CN106518751B - Method for preparing pimavanserin - Google Patents
Method for preparing pimavanserin Download PDFInfo
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- CN106518751B CN106518751B CN201510577381.4A CN201510577381A CN106518751B CN 106518751 B CN106518751 B CN 106518751B CN 201510577381 A CN201510577381 A CN 201510577381A CN 106518751 B CN106518751 B CN 106518751B
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- pimavanserin
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- 238000000034 method Methods 0.000 title claims abstract description 40
- RKEWSXXUOLRFBX-UHFFFAOYSA-N pimavanserin Chemical compound C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1 RKEWSXXUOLRFBX-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 229960003300 pimavanserin Drugs 0.000 title claims abstract description 27
- 238000005580 one pot reaction Methods 0.000 claims abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 13
- 230000006315 carbonylation Effects 0.000 claims abstract description 12
- 238000005810 carbonylation reaction Methods 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 10
- JBVKKHDTYSDPHA-UHFFFAOYSA-N [4-(2-methylpropoxy)phenyl]methanamine Chemical compound CC(C)COC1=CC=C(CN)C=C1 JBVKKHDTYSDPHA-UHFFFAOYSA-N 0.000 claims abstract description 9
- PLYWEOOWONUOBN-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine Chemical compound C1CN(C)CCC1NCC1=CC=C(F)C=C1 PLYWEOOWONUOBN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 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 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 8
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 claims description 2
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000012074 organic phase Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 14
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- XVTYAGNMAWWGPF-UHFFFAOYSA-N 1-isocyanato-4-(2-methylpropoxy)benzene Chemical compound CC(C)COC1=CC=C(N=C=O)C=C1 XVTYAGNMAWWGPF-UHFFFAOYSA-N 0.000 description 5
- -1 4-isobutoxyphenylmethyl acetate Chemical compound 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 5
- 229940011051 isopropyl acetate Drugs 0.000 description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- VPEGFBXWSGBVDN-UHFFFAOYSA-N acetic acid;[4-(2-methylpropoxy)phenyl]methanamine Chemical compound CC(O)=O.CC(C)COC1=CC=C(CN)C=C1 VPEGFBXWSGBVDN-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 description 2
- APXLSLWSMWRTTL-UHFFFAOYSA-N 2-[4-(2-methylpropoxy)phenyl]acetic acid Chemical compound CC(C)COC1=CC=C(CC(O)=O)C=C1 APXLSLWSMWRTTL-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- WWRHBQHLQUOKQV-UHFFFAOYSA-N n-(4-fluorophenyl)-1-methylpiperidin-4-amine Chemical compound C1CN(C)CCC1NC1=CC=C(F)C=C1 WWRHBQHLQUOKQV-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- WRTCOTWKXLHMJW-UHFFFAOYSA-N (4-hydroxyphenyl)methyl acetate Chemical compound CC(=O)OCC1=CC=C(O)C=C1 WRTCOTWKXLHMJW-UHFFFAOYSA-N 0.000 description 1
- WRUADNPYZJXUNN-KPKJPENVSA-N (ne)-n-[[4-(2-methylpropoxy)phenyl]methylidene]hydroxylamine Chemical compound CC(C)COC1=CC=C(\C=N\O)C=C1 WRUADNPYZJXUNN-KPKJPENVSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XTTVNKCYECPJOF-UHFFFAOYSA-N 2,3-dihydroxybutanedioic acid;1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[[4-(2-methylpropoxy)phenyl]methyl]urea Chemical compound OC(=O)C(O)C(O)C(O)=O.C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1 XTTVNKCYECPJOF-UHFFFAOYSA-N 0.000 description 1
- PWASYRSZCSTUIW-UHFFFAOYSA-N 4-(2-methylpropoxy)benzaldehyde Chemical compound CC(C)COC1=CC=C(C=O)C=C1 PWASYRSZCSTUIW-UHFFFAOYSA-N 0.000 description 1
- 102100036321 5-hydroxytryptamine receptor 2A Human genes 0.000 description 1
- 101710138091 5-hydroxytryptamine receptor 2A Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- BHKUKNJDPIWLRY-UHFFFAOYSA-N [4-(2-methylpropoxy)phenyl]methanamine;hydrochloride Chemical compound Cl.CC(C)COC1=CC=C(CN)C=C1 BHKUKNJDPIWLRY-UHFFFAOYSA-N 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- JYWJULGYGOLCGW-UHFFFAOYSA-N chloromethyl chloroformate Chemical compound ClCOC(Cl)=O JYWJULGYGOLCGW-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 229940125425 inverse agonist Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- XGDZEDRBLVIUMX-UHFFFAOYSA-N methyl 2-(4-hydroxyphenyl)acetate Chemical compound COC(=O)CC1=CC=C(O)C=C1 XGDZEDRBLVIUMX-UHFFFAOYSA-N 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention relates to a method for preparing pimavanserin by a one-pot method. The method takes 4-isobutoxybenzylamine shown in formula (II) or salt thereof, carbonylation reagent shown in formula (III), and N- (4-fluorobenzyl) -1-methylpiperidine-4-amine shown in formula (I) or salt thereof as raw materials to prepare the pimavanserin (compound IV) by a one-pot method. The method has the advantages of high efficiency, high yield, low cost, safety and environmental protection, is suitable for industrial production and has great application value.
