CN117069561A - 一种2-乙基戊酸的制备方法 - Google Patents
一种2-乙基戊酸的制备方法 Download PDFInfo
- Publication number
- CN117069561A CN117069561A CN202311007251.8A CN202311007251A CN117069561A CN 117069561 A CN117069561 A CN 117069561A CN 202311007251 A CN202311007251 A CN 202311007251A CN 117069561 A CN117069561 A CN 117069561A
- Authority
- CN
- China
- Prior art keywords
- acetoacetate
- acid
- preparation
- bromide
- chloride
- 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.)
- Granted
Links
- BAZMYXGARXYAEQ-UHFFFAOYSA-N alpha-ethyl valeric acid Chemical compound CCCC(CC)C(O)=O BAZMYXGARXYAEQ-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 claims abstract description 46
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 claims abstract description 21
- 229940084026 sodium valproate Drugs 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 239000012535 impurity Substances 0.000 claims abstract description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960000604 valproic acid Drugs 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 10
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims abstract description 10
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 claims abstract description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 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
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims abstract description 6
- 238000004451 qualitative analysis Methods 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
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 4
- 238000004445 quantitative analysis Methods 0.000 claims abstract description 4
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims abstract description 3
- 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 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 description 3
- SZEMGTQCPRNXEG-UHFFFAOYSA-M trimethyl(octadecyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCCCC[N+](C)(C)C SZEMGTQCPRNXEG-UHFFFAOYSA-M 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-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
- -1 acetoacetate ester Chemical class 0.000 claims description 8
- 230000003197 catalytic effect Effects 0.000 claims description 8
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims description 7
- 230000006207 propylation Effects 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 5
- LFQSALQNLFIFMU-UHFFFAOYSA-N 2-acetylpentanoic acid Chemical compound CCCC(C(C)=O)C(O)=O LFQSALQNLFIFMU-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 claims description 2
- WOFAGNLBCJWEOE-UHFFFAOYSA-N Benzyl acetoacetate Chemical compound CC(=O)CC(=O)OCC1=CC=CC=C1 WOFAGNLBCJWEOE-UHFFFAOYSA-N 0.000 claims description 2
- 239000004412 Bulk moulding compound Substances 0.000 claims description 2
- REIYHFWZISXFKU-UHFFFAOYSA-N Butyl acetoacetate Chemical compound CCCCOC(=O)CC(C)=O REIYHFWZISXFKU-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 2
