CN116768697B - 一种氯丙烷作烷化剂制备二丙基丙二酸的方法与应用 - Google Patents
一种氯丙烷作烷化剂制备二丙基丙二酸的方法与应用 Download PDFInfo
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- DIRSQLKNZQKDBK-UHFFFAOYSA-N 2,2-dipropylpropanedioic acid Chemical compound CCCC(C(O)=O)(C(O)=O)CCC DIRSQLKNZQKDBK-UHFFFAOYSA-N 0.000 title claims abstract description 44
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims description 23
- 239000002168 alkylating agent Substances 0.000 title description 5
- 229940100198 alkylating agent Drugs 0.000 title description 5
- -1 malonic acid diester Chemical class 0.000 claims abstract description 33
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- 239000002808 molecular sieve Substances 0.000 claims abstract description 15
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 11
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 6
- 239000002585 base Substances 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 4
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims abstract description 3
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000004412 Bulk moulding compound Substances 0.000 claims abstract description 3
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 claims abstract description 3
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims abstract description 3
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims abstract description 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910021536 Zeolite Inorganic materials 0.000 claims description 10
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 10
- 239000010457 zeolite Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 8
- BGQMOFGZRJUORO-UHFFFAOYSA-M tetrapropylammonium bromide Chemical compound [Br-].CCC[N+](CCC)(CCC)CCC BGQMOFGZRJUORO-UHFFFAOYSA-M 0.000 claims description 7
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 4
- GKXDJYKZFZVASJ-UHFFFAOYSA-M tetrapropylazanium;iodide Chemical compound [I-].CCC[N+](CCC)(CCC)CCC GKXDJYKZFZVASJ-UHFFFAOYSA-M 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 claims description 3
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 claims description 3
- UQFSVBXCNGCBBW-UHFFFAOYSA-M tetraethylammonium iodide Chemical compound [I-].CC[N+](CC)(CC)CC UQFSVBXCNGCBBW-UHFFFAOYSA-M 0.000 claims description 3
- FBEVECUEMUUFKM-UHFFFAOYSA-M tetrapropylazanium;chloride Chemical compound [Cl-].CCC[N+](CCC)(CCC)CCC FBEVECUEMUUFKM-UHFFFAOYSA-M 0.000 claims description 3
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 2
- 150000005690 diesters Chemical class 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- DDFYFBUWEBINLX-UHFFFAOYSA-M tetramethylammonium bromide Chemical compound [Br-].C[N+](C)(C)C DDFYFBUWEBINLX-UHFFFAOYSA-M 0.000 claims description 2
- RXMRGBVLCSYIBO-UHFFFAOYSA-M tetramethylazanium;iodide Chemical compound [I-].C[N+](C)(C)C RXMRGBVLCSYIBO-UHFFFAOYSA-M 0.000 claims description 2
- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 abstract description 26
- 239000007787 solid Substances 0.000 abstract description 24
- 229960000604 valproic acid Drugs 0.000 abstract description 8
- 239000002202 Polyethylene glycol Substances 0.000 abstract description 7
- 229920001223 polyethylene glycol Polymers 0.000 abstract description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 abstract description 6
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 6
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 abstract 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 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
- 150000003983 crown ethers Chemical class 0.000 abstract description 2
- 230000000911 decarboxylating effect Effects 0.000 abstract description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 abstract 1
- 150000003512 tertiary amines Chemical class 0.000 abstract 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 229940084026 sodium valproate Drugs 0.000 description 8
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000010025 steaming Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 4
- 101150065749 Churc1 gene Proteins 0.000 description 4
- 102100038239 Protein Churchill Human genes 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000001376 precipitating effect Effects 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- LGIUQPZVYULVIG-UHFFFAOYSA-N 1-o-methyl 3-o-propyl propanedioate Chemical compound CCCOC(=O)CC(=O)OC LGIUQPZVYULVIG-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- OLGXVKQPZBFKBA-UHFFFAOYSA-N 1-o-ethyl 3-o-propyl propanedioate Chemical compound CCCOC(=O)CC(=O)OCC OLGXVKQPZBFKBA-UHFFFAOYSA-N 0.000 description 1
- LIRDIZPKBSSVBK-UHFFFAOYSA-N 3-o-ethyl 1-o-methyl propanedioate Chemical compound CCOC(=O)CC(=O)OC LIRDIZPKBSSVBK-UHFFFAOYSA-N 0.000 description 1
- HDXXKLJVUKAUHH-UHFFFAOYSA-N 3-oxo-3-propoxypropanoic acid Chemical compound CCCOC(=O)CC(O)=O HDXXKLJVUKAUHH-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 description 1
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 1
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- ZFMAHACGDXIMSE-UHFFFAOYSA-N dimethyl 2,2-dipropylpropanedioate Chemical compound CCCC(CCC)(C(=O)OC)C(=O)OC ZFMAHACGDXIMSE-UHFFFAOYSA-N 0.000 description 1
