CN104860980B - It is a kind of to be used to synthesize intermediate of Ezetimibe and its preparation method and application - Google Patents
It is a kind of to be used to synthesize intermediate of Ezetimibe and its preparation method and application Download PDFInfo
- Publication number
- CN104860980B CN104860980B CN201510198353.1A CN201510198353A CN104860980B CN 104860980 B CN104860980 B CN 104860980B CN 201510198353 A CN201510198353 A CN 201510198353A CN 104860980 B CN104860980 B CN 104860980B
- Authority
- CN
- China
- Prior art keywords
- preparation
- reaction
- compound
- formula
- ezetimibe
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 title abstract description 24
- 229960000815 ezetimibe Drugs 0.000 title abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 102000004190 Enzymes Human genes 0.000 claims abstract description 9
- 108090000790 Enzymes Proteins 0.000 claims abstract description 9
- -1 hydroxyl group compound Chemical class 0.000 claims abstract description 9
- 238000006722 reduction reaction Methods 0.000 claims abstract description 8
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- 150000001299 aldehydes Chemical class 0.000 claims description 11
- 108010031132 Alcohol Oxidoreductases Proteins 0.000 claims description 10
- 102000005751 Alcohol Oxidoreductases Human genes 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 230000004224 protection Effects 0.000 claims description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
- 108010050375 Glucose 1-Dehydrogenase Proteins 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 239000008103 glucose Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- GQNZGCARKRHPOH-RQIKCTSVSA-N miocamycin Chemical compound C1[C@](OC(C)=O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](OC(C)=O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C GQNZGCARKRHPOH-RQIKCTSVSA-N 0.000 claims description 4
- 229910052710 silicon Inorganic materials 0.000 claims description 4
- 239000010703 silicon Substances 0.000 claims description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 4
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical group CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 3
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 150000002148 esters Chemical group 0.000 claims description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 2
- XJLXINKUBYWONI-NNYOXOHSSA-O NADP(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-O 0.000 claims 2
- XXSSRSVXDNUAQX-QGZVFWFLSA-N 1-(4-fluorophenyl)-5-[(4s)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]pentane-1,5-dione Chemical compound C1=CC(F)=CC=C1C(=O)CCCC(=O)N1C(=O)OC[C@@H]1C1=CC=CC=C1 XXSSRSVXDNUAQX-QGZVFWFLSA-N 0.000 claims 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 125000003916 ethylene diamine group Chemical group 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 21
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 230000008569 process Effects 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000003287 optical effect Effects 0.000 abstract description 4
- 238000007363 ring formation reaction Methods 0.000 abstract description 4
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229910007161 Si(CH3)3 Inorganic materials 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 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 description 3
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 3
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- 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 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 0 COC(CC(c1ccc(*)cc1)=O)=O Chemical compound COC(CC(c1ccc(*)cc1)=O)=O 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910003074 TiCl4 Inorganic materials 0.000 description 2
- 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 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 description 1
- GRHQDJDRGZFIPO-UHFFFAOYSA-N 4-bromobutanoic acid Chemical class OC(=O)CCCBr GRHQDJDRGZFIPO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- PQRDKLNYMZGFRW-LBPRGKRZSA-N CCOC(C[C@@H](c(cc1)ccc1OC(C)=O)O)=O Chemical compound CCOC(C[C@@H](c(cc1)ccc1OC(C)=O)O)=O PQRDKLNYMZGFRW-LBPRGKRZSA-N 0.000 description 1
- SLSMILXGFSQOHY-UHFFFAOYSA-N COC(CC(c(cc1)ccc1OC)O)=O Chemical compound COC(CC(c(cc1)ccc1OC)O)=O SLSMILXGFSQOHY-UHFFFAOYSA-N 0.000 description 1
- KBQMWOVHEGHXDR-HNNXBMFYSA-N COc1ccc([C@H](CC2=O)N2c(cc2)ccc2F)cc1 Chemical compound COc1ccc([C@H](CC2=O)N2c(cc2)ccc2F)cc1 KBQMWOVHEGHXDR-HNNXBMFYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 101001110310 Lentilactobacillus kefiri NADP-dependent (R)-specific alcohol dehydrogenase Proteins 0.000 description 1
- HWFFFQWCACGJBD-UHFFFAOYSA-N NC1=CC=CC=C1.[F] Chemical compound NC1=CC=CC=C1.[F] HWFFFQWCACGJBD-UHFFFAOYSA-N 0.000 description 1
