CN104768955B - 用于美登醇酰化的改进的方法 - Google Patents
用于美登醇酰化的改进的方法 Download PDFInfo
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- CN104768955B CN104768955B CN201380049853.8A CN201380049853A CN104768955B CN 104768955 B CN104768955 B CN 104768955B CN 201380049853 A CN201380049853 A CN 201380049853A CN 104768955 B CN104768955 B CN 104768955B
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- 238000000034 method Methods 0.000 title claims abstract description 76
- QWPXBEHQFHACTK-KZVYIGENSA-N (10e,12e)-86-chloro-12,14,4-trihydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-15,16-dihydro-14h-7-aza-1(6,4)-oxazina-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-6-one Chemical compound CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-KZVYIGENSA-N 0.000 title claims abstract description 48
- QWPXBEHQFHACTK-UHFFFAOYSA-N Maytansinol Natural products CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)C=CC=C(C)CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-UHFFFAOYSA-N 0.000 title claims abstract description 45
- -1 carboxy acid anhydrides Chemical class 0.000 claims abstract description 71
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 239000011541 reaction mixture Substances 0.000 claims abstract description 27
- 150000001413 amino acids Chemical class 0.000 claims abstract description 14
- 229910052751 metal Inorganic materials 0.000 claims description 31
- 239000002184 metal Substances 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 23
- 239000002585 base Substances 0.000 claims description 20
- 239000002841 Lewis acid Substances 0.000 claims description 17
- 150000002148 esters Chemical class 0.000 claims description 17
- 150000007517 lewis acids Chemical class 0.000 claims description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 239000002516 radical scavenger Substances 0.000 claims description 11
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 9
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 8
- 125000001118 alkylidene group Chemical group 0.000 claims description 8
- 125000000524 functional group Chemical group 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 239000002808 molecular sieve Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 8
- NGOCMUBXJDDBLB-UHFFFAOYSA-N trifluoromethanesulfonic acid;zinc Chemical compound [Zn].OS(=O)(=O)C(F)(F)F NGOCMUBXJDDBLB-UHFFFAOYSA-N 0.000 claims description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 7
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000005270 trialkylamine group Chemical group 0.000 claims description 7
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 6
- 150000001718 carbodiimides Chemical group 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 235000011152 sodium sulphate Nutrition 0.000 claims description 5
- 230000004913 activation Effects 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- 125000006725 C1-C10 alkenyl group Chemical group 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 3
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 3
- 229910052987 metal hydride Inorganic materials 0.000 claims description 3
- 150000004681 metal hydrides Chemical class 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 claims description 3
- 229910052710 silicon Inorganic materials 0.000 claims description 3
- 239000010703 silicon Substances 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 235000011148 calcium chloride Nutrition 0.000 claims description 2
- 235000011132 calcium sulphate Nutrition 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- RXUUYDXKHLUSHV-UHFFFAOYSA-N magnesium;trifluoromethanesulfonic acid Chemical compound [Mg].OS(=O)(=O)C(F)(F)F RXUUYDXKHLUSHV-UHFFFAOYSA-N 0.000 claims description 2
- 150000003003 phosphines Chemical class 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims 2
- 229910001623 magnesium bromide Inorganic materials 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- CZFUXBACHAPLLA-UHFFFAOYSA-N [Mg].CS(=O)(=O)O.[F] Chemical compound [Mg].CS(=O)(=O)O.[F] CZFUXBACHAPLLA-UHFFFAOYSA-N 0.000 claims 1
- 150000001298 alcohols Chemical class 0.000 claims 1
- 150000001805 chlorine compounds Chemical group 0.000 claims 1
- 238000000151 deposition Methods 0.000 claims 1
- 239000010931 gold Substances 0.000 claims 1
- 229910052737 gold Inorganic materials 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims 1
- PANBYUAFMMOFOV-UHFFFAOYSA-N sodium;sulfuric acid Chemical compound [Na].OS(O)(=O)=O PANBYUAFMMOFOV-UHFFFAOYSA-N 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 239000000203 mixture Substances 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- 150000001721 carbon Chemical group 0.000 description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 10
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 229930126263 Maytansine Natural products 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 150000001768 cations Chemical class 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- WTFJJYYGWFKOQH-VKHMYHEASA-N (4s)-3,4-dimethyl-1,3-oxazolidine-2,5-dione Chemical compound C[C@@H]1N(C)C(=O)OC1=O WTFJJYYGWFKOQH-VKHMYHEASA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 235000019260 propionic acid Nutrition 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 235000019580 granularity Nutrition 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 3
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 125000000199 N-methyl-L-alanine group Chemical group 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- PVNFMCBFDPTNQI-UIBOPQHZSA-N [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] acetate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 3-methylbutanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 2-methylpropanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] propanoate Chemical compound CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(C)=O)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CCC(=O)O[C@H]1CC(=O)N(C)c2cc(C\C(C)=C\C=C\[C@@H](OC)[C@@]3(O)C[C@H](OC(=O)N3)[C@@H](C)C3O[C@@]13C)cc(OC)c2Cl.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)C(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)CC(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2 PVNFMCBFDPTNQI-UIBOPQHZSA-N 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000003275 alpha amino acid group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 230000005875 antibody response Effects 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000010953 base metal Substances 0.000 description 2
- BPOPGHPHBCLJOK-UHFFFAOYSA-N butanedithioic acid Chemical compound CCCC(S)=S BPOPGHPHBCLJOK-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 125000001425 triazolyl group Chemical group 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
- 239000003643 water by type Substances 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- KEIFWROAQVVDBN-UHFFFAOYSA-N 1,2-dihydronaphthalene Chemical compound C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- 150000008081 1H-pyrimidin-4-ones Chemical class 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 150000001478 2,5-oxazolidinediones Chemical class 0.000 description 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
- MHNNAWXXUZQSNM-UHFFFAOYSA-N 2-methylbut-1-ene Chemical compound CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 241001614291 Anoplistes Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- QRDJCCQTEQVLKC-UHFFFAOYSA-N CC1C(C2)C2CC1 Chemical compound CC1C(C2)C2CC1 QRDJCCQTEQVLKC-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical group [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GDFAOVXKHJXLEI-VKHMYHEASA-N N-methyl-L-alanine Chemical class C[NH2+][C@@H](C)C([O-])=O GDFAOVXKHJXLEI-VKHMYHEASA-N 0.000 description 1
- RQQDJYROSYLPPK-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 Chemical compound N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 RQQDJYROSYLPPK-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- AXNBHOOQHIIQFA-UHFFFAOYSA-N [S].C(F)(F)F Chemical compound [S].C(F)(F)F AXNBHOOQHIIQFA-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000001588 bifunctional effect Effects 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
- 239000007853 buffer solution Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 244000240602 cacao Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 150000002012 dioxanes Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-O guanidinium Chemical compound NC(N)=[NH2+] ZRALSGWEFCBTJO-UHFFFAOYSA-O 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 125000005945 imidazopyridyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000005040 ion trap Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 1
- CQVASCVNSMTDJH-UHFFFAOYSA-N lithium;2,2,3,3-tetramethylpiperidin-1-ide Chemical compound [Li+].CC1(C)CCC[N-]C1(C)C CQVASCVNSMTDJH-UHFFFAOYSA-N 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XCVNDBIXFPGMIW-UHFFFAOYSA-N n-ethylpropan-1-amine Chemical compound CCCNCC XCVNDBIXFPGMIW-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000005054 naphthyridines Chemical class 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01R—ELECTRICALLY-CONDUCTIVE CONNECTIONS; STRUCTURAL ASSOCIATIONS OF A PLURALITY OF MUTUALLY-INSULATED ELECTRICAL CONNECTING ELEMENTS; COUPLING DEVICES; CURRENT COLLECTORS
- H01R12/00—Structural associations of a plurality of mutually-insulated electrical connecting elements, specially adapted for printed circuits, e.g. printed circuit boards [PCB], flat or ribbon cables, or like generally planar structures, e.g. terminal strips, terminal blocks; Coupling devices specially adapted for printed circuits, flat or ribbon cables, or like generally planar structures; Terminals specially adapted for contact with, or insertion into, printed circuits, flat or ribbon cables, or like generally planar structures
- H01R12/50—Fixed connections
- H01R12/51—Fixed connections for rigid printed circuits or like structures
- H01R12/55—Fixed connections for rigid printed circuits or like structures characterised by the terminals
- H01R12/58—Fixed connections for rigid printed circuits or like structures characterised by the terminals terminals for insertion into holes
- H01R12/585—Terminals having a press fit or a compliant portion and a shank passing through a hole in the printed circuit board
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/16—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- H—ELECTRICITY
- H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
- H05K—PRINTED CIRCUITS; CASINGS OR CONSTRUCTIONAL DETAILS OF ELECTRIC APPARATUS; MANUFACTURE OF ASSEMBLAGES OF ELECTRICAL COMPONENTS
- H05K1/00—Printed circuits
- H05K1/02—Details
- H05K1/0201—Thermal arrangements, e.g. for cooling, heating or preventing overheating
- H05K1/0203—Cooling of mounted components
-
- H—ELECTRICITY
- H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
- H05K—PRINTED CIRCUITS; CASINGS OR CONSTRUCTIONAL DETAILS OF ELECTRIC APPARATUS; MANUFACTURE OF ASSEMBLAGES OF ELECTRICAL COMPONENTS
- H05K1/00—Printed circuits
- H05K1/02—Details
- H05K1/11—Printed elements for providing electric connections to or between printed circuits
- H05K1/115—Via connections; Lands around holes or via connections
- H05K1/116—Lands, clearance holes or other lay-out details concerning the surrounding of a via
-
- H—ELECTRICITY
- H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
- H05K—PRINTED CIRCUITS; CASINGS OR CONSTRUCTIONAL DETAILS OF ELECTRIC APPARATUS; MANUFACTURE OF ASSEMBLAGES OF ELECTRICAL COMPONENTS
- H05K1/00—Printed circuits
- H05K1/18—Printed circuits structurally associated with non-printed electric components
- H05K1/181—Printed circuits structurally associated with non-printed electric components associated with surface mounted components
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Microelectronics & Electronic Packaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polyamides (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种通过在干燥剂的存在下使美登醇与氨基酸的N‑羧基酸酐(NCA)反应来制备由下式表示的美登醇的氨基酸酯的方法。本发明还公开一种制备美登醇的氨基酸酯的改进的方法,其中在美登醇与氨基酸的N‑羧基酸酐之间的反应完成后向反应混合物中添加亲核试剂。
Description
相关申请的引用
本申请根据美国法典第35篇第119条(e)款要求2012年9月26日提交的美国临时申请No.61/705,731的申请日的权益,该临时申请的全部内容以引用方式并入本文中。
发明领域
本发明是一种用于制备类美登素及其抗体偶联物的合成中的中间体的改进的方法。
发明背景
类美登素是高度细胞毒性化合物,包括美登醇和美登醇的C-3酯(美国专利No.4,151,042),如下所示:
天然存在的和合成的美登醇的C-3酯可分为两类:(a)美登素(2)及其类似物(例如,DM1和DM4),其为与N-甲基-L-丙氨酸或N-甲基-L-丙氨酸的衍生物的C-3酯(美国专利No.4,137,230;4,260,608;5,208,020;和Chem.Pharm.Bull.12:3441(1984));(b)安丝菌素,其为与简单羧酸的C-3酯(美国专利No.4,248,870;4,265,814;4,308,268;4,308,269;4,309,428;4,317,821;4,322,348;和4,331,598)。
美登素(2)、其类似物以及安丝菌素物种中的每一种为可通过酯化美登醇而得到的美登醇(1)的C3酯。美国专利No.7,301,019和7,598,375描述了在碱的存在下用氨基酸的N-羧基酸酐(NCA,5)酰化美登醇(1)以形成美登醇的氨基酸酯(May-AA,6)的方法,如下所示:
美登醇的氨基酸酯是可与羧酸偶联以提供类美登素的有价值的中间体。例如,美登醇与(4S)-3,4-二甲基-2,5-噁唑烷二酮(5a)反应形成N2’-去乙酰基-美登素(6a),其又可利用N-(3-二甲基氨丙基)-N’-乙基碳二亚胺盐酸盐(EDAC)与3-(甲基二硫代)丙酸(7)偶联,从而形成DM1-SMe(8),如下所示:
形成美登醇的氨基酸酯的酰化反应的显著缺点是,其也形成在C3侧链中包含额外N-甲基-丙氨酰部分的副产物,所述部分被称为“额外-NMA”(9)。当N2’-去乙酰基-美登素被酰化时,额外NMA(9)也被酰化形成额外NMA-DM1-SMe(9a)。额外-NMA(9)和额外-NMA-DM1-SMe(9a)的结构在下面示出:
DM1(3)可通过还原由DM1-SMe(8)制备,其还将任何额外-NMA-DM1-SMe(9a)转化成额外-NMA-DM1(10),如下所示:
额外-NMA-DM1(10)难以从DM1(3)中去除,因为,因为两种化合物具有相似的极性并且在纯化DM1(3)的HPLC迹线中具有重叠峰。DM1(3)和DM4(4)用于制备抗体偶联物,其中若干种已在进行临床试验。
因此,需要提高用于制备这些类美登素的方法的收率和稳健性并且将这些类美登素制备中所用反应期间形成的副产物减至最少。
发明概述
现已发现,向美登醇与氨基酸的N-羧基酸酐之间的反应中添加干燥剂会显著增加美登醇的氨基酸酯的收率,如实施例1-4中所示。还已发现,在美登醇与氨基酸的N-羧基酸酐反应之后加入使用亲核试剂的预淬灭步骤会显著减少不需要的副产物(诸如额外-NMA)的形成,如实施例6-8中所示。基于这些发现,本文中公开了制备美登醇的氨基酸酯的改进的方法。
本发明的第一实施方案是一种制备由式(I)表示的美登醇的氨基酸酯的方法:
其中R1为氢、任选取代的C1-C10烷基或氨基酸侧链,条件是,如果氨基酸侧链具有官能团,则所述官能团被任选地保护;并且R2为氢或任选取代的C1-C10烷基。
所述方法包括使美登醇与N-羧基酸酐在另外包含碱和干燥剂的反应混合物中反应。N-羧基酸酐由下式表示:
式(II)中的所有变量均如式(I)中所定义。
本发明的第二实施方案为一种制备由式(I)表示的美登醇的氨基酸酯的方法,其包括:a)使美登醇与由式(II)表示的N-羧基酸酐在另外包含碱的反应混合物中反应;和b)使来自步骤a)的未反应的N-羧基酸酐与亲核试剂反应。式(I)和(II)中的所有变量均如本发明的第一实施方案中所定义。
附图简述
图1-2为示出用羧酸和缩合剂酰化N2’-去乙酰基-美登素的示意图。
图3-4为示出用活化的羧酸酰化N2’-去乙酰基-美登素的示意图。
发明详述
本发明涉及从美登醇和由式(II)表示的N-羧基酸酐制备由式(I)表示的氨基酸酯的方法。可将氨基酸酯进一步酯化以制备诸如DM1和DM4的类美登素,然后进一步加工成类美登素的抗体偶联物。优选地,氨基酸酯由式(Ia)表示,并且N-羧基酸酐由式(IIa)表示:
式(Ia)和(IIa)中的变量如针对式(I)和(II)所述。
优选地,对于式(I)、(II)、(Ia)和(IIa),R1为天然存在的氨基酸的侧链,条件是,如果所述侧链具有反应性官能团,则所述官能团被任选地保护;并且R2为甲基。或者,R1为烷基并且R2为甲基。更优选地,R1和R2均为甲基。
在本发明的第一实施方案中,所述方法包括使美登醇与由式(II)或(IIa)表示的N-羧基酸酐在另外包含碱和干燥剂的反应混合物中反应。
在一个优选实施方案中,所述反应混合物还包含路易斯酸。优选的路易斯酸包含金属阳离子。
在另一个优选实施方案中,首先使美登醇和N-羧基酸酐反应,然后使应混合物与含有碳酸氢盐或碳酸盐的水溶液接触或使反应混合物与金属清除剂接触。可使用本领域中已知的金属清除剂(参见,例如“The Power of Functional Resin in OrganicSynthesis”的第9章,Aubrey Mendoca,Wiley-VCH Verlag GmbH&Co.KGaA,2008)。金属清除剂的实例包括但不限于聚合物和二氧化硅基金属清除剂(例如Sigma-Aldrich的QuadraPureTM和QuadraSilTM、SiliCycle的Johnson Matthey的和Biotage金属清除剂)、碳基清除剂(例如Sigma-Aldrich的QuadraPureTMC)。
在另一个优选实施方案中,首先使美登醇与N-羧酸酐反应,然后将来自路易斯酸的金属阳离子从反应混合物中去除。例如,通过使反应混合物与含有碳酸氢盐或碳酸盐的水溶液接触或使反应混合物与金属清除剂接触来将来自路易斯酸的金属阳离子从反应混合物中去除。
在第二实施方案中,所述方法包括:a)使美登醇与由式(II)或(IIa)表示的N-羧基酸酐在另外包含碱的反应混合物中反应;和b)使来自步骤a)的未反应的N-羧基酸酐与亲核试剂反应。
在一个优选实施方案中,步骤a)的反应混合物还包含路易斯酸。优选的路易斯酸包含金属阳离子。
在另一个优选实施方案中,在步骤b)之后使反应混合物与含有碳酸氢盐或碳酸盐的水溶液接触或与金属清除剂接触。
在另一个优选实施方案中,在进行步骤b)之后,即,在亲核试剂与未反应的N-羧基酸酐反应之后,将来自路易斯酸的金属阳离子从反应混合物中去除。例如,通过使应混合物与含有碳酸氢盐或碳酸盐的水溶液接触或使反应混合物与金属清除剂接触来将来自路易斯酸的金属阳离子从反应混合物中去除。
在另一个优选实施方案中,步骤a)的反应混合物还包含干燥剂。
术语“碱”是指可接受氢离子(质子)或供出一对价电子的物质。示例性碱对由式(II)表示的N-羧基酸酐不具有亲核性和反应性。合适的碱的实例包括三烷基胺(例如二异丙基乙胺、三乙胺和1,8-二氮杂双环十一-7-烯)、金属醇盐(例如叔丁醇钠和叔丁醇钾)、烷基金属(例如叔丁基锂、甲基锂、正丁基锂、叔丁基锂、二异丙基氨基锂、戊基钠和2-苯基异丙基钾)、芳基金属(例如苯基锂)、金属氢化物(例如氢化钠)、金属氨化物(例如氨基钠、氨基钾、二异丙氨基锂和四甲基哌啶基锂)和硅基酰胺(例如双(三甲基甲硅烷基)氨基化钠和双(三甲基甲硅烷基)氨基化钾)。优选地,碱为三烷基胺。更优选地,碱为二异丙基乙胺。
术语“干燥剂”是指可从溶液中去除水的试剂。合适的干燥剂的实例包括但不限于分子筛、硫酸钠、硫酸钙、氯化钙和硫酸镁。干燥剂的物理形式包括但不限于颗粒状珠或粉末。优选地,干燥剂为分子筛。或者,干燥剂为硫酸钠。
术语“路易斯酸”是指利用来自另一分子的孤对电子使其本身原子之一的原子团稳定的酸性物质。在所公开的方法中使用的示例性路易斯酸包括三氟甲磺酸锌、氯化锌、溴化镁、三氟甲磺酸镁、三氟甲磺酸铜、溴化铜(II)、氯化铜(II)和氯化镁。优选地,路易斯酸为三氟甲磺酸锌。
术语“亲核试剂”是指与由式(II)表示的N-羧基酸酐中的正电性中心反应以分解N-羧基酸酐的反应物。合适的亲核试剂的实例包括水、醇(甲醇、乙醇、正丙醇、异丙醇或叔丁醇)和胺伯或仲胺(例如甲胺、乙胺、二甲胺、二乙胺等)。优选地,亲核试剂为醇。或者,亲核试剂为水。
用于制备由式(I)表示的美登醇的氨基酸酯的示例性反应条件如下所提供。具体条件在范例中提供。
尽管可使用摩尔量的美登醇与N-羧基酸酐,但更通常的是过量使用N-羧基酸酐。美登醇与N-羧基酸酐的示例性摩尔比的范围为1:1至1:10,更通为1:2至1:7或1:1至1:4。在一个优选实施方案中,美登木醇与N-羧基酸酐的摩尔比为约1:5。
路易斯酸任选地用于所公开的方法中。当存在时,其相对于美登醇通常过量使用,例如高达20倍过量。更通常地,美登醇与路易斯酸的摩尔比的范围为1:5至1:8,更优选地为约1:7。也可使用较少量的路易斯酸。
使用足量的干燥剂以从反应溶剂中去除溶解的水。干燥剂的量并不关键,条件是使反应溶液基本上无水。干燥剂可直接用于反应容器中,或通过半渗透屏障(诸如烧结玻璃容器)容纳在容器中来使用。
本领域技术人员可容易地使用包括但不限于高压液相色谱法和薄层色谱法的技术来监测反应所需的时间。典型的反应在搅拌24小时后完成,但也可以较慢或较快的速率进行,这取决于多种因素,诸如反应温度和反应物的浓度。
反应可在介于-20℃和80℃之间进行,优选地在介于-10℃和60℃之间进行,更优选地在介于-10℃和40℃之间进行,最优选地在介于0℃和35℃之间进行。
合适的溶剂可容易地由本领域的普通技术人员确定,并且包括但不限于极性非质子溶剂诸如无水二甲基甲酰胺、二甲基亚砜(DMSO)或二甲基乙酰胺(DMA)、己烷、醚(诸如四氢呋喃、二乙醚、二甲氧基乙烷、二噁烷)、二氯甲烷或其混合物。
如果路易斯酸是存在于反应混合物中,则在美登醇和N-羧基酸酐反应之后使反应混合物优选地与含有碳酸氢盐或碳酸盐的水溶液或金属清除剂接触。优选地,在反应混合物优选地与含有碳酸氢盐或碳酸盐的水溶液或金属清除剂接触之前,使反应混合物与亲核试剂反应以分解过量的N-羧基酸酐。
如果包含金属阳离子的路易斯酸存在于反应混合物中,则作为反应后处理的一部分,优选地将金属阳离子从反应混合物中去除。可通过使反应混合物与含有碳酸氢盐或碳酸盐的水溶液接触或与金属清除剂接触来实现金属阳离子的去除。优选地,在去除金属阳离子之前使N-羧基酸酐与亲核试剂反应。
步骤b)中的亲核试剂的量可由本领域的技术人员容易地确定。优选地,使用足量的亲核试剂来分解未反应的N-羧基酸酐。这通常是等摩尔量的亲核试剂,然而也可使用过量的亲核试剂。典型的反应在搅拌1小时后完成,但也可以较慢或较快的速率进行,这取决于多种因素,诸如温度。
另外,本发明涵盖一种酰化美登醇的氨基酸酯的方法。所述方法包括使如上所述制备的由式(I)或式(Ia)表示的美登醇的氨基酸酯在缩合剂的存在下与具有式“R3COOH”的羧酸反应,或与具有式“R3COX”的活化的羧酸反应,以分别形成由下式之一表示的化合物:
在式(III)或(IIIa)中,R1和R2如式(I)、(II)、(Ia)和(IIa)中所定义;R3为烷基或取代的烷基;并且R3COX中的X为离去基团。优选地,X为卤素离子、烷氧基、芳氧基、咪唑、–S-苯基(其中苯基任选地被硝基或氯化物取代)或–OCOR,其中R为直链C1-C10烷基、支链C1-C10烷基、环状C3-C10烷基或C1-C10烯基。在一个实施方案中,在上述式“R3COX”中,-COX为反应性酯;例如任选取代的N-琥珀酰亚胺酯。反应性酯的实例包括但不限于N-琥珀酰亚胺酯、N-磺基琥珀酰亚胺酯、N-邻苯二甲酰亚胺酯、N-磺基邻苯二甲酰亚胺酯、2-硝基苯酯、4-硝基苯酯、2,4-二硝基苯酯、3-磺酰基-4-硝基苯酯和3-羧基-4-硝基苯酯。
优选地,R3为-Y–S-SR4,Y为C1-C10亚烷基,并且R4为C1-C10烷基、芳基或杂芳基。在另一个替代方案中,Y为-CH2CH2-或-CH2CH2C(CH3)2-并且R4为甲基。
在另一个实施方案中,R3为–L-E;L为或–(CH2CH2O)mCH2CH2NHC(=O)CH2CH2-或E为 X’为卤素离子;n为1、2、3、4、5或6;m为0或1至20的整数;并且q为0或1。或者,L为–(CH2)n-;并且n如上述定义或n为5。在另一个替代方案中,L为并且n和m如上所定义;或可选地,n为4且m为3。
在另一个实施方案中,R3选自下式:
术语“缩合剂”是与羧酸的羟基反应并将其转化成可被胺或羟基置换的离去基团的试剂。合适的缩合剂的实例包括碳二亚胺(N-(3-二甲基氨丙基)-N’-乙基碳二亚胺盐酸盐)、脲鎓、活性酯、鏻鎓、2-烷基-1-烷基羰基-1,2-二氢喹啉(2-异丁氧基-1-异丁氧基羰基-1,2-二氢喹啉)、2-烷氧基-1-烷氧羰基-1,2-二氢喹啉(2-乙氧基-1-乙氧羰基-1,2-二氢喹啉)或氯甲酸烷基酯(氯甲酸异丁酯)。优选地,缩合剂为碳二亚胺。更优选地,N-(3-二甲基氨丙基)-N’-乙基碳二亚胺盐酸盐。
术语“离去基团”是指可容易地被诸如胺的亲核试剂置换的带电荷或不带电荷的基团。此类离去基团为本领域所熟知,包括但不限于卤素离子、酯基、烷氧基、羟基、烷氧基、甲苯磺酸根、三氟甲磺酸根、甲磺酸根、腈、叠氮化物、、咪唑、氨基甲酸根、二硫化物、硫酯基、硫醚基(即被任选取代的–S-苯基)和重氮化合物。优选地,离去基团为卤素离子、烷氧基、芳氧基、咪唑、被-NO2或氯任选取代的–S-苯基,或–OCOR,其中R为直链C1-C10烷基、支链C1-C10烷基、环状C3-C10烷基或C1-C10烯基。在另一个优选实施方案中,离去基团为反应性酯中可被置换的部分(例如-COX)。反应性酯包括但不限于N-琥珀酰亚胺酯、N-磺基琥珀酰亚胺酯、N-邻苯二甲酰亚胺酯、N-磺基邻苯二甲酰亚胺酯、2-硝基苯酯、4-硝基苯酯、2,4-二硝基苯酯、3-磺酰基-4-硝基苯酯和3-羧基-4-硝基苯酯。
本发明还包括一种使用美登醇的C3酯来制备其衍生物的方法。所述方法包括使如上制备的由式(III)或(IIIa)表示的美登醇的C3酯与还原剂反应,以形成由下式之一表示的化合物:
在式(IV)和(IVa)中,R1和R2如式(I)、(II)、(Ia)和(IIa)中所定义;并且Y如式(III)或(IIIa)中所定义。
术语“还原剂”是还原-氧化反应中将二硫键转化成巯基的元素或化合物。合适的还原剂的实例包括二硫苏糖醇(DTT)、(三(2-羧乙基)膦)(TCEP)和NaBH4。
当R3为–L-E时,式(III)或(IIIa)的化合物或式(IV)或(IVa)的化合物可与抗体或经修饰的抗体反应形成抗体-类美登素偶联物。参见例如美国专利No.7,521,541、No.5,208,020和No.7,811,872。或者,式(IV)或(IVa)的化合物可与双官能交联剂反应以形成携带可与抗体反应形成抗体-类美登素偶联物的反应性基团的连接子化合物。参见例如US 6,441,163、US 2011/0003969A1和US 2008/0145374。
如本文所用,“烷基”是指直链、支链或环状烷基。
如本文所用,“直链或支链烷基”是指具有一至二十个碳原子的饱和直链或支链一价烃基。烷基的实例包括但不限于甲基、乙基、1-丙基、2-丙基、1-丁基、2-甲基-1-丙基、-CH2CH(CH3)2、2-丁基、2-甲基-2-丙基、1-戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、-CH2CH2CH(CH3)2、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、1-庚基、1-辛基等等。优选地,烷基具有一至十个碳原子。更优选地,烷基具有一至四个碳原子。
如本文所用,“亚烷基”是指直链、支链或环状亚烷基。
如本文所用,“直链或支链亚烷基”是指具有一至二十个碳原子的饱和直链或支链二价烃基。烷基的实例包括但不限于亚甲基、亚乙基、1-亚丙基、2-亚丙基、1-亚丁基、2-甲基-1-亚丙基、-CH2CH(CH3)2-、2-亚丁基、2-甲基-2-亚丙基、1-亚戊基、2-亚戊基、3-亚戊基、2-甲基-2-亚丁基、3-甲基-2-亚丁基、3-甲基-1-亚丁基、2-甲基-1-亚丁基、-CH2CH2CH(CH3)2-、1-己基、2-亚己基、3-亚己基、2-甲基-2-亚戊基、3-甲基-2-亚戊基、4-甲基-2-亚戊基、3-甲基-3-亚戊基、2-甲基-3-亚戊基、2,3-二甲基-2-亚丁基、3,3-二甲基-2-亚丁基、1-亚庚基、1-亚辛基等等。优选地,亚烷基具有一至十个碳原子。更优选地,亚烷基具有一至四个碳原子。
“直链或支链烯基”是指具有至少一个不饱和位点,即碳-碳双键的直链或支链一价烃基,其中烯基包括具有“顺式”和“反式”取向或“E”和“Z”取向的基团。实例包括但不限于乙烯基(-CH=CH2)、烯丙基(-CH2CH=CH2)等等。优选地,烯基具有二至十个碳原子。更优选地,烯基具有二至四个碳原子。
“环状烷基”是指一价饱和碳环基团。优选地,环状烷基为三至十元单环基团。更优选地,环状烷基为环己基。
“芳基”是指通过从母体芳族环系的单个碳原子除去一个氢原子而衍生的具有6-18个碳原子的一价芳族烃基。芳基还包括二环基团,其包含与饱和、部分不饱和环或芳族碳环或杂环稠合的芳族环。典型的芳基包括但不限于衍生自苯(苯基)、取代的苯(例如对硝基苯基、邻硝基苯基和二硝基苯基)、萘、蒽、茚基、茚满基、1,2-二氢萘、1,2,3,4-四氢萘基等等的基团。优选地,芳基为任选取代的苯基(例如苯基、苯酚或受保护的酚)。
“杂芳基”是指5或6元环的一价芳族基团,并且包括含有一个或多个独立地选自氮、氧和硫的杂原子的具有5-18个原子的稠环系(其中至少一个为芳族)。杂芳基的实例为吡啶基(例如2-羟基吡啶基)、咪唑基、咪唑并吡啶基、嘧啶基(例如4-羟基嘧啶基)、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、三唑基、噻二唑基、呋吖基、苯并呋吖基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基和呋喃并吡啶基。
烷基的合适取代基为不显著干扰所公开的反应的取代基。不干扰所公开的反应的取代基可根据本领域普通技术人员所熟知的方法进行保护,例如T.W.Greene和P.G.M.Wuts“Protective Groups in Organic Synthesis”John Wiley&Sons,Inc.,New York 1999中的方法。示例性取代基包括芳基(例如苯基、苯酚和受保护的苯酚)、杂芳基(例如吲哚基和咪唑基)、卤素、鈲[-NH(C=NH)NH2]、-OR100、NR101R102、-NO2、-NR101COR102、-SR100、-SOR101所表示的亚砜、-SO2R101所表示的砜、硫酸根-SO3R100、磺酸根-OSO3R100、-SO2NR101R102所表示的磺酰胺、氰基、叠氮基、-COR101、-OCOR101、-OCONR101R102;R101和R102各自独立地选自H、具有1至10个碳原子的直链、支链或环状烷基、烯基或炔基。
术语“卤素离子”是指-F、-Cl、-Br或-I。
术语“氨基酸”是指由NH2-C(Raa’Raa)-C(=O)OH表示的天然存在的氨基酸或非天然存在的氨基酸,其中Raa和Raa’各自独立地为H、具有1至10个碳原子的任选取代的直链、支链或环状烷基、烯基或炔基、芳基、杂芳基或杂环基。术语“氨基酸”还指从氨基酸的胺和/或羧基端除去一个氢原子时的相应残基,诸如-NH-C(Raa’Raa)-C(=O)O-。下面的具体实施例应被解释为仅仅是说明性的,并且不以任何方式对本公开的其余部分进行限制。在不进一步详细描述下,据信本领域技术人员可可基于本文中的描述在本发明的最大程度上利用本发明。本文所引用的所有出版物均据此以引用方式全文并入。另外,以下提出的任何机制不以任何方式限制所要求保护的本发明的范围。
范例
材料和方法
技术人员可采用和调整下面给出的工艺参数以适于其特定需求。
所有反应均在磁力搅拌下于氩气氛下进行。四氢呋喃和二甲基甲酰胺以无水溶剂的形式购自Aldrich。美登醇如文献中所述进行制备(Widdison等,J.Med.Chem.,49:4392-4408(2006))。N-甲基-丙氨酸的N-羧基酸酐(4S)-3,4-二甲基-2,5-噁唑烷二酮如文献中所述进行制备(Akssira,M.等,J.Marocain de Chimie Heterocyclique,1:44–47(2002))。核磁共振(NMR)谱(1H 400MHz,13C 100MHz)通过Bruker ADVANCETM系列NMR获得。使用串联Agilent 1100系列HPLC的Bruker ESQUIRETM3000离子阱质谱仪获得HPLC/MS数据。使用HPLC方法1分析DM1。使用HPLC方法2进行所有其它分析。
分析型HPLC方法1:
具有紫外检测器或等效物的水HPLC系统
柱:YMC-Pack ODS-AQ 250×4.6mm;5μm(部件编号=AQ12S05-2546WT)
流速:1mL/min(梯度)
流动相:A=1ml 85%H3PO4在1升水中;B=乙腈/四氢呋喃30:70(v/v)(注意:LC/MS分析的流动相A中用0.1%TFA代替H3PO4
梯度表:
时间,分钟 | 流速 | %A | %B | |
1 | 0.0 | 1.00 | 62 | 38 |
2 | 25 | 1.00 | 62 | 38 |
3 | 40 | 1.00 | 40 | 60 |
4 | 60 | 1.00 | 40 | 60 |
运行时间:60分钟+后运行时间:10分钟
紫外检测:252nm
进样量=5μL的约1mg/ml DM1乙腈溶液
柱温=15℃(除非另有说明)
样品温度=2-8℃
分析型HPLC/MS方法2:
柱:150×4.6mm C8,粒度5微米,Zorbax P/N 993967-906
溶剂:A去离子水+0.1%TFA
溶剂B:乙腈
流速1.0mL/min 温度:环境温度
进样量:15μL
梯度
显示HPLC迹线中0-25分钟的数据。
分析型HPLC方法2的样品制备:
将给定混合物的等分试样(20μL)加入自动进样器小瓶中的乙腈(1.5mL)中。将小瓶封盖并摇振,然后置于15℃自动进样器中。分析每次HPLC运行的进样量(15μL)。
实施例1.以4A分子筛作为干燥剂来制备DM1-SMe
将在250℃下真空预干燥然后冷却至环境温度的美登醇(50.1mg,0.0888mmol)、(4S)-3,4-二甲基-2,5-噁唑烷二酮(30.2mg,0.233mmol,2.6当量)、三氟甲磺酸锌(133mg,0.366mol)和4A分子筛(0.50g)加入10ml烧瓶中。将内容物溶于其中加入二异丙基乙胺(62μL,0.357mmol)的无水二甲基甲酰胺(0.75mL)中。将混合物在环境温度下搅拌24小时。将粗混合物的样品通过HPLC分析,N2’-去乙酰基-美登素产物占总HPLC面积的80%。将反应混合物用1:1饱和NaHCO3:饱和NaCl(1.2mL)和乙酸乙酯(3mL)稀释,混合,然后用硅藻土过滤,再用磷酸钾缓冲液(1mL,400mM,pH 7.5)洗涤。将有机层经无水硫酸镁干燥,过滤,然后蒸发,形成黄色固体。向固体中加入3-甲基二硫代丙酸(25mg,0.16mmol)、N-(3-二甲基氨丙基)-N’-乙基碳二亚胺盐酸盐(30mg,0.16mmol)和二氯甲烷(3mL)。搅拌2小时后,将混合物用乙酸乙酯(8mL)稀释,用1.0M,pH 6.5的磷酸钾缓冲液(2mL)洗涤,并将水溶液用乙酸乙酯(2×8mL)萃取。将有机层合并,经无水硫酸镁干燥,浓缩,并通过硅胶色谱法(95:5二氯甲烷:甲醇)纯化,得到51mg(70%)DM1-SMe。
实施例2.实施例1按10倍比例扩大
将实施例1中的反应以10倍的比例扩大,得到490mg(68%)DM1-SMe。
实施例3.不添加干燥剂制备DM1-SMe
将美登醇(1.0g,1.77mmol)溶解于25mL烧瓶中的无水二甲基甲酰胺(15mL)中,烧瓶在冰/水浴中冷却。2分钟后,在磁力搅拌下加入二异丙基乙胺(DIPEA,0.92g 7.07mmol)和三氟甲磺酸锌(3.8g,10.6mmol),然后快速添加(4S)-3,4-二甲基-2,5-噁唑烷二酮(0.913g,7.07mmol),将混合物搅拌24小时。将粗混合物的样品通过HPLC分析,N2’-去乙酰基-美登素产物占总HPLC面积的65%。将反应混合物用1:1饱和NaHCO3:饱和NaCl(25mL)和乙酸乙酯(40mL)稀释,混合,然后用硅藻土过滤,再用饱和NaCl洗涤。将有机层经无水硫酸钠干燥,过滤,然后蒸发。将残余物溶于其中快速添加3-甲基二硫代丙酸(1.1g,7.0mmol)和N-(3-二甲基氨丙基)-N’-乙基碳二亚胺盐酸盐(1.34g,7.0mmol)的二氯甲烷(30mL)中,将反应在氩气下于环境温度搅拌2小时。将混合物用乙酸乙酯(30mL)稀释,用pH 6.5的1.0M磷酸钾缓冲液(30mL)洗涤,并将水溶液用乙酸乙酯(2×40mL)萃取。将有机层合并,经无水硫酸钠干燥,浓缩,并通过硅胶色谱法(95:5二氯甲烷:甲醇)纯化,得到698mg(50%)DM1-SMe。
实施例4.重复实施例3
将实施例3中的反应以相同的规模重复,得到735mg(53%)DM1-SMe。
实施例5.粗N2’-去乙酰基-美登素储液
将美登醇(0.5g,0.89mmol)溶解于25mL烧瓶中的无水二甲基甲酰胺(7mL)中,烧瓶在冰-水浴中冷却。2分钟后,在磁力搅拌下加入二异丙基乙胺(0.5g,3.5mmol)和三氟甲磺酸锌(1.9g,5.3mmol),然后快速添加(4S)-3,4-二甲基-2,5-噁唑烷二酮(4.52g,3.5mmol),将混合物搅拌24小时。将此储液的等分试样(每份0.5mL)用于下面的实验中,使得由大约0.13mmol美登醇生成一份等分试样。
实施例6.N2’-去乙酰基-美登素萃取,然后偶联至丙酸(对照)
将N2’-去乙酰基-美登素储液(0.50mL)加入容纳有乙酸乙酯(1.5mL)和1:1饱和NaCl:NaHCO3(0.75mL)的6mL容量小瓶中,快速封盖并混合。保留有机层并经无水Na2SO4(120mg)干燥。取有机层(1.0mL)并添加丙酸(20.0μL,0.27mmol)。然后将溶液转移到容纳有N-(3-二甲基氨丙基)-N’-乙基碳二亚胺盐酸盐(40mg,0.209mmol)的小瓶中。使反应进行2.5小时,然后将其通过HPLC分析。
前面反应中的副产物May-NMA2还产生下面的副产物,如下所示:
17:16的HPLC百分比面积的比率为3.0:71.7。MS:16(M+H+)706(M+Na+)728;MS:17(M+Na+)813。
实施例7.重复实施例6的实验。
17:16的HPLC百分比面积的比率为3.0:70.9。
实施例8.进行N2’-去乙酰基-美登素萃取,然后进行甲醇预淬灭,再偶联至丙酸(预淬灭以消除过量5a)
将N2’-去乙酰基-美登素储液(0.50mL)加入添加有甲醇(75μL,1.8mmol)的6mL容量小瓶中,将小瓶封盖并将内容物磁力搅拌1小时。然后加入乙酸乙酯(1.5mL)和1:1饱和NaCl:NaHCO3(0.75mL),将小瓶封盖并混合。保留有机层并经无水Na2SO4(120mg)干燥。取有机层(1.0mL)并添加丙酸(20.0μL,0.27mmol)。然后将溶液转移到容纳有N-(3-二甲基氨丙基)-N’-乙基碳二亚胺盐酸盐(40mg,0.209mmol)的小瓶中。使反应进行2.5小时,然后将其通过HPLC分析。17的HPLC峰几乎检测不到,不能进行积分。重复此反应,17同样几乎检测不到,不能进行积分。因此,预淬灭法产生较少的不需要的化合物15和17。
实施例9.额外-NMA-DM1-SMe(9a)的合成
将美登醇(1.2mg,2.1mmol)称入50mL烧瓶中,并溶解于二甲基甲酰胺(12mL)和四氢呋喃(6mL)的混合物中。将烧瓶在冰-水浴中冷却。5分钟后,相继添加二异丙基乙胺(1.5mL,8.5mmol)、三氟甲烷磺酸锌(4.5g,12.6mmol)和2,5-噁唑烷二酮,3,4-二甲基(4S)(1.1g,8.5mmol)。搅拌17小时后,将反应物用1:1饱和NaCl水溶液:饱和NaHCO3水溶液(14mL)和乙酸乙酯(100mL)萃取。保留有机层并经无水Na2SO4干燥。除去干燥剂,并通过真空下旋转蒸发除去大约2/3的溶剂。添加N-甲基-N-[(2-甲基二硫代)-1-氧代丙基]-L-丙氨酸(1.0g,4.2mmol),然后添加N-(3-二甲基氨丙基)-N-乙基碳二亚胺盐酸盐(0.889g,4.6mmol)。添加二氯甲烷(10mL)以溶解混合物。搅拌4小时后,将反应用二氯甲烷(70mL)和1:4饱和NaCl水溶液:饱和NaHCO3水溶液(20mL)萃取。保留有机层并经无水Na2SO4干燥。通过真空下旋转蒸发除去溶剂。将所得粘稠油状物溶解于乙腈(3mL)中并将大约1/2的材料通过HPLC在waters symmetry shield C8柱(19×150mm微米,5微米粒度)上纯化。将柱用含有0.2%甲酸的去离子水以乙腈梯度(30%-60%乙腈,经18分钟)进行洗脱。将柱用95%乙腈冲洗5分钟,然后在运行期间用30%乙腈重新平衡6分钟。进样量的范围为100-800uL。将未反应的美登醇在8.5分钟洗脱,额外-NMA-DM1-SMe的非所需异构体在13.8分钟洗脱并且额外-NMA-DM1-SMe的所需异构体在15.1分钟洗脱。将来自几次运行的所需产物的级分合并并通过真空旋转蒸发除去溶剂。将残余物溶于最低量的乙酸乙酯中,并将少量的杂质通过HPLC在Kromasil氰基柱(250mm×21mm,10微米粒度)上除去。采用21mL/min的67:9:24己烷:2-丙醇:乙酸乙酯的等度流动相运行柱。所需产物在22.6分钟洗脱而杂质在12.6分钟洗脱。将来自几次运行的产物级分合并并通过真空旋转蒸发除去溶剂,得到95mg产物(10%收率)。1H NMR(400MHz,CDCl3-d)δ=7.26,6.81(d,J=1.6Hz,1H),6.67(d,J=11.1Hz,1H),6.56(d,J=1.6Hz,1H),6.42(dd,J=11.4,15.2Hz,1H),6.30(s,1H),5.67(dd,J=9.1,15.2Hz,1H),5.52-5.40(m,1H),5.27(d,J=7.1Hz,1H),4.85-4.69(m,1H),4.26(t,J=10.9Hz,1H),3.96(s,3H),3.7(bs,1),3.57(d,J=12.6Hz,1H),3.48(d,J=8.8Hz,1H),3.34(s,3H),3.23(s,3H),3.10(d,J=12.6Hz,1H),3.03-2.90(m,3H),2.87(s,3H),2.82-2.64(m,5H),2.63-2.50(m,1H),2.45-2.30(m,3H),2.15(d,J=14.1Hz,1H),1.62(s,3H),1.57(d,J=13.6Hz,1H),1.45(d,J=6.3Hz,1H),1.29(d,J=7.1Hz,3H),1.26(d,J=6.3Hz,4H),1.18(d,J=6.3Hz,3H),0.79(s,3H)13C NMR(CDCl3,100MHz)δ170.86,170.50,170.35,168.69,156.19,152.35,142.2,140.90,139.29,133.27,128.05,125.1,122.07,119.15,113.31,88.72,80.96,78.51,74.23,66.19,60.66,60.13,56.81,56.71,54.97,47.90,46.72,38.99,36.41,35.68,33.19,32.54,30.90,30.02,23.01,15.62,14.75,14.59,13.54,12.35。C40H57ClN4O11S2(M+Na+)m/z的HRMS计算值=891.3052;实测值891.3049。
实施例10.额外-NMA-DM1(10)的合成
将N2’-去乙酰基-N2’-(3-甲基二硫代-1-氧代丙基-N-甲基-L-丙氨酰)-美登素(95mg,0.109mmol)溶解于其中加入二硫苏糖醇(110mg,mmol)的2:1二甲氧基乙烷:100mM磷酸钾缓冲液pH 7.5中。2小时后,将溶液用混合物乙酸乙酯:二氯甲烷=2:1(5mL)和饱和NaCl(1mL)水溶液萃取。保留有机层并经无水Na2SO4干燥。通过真空过滤除去干燥剂,并通过真空下旋转蒸发除去溶剂。将残余物溶于最低体积的1:1乙酸乙酯:二氯甲烷中,并通过HPLC在Kromasil氰基柱(250mm×21mm,10微米粒度)上纯化。采用21mL/min的64:19:17己烷:2-丙醇:乙酸乙酯的等度流动相运行柱。所需产物在16分钟洗脱。将来自几次运行的产物级分合并并通过旋转蒸发除去溶剂,得到62mg产物(69%收率)。1H NMR(400MHz,CDCl3)δ6.81(d,J=1.6Hz,1H),6.67(d,J=11.1Hz,1H),6.58(d,J=1.6Hz,1H),6.43(dd,J=15.3Hz,11.1Hz,1H),6.26(s,1H),5.67(dd,J=15.3Hz,9.0Hz,1H),5.47(q,J=6.6Hz,1H),5.28-5.22(m,J=6.7Hz,1H),4.81(dd,J=12.0Hz,2.9Hz,1H),4.26(t,J=10.5Hz,1H),3.96(s,3H),3.59(d,J=12.7Hz,1H),3.49(d,J=9.0Hz,1H),3.41(bs,1H),3.36(s,3H),3.24(s,3H),3.11(d,J=12.7Hz,1H),2.98(d,J=9.6Hz,1H),2.85(s,3H),2.84–2.80(m,1H),2.79(s,3H),2.76(s,1H),2.68–2.61(m,2H),2.58(d,J=12.1Hz,1H),2.17(dd,J=14.3Hz,J=2.8Hz,1H),1.71(t,J=8.4Hz,1H),1.64(s,3H),1.62-1.59(m,1H),1.49-1.40(m,,1H),1.31(d,J=6.9Hz,3H),1.29(d,J=6.4Hz,3H),1.27-1.23(m,1H),1.20(d,J=6.7Hz,3H),0.81(s,3H)。13C NMR(CDCl3,100MHz)δ170.37,170.30,170.25,168.53,156.07,152.16,142.31,140.74,139.16,133.12,127.09,125.32,121.92,119.92,113.15,88.57,80.83,78.37,74.08,67.01,59.97,58.66,56.56,53.54,49.17,46.58,38.86,37.33,36.25,35.53,32.39,30.81,29.80,21.02,19.87,15.47,14.80,13.4,12.22。C39H55ClN4O11S(M+Na+)m/z的HRMS计算值=845.3174;实测值845.3166。
Claims (43)
1.一种制备由下式表示的化合物的方法:
其中R1为氢、C1-C10烷基或氨基酸侧链,条件是,如果所述氨基酸侧链具有反应性官能团,则所述反应性官能团被任选地保护;并且R2为氢或C1-C10烷基,所述方法包括:
使美登醇与N-羧基酸酐在另外包含碱和干燥剂的反应混合物中反应,其中所述N-羧基酸酐由下式表示:
从而形成所述式(I)化合物,其中式(II)的R1和R2如式(I)中所定义的。
2.根据权利要求1所述的方法,其中所述式(I)化合物由下式表示:
并且所述N-羧基酸酐由下式表示:
3.根据权利要求1所述的方法,其中所述反应混合物还包含路易斯酸。
4.根据权利要求3所述的方法,其中所述路易斯酸选自三氟甲磺酸锌、氯化锌、溴化镁、三氟甲磺酸镁、三氟甲磺酸铜、溴化铜(II)、氯化铜(II)和氯化镁。
5.根据权利要求3所述的方法,其中所述路易斯酸为三氟甲磺酸锌。
6.根据权利要求5所述的方法,其中还包括在美登醇与所述N-羧基酸酐反应后使所述反应混合物与含有碳酸氢盐或碳酸盐的水溶液接触或使所述反应混合物与金属清除剂接触。
7.根据权利要求1-6中任一项所述的方法,其还包括使所述式(I)化合物在缩合剂的存在下与具有式R3COOH的羧酸,或与具有式R3COX的活化的羧酸反应,以形成由下式表示的化合物:
其中R3为-Y–S-SR4或-L-E;
X为离去基团;
Y为C1-C10亚烷基;
R4为C1-C10烷基、芳基或杂芳基;
L为-(CH2CH2O)mCH2CH2NHC(=O)CH2CH2-或
E为
X’为卤素离子;
n为2、3、4、5或6;
m为0或1至20的整数;并且
q为0或1。
8.根据权利要求7所述的方法,其中X为卤素离子、烷氧基、芳氧基、咪唑、任选地被硝基或氯化物取代的–S-苯基,或–OCOR,其中R为直链C1-C10烷基、支链C1-C10烷基、环状C3-C10烷基或C1-C10烯基。
9.根据权利要求7所述的方法,其中-COX为反应性酯。
10.根据权利要求7所述的方法,其中R3为-Y–S-SR4,其中Y为C1-C10亚烷基,并且R4为C1-C10烷基、芳基或杂芳基。
11.根据权利要求10所述的方法,其中R4为C1-C10烷基、苯基、对硝基苯基、邻硝基苯基、二硝基苯基或吡啶基。
12.根据权利要求10所述的方法,其中Y为-CH2CH2-或-CH2CH2C(CH3)2-,并且R4为-CH3。
13.根据权利要求10所述的方法,其还包括使所述式(III)化合物与还原剂反应以形成由下式表示的化合物:
14.根据权利要求7所述的方法,其中R3为–L-E;
L为或-(CH2CH2O)mCH2CH2NHC(=O)CH2CH2-或
E为
X’为卤素离子;
n为2、3、4、5或6;
m为0或1至20的整数;并且
q为0或1。
15.根据权利要求14所述的方法,其中L为–(CH2)n-。
16.根据权利要求15所述的方法,其中n为5。
17.根据权利要求14所述的方法,其中L为
18.根据权利要求17所述的方法,其中n为4并且m为3。
19.根据权利要求14所述的方法,其中R3由下式之一表示:
20.根据权利要求7所述的方法,其中所述缩合剂为碳二亚胺、脲鎓、活性酯、鏻鎓、2-烷基-1-烷基羰基-1,2-二氢喹啉、2-烷氧基-1-烷氧羰基-1,2-二氢喹啉或氯甲酸烷基酯。
21.根据权利要求20所述的方法,其中所述缩合剂为碳二亚胺。
22.根据权利要求21所述的方法,其中所述缩合剂为N-(3-二甲基氨丙基)-N’-乙基碳二亚胺盐酸盐。
23.根据权利要求1所述的方法,其中R1为天然存在的氨基酸的侧链,条件是,如果所述侧链具有官能团,则所述官能团被任选地保护;并且R2为甲基。
24.根据权利要求1所述的方法,其中R1为甲基。
25.根据权利要求1所述的方法,其中所述碱为三烷基胺、金属醇盐、烷基金属、芳基金属、金属氢化物、金属氨化物或硅基酰胺。
26.根据权利要求25所述的方法,其中所述碱为三烷基胺。
27.根据权利要求26所述的方法,其中所述三烷基胺为二异丙基乙胺。
28.根据权利要求1所述的方法,其中所述干燥剂为分子筛、硫酸钠、硫酸钙、氯化钙或硫酸镁。
29.根据权利要求28所述的方法,其中所述干燥剂为分子筛。
30.根据权利要求28或29所述的方法,其中所述干燥剂呈颗粒状珠或粉末的形式。
31.根据权利要求1所述的方法,其中所述方法用于制备由下式表示的化合物:
所述方法包括使美登醇与N-羧基酸酐在另外包含碱、干燥剂和路易斯酸的反应混合物中反应,其中所述N-羧基酸酐由下式表示:
从而形成所述式(Ib)化合物,其中所述路易斯酸为三氟甲磺酸锌、氯化锌、溴化镁、三氟甲磺酸镁、三氟甲磺酸铜、溴化铜(II)、氯化铜(II)或氯化镁;所述碱为三烷基胺、金属醇盐、烷基金属、芳基金属、金属氢化物、金属氨化物或硅基酰胺;所述干燥剂为分子筛、硫酸钠、硫酸钙、氯化钙和硫酸镁。
32.根据权利要求31所述的方法,其中所述路易斯酸为三氟甲磺酸锌。
33.根据权利要求32所述的方法,其中所述碱为三烷基胺。
34.根据权利要求33所述的方法,其中所述碱为二异丙基乙胺。
35.根据权利要求33所述的方法,其中所述干燥剂为分子筛。
36.根据权利要求31-35任一项所述的方法,其中所述方法还包括使所述式(Ib)化合物在缩合剂的存在下与具有式R3COOH的羧酸,或与具有式R3COX的活化的羧酸反应,以形成由下式表示的化合物:
其中R3为-Y–S-SR4,其中Y为C1-C10亚烷基,并且R4为C1-C10烷基、芳基或杂芳基;所述缩合剂为碳二亚胺、脲鎓、活性酯、鏻鎓、2-烷基-1-烷基羰基-1,2-二氢喹啉、2-烷氧基-1-烷氧羰基-1,2-二氢喹啉或氯甲酸烷基酯。
37.根据权利要求36所述的方法,其中Y为-CH2CH2-或-CH2CH2C(CH3)2-,并且R4为-CH3。
38.根据权利要求36所述的方法,其中所述缩合剂为碳二亚胺。
39.根据权利要求36所述的方法,其中所述缩合剂为N-(3-二甲基氨丙基)-N’-乙基碳二亚胺盐酸盐。
40.根据权利要求37所述的方法,其还包括使式(IIIb)化合物与还原剂反应以形成由下式表示的化合物:
41.根据权利要求40所述的方法,其中所述还原剂为二硫苏糖醇、三(2-羧乙基)膦或NaBH4。
42.根据权利要求28所述的方法,其中所述干燥剂为硫酸钠。
43.根据权利要求34所述的方法,其中所述干燥剂为硫酸钠。
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WO2006078809A2 (en) * | 2005-01-21 | 2006-07-27 | Immunogen, Inc. | Method for the preparation of maytansinoid esters |
WO2007021674A2 (en) * | 2005-08-09 | 2007-02-22 | Millennium Pharmaceuticals, Inc. | Method of acylating maytansinol with chiral amino acids |
CN1956722A (zh) * | 2003-05-20 | 2007-05-02 | 伊缪诺金公司 | 含有新的美登素类的改进的细胞毒剂 |
WO2012074757A1 (en) * | 2010-11-17 | 2012-06-07 | Genentech, Inc. | Alaninyl maytansinol antibody conjugates |
Family Cites Families (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4151042A (en) | 1977-03-31 | 1979-04-24 | Takeda Chemical Industries, Ltd. | Method for producing maytansinol and its derivatives |
JPS6034556B2 (ja) * | 1977-03-31 | 1985-08-09 | 武田薬品工業株式会社 | 抗生物質c−15003 |
US4137230A (en) | 1977-11-14 | 1979-01-30 | Takeda Chemical Industries, Ltd. | Method for the production of maytansinoids |
US4265814A (en) | 1978-03-24 | 1981-05-05 | Takeda Chemical Industries | Matansinol 3-n-hexadecanoate |
JPS5562090A (en) | 1978-10-27 | 1980-05-10 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS5566585A (en) | 1978-11-14 | 1980-05-20 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55164687A (en) | 1979-06-11 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55162791A (en) | 1979-06-05 | 1980-12-18 | Takeda Chem Ind Ltd | Antibiotic c-15003pnd and its preparation |
JPS55164685A (en) | 1979-06-08 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55164686A (en) | 1979-06-11 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
US4309428A (en) | 1979-07-30 | 1982-01-05 | Takeda Chemical Industries, Ltd. | Maytansinoids |
JPS5622790A (en) * | 1979-07-31 | 1981-03-03 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS5645483A (en) | 1979-09-19 | 1981-04-25 | Takeda Chem Ind Ltd | C-15003phm and its preparation |
JP3054741B2 (ja) * | 1989-09-29 | 2000-06-19 | 武田薬品工業株式会社 | Tan―1313およびそのアシル誘導体 |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
EP2266607A3 (en) * | 1999-10-01 | 2011-04-20 | Immunogen, Inc. | Immunoconjugates for treating cancer |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
TWI298067B (en) * | 2002-01-31 | 2008-06-21 | Daiso Co Ltd | New optically active compound, method for kinetic resolution of carbonic acid derivatives and catalyst thereof |
US8088387B2 (en) | 2003-10-10 | 2012-01-03 | Immunogen Inc. | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
CN1894259A (zh) * | 2003-08-22 | 2007-01-10 | 活跃生物工艺学公司 | 利福霉素类似物及其应用 |
KR101270829B1 (ko) | 2004-09-23 | 2013-06-07 | 제넨테크, 인크. | 시스테인 유전자조작 항체 및 접합체 |
ES2539126T3 (es) * | 2004-12-09 | 2015-06-26 | Janssen Biotech, Inc. | Inmunoconjugados anti integrina, métodos para su producción y su uso |
WO2007011721A1 (en) * | 2005-07-15 | 2007-01-25 | Kalypsys, Inc. | Inhibitors of mitotic kinesin |
US20090082386A1 (en) * | 2006-11-06 | 2009-03-26 | Erzsebet Meszarosne Sos | Ascomycin and pimecrolimus having reduced levels of desmethylascomycin and 32-deoxy-32-epichloro-desmethylascomycin respectively, and methods for preparation thereof |
JP2008288289A (ja) | 2007-05-16 | 2008-11-27 | Oki Electric Ind Co Ltd | 電界効果トランジスタとその製造方法 |
CN102448500A (zh) | 2009-06-03 | 2012-05-09 | 免疫基因公司 | 轭合方法 |
EP2480557A2 (en) * | 2009-09-25 | 2012-08-01 | Cadila Healthcare Limited | Process for the preparation of rapamycin derivatives |
BR112015006505B1 (pt) | 2012-09-26 | 2022-03-15 | Immunogen, Inc | Métodos de preparo de intermediários na síntese de maitansinoides |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1956722A (zh) * | 2003-05-20 | 2007-05-02 | 伊缪诺金公司 | 含有新的美登素类的改进的细胞毒剂 |
WO2006078809A2 (en) * | 2005-01-21 | 2006-07-27 | Immunogen, Inc. | Method for the preparation of maytansinoid esters |
WO2007021674A2 (en) * | 2005-08-09 | 2007-02-22 | Millennium Pharmaceuticals, Inc. | Method of acylating maytansinol with chiral amino acids |
WO2012074757A1 (en) * | 2010-11-17 | 2012-06-07 | Genentech, Inc. | Alaninyl maytansinol antibody conjugates |
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