CN116874347B - 一种丙戊酸工艺杂质二丙基戊酸的制备方法 - Google Patents
一种丙戊酸工艺杂质二丙基戊酸的制备方法 Download PDFInfo
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- CN116874347B CN116874347B CN202310840136.2A CN202310840136A CN116874347B CN 116874347 B CN116874347 B CN 116874347B CN 202310840136 A CN202310840136 A CN 202310840136A CN 116874347 B CN116874347 B CN 116874347B
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- bromide
- dipropyl
- chloride
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- UMJGAWHIMHSGMU-UHFFFAOYSA-N 2,2-dipropylpentanoic acid Chemical compound CCCC(CCC)(CCC)C(O)=O UMJGAWHIMHSGMU-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 23
- 230000008569 process Effects 0.000 title claims abstract description 13
- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 title abstract description 21
- 239000012535 impurity Substances 0.000 title abstract description 11
- 229960000604 valproic acid Drugs 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 12
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 claims abstract description 11
- KLUDQUOLAFVLOL-UHFFFAOYSA-N acetyl propanoate Chemical compound CCC(=O)OC(C)=O KLUDQUOLAFVLOL-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims abstract description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 8
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 7
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 claims abstract description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 6
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims abstract description 5
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 claims abstract description 5
- UQFSVBXCNGCBBW-UHFFFAOYSA-M tetraethylammonium iodide Chemical compound [I-].CC[N+](CC)(CC)CC UQFSVBXCNGCBBW-UHFFFAOYSA-M 0.000 claims abstract description 5
- DDFYFBUWEBINLX-UHFFFAOYSA-M tetramethylammonium bromide Chemical compound [Br-].C[N+](C)(C)C DDFYFBUWEBINLX-UHFFFAOYSA-M 0.000 claims abstract description 5
- RXMRGBVLCSYIBO-UHFFFAOYSA-M tetramethylazanium;iodide Chemical compound [I-].C[N+](C)(C)C RXMRGBVLCSYIBO-UHFFFAOYSA-M 0.000 claims abstract description 5
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims abstract description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 3
- BGQMOFGZRJUORO-UHFFFAOYSA-M tetrapropylammonium bromide Chemical compound [Br-].CCC[N+](CCC)(CCC)CCC BGQMOFGZRJUORO-UHFFFAOYSA-M 0.000 claims abstract description 3
- FBEVECUEMUUFKM-UHFFFAOYSA-M tetrapropylazanium;chloride Chemical compound [Cl-].CCC[N+](CCC)(CCC)CCC FBEVECUEMUUFKM-UHFFFAOYSA-M 0.000 claims abstract description 3
- GKXDJYKZFZVASJ-UHFFFAOYSA-M tetrapropylazanium;iodide Chemical compound [I-].CCC[N+](CCC)(CCC)CCC GKXDJYKZFZVASJ-UHFFFAOYSA-M 0.000 claims abstract 2
- -1 propionyl ethyl Chemical group 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 230000006207 propylation Effects 0.000 claims description 8
- 230000003197 catalytic effect Effects 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229940070710 valerate Drugs 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- PRRBQHNMYJRHFW-UHFFFAOYSA-M 3-oxoheptanoate Chemical compound CCCCC(=O)CC([O-])=O PRRBQHNMYJRHFW-UHFFFAOYSA-M 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- BDCLDNALSPBWPQ-UHFFFAOYSA-M 3-oxohexanoate Chemical compound CCCC(=O)CC([O-])=O BDCLDNALSPBWPQ-UHFFFAOYSA-M 0.000 claims description 2
- IPQVXPVTZFDVBW-UHFFFAOYSA-N butyl 3-oxopentanoate Chemical compound CCCCOC(=O)CC(=O)CC IPQVXPVTZFDVBW-UHFFFAOYSA-N 0.000 claims description 2
- FANTXZJNXUOWGT-UHFFFAOYSA-N propan-2-yl 3-oxopentanoate Chemical compound CCC(=O)CC(=O)OC(C)C FANTXZJNXUOWGT-UHFFFAOYSA-N 0.000 claims description 2
- JHNRDQVZFDRPIV-UHFFFAOYSA-N propyl 3-oxopentanoate Chemical compound CCCOC(=O)CC(=O)CC JHNRDQVZFDRPIV-UHFFFAOYSA-N 0.000 claims description 2
- AGFWFCUOAZIKPK-UHFFFAOYSA-N tert-butyl 3-oxopentanoate Chemical compound CCC(=O)CC(=O)OC(C)(C)C AGFWFCUOAZIKPK-UHFFFAOYSA-N 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims 8
- 230000029936 alkylation Effects 0.000 claims 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 abstract description 5
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 abstract description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 2
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- SZEMGTQCPRNXEG-UHFFFAOYSA-M trimethyl(octadecyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCCCC[N+](C)(C)C SZEMGTQCPRNXEG-UHFFFAOYSA-M 0.000 abstract description 2
- 239000012071 phase Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 229940084026 sodium valproate Drugs 0.000 description 14
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 14
- 239000003921 oil Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000007789 gas Substances 0.000 description 9
- AWAHTDIOUIVENZ-UHFFFAOYSA-N 2,2-dipropylpentanenitrile Chemical compound CCCC(CCC)(CCC)C#N AWAHTDIOUIVENZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- MFPLOZTTYKIUQU-UHFFFAOYSA-N methyl 2-cyano-2-propylpentanoate Chemical compound CCCC(CCC)(C#N)C(=O)OC MFPLOZTTYKIUQU-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 4
- WUWPVNVBYOKSSZ-UHFFFAOYSA-N 2-ethyl-2-methyl valeric ccid Chemical compound CCCC(C)(CC)C(O)=O WUWPVNVBYOKSSZ-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- ACBLZFZDCOGNHD-UHFFFAOYSA-N 2,2-dipropylpentanamide Chemical compound CCCC(CCC)(CCC)C(N)=O ACBLZFZDCOGNHD-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- ZUAOJBFPBKAUJX-UHFFFAOYSA-N ethyl 2,2-dipropylpentanoate Chemical compound C(C)OC(C(CCC)(CCC)CCC)=O ZUAOJBFPBKAUJX-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910017053 inorganic salt Inorganic materials 0.000 description 3
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 238000004451 qualitative analysis Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 3
- UZRGQIZTJOPZGE-UHFFFAOYSA-N 2-cyano-2-propylpentanoic acid Chemical compound CCCC(C(O)=O)(C#N)CCC UZRGQIZTJOPZGE-UHFFFAOYSA-N 0.000 description 2
- FHBWGXDQIOWTCK-UHFFFAOYSA-N 2-methylpentanenitrile Chemical compound CCCC(C)C#N FHBWGXDQIOWTCK-UHFFFAOYSA-N 0.000 description 2
- OVBFMEVBMNZIBR-UHFFFAOYSA-N 2-methylvaleric acid Chemical compound CCCC(C)C(O)=O OVBFMEVBMNZIBR-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- WNZKWBYFYOMJRC-UHFFFAOYSA-N methyl 2-cyanopentanoate Chemical compound CCCC(C#N)C(=O)OC WNZKWBYFYOMJRC-UHFFFAOYSA-N 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- QENJZWZWAWWESF-UHFFFAOYSA-N tri-methylbenzoic acid Natural products CC1=CC(C)=C(C(O)=O)C=C1C QENJZWZWAWWESF-UHFFFAOYSA-N 0.000 description 2
