JP2009501134A - ドセタキセルの製造法 - Google Patents
ドセタキセルの製造法 Download PDFInfo
- Publication number
- JP2009501134A JP2009501134A JP2008515928A JP2008515928A JP2009501134A JP 2009501134 A JP2009501134 A JP 2009501134A JP 2008515928 A JP2008515928 A JP 2008515928A JP 2008515928 A JP2008515928 A JP 2008515928A JP 2009501134 A JP2009501134 A JP 2009501134A
- Authority
- JP
- Japan
- Prior art keywords
- lactam
- hydroxy
- mixture
- dab
- mol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960003668 docetaxel Drugs 0.000 title claims abstract description 41
- 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 32
- 238000004519 manufacturing process Methods 0.000 title abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 54
- 125000006239 protecting group Chemical group 0.000 claims abstract description 48
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 28
- 239000010703 silicon Substances 0.000 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 claims description 128
- 239000000203 mixture Substances 0.000 claims description 104
- 150000003952 β-lactams Chemical group 0.000 claims description 51
- -1 2-methoxy-2-propyl Chemical group 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 48
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 31
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 27
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 24
- 239000002243 precursor Substances 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 238000000926 separation method Methods 0.000 claims description 17
- 150000001412 amines Chemical class 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 150000004820 halides Chemical class 0.000 claims description 14
- 238000001212 derivatisation Methods 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 150000002466 imines Chemical class 0.000 claims description 11
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 10
- 229910003849 O-Si Inorganic materials 0.000 claims description 9
- 229910003872 O—Si Inorganic materials 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 5
- DMEXFOUCEOWRGD-UHFFFAOYSA-N chloro-[chloro(dimethyl)silyl]oxy-dimethylsilane Chemical compound C[Si](C)(Cl)O[Si](C)(C)Cl DMEXFOUCEOWRGD-UHFFFAOYSA-N 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- GJIYNWRLGOMDEX-UHFFFAOYSA-N bis[[chloro(dimethyl)silyl]oxy]-dimethylsilane Chemical compound C[Si](C)(Cl)O[Si](C)(C)O[Si](C)(C)Cl GJIYNWRLGOMDEX-UHFFFAOYSA-N 0.000 claims description 3
- VGQOKOYKFDUPPJ-UHFFFAOYSA-N chloro-[2-[chloro(dimethyl)silyl]ethyl]-dimethylsilane Chemical compound C[Si](C)(Cl)CC[Si](C)(C)Cl VGQOKOYKFDUPPJ-UHFFFAOYSA-N 0.000 claims description 3
- 150000003951 lactams Chemical group 0.000 claims 2
- XWKUGBVPSRCDNQ-UHFFFAOYSA-N acetic acid;ethenone Chemical compound C=C=O.CC(O)=O XWKUGBVPSRCDNQ-UHFFFAOYSA-N 0.000 claims 1
- QNXUEHHVVZBQHD-UHFFFAOYSA-N chloro-(chloro-ethenyl-methylsilyl)oxy-ethenyl-methylsilane Chemical compound C=C[Si](Cl)(C)O[Si](C)(Cl)C=C QNXUEHHVVZBQHD-UHFFFAOYSA-N 0.000 claims 1
- AUWRUFAJYVQXSH-UHFFFAOYSA-N chloro-(chloro-methyl-phenylsilyl)oxy-methyl-phenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C)O[Si](C)(Cl)C1=CC=CC=C1 AUWRUFAJYVQXSH-UHFFFAOYSA-N 0.000 claims 1
- XJYPEWPGZBASNR-UHFFFAOYSA-N chloro-[3-[chloro(dimethyl)silyl]propyl]-dimethylsilane Chemical compound C[Si](C)(Cl)CCC[Si](C)(C)Cl XJYPEWPGZBASNR-UHFFFAOYSA-N 0.000 claims 1
- QRGNIFCMKCRMQY-UHFFFAOYSA-N chloro-[8-[chloro(dimethyl)silyl]octyl]-dimethylsilane Chemical compound C[Si](C)(Cl)CCCCCCCC[Si](C)(C)Cl QRGNIFCMKCRMQY-UHFFFAOYSA-N 0.000 claims 1
- UHRAUGIQJXURFE-UHFFFAOYSA-N chloro-[[[chloro(dimethyl)silyl]oxy-dimethylsilyl]oxy-dimethylsilyl]oxy-dimethylsilane Chemical compound C[Si](C)(Cl)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)Cl UHRAUGIQJXURFE-UHFFFAOYSA-N 0.000 claims 1
- YQULWRCMYAXEAV-UHFFFAOYSA-N chloro-[chloro(diphenyl)silyl]oxy-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(Cl)O[Si](Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 YQULWRCMYAXEAV-UHFFFAOYSA-N 0.000 claims 1