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 2
- GVIIRWAJDFKJMJ-UHFFFAOYSA-N propan-2-yl 3-oxobutanoate Chemical compound CC(C)OC(=O)CC(C)=O GVIIRWAJDFKJMJ-UHFFFAOYSA-N 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- DHGFMVMDBNLMKT-UHFFFAOYSA-N propyl 3-oxobutanoate Chemical compound CCCOC(=O)CC(C)=O DHGFMVMDBNLMKT-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- JKUYRAMKJLMYLO-UHFFFAOYSA-N tert-butyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OC(C)(C)C JKUYRAMKJLMYLO-UHFFFAOYSA-N 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims 4
- 230000029936 alkylation Effects 0.000 claims 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000012071 phase Substances 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- 238000001514 detection method Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- DIRSQLKNZQKDBK-UHFFFAOYSA-N 2,2-dipropylpropanedioic acid Chemical compound CCCC(C(O)=O)(C(O)=O)CCC DIRSQLKNZQKDBK-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- DWTUXMIVGUYEQK-UHFFFAOYSA-N ethyl 2-ethylpentanoate Chemical compound CCCC(CC)C(=O)OCC DWTUXMIVGUYEQK-UHFFFAOYSA-N 0.000 description 3
- 229910017053 inorganic salt Inorganic materials 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229910021536 Zeolite Inorganic materials 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 2
- VHOACUZAQKMOEQ-UHFFFAOYSA-N ethyl 2-acetylpentanoate Chemical compound CCCC(C(C)=O)C(=O)OCC VHOACUZAQKMOEQ-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 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
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 2
- 238000000967 suction filtration Methods 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
- 229940070710 valerate Drugs 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 239000010457 zeolite Substances 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- UMJGAWHIMHSGMU-UHFFFAOYSA-N 2,2-dipropylpentanoic acid Chemical compound CCCC(CCC)(CCC)C(O)=O UMJGAWHIMHSGMU-UHFFFAOYSA-N 0.000 description 1
- WUWPVNVBYOKSSZ-UHFFFAOYSA-N 2-ethyl-2-methyl valeric ccid Chemical compound CCCC(C)(CC)C(O)=O WUWPVNVBYOKSSZ-UHFFFAOYSA-N 0.000 description 1
- ODPKTGAWWHZBOY-UHFFFAOYSA-N 2-propan-2-ylpentanoic acid Chemical compound CCCC(C(C)C)C(O)=O ODPKTGAWWHZBOY-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 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
- 230000001276 controlling effect Effects 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- LWIWFCDNJNZEKB-UHFFFAOYSA-N dipropyl propanedioate Chemical compound CCCOC(=O)CC(=O)OCCC LWIWFCDNJNZEKB-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- UKFXDFUAPNAMPJ-UHFFFAOYSA-N ethylmalonic acid Chemical compound CCC(C(O)=O)C(O)=O UKFXDFUAPNAMPJ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- HKWQDBQONIKHSN-UHFFFAOYSA-N methyl 2-cyano-2-ethylpentanoate Chemical compound CCCC(CC)(C#N)C(=O)OC HKWQDBQONIKHSN-UHFFFAOYSA-N 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
