CN115323011A - Preparation method of eribulin intermediate - Google Patents
Preparation method of eribulin intermediate Download PDFInfo
- Publication number
- CN115323011A CN115323011A CN202211142922.7A CN202211142922A CN115323011A CN 115323011 A CN115323011 A CN 115323011A CN 202211142922 A CN202211142922 A CN 202211142922A CN 115323011 A CN115323011 A CN 115323011A
- Authority
- CN
- China
- Prior art keywords
- compound
- lipase
- isopropenyl
- vinyl
- straight
- 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.)
- Pending
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 229960003649 eribulin Drugs 0.000 title claims abstract description 12
- UFNVPOGXISZXJD-XJPMSQCNSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-XJPMSQCNSA-N 0.000 title claims abstract 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 194
- 102000004190 Enzymes Human genes 0.000 claims abstract description 40
- 108090000790 Enzymes Proteins 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 16
- 150000007530 organic bases Chemical class 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000005917 acylation reaction Methods 0.000 claims abstract description 14
- 238000000926 separation method Methods 0.000 claims abstract description 12
- 230000009471 action Effects 0.000 claims abstract description 11
- 150000008065 acid anhydrides Chemical class 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 229940125898 compound 5 Drugs 0.000 claims abstract description 10
- 230000007062 hydrolysis Effects 0.000 claims abstract description 8
- 230000010933 acylation Effects 0.000 claims abstract description 5
- 108090001060 Lipase Proteins 0.000 claims description 84
- 102000004882 Lipase Human genes 0.000 claims description 84
- 239000004367 Lipase Substances 0.000 claims description 80
- 229940040461 lipase Drugs 0.000 claims description 80
- 235000019421 lipase Nutrition 0.000 claims description 80
- -1 hydroxy, amino Chemical group 0.000 claims description 76
- 238000000034 method Methods 0.000 claims description 68
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 57
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Natural products CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 40
- 229940088598 enzyme Drugs 0.000 claims description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N methyl tert-butyl ether Substances COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 24
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 23
- 239000003960 organic solvent Substances 0.000 claims description 23
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 18
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 11
- 150000001348 alkyl chlorides Chemical class 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 10
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims description 10
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 241000589513 Burkholderia cepacia Species 0.000 claims description 9
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- 150000002825 nitriles Chemical class 0.000 claims description 9
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 8
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 8
- 241001661345 Moesziomyces antarcticus Species 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 8
- 238000005886 esterification reaction Methods 0.000 claims description 8
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- 239000008096 xylene Substances 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- 241000589540 Pseudomonas fluorescens Species 0.000 claims description 6
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical group CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 229940043279 diisopropylamine Drugs 0.000 claims description 6
- QVQPFHVJHZPVDM-UHFFFAOYSA-N prop-1-en-2-yl benzoate Chemical compound CC(=C)OC(=O)C1=CC=CC=C1 QVQPFHVJHZPVDM-UHFFFAOYSA-N 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 6
- KOZCZZVUFDCZGG-UHFFFAOYSA-N vinyl benzoate Chemical compound C=COC(=O)C1=CC=CC=C1 KOZCZZVUFDCZGG-UHFFFAOYSA-N 0.000 claims description 6
- 229920001567 vinyl ester resin Polymers 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 5
- 108090000371 Esterases Proteins 0.000 claims description 5
- 101710098554 Lipase B Proteins 0.000 claims description 5
- 241000179532 [Candida] cylindracea Species 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 239000004925 Acrylic resin Substances 0.000 claims description 4
- 229920000178 Acrylic resin Polymers 0.000 claims description 4
- 241000588986 Alcaligenes Species 0.000 claims description 4
- 240000006439 Aspergillus oryzae Species 0.000 claims description 4
- 235000002247 Aspergillus oryzae Nutrition 0.000 claims description 4
- 108010031797 Candida antarctica lipase B Proteins 0.000 claims description 4
- HETCEOQFVDFGSY-UHFFFAOYSA-N Isopropenyl acetate Chemical compound CC(=C)OC(C)=O HETCEOQFVDFGSY-UHFFFAOYSA-N 0.000 claims description 4
- 101710098556 Lipase A Proteins 0.000 claims description 4
- 101710099648 Lysosomal acid lipase/cholesteryl ester hydrolase Proteins 0.000 claims description 4
- 102100026001 Lysosomal acid lipase/cholesteryl ester hydrolase Human genes 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 108010084311 Novozyme 435 Proteins 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- FBOFHVFMPNNIKN-UHFFFAOYSA-N dimethylquinoline Natural products C1=CC=C2N=C(C)C(C)=CC2=C1 FBOFHVFMPNNIKN-UHFFFAOYSA-N 0.000 claims description 4
- MEGHWIAOTJPCHQ-UHFFFAOYSA-N ethenyl butanoate Chemical compound CCCC(=O)OC=C MEGHWIAOTJPCHQ-UHFFFAOYSA-N 0.000 claims description 4
- BLCTWBJQROOONQ-UHFFFAOYSA-N ethenyl prop-2-enoate Chemical compound C=COC(=O)C=C BLCTWBJQROOONQ-UHFFFAOYSA-N 0.000 claims description 4
- UIWXSTHGICQLQT-UHFFFAOYSA-N ethenyl propanoate Chemical compound CCC(=O)OC=C UIWXSTHGICQLQT-UHFFFAOYSA-N 0.000 claims description 4
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 4
- PDBWEHKCAUAROT-UHFFFAOYSA-N prop-1-en-2-yl butanoate Chemical compound CCCC(=O)OC(C)=C PDBWEHKCAUAROT-UHFFFAOYSA-N 0.000 claims description 4
- USYCSHPNZNNCCU-UHFFFAOYSA-N prop-1-en-2-yl prop-2-enoate Chemical compound CC(=C)OC(=O)C=C USYCSHPNZNNCCU-UHFFFAOYSA-N 0.000 claims description 4
- NLDFTWSUPLJCQD-UHFFFAOYSA-N prop-1-en-2-yl propanoate Chemical compound CCC(=O)OC(C)=C NLDFTWSUPLJCQD-UHFFFAOYSA-N 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- 241000228245 Aspergillus niger Species 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 241000235403 Rhizomucor miehei Species 0.000 claims description 3
- 240000005384 Rhizopus oryzae Species 0.000 claims description 3
- 235000013752 Rhizopus oryzae Nutrition 0.000 claims description 3
- 241000223258 Thermomyces lanuginosus Species 0.000 claims description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 3
- 239000004210 ether based solvent Substances 0.000 claims description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
- KZDSIZCJICMHJW-UHFFFAOYSA-N 2-methyl-1h-pyridin-4-one Chemical compound CC1=CC(O)=CC=N1 KZDSIZCJICMHJW-UHFFFAOYSA-N 0.000 claims description 2
- 241000590020 Achromobacter Species 0.000 claims description 2
- ACSDBBZWWBUXLR-UHFFFAOYSA-N CCC(C)C(=O)OC(=C)C Chemical compound CCC(C)C(=O)OC(=C)C ACSDBBZWWBUXLR-UHFFFAOYSA-N 0.000 claims description 2
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 2
- 102000004157 Hydrolases Human genes 0.000 claims description 2
- 108090000604 Hydrolases Proteins 0.000 claims description 2
- 102000019280 Pancreatic lipases Human genes 0.000 claims description 2
- 108050006759 Pancreatic lipases Proteins 0.000 claims description 2
- 241000589516 Pseudomonas Species 0.000 claims description 2
- 241000589614 Pseudomonas stutzeri Species 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- YCUBDDIKWLELPD-UHFFFAOYSA-N ethenyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC=C YCUBDDIKWLELPD-UHFFFAOYSA-N 0.000 claims description 2
- XPXNIPXOZCUJDF-UHFFFAOYSA-N ethenyl 2-methylbutanoate Chemical compound CCC(C)C(=O)OC=C XPXNIPXOZCUJDF-UHFFFAOYSA-N 0.000 claims description 2
- ZAPBLOWGJNQWBJ-UHFFFAOYSA-N ethenyl 2-methylpentanoate Chemical compound CCCC(C)C(=O)OC=C ZAPBLOWGJNQWBJ-UHFFFAOYSA-N 0.000 claims description 2
- WNMORWGTPVWAIB-UHFFFAOYSA-N ethenyl 2-methylpropanoate Chemical compound CC(C)C(=O)OC=C WNMORWGTPVWAIB-UHFFFAOYSA-N 0.000 claims description 2
- BTFFUEGVQBZTMY-UHFFFAOYSA-N ethenyl 3-methylbutanoate Chemical compound CC(C)CC(=O)OC=C BTFFUEGVQBZTMY-UHFFFAOYSA-N 0.000 claims description 2
- ZYYVTDQWKWHSOP-UHFFFAOYSA-N ethenyl 3-methylpentanoate Chemical compound CCC(C)CC(=O)OC=C ZYYVTDQWKWHSOP-UHFFFAOYSA-N 0.000 claims description 2
- GLVVKKSPKXTQRB-UHFFFAOYSA-N ethenyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC=C GLVVKKSPKXTQRB-UHFFFAOYSA-N 0.000 claims description 2
- LZWYWAIOTBEZFN-UHFFFAOYSA-N ethenyl hexanoate Chemical compound CCCCCC(=O)OC=C LZWYWAIOTBEZFN-UHFFFAOYSA-N 0.000 claims description 2
- 229940116369 pancreatic lipase Drugs 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- BABVAJYEVDTDEY-UHFFFAOYSA-N prop-1-en-2-yl 2,2-dimethylpropanoate Chemical compound CC(=C)OC(=O)C(C)(C)C BABVAJYEVDTDEY-UHFFFAOYSA-N 0.000 claims description 2
- LSJFMTWFOIHWKQ-UHFFFAOYSA-N prop-1-en-2-yl 2-methylpropanoate Chemical compound CC(C)C(=O)OC(C)=C LSJFMTWFOIHWKQ-UHFFFAOYSA-N 0.000 claims description 2
- ZSTYAGGGSCKOCD-UHFFFAOYSA-N prop-1-en-2-yl 3-methylbutanoate Chemical compound CC(C)CC(=O)OC(C)=C ZSTYAGGGSCKOCD-UHFFFAOYSA-N 0.000 claims description 2
- DDMNQVDSFOOPCE-UHFFFAOYSA-N prop-1-en-2-yl 3-methylpentanoate Chemical compound CCC(C)CC(=O)OC(C)=C DDMNQVDSFOOPCE-UHFFFAOYSA-N 0.000 claims description 2
- VGMRJSWQULGOOO-UHFFFAOYSA-N prop-1-en-2-yl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC(C)=C VGMRJSWQULGOOO-UHFFFAOYSA-N 0.000 claims description 2
- FZNRKIBWFTTZJK-UHFFFAOYSA-N prop-1-en-2-yl hexanoate Chemical compound CCCCCC(=O)OC(C)=C FZNRKIBWFTTZJK-UHFFFAOYSA-N 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 claims 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims 1
- 102100024025 Heparanase Human genes 0.000 claims 1
- 241000698291 Rugosa Species 0.000 claims 1
- 239000003480 eluent Substances 0.000 claims 1
- 238000006911 enzymatic reaction Methods 0.000 claims 1
- HAKBVZWOUUNFLW-UHFFFAOYSA-N ethenyl 4-methylpentanoate Chemical compound CC(C)CCC(=O)OC=C HAKBVZWOUUNFLW-UHFFFAOYSA-N 0.000 claims 1
- 108010037536 heparanase Proteins 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 19
- 238000000605 extraction Methods 0.000 abstract description 3
- 239000013067 intermediate product Substances 0.000 abstract description 3
- 230000003321 amplification Effects 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 40
- 238000005160 1H NMR spectroscopy Methods 0.000 description 39
- 230000006872 improvement Effects 0.000 description 29
- 239000000047 product Substances 0.000 description 22
- UFNVPOGXISZXJD-JBQZKEIOSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-JBQZKEIOSA-N 0.000 description 16
- 239000012071 phase Substances 0.000 description 11
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229960000439 eribulin mesylate Drugs 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
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- 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 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
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- 102000004243 Tubulin Human genes 0.000 description 1
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- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
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- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
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- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
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- 229920000570 polyether Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P9/00—Preparation of organic compounds containing a metal or atom other than H, N, C, O, S or halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/20—Purification, separation
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- Microbiology (AREA)
- Biotechnology (AREA)
- General Chemical & Material Sciences (AREA)
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- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemistry, relates to preparation of eribulin intermediate, and particularly relates to a preparation method of a compound shown in a formula I, which comprises the following steps: starting from a compound 3A or a compound 3B, after selective acylation by a biological enzyme A or selective hydrolysis by a biological enzyme B, reacting hydroxyl with acid anhydride in a required configuration under the action of organic base and a catalyst to obtain a compound 5, increasing the water solubility of the intermediate product, realizing separation of two configurations by extraction separation, wherein the ee value can reach more than 99 percent, and the preparation method has the advantages of simple operation, high conversion rate, good selectivity and low cost, and is beneficial to industrial amplification production.
Description
The present application claims priority of the chinese patent application entitled "a method for preparing eribulin intermediate" filed by the chinese patent office at 29/7/2022, application No. 202210904052.6, which is incorporated herein by reference in its entirety.
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of an eribulin intermediate.
Background
Eribulin Mesylate (Eribulin Mesylate) is a synthetic analog of halichondrin B, having the biologically active macrocyclic moiety of halichondrin B. Halichondrin B is a polyether macrolide that exhibits potent anticancer effects in both cells and animal models. Eribulin mesylate can inhibit cellular tubulin mitosis, thereby causing irreversible cell cycle G2/M phase arrest and mitotic spindle fragmentation, apoptosis occurs after long-term arrest of cellular mitosis, and cell proliferation is inhibited. The eribulin mesylate injection is developed by Eisai inc, approved by the FDA in the united states to be marketed in the 11 th month in 2010, and has a trade name of Halaven, and the approved indications are: (ii) is suitable for metastatic breast cancer patients who have previously received at least two metastatic cancer treatment regimens; the results based on subset analysis show that eribulin mesylate can be used actively and effectively to treat triple negative metastatic breast cancer, a malignant breast cancer, with a poor prognosis. In many countries, eribulin mesylate has been considered as a three-line and even more advanced drug therapy for the treatment of metastatic breast cancer, however, the drug is the only chemotherapeutic agent that is effective in improving patient survival during treatment. Eribulin mesylate is the only drug with good clinical and market prospects in the field at present.
The structure of the early eribulin intermediate is shown as the following formula I:
the synthesis of compounds of formula i is known in the prior art as follows:
the process route for synthesizing the early intermediate I of the eribulin raw material medicine by using the sanitary material of the original manufacturer is as follows:
wherein TBDPS is tert-butyl diphenyl silicon base.
The compound I has chirality to hydroxy carbon protected by tosyl, a racemate is obtained in the synthesis process, and a single configuration is obtained by preparing and separating the compound shown in the formula 3 through a chiral Simulated Moving Bed (SMB) in a literature report (Synlett (2013), 24 (3), 327-332, WO2005118565 and the like), so that the preparation efficiency is low, the cost is high, and the amplification production is not facilitated. In addition, there is a document (org.lett., vol.10, no.14,2008) that reports that a single configuration of the product is obtained under catalysis of a chiral ligand and metallic chromium, but at high cost.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for preparing the compound shown in the formula I, which is completely different from the prior art, the related reaction conditions are mild and environment-friendly, the route is novel, the post-treatment and the purification are simple, the prepared compound shown in the formula I has high purity, the preparation method is simple to operate, the conversion rate is high, the selectivity is good, the cost is low, and the industrial scale-up production is facilitated; the compound shown in the formula I can be used for preparing eribulin medicaments.
In a first aspect, the present invention provides a process for the enzymatic preparation of a chiral compound I, comprising the steps of:
the method comprises the following steps:
the method comprises the steps of firstly, taking a compound shown as a formula 3A as a raw material, carrying out acylation reaction with an acylation reagent under the action of a biological enzyme A to obtain a compound 4 and a compound I, and selectively separating a mixture of the compound 4 and the compound I;
the second method comprises the following steps:
in the second method, a compound shown as a formula 3B is used as a raw material, a hydrolysis reaction is carried out under the action of a biological enzyme B and alkali to obtain a compound 4 and a compound I, and a mixture of the compound 4 and the compound I is selectively separated;
wherein R is 1 Is C substituted or unsubstituted by Ra 1 -C 12 Straight or branched acyl, benzoyl, C substituted or unsubstituted by Ra 3 -C 6 Straight or branched alkenoyl; the substituents Ra of each group are each independently selected from C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight or branched alkoxy, hydroxy, amino, halogen, nitro, cyano, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, C 1 -C 6 Sulfanyl, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, phenyl or C 3 -C 18 A heterocyclic aromatic group, wherein hetero atoms on the heterocyclic aromatic group are selected from O, N or S; r 1 Preferably acetyl, propionyl, butyryl, isobutyryl, 2-methylbutyryl, 3-methylbutyryl, pivaloyl, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, hexanoyl, lauroyl, benzoyl or acryloyl, more preferably acetyl, propionyl, butyryl, benzoyl or acryloyl.