- DDYAZDRFUVZBMM-UHFFFAOYSA-N chloro-[chloro-di(propan-2-yl)silyl]oxy-di(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)O[Si](Cl)(C(C)C)C(C)C DDYAZDRFUVZBMM-UHFFFAOYSA-N 0.000 claims 1
- JQYKSDDVPXVEOL-UHFFFAOYSA-N chloro-hexyl-dimethylsilane Chemical compound CCCCCC[Si](C)(C)Cl JQYKSDDVPXVEOL-UHFFFAOYSA-N 0.000 claims 1
- YWLXLRUDGLRYDR-UHFFFAOYSA-N 10-deacetylbaccatin Chemical compound CC(=O)OC12COC1CC(O)C(C(C(O)C1=C(C)C(O)CC3(O)C1(C)C)=O)(C)C2C3OC(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-UHFFFAOYSA-N 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 167
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 94
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 92
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 83
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 82
- 238000006243 chemical reaction Methods 0.000 description 64
- 239000000243 solution Substances 0.000 description 62
- 235000019439 ethyl acetate Nutrition 0.000 description 53
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 239000013078 crystal Substances 0.000 description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 26
- 239000000047 product Substances 0.000 description 26
- 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 24
- 239000007787 solid Substances 0.000 description 23
- 239000000706 filtrate Substances 0.000 description 21
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 20
- 239000000741 silica gel Substances 0.000 description 20
- 229910002027 silica gel Inorganic materials 0.000 description 20
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 20
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- 238000004809 thin layer chromatography Methods 0.000 description 19
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- 238000002390 rotary evaporation Methods 0.000 description 16
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 239000012267 brine Substances 0.000 description 13
- 150000002148 esters Chemical group 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- 238000003828 vacuum filtration Methods 0.000 description 13
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 12
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 11
- 150000002560 ketene acetals Chemical class 0.000 description 11
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 11
- MAEQOWMWOCEXKP-UHFFFAOYSA-N trimethylsilyl 2-trimethylsilyloxyacetate Chemical compound C[Si](C)(C)OCC(=O)O[Si](C)(C)C MAEQOWMWOCEXKP-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- FBZSDKXFQUKDLD-SFYZADRCSA-N (3s,4r)-3-hydroxy-4-phenylazetidin-2-one Chemical compound N1C(=O)[C@@H](O)[C@H]1C1=CC=CC=C1 FBZSDKXFQUKDLD-SFYZADRCSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 238000005755 formation reaction Methods 0.000 description 9
- 229960002429 proline Drugs 0.000 description 9
- 239000002585 base Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 7
- 238000011065 in-situ storage Methods 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- RBLGHIMEHDNFAV-MNOVXSKESA-N (3s,4r)-4-phenyl-3-trimethylsilyloxyazetidin-2-one Chemical compound N1C(=O)[C@@H](O[Si](C)(C)C)[C@H]1C1=CC=CC=C1 RBLGHIMEHDNFAV-MNOVXSKESA-N 0.000 description 5
- FCZGHPGTZRTDNN-UHFFFAOYSA-N 1,2-bis(trimethylsilyloxy)ethenoxy-trimethylsilane Chemical compound C[Si](C)(C)OC=C(O[Si](C)(C)C)O[Si](C)(C)C FCZGHPGTZRTDNN-UHFFFAOYSA-N 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 5
- 229940123237 Taxane Drugs 0.000 description 5
- 150000001241 acetals Chemical class 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 229940043279 diisopropylamine Drugs 0.000 description 5
- 230000008034 disappearance Effects 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000005909 Kieselgur Substances 0.000 description 4
- 229930182821 L-proline Natural products 0.000 description 4
