CN101346349B - 依泽替米贝的制备方法及该方法中所用的中间体 - Google Patents
依泽替米贝的制备方法及该方法中所用的中间体 Download PDFInfo
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- CN101346349B CN101346349B CN2006800485754A CN200680048575A CN101346349B CN 101346349 B CN101346349 B CN 101346349B CN 2006800485754 A CN2006800485754 A CN 2006800485754A CN 200680048575 A CN200680048575 A CN 200680048575A CN 101346349 B CN101346349 B CN 101346349B
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- fluorophenyl
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- phenyl
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- 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 claims abstract description 23
- 229960000815 ezetimibe Drugs 0.000 title claims description 17
- 238000000034 method Methods 0.000 title abstract description 43
- 230000008569 process Effects 0.000 title abstract description 9
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 239000000543 intermediate Substances 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 230000000903 blocking effect Effects 0.000 claims description 18
- 238000006884 silylation reaction Methods 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- -1 dioxolane-2-yl Chemical group 0.000 claims description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- 239000007795 chemical reaction product Substances 0.000 claims description 9
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 8
- 150000002466 imines Chemical group 0.000 claims description 6
- ZBQROUOOMAMCQW-UHFFFAOYSA-N 5-(4-fluorophenyl)-5-oxopentanoic acid Chemical compound OC(=O)CCCC(=O)C1=CC=C(F)C=C1 ZBQROUOOMAMCQW-UHFFFAOYSA-N 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims 1
- 238000005917 acylation reaction Methods 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 230000007704 transition Effects 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 239000000047 product Substances 0.000 description 27
- 239000000203 mixture Substances 0.000 description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 13
- 230000008020 evaporation Effects 0.000 description 13
- 238000006722 reduction reaction Methods 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- 229910000085 borane Inorganic materials 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 238000013507 mapping Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 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 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 239000010936 titanium Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 0 *[C@](C(*=*)O1)NC1=* Chemical compound *[C@](C(*=*)O1)NC1=* 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 5
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical group O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000002444 silanisation Methods 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- 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 4
- XSSTWZINYCULLM-UHFFFAOYSA-N 4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]butanoic acid Chemical compound C=1C=C(F)C=CC=1C1(CCCC(=O)O)OCCO1 XSSTWZINYCULLM-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000011010 flushing procedure Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229910000077 silane Inorganic materials 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N dimethylsulfide Substances CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 229910052901 montmorillonite Inorganic materials 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical compound CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 description 2
- FLALGSYYVIWTFQ-UHFFFAOYSA-K propan-2-olate;titanium(4+);trichloride Chemical compound [Cl-].[Cl-].[Cl-].CC(C)O[Ti+3] FLALGSYYVIWTFQ-UHFFFAOYSA-K 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- FWIBCWKHNZBDLS-VKHMYHEASA-N (3s)-3-hydroxyoxolan-2-one Chemical compound O[C@H]1CCOC1=O FWIBCWKHNZBDLS-VKHMYHEASA-N 0.000 description 1
- MDQHTWMXYBVSHU-UHFFFAOYSA-N 2-trimethylsilylacetamide Chemical compound C[Si](C)(C)CC(N)=O MDQHTWMXYBVSHU-UHFFFAOYSA-N 0.000 description 1
- PHCDQOGLUIFYII-UHFFFAOYSA-N 3-phenylprop-2-enoyl bromide Chemical compound BrC(=O)C=CC1=CC=CC=C1 PHCDQOGLUIFYII-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- YAIXFEVBIPYUCZ-UHFFFAOYSA-N C=Nc(cc1)ccc1F Chemical compound C=Nc(cc1)ccc1F YAIXFEVBIPYUCZ-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 238000005750 Corey-Bakshi-Shibata reduction reaction Methods 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 102220471968 Single-stranded DNA cytosine deaminase_K10A_mutation Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- COGNCXJCCDGTDV-UHFFFAOYSA-N [O].N1C=CC=CC=C1 Chemical compound [O].N1C=CC=CC=C1 COGNCXJCCDGTDV-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000010568 chiral column chromatography Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000002734 clay mineral Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000007483 microbial process Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- BDOLXPFAFMNDOK-UHFFFAOYSA-N oxazaborolidine Chemical compound B1CCON1 BDOLXPFAFMNDOK-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000012958 reprocessing Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
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Abstract
Description
发明领域
本发明涉及依泽替米贝的新制备方法,即,式I的1-(4-氟苯基)-3(R)-[3(S)-(4-氟苯基)-3-羟丙基]-4(S)-(4-羟苯基)-2-氮杂环丁酮。此外,本发明还涉及该方法中所用的新的中间体。
发明背景
在发达国家,相当大的一部分死亡是由心血管疾病引起的。这些疾病大部分是由冠状动脉的动脉粥样硬化改变引发的。在疾病发展的危险因素例如高血压、糖尿病、吸烟等中,最重要的是血清中高浓度的胆固醇。能降低血清胆固醇浓度的活性成分和制剂是治疗和预防动脉粥样硬化中有用的药剂。
依泽替米贝,即,式I的1-(4-氟苯基)-3(R)-[3(S)-(4-氟苯基)-3-羟丙基]-4(S)-(4-羟苯基)-2-氮杂环丁酮,是一些最近销售的治疗和预防动脉粥样硬化中所用的具有显著减少血胆固醇作用的药物制剂中的活性成分,这在U.S.专利5,767,115(Schering Co.U.S.A.)和欧洲专利720,599中都有公开。
这些说明书中公开了制备依泽替米贝和相关物质的第一种合成方法。根据他们的方法之一,在一步法中制得合适的反式氮杂环丁酮衍生物,使用[4-(苯甲氧基)-苯亚甲基]-(4-氟苯基)-胺和甲基-4-(氯甲酰)-丁酸酯碱的反应,并且在水解并与所给的3-[2-(4-苯甲基-氧-苯基)-1-(4-氟苯基)-4-氧-氮杂环丁烷-3-基]-丙酰氯形成酰氯后,(4-氟苯基)-锌-氯化物在四(三苯膦)钯存在下酰化。通过手性HPLC分离获得纯的1-(4-氟苯基)-3(R)-[3-氧-3-(4-氟苯基)-丙基]-4(S)-(4-苯甲氧基-苯基)-2-氮杂环丁酮,通过随后的对映选择性还原和催化氢化制得终产物依泽替米贝。在该方法中,通过对映选择性方法没有形成取代的氮杂环丁酮环,因此通过手性柱色谱法纯化了最后的一种中间体。以这种方法至少损失50%的后期中间体,显著提高了工艺成本。
为了避免使用昂贵的手性色谱法,U.S.专利5,919,672(Schering Co.)介绍了微生物和酶分离方法。虽然微生物方法降低了拆分外消旋物的成本,但是即使以这种方式,拆分的产率也没能提高超过50%。
在欧洲专利720,599(Schering Co.)中公开了一些具有减少血胆固醇活性的三取代氮杂环丁酮衍生物的制备方法。为了形成β-内酰胺环,描述了一步法和两步法,同时通过若干方法进行芳基-羟基-烷基侧链的构建。为了依泽替米贝的合成,揭示了一种对映选择性方法。首先,从5-氧-5-((S)-2-氧-4-苯基-噁唑烷-3-基)-戊烷酸甲酯和[4-(苯甲氧基)-苯亚甲基]-(4-氟苯基)-胺在两步合成中形成氮杂环丁酮环。在(4-氟苯基)-锌-氯化物四(三苯膦)钯存在下借助所得的3-[(2S,3R)-2-(4-苯甲基-氧-苯基)-1-(4-氟苯基)-4-氧-氮杂环丁烷-3-基]-丙酰氯进行酰化。通过柱色谱纯化所给出的1-(4-氟苯基)-3(R)-[3-氧-3-(4-氟苯基)丙基]-4(S)-(4-苯甲氧基-苯基)-2-氮杂环丁酮中间体,然后在氧代基团的对映选择性还原反应并除去保护基团后,获得活性成分。
在国际申请No.WO 97/45,406和U.S.专利5,739,321(ScheringCo)中公开了在策略上与之前的操作程序不同的方法。根据这些公开内容,通过进行以下的反应对映选择性地形成反式取代的氮杂环丁酮中间体:在碱的存在下4(S)-羟基-丁内酯与受保护的亚胺反应,然后在若干步合成中通过所述的1-(4-氟苯基)-3(R)-[3-氧-3-(4-氟苯基)-丙基]-4(S)-(4-苯甲氧基-苯基)-2-氮杂环丁酮中间体构建3-(4-氟苯基)-3-羟丙基侧链。通过催化氢化作用除去苯甲基保护基团。
另一种反应途径公开于U.S.专利5,856,473(Schering Co.)。根据描述,通过用1-(4-氟苯基)-4(S)-(4-苯甲基-氧-苯基)-2-氮杂环丁酮烷化4-氟肉桂酰基-溴化物,或通过从(S)-3-[5-(4-氟苯基)-戊-3-烯酰]-4-苯基-噁唑烷-2-酮开始的对映选择性合成,来制得在侧链中包括一个双键的(3R,4S)-4-(4-苯甲氧基-苯基)-1-(4-氟苯基)-3-[(E)-3-(4-氟苯基)-烯丙基]-氮杂环丁烷-2-酮。通过氧化侧链获得1-(4-氟苯基)-3(R)-[3-氧-3-(4-氟苯基)丙基]-4(S)-(4-苯甲氧基-苯基)-2-氮杂环丁酮中间体,由此通过所述的对映选择性还原作用除去保护基团后获得终产物依泽替米贝。
这些对映选择性方法在后来使用的多步合成方法中是很普遍的,通过相对昂贵的对映选择性合成方法制备光学纯的氮杂环丁酮衍生物。关键中间体1-(4-氟苯基)-3(R)-[3-氧-3-(4-氟苯基)丙基]-4(S)-(4-苯甲氧基-苯基)-2-氮杂环丁酮只能通过显著提高工业方法成本的色谱法来纯化。
在WO 2000/34,240(Schering Co.)和WO 1995/08,532专利申请以及欧洲专利No.0,720,599(Schering Co.)中,发现了一种改良且更有效的对映选择性的依泽替米贝合成途径。根据该方法,首先从合适的氧代化合物通过对映选择性还原反应制得98%de(非对映体过量)纯度的3-[(S)-5-(4-氟苯基)-5-羟基-戊酰]-噁唑烷-2-酮。在一个容器中用三甲基氯硅烷在原位硅烷化3-[(S)-5-(4-氟苯基)-5-羟基-戊酰]-噁唑烷-2-酮和N-(4-羟基-苯亚甲基)-4-氟苯胺。使用本领域公知的方法在碱存在下用TiCl4试剂处理所得到的混合物制得合适的β-氨基-酰胺产物。作者惊讶地发现了酚OH基团的三甲基硅烷基保护基团的稳定性。尽管所述甲硅烷基的稳定性,但在后处理和进一步硅烷化步骤后,中间体仅能以65%的产率分离。β-氨基-酰胺环化接着除去保护基团后获得依泽替米贝。在该方法中,在合成开始时进行相对昂贵的对映选择方法形成3(S)-羟基,然后在进一步的反应步骤和纯化操作后分离产物。
3(S)-OH基团的立体选择性形成是制备依泽替米贝的关键步骤之一。每种所述的方法应用了由CBS-氧氮杂硼烷(oxazaborolidine)催化的对映选择还原方法的一种形式,该方法由文献(E.J.Corey等,J.Am.Chem.Soc.1987,109,5551-5553)中公知。所达到的de值(非对映体过量)为88-98%,这是通常所预期的。
U.S.专利No.5,886,171和5,856,473(Schering Co.)描述了使用CBS-氧氮杂硼烷催化剂的对映选择还原方法,其中受保护的1-(4-氟苯基)-3(R)-[3-氧-3-(4-氟苯基)丙基]-4(S)-(4-羟苯基)-2-氮杂环丁酮转化成受保护的1-(4-氟苯基)-3(R)-[3(S)-羟基-3-(4-氟苯基)丙基]-4(S)-(4-羟苯基)-2-氮杂环丁酮。
U.S.专利No.6,207,822和U.S.6,627,757(Schering Co.)描述了应用相似的还原剂和手性催化剂将3-[5-(4-氟苯基)-5-氧-戊酰]-4(S)-4-苯基-1,3-噁唑烷-2-酮转变成3-[5(S)-5-(4-氟苯基)-5-羟基-戊酰]-4(S)-4-苯基-1,3-噁唑烷-2-酮。
U.S.专利5,618,707和专利申请WO 1997/12,053(Schering Co.)中描述了另一种对映选择还原反应可能性,其中通过立体选择微生物还原将早期的中间体3-[5-(4-氟苯基)-5-氧戊酰]-4(S)-4-苯基-1,3-噁唑烷-2-酮转化成3-[5(s)-5-(4-氟苯基)-5-羟戊酰]-4(S)-4-苯基-1,3-噁唑烷-2-酮。所达到的de值≥95%(非对映体过量),与由CBS-氧氮杂硼烷催化所得值相似。
U.S.专利No.6,133,001中,描述了立体选择微生物还原反应,用于将1-(4-氟苯基)-3(R)-[3-氧-3-(4-氟苯基)丙基])-4(S)-(4-羟苯基)-2-氮杂环丁酮转化成1-(4-氟苯基)-3(R)-[3(S)-羟基-3-(4-氟苯基)丙基]-4(S)-(4-羟苯基)-2-氮杂环丁酮(依泽替米贝)。以少量制得终产物,并且通过制备型薄层色谱法纯化。
在国际申请WO 2005/066,120(Ranbaxy Ltd.)中,通过(-)-B-氯-二异松蒎基硼烷进行3-[5-(4-氟苯基)-5-氧-戊酰]-4(S)-4-苯基-1,3-噁唑烷-2-酮和1-(4-氟苯基)-3(R)-[3-氧-3-(4-氟苯基)丙基]-4(S)-(4-羟苯基)-2-氮杂环丁酮的氧代基团的对映选择还原反应,获得与CBS-还原反应相似的选择性。然而,有趣的是,以这种方式,在20g 1-(4-氟苯基)-3(R)-[3-氧-3-(4-氟苯基)丙基]-4(S)-(4-羟苯基)-2-氮杂环丁酮的还原反应中,在柱色谱纯化后只获得了少到3g的依泽替米贝终产物。
发明概述
本发明提供了一种新的、工业上容易实现的、只包括很少步骤并建立在新的中间体上的经济方法,该方法根据以下反应方案用于生产1-(4-3(R)-[3(S)-(4-氟苯基)-3-羟丙基]-4(S)-(4-羟苯基)-2-氮杂环丁酮(依泽替米贝):
其中:
●通式II,IV,VI,VIII,IX,X和XI的物质是新的
●式III是未分离的中间体
●R1,R2和R3由式Va-Vd的化合物来表示,
而R4是硅烷基,例如叔丁基-二甲基-硅烷基,叔丁基-二苯基-硅烷基基团。
发明详述
考虑到已知依泽替米贝合成方法的缺点,我们努力完成了一种工业规模的安全生产方法,包括经济简单的技术步骤,提供具有满足药典要求的纯度的活性成分。我们决定设计出一种不包括繁复的工艺步骤或需要极端环境的合成策略,并且中间体可以通过高效的简单方法制得,同时可以以高纯度分离。为了保护官能团,我们努力使用在合成过程中稳定的,可以通过简单而廉价的方式构建并且可以选择性除去的保护基团。我们有意在合成结束时执行更昂贵的工艺步骤,以收回昂贵的辅助原料(例如,光学活性的那些)。
在我们的实验过程中,我们惊讶地发现在以下合成途径中,通过使用特定保护基团组合,在大多数情况中,获得这类可以以简单方式且高效地容易纯化(因为它们突出的结晶能力)的极好的中间体。非结晶中间体可以不经纯化而用于后续步骤。发现了先前文献中未公开的新反应,其中作为Ti(IV)催化的Mannich型反应的副产物形成的立体异构化合物可以转变成所需的中间体。
本发明应用新中间体的方法包括7个步骤,如下所列。
步骤1:
4-(4-氟-苯甲酰)-丁酸(II)通过未分离的中间体化合物(III)转化成4-[2-(4-氟-苯基)-[1,3]二氧杂环戊烷-2-基]-丁酸(IV)
步骤2:
用4-[2-(4-氟-苯基)-[1,3]二氧杂环戊烷-2-基]-丁酸(IV)酰化手性噁唑烷酮(V)以得到噁唑烷酮衍生物(VI)
其中R1,R2和R3在下列结构(Va-Vd)中表示:
步骤3:
将以下酰化的噁唑烷酮(VI)与亚胺(VII)反应,分离了式(VIII)的化合物,
其中R4表示硅烷基,例如,叔丁基-二甲基-硅烷基(TBDMS),叔丁基-二苯基-硅烷基基团。
步骤4:
通过式(VIII)化合物的环化获得受保护的氮杂环丁酮(IX)。
步骤5:
通过式(IX)的化合物的缩酮基团的水解获得式(X)的化合物。
步骤6:
通过式X的化合物的对映选择性还原作用,获得式XI的化合物。
步骤7:
除去式XI的化合物的硅烷基保护基团,获得终产物依泽替米贝(I)。
在以下部分中详细描述所有的步骤:
步骤1:
在惰性无水溶剂中,例如在二氯甲烷中,在强酸(例如,浓硫酸或对甲苯磺酸,优选为浓硫酸)和水结合辅助材料(例如,三甲基原甲酸酯)存在下,将4-(4-氟-苯甲酰)-丁酸(II)在20-25℃温度与乙二醇发生一步反应。加入碱,例如NaHCO3,来终止反应。将溶剂变成醇性溶剂,优选甲醇,并通过碱溶液(优选使用氢氧化钾溶液)来水解所形成的酯中间体(III)。在反应混合物浓缩,然后用弱酸(例如,使用酒石酸、柠檬酸,优选柠檬酸)酸化,接着用适当的溶剂(例如,乙酸乙酯)萃取后,分离所形成的4-[2-(4-氟-苯基)-[1,3]二氧杂环戊烷-2-基]-丁酸(IV)。通过从非极性溶剂例如从正己烷或正庚烷结晶来纯化产物。
步骤2:
使用1-1.7倍摩尔量,优选1,05-1,10当量的酰氯,例如新戊酰氯,步骤1的产物在惰性无水溶剂(例如,四氢呋喃或二氯甲烷,优选四氢呋喃)中,在三乙胺存在下,在-20至-10℃的温度转化成混合的酐。在适当的活化剂(例如氯化锂(LiCl)或4-二甲基-胺-吡啶,优选氯化锂)存在下,将式V的噁唑烷酮,优选S-(+)-4-苯基-2-噁唑烷酮(Va)加入所获得的混和酐的溶液中,然后将溶液在-20至25℃的温度搅拌4-8小时。通过萃取分离产物并通过结晶来纯化。
步骤3:
方法A:
将步骤2的产物与式VII的胺(其中R4优选表示叔丁基-二甲基-硅烷基基团)在惰性无水溶剂(例如,二氯甲烷)和N2气氛中在-40至-25℃的温度反应,在TiCl4和Ti(IV)-异丙氧化物的存在下和在叔碱例如二异丙基乙胺的存在下,反应1-2小时。用醇优选异丙醇来终止反应,并且通过萃取分离产物(VIII),在蒸发后通过使用甲醇搅拌来纯化。
对于酚羟基的保护,使用硅烷基型保护基团,优选为叔丁基-二甲基-硅烷基基团,这与在甚至更温和环境下倾向于裂解的其他硅烷基型基团相比以及与其他烷基型和酰基型保护基团相比尤其有利。因为叔丁基-二甲基-硅烷基保护基团在合成环境下是稳定的,因此不需要在分离之前再重新硅烷化在后处理期间会部分丢失其保护基团的中间体。此外,用酸性处理可以容易地除去叔丁基-二甲基-硅烷基保护基团,而避免副反应。另一方面,为了除去苯甲基型保护基团需要技术上更繁琐和更危险的催化氢化作用或更强的酸性除去过程。不幸的是,在酸性介质中苯甲基和烷基型保护基团裂解过程中形成的碳阳离子导致大量副产物(苯环烷基化)。如从文献中所公知的,用碱除去酰基型保护基团伴随有显著的副反应(例如,内酰胺环的打开)。
我们的实验证明了在Ti(IV)催化的Mannich型平衡反应中,除期望的R4=叔丁基-二甲基-硅烷基产物(VIIIa)以外,还显著程度地形成了异构体副产物(VIIIb)。我们证明了在所述反应环境下,从(VIIIa)和(VIIIb)开始,可以得到与反应从(VIa)和(VIIa)开始的情况中相同的产物。通过对实验参数的适当选择,平衡可以转变为有利于形成(VIIIa)产物的方向,并且其可以以73-78%的产率分离。
可以存在于从甲醇悬浮液过滤产物而得到的母液中的(VIIIb)异构体,可以在Ti(IV)-催化的Mannich型反应环境下转变成(VIIIa)。以这种方式,反应产率可得到相当大的提高。
为了这些目的,蒸发甲醇母液,将溶剂变成合适的溶剂,例如甲苯,通过硅胶将溶液脱色,然后,在过滤后将其蒸发。使用这种方法,如下从这种混合物中可以获得更多式VIII的产物:
将蒸发残余物溶解于二氯甲烷中,在Ti(IV)-异丙氧化物和叔碱例如二异丙基乙胺的存在下,在惰性气氛例如N2下,在-40至-25℃的温度将该溶液搅拌1-2小时。用上述的方法分离式VIIIa的纯产物。
方法B:
在可替换的方法中,首先在二异丙基乙胺(DIPEA)存在下在二氯甲烷中原位生产式VIIa的化合物,该化合物由(E)-(4-羟基-苯亚甲基)-(4-氟苯基)-胺(VIIb)与叔丁基-二甲基-硅烷基-氯化物(TBDMS-Cl)的反应制得,然后根据方法A中的描述使用所获得的式VIIa产物的溶液。
步骤4:
将步骤4的式VIII的产物用合适的硅烷化剂(例如,二(三甲基-硅烷基)-乙酰胺)在20至25℃的温度在适当的溶剂(例如,四氢呋喃,甲苯,甲基-叔丁基-醚,或乙腈,优选乙腈)中硅烷化1-3小时。将氟化物化合物优选为四丁基铵-氟化物-三水合物以催化量(0.1-10mol%)优选0.5-1mol%加入混合物中。将该环化反应混合物再搅拌0.5-3小时,优选为0.5小时,然后通过水终止反应,用链烷型溶剂例如正己烷分离式IX的产物。浓缩后,用二氯甲烷萃取乙腈相中形成的手性辅助原料S-(+)-4-苯基-2-噁唑烷酮(Va),并且通过结晶纯化。
步骤5:
用酸性型粘土矿物(优选蒙脱石)在20至25℃的温度在惰性溶剂(例如,二氯甲烷)中处理步骤4获得的式IX的化合物3-6小时。在这些环境下,叔丁基-二甲基-硅烷基保护基团是稳定的,并且可以选择性地除去缩酮保护基团。通过简单过滤分离如此获得的式X的产物,并在蒸发后通过结晶来纯化。
步骤6:
在我们的方法中,在合成结束时进行形成3-(S)-羟基的对映选择还原反应。以该方式,昂贵手性催化剂的具体消耗较少。因为在光学纯均一的异构体中构建了不对称中心,将终产物的纯化简化为分离两个非对映体。因此,在手性CBS-氧氮杂硼烷型催化剂的存在下(对该目的是公知的),在例如二氯甲烷的惰性溶剂中,在例如N2的惰性气氛中,在-20至20℃的温度,优选为-5至+5℃,用硼烷型还原剂(例如,硼烷-二甲基-硫化物,硼烷-四氢呋喃,硼烷-二乙基-苯胺,或邻苯二酚-硼烷,优选硼烷-二甲基-硫化物和硼烷-四氢呋喃的混合物)还原步骤5中如此获得的式X的化合物。将手性CBS-氧氮杂硼烷(化合物XIIa-XIId),优选氧氮杂硼烷(化合物XIIa)用作催化剂。
通过萃取分离产物,同时不经纯化进一步参与下一反应。
步骤7:
将如此获得的式XI的产物与稀释的盐酸或硫酸水溶液(优选与硫酸溶液)和醇性溶剂(例如甲醇或异丙醇,优选异丙醇)的混合物在50至70℃的温度加热1-3小时。通过加入水从反应混合物结晶终产物,然后通过重结晶纯化。
本发明的优点概括如下:
a)在我们的方法中,在基于新化合物的新途径中,关键的中间体由于其极好的结晶能力,可以在简单结晶操作中有效地纯化。
b)为了保护酚OH基团,使用了硅烷基型,优选为叔丁基-二甲基-硅烷基基团,这比其它在更温和环境中容易裂解的那些基团更为有利,例如与烷基和酰基型基团相比。
c)在对映选择性的Ti(IV)-催化的Mannich型反应中,以高产率(85-90%)制得合适的中间体(VIIIa),然而,立体异构的副产物在平衡反应中没有损失,而是大部分转变成所需的中间体,
d)因此,在合成过程中通过简单的方法再生大部分手性辅助剂S-(+)-4-苯基-2-噁唑烷酮(>70%的引入量)。
e)在本方法中,在合成结束时进行形成3-(S)-羟基的对映选择还原反应。以该方式,昂贵手性催化剂的具体消耗较少。因为在光学纯均一的异构体中构建了不对称中心,将终产物的纯化简化为分离两个非对映体。
总之,在我们的发明中,发现了这样一种新方法,它适用于工业规模的依泽替米贝的经济生产。通过本方法获得的活性成分的纯度可以满足当今对药物活性成份要求越来越高的质量要求。
实施例
以下实施例是说明性的,不意在限制要求保护的发明的范围。
实施例1
4-[2-(4-氟-苯基)-[1,3]二氧杂环戊烷-2-基]-丁酸(IV)的制备