As a further improvement of the invention, the biological enzyme A is Lipase or esterase, the biological enzyme A is selected from Lipase AK (Lipase AK "Amano"), lipase from Pseudomonas fluorescens (Amano Lipase from Pseudomonas fluorescens), candida antarctica Lipase B (CAL-B Lipase immobilized on acrylic resin (Novozym 435)), lipase AS (Lipase AS "Amano"), lipase PS (Lipase PS "Amano" SD), lipase from Thermomyces lanuginosus, lipase from Candida (Lipase from Candida Rugosa), lipase AYS (Lipase AYS "Amano"), triacylglycerol Lipase (Triacylglycerol Lipase), lipase from Mucor miehei (Lipase from Mucor miehei) or Lipase from Rhizopus oryzae (Lipase from Rhizopus oryzae), lipase B from Candida antarctica immobilized on Immobead 150, recombinant Lipase from Aspergillus oryzae (Lipase B Candida antarctica immobilized on Immobead 150, recombinant Lipase from Aspergillus oryzae); the biological enzyme A is preferably Lipase AK (Lipase AK "Amano"), a Lipase from Pseudomonas fluorescens (Amano Lipase from Pseudomonas fluorescens) or Candida antarctica Lipase B Novozym 435 (CAL-B Lipase (Novozym 435) immobilized on acrylic resin.
As a further improvement of the invention, the biological enzyme B of process two is a lipase, esterase or hydrolase, such AS lipase TL, lipase PS-30 from Pseudomonas cepacia, lipase QLM, lipase from Thermomyces lanuginosus, lipase P2 from Pseudomonas cepacia (Pseudomonas cepacia), lipase PS from Pseudomonas stutzeri, lipase RS from the genus Rhizopus (Rhizopus sp.), lipase PS from Pseudomonas cepacia, lipase AN from Aspergillus niger (Aspergillus niger), lipase A from Achromobacter (Achromobacter sp.), lipase AS1 from Alcaligenes (Alcaligenes sp.), lipase AS2 from Alcaligenes, lipase C2 from Candida cylindracea (Candida cylindracea), lipase C1 from Candida cylindracea, lipase lipozym TL IM, lipase lipozym TL 100L, candida antarctica (Candida antarctica) lipase B (CALB), CHIRAZYME E E-1 porcine liver esterase, lipase from Pseudomonas L-6, candida Antarctica Lipase A (CALA), candida rugosa (Candida rugosa) lipase (L-3), or pancreatic lipase USP Grade.
As a further improvement of the invention, the acylating agent of the first method is selected from vinyl ester or isopropenyl ester, wherein the vinyl ester is selected from C substituted or unsubstituted by Rc 1 -C 12 Vinyl esters of straight-chain or branched acids, vinyl benzoate, C substituted or unsubstituted by Rc 3 -C 6 Linear or branched vinyl enoates; the isopropenyl ester is selected from C substituted or unsubstituted by Rc 1 -C 12 Isopropenyl esters of linear or branched acids, isopropenyl benzoate, C substituted or not by Rc 3 -C 6 Linear or branched isopropenyl alkenoates. The substituent Rc of each group is independently selected from C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight or branched alkoxy, hydroxy, amino, halogen, nitro, cyano, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, C 1 -C 6 Sulfanyl, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, phenyl or C 3 -C 18 A heterocyclic aromatic group, wherein hetero atoms on the heterocyclic aromatic group are selected from O, N or S.
As a further improvement of the present invention, the acylating agent of method one is preferably vinyl acetate, isopropenyl acetate, vinyl propionate, isopropenyl propionate, vinyl butyrate, isopropenyl butyrate, vinyl isobutyrate, isopropenyl isobutyrate, vinyl 2-methylbutyrate, isopropenyl 2-methylbutyrate, vinyl 3-methylbutyrate, isopropenyl 3-methylbutyrate, vinyl pivalate, isopropenyl pivalate, vinyl 2-methylpentanoate, isopropenyl 2-methylpentanoate, vinyl 3-methylpentanoate, isopropenyl 3-methylpentanoate, 4-methylpentanoate, vinyl hexanoate, isopropenyl hexanoate, vinyl laurate, isopropenyl laurate, vinyl benzoate, isopropenyl benzoate, vinyl acrylate or isopropenyl acrylate, more preferably vinyl acetate, isopropenyl acetate, vinyl propionate, isopropenyl propionate, vinyl butyrate, isopropenyl butyrate, vinyl benzoate, isopropenyl benzoate, vinyl acrylate or isopropenyl acrylate.
According to the method I provided by the invention, the alcohol shown in the formula 3A can be selectively acylated by using the biological enzyme A to generate an acylated compound shown in a single isomer of a formula 4; the compound of formula I can then be conveniently isolated from the compound of formula 4. The acylation reaction may be carried out in an organic solvent. The enantiomeric excess of the product of formula I is preferably at least 96% ee, more preferably at least 99% ee. The enzyme can be immobilized on a carrier to facilitate recovery of the enzyme and post-treatment of the reaction, and has the characteristics of high selectivity, good stability, high enzyme activity and low cost.
As a further improvement of the invention, the acylation reaction in the first method is carried out in an organic solvent A, wherein the organic solvent A is one or any combination of alkane, aromatic hydrocarbon, chloroalkane, nitrile or ether solvents; for example, the alkane is selected from n-hexane, cyclohexane, n-pentane, cyclopentane or n-heptane, or any combination thereof; the aromatic hydrocarbon is selected from one or any combination of toluene, xylene or chlorobenzene; the chloroalkanes are selected from dichloromethane and chloroform; the nitrile is selected from one or any combination of acetonitrile, propionitrile or benzonitrile; the ethers are selected from one or any combination of petroleum ether, tetrahydrofuran, 1, 4-dioxane, diethyl ether, diisopropyl ether or methyl tert-butyl ether (MTBE); the organic solvent A is preferably one or any combination of petroleum ether, diethyl ether, methyl tert-butyl ether, dichloromethane, n-hexane, cyclohexane, n-pentane, cyclopentane, n-heptane, toluene or acetonitrile; more preferably n-hexane or n-heptane or any combination thereof.
As a further improvement of the invention, in the first method, the mass volume ratio of the compound 3A to the organic solvent A is 1g to 15mL, and more preferably is 1 g.
As a further improvement of the invention, in the first method, the acylation reaction temperature is 30-80 ℃, preferably 55-60 ℃; the enzyme has good activity, high reaction rate and high efficiency in the temperature range.
As a further improvement of the invention, in the first method, the mass ratio of the compound 3A to the biological enzyme a is 1.
As a further improvement of the present invention, in the first method, the molar ratio of the compound 3A to the acylating agent is 1; the acylation reagent is combined with biological enzyme for use, can selectively carry out acylation reaction on the S configuration compound in the racemic compound 3A to obtain the compound 4, and has high reaction yield and good isomer purity.
As a further development of the invention, the enantioselective acylation according to the invention gives a product which comprises a mixture of the compound of the formula I in the R-form and the compound of the formula 4 in the S-form. Likewise, enantioselective enzymatic hydrolysis may yield a mixture comprising the R-form of the compound of formula I and the S-form of the compound of formula 4. The optical purity of the compound of the formula I obtained by the optical resolution method of the present invention is usually at least 96% ee, preferably at least 97% ee, more preferably at least 98% ee, and most preferably at least 99% ee.
As a further improvement of the invention, the hydrolysis reaction of the second method is carried out in water and an organic solvent B, wherein the organic solvent B comprises one or any combination of alkane, aromatic hydrocarbon, chloroalkane, nitrile solvent or ether solvent; for example, the alkane is selected from n-hexane, cyclohexane, n-pentane, cyclopentane or n-heptane, or any combination thereof; the aromatic hydrocarbon is selected from one or any combination of toluene, xylene or chlorobenzene; the chloroalkane is selected from one or any combination of dichloromethane or chloroform; the nitrile is selected from one or any combination of acetonitrile, propionitrile or benzonitrile; the ether is selected from one or any combination of petroleum ether, tetrahydrofuran, 1, 4-dioxane, diethyl ether, diisopropyl ether or methyl tert-butyl ether (MTBE); the organic solvent B is preferably selected from one or any combination of toluene, xylene, methyl tert-butyl ether or acetonitrile.
As a further improvement of the present invention, the base is selected from organic or inorganic bases, the organic base is selected from one or any combination of diethylamine, triethylamine (TEA), diisopropylamine, morpholine, N-methylmorpholine, piperazine or N-methylpiperazine; the inorganic base comprises, for example, one or any combination of an alkali metal hydroxide, carbonate or bicarbonate, or an alkaline earth metal hydroxide. Preferably, the base is one of or any combination of a hydroxide, a carbonate or a bicarbonate of an alkali metal, and more preferably, the base is an alkali metal carbonate. The alkali is preferably selected from one or any combination of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, sodium bicarbonate or potassium carbonate; most preferred is one or any combination of sodium or potassium carbonate. The alkali and the biological enzyme B are used in combination, the R configuration in the racemic compound 3B can be selectively hydrolyzed to obtain the compound I, the reaction yield is high, and the isomer purity is good.
In a further improvement of the present invention, in the second method, the mass ratio of the compound 3B to the biological enzyme B is 1.
As a further improvement of the present invention, in the second process, the molar ratio of the compound 3B to the base is 1.
In a further improvement of the present invention, in the second method, the mass-to-volume ratio of the compound 3B to the organic solvent B is 1g to 15mL, more preferably 1 g.
As a further improvement of the invention, the hydrolysis reaction temperature in the method II is 30-80 ℃, preferably 35-40 ℃; the enzyme has good activity, high reaction rate and high efficiency in the temperature range.
As a further improvement of the present invention, the method for selectively separating a mixture of compound 4 and compound I comprises:
1) Separating the mixture of the compound 4 and the compound I by a column chromatography method to obtain a compound I; or
2) A, step a: under the action of a catalyst and an organic base, selectively carrying out an esterification reaction on a compound I in a mixture of a compound 4 and a compound I and an anhydride, and separating to obtain a compound 4 and a compound 5, wherein the step b: hydrolyzing compound 5 to provide compound I, having the following reaction formula:
wherein R is 1 Is C substituted or unsubstituted by Ra 1 -C 12 Straight or branched acyl, benzoyl, C substituted or unsubstituted by Ra 3 -C 6 Straight-chain or branched alkenoyl, the substituents Ra of each radical being independently selected from C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight or branched alkoxy, hydroxy, amino, halogen, nitro, cyano, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, C 1 -C 6 Sulfanyl, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, phenyl or C 3 -C 18 A heterocyclic aromatic group, wherein hetero atoms on the heterocyclic aromatic group are selected from O, N or S; r 1 Preferably acetyl, propionyl, butyryl, isobutyryl, 2-methylbutyryl, 3-methylbutyryl, pivaloyl, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, hexanoyl, lauroyl, benzoyl or acryloyl; r is 2 Is selected from
As a further improvement of the invention, the separation conditions of the column chromatography method are that petroleum ether and ethyl acetate in the volume ratio of 20-5.
As a further development of the invention, the catalyst in step a is selected from 4-Dimethylaminopyridine (DMAP).
As a further improvement of the present invention, the molar ratio of compound I to catalyst in step a is 1.
As a further improvement of the present invention, the organic base in step a is selected from one or any combination of diethylamine, triethylamine, diisopropylamine, pyridine, α -methylpyridine, 1, 2-dimethylpyridine, 4-hydroxy-2-methylpyridine, γ -trimethylpyridine, quinoline or dimethylquinoline, and the organic base in step a is preferably selected from one or any combination of triethylamine, diisopropylamine, pyridine or α -methylpyridine; the molar ratio of the compound I to the organic base in the step a is 1; the temperature of the esterification reaction is 0 to 50 ℃, preferably 10 to 30 ℃.
As a further improvement of the invention, the acid anhydride in step a is selected from
The molar ratio of the compound I to the acid anhydride is 1 to 10, preferably 1 to 5, more preferably 1.1 to 1.8.
As a further improvement of the invention, the esterification reaction in step a is carried out in a reaction solvent C, wherein the reaction solvent C comprises one or any combination of aromatic hydrocarbon, chloroalkane, nitrile solvent or ether solvent; for example, the aromatic hydrocarbon is selected from one of toluene, xylene or chlorobenzene or any combination thereof; the chloroalkane is selected from one or any combination of dichloromethane or chloroform; the nitrile is selected from one or any combination of acetonitrile, propionitrile or benzonitrile; the ether is selected from one or any combination of petroleum ether, tetrahydrofuran, 1, 4-dioxane, diethyl ether, diisopropyl ether or methyl tert-butyl ether; the reaction solvent C is preferably selected from one or any combination of toluene, xylene, methyl tert-butyl ether or acetonitrile.
As a further improvement of the present invention, the separation in step a includes conventional separation steps, such as liquid separation, extraction, water washing or concentration, etc., the solvent for liquid separation or extraction is not particularly limited in the present invention, and one or any combination of alkane, chloroalkane or ether solvents can be used; for example, the alkane is selected from n-hexane, cyclohexane, n-pentane, cyclopentane or n-heptane, or any combination thereof; the chloroalkane is selected from one or any combination of dichloromethane or chloroform; the ethers are selected from one of petroleum ether, tetrahydrofuran, 1, 4-dioxane, diethyl ether, diisopropyl ether or methyl tert-butyl ether (MTBE) or any combination thereof.
As a further improvement of the invention, the hydrolysis in step b is carried out in water and an organic solvent D, wherein the organic solvent which does not produce negative effects is suitable for the hydrolysis reaction, and the organic solvent D is selected from the organic solvents which do not produce negative effects; the organic solvent D is preferably selected from the reaction solvents C in step a above, preferably the hydrolysis is carried out in water and acetonitrile; the reaction temperature is preferably room temperature.
As a further improvement of the present invention, the hydrolysis of step b is carried out in an inorganic base selected from one or any combination of alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate or alkaline earth metal hydroxide. Preferably, the base is selected from one or any combination of hydroxides of alkali metals or hydroxides of alkaline earth metals, more preferably, the base is a hydroxide of an alkali metal. The alkali is preferably selected from one or any combination of lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide; more preferably sodium hydroxide or potassium hydroxide, or any combination thereof.
As a further improvement of the present invention, the molar ratio of compound 5 to inorganic base in step b is 1.
In a second aspect, the present invention provides a process for the preparation of chiral compound I comprising the step of separating a mixture of compound 4 and compound I, said separation process comprising:
3) Separating the mixture of the compound 4 and the compound I by a column chromatography method to obtain a compound I; or
4) A, step a: under the action of a catalyst and an organic base, selectively carrying out esterification reaction on a compound I in a mixture of a compound 4 and the compound I and acid anhydride, and separating to obtain a compound 4 and a compound 5; step b: hydrolyzing said compound 5 to provide compound I having the following reaction formula:
wherein R is 1 Is C substituted or unsubstituted by Ra 1 -C 12 Straight or branched acyl, benzoyl, substituted or unsubstituted C 3 -C 6 Straight-chain or branched alkenoyl, the substituents Ra of each radical being independently selected from C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight or branched alkoxy, hydroxy, amino, halogen, nitro, cyano, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, C 1 -C 6 Sulfanyl, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, phenyl or C 3 -C 18 A heterocyclic aromatic group, wherein hetero atoms on the heterocyclic aromatic group are selected from O, N or S; r 1 Preferably acetyl, propionyl, butyryl, isobutyryl, 2-methylbutyryl, 3-methylbutyryl, pivaloyl, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, hexanoyl, lauroyl, benzoyl or acryloyl; r 2 Is selected from
As a further improvement of the present invention, the reaction conditions of the compound I of the second aspect in each step can be referred to the reaction condition parameters of each step in the first aspect of the present invention; during continuous feeding, no matter compound 3A is subjected to acylation reaction in biological enzyme A or compound 3B is subjected to hydrolysis reaction in biological enzyme B, a mixture of compound I and compound 4 is obtained, the feeding is accurate according to 50% of theoretical yield or quantity detection by High Performance Liquid Chromatography (HPLC), and the reaction with the anhydride step a in the next step is not influenced.
As a further improvement of the present invention, compound 4 can be directly transformed to compound I by the method described in reference Synlett (2013), 24 (3), 327-332 (which is incorporated herein by reference in its entirety) after hydrolysis.
As a further improvement of the present invention, the preparation of the mixture of compound 4 and compound I comprises: selectively acylating or hydrolyzing the compound 3A or the compound 3B under the action of a biological enzyme A and a biological enzyme B respectively to obtain a mixture of a compound 4 and a compound I. The reaction formula is as follows:
as a further improvement of the present invention, the reaction conditions in the preparation of the mixture of Compound 4 and Compound I of the second aspect may be referred to the reaction conditions of the above-mentioned steps of the first aspect of the present invention.
In a third aspect, the present invention provides a key intermediate for the preparation of compound i. In certain embodiments, key intermediate compound C is represented as follows:
Wherein the substituents Ra of each radical are each independently selected from C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight or branched alkoxy, hydroxy, amino, halogen, nitro, cyano, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Sulfanyl, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, phenyl or C 3 -C 18 And the hetero atom on the heterocyclic aromatic group is selected from O, N or S.
Preferably, when the chiral carbon is represented by S configuration, the structure is:
wherein: r 1 Is C substituted or unsubstituted by Ra 1 -C 12 Straight or branched acyl, C substituted or unsubstituted by Ra 3 -C 6 Straight-chain or branched alkenoyl, the substituents Ra of each radical being independently selected from C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight or branched alkoxy, hydroxy, amino, halogen, nitro, cyano, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Sulfanyl, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, phenyl or C 3 -C 18 A heterocyclic aromatic group, wherein hetero atoms on the heterocyclic aromatic group are selected from O, N or S; r 1 Preferably propionyl, butyryl, isobutyryl, 2-methylbutyryl, 3-methylbutyryl, pivaloyl, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, hexanoyl, lauroyl or acryloyl.
As a further development of the invention, the key intermediate compounds are selected from the following compounds without limitation:
when the chiral carbon is in an R configuration, the structure is as follows:
wherein: r 2 Is selected from
As a further development of the invention, the key intermediate compounds are selected from the following compounds without limitation:
in a third aspect, the present application provides a method of preparing an eribulin medicament, comprising the method provided in the first aspect of the present application or the method provided in the second aspect of the present application.
Compared with the prior art, the invention provides a novel method for preparing the compound shown in the formula I, the related reaction conditions are mild and environment-friendly, the route is novel, the post-treatment and purification are simple, the prepared compound shown in the formula I has high purity, the preparation method is simple to operate, the conversion rate is high, the selectivity is good, the cost is low, and the industrial scale-up production is facilitated; the compound shown in the formula I can be used for preparing eribulin medicaments; the preparation method of the compound I has the advantages that:
1) The racemic compound 3 (including 3A or 3B) can be separated by selective resolution of screened biological enzyme (A or B) only by means of column chromatography purification without high-cost SMB operation or by utilizing the catalytic action of chiral ligand and metallic chromium, and can be separated by conventional filtration operation.
2) The biological enzyme screened by the invention has the characteristics of high selectivity, good stability, high enzyme activity, recyclability and low cost.
3) The invention selectively acidylates by biological enzyme and realizes the resolution of racemic compound by utilizing polarity difference, the yield of compound I is more than 93 percent, and the ee value is more than 99 percent.
4) The invention more specifically adopts a biological enzyme resolution method to selectively protect the unwanted configuration by acyl, reduces the polarity of the intermediate product, uses acid anhydride to react the needed configuration hydroxyl with the acid anhydride under the action of organic base and catalyst, increases the water solubility of the intermediate product, adopts a small polar solvent to extract and remove the unwanted configuration (the product protected by acyl), can realize the separation of the two configurations without column chromatography purification means, and can achieve an ee value of more than 99 percent.
Detailed Description
To facilitate understanding of the present invention by those skilled in the art, the technical solutions of the present invention will be further described below with reference to specific examples, but the following contents are not intended to limit the scope and spirit of the present invention as claimed in the claims. The starting materials, reagents or solvents used in the present invention are commercially available without specific mention, and the experimental procedures under specific conditions not specifically mentioned are carried out under the ordinary operating conditions in the art.
In the present invention, the yield is a molar percentage of an actual yield to a theoretical yield of a product. "w" is a mass ratio, for example, 0.2w of the biological enzyme means that the mass ratio of the biological enzyme to the raw material (compound 3A/compound 3B) is 0.2.
Example 1
Dissolving compound 3A (20.0 g, 44.70mmol) in 120mL of n-heptane, adding vinyl acetate (15.4 g, 223.48mmol) and biological enzyme (enzyme) Lipase AK "Amano" (4.0 g, 0.2w), heating to 55-60 ℃ under the protection of nitrogen, and reacting at 55-60 ℃ until the ee value of compound I is more than or equal to 99% by HPLC detection. Directly filtering the reaction solution, recovering a filter cake, concentrating the filtrate to obtain a crude product, separating by silica gel column chromatography, distilling under reduced pressure, and concentrating to dryness to obtain 10.5g of a compound 4-1, wherein the yield is 48.0%; and 9.44g of Compound I in 47.2% yield with an ee of 99.8%.
Preparation of Compound 4-1 1 H-NMR(400MHz,CDCl 3 ):δ＝7.68-7.65(m,4H),7.45-7.37(m,6H),5.62(s,1H),5.48(s,1H),5.22-5.16(m,1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),2.03(s,3H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m/z calcd for[C 25 H 33 BrO 3 Si] + 490.3,found 490.3.
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Example 2
The product obtained in the same manner as in example 1 except that the following synthetic route was followed and the parameters were adjusted in accordance with Table 1 was subjected to nuclear magnetic resonance as follows.
Preparation of Compound 4-2 1 H-NMR(400MHz,CDCl 3 ):δ＝7.67-7.64(m,4H),7.45-7.37(m,6H),5.61(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.67(m,1H)2.61-2.56(m,1H),2.38-2.29(m,2H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.13(t,3H,J＝12.0Hz),1.05(s,9H).LC-MS(ESI):m/z calcd for[C 26 H 35 BrO 3 Si] + 504.5,found 504.5.
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Example 3
The product obtained in the same manner as in example 1 except for adjusting the parameters according to the following synthetic route and according to Table 1 had the following nuclear magnetic properties.
Of Compounds 4 to 3 1 H-NMR(400MHz,CDCl 3 ):δ＝8.07(d,2H,J＝9.2Hz),7.70-7.67(m,4H),7.55-7.31(m,9H),5.63(s,1H),5.49(s,1H),5.23-5.17(m,1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m/z calcd for[C 30 H 35 BrO 3 Si] + 552.4,found 552.4.
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63–1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Example 4
The product obtained in the same manner as in example 1 except for adjusting the parameters according to the following synthetic route and according to Table 1 had the following nuclear magnetic properties.
Of Compounds 4 to 4 1 H-NMR(400MHz,CDCl 3 ):δ＝7.67-7.64(m,4H),7.45-7.37(m,6H),6.27(dd,1H,10.1Hz,4.4Hz),6.05(dd,1H,9.8Hz,7.6Hz),5.61-5.59(m,2H),(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.67(m,1H)2.61-2.56(m,1H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.07(s,9H).LC-MS(ESI):m/z calcd for[1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m/z calcd for C 26 H 33 BrO 3 Si] + 504.5,found 504.5.
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Example 5
Compound I (2.0g, 4.47mmol) was dissolved in 20mL of acetonitrile, and pyridine (1.06g, 13.41mmol), (0.11g, 0.894mmol) 4-Dimethylaminopyridine (DMAP) and (0.67g, 6.705mmol) succinic anhydride were added thereto, and the mixture was reacted at room temperature under nitrogen atmosphere until the raw material spots were observed by Thin Layer Chromatography (TLC) to disappear and the reaction was completed. The reaction solution was concentrated to give a pale yellow oily substance, which was subjected to silica gel column chromatography, distillation under reduced pressure, and concentration to dryness to give 2.35g of compound 5-1 as a pale yellow oily substance with a yield of 96.0%.
1 H-NMR(400MHz,CDCl 3 ):δ＝10.98(s,1H),7.67-7.65(m,4H),7.43-7.37(m,6H),5.61(s,1H),5.48(s,1H),5.24-5.18(m,1H),3.70-3.63(m,2H),2.74-2.54(m,6H),1.79-1.72(m,1H),1.69-1.52(m,3H),1.05(s,9H),LC-MS(ESI):m/z calcd for[C 27 H 35 BrO5Si] + 548.3,found 548.3.
Example 6
The product obtained in the same manner as in example 5 except that the synthetic route and the parameters were adjusted in accordance with Table 2 were as follows.
1 H-NMR(400MHz,CDCl 3 ):δ＝10.98(s,1H),7.67-7.65(m,4H),7.43-7.37(m,6H),6.30(dd,2H,J＝21.4,15.1Hz),5.61(s,1H),5.49(s,1H),5.24-5.18(m,1H),3.70-3.63(m,2H),2.59-2.56(m,2H),1.79-1.72(m,1H),1.69-1.52(m,3H),1.05(s,9H),LC-MS(ESI):m/z calcd for[C 27 H 33 BrO 5 Si] + 546.4,found 546.4.
Example 7
The product obtained in the same manner as in example 5 except for adjusting the parameters according to the following synthetic route and according to Table 2 had the following nuclear magnetic properties.
1 H-NMR(400MHz,CDCl 3 ):δ＝10.98(s,1H),8.33-8.29(m,2H),7.91-7.87(m,2H),7.67-7.65(m,4H),7.43-7.37(m,6H),5.61(s,1H),5.49(s,1H),5.24-5.18(m,1H),3.70-3.63(m,2H),2.59-2.56(m,2H),1.79-1.72(m,1H),1.69-1.52(m,3H),1.05(s,9H),LC-MS(ESI):m/z calcd for[C 31 H 35 BrO 5 Si] + 596.2,found 596.2.
Example 8
Dissolving compound 3B-1 (10.0g, 20.43mmol) in 50mL of toluene, adding sodium carbonate (2.17g, 20.43mmol), lipase TL (1.0g, 0.1w) and water (1.5g, 0.1w), and stirring under the protection of nitrogen at 35-40 ℃ for reaction until the ee value of compound I is more than or equal to 99% through HPLC detection, and finishing the reaction. Directly filtering the reaction solution, recovering a filter cake, washing the filtrate with saturated saline solution, concentrating an organic phase to obtain a crude product, and separating by silica gel column chromatography to obtain 4.81g of a compound 4-1 with the yield of 48.1%; and 4.37g of Compound I, 47.8% yield, 99.8% ee.
Preparation of Compound 4-1 1 H-NMR(400MHz,CDCl 3 ):δ＝7.68-7.65(m,4H),7.45-7.37(m,6H),5.62(s,1H),5.48(s,1H),5.22-5.16(m,1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),2.03(s,3H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m/z calcd for[C 25 H 33 BrO 3 Si] + 490.3,found 490.3.
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Example 9
The product obtained in the same manner as in example 8 except for adjusting the parameters according to the following synthetic route and according to Table 3 had the following nuclear magnetic properties.
Preparation of Compound 4-2 1 H-NMR(400MHz,CDCl 3 ):δ＝7.67-7.64(m,4H),7.45-7.37(m,6H),5.61(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.67(m,1H)2.61-2.56(m,1H),2.38-2.29(m,2H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.13(t,3H,J＝12.0Hz).LC-MS(ESI):m/z calcd for[C 26 H 35 BrO 3 Si] + 504.5,found 504.5
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Example 10
The product obtained in the same manner as in example 8 except for adjusting the parameters according to the following synthetic route and according to Table 3 had the following nuclear magnetic properties.
Process for preparation of compound 4-3 1 H-NMR(400MHz,CDCl 3 ):δ＝8.07(d,2H,J＝9.2Hz),7.70-7.67(m,4H),7.55-7.31(m,9H),5.63(s,1H),5.49(s,1H),5.23-5.17(m,1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m/z calcd for[C 30 H 35 BrO 3 Si] + 552.4,found 552.4；
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Example 11
The product obtained in the same manner as in example 8 except that the synthetic route and the parameters were adjusted in accordance with Table 3 were as follows.
Of Compounds 4 to 4 1 H-NMR(400MHz,CDCl 3 ):δ＝7.67-7.64(m,4H),7.45-7.37(m,6H),6.27(dd,1H,10.1Hz,4.4Hz),6.05(dd,1H,9.8Hz,7.6Hz),5.61-5.59(m,2H),(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.67(m,1H)2.61-2.56(m,1H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 26 H 33 BrO 3 Si] + 502.5,found 502.5.
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Example 12
Dissolving (20.0 g, 44.70mmol) compound 3A in 100mL n-hexane, adding (19.24g, 223.48mmol) vinyl acetate and (4.0 g, 0.2w) biological enzyme Lipase AK "Amano", raising the internal temperature to 55-60 ℃ under the protection of nitrogen, keeping the internal temperature at 55-60 ℃ for reaction until the ee value of compound I is detected to be more than or equal to 99% by HPLC, and finishing the reaction. Directly filtering the reaction liquid, recovering a filter cake, concentrating the filtrate to obtain a crude product, dissolving the crude product by using 40mL of acetonitrile, adding (7.92g, 78.23mmol) Triethylamine (TEA), (0.55g, 4.47mmol) DMAP (DMAP), (3.35g, 33.53mmol) succinic anhydride, reacting at room temperature until raw material spots disappear after TLC observation, adding n-heptane and water into the reaction liquid after the reaction is finished, collecting an n-heptane phase, extracting an acetonitrile water phase by using n-heptane, combining the n-heptane phases, and concentrating and drying the n-heptane phase at 35-40 ℃ under reduced pressure to obtain 10.4g of a compound 4-1, wherein the yield is 47.6%.
Acetonitrile in water (3.58g, 89.40mmol) was added to sodium hydroxide as a solid, reacted at room temperature until the starting spot disappeared by TLC observation, the mixture was separated, and the acetonitrile phase was collected and concentrated to dryness at 35-40 ℃ under reduced pressure to give 9.26g of Compound I in 46.3% yield with an ee value of 99.7%.
Process for preparation of compound 4-1 1 H-NMR(400MHz,CDCl 3 ):δ＝7.68-7.65(m,4H),7.45-7.37(m,6H),5.62(s,1H),5.48(s,1H),5.22-5.16(m,1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),2.03(s,3H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m/z calcd for[C 25 H 33 BrO 3 Si] + 490.3,found 490.3.
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Example 13
The product obtained in the same manner as in example 12 except that the synthetic route and the parameters were adjusted in accordance with Table 4 below was subjected to nuclear magnetic resonance as follows.
Preparation of Compound 4-2 1 H-NMR(400MHz,CDCl 3 ):δ＝7.67-7.64(m,4H),7.45-7.37(m,6H),5.61(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.67(m,1H)2.61-2.56(m,1H),2.38-2.29(m,2H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.13(t,3H,J＝12.0Hz),1.05(s,9H).LC-MS(ESI):m/z calcd for[C 26 H 35 BrO 3 Si] + 504.5,found 504.5.
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Example 14
The product obtained in the same manner as in example 12 except that the following synthetic route was followed and the parameters were adjusted in accordance with Table 4 was subjected to nuclear magnetic resonance as follows.
Of Compounds 4 to 3 1 H-NMR(400MHz,CDCl 3 ):δ＝8.07(d,2H,J＝9.2Hz),7.70-7.67(m,4H),7.55-7.31(m,9H),5.63(s,1H),5.49(s,1H),5.23-5.17(m,1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m/z calcd for[C 30 H 35 BrO 3 Si] + 552.4,found 552.4.
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Example 15
The product obtained in the same manner as in example 12 except that the following synthetic route was followed and the parameters were adjusted in accordance with Table 4 was subjected to nuclear magnetic resonance as follows.
Of Compounds 4 to 4 1 H-NMR(400MHz,CDCl 3 ):δ＝7.67-7.64(m,4H),7.45-7.37(m,6H),6.27(dd,1H,10.1Hz,4.4Hz),6.05(dd,1H,9.8Hz,7.6Hz),5.61-5.59(m,2H),(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.67(m,1H)2.61-2.56(m,1H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 26 H 33 BrO 3 Si] + 504.5,found 504.5.
Of the Compound I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63–1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Example 16
(20.0 g, 44.69mmol) of Compound 3A was dissolved in 100mL of Dichloromethane (DCM), triethylamine (13.57g, 134.07mmol), (2.73g, 22.34mmol) DMAP (6.84g, 67.035mmol) was added, and the reaction was completed under nitrogen atmosphere at room temperature until the spot of the starting material disappeared as observed by TLC. The reaction mixture was added with 50mL of saturated brine, stirred, separated, and the organic phase was concentrated to give a crude pale yellow oily substance, which was slurried with 100mL of n-heptane, filtered, and the filtrate was concentrated to give 21.34g of Compound 3B-1 as a pale yellow oily substance with a yield of 97.53%.
H-NMR (400MHz, CDCl) of Compound 3B-1 3 ):δ＝7.68-7.65(m,4H),7.45-7.37(m,6H),5.62(s,1H),5.48(s,1H),5.22-5.16(m,1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),2.03(s,3H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m/z calcd for[C 25 H 33 BrO 3 Si] + 490.3,found 490.3.
Example 17
Compound 3B-1 (10.0g, 20.43mmol) was dissolved in 50mL of toluene, and sodium carbonate (2.17g, 20.43mmol), (1.0g, 0.1w) of lipase PS-30 derived from Pseudomonas cepacia, and (1.0g, 0.1w) of water were added thereto, and the reaction was stirred at 35 to 40 ℃ under nitrogen atmosphere until the compound 5ee value was 99% or more as determined by HPLC, and the reaction was completed. Directly filtering the reaction liquid, recovering a filter cake, washing the filtrate with 10mL of saturated common salt for 1 time, concentrating an organic phase to obtain a crude product, dissolving the crude product with 20mL of acetonitrile, adding (3.62g, 35.75mmol) TEA, (0.25g, 2.043mmol) DMAP, (1.50g, 15.32mmol) maleic anhydride, reacting at room temperature until a raw material spot disappears when TLC is observed, adding 20mL of n-heptane and 25mL of water into the reaction liquid after the reaction is finished, collecting an n-heptane phase, extracting an acetonitrile water phase with n-heptane, combining the n-heptane phases, and concentrating the n-heptane phase at 35-40 ℃ under reduced pressure to obtain 4.79g of the compound 4-1, wherein the yield is 47.9%.
Acetonitrile in water (1.63g, 40.86mmol) is added with sodium hydroxide solid, the mixture is reacted at room temperature until raw material spots disappear when observed by TLC, liquid separation is carried out, the acetonitrile phase is collected, and the acetonitrile phase is concentrated under reduced pressure at 35-40 ℃ to obtain 4.39g of compound I, wherein the yield is 48.1%, and the ee value is 99.8%.
Preparation of Compound 4-1 1 H-NMR(400MHz,CDCl 3 ):δ＝7.68-7.65(m,4H),7.45-7.37(m,6H),5.62(s,1H),5.48(s,1H),5.22-5.16(m,1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),2.03(s,3H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m/z calcd for[C 25 H 33 BrO 3 Si] + 490.3,found 490.3.
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Example 18
The product obtained in the same manner as in example 16 except for adjusting the parameters according to the following synthetic route and according to Table 5 had the following nuclear magnetic properties.
Of compound 3B-2 1 H-NMR(400MHz,CDCl 3 ):δ＝7.67-7.64(m,4H),7.45-7.37(m,6H),5.61(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.67(m,1H)2.61-2.56(m,1H),2.38-2.29(m,2H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.13(t,3H,J＝12.0Hz).LC-MS(ESI):m/z calcd for[C 26 H 35 BrO 3 Si] + 504.5,found 504.5.
Example 19
The product obtained in the same manner as in example 17 except that the following synthetic route was followed and the parameters were adjusted in accordance with Table 6 had the following nuclear magnetic properties.
Preparation of Compound 4-2 1 H-NMR(400MHz,CDCl 3 ):δ＝7.67-7.64(m,4H),7.45-7.37(m,6H),5.61(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.67(m,1H)2.61-2.56(m,1H),2.38-2.29(m,2H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.13(t,3H,J＝12.0Hz).LC-MS(ESI):m/z calcd for[C 26 H 35 BrO 3 Si] + 504.5,found 504.5.
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63–1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Example 20
The product obtained in the same manner as in example 16 except for adjusting the parameters according to the following synthetic route and according to Table 5 had the following nuclear magnetic properties.
Of compound 3B-3 1 H-NMR(400MHz,CDCl 3 ):δ＝8.07(d,2H,J＝9.2Hz),7.70-7.67(m,4H),7.55-7.31(m,9H),5.63(s,1H),5.49(s,1H),5.23-5.17(m,1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m/z calcd for[C 30 H 35 BrO 3 Si] + 552.4,found 552.4.
Example 21
The product obtained in the same manner as in example 17 except that the following synthetic route was followed and the parameters were adjusted in accordance with Table 6 had the following nuclear magnetic properties.
Of Compounds 4 to 3 1 H-NMR(400MHz,CDCl 3 ):δ＝8.07(d,2H,J＝9.2Hz),7.70-7.67(m,4H),7.55-7.31(m,9H),5.63(s,1H),5.49(s,1H),5.23-5.17(m,1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m/z calcd for[C 30 H 35 BrO 3 Si] + 552.4,found 552.4.
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63–1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2
Example 22
The product obtained in the same manner as in example 16 except for adjusting the parameters according to the following synthetic route and according to Table 5 had the following nuclear magnetic properties.
Of compound 3B-4 1 H-NMR(400MHz,CDCl 3 ):δ＝7.67-7.64(m,4H),7.45-7.37(m,6H),6.27(dd,1H,10.1Hz,4.4Hz),6.05(dd,1H,9.8Hz,7.6Hz),5.61-5.59(m,2H),(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.67(m,1H)2.61-2.56(m,1H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 26 H 33 BrO 3 Si] + 502.5,found 502.5.
Example 23
The product obtained in the same manner as in example 17 except that the following synthetic route was followed and the parameters were adjusted in accordance with Table 6 had the following nuclear magnetic properties.
Of compounds 4 to 4 1 H-NMR(400MHz,CDCl 3 ):δ＝7.67-7.64(m,4H),7.45-7.37(m,6H),6.27(dd,1H,10.1Hz,4.4Hz),6.05(dd,1H,9.8Hz,7.6Hz),5.61-5.59(m,2H),(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.67(m,1H)2.61-2.56(m,1H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 26 H 33 BrO 3 Si] + 502.5,found 502.5.
Process for preparing compounds I 1 H-NMR(400MHz,CDCl 3 ):δ＝7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.74-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m/z calcd for[C 23 H 31 BrO 2 Si] + 448.2,found 448.2.
Relevant parameters in the above examples 1 to 23 are shown in tables 1 to 6.
Claims (10)
1. A method for preparing chiral compound I by an enzymatic method comprises the following steps:
the method comprises the following steps:
according to the first method, a compound shown as a formula 3A is used as a raw material, and is subjected to acylation reaction with an acylation reagent under the action of a biological enzyme A to obtain a compound 4 and a compound I, and a mixture of the compound 4 and the compound I is selectively separated;
the second method comprises the following steps:
in the second method, a compound shown as a formula 3B is used as a raw material, the compound 4 and the compound I are obtained through hydrolysis reaction under the action of a biological enzyme B and alkali, and the mixture of the compound 4 and the compound I is selectively separated;
wherein R is 1 Is C substituted or unsubstituted by Ra 1 -C 12 Straight or branched acyl, benzoyl, C substituted or unsubstituted by Ra 3 -C 6 Straight-chain or branched alkenoyl, the substituents Ra of each radical being independently selected from C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight or branched alkoxy, hydroxy, amino, halogen, nitro, cyano, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Sulfanyl, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, phenyl or C 3 -C 18 A heterocyclic aromatic group, wherein hetero atoms on the heterocyclic aromatic group are selected from O, N or S; r 1 Preferably acetyl, propionyl, butyryl, isobutyryl, 2-methylbutyryl, 3-methylbutyryl, pivaloyl, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, hexanoyl, lauroyl, benzoyl or acryloyl, more preferably acetyl, propionyl, butyryl, benzoyl or acryloyl;
the biological enzyme A is lipase or esterase, and is selected from lipase AK, lipase from pseudomonas fluorescens, lipase B from candida antarctica immobilized on acrylic resin, lipase AS, lipase PS, lipase from thermophilic mould, lipase from candida, lipase AYS, triacylglycerol lipase, lipase from mucor miehei or lipase from rhizopus oryzae, lipase B from candida antarctica immobilized on Immobead 150, and recombinant lipase from aspergillus oryzae; the biological enzyme A is preferably lipase AK, lipase from pseudomonas fluorescens or candida antarctica lipase B Novozym 435 immobilized on acrylic resin;
the biological enzyme B is lipase, esterase or hydrolase, the biological enzyme B is selected from lipase TL, lipase PS-30 from Pseudomonas cepacia, lipase QLM, lipase from Thermomyces lanuginosus, lipase P2 from Pseudomonas cepacia, lipase PS from Pseudomonas stutzeri, lipase RS from Aspergillus oryzae, lipase PS from Pseudomonas cepacia, lipase AN from Aspergillus niger, lipase A from Achromobacter, lipase AS1 from Alcaligenes, lipase AS2 from Alcaligenes, lipase C2 from Candida cylindracea, lipase C1 from Candida cylindracea, lipase TL, IM, lipase TL 100L, candida antarctica lipase B, CHIRAZYME E-1 heparanase, lipase from Pseudomonas L-6, candida antarctica lipase A, rugosa lipase L-3 or pancreatic lipase, the biological enzyme B is preferably lipase TL or lipase PS-30 from Pseudomonas cepacia.
2. The method of claim 1, wherein: the acylating agent of the first method is selected from vinyl ester or isopropenyl ester, wherein the vinyl ester is selected from C substituted or unsubstituted by Rc 1 -C 12 Vinyl esters of straight-chain or branched acids, vinyl benzoate, C substituted or unsubstituted by Rc 3 -C 6 Linear or branched vinyl enoates; the isopropenyl ester is selected from C substituted or unsubstituted by Rc 1 -C 12 Isopropenyl esters of linear or branched acids, isopropenyl benzoate, C substituted or not by Rc 3 -C 6 Linear or branched isopropenyl alkenoates; the substituent Rc of each group is independently selected from C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight or branched alkoxy, hydroxy, amino, halogen, nitro, cyano, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, C 1 -C 6 Sulfanyl, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, phenyl or C 3 -C 18 A heterocyclic aromatic group, wherein hetero atoms on the heterocyclic aromatic group are selected from O, N or S;
the acylating agent is preferably vinyl acetate, isopropenyl acetate, vinyl propionate, isopropenyl propionate, vinyl butyrate, isopropenyl butyrate, vinyl isobutyrate, isopropenyl isobutyrate, vinyl 2-methylbutyrate, isopropenyl 2-methylbutyrate, vinyl 3-methylbutyrate, isopropenyl 3-methylbutyrate, vinyl pivalate, isopropenyl pivalate, vinyl 2-methylpentanoate, isopropenyl 2-methylpentanoate, vinyl 3-methylpentanoate, isopropenyl 3-methylpentanoate, vinyl 4-methylpentanoate, vinyl hexanoate, isopropenyl hexanoate, vinyl laurate, isopropenyl laurate, vinyl benzoate, isopropenyl benzoate, vinyl acrylate or isopropenyl acrylate, more preferably vinyl acetate, isopropenyl acetate, vinyl propionate, isopropenyl propionate, vinyl butyrate, isopropenyl butyrate, vinyl benzoate, isopropenyl benzoate, vinyl acrylate or isopropenyl acrylate.
3. The method of claim 1, wherein: the acylation reaction in the first method is carried out in an organic solvent A, wherein the organic solvent A is selected from one or any combination of alkane, aromatic hydrocarbon, chloroalkane, nitrile or ether solvents; the organic solvent A is preferably one or any combination of petroleum ether, diethyl ether, methyl tert-butyl ether, dichloromethane, n-hexane, cyclohexane, n-pentane, cyclopentane, n-heptane, toluene or acetonitrile; more preferably one or any combination of n-hexane and n-heptane;
and/or the mass-to-volume ratio of the compound 3A to the organic solvent A in the first method is 1g to 15mL, more preferably 1 g;
and/or the acylation reaction temperature in the first method is 30-80 ℃, preferably 55-60 ℃;
and/or the mass ratio of compound 3A to the biological enzyme a in the first method is 1;
and/or the molar ratio of compound 3A to the acylating agent in the first process is 1.
4. The method of claim 1, wherein: the hydrolysis reaction of the second method is carried out in water and an organic solvent B, wherein the organic solvent B is selected from one or any combination of alkane, aromatic hydrocarbon, chloroalkane, nitrile solvent or ether solvent; the organic solvent B is preferably selected from one or any combination of toluene, xylene, methyl tert-butyl ether or acetonitrile;
and/or the base is selected from organic base or inorganic base, the organic base is selected from one or any combination of diethylamine, triethylamine, diisopropylamine, morpholine, N-methylmorpholine, piperazine or N-methylpiperazine; the inorganic base is selected from one or any combination of alkali metal hydroxide, carbonate or bicarbonate or alkaline earth metal hydroxide; the alkali is preferably one or any combination of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, sodium bicarbonate or potassium carbonate; most preferably sodium carbonate or potassium carbonate, or any combination thereof;
and/or the mass ratio of the compound 3B to the biological enzyme B in the second method is 1;
and/or the molar ratio of compound 3B to the base in method two is 1;
and/or the mass-to-volume ratio of the compound 3B to the organic solvent B in the second method is 1g to 15mL, more preferably 1 g.
And/or the temperature of the hydrolysis reaction in the second method is 30-80 ℃, preferably 35-40 ℃.
5. The method according to claim 1, wherein the method for selectively separating a mixture of compound 4 and compound I comprises:
1) Separating the mixture of the compound 4 and the compound I by a column chromatography method to obtain a compound I; or
2) A, step a: under the action of a catalyst and an organic base, selectively carrying out esterification reaction on a compound I in a mixture of a compound 4 and the compound I and acid anhydride, and separating to obtain a compound 4 and a compound 5; step b: hydrolyzing said compound 5 to provide compound I having the formula:
wherein R is 1 Is C substituted or unsubstituted by Ra 1 -C 12 Straight or branched acyl, benzoyl, C substituted or unsubstituted by Ra 3 -C 6 Straight-chain or branched alkenoyl, the substituents Ra of each radical being independently selected from C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight or branched alkoxy, hydroxy, amino, halogen, nitro, cyano, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, C 1 -C 6 Sulfanyl, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, phenyl or C 3 -C 18 A heterocyclic aromatic group, wherein hetero atoms on the heterocyclic aromatic group are selected from O, N or S; r is 1 Preferably acetyl, propionyl, butyryl, isobutyryl, 2-methylbutyryl, 3-methylbutyryl, pivaloyl, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, hexanoyl, lauroyl, benzoyl or acryloyl; r 2 Is selected from
6. A process for the preparation of chiral compound I comprising the step of separating a mixture of compound 4 and compound I, said method of separation comprising:
3) Separating the mixture of the compound 4 and the compound I by a column chromatography method to obtain a compound I; or
4) A, step a: under the action of a catalyst and an organic base, selectively carrying out esterification reaction on a compound I in a mixture of a compound 4 and the compound I and an acid anhydride, and separating to obtain a compound 4 and a compound 5; step b: hydrolyzing said compound 5 to provide compound I having the following reaction formula:
wherein R is 1 Is C substituted or unsubstituted by Ra 1 -C 12 Straight or branched acyl, benzoyl, C substituted or unsubstituted by Ra 3 -C 6 Straight-chain or branched alkenoyl, the substituents Ra of each radical being independently selected from C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight or branched alkoxy, hydroxy, amino, halogen, nitro, cyano, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Sulfanyl, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, phenyl or C 3 -C 18 A heterocyclic aromatic group, wherein hetero atoms on the heterocyclic aromatic group are selected from O, N or S; r is 1 Preferably acetyl, propionyl, butyryl, isobutyryl, 2-methylbutyryl, 3-methylbutyryl, pivaloyl, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, hexanoyl, lauroyl, benzoyl or acryloyl; r 2 Is selected from
7. The method according to claim 5 or 6, characterized in that: the column chromatography method comprises the step of performing silica gel column chromatography separation by using petroleum ether and ethyl acetate as eluents in a volume ratio of 20-5.
8. The method according to claim 5 or 6, characterized in that: the catalyst in the step a is selected from 4-dimethylaminopyridine;
and/or the molar ratio of compound I to the catalyst in step a is 1;
and/or the organic base in the step a is selected from one or any combination of diethylamine, triethylamine, diisopropylamine, pyridine, alpha-picoline, 1, 2-lutidine, 4-hydroxy-2-picoline, gamma-collidine, quinoline or dimethylquinoline, preferably from one or any combination of triethylamine, diisopropylamine, pyridine or alpha-picoline;
and/or the molar ratio of compound I to the organic base in step a is 1; the temperature of the esterification reaction is 0-50 ℃, preferably 10-30 ℃;
and/or the acid anhydride in step a is selected from
The molar ratio of the compound I to the acid anhydride is 1 to 10, preferably 1 to 5, more preferably 1.1 to 1.8;
and/or the esterification reaction in the step a is carried out in a reaction solvent C, wherein the reaction solvent C is one or any combination of aromatic hydrocarbon, chloroalkane, nitrile solvent or ether solvent; the reaction solvent C is preferably selected from one or any combination of toluene, xylene, methyl tert-butyl ether or acetonitrile;
and/or the hydrolysis in step b is carried out in water and an organic solvent D selected from the reaction solvents C in step a, preferably the hydrolysis is carried out in water and acetonitrile; the reaction temperature is preferably room temperature;
and/or the hydrolysis in step b is carried out in an inorganic base selected from one or any combination of alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate or alkaline earth metal hydroxide; preferably selected from one or any combination of lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide; more preferably selected from sodium hydroxide or potassium hydroxide, or any combination thereof.
9. An intermediate compound having the structure:
preferably, when the chiral carbon is represented by S configuration, the structure is:
wherein R is 1 Is C substituted or unsubstituted by Ra 1 -C 12 Straight or branched acyl, C substituted or unsubstituted by Ra 3 -C 6 Straight-chain or branched alkenoyl, the substituents Ra of each radical being independently selected from C 1 -C 6 Straight or branched chainAlkyl radical, C 1 -C 6 Straight or branched alkoxy, hydroxy, amino, halogen, nitro, cyano, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Sulfanyl, C 1 -C 6 Amide group, C 3 -C 6 Cycloalkyl, phenyl or C 3 -C 18 A heterocyclic aromatic group, wherein hetero atoms on the heterocyclic aromatic group are selected from O, N or S; r 1 Preferably propionyl, butyryl, isobutyryl, 2-methylbutyryl, 3-methylbutyryl, pivaloyl, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, hexanoyl, lauroyl or acryloyl;
the intermediate compound is preferably the following compound:
when the chiral carbon is in R configuration, the structure is as follows:
wherein R is 2 Is selected from
The intermediate compound is preferably the following compound:
10. a method for preparing eribulin medicine is characterized by comprising the following steps: preparation of eribulin comprising the process of any one of claims 1-5 or the process of any one of claims 6-8 or using the intermediate compound of claim 9.
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| RU2710545C2 (en) * | 2013-11-04 | 2019-12-27 | Эйсай Ар Энд Ди Менеджмент Ко., Лтд. | Macrocyclization reactions and intermediate compounds and other fragments suitable for preparing analogues of halichondrin b |
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