CN117430509A - Preparation and hydrolysis method of 2-alkyl-2-propyl malonic acid diester - Google Patents

Preparation and hydrolysis method of 2-alkyl-2-propyl malonic acid diester Download PDF

Info

Publication number
CN117430509A
CN117430509A CN202311398306.2A CN202311398306A CN117430509A CN 117430509 A CN117430509 A CN 117430509A CN 202311398306 A CN202311398306 A CN 202311398306A CN 117430509 A CN117430509 A CN 117430509A
Authority
CN
China
Prior art keywords
alkyl
acid
propyl
isopropyl
diester
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.)
Pending
Application number
CN202311398306.2A
Other languages
Chinese (zh)
Inventor
彭辉
曾顺
胡艾希
刘晨
曾乐乐
叶姣
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hunan Province Xiangzhong Pharmaceutical Co ltd
Hunan University
Original Assignee
Hunan Province Xiangzhong Pharmaceutical Co ltd
Hunan University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Hunan Province Xiangzhong Pharmaceutical Co ltd, Hunan University filed Critical Hunan Province Xiangzhong Pharmaceutical Co ltd
Priority to CN202311398306.2A priority Critical patent/CN117430509A/en
Publication of CN117430509A publication Critical patent/CN117430509A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a preparation method of 2-alkyl-2-propyl malonic acid diester shown in a formula I: the method is characterized in that malonic diester and 1-chloropropane are catalyzed to dipropylate under the action of alkali to prepare 2-alkyl-2-propyl malonic diester shown in formula IEsters:R 1 ，R 2 selected from benzyl, C1-C5 straight chain alkyl or C3-C5 branched alkyl; r is R 1 And R is 2 The same or different; r is R 3 Selected from methyl, ethyl, propyl, butyl or isopropyl. Hydrolyzing the 2-alkyl-2-propyl malonic acid diester (I) to obtain 2-alkyl-2-propyl malonic acid (II); decarboxylation of II to obtain 2-alkyl valeric acid (III). II, recrystallizing by ethanol aqueous solution or methanol aqueous solution to obtain dipropylmalonic acid (IIa); the IIa is decarboxylated to obtain valproic acid, the yield of valproic acid is more than 85.0 percent (calculated by malonic diester), and the content is more than 99.85 percent (GC).