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 239000004412 Bulk moulding compound Substances 0.000 description 1
- HJTVQHVGMGKONQ-LUZURFALSA-N Curcumin II Natural products C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=CC(O)=CC=2)=C1 HJTVQHVGMGKONQ-LUZURFALSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 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
- BAZMYXGARXYAEQ-UHFFFAOYSA-N alpha-ethyl valeric acid Chemical compound CCCC(CC)C(O)=O BAZMYXGARXYAEQ-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- ZRIZDTNKLLTMDO-UHFFFAOYSA-N benzyl 3-oxopentanoate Chemical compound CCC(=O)CC(=O)OCC1=CC=CC=C1 ZRIZDTNKLLTMDO-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000006229 carbon black Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000003442 catalytic alkylation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NNDOHYGFLASMFR-UHFFFAOYSA-N diethyl 2,2-dipropylpropanedioate Chemical compound CCOC(=O)C(CCC)(CCC)C(=O)OCC NNDOHYGFLASMFR-UHFFFAOYSA-N 0.000 description 1
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 230000006203 ethylation Effects 0.000 description 1
- 238000006200 ethylation reaction Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- PWWZVTGTXDUQKB-UHFFFAOYSA-N methyl 3-oxo-4-propylheptanoate Chemical compound C(CC)C(C(=O)CC(=O)OC)CCC PWWZVTGTXDUQKB-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- JQQDMANRHUASPT-UHFFFAOYSA-M sodium;2,2-dipropylpentanoate Chemical compound [Na+].CCCC(CCC)(CCC)C([O-])=O JQQDMANRHUASPT-UHFFFAOYSA-M 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000010729 system oil Substances 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 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
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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Abstract
