CN111848369B - 艾日布林的中间体及其合成方法和用途 - Google Patents
艾日布林的中间体及其合成方法和用途 Download PDFInfo
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- CN111848369B CN111848369B CN201910346140.7A CN201910346140A CN111848369B CN 111848369 B CN111848369 B CN 111848369B CN 201910346140 A CN201910346140 A CN 201910346140A CN 111848369 B CN111848369 B CN 111848369B
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- 229960003649 eribulin Drugs 0.000 title claims abstract description 20
- 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 7
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 208
- 238000006243 chemical reaction Methods 0.000 claims abstract description 78
- 238000002360 preparation method Methods 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 30
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 239000012634 fragment Substances 0.000 claims abstract description 8
- -1 hydroxy, amino Chemical group 0.000 claims description 139
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 230000008569 process Effects 0.000 claims description 25
- 230000009471 action Effects 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- 239000007800 oxidant agent Substances 0.000 claims description 14
- 238000004440 column chromatography Methods 0.000 claims description 13
- 239000012046 mixed solvent Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 230000002378 acidificating effect Effects 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 239000012285 osmium tetroxide Substances 0.000 claims description 6
- 229910000489 osmium tetroxide Inorganic materials 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 6
- ZVQAVWAHRUNNPG-LMVFSUKVSA-N 2-deoxy-alpha-D-ribopyranose Chemical compound O[C@@H]1C[C@H](O)[C@H](O)CO1 ZVQAVWAHRUNNPG-LMVFSUKVSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 238000007142 ring opening reaction Methods 0.000 claims description 5
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 5
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 4
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 4
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 4
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 3
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 238000003541 multi-stage reaction Methods 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 125000005251 aryl acyl group Chemical group 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 238000005906 dihydroxylation reaction Methods 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 150000007530 organic bases Chemical group 0.000 claims description 2
- 150000002905 orthoesters Chemical class 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical class C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000005809 transesterification reaction Methods 0.000 claims description 2
- BQFPCTXLBRVFJL-UHFFFAOYSA-N triethoxymethylbenzene Chemical compound CCOC(OCC)(OCC)C1=CC=CC=C1 BQFPCTXLBRVFJL-UHFFFAOYSA-N 0.000 claims description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 2
- IECKAVQTURBPON-UHFFFAOYSA-N trimethoxymethylbenzene Chemical compound COC(OC)(OC)C1=CC=CC=C1 IECKAVQTURBPON-UHFFFAOYSA-N 0.000 claims description 2
- 238000012015 optical character recognition Methods 0.000 claims 2
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- DXOKBYGKGLTZMX-UHFFFAOYSA-N oxoosmium;potassium Chemical compound [K].[Os]=O DXOKBYGKGLTZMX-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 29
- 238000003786 synthesis reaction Methods 0.000 abstract description 29
- 230000003287 optical effect Effects 0.000 abstract description 12
- 238000000746 purification Methods 0.000 abstract description 10
- 239000000543 intermediate Substances 0.000 abstract description 7
- ZBLLGPUWGCOJNG-UHFFFAOYSA-N Halichondrin B Natural products CC1CC2(CC(C)C3OC4(CC5OC6C(CC5O4)OC7CC8OC9CCC%10OC(CC(C(C9)C8=C)C%11%12CC%13OC%14C(OC%15CCC(CC(=O)OC7C6C)OC%15C%14O%11)C%13O%12)CC%10=C)CC3O2)OC%16OC(CC1%16)C(O)CC(O)CO ZBLLGPUWGCOJNG-UHFFFAOYSA-N 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 5
- FXNFULJVOQMBCW-VZBLNRDYSA-N halichondrin b Chemical compound O([C@@H]1[C@@H](C)[C@@H]2O[C@@H]3C[C@@]4(O[C@H]5[C@@H](C)C[C@@]6(C[C@@H]([C@@H]7O[C@@H](C[C@@H]7O6)[C@@H](O)C[C@@H](O)CO)C)O[C@H]5C4)O[C@@H]3C[C@@H]2O[C@H]1C[C@@H]1C(=C)[C@H](C)C[C@@H](O1)CC[C@H]1C(=C)C[C@@H](O1)CC1)C(=O)C[C@H](O2)CC[C@H]3[C@H]2[C@H](O2)[C@@H]4O[C@@H]5C[C@@]21O[C@@H]5[C@@H]4O3 FXNFULJVOQMBCW-VZBLNRDYSA-N 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 238000001953 recrystallisation Methods 0.000 abstract description 4
- 229930195695 Halichondrin Natural products 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 22
- 125000004432 carbon atom Chemical group C* 0.000 description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 16
- 125000001072 heteroaryl group Chemical group 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- 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 14
- 239000007787 solid Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 12
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 125000003342 alkenyl group Chemical group 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 9
- 125000002619 bicyclic group Chemical group 0.000 description 9
- 150000002430 hydrocarbons Chemical class 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- 238000010791 quenching Methods 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 6
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
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Abstract
本发明属于药物合成领域,具体涉及艾日布林的中间体及其合成方法和用途。本发明提供了可用于合成软海绵素B、艾日布林或其类似物,特别是其C27‑C35结构片段的中间体、其制备方法和用途。本发明的合成路线的起始原料廉价易得,其光学纯度可以得到保障,从而保证了软海绵素、艾日布林或其类似物中C27‑C35结构片段的光学纯度;构建C27‑C35结构片段手性中心的步骤方法,具有较高的非对映选择性和产率,尤其是式(X)、式(XI)、式(XVI)和式(XV)所示化合物的制备方法;部分反应的副产物仅需重结晶即可除去,便于纯化,大大降低了成本。
Description
技术领域
本发明属于药物合成领域,具体涉及艾日布林的中间体及其合成方法和用途。
背景技术
软海绵素B(Halichondrin B)是一种存在于海绵体内的复杂结构天然产物,具有强烈的抗肿瘤作用和广阔的药用前景。然而由于天然来源的软海绵素B供应量有限,其研发进展也受到了限制。
艾日布林(Eribulin)是由软海绵素B经结构优化得到的一种大环酮类似物。甲磺酸艾日布林注射剂已获美国FDA批准用于治疗转移性乳腺癌。
艾日布林结构复杂,其分子中含有19个手性碳原子,目前使用的全合成路线长达62步,且其全合成过程中的立体控制是一项技术难题,甚至有业内人士称其为化学药物合成界的“珠穆朗玛峰”。
现有的艾日布林、或其类似物的合成方法存在诸多缺陷。例如,合成路线过于冗长,起始原料光学纯度难以控制,而且中间体纯化复杂,成本高。此外,上述合成方法中使用的某些反应还存在立体选择性不佳的缺点,加之产品分子中手性碳原子众多,合成过程中极易形成性质相近、难以除去的异构体,不利于保证产品的纯度。
因此,亟需开发一条既可改善合成效率,又可提高立体选择性,同时纯化操作更为简便的艾日布林、或其类似物的中间体的合成方法。
发明内容
为了改善上述问题,本发明提供下式(Ⅸ)化合物:
其中,PG1、PG2相同或不同,彼此独立地选自羟基保护基。
其手性中心绝对构型为(2R,3S)。
根据本发明的实施方案,所述羟基保护基可以选自取代或未取代的下列基团:烷基、烯基、环烷基、芳基、杂芳基、杂环基、酰基、磺酰基、烷基氧基羰基、芳基烷基氧基羰基、由无机酸通过除去OH基团得到的基团、硫膦基、硅烷基。
根据本发明的实施方案,PG1、PG2相同或不同,彼此独立地选自取代或未取代的烷基、烯基、环烷基、芳基、杂芳基、杂环基、硅烷基;
作为实例,可以选自甲氧基苄基(PMB)、苄基(Bn)、三苯基甲基(Tr)、三甲基硅基(TMS)、叔丁基二苯基硅基(TBDPS)、叔丁基二甲基硅基(TBS)。
本发明还提供式(Ⅸ)化合物的制备方法,包括如下步骤:以D-2-脱氧核糖(I)为原料,经氧化、羟基保护、还原开环、脱除羟基保护等多步反应,得到式(Ⅸ)化合物。
根据本发明的实施方案,式(Ⅸ)化合物可以D-2-脱氧核糖(I)为原料通过下列路线制备:
其中,PG1、PG2具有上文所述的定义;
PG3独立地选自上文所述的羟基保护基;
每一个X相同或不同,独立地选自卤素。
优选地,式(II)化合物由式(I)化合物经液溴氧化反应得到;
式(III)化合物由式(II)化合物与TrX在DMAP、吡啶的作用下发生取代反应得到;
式(IV)化合物由式(III)化合物与PG3X在DMAP、咪唑的作用下反应得到;
式(V)化合物由式(IV)化合物在BX3作用下低温脱除Tr得到;
式(VII)化合物由式(VI)化合物在硼烷二甲硫醚作用下还原开环得到;
式(IX)化合物由式(VIII)化合物在TBAF作用下脱除PG3得到;
其中,PG1、PG2、PG3、X具有上文所述的定义。
据本发明的实施方案,所述的碱可以选自有机碱或无机碱,例如选自下列中的一种、两种或更多种:碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化锂、烷基锂、甲醇钠、乙醇钠、甲胺、乙胺、丙胺、异丙胺、二甲胺、二乙胺、二异丙胺、三乙胺;
X可以选自氟、氯、溴、碘,例如氯或溴。
鉴于市售D-2-脱氧核糖(I)价格低廉,且光学纯度可达100%,根据本发明的实施方案,式(Ⅸ)化合物的光学纯度可达99.9%以上。
本发明还提供以式(Ⅸ)化合物为原料的下式(X)化合物的制备方法,包括如下步骤:
(3)式(Ⅸb-1)化合物和/或式(Ⅸb-2)化合物在碱性条件下醇解并进一步发生分子内SN2关环反应,得到式(X)化合物;
其中,PG1、PG2和每一个X独立地具有上文所述的定义;
R1、R2、R3相同或不同,彼此独立地选自H、烷基或芳基;
R6选自烷基。
根据本发明的实施方案,其中:
步骤(1)中,反应可在催化剂,优选酸性催化剂的存在下进行。所述酸性催化剂可以选自适用于酯交换的酸性催化剂,例如选自吡啶对甲苯磺酸盐(PPTs)或质子酸(如硫酸、磷酸、氯化氢)中的一种、两种或更多种;
反应温度可以为10℃~40℃,例如可以为20℃~30℃;反应时间可以为0.5~2h,例如1h;
式(IX)化合物与的摩尔比可以为1:(1~5),例如1:(1~3),例如1:(1.2~1.8),如1:1.5;当催化剂存在时,式(IX)化合物与催化剂的摩尔比可以为1:(0.01~0.2),例如1:(0.01~0.1),如1:0.05;
步骤(2)中,反应温度可以为10℃~40℃,例如20℃~30℃;反应时间可以为0.1~2h,例如0.5h;
步骤(3)中,反应可在碱的存在下进行;反应温度可以为10℃~40℃,例如20℃~30℃;反应时间可以为5~15h,例如8~12h;
式(Ⅸb-1)化合物和/或式(Ⅸb-2)化合物与碱的摩尔比可以为1:(1~10),例如1:(1~5),例如1:(1.5~2.5),如1:2。
根据本发明的实施方案,步骤(3)可以在溶剂中进行,所述溶剂例如为醇类溶剂(如甲醇、乙醇、异丙醇、乙二醇)、水或其混合物;例如,式(IX)化合物与所述溶剂的重量体积比可以为1g:(1~20)mL,例如可以为1g:10mL。
上述制备方法可以保证式(Ⅸ)化合物至式(X)化合物的转化过程中,两个手性中心的绝对构型均保持不变,从而保证了式(X)化合物的光学纯度与式(Ⅸ)化合物的光学纯度之间的相关性,即以高纯度式(Ⅸ)化合物为原料制得的式(X)化合物也具有相应的高纯度。
本发明还提供下式(XI)化合物:
其中,PG1、PG2具有上文所述的定义;
R7为氢或端炔保护基。保护基可选自硅烷基,例如三烷基硅基(如三甲基硅基、三乙基硅基、三异丙基硅基)、叔丁基二苯基硅基、叔丁基二甲基硅基、三苄基硅基和三苯基硅基。
式(XI)化合物的制备方法,包括式(X)化合物与R7-C≡CH在强碱,如烷基锂或烷基格氏试剂,的存在下反应,得到式(XI)所示化合物。
其中,PG1、PG2、R7具有上文所述的定义。
根据本发明的实施方案,所述反应可以在催化剂的存在下进行。例如,所述催化剂可以选自路易斯酸,例如三氟化硼或其络合物,例如三氟化硼或三氟化硼甲醇络合物、三氟化硼乙醚络合物、三氟化硼乙腈络合物、三氟化硼四氢呋喃络合物、三氟化硼乙胺络合物中的一种、两种或更多种;
根据本发明的实施方案,所述式(X)化合物与R7-C≡CH的摩尔比可以为1:(1~10),例如1:(1~5),如1:(1.5~3),如1:2;所述式(X)化合物与烷基锂的摩尔比可以为1:(1~10),例如1:(1~5),如1:(1.5~3),如1:2;所述式(X)化合物与催化剂的摩尔比可以为1:(1~10),例如1:(1~5),如1:(1.5~3),如1:2;
根据本实施方案,所述强碱可以为烷基锂,例如甲基锂、乙基锂、丙基锂、异丙基锂、正丁基锂、仲丁基锂、叔丁基锂、戊基锂、己基锂中的一种、两种或更多种;或烷基格氏试剂,如甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、己基、苯基等格氏试剂中的一种、两种或更多种,其中格氏试剂所含卤素可以是氯、溴或者碘。
根据本发明的实施方案,所述反应可以在有机溶剂的存在下进行。所述有机溶剂可以是惰性有机溶剂,其可选自在反应条件下呈惰性,特别是不与原料和产品发生化学反应的有机溶剂,包括例如选自下列的一种、两种或多种的混合物:碳氢化合物类溶剂,例如苯、甲苯、二甲苯、己烷和环己烷;卤代烃类溶剂,例如二氯甲烷、三氯甲烷、1,2-二氯乙烷和氯苯;或者其它溶剂,例如N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、乙腈或者吡啶;醚类溶剂,例如乙醚、四氢呋喃等。根据本发明的实施方案,反应温度可以为-80℃~0℃,例如-60℃~-30℃;反应时间可以为0.5~5h,例如1~3h。
根据本发明的实施方案,在上述式(XI)化合物的制备方法中,产品还包含下式(XIa)化合物:
根据本发明的实施方案,在上述式(XI)化合物的制备方法的产品中,除式(XIa)化合物外,式(XI)化合物的其他异构体的含量≤0.1%。
根据本发明的一个实施方案,上述式(XI)化合物的制备方法中,还包括色谱方式(如柱色谱)分离XI和XIa化合物的步骤。
根据示例性的实施方案,所述柱色谱的填充介质可以为硅胶;
所述柱色谱的洗脱剂可以为石油醚和乙酸乙酯的混合物,所述混合物的体积比可以为(5~20):1,如10:1。
优选地,经色谱分离后,上述式(XI)化合物的制备方法的产品中式(XIa)化合物的含量≤0.1%。
本发明还提供下式(XI)、(XII)、(XIII)、(XIV)、(XV)或(XVI)所示的化合物:
其中,PG1、PG2、R7具有上文所述定义;
PG4、PG5相同或不同,彼此独立地选自上文所述的羟基保护基;
条件是PG4和PG5中的任一个与PG1或PG2均不相同,且PG1和PG2在脱除PG4和PG5的条件下不发生反应。
根据本发明的实施方案,PG4、PG5相同或不同,彼此独立地选自硅烷基;例如,PG4、PG5相同或不同,彼此独立地选自三烷基硅基(如三甲基硅基、三乙基硅基、三异丙基硅基)、叔丁基二苯基硅基、叔丁基二甲基硅基、三苄基硅基和三苯基硅基,而PG1和PG2相同或不同,彼此独立地选自除硅烷基以外的羟基保护基,例如烷基、烯基、环烷基、芳基、杂芳基、杂环基、四氢吡喃基、酰基、磺酰基、烷基氧基羰基、芳基烷基氧基羰基、由无机酸通过除去OH基团得到的基团、硫膦基。
本发明还提供下式(XVI)化合物的制备方法,包括如下步骤:将式(XIII)化合物与式(XIV)化合物发生环氧开环反应得到式(XV)所示化合物,再将式(XV)所示化合物在脱除PG4和PG5的条件下反应,得到式(XVI)化合物:
其中,PG1、PG2、PG4、PG5具有上文所述定义。
优选地,所述式(XIII)化合物与式(XIV)化合物的反应在正丁基锂与BF3Et2O的存在下进行。
根据本发明示例性的实施方案,所述脱除PG4和PG5的条件可以选自本领域已知的脱除该类羟基保护基的条件下进行,例如硅烷基的脱除可以在酸性条件下(如含HCl的有机溶剂体系、醋酸和四氢呋喃的体系,三氟乙酸,氟化氢和吡啶的体系,氟化钾和乙腈的体系等)或氟化铵类化合物(如四甲基氟化铵,四乙基氟化铵,四丁基氟化铵)的存在下进行。
根据本发明优选的实施方案,当所使用的式(XIV)化合物的对映体纯度低于99.9%时,可在得到式(XVI)化合物粗品后,通过重结晶对其进行纯化,使其中所含下式(XVIa)化合物的含量≤0.1%。
根据本发明的实施方案,所述重结晶的操作包括:将含有式(XVIa)化合物的式(XVI)化合物粗品溶于良溶剂中,加热溶解后加入不良溶剂,冷却,得到纯化后的式(XVI)化合物。
根据本发明示例性的实施方案,所述良溶剂可以为甲醇、异丙醇、乙醇、乙腈、乙酸乙酯、四氢呋喃、甲基叔丁基醚、异丙醚、氯仿、丙酮、二氧六环中的任一种;所述不良溶剂可以为石油醚、正辛烷、环己烷、正己烷、庚烷、苯、甲苯中的任一种;所述式(XVI)化合物粗品与良溶剂、不良溶剂的重量体积比可以为1g:(1~5)mL:(1~5)mL,例如1g:(1~2)mL:(1~2)mL;
根据需要,所述重结晶操作可重复多次,例如可以重复1~3次。
根据本发明示例性的实施方案,式(XIII)所示化合物可通过下列步骤中的一个或多个制备:
其中,PG1、PG2、PG5、R7具有上文所述定义,L为离去基团,例如OTS,OMS,OTf,Cl,Br,I等。
本发明还提供下式(XIX)所示化合物及其制备方法:
其中,PG1、PG2具有上文所述定义;
PG6独立地选自取代或未取代的芳香酰基,如取代或未取代的苯甲酰基、萘甲酰基。
PG7为邻二羟基保护基。
所述邻二羟基保护基与其结合的氧形成:环缩醛和缩酮;环亚甲硅基衍生物;环碳酸酯和环硼酸酯。缩醛指-CHR-;缩酮是指-CR2-;环碳酸酯是指-OC(O)O-;环硼酸酯是指OBRO-;其中R为H,烷基、烯基、芳基、或芳烷基。
根据本发明的实施方案,所述邻二羟基保护基可以选自取代或未取代的下列基团:亚烷基、亚环烷基、亚硅烷基、酰基。例如可以为取代或未取代的亚甲基、亚乙基、亚异丙基、亚环己基、亚环戊基、苯基亚甲基、二苯基亚甲基、对甲氧基苯基亚甲基、2,4,6-三甲基苯基亚甲基、二叔丁基亚硅烷基、1,1,3,3-四异丙基硅氧烷基,碳酰基等。
根据本发明的一个实施方案,式(XIX)所示化合物可通过下列步骤制备:
其中,PG1、PG2、PG6具有上文所述定义,
PG7选自取代或未取代的亚烷基,例如二烷基取代的亚甲基,如二乙基取代的亚甲基。
式(XVIII)化合物由式(XVII)化合物在Lindlar催化剂作用下加氢还原得到;
式(XIX)化合物由式(XVIII)化合物与PG6X在DMAP、吡啶的作用下反应得到;
其中,PG6、PG7、X具有上文所述定义。
本发明还提供式(XX)化合物:
其中,PG1、PG2、PG6、PG7具有上文所述定义。
本发明还提供式(XX)化合物的制备方法,包括将式(XIX)化合物在氧化剂的作用下进行双羟化氧化反应,得到式(XX)化合物:
其中,PG1、PG2、PG6、PG7具有上文所述定义。
根据本发明的实施方案,所述氧化剂可以选自高锰酸钾、高碘酸钠、过氧化氢、铁氰化钾、N-甲基-N-氧化吗啉(NMO)中的一种或多种。
根据本发明的实施方案,所述反应中可根据需要加入共氧化剂,所述共氧化剂可以为四氧化锇、锇酸钾中的任一种。
根据本发明的实施方案,所述反应可在碱的催化作用下进行,所述碱可以为1,4-二氮杂二环[2.2.2]辛烷(DABCO)、三乙胺、N,N-二异丙基乙胺中的一种或多种。
根据本发明的实施方案,所述式(XIX)化合物与氧化剂的摩尔比为1:(1~5),优选为1:(1~3);所述式(XIX)化合物与所述共氧化剂的摩尔比为1:(0.005~0.15),优选为1:(0.005~0.1);所述式(XIX)化合物与所述碱的摩尔比为1:(0.4~2),优选为1:(0.5~1.5)。
根据本发明的实施方案,所述反应可以在混合溶剂下进行,所述混合溶剂可以为有机溶剂与水的混合物,例如选自下列体系中的一种:叔丁醇/水、丙酮/水、乙腈/水;所述混合溶剂中,有机溶剂与水的体积比可以为(1:5)~(5:1),例如(2~2.5):(2.5~2);
根据本发明的实施方案,所述式(XIX)化合物的重量与混合溶剂总体积的比可以为1g:(2~50mL),例如1g:4mL,1g:22.2mL;
根据本发明的实施方案,所述反应温度为-10℃~50℃,例如可以为35℃~45℃;反应时间可以为10~60h,例如可以为24h。
根据本发明优选的实施方案,鉴于采用了与现有技术不同的PG6,通过对反应时间、反应温度以及反应溶剂的优化,大幅提高了反应的立体选择性。所述反应得到的产物中,目标产物式(XX)化合物的含量可高于95%,副产物式(XXa)化合物的含量低于5%。相应的利用现有技术(PG6为乙酰基时),目标产物式(XX)化合物含量低于85%。本发明使用的技术明显降低了产物中副产物的比例,显著降低了式(XX)化合物及其后续衍生产物,如式(XXIIIa)所示化合物的分离难度。
本发明还提供下式(XXIII)化合物的制备方法,包括上述式(IX)、式(X)、式(XI)、式(XVI)、式(XX)化合物的制备方法中的一种、两种或更多种:
其中,PG1、PG2、PG7具有上文所述的定义。
优选地,所述式(XXIII)化合物的制备方法还包括柱层析分离得到的产品。
优选地,所述式(XXIII)化合物的制备方法中,柱层析分离后得到的产品中,下式所示化合物(XXIIIa)的含量≤0.1%。
其中,PG1、PG2、PG7具有上文所述的定义。
作为实例,本发明还提供下式23化合物的制备方法,包括下列步骤中的至少一种:
优选地,式2化合物由式1化合物经液溴氧化反应得到;
式3化合物由式2化合物与TrX在DMAP、吡啶的作用下发生取代反应得到;
式4化合物由式3化合物与TBDPSX在DMAP、咪唑的作用下反应得到;
式5化合物由式4化合物在BX3作用下低温脱除Tr得到;
式7化合物由式6化合物在硼烷二甲硫醚作用下开环得到;
式9化合物由式8化合物在TBAF作用下脱除TBDPS得到;
式13化合物与式14化合物的反应在正丁基锂与BF3Et2O的存在下进行;
式18化合物由式17化合物在Lindlar催化剂作用下加氢还原得到;
式19化合物由式18化合物与BzX在DMAP、吡啶的作用下反应得到;
式21化合物由式20化合物与MsX在DMAP、碱的作用下反应得到;