Description

Preparation and hydrolysis method of 2-alkyl-2-propyl malonic acid diester
Technical Field
The invention relates to a preparation and hydrolysis method of 2-alkyl-2-propyl malonic acid diester.
Background
The pharmaceutical company of Hunan Xiang, inc. [ method for preparing valproic acid, CN2022111446576, 2023.3.21] discloses that cyclopropylester malonate (2, 2-dimethyl-1, 3-dioxane-4, 6-dione) is reacted with 1-chloropropane to prepare 2, 2-dimethyl-5, 5-dipropyl-1, 3-dioxane-4, 6-dione, which is hydrolyzed to prepare dipropylmalonic acid (IIa):
north geneva group limited et al [ ceramic, lin Songwen, zhong Xuechao, deng Xiaobing. Preparation of dipropylmalonic acid diester chinese invention patent CN103183612a,2013.07.03; ceramic crystals, lin Songwen, zhong Xuechao, deng Xiaobing a process for preparing 2-propylvaleric acid, CN103183599B,2015.04.01] describes a process for preparing valproic acid; wherein, methyl propyl malonate and 1-chloropropane are selected as raw materials to prepare valproic acid, and the dialkyl reaction of the 1-chloropropane as an alkylating agent prepares dipropyl methyl propyl malonate, and the yield of the crude product (dipropyl methyl propyl malonate) is 70.5%.
The crystallization method of 2, 2-dipropylmalonic acid is described by North Daku-Zheng group Co., ltd. [ ceramic crystals, lin Songwen, zhong Xuechao, deng Xiaobing, crystallization method of 2, 2-dipropylmalonic acid, ZL 20110457073. X,2015.8.12 ]: crystallizing the 2, 2-dipropylmalonic acid crude product in two mixed organic solvents (ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile and dioxane and n-hexane, cyclohexane or petroleum ether respectively) to obtain the 2, 2-dipropylmalonic acid with the recovery rate of 65.0-74.5 and the purity of 99.50-99.78%.
Preparation method of diethyl dipropylmalonate, CN 202210872174.1, 2022.12.6], is disclosed in the pharmaceutical technology and technology of the scientific and technological company of beijing yuekang [ Song Gengshen, liu Zhaoguo, wei Junming ], the preparation method of diethyl dipropylmalonate: diethyl malonate, 1-bromopropane, a strong organic base (RONa) and an organic solvent (ROH) are mixed and reacted to prepare diethyl dipropylmalonate.
Sichuan Ruider pharmaceutical Co., ltd. [ Yang Hai, U.S. Pat. No. Yu Linqing, gan Chang, deng Li, yangfan, homex, fu Lin, chen-gang. A process for preparing the valproic acid intermediate diethyl dipropylmalonate, CN202111473302.7, 2023.6.6; liu Zerong, xu Jinlong, chen Hao, chen gang, qu Chunmi, dong Xiaofeng. A method for detecting impurities associated with dipropylmalonic acid, ZL2019112294367, 2022.10.28 authorization ] the impurities in dipropylmalonic acid (iia) are diethyl dipropylmalonate, monoethyl dipropylmalonate, monomethyl dipropylmalonate, monoethyl propylmalonate, monomethyl propylmalonate, propylmalonic acid or diethyl propylmalonate, respectively, detected by high performance liquid chromatography:
disclosure of Invention
The invention aims to provide a preparation method of 2-alkyl-2-propyl malonic acid diester shown in a formula I: the method is characterized in that malonic diester and 1-chloropropane (containing a trace amount of 1-chlorobutane and 2-chloropropane) are subjected to catalytic dialkylation under the action of alkali to prepare 2-alkyl-2-propyl malonic diester:
R 1 ，R 2 selected from benzyl, C1-C5 straight chain alkyl or C3-C5 branched alkyl; r is R 1 And R is 2 The same or different; r is R 3 Selected from methyl, ethyl, propyl, butyl or isopropyl.
The catalyst in the catalytic dialkylation reaction consists of PTC and molecular sieve; the molecular sieve is selected from: ZSM-12, ZSM-23 zeolite molecular sieve.
The PTC is selected from tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), tetraethylammonium fluoride, tetraethylammonium chloride (TEAC), tetraethylammonium bromide (TEAB), tetraethylammonium iodide (TEAI), tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetrapropylammonium chloride (TPAC), tetrapropylammonium iodide (TPAI) or tetrapropylammonium bromide (TPAB).
The solvent in the dialkylation reaction is one or two selected from THF, DMF, DEF (N, N-diethylformamide), DMC, DMSO, acetonitrile, propionitrile, butyronitrile, 1, 4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether.
The base in the dialkylation reaction is selected from: solid MOH or solid M 2 CO 3 Wherein m=na or K; the solid MOH is selected from granular or powdery MOH; solid M 2 CO 3 Selecting particles M 2 CO 3 Or in powder form M 2 CO 3 The method comprises the steps of carrying out a first treatment on the surface of the Where m=na or K.
Powdery M 2 CO 3 Selected from 100 mesh M 2 CO 3 M of 150 meshes 2 CO 3 200 mesh M 2 CO 3 250 mesh M 2 CO 3 300 mesh M 2 CO 3 Or 350 mesh M 2 CO 3 Where m=na or K.
The invention also provides a method for preparing 2-alkyl-2-propyl malonic acid (II) by hydrolyzing the 2-alkyl-2-propyl malonic acid diester shown in the formula I; recrystallizing the 2-alkyