CN114671905B - Derivative of eribulin intermediate and salt thereof, and preparation, purification method and application thereof - Google Patents
Derivative of eribulin intermediate and salt thereof, and preparation, purification method and application thereof Download PDFInfo
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- CN114671905B CN114671905B CN202011550087.1A CN202011550087A CN114671905B CN 114671905 B CN114671905 B CN 114671905B CN 202011550087 A CN202011550087 A CN 202011550087A CN 114671905 B CN114671905 B CN 114671905B
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- formula
- eribulin intermediate
- compound shown
- derivative
- eribulin
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 55
- 238000000746 purification Methods 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 150000003839 salts Chemical class 0.000 title claims abstract description 23
- UFNVPOGXISZXJD-XJPMSQCNSA-N eribulin Chemical class 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 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 84
- 229960003649 eribulin Drugs 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 230000001590 oxidative effect Effects 0.000 claims abstract description 14
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 9
- 238000001953 recrystallisation Methods 0.000 claims abstract description 9
- 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 claims abstract description 6
- 238000006722 reduction reaction Methods 0.000 claims abstract description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 4
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims abstract description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 46
- 239000007800 oxidant agent Substances 0.000 claims description 21
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 16
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims description 16
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- -1 triethylsilyl Chemical group 0.000 claims description 15
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003638 chemical reducing agent Substances 0.000 claims description 11
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 9
- 229960002218 sodium chlorite Drugs 0.000 claims description 9
- 239000003810 Jones reagent Substances 0.000 claims description 8
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052782 aluminium Inorganic materials 0.000 claims description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 8
- SOCTUWSJJQCPFX-UHFFFAOYSA-N dichromate(2-) Chemical compound [O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O SOCTUWSJJQCPFX-UHFFFAOYSA-N 0.000 claims description 8
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 claims description 8
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 8
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 8
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 8
- 150000002978 peroxides Chemical class 0.000 claims description 8
- 239000012286 potassium permanganate Substances 0.000 claims description 8
- 229910001923 silver oxide Inorganic materials 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 5
- 239000012448 Lithium borohydride Substances 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 229910000085 borane Inorganic materials 0.000 claims description 4
- 229910001919 chlorite Inorganic materials 0.000 claims description 4
- 229910052619 chlorite group Inorganic materials 0.000 claims description 4
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical compound OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000007787 solid Substances 0.000 abstract description 17
- 238000009776 industrial production Methods 0.000 abstract description 6
- 239000006227 byproduct Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical group OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 abstract 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 abstract 1
- UFNVPOGXISZXJD-JBQZKEIOSA-N eribulin Chemical class 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 40
- 239000000543 intermediate Substances 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 229960000439 eribulin mesylate Drugs 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical class CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 238000004296 chiral HPLC Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 230000000394 mitotic effect Effects 0.000 description 2
- 150000004885 piperazines Chemical class 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- KKWVSPRXEUBOHT-UHFFFAOYSA-N CC1=CC=CC=C1.[AlH3] Chemical compound CC1=CC=CC=C1.[AlH3] KKWVSPRXEUBOHT-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 239000004381 Choline salt Substances 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 125000003580 L-valyl group Chemical class [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical class NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 125000000637 arginyl group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 235000019417 choline salt Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- 150000004656 dimethylamines Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- NWYYWIJOWOLJNR-RXMQYKEDSA-N l-valinol Chemical compound CC(C)[C@H](N)CO NWYYWIJOWOLJNR-RXMQYKEDSA-N 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- MIEJSEPCTMXSCI-SUCSLEJPSA-N methyl 2-[(2S,3R,4S,4aS,6R,8aS)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-2-[(E,1S)-1-[tert-butyl(dimethyl)silyl]oxy-3-iodoprop-2-enyl]-2,3,4,4a,6,7,8,8a-octahydropyrano[3,2-b]pyran-6-yl]acetate Chemical compound O1[C@@H]([C@@H](O[Si](C)(C)C(C)(C)C)\C=C\I)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]2O[C@@H](CC(=O)OC)CC[C@@H]21 MIEJSEPCTMXSCI-SUCSLEJPSA-N 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical class C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical class CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a derivative of eribulin intermediate, a salt thereof, a preparation method, a purification method and an application thereof, wherein the structure of the derivative of eribulin intermediate is shown as a formula II, and R is selected from TBDPS, TBDMS, TMS, TES or TIPS. Wherein the purification method of the eribulin intermediate shown in the formula I comprises (1') oxidizing the eribulin intermediate shown in the formula I to obtain a compound shown in the formula II; (2') purifying the compound shown in the formula II, and carrying out reduction reaction to obtain a compound shown in the formula III; (3') carrying out oxidation reaction on the compound shown in the formula III to obtain the purified eribulin intermediate shown in the formula I. The purification method is to oxidize the oily compound shown in the formula I into a solid compound shown in the formula II, and then to purify the compound shown in the formula II by recrystallization so as to remove chiral isomers of the compound shown in the formula I. The purification method has the advantages of simple operation, high raw material conversion rate, less by-product amount, obviously reduced production cost and suitability for industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis, relates to a derivative of an eribulin intermediate, a salt thereof, a preparation method, a purification method and an application thereof, and in particular relates to a derivative of an eribulin intermediate, a salt thereof, a preparation method, a purification method thereof, an application thereof in preparation of an eribulin intermediate and an application thereof in purification of an eribulin intermediate.
Background
Eribulin mesylate (Eribulin mesylate) blocks the G2/M cell loop via the tubulin anti-mitotic pathway, affecting the mitotic spindle, and eventually the mitotic process is blocked, and cell death, and is useful for treating metastatic breast cancer patients who have received at least 2 chemotherapy regimens. Eribulin mesylate (Eribulin mesylate) contains 19 chiral centers, is numerous in isomers, is difficult to synthesize, and most intermediates are oily liquids, making industrial production and refining extremely difficult. Therefore, it is particularly important to improve the optical purity of eribulin mesylate by controlling the chiral purity of eribulin mesylate intermediate.
WO2014183211A1 and CN104024237B disclose a process for the preparation of eribulin mesylate, which provides in the route a side chain structure compound for eribulin mesylate, as follows:
it is an oily liquid at room temperature, is unstable to heat, and is difficult to purify by conventional distillation or the like. The prior art is purified by means of repeated column chromatography, which produces chiral isomers as shown below, resulting in reduced purity:
the method is simple, but has low reproducibility and difficult amplification, and a large amount of organic solvents are used in the column chromatography process, so that the cost is high and the waste liquid is much. Therefore, how to provide a simple and high-purity purification method for the compound of formula I-1 is a problem to be solved.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a derivative of an eribulin intermediate, a salt thereof, a preparation method, a purification method and an application thereof, in particular to a derivative of an eribulin intermediate, a salt thereof, a preparation method, a purification method thereof, an application thereof in preparation of the eribulin intermediate and an application thereof in purification of the eribulin intermediate.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
in a first aspect, the invention provides a derivative of an eribulin intermediate and a salt thereof, wherein the structure of the derivative of the eribulin intermediate is shown as a formula II:
wherein R is selected from TBDPS (tert-butyldiphenylsilyl), TBDMS (tert-butyldimethylsilyl), TMS (trimethylsilyl), TES (triethylsilyl) or TIPS (triisopropylsilyl).
Further preferably, the R is TBDPS (tert-butyldiphenylsilyl).
In some embodiments, the salt is selected from an organic salt or an inorganic salt; the organic salt is selected from any one of N, N-diisopropylethylamine salt, morpholine salt, L-valine salt, triethylamine salt, pyridine salt, methylamine salt, ethylamine salt, dimethylamine salt, diethylamine salt, triethylamine salt, guanidine salt, tromethamine salt, ethylenediamine salt, ethanolamine salt, meglumine salt, piperazine salt, tert-butylamine salt, procaine salt, glucammonium salt, piperazine salt, lysine salt, N' -dibenzylethylenediamine salt, chloroprocaine salt, diethanolamine salt, dicyclohexylamine salt, choline salt, arginine salt, benzamide salt or phenethylamine salt; the inorganic salt is selected from any one of sodium salt, potassium salt, lithium salt, magnesium salt, calcium salt or ammonium salt.
In a second aspect, the present invention provides a method for preparing a derivative of eribulin intermediate and a salt thereof according to the first aspect, the method for preparing the derivative of eribulin intermediate comprising the steps of: carrying out oxidation reaction on the compound shown in the formula I to obtain a derivative of the eribulin intermediate shown in the formula II, wherein the reaction process is as follows:
wherein R is as defined above.
The preparation method of the eribulin intermediate derivative shown in the formula II is simple to operate and easy for large-scale industrial production.
In the present invention, the oxidizing agent used in the oxidation reaction is selected from chlorite, hypochlorite, jones reagent, pyridinium dichromate, potassium permanganate, perchlorate, periodate, permanganate, dichromate, silver oxide, selenium dioxide, peroxide, or dess-martin reagent; sodium chlorite is preferred.
In the present invention, the molar ratio of the compound of formula I to the oxidizing agent is 1 (1.4-2), for example, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.0, etc., and other specific values within the numerical range may be selected, and will not be described herein again.
In the present invention, the temperature of the oxidation reaction is 15-25 ℃, for example 15 ℃, 16 ℃, 18 ℃, 19 ℃, 20 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, etc., and other specific values within the numerical range can be selected, and will not be described in detail herein.
In a third aspect, the present invention provides a method for purifying a derivative of eribulin intermediate and a salt thereof according to the first aspect, the method for purifying a derivative of eribulin intermediate comprising the steps of: recrystallizing the derivative of eribulin intermediate shown in the formula II to obtain a pure product.
The recrystallization process can remove the chiral isomer by-product of the compound shown in the formula I, so that the purity of the compound shown in the formula I obtained by further reaction is improved, wherein the chiral isomer by-product of the compound shown in the formula I has the following structure:
wherein R is as defined above.
In the present invention, the solvent used for the recrystallization is selected from pentane, hexane, n-heptane, petroleum ether, methyl tertiary butyl ether, toluene, tetrahydrofuran, methylene chloride, ethyl acetate, isopropyl acetate, acetonitrile, acetone, ethanol, methanol, isopropanol or n-propanol; n-heptane is preferred.
In the present invention, the crystallization temperature of the recrystallization is-20 to 20 ℃, for example, -20 ℃, -15 ℃, -10 ℃, -5 ℃, 0 ℃, 5 ℃, 10 ℃,15 ℃, 20 ℃, etc., and other specific values within the numerical range can be selected, and will not be described in detail herein.
In the present invention, the crystallization time of the recrystallization is 2-4h, for example, 2h, 2.5h, 3h, 3.5h or 4h, etc., and other specific point values within the numerical range can be selected, which will not be described in detail herein.
In a fourth aspect, the invention provides an eribulin intermediate derivative according to the first aspect and application of the eribulin intermediate salt in preparation of eribulin intermediate shown in formula I;
wherein R is as defined above.
In a fifth aspect, the present invention provides a method for preparing an eribulin intermediate represented by formula i, the method comprising the steps of:
(1) Reducing the compound shown in the formula II by using a reducing agent to obtain a compound shown in the formula III;
(2) Oxidizing the compound shown in the formula III obtained in the step (1) by using an oxidant to obtain an eribulin intermediate shown in the formula I;
the preparation process is as follows:
wherein R is as defined above.
The preparation method of the eribulin intermediate shown in the formula I is simple and easy to operate, and is suitable for large-scale industrial production.
In some embodiments, the reducing agent of step (1) is selected from any one of red aluminum, lithium aluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, borane, or a complex thereof; red aluminum is preferred.
In some embodiments, the molar ratio of the compound of formula II to the reducing agent in step (1) is 1 (2.5-3.5), such as 1:2.5, 1:2.8, 1:3.0, 1:3.2, or 1:3.5, and other specific values within the numerical range may be selected, and will not be described in detail herein.
In some embodiments, the temperature of the reduction reaction in step (1) is 5-15 ℃, such as 5 ℃,8 ℃, 10 ℃, 12 ℃,15 ℃, etc., and other specific values within the range of values can be selected, and will not be described in detail herein.
In some embodiments, the oxidizing agent of step (2) is selected from dess-martin reagent, sodium chlorite, hypochlorite, jones reagent, pyridinium dichromate, potassium permanganate, perchlorate, periodate, permanganate, dichromate, silver oxide, selenium dioxide, or peroxide; dess-martin reagent is preferred.
In some embodiments, the molar ratio of the compound of formula III to the oxidizing agent in step (2) is 1 (1.1-1.5), e.g., 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5, and other specific values within the numerical range may be selected, and will not be described in detail herein.
In some embodiments, the temperature of the oxidation reaction in step (2) is 15-20 ℃, such as 15 ℃, 16 ℃, 17 ℃, 18 ℃, 19 ℃, 20 ℃, etc., and other specific values within the range of values can be selected, and will not be described in detail herein.
In a sixth aspect, the present invention provides a method for purifying eribulin intermediate of formula i, the method comprising the steps of:
(1') oxidizing the eribulin intermediate shown in the formula I by using an oxidant to obtain a compound shown in the formula II;
(2 ') purifying the compound shown in the formula II obtained in the step (1'), and then carrying out reduction reaction with a reducing agent to obtain a compound shown in the formula III;
(3 ') oxidizing the compound shown in the formula III obtained in the step (2') by using an oxidant to obtain a purified eribulin intermediate shown in the formula I;
the purification process is as follows:
wherein R is as defined above.
The purification process is to oxidize the oily compound shown in the formula I into a solid compound shown in the formula II, further purify the compound shown in the formula II by recrystallization to remove chiral isomer of the compound shown in the formula I, and then obtain the compound shown in the formula I through a series of reactions. The method for purifying the compound shown in the formula I has the advantages of simple operation, high raw material conversion rate, low byproduct content and obviously reduced production cost, and is suitable for industrial production.
In some embodiments, the eribulin intermediate of formula I is specifically a compound of formula I-1, and the purification method is as follows:
the purification method of the compound shown in the formula I-1 through the compound shown in the formula I comprises the steps of (1 '), step (2 ') and step (3 ').
In some embodiments, the oxidizing agent of step (1') is selected from chlorite, hypochlorite, jones reagent, pyridinium dichromate, potassium permanganate, perchlorate, periodate, permanganate, dichromate, silver oxide, selenium dioxide, peroxide, dess-martin reagent; sodium chlorite is preferred.
In some embodiments, the reducing agent of step (2') is selected from any one of red aluminum, lithium aluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, borane, or a complex thereof; red aluminum is preferred.
In some embodiments, the oxidizing agent of step (3') is selected from dess-martin reagent, sodium chlorite, hypochlorite, jones reagent, pyridinium dichromate, potassium permanganate, perchlorate, periodate, permanganate, dichromate, silver oxide, selenium dioxide, or peroxide; dess-martin reagent is preferred.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a derivative of eribulin intermediate, a salt thereof, a preparation method thereof, a purification method thereof, application thereof in preparation of eribulin intermediate and application thereof in purification of eribulin intermediate. The purification method of the eribulin intermediate comprises the steps of oxidizing an oily compound shown in a formula I into a solid compound shown in a formula II, purifying the compound shown in the formula II by recrystallization to remove chiral isomers of the compound shown in the formula I, and obtaining the compound shown in the formula I by a series of reactions to finally purify the compound shown in the formula I. The method for purifying the compound shown in the formula I has the advantages of simple operation, high raw material conversion rate, low byproduct content and obviously reduced production cost, and is suitable for industrial production.
Drawings
FIG. 1 is a chiral HPLC plot of crude compounds of formula II provided in example 1;
FIG. 2 is a pure form of the compound of formula II provided in example 2 1 H NMR spectrum;
FIG. 3 is a pure product of the compound represented by formula II provided in example 2 13 C NMR spectrum;
FIG. 4 is an X-ray diffraction (XRD) pattern of a pure product of the compound of formula II provided in example 2;
FIG. 5 is a thermogravimetric analysis (TGA) spectrum of a pure product of a compound of formula II provided in example 2;
FIG. 6 is a Differential Scanning Calorimetry (DSC) analysis chart of a pure compound of formula II provided in example 2;
FIG. 7 is a chiral HPLC plot of pure compounds of formula II provided in example 2.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
In the following examples, the crude compound of formula I-1 was obtained from WO2014183211A1, ee=84%.
The reaction schemes involved in the following examples are shown below:
example 1
Preparation of the compound of formula II-1: 1.72kg (chiral isomerism about 4-8%) of crude compound shown in formula I-1, 5.16kg of tertiary butanol and 1.7kg of water are sequentially added into a clean and dry 100L reaction kettle, the temperature is stirred and controlled at 20 ℃, 1.0kg of 2-methyl-2-butene is added, 1.04kg of sodium dihydrogen phosphate, 8.6kg of water and 0.71kg of 80% sodium chlorite are prepared into a solution, and then the solution is added into the reaction kettle in a dropwise manner. After the raw materials disappear, 1.72kg of n-heptane is added into the reaction kettle, stirred, stood and separated. The organic phase was desolventized to constant weight to give crude compound of formula II-1, which was tested for chiral purity, see figure 1, ee=86%.
Example 2
Purification of the compound of formula II-1: 15.0g of the crude compound of formula II-1 prepared in accordance with the method of example 1, 30g of n-heptane, are added into a reaction flask, heated under stirring until the mixture is refluxed, dissolved and clarified, slowly cooled to 40 ℃,75 mg of seed crystal is added, and the mixture is continuously slowly cooled to-10 ℃, and the temperature is kept for 2 hours. After suction filtration, the solid was rinsed with a small amount of n-heptane. The solid was dried in vacuo to give 13.2g of pure compound of formula II-1. Respectively carry out the following steps 1 H NMR、 13 C NMR, XRD, TGA, DSC characterization, results are shown in FIGS. 2-6, respectively.
Wherein, the nuclear magnetic data is as follows: 1 H NMR(400MHz,DMSO-d 6 )δ12.05(s,1H),7.74–7.54(m,4H),7.54–7.31(m,6H),4.98(q,J＝2.1Hz,1H),4.88(q,J＝2.2Hz,1H),4.29(ddd,J＝8.6,4.2,1.9Hz,1H),3.92(p,J＝6.4Hz,1H),3.67(t,J＝5.8Hz,2H),3.37(s,1H),2.76–2.55(m,1H),2.27(dd,J＝8.3,6.8Hz,2H),2.16(ddt,J＝15.8,7.0,2.4Hz,1H),1.76(dp,J＝12.0,4.1Hz,1H),1.72–1.38(m,5H),1.00(s,9H)。
13 C NMR(101MHz,DMSO-d 6 )δ174.29,151.38,134.99,133.30,129.74,127.81,104.87,78.06,76.25,63.40,38.31,31.03,29.98,28.58,26.65,18.76。
chiral purity was further tested by chiral HPLC, and the test results are shown in fig. 7, which shows that: ee= 99.43%, recovery 88%.
Example 3
Purification of the compound of formula II-1: 50.0g of the crude compound of formula II-1 prepared in accordance with the method of example 1 and 75g of ethyl acetate are added into a reaction flask, the mixture is heated under stirring until the mixture is refluxed, dissolved and clarified, the temperature is slowly reduced to 50 ℃, 150mg of seed crystal is added, the temperature is continuously reduced slowly to 20 ℃, and the temperature is kept for 4 hours. After suction filtration, the solid was rinsed with a small amount of n-heptane. The solid was dried in vacuo to give 36.5g of the pure compound of formula II-1 at a recovery of 73%.
Example 4
Purification of the compound of formula II-1: 86.0g of the crude compound of formula II-1 prepared in accordance with the method of example 1, 86g of methanol, are added into a reaction flask, heated under stirring until reflux, dissolved and clarified, slowly cooled to 35 ℃, 400mg of seed crystal is added, and the temperature is kept at 0 ℃ for 4 hours. After suction filtration, the solid was rinsed with a small amount of n-heptane. The solid was dried in vacuo to give 56.7g of the pure compound of formula II-1 with a recovery of 66%.
Example 5
Purification of the compound of formula II-1: 15.0g of the crude compound of formula II-1 prepared in the method of example 1, 30g of N-heptane, heated under stirring until the mixture is refluxed, dissolved and clarified, then 4.28g of N, N-diisopropylethylamine is added dropwise, the temperature is slowly reduced to 55 ℃,75 mg of seed crystal is added, the temperature is continuously slowly reduced to 10 ℃, and the temperature is kept for 2 hours. After suction filtration, the solid was rinsed with a small amount of n-heptane. The solid was dried in vacuo to give 13.2g of pure compound of formula II-1 at a recovery rate of 92%.
Example 6
Purification of the compound of formula II-1: 42.0g of the crude compound of formula II-1 prepared according to the method of example 1 and 84g of n-heptane are added into a reaction flask, the mixture is heated under stirring until the mixture is refluxed, dissolved and clarified, 8.08g of morpholine is then added dropwise, the temperature is slowly reduced to 55 ℃, 175mg of seed crystal is added, the temperature is continuously slowly reduced to-10 ℃, and the temperature is kept for 2 hours. After suction filtration, the solid was rinsed with a small amount of n-heptane. The solid was dried in vacuo to give 45.07g of pure compound of formula II-1 with a recovery of 90%.
Example 7
Purification of the compound of formula II-1: 42.0g of the crude compound of formula II-1 prepared in accordance with the method of example 1, 84g of n-heptane, are added into a reaction flask, heated under stirring until reflux, dissolved and clarified, 9.57g of L-valinol is then added dropwise, the temperature is slowly reduced to 55 ℃, 175mg of seed crystal is added, the temperature is continuously slowly reduced to-20 ℃, and the temperature is kept for 2 hours. After suction filtration, the solid was rinsed with a small amount of n-heptane. After the solid is dried in vacuum, 43.85g of pure compound shown in the formula II-1 is obtained, and the recovery rate is 85%.
Example 8
Purification of the compound of formula II-1: 15.0g of the crude compound of formula II-1 prepared in accordance with the method of example 1 and 15g of methanol are added into a reaction bottle, heated under stirring until reflux, dissolved and clarified, then 8.98g of methanol solution containing 20% sodium methoxide is added dropwise, the temperature is slowly reduced to 45 ℃,75 mg of seed crystal is added, the temperature is continuously slowly reduced to 10 ℃, and the temperature is kept for 2 hours. After suction filtration, the solid was rinsed with a small amount of n-heptane. The solid was dried in vacuo to give 9.9g of the pure compound of formula II-1 at a recovery rate of 63%.
Example 9
Preparation of the compound of formula III-1: to the clean dry reactor was added 70% red aluminum toluene solution (4.5 kg) and toluene (4.8 kg) was added dropwise. The internal temperature was kept at 10℃and a solution of the purified compound of formula II-1 (2.4 kg) in toluene (5.2 kg) was added dropwise thereto for reaction. In another post-treatment tank, the solution of potassium sodium tartrate (9.68 kg) and water (19.4 kg) prepared with stirring was cooled to-5 ℃. After the reaction is finished, the temperature of the reaction kettle is reduced to minus 15 ℃, and the reaction kettle is slowly transferred into a post-treatment kettle, and the internal temperature is kept within the range of minus 5 to 5 ℃. And after quenching is finished, standing and separating liquid. The aqueous phase was extracted with ethyl acetate (10 kg) and allowed to stand for separation. The organic phases were combined, washed with 25% brine (7.2 kg), and left to stand for separation. The organic phase was filtered off with a pad of silica gel on a buchner funnel. The organic phase was concentrated under reduced pressure to give 2.12kg of the compound represented by formula III-1 in 93% yield.
Example 10
Preparation of the compound of formula I-1: to the dried reaction vessel were added dichloromethane (76 kg) and dess-martin reagent (9.55 kg), and the temperature was reduced to 20 ℃ with stirring. In another preparation vessel, the compound of formula III-1 (7.6 kg) prepared in the method of example 9 and methylene chloride (16 kg) were added, and after preparing a solution, the mixture was added dropwise to the reaction vessel, and the internal temperature was controlled to be in the range of 15 to 20 ℃. After the completion of the reaction, water (36 kg) was added thereto, followed by stirring for 0.5 hours and suction filtration. The filtrate was left to stand for separation and the organic phase was washed with a solution of sodium bicarbonate (4.4 kg), sodium thiosulfate pentahydrate (4.3 kg) and water (38 kg). The aqueous phases were combined, extracted with dichloromethane (25 kg) and allowed to stand for separation. After combining the organic phases, suction filtration on a buchner funnel with a pad of silica gel and concentration gave 6.7kg of the compound of formula I-1 in 89% yield, determined ee=99.6%.
As can be seen from the data of examples 1-10, the ee value of the compound shown in the formula I-1 purified by the purification method disclosed by the invention is obviously improved from 84% to 99.6%, the chiral purity is greatly improved, the chiral isomer of the compound shown in the formula I-1 is largely removed by the purification method, the operation is simple, the production cost is obviously reduced, and the improvement of the purification method disclosed by the invention is fully embodied.
The applicant states that the present invention is illustrated by the above examples as a derivative of eribulin intermediate and its salt, and its preparation, purification method and application, but the present invention is not limited to the above examples, i.e. it does not mean that the present invention must be practiced depending on the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Claims (22)
1. The derivative of the eribulin intermediate and the salt thereof are characterized in that the structure of the derivative of the eribulin intermediate is shown as a formula II:
wherein R is selected from tert-butyldiphenylsilyl, tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl or triisopropylsilyl.
2. The eribulin intermediate derivative and salt thereof according to claim 1, wherein R is t-butyldiphenylsilyl.
3. The preparation method of the eribulin intermediate derivative and the salt thereof according to claim 1, wherein the preparation method of the eribulin intermediate derivative comprises the following steps: carrying out oxidation reaction on the compound shown in the formula I to obtain a derivative of the eribulin intermediate shown in the formula II, wherein the reaction process is as follows:
wherein R is as defined in claim 1.
4. A method of preparation according to claim 3 wherein the oxidizing agent used in the oxidation reaction is selected from chlorite, hypochlorite, jones reagent, pyridinium dichromate, potassium permanganate, perchlorate, periodate, permanganate, dichromate, silver oxide, selenium dioxide, peroxide or dess-martin reagent.
5. A method of preparation according to claim 3, wherein the oxidizing agent used in the oxidation reaction is sodium chlorite.
6. The process according to claim 4, wherein the molar ratio of the compound of formula I to the oxidizing agent is 1 (1.4-2).
7. A method of preparation according to claim 3, wherein the temperature of the oxidation reaction is 15-25 ℃.
8. The purification method of eribulin intermediate derivatives and salts thereof according to claim 1 or 2, wherein the purification method of eribulin intermediate derivatives comprises the steps of: recrystallizing the derivative of eribulin intermediate shown in the formula II to obtain a pure product;
the solvent used for the recrystallization is selected from n-heptane, ethyl acetate or methanol.
9. The method for purifying a derivative of eribulin intermediate and a salt thereof according to claim 8, wherein the solvent used for recrystallization is n-heptane.
10. Use of a derivative of eribulin intermediate according to claim 1 and a salt thereof for the preparation of eribulin intermediate of formula i;
wherein R is as defined in claim 1.
11. A preparation method of an eribulin intermediate shown in a formula I is characterized by comprising the following steps:
(1) Reducing the compound shown in the formula II by using a reducing agent to obtain a compound shown in the formula III;
(2) Oxidizing the compound shown in the formula III obtained in the step (1) by using an oxidant to obtain an eribulin intermediate shown in the formula I;
the preparation process is as follows:
wherein R is as defined in claim 1.
12. The method according to claim 11, wherein the reducing agent in step (1) is selected from any one of red aluminum, lithium aluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, borane, or a complex thereof.
13. The method of claim 12, wherein the reducing agent in step (1) is red aluminum.
14. The method of claim 11, wherein the oxidizing agent of step (2) is selected from the group consisting of dess-martin reagent, sodium chlorite, hypochlorite, jones reagent, pyridinium dichromate, potassium permanganate, perchlorate, periodate, permanganate, dichromate, silver oxide, selenium dioxide, and peroxide.
15. The method of claim 14, wherein the oxidizing agent is dess-martin reagent.
16. A method for purifying eribulin intermediate of formula i, comprising the steps of:
(1') oxidizing the eribulin intermediate shown in the formula I by using an oxidant to obtain a compound shown in the formula II;
(2 ') purifying the compound shown in the formula II obtained in the step (1'), and then carrying out reduction reaction with a reducing agent to obtain a compound shown in the formula III;
(3 ') oxidizing the compound shown in the formula III obtained in the step (2') by using an oxidant to obtain a purified eribulin intermediate shown in the formula I;
the purification process is as follows:
wherein R is as defined in claim 1.
17. The purification process according to claim 16, wherein the oxidizing agent of step (1') is selected from chlorite, hypochlorite, jones reagent, pyridinium dichromate, potassium permanganate, perchlorate, periodate, permanganate, dichromate, silver oxide, selenium dioxide, peroxide, dess-martin reagent.
18. The purification process according to claim 17, wherein the oxidizing agent of step (1') is sodium chlorite.
19. The purification method according to claim 16, wherein the reducing agent of step (2') is selected from any one of red aluminum, lithium aluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, borane, or a complex thereof.
20. The purification process according to claim 19, wherein the reducing agent of step (2') is red aluminum.
21. The purification process according to claim 16, wherein the oxidizing agent of step (3') is selected from dess-martin reagent, sodium chlorite, hypochlorite, jones reagent, pyridinium dichromate, potassium permanganate, perchlorate, periodate, permanganate, dichromate, silver oxide, selenium dioxide or peroxide.
22. The purification process according to claim 21, wherein the oxidizing agent of step (3') is dess-martin reagent.
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