- 229930012538 Paclitaxel Natural products 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004423 acyloxy group Chemical group 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 4
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229960001592 paclitaxel Drugs 0.000 description 4
- 238000011027 product recovery Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 4
- JXGVXCZADZNAMJ-NSHDSACASA-N (2s)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1=CC=CC=C1 JXGVXCZADZNAMJ-NSHDSACASA-N 0.000 description 3
- ATGAAABKKYCMRZ-PKNBQFBNSA-N (e)-1-phenyl-n-trimethylsilylmethanimine Chemical compound C[Si](C)(C)\N=C\C1=CC=CC=C1 ATGAAABKKYCMRZ-PKNBQFBNSA-N 0.000 description 3
- GUIMGQMKYJANOP-UHFFFAOYSA-N 1,1-bis(trimethylsilyloxy)ethoxy-trimethylsilane Chemical compound C[Si](C)(C)OC(C)(O[Si](C)(C)C)O[Si](C)(C)C GUIMGQMKYJANOP-UHFFFAOYSA-N 0.000 description 3
- YOWQWFMSQCOSBA-UHFFFAOYSA-N 2-methoxypropene Chemical compound COC(C)=C YOWQWFMSQCOSBA-UHFFFAOYSA-N 0.000 description 3
- LHBHZALHFIQJGJ-UHFFFAOYSA-N 3-hydroxy-2-(4-methoxyphenyl)-3,5-dihydro-2h-1,5-benzothiazepin-4-one Chemical compound C1=CC(OC)=CC=C1C1C(O)C(=O)NC2=CC=CC=C2S1 LHBHZALHFIQJGJ-UHFFFAOYSA-N 0.000 description 3
- ANMMVLKRULNAAI-UHFFFAOYSA-N 4-phenyl-1-trimethylsilyl-3-trimethylsilyloxyazetidin-2-one Chemical compound C[Si](C)(C)N1C(=O)C(O[Si](C)(C)C)C1C1=CC=CC=C1 ANMMVLKRULNAAI-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 0 C*(C)N(C=*)[Si](C)(C)C Chemical compound C*(C)N(C=*)[Si](C)(C)C 0.000 description 3
- 229930194542 Keto Natural products 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 125000000468 ketone group Chemical group 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 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 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 3
- 239000005051 trimethylchlorosilane Substances 0.000 description 3
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 239000013065 commercial product Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- OXOZHAWWRPCVGL-UHFFFAOYSA-N lithium;trimethyl(oxido)silane Chemical compound [Li+].C[Si](C)(C)[O-] OXOZHAWWRPCVGL-UHFFFAOYSA-N 0.000 description 2
- 238000006140 methanolysis reaction Methods 0.000 description 2
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000002902 organometallic compounds Chemical class 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- MNWPCLYIIKCFKO-UHFFFAOYSA-N triethyl-(2-triethylsilyloxy-1-trimethylsilyloxyethenoxy)silane Chemical compound CC[Si](CC)(CC)OC=C(O[Si](C)(C)C)O[Si](CC)(CC)CC MNWPCLYIIKCFKO-UHFFFAOYSA-N 0.000 description 2
- PTMKGXGARZCNGL-UHFFFAOYSA-N triethylsilyl 2-triethylsilyloxyacetate Chemical compound CC[Si](CC)(CC)OCC(=O)O[Si](CC)(CC)CC PTMKGXGARZCNGL-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 238000007738 vacuum evaporation Methods 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- ARECGRJPMILWGK-KSMMKXTCSA-N (2S)-1-[(2-methylpropan-2-yl)oxycarbonyl]-2-[(3R,4S)-2-oxo-4-phenylazetidin-3-yl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@]1([C@H]2[C@H](NC2=O)C3=CC=CC=C3)C(=O)O ARECGRJPMILWGK-KSMMKXTCSA-N 0.000 description 1
- YCDDDWNPIABFGA-RITPCOANSA-N (3s,4s)-4-(furan-2-yl)-3-hydroxyazetidin-2-one Chemical compound N1C(=O)[C@@H](O)[C@H]1C1=CC=CO1 YCDDDWNPIABFGA-RITPCOANSA-N 0.000 description 1
- DMJXZYQWCODZTQ-UHFFFAOYSA-N 1,1-bis(triethylsilyloxy)ethoxy-triethylsilane Chemical compound CC[Si](CC)(CC)OC(C)(O[Si](CC)(CC)CC)O[Si](CC)(CC)CC DMJXZYQWCODZTQ-UHFFFAOYSA-N 0.000 description 1
- LUKUSMNVBAFQGN-UHFFFAOYSA-N 1,2-bis(triethylsilyloxy)ethenoxy-triethylsilane Chemical compound CC[Si](CC)(CC)OC=C(O[Si](CC)(CC)CC)O[Si](CC)(CC)CC LUKUSMNVBAFQGN-UHFFFAOYSA-N 0.000 description 1
- CUFNUQSBSOKXJH-UHFFFAOYSA-N 1,2-bis(trimethylsilyl)ethenyl-trimethylsilane Chemical compound C[Si](C)(C)C=C([Si](C)(C)C)[Si](C)(C)C CUFNUQSBSOKXJH-UHFFFAOYSA-N 0.000 description 1
- HJRJRUMKQCMYDL-UHFFFAOYSA-N 1-chloro-2,4,6-trinitrobenzene Chemical compound [O-][N+](=O)C1=CC([N+]([O-])=O)=C(Cl)C([N+]([O-])=O)=C1 HJRJRUMKQCMYDL-UHFFFAOYSA-N 0.000 description 1
