CN111471003B - 一种立他司特中间体的制备方法 - Google Patents
一种立他司特中间体的制备方法 Download PDFInfo
- Publication number
- CN111471003B CN111471003B CN201910068983.5A CN201910068983A CN111471003B CN 111471003 B CN111471003 B CN 111471003B CN 201910068983 A CN201910068983 A CN 201910068983A CN 111471003 B CN111471003 B CN 111471003B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- stirring
- reagent
- solution
- 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 10
- WJPYOCIWVYDFDT-UHFFFAOYSA-N ethyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate Chemical compound CCOC(=O)CC(=O)CC1=CC(F)=C(F)C=C1F WJPYOCIWVYDFDT-UHFFFAOYSA-N 0.000 title abstract description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 28
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 23
- 239000011701 zinc Substances 0.000 claims abstract description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 7
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 7
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 6
- 239000003446 ligand Substances 0.000 claims abstract description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 5
- 239000011574 phosphorus Substances 0.000 claims abstract description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 125000006239 protecting group Chemical group 0.000 claims abstract description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000005859 coupling reaction Methods 0.000 claims abstract description 3
- 229910052751 metal Inorganic materials 0.000 claims abstract description 3
- 239000002184 metal Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 31
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 30
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical group [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 abstract description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 abstract description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 abstract description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 abstract description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 abstract description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 abstract description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 abstract description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 abstract description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 abstract description 2
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 abstract description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 63
- 239000000243 solution Substances 0.000 description 39
- 238000003756 stirring Methods 0.000 description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- -1 amino acid compound Chemical class 0.000 description 22
- 238000001816 cooling Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
- WBOMXUMQOVQNKT-UHFFFAOYSA-N 1-bromo-3-methylsulfonylbenzene Chemical compound CS(=O)(=O)C1=CC=CC(Br)=C1 WBOMXUMQOVQNKT-UHFFFAOYSA-N 0.000 description 7
- 229940098779 methanesulfonic acid Drugs 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 108010044426 integrins Proteins 0.000 description 4
- 102000006495 integrins Human genes 0.000 description 4
- 239000000543 intermediate Substances 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
- GDMOHOYNMWWBAU-QMMMGPOBSA-N (2s)-2-amino-3-(3-bromophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CC(Br)=C1 GDMOHOYNMWWBAU-QMMMGPOBSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 102000015271 Intercellular Adhesion Molecule-1 Human genes 0.000 description 3
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 2
- 206010013774 Dry eye Diseases 0.000 description 2
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- FBUDYESOPLBQIR-NSHDSACASA-N (2s)-3-(3-bromophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC(Br)=C1 FBUDYESOPLBQIR-NSHDSACASA-N 0.000 description 1
- UKJFYKYKLBOEFP-UHFFFAOYSA-N 1-(benzenesulfonyl)-3-bromobenzene Chemical compound BrC1=CC=CC(S(=O)(=O)C=2C=CC=CC=2)=C1 UKJFYKYKLBOEFP-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- YZZAYCXETGMEPP-UHFFFAOYSA-N 1-naphthalen-1-yl-2h-naphthalen-1-ol Chemical compound C1=CC=C2C(C3(C4=CC=CC=C4C=CC3)O)=CC=CC2=C1 YZZAYCXETGMEPP-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ZUQWRIONDCCVSG-LBPRGKRZSA-N C[C@H](C(OCC(C=CC=C1S(C)(=O)=O)=C1N)=O)C1=CC=CC=C1 Chemical compound C[C@H](C(OCC(C=CC=C1S(C)(=O)=O)=C1N)=O)C1=CC=CC=C1 ZUQWRIONDCCVSG-LBPRGKRZSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- VZDYWEUILIUIDF-UHFFFAOYSA-J cerium(4+);disulfate Chemical compound [Ce+4].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O VZDYWEUILIUIDF-UHFFFAOYSA-J 0.000 description 1
- 229910000355 cerium(IV) sulfate Inorganic materials 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- YJJCBPAEWVURMJ-UHFFFAOYSA-N ethyl propanoate;hydrochloride Chemical compound Cl.CCOC(=O)CC YJJCBPAEWVURMJ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000005732 intercellular adhesion Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960005381 lifitegrast Drugs 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- OJVSEHLMRCLAFY-UHFFFAOYSA-N methyl propanoate;hydrochloride Chemical compound Cl.CCC(=O)OC OJVSEHLMRCLAFY-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- LYPGDCWPTHTUDO-UHFFFAOYSA-M sodium;methanesulfinate Chemical compound [Na+].CS([O-])=O LYPGDCWPTHTUDO-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical group CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims (2)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910068983.5A CN111471003B (zh) | 2019-01-24 | 2019-01-24 | 一种立他司特中间体的制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910068983.5A CN111471003B (zh) | 2019-01-24 | 2019-01-24 | 一种立他司特中间体的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111471003A CN111471003A (zh) | 2020-07-31 |
CN111471003B true CN111471003B (zh) | 2022-09-23 |
Family
ID=71743623
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910068983.5A Active CN111471003B (zh) | 2019-01-24 | 2019-01-24 | 一种立他司特中间体的制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111471003B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113072471B (zh) * | 2021-03-02 | 2022-09-16 | 四川美大康华康药业有限公司 | 一种利非司特中间体及其制备方法 |
CN114656379B (zh) * | 2022-04-27 | 2024-06-04 | 成都道合尔医药技术有限公司 | 一种立他司特中间体的合成方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104797574A (zh) * | 2012-07-25 | 2015-07-22 | 原生质生物科学股份有限公司 | Lfa-1抑制剂及其多晶型物 |
CN104974073A (zh) * | 2014-04-10 | 2015-10-14 | 江苏和成新材料有限公司 | 一种制备西洛多辛中间体的方法 |
CN107129444A (zh) * | 2016-02-29 | 2017-09-05 | 尚科生物医药(上海)有限公司 | 高纯度(s)-2-叔丁氧羰基氨基-3-(4-氨甲酰基-2,6-二甲基苯基)丙酸的制备方法 |
CN108084067A (zh) * | 2016-11-22 | 2018-05-29 | 重庆圣华曦药业股份有限公司 | 一种立他司特中间体的制备方法 |
-
2019
- 2019-01-24 CN CN201910068983.5A patent/CN111471003B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104797574A (zh) * | 2012-07-25 | 2015-07-22 | 原生质生物科学股份有限公司 | Lfa-1抑制剂及其多晶型物 |
CN104974073A (zh) * | 2014-04-10 | 2015-10-14 | 江苏和成新材料有限公司 | 一种制备西洛多辛中间体的方法 |
CN107129444A (zh) * | 2016-02-29 | 2017-09-05 | 尚科生物医药(上海)有限公司 | 高纯度(s)-2-叔丁氧羰基氨基-3-(4-氨甲酰基-2,6-二甲基苯基)丙酸的制备方法 |
CN108084067A (zh) * | 2016-11-22 | 2018-05-29 | 重庆圣华曦药业股份有限公司 | 一种立他司特中间体的制备方法 |
Non-Patent Citations (2)
Title |
---|
用有机锌试剂制备芳基硼酸及其联反应的研究;苟蓓蕾;《中国优秀硕士学位论文全文数据库 (工程科技Ⅰ辑)》;20170415;第B014-47页 * |
经布莱斯反应—锅法制备多取代吡咯、吡啶;陈怡宁;《中国优秀硕士学位论文全文数据库 (医药卫生科技辑)》;20150515;第E079-3页 * |
Also Published As
Publication number | Publication date |
---|---|
CN111471003A (zh) | 2020-07-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8394961B2 (en) | Method for the preparation of dabigatran | |
RU2430092C2 (ru) | Способ получения телмисартана | |
NO340420B1 (no) | Metode for fremstilling av 1-(3-(2-(1-benzotiofen-5-yl)-etoksy)propyl)azetidin-3-ol eller salter derav | |
CN111471003B (zh) | 一种立他司特中间体的制备方法 | |
JP5016575B2 (ja) | ストロンチウムラネレートおよびその水和物の新規な合成法 | |
CN110590635A (zh) | 左乙拉西坦及其中间体的制备方法 | |
CN110498770A (zh) | 一种制备恶拉戈利中间体的方法 | |
CN110396080B (zh) | 一种富马酸沃诺拉赞代谢物及其氘代物的制备方法 | |
CN107810189A (zh) | 用于制备氮芥衍生物的方法 | |
CA2889650A1 (en) | Process and intermediates for preparing lacosamide | |
JP5899204B2 (ja) | キラルなβ−アミノカルボキサミド誘導体の製造方法 | |
KR20170129191A (ko) | (4s)-4-[4-사이아노-2-(메틸설폰일)페닐]-3,6-다이메틸-2-옥소-1-[3-(트라이플루오로메틸)페닐]-1,2,3,4-테트라하이드로 피리미딘-5-카보나이트릴의 생성 방법 | |
CN108148044B (zh) | 酰胺类化合物及该化合物制备富马酸沃诺拉赞的方法 | |
CN117383994A (zh) | 一种不对称脲类化合物的制备方法及不对称脲类化合物 | |
CN108864084B (zh) | 一组阿哌沙班有关物质及其制备方法 | |
CN104177372A (zh) | 抗结核候选药物pa-824的合成方法 | |
CN103435526B (zh) | 一种维达列汀的合成方法 | |
CN107814757B (zh) | 一种合成多取代吡咯衍生物的方法 | |
JP6233934B2 (ja) | デスモシン、イソデスモシン、およびその誘導体の製造方法 | |
EP2888250A1 (en) | Process for the synthesis of substituted gamma lactams | |
CN110590641B (zh) | 一种3-羟基异吲哚-1-酮系列化合物的绿色制备方法 | |
RU2053226C1 (ru) | 5-аминонафталин-1-замещенные (алкоксиэтил)сульфониламиды и способ получения 5-аминонафталин-1-замещенных (алкоксиэтил)сульфониламидов | |
CN106111189B (zh) | 一种手性吡哆胺催化剂及其合成方法和应用 | |
JP6997769B2 (ja) | 2-(6-ニトロピリジン-3-イル)-9H-ジピリド[2,3-b;3’,4’-d]ピロールの製造方法 | |
CN108997250B (zh) | 多步合成2-苄基-1,5-二氢苯并[e][1,4]氧氮杂卓的方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20200731 Assignee: Shanghai Haohong Biomedical Technology Co.,Ltd. Assignor: SHANGHAI HAOYUAN CHEMEXPRESS CO.,LTD. Contract record no.: X2023980041206 Denomination of invention: A preparation method for intermediate of rituximab Granted publication date: 20220923 License type: Exclusive License Record date: 20230905 |
|
EE01 | Entry into force of recordation of patent licensing contract | ||
EC01 | Cancellation of recordation of patent licensing contract |
Assignee: Shanghai Haohong Biomedical Technology Co.,Ltd. Assignor: SHANGHAI HAOYUAN CHEMEXPRESS CO.,LTD. Contract record no.: X2023980041206 Date of cancellation: 20240628 |