式22化合物由式21化合物在碱的作用下发生关环反应得到;
式23化合物由式22化合物在烷基格氏试剂作用下脱除Ms保护基得到;
其中,每一个X相同或不同,彼此独立地选自卤素。
本发明还提供一种制备艾日布林、其类似物或它们的C27-C35部分的方法,包括使用上述式(I)至(XXIII)中的任一化合物,和/或使用上述一种或多种制备方法。
本发明还提供上述式(I)至(XIII)中的任一种化合物在制备艾日布林、其类似物或它们的C27-C35部分中的用途。
术语和定义
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当属于本申请说明书记载的范围内。
除非另有说明,本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如,数值范围“1-40”应被理解为至少记载了数值范围“1-10”中的每一个整数数值即1、2、3、4、5、6、7、8、9、10,以及数值范围“11-40”中的每一个整数数值即11、12、13、14、15、......、35、36、37、38、39、40。
如果可能,当某些数值范围被定义为“数”时,应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如,“0~10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数,还至少记载了其中每一个整数分别独立地与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8或0.9的加和。
应当理解,本文在描述一个、两个或更多个时,“更多个”应当是指≥3的整数,例如3、4、5、6、7、8、9或10。
术语“烷基”应理解为优选表示具有1~40个碳原子的直连或支链饱和一价烃基,优选为C1-10烷基。“C1-10烷基”应理解为优选表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直连或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地,所述基团具有1、2、3、4、5、6个碳原子(“C1-6烷基”),例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基,更特别地,所述基团具有1、2或3个碳原子(“C1-3烷基”),例如甲基、乙基、正丙基或异丙基。
术语“烯基”应理解为优选表示直连或支链的一价烃基,其包含一个或多个双键并且具有2~40个碳原子,优选“C2-6烯基”。“C2-6烯基”应理解为优选表示直连或支链的一价烃基,其包含一个或多个双键并且具有2、3、4、5或6个碳原子,特别是2或3个碳原子(“C2-3烯基”),应理解,在所述烯基包含多于一个双键的情况下,所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“环烷基”应理解为优选表示饱和或不饱和的的一价单环、双环烃环或桥环烷烃,其具有3~40个碳原子,优选“C3-10环烷基”。术语“C3-10环烷基”应理解为表示饱和的一价单环、双环烃环或桥环烷烃,其具有3、4、5、6、7、8、9或10个碳原子。所述C3-10环烷基可以是单环烃基,如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基,或者是双环烃基如十氢化萘环。
术语“杂环基”应理解为优选表示饱和或不饱和的的一价单环、双环烃环或桥环烷烃,其包含1-5个独立选自N、O和S的杂原子的总成环原子数为3-20(如原子数为3、4、5、6、7、8、9、10等)的非芳族环状基团,优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的一价单环、双环烃环或桥环烷烃,其包含1-5个,优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地,所述杂环基可以包括但不限于:4元环,如氮杂环丁烷基、氧杂环丁烷基;5元环,如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基;或6元环,如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基;或7元环,如二氮杂环庚烷基。任选地,所述杂环基可以是苯并稠合的。所述杂环基可以是双环的,例如但不限于5,5元环,如六氢环戊并[c]吡咯-2(1H)-基环,或者5,6元双环,如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的,即它可以包含一个或多个双键,例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢恶唑基或4H-[1,4]噻嗪基,或者,它可以是苯并稠合的,例如但不限于二氢异喹啉基。根据本发明,所述杂环基是无芳香性的。
术语“芳基”应理解为优选表示具有6~20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环,优选“C6-14芳基”。术语“C6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-14芳基”),特别是具有6个碳原子的环(“C6芳基”),例如苯基;或联苯基,或者是具有9个碳原子的环(“C9芳基”),例如茚满基或茚基,或者是具有10个碳原子的环(“C10芳基”),例如四氢化萘基、二氢萘基或萘基,或者是具有13个碳原子的环(“C13芳基”),例如芴基,或者是具有14个碳原子的环(“C14芳基”),例如蒽基。当所述C6-20芳基被取代时,其可以为单取代或者多取代。并且,对其取代位点没有限制,例如可以为邻位、对位或间位取代。
术语“杂芳基”应理解为优选包括这样的一价单环、双环或三环芳族环系:其具有5~20个环原子且包含1-5个独立选自N、O和S的杂原子,例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5、6、7、8、9、10、11、12、13或14个环原子,特别是5或6或9或10个碳原子,且其包含1-5个,优选1-3各独立选自N、O和S的杂原子并且,另外在每一种情况下可为苯并稠合的。特别地,杂芳基选自噻吩基、呋喃基、吡咯基、恶唑基、噻唑基、咪唑基、吡唑基、异恶唑基、异噻唑基、恶二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物,例如苯并呋喃基、苯并噻吩基、苯并恶唑基、苯并异恶唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等,以及它们的苯并衍生物,例如喹啉基、喹唑啉基、异喹啉基等;或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩恶嗪基等。当所述5-20元杂芳基与其它基团相连构成本发明的化合物时,可以为5-20元杂芳基环上的碳原子与其它基团相连,也可以为5-20元杂芳基环上的杂原子与其它基团相连。当所述5-20元杂芳基被取代时,其可以为单取代或者多取代。并且,对其取代位点没有限制,例如可以为杂芳基环上与碳原子相连的氢被取代,或者杂芳基环上与杂原子相连的氢被取代。
除非另有说明,杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式,例如其位置异构体。因此,对于一些说明性的非限制性实例,可以包括在其1-、2-、3-、4-、5-、6-、7-、8-、9-、10-、11-、12-位等(如果存在)中的一个、两个或更多个位置上取代或与其他基团键合的形式,包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基;噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基;吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基。
上述的烷基、烯基、环烷基、杂环基、芳基、杂芳基可被以下基团取代:卤素、羟基、氨基(取代或未取代的氨基,例如-N(C1-6烷基)2、-NHC1-6烷基)、硝基、氰基、羧基、叠氮基、烷基、烷氧基、环烷基、酰基、芳基、杂芳基。
术语“卤素”表示氟、氯、溴和碘。
除非另有说明,本文中术语的定义同样适用于包含该术语的基团,例如C1-6烷基的定义也适用于C1-6烷基氧基、-N(C1-6烷基)2、-NHC1-6烷基或-S(O)2-C1-6烷基等。
本发明所述的“羟基保护基”意指在合成过程中引入的保护羟基的基团,目的是避免羟基在反应性条件下发生不期望的化学反应,并且该羟基保护基将在随后的合成步骤中除去,以使羟基恢复。示例性的羟基保护基包括但不限于下列基团:
取代或未取代的烷基,例如:甲基、叔丁基和其它C1-C6烷基;甲氧基甲基、甲硫基甲基、苄氧基甲基、叔丁氧基甲基、2-甲氧基乙氧基甲基、2,2,2-三氯乙氧基甲基、双(2-氯乙氧基)甲基和2-(三甲基甲硅烷基)乙氧基甲基;1-乙氧基乙基、1-甲基-1-甲氧基乙基、1-异丙氧基乙基、2,2,2-三氯乙基和2-甲氧基乙基;1-羟基烷基,如1-羟基乙基、1-羟基己基、1-羟基癸基、1-羟基十六烷基和1-羟基-1-苯基甲基;取代或未取代的芳基烷基,例如苄基、甲氧基苄基、2,6-二氯苄基、3-溴苄基、2-硝基苄基和三苯基甲基;取代或未取代的杂芳基烷基;取代或未取代的杂环基烷基;
取代或未取代的烯基,例如烯丙基;
取代或未取代的环烷基,例如环己基;
取代或未取代的芳基,例如苯基、2,4-二硝基苯基;
取代或未取代的杂芳基;
取代或未取代的杂环基;
取代或未取代的四氢吡喃基、取代或未取代的四氢呋喃基,和其它能够与羟基形成缩醛基或半缩醛基的基团;
取代或未取代的酰基,例如甲酰基、取代或未取代的烷基羰基,如甲基羰基、乙基羰基、丙基羰基、丁基羰基、异丁基羰基、戊基羰基、新戊基羰基、己基羰基、庚基羰基、辛基羰基、癸基羰基、壬基羰基、十二烷基羰基、十四烷基羰基、十六烷基羰基、十八烷基羰基和其它取代或未取代的烷基羰基;乙酰乙酰基;取代或未取代的环烷基羰基,如环戊基羰基、环己基羰基;取代或未取代的芳基酰基,如苯甲酰基、萘甲酰基;取代或未取代的氨基甲酰基,如氨基甲酰基、甲基氨基甲酰基和苯基氨基甲酰基;
取代或未取代的磺酰基,例如甲磺酰基、乙磺酰基、三氟甲磺酰基、苯磺酰基、对甲苯磺酰基和萘磺酰基;
取代或未取代的烷基氧基羰基,例如甲氧基羰基、乙氧基羰基、叔丁氧基羰基和其它C1-C6烷氧基羰基;
取代或未取代的芳基烷基氧基羰基,例如苄基氧基羰基和对甲氧基苄基氧基羰基;
由无机酸(例如硫酸、硝酸、磷酸和硼酸)通过除去OH基团得到的基团;
硫膦基,例如二烷基硫膦基(例如二甲基硫膦基)、二芳基硫膦基(例如二苯基硫膦基);
硅烷基,其中烷基的定义同前。例如三烷基硅基(如三甲基硅基、三乙基硅基、三异丙基硅基)、叔丁基二苯基硅基、叔丁基二甲基硅基、三苄基硅基和三苯基硅基。
本发明的“羟基保护基”与之结合的氧原子可形成如下的具体实例:甲酸酯、苯甲酰甲酸酯、氯乙酸酯、三氟乙酸酯、甲氧基乙酸酯、三苯基甲氧基乙酸酯、对氯苯氧乙酸酯、3-苯基丙酸酯、4-氧代无酸酯、4,4-(亚乙基二硫代)戊酸酯、新戊酸酯(三甲基乙酰基)、巴豆酸酯、4-甲氧基巴豆酸酯、苯甲酸酯、对苄基苯甲酸酯、2,4,6-三甲基苯甲酸酯;或者是下述基团的碳酸酯:甲基、9-芴基甲基、乙基、2,2,2-三氯乙基、2-(三甲基甲硅烷基)乙基、2-(苯磺酰)乙基、乙烯基、丙烯基、对硝基苯基;下述的甲硅烷基醚:三甲基甲硅烷基醚、三乙基甲硅烷基醚、叔丁基二甲基甲硅烷基醚、叔丁基二苯基甲硅烷基醚、三异丙基甲硅烷基醚;家属的烷基醚:甲基醚、苄基醚、对甲氧基苄基醚、3,4-二甲氧基苄基醚、三苯甲基醚、叔丁基醚、烯丙基醚、烯丙氧羰基醚;下述的烷氧基烷基醚:甲氧基甲基醚、甲硫基甲基醚、(2-甲氧基乙氧基)甲基醚、苄氧基甲基醚、β-(三甲基甲硅烷基)乙氧基甲基醚、四氢吡喃基醚;如下的芳基烷基醚:苄基醚、2,6-二氯苄基醚、对氰基苄基醚、2-和4-吡啶甲基醚。
本发明所述的“邻二羟基保护基”意指在合成过程中引入的保护邻二羟基的基团,目的是避免邻二羟基在反应性条件下发生不期望的化学反应,并且该邻二羟基保护基将在随后的合成步骤中除去,以使邻二羟基恢复。所述二羟基保护基与其结合的氧形成环缩醛和缩酮;环亚甲硅基衍生物;环碳酸酯和环硼酸酯。缩醛指-CHR-;缩酮是指-CR2-;环碳酸酯是指-OC(O)O-;环硼酸酯是指OBRO-;其中R为H,烷基、烯基、芳基、或芳烷基;示例性的邻二羟基保护基包括但不限于取代或未取代的下列基团例如亚烷基(如亚甲基、亚乙基、亚异丙基、苯基亚甲基、二苯基亚甲基、对甲氧基苯基亚甲基、2,4,6-三甲基苯基亚甲基);亚环烷基(如亚环己基、亚环戊基)、二(C1-6烷基)亚硅烷基(如二叔丁基亚硅烷基、1,1,3,3-四异丙基硅氧烷基)、甲基硼酸酯、乙基硼酸酯、苯基硼酸酯、2,6-二乙酰氨基苯基硼酸酯。
除非另有说明,本发明中的溶剂优选为无水溶剂。
本发明的有益效果:
本发明提供了可用于合成艾日布林或其类似物,特别是其C27-C35结构片段的中间体、其制备方法和用途。本发明合成路线的设计,改变了现有技术已有方法的原料和路线步骤,因其起始原料廉价易得,光学纯度可控,构建手性中心的步骤方法具有较高的非对映选择性和产率(尤其是式(X)、式(XI)、式(XVI)和式(XV)所示化合物的合成步骤),从而保证了艾日布林或其类似物中C27-C35结构片段终产物的光学纯度,其杂质种类少,所有立体异构体杂质含量可控制在千分之一以下,满足原料药相关杂质控制指导原则的界限,减少了后续杂质研究和纯化的步骤;多步反应不需要柱层析纯化即可投入下一步,从而降低了纯化成本;部分反应只需简单后处理后,进行重结晶即可除去副产物以及部分异构体,使其纯度高于99.9%,不仅简化了纯化步骤,而且对终产物的光学纯度也有了保证,大大降低了杂质合成以及分离纯化的成本。
附图说明
图1为化合物16的HPLC谱图。
图2为化合物23的HPLC谱图。
具体实施方式
下文将结合具体实施例对本发明的制备方法做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
下述实施例中所使用的实验方法如无特殊说明,均为常规方法;下述实施例中所用的试剂、材料等,如无特殊说明,均可从商业途径得到。
实施例1化合物9的合成
1.1化合物4的合成
将脱氧核糖1(100g)溶于水(400mL)中,降温至5℃左右,经3h慢慢滴加液溴(200g),滴毕升至30℃反应24h(点板检测原料消失)。后处理:1)加乙酸乙酯(100mL×2)提取,有机相在下层,第三次加乙酸乙酯(50mL)提取,有机相在上层;2)合并有机相,用水(50mL×2)提取其中所含产物;3)合并水相,用饱和硫代硫酸钠中和溴素(用量很少),然后又降温至0℃,调节溶液的pH至3左右(固体NaOH用量约61g),硅藻土过滤;4)滤液浓缩至含少量固体的粘稠液体时加异丙醇(200mL),搅拌加热至80℃,趁热过滤,固体用异丙醇(100mL)洗,滤液浓缩,残留物加异丙醇(100mL)溶解,过滤,固体用异丙醇(40mL)洗,滤液浓缩,残留物加入丙酮(100mL)溶解,过滤,固体用丙酮(100mL×2)加热至80℃提取,合并滤液,蒸干得化合物2粗品为油状物(含少量固体)约95g。
将化合物2粗品(44g)溶于吡啶(200mL)中,加入三苯甲基氯(88g),4-二甲氨基吡啶即DMAP(4.5g),加热至50℃反应过夜。后处理:减压蒸除吡啶,加入二氯甲烷即DCM(500mL),加入1N盐酸(300+200mL)分液,饱和碳酸氢钠(200mL)洗,每次水相用DCM(100mL)提取,合并有机相,干燥,过滤,浓缩直接下一步。
将化合物3的粗品溶于DCM(400mL)中,然后加入咪唑(29g),DMAP(4.5g),降温至0℃,慢慢滴加叔丁基二苯基氯硅烷(TBDPSCl,77mL),滴毕升至室温反应2-6h。后处理:加水(300mL×2),分液,每次用二氯甲烷(100mL)提取,合并有机相,干燥,浓缩,加甲醇(150mL×2)浓缩带两遍,最后加甲醇(300mL),正己烷(100mL),减压浓缩至200-300mL左右,搅拌降温至10℃左右溶液析出白色固体,过滤,固体用少量冷甲醇洗涤。取出固体,减压蒸除残留的溶剂可得产物化合物4约136g。1H NMR(500MHz,CDCl3)δ7.58–7.25(m,25H),4.41(d,J=3.5Hz,1H),4.37(d,J=6.4Hz,1H),3.32(dd,J=10.6,3.2Hz,1H),2.88(dd,J=17.8,6.6Hz,1H),2.70(dd,J=10.7,3.0Hz,1H),2.55(dd,J=17.8,1.8Hz,1H),1.07(s,9H).
1.2化合物7的合成
将化合物4(286g)溶于二氯甲烷中,降温至-20℃,经1h慢慢滴加三氯化硼(1M的二氯甲烷溶液233mL),滴毕继续反应0.5h。后处理:加无水甲醇(700mL),搅拌十分钟,然后加入碳酸氢钠溶液调节pH至碱性,分液,水相用二氯甲烷(500mL×2)提取,干燥,过滤,浓缩。残留物溶于无水甲醇(350mL)中,搅拌十分钟,过滤,固体用少量甲醇洗(此步可除掉80%以上的TrOMe),滤液浓缩,残留物用甲苯带两遍以除去残留的甲醇,最终的产物约190g。
将上一步粗品5溶于二氯甲烷(1500mL)中,加入樟脑磺酸(外消旋体,16g),降温至水浴,然后慢慢滴加PMB的三氯亚胺酯(158g),滴毕升至室温反应过夜。后处理:加饱和碳酸氢钠溶液,分液,水相二氯甲烷提取,有机相过滤除掉樟脑磺酸盐固体,用饱和氯化钠洗,干燥,过滤,浓缩,得化合物6粗品约313g。
将上一步得到的化合物6粗品溶于四氢呋喃(700mL)中,降温至冰浴,氩气保护,慢慢滴加硼烷二甲硫醚(10M,70mL),滴毕升至室温反应十分钟,然后加热至55℃~60℃反应过夜。后处理:至冰浴中降温,慢慢滴加甲醇淬灭反应(至不产生气泡为止),减压浓缩,残留物溶于乙酸乙酯中,饱和碳酸氢钠洗,乙酸乙酯提取,干燥,浓缩,残留物加甲醇蒸干,重复两次,柱层析得化合物7约156g,总收率68%。1H NMR(500MHz,CDCl3)δ7.72(t,J=6.7Hz,4H),7.57–7.48(m,2H),7.43(t,J=7.5Hz,4H),7.22(d,J=8.2Hz,2H),6.91(d,J=8.2Hz,2H),4.50–4.34(m,2H),3.96(dt,J=7.8,4.5Hz,2H),3.87(s,3H),3.79(td,J=7.1,3.5Hz,1H),3.55(td,J=8.5,7.3,4.1Hz,2H),3.43(dd,J=9.7,6.7Hz,1H),1.83(ddt,J=11.3,7.8,3.9Hz,1H),1.76(q,J=12.7,1H),1.10(s,9H)。
1.3化合物9的合成
将化合物7(103.4g)溶于乙腈(1L)中,加入SM2(4.7g),碳酸钾(37.5g),碘化钾(38.2g)和溴苄(37.3mL),加热至70℃~80℃反应3-5小时(点板检测原料消失或仅剩余很少且不再变化)。后处理:加水,乙酸乙酯提取2-3遍,干燥,浓缩,直接进行下一步反应。
将化合物8的粗品溶于四氢呋喃(314mL)中,加入四丁基氟化铵(TBAF,314mL),25℃反应过夜。后处理:减压浓缩,残留物溶于水和乙酸乙酯中,分液,乙酸乙酯提取,干燥,浓缩,柱层析(石油醚:乙酸乙酯=2:1-1:1)。最后得化合物9约62g,两步总收率约为86%。1HNMR(400MHz,CDCl3)δ7.44–7.21(m,7H),6.85(s,2H),4.50(s,2H),4.47(s,2H),3.82(m,1H),3.79(s,3H),3.76–3.64(m,3H),3.65–3.54(m,2H),1.89(m,1H),1.85–1.72(m,1H).
实施例2化合物10的合成
将化合物9(149.5g)溶于DCM(818mL)中,加入PPTs(5.4g),滴加原乙酸三甲酯(82.4mL),滴毕室温反应1h,蒸干溶剂得产物差向异构体混合物9a。
以上所得化合物9a重新溶于DCM(818mL)中,滴加乙酰溴(47.9mL),滴毕室温反应0.5h,蒸干溶剂得化合物9b-1与9b-2的混合物。
上述化合物9b-1与9b-2混合物溶于无水甲醇(1500mL)中,加入碳酸钾(119g),室温反应8h。后处理:加饱和氯化铵溶液,DCM提取,干燥,过滤,浓缩,硅胶柱层析得化合物10精制品123g,收率87%。1H NMR(400MHz,CDCl3)δ7.38–7.25(m,7H),6.87(d,J=13.2Hz,2H),4.60–4.38(m,4H),3.79(s,3H),3.73–3.65(m,1H),3.62(d,J=11.5Hz,2H),3.56–3.44(m,1H),3.25–3.17(m,1H),3.13(s,1H),2.00–1.66(m,2H).
实施例3化合物11的合成
氩气保护条件下,将三甲基硅基乙炔(15.5g)溶于300mL无水甲苯中,冷至-50℃,缓慢滴加64mL 2.5M n-BuLi的正己烷溶液,滴毕,搅拌反应30min后,滴加化合物10的甲苯溶液(26g化合物10溶于100mL甲苯),滴毕,缓慢滴加BF3Et2O(22.6g),保持温度不高于-30℃,滴毕反应3h后,TLC检测反应完全。加入300mL饱和氯化铵处理反应,分液,水相用乙酸乙酯萃取两次(200mL×2),合并有机相,饱和氯化钠洗涤(300mL×2),无水硫酸钠干燥,滤去干燥剂,浓缩,得到粗品44g,硅胶柱层析分离。柱层析结果如下:化合物11有22g,收率65%,下式11’所示的区域异构体10g。
化合物11 1H NMR(500MHz,CDCl3)δ7.38–7.15(m,7H),6.87(d,J=6.8Hz,2H),4.56–4.45(m,4H),4.00(tt,J=6.3,3.2Hz,1H),3.80(d,J=2.3Hz,3H),3.75–3.57(m,4H),2.81(tt,J=5.0,2.8Hz,1H),2.61(d,J=6.5Hz,1H),1.95(h,J=6.5Hz,1H),1.89–1.80(m,1H),0.15(d,J=2.4Hz,9H).
HPLC显示化合物11中11’的含量≤0.1%;化合物11的其他差向异构体含量≤0.1%。
实施例4化合物16的合成
4.1化合物13的合成
冰水浴条件下,将化合物11(21g)溶于无水二氯甲烷(160mL)中,加入6.8g 2,6-二甲基吡啶后,滴加TBSOTf(叔丁基二甲硅基三氟甲磺酸酯,15.6g),滴毕,升至室温反应1h后,TLC检测反应完全。加入饱和氯化铵(200mL)水溶液淬灭反应,分液,水相用二氯甲烷萃取(200mL×2),合并有机相,用1N盐酸洗掉2,6-二甲基吡啶,再用饱和氯化钠洗(200mL×2),无水硫酸钠干燥,过滤,滤液浓缩,得到粗品25.7g棕黄色油状物(化合物12)。
将上述化合物12粗品溶于200mL无水甲醇中,加入碳酸钾粉末(13.5g),室温反应过夜,TLC检测反应完全,加入200mL乙酸乙酯稀释反应液,硅藻土助滤滤去固体,固体用乙酸乙酯洗涤至无产物残留,浓缩滤液,得到棕黄色粘稠物,加入200mL乙酸乙酯充分搅拌溶解,硅藻土助滤,滤饼用乙酸乙酯洗至无产物残留,浓缩滤液,得到棕黄色油状物粗品30g,硅胶柱层析分离,得到无色油状物化合物13约20.7g,两步收率90%。
化合物13 1H NMR(400MHz,CDCl3)δ7.30–7.22(m,3H),7.24–7.13(m,4H),6.85–6.72(m,2H),4.77(s,1H),4.50–4.24(m,4H),4.13–3.80(m,1H),3.64–3.39(m,3H),2.84–2.65(m,1H),2.07–1.97(m,1H),1.90(dt,J=12.7,6.1Hz,1H),1.72(dd,J=13.8,7.0Hz,1H),0.81(s,9H),-0.01(s,6H).
4.2化合物15的合成
氩气保护条件下,将化合物13(10.8g)溶于100mL无水甲苯中,降至-78℃,滴加2.5N正丁基锂的正己烷溶液(11mL),滴毕,反应30min后,将5.64g化合物14(市售商品,光学纯度>99%)溶于50mL甲苯后滴加至反应体系中,滴毕,缓慢滴加BF3Et2O(4.0g),滴毕,保持此温度下继续反应2h后,TLC检测,反应完全。加入饱和氯化铵150mL淬灭反应,分液,水相用乙酸乙酯萃取(150mL×2),合并有机相,饱和氯化钠洗(150mL×2),无水硫酸钠干燥,过滤,滤液浓缩,得到油状物粗品17.8g,硅胶柱层析分离,得到化合物15约14.5g,收率96%.
化合物15 1H NMR(500MHz,CDCl3)δ7.42–7.24(m,7H),6.90(d,J=8.0Hz,2H),4.60–4.40(m,4H),4.07(d,J=7.3Hz,1H),3.90–3.74(m,5H),3.75–3.59(m,2H),3.53(q,J=6.1,5.1Hz,3H),2.79(d,J=6.8Hz,1H),2.45(d,J=6.0Hz,1H),2.13–1.97(m,1H),1.88–1.71(m,2H),1.42–1.22(m,2H),1.02–0.84(m,18H),0.10(s,6H),0.07(s,6H).
4.3化合物16的合成
室温条件下,将化合物15(46g)溶于500mL无水甲醇中,加入3N的HCl/MeOH溶液13mL,室温反应过夜,TLC检测反应完全,加入8mL氨水(25-28%),搅拌淬灭反应,加入无水硫酸钠干燥,除掉水,过滤,残渣用乙酸乙酯洗涤,滤液浓缩得到淡黄色油状物34.2g,用乙酸乙酯/正己烷重结晶,得到白色晶体26g,TLC检测为单一产物。此白色晶体进行二次重结晶,得到化合物16为白色晶体25.2g,收率83.3%,光学纯度>99.9%,HPLC谱图如图1所示。
化合物16 1H NMR(500MHz,甲醇-d4)δ7.35–7.24(m,7H),6.90(dd,J=8.6,2.9Hz,2H),4.66–4.32(m,4H),3.99(dd,J=8.1,4.3Hz,1H),3.80(s,3H),3.74–3.34(m,7H),2.74(s,1H),2.56–2.24(m,2H),1.91(td,J=7.9,6.9,3.1Hz,2H).
实施例5化合物20的合成
5.1化合物17的合成
将化合物16(24.2g)于70mL乙腈中,加入25mL戊酮和9.8mL原甲酸三甲酯,最后加入270m g三氟甲磺酸钪,室温反应1h后,TLC检测反应完全,向反应液中加入三乙胺淬灭反应,蒸去溶剂,得到粗品29.4g,柱层析分离,得到化合物17 26.6g,收率95%。1H NMR(500MHz,CDCl3)δ7.50–7.08(m,7H),6.87(d,J=8.2Hz,2H),4.60–4.33(m,4H),4.19(t,J=6.4Hz,1H),4.08(t,J=7.1Hz,1H),4.04–3.92(m,1H),3.80(s,3H),3.76–3.43(m,5H),2.87–2.64(m,2H),2.56(dd,J=16.4,4.7Hz,1H),2.42(dd,J=16.5,7.6Hz,1H),1.93(dd,J=14.9,7.9Hz,1H),1.79(dq,J=9.6,4.7Hz,1H),1.63(dq,J=22.5,7.9,7.4Hz,4H),0.89(q,J=7.0Hz,6H)
5.2化合物18的合成
将23.8g化合物17溶于150mL无水甲醇中,加入Lindlar催化剂2.4g,常压氢化反应,TLC监测反应进程,至原料反应完全,滤去催化剂,浓缩滤液,得到化合物18粗品23.6g,未经进一步纯化,直接投入下一步。1H NMR(500MHz,CDCl3)δ7.35-7.23(m,7H),6.86(d,J=8.2Hz,2H),5.61-5.55(m,2H),4.51(s,2H),4.44(t,J=12.3Hz,2H),4.10-4.05(m,1H),4.03-3.99(m,2H),3.80(s,3H),3.70-3.61(m,2H),3.57(t,J=8.0Hz,1H),3.49-3.43(m,2H),3.06(s,1H),2.70(s,1H),2.40(dt,J=12.6,5.7Hz,1H),2.27(dt,J=14.1,5.9Hz,1H),1.83-1.74(m,1H),1.62(dt,J=15.6,7.9Hz,4H),0.89(q,J=7.7Hz,6H).
5.3化合物19的合成
冰水浴条件下,将化合物18(8.3g)溶于50mL吡啶中,缓慢加入2.58g BzCl(苯甲酰氯),最后加入200mgDMAP,升至室温反应,3h后,TLC检测反应完全,用100mL乙酸乙酯稀释反应液,加入100mL水淬灭反应,分液,水相用乙酸乙酯萃取(100mL×2),合并有机相,先用水洗(200mL×2),再用1N稀盐酸洗至中性,用饱和碳酸氢钠洗去残留HCl,最后用饱和氯化钠洗,无水硫酸钠干燥,过滤,浓缩滤液,得到粗品17g,柱层析分离,得到化合物19约10.1g,收率99%。1H NMR(400MHz,CDCl3)δ8.02–7.95(m,2H),7.58-7.54(m,1H),7.44–7.41(m,2H),7.28-7.26(m,5H),7.20(d,J=9.4Hz,2H),6.78(d,J=8.0Hz,2H),5.68–5.56(m,3H),4.43(d,J=2.9Hz,3H),4.36(d,J=2.8Hz,2H),4.09–4.02(m,1H),3.97–3.93(m,1H),3.75(s,3H),3.53–3.50(m,2H),3.49–3.42(m,2H),3.33(dd,J=9.3,6.3Hz,1H),3.03–2.97(m,1H),2.44–2.28(m,2H),2.07–1.99(m,2H),1.96-1.88(m,1H),1.66–1.57(m,4H),0.89(dd,J=14.7,7.2Hz,6H).
5.4化合物20的合成
室温条件下,将化合物19(10g)溶于叔丁醇/水(20mL/20mL)的混合溶剂中,加入NMO(5.9g),最后加入四氧化锇的0.05M甲苯溶液(11mL),加热至45℃搅拌反应24h后,TLC检测反应基本完全,加入饱和亚硫酸钠(50mL)搅拌淬灭反应,用乙酸乙酯(100mL×3)萃取反应液,合并有机相,水洗(200mL×2),饱和氯化钠洗(200mL×2),无水硫酸钠干燥,过滤,滤液浓缩,得到粗品11g,硅胶柱层析分离,得到化合物20约9.8g,收率92%。1H NMR(400MHz,CDCl3)δ7.98(dt,J=8.4,1.6Hz,2H),7.55(tt,J=7.0,1.3Hz,1H),7.46–7.39(m,2H),7.30–7.14(m,7H),6.82(dq,J=8.7,2.2,1.6Hz,2H),5.51(ddd,J=8.9,7.4,3.1Hz,1H),4.51–4.35(m,4H),4.35–4.24(m,1H),4.04(dd,J=8.0,6.0Hz,1H),3.89–3.64(m,7H),3.62–3.51(m,2H),3.47(td,J=8.1,5.0Hz,1H),3.30(t,J=5.5Hz,2H),2.41(tt,J=5.4,2.3Hz,1H),2.21(dtd,J=14.5,7.2,3.2Hz,1H),2.13–1.91(m,2H),1.74(ddd,J=14.2,7.6,4.5Hz,1H),1.57(dq,J=15.1,7.5Hz,4H),0.84(dt,J=9.8,7.5Hz,6H).
5.5化合物20的合成
室温条件下,将化合物19(90mg)溶于叔丁醇/水(1mL/1mL)的混合溶剂中,加入DABCO(17mg)和NMO(53mg),最后加入四氧化锇的0.05M甲苯溶液(0.15mL),搅拌反应24h后,TLC检测反应基本完全,加入饱和亚硫酸钠(5mL)搅拌淬灭反应,用乙酸乙酯(10mL×3)萃取反应液,合并有机相,水洗(10mL×2),饱和氯化钠洗(10mL×2),无水硫酸钠干燥,过滤,滤液浓缩,得到粗品110mg,硅胶柱层析分离,得到化合物20 67mg,收率70%。
5.6化合物20-Ac的合成
室温条件下,将化合物19-Ac(55g)溶于叔丁醇/水(425mL/425mL)的混合溶剂中,降至0℃,加入NMO(36g),最后加入四氧化锇的0.05M甲苯溶液(100mL),升至室温搅拌反应24h后,TLC检测反应有部分原料剩余,处理,加入饱和亚硫酸钠(500mL)搅拌淬灭反应,用乙酸乙酯(500mL×3)萃取反应液,合并有机相,水洗(500mL×2),饱和氯化钠洗(500mL×2),无水硫酸钠干燥,过滤,滤液浓缩,得到粗品65g,硅胶柱层析分离,回收原料化合物19-Ac14.8g,得到化合物20-Ac约38.2g,收率89.6%,纯度85%(其中异构体以化合物20-Ac’为主)。1H NMR(400MHz,Chloroform-d)δ7.35-7.27(m,5H),7.21(d,J=8.2Hz,2H),6.86(d,J=8.2Hz,2H),5.32–5.20(m,1H),4.48-4.40(m,4H),4.34-4.30(m,1H),4.10-4.05(m,1H),3.80(s,3H),3.73(td,J=9.9,4.7Hz,2H),3.69–3.58(m,2H),3.55–3.38(m,4H),3.18(s,2H),2.31–2.20(m,1H),2.08-2.00(m,1H),1.98(s,3H),1.90-1.82(m,1H),1.78-1.72(m,1H),1.67-1.60(m,5H),0.90(t,J=7.4Hz,6H).
实施例6化合物23的合成
6.1化合物22的合成
冰水浴条件下,将化合物20(32g)溶于无水二氯甲烷(160mL)中,加入三乙胺(36.5mL)和DMAP(640mg),滴加MsCl(19.5mL),滴毕升至室温反应1h后,TLC检测反应完全,加入饱和氯化铵(200mL)淬灭反应,分液,水相用二氯甲烷(200mL×2)萃取,合并有机相,水洗(250mL×2),饱和氯化钠洗(250mL×2),无水硫酸钠干燥,浓缩,得到棕红色油状物粗品化合物21约39.4g(理论产量39.8g)。未经进一步纯化直接投入下一步。
将化合物21粗品(39.4g)溶于无水甲醇(300mL)中,加入无水碳酸钾粉末(19g),搅拌过夜反应,TLC检测反应完全,减压浓缩蒸去溶剂,加入水300mL,用二氯甲烷萃取(300mL×2),合并有机相,饱和氯化钠洗(300mL×2),无水硫酸钠干燥,过滤,滤液浓缩,得到粗品33g,硅胶柱层析分离,得到化合物22约27g,两步总收率90%。
化合物22 1H NMR(500MHz,CDCl3)δ7.38–7.17(m,7H),6.86(d,J=8.0Hz,2H),5.03(s,1H),4.53–4.36(m,4H),4.24(h,J=6.5Hz,1H),4.06(t,J=6.9Hz,1H),3.89(q,J=5.9,5.5Hz,1H),3.80(s,3H),3.67(q,J=6.6Hz,1H),3.62–3.51(m,4H),3.37(t,J=8.6Hz,1H),2.96(s,3H),2.40(q,J=6.6Hz,1H),2.04(dt,J=14.0,6.8Hz,1H),1.96(dq,J=12.4,6.3,5.5Hz,3H),1.62(p,J=7.7Hz,4H),0.89(t,J=7.5Hz,6H).
6.2化合物23的合成
冰水浴条件下,将化合物22(7.8g)溶于无水四氢呋喃(80mL)中,滴加3M甲基溴化镁的四氢呋喃溶液(13.5mL),滴毕,升至室温反应过夜,TLC检测反应完全,滴加饱和氯化铵(100mL)淬灭反应,乙酸乙酯萃取(100mL×3),合并有机相,饱和氯化钠洗(200mL×2),无水硫酸钠干燥,过滤,滤液浓缩,得到无色油状物粗品8g,硅胶柱层析分离,得到5.8g化合物23,收率86%;同时得到0.2g化合物23’。化合物23的纯度>99.9%,HPLC谱图如图2所示,下式所示的杂质23’含量0.09%:
1H NMR(500MHz,CDCl3)δ7.35-7.28(m,5H),7.22(d,J=8.1Hz,2H),6.85(d,J=8.0Hz,2H),4.49(s,2H),4.43(s,2H),4.32-4.27(m,1H),4.08–4.04(m,2H),3.86(q,J=5.9Hz,1H),3.79(s,3H),3.72–3.63(m,2H),3.58(dt,J=21.2,7.5Hz,2H),3.47(d,J=6.3Hz,2H),2.13(dd,J=7.1,3.9Hz,1H),2.10–1.97(m,3H),1.93(dt,J=19.8,6.3Hz,2H),1.63(dq,J=14.9,7.4Hz,4H),0.89(q,J=7.3Hz,6H).
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (18)
1.一种式(Ⅸ)所示化合物:
其手性中心绝对构型为(2R,3S);
其中,PG1、PG2相同或不同,彼此独立地选自取代或未取代的下列基团:C3-10环烷基、C6-14芳基、C6-14芳基C1-10烷基、5-14元杂芳基、3-10元杂环基;所述基团可被以下基团取代:卤素、羟基、氨基、-N(C1-6烷基)2、-NHC1-6烷基、硝基、氰基、羧基、叠氮基、C1-10烷基、C1-10烷氧基、C3-10环烷基、C6-14芳基、5-14元杂芳基;
或者,PG1、PG2相同或不同,彼此独立地选自以下基团:甲酰基、C1-10烷基羰基、C3-10环烷基羰基、C6-14芳基酰基、氨基甲酰基;甲磺酰基、乙磺酰基、三氟甲磺酰基、苯磺酰基、对甲苯磺酰基、萘磺酰基、C1-10烷基氧基羰基、C6-14芳基C1-10烷基氧基羰基、由硫酸、硝酸、磷酸或硼酸通过除去OH基团得到的基团、二C1-10烷基硫膦基、二C6-14芳基硫膦基。
2.根据权利要求1所述的式(Ⅸ)化合物,
其中PG1、PG2相同或不同,选自甲氧基苄基、苄基、三苯基甲基。
4.根据权利要求3所述式(Ⅸ)化合物的制备方法,其中所述的碱选自下列中的一种、两种或更多种:碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化锂、烷基锂、甲醇钠、乙醇钠、甲胺、乙胺、丙胺、异丙胺、二甲胺、二乙胺、二异丙胺、三乙胺。
6.根据权利要求5所述的制备方法,其特征在于:
步骤(1)中,所述反应在酸性催化剂的存在下进行,所述酸性催化剂选自适用于酯交换的酸性催化剂;
所述式(IX)化合物与所述催化剂的摩尔比为1:(0.01~0.2);
步骤(3)中,反应在碱的存在下进行,所述式(Ⅸb-1)化合物和/或式(Ⅸb-2)化合物与所述碱的摩尔比为1:(1~10);
步骤(3)在溶剂中进行,所述溶剂为醇类溶剂、水或其混合物;所述式(IX)化合物与所述溶剂的重量体积比为1 g : (1~20) mL。
7.根据权利要求6所述的制备方法,
步骤(1)中,所述酸性催化剂选自吡啶对甲苯磺酸盐(PPTs)或质子酸中的一种、两种或更多种;所述原酸酯类化合物选自原甲酸三甲酯、原甲酸三乙酯、原乙酸三甲酯、原乙酸三乙酯、原苯甲酸三甲酯、原苯甲酸三乙酯中的任一种;
步骤(3)中,所述醇类溶剂选自甲醇、乙醇、异丙醇或乙二醇。
9.根据权利要求8所述的化合物,
所述硅烷基选自三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二苯基硅基、叔丁基二甲基硅基、三苄基硅基和三苯基硅基。
10.下式(XIX)所示化合物:
其中,PG1、PG2具有权利要求1所述定义;
PG6独立地选自取代或未取代的苯甲酰基,所述苯基可被以下基团取代:卤素、羟基、氨基、-N(C1-6烷基)2、-NHC1-6烷基、硝基、氰基、羧基、叠氮基、C1-10烷基、C1-10烷氧基;
PG7为邻二羟基保护基;
所述邻二羟基保护基与其结合的氧形成: -OCH(R)O-; -OCR2O-; -OC(O)O-; -OBRO-;其中R为H,C1-10烷基、C2-6烯基、C6-14芳基、或C6-14芳基C1-10烷基;
或者所述PG7选自亚乙基、亚异丙基、亚环己基、亚环戊基、对甲氧基苯基亚甲基、2,4,6-三甲基苯基亚甲基、二叔丁基亚硅烷基、1,1,3,3-四异丙基硅氧烷基。
11.式(XX)化合物的制备方法,包括将权利要求10所述的式(XIX)化合物在氧化剂的作用下进行双羟化氧化反应,得到式(XX)化合物:
其中,PG1、PG2、PG6、PG7具有权利要求10所述的定义;
所述氧化剂选自高锰酸钾、高碘酸钠、过氧化氢、铁氰化钾、N-甲基-N-氧化吗啉中的一种或多种;
所述反应中可根据需要加入共氧化剂,所述共氧化剂为四氧化锇、锇酸钾中的任一种;
所述反应可以在碱的催化作用下进行,所述碱为1,4-二氮杂二环[2.2.2]辛烷(DABCO)、三乙胺、N,N-二异丙基乙胺中的一种或多种;
所述式(XIX)化合物与氧化剂的摩尔比为1 : (1~5);所述式(XIX)化合物与所述共氧化剂的摩尔比为1: (0.005~0.15);所述式(XIX)化合物与所述碱的摩尔比为1:(0.4~2);
所述反应在混合溶剂下进行,所述混合溶剂为有机溶剂与水的混合物;所述混合溶剂中,有机溶剂与水的体积比为(1:5)~(5:1);
所述式(XIX)化合物的重量与混合溶剂总体积的比为1 g : (2~50) mL;
所述反应温度为-10℃~50℃;反应时间为10~60 h。
12.根据权利要求11所述的制备方法,其中,
所述式(XIX)化合物与氧化剂的摩尔比为1 : (1~3);
所述式(XIX)化合物与所述共氧化剂的摩尔比为1 : (0.005~0.1);
所述式(XIX)化合物与所述碱的摩尔比为1 : (0.5~1.5);
所述混合溶剂选自下列体系中的一种:叔丁醇/水、丙酮/水、乙腈/水;
所述混合溶剂中,有机溶剂与水的体积比为 (2~2.5):(2.5~2);
所述反应温度为35℃~45℃;反应时间为24 h。
14.根据权利要求13所述的制备方法,
所述式(XXIII)化合物的制备方法还包括柱层析分离得到的产品。
16.一种制备艾日布林或其C27-C35结构片段的方法,包括使用权利要求1所述的式(Ⅸ)化合物,权利要求8所述的式(XI)、(XII)、(XIII)、(XV)或(XVI)化合物,和/或权利要求10所述的式(XIX)化合物。
17.一种制备艾日布林或其C27-C35结构片段的方法,包括权利要求3所述的式(Ⅸ)化合物的制备方法,权利要求5所述的式(X)化合物的制备方法,权利要求11所述的式(XX)化合物的制备方法,和/或权利要求13所述的式(XXIII)化合物的制备方法。
18.权利要求1所述的式(Ⅸ)化合物,权利要求8所述的式(XI)、(XII)、(XIII)、(XV)或(XVI)化合物,和/或权利要求10所述的式(XIX)化合物在制备艾日布林或其C27-C35结构片段中的用途。
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