- UPUNPNQSFNXVJX-UHFFFAOYSA-N 1-hydroxy-4-phenylazetidin-2-one Chemical compound C1C(=O)N(O)C1C1=CC=CC=C1 UPUNPNQSFNXVJX-UHFFFAOYSA-N 0.000 description 1
- 125000003241 10-deacetylbaccatin III group Chemical group 0.000 description 1
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 1
- WDZACGWEPQLKOM-UHFFFAOYSA-N 2-chloro-1,3,5-trimethylbenzene Chemical compound CC1=CC(C)=C(Cl)C(C)=C1 WDZACGWEPQLKOM-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- LDZNCSVWVMBVST-UHFFFAOYSA-N 2-trimethylsilylethyl hydrogen carbonate Chemical compound C[Si](C)(C)CCOC(O)=O LDZNCSVWVMBVST-UHFFFAOYSA-N 0.000 description 1
- REEPMXWBVSRGLU-UHFFFAOYSA-N 3-hydroxy-4-thiophen-2-ylazetidin-2-one Chemical compound N1C(=O)C(O)C1C1=CC=CS1 REEPMXWBVSRGLU-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- WLWXEDJMZHONIG-UHFFFAOYSA-N 4-methylbenzenesulfonate;1-methyl-1h-imidazol-1-ium Chemical compound C[NH+]1C=CN=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 WLWXEDJMZHONIG-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- JQPZAQWDUIIZHH-RMOZTFSWSA-N O[C@@H]1C(N[C@@H]1C1=CC=CC=C1)=O.O[C@@H]1C(N[C@@H]1C1=CC=CC=C1)=O Chemical compound O[C@@H]1C(N[C@@H]1C1=CC=CC=C1)=O.O[C@@H]1C(N[C@@H]1C1=CC=CC=C1)=O JQPZAQWDUIIZHH-RMOZTFSWSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241001116498 Taxus baccata Species 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007824 aliphatic compounds Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- GOPDFXUMARJJEA-UHFFFAOYSA-N amino(nitro)azanide Chemical compound N[N-][N+]([O-])=O GOPDFXUMARJJEA-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- FHCIILYMWWRNIZ-UHFFFAOYSA-N benzhydryl(chloro)silane Chemical compound C=1C=CC=CC=1C([SiH2]Cl)C1=CC=CC=C1 FHCIILYMWWRNIZ-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- IEPBPSSCIZTJIF-UHFFFAOYSA-N bis(2,2,2-trichloroethyl) carbonate Chemical compound ClC(Cl)(Cl)COC(=O)OCC(Cl)(Cl)Cl IEPBPSSCIZTJIF-UHFFFAOYSA-N 0.000 description 1
- JKJWYKGYGWOAHT-UHFFFAOYSA-N bis(prop-2-enyl) carbonate Chemical compound C=CCOC(=O)OCC=C JKJWYKGYGWOAHT-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000005828 desilylation reaction Methods 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- GPKUICFDWYEPTK-UHFFFAOYSA-N methoxycyclohexatriene Chemical compound COC1=CC=C=C[CH]1 GPKUICFDWYEPTK-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- KQPMFNHZHBLVRR-UHFFFAOYSA-N oxalic acid;hydrochloride Chemical compound Cl.OC(=O)C(O)=O KQPMFNHZHBLVRR-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical group 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 150000003147 proline derivatives Chemical class 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000005374 siloxide group Chemical group 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- JEBQZDUVSXAILJ-UHFFFAOYSA-N tert-butyl 2-oxo-4-phenyl-3-trimethylsilyloxyazetidine-1-carboxylate Chemical compound C[Si](C)(C)OC1C(=O)N(C(=O)OC(C)(C)C)C1C1=CC=CC=C1 JEBQZDUVSXAILJ-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- YSXDYPPIRNBTDT-UHFFFAOYSA-N trimethyl-(1-triethylsilyloxy-2-trimethylsilyloxyethoxy)silane Chemical compound CC[Si](CC)(CC)OC(O[Si](C)(C)C)CO[Si](C)(C)C YSXDYPPIRNBTDT-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epoxy Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
(a) 10-デアセチルバッカチンIII(10-DAB)のC(7)およびC(10)ヒドロキシ基を、架橋珪素に基づく保護基で保護して、10-DAB誘導体を生成する工程;
(b) 10-DAB誘導体をさらに誘導体化する工程であって、さらなる誘導体化が、10-DAB誘導体をβ-ラクタム側鎖先駆物質で処理して、側鎖を有する10-DAB誘導体を生成することを含んで成る工程;および
(c) 工程(b)の生成物を脱保護して、ドセタキセルを生成する工程。
G1、G2、G3およびG4は、独立して、ヒドロカルビル、置換ヒドロカルビル、アルコキシまたはヘテロシクロであり;
L1およびL2は、独立して、アミン、ハライドまたはスルホネート脱離基であり;
Zは、ヒドロカルビル、置換ヒドロカルビル、ヘテロシクロ、-[O-Si(Z10)(Z11)-]nO-または-O-であり;
各Z10およびZ11は、独立して、ヒドロカルビルであり;
nは、1または2である]。
下記の定義および方法は、本発明をよりよく規定し、本発明の実施において当業者を導くために記載する。他に記載しないかぎり、用語は、当業者による一般的使用に従って理解されるものとする。
THF中のLHMDSの1M溶液(100mL、0.1mol)を0℃に冷却し、実施例1のように調製したTHF中のトリメチルシリル2-(トリメチルシリルオキシ)アセテート(22.0g、0.1mol)の1M溶液を滴下して、発熱を調節し、温度を0℃〜5℃に維持した。この溶液に、1当量のトリメチルシリルクロリドを添加し、次に、1当量のLHMDSおよび1当量のベンズアルデヒドを攪拌しながら0〜15℃で14時間にわたって添加した。3-トリメチルシリルオキシ-β-ラクタム生成物が、5:1のシス:トランス比において定量的収量で観察された(反応混合物のHNMRによる)。この方法は下記の式4に示されている。
典型には、リチウムヘキサメチルジシラジドの1.0M THF溶液(140mL、0.14mol)を窒素下に、THF(140mL)で希釈し、氷水浴で0〜5℃に冷却した。トリメチルシリル2-(トリメチルシリルオキシ)アセテート(33.4g、0.14mol)を20分間にわたって滴下した。このエノラート溶液に、トリメチルシリルクロリド(17.7mL、0.14mol)を添加し、5分間攪拌した後、第二部分のTHF中のLHMDS溶液(100mL、0.10mol)を10分間にわたって添加した。この溶液に2-チオフェンカルボキシアルデヒド(11.2g、0.1mol)を15〜20分間にわたって滴下して、発熱を5℃未満に調節した。この溶液を0〜5℃で14時間攪拌して、イミンを完全に消失させた。
ケテンアセタールトリス(トリメチルシリルオキシ)エテンは、市販製品であり、下記の反応式7に示されているように、種々のアルデヒドから出発するβ-ラクタムの合成に使用することができる。従って、ベンズアルデヒドをリチウムヘキサメチルジシラジドのTHF溶液で0℃において処理した場合、N-トリメチルシリルベンズアルジミンが、当量のリチウムトリメチルシラノレートと共に同時に生成した。この混合物をケテンアセタールと共に10〜15℃で14時間攪拌して、反応式5における反応と同様にβ-ラクタムを生成した。このケテンアセタール反応は、我々が試験した種々の芳香族およびエノール化可能脂肪族化合物に一般的であることが見出され(表2参照)、あらゆる場合に、主にシス-β-ラクタムを生成した。
1H NMR(400MHz、CDCl3)δ(ppm):0.64(q, J=8.04Hz, 6H), 0.78(q, J=8.04, 6H), 0.97 (t, J=8.04, 2x9H), 4.2(s, 2H)
(±)-シス-3-ヒドロキシ-4-(2-フリル)-アゼチジン-2-オン(500g、3.265mol)を、0.5当量のp-トルエンスルホニルクロリド(335.53g、1.76mol)および1-メチルイミダゾール(303.45g、3.7mol)の存在下に、-78℃で12時間にわたってN-t-Boc-L-プロリン(378.83g、1.76mol)で処理した。混合物をシリカゲル5kgで濾過した。t-Boc-L-プロリンエステルの望ましくない(-)-β-ラクタムエナンチオマーを、水でのトリチュレーションによって除去した。2-メチル-1-プロパノールを用いた水の共沸除去によって所望のエナンオマーを回収し、酢酸エチルから再結晶して、所望の(+)-シス-3-ヒドロキシ-4-(2-フリル)-アゼチジン-2-オンを得た。酢酸エチルからの再結晶後の光学純度は98%超であった。融点:133〜135℃。[α]20D=+109.5(MeOH, c=1.0)、1H NMR(400MHz、CDCl3)(ppm):2.69(bs, 1H), 4.91(d, J=4.96Hz, 1H), 5.12(bs, 1H), 6.10(bs, 1H), 6.34(dd, J=3.32, 3.32Hz, 1H), 6.47(d, J=3.32Hz, 1H), 7.49(m, 1H)
(±)-シス-3-ヒドロキシ-4-フェニル-アゼチジン-2-オン(60g、0.368mol)を、0.5当量のp-トルエンスルホニルクロリド(35g、0.184mol)および1-メチルイミダゾール(45mL、0.56mol)の存在下に、-78℃で12時間にわたってN-cBz-L-プロリン(45g、0.184mol)で処理した。反応混合物を濃縮し、シリカゲルで濾過して、1-メチルイミダゾリウムトシラート塩を除去した後に、所望のジアステレオマーを酢酸エチルから結晶化して、白色固形物14.5g(48%)を得た。このプロトコールはエナンチオマー混合物の動的分離を生じて、所望の(+)-シス-3-ヒドロキシ-4-フェニル-アゼチジン-2-オンを与えた。酢酸エチルからの再結晶後の光学純度は98%超であった。融点:175〜180℃;[α]578 20=+202(MeOH, c=1.0)、1H NMR(400MHz、CDCl3)(ppm):2.26(d, J=9.4Hz, 1H), 4.96(d, J=4.96Hz, 1H), 5.12(m, 1H), 4.15(bm, 1H), 7.41(m, 5H)
1H NMR (400 MHz, CDCl3) δ (ppm): 0.07 (s, 3H), 0.11 9 (s, 3H), 0.14 (s, 3H), 0.41 (s, 3H), 1.09 (s, 6H), 1.51 (s, 1H), 1.89 (ddd, J=13.9, 12.4,2.2 Hz, 1H), 1.99 (d, J=4.6 Hz) 1.56 (s, 3H), 2.04 (bs, 3H), 2.27 (m, 1H), 2.29 (s, 3H), 2.33 (m, 1H), 3.92 (d, 7.5 Hz, 1H), 4.19 (d, J=8.5 Hz, 1H), 4.3 (d, J=8.5 Hz, 1H), 4.51 (dd, J=10.6,6.7 Hz, 1H), 4.87 (bm, 1H), 4.95 (dd, J=9.4, 1.7 Hz, 1H), 5.60 (d, J=7.5, 1H), 5.61 (s, 1H), 7.48 (dd, J=7.8,7.7 Hz, 2H), 7.6 (dd, J=7.8, 7.7 Hz, 1H)8.1 (d J=7.8, 2H)
フレキシブル側鎖プロトン化学シフトは、CDCl3溶媒中の水レベルに依存して変動を示す。
1H NMR (400 MHz, CDCl3) δ (ppm): 1.13 (s, 3H, H-17), 1.24 (s, 3H, H-16), 1.34 (s, 9H, H-t-Boc), 1.64 (s, 1H, HO-1), 1.76 (s, 3H, H-19), 1.85 (s, 3H, H-18), 1.79 to 1.88 (m, 1H, H-6), 2.27 (m, J=8.8 Hz, 2H, H-14), 2.38 (s, 3H, Ac-4), 2.60(m, 1H, H-6), 3.32 (bd, J=4.8 Hz, 1H, HO-2’), 3.92 (d, J=6.9 Hz, 1H, H-3), 4.18 (d, J=8.5 Hz, 1H, H-20), 4.19 (bs, 1H, HO-10), 4.23 (m, 1H, H-7), 4.32 (d, J=8.5 Hz, 1H, H-20), 4.62 (bm, 1H, H-2’), 4.94 (m, 1H, H-5), 5.20 (bd, J=1.7 Hz, H-10), 5.26 (bm, 1H, H-3’), 5.40 (bd, J=9.6 Hz, H-N), 5.68 (d, J=6.9 Hz, 1H, H-2), 6.22 (bm, 1H, H-13), 7.29 to 7.4 (m, 5H, H-Ph), 7.50 (dd, J=7.9, 7.6 Hz, 2H, H-mBz), 7.62 (dd, J=7.25, 7.6 Hz, 1H-pBz), 8.10 (d, J=7.9 Hz, 2H, H-oBz)
文献と一致:(a) Journal of Labelled Compounds and Radiopharmaceuticals, 2004;47:763-777、および(b) Tetrahedron, 1989, 45:13, p.4177-4190
THF(10mL)中の7,10-O-(1,1,3,3-テトラメチル-1,3-ジシロキサンジイル)-10-DAB(0.84g、1.24mmol)の溶液に、-45℃で窒素下に、ヘキサン中の1.0Mブチルリチウム(0.93mL)を添加した。この温度で30分後、THF(2mL)中の(+)-N-t-ブトキシカルボニル-3-トリメチルシリルオキシ-4-フェニル-アゼチジン-2-オン(0.5g、1.5mmol)の溶液を添加し、混合物を攪拌し、0℃に4時間温めた。反応を、トリエチルアミン(1当量)および酢酸(1当量)で鎮め、ヘプタン25mLで希釈し、シリカゲル(30g)で濾過した。濾液を回転蒸発によって濃縮して、白色結晶(0.69g、55%)を得た。粗生成物の1HNMRは、2’-(トリメチルシリルオキシ)-7,10-O- (1,1,3,3-テトラメチル-1,3-ジシロキサンジイル)-ドセタキセルの構造と一致していた。
