FI95467B - Förfarande för framställning av 1-//1-/2-(trifluormetyl)-4-pyrimidinyl/-4-piperidinyl/metyl/-2-pyrrolidinon i stor skala - Google Patents
Förfarande för framställning av 1-//1-/2-(trifluormetyl)-4-pyrimidinyl/-4-piperidinyl/metyl/-2-pyrrolidinon i stor skala Download PDFInfo
- Publication number
- FI95467B FI95467B FI905225A FI905225A FI95467B FI 95467 B FI95467 B FI 95467B FI 905225 A FI905225 A FI 905225A FI 905225 A FI905225 A FI 905225A FI 95467 B FI95467 B FI 95467B
- Authority
- FI
- Finland
- Prior art keywords
- formula
- compound
- pyrrolidinone
- trifluoromethyl
- piperidinyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 56
- 230000008569 process Effects 0.000 title claims description 32
- -1 2- (trifluoromethyl) -4-pyrimidinyl Chemical group 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 25
- KEWFMWJJMGQBAN-UHFFFAOYSA-N 1-[[1-[2-(trifluoromethyl)pyrimidin-4-yl]piperidin-4-yl]methyl]pyrrolidin-2-one Chemical compound FC(F)(F)C1=NC=CC(N2CCC(CN3C(CCC3)=O)CC2)=N1 KEWFMWJJMGQBAN-UHFFFAOYSA-N 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 7
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- 230000003197 catalytic effect Effects 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 5
- 150000001805 chlorine compounds Chemical group 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 238000011031 large-scale manufacturing process Methods 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims description 3
- 230000026030 halogenation Effects 0.000 claims description 3
- 238000005658 halogenation reaction Methods 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical group [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical group I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 2
- 125000006513 pyridinyl methyl group Chemical group 0.000 claims 1
- 239000000543 intermediate Substances 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000012986 modification Methods 0.000 description 8
- 230000004048 modification Effects 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- 239000006260 foam Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000005187 foaming Methods 0.000 description 5
- 230000002140 halogenating effect Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000005292 vacuum distillation Methods 0.000 description 5
- SFFUEHODRAXXIA-UHFFFAOYSA-N 2,2,2-trifluoroacetonitrile Chemical compound FC(F)(F)C#N SFFUEHODRAXXIA-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000001311 chemical methods and process Methods 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- NITMACBPVVUGOJ-UHFFFAOYSA-N 2,2,2-trifluoroethanimidamide Chemical compound NC(=N)C(F)(F)F NITMACBPVVUGOJ-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical group CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000011097 chromatography purification Methods 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- 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 description 2
- ROGIKWDBLZYABK-UHFFFAOYSA-N 1-(pyridin-4-ylmethyl)pyrrolidin-2-one Chemical compound O=C1CCCN1CC1=CC=NC=C1 ROGIKWDBLZYABK-UHFFFAOYSA-N 0.000 description 2
- JPMRGPPMXHGKRO-UHFFFAOYSA-N 2-(chloromethyl)pyridine hydrochloride Chemical compound Cl.ClCC1=CC=CC=N1 JPMRGPPMXHGKRO-UHFFFAOYSA-N 0.000 description 2
- QFWVAJQVYBRTCL-UHFFFAOYSA-N 4,6-dichloro-2-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=NC(Cl)=CC(Cl)=N1 QFWVAJQVYBRTCL-UHFFFAOYSA-N 0.000 description 2
- AMGBKPNVGVAFEN-UHFFFAOYSA-N 4-hydroxy-2-(trifluoromethyl)-1h-pyrimidin-6-one Chemical compound OC1=CC(=O)NC(C(F)(F)F)=N1 AMGBKPNVGVAFEN-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical group CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- WRIRWRKPLXCTFD-UHFFFAOYSA-N malonamide Chemical compound NC(=O)CC(N)=O WRIRWRKPLXCTFD-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 239000002341 toxic gas Substances 0.000 description 2
- VOLGAXAGEUPBDM-UHFFFAOYSA-N $l^{1}-oxidanylethane Chemical compound CC[O] VOLGAXAGEUPBDM-UHFFFAOYSA-N 0.000 description 1
- NJWIMFZLESWFIM-UHFFFAOYSA-N 2-(chloromethyl)pyridine Chemical compound ClCC1=CC=CC=N1 NJWIMFZLESWFIM-UHFFFAOYSA-N 0.000 description 1
- PDCVDVCPQWFGAX-UHFFFAOYSA-N 2-(trifluoromethyl)-1h-pyrimidin-6-one Chemical compound OC1=CC=NC(C(F)(F)F)=N1 PDCVDVCPQWFGAX-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- GKSFWALDQDWMFD-UHFFFAOYSA-N 3-(chloromethyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=C1CCl GKSFWALDQDWMFD-UHFFFAOYSA-N 0.000 description 1
- VMLIVFUOTCQFBU-UHFFFAOYSA-N 3-oxopropyl acetate;sodium Chemical compound [Na].CC(=O)OCCC=O VMLIVFUOTCQFBU-UHFFFAOYSA-N 0.000 description 1
- DUFGYCAXVIUXIP-UHFFFAOYSA-N 4,6-dihydroxypyrimidine Chemical compound OC1=CC(O)=NC=N1 DUFGYCAXVIUXIP-UHFFFAOYSA-N 0.000 description 1
- ZDHKVKPZQKYREU-UHFFFAOYSA-N 4-(chloromethyl)pyridine;hydron;chloride Chemical compound Cl.ClCC1=CC=NC=C1 ZDHKVKPZQKYREU-UHFFFAOYSA-N 0.000 description 1
- VNJDNLUHJHGHKK-UHFFFAOYSA-N 4-(pyridin-2-ylmethyl)pyrrolidin-2-one Chemical compound C1NC(=O)CC1CC1=CC=CC=N1 VNJDNLUHJHGHKK-UHFFFAOYSA-N 0.000 description 1
- OVEGSCLVOXWLIV-UHFFFAOYSA-N 4-chloro-2-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=NC=CC(Cl)=N1 OVEGSCLVOXWLIV-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 150000005694 halopyrimidines Chemical class 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
- Silicon Polymers (AREA)
- Macromonomer-Based Addition Polymer (AREA)
Claims (6)
1. Förbättrat förfarande, som lämpar sig för produktion i stor skala av l-[[l-[2-(trifluormetyl)-4-pyrimi-5 dinyl]-4-piperidinyl]metyl]-2-pyrrolidinon med formeln öod"’ 10 kännetecknat av, att det omfattar stegen, väri a) en blandning av 2-pyrrolidinon och 4-halogen-metylpyridin tillsätts i en N,N-dimetylformamidsuspension av natriumhydrid i cirka 15 - 20 °C, varvid en l-(-4-pyri- 15 dinylmetyl)-2-pyrrolidinon med formeln (IV) bildas 0 20 IV och föreningen med formeln (IV) tillvaratages genom ektra-hering med het isopropyleter, b) hydreras katalytiskt en syrgjord vattenlösning 25 av föreningen med formeln (IV), varvid en förening med formeln (III) erhälls 0 c3i"*~sCI/h‘hy 30 . , m väri Y är klorid, bromid eller jodid, vattenlösningen görs basisk och en förening med formeln (V) tillsätts, 95467 -/1 ~Ö \ 5 v varvid en mellanprodukt med formeln (II) erhälls A^y-\ *-<Γ3 WQn . 10 \_/ \W/ \ . 1 1 ooh c) omvandlas föreningen med formeln (II) genom ka-talytisk hydrogenolys l-[ [l-[2-(trifluormetyl)-4-pyrimidi-15 nyl]-4-piperidinyl]metyl]-2-pyrrolidinon.