Description
Technical Field
The invention relates to the technical field of a preparation method of pimavanserin.
Background
Pimavanserin (pimavanserin), the chemical name of which is 1- (4-fluorobenzyl) -3- (4-isobutyloxybenzyl) -1- (1-methylpiperidin-4-yl) urea tartrate, and the structure of the free base of the tartrate is shown as the formula (I). Pimavanserin, originally developed by ACADIA pharmaceutical Inc, is a selective 5-HT2A inverse agonist and has been shown to be effective and well tolerated in the treatment of parkinson's disease psychotic disorders, and it does not block dopamine receptors and therefore does not lead to worsening of parkinson's disease symptoms.
The synthesis of pimavanserin is described in patents CN1443167 and CN 1816524.
At present, the preparation of pimavanserin by the following method is disclosed at home and abroad:
a) US2008/0280886 discloses the preparation of pimavanserin starting from methyl 4-hydroxyphenylacetate. The route is as follows:
route a) takes 4-hydroxyphenylmethyl acetate and isobutyl bromide as raw materials, and the raw materials are reacted to obtain 4-isobutoxyphenylmethyl acetate, which is hydrolyzed to obtain 4-isobutoxyphenylacetic acid, and then the 4-isobutoxyphenylacetic acid is reacted with diphenylphosphoryl azide to generate 4-isobutoxyphenylisocyanate, and finally the 4-isobutoxyphenylisocyanate is reacted with N- (4-fluorophenyl) -1-methylpiperidine-4-amine to obtain the pimavanserin free base. The method has more steps, wherein the synthesis condition of the key intermediate 4-isobutoxy phenyl isocyanate is more complex, and the used diphenyl phosphorazide is active in property, is not easy to store and is not suitable for large-scale industrial production.
b) Patent US2007/0260064 discloses a similar synthetic method and synthesizes pimavanserin.
Route b) p-hydroxybenzaldehyde and isobutyl bromide are used as raw materials to react to obtain 4-isobutoxy benzaldehyde, 4-isobutoxy benzaldehyde oxime is further synthesized, 4-isobutoxy benzylamine is obtained by reduction, 4-isobutoxy phenyl isocyanate is obtained by condensation with phosgene, and finally the p-moplanin free alkali is obtained by reaction with N- (4-fluorophenyl) -1-methylpiperidine-4-amine. The method also needs to pass through a 4-isobutoxy phenyl isocyanate intermediate process, and has more steps and more complex synthesis conditions.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the method for preparing the pimavanserin, which has the advantages of high efficiency, high yield, low cost, safety, environmental protection, suitability for industrial production and higher application value.
In order to realize the purpose, the invention uses 4-isobutoxybenzylamine or salt thereof, a carbonylation reagent and N- (4-fluorobenzyl) -1-methylpiperidine-4-amine or salt thereof as raw materials to prepare the pimavanserin by a condensation one-pot method.
The invention specifically adopts the following technical scheme:
the method for preparing the pimavanserin shown in the formula (IV) by a one-pot method is characterized in that the pimavanserin (compound IV) is prepared by the one-pot method by taking a compound shown in the formula (II), a carbonylation reagent shown in the formula (III) and a compound shown in the formula (I) as raw materials, and the reaction equation is shown as follows:
wherein:
i is N- (4-fluorobenzyl) -1-methylpiperidin-4-amine or a salt thereof;
II is 4-isobutoxy benzylamine or salt thereof;
III is a carbonylation reagent, which is selected from one or more of phosgene, chloroformic acid chloromethyl ester, bis (trichloromethyl) carbonate, N-carbonyl diimidazole, dimethyl carbonate, diethyl carbonate and p-nitro phenyl chloroformate.
In the present invention, the salts of the compounds I and II are not particularly limited, and pharmaceutically acceptable salts known in the art may be used.
Next, the present invention does not specifically require the order of the reaction of the compound of formula (II), the carbonylation reagent of formula (III) and the compound of formula (I), and it is preferred that the compound of formula (II) is used as a starting material, reacted with the carbonylation reagent of formula (III), and then reacted with the compound of formula (I) to prepare pimavanserin (compound IV) by a one-pot method.
The method for preparing the pimavanserin by the one-pot method is characterized by further comprising the step of adding alkali into the reaction.
The one-pot method for preparing pimavanserin is characterized in that the molar ratio of the compound (II) to the carbonylation reagent shown in the formula (III) is 1: (0.5 to 3.0), preferably 1: (0.5 to 2.0), more preferably 1: (0.5 to 1.5).
The one-pot method for preparing pimavanserin is characterized in that the molar ratio of the compound (II) to the compound (I) is 1.0: (0.5 to 2.0), preferably 1.0: (0.8 to 1.2), more preferably 1.0 (0.9 to 1.1).
The method for preparing the pimavanserin by the one-pot method is characterized in that the reaction temperature is-20 ℃ to the boiling point of a solvent, and the reaction time is 2.5-24 hours.
More preferably, the reaction temperature is-5 to 25 ℃ and the reaction time is 5.5 to 13 hours.
The base is not particularly limited in the present invention, and any base known in the art for converting an organic salt into a corresponding free base or neutralizing an acid generated in a condensation reaction may be used, and preferably one or a mixture of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, silver carbonate, sodium hydrogen carbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate, trimethylamine, triethylamine, tributylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1, 8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine, N, N-diisopropylethylamine, pyridine, 2, 6-dimethylpyridine, imidazole, N, N, N ', N' -tetramethylethylenediamine is used.
The amount of base is not particularly critical in the present invention, and any amount known in the art to convert an organic salt to the corresponding free base or to neutralize the acid produced in the condensation may be used.
The solvent for the reaction is not particularly required in the invention, and any solvent which is known in the art and can dissolve the reaction raw materials and can not react with the raw materials can be used, and one or a mixture of several of N, N-dimethylformamide, dichloromethane, chloroform, methanol, ethanol, isopropanol, butanol, tert-butanol, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1, 4-dioxane, ethyl acetate, dimethyl sulfoxide, toluene and water is preferred.
In addition, when the compound of the formula (II) is used as a raw material, reacts with a carbonylation reagent shown in the formula (III) and then reacts with the compound of the formula (I) to prepare the pimavanserin (compound IV) by a one-pot method, the method for preparing the pimavanserin by the one-pot method is characterized in that the temperature of the compound of the formula (II) and the formula (III) is-20-25 ℃, and the reaction time is 0.5-2 hours; preferably, the temperature of the formula (II) and the formula (III) is-5 to 15 ℃, and the reaction time is 0.5 to 1 hour.
The method for preparing the pimavanserin by the one-pot method is characterized in that the reaction temperature of the pimavanserin and the formula (I) is-5-boiling point of a solvent, and the reaction time is 0.5-24 hours; preferably, the reaction temperature with the formula (I) is-5 to 25 ℃, and the reaction time is 2 to 20 hours, more preferably 5 to 12 hours.
Compared with the prior art, the invention has the following beneficial effects: the original multi-step reaction is combined into one step, the material transfer and unit operation are reduced, the production efficiency is improved, the yield is greatly improved (the yield is more than 60 percent), the production cost is reduced, and the used reagent is safe and environment-friendly.
The present invention is further illustrated by the following examples, which are intended to provide further details of the practice of the invention, but are not intended to limit the scope of the invention.
Detailed description of the preferred embodiments
Example 1: adding dichloromethane (5.0g) and 4-isobutoxybenzylamine (1.0g) into a reaction tube, cooling to 0-5 ℃, adding N, N' -carbonyldiimidazole (1.0g), keeping at 0-5 ℃ for half an hour, adding N- (4-fluorobenzyl) -1-methylpiperidine-4-amine (1.0g), stirring at 0-5 ℃ for 6 hours, heating to 22 ℃, keeping overnight (12 hours), adding water (3 multiplied by 10g), washing, taking an organic phase, concentrating to obtain a viscous oily substance, and separating white powdery solid by column chromatography (1.17g, yield 61.0%).
1H NMR:(400MHz,d-DMSO)δ:7.27-7.23(m,2H),7.13-7.09(m,2H),6.88-6.85(t,1H),6.85-6.83(m,2H),4.41(d,J＝5.6Hz,2H),3.93-3.88(m,1H),3.71(d,J＝5.6Hz,2H),2.70(d,J＝11.2Hz,2H),2.31(s,1H),2.10(s,3H),2.03-1.96(m,1H),1.90-1.85(m,2H),1.56-1.50(m,2H),1.44-1.41(m,2H),0.98(s,3H),0.96(s,3H)；
13C NMR:(100MHz,d-DMSO)δ:162.5,160.1,158.0,157.9,137.8,137.6,137.5,133.6,129.4,128.9,128.8,128.7,128.6,125.8,115.3,115.1,114.5,74.2,55.4,52.8,46.3,44.4,43.6,30.4,28.2,21.5,19.5；
MS-ESI(M+1)：428.
Example 2: dissolving 4-isobutoxybenzylamine (100.0g) in dichloromethane (500ml), cooling to 0-5 ℃, slowly adding N, N' -carbonyldiimidazole (100.0g), keeping the temperature at 0-5 ℃ for half an hour, adding N- (4-fluorobenzyl) -1-methylpiperidine-4-amine (100.0g), slowly heating to 18-22 ℃, keeping stirring for 12 hours, adding water (3 x 500g) to wash an organic phase for three times, evaporating the solvent by organic phase under reduced pressure, adding isopropyl acetate (600g), stirring for crystallization, filtering, and drying a filter cake to obtain a target product (163.0 g of white powdery solid, 85.0%).
Example 3: dissolving triphosgene (14.8g) in dichloromethane (200ml), cooling to-5 ℃, slowly and sequentially dropwise adding 4-isobutoxybenzylamine (17.9g) and triethylamine (30.3g), continuously keeping for 1 hour after adding, slowly and dropwise adding N- (4-fluorobenzyl) -1-methylpiperidine-4-amine (22.0g), slowly heating to 15-25 ℃ after adding, keeping stirring for 5 hours, washing an organic phase with water (3 x 200g) for three times, evaporating the solvent by organic phase under reduced pressure, adding isopropyl acetate (110g), stirring for crystallization, filtering, and drying a filter cake to obtain a target product (34.5 g of white powdery solid, 81.6%).
Example 4: triphosgene (14.8g) is dissolved in toluene (200ml), the temperature is reduced to-20 ℃, 4-isobutoxybenzylamine (17.9g) and triethylamine (30.3g) are sequentially and slowly added dropwise, the temperature is raised to 5 ℃ after the addition, the temperature is kept for 1 hour, N- (4-fluorobenzyl) -1-methylpiperidine-4-amine (22.0g) is slowly added dropwise, the temperature is slowly raised to 80 ℃ after the addition, the stirring is kept for 5 hours, the organic phase is washed three times by water (3 x 200g), heptane (100ml) is added into the organic phase, precipitated solid is filtered and dried, and the target product (light yellow solid powder, 21.6g, 51.0%) is obtained.
Example 5: dissolving triphosgene (14.8g) in trichloromethane (300ml), cooling to-5 ℃, adding 4-isobutoxybenzylamine hydrochloride (21.6g), slowly dropwise adding N, N-diisopropylethylamine (13.0g), continuously keeping for 1 hour after adding, slowly adding N- (4-fluorobenzyl) -1-methylpiperidine-4-amine p-toluenesulfonate (39.0g), slowly dropwise adding N, N-diisopropylethylamine (13.0g), slowly heating to 15-25 ℃ after adding, keeping stirring for 6 hours, washing an organic phase with water (3 x 200g) for three times, evaporating the solvent by organic phase under reduced pressure, adding isopropyl acetate (110g), stirring for crystallization, filtering, and drying to obtain a target product (35.2 g of white powder, 82.4%).
Example 6: dissolving 4-isobutoxy benzylamine acetate (23.9g) in dichloromethane (120ml), cooling to 0-5 ℃, slowly adding N, N' -carbonyl diimidazole (17.0g), slowly dropwise adding N, N-diisopropylethylamine (13.5g), keeping at 0-5 ℃ for half an hour after adding, adding N- (4-fluorobenzyl) -1-methylpiperidine-4-amine oxalate (26.0g), slowly dropwise adding N, N-diisopropylethylamine (13.0g), slowly heating to 15-25 ℃, keeping stirring for 10 hours, the organic phase was washed three times with water (3X 200g), the solvent was evaporated under reduced pressure from the organic phase, isopropyl acetate (110g) was added, heptane (55g) was added after stirring uniformly, and the precipitated solid was filtered and dried to obtain the objective product (37.6 g, 90.4% as a white powder).
Example 7: dissolving 4-isobutoxy benzylamine acetate (23.9g) in dichloromethane (120ml), cooling to 0-5 ℃, slowly adding p-nitrochloroformic acid phenyl ester (20.1g), slowly dropwise adding triethylamine (11.0g), keeping the temperature at 0-5 ℃ for half an hour after adding, adding N- (4-fluorobenzyl) -1-methylpiperidine-4-amine oxalate (26.0g), slowly dropwise adding triethylamine (11.0g), slowly heating to 15-25 ℃ after adding, keeping stirring for 10 hours, adding water (4 x 200g), washing an organic phase for four times, evaporating the solvent by organic phase under reduced pressure, adding ethyl acetate (100g), adding N-heptane (50g) after uniformly stirring, filtering and drying a precipitated solid to obtain a target product (32.5 g of white to light yellow powder, 78.1%).
Example 8: dissolving 4-isobutoxy benzylamine acetate (24.0g) in dichloromethane (150ml), cooling to 0-5 ℃, slowly adding N, N' -carbonyldiimidazole (17.0g), slowly dropwise adding triethylamine (11.0g), keeping the temperature at 0-5 ℃ for half an hour after adding, adding N- (4-fluorobenzyl) -1-methylpiperidine-4-amine (22.0g), slowly heating to 15-25 ℃ after adding, keeping stirring for 8 hours, adding water (3 x 200g) to wash an organic phase for three times, evaporating the solvent under the organic phase pressure, adding isopropyl acetate (100g), adding N-heptane (60g) after uniformly stirring, filtering to separate out a solid, and drying to obtain a target product (38.2 g of white powder and 90.3%).
Claims (10)
1. The method for preparing the pimavanserin shown in the formula (IV) by a one-pot method is characterized in that the pimavanserin (compound IV) is prepared by the one-pot method by taking a compound shown in the formula (II), a carbonylation reagent shown in the formula (III) and a compound shown in the formula (I) as raw materials, and the reaction equation is shown as follows:
wherein:
i is N- (4-fluorobenzyl) -1-methylpiperidin-4-amine or a salt thereof;
II is 4-isobutoxy benzylamine or salt thereof;
III is a carbonylation reagent, which is selected from one or more of chloroformic ether, bis (trichloromethyl) carbonic ester, N-carbonyl diimidazole, dimethyl carbonate, diethyl carbonate and p-nitro phenyl chloroformate.
2. The method of claim 1, further comprising adding a base to the reaction.
3. The process according to claim 1 or 2, characterized in that the molar ratio of compound (II) to carbonylation reagent of formula (III) is 1: (0.5 to 3.0).
4. The process according to claim 3, wherein the molar ratio of compound (II) to the carbonylation reagent of formula (III) is 1: (0.5 to 1.5).
5. The process according to claim 1 or 2, characterized in that the molar ratio of compound (II) to compound (I) is 1.0: (0.5-2.0).
6. The process according to claim 5, wherein the molar ratio of compound (II) to compound (I) is 1.0: (0.8 to 1.2).
7. The method according to claim 1 or 2, wherein the reaction temperature is from-20 ℃ to the boiling point of the solvent, and the reaction time is from 2.5 to 24 hours.
8. The method according to claim 7, wherein the reaction temperature is-5 to 25 ℃ and the reaction time is 5.5 to 13 hours.
9. The method according to claim 1 or 2, wherein the solvent for the reaction is selected from one or more of N, N-dimethylformamide, dichloromethane, chloroform, methanol, ethanol, isopropanol, butanol, tert-butanol, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1, 4-dioxane, ethyl acetate, dimethyl sulfoxide, toluene and water.
10. The method of claim 2, wherein the base is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, silver carbonate, sodium bicarbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate, trimethylamine, triethylamine, tributylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1, 8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine, N, N-diisopropylethylamine, pyridine, 2, 6-dimethylpyridine, imidazole, N, N, N ', N' -tetramethylethylenediamine, and mixtures thereof.
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| CN104844502A (en) * | 2015-06-05 | 2015-08-19 | 济南涛瑞医药科技有限公司 | Preparation method of Pimavanserin |
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