称重21.0g(0.1mol)4-(4-氟-苯甲酰)-丁酸(II)至500ml圆底烧瓶中,并悬浮于210ml二氯甲烷中。在连续搅拌的过程中,将28ml(31.2g,0.5mol)乙二醇,32ml(31.04g,0.3mol)三甲基原甲酸酯和0.5ml浓硫酸逐滴加入悬浮液中。在20-25℃将反应混合物搅拌3-6小时。通过薄层色谱分析控制该反应。当酮走至终点时,即它的斑点在薄层色谱中消失时,加入5g固体NaHCO3终止反应。将悬浮液搅拌05分钟,然后通过蒸发除去溶剂,并将残余物溶解于150ml甲醇中。该溶液在冰水浴中冷却,在冷却过程中,加入100ml 10%NaOH溶液。将烧瓶密封,并将混浊的混合物在20-25℃搅拌约1小时。通过薄层色谱分析控制水解作用。当酯走到终点时,即它的斑点在薄层色谱中消失时,通过真空蒸发除去甲醇,并且在冰水浴中的强烈冷却过程中,将350ml 10%柠檬酸溶液加入残余物中以获得3-4的酸性pH值。用200ml乙酸乙酯萃取沉淀的产物。用50-50ml乙酸乙酯将水相萃取两次,然后用5×50ml的水将合并的有机相洗至中性。将乙酸乙酯溶液在无水Na2SO4上干燥,将干燥剂滤出,并在真空中蒸发滤液。在0℃通过加入50ml正己烷来结晶蒸发残余物。通过过滤分离(IV)的结晶物质,并且干燥。
产率:23g,(90%)
熔点:65-67℃
1H NMR数据:(500MHz,DMSO-d6,25℃)δ1.41-1.52(m,2H),1.79-1.87(m,2H),2.18(t,J=7.5Hz,2H),3.63-3.73(m,2H),3.91-4.01(m,2H),7.13-7.22(m,2H),7.37-7.45(m,2H),11.97(br s,1H)ppm。
实施例2
(S)-3-{4-[2-(4-氟苯基)-[1,3]二氧杂环戊烷-2-基]-丁酰}-4-苯基-噁唑烷-2-酮(VIa)的制备
将42g(165mmol)式IV的化合物(实施例1的产物)溶解于340ml无水四氢呋喃中,并用干燥的N2气冲洗容器。将溶液冷却至20℃,并加入55ml(390mmol)三乙胺。通过滴液漏斗在-10℃至-20℃的温度添加40ml四氢呋喃和20.2ml新戊酰氯(19.8g,164mmol)的混合物约30分钟。将含有沉淀物的混合物在-10℃至-20℃的温度搅拌2小时,然后将24.45g(150mmol)固体S(+)-4-苯基-2-噁唑烷酮(Va)和7.5g (177mmol)无水氯化锂连续地喷洒到混合物中。然后将悬浮液搅拌4小时,同时温热至20-25℃。
通过薄层色谱分析控制该反应。当S(+)-4-苯基-2-噁唑烷酮的斑点降至3%时,加入300ml甲苯和150ml饱和氯化铵溶液来终止反应。分离各相,然后通过50ml甲苯萃取水相。通过2×150ml 10%柠檬酸溶液,2×150ml 1M NaOH溶液和最后3×150ml水来清洗合并的甲苯溶液。将有机相在无水Na2SO4上干燥,滤出干燥剂,并在真空中蒸发滤液。在0℃用150ml异丙醇结晶残余物。在P2O5存在下在真空中干燥产物(VIa)。
产率:55.7g(93%)
熔点:100-102℃
(c=1,二氯甲烷)
1H NMR数据:(500MHz,DMSO-d6,25℃)δ1.42-1.56(m,2H),1.76-1.85(m,2H),2.80(dt,J=17.2,7.5Hz,1H),2.90(dt,J=17.2,7.5Hz,1H),3.61-3.71(m,2H),3.89-3.99(m,2H),4.13(dd,J=8.7,3.6Hz,1H),4.71(t,J=8.7Hz,1H),5.43(dd,J=8.7,3.6Hz,1H),7.12-7.19(m,2H),7.23-7.28(m,2H),7.29-7.34(m,1H),7.34-7.42(m,4H)ppm。
实施例3
(S)-3-{(R)-2-[(S)-[4-(叔丁基-二甲基-硅烷基-氧)-苯基]-(4-氟-苯基-胺)-甲基]-4-[2-(4-氟-苯基)-[1,3]二氧杂环戊烷-2-基]-丁酰}-4-苯基-噁唑烷-2-酮(VIIIa)的制备。
钛-三氯化物-异丙氧化物试剂的制备:
将0.95ml(0.9g,3.2mmol)Ti(IV)-异丙氧化物加入在0℃的温度和N2气氛下在34ml二氯甲烷中制备的0.99ml(1.71g,9mmol)TiCl4溶液中。将混合物在0℃搅拌15分钟。将该溶液用于下面的偶合步骤中。
偶合(方法A)
称重4.0g(10mmol)式VIa的化合物和6.6g(20mmol)式VIIa的亚胺化合物至带有磁力搅拌器,温度计,滴液漏斗和N2-进口的250ml容器中,并溶解在50ml的二氯甲烷中。将混合物冷却至-40℃,并加入3.6ml(20.7mmol)DIPEA。通过滴液漏斗逐渐加入钛-三氯化物-异丙氧化物试剂溶液大约30分钟。将混合物在-30至-40℃的温度搅拌1小时,然后通过在-30至-40℃的温度加入25ml异丙醇和50ml二氯甲烷,在相同的温度下进一步搅拌30分钟后,终止反应。将如此获得的橙色悬浮液缓慢倒入100ml pH=7的酒石酸盐缓冲液中,然后在15分钟的搅拌后,将各相分开。用另外的3×30ml二氯甲烷萃取水相,然后用30ml水清洗合并的二氯甲烷溶液,并用无水Na2SO4干燥,滤出干燥剂,在真空中蒸发滤液。将50ml甲醇加入残余物中,将如此获得的悬浮液在20-25℃搅拌10分钟,然后通过过滤分离产物。在真空中在P2O5存在下干燥白色结晶化合物(VIIIa)。
产率:5,5g(76%)
偶合(方法B)
称量25.8g(120mmol)(E)-(4-羟基-苯亚甲基)-(4-氟苯基)-胺至带有磁力搅拌器,温度计,滴液漏斗和N2-进口的2l容器中,将其溶解于500ml二氯甲烷中,然后在20-25℃加入57.8ml(332mmol)二异丙基乙胺(DIPEA)。加入19.9g(132mmol)叔丁基-二甲基-硅烷基-氯化物,并将溶液在20-25℃搅拌1-2小时。
通过薄层色谱分析控制该反应。当原料(E)-(4-羟基-苯亚甲基)-(4-氟苯基)-胺的点从色谱图上消失时,加入40g(100mmol)(VIa)化合物,然后将混合物冷却至-25至-30℃的温度。在约30分钟内通过滴液漏斗,在0℃逐渐加入340ml二氯甲烷中的9.5ml(9g,32mmol)钛-四异丙氧化物和9.9ml(17.1g,90mmol)四氯化钛(TiCl4)的溶液。
将混合物在-25至-30℃的温度搅拌0.5,然后通过在-30至-40℃的温度加入250ml异丙醇和500ml二氯甲烷,在相同的温度下再搅拌30分钟后,终止混合物中的反应。将如此获得的混合物缓慢倒入1000ml pH=7的酒石酸盐缓冲液中,然后在15分钟搅拌以后,将各相分开。用另外的3×250ml二氯甲烷萃取水相,然后用300ml水清洗合并的二氯甲烷溶液,并用无水Na2SO4干燥,滤出干燥剂,并在真空中蒸发滤液。将500ml甲醇加入残余物中,将如此获得的悬浮液在20-25℃搅拌10分钟,然后通过过滤分离产物。在真空中在P2O5存在下干燥白色结晶化合物(VIIIa)。
产率:57g(78%)
熔点:211-213℃
1H NMR数据:(500MHz,CDCl3,25℃)δ0.17(s,6H),0.97(s,9H),1.22-1.35(m,1H),1.66-1.90(m,3H),3.58-3.77(m,2H),3.84-3.96(m,2H),4.21(dd,J=8.7,2.9Hz,1H),4.26(d,J=9.1Hz,1H),4.46-4.57(m,1H),4.66(t,J=8.7Hz,1H),5.06(brm,1H),5.44(dd,J=8.7,2.9Hz,1H),6.33-6.41(m,2H),6.65-6.78(m,4H),6.91-6.98(m,2H),7.02-7.13(m,6H),7.13-7.19(m,1H),7.25-7.31(m,2H)ppm。
母液的再加工
将所获得的甲醇母液蒸发,将溶剂变为200ml甲苯。将10g硅胶Si 60加入甲苯溶液中,将悬浮液在20-25℃搅拌15分钟。将硅胶滤出,用甲苯冲洗,并蒸发滤液。将蒸发残余物溶解于100ml二氯甲烷中,将混合物冷却至-30℃,并且在N2气氛中加入7ml(40mmol)DIPEA。将2ml由(1.9g,6.74mmol)钛-四异丙氧化物和1.81ml(3.12g,16.3mmol)TiCl4制得的钛-三氯化物-异丙氧化物试剂溶液通过滴液漏斗在30分钟时间内加入。将反应混合物在-30至-40℃的温度下搅拌,然后,以与偶合反应中相同的方式分离纯的式VIIIa的产物。
产率:8.0g。联合产率:65g(89%)
实施例4
(3R,4S)-4-[4-(叔丁基-二甲基-硅烷基-氧)-苯基]-1-(4-氟苯基)-3-{2-[2-(4-氟苯基)-[1,3]二氧杂环戊烷-2-基]-乙基}-氮杂环丁烷-2-酮(IX,R4=TBDMS)的制备
将20.25g(28mmol)式VIIIa的化合物在20-25℃悬浮于556ml无水乙腈中,然后加入13.6ml(56mmol)N,O-二(三甲基硅烷基)-乙酰胺。将反应混合物在20-25℃搅拌2小时,然后加入0.1g(0.28mmol)四丁基铵-氟化物-三水合物,并在相同的温度下进一步搅拌。在反应结束的时候(0.5-1小时),悬浮液变成澄清溶液。通过薄层色谱分析控制反应。当开链胺化合物原料(VIIIa)的斑点消失时,用556ml水和556ml正己烷稀释反应混合物。相分离后,用556ml正己烷萃取含水乙腈相。用无水Na2SO4干燥合并的正己烷相,滤出干燥剂,在真空中蒸发滤液。如此获得的化合物(IXa)是油,将其在接下来的反应步骤中不经纯化而用完。
1H NMR数据:(500MHz,DMSO-d6,25℃)δ(ppm)0.16(s,3H),0.16(s,3H),0.92(s,9H),1.70-1.82(m,2H),1.89-2.09(m,2H),3.07(t d,J=7.7,2.3Hz,1H),3.62-3.72(m,2H),3.91-4.01(m,2H),4.85(d,J=2.3Hz,1H),6.80-6.86(m,2H),7.07-7.22(m,6H),7.24-7.29(m,2H),7.38-7.43(m,2H)ppm。
S(+)-4-苯基-2-噁唑烷酮的再生,其从含水的乙腈相作为副产物形成回来:
将如上获得的乙腈水相浓缩至约500ml体积,并用2×100ml二氯甲烷萃取从残余物中沉淀出的产物。蒸发合并的二氯甲烷溶液,从乙酸乙酯和正己烷的混合物中结晶残余物。通过过滤分离再生的S(+)-4-苯基-2-噁唑烷酮。
产率:大约3.9g(大约85%,以引入的VIIIa计)
实施例5
(3R,4S)-4-[4-(叔丁基-二甲基-硅烷基-氧)-苯基]-1-(4-氟苯基)-3-[3-(4-氟苯基)-3-氧-丙基]-氮杂环丁烷-2-酮(X,R4=TBDMS)的制备
将约17g根据实施例4获得的化合物(IX,R4=TBDMS)(含量至少为:15.8g,28mmol)溶解于330ml二氯甲烷中,在20-25℃加入42g蒙脱石K10。将该异质混合物在20-25℃搅拌2-4小时。通过薄层色谱分析控制反应。当原料的斑点在色谱图中消失时,将反应混合物过滤,先用50ml二氯甲烷冲洗滤出的蒙脱石K10A,然后用3×50ml二氯甲烷和甲醇(2∶1v/v)的混合物冲洗。蒸发合并的滤液,在0℃从乙醇和水的混合物中结晶残余物。
产率:11.6g干燥产物(80%,步骤4和5一起)
熔点:110-112℃
1H NMR数据:(500MHz,DMSO-d6,25℃)δ0.16(s,3H),0.17(s,3H),0.93(s,9H),2.12-2.23(m,2H),3.14-3.30(m,3H),4.99(d,J=2.3Hz,1H),6.81-6.88(m,2H),7.10-7.18(m,2H),7.20-7.27(m,2H),7.29-7.38(m,4H),7.99-8.07(m,2H)ppm。
实施例6
(3R,4S)-4-[4-(叔丁基-二甲基-硅烷基-氧)-苯基]-1-(4-氟苯基)-3-[(S)-3-(4-氟苯基)-3-羟丙基]-氮杂环丁烷-2-酮(XIa)的制备
将5.00g(9.6mmol)(3R,4S)-4-[4-(叔丁基-二甲基-硅烷基-氧)-苯基]-1-(4-氟苯基)-3-[3-(4-氟苯基)-3-氧-丙基]-氮杂环丁烷-2-酮溶解于9.6ml无水二氯甲烷中,然后加入1.92ml(0.96mmol)(R)-邻甲苯基-CBS-氧氮杂硼烷0.5M-甲苯溶液。将混合物冷却至0至-5℃的温度,在该温度下,加入1.9ml 1.0M硼烷-二甲基的二氯甲烷溶液6小时。在该温度下将反应混合物搅拌直至依照薄层色谱研究发现起始酮的斑点消失时。然后加入10ml甲醇,0.5ml 5%过氧化氢溶液和10ml 2M硫酸。将混合物搅拌0.5小时后,将各相分开。用50ml 2N硫酸清洗有机相,然后用50ml 5%亚硫酸盐溶液清洗。用无水硫酸钠干燥溶液,过滤并蒸发。
产率:5.05g无色油
非对映体过量:>98%de(手性HPLC)
1H NMR数据:(500MHz,DMSO-d6,25℃)δ0.17(s,3H),0.18(s,3H),0.93(s,9H),1.65-1.94(m,4H),3.07-3.15(m,1H),4.46-4.54(m,1H),4.88(d,J=2.3Hz,1H),5.29(d,J=4.5Hz,1H),6.83-6.89(m,2H),7.07-7.17(m,4H),7.19-7.25(m,2H),7.27-7.34(m,4H)ppm。
实施例7
(3R,4S)-1-(4-氟苯基)-3-[(S)-3-(4-氟苯基)-3-羟丙基]-4-(4-羟丙基)-氮杂环丁烷-2-酮(I,依泽替米贝)的制备
将5.0g(9.6mmol)(3R,4S)-4-[4-(叔丁基-二甲基-硅烷基-氧)-苯基]-1-(4-氟苯基)-3-[(S)-3-(4-氟苯基)-3-羟丙基]-氮杂环丁烷-2-酮(XI,R4=TBDMS)溶解于35ml 2-丙醇中,并加入10ml 2M硫酸溶液。将溶液在60-70℃加热1-2小时,然后使其冷却。通过加入去离子水使产物结晶。将结晶产物滤出,用水洗至中性。
产率:3.2g(81%,步骤7和8一起)
1H NMR数据:(500MHz,DMSO-d6,25℃)δ1.65-1.92(m,4H),3.05-3.13(m,1H),4.46-4.55(m,1H),4.81(d,J=2.3Hz,1H),5.29(d,J=3.7Hz,1H),6.74-6.80(m,2H),7.08-7.17(m,4H),7.19-7.26(m,4H),7.28-7.35(m,2H),9.54(s,1H)ppm。
实施例8
(E)-[4-(叔丁基-二甲基-硅烷基氧)-苯亚甲基]-(4-氟苯基)-胺(VIIa)的制备
将21.5g(0.1mol)(E)-(4-羟基-苯亚甲基)-(4-氟苯基)-胺(VIIb)溶解于125ml无水四氢呋喃中,将10.2g(0.15mol)咪唑加入到溶液中,然后将40ml 18.8g(0.125mol)叔丁基-二甲基-硅烷基-氯化物的四氢呋喃溶液在20-25℃逐滴加入其中。在该温度下搅拌反应混合物直至通过薄层色谱在反应混合物中检测不到原料。预期的反应时间为1-2小时。用50ml甲苯稀释反应混合物,然后倒到100ml水上。用50ml甲苯萃取水相,然后用3×50水将合并的有机相洗至中性。将溶液蒸发,并且从冷正己烷中结晶产物。
产率:28g(85%)。
Claims (2)
1.式I的依泽替米贝的制备方法,
包括以下步骤:
a)将式II的4-(4-氟苯甲酰)-丁酸和乙二醇通过未分离的式III的过渡化合物转变成式IV的4-[2-(4-氟-苯基)-[1,3]二氧杂环戊烷-2-基]-丁酸,
其中式V的化合物选自式Va,Vb,Vc或Vd的化合物,
并且其中R1,R2和R3表示:
在Va的情况中:R1=Ph,R2=R3=H,
在Vb的情况中:R1=R2=R3=Ph,
在Vc的情况中:R1=甲基,R2=Ph,R3=H,和
在Vd的情况中:R1=异丙基,R2=R3=Ph,
并且其中Ph代表苯基
环化式VIII的化合物来获得通式IX的受保护的氮杂环丁酮衍生物,
d)水解式IX的化合物的缩酮基来获得式X的化合物,
e)对映选择性地还原通式X的化合物来获得式XI的化合物,
其中选择式XIIa,XIIb,XIIc,XIId的手性CBS-氧氮杂硼烷化合物之一作为催化剂,以及
f)除去通式XI化合物的硅烷基保护基团来获得式I的终产物依泽替米贝
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- 2006-12-18 CA CA002630737A patent/CA2630737A1/en not_active Abandoned
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PL1963260T3 (pl) | 2011-04-29 |
CY1111307T1 (el) | 2015-08-05 |
HRP20110013T1 (hr) | 2011-02-28 |
CA2630737A1 (en) | 2007-06-28 |
PT1963260E (pt) | 2010-12-27 |
CN101346349A (zh) | 2009-01-14 |
EA014331B1 (ru) | 2010-10-29 |
HK1128156A1 (en) | 2009-10-16 |
EP1963260B1 (en) | 2010-11-03 |
RS51613B (en) | 2011-08-31 |
SI1963260T1 (sl) | 2011-02-28 |
ES2354728T3 (es) | 2011-03-17 |
HU0501164D0 (en) | 2006-02-28 |
ATE486848T1 (de) | 2010-11-15 |
US20090216009A1 (en) | 2009-08-27 |
DE602006018063D1 (de) | 2010-12-16 |
HUP0501164A2 (en) | 2007-07-30 |
EA200801548A1 (ru) | 2008-10-30 |
DK1963260T3 (da) | 2011-01-17 |
WO2007072088A1 (en) | 2007-06-28 |
EP1963260A1 (en) | 2008-09-03 |
US8178665B2 (en) | 2012-05-15 |
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