2. Förbättrat förfarande, som lämpar sig för produktion i stor skala av 1-[[1-[2—(trifluormetyl)-4-pyrimi-dinyl]-4-piperidinyl]metyl]-2-pyrrolidinon med formeln 0^odr’ kännetecknat av, att det omf attar stegen, väri 25 a) en blandning av 2-pyrrolidinon och 4-halogenme- ♦ tylpyridin tillsätts i en Ν,Ν-dimetylformamidsuspension av natriumhydrid i cirka 15 - 20 °C, varvid en l-(-4-pyridi-nylmetyl)-2-pyrrolidinon med formeln (IV) bildas IV „ «467 och föreningen med formeln (IV) tillvaratages genom ektra-hering med het isopropyleter, b) 4,6-dihydroxi-2-trifluorpyrimidin halogeneras med en halogeneringsreagens, varvid 4,6-dihalogen-2-tri- 5 fluor-pyrimidin med formeln (V) erhälls io v c) hydreras katalytiskt en syrgjord vattenlösning av föreningen med formeln (IV), varvid en förening med formeln (III) erhälls 15 /° \h · H Y lit 20 väri Y är klorid, bromid eller jodid, vattenlösningen görs basisk och en förening med formeln (V) tillsätts, varvid en mellanprodukt med formeln (II) erhälls Y och 11 d) omvandlas föreningen med formeln (II) genom ka-30 talytis hydrogenolys l-[[l-[2-(trifluormetyl)-4-pyrimidi- nyl]-4-piperidinyl]metyl]-2-pyrrolidinon.
3. Förfarande enligt patentkrav 2, känne-t e c k n a t av, att Y är klorid. 24 95467
4. Förfarande enligt patentkrav 2, känne- t e c k n a t av, att halogeneringsreagensen i steget b) är fosforoxiklorid.
5. Förfarande enligt patentkrav 2, känne- 5 tecknat av, att hydreringskatalysatoren i steget c) är platin(IV)oksid.
6. Förfarande enligt patentkrav 2, känne-tecknat av, att i det katalytiska hydrogenolyset i steget d) en 10-procentisk Pd/C-katalysator används. » • · 1 · f . I· «,( (Iltl Ι,ΙΙΜ,.Ι
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US42754689 | 1989-10-27 | ||
| US07/427,546 US4963678A (en) | 1989-10-27 | 1989-10-27 | Process for large-scale production of BMY 21502 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI905225A0 FI905225A0 (sv) | 1990-10-24 |
| FI95467B true FI95467B (sv) | 1995-10-31 |
| FI95467C FI95467C (sv) | 1996-02-12 |
Family
ID=23695332
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI905225A FI95467C (sv) | 1989-10-27 | 1990-10-24 | Förfarande för framställning av 1-//1-/2-(trifluormetyl)-4-pyrimidinyl/-4-piperidinyl/metyl/-2-pyrrolidinon i stor skala |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US4963678A (sv) |
| KR (1) | KR910007917A (sv) |
| CN (1) | CN1032916C (sv) |
| AT (1) | AT397961B (sv) |
| EG (1) | EG19764A (sv) |
| ES (1) | ES2026059A6 (sv) |
| FI (1) | FI95467C (sv) |
| GR (1) | GR1001125B (sv) |
| HU (1) | HU206878B (sv) |
| NO (1) | NO177303C (sv) |
| PT (1) | PT95711B (sv) |
| YU (1) | YU203290A (sv) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT398972B (de) * | 1989-10-27 | 1995-02-27 | Bristol Myers Squibb Co | Verfahren zur herstellung von 1-((diazinylpiperidinyl)-methyl)-2-pyrrolidinon n |
| US4963678A (en) * | 1989-10-27 | 1990-10-16 | Bristol-Myers Squibb Co. | Process for large-scale production of BMY 21502 |
| US5098904A (en) * | 1990-06-27 | 1992-03-24 | Bristol-Myers Squibb Company | Cerebral function enhancing pyrimidinyl derivatives |
| US5401744A (en) * | 1993-10-04 | 1995-03-28 | Bristol-Myers Squibb Company | Useful hemi-hydrate form of a cerebral function enhancing agent |
| US5538985A (en) * | 1994-01-27 | 1996-07-23 | Mitsui Toatsu Chemicals, Inc. | Pyrrolidinone derivatives |
| MXPA03008121A (es) | 2001-03-15 | 2003-12-12 | Basf Ag | 5-fenilpirimidinas, metodos y productos intermedios para su produccion y uso de las mismas para controlar hongos patogenicos. |
| US7073271B2 (en) * | 2002-02-14 | 2006-07-11 | Faro Technologies Inc. | Portable coordinate measurement machine |
| CN106883185B (zh) * | 2015-12-15 | 2021-07-09 | 重庆博腾制药科技股份有限公司 | 一种4-氯-2-三氟甲基嘧啶的制备方法 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ216720A (en) * | 1985-07-08 | 1990-09-26 | Bristol Myers Co | Diazinylpiperidine derivatives and pharmaceutical compositions |
| US4826843A (en) * | 1985-07-08 | 1989-05-02 | Bristol-Myers | Cerebral function enhancing diazinylpiperidine derivatives |
| DE3703103A1 (de) * | 1987-02-03 | 1988-08-11 | Bayer Ag | Mittel gegen fischparsiten |
| US4963678A (en) * | 1989-10-27 | 1990-10-16 | Bristol-Myers Squibb Co. | Process for large-scale production of BMY 21502 |
-
1989
- 1989-10-27 US US07/427,546 patent/US4963678A/en not_active Expired - Lifetime
- 1989-10-27 HU HU9150A patent/HU206878B/hu not_active IP Right Cessation
-
1990
- 1990-10-22 AT AT0212290A patent/AT397961B/de not_active IP Right Cessation
- 1990-10-24 NO NO904587A patent/NO177303C/no not_active IP Right Cessation
- 1990-10-24 FI FI905225A patent/FI95467C/sv active IP Right Grant
- 1990-10-25 CN CN90108716A patent/CN1032916C/zh not_active Expired - Fee Related
- 1990-10-25 KR KR1019900017161A patent/KR910007917A/ko not_active Application Discontinuation
- 1990-10-25 EG EG63690A patent/EG19764A/xx active
- 1990-10-26 YU YU203290A patent/YU203290A/sh unknown
- 1990-10-26 ES ES9002730A patent/ES2026059A6/es not_active Expired - Lifetime
- 1990-10-26 PT PT95711A patent/PT95711B/pt not_active IP Right Cessation
- 1990-10-29 GR GR900100776A patent/GR1001125B/el not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NO904587L (no) | 1991-04-29 |
| ATA212290A (de) | 1993-12-15 |
| GR1001125B (el) | 1993-04-28 |
| FI905225A0 (sv) | 1990-10-24 |
| GR900100776A (en) | 1992-03-20 |
| NO904587D0 (no) | 1990-10-24 |
| PT95711A (pt) | 1991-09-13 |
| HU206878B (en) | 1993-01-28 |
| US4963678A (en) | 1990-10-16 |
| EG19764A (en) | 1996-01-31 |
| PT95711B (pt) | 1997-12-31 |
| ES2026059A6 (es) | 1992-04-01 |
| KR910007917A (ko) | 1991-05-30 |
| NO177303C (no) | 1995-08-23 |
| NO177303B (no) | 1995-05-15 |
| HU910050D0 (en) | 1991-08-28 |
| CN1051175A (zh) | 1991-05-08 |
| AT397961B (de) | 1994-08-25 |
| FI95467C (sv) | 1996-02-12 |
| CN1032916C (zh) | 1996-10-02 |
| YU203290A (sh) | 1993-10-20 |
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Legal Events
| Date | Code | Title | Description |
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| BB | Publication of examined application | ||
| FG | Patent granted |
Owner name: BRISTOL-MYERS SQUIBB COMPANY |