CN116023232B - 一种丙基丙二酸及其同系物的制备方法 - Google Patents
一种丙基丙二酸及其同系物的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- KLFHRQOZJWCFOI-UHFFFAOYSA-N 3-methyl-1-[(3-methylpiperidin-1-yl)methyl]piperidine Chemical compound C1C(C)CCCN1CN1CC(C)CCC1 KLFHRQOZJWCFOI-UHFFFAOYSA-N 0.000 title description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 26
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 17
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- -1 malonic acid diester Chemical class 0.000 claims description 9
- OLGXVKQPZBFKBA-UHFFFAOYSA-N 1-o-ethyl 3-o-propyl propanedioate Chemical compound CCCOC(=O)CC(=O)OCC OLGXVKQPZBFKBA-UHFFFAOYSA-N 0.000 claims description 6
- LGIUQPZVYULVIG-UHFFFAOYSA-N 1-o-methyl 3-o-propyl propanedioate Chemical compound CCCOC(=O)CC(=O)OC LGIUQPZVYULVIG-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical group COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 3
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 claims description 2
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 2
- NFKGQHYUYGYHIS-UHFFFAOYSA-N dibutyl propanedioate Chemical compound CCCCOC(=O)CC(=O)OCCCC NFKGQHYUYGYHIS-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
- LWIWFCDNJNZEKB-UHFFFAOYSA-N dipropyl propanedioate Chemical compound CCCOC(=O)CC(=O)OCCC LWIWFCDNJNZEKB-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 claims description 2
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 claims description 2
- UQFSVBXCNGCBBW-UHFFFAOYSA-M tetraethylammonium iodide Chemical compound [I-].CC[N+](CC)(CC)CC UQFSVBXCNGCBBW-UHFFFAOYSA-M 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
- BGQMOFGZRJUORO-UHFFFAOYSA-M tetrapropylammonium bromide Chemical compound [Br-].CCC[N+](CCC)(CCC)CCC BGQMOFGZRJUORO-UHFFFAOYSA-M 0.000 claims description 2
- FBEVECUEMUUFKM-UHFFFAOYSA-M tetrapropylazanium;chloride Chemical compound [Cl-].CCC[N+](CCC)(CCC)CCC FBEVECUEMUUFKM-UHFFFAOYSA-M 0.000 claims description 2
- GKXDJYKZFZVASJ-UHFFFAOYSA-M tetrapropylazanium;iodide Chemical compound [I-].CCC[N+](CCC)(CCC)CCC GKXDJYKZFZVASJ-UHFFFAOYSA-M 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- 239000000843 powder Substances 0.000 claims 2
- LIRDIZPKBSSVBK-UHFFFAOYSA-N 3-o-ethyl 1-o-methyl propanedioate Chemical compound CCOC(=O)CC(=O)OC LIRDIZPKBSSVBK-UHFFFAOYSA-N 0.000 claims 1
- 230000029936 alkylation Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000002245 particle Substances 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 6
- 150000005690 diesters Chemical class 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract 1
- VQDJODAWOFNASI-UHFFFAOYSA-N 2-propylpropanedioic acid Chemical compound CCCC(C(O)=O)C(O)=O VQDJODAWOFNASI-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- DIRSQLKNZQKDBK-UHFFFAOYSA-N 2,2-dipropylpropanedioic acid Chemical compound CCCC(C(O)=O)(C(O)=O)CCC DIRSQLKNZQKDBK-UHFFFAOYSA-N 0.000 description 6
- MCRZWYDXIGCFKO-UHFFFAOYSA-N 2-butylpropanedioic acid Chemical compound CCCCC(C(O)=O)C(O)=O MCRZWYDXIGCFKO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UPFSMSDGKQSRLD-UHFFFAOYSA-N 2-hexylpropanedioic acid Chemical compound CCCCCCC(C(O)=O)C(O)=O UPFSMSDGKQSRLD-UHFFFAOYSA-N 0.000 description 3
- LAWHHRXCBUNWFI-UHFFFAOYSA-N 2-pentylpropanedioic acid Chemical compound CCCCCC(C(O)=O)C(O)=O LAWHHRXCBUNWFI-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000010025 steaming Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229960000604 valproic acid Drugs 0.000 description 3
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000013068 control sample Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MLRVZFYXUZQSRU-UHFFFAOYSA-N 1-chlorohexane Chemical compound CCCCCCCl MLRVZFYXUZQSRU-UHFFFAOYSA-N 0.000 description 1
- SQCZQTSHSZLZIQ-UHFFFAOYSA-N 1-chloropentane Chemical compound CCCCCCl SQCZQTSHSZLZIQ-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
- 239000004412 Bulk moulding compound Substances 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 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
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 239000001961 anticonvulsive agent 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- RYFCSKVXWRJEOB-UHFFFAOYSA-N dibenzyl propanedioate Chemical compound C=1C=CC=CC=1COC(=O)CC(=O)OCC1=CC=CC=C1 RYFCSKVXWRJEOB-UHFFFAOYSA-N 0.000 description 1
- RPNFNBGRHCUORR-UHFFFAOYSA-N diethyl 2-butylpropanedioate Chemical compound CCCCC(C(=O)OCC)C(=O)OCC RPNFNBGRHCUORR-UHFFFAOYSA-N 0.000 description 1
- GRRSDGHTSMJICM-UHFFFAOYSA-N diethyl 2-propylpropanedioate Chemical compound CCOC(=O)C(CCC)C(=O)OCC GRRSDGHTSMJICM-UHFFFAOYSA-N 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- QRVSDVDFJFKYKA-UHFFFAOYSA-N dipropan-2-yl propanedioate Chemical compound CC(C)OC(=O)CC(=O)OC(C)C QRVSDVDFJFKYKA-UHFFFAOYSA-N 0.000 description 1
- CLPHAYNBNTVRDI-UHFFFAOYSA-N ditert-butyl propanedioate Chemical compound CC(C)(C)OC(=O)CC(=O)OC(C)(C)C CLPHAYNBNTVRDI-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
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 238000001704 evaporation Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000009731 jinlong Substances 0.000 description 1
- 229940023568 magnesium valproate Drugs 0.000 description 1
- LKLLHOIUJVEAGU-UHFFFAOYSA-L magnesium;2-propylpentanoate Chemical compound [Mg+2].CCCC(C([O-])=O)CCC.CCCC(C([O-])=O)CCC LKLLHOIUJVEAGU-UHFFFAOYSA-L 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012546 transfer Methods 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
- 229940005605 valeric acid Drugs 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Ⅰ所示的化合物的制备方法:选择丙二酸二酯与1‑氯代烷,在碱作用下,单烷基化制得Ⅰ所示的单烷基丙二酸;其制备反应如下:R1和R2分别选自:苄基、C1~C5直链烷基或C3~C5支链烷基;Y选自:C1~C4直链烷基或C3~C4支链烷基;催化剂PTC选择:R4NX或R3R1NX;其中R选自: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。
Description
技术领域
本发明涉及一种丙基丙二酸及其同系物(单烷基丙二酸)的相转移复合催化制备方法。
背景技术
二丙基丙二酸、二丙基丙二酸二甲酯和二丙基丙二酸二乙酯是制备一种不含氮的广谱抗癫痫药——丙戊酸钠和丙戊酸镁的关键中间体:
在选择丙二酸酯制备二丙基丙二酸时,会残留少许2-丙基丙二酸副产物,其制备反应如下:
湖南省湘中制药有限公司[段世辉等.一种2-丙基丙二酸的回收及其制备丙戊酸的方法,ZL2020111384994,2022.01.28]在选择丙二酸二乙酯制备二丙基丙二酸时,采取回收生成2-丙基丙二酸副产物的方法[(1)将离心二丙基丙二酸后的酸水收集,加入醚、酯、氯代烃、醇类(与水不混溶)溶剂,搅拌萃取,分层,干燥,得到2-丙基丙二酸,回收率达到90%以上;(2)将2-丙基丙二酸酯化,丙基化,水解,酸化得到二丙基丙二酸]降低生产成本,其制备反应如下:
2-丙基丙二酸杂质(脱羧生成戊酸)的存在,会影响最终产品丙戊酸的质量。
四川科瑞德制药股份有限公司[刘泽荣、徐金龙、陈皓、陈刚、瞿春密和董小峰.一种二丙基丙二酸相关杂质的检测方法,ZL2019112294367,2022.10.28授权]描述的相关杂质中有丙基丙二酸单乙酯(D)、丙基丙二酸单甲酯(E)和丙基丙二酸(F):
为更好地控制丙戊酸原料药的质量,需要杂质确认;对照样的制备是做好检测和鉴定工作的关键环节。因此特设计合成该潜在的工艺杂质。
采用相同的方法也合成其同系物,其中2-丁基丙二酸的制备反应如下:
发明内容
本发明的目的是提供化学结构式Ⅰ所示的单烷基丙二酸的制备方法:其特征在于丙二酸二酯与1-氯代烷,在溶剂中和碱作用下,单烷基化制得Ⅰ所示的单烷基丙二酸;其制备反应如下:
R1和R2分别选自:苄基、C1~C5直链烷基或C3~C5支链烷基;R1和R2相同或不同。
Y选自:C1~C4直链烷基或C3~C4支链烷基;Y选自:甲基、乙基、丙基(n-Pr)、丁基(n-Bu)、异丙基(i-Pr)、异丁基(i-Bu)、仲丁基(s-Bu)或叔丁基(t-Bu)。
Ⅰa所示的2-丙基丙二酸;其制备反应如下:
R1和R2分别选自:苄基、C1~C5直链烷基或C3~C5支链烷基;R1和R2相同或不同;
Ⅰb所示的2-丁基丙二酸;其制备反应如下:
R1和R2分别选自:苄基、C1~C5直链烷基或C3~C5支链烷基;R1和R2相同或不同。
Ⅰc所示的2-戊基丙二酸,其制备反应如下:
R1和R2分别选自:苄基、C1~C5直链烷基或C3~C5支链烷基;R1和R2相同或不同。
Ⅰd所示的2-己基丙二酸,其制备反应如下:
R1和R2分别选自: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PTC选择:R4NX或R3R1NX;其中R选自: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、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、四丙基溴化铵或四丙基碘化铵。
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。
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:40℃~90℃;反应时间选择:1.0h~6.0h;
投料用量选择:丙二酸二酯∶1-氯丙烷=1∶1~2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∶K2CO3=1∶1~1.5摩尔比。
丙二酸二酯选自:丙二酸二甲酯、丙二酸二乙酯、丙二酸二正丙酯、丙二酸二异丙酯、丙二酸二正丁酯、丙二酸二叔丁酯、丙二酸二苄酯,丙二酸甲酯乙酯、丙二酸乙酯丙酯或丙二酸甲酯丙酯。
本发明与现有技术相比具有以下优点:
为更好地控制丙戊酸原料药的质量,对照样的制备是做好检测和鉴定工作的关键节点。本发明中设计合成了潜在的工艺杂质,解决了确认杂质的关键问题。
采用选择1-氯代烷作烷基化剂的新方法制备2-烷基丙二酸。
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-丙基丙二酸的制备
依次加入0.1mol丙二酸二乙酯,2.0mmol TPAB,13.80g K2CO3(200目),20ml乙二醇二甲醚或乙二醇二乙醚,0.18mol 1-氯丙烷,80℃搅拌反应3.5h,加100ml水,溶解固体,石油醚萃取,氢氧化钠溶液洗涤,无水硫酸钠干燥,抽滤,旋蒸,得无色透明液体。在所得丙基丙二酸二乙酯中,加入氢氧化钾水溶液(KOH 15g,H2O 40g),5ml乙醇,升温85℃水解3h,浓盐酸调pH1,乙酸乙酯萃取,稀盐酸洗涤,无水硫酸钠干燥,抽滤,旋蒸,得白色固体,加入二氯甲烷溶解,再加入5倍量石油醚(以二氯甲烷计),析出固体,抽滤,烘干得白色固体丙基丙二酸,收率89.3%(以丙二酸二乙酯计),m.p.95~96℃。1HNMR(400MHz,DMSO-d6)δ12.64(s,2H,CO2H×2),3.20(t,J=7.4Hz,1H,CH),1.74–1.63(m,2H,CH2),1.34–1.22(m,2H,CH2),0.88(t,J=7.3Hz,3H,CH3)。
实施例2
2-丁基丙二酸的制备
依次加入0.1mol丙二酸二乙酯,3.0mmol TBAI,13.80g K2CO3(100目),20ml DMSO或DMF,0.17mol1-氯丁烷,75℃搅拌反应4.5h,加100ml水,溶解固体,石油醚萃取,氢氧化钠溶液洗涤,无水硫酸钠干燥,抽滤,旋蒸,得无色透明液体;在所得丁基丙二酸二乙酯中,加入氢氧化钾水溶液(KOH 15g,H2O 40g),5ml乙醇,升温85℃水解3h,浓盐酸调pH1,乙酸乙酯萃取,稀盐酸洗涤,无水硫酸钠干燥,抽滤,旋蒸,得白色固体,加入二氯甲烷溶解,再加入5倍量石油醚(以二氯甲烷计),析出固体,抽滤,烘干得白色固体丁基丙二酸,收率86.0%(以丙二酸二乙酯计),m.p.102~103℃。1HNMR(400MHz,DMSO-d6)δ12.63(s,2H,CO2H×2),3.18(t,J=7.4Hz,1H,CH),1.76–1.64(m,2H,CH2),1.34–1.18(m,4H,CH2CH2),0.86(t,J=6.8Hz,3H,CH3)。
实施例3
2-丙基丙二酸的制备
选择丙二酸二甲酯和1-氯丙烷作原料,TPAB作催化剂,按实施例1方法操作,得到2-丙基丙二酸,收率87.0%(以丙二酸二甲酯计)。
实施例4
2-丙基丙二酸的制备
选择丙二酸甲酯丙酯和1-氯丙烷作原料,TPAI作催化剂,按实施例1方法操作,得到2-丙基丙二酸,收率85.0%(以丙二酸甲酯丙酯计)。
实施例5
2-戊基丙二酸的制备
选择丙二酸二乙酯和1-氯戊烷作原料,TBAC作催化剂,按实施例1方法操作,得到2-戊基丙二酸,收率87.0%(以丙二酸二乙酯计)。
实施例6
2-己基丙二酸的制备
选择丙二酸二乙酯和1-氯己烷作原料,TBAB作催化剂,按实施例1方法操作,得到2-己基丙二酸,收率88.0%(以丙二酸二乙酯计)。
实施例7
2-丙基丙二酸的制备
选择丙二酸乙酯丙酯和1-氯丙烷作原料,TPAC作催化剂,按实施例1方法操作,得到2-丙基丙二酸,收率89.0%(以丙二酸乙酯丙酯计)。
实施例8
2-丁基丙二酸的制备
选择丙二酸甲酯丙酯和1-氯丁烷作原料,TBAB作催化剂,按实施例2方法操作,得到2-丁基丙二酸,收率86.0%(以丙二酸甲酯丙酯计)。
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 (6)
1.化学结构式Ⅰ所示的单烷基丙二酸的制备方法,其特征在于丙二酸二酯与1-氯代烷,在溶剂中和碱作用下,单烷基化制得式Ⅰ所示的单烷基丙二酸;其制备反应如下:
R1和R2分别选自:C1~C5直链烷基;R1和R2相同或不同;Y选自:C1~C4直链烷基;
催化剂PTC选自四丁基氯化铵、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;
溶剂选自DMF、N,N-二乙基甲酰胺、DMSO、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;K2CO3选择颗粒K2CO3或粉状K2CO3;
烷基化反应温度选自40℃~90℃,反应时间1.0h~6.0h。
2.如权利要求1所述的单烷基丙二酸的制备方法,其特征在于粉状K2CO3选自100目K2CO3、150目K2CO3、200目K2CO3、250目K2CO3、300目K2CO3或350目K2CO3。
3.如权利要求1所述的单烷基丙二酸的制备方法,其特征在于投料用量选自丙二酸二酯∶1-氯丙烷=1∶1~2摩尔比。
4.如权利要求1所述的单烷基丙二酸的制备方法,其特征在于催化剂PTC用量选自丙二酸二酯∶催化剂PTC=1∶0.001~0.15摩尔比。
5.如权利要求1所述的单烷基丙二酸的制备方法,其特征在于碳酸钾用量选自丙二酸二酯∶K2CO3=1∶1~1.5摩尔比。
6.如权利要求1所述的单烷基丙二酸的制备方法,其特征在于丙二酸二酯选自丙二酸二甲酯、丙二酸二乙酯、丙二酸二正丙酯、丙二酸二正丁酯、丙二酸甲酯乙酯、丙二酸乙酯丙酯、丙二酸甲酯丙酯或其混合物。
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Publication number | Priority date | Publication date | Assignee | Title |
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CN102863474A (zh) * | 2011-07-09 | 2013-01-09 | 陈小平 | 一类治疗细胞增殖性疾病的铂化合物、其制备方法和应用 |
CN104030922A (zh) * | 2014-06-04 | 2014-09-10 | 上海应用技术学院 | 一种制备正丁基丙二酸二甲酯的方法 |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN102863474A (zh) * | 2011-07-09 | 2013-01-09 | 陈小平 | 一类治疗细胞增殖性疾病的铂化合物、其制备方法和应用 |
CN104030922A (zh) * | 2014-06-04 | 2014-09-10 | 上海应用技术学院 | 一种制备正丁基丙二酸二甲酯的方法 |
CN108047028A (zh) * | 2017-12-15 | 2018-05-18 | 中国石油大学(华东) | 一种电容级2,7-二丁基辛二酸的制备方法 |
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