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 238000005406 washing 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
-
- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- 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
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/025—Gas chromatography
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及化学结构式B所示的2‑乙基戊酸的制备方法:选择乙酰乙酸酯与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2‑乙基戊酸;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、四乙基溴化铵或四乙基碘化铵、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、三甲基苄基氯化铵。2‑乙基戊酸用于丙戊酸或丙戊酸钠生产工艺中杂质的定性或定量分析。
Description
技术领域
本发明涉及医药工业领域;具体是采用原子经济性反应制备丙二酸二乙酯法生产丙戊酸中存在的杂质——2-乙基戊酸(B)。
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-异丙基戊酸(C)、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[魏正华,韦建国,顾玉仅,景涛.一种2-R1戊酸的制备方法,CN 202110336630.6,2021.7.23公开]描述了氰基乙酸甲酯、甲醇和1-溴丙烷在45~60℃,滴加30~40%甲醇钠甲醇溶液,反应结束后,旋蒸甲醇得到粗品,然后纯化得到2-氰基戊酸甲酯,2-氰基戊酸甲酯再乙基化,水解和脱羧得到2-乙基戊酸(B)。
重庆健能医药开发有限公司在中国发明专利[李朝阳,王祖焕,刘萍.一种丙戊酸钠原料中微量杂质HPLC-MS定性分析方法,CN2020115724317,2021.5.7]中描述了丙戊酸钠产品中检测到微量杂质L和B:
北京悦康科创医药科技股份有限公司[一种丙戊酸钠的制备方法,CN202310028759.X,2023.5.9公开]和四川科瑞德制药股份有限公司[一种二丙基丙二酸相关杂质的检测方法,ZL2019112294367,2022.10.28授权;一种制备丙戊酸中间体二丙基丙二酸二乙酯的方法,CN202111473302.7,2023.6.6公开]采用气相色谱法检测由丙二酸乙酯法制备的丙戊酸钠产品,其中一种主要杂质是2-乙基戊酸(B)。
2-乙基戊酸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2-乙基戊酸(B)的研究及控制应用问题。因此,对于丙戊酸钠中杂质B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B所示的2-乙基戊酸原子经济性制备方法:其特征在于乙酰乙酸酯与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2-乙基戊酸;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2-乙基戊酸原子经济性制备方法:其特征在于乙酰乙酸乙酯与1-氯丙烷,在碱作用下,催化丙基化,再经还原和水解制得2-乙基戊酸;其制备反应如下:
本发明的目的是提供2-乙基戊酸原子经济性制备方法:其特征在于乙酰乙酸甲酯与1-氯丙烷,在碱作用下,催化丙基化,再经还原和水解制得2-乙基戊酸;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:乙酰乙酸酯∶PTC=1∶0.005~0.10摩尔比;乙酰乙酸酯选自:乙酰乙酸甲酯、乙酰乙酸乙酯、乙酰乙酸正丙酯、乙酰乙酸异丙酯、乙酰乙酸正丁酯、乙酰乙酸叔丁酯、乙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-乙酰基戊酸酯还原为2-乙基戊酸酯,Clemmenese反应如下:
2-乙酰基戊酸酯在5% HCl和甲苯回流中,Zn-Hg还原制得2-乙基戊酸酯。
本发明的目的第三方面是提供2-乙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,采用乙酰乙酸酯和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2-乙基戊酸的方法,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为2-乙基戊酸气相色谱图
附图2丙戊酸气相色谱图
附图3丙戊酸与2-乙基戊酸混合的气相色谱图
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-乙酰基戊酸乙酯的制备
0.20mol乙酰乙酸乙酯、10mmol四乙基溴化铵(TEAB)、60.8g(0.44mol)K2CO3(200目)、80ml DMF和0.30mol 1-氯丙烷,50℃搅拌反应3.0h,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,精馏得到24.5g2-乙酰基戊酸酯,收率71.1%。
实施例2
2-乙基戊酸乙酯的制备
0.20mol 2-乙酰基戊酸乙酯在5% HCl和甲苯中回流,经Zn-Hg还原制得12.3g 2-乙基戊酸乙酯,收率38.9%。
实施例3
2-乙基戊酸(B)的制备
在0.20mol 2-乙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23.8g 2-乙基戊酸B,收率91.4%。1H NMR(CDCl3,400MHz)δ:0.91(t,J=7.2Hz,3H,CH3),0.93(t,J=7.2Hz,3H,CH3),1.25~1.79(m,6H,CH2CH2+CH2),2.25~2.36(m,1H,CH),11.5(brs,1H,CO2H)。
实施例4
2-乙基戊酸(B)的制备
选择乙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2-乙基戊酸B。