一种丙戊酸工艺杂质二丙基戊酸的制备方法。本发明涉及化学结构式D所示的二丙基戊酸制备方法：选择丙酰乙酸酯与1‑氯丙烷，在碳酸钾作用下，催化丙基化，再经还原和水解制得二丙基戊酸；其制备反应如下：R＝苄基、C1～C5直链烷基或C3～C5支链烷基；H+选自盐酸、硫酸或磷酸。PTC选自：四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、四丙基氯化铵、四丙基溴化铵、四丙基碘化铵、四乙基氯化铵、四乙基溴化铵、四乙基碘化铵、四甲基氯化铵、四甲基溴化铵、四甲基碘化铵、十六烷基三甲基溴化铵、十八烷基三甲基溴化铵、三乙基苄基氯化铵或三甲基苄基氯化铵。
Description
技术领域
本发明涉及采用原子经济性方法制备丙戊酸工艺杂质——二丙基戊酸(D)。
背景技术
欧洲药典EP9.0和英国药典BP2019报道了丙戊酸钠中杂质2-甲基戊酸(L)、2-乙基戊酸(B)、2-甲基-2-乙基戊酸(K)和二丙基戊酸(D)：
周启群等[丙戊酸钠合成工艺改进.中国医药工业杂志.1993，24(8)：347-348]选择乙酰乙酸甲酯经TEBA固液相转移催化烷基化、脱酰基、水解、成盐制得丙戊酸钠：
1999年王学勤等[丙戊酸钠合成新工艺.中国医药工业杂志，1999，30(9):389-390]选择乙酰乙酸甲酯和碳酸钾，在TBAB催化下，与1-溴丙烷缩合得二丙基乙酰乙酸甲酯，收率88％；2019年林凡友[一种丙戊酸钠的合成工艺，CN110563572A，2019-12-13]也采用TBAB相转移催化制备一种丙戊酸钠。
上海青平药业有限公司[韦建国，魏正华，顾玉仅，杨益超.一种同时制备三丙基乙腈、三丙基酰胺、三丙基乙酸的方法，CN202211625646.X，2023.5.23]描述了氰基乙酸甲酯、甲醇钠和1-溴丙烷反应制得2-氰基-2-丙基戊酸甲酯(87～89℃/290Pa，87～89℃/2mmHg)馏分)，2-氰基-2-丙基戊酸甲酯经水解脱羧制得丙戊腈；丙戊腈再经丙基化制得二丙基戊腈J，后者水解制得二丙基戊酰胺G和二丙基戊酸D；制备反应如下：
上海青平药业有限公司[韦建国，顾玉仅，魏正华，杨益超.一种2-乙基-2-甲基戊酸的制备方法，CN202211625610.1，2023.5.23]描述了氰基乙酸甲酯、甲醇钠和1-溴丙烷制得2-氰基戊酸甲酯；2-氰基戊酸甲酯经甲基化、水解和脱羧制得2-甲基戊腈；2-甲基戊腈再经乙基化等二步反应制得2-甲基-2乙基戊酸K；制备反应如下：
重庆健能医药开发有限公司[王祖焕，蔡鹏飞，李朝阳.一种丙戊酸钠杂质K的制备方法，ZL202011055938.5，2023.3.24]选择乙酰乙酸乙酯经丙基化和甲基化制得2-甲基-2-乙酰基戊酸乙酯；后者经NaBH4-I2复合还原和水解制得2-甲基-2-乙基戊酸K；其制备反应如下：
二丙基戊酸D是丙戊酸钠原料药制备过程中容易产生的杂质，对丙戊酸钠原料药生产中有关物质的检测和控制中起到关键的作用。欧洲药典EP9.0和英国药典BP2019报道了丙戊酸钠中杂质二丙基戊酸(D)的研究及控制应用问题。因此，对于丙戊酸钠中杂质D的相关研究具有现实意义，可以用于丙戊酸钠生产中杂质的定性及定量分析，从而可以提高丙戊酸钠的质量标准，为安全用药提供指导。
发明内容
本发明的目的一方面是提供化学结构式D所示的二丙基戊酸原子经济性制备方法：其特征在于丙酰乙酸酯与1-氯丙烷，在碳酸钾作用下，催化丙基化，再经还原和水解制得二丙基戊酸；其制备反应如下：
R＝苄基、C1～C5直链烷基或C3～C5支链烷基；H+选自盐酸、硫酸或磷酸。
本发明的目的是提供二丙基戊酸原子经济性制备方法：其特征在于丙酰乙酸乙酯与1-氯丙烷，在碱作用下，催化丙基化，再经还原和水解制得二丙基戊酸；其制备反应如下：
本发明的目的是提供二丙基戊酸原子经济性制备方法：其特征在于丙酰乙酸甲酯与1-氯丙烷，在碱作用下，催化丙基化，再经还原和水解制得二丙基戊酸；其制备反应如下：
PTC选择：R4NX或R3R1NX；其中R＝C1～C5直链烷基；R1＝PhCH2、C16直链烷基或C18直链烷基；其中X＝Cl、Br或I；
R4NX选自：TBAC、TBAB、TBAI、TPAC、TPAB、TPAI、TEAC、TEAB、TEAI、TMAC、TMAB或TMAI；TBAC、TBAB或TBAI分别为四丁基氯化铵、四丁基溴化铵或四丁基碘化铵；TPAC、TPAB或TPAI分别为四丙基氯化铵、四丙基溴化铵或四丙基碘化铵；TEAC、TEAB或TEAI分别为四乙基氯化铵、四乙基溴化铵或四乙基碘化铵；TMAC、TMAB或TMAI分别为四甲基氯化铵、四甲基溴化铵或四甲基碘化铵。
R3R1NX选自：1631、1831、TEBA或TMBA；1631为十六烷基三甲基溴化铵；1831为十八烷基三甲基溴化铵；TEBA为三乙基苄基氯化铵；TMBA为三甲基苄基氯化铵。
溶剂选择：THF、DMF、DMC、DMSO、乙腈、丙腈、丁腈、1，4-二氧六环、乙二醇二甲醚、乙二醇二乙醚、二乙二醇二甲醚、二乙二醇二乙醚中的一种或二种。
K2CO3选自：粉状K2CO3；粉状K2CO3选择：100目K2CO3、150目K2CO3、200目K2CO3、250目K2CO3、300目K2CO3或350目K2CO3。
反应温度选择：30℃～80℃；反应时间选择：1.0h～12h；
催化用量选择：丙酰乙酸酯∶PTC＝1∶0.005～0.10摩尔比；丙酰乙酸酯选自：丙酰乙酸甲酯、丙酰乙酸乙酯、丙酰乙酸正丙酯、丙酰乙酸异丙酯、丙酰乙酸正丁酯、丙酰乙酸叔丁酯、丙酰乙酸苄酯中一种或二种。
本发明的目的第二方面是提供选择Clemmenese反应将2-丙基-2-丙酰基戊酸酯还原为二丙基戊酸酯，Clemmenese反应如下：
2-丙基-2-丙酰基戊酸酯在5％HCl和甲苯回流中，Zn-Hg还原制得二丙基戊酸酯。
本发明的目的第三方面是提供二丙基戊酸在丙戊酸钠生产工艺中杂质的定性或定量分析中应用。
本发明与现有技术相比具有以下优点：
1.本发明中，采用丙酰乙酸酯和1-氯丙烷的催化丙基化方法：1-氯丙烷来源丰富，且价廉。
2.本发明的工艺是原子经济性制备二丙基戊酸的方法，绿色环保；工艺中没断裂C—C键，工艺中不对空排放二氧化碳，碳原子利用率高。
附图说明
附图1二丙基戊酸气相色谱图
具体实施方式
下面结合实施例对本发明进行进一步的详细说明。
实施例1
2-丙基-2-丙酰基戊酸乙酯的制备
0.20mol丙酰乙酸乙酯、10mmol四乙基溴化铵(TEAB)、60.8g(0.44mol)、K2CO3(200目)、80ml DMF和0.50mol 1-氯丙烷，70℃搅拌反应6.0h，反应毕，冷却，过滤固体无机盐；加水300mL溶解固体无机盐，静置，分层，分液，下层为水相，上层液体与滤液(过滤无机盐的滤液)合并后，在15mmHg下减压回收DMF，得残液(滤液1)，与水相合并后，用石油醚(60mL×3)萃取，有机相用水洗涤60mL×3，无水硫酸钠干燥，抽滤，旋蒸回收石油醚，精馏39.8g二丙基丙二酸二乙酯，收率87.2％。
实施例2
二丙基戊酸乙酯的制备
0.20mol 2-丙基-2-丙酰基戊酸乙酯在5％HCl和甲苯中回流，经Zn-Hg还原制得18.8g二丙基戊酸乙酯，收率43.9％。
实施例3
二丙基戊酸(D)的制备
在0.20mol二丙基戊酸乙酯中滴加氢氧化钾水溶液(KOH：60g，H2O：100ml)，升温85℃搅拌水解5.0h；冷却，分离水层；有机相加入180ml水，静置分层，分离油相，水相加盐酸调pH至1，静置分层，油相干燥，减压精馏得到33.9g二丙基戊酸D，收率91.0％。1H NMR(DMSO-d6，400MHz)δ：11.98(brs，1H，CO2H)，1.60～1.47(m，6H，CH2×3)，1.32～1.13(m，6H，CH2×3)，0.89(t，J＝7.2Hz，9H，CH3×3)。
实施例4
二丙基戊酸(D)的制备
选择丙酰乙酸甲酯为起始原料，以四丁基溴化铵(TBAB)为催化剂，按实施例1～3中描述的方法制得二丙基戊酸D。
实施例5(对照例)
2-氰基-2-丙基戊酸甲酯的制备
按上海青平药业有限公司[CN202211625646.X，2023.5.23]中实施例1方法制备：
在3L反应瓶中加入氰乙酸甲酯(270g)，1-溴丙烷845g，甲醇540ml，水浴，控温30～65℃，滴加1108g30％甲醇钠甲醇溶液，50～65℃保温3h，反应结束，得到固液混合物。40℃旋蒸甲醇，得到固液混合物，加入200g乙酸异丙酯，过滤，溴化钠固体用200g×2乙酸异丙酯漂洗、滤液和洗液合并，用150ml×2水萃取，油相减压35～60℃蒸馏，得到472g粗品。使用40cm刺型柱在290Pa(2mmHg)压力下蒸馏，收集气相温度为87～89℃馏分，得到2-氰基-2-丙基戊酸甲酯(406g，纯度99.21％，收率81％)。
实施例6(对照例)
丙戊腈的制备
按上海青平药业有限公司[CN202211625646.X，2023.5.23]中实施例1方法制备：
(1)在2L反应瓶中加入1395g20％氢氧化钠水溶液，300g2-氰基-2-丙基戊酸甲酯，50～70℃反应5.5h；反应液冰水浴下用923g浓盐酸中和至pH＝1，分相，得到2-氰基-2-丙基戊酸粗品(316g)。
(2)2-氰基-2-丙基戊酸粗品(316g)加入三口烧瓶。反应瓶连接常压蒸馏装置，缓慢升温至140℃～205℃，收集气相温度为160～180℃馏分，得到丙戊腈(121g，纯度99.7％，以2-氰基-2-丙基戊酸甲酯计，收率59％)。
实施例7(对照例)
二丙基戊腈(J)的制备
按上海青平药业有限公司[CN202211625646.X，2023.5.23]中实施例1方法制备：
在1L反应瓶中加入氢化钠53g、THF(220ml)、丙戊腈(102g)，1-碘丙烷(153g)，用N2抽真空置换五次，体系油封保护，升温至50℃，有气体生成，50～64℃反应7.0h，直到没有气体产生；反应液缓慢加45g水焠灭，50℃以下，移出上清液，上清液40～45℃减压浓缩至161g，加入200ml甲苯，油相使用190g20％氢氧化钠水溶液萃取、100ml×3水洗、10％浓盐酸洗、50ml×2水洗，分相；油相使用水泵减压(95kPa，710mmHg)50℃旋蒸2h得到145g油相；145g油相倒入1L单口瓶中，使用水泵减压(9.5kPa，71mmHg)蒸馏，收集气相温度为138℃馏分，得到二丙基戊腈馏分(J，78g，纯度98.3％，收率57％)。
实施例8(对照例)
二丙基戊酰胺(G)和二丙基戊酸(D)的制备
按上海青平药业有限公司[CN202211625646.X，2023.5.23]中实施例2方法制备：
(1)在100ml反应瓶中加入2，2-二丙基戊腈(25g)，加到50％硫酸水溶液中(64g)。安装分水器，冷凝管温度计，磁力搅拌下，缓慢升温分水，直到内温到达140℃时停止分水，内温140℃保温28h，停止反应；降至室温，加50ml甲苯和70ml水，过滤炭黑，加入10g氯化钠溶解，分相，油相用20ml水萃取。油相加入40g15％氢氧化钠水溶液，加入10ml水，回流20min，降温至25℃，50ml×5二氯甲烷萃取，分相，得到二丙基戊酰胺二氯甲烷溶液，得到二丙基戊酸钠水相。
(2)二丙基戊酸钠水相加入15ml浓盐酸酸化pH＝1，30ml×2二氯甲烷反萃，分相，二氯甲烷相水浴30℃减压浓缩干，使用油泵60℃减压(290Pa，2mmHg)抽1h，得到二丙基戊酸(D，10.8g，纯度99.6％，收率38％)。二丙基戊酰胺二氯甲烷溶液经旋蒸30～70℃减压浓缩至干，使用油泵在70℃下减压(290Pa，2mmHg)抽0.5h，得到固体二丙基戊酰胺(G，10.0g，纯度99.1％，收率36％)。
实施例9
二丙基戊酸的GC
选择气相色谱仪(Agilent 8890)采用气相色谱法检测制备的丙戊酸。
色谱检测条件如下：色谱柱：DB-FFAP(0.32mm×60m，0.5μm)；载气：氮气；检测器：FID；流速：2ml/min；进样体积：2μl；进样口温度：220℃；柱温：100℃；升温程序：起始温度为100℃，保持5min，再以4℃/min的速率升温至140℃，保持5min，再以4℃/min的速率升温至200℃，保持15min。运行时间：50min；检测器温度：220℃；进样方式：直接进样。
取稀释剂、对照品溶液及供试品溶液各2μl，注入气相色谱仪，记录色谱图。
二丙基戊酸D的气相色谱图检测结果见附图1，保留时间36.027min。
二丙基戊酸用于丙戊酸钠生产工艺中杂质的定性分析。
在本说明书中，本发明已参照其特定的实施例作了描述。但是，很显然仍可以作出各种修改和变换而不背离本发明的精神和范围。因此，说明书应被认为是说明性的而非限制性的。
Claims (7)
1.化学结构式D所示的二丙基戊酸制备方法，其特征在于丙酰乙酸酯与1-氯丙烷，在碳酸钾作用下，催化丙基化，再经还原和水解制得二丙基戊酸；其制备反应如下：
R＝C1～C5直链烷基或C3～C5支链烷基；H+选自盐酸、硫酸或磷酸；
烷基化PTC选自：四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、四丙基氯化铵、四丙基溴化铵、四丙基碘化铵、四乙基氯化铵、四乙基溴化铵、四乙基碘化铵、四甲基氯化铵、四甲基溴化铵或四甲基碘化铵；
烷基化溶剂选择：DMF或DMC；
烷基化K2CO3选择：100目K2CO3、150目K2CO3、200目K2CO3、250目K2CO3、300目K2CO3或350目K2CO3；
烷基化反应温度选择30℃～80℃；烷基化反应时间1.0h～12.0h。
2.化学结构式D所示的二丙基戊酸制备方法，其特征在于丙酰乙酸乙酯与1-氯丙烷，在碳酸钾作用下，催化丙基化，再经还原和水解制得二丙基戊酸；其制备反应如下：
烷基化PTC、溶剂、K2CO3，烷基化反应温度和烷基化反应时间的定义如权利要求1所述。
3.化学结构式D所示的二丙基戊酸制备方法，其特征在于丙酰乙酸甲酯与1-氯丙烷，在碳酸钾作用下，催化丙基化，再经还原和水解制得二丙基戊酸；其制备反应如下：
烷基化PTC、溶剂、K2CO3，烷基化反应温度和烷基化反应时间的定义如权利要求1所述。
4.如权利要求1～3中任一项所述的二丙基戊酸制备方法，其特征在于投料用量选择：丙酰乙酸酯∶1-氯丙烷＝1∶2.2～3.0摩尔比。
5.如权利要求1～3中任一项所述的二丙基戊酸制备方法，其特征在于PTC用量选择：丙酰乙酸酯∶PTC＝1∶0.005～0.10摩尔比。
6.如权利要求1所述的二丙基戊酸制备方法，其特征在于丙酰乙酸酯选自：丙酰乙酸甲酯、丙酰乙酸乙酯、丙酰乙酸正丙酯、丙酰乙酸异丙酯、丙酰乙酸正丁酯或丙酰乙酸叔丁酯。
7.如权利要求1所述的二丙基戊酸制备方法，其特征在于2-丙基-2-丙酰基戊酸酯经Clemmenese反应还原为二丙基戊酸酯；其Clemmenese反应如下：
2-丙基-2-丙酰基戊酸酯在5％HCl和甲苯中回流，经Zn-Hg还原，制得二丙基戊酸酯；R的定义如权利要求1所述。
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