アセトニトリル(2.5mL)中の2’-(トリメチルシリルオキシ)-7,10-O-(1,1,3,3-テトラメチル-1,3-ジシロキサンジイル)-ドセタキセル(0.5g、0.495mmol)の溶液に、周囲温度で、0.2M HClの溶液を添加し、生成物(Rf=0.15)への完全な変換がTLC(3:1 酢酸エチル:ヘプタン)によって観察されるまで、混合物を周囲温度(22℃〜25℃)で2〜3時間攪拌した。次に、混合物を酢酸エチル(5mL)で希釈し、水(2mL)、塩水(2mL)、炭酸水素ナトリウム飽和水溶液(2mL)、塩水(2mL)で洗浄し、硫酸ナトリウム(6g)で乾燥した。混合物をシリカゲル(5g)で濾過し、フィルターケーキを酢酸エチル(5mL)で濯いだ。合わせた濾液を約1mLに濃縮し、ヘプタン(5mL)を添加して、結晶化を誘発した。次に、混合物を濃縮して、約1〜2mLの溶媒を除去した。混合物を周囲温度に冷却し、次に、結晶をブフナー漏斗での真空濾過によって収集し、ドセタキセルと一致するHNMRスペクトルを有する結晶性生成物の0.399g(収率93%)の恒量になるまで乾燥した。
Claims (12)
- (a) 10-デアセチルバッカチンIII(10-DAB)のC(7)およびC(10)ヒドロキシ基を、架橋珪素に基づく保護基で保護して、10-DAB誘導体(12)を生成する工程;
(b) 10-DAB誘導体(12)を誘導体化する工程であって、該誘導体化が、10-DAB誘導体(12)をβ-ラクタム側鎖先駆物質で処理して、10-DAB誘導体(13)を生成することを含んで成る工程、および
(c) 10-DAB誘導体(13)を脱保護して、ドセタキセルを生成する工程;
[ここで、
10-DAB誘導体(12)および10-DAB誘導体(13)は、それぞれ、式(12)および(13)に相当し:
L1およびL2は、独立して、アミン、ハライドまたはスルホネート脱離基であり;
X6は、ヒドロキシ保護基であり;
Zは、ヒドロカルビル、置換ヒドロカルビル、ヘテロシクロ、-[O-Si(Z10)(Z11)-]nO-または-O-であり;
各Z10およびZ11は、独立して、ヒドロカルビルであり;
nは、1または2である]
を含んで成る、ドセタキセルの製造法。 - Zは、-(CH2)y-、-[(Z12)-(Z13)]k-[(Z14)]m-、-[O-Si(Z10)(Z11)-]nO-、または-O-であり;
Z12、Z13およびZ14は、それぞれ独立して、-(CH2)y-、またはヘテロ原子であり、但し、Z12およびZ13の少なくとも1つはヘテロ原子であるものとし;
kは、1〜約4の正の整数であり;
mは、0または1であり;
nは、1または2であり;
yは、1〜約8の正の整数である、請求項1に記載の方法。 - G1、G2、G3およびG4が、独立して、置換または非置換アルキル、アルケニル、アルキニル、アリール、ヘテロアリールまたはシクロアルキルである、請求項1または2に記載の方法。
- G1、G2、G3およびG4が、独立して、約1〜約4個の炭素原子を有する直鎖または分岐鎖アルキルまたはアルケニル、約1〜約6個の炭素原子を有するシクロアルキル、またはフェニルである、請求項1〜3のいずれか1つに記載の方法。
- L1およびL2が、ハライド脱離基である、請求項1〜4のいずれか1つに記載の方法。
- L1およびL2が、クロロ脱離基である、請求項1〜5のいずれか1つに記載の方法。
- L1およびL2が、アミン脱離基である、請求項1〜4のいずれか1つに記載の方法。
- L1およびL2が、スルホネート脱離基である、請求項1〜4のいずれか1つに記載の方法。
- 架橋珪素に基づく保護基が、1,3-ジクロロテトラメチルジシロキサン;1,5-ジクロロヘキサメチルトリシロキサン;1,7-ジクロロオクタメチルテトラシロキサン;1,3-ジクロロ-1,3-ジフェニル-1,3-ジメチルジシロキサン;1,3-ジクロロテトラフェニルジシロキサン;1,3-ジビニル-1,3-ジメチル-1,3-ジクロロジシロキサン;1,1,3,3-テトラシクロペニルジクロロジシロキサン;1,1,3,3-テトライソプロピル-1,3-ジクロロジシロキサン;1,2-ビス(クロロジメチルシリル)エタン;1,3-ビス(クロロジメチルシリル)プロパン;1,6-ビス(クロロジメチルシリル)ヘキサン;および1,8-ビス(クロロジメチルシリル)オクタンから成る群から選択される、請求項1〜4のいずれか1つに記載の方法。
- X6が2-メトキシ-2-プロピル(MOP)である、請求項1〜9のいずれか1つに記載の方法。
- 式(3)に相当するラクタム側鎖先駆物質は、
(a) N-非置換β-ラクタム(8)を生成する工程であって、
(i) ベンズアルデヒドをジシラジドと反応させて、イミンを生成すること、
(ii) 該イミンをケテンアセテールと反応させて、N-非置換β-ラクタム(8)を生成すること、
によって行う工程;および
(b) N-置換β-ラクタム(8)を誘導体化する工程であって、該誘導体化が、
(i) ヒドロキシ保護基をC(3)ヒドロキシ基に導入すること、
(ii) tert-ブトキシカルボニル基を-NH基に導入して、式(3)に相当するβ-ラクタム側鎖先駆物質を生成すること
を含んで成る工程;
[ここで、
N-非置換β-ラクタムは、式(8):
R21、R22およびR23は、独立して、アルキル、アリールまたはアラルキルである]
を含んで成る方法によって製造する、請求項1〜10のいずれか1つに記載の方法。 - 工程(a)(ii)で生成したN-非置換β-ラクタム(8)が、第一および第二C(3)-ヒドロキシ置換β-ラクタムエナンチオマーのエナンチオマー混合物として存在し、式(3)に相当するβ-ラクタム側鎖先駆物質を製造する方法がエナンチオマー混合物を分離する工程をさらに含んで成り、該分離が、
(a) エナンチマー混合物を光学活性プロリンアシル化剤で、アミンの存在下に処理して、生成物混合物を形成し、該生成物混合物が、第一および第二C(3)-ヒドロキシ置換β-ラクタムエナンチオマーを、それぞれ、光学活性プロリンアシル化剤と反応させることによって生成された第一および第二C(3)-エステル置換β-ラクタムジアステレオマーを含有し、該生成物混合物が、未反応第二C(3)-ヒドロキシβ-ラクタムエナンチオマーを含有する場合もあること、および
(b) 第一C(3)-エステル置換β-ラクタムジアステレオマーを、未反応第二C(3)-ヒドロキシβ-ラクタムエナンチオマーまたは第二C(3)-ヒドロキシ置換β-ラクタムジアステレオマーから分離すること
を含んで成る請求項11に記載の方法。
Applications Claiming Priority (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US68942505P | 2005-06-10 | 2005-06-10 | |
US60/689,425 | 2005-06-10 | ||
US70893105P | 2005-08-17 | 2005-08-17 | |
US70892905P | 2005-08-17 | 2005-08-17 | |
US60/708,931 | 2005-08-17 | ||
US60/708,929 | 2005-08-17 | ||
US72452705P | 2005-10-07 | 2005-10-07 | |
US60/724,527 | 2005-10-07 | ||
US78894306P | 2006-04-04 | 2006-04-04 | |
US60/788,943 | 2006-04-04 | ||
PCT/US2006/022335 WO2006135692A2 (en) | 2005-06-10 | 2006-06-08 | Processes for the preparation of docetaxel |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2009501134A true JP2009501134A (ja) | 2009-01-15 |
JP5113745B2 JP5113745B2 (ja) | 2013-01-09 |
Family
ID=37467606
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008515928A Expired - Fee Related JP5113745B2 (ja) | 2005-06-10 | 2006-06-08 | ドセタキセルの製造法 |
JP2008515900A Pending JP2008543763A (ja) | 2005-06-10 | 2006-06-08 | パクリタキセルの製造法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008515900A Pending JP2008543763A (ja) | 2005-06-10 | 2006-06-08 | パクリタキセルの製造法 |
Country Status (11)
Country | Link |
---|---|
US (2) | US7358378B2 (ja) |
EP (2) | EP1891033A2 (ja) |
JP (2) | JP5113745B2 (ja) |
KR (2) | KR101333438B1 (ja) |