实施例5(对照例)
2-乙基戊酸(B)的制备
按上海青平药业有限公司[CN 202110336630.6,2021.7.23公开]实施例2中描述的方法制备:
(1)2-氰基-2-乙基戊酸甲酯的制备
在反应瓶中加入2-氰基戊酸甲酯70g、甲醇110g、碘乙烷81.2g(1.05eq),控温至40~50℃,滴加102g 30%的甲醇钠甲醇溶液(甲醇钠1.2eq),滴加结束升温至回流保温3h至原料反应结束。反应结束的反应液减压浓缩至干,加入150ml乙酸异丙酯和100ml水萃取除盐,分相,油相加入100ml乙酸乙丙酯萃取一次,油相浓缩得到粗品75g,使用20厘米刺型柱蒸馏,得到2-氰基-2-乙基戊酸甲酯60.4g(纯度98%,收率72%)。
(2)2-乙基戊酸(B)的制备
在反应瓶中加入26g 50%硫酸水溶液,然后加入2-氰基-2-乙基戊酸甲酯10g,升温至回流分水,缓慢分水,直到内温达到140℃结束分水,保温在140℃反应15h以上,直到中间产物2-乙基戊酸酰胺反应完成。反应液中加入10g水,分相,油相用10g×3水洗至中性,油相加入16g浓度为20%的氢氧化钠水溶液,60℃保温水解5h。水解结束后静置分层,所得水相使用10ml×3的二氯甲烷洗涤三次,分相,水相加入4g硫酸酸化为pH=1,加入10ml×3水洗涤,得到的油相加入无水硫酸钠干燥,过滤除盐,在60℃条件使用油泵减压浓缩至无气泡产生,得到3g 2-乙基戊酸(纯度99%,收率39%)。
实施例6
2-乙基戊酸的应用
2-乙基戊酸用于丙戊酸钠生产工艺中杂质的定性分析。选择气相色谱仪(Agilent8890)采用气相色谱法检测采用丙二酸二乙酯法生产丙戊酸或丙戊酸钠产品。
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。
2-乙基戊酸(B)的气相色谱图检测结果见附图1,保留时间27.071min。
丙二酸二乙酯法制备丙戊酸:
依次加入16.02g(0.1mol)丙二酸二乙酯,0.005mol TBAB,2.0g ZSM-23沸石分子筛,41.46g(0.30mol)K2CO3(200目),25ml N,N-二甲基甲酰胺和30ml乙腈,27.49g(0.35mol)氯丙烷,75℃搅拌反应11h,加250ml水,溶解固体,过滤回收ZSM-12沸石分子筛,滤液用石油醚萃取(40ml×4),水洗涤(40ml×4),无水硫酸钠干燥,抽滤,旋蒸,干燥得淡黄色透明液体。在所得丙二酸二乙酯中,加入氢氧化钾水溶液(KOH 30g,H2O 40g),5ml乙醇,升温85℃水解3h,旋蒸得到固体。加水50ml溶解固体,浓盐酸调节pH1~1.5,有固体析出,抽滤,石油醚洗涤得白色固体,干燥得到17.4g二丙基丙二酸,熔点157~158℃,收率92.5%(以丙二酸二乙酯计)。
按专利[一种制备2-丙基戊酸的方法,CN103183599B,2015-04-01]实施例1中的方法:将实施例1~9制得的二丙基丙二酸31g加入200mL圆底瓶中,用氮气置换三次,放入预先稳定170℃油浴中反应3h(放出CO2),反应3h,降温,得23g丙戊酸。
其气相色谱图检测结果见附图2。
其中5号峰保留时间27.076min,RRT=0.90,峰面积0.038%:2-乙基戊酸;7号峰保留时间30.061min,RRT=1.00:丙戊酸。
丙戊酸和2-乙基戊酸混合气相色谱图检测结果见附图3;其中5号峰保留时间27.075min,RRT=0.90,峰面积升到0.134%:2-乙基戊酸;7号峰保留时间30.088min,RRT=1.00:丙戊酸。
结论:附图2和附图3中5号峰(RRT=0.90)为2-乙基戊酸(B);丙二酸二乙酯法生产丙戊酸或丙戊酸钠产品中一种主要杂质是2-乙基戊酸,其结构式为:
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 (10)
1.化学结构式B所示的2-乙基戊酸的制备方法:其特征在于乙酰乙酸酯与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2-乙基戊酸;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;
烷基化PTC选自: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;
烷基化溶剂选择: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;
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。
2.化学结构式B所示的2-乙基戊酸的制备方法:其特征在于乙酰乙酸乙酯与1-氯丙烷,在碱作用下,催化丙基化,再经还原和水解制得2-乙基戊酸;其制备反应如下:
烷基化PTC、溶剂和K2CO3的定义如权利要求1所述。
3.化学结构式B所示的2-乙基戊酸的制备方法:其特征在于乙酰乙酸甲酯与1-氯丙烷,在碱作用下,催化丙基化,再经还原和水解制得2-乙基戊酸;其制备反应如下:
烷基化PTC、溶剂和K2CO3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2-乙基戊酸的制备方法,其特征在于烷基化反应温度选择:30℃~80℃,烷基化反应时间1.0h~12.0h。
5.如权利要求1~3中任一项所述的2-乙基戊酸的制备方法,其特征在于投料用量选择:乙酰乙酸酯∶1-氯丙烷=1∶1.2~1.6摩尔比;PTC用量选择:乙酰乙酸酯∶PTC=1∶0.005~0.10摩尔比。
6.如权利要求1所述的2-乙基戊酸的制备方法,其特征在于乙酰乙酸酯选自:乙酰乙酸甲酯、乙酰乙酸乙酯、乙酰乙酸正丙酯、乙酰乙酸异丙酯、乙酰乙酸正丁酯、乙酰乙酸叔丁酯、乙酰乙酸苄酯中一种或二种。
7.如权利要求1所述的2-乙基戊酸的制备方法,其特征在于R4NX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。
8.如权利要求1所述的2-乙基戊酸的制备方法,其特征在于R3R1NX选自: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。
9.如权利要求1所述的2-乙基戊酸的制备方法,其特征在于2-乙酰基戊酸酯还原为2-乙基戊酸酯,其Clemmenese反应如下:
2-乙酰基戊酸酯在5%HCl和甲苯回流中,Zn-Hg还原制得2-乙基戊酸酯;R的定义如权利要求1所述。
10.2-乙基戊酸在丙戊酸或丙戊酸钠生产工艺中杂质的定性或定量分析中应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311007251.8A CN117069561B (zh) | 2023-08-10 | 一种2-乙基戊酸的制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311007251.8A CN117069561B (zh) | 2023-08-10 | 一种2-乙基戊酸的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN117069561A true CN117069561A (zh) | 2023-11-17 |
CN117069561B CN117069561B (zh) | 2024-05-31 |
Family
ID=
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5101070A (en) * | 1985-10-30 | 1992-03-31 | Nippon Gohsei Kagaku Kogyo Kabushiki Kaisha | Process for preparing valproic acid |
CN114763319A (zh) * | 2022-05-16 | 2022-07-19 | 湖南大学 | 一种联产丙戊酰胺和丙戊酸钠的方法 |
CN114790151A (zh) * | 2022-02-14 | 2022-07-26 | 湖南省湘中制药有限公司 | 一种2-氰基-2-丙戊酸甲酯的复合催化制备方法 |
CN116023232A (zh) * | 2023-01-03 | 2023-04-28 | 湖南省湘中制药有限公司 | 一种丙基丙二酸及其同系物的制备方法 |
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5101070A (en) * | 1985-10-30 | 1992-03-31 | Nippon Gohsei Kagaku Kogyo Kabushiki Kaisha | Process for preparing valproic acid |
CN114790151A (zh) * | 2022-02-14 | 2022-07-26 | 湖南省湘中制药有限公司 | 一种2-氰基-2-丙戊酸甲酯的复合催化制备方法 |
CN114763319A (zh) * | 2022-05-16 | 2022-07-19 | 湖南大学 | 一种联产丙戊酰胺和丙戊酸钠的方法 |
CN116023232A (zh) * | 2023-01-03 | 2023-04-28 | 湖南省湘中制药有限公司 | 一种丙基丙二酸及其同系物的制备方法 |
Non-Patent Citations (2)
Title |
---|
"欧洲药典10.0", 31 December 2017, pages: 3849 - 3850 * |
ALEXANDER UTTRY, 等: "Late-Stage β‑C(sp3)−H Deuteration of Carboxylic Acids", J. AM. CHEM. SOC., vol. 143, 19 July 2021 (2021-07-19) * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA3158166A1 (en) | Process for the preparation of 2-cyanoethyl (4s)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate by resolution of racemates by means of diastereomeric tartaric acid esters | |
CN101830821A (zh) | 一种n-烷氧草酰丙氨酸酯的化学合成方法 | |
JP2022552713A (ja) | ジアステレオマー酒石酸エステルによるラセミ体分離により2-シアノエチル(4s)-4-(4-シアノ-2-メトキシフェニル)-5-ヒドロキシ-2,8-ジメチル-1,4-ジヒドロ-1,6-ナフチリジン-3-カルボキシレートを調製する方法 | |
WO2005105728A1 (en) | Process for preparing cinnamic acids and alkyl esters thereof | |
Pietruszka et al. | Diastereo‐and Enantiomerically Pure Allylboronates: Their Synthesis and Scope | |
CN117069561B (zh) | 一种2-乙基戊酸的制备方法 | |
CN112142660B (zh) | 一种简便高效合成4-芳基丁酸衍生物的方法 | |
CN117069561A (zh) | 一种2-乙基戊酸的制备方法 | |
CN113372271A (zh) | 一种顺苯磺酸阿曲库铵的制备方法 | |
CN116947600B (zh) | 一种丙戊酸工艺杂质2-异丙基戊酸的制备方法 | |
CN108409589B (zh) | 一种带手性的β-氨基酸酯的制备方法 | |
CN115697968B (zh) | (s)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基丙酸甲酯及其盐的制备方法 | |
CN104193645A (zh) | 一种手性二甲基环丙甲酰胺的制备方法 | |
CN113149823B (zh) | 一种2-r1戊酸的制备方法 | |
CN116874347B (zh) | 一种丙戊酸工艺杂质二丙基戊酸的制备方法 | |
JPH09268155A (ja) | α,β−不飽和−β−トリフロオロメチル カルボキシレートの製造方法 | |
CN116854578A (zh) | 一种丙戊酸钠工艺杂质2-甲基戊酸的制备方法 | |
CN101417942B (zh) | 一种制备对羟基扁桃酸的方法 | |
CN111056997A (zh) | 一种苯甲酰胺化合物的合成方法 | |
RU2807294C1 (ru) | Способ получения метиллактата | |
CN116730832B (zh) | 一种2-丙基己酸的制备方法 | |
CN110862318B (zh) | 一种叔丁基取代羟基苯甲酸酯的制备方法 | |
CN110256387B (zh) | 一种医药中间体的制备方法 | |
CN1045437C (zh) | 恩丹西酮及其生理盐的合成 | |
JP3818785B2 (ja) | α,β−ジカルボニル化化合物のための製造方法 |
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 |