、Y、n、W1和W如权利要求1中所定义。 - 如权利要求4所述的方法，其特征在于：步骤e包括将所述式1的化合物氢解，从而得到式7的化合物。
- 如权利要求4所述的方法，其特征在于：步骤f包括使式7的化合物与所述药学可接受的酸A的盐反应，从而得到所述式2的化合物。
- 如权利要求6所述的方法，其特征在于：当A为甲磺酸时，所述A的盐为甲磺酸银。
- 如权利要求1所述的方法，其特征在于：所述式1的化合物是经由以下反应路线2制得的：
其中R1、R2、R3、R4、X、Y、n和W1如权利要求1中所定义；且G为羟基或卤素，优选为羟基、Cl或Br。 - 如权利要求8所述的方法，其特征在于：步骤a中的酰化试剂为氯甲酸苄酯、3-氯苄基氯甲酸酯、4-氯苄基氯甲酸酯或氯甲酸烯丙酯。
- 如权利要求8所述的方法，其特征在于：步骤b在诸如氢化钠、双 (三甲基硅烷基)氨基钠、正丁基锂、二异丙基氨基锂或其组合的碱性试剂的存在下进行，所述碱性试剂优选为氢化钠。
- 如权利要求8所述的方法，其特征在于：步骤c在酸性条件下进行。
- 如权利要求8所述的方法，其特征在于：当G为卤素时，步骤d在含氮碱性有机试剂的存在下进行；当G为羟基时，步骤d在含氮碱性有机试剂与具有碳二亚胺结构的化合物组成的混合试剂的存在下进行，所述含氮碱性有机试剂优选为三乙胺、吡啶、4-N,N-二甲基氨基吡啶、4-吡咯烷基吡啶或其组合；所述具有碳二亚胺结构的化合物优选为二环己基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐或其组合。
- 式1的化合物或其多晶型物、溶剂合物或水合物：
其中：R1为叔丁氧基或苯基；R3为乙酰基、任选地被一个或多个卤素取代的苄氧羰基、或烯丙氧羰基，优选为乙酰基、任选地被一个或多个氯取代的苄氧羰基、或烯丙氧羰基，更优选为乙酰基、苄氧羰基、3-氯苄氧羰基、4-氯苄氧羰基或烯丙氧羰基；R4为任选地被一个或多个卤素取代的苄氧羰基、或烯丙氧羰基，优选为任选地被一个或多个氯取代的苄氧羰基、或烯丙氧羰基，更优选为苄氧羰基、3-氯苄氧羰基、4-氯苄氧羰基或烯丙氧羰基；X为H、C1-6烷基或F，优选为H、甲基、乙基、丙基、异丙基、丁基、 异丁基或F，更优选为H、甲基或F；Y为F或者被一个或多个F取代的C1-6烷基，优选为F或者被一个或多个F取代的甲基、乙基、丙基、异丙基、丁基或异丁基，更优选为F、CF3、CH2F或CHF2；n为1、2、3、4、5或6，优选为1、2或3；W1为NR5R6·B或
R5、R6各自独立地为H、任选地被苯基取代的C1-6烷基、或C3-6环烷基，优选地，R5、R6各自独立地为H、甲基、乙基、丙基、异丙基、丁基、异丁基、苄基、环丙基、环丁基、环戊基或环己基，更优选地，R5、R6各自独立地为H、甲基、乙基或异丙基；m为0、1、2或3，优选为2或3；B为酸，优选为盐酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、硝酸、甲酸、乙酸、丙酸、丁酸、特戊酸、三氟乙酸、二氟乙酸、氟乙酸、乙酰乙酸、苯甲酸、甲磺酸、乙磺酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸或樟脑磺酸，更优选为盐酸。 - 如权利要求13所述的化合物或其多晶型物、溶剂合物或水合物，其特征在于：当X与Y不同时，同时与X和Y连接的碳原子为单一的R构型、单一的S构型，或R与S构型的混合物。
- 如权利要求13所述的化合物或其多晶型物、溶剂合物或水合物，所述化合物选自：
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|---|---|---|---|---|
| CN1709516A (zh) * | 2005-05-31 | 2005-12-21 | 赵洪 | 高水溶性前体药物及其制备方法和在制药中的应用 |
| CN101648973A (zh) * | 2009-09-03 | 2010-02-17 | 漆又毛 | 水溶性紫杉烷及制备方法 |
| US20100093935A1 (en) * | 2008-10-15 | 2010-04-15 | Nitto Denko Corporation | Method of preparing polyglutamate conjugates |
| CN101935336A (zh) * | 2010-09-01 | 2011-01-05 | 北京大学 | 一类水溶性紫杉烷类药物的制备方法和应用 |
| CN104693252A (zh) * | 2013-12-05 | 2015-06-10 | 中国科学院上海药物研究所 | 糖苷化紫杉烷类化合物及其制备方法 |
| WO2015120822A1 (zh) * | 2014-02-17 | 2015-08-20 | 江苏恩华络康药物研发有限公司 | 一类水溶性紫杉烷类衍生物及其用途 |
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| CN1709516A (zh) * | 2005-05-31 | 2005-12-21 | 赵洪 | 高水溶性前体药物及其制备方法和在制药中的应用 |
| US20100093935A1 (en) * | 2008-10-15 | 2010-04-15 | Nitto Denko Corporation | Method of preparing polyglutamate conjugates |
| CN101648973A (zh) * | 2009-09-03 | 2010-02-17 | 漆又毛 | 水溶性紫杉烷及制备方法 |
| CN101935336A (zh) * | 2010-09-01 | 2011-01-05 | 北京大学 | 一类水溶性紫杉烷类药物的制备方法和应用 |
| CN104693252A (zh) * | 2013-12-05 | 2015-06-10 | 中国科学院上海药物研究所 | 糖苷化紫杉烷类化合物及其制备方法 |
| WO2015120822A1 (zh) * | 2014-02-17 | 2015-08-20 | 江苏恩华络康药物研发有限公司 | 一类水溶性紫杉烷类衍生物及其用途 |
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