AU (2) | AU2006258012B2 (ja) |
BR (2) | BRPI0611737A2 (ja) |
CA (2) | CA2610908A1 (ja) |
IL (2) | IL187824A0 (ja) |
MX (2) | MX2007015597A (ja) |
TW (2) | TW200716656A (ja) |
WO (2) | WO2006135692A2 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2006258079A1 (en) * | 2005-06-10 | 2006-12-21 | Florida State University Research Foundation, Inc. | Resolution of enantiomeric mixtures of beta-lactams |
GB0701523D0 (en) * | 2007-01-26 | 2007-03-07 | Chatham Biotec Ltd | Semi-synthetic process for the preparation of taxane derivatives |
CA2723654A1 (en) * | 2008-05-07 | 2009-11-12 | Ivax Research, Llc | Processes for preparation of taxanes and intermediates thereof |
PL388144A1 (pl) | 2009-05-29 | 2010-12-06 | Przedsiębiorstwo Produkcyjno-Wdrożeniowe Ifotam Spółka Z Ograniczoną Odpowiedzialnością | Solwaty (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylopropionianu 4-acetoksy-2α-benzoiloksy -5β,20-epoksy-1,7β,10β-trihydroksy-9-okso-taks-11-en-13α-ylu, sposób ich otrzymywania i zastosowanie |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0386860A (ja) * | 1989-05-31 | 1991-04-11 | Univ Florida | タキソールの製造方法 |
JPH08506339A (ja) * | 1993-02-01 | 1996-07-09 | ザ、リサーチ、ファウンデーション、オブ、ステイト、ユニバーシティー、オブ、ニューヨーク | タキサン誘導体の製造法およびそのためのβ‐ラクタム中間体 |
JP2000500437A (ja) * | 1995-10-27 | 2000-01-18 | ソシエテ・デテユード・エ・ド・ルシエルシユ・アン・アンジエニエリ・フアルマスーテイツク・セリフアルム | タキサンの半合成のための中間体およびそれらの製造方法 |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2629818B1 (fr) * | 1988-04-06 | 1990-11-16 | Centre Nat Rech Scient | Procede de preparation du taxol |
MY110249A (en) * | 1989-05-31 | 1998-03-31 | Univ Florida State | Method for preparation of taxol using beta lactam |
US5015744A (en) * | 1989-11-14 | 1991-05-14 | Florida State University | Method for preparation of taxol using an oxazinone |
US5399726A (en) * | 1993-01-29 | 1995-03-21 | Florida State University | Process for the preparation of baccatin III analogs bearing new C2 and C4 functional groups |
US5284865A (en) * | 1991-09-23 | 1994-02-08 | Holton Robert A | Cyclohexyl substituted taxanes and pharmaceutical compositions containing them |
US5430160A (en) * | 1991-09-23 | 1995-07-04 | Florida State University | Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides |
US5602246A (en) * | 1992-11-25 | 1997-02-11 | Schering Aktiengesellschaft | Process for the preparation of fludarabine or fludarabine phosphate from guanosine |
US5703247A (en) | 1993-03-11 | 1997-12-30 | Virginia Tech Intellectual Properties, Inc. | 2-Debenzoyl-2-acyl taxol derivatives and methods for making same |
US5763477A (en) * | 1994-07-22 | 1998-06-09 | Dr. Reddy's Research Foundation | Taxane derivatives from 14-β-hydroxy-10 deacetylbaccatin III |
US5760251A (en) | 1995-08-11 | 1998-06-02 | Sepracor, Inc. | Taxol process and compounds |
US7288665B1 (en) * | 1997-08-18 | 2007-10-30 | Florida State University | Process for selective derivatization of taxanes |
EP0933360A1 (en) * | 1997-12-22 | 1999-08-04 | Pharmachemie B.V. | Synthesis of new beta-lactams |
US6479679B1 (en) | 2001-04-25 | 2002-11-12 | Napro Biotherapeutics, Inc. | Two-step conversion of protected taxane ester to paclitaxel |
AU2003256861C1 (en) | 2002-08-04 | 2008-08-28 | Phyton Holdings, Llc | Methods and compositions for converting taxane amides to paclitaxel or other taxanes |
US20050288521A1 (en) | 2004-06-29 | 2005-12-29 | Phytogen Life Sciences Inc. | Semi-synthetic conversion of paclitaxel to docetaxel |
EP3345632A1 (en) | 2005-02-18 | 2018-07-11 | Abraxis BioScience, LLC | Drugs with improved hydrophobicity for incorporation in medical devices |
-
2006
- 2006-06-08 CA CA002610908A patent/CA2610908A1/en not_active Abandoned
- 2006-06-08 BR BRPI0611737-6A patent/BRPI0611737A2/pt not_active Application Discontinuation
- 2006-06-08 EP EP06784670A patent/EP1891033A2/en not_active Withdrawn
- 2006-06-08 MX MX2007015597A patent/MX2007015597A/es active IP Right Grant
- 2006-06-08 KR KR1020087000674A patent/KR101333438B1/ko active IP Right Grant
