WO2007143839A1 - Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii - Google Patents
Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii Download PDFInfo
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- WO2007143839A1 WO2007143839A1 PCT/CA2007/001051 CA2007001051W WO2007143839A1 WO 2007143839 A1 WO2007143839 A1 WO 2007143839A1 CA 2007001051 W CA2007001051 W CA 2007001051W WO 2007143839 A1 WO2007143839 A1 WO 2007143839A1
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- 229960001592 paclitaxel Drugs 0.000 title claims abstract description 63
- 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 title claims abstract description 63
- 229930012538 Paclitaxel Natural products 0.000 title claims abstract description 61
- 229960003668 docetaxel Drugs 0.000 title claims abstract description 42
- 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 title claims abstract description 40
- WPPPFZJNKLMYBW-FAEUQDRCSA-N 13-acetyl-9-dihydrobaccatin iii Chemical compound O([C@@H]1[C@]2(O)C[C@@H](C(=C([C@@H](OC(C)=O)[C@H](O)[C@]3(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]31)OC(C)=O)C2(C)C)C)OC(=O)C)C(=O)C1=CC=CC=C1 WPPPFZJNKLMYBW-FAEUQDRCSA-N 0.000 title claims abstract description 28
- FFCWRLFQIKDRNO-UHFFFAOYSA-N 9-dihydro-13-acetyl baccatin III Natural products CC(=O)OC1C2C(O)CC(OC(=O)C)C3(CO3)C2C(OC(=O)C)C4(O)CC(OC(=O)C)C(=C(C1OC(=O)C)C4(C)C)C FFCWRLFQIKDRNO-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 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 title claims description 61
- 238000002360 preparation method Methods 0.000 title abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 63
- 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 claims abstract description 16
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 6
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N Benzylformate Chemical compound O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 15
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- AYTAKQFHWFYBMA-UHFFFAOYSA-N chromium dioxide Chemical compound O=[Cr]=O AYTAKQFHWFYBMA-UHFFFAOYSA-N 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 12
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- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
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- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 claims description 8
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
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- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
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- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 6
- 230000000850 deacetylating effect Effects 0.000 claims description 6
- 125000000532 dioxanyl group Chemical group 0.000 claims description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 6
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- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 5
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 claims description 4
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000005001 aminoaryl group Chemical group 0.000 claims description 4
- 125000005214 aminoheteroaryl group Chemical group 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 4
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 4
- 125000002088 tosyl group Chemical class [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 4
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- XHSOADPDMLUHPW-JQXSQYPDSA-N (2R,3S)-3-[1-ethoxyethyl-[(2-methylpropan-2-yl)oxycarbonyloxy]amino]-2-hydroxy-3-phenylpropanoic acid Chemical compound C(=O)(OC(C)(C)C)ON([C@H]([C@@H](O)C(=O)O)C1=CC=CC=C1)C(C)OCC XHSOADPDMLUHPW-JQXSQYPDSA-N 0.000 claims description 2
- IKGZHVRGUUZPII-CXRLMVSZSA-N (2R,3S)-3-[benzoyloxy(1-ethoxyethyl)amino]-2-hydroxy-3-phenylpropanoic acid Chemical compound C(C1=CC=CC=C1)(=O)ON([C@H]([C@@H](O)C(=O)O)C1=CC=CC=C1)C(C)OCC IKGZHVRGUUZPII-CXRLMVSZSA-N 0.000 claims description 2
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- 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 claims description 2
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical class [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims 3
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- XSYLUBKWRZCOQP-CXRLMVSZSA-N (3r,4s)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one Chemical compound N1([C@H]([C@H](C1=O)OC(C)OCC)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 XSYLUBKWRZCOQP-CXRLMVSZSA-N 0.000 claims 1
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- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)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)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 description 18
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- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
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- 150000004579 taxol derivatives Chemical class 0.000 description 2
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- ZOJKRWXDNYZASL-NSCUHMNNSA-N (e)-4-methoxybut-2-enoic acid Chemical compound COC\C=C\C(O)=O ZOJKRWXDNYZASL-NSCUHMNNSA-N 0.000 description 1
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 description 1
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- 125000006494 2-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 description 1
- GPVOTFQILZVCFP-UHFFFAOYSA-N 2-trityloxyacetic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(=O)O)C1=CC=CC=C1 GPVOTFQILZVCFP-UHFFFAOYSA-N 0.000 description 1
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- PVZFSFXWKJSMLV-UHFFFAOYSA-N 3-(1-ethoxyethylamino)-2-hydroxy-3-phenylpropanoic acid Chemical compound C(C)OC(C)NC(C(O)C(=O)O)C1=CC=CC=C1 PVZFSFXWKJSMLV-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- TUXYZHVUPGXXQG-UHFFFAOYSA-M 4-bromobenzoate Chemical compound [O-]C(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-M 0.000 description 1
- OTLNPYWUJOZPPA-UHFFFAOYSA-M 4-nitrobenzoate Chemical compound [O-]C(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-M 0.000 description 1
- NNJMFJSKMRYHSR-UHFFFAOYSA-M 4-phenylbenzoate Chemical compound C1=CC(C(=O)[O-])=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229930190007 Baccatin Natural products 0.000 description 1
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- 229910002651 NO3 Inorganic materials 0.000 description 1
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- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000027697 autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency Diseases 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
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- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229940120124 dichloroacetate Drugs 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 150000004141 diterpene derivatives Chemical group 0.000 description 1
- 125000000567 diterpene group Chemical group 0.000 description 1
- 150000004625 docetaxel anhydrous derivatives Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 230000032050 esterification Effects 0.000 description 1
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
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- 125000000524 functional group Chemical group 0.000 description 1
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- 125000006328 iso-butylcarbonyl group Chemical group [H]C([H])([H])C([H])(C(*)=O)C([H])([H])[H] 0.000 description 1
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- RMIODHQZRUFFFF-UHFFFAOYSA-M methoxyacetate Chemical compound COCC([O-])=O RMIODHQZRUFFFF-UHFFFAOYSA-M 0.000 description 1
- NYEBKUUITGFJAK-UHFFFAOYSA-N methylsulfanylmethanethioic s-acid Chemical compound CSC(O)=S NYEBKUUITGFJAK-UHFFFAOYSA-N 0.000 description 1
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- 239000011664 nicotinic acid Substances 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- HVAMZGADVCBITI-UHFFFAOYSA-M pent-4-enoate Chemical compound [O-]C(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-M 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- FAQJJMHZNSSFSM-UHFFFAOYSA-N phenylglyoxylic acid Chemical compound OC(=O)C(=O)C1=CC=CC=C1 FAQJJMHZNSSFSM-UHFFFAOYSA-N 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- 125000005547 pivalate group Chemical group 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- BEHTXUBGUDGCNQ-IEAAAIHOSA-N taxol c Chemical compound O([C@@H]1[C@]2(O)C[C@@H](C(=C([C@@H](OC(C)=O)C(=O)[C@]3(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]31)OC(C)=O)C2(C)C)C)OC(=O)[C@H](O)[C@@H](NC(=O)CCCCC)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 BEHTXUBGUDGCNQ-IEAAAIHOSA-N 0.000 description 1
- FREIOWMEKIXEPN-JQXSQYPDSA-N tert-butyl (3r,4s)-3-(1-ethoxyethyl)-2-oxo-4-phenylazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C(=O)[C@@H](C(C)OCC)[C@H]1C1=CC=CC=C1 FREIOWMEKIXEPN-JQXSQYPDSA-N 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- the present invention relates to a semi-synthetic process for the preparation of paclitaxel, docetaxel, the anticancer drugs, and 10-deacetylbaccatin III, a useful precursor for making them, the most popular anticancer drugs, and other taxane compounds. More particularly, this invention relates to a novel semisynthetic route to synthesize paclitaxel, docetaxel and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III, a taxane compound which is isolated from Taxus Canadensis, an evergreen bush found in Eastern Canada and Northeastern United States. (b) Description of Prior Art
- Taxanes are substances occurring naturally in yew trees such as Taxus brevifolia, Taxus baccata and Taxus canadensis, which is common in Eastern Canada and Northeast United States.
- One of the chemicals extracted from the needles of Taxus canadensis is 9-dihydro-13-acetylbaccatin III, which is used to produce 10-deacetylbaccatin III, a useful intermediate for the preparation of paclitaxel, docetaxel and their analogues thereof.
- taxane family of diterpenes is considered to be an exceptionally promising group of cancer chemotherapeutic agents.
- Many taxane derivatives including paclitaxel, docetaxel, taxol C and cephalomannine are highly cytotoxic and possess strong in vivo activities in a number of leukemic and other tumor systems.
- Paclitaxel, and a number of its derivatives have been shown to be effective against advanced breast and ovarian cancers in clinical trials. They have also exhibited promising activity against a number of other tumor types in preliminary investigations.
- Paclitaxel, docetaxel have recently been approved in the U.S. and Canada for the treatment of ovarian and breast cancers.
- paclitaxel The only available natural source of paclitaxel to date are several species of a slow growing yew trees (genus Taxus), wherein paclitaxel is found in very low concentrations (less than 400 parts per million) in the bark or needles of these trees.
- paclitaxel can be isolated from the bark of the pacific yew tree (Taxus brevifolia) and ground hemlock (Taxus Canadensis), but the yield is very low (0.01%-0.02%), and the isolation and purification process is too complicate. Furthermore the extraction is difficult, and the process is expensive.
- Taxus baccata Since removal of the bark destroys the trees and endangers the species, isolation of taxanes from the stems and needles of various Taxus species was believed to offer hope that the supply of taxanes, in particular paclitaxel, would become more abundant. This led to the switching of paclitaxel derived from natural to the production of semi- synthetic, starting from 10-deacetylbaccatin III, which was isolated from the needles of English yew (Taxus baccata).
- 10-deacetylbaccatin III 10- DAB III
- 10-DAB III has the basic diterpenoid structure of paclitaxel without the acetyl group at C-10 and side chain at the C- 13 position. Since 10-DAB III is an important staring material in paclitaxel semi-synthesis, the significance of 10-DAB III will likely increase as more clinical studies are performed using paclitaxel.
- the conversion of 10- deacetylbaccatin III into paclitaxel is typically achieved by protecting the hydroxy at C-7, attachment of an acetyl group at the C-IO position, attachment of a C- 13 ⁇ - amido ester side chain at the C- 13 position through esterification of the C- 13 alcohol with the side chain moiety, and deprotecting C-7. Since the supply of 10- deacetylbaccatin III is limited, other sources should be pursued.
- Holton et al provided a process for the preparation of a derivative or analog of baccatin III, or 10-deacetylbaccatin III, having a C9 substituent other than a keto, in which the C9 keto substituent of taxol, a taxol analog, baccatin III, or 10- deacetylbaccatin III was selectively reduced to the corresponding hydroxyl group.
- taxane derivatives as paclitaxel, docetaxel, cephalomannine and other taxanes structurally related to baccatin III.
- US Patent No. 5,616,740 issued on Apr 1, 1997 in the name of Abbott Laboratories, US Patent No 5,594,157, issued on Jan 14, 1997 in the name of Abbott Laboratories and US Patent No. 5,530,020 issued on Jun 25, 1996 in the name of Abbott Laboratories each provided deoxygenated taxol compounds which were prepared from a natural product, 9-dihydro-13-acetylbaccatin III, which was isolated from Taxus canadensis, as well as analogs of taxol which were prepared therefrom.
- Abbott Laboratories provided deoxygenated taxol products prepared from a natural product, 9-dihydro-13-acetylbaccatin III, which is isolated from Taxus canadensis.
- Ri is a hydrogen atom or a suitable protecting group for a hydroxyl group
- R 2 is a hydrogen atom or a suitable protecting group for a hydroxyl group
- R 3 is a hydrogen atom or a suitable protecting group for a hydroxyl group
- R 4 is a hydrogen atom, a Ci-C 20 alkyl linear or branched, Ci-C 2 O acyl group, Ci-C 20 halogenated acyl group, C 3 -Ci 2 cycloalkyl, Ci-Ci 2 heterocyclyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 6 -C] 2 aryl, C 6 -C 20 aralkyl, Ci-C 20 alkyloxy C 6 -C 20 alkylaryl, C1-C 12 heteroaryl, C 2 -C 20 alkylheterocyclyl, or C 2 -C 20 alkylheteroaryl, said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with
- R 6 is a Ci-C 6 alkyl, C]-Ci 2 alkyl linear or branched, C 6 -Ci 2 aryl, C 2 -C 20 alkenyl, Ci-C 20 alkoxy, C-C 20 alkyl, C 2 -C 20 alkynyl, C 6 -C 20 aralkyl, C 6 -C, 2 aryl, C 3 -C 8 cycloalkyl, Ci-C 20 aminoalkyl, C 6 -Ci 2 aminoaryl, Ci-Cu aminoheteroaryl ,Ci-C 20 hydroxyalkyl, C 6 -Ci 2 hydroxyaryl, Ci-Cj 2 hydroxyheteroaryl, Ci-C] 2 heterocyclyl, Ci-Ci 2 heteroaryl, C 2 -C 20 alkylheterocyclyl, or C 2 -C 20 alkylheteroaryl.
- suitable protecting group for a hydroxyl group is chosen from Ci-C 25 ethers, Ci-C 25 substituted methyl ethers, C]-C 25 substituted ethyl ethers, Ci-C 25 acyl groups, Ci-C 25 halogenated acyl groups, Ci-C 25 substituted benzyl ethers, CpC 25 silyl ethers, Ci-C 25 esters, Ci-C 25 carbonates, and Ci-C 25 sulfonates.
- suitable protecting group for a hydroxyl group is chosen from methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-(trimethylsilyl)ethoxymethyl, dioxanyl, 1- ethoxyethyl, l-(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, /-butyl, allyl, propargyl, benzyl, /7-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, /-butyldimethylsilyl, /-butyldiphenylsilyl, tribenzylsilyl, triphenyl
- Ri is triethylsilyl.
- Ri is triethylsilyl.
- R 2 is acetyl.
- R 3 is ethoxyethyl.
- R 4 is a Ci-C 6 alkyl, phenyl, r-butyloxyl, a C 2 -C 6 alkenyl, tetrahydrofuranyl, or tetrahy dropy r any 1.
- R 4 is a pentyl, phenyl, r-butyloxyl, but-2-enyl, tetrahydrofuranyl, or tetrahydropyranyl.
- Ri is a hydrogen atom or a suitable protecting group for a hydroxyl group
- R 2 is a hydrogen atom or a suitable protecting group for a hydroxyl group
- R 3 is a hydrogen atom or a suitable protecting group for a hydroxyl group
- R 4 is a hydrogen atom, a C]-C 20 alkyl linear or branched, C 1 -C20 acyl group, Ci-C 20 halogenated acyl group, C 3 -Ci 2 cycloalkyl, Ci-Ci 2 heterocyclyl, C 2 -C 2 O alkenyl, C 2 -C 20 alkynyl, C 6 -C] 2 aryl, C 6 -C 20 aralkyl, C]-C 20 alkyloxy C 6 -C 20 alkylaryl, Ci-Ci 2 heteroaryl, C 2 -C 20 alkylheterocyclyl, C 2 -C 20 alkylheteroaryl, or a suitable protecting group for an amino group; and
- R 5 is a hydrogen atom or a suitable protecting group for a hydroxyl group, said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, Cl, Br, I, OH, SH, NH 2 , NO 2 , CN, CF 3 , -SH, -OCH 2 Ph, -OPh, -SCH 3 , - SPh, -SCH 2 Ph, -COOH, -COOR 6 in which R 6 is a C 1 -C 6 alkyl, C 1 -C 2 alkyl linear or branched, C 6 -Ci 2 aryl C 2 -C 20 alkenyl, C 1 -C 20 alkoxy, Ci-
- the suitable protecting group for a hydroxyl group is chosen from C]-C 25 ethers, Ci-C 25 substituted methyl ethers, C 1 -C25 substituted ethyl ethers, Q-C 25 acyl groups, C 1 -C 25 halogenated acyl groups, Ci-C 25 substituted benzyl ethers, C 1 -C 25 silyl ethers, C 1 -C 25 esters, Ci-C 25 carbonates, and C 1 -C 25 sulfonates.
- the suitable protecting group for a hydroxyl group is chosen from methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl)ethoxymethyl, dioxanyl, 1-ethoxy ethyl, 1 -(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, r-butyl, allyl, propargyl, benzyl, /?-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, 7-butyldiphenylsilyl, tribenzylsily
- R- 2 is acetyl. In accordance with the present invention, in a preferred compound R- 2 is acetyl. In accordance with the present invention, in a preferred compound
- R 3 is ethoxy ethyl.
- R 4 is a C]-C 6 alkyl, phenyl, f-butyloxyl, a C 2 -C 6 alkenyl, tetrahydrofuranyl, or tetrahy dropyrany 1.
- R 4 is a C]-C 6 alkyl, phenyl, f-butyloxyl, a C 2 -C 6 alkenyl, tetrahydrofuranyl, or tetrahy dropyrany 1.
- R 4 is a pentyl, phenyl, Mmtyloxyl, but-2-enyl, tetrahydrofuranyl, or tetr ahy dropyrany 1.
- R 5 is triethylsilyl.
- Ri is a hydrogen atom or a suitable protecting group for a hydroxyl group
- R 2 is a hydrogen atom or a suitable protecting group for a hydroxyl group.
- the suitable protecting group for a hydroxyl group is chosen from C]-C 25 ethers, Ci-C 25 substituted methyl ethers, Ci-C 25 substituted ethyl ethers, Ci-C 25 acyl groups, Ci-C 25 halogenated acyl groups, Ci-C 25 substituted benzyl ethers, Cj-C 25 SiIyI ethers, C i-C 25 esters, Ci-C 25 carbonates, and Cj-C 25 sulfonates.
- the suitable protecting group for a hydroxyl group is chosen from methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl)ethoxymethyl, dioxanyl, 1 -ethoxyethyl, l-(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, r-butyl, allyl, propargyl, benzyl, />-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, trip
- Ri is triethylsilyl.
- R 2 is acetyl.
- the oxidizing agent is chosen from tetra-n-propylammonium perruthenate, Collin's reagent, Swern reagent [(COCl) 2 , DMSO, Et 3 N], acidic pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), CrO 2 , and John's reagent.
- a process for converting 9-dihydro-13-acetylbaccatin III into a taxane derivative comprising the step of removing 10-acetyl group and oxidizing the C-9 and C-IO positions of the 9-dihydro-13-acetylbaccatin III.
- the oxidizing step is achieved by the addition of an oxidizing agent chosen from tetra-n- propylammonium perruthenate, Collin's reagent, Swern reagent, PCC, PDC, CrO 2 and John's reagent.
- an oxidizing agent chosen from tetra-n- propylammonium perruthenate, Collin's reagent, Swern reagent, PCC, PDC, CrO 2 and John's reagent.
- a process for preparing paclitaxel, docetaxel and a derivative thereof comprising the steps of:
- the protecting group is chosen from benzyl, Ci-C 25 substituted benzyl, benzylformate, Ci-C 25 substituted benzylformate, tosyl, substituted tosyl, dihydropyrannyl, methoxymethyl, benzoyl, Ci-C 25 substituted benzoyl, Ci-C 25 trialkylsilyl, 2-
- the oxidizing step is achieved by the addition of an oxidizing reagent chosen from of tetra-n- propylammonium perruthenate, Collin's reagent, Swern reagent, PCC, PDC, CrO 2 and John' reagent.
- an oxidizing reagent chosen from of tetra-n- propylammonium perruthenate, Collin's reagent, Swern reagent, PCC, PDC, CrO 2 and John' reagent.
- it further comprises the step of deprotecting the C- 7 position to obtain 10-deacetylbaccatin III.
- it further comprises the steps of adding a suitable side chain to the C- 13 position, reducing C-IO and selectively deprotecting to obtain a desired product.
- the deprotection is done at the C-7 and 2' positions to obtain paclitaxel and docetaxel.
- the side chain is chosen from (2R, 3S)-N-benzoyl-O-(l-ethoxyethyl)-3-phenylisoserine; (3R,
- the taxane derivative is paclitaxel or docetaxel.
- Fig. 1 illustrates taxane derivatives.
- Fig. 2 illustrates the reaction scheme 1 for preparing compound 2.
- Fig. 3 illustrates the reaction scheme 2 for preparing compound 4.
- Fig. 4 illustrates the reaction scheme 3 for preparing compounds 3 and 4.
- DETAILED DESCRIPTION OF THE INVENTION The present invention concerns 9,10-diketo taxane derivatives formed in chemical conversion from 9-dihydro-13-acetylbacatin III (9-DHAB) for the efficient production of paclitaxel and docetaxel analogs and their intermediate.
- Such conversion processes may include protection of 7-OH of the 9-DHAB, deacelaytion of C-IO position, and oxidation of C-9, and C-10 hydroxyl groups to yield a intermediate compound 7-triethylsilyl-9, 10-diketo- 13-acetylbaccatin III (6).
- a first broad aspect of the present invention provides a novel process for making paclitaxel and docetaxel by using a novel precursor, 9-dihydro- 13-acetylbaccatin III, which is abundant in Taxus canadensis, the species commonly found in Eastern Canada and Northeast United States. The isolation yield for this compound is 0.1-0.2%.
- a second broad aspect of the present invention provides a novel synthetic route in a process for the conversion of 9-dihydro-l 3-acetylbaccatin III to paclitaxel and docetaxel, the process comprising the two steps of firstly, reacting a protected paclitaxel or docetaxel side chain precursor with 7-O-triethylsilyl-9,10- diketobaccatin III (T), thereby to produce 7-O-triethylsilyl-9,10-diketodocetaxel (12), and 7-O-triethylsilyl-9, 10-diketopaclitaxel (14) containing a protected side chain.
- a third broad aspect of the present invention provides a process for the conversion of 9-dihydro-13-acetylbaccatin III to 10-deacetylbacatin III, comprising the sequential steps of converting 7-O-triethylsilyl-9,10-diketo-13- acetyllbaccatin III to 7-O-triethylsilyl-9,10-diketo-lbaccatin III, reducing said 7-0- triethylsilyl-9,10-diketobaccatin III to 7-0-triethylsilyl-lO-deacetylbaccatin III, removing the 7-0-triethylsilyl protecting group to yield 10-deacetylbaccatin III.
- a fourth broad aspect of the present invention provides a novel process for the conversion of 9-dihydro-13-acetylbaccatinIII to paclitaxel and docetaxel which comprises the sequential steps of: effecting a triethylsilylation reaction on the 7-hyroxy group of 9-dihydro-13-acetylbaccatin III while substantially-simultaneously deacetylating the 10-acetyl group to yield a 10- hyroxy group, thereby to produce 7-0-triethylsilyl- lO-deacetyl-9-dihydro- 13- acetylbaccatin III (5); oxidizing the 9-, and 10-hydroxyl group of compound 5 to produce 13-acetyl-9,10-diketo-7-triethylsilylbaccatin III 6, removing the 13-acetyl group of 7-O-triethylsilyl-9,10-diketo-13-acetylbaccat
- the suitable protecting groups for hydroxyl groups can be any protecting group that would be used by a person skilled in the art.
- Such protecting groups can be those described in Theodora W. Greene et al., Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, Inc., 1999, pp. 17-21, which is hereby incorporated by reference.
- the protecting groups for hydroxyl groups can be, for example, ethers (such as methyl), or substituted methyl ethers (such as methoxymethyl; methylthiomethyl; (phenyldimethylsilyl)methoxymethyl; benzyloxymethyl; p- methoxybenzyloxymethyl; p-nitrobenzyloxymethyl; o-nitrobenzyloxymethyl; (4- methoxyphenoxy)methyl; guaiacolmethyl; /-butoxymethyl; 4-pentenyloxymethyl; siloxymethyl; 2-methoxyethoxymethyl; 2,2,2-trichloroethoxymethyl; bis(2- chloroethoxy)methyl; 2-(trimethylsilyl)ethoxymethyl; menthoxymethyl; tetrahydropyranyl; 3-bromotetrahydropyranyl; tetrahydrothiopyranyl; 1- methoxycyclohexyl; 4-methoxy tetrahydropyranyl; 4- methoxytetrahydr
- the protecting groups for hydroxyl groups can be, for example, substituted ethyl ethers (such as 1 -ethoxy ethyl; l-(2-chloroethoxy)ethyl; l-[2- (trimethylsilyl)ethoxy]ethyl; 1 -methyl- 1 -methoxyethyl; 1 -methyl- 1 - benzyloxyethyl; 1 -methyl- l-benzyloxy-2-fluoroethyl; 1 -methyl- 1-phenoxy ethyl; 2,2,2-trichloroethyl; 1 , 1 -dianisyl-2,2,2-trichloroethyl; 1,1,1 , 3,3,3 -hexafluoro-2- phenylisopropyl; 2-trimethylsilylethyl; 2-(benzylthio)ethyl; 2-(phenylselenyl)ethyl; /-buty
- Step A To a solution of 95% of ethanol, 45 mg of the compound 6 was added and stirred until the solid was completely dissolved, and then hydrazine monohydrate (0.6ml) was added, then the solution was stirred for 8 hours at room temperature, after that the reaction was quenched by brine and extracted with dichloromethane and organic phase was collected and concentrated to dryness in vacuum. The residue was purified through silica gel column.
- the product from step A was dissolved in 10 ml of THF, 5 mg of LiAlH 4 was then slowly added with stirring. After stirring for 2 hours at room temperature, the reaction was quenched by adding of 1% HCl (0.5 ml) and brine, the product was extracted with CH 2 Cl 2 .
- Step B 7-TES-lO-deacetylbaccatin III was dissolved in a mixture of acetonitrile and acetone (3:1), the solution then was stirred at room temperature for a few minutes before 5 ml of sodium hypochloride (NaOCl) was added dropwise. The mixture was reacted at room temperature for 2 hours and then quenched with brine and extracted with ethyl acetate. The ethyl acetate phase was concentrated to dryness and the residue was re-crystallized from acetonitrile to yield 10-deacetylbaccatin III as a white powder (shown as compound 2).
- NaOCl sodium hypochloride
- Step B 35 mg of 7-TES-9, 10-diketobaccatin III was placed in a 25 ml round bottom flask, and 3 mole equivalents of protected docetaxel side chain precursor, (2R,3S)-N-boc-O-(l-ethoxyethyl)-3-phenylisoserine or (3R,4S)-3-(l- ethoxyethyl)-4-(phenyl)-N-boc-2-azetidinone, were dissolved in 20 ml of tetrahydrofuran (THF) at -45 0 C, then 6 mole equivalents of LiHMDS and 1 mole equivalent of CeCl 3 were added slowly.
- THF tetrahydrofuran
- Step B The residue was re-dissolved in THF, and sodium hypochloride (NaOCl) was added dropwise. The mixture was stirred for 2 hours at room temperature then work-up as above. The residue was purified through flash column chromatography. Docetaxel was obtained as white needles (see compound 4 on Fig. 4). 7-triethylsilyl-2'-EE-10-deacetylpaclitaxeI (compound JJQ can be made through the same manner as for making intermediate compound 13 by using a paclitaxel side chain attached to 13-C position.
- 7-triethyl-2'-EE-paclitaxel 1.5g of 7-triethylsilyl-2'-EE-10- deacetylpaclitaxel (18) was dissolved in THF (20 ml), the solution was poured into a 50 ml round-bottom flask equipped with a magnetic stirrer, then 5 ml of DMAP was added and the mixture was cooled to 0 0 C, and 5 ml of acetyl chloride was added and the mixture was stirred for 10 hours at 0 0 C, then the temperature was slowly raised to room temperature and kept for another hour. After the reaction was completed, the reaction was quenched by adding 50 ml of brine.
- paclitaxel can be obtained as white powder.
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Abstract
A novel semi-synthetic route has been provided in the preparation of docetaxel and paclitaxel. This new process involves the conversion of 9-dihydro-13-acetylbaccatinIII to docetaxel and paclitaxel by the step of converting 9-dihydro-13-acetylbaccatin III into 7-O-triethylsilyl-9,10-diketobaccatin III, and adding docetaxel and paclitaxel side chain precursors, respectively, to form a new class of taxane intermediates, such as 7-O-triethylsilyl-9,10-diketodocetaxel and 7-O-triethylsilyl-9,10-diketopaclitaxeltaxel. These new intermediates then by a series reduction, acetylation of the 10-hydroxyl position for paclitaxel and finally deprotection to yield docetaxel and paclitaxel, the most important anti-cancer drugs.
Description
SEMI-SYNTHETIC ROUTE FOR THE PREPARATION OF PACLIT AXEL, DOCETAXEL AND lO-DEACETYLBACCATIN III FROM 9-DIHYDRO-
13-ACETYLBACCATIN III BACKGROUND OF THE INVENTION
(a) Field of the Invention
The present invention relates to a semi-synthetic process for the preparation of paclitaxel, docetaxel, the anticancer drugs, and 10-deacetylbaccatin III, a useful precursor for making them, the most popular anticancer drugs, and other taxane compounds. More particularly, this invention relates to a novel semisynthetic route to synthesize paclitaxel, docetaxel and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III, a taxane compound which is isolated from Taxus Canadensis, an evergreen bush found in Eastern Canada and Northeastern United States. (b) Description of Prior Art
Taxanes are substances occurring naturally in yew trees such as Taxus brevifolia, Taxus baccata and Taxus canadensis, which is common in Eastern Canada and Northeast United States. One of the chemicals extracted from the needles of Taxus canadensis is 9-dihydro-13-acetylbaccatin III, which is used to produce 10-deacetylbaccatin III, a useful intermediate for the preparation of paclitaxel, docetaxel and their analogues thereof.
The taxane family of diterpenes is considered to be an exceptionally promising group of cancer chemotherapeutic agents. Many taxane derivatives, including paclitaxel, docetaxel, taxol C and cephalomannine are highly cytotoxic and possess strong in vivo activities in a number of leukemic and other tumor systems. Paclitaxel, and a number of its derivatives, have been shown to be effective against advanced breast and ovarian cancers in clinical trials. They have also exhibited promising activity against a number of other tumor types in preliminary investigations. Paclitaxel, docetaxel have recently been approved in the U.S. and Canada for the treatment of ovarian and breast cancers.
The only available natural source of paclitaxel to date are several species of a slow growing yew trees (genus Taxus), wherein paclitaxel is found in
very low concentrations (less than 400 parts per million) in the bark or needles of these trees. Thus, paclitaxel can be isolated from the bark of the pacific yew tree (Taxus brevifolia) and ground hemlock (Taxus Canadensis), but the yield is very low (0.01%-0.02%), and the isolation and purification process is too complicate. Furthermore the extraction is difficult, and the process is expensive. Since removal of the bark destroys the trees and endangers the species, isolation of taxanes from the stems and needles of various Taxus species was believed to offer hope that the supply of taxanes, in particular paclitaxel, would become more abundant. This led to the switching of paclitaxel derived from natural to the production of semi- synthetic, starting from 10-deacetylbaccatin III, which was isolated from the needles of English yew (Taxus baccata).
Due to the structural complexity of paclitaxel, and docetaxel, partial synthesis is a far more viable approach to providing adequate supplies of paclitaxel and docetaxel. Docetaxel was first commercialized by Aventis, It went to the market in 1995 and it is a fast growing anticancer drug. This drug is semi-synthetic product, also starting from 10-deacetylbacatin III. So far the commercial supply of docetaxel comes substantially completely from 10-deacetylbaccatin III. To date, however, the supply of 10-deacetylbaccatin III is limited due to the limited biomass resource and low isolation yield (ranging from 50-165 mg per kilogram of needles of Taxus baccata).
Various processes of converting 9-dihydro-13-acetylbaccatin III (9- DHAB) into 10-deacetylbaccatin III have been proposed. However, it has been found that such processes result in poor yields of final product. Thus, a need still exists for an efficient method for converting 9-dihydro-13-acetylbaccatin III to 10- deacetylbaccatin III ( 10-DAB III).
The preparation of paclitaxel derivatives, some of which have been reported to demonstrate enhanced chemotherapeutic activity, ultimately depends upon the supply of the precursor compound, namely, 10-deacetylbaccatin III (10- DAB III). The structure of 10-DAB III has the basic diterpenoid structure of paclitaxel without the acetyl group at C-10 and side chain at the C- 13 position.
Since 10-DAB III is an important staring material in paclitaxel semi-synthesis, the significance of 10-DAB III will likely increase as more clinical studies are performed using paclitaxel. One such reason is that it appears that water-soluble paclitaxel-like compounds with slightly modified C- 13 side chains may be more desirable as cancer chemotherapeutic agents than the naturally- occurring, less water soluble paclitaxel. This increases the urgent need for the production of 10-DAB III as a starting material to synthesize both paclitaxel and second or third generation paclitaxel-like compounds. There is, therefore, a need for an improved method of isolating and/or synthesizing 10-DAB III. In fact, most of the research to date regarding the semi-synthesis of paclitaxel has involved 10-deacetylbaccatin III. The conversion of 10- deacetylbaccatin III into paclitaxel is typically achieved by protecting the hydroxy at C-7, attachment of an acetyl group at the C-IO position, attachment of a C- 13 β- amido ester side chain at the C- 13 position through esterification of the C- 13 alcohol with the side chain moiety, and deprotecting C-7. Since the supply of 10- deacetylbaccatin III is limited, other sources should be pursued.
Canadian Patent Application No. 2,188,190, published on Apr. 18, 1998, in the name of Zamir et al, described a semi-synthetic process to convert a naturally occurring taxane, 9-dihydro-13-acetylbaccatin III, into a suitable starting material for the synthesis of such taxane derivatives as paclitaxel, cephelomanine and other taxanes, which are structurally related to baccatin III.
US Patent No. 6,812,356, issued on Nov 2, 2004, in the name of Findly, provided a process for the use of 9-dihydro-13-acetylbaccatin III for the production of 10-deacetylbaccatin III. US Patent No. 6,734,304, issued on Aug 31, 2004, in the name of
Bristol-Myers Squibb Company provided novel oxazolidines, which found utility as intermediates in the preparation of C- 13 side chain-bearing taxanes, e.g., paclitaxel and analogs thereof. It related more specifically, to procedures for coupling the oxazolidines to form the taxanes. US Patent 6,710,191, issued on Mar 23, 2004 in the name of R.A.
Holton et al, provided a process for the preparation of a derivative or analog of
baccatin III, or 10-deacetylbaccatin III, having a C9 substituent other than a keto, in which the C9 keto substituent of taxol, a taxol analog, baccatin III, or 10- deacetylbaccatin III was selectively reduced to the corresponding hydroxyl group.
US Patent No. 6,593,482, issued on JuI 15, 2003 in the name of H. Bouchard et al, provided a procedure for preparing methylthiomethyl taxoids from baccatin III and β-lactam.
US Patent No. 6,576,777, issued on Jun 10 2003 in the name of L. Zamir et al, provided a semi-synthetic process to convert a naturally occurring taxane into a suitable starting compound for the synthesis of paclitaxel and related compounds. It specifically related to a process for the conversion of 9-dihydro-13- acetylbaccatin III into a 7-protected baccatin III, which can be used for the synthesis of taxol derivatives, e.g., paclitaxel, docataxel, cephalomannine and other taxanes, which were structurally related to baccatin III.
Other patents which provided processes for the preparation of novel taxoids included U.S. Patent No. 6,384,071 issued on May 7, 2002 in the name of
Aventis Pharma S. A, US Patent No. 6,331 , 635 issued on Dec 18 2001, in the name of Aventis Pharma S. A. and US Patent No. 6,232,477 issued on May 15,
2001 in the name of Aventis Pharma S. A.
US Patent No. 6,222,053, issued on Apr 24, 2001, in the name of Institut National de Ia Research Scientific, provided a semi-synthetic process to convert a naturally occurring taxane into a suitable starting material for the synthesis of paclitaxel and related compounds. Specifically, it related to a process for the conversion of 9-dihydro-13-acetylbaccatin III into a 7-protected baccatin
III, which can then be used as starting material for the synthesis of such taxane derivatives as paclitaxel, docetaxel, cephalomannine and other taxanes structurally related to baccatin III.
US Patent No 6,197,981, issued on Mar 6, 2001, in the name of J. Liu, provided a process for preparing taxol, baccatin III and 10-deacetylbaccatin III by oxidation of 9-dihydro-13-acetylbaccatin.
US Patent No. 6, 175,023, issued on Jan 16, 2001 in the name of J. Liu, provided for the semi-synthesis of 9-dihydrotaxanes using 9-dihydro-13- acetylbaccatinIII as the initial compound.
US Patent No 6,066,747, issued on May 23 2000 in the name of R.H.Holton et al, provided a process for the preparation of taxol, baccatin III and 10-deacetylbaccatin III derivatives or other taxanes having new C9 functional groups.
US Patent No. 5,616,740, issued on Apr 1, 1997 in the name of Abbott Laboratories, US Patent No 5,594,157, issued on Jan 14, 1997 in the name of Abbott Laboratories and US Patent No. 5,530,020 issued on Jun 25, 1996 in the name of Abbott Laboratories each provided deoxygenated taxol compounds which were prepared from a natural product, 9-dihydro-13-acetylbaccatin III, which was isolated from Taxus canadensis, as well as analogs of taxol which were prepared therefrom. US Patent No. 5,440,056, issued on Aug 8, 1995 in the name of
Abbott Laboratories, provided deoxygenated taxol products prepared from a natural product, 9-dihydro-13-acetylbaccatin III, which is isolated from Taxus canadensis.
US Patent No. 4,924,011, re-issued as U.S. Patent No. 34,277 in the name of Denis et al provided the first successful semi-synthesis of paclitaxel using the starting material 10-deacetylbaccatin III which can be extracted in relatively high yield from the needles of Taxus baccata species.
It would be highly desirable to be provided with a novel semisynthetic process for the preparation of paclitaxel, docetaxel, the anticancer drugs, and 10-deacetylbaccatin III, a useful precursor for making them, the most popular anticancer drugs, and other taxane compounds.
SUMMARY OF THE INVENTION
In accordance with the present invention there is provided a novel semi-synthetic process for the preparation of paclitaxel, docetaxel, the anticancer
drugs, and 10-deacetylbaccatin III, a useful precursor for making paclitaxel and docetaxel, the most popular anticancer drugs, and other taxane compounds
It is also desirable to provide a semi-synthesis process for 10- deacetylbaccatin III. It is also desirable provide a semi-synthetic process for the preparation of paclitaxel, docataxel and 10-deacetylbaccatin III from 9-dihydro-13- acetylbaccatin III.
A need still exists for an efficient process for converting 9-dihydro- 13 acetylbaccatin III to 10-deacetylbaccatin III (DAB III). In accordance with the present invention there is provided a compound of formula (I), (II), (III) or (IV):
Ri is a hydrogen atom or a suitable protecting group for a hydroxyl group;
R2 is a hydrogen atom or a suitable protecting group for a hydroxyl group;
R3 is a hydrogen atom or a suitable protecting group for a hydroxyl group; and
R4 is a hydrogen atom, a Ci-C20 alkyl linear or branched, Ci-C2O acyl group, Ci-C20 halogenated acyl group, C3-Ci2 cycloalkyl, Ci-Ci2 heterocyclyl, C2-C20 alkenyl, C2-C20 alkynyl, C6-C]2 aryl, C6-C20 aralkyl, Ci-C20 alkyloxy C6-C20
alkylaryl, C1-C12 heteroaryl, C2-C20 alkylheterocyclyl, or C2-C20 alkylheteroaryl, said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, Cl, Br, I, OH, SH, NH2, NO2, CN, CF3, -SH, -OCH2Ph, -OPh, -SCH3, -SPh, -SCH2Ph, -COOH,
-COORs in which R6 is a Ci-C6 alkyl, C]-Ci2 alkyl linear or branched, C6-Ci2 aryl, C2-C20 alkenyl, Ci-C20 alkoxy, C-C20 alkyl, C2-C20 alkynyl, C6-C20 aralkyl, C6-C,2 aryl, C3-C8 cycloalkyl, Ci-C20 aminoalkyl, C6-Ci2 aminoaryl, Ci-Cu aminoheteroaryl ,Ci-C20 hydroxyalkyl, C6-Ci2 hydroxyaryl, Ci-Cj2 hydroxyheteroaryl, Ci-C]2 heterocyclyl, Ci-Ci2 heteroaryl, C2-C20 alkylheterocyclyl, or C2-C20 alkylheteroaryl.
In accordance with the present invention, suitable protecting group for a hydroxyl group is chosen from Ci-C25 ethers, Ci-C25 substituted methyl ethers, C]-C25 substituted ethyl ethers, Ci-C25 acyl groups, Ci-C25 halogenated acyl groups, Ci-C25 substituted benzyl ethers, CpC25 silyl ethers, Ci-C25 esters, Ci-C25 carbonates, and Ci-C25 sulfonates.
In accordance with the present invention, suitable protecting group for a hydroxyl group is chosen from methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-(trimethylsilyl)ethoxymethyl, dioxanyl, 1- ethoxyethyl, l-(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, /-butyl, allyl, propargyl, benzyl, /7-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, /-butyldimethylsilyl, /-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and/?-toluenesulfonyl.
In accordance with the present invention, in a preferred compound Ri is triethylsilyl. In accordance with the present invention, in a preferred compound
R2 is acetyl.
In accordance with the present invention, in a preferred compound R3 is ethoxyethyl.
In accordance with the present invention, in a preferred compound R4 is a Ci-C6 alkyl, phenyl, r-butyloxyl, a C2-C6 alkenyl, tetrahydrofuranyl, or tetrahy dropy r any 1.
In accordance with the present invention, in a preferred compound R4 is a pentyl, phenyl, r-butyloxyl, but-2-enyl, tetrahydrofuranyl, or tetrahydropyranyl.
In accordance with the present invention, there is provided a compound of formula (V) or (VI):
wherein
Ri is a hydrogen atom or a suitable protecting group for a hydroxyl group;
R2 is a hydrogen atom or a suitable protecting group for a hydroxyl group;
R3 is a hydrogen atom or a suitable protecting group for a hydroxyl group; and
R4 is a hydrogen atom, a C]-C20 alkyl linear or branched, C1-C20 acyl group, Ci-C20 halogenated acyl group, C3-Ci2 cycloalkyl, Ci-Ci2 heterocyclyl, C2-C2O alkenyl, C2-C20 alkynyl, C6-C]2 aryl, C6-C20 aralkyl, C]-C20 alkyloxy C6-C20
alkylaryl, Ci-Ci2 heteroaryl, C2-C20 alkylheterocyclyl, C2-C20 alkylheteroaryl, or a suitable protecting group for an amino group; and
R5 is a hydrogen atom or a suitable protecting group for a hydroxyl group, said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, Cl, Br, I, OH, SH, NH2, NO2, CN, CF3, -SH, -OCH2Ph, -OPh, -SCH3, - SPh, -SCH2Ph, -COOH, -COOR6 in which R6 is a C1-C6 alkyl, C1-C2 alkyl linear or branched, C6-Ci2 aryl C2-C20 alkenyl, C1-C20 alkoxy, Ci-C20 alkyl, C2-C20 alkynyl, C6-C2O aralkyl, C6-Ci2 aryl, C3-C8 cycloalkyl, Ci-C2O aminoalkyl, C6-Ci2 aminoaryl, Ci-Ci2 aminoheteroaryl, Ci-C20 hydroxyalkyl, C6-C12 hydroxyaryl, Ci- C)2 hydroxyheteroaryl, C1-C]2 heterocyclyl, Ci-C12 heteroaryl, C2-C20 alkylheterocyclyl, or C2-C2O alkylheteroaryl. In accordance with the present invention, in a preferred compound the suitable protecting group for a hydroxyl group is chosen from C]-C25 ethers, Ci-C25 substituted methyl ethers, C1-C25 substituted ethyl ethers, Q-C25 acyl groups, C1-C25 halogenated acyl groups, Ci-C25 substituted benzyl ethers, C1-C25 silyl ethers, C1-C25 esters, Ci-C25 carbonates, and C1-C25 sulfonates. In accordance with the present invention, in a preferred compound the suitable protecting group for a hydroxyl group is chosen from methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl)ethoxymethyl, dioxanyl, 1-ethoxy ethyl, 1 -(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, r-butyl, allyl, propargyl, benzyl, /?-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, 7-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and/?-toluenesulfonyl.
In accordance with the present invention, in a preferred compound Ri is triethylsilyl.
In accordance with the present invention, in a preferred compound R-2 is acetyl. In accordance with the present invention, in a preferred compound
R3 is ethoxy ethyl.
In accordance with the present invention, in a preferred compound R4 is a C]-C6 alkyl, phenyl, f-butyloxyl, a C2-C6 alkenyl, tetrahydrofuranyl, or tetrahy dropyrany 1. In accordance with the present invention, in a preferred compound
R4 is a pentyl, phenyl, Mmtyloxyl, but-2-enyl, tetrahydrofuranyl, or tetr ahy dropyrany 1.
In accordance with the present invention, in a preferred compound R5 is triethylsilyl. In accordance with the present invention, there is provided a process for preparing a compound of formula (II):
Ri is a hydrogen atom or a suitable protecting group for a hydroxyl group; and R2 is a hydrogen atom or a suitable protecting group for a hydroxyl group.
In accordance with the present invention, the suitable protecting group for a hydroxyl group is chosen from C]-C25 ethers, Ci-C25 substituted methyl ethers, Ci-C25 substituted ethyl ethers, Ci-C25 acyl groups, Ci-C25 halogenated acyl groups, Ci-C25 substituted benzyl ethers, Cj-C25 SiIyI ethers, C i-C25 esters, Ci-C25 carbonates, and Cj-C25 sulfonates.
In accordance with the present invention, the suitable protecting group for a hydroxyl group is chosen from methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl)ethoxymethyl, dioxanyl, 1 -ethoxyethyl, l-(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, r-butyl, allyl, propargyl, benzyl, />-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and/»-toluenesulfonyl.
In accordance with the present invention, Ri is triethylsilyl.
In accordance with the present invention, R2 is acetyl. In accordance with a process of the present invention, the oxidizing agent is chosen from tetra-n-propylammonium perruthenate, Collin's reagent,
Swern reagent [(COCl)2, DMSO, Et3N], acidic pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), CrO2, and John's reagent.
In accordance with the present invention, there is provided a process for converting 9-dihydro-13-acetylbaccatin III into a taxane derivative comprising the step of removing 10-acetyl group and oxidizing the C-9 and C-IO positions of the 9-dihydro-13-acetylbaccatin III.
In accordance with the present invention, the oxidizing step is achieved by the addition of an oxidizing agent chosen from tetra-n- propylammonium perruthenate, Collin's reagent, Swern reagent, PCC, PDC, CrO2 and John's reagent.
In accordance with the present invention, there is provided a process for preparing paclitaxel, docetaxel and a derivative thereof comprising the steps of:
(a) protecting the C-7 hydroxy group of 9-dihydro-13- acetylbaccatin III with a suitable protecting group to obtain a protected product;
(b) deacetylating the 10-acetyl group of the protected product; and
(c) oxidizing the C-9 and C-IO hydroxyl group of the protected product.
In accordance with a process of the present invention, the protecting group is chosen from benzyl, Ci-C25 substituted benzyl, benzylformate, Ci-C25 substituted benzylformate, tosyl, substituted tosyl, dihydropyrannyl, methoxymethyl, benzoyl, Ci-C25 substituted benzoyl, Ci-C25 trialkylsilyl, 2-
(trimethylsilyl)ethoxymethyl, benzyloxycarbonyl,
In accordance with a process of the present invention, the oxidizing step is achieved by the addition of an oxidizing reagent chosen from of tetra-n- propylammonium perruthenate, Collin's reagent, Swern reagent, PCC, PDC, CrO2 and John' reagent.
In accordance with a process of the present invention, it further comprises the step of deacetylating the C- 13 position. In accordance with a process of the present invention, it further comprises the step of reducing the C-IO ketone into C-IO hydroxyl group.
In accordance with the present invention, there is provided a process for preparing a compound of formula 8:
comprising the step of reducing the C- 10 ketone of a compound of formula 7:
In accordance with a process of the present invention, it further comprises the step of deprotecting the C- 7 position to obtain 10-deacetylbaccatin III.
In accordance with a process of the present invention, it further comprises the steps of adding a suitable side chain to the C- 13 position, reducing C-IO and selectively deprotecting to obtain a desired product.
In accordance with a process of the present invention, the deprotection is done at the C-7 and 2' positions to obtain paclitaxel and docetaxel.
In accordance with a process of the present invention, the side chain is chosen from (2R, 3S)-N-benzoyl-O-(l-ethoxyethyl)-3-phenylisoserine; (3R,
4S)-3-(l-ethoxyethoxy)-4-(phenyl)-N-benzoyl-2-azetidinone; (2R, 3S)-N-boc-O-
(l-ethoxyethyl)-3-phenylisoserine and (3R, 4S)-3-(l-ethoxyethoxy)-4-(phenyl)-N- boc-2-azetidinone.
In accordance with a process of the present invention, the taxane derivative is paclitaxel or docetaxel. BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates taxane derivatives. Fig. 2 illustrates the reaction scheme 1 for preparing compound 2.
Fig. 3 illustrates the reaction scheme 2 for preparing compound 4. Fig. 4 illustrates the reaction scheme 3 for preparing compounds 3 and 4. DETAILED DESCRIPTION OF THE INVENTION The present invention concerns 9,10-diketo taxane derivatives formed in chemical conversion from 9-dihydro-13-acetylbacatin III (9-DHAB) for the efficient production of paclitaxel and docetaxel analogs and their intermediate. Such conversion processes may include protection of 7-OH of the 9-DHAB, deacelaytion of C-IO position, and oxidation of C-9, and C-10 hydroxyl groups to yield a intermediate compound 7-triethylsilyl-9, 10-diketo- 13-acetylbaccatin III (6). These process also may include the attachment of the paclitaxel and docetaxel side chai to the 9,10-diketo moiety (compound T), which allows for the synthesis of paclitaxel, docetaxel and their analogs as well as their intermediates with variable C- 13 side chain structure. A first broad aspect of the present invention provides a novel process for making paclitaxel and docetaxel by using a novel precursor, 9-dihydro- 13-acetylbaccatin III, which is abundant in Taxus canadensis, the species commonly found in Eastern Canada and Northeast United States. The isolation yield for this compound is 0.1-0.2%. A second broad aspect of the present invention provides a novel synthetic route in a process for the conversion of 9-dihydro-l 3-acetylbaccatin III to paclitaxel and docetaxel, the process comprising the two steps of firstly, reacting a protected paclitaxel or docetaxel side chain precursor with 7-O-triethylsilyl-9,10- diketobaccatin III (T), thereby to produce 7-O-triethylsilyl-9,10-diketodocetaxel (12), and 7-O-triethylsilyl-9, 10-diketopaclitaxel (14) containing a protected side chain. The second step of reducing the C-10 keto of the intermediates 1_2_ and 14, to
yield intermediates 7-O-triethylsilyl-2'-EE-docetaxel 13 and 7-O-triethylsilyl-2'- EE- 10-deacetylpaclitaxel (.15), and final step of removing the protecting groups from 7-O-triethylsilyl-2'-EE-docetaxel, or acetylating C-IO hydroxyl then removing protection groups from 7-O-triethylsilyl-2' -EE-I O-deacetylpaclitaxel, to yield the designed products, docetaxel or paclitaxel.
A third broad aspect of the present invention provides a process for the conversion of 9-dihydro-13-acetylbaccatin III to 10-deacetylbacatin III, comprising the sequential steps of converting 7-O-triethylsilyl-9,10-diketo-13- acetyllbaccatin III to 7-O-triethylsilyl-9,10-diketo-lbaccatin III, reducing said 7-0- triethylsilyl-9,10-diketobaccatin III to 7-0-triethylsilyl-lO-deacetylbaccatin III, removing the 7-0-triethylsilyl protecting group to yield 10-deacetylbaccatin III.
A fourth broad aspect of the present invention provides a novel process for the conversion of 9-dihydro-13-acetylbaccatinIII to paclitaxel and docetaxel which comprises the sequential steps of: effecting a triethylsilylation reaction on the 7-hyroxy group of 9-dihydro-13-acetylbaccatin III while substantially-simultaneously deacetylating the 10-acetyl group to yield a 10- hyroxy group, thereby to produce 7-0-triethylsilyl- lO-deacetyl-9-dihydro- 13- acetylbaccatin III (5); oxidizing the 9-, and 10-hydroxyl group of compound 5 to produce 13-acetyl-9,10-diketo-7-triethylsilylbaccatin III 6, removing the 13-acetyl group of 7-O-triethylsilyl-9,10-diketo-13-acetylbaccatin III thereby to produce 7- O-triethylsilyl-9,10-diketobaccatin III 7; attaching a paclitaxel or docetaxel side chain precursor to the intermediate 7, thereby to produce 7-triethylsilyl-9,10- diketo- 1 O-deacetylpaclitaxel 14 or 7-triethylsilyl-9,10-diketodocetaxel JjJ, reducing the 10-keto group on the intermediates YL. and L4, thereby to produce 7- O-triethylsilyl-2'-EE-docetaxel and 7-O-triethylsilyl-2'-EE-10-deacetylpaclitaxel; acetylating the C-IO hydroxy of intermediate 14 to yield compound 1J8, then deprotection on intermediates 12 and IjS to produce docetaxel and paclitaxel.
The suitable protecting groups for hydroxyl groups can be any protecting group that would be used by a person skilled in the art.
Such protecting groups can be those described in Theodora W. Greene et al., Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, Inc., 1999, pp. 17-21, which is hereby incorporated by reference.
The protecting groups for hydroxyl groups can be, for example, ethers (such as methyl), or substituted methyl ethers (such as methoxymethyl; methylthiomethyl; (phenyldimethylsilyl)methoxymethyl; benzyloxymethyl; p- methoxybenzyloxymethyl; p-nitrobenzyloxymethyl; o-nitrobenzyloxymethyl; (4- methoxyphenoxy)methyl; guaiacolmethyl; /-butoxymethyl; 4-pentenyloxymethyl; siloxymethyl; 2-methoxyethoxymethyl; 2,2,2-trichloroethoxymethyl; bis(2- chloroethoxy)methyl; 2-(trimethylsilyl)ethoxymethyl; menthoxymethyl; tetrahydropyranyl; 3-bromotetrahydropyranyl; tetrahydrothiopyranyl; 1- methoxycyclohexyl; 4-methoxy tetrahydropyranyl; 4- methoxytetrahydrothiopyranyl; 4-methoxytetrahydrothiopyranyl s,s-dioxide; l-[(2- chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl; 1 -(2-fluorophenyl)-4- methoxypiperidin-4-yl; l,4-dioxan-2-yl; tetrahydrofuranyl; tetrahydrothiofuranyl; 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl).
The protecting groups for hydroxyl groups can be, for example, substituted ethyl ethers (such as 1 -ethoxy ethyl; l-(2-chloroethoxy)ethyl; l-[2- (trimethylsilyl)ethoxy]ethyl; 1 -methyl- 1 -methoxyethyl; 1 -methyl- 1 - benzyloxyethyl; 1 -methyl- l-benzyloxy-2-fluoroethyl; 1 -methyl- 1-phenoxy ethyl; 2,2,2-trichloroethyl; 1 , 1 -dianisyl-2,2,2-trichloroethyl; 1,1,1 , 3,3,3 -hexafluoro-2- phenylisopropyl; 2-trimethylsilylethyl; 2-(benzylthio)ethyl; 2-(phenylselenyl)ethyl; /-butyl; allyl; propargy; p-chlorophenyl; p-methoxyphenyl; p-nitrophenyl; 2,4- dinitrophenyl; 2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl; benzyl), substituted benzyl ethers (such as p-methoxy benzyl; 3,4-dimethoxybenzyl; o-nitrobenzyl; p- nitrobenzyl; p-halobenzyl; 2,6-dichlorobenzyl; p-cyanobenzyl; p-phenylbenzyl; 2,6-difluorobenzyl; p-acylaminobenzyl; p-azidobenzyl; 4-azido-3-chlorobenzyl; 2- trifluoromethylbenzyl; p-(methylsulfinyl)benzyl; 2- and 4-picolyl; 3-methyl-2- picolyl rø-oxido; 2-quinolinylmethyl; 1-pyrenylmethyl; diphenylmethyl; p,p'- dinitrobenzhydryl; 5-dibenzosuberyl; triphenylmethyl; α-naphthyldiphenylmethyl; p-methoxyphenyldiphenylmethyl; di(p-methoxyphenyl)phenylmethyl; tri(p-
methoxyphenyl)methyl; 4-(4'-bromophenacyloxy)phenyldiphenylmethyI; 4,4',4"- tris(4,5-dichlorophthalimidophenyl)methyl; 4,4',4"- tris(levulinoyloxyphenyl)methyl; 4,4',4"-tris(benzoyloxyphenyl)methyl; 4,4'- dimethoxy-3"-[n-(imidazolylmethyl)]trityl; 4,4'-dimethoxy-3"-[«- (imidazolylethyl)carbamoyl]trityl; l,l-bis(4-methoxyphenyl)-l'-pyrenylmethyl; 4- (17-tetrabenzo[a,c,g,i]fluorenylmethyl)-4,4"-dimethoxytrityl; 9-anthryl; 9-(9- phenyl)xanthenyl; 9-(9-phenyl- 10-oxo)anthryl; 1 ,3-benzodithiolan-2-yl; benzisothiazolyl s,s-dioxido) silyl ethers (such as trimethylsilyl; triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl; diethylisopropylsilyl; dimethylthexylsilyl; /-butyldimethylsilyl; t-butyldiphenylsilyl; tribenzylsilyl; tri-p-xylylsilyl; triphenylsilyl; diphenylmethylsilyl; di-/-butylmethylsilyl; tris(trimethylsilyl)silyl: sisyl; (2-hydroxystyryl)dimethylsilyl; (2-hydroxystyryl)diisopropylsilyl; t- butylmethoxyphenylsilyl; t-butoxydiphenylsilyl), esters (such as formate; benzoylformate; acetate; chloroacetate; dichloroacetate; trichloroacetate; trifluoroacetate; methoxy acetate; triphenylmethoxyacetate; phenoxyacetate; p- chlorophenoxyacetate; phenylacetate; p-p-phenylacetate; diphenylacetate; nicotinate; 3-phenylpropionate; 4-pentenoate; 4-oxopentanoate (levulinate); 4,4- (ethylenedithio)pentanoate; 5-[3-bis(4- methoxyphenyl)hydroxymethylphenoxy]levulinate; pivaloate; 1 -adamantoate; crotonate; 4-methoxycrotonate; benzoate; p-phenylbenzoate; 2,4,6- trimethylbenzoate (mesitoate), carbonates (such as methylcarbonyl; methoxymethylcarbonyl; 9-fluorenylmethylcarbonyl; ethylcarbonyl; 2,2,2- trichloroethylcarbonyl; 1 , 1 -dimethyl-2,2,2-trichloroethylcarbonyl; 2-
(trimethylsilyl)ethylcarbonyl; 2-(phenylsulfonyl)ethylcarbonyl; 2- (triphenylphosphonio)ethylcarbonyl; isobutylcarbonyl; vinylcarbonyl; allylcarbonyl; p-nitrophenylcarbonyl; benzylcarbonyl; p-methoxybenzylcarbonyl; 3,4-dimethoxybenzylcarbonyl; o-nitrobenzylcarbonyl; p-nitrobenzylcarbonyl), carbonates cleaved by b-elimination (such as 2-dansylethyl; 2-(4-nitrophenyl)ethyl; 2-(2,4-dinitrophenyl)ethyl; 2-cyano-l-phenylethyl; s-benzyl thiocarbonate; 4- ethoxy-1-naphthyl; methyl dithiocarbonate), miscellaneous esters (such as 2,6- dichloro-4-methylphenoxyacetate; 2,6-dichloro-4-( 1, 1,3,3-
tetramethylbutyl)phenoxyacetate; 2,4-bis( 1 , 1 -dimethylpropyl)phenoxyacetate; chlorodiphenylacetate; isobutyrate; monosuccinoate; (e)-2-methyl-2-butenoate (tigloate); o- (methoxycarbonyl)benzoate; p-p-benzoate; α-naphthoate; nitrate; alkyl n,n,n',n'-tetramethylphosphorodiamidate; 2-chlorobenzoate; 4- bromobenzoate; 4-nitrobenzoate; 3'5'-dimethoxybenzoin; «-phenylcarbamate; borate; dimethylphosphinothioyl; 2,4-dinitrophenylsulfenate), and sulfonate (such as sulfate; al IyI sulfonate; methanesulfonate (mesylate); benzylsulfonate; tosylate; 2-[(4-nitrophenyl)ethyl]sulfonate).
The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its scope.
EXAMPLE 1
PREPARATION OF 7-TES-10-DEACETYL-9-DIHYDRO-13- ACETYLBACCATIN IH (S) To 10 ml of acetonitrile, 102 mg of 9-dihydro-13-acetylbaccatin III
(shown in Fig. 1 as compound 1) and 73 mg of n-tetrabutylammonium iodide were added, the mixture was stirred for 5 minutes until 9-dihydro-13-acetylbaccatin III was completely dissolved. The mixture was kept in -10 0C, then chlorotriethylsilane was added dropwise. The mixture was stirred for another 5-10 minutes at -1O0C before 26 mg of sodium methoxide was poured into the round bottom flask. This mixture was kept stirred for another one hour at the same temperature then the temperature was raised to O0C, and maintained at O0C for about 1 hour. Then the temperature was raised to room temperature the mixture was kept stirred for 2 more hours. The reaction was quenched by dilution with brine, and extracted with ethyl acetate for three times. The organic phase was combined and evaporated to dryness in vacuum. The residue was purified by preparative TLC to yield 7-O-triethylsilyl-10-deacetyl-9-dihydro-13-acetylbaccatin III (shown in Fig. 2 as compound 5) as a white solid (85 mg, 85%).
EXAMPLE 2 PREPARATION OF 7-TES-9,10-DIKETO-13-ACETYLBACCATIN IH (6)
73 mg of 7-TES-10-deacetyl-9-dihydro-13-acetylbaccatin III (shown in Fig. 2 as compound 5) and 35 mg of 4-methylmorpholine-N-oxide (NMO) were added into a round bottom flask, and 10 ml of acetonitrile/acetone (3: 1) mixture was added. Then a molecular sieve was added to the mixture which stirred for 5 minutes, 10 mg of tetra-n-propylammonium perruthenate (TPAP) was then added, and the mixture was stirred for about 6 hours at room temperature, following which the temperature was raised to 400C. The mixture was maintained at that temperature overnight until the reaction was completed. Once the reaction was completed, the mixture was poured into a short silica gel column. The column was eluted with 50 ml of dichloromethane (CH2Cl2) to give a CH2Cl2 fraction, which was concentrated to dryness. The residue was purified by preparative TLC to yield 65 mg white solid which identified as 7-TES-9, 10-diketo-13- acetylbaccatin III as shown in Fig. 2 as compound 6.
EXAMPLE 3 PREPARATION OF lO-DEACETYLBACCATIN III (2)
Step A: To a solution of 95% of ethanol, 45 mg of the compound 6 was added and stirred until the solid was completely dissolved, and then hydrazine monohydrate (0.6ml) was added, then the solution was stirred for 8 hours at room temperature, after that the reaction was quenched by brine and extracted with dichloromethane and organic phase was collected and concentrated to dryness in vacuum. The residue was purified through silica gel column. The product from step A was dissolved in 10 ml of THF, 5 mg of LiAlH4 was then slowly added with stirring. After stirring for 2 hours at room temperature, the reaction was quenched by adding of 1% HCl (0.5 ml) and brine, the product was extracted with CH2Cl2. The organic phase was concentrated to dryness under vacuum to give final product. Product 7-TES-lO-deacetylbaccatin III as shown in Fig. 2 as compound 8 was obtained as slightly yellow crystals.
Step B: 7-TES-lO-deacetylbaccatin III was dissolved in a mixture of acetonitrile and acetone (3:1), the solution then was stirred at room temperature for a few minutes before 5 ml of sodium hypochloride (NaOCl) was added dropwise. The mixture was reacted at room temperature for 2 hours and then quenched with brine and extracted with ethyl acetate. The ethyl acetate phase was concentrated to dryness and the residue was re-crystallized from acetonitrile to yield 10-deacetylbaccatin III as a white powder (shown as compound 2).
EXAMPLE 4 PREPARATION OF 7-TES-9,10-DIKETODOCETAXEL (12) Step A: To a solution of 95% ethanol, 40 mg of compound 6 was added and stirred for a few minutes until the solid was dissolved, then ImI of hydrazine monohydrate was added. The mixture was stirred at room temperature for 8 hours, then diluted with ethyl acetate (50 ml) and poured into saturated NH4Cl solution (40 ml). The organic layer was separated and concentrated. The residue was purified by preparative TLC to give 30 mg of 7-TES-9, 10- diketobaccatin III (see compound 7 on Fig. 4).
Step B: 35 mg of 7-TES-9, 10-diketobaccatin III was placed in a 25 ml round bottom flask, and 3 mole equivalents of protected docetaxel side chain precursor, (2R,3S)-N-boc-O-(l-ethoxyethyl)-3-phenylisoserine or (3R,4S)-3-(l- ethoxyethyl)-4-(phenyl)-N-boc-2-azetidinone, were dissolved in 20 ml of tetrahydrofuran (THF) at -450C, then 6 mole equivalents of LiHMDS and 1 mole equivalent of CeCl3 were added slowly. The mixture was stirred at -450C for 30minutes then warmed to room temperature. The reaction progress was detected by TLC until completion. Once completed, the mixture was diluted with dichloromethane (50 ml) and poured into saturated NH4CI solution (40 ml). The organic layer was separated and concentrated. The residue was purified by preparative TLC to yield 7-TES-9, 10-diketodocetaxel (see compound 12 on Fig. 4).
EXAMPLE 5
PREPARATION OF DOCETAXEL (4)
Step A: 7-triethylsilyl-2'-EE-docetaxel (13): Compound 12 (1.Og) was dissolved in THF (30ml), and the solution was poured into a 50 ml round-bottom flask equipped with a magnetic stirrer, then 0.4 M solution of CeCl3-7H2O in THF/MeOH (2/1, 3ml) was added. The mixture was stirred for 5 minutes at room temperature. NaBH4 (45 mg, 1.2 mmol) was then slowly added with stirring. The mixture was stirred for another 10 minutes at room temperature or until the reaction completed, then the reaction was quenched by adding of 5% HCl (2 ml) and the product 13 was extracted with 50 ml of CH2Cl2 and saturated NH4Cl mixture (3:1) The organic layer was separated and evaporated to dryness under reduced pressure, the residue was took to next step without purification (see compound 13 on Fig. 4). Step B: The residue was re-dissolved in THF, and sodium hypochloride (NaOCl) was added dropwise. The mixture was stirred for 2 hours at room temperature then work-up as above. The residue was purified through flash column chromatography. Docetaxel was obtained as white needles (see compound 4 on Fig. 4). 7-triethylsilyl-2'-EE-10-deacetylpaclitaxeI (compound JJQ can be made through the same manner as for making intermediate compound 13 by using a paclitaxel side chain attached to 13-C position.
7-triethyl-2'-EE-paclitaxel (15): 1.5g of 7-triethylsilyl-2'-EE-10- deacetylpaclitaxel (18) was dissolved in THF (20 ml), the solution was poured into a 50 ml round-bottom flask equipped with a magnetic stirrer, then 5 ml of DMAP was added and the mixture was cooled to 0 0C, and 5 ml of acetyl chloride was added and the mixture was stirred for 10 hours at 0 0C, then the temperature was slowly raised to room temperature and kept for another hour. After the reaction was completed, the reaction was quenched by adding 50 ml of brine. The aqueous solution is extracted twice with ethyl acetate. The combined organic phase are washed with saturated aqueous copper sulphate solution until the DMAP has been
completely removed, then with saturated sodium chloride solution and then with water. The organic phase finally dried over anhydrous sodium sulphate, and concentrated to dryness under vacuum. The residue was purified through a silica gel column chromatography to yield 7-triethyl-2'-EE-paclitaxel (15). After de-protection of .15 by the same manner as to making docetaxel, paclitaxel can be obtained as white powder.
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.
Claims
1. A compound of formula (I), (II), (III) or (IV):
Ri is a hydrogen atom or a suitable protecting group for a hydroxyl group; R2 is a hydrogen atom or a suitable protecting group for a hydroxyl group;
R3 is a hydrogen atom or a suitable protecting group for a hydroxyl group; and
R4 is a hydrogen atom, a Ci -C20 alkyl linear or branched, C1-C20 acyl group, C]-C2O halogenated acyl group, C3-Cj2 cycloalkyl, Ci-Ci2 heterocyclyl, C2-C2O alkenyl, C2-C2O alkynyl, C6-Ci2 aryl, C6-C20 aralkyl, Ci-C20 alkyloxy C6-C20 alkylaryl, C1-C12 heteroaryl, C2-C20 alkylheterocyclyl, or C2-C2O alkylheteroaryl, said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, Cl, Br, I, OH, SH, NH2, NO2, CN, CF3, -SH, -OCH2Ph, -OPh, -SCH3, -SPh, -SCH2Ph, -COOH, - COOR6 in which R6 is a Ci-C6 alkyl, Ci-Ci2 alkyl linear or branched, C6-Ci2 aryl, C2-C20 alkenyl, Ci-C20 alkoxy, Ci-C20 alkyl, C2-C20 alkynyl, C6-C20 aralkyl, C6-C12 aryl, C3-C8 cycloalkyl, Ci-C20 aminoalkyl, C6-Ci2 aminoaryl, C]-Ci2 aminoheteroaryl ,C]-C2O hydroxyalkyl, C6-C]2 hydroxyaryl, C]-C]2 hydroxyheteroaryl, C]-Ci2 heterocyclyl, C]-C]2 heteroaryl, C2-C20 alkylheterocyclyl, or C2-C2O alkylheteroaryl.
2. The compound of claim 1, wherein said suitable protecting group for a hydroxyl group is chosen from Ci-C25 ethers, Ci-C25 substituted methyl ethers, Cj-C25 substituted ethyl ethers, C]-C25 acyl groups, Ci-C25 halogenated acyl groups, C]-C25 substituted benzyl ethers, Ci-C25 silyl ethers, Ci-C25 esters, C]-C25 carbonates, and Ci- C25 sulfonates.
3. The compound of claim 1, wherein said suitable protecting group for a hydroxyl group is chosen from methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-(trimethylsilyl)ethoxymethyl, dioxanyl, 1- ethoxyethyl, l-(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, f-butyl, allyl, propargyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, ?-butyldimethylsilyl, /-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, andp-toluenesulfonyl.
4. The compound of claim 1, wherein Ri is triethylsilyl.
5. The compound of claim 1, wherein R2 is acetyl.
6. The compound of claim 1, wherein R3 is ethoxyethyl.
7. The compound of claim 1, wherein R4 is a Ci-C6 alkyl, phenyl, /-butyloxyl, a C2-C6 alkenyl, tetrahydrofuranyl, or tetrahydropyranyl.
8. The compound of claim 1, wherein R4 is a pentyl, phenyl, ^-butyloxyl, but-2- enyl, tetrahydrofuranyl, or tetrahydropyranyl.
9. A compound of formula (V) or (VI):
Ri is a hydrogen atom or a suitable protecting group for a hydroxyl group;
R2 is a hydrogen atom or a suitable protecting group for a hydroxyl group;
R3 is a hydrogen atom or a suitable protecting group for a hydroxyl group; and
R4 is a hydrogen atom, a Ci-C2O alkyl linear or branched, Ci- C2o acyl group, Ci-C20 halogenated acyl group, C3-C12 cycloalkyl, Ci-Ci2 heterocyclyl,
C2-C2O alkenyl, C2-C20 alkynyl, C6-Ci2 aryl, C6-C20 aralkyl, Ci-C20 alkyloxy C6-C20 alkylaryl, Ci-Ci2 heteroaryl, C2-C2O alkylheterocyclyl, C2-C2O alkylheteroaryl, and
R5 is a hydrogen atom or a suitable protecting group for a hydroxyl group, said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, Cl, Br, I, OH, SH, NH2, NO2, CN, CF3, -SH, -OCH2Ph, -OPh, -SCH3, -SPh, -SCH2Ph, -COOH, - COOR6 in which R6 is a Ci-C6 alkyl, C1-C12 alkyl linear or branched, C6-Ci2 aryl, C2-C20 alkenyl, Ci-C20 alkoxy, Ci-C20 alkyl, C2-C20 alkynyl, C6-C20 aralkyl, C6-Ci2 aryl, C3-Cg cycloalkyl, Ci-C20 aminoalkyl, C6-Cj2 aminoaryl, Ci-C)2 aminoheteroaryl ,Ci-C20 hydroxyalkyl, C6-Ci2 hydroxyaryl, Ci-Ci2 hydroxyheteroaryl, Ci-Ci2 heterocyclyl, Cj-Ci2 heteroaryl, C2-C20 alkylheterocyclyl, or C2-C20 alkylheteroaryl.
10. The compound of claim 9, wherein said suitable protecting group for a hydroxyl group is chosen from Ci-C25 ethers, Ci-C25 substituted methyl ethers, Cj-C25 substituted ethyl ethers, Ci-C25 acyl groups, Ci-C25 halogenated acyl groups, Ci-C25 substituted benzyl ethers, Ci-C25 silyl ethers, Ci-C25 esters, Ci-C25 carbonates, and Ci- C25 sulfonates.
1 1. The compound of claim 9, wherein said suitable protecting group for a hydroxyl group is chosen from methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-(trimethylsilyl)ethoxymethyl, dioxanyl, 1- ethoxyethyl, l-(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, ?-butyl, allyl, propargyl, benzyl, />-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, r-butyldimethylsilyl, r-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and/7-toluenesulfonyl.
12. The compound of claim 9, wherein Ri is triethylsilyl.
13. The compound of claim 9, wherein R2 is acetyl.
14. The compound of claim 9, wherein R3 is ethoxyethyl.
15. The compound of claim 9, wherein R4 is a Ci-C6 alkyl, phenyl, t-butyloxyl, a C2-C6 alkenyl, tetrahydrofuranyl, or tetrahydropyranyl.
16. The compound of claim 9, wherein R4 is a pentyl, phenyl, /-butyloxyl, but-2- enyl, tetrahydrofuranyl, or tetrahydropyranyl.
17. The compound of claim 9, wherein R5 is triethylsilyl.
18. A process for preparing a compound of formula (II): said process comprising reacting an oxidizing agent with a compound of formula (I):
wherein
Ri is a hydrogen atom or a suitable protecting group for a hydroxyl group; and
R2 is a hydrogen atom or a suitable protecting group for a hydroxyl group.
19. The process of claim 18, wherein said suitable protecting group for a hydroxyl group is chosen from Ci-C25 ethers, Ci-C25 substituted methyl ethers, Ci-C25 substituted ethyl ethers, Ci-C25 acyl groups, Ci-C25 halogenated acyl groups, Ci-C25 substituted benzyl ethers, Ci-C25 silyl ethers, Ci-C25 esters, Ci-C25 carbonates, and Cr C25 sulfonates.
20. The process of claim 18, wherein said suitable protecting group for a hydroxyl group is chosen from methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-(trimethylsilyl)ethoxymethyl, dioxanyl, 1-ethoxyethyl, l-(2- chloroethoxy)ethyl, 2,2,2-trichloroethyl, /-butyl, allyl, propargyl, benzyl, p- methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, r-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and /?-toluenesulfonyl.
21. The process of claim 18, wherein Ri is triethylsilyl.
22. The process of claim 18, wherein R2 is acetyl.
23. The process of claim 18, wherein said oxidizing agent is chosen from tetra-n- propylammonium perruthenate, Collin's reagent, PCC, PDC, CrO2, activated methyl sulfoxide (Swern reagent), and John's reagent.
24. A process for converting 9-dihydro-13-acetylbaccatin III into a taxane derivative comprising the step of removing 10-acetyl group and oxidizing the C-9 and C-IO positions of the 9-dihydro-13-acetylbaccatin III.
25. The process of claim 24, wherein the oxidizing step is achieve by the addition of an oxidizing agent chosen from tetra-n-propylammonium perruthenate, Collin's reagent, PCC, PDC, CrO2, activated methyl sulfoxide (Swern reagent), and John's reagent.
26. A process for preparing paclitaxel, docetaxel and a derivative thereof comprising the steps of:
(a) protecting the C-7 hydroxy group of 9-dihydro-13-acetylbaccatin III with a suitable protecting group to obtain a protected product;
(b) deacetylating the 10-acetyl group of the protected product; and
(c) oxidizing the C-9 and C-IO hydroxy group of the protected product.
27. The process of claim 26, wherein the protecting group is chosen from benzyl, C1-C25 substituted benzyl, benzylformate, Ci-C25 substituted benzylformate, tosyl, Cp C25 substituted tosyl, dihydropyrannyl, methoxymethyl, benzoyl, Ci-C25 substituted benzoyl, Ci-C25 trialkylsilyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxycarbonyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, f-butyldiphenylsilyl,
28. The process of claim 26, wherein the oxidizing step is achieved by the addition of an oxidizing reagent chosen from of tetra-n-propylammonium perruthenate, Collin's reagent, PDC, PCC, CrO2 and activated methyl sulfoxide.
29. The process of claim 26, further comprising the step of deacetylating the C- 13 position.
30. The process of claim 29, wherein the deacetylating step is achieved by the addition of an strong base chosen from n-BuLi, CH3Li, NaBH4, red-Al, and hydrazine monohydrate.
31. The process of claim 29, further comprising the step of reducing the C-IO ketone into C-IO hydroxyl group.
32. The process of claim 31, wherein the reducing the C-IO ketone step is achieved by the addition of an reduction agents chosen from Pd/C, NaBH4/CeCl3, LiAlH4, and BINAP, and (s)-diam-BINAP.
33. A process for preparing a compound of formula 8:
34. The process of claim 33, wherein the reducing the C-IO ketone step is achieved by the addition of an reduction agents chosen from Pd/C, NaBI-VCeCl3, LiAlH4, and BINAP, and (s)-diam-BINAP.
35. The process of claim 34, further comprising the step of deprotecting the C-7 position to obtain 10-deacetylbaccatin III.
36. The process of claim 29, further comprising the steps of adding a suitable side chain to the C- 13 position, reducing C-IO and selectively deprotecting to obtain a desired product.
37. The process of claim 36, wherein the deprotection is done at the C-7 and 2' positions to obtain paclitaxel and docetaxel.
38. The process of claim 37, wherein the deprotection is achieved by addition of a deprotection agents chosen from diluted HCl, HF, and NaOCl.
39. The process of claim 36, wherein the side chain is chosen from (2R, 3S)-N- benzoyl-O-(l-ethoxyethyl)-3-phenylisoserine; (3R, 4S)-3-(l-ethoxyethoxy)-4- (phenyl)-N-benzoyl-2-azetidinone; (2R, 3S)-N-boc-O-(l-ethoxyethyl)-3- phenylisoserine and (3R, 4S)-3-(l-ethoxyethoxy)-4-(phenyl)-N-boc-2-azetidinone.
40. The process of claim 24, wherein said taxane derivative is paclitaxel or docetaxel.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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EP07719967A EP2029563A4 (en) | 2006-06-12 | 2007-06-12 | Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii |
Applications Claiming Priority (4)
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CA2,549,951 | 2006-06-12 | ||
CA002549951A CA2549951A1 (en) | 2006-06-12 | 2006-06-12 | Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii |
US11/425,034 US7847111B2 (en) | 2006-06-19 | 2006-06-19 | Semi-synthetic route for the preparation of paclitaxel, docetaxel, and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III |
US11/425,034 | 2006-06-19 |
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Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2215682A1 (en) * | 1995-03-17 | 1996-09-26 | Indena S.P.A. | 10-deacetylbaccatine iii and 10-deacetyl 14.beta.-hydroxybaccatine iii derivatives, a process for the preparation thereof and pharmaceutical compositions containing them |
CA2231837A1 (en) * | 1995-09-13 | 1997-03-20 | Florida State University | Radiosensitizing taxanes and their pharmaceutical preparations |
CA2188190A1 (en) * | 1996-10-18 | 1998-04-18 | Sarala Balachandran | The semi-synthesis of a protected bacatin iii compound |
CA2307548A1 (en) * | 1997-05-01 | 1998-11-12 | Jian Liu | Process for converting 9-dihydro-13-acetylbaccatin iii into taxol and derivatives thereof |
CA2403429A1 (en) * | 2000-03-21 | 2001-09-27 | Gertrude C. Kasitu | Conversion of 9-dihydro-13-acetylbaccatin iii to baccatin iii and 10-deacetylbaccatin iii |
US6593482B2 (en) * | 1993-02-01 | 2003-07-15 | Aventis Pharma S.A. | Methods for preparing new taxoids and pharmaceutical compositions containing them |
US6710191B2 (en) * | 1993-03-05 | 2004-03-23 | Florida State University | 9β-hydroxytetracyclic taxanes |
CA2444693A1 (en) * | 2002-09-26 | 2004-03-26 | University Of New Brunswick | Conversion of 9-dihydro-13-acetylbaccatin iii into 10-deacetylbaccatin iii |
WO2005030150A2 (en) * | 2003-09-25 | 2005-04-07 | Tapestry Pharmaceuticals, Inc. | 9,10-α,α-OH-TAXANE ANALOGS AND METHODS FOR PRODUCTION THEREOF |
WO2007073383A1 (en) * | 2005-12-21 | 2007-06-28 | Tapestry Pharmaceuticals, Inc. | Novel compounds and methods for forming taxanes and using the same |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
US5136060A (en) * | 1989-11-14 | 1992-08-04 | Florida State University | Method for preparation of taxol using an oxazinone |
-
2007
- 2007-06-12 WO PCT/CA2007/001051 patent/WO2007143839A1/en active Search and Examination
- 2007-06-12 EP EP07719967A patent/EP2029563A4/en not_active Withdrawn
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6593482B2 (en) * | 1993-02-01 | 2003-07-15 | Aventis Pharma S.A. | Methods for preparing new taxoids and pharmaceutical compositions containing them |
US6710191B2 (en) * | 1993-03-05 | 2004-03-23 | Florida State University | 9β-hydroxytetracyclic taxanes |
CA2215682A1 (en) * | 1995-03-17 | 1996-09-26 | Indena S.P.A. | 10-deacetylbaccatine iii and 10-deacetyl 14.beta.-hydroxybaccatine iii derivatives, a process for the preparation thereof and pharmaceutical compositions containing them |
CA2231837A1 (en) * | 1995-09-13 | 1997-03-20 | Florida State University | Radiosensitizing taxanes and their pharmaceutical preparations |
CA2188190A1 (en) * | 1996-10-18 | 1998-04-18 | Sarala Balachandran | The semi-synthesis of a protected bacatin iii compound |
US6576777B2 (en) * | 1996-10-18 | 2003-06-10 | Institut National De La Recherche Scientifique | Semi-synthesis of a protected baccatin III compound |
CA2307548A1 (en) * | 1997-05-01 | 1998-11-12 | Jian Liu | Process for converting 9-dihydro-13-acetylbaccatin iii into taxol and derivatives thereof |
CA2403429A1 (en) * | 2000-03-21 | 2001-09-27 | Gertrude C. Kasitu | Conversion of 9-dihydro-13-acetylbaccatin iii to baccatin iii and 10-deacetylbaccatin iii |
CA2444693A1 (en) * | 2002-09-26 | 2004-03-26 | University Of New Brunswick | Conversion of 9-dihydro-13-acetylbaccatin iii into 10-deacetylbaccatin iii |
WO2005030150A2 (en) * | 2003-09-25 | 2005-04-07 | Tapestry Pharmaceuticals, Inc. | 9,10-α,α-OH-TAXANE ANALOGS AND METHODS FOR PRODUCTION THEREOF |
WO2007073383A1 (en) * | 2005-12-21 | 2007-06-28 | Tapestry Pharmaceuticals, Inc. | Novel compounds and methods for forming taxanes and using the same |
Non-Patent Citations (1)
Title |
---|
See also references of EP2029563A4 * |
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