- VVNBOKHXEBSBQJ-UHFFFAOYSA-M dodecyl(triethyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](CC)(CC)CC VVNBOKHXEBSBQJ-UHFFFAOYSA-M 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- FZPXKEPZZOEPGX-UHFFFAOYSA-N n,n-dibutylaniline Chemical compound CCCCN(CCCC)C1=CC=CC=C1 FZPXKEPZZOEPGX-UHFFFAOYSA-N 0.000 description 1
- BBDGYADAMYMJNO-UHFFFAOYSA-N n-butyl-n-ethylbutan-1-amine Chemical compound CCCCN(CC)CCCC BBDGYADAMYMJNO-UHFFFAOYSA-N 0.000 description 1
- GNVRJGIVDSQCOP-UHFFFAOYSA-N n-ethyl-n-methylethanamine Chemical compound CCN(C)CC GNVRJGIVDSQCOP-UHFFFAOYSA-N 0.000 description 1
- XWCCTMBMQUCLSI-UHFFFAOYSA-N n-ethyl-n-propylpropan-1-amine Chemical compound CCCN(CC)CCC XWCCTMBMQUCLSI-UHFFFAOYSA-N 0.000 description 1
- ISRXMEYARGEVIU-UHFFFAOYSA-N n-methyl-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C)C(C)C ISRXMEYARGEVIU-UHFFFAOYSA-N 0.000 description 1
- UVBMZKBIZUWTLV-UHFFFAOYSA-N n-methyl-n-propylpropan-1-amine Chemical compound CCCN(C)CCC UVBMZKBIZUWTLV-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
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- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- QSUJAUYJBJRLKV-UHFFFAOYSA-M tetraethylazanium;fluoride Chemical compound [F-].CC[N+](CC)(CC)CC QSUJAUYJBJRLKV-UHFFFAOYSA-M 0.000 description 1
- HNJXPTMEWIVQQM-UHFFFAOYSA-M triethyl(hexadecyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](CC)(CC)CC HNJXPTMEWIVQQM-UHFFFAOYSA-M 0.000 description 1
- NAWZSHBMUXXTGV-UHFFFAOYSA-M triethyl(hexyl)azanium;bromide Chemical compound [Br-].CCCCCC[N+](CC)(CC)CC NAWZSHBMUXXTGV-UHFFFAOYSA-M 0.000 description 1
- SZEMGTQCPRNXEG-UHFFFAOYSA-M trimethyl(octadecyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCCCC[N+](C)(C)C SZEMGTQCPRNXEG-UHFFFAOYSA-M 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及化学结构式Ⅱ所示的二丙基丙二酸的制备方法:选择丙二酸二酯与1‑氯丙烷,在碱作用下,催化二丙基化制得式Ⅰ所示的二丙基丙二酸二酯,后者水解制得二丙基丙二酸(Ⅱ);其制备反应如下:R1选择:苄基、C1~C5直链烷基或C3~C5支链烷基;R1和R2相同或不同;催化剂由聚乙二醇、聚乙二醇单醚、聚乙二醇双醚、冠醚、三级胺、季铵盐和分子筛组成;溶剂选择:THF、DMF、DEF、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、二乙二醇二甲醚或二乙二醇二乙醚中的一种或二种。碱选自:固体MOH或固体M2CO3,其中M=Na、Li、Cs或K。二丙基丙二酸(Ⅱ)脱羧制得丙戊酸。
Description
技术领域
本发明属于化学制药领域,具体而言是由一种氯丙烷作烷化剂制备二丙基丙二酸的相转移催化方法及其在制备丙戊酸中的应用。
背景技术
湖南医药工业研究所等[抗癫痫药物抗癫灵的合成方法.中国医药工业杂志,1978,1:34-35;曲迪.山东化工,2012,41(3):30-31,35]选择以丙二酸二乙酯和1-溴丙烷,经烷基化、水解制得二丙基丙二酸,后者脱羧和成盐四步反应制得丙戊酸钠。
宗智慧等[丙戊酸钠的合成工艺改进.长春师范大学学报,2016,08:64-67]描述了以丙二酸二乙酯和1-溴丙烷为原料制得二丙基丙二酸,对丙戊酸钠的制备工艺进行优化;并探究出乙酸乙酯和丙酮作为重结晶溶剂,对丙戊酸钠重结晶收率分别达96%和90%。
张晶[丙戊酸钠的合成工艺,CN105622390A.2016-06-01]描述了以丙二酸二乙酯和1-溴丙烷为原料,制得二丙基丙二酸,发明了一种丙戊酸钠的制备工艺:
付金广[丙戊酸钠的合成工艺改进.山东化工,2012,41(10):3-4]选择丙二酸二甲酯,在PEG-400催化下,在甲醇钠作用下,与1-溴丙烷反应,再经氢氧化钠水解制得二丙基丙二酸,后者加热脱羧,最后成盐得到丙戊酸钠。
陶晶等[二丙基丙二酸二酯的制备方法.中国发明专利.CN103183612A,2013-07-03;一种制备2-丙基戊酸的方法,CN103183599B,2015-04-01]描述了丙戊酸的制备方法;其中选择一种以丙二酸甲酯丙酯和1-氯丙烷为原料制备丙戊酸,其中1-氯丙烷作烷化剂的二丙基化反应制得二丙基丙二酸甲酯丙酯,粗品(二丙基丙二酸甲酯丙酯)收率70.5%。
丙二酸二酯法制备丙戊酸,目前主要是选择1-溴丙烷作烷化剂,醇钠作碱,在醇中发生二丙基化;1-溴丙烷且价贵,醇钠碱性强。
1-氯丙烷为原料制备丙戊酸,由于1-氯丙烷活性低,二丙基化反应制得二丙基丙二酸二酯,收率较低(小于70.5%),这是生产工艺技术中的难题。
使用强碱甲醇钠、乙醇钠或叔丁醇钾;使用价格较贵的1-溴丙烷;在该条件下可能发生副反应,生成副产物:
发明内容
本发明的目的一方面是提供二丙基丙二酸的制备方法:其特征在于丙二酸二酯与1-氯丙烷,在碱作用下,催化二丙基化制得式Ⅰ所示的二丙基丙二酸二酯,后者水解制得二丙基丙二酸(Ⅱ);其制备反应如下:
R1和R2分别选择:苄基、C1~C5直链烷基或C3~C5支链烷基;R1和R2相同或不同;
R1R2选择:CH2,CHCH3,CHCH2CH3,CHCH2CH2CH3,CHCH(CH3)2,CH2CH2,CH(CH3)CH2,CH(CH3)CH(CH3),CH2CH2CH2,CH(CH3)CH2CH2,CH2CH(CH3)CH2或CH2C(CH3)2CH2。
二丙基丙二酸二酯选自下列化合物或其混合物:
催化剂由催化剂PTC和分子筛组成;分子筛选自:ZSM-12,ZSM-23沸石分子筛;
催化剂PTC选择:PEG(聚乙二醇)、聚乙二醇单醚、聚乙二醇双醚、冠醚、R3N、R2R1N、PhNR2、R4NX或R3R1NX;其中R=C1~C4直链烷基、C5~C8直链烷基;R1=PhCH2、C1~C5直链烷基、C6~C18直链烷基;其中X=Cl、Br或I;
R4NX选自:四丁基氯化铵(TBAC)、四丁基溴化铵(TBAB)、四丁基碘化铵(TBAI)、四乙基氟化铵、四乙基氯化铵(TEAC)、四乙基溴化铵(TEAB)、四乙基碘化铵(TEAI)、四甲基氯化铵、四甲基溴化铵、四甲基碘化铵、四丙基氯化铵(TPAC)、四丙基碘化铵(TPAI)或四丙基溴化铵(TPAB)。
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、三甲基苄基氯化铵、三乙基苄基溴化铵、十六烷基三乙基溴化铵、十二烷基三乙基溴化铵、十烷基三乙基溴化铵、辛基三乙基溴化铵、己基三乙基溴化铵或三辛基甲基氯化铵。
R3N选自:三甲胺、三乙胺、三丙胺、三丁胺;PhNR2选自:N,N-二甲苯胺、N,N-二乙苯胺、N,N-二丙苯胺或N,N-二丁苯胺;R2R1N选自:二乙基甲胺、二丙基甲胺、二异丙基甲胺、二丙基乙胺、二异丙基乙胺、二丁基乙胺。
溶剂选择:THF、DMF、DEF(N,N-二乙基甲酰胺)、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、二乙二醇二甲醚或二乙二醇二乙醚中的一种或二种。
碱选自:固体MOH或固体M2CO3,其中M=Na、Li、Cs或K;固体MOH选择颗粒或粉状MOH;固体M2CO3选择颗粒M2CO3或粉状M2CO3;其中M=Na、Li、Cs或K。
粉状M2CO3选择:100目M2CO3、150目M2CO3、200目M2CO3、250目M2CO3、300目M2CO3或350目M2CO3,其中M=Na、Li、Cs或K。
丙二酸二酯选自下列化合物:
投料用量选择:丙二酸二酯∶1-氯丙烷=1∶2~4摩尔比;催化用量选择:丙二酸二酯∶催化剂PTC=1∶0.001~0.15摩尔比;碱用量选择:丙二酸二酯∶M2CO3=1∶2~4摩尔比或丙二酸二酯∶MOH=1∶1.2~2.5摩尔比;烷基化反应温度选择:40℃~140℃,反应时间4h~18h。
本发明与现有技术相比具有以下优点:
1.本发明中,采用丙二酸二酯和1-氯丙烷的催化二丙基化方法:1-氯丙烷供应充足,来源丰富,且价廉;该关键性二丙基化反应完全,为最终产品高质量提供保障。
2.本发明生产工艺路线中不使用强碱甲醇钠、乙醇钠或叔丁钾,也不使用价格较贵的1-溴丙烷;创造性地避免了下列副产物的产生:
3.工艺中的中间体和产品纯度高,分离简单;原料药生产成本低,质量好。具有很好的社会效益与经济效益。
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
二丙基丙二酸的制备
依次加入16.02g(0.1mol)丙二酸二乙酯,4.83g(0.015mol)TBAB,2gZSM-12沸石分子筛,41.46g(0.30mol)K2CO3(300目),55ml乙二醇二甲醚,27.49g(0.35mol)氯丙烷,75℃搅拌反应16h,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),10ml乙醇,升温82℃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,干燥得17.0g二丙基丙二酸,熔点157~158℃,收率90.4%(以丙二酸二乙酯计),1H NMR(400MHz,DMSO-d6)δ:12.56(s,2H,COOH×2),1.74–1.65(m,4H,CH2×2),1.19–1.07(m,4H,CH2×2),0.87(t,J=7.3Hz,6H,CH3×2)。
实施例2
二丙基丙二酸的制备
依次加入16.02g(0.1mol)丙二酸二乙酯,1.33g(0.005mol)TPAB,2.0g ZSM-23沸石分子筛,41.46g(0.30mol)K2CO3(300目),55mlN,N-二乙基甲酰胺,27.49g(0.35mol)氯丙烷,85℃搅拌反应11h,加250ml水,溶解固体,过滤回收ZSM-23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17.7g二丙基丙二酸,熔点157~158℃,收率94.0%(以丙二酸二乙酯计),1HNMR(400MHz,DMSO-d6)δ:12.56(s,2H,COOH×2),1.74–1.65(m,4H,CH2×2),1.19–1.07(m,4H,CH2×2),0.87(t,J=7.3Hz,6H,CH3×2)。
实施例3
二丙基丙二酸的制备
依次加入16.02g(0.1mol)丙二酸二乙酯,1.33g(0.005mol)TPAB,2.0g ZSM-23沸石分子筛,41.46g(0.30mol)K2CO3(100目),55mlN,N-二甲基甲酰胺,27.49g(0.35mol)氯丙烷,90℃搅拌反应12h,加250ml水,溶解固体,过滤回收ZSM-23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17.6g二丙基丙二酸,熔点157~158℃,收率93.5%(以丙二酸二乙酯计),1HNMR(400MHz,DMSO-d6)δ:12.56(s,2H,COOH×2),1.74–1.65(m,4H,CH2×2),1.19–1.07(m,4H,CH2×2),0.87(t,J=7.3Hz,6H,CH3×2)。
实施例4
二丙基丙二酸的制备
依次加入16.02g(0.1mol)丙二酸二乙酯,0.005mol TBAB,2.0gZSM-23沸石分子筛,41.46g(0.30mol)K2CO3(200目),25mlN,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-23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),1HNMR(400MHz,DMSO-d6)δ:12.56(s,2H,COOH×2),1.74–1.65(m,4H,CH2×2),1.19–1.07(m,4H,CH2×2),0.87(t,J=7.3Hz,6H,CH3×2)。
实施例5
二丙基丙二酸的制备
选择丙二酸二乙酯作原料,TPAI作催化剂,按实施例1方法操作,得到二丙基丙二酸。
实施例6
经二丙基丙二酸二甲酯中间体制备二丙基丙二酸
选择丙二酸二甲酯作原料,TPAB作催化剂,按实施例2方法操作,得到二丙基丙二酸。
实施例7
经二丙基丙二酸甲酯乙酯中间体制备二丙基丙二酸
选择丙二酸甲酯乙酯作原料,三丁胺作催化剂,按实施例2方法操作,得到二丙基丙二酸。
实施例8
经二丙基丙二酸甲酯丙酯中间体制备二丙基丙二酸
选择丙二酸甲酯丙酯作原料,TPAB作催化剂,按实施例2方法操作,得到二丙基丙二酸,熔点157~158℃,收率92.0%(以丙二酸甲酯丙酯计)。
实施例9
经二丙基丙二酸乙酯丙酯中间体制备二丙基丙二酸
选择丙二酸乙酯丙酯作原料,TBAI作催化剂,按实施例2方法操作,得到二丙基丙二酸。
实施例10(对比实验)
甲醇钠作为碱,甲醇作为反应溶剂,制备二丙基丙二酸甲酯丙酯。
按陶晶等[二丙基丙二酸二酯的制备方法.中国发明专利.CN103183612A,2013-07-03]描述的专利说明书中实施例8方法制备:
500mL三口瓶中加入甲醇60mL,搅拌下加入丙二酸甲酯丙酯10g(62.5mmol)、1-氯丙烷30.6g(250mmol)、甲醇钠13.5g(250mmol),升温至回流,11h后补加1-氯丙烷7.6g(63.6mmol)和甲醇钠3.38g(63.6mmol),再反应3.5h,取样TLC检测反应完全,降至室温后抽滤,滤饼使用50mL乙酸乙酯洗涤,合并滤液,自来水洗滤液两次(50mL×2),饱和氯化钠水溶液洗滤液两次(50mL×2),无水硫酸钠干燥,旋干滤液,得粗品(二丙基丙二酸甲酯丙酯)10.77g,粗品收率70.5%。
实施例11
丙戊酸的制备
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,放入预先稳定的170℃油浴中反应,反应过程中放出CO2,反应3h,降温,得23g丙戊酸。HPLC结果显示,纯度为99.84%。1HNMR(400MHz,DMSO-d6)δ:11.99(s,1H,COOH),2.24–2.18(m,1H,CH),1.53–1.44(m,2H,CH2),1.39–1.34(m,2H,CH2),1.32–1.22(m,4H,CH2×2),0.86(t,J=7.2Hz,6H,CH3×2)。
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 (5)
1.化学结构式Ⅱ所示的二丙基丙二酸的制备方法:其特征在于丙二酸二酯与1-氯丙烷,在碱作用下,催化二丙基化制得式Ⅰ所示的二丙基丙二酸二酯,后者水解制得式Ⅱ所示的二丙基丙二酸;其制备反应如下:
R1和R2分别选择:C1~C5直链烷基或C3~C5支链烷基;R1和R2相同或不同;
催化剂由催化剂PTC和分子筛组成;分子筛选自:ZSM-12,ZSM-23沸石分子筛;
催化剂PTC选择:四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、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、四丙基氯化铵、四丙基碘化铵或四丙基溴化铵;
溶剂选择:DMF、N,N-二乙基甲酰胺、DMC、乙腈、丙腈、丁腈、乙二醇二甲醚、乙二醇二乙醚、二乙二醇二甲醚或二乙二醇二乙醚中的一种或二种;
碱选自颗粒M2CO3或粉状M2CO3,其中M=Na或K;
烷基化反应温度选择:40℃~140℃;反应时间4h~18h。
2.如权利要求1所述的二丙基丙二酸的制备方法,其特征在于粉状M2CO3选择:100目M2CO3、150目M2CO3、200目M2CO3、250目M2CO3、300目M2CO3或350目M2CO3,其中M=Na或K。
3.如权利要求1所述的二丙基丙二酸的制备方法,其特征在于投料用量选择:丙二酸二酯∶1-氯丙烷=1∶2~4摩尔比;催化用量选择:丙二酸二酯∶催化剂PTC=1∶0.001~0.15摩尔比。
4.如权利要求1所述的二丙基丙二酸的制备方法,其特征在于碱用量选择:丙二酸二酯∶M2CO3=1∶2~4摩尔比或丙二酸二酯∶MOH=1∶1.2~2.5摩尔比。
5.如权利要求1所述的二丙基丙二酸的制备方法,其特征在于Ⅰ所示的二丙基丙二酸二酯选自下列化合物或其混合物:
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