- 2006-06-08 WO PCT/US2006/022335 patent/WO2006135692A2/en active Application Filing
- 2006-06-08 BR BRPI0611771-6A patent/BRPI0611771A2/pt not_active Application Discontinuation
- 2006-06-08 JP JP2008515928A patent/JP5113745B2/ja not_active Expired - Fee Related
- 2006-06-08 KR KR1020087000673A patent/KR20080033252A/ko not_active Application Discontinuation
- 2006-06-08 US US11/449,075 patent/US7358378B2/en not_active Expired - Fee Related
- 2006-06-08 MX MX2007015596A patent/MX2007015596A/es not_active Application Discontinuation
- 2006-06-08 US US11/449,048 patent/US7550608B2/en not_active Expired - Fee Related
- 2006-06-08 AU AU2006258012A patent/AU2006258012B2/en not_active Ceased
- 2006-06-08 JP JP2008515900A patent/JP2008543763A/ja active Pending
- 2006-06-08 AU AU2006258066A patent/AU2006258066A1/en not_active Abandoned
- 2006-06-08 WO PCT/US2006/022214 patent/WO2006135656A2/en active Application Filing
- 2006-06-08 EP EP06772493A patent/EP1893594A2/en not_active Withdrawn
- 2006-06-08 CA CA2610898A patent/CA2610898C/en not_active Expired - Fee Related
- 2006-06-09 TW TW095120725A patent/TW200716656A/zh unknown
- 2006-06-09 TW TW095120758A patent/TW200718705A/zh unknown
-
2007
- 2007-12-02 IL IL187824A patent/IL187824A0/en unknown
- 2007-12-03 IL IL187855A patent/IL187855A/en not_active IP Right Cessation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0386860A (ja) * | 1989-05-31 | 1991-04-11 | Univ Florida | タキソールの製造方法 |
JPH08506339A (ja) * | 1993-02-01 | 1996-07-09 | ザ、リサーチ、ファウンデーション、オブ、ステイト、ユニバーシティー、オブ、ニューヨーク | タキサン誘導体の製造法およびそのためのβ‐ラクタム中間体 |
JP2000500437A (ja) * | 1995-10-27 | 2000-01-18 | ソシエテ・デテユード・エ・ド・ルシエルシユ・アン・アンジエニエリ・フアルマスーテイツク・セリフアルム | タキサンの半合成のための中間体およびそれらの製造方法 |
Also Published As
Publication number | Publication date |
---|---|
KR20080027829A (ko) | 2008-03-28 |
MX2007015596A (es) | 2008-02-21 |
US7358378B2 (en) | 2008-04-15 |
TW200716656A (en) | 2007-05-01 |
AU2006258066A1 (en) | 2006-12-21 |
WO2006135656A3 (en) | 2007-06-28 |
EP1891033A2 (en) | 2008-02-27 |
JP5113745B2 (ja) | 2013-01-09 |
BRPI0611737A2 (pt) | 2011-12-27 |
US20060281932A1 (en) | 2006-12-14 |
US7550608B2 (en) | 2009-06-23 |
JP2008543763A (ja) | 2008-12-04 |
BRPI0611771A2 (pt) | 2011-12-20 |
CA2610898A1 (en) | 2006-12-21 |
IL187824A0 (en) | 2008-03-20 |
CA2610898C (en) | 2013-01-22 |
US20060281933A1 (en) | 2006-12-14 |
TW200718705A (en) | 2007-05-16 |
MX2007015597A (es) | 2008-02-21 |
IL187855A0 (en) | 2008-03-20 |
WO2006135692A2 (en) | 2006-12-21 |
CA2610908A1 (en) | 2006-12-21 |
KR101333438B1 (ko) | 2013-11-27 |
KR20080033252A (ko) | 2008-04-16 |
AU2006258012A1 (en) | 2006-12-21 |
WO2006135656B1 (en) | 2007-08-16 |
AU2006258012B2 (en) | 2011-04-07 |
EP1893594A2 (en) | 2008-03-05 |
IL187855A (en) | 2013-08-29 |
WO2006135692A3 (en) | 2007-02-08 |
WO2006135656A2 (en) | 2006-12-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5475011A (en) | Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment | |
JPH08508254A (ja) | β−ラクタムおよびアンモニウムアルコキシドから合成したタキサン | |
HU225914B1 (en) | Process for producing of new metal alkoxides | |
HU222175B1 (hu) | Oldalláncot hordozó taxánszármazékok és eljárások előállításukra | |
IL168553A (en) | History of Bakatin for the process of making a C-4 methylcarbonate analogue of Paclitaxel | |
JP5113745B2 (ja) | ドセタキセルの製造法 | |
JP2008545792A (ja) | β−ラクタムの合成 | |
JP2008545791A (ja) | 多環式縮合環化合物の製造法 | |
KR100921036B1 (ko) | 탁산유도체의 제조방법 및 이에 사용되는 중간체 | |
CN101243061A (zh) | 制备多西他赛的方法 | |
JP2008546646A (ja) | β−ラクタムの鏡像異性体混合物の分離 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20090603 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120612 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120724 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20120925 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20121012 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20151019 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |