CN114685553A - 一种艾地骨化醇中间体的制备方法及其中间体 - Google Patents
一种艾地骨化醇中间体的制备方法及其中间体 Download PDFInfo
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- CN114685553A CN114685553A CN202011596365.7A CN202011596365A CN114685553A CN 114685553 A CN114685553 A CN 114685553A CN 202011596365 A CN202011596365 A CN 202011596365A CN 114685553 A CN114685553 A CN 114685553A
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- 229950005556 eldecalcitol Drugs 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- FZEXGDDBXLBRTD-SJSKTVLPSA-N eldecalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@H](O)[C@H](OCCCO)[C@@H](O)C1=C FZEXGDDBXLBRTD-SJSKTVLPSA-N 0.000 title claims abstract 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 113
- 238000000034 method Methods 0.000 claims abstract description 27
- -1 cyclohexanol triol derivative Chemical class 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 57
- 150000001875 compounds Chemical class 0.000 claims description 42
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- 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 description 14
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000010511 deprotection reaction Methods 0.000 claims description 10
- 125000004185 ester group Chemical group 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 7
- 229940125782 compound 2 Drugs 0.000 claims description 7
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 7
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 6
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 6
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229940125797 compound 12 Drugs 0.000 claims description 6
- 229940126543 compound 14 Drugs 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 6
- 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 claims description 5
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 5
- 150000001336 alkenes Chemical class 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims description 5
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 5
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 4
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- 229940125773 compound 10 Drugs 0.000 claims description 4
- 229940125810 compound 20 Drugs 0.000 claims description 4
- 229940126086 compound 21 Drugs 0.000 claims description 4
- 229940126208 compound 22 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 239000012025 fluorinating agent Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 229910000077 silane Inorganic materials 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims description 2
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 2
- IKGLACJFEHSFNN-UHFFFAOYSA-N hydron;triethylazanium;trifluoride Chemical compound F.F.F.CCN(CC)CC IKGLACJFEHSFNN-UHFFFAOYSA-N 0.000 claims description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 150000003138 primary alcohols Chemical class 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 49
- 238000003786 synthesis reaction Methods 0.000 abstract description 49
- XDIYNQZUNSSENW-KZXKDKCNSA-N (2s,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O XDIYNQZUNSSENW-KZXKDKCNSA-N 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 2
- 238000009776 industrial production Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 190
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 238000001816 cooling Methods 0.000 description 47
- 238000003756 stirring Methods 0.000 description 45
- 239000000243 solution Substances 0.000 description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000007788 liquid Substances 0.000 description 36
- 239000012043 crude product Substances 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
- 239000000706 filtrate Substances 0.000 description 32
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 27
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
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- 239000000203 mixture Substances 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 239000000543 intermediate Substances 0.000 description 19
- 229910052938 sodium sulfate Inorganic materials 0.000 description 19
- 235000011152 sodium sulphate Nutrition 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 239000012071 phase Substances 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 16
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- FZEXGDDBXLBRTD-AYIMTCTASA-N 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)[C@@H](OCCCO)[C@H](O)C1=C FZEXGDDBXLBRTD-AYIMTCTASA-N 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
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- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 5
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- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 5
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- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
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- BGXZIBSLBRKDTP-UHFFFAOYSA-N methyl 9-(4-chloroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical compound C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Cl)C=C1 BGXZIBSLBRKDTP-UHFFFAOYSA-N 0.000 description 1
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- 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
- 238000004321 preservation Methods 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
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- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
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- 239000011593 sulfur Substances 0.000 description 1
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- 230000002194 synthesizing effect Effects 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 150000003704 vitamin D3 derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
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Abstract
本发明涉及一种艾地骨化醇中间体的制备方法及其中间体。提供一种合成艾地骨化醇中间体的路线及新颖中间体,其起始原料D‑甘露糖(D‑Mannose)易得价格便宜,巧妙利用了原料D‑甘露糖(D‑Mannose)的手性并完美转化到关键艾地骨化醇中间体环己醇三醇衍生物,避免了合成中的手性控制,各步反应条件温和,提纯较易,操作简单,收率较高,产物手性纯度高,从而经济和高效的制备艾地骨化醇中间体,极大的缩短了生产周期,降低了生产成本,适合工业化生产。
Description
技术领域
本发明属于化学药物合成技术领域,具体涉及一种高效而经济的艾地骨化醇中间体的制备方法及其中间体。
背景技术
艾地骨化醇((1R,2R,3R,5Z,7E)-2-(3-羟基丙氧基)-9,10-开环胆甾-5,7,10(19)-三烯-1,3,25- 三醇)是作为骨质疏松症治疗剂Edirol的活性药物成分(API)。是由日本中外制药与正大制药联合研发的维生素D类药物,用于治疗骨质疏松,于2011年首次在日本上市,商品名为Edirol。艾地骨化醇是继阿法骨化醇后又一新的用于治疗骨质疏松症的活性维生素D3衍生物。一项由1054例骨质疏松症患者参加的历时3年的Ⅲ期临床数据显示,艾地骨化醇疗效优于阿法骨化醇,且安全性与阿法骨化醇相似,具有较好的应用前景。
目前艾地骨化醇重要的合成工艺之一是通过关键中间体的A环部分和CD环部分进行偶联,特别是立体专一性构建关键中间体的A环尤为重要。
艾地骨化醇重要的中间体结构如下式1,是制备艾地骨化醇中间体的A的关键。
R5和R6为羟基保护基;R5优选为(C1-10烷基或芳基)3硅烷基,更优选为TBS和TBDPS。 R6优选为(C1-10烷基或芳基)3硅烷基,进一步优选为TBS和TBDPS。
现有技术需要经过很长步骤构建手性,构建手性过程中异构体很难控制,需要多步骤柱层析,整体收率很低,成本很高。
发明内容
本发明所要解决的技术问题是提供一种合成路线及新颖中间体,其起始原料D-甘露糖 (D-Mannose)易得价格便宜,巧妙利用了起始原料D-甘露糖(D-Mannose)的手性并完美转化到关键艾地骨化醇中间体环己醇三醇衍生物,避免了合成中的手性控制,各步反应条件温和,提纯较易,操作简单,收率较高,产物手性纯度高,从而经济和高效的制备艾地骨化醇中间体。
本发明提供一种经济和高效的艾地骨化醇中间体的制备方法及其中间体。
本发明通过以下技术方案,即可实现上述目的,本发明提供了一条合成式1所示的艾地骨化醇中间体的新方法,
其中,上述化合物4制备中间体12可以通过上述方法即先还原酯基再构建烯烃,同理也可以构建烯烃再还原酯基,方法如下:
具体来说,该制备方法包括以下步骤:
(1)将式化合物2进行选择性伯醇保护转化为化合物3
其中R1为羟基保护基,选自Piv,Bn,PMB,Bz,THP,Ac,TMS,TBS,TBDPS,TES,TIPS,MOM, SEM,Tr,Cbz,Allyl,更优选为(C1-C10烷基或芳基)3硅烷基,进一步优选为TBS和TBDPS。有机碱选自三乙胺,NMM,DIPEA,吡啶,2,6-二甲基吡啶中的一种。反应溶剂选自二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺中的一种
(2)化合物3发生加成反应得到化合物4
其中R2为烷基或芳基,选自Me,Et,Pr,i-Pr,n-Bu,i-Bu,t-Bu,n-pentyl,i-pentyl,新戊基,Bn, PMB,Allyl,更优选为Me,Et,n-Bu,t-Bu。反应所有用碱选自叔丁醇钾,碳酸铯,碳酸钾,碳酸钠,氢氧化钠,DBU中的一种,反应溶剂选自叔丁醇、丙烯酸甲酯、四氢呋喃、甲苯中的一种。
(3)化合物4经过将酯基还原生成化合物5
还原剂选自DIBAL-H,LAH,NaBH4,反应溶剂选自四氢呋喃、2-甲基四氢呋喃、甲苯中的一种。
(4)化合物5经过酰化或取代反应生成化合物6
其中R3为羟基保护基,选自甲酯,异丙酯,Piv,Bz,Ac,Bn,THP,MOM,SEM,Tr,Cbz,Allyl。 (5)化合物6经过选择性脱保护基反应生成化合物7
氟化试剂选自KF、吡啶氢氟酸、氟化铵、三乙胺三氢氟酸盐和TBAF·3H2O等氟化物的一种,反应溶剂选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃、甲苯中的一种。
(6)化合物7的羟基经过Mitsnobu反应或者取代反应生成化合物8
其中R4为易离去基团,选自Br,I,Cl,OTS,OMs,OTf。
(7)化合物8经过还原反应生成化合物9
(8)化合物9经过脱保护基生成化合物10
(9)化合物10经过选择性上保护基生成化合物11
(10)化合物11经过上保护基生成化合物12
其中R5和R6均为羟基保护基,选自Piv,Bn,PMB,Bz,THP,Ac,TMS,TBS,TBDPS,TES,TIPS, MOM,SEM,Tr,Cbz,Allyl,更优选为更优选为(C1-C10烷基或芳基)3硅烷基,进一步优选为TBS和TBDPS。
(11)化合物12经过选择性脱保护基生成化合物13
其中酸包括盐酸,醋酸,硫酸,三氟乙酸,路易斯酸如CuSO4等,反应溶剂为二氯甲烷与水的混合物溶剂。
(12)化合物13经过选择性上保护基生成化合物14
其中R7为烷基磺酰基或芳基磺酰基。有机碱选自三乙胺,NMM,DIPEA,吡啶,2,6-二甲基吡啶等中的一种。反应溶剂选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃、甲苯、N,N-二甲基甲酰胺中的一种。
(13)化合物14经过分子内关环反应生成化合物1
其中,上述化合物4制备中间体12可以通过上述方法即先还原酯基再构建烯烃得到中间体 12,也可以构建烯烃再还原酯基,其特征包括下列步骤:
(14)化合物4经过选择性脱保护基反应生成化合物18
其中R1为羟基保护基,R2为烷基或芳基,同上述步骤中R1和R2定义。化合物4与氟化试剂摩尔比约为1:1.2,氟化试剂选自KF、吡啶氢氟酸、氟化铵、TBAF·3H2O等氟化试剂的一种反应溶剂选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃、甲苯、乙酸乙酯、N,N-二甲基甲酰胺中的一种。
(15)化合物18的羟基经过Mitsnobu反应生成或者取代反应生成化合物19
其中R4为易离去基团,同上文步骤中R4所定义。
(16)化合物19经还原反应生成化合物20
(17)化合物20经羟基上保护基生成化合物21
(18)化合物21经酯基还原生成化合物22
其中还原剂选自DIBAL-H,LAH,NaBH4,反应溶剂选自四氢呋喃、2-甲基四氢呋喃、甲苯中的一种。
(19)化合物22经羟基上保护基生成化合物12
其中R5和R6均为羟基保护基,同上文步骤中R5和R6所定义。有机碱选自三乙胺,NMM, DIPEA,吡啶,2,6-二甲基吡啶中的一种,反应溶剂选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃、甲苯、N,N-二甲基甲酰胺中的一种。
本发明还提供根据本发明制备艾地骨化醇中间体1方法中的新颖中间体化合物4,化合物5,化合物6,化合物7,化合物8,化合物14,化合物18,化合物19,其结构如下:
其中R1如权利要求2所定义,R2如权利要求3所定义。
其中R1如权利要求2所定义。
其中R1如权利要求2所定义,R3如权利要求5所定义。
其中R3如权利要求5所定义。
其中R3如权利要求5所定义,R4如权利要求7所定义。
其中R5如权利要求10所定义,R6如权利要求11所定义,R7如权利要求13所定义。
其中R2如权利要求3所定义。
其中R2如权利要求3所定义,R4如权利要求7所定义。
本发明的羟基保护基是本领域已知的适当用于羟基保护的基团,作为示例,优选的,所述的羟基保护基可以是(C1-C10烷基或芳基)3硅烷基,例如:TMS,TBS,TBDPS,TES,TIPS,可以是C1-C10烷基或取代烷基,例如:Me,Et,Pr,i-Pr,n-Bu,i-Bu,t-Bu,n-pentyl,i-pentyl,新戊基, Bn,PMB,Allyl等,可以是(C1-C10烷基或芳基)3酰基,例如:Piv,Bz,Cbz;可以是(C1-C6烷基或芳基)磺酰基,例如:Ts,Ms,乙基磺酰基,2-甲基苯磺酰基,2,6-二甲基苯磺酰基;
本发明一个优选的实施方案中,羟基保护基R5为TBDPS,羟基保护基R6为TBS。
本发明另一个优选的实施方案中,羟基保护基R5为TBS,羟基保护基R6为TBDPS。
本发明另一个优选的实施方案中,羟基保护基R5为TBS,羟基保护基R6为TBDPS。
本发明另一个优选的实施方案中,羟基保护基R5为TBDPS,羟基保护基R6为TBS。
在一个优选的实施例中,本发明提供如式1a所示化合物的合成路线如下:
其中式4a化合物制备式12a同理也可以通过先构建烯烃再还原酯基合成,方法如下:
为了达到本发明的目的,本发明人通过大量试验反应研究,最终获得了如下技术方案:下表为实施例中所涉及的化合物的结构式
具体实施方式
为了更清晰地了解本发明,我们结合反应实例进一步说明,应理解,这些实施例仅用于说明本发明,并不用于限制本发明的范围。
本发明中使用的缩写具有本领域常规含义:如:DCM表示二氯甲烷,DIPEA表示二异丙基乙基胺,TBDPSCl表示叔丁基二苯基氯硅烷,SEMCl表示2-(三甲硅烷基)乙氧甲基氯。
1、化合物3a的合成
准备一个20L三口反应瓶,向反应瓶中加入1000g化合物2,46.5g DMAP,771g三乙胺和 12L二氯甲烷,N2置换,降温至-5-0℃。控温-5-10℃滴加467g的TBDPSCl,加完后保温反应1小时,20-30℃反应1-2小时。向体系中加入5L的饱和碳酸氢钠水溶液,搅拌30min,分液,水相加入2L的二氯甲烷萃取,分液,水相加入2L的乙酸乙酯萃取,分液,合并有机相,用4L的饱和食盐水洗,分液,干燥有机相。抽滤,母液30℃减压浓缩,得油状物2490g,粗品直接进行下一步反应。1H NMR(400MHz,CDCl3)δ7.72(dd,J=10.9,7.1Hz,4H),7.60–7.31(m,6H),4.45(d,J=7.0Hz,1H),4.39–4.22(m,1H),4.22–3.94(m,4H),3.95–3.61(m, 2H),2.91(d,J=6.9Hz,1H),1.46–1.21(m,12H),1.10(s,9H).
2、化合物3b的合成
准备一个3L三口反应瓶,向反应瓶中加入100g化合物2,4.7g DMAP,77g三乙胺和1.2L 二氯甲烷,N2置换,降温至-5-0℃。控温-5-10℃滴加25.6g的TBSCl,加完后保温反应1小时,20-30℃反应1-2小时。向体系中加入500ml的饱和碳酸氢钠水溶液,搅拌10min,分液,水相加入200ml的二氯甲烷萃取,分液,水相加入200ml的乙酸乙酯萃取,分液,合并有机相,用400ml的饱和食盐水洗,分液,干燥有机相。抽滤,母液30℃减压浓缩,得油状物226g,粗品直接进行下一步反应。
3、化合物3c的合成
准备一个150ml三口反应瓶,向反应瓶中加入10g化合物2,11mL氯化苄和15.8mL的DIPEA,所得反应混合物于90℃油浴搅拌5小时。将反应液约45℃减压浓缩,硅胶柱层析(PE:EA=50:1 至8:1)洗脱得油状物9.8g,收率73%。1H NMR(400MHz,CDCl3)δ7.42–7.29(m,5H),4.60(d, J=12.0Hz,2H),4.47–4.36(m,2H),4.15–4.04(m,2H),4.01(dd,J=7.5,4.7Hz,1H),3.81(ddd, J=26.7,10.3,4.9Hz,2H),3.52(t,J=7.4Hz,1H),2.83(d,J=7.0Hz,1H),1.43(dd,J=38.8, 31.2Hz,12H).
4、化合物3d的合成
准备一个500ml三口反应瓶,向反应瓶中加入18g化合物2,用180mL二氯甲烷溶解,再加入15.9mL的三乙胺,和830mg的DMAP,N2置换,降温至-5-0℃。向其中滴加29.7g的TrCl二氯甲烷(40mL)溶液,控制内温<10℃,滴加毕升至室温搅过夜。加入50ml碳酸氢钠水溶液,搅拌15min,分液,有机相加硫酸钠干燥,抽滤,母液约30℃浓缩,得油状物35.6g,粗品直接进行下一步反应。
5、化合物3f的合成
准备一个500ml三口反应瓶,向反应瓶中加入10g化合物2,用100mL二氯甲烷溶解,再加入5.4mL的DIPEA,N2置换,降温至-5-0℃。向其中滴加8.1mL的SEMCl,控制内温<10℃,滴加毕升至室温搅过夜。加入30ml碳酸氢钠水溶液,搅拌15min,分液,有机相加硫酸钠干燥,抽滤,母液约30℃浓缩,得油状物16.5g,粗品直接进行下一步反应。
6、化合物4a的合成
准备一个40L三口反应瓶,向反应瓶中加入1906g化合物3a,19L丙烯酸甲酯,5830g碳酸铯和 15.2L叔丁醇,N2置换,控温20-30℃反应17小时。减压抽滤,滤液约30℃减压浓缩,向残留液中加入4.8L乙酸乙酯和2.5L的5%食盐水,反应混合液搅15分钟,分液,有机相用1.9L 的5%食盐水洗两次,无水硫酸钠干燥,减压抽滤,滤液于约30℃减压浓缩,得油状物3050g,粗品直接投入下一步。
7、化合物4b的合成
准备一个1L三口反应瓶,向反应瓶中加入19g化合物3a,220ml丙烯酸乙酯,20g叔丁醇钾和 150ml叔丁醇,N2置换,控温20-30℃反应14小时。减压抽滤,滤液约30℃减压浓缩,向残留液中加入50ml乙酸乙酯和25ml的5%食盐水,反应混合液搅15分钟,分液,有机相用20ml 的5%食盐水洗两次,无水硫酸钠干燥,减压抽滤,滤液于约30℃减压浓缩,得油状物31.2g,粗品直接投入下一步。
8、化合物4c的合成
准备一个1L三口反应瓶,向反应瓶中加入19g化合物3a,283ml丙烯酸叔丁酯,24.6g碳酸钾和150ml叔丁醇,N2置换,控温20-30℃反应14小时。减压抽滤,滤液约30℃减压浓缩,向残留液中加入50ml乙酸乙酯和25ml的5%食盐水,反应混合液搅15分钟,分液,有机相用 20ml的5%食盐水洗两次,无水硫酸钠干燥,减压抽滤,滤液于约30℃减压浓缩,得油状物 31.7g,粗品直接投入下一步。
9、化合物5a的合成
准备一个500ml三口反应瓶,向反应瓶中加入10g化合物4a(粗品折算)和100mL四氢呋喃,N2置换,降温至-5-0℃。降至,控温-5-10℃分批加入2.5g四氢铝锂,加完后保温反应1 小时,向反应液中加入2.5mL的水,2.5mL的10%氢氧化钠水溶液淬灭反应,搅拌15分钟,再加入7.5mL水,搅拌15分钟,恢复至室温,用50毫升四氢呋喃稀释,加入无水硫酸镁干燥搅拌30分钟。抽滤,母液约30℃减压浓缩得9.9g无色油状物。硅胶柱层析(PE:EA=15:1至6:1)洗脱得油状物6.1g,3步收率64.2%。
10、化合物6a的合成
准备一个1000ml三口反应瓶,向反应瓶中加入33.6g的化合物5a和340mL的二氯甲烷,N2置换,降温至-5-0℃。一次性加入0.734g的DMAP,36.5g的三乙胺,N2置换,降温至-5-0℃。降至,滴加21.7g的pivCl,控制内温<10℃,滴加毕升至室温搅拌过夜。控温10℃以下滴加20ml 的甲醇,搅拌1h,加入300ml碳酸氢钠水溶液,搅拌15分钟,分液,水相加入100ml二氯甲烷萃取,萃取,分液。有机相加硫酸钠干燥,抽滤,母液约30℃浓缩,得油状物41.8g,粗品直接进行下一步反应。1H NMR(400MHz,CDCl3)δ7.71(dd,J=6.2,4.4Hz,4H),7.50– 7.32(m,6H),4.28(dd,J=11.7,5.8Hz,1H),4.18(dd,J=11.4,7.2Hz,1H),4.12(dd,J=9.7,4.2Hz,1H),4.05(dt,J=13.9,6.8Hz,3H),3.93(t,J=7.9Hz,1H),3.85(ddd,J=22.6,10.6,6.1Hz, 2H),3.75(dd,J=15.5,6.6Hz,1H),3.70(t,J=4.0Hz,1H),3.46(dd,J=15.2,6.2Hz,1H),1.81– 1.67(m,2H),1.42(s,3H),1.37(s,3H),1.34(s,6H),1.19(s,9H),1.09(s,9H).
11、化合物6b的合成
准备一个1000ml三口反应瓶,向反应瓶中加入33.6g的化合物5a和340mL的二氯甲烷,N2置换,降温至-5-0℃。一次性加入0.735g的DMAP,36.5g的三乙胺,586g化合物14.5g的MOMOCl,控制内温<10℃,滴加毕升至室温搅拌过夜。控温10℃以下滴加20ml的甲醇,搅拌1h,加入300ml碳酸氢钠水溶液,搅拌15分钟,分液,水相加入100ml二氯甲烷萃取,萃取,分液。有机相加硫酸钠干燥,抽滤,母液约30℃浓缩,得油状物36.5g,粗品直接进行下一步反应。
12、化合物6c的合成
准备一个1000ml三口反应瓶,向反应瓶中加入33.5g的化合物5a和340mL的二氯甲烷,N2置换,降温至-5-0℃。一次性加入0.734g的DMAP,36.5g的三乙胺,N2置换,降温至-5-0℃。降至,滴加22.8g的BzCl,控制内温<10℃,滴加毕升至室温搅拌过夜。控温10℃以下滴加20ml 的甲醇,搅拌1h,加入300ml碳酸氢钠水溶液,搅拌15分钟,分液,水相加入100ml二氯甲烷萃取,萃取,分液。有机相加硫酸钠干燥,抽滤,母液约30℃浓缩,得油状物43.2g,粗品直接进行下一步反应。
13、化合物6d的合成
准备一个1000ml三口反应瓶,向反应瓶中加入33.5g的化合物5a和340mL的二氯甲烷,N2置换,降温至-5-0℃。一次性加入0.734g的DMAP,36.5g的三乙胺,N2置换,降温至-5-0℃。降至,滴加30.7g的CbzCl,控制内温<10℃,滴加毕升至室温搅拌过夜。控温10℃以下滴加 20ml的甲醇,搅拌1h,加入300ml碳酸氢钠水溶液,搅拌15分钟,分液,水相加入100ml 二氯甲烷萃取,萃取,分液。有机相加硫酸钠干燥,抽滤,母液约30℃浓缩,得油状物45.9g,粗品直接进行下一步反应。
14、化合物7a的合成
准备一个1000ml三口反应瓶,向反应瓶中加入41.8g化合物6a和294ml四氢呋喃。N2置换,降温至-5-0℃,滴加23.2g的TBAF的126ml四氢呋喃的溶液,控制内温<10℃,滴加毕升至室温搅拌2h,于约30℃减压蒸除溶剂,加水200ml,用乙酸乙酯100mlx3萃取,合并有机相,饱和食盐水溶液洗,无水硫酸钠干燥,过滤,滤液约30℃减压浓缩得油状物46.1g,硅胶柱层析(PE:EA=5:1至2:1)洗脱得无色油状物19.4g,两步收率79.1%。1H NMR(400MHz,CDCl3) δ4.22–4.01(m,6H),3.88(t,J=10.4Hz,1H),3.81–3.62(m,4H),3.52(t,J=5.2Hz,1H),2.56 (s,1H),1.92–1.78(m,2H),1.44(s,3H),1.38(s,3H),1.32(s,3H),1.28(d,J=11.6Hz,3H),1.16 (s,9H).
15、化合物8a的合成
准备一个10L三口反应瓶,向反应瓶中加入586g化合物7a和1.56L乙腈搅拌溶解,加入3.1L 甲苯,456g三苯基膦和235g咪唑,N2置换三次,冰水浴降温。T=0-5℃时,分批加入441g 的I2,加完后升至室温反应3.5h,降温至5-10℃,滴加600ml饱和硫代硫酸钠水溶液,加完搅拌15min,加入4L水,搅拌10min,分液,水相用2L二氯甲烷萃取两次,合并有机相。有机相用2.5L饱和食盐水洗两次,加1.5kg硫酸钠干燥有机相,抽滤,滤液约30℃减压蒸馏除二氯甲烷,再升至约45℃除甲苯得到浓缩物。向残留液中加入1.2L石油醚打浆,抽滤,滤渣用600ml石油醚二次打浆,合并滤液,旋干,得到粗品764g,直接投入下一步。1H NMR(400MHz,CDCl3)δ4.42(dt,J=8.8,5.5Hz,1H),4.22–4.05(m,5H),3.93(t,J=6.2Hz,1H),3.79(dtd,J=15.4,9.2,6.2Hz,2H),3.64(t,J=5.1Hz,1H),3.43(dd,J=9.8,5.3Hz,1H),3.26(t,J= 9.2Hz,1H),1.88(p,J=6.2Hz,2H),1.49(s,3H),1.44(s,3H),1.36(t,J=6.7Hz,6H),1.21(s, 9H).
16、化合物8b的合成
准备一个500ml三口反应瓶,向反应瓶中加入20g化合物7a,用150mL二氯甲烷溶解,再加入13.7mL三乙胺和300mg的DMAP,N2置换,降温至-5-0℃。向其中滴加10.4g的TsCl的二氯甲烷(50mL)溶液,控制内温<10℃,滴加毕升至室温搅拌过夜。加入50ml碳酸氢钠水溶液,搅拌5min,分液,有机相加硫酸钠干燥,抽滤,母液约30℃浓缩,得油状物29.1g,粗品直接进行下一步反应。
17、化合物8c的合成
准备一个500ml三口反应瓶,向反应瓶中加入15g化合物7a,用150mL二氯甲烷溶解,再加入10.3mL三乙胺,N2置换,降温至-5-0℃。向其中滴加6.9mL的Tf2O,控制内温<10℃,滴加毕升至室温搅拌5小时。加入50ml碳酸氢钠水溶液,搅拌15min,分液,有机相加硫酸钠干燥,抽滤,母液约30℃浓缩,得油状物20.5g,粗品直接进行下一步反应。
18、化合物9a的合成
准备一个10L三口反应瓶,向反应瓶中加入754g化合物8a和4.75L乙醇搅拌溶解,加入79g 氯化铵和290g锌粉,N2置换三次,85℃加热,弱回流反应1h。降温至室温,过硅藻土抽滤,滤饼用1.5L乙醇冲洗,35-40℃减压旋去大部分乙醇,倒入到冰浴冷却的5L饱和碳酸氢钠中,加入3L二氯甲烷,搅拌20min,硅藻土抽滤,加入1L二氯甲烷,冲洗滤饼,滤液分液。水相用2L二氯甲烷萃取两次,合并有机相,用2L氯化钠水溶液洗两次,有机相加500g的无水硫酸钠干燥,过滤,滤液于约35℃减压浓缩,得油状液体498g,粗品直接投入下一步。1H NMR(400MHz,CDCl3)δ6.05–5.87(m,1H),5.39(d,J=17.1Hz,1H),5.25(d,J=10.6Hz, 1H),4.28–4.14(m,4H),4.09–4.02(m,1H),3.93–3.86(m,1H),3.71(t,J=6.1Hz,2H),3.43 (dd,J=6.1,3.8Hz,1H),2.69(d,J=6.4Hz,1H),1.89(p,J=6.2Hz,2H),1.44(s,3H),1.35(s,3H),1.21(s,9H).
19、化合物10a的合成
准备一个10L三口反应瓶,向反应瓶中加入498g的化合物9a和3.9L甲醇,搅拌溶解,干冰冷却,内温降至4℃开始滴加88.6g的NaOH的392ml水溶液,30min滴完,内温处于6-8℃。移除冰浴,内温20-30℃,室温反应20h。约35℃减压旋甲醇,剩余1L左右停止,加入2L 的二氯甲烷,冰水浴降温。T=20-22℃时,滴加1L水,加完后搅拌分层,水相用300ml的二氯甲烷萃取5次,水相pH=10,合并有机相,加1.5L的饱和氯化铵溶液,加完后搅拌分层,水相pH=6,加300ml的DCM,萃取5次,合并有机相,加1kg的硫酸钠干燥,抽滤,滤液约35℃减压旋干,得到粗品。硅胶柱层析(PE:EA=3:1至1:1)洗脱,产物硫分馏减压于约35℃减压旋干,得淡黄色油状液体151g,3步产率42%。1H NMR(400MHz,CDCl3)δ7.80 –7.38(m,3H),5.96(ddd,J=17.1,10.5,5.6Hz,1H),5.37(dt,J=17.2,1.5Hz,1H),5.24(dt,J= 10.5,1.3Hz,1H),4.18(dd,J=12.1,6.3Hz,2H),4.04(dd,J=8.3,6.4Hz,1H),3.93(dd,J=8.3, 6.5Hz,1H),3.89–3.84(m,1H),3.84–3.79(m,1H),3.76(ddd,J=7.5,5.6,2.5Hz,3H),3.46(dd, J=5.4,4.4Hz,1H),3.06(s,1H),2.48(s,1H),1.87–1.75(m,2H),1.44(s,3H),1.35(s,3H).
20、化合物11a的合成
准备一个5L三口反应瓶,向反应瓶中加入150g化合物10a,1.5L二氯甲烷,N2保护,搅拌溶解,加入49g咪唑,N2置换三次,冰水浴降温。T=6℃时,滴加150ml的TBDPSCl,内温维持4-6℃,滴加完后保持5-10℃反应1h,反应结束,滴加800mL水,搅拌10min,分层,水相用400mL二氯甲烷萃取两次,合并有机相,用300ml饱和食盐水洗一次,有机相加300g 无水硫酸钠干燥。过滤,滤液于约35℃减压浓缩,得淡黄色油状液体300g,粗品直接投入下一步。
21、化合物11b的合成
准备一个500ml三口反应瓶,向反应瓶中加入15g化合物10a,150ml二氯甲烷,N2保护,搅拌溶解,加入4.9g咪唑,N2置换三次,冰水浴降温。T=6℃时,滴加82ml的TBSCl,内温维持4-6℃,滴加完后保持5-10℃反应1h,反应结束,滴加80mL水,搅拌10min,分层,水相用40mL二氯甲烷萃取两次,合并有机相,用30ml饱和食盐水洗一次,有机相加30g无水硫酸钠干燥。过滤,滤液于约35℃减压浓缩,得淡黄色油状液体26.8g,粗品直接投入下一步。
22、化合物12a的合成
准备一个5L三口反应瓶,向反应瓶中加入300g的化合物11a和1.3L的DMF,N2保护,搅拌溶解,加入71.5g咪唑,N2保护,冰水浴降温。T=7℃时,滴加130.6g的TBSCl的700
ml的DMF溶液,内温温控6-7℃,加完后升至室温反应,内温20-30℃反应16h。反应结束,冰水浴冷却,内温12℃,滴加1L水,内温15-18℃,搅拌10min,加入1L石油醚,分液。水层加入2L石油醚和3L水,分层萃取,有机相用1.5L水洗三次,每次的水相用200ml 石油醚反萃一次,合并所有有机相,加入200g硫酸钠干燥有机相,过滤,滤液减压浓缩,得黄色油状液体376g。硅胶柱层析(PE:EA=100:0至50:1)洗脱,将目标组分于约35℃减压浓缩,得无色油状液体321g,两步收率88%。1H NMR(400MHz,CDCl3)δ7.69(d,J=6.9Hz, 4H),7.48–7.35(m,6H),5.95–5.79(m,1H),5.26(d,J=17.2Hz,1H),5.12(d,J=10.5Hz,1H), 4.24(td,J=7.1,3.7Hz,2H),3.92–3.70(m,6H),3.62–3.46(m,1H),1.84(p,J=6.3Hz,2H), 1.39(s,3H),1.36(s,3H),1.11–1.03(m,9H),0.93(s,9H),0.10(s,3H),0.07(s,3H).
23、化合物12b的合成
准备一个1L三口反应瓶,向反应瓶中加入22.3g的化合物11b和130ml的DMF,N2保护,搅拌溶解,加入6.9g咪唑,N2保护,冰水浴降温。T=5℃时,滴加13.1g的TBSCl的70ml 的DMF溶液,内温温控6-7℃,加完后升至室温反应,内温20-30℃反应16h。反应结束,冰水浴冷却,内温12℃,滴加100ml水,内温15-18℃,搅拌10min,加入100ml石油醚,分液。水层加入200ml石油醚和300ml水,分层萃取,有机相用150ml水洗三次,每次的水相用20ml石油醚反萃一次,合并所有有机相,加入20g硫酸钠干燥有机相,过滤,滤液减压浓缩,得黄色油状液体35.6g。硅胶柱层析洗脱,将目标组分于约35℃减压浓缩,得无色油状液体26.6g。
24、化合物12c的合成
准备一个500ml三口反应瓶,向反应瓶中加入30g的化合物11a和130ml的DMF,N2保护,搅拌溶解,加入7.0g咪唑,N2保护,冰水浴降温。T=7℃时,滴加23.7g的TBDPSCl的70ml的DMF溶液,内温温控6-7℃,加完后升至室温反应,内温20-30℃反应16h。反应结束,冰水浴冷却,内温12℃,滴加100ml水,内温15-18℃,搅拌10min,加入100ml石油醚,分液。水层加入200ml石油醚和300ml水,分层萃取,有机相用150ml水洗三次,每次的水相用20ml石油醚反萃一次,合并所有有机相,加入20g硫酸钠干燥有机相,过滤,滤液减压浓缩,得黄色油状液体。硅胶柱层析洗脱,将目标组分于约35℃减压浓缩,得无色油状液体 38.2g。
25、化合物12d的合成
准备一个1L三口反应瓶,向反应瓶中加入22.4g的化合物11b和130ml的DMF,N2保护,搅拌溶解,加入7.0g咪唑,N2保护,冰水浴降温。T=7℃时,滴加23.7g的TBDPSCl的70ml的DMF溶液,内温温控6-7℃,加完后升至室温反应,内温20-30℃反应16h。反应结束,冰水浴冷却,内温12℃,滴加100ml水,内温15-18℃,搅拌10min,加入100ml石油醚,分液。水层加入200ml石油醚和300ml水,分层萃取,有机相用150ml水洗三次,每次的水相用20ml石油醚反萃一次,合并所有有机相,加入20g硫酸钠干燥有机相,过滤,滤液减压浓缩,得黄色油状液体。硅胶柱层析洗脱,将目标组分于约35℃减压浓缩,得无色油状液体 32.3g。
26、化合物13a的合成
准备一个5L三口反应瓶,向反应瓶中加入330g的化合物12a和3.3L二氯甲烷,N2保护,降温至0-5℃,加入41.25ml水,滴加82.5ml三氟乙酸,控制内温0~5℃,滴完后于0-5℃下搅拌1h。向体系中滴加饱和碳酸氢钠水溶液调PH至7,分液,水相用二氯甲烷500mL萃取三次,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩得淡黄色油状物液体315.3g,粗品直接投入下一步。1H NMR(400MHz,CDCl3)δ7.66(d,J=6.7Hz,4H),7.48–7.31(m,6H), 6.00(ddd,J=17.2,10.7,4.6Hz,1H),5.34(d,J=17.3Hz,1H),5.26(d,J=10.7Hz,1H),4.54(t,J=4.5Hz,1H),3.87–3.80(m,2H),3.77–3.58(m,6H),3.43(dd,J=8.2,4.5Hz,1H),2.25(dd,J =7.5,5.1Hz,1H),1.79(p,J=6.1Hz,2H),1.06(s,9H),0.94(s,9H),0.14(s,3H),0.11(s,3H).
27、化合物13b的合成
准备一个1L三口反应瓶,向反应瓶中加入26.2g的化合物12b和260ml二氯甲烷,N2保护,降温至0-5℃,加入4ml水,滴加8ml三氟乙酸,控制内温0~5℃,滴完后于0-5℃下搅拌1h。向体系中滴加饱和碳酸氢钠水溶液调PH至7,分液,水相用二氯甲烷50mL萃取三次,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩得淡黄色油状物液体29.8g,粗品直接投入下一步。
28、化合物13c的合成
准备一个1L三口反应瓶,向反应瓶中加入39.8g的化合物12c和400ml二氯甲烷,N2保护,降温至0-5℃,加入4ml水,滴加8ml三氟乙酸,控制内温0~5℃,滴完后于0-5℃下搅拌1h。向体系中滴加饱和碳酸氢钠水溶液调PH至7,分液,水相用二氯甲烷50mL萃取三次,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩得淡黄色油状物液体29.8g,粗品直接投入下一步。
29、化合物13d的合成
准备一个1L三口反应瓶,向反应瓶中加入33g的化合物12d和330ml二氯甲烷,N2保护,降温至0-5℃,加入4ml水,滴加8.3ml三氟乙酸,控制内温0~5℃,滴完后于0-5℃下搅拌1h。向体系中滴加饱和碳酸氢钠水溶液调PH至7,分液,水相用二氯甲烷50mL萃取三次,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩得淡黄色油状物液体31.2g,粗品直接投入下一步。
30、化合物14a的合成
准备一个5L三口反应瓶,向反应瓶中加入315.3g化合物13a和2500mL二氯甲烷,N2置换,降温至-5-0℃。一次性加入6.89g的DMAP和72.5g三乙胺,于该温度下滴加119.4g的对甲苯磺酰氯的600mL二氯甲烷溶液,滴加完毕后,反应体系升至室温搅拌过夜。将反应体系温度降低至内温<5℃,滴加500mL饱和食盐水,搅拌10min,分液。有机相加硫酸钠干燥,抽滤,滤液约30℃减压浓缩,得黄色油状物435.6g,粗品直接投入下一步。1H NMR(400MHz,CDCl3)δ7.78(d,J=8.1Hz,2H),7.65(d,J=7.5Hz,4H),7.48–7.34(m,6H),7.28(d,J=8.0Hz, 2H),5.97–5.84(m,1H),5.32–5.25(m,1H),5.21(d,J=10.7Hz,1H),4.50(s,1H),4.21–4.06 (m,2H),3.86–3.75(m,2H),3.70(td,J=10.3,4.3Hz,2H),3.61–3.51(m,2H),3.36(dd,J=8.3, 4.3Hz,1H),2.40(s,3H),1.72(p,J=6.1Hz,2H),1.05(s,9H),0.90(s,9H),0.10(s,3H),0.07(s, 3H).
31、化合物14b的合成
准备一个1L三口反应瓶,向反应瓶中加入24.5g化合物13b和250mL二氯甲烷,N2置换,降温至-5-0℃。一次性加入0.7g的DMAP和7.23g三乙胺,于该温度下滴加7.2g的甲磺酰氯的60mL二氯甲烷溶液,滴加完毕后,反应体系升至室温搅拌过夜。将反应体系温度降低至内温<5℃,滴加50mL饱和食盐水,搅拌10min,分液。有机相加硫酸钠干燥,抽滤,滤液约30℃减压浓缩,得黄色油状物32.1g,粗品直接投入下一步。
32、化合物14c的合成
准备一个1L三口反应瓶,向反应瓶中加入38.5g化合物13c和250mL二氯甲烷,N2置换,降温至-5-0℃。一次性加入0.7g的DMAP和7.2g三乙胺,于该温度下滴加8.1g的乙基磺酰氯的60mL二氯甲烷溶液,滴加完毕后,反应体系升至室温搅拌过夜。将反应体系温度降低至内温<5℃,滴加50mL饱和食盐水,搅拌10min,分液。有机相加硫酸钠干燥,抽滤,滤液约30℃减压浓缩,得黄色油状物47g,粗品直接投入下一步。
33、化合物14d的合成
准备一个1L三口反应瓶,向反应瓶中加入31.5g化合物13d和250mL二氯甲烷,N2置换,降温至-5-0℃。一次性加入0.7g的DMAP和7.2g三乙胺,于该温度下滴加7.18g的甲磺酰氯的60mL二氯甲烷溶液,滴加完毕后,反应体系升至室温搅拌过夜。将反应体系温度降低至内温<5℃,滴加500mL饱和食盐水,搅拌10min,分液。有机相加硫酸钠干燥,抽滤,滤液约30℃减压浓缩,得黄色油状物42.8g,粗品直接投入下一步。
34、化合物1a的合成
准备一个10L三口反应瓶,带温度计,机械搅拌。向反应瓶中加入435.6g化合物14a和4.3L 甲醇,N2置换,降温至-5-0℃。降至,加入169.0g碳酸钾,控制内温<10℃,加毕升至室温搅拌1h,减压浓缩溶剂,粗品硅胶柱层析(PE:EA=100:1至50:1)洗脱得无色油状物241.9g,3 步总收率81.3%。1H NMR(400MHz,CDCl3)δ7.72–7.61(m,4H),7.49–7.32(m,6H),5.91 (ddd,J=17.1,10.5,5.4Hz,1H),5.27(dt,J=17.2,1.6Hz,1H),5.13(dd,J=10.5,1.4Hz,1H), 4.30(t,J=5.2Hz,1H),3.73(t,J=6.2Hz,2H),3.70–3.60(m,2H),3.34–3.26(m,1H),3.09(dd, J=6.6,3.7Hz,1H),2.73(dd,J=5.6,2.7Hz,1H),2.66(dd,J=5.5,4.1Hz,1H),1.78(p,J=6.3 Hz,2H),1.05(s,9H),0.92(s,9H),0.09(s,3H),0.06(s,3H).
35、化合物1b的合成
准备一个1L三口反应瓶,带温度计,机械搅拌。向反应瓶中加入3.2g化合物14b和320ml 甲醇,N2置换,降温至-5-0℃。降至,加入17.1g碳酸钾,控制内温<10℃,加毕升至室温搅拌 1h,减压浓缩溶剂,粗品硅胶柱层析(PE:EA=100:1至50:1)洗脱得无色油状物18.5g。
36、化合物1c的合成
准备一个1L三口反应瓶,带温度计,机械搅拌。向反应瓶中加入4.8g化合物14c和480ml 甲醇,N2置换,降温至-5-0℃。降至,加入1.71g碳酸钾,控制内温<10℃,加毕升至室温搅拌 1h,减压浓缩溶剂,粗品硅胶柱层析(PE:EA=100:1至50:1)洗脱得无色油状物2.9g。
37、化合物1d的合成
准备一个1L三口反应瓶,带温度计,机械搅拌。向反应瓶中加入4.36g化合物14d和436ml 甲醇,N2置换,降温至-5-0℃。降至,加入17g碳酸钾,控制内温<10℃,加毕升至室温搅拌 1h,减压浓缩溶剂,粗品硅胶柱层析(PE:EA=100:1至50:1)洗脱得无色油状物24.3g。
38、化合物18a的合成
准备一个20L三口反应瓶,向反应瓶中加入1130g化合物4a(粗品折算)和11.3L的四氢呋喃,N2置换,控温0-10℃加入546g的TBAF·3H2O,保温反应1h后升温至20-30℃反应1-2h。反应液约30℃减压浓缩,向残留液中加入3.3L乙酸乙酯和3.3L水,搅拌,分液,水相加1.1L 乙酸乙酯,萃取,分液,重复操作3-5次。合并有机相加2.2L饱和食盐水,分液,干燥有机相。抽滤,料液约30℃减压浓缩。硅胶柱层析(PE:EA=20:1至8:1)洗脱得油状液体376g,3步收率56%。
39、化合物18b的合成
准备一个1L三口反应瓶,向反应瓶中加入11.5g化合物4b(粗品折算)和115ml的四氢呋喃,N2置换,控温0-10℃加入5.5g的TBAF·3H2O,保温反应1h后升温至20-30℃反应1-2h。反应液约30℃减压浓缩,向残留液中加入330ml乙酸乙酯和330ml水,搅拌,分液,水相加115ml乙酸乙酯,萃取,分液,重复操作3-5次。合并有机相加230ml饱和食盐水,分液,干燥有机相。抽滤,料液约30℃减压浓缩。硅胶柱层析(PE:EA=20:1至8:1)洗脱得油状液体3.81g,3步收率56%。
40、化合物19a的合成
准备一个20L三口反应瓶,向反应瓶中加入928g的化合物18a,838g三苯基膦,435g咪唑, 9.3L甲苯和4.6L乙腈,N2置换,控温-5-5℃加入811g碘,加完后,冰水浴保温1h,升温至 20-30℃搅拌3h。向反应中加入0.9L的5%硫代硫酸钠水溶液淬灭反应,反应液约30℃减压浓缩,向残留液中加入5L二氯甲烷,4.5L的5%食盐水搅拌,分液,水相加0.9L二氯甲烷萃取,分液,合并有机相加入0.9L饱和食盐水洗涤,分液,重复操作一次,分液干燥有机相。抽滤,滤液约30℃减压浓缩。向残留液中加入5L正己烷打浆,得油状物1022g,收率76%。
41、化合物19b的合成
准备一个500ml三口反应瓶,向反应瓶中加入12g化合物18b,用120mL二氯甲烷溶解,再加入9.2mL三乙胺,N2置换,降温至-5-0℃。向其中滴加6.1mL的Tf2O,控制内温<10℃,滴加毕升至室温搅拌5小时。加入40ml碳酸氢钠水溶液,搅拌15min,分液,有机相加硫酸钠干燥,抽滤,母液约30℃浓缩,得油状物16.2g,粗品直接进行下一步反应。
42、化合物20a的合成
准备一个10L三口反应瓶,向反应瓶中加入1000g化合物19a,570.6g锌粉,23.34g氯化铵和5L甲醇,N2置换,升温至回流,反应1h。降温至50℃后加0.1L水淬灭,约0℃减压浓缩,向残留液中加入4L二氯甲烷搅洗,抽滤,硅藻土助滤,滤饼用1L二氯甲烷打浆3次,合并滤液,加入2L的5%食盐水洗涤2次,合并水相,加1L二氯甲烷反萃一次,合并有机相,干燥,抽滤,滤液约30℃减压浓缩,得油状物680g,粗品直接下一步反应。1H NMR(400 MHz,CDCl3)δ6.02–5.89(m,1H),5.39(dt,J=17.2,1.4Hz,1H),5.25(dd,J=10.5,1.3Hz,1H), 4.20–4.09(m,2H),4.01(dd,J=8.2,6.4Hz,1H),3.99–3.87(m,3H),3.72(s,3H),3.48(t,J=5.2Hz,1H),3.21(dd,J=17.9,6.4Hz,1H),2.67–2.51(m,2H),1.44(s,3H),1.36(s,3H).
43、化合物21a的合成
准备一个20L三口反应瓶,向反应瓶中加入680g化合物20a,303g咪唑,4.5L的DMF,N2置换,降温0-10℃。降至,控温10℃以下滴加523g的TBSCl的DMF(1L)溶液,滴加完毕后,保温反应1h后升温至20-30℃,反应15-18h。向反应液中加入2L饱和碳酸氢钠,5L水和2L石油醚搅拌,分液,水相加2L石油醚萃取,合并有机相,加2L水洗两次,用无水硫酸钠干燥有机相。抽滤,滤液约30℃减压浓缩。粗品硅胶柱层析(PE:EA=100:1至75:1) 洗脱得油状物594g,2步收率70%。
44、化合物22a的合成
准备一个10L三口反应瓶,向反应瓶中加入360g化合物21a和3.6L四氢呋喃,N2置换,控温-20--10℃滴加1.85L的DIBAL-H甲苯溶液(1.5M),滴毕,保温-10-0℃反应1h。用饱和氯化铵溶液调PH至7-8。向反应液中加入1080g酒石酸钾钠的水溶液和1L二氯甲烷搅拌,分液,水相加1L二氯甲烷,萃取,分液,合并有机相加1L饱和食盐水,洗涤,分液,重复操作两次,分液干燥有机相。抽滤,滤液约30℃减压浓缩,得油状物3050g,收率84.4%,粗品直接进行下一步反应。1H NMR(400MHz,CDCl3)δ5.89(ddd,J=17.1,10.5,5.5Hz,1H), 5.33–5.27(m,1H),5.17(dt,J=10.5,1.5Hz,1H),4.28(dd,J=5.4,3.9Hz,1H),4.23(td,J=6.7,4.1Hz,1H),3.96–3.91(m,1H),3.89–3.73(m,5H),3.48(t,J=4.0Hz,1H),2.77(s,1H),1.91– 1.73(m,2H),1.44(s,4H),1.33(s,3H),0.92(s,9H),0.09(s,3H),0.05(s,3H).
45、化合物12a的合成
准备一个20L三口反应瓶,向反应瓶中加入275g化合物22a,9.32g的DMAP,123.5g三乙胺和2750mL二氯甲烷,N2置换,降温至0-5℃。降至,控温0-10℃滴加272.5g的TBDPSCl,加完于该温度反应0.5h,后20-30℃反应4h。向反应液中加入1400mL饱和碳酸氢钠,搅拌30min,分液,水相加550mL二氯甲烷萃取,分液,至水相无产品点,合并有机相加1100mL 饱和食盐水洗,无水硫酸钠干燥,过滤,滤液约30℃减压浓缩。粗品硅胶柱层析(PE:EA=100:0至100:1)洗脱得油状物360g,收率80%。
以上显示和描述了本发明的具体实施实例以及本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还需不断变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (27)
1.一种艾地骨化醇中间体化合物1的制备方法,其特征在于包括下列步骤:
(1)将式化合物2进行选择性伯醇保护转化为化合物3
其中R1为羟基保护基
(2)化合物3发生加成反应得到化合物4
其中R2为烷基或芳基
(3)化合物4经过将酯基还原生成化合物5
(4)化合物5经过酰化或取代反应生成化合物6
其中R3为羟基保护基
(5)化合物6经过选择性脱保护基反应生成化合物7
(6)化合物7的羟基经过Mitsnobu反应或者酰化反应生成化合物8
其中R4为易离去基团
(7)化合物8经过还原反应生成化合物9
(8)化合物9经过脱保护基生成化合物10
(9)化合物10经过选择性上保护基生成化合物11
(10)化合物11经过上保护基生成化合物12
其中R5和R6均为羟基保护基
(11)化合物12经过选择性脱保护基生成化合物13
(12)化合物13经过选择性上保护基生成化合物14
其中R7为烷基磺酰基或芳基磺酰基
(13)化合物14经过分子内关环反应生成化合物1
其中,上述化合物4制备中间体12可以通过上述方法即先还原酯基再构建烯烃得到中间体12,也可以构建烯烃再还原酯基,其特征包括下列步骤:
(14)化合物4经过选择性脱保护基反应生成化合物18
其中R1为羟基保护基,R2为烷基或芳基
(15)化合物18的羟基经过Mitsnobu反应生成或者酰化反应生成化合物19
其中R4为易离去基团
(16)化合物19经还原反应生成化合物20
(17)化合物20经羟基上保护基生成化合物21
其中R2为烷基或芳基,R6为羟基保护基
(18)化合物21经酯基还原生成化合物22
其中R2为烷基或芳基,R6为羟基保护基
(19)化合物22经羟基上保护基生成化合物12
其中R5和R6均为羟基保护基。
2.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(1)中,R1为羟基保护基,更优选为(C1-C10烷基或芳基)3硅烷基,进一步优选为TBS和TBDPS,通过在碱条件下进行羟基保护,有机碱选自三乙胺,NMM,DIPEA,吡啶,2,6-二甲基吡啶中的一种。
3.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(2)中,R2为烷基或芳基,更优选为甲基,乙基,叔丁基,异丙基。
4.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(3)中,R1如权利要求2中定义,R2如权利要求3所定义。还原剂选自DIBAL-H,LAH,NaBH4的一种,更优选为DIBAL-H。
5.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(4)中,R3为羟基保护基,更优选为Piv,Bz,Cbz,Allyl。
6.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(5)中,氟化试剂选自KF、吡啶氢氟酸、氟化铵、三乙胺三氢氟酸盐和TBAF·3H2O等氟化物的一种,更优选为TBAF·3H2O。
7.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(6)中,R4为易离去基团,更优选为I,Br,OTs,OMs,OTf。
8.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(7)中,还原剂选自锌粉和铁粉,更优选为锌粉。
9.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(8)中,R3如权利要求5所定义。
10.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(9)中,R5为羟基保护基,R5为(C1-C10烷基或芳基)3硅烷基或SEM,进一步优选为TBS和TBDPS。
11.根据权利要求1所述一种制备艾地骨化醇中间体的方法,其特征在于:步骤(10)中,R6为羟基保护基,R6为(C1-C10烷基或芳基)3硅烷基或SEM,进一步优选为TBS和TBDPS。
12.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(11)中,R5如权利要求10所定义,R6如权利要求11所定义,通过在酸存在下进行脱保护。
13.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(12)中,R5如权利要求10所定义,R6如权利要求11所定义,R7为烷基磺酰基或芳基磺酰基,进一步优选为甲磺酰基,乙基磺酰基,2-甲基苯磺酰基,2,6-二甲基苯磺酰基。
14.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(13)中,R5如权利要求10所定义,R6如权利要求11所定义,通过在碱存在下进行关环反应。
15.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(14)中,R1如权利要求2所定义,R2如权利要求3所定义,通过在氟化剂存在下进行脱保护反应。
16.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(15),(16)中R2如权利要求2所定义,R4如权利要求7所定义。
17.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(17)中,R2如权利要求3所定义,R6如权利要求11所定义。
18.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(18)中,R2如权利要求2所定义,R6如权利要求11所定义,还原剂选自DIBAL-H,LAH,NaBH4,更优选为DIBAL-H。
19.根据权利要求1所述一种艾地骨化醇中间体的制备方法,其特征在于:步骤(19)中,R5如权利要求10所定义,R6如权利要求11所定义,通过在碱存在下进行羟基保护。
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