- YTKHATNFOMQGFZ-UHFFFAOYSA-N Obtusilic acid Natural products CC1C(CCC2(C)CCC3(COC(=O)C=C/c4ccc(O)cc4)C(=CCC5C6(C)CCC(O)C(C)(C)C6CCC35C)C12)C(=O)O YTKHATNFOMQGFZ-UHFFFAOYSA-N 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- DVVKRMISXLKYIF-UHFFFAOYSA-N [Br].FC1=CC=C(C=C1)[Mg] Chemical compound [Br].FC1=CC=C(C=C1)[Mg] DVVKRMISXLKYIF-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910000765 intermetallic Inorganic materials 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000003951 lactams Chemical group 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- WDWDWGRYHDPSDS-UHFFFAOYSA-N methanimine Chemical compound N=C WDWDWGRYHDPSDS-UHFFFAOYSA-N 0.000 description 1
- 210000000110 microvilli Anatomy 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Abstract
The present invention disclose it is a kind of be used for synthesize intermediate of Ezetimibe and preparation method thereof.The intermediate has the structure as shown in formula III, and synthesis is generated chiral hydroxyl group compound through asymmetric reduction reaction in the case where aldehyde ketone restores enzyme catalysis, then obtained product through ring-closure reaction using enzymology method, raw material compound.The intermediate is used to prepare Ezetimibe, simple for process, and products therefrom concentration is high, and have the advantages that product optical purity is high, reaction condition is mild, it is environmentally friendly, easy to operate, be easy to industry amplification, with good prospects for commercial application.
Description
Technical field
The invention belongs to organic chemistry fileds, and in particular to a kind of intermediate and its preparation side for being used to synthesize Ezetimibe
Method and application.
Background technology
Ezetimibe is a breakthrough in blood lipid-lowering medicine research, and U.S. FDA approval was obtained in 2002, into
For from after statins, the first lipid-regulation medicine with complete innovation effect mechanism.The medicine is by inhibiting food and bile
In cholesterol and phytosterol in the absorption of intestinal brush border, reduce transhipment of the cholesterol from enteron aisle to liver, reduce liver
The storage capacity of middle cholesterol increases the removing of Blood Cholesterol, so as to reduce blood plasma cholesterol level.Cut-off 2011, according to
The original of Ezetimibe grinds folk prescription tablet and composite tablet and obtains SFDA approvals respectively, in Discussion on Chinese Listed.The structural formula of Ezetimibe
It is as follows：
About Ezetimibe synthesis it has been reported that by starting material, synthesis step or intermediate difference, these
There are mainly four types of synthetic methods, including：
Route one：
A kind of synthetic method is provided in patent US5767115：With glutaric anhydride in CH3The lower open loop of OH effects obtains mono-methyl
Compound, then chloride compounds are obtained after chloride, compound is then recrystallized to obtain after amidation, in DIPEA, TiCl4Condition
Lower and imines cyclization, then through hydrolysis, chloride and bromine 4- fluorophenyl magnesium in ZnCl2、Pd(PPh3)4Effect it is lower (3S, 4R)-interior
Amide ring finally uses (R)-MeCBS/BH3Reduction, palladium carbon hydrogenation debenzylation protect to obtain Ezetimibe.Specific route is as follows：
For this method using the grignard reaction synthesis key intermediate of condition harshness, yield is relatively low, needs to use column chromatography
Purifying, and synthetic route is relatively complicated, needs using four expensive triphenyl phosphorus palladium catalysts.
Similar approach is also used in relation to document and patent US5919672, difference lies in allow it after synthesis chloride compounds
Optical isomerism mixture is obtained by the reaction with group with imine moiety, it is chiral to split (3R, 4S)-lactam nucleus.Route is as follows：
Although the method reduces step, but need to obtain the intermediate with optical purity using chiral resolution, bright
Aobvious unsuitable industrialized production.
Route two：
In patent US5856473, use using 5- (4- fluorophenyls) -4- penetenoic acids as raw material and key intermediate, through four steps
Reaction structure has the compound there are two chiral centre, then obtains Ezetimibe in the hydroxyl of one S configuration of benzyl position introducing, entirely
Seven step of synthetic route, total recovery 16% or so.Route is as follows：
Patent WO2010012775 also uses similar route, the difference is that being made with triphenylphosphine and 4- bromobutyrates
Wittig reagents are reacted with 4- fluobenzoic acids, mainly generate (Z) -5- (4- fluorophenyls) amyl- obtusilic acid.
Patent WO9716424 also when only synthesizing (3R, 4S)-lactam nucleus is acted in LDA/THF using similar route
Under be condensed to yield enantiomeric mixture.Through isolated (3R, the 4S)-lactam nucleus of chromatographic column, then with upper same procedure
Obtain Ezetimibe.The shortcomings that chiral resolution is needed to be the method, and prepare wherein (3R, 4S)-lactam nucleus when, reaction need
It is carried out at -76 DEG C to -78 DEG C.
This route raw material is expensive, route is long, complex process and operation are relatively difficult, and chirality is difficult to control.
Route three：
It is anti-to carry out Fu Ke mainly using fluorobenzene and glutaric anhydride as raw material under the action of lewis acid by patent US6207822
Compound 4 should be obtained, amidation obtains compound 17, and compound 17 is carried out in the presence of (R)-methyl-CBS- oxazaborolidines
Chiral reduction reacts, prepare compound 18, while the compound 18 protected and the group with imine moiety of protection, via Mannich idols
Reaction generation compound 19 is closed, compound 19 is with tetrabutyl ammonium fluoride and the bis- trimethyl silicane alkyl acetamide reaction generations of N, O- according to folding
Mai Bu, route are as follows：
4US6207822, WO2007120824, WO2010071358 etc. also employ similar route, and difference is the introduction of
Different ketal protections and hydroxylation reagent, and the sequencing of chiral reduction has narrow difference.
Route four：
Patent US5886171 and WO9745406 is with (4S)-hydroxyl tetrahydrofuran -2- ketone and N- (4- fluorophenyls) -4- benzyloxies
Base benzene methylene amine is starting material, under cryogenic, (3R, 4S)-amide is obtained with LDA cyclizations.Entire building-up process
Totally seven step, total recovery is 20%.Synthetic route is as follows：
The deficiency of this route be repeatedly to be related in building-up process metallic compound Li, LDA to air-sensitive,
TiCl4Deng use and -78 DEG C of low-temp reaction, and using the reaction of catalytic hydrogenation ethylene linkage under Pd/C high pressures, grasped in technique
Make complexity, and severe reaction conditions.
From the existing route of synthesis Ezetimibe as can be seen that the structure of chiral hydroxyl group and lactam structure be synthesis according to
The committed step of Ezetimibe, and these routes are in the prevalence of complex process, of high cost, the bad, prospects for commercial application of selectivity
Low defect.To solve problem in the prior art, the technical barrier of external drugmaker is captured, urgent need finds a work
The synthetic route that skill is simple, of low cost, selectivity is good, is easy to efficiently separate and is suitble to scale industrial production.
Invention content
The present invention is intended to provide it is a kind of for synthesizing the intermediate of Ezetimibe, there is the structure as shown in formula III, i.e.,
(S) -1- (4- fluorophenyls) -4- (4- substituted-phenyls)-nitrogen heterocyclic din-2-ketone.The intermediate is synthesized using enzyme-chemical method, former
Expect that compound generates chiral hydroxyl group compound in the case where aldehyde ketone restores enzyme catalysis through asymmetric reduction reaction, it is then anti-through cyclization
It should obtain product.The intermediate passes through two-step process, you can Ezetimibe is made, step is few, simple for process, high income.
Specifically, the purpose of the present invention is realized by the following aspects.
The first aspect of the invention is to provide a kind of intermediate for being used to synthesize Ezetimibe, has such as formula III institute
The chemical constitution shown：
Wherein, R is hydroxyl protection base, preferably silicon ether protecting group (such as TMS, TBDPS, TBDMS, TIPS), acetyl group,
Benzoyl, benzyl, MOM, C1-C4Alkyl, THP etc..
The second aspect of the invention is to provide the preparation method of intermediate shown in above-mentioned formula III, includes the following steps：
A) in the case where aldehyde ketone restores enzyme catalysis, asymmetric reduction reaction, production IV compounds occur for Formula V compound；
B) with bromide reagent bromo-reaction occurs for formula IV compound in organic solvent, then under weak base effect and to fluorine
Aniline reaction obtains formula III compound；
Reaction equation is as follows：
Wherein, R is hydroxyl protection base, preferably silicon ether protecting group (such as TMS, TBDPS, TBDMS, TIPS), acetyl group,
Benzoyl, benzyl, MOM, C1-C4Alkyl, THP etc.；R ' is ester residue, such as alkyl, preferably C1-C4Alkyl.
The reaction of step a) carries out in the aqueous solution of pH value 5.0-8.0.Wherein, the Formula V compound is in reactant
Preferred concentration in system is 10-1000g/L.Aldehyde ketone restores enzyme dosage as catalytically effective amount, preferably 1-20g/L.
Preferably, isopropanol or the group containing NADP+, glucose and glucose dehydrogenase are also contained in reaction system
It closes.The dosage of isopropanol is the 2%-10% of reaction system volume.Glucose dosage is preferably 1-20g/L, glucose dehydrogenase
Dosage be preferably 100-1000U/L, the dosage of NADP+ is catalytic amount, preferably 0.02-0.1mmol/L.
The aldehyde ketone reductase is that application No. is 201410706195.1 Chinese patent application (referred to as " citation Shens
Please ", it is the same below) disclosed in aldehyde ketone reductase, herein by the full text of this application introduce using as supplement and reference.The aldehyde
The SEQ ID NO of the amino acid sequence of ketoreductase such as the application:(the SEQ ID NO i.e. in citation application shown in 1:4).
It is easily understood that the recombination aldehyde ketone reductase or catalyst in being applied using citation are to substitute aldehyde ketone reductase
When, it can equally obtain formula III intermediate through the above method.It is included into the understanding scope of aldehyde ketone reductase in this together.
In step b), the organic solvent is with dissolution type IV compounds and para-fluoroaniline but can be not involved in chemically reacting
Those solvents, such as can be dimethylbenzene, toluene, dichloromethane, tetrahydrofuran etc..It is normal that this field may be used in bromo-reaction
Bromo-reaction condition, wherein bromide reagent are preferably phosphorus tribromide, phosphorus pentabromide, carbon tetrabromide etc..The weak base can
Selected from ethylenediamine, diisopropyl ethyl amine, N-methylmorpholine, to dimethylaminopyridine, triethylamine etc..
Preferably, formula IV compound and the molar ratio of bromide reagent are 1:1-3；Mole of formula IV compound and para-fluoroaniline
Than being 1:1-3；The molar ratio of weak base and para-fluoroaniline is 1:2-6.
The third aspect of the invention is to provide a kind of method for preparing Ezetimibe using above-mentioned formula III compound, packet
Include the following steps：
A) formula III compound is reacted with Formula IV compound under alkali effect, production II compounds；
B) Formula II compound eliminating hydroxide protecting group generates Ezetimibe；
Reaction equation is as follows：
Wherein, R and R " is hydroxyl protection base, can preferably be selected from each independently silicon ether protecting group (such as TMS, TBDPS,
TBDMS, TIPS etc.), acetyl group, benzoyl, benzyl, MOM, C1-C4Alkyl, THP etc..
In step a), formula III compound represented is dissolved in organic solvent, with Formula IV compound under alkali effect, in 60-
Production II compounds are reacted at 180 DEG C.The organic solvent is with dissolution type III and VI compound and can be not involved in reacting
Solvent, such as can be DMSO, toluene, tetrahydrofuran etc..The alkali preferably is selected from NaH, LDA, n-BuLi etc..
In the reaction system of step a), the molar ratio of the formula III compound and Formula IV compound is preferably 1:1-3；
The formula III compound and the molar ratio of alkali are preferably 1：1-3.
In step b), Formula II compound eliminating hydroxide protecting group preferably carries out in acid condition, such as in lewis acid or
It is hydrolyzed under the conditions of Bronsted acid, such as trifluoroacetic acid, hydrochloric acid, sulfuric acid etc..
The raw materials and reagents used in the present invention are commercially available or can be by existing known synthetic method easily
It is prepared.
The positive effect of the present invention is：For the deficiency in existing Ezetimibe synthesis technology (especially not
The defects of energy industrialization), the present invention provides a kind of for synthesizing new intermediate of Ezetimibe and preparation method thereof.Utilize this
New intermediate synthesizes Ezetimibe, and products therefrom concentration is high, and with product optical purity is high, reaction condition is mild, to ring
Border is friendly, it is easy to operate, be easy to the advantages of industry amplification, therefore with good prospects for commercial application.
Specific embodiment
The present invention is further described, but the present invention is not intended to be limited thereto with reference to embodiment.The following example
In the experimental procedures of actual conditions is not specified, carry out usually according to normal condition or according to the normal condition proposed by manufacturer.
(protein concentration of aldehyde ketone reductase is the aldehyde ketone reductase freeze-dried powder and crude enzyme liquid used in embodiment in crude enzyme liquid
10-15mg/mL) it is prepared with reference to the method that specification embodiment 3 is recorded in citation application, the aldehyde ketone reductase
Amino acid sequence such as the application SEQ ID NO:Shown in 1.
TLC conditions：EA:PE=1:3, the colour developing of iodine cylinder.
E.e. it is worth determination condition：Using equipped with Chiralpak IA columns (4.6 × 150mm：Second/heptane 90：10, flow velocity
1.5mL/min；40 DEG C of column temperature) 1100 liquid chromatograies of Agilent determine product configuration.
D.e. it is worth determination condition：Using equipped with Chiralpak IA columns (4.6 × 150mm：Second/heptane 90：10, flow velocity
1.5mL/min；40 DEG C of column temperature) 1100 liquid chromatograies of Agilent determine product configuration.
The synthesis of formula IV compound
Embodiment 1
Under stirring, by 20g substratesIt is added in the reaction solution containing following component：
700mL water, aldehyde ketone reductase freeze-dried powder 2g, glucose 7g and glucose dehydrogenase 500U (being purchased from sigma) and 0.1mM
NADP+ is stirred to react at 30 DEG C 16 hours, during which using the NaOH aqueous solution control system pH value of 1M between 6.5-7.5,
TLC detects reaction process.
After reaction, pH value is adjusted to be extracted 3 times with isometric ethyl acetate to about 9.0, merge organic phase, anhydrous slufuric acid
Sodium is dried, and decompression is spin-dried for solvent and obtains product 18.5g, yield 91.8%, purity 97.0%.
Product structure is confirmed by nuclear magnetic resonance spectroscopy, electrospray ionization mass spectrometry and e.e. values measure.
1H NMR(300MHz,CDCl3)：δ6.66-7.02(4H,m,Ar-H),5.14(1H,t,-CHOH),3.67(3H,
s,-OCH3),2.61-2.86(2H,d,-CH2CO2CH3),2.0(1H,s,-OH),0.08(9H,s,-Si(CH3)3).
MS(ESI)m/z：(M+H)=269.1.
Product retention time：R- types, 5.3min, S- types, 7.2min, e.e. values>99%.
Embodiment 2-4
With reference to the method for embodiment 1, using the substrate listed in table 1, embodiment 2-4 is carried out.
As a result as shown in table 1.
Table 1
Embodiment 5
Under stirring, by 20g substratesIt is added in the reaction solution containing following component：
The isopropanol of 700mL water, 200mL crude enzyme liquids and 20mL is stirred to react 16 hours at 30 DEG C, during which with the water-soluble hydraulic controls of the NaOH of 1M
System pH processed is between 6.5-7.5, TLC detection reaction process.
After reaction, pH value is adjusted to be extracted 3 times with isometric ethyl acetate to 9.0, merge organic phase, anhydrous sodium sulfate
Dry, decompression is spin-dried for solvent and obtains product 18.3g, yield 90.8%, purity 96.9%.
Product structure is confirmed by nuclear magnetic resonance spectroscopy, electrospray ionization mass spectrometry and e.e. values measure.
1H NMR(300MHz,CDCl3)：δ6.66-7.02(4H,m,Ar-H),5.14(1H,t,-CHOH),3.67(3H,
s,-OCH3),2.61-2.86(2H,d,-CH2CO2CH3),2.0(1H,s,-OH),0.08(9H,s,-Si(CH3)3).
MS(ESI)m/z：(M+H)=269.1.
Chiral purity is detected with embodiment 1, e.e. values>99%.
Embodiment 6-8
With reference to the method for embodiment 5, using the substrate listed in table 2, embodiment 6-8 is carried out.
As a result as shown in table 2.
Table 2
The synthesis of formula III compound
Embodiment 9
4 compound of formula (2.68g) is dissolved in 20mL dimethylbenzene, addition phosphorus tribromide (1.1mL), back flow reaction 5h, so
Use 20mL saturated sodium bicarbonate aqueous solutions and water washing successively afterwards, filtrate is dried with anhydrous sodium sulfate, filters.
Triethylamine (2.1mL) and para-fluoroaniline (1.1g) are added in filtrate, reaction 6h is stirred at room temperature, is then heated to 90
DEG C air-distillation, TLC monitoring reaction process.
After reaction, reaction solution is washed with water once, anhydrous sodium sulfate drying, filtering, and filtrate decompression concentration removes molten
Agent obtains 3 compound 2.84g of formula, yield 86.5%.
Product structure is confirmed by nuclear magnetic resonance spectroscopy, electrospray ionization mass spectrometry and e.e. values measure.
1H NMR(300MHz,CDCl3):δ7.02-7.08(4H,s,Ar-H),6.68-6.95(4H,s,Ar-H),4.85
(1H,t,ArCHN-),3.24-3.49(2H,d,-CH2CO-),0.08(9H,s,-Si(CH3)3).
MS(ESI)m/z：(M+H)=330.1.
Product retention time：R- types, 6.4min, S- types, 7.9min, e.e. values>95%.
Embodiment 10-12
With reference to the method for embodiment 9, using the substrate listed in table 3, embodiment 10-12 is carried out.
As a result as shown in table 3.
Table 3
Embodiment 13The synthesis of Ezetimibe
Step a)
3 compound of formula (6.58g) is dissolved in 40mL DMSO, 6 compound of formula (5.72g) and LDA (3.3g) is added in, stirs
It mixes and is heated to 120 DEG C of back flow reaction 48h, cooled and filtered removes solid salt, and filtrate decompression is concentrated to give 2 compound of formula
8.82g, yield 79.8%.
The structure of 2 compound of formula is confirmed by nuclear magnetic resonance spectroscopy, electrospray ionization mass spectrometry and d.e. values measure, table
It is as follows to levy result.
1H NMR(300MHz,CDCl3):δ6.90-7.17(4H,s,Ar-H),7.02-7.08(4H,s,Ar-H),6.68-
6.95(4H,s,Ar-H),4.84(1H,d,ArCHN-),4.50(1H,t,-CHOSiMe3),3.45(1H,d,-COCH-),1.77
(2H,t,Me3SiOCHCH2-),1.63(2H,t,-COCHCH2-),0.08(18H,s,OSi(CH3)3).
MS(ESI)m/z：(M+H)=554.2.
Product chirality HPLC retention times：R- types, 9.6min, S- types, 10.9min, d.e. values>90%.Step b)
Compound 2 (5.53g) is dissolved in 50mL dichloromethane, trifluoroacetic acid (0.07mL) is added in, reaction is stirred at room temperature
5h, TLC monitor reaction process.It after the reaction was complete, is concentrated under reduced pressure and removes solvent, ethyl alcohol recrystallization obtains 1 compound of formula i.e. according to folding
Wheat cloth 3.58g, yield 87.5%.
Ezetimibe structure is confirmed by nuclear magnetic resonance spectroscopy, electrospray ionization mass spectrometry and d.e. values measure, is characterized
As a result it is as follows.
1H NMR(300MHz,CDCl3):δ6.90-7.17(4H,m,Ar-H),7.02-7.08(4H,m,Ar-H),6.68-
6.95(4H,m,Ar-H),5.0(1H,s,Ar-OH),4.84(1H,d,-CH-),4.50(1H,t,-CHOH),3.45(1H,dt,-
CH-),1.77(2H,dt,-CH2-),1.63(2H,dt,-CH2-).
MS(ESI)m/z：(M+H)=410.2.
Product chirality HPLC retention times：R- types, 9.6min, S- types, 10.9min, d.e. values>95%.
Claims (11)
1. the preparation method of Ezetimibe intermediate, includes the following steps shown in a kind of formula III：
A) in the case where aldehyde ketone restores enzyme catalysis, asymmetric reduction reaction, production IV compounds occur for Formula V compound；
B) formula IV compound in organic solvent with bromide reagent occur bromo-reaction, then weak base effect under with para-fluoroaniline
Formula III compound is obtained by the reaction；
Reaction equation is as follows：
Wherein, R is hydroxyl protection base, and R ' is ester residue；
Wherein, aldehyde ketone reductase has SEQ ID NO：Amino acid sequence shown in 1.
2. preparation method according to claim 1, it is characterised in that：R be selected from silicon ether protecting group, acetyl group, benzoyl,
Benzyl, MOM, C1-C4Alkyl, THP.
3. preparation method according to claim 1, it is characterised in that：R ' is C1-C4Alkyl.
4. preparation method according to claim 1, it is characterised in that：The reaction of step a) is the water in pH value 5.0-8.0
It is carried out in solution.
5. according to the preparation method described in any one of claim 1-4, it is characterised in that：In step a), the Formula V chemical combination
A concentration of 10-1000g/L of object in the reaction system, aldehyde ketone reduction enzyme dosage is 1-20g/L.
6. preparation method according to claim 1, it is characterised in that：Also contain isopropanol in the reaction system of step a),
Or the combination containing NADP+, glucose and glucose dehydrogenase.
7. preparation method according to claim 6, it is characterised in that：The dosage of isopropanol is the 2%- of reaction system volume
10%.
8. preparation method according to claim 6, it is characterised in that：Glucose dosage be 1-20g/L, glucose dehydrogenase
Dosage for 100-1000U/L, the dosage of NADP+ is 0.02-0.1mmol/L.
9. preparation method according to claim 1, it is characterised in that：The bromide reagent is selected from phosphorus tribromide, pentabromo-
Change phosphorus, carbon tetrabromide.
10. preparation method according to claim 1, it is characterised in that：The weak base is selected from ethylenediamine, diisopropyl second
Base amine, N-methylmorpholine, to dimethylaminopyridine, triethylamine.
11. preparation method according to claim 1, it is characterised in that：In step b), formula IV compound and bromide reagent
Molar ratio is 1:The molar ratio of 1-3, formula IV compound and para-fluoroaniline is 1:The molar ratio of 1-3, weak base and para-fluoroaniline is
1:2-6。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510198353.1A CN104860980B (en) | 2015-04-23 | 2015-04-23 | It is a kind of to be used to synthesize intermediate of Ezetimibe and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510198353.1A CN104860980B (en) | 2015-04-23 | 2015-04-23 | It is a kind of to be used to synthesize intermediate of Ezetimibe and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104860980A CN104860980A (en) | 2015-08-26 |
| CN104860980B true CN104860980B (en) | 2018-06-19 |
Family
ID=53907208
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510198353.1A Active CN104860980B (en) | 2015-04-23 | 2015-04-23 | It is a kind of to be used to synthesize intermediate of Ezetimibe and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104860980B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107022587A (en) * | 2017-04-27 | 2017-08-08 | 江苏理工学院 | A kind of method that enzyme law catalysis synthesizes Ezetimibe intermediate |
| CN111458440B (en) * | 2020-05-13 | 2022-08-23 | 北京阳光德美医药科技有限公司 | Method for detecting free ezetimibe and total ezetimibe in plasma by liquid chromatography-tandem quadrupole mass spectrometry |
| CN114349710A (en) * | 2021-12-31 | 2022-04-15 | 南京望知星医药科技有限公司 | Synthetic method of ezetimibe impurities |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1144522A (en) * | 1994-03-25 | 1997-03-05 | 先灵公司 | Substituted azetidinone compounds useful as hypocholesterolemic agents |
| US5618707A (en) * | 1996-01-04 | 1997-04-08 | Schering Corporation | Stereoselective microbial reduction of 5-fluorophenyl-5-oxo-pentanoic acid and a phenyloxazolidinone condensation product thereof |
| US20040254369A1 (en) * | 2003-06-16 | 2004-12-16 | Framroze Bomi Patel | Process for the preparation of 1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-azetidin-2-one |
| US20070129540A1 (en) * | 2005-12-01 | 2007-06-07 | Opus Organics Pvt Limited | Process for the preparation of chiral azetidinones |
| CN104099305A (en) * | 2014-07-18 | 2014-10-15 | 华东理工大学 | Carbonyl reductase mutant as well as gene and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997016424A1 (en) * | 1995-11-02 | 1997-05-09 | Schering Corporation | Process for preparing 1-(4-fluorophenyl)-3(r)-(3(s)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(s)-(4-hydroxyphenyl)-2-azetidinone |
| TWI291957B (en) * | 2001-02-23 | 2008-01-01 | Kotobuki Pharmaceutical Co Ltd | Beta-lactam compounds, process for repoducing the same and serum cholesterol-lowering agents containing the same |
-
2015
- 2015-04-23 CN CN201510198353.1A patent/CN104860980B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1144522A (en) * | 1994-03-25 | 1997-03-05 | 先灵公司 | Substituted azetidinone compounds useful as hypocholesterolemic agents |
| US5618707A (en) * | 1996-01-04 | 1997-04-08 | Schering Corporation | Stereoselective microbial reduction of 5-fluorophenyl-5-oxo-pentanoic acid and a phenyloxazolidinone condensation product thereof |
| US20040254369A1 (en) * | 2003-06-16 | 2004-12-16 | Framroze Bomi Patel | Process for the preparation of 1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-azetidin-2-one |
| US20070129540A1 (en) * | 2005-12-01 | 2007-06-07 | Opus Organics Pvt Limited | Process for the preparation of chiral azetidinones |
| CN104099305A (en) * | 2014-07-18 | 2014-10-15 | 华东理工大学 | Carbonyl reductase mutant as well as gene and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| A Formal Synthesis of Ezetimibe via Cycloaddition/Rearrangement cascade reaction;Michalak M等;《The Journal of Organic Chemistry》;20110711;第76卷;第6931-6936页 * |
| 依折麦布的合成研究;蔡金刚;《中国优秀硕士学位论文全文数据库医药卫生科技辑》;20121015;E079-7 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104860980A (en) | 2015-08-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104447445B (en) | A kind of preparation method synthesizing Apremilast intermediate | |
| CN104370755A (en) | Preparation method for optical activity active 3-amino butanol and optical activity 3-amino butyric acid | |
| CN104860980B (en) | It is a kind of to be used to synthesize intermediate of Ezetimibe and its preparation method and application | |
| WO2022222914A1 (en) | Preparation method of l-nicotine | |
| CN107141246B (en) | A kind of preparation method of Isatine derivatives | |
| CN110684025B (en) | Preparation method of tadalafil | |
| WO2022222913A1 (en) | Preparation method for l-nicotine | |
| CN106749117A (en) | A kind of preparation method of 3 amino methyl tetrahydrofuran | |
| WO2014068333A2 (en) | New process | |
| CN104370953B (en) | (R)-tert-butyl dimethyl siloxy-glutaric acid monoester preparation method | |
| CN107176906A (en) | A kind of synthetic method of substitution indone | |
| CN105330550B (en) | A kind of preparation method of optically active 1 cyclohexylethylamine | |
| Wen et al. | Perfectly green organocatalysis: quaternary ammonium base triggered cyanosilylation of aldehydes | |
| CN114702425A (en) | Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate | |
| CN107216332A (en) | The synthetic method of (6H) the formic acid base ester of 7 methylol of the tert-butyl group, 7,8 dihydro 4H pyrazolos diazepine 5 | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| CN109265385B (en) | Synthesis process of chiral catalyst | |
| CN110724098A (en) | Synthetic method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid hydrochloride | |
| CN111116510B (en) | 2-substituted methylene dihydrobenzo [ d ] thiazole derivatives and synthesis method and application thereof | |
| CN108976182A (en) | A method of preparing Dapagliflozin five-membered ring impurity | |
| CN107954886A (en) | A kind of method for preparing anti-heart failure enkephalinase inhibitor Sha Kubi song intermediates | |
| CN111848430B (en) | Synthetic method of 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine compound | |
| CN113620869B (en) | Preparation method of betrixaban | |
| CN107721917A (en) | A kind of green synthesis method of polysubstituted nicotinate compound | |
| CN107383021A (en) | A kind of bulk drug Pa Lipuwei preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20180211 Address after: 201203 Shanghai City, Pudong New Area China (Shanghai) free trade zone fanchun Road No. 400 Building 1 room 436 4 Applicant after: ABIOCHEM BIOTECHNOLOGY Co.,Ltd. Address before: Pu Si Road in Pukou District of Nanjing City, Jiangsu province 210032 No. 18 Taishan street, science and Technology Innovation Park 1 building 408 room Applicant before: NANJING ABIOCHEM BIOMEDICAL TECHNOLOGY CO.,LTD. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: Room 3114, Building B, 555 Dongchuan Road, Minhang District, Shanghai, 200241 Patentee after: Ecolab Biotechnology (Shanghai) Co.,Ltd. Address before: 201203 Shanghai, Pudong New Area, China (Shanghai) free trade trial area, No. 1, 4 floor, 1 room, 400 Fang Chun road. Patentee before: ABIOCHEM BIOTECHNOLOGY Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: Room 3114, Building B, 555 Dongchuan Road, Minhang District, Shanghai, 200241 Patentee after: Yikelai Biotechnology (Group) Co.,Ltd. Address before: Room 3114, Building B, 555 Dongchuan Road, Minhang District, Shanghai, 200241 Patentee before: Ecolab Biotechnology (Shanghai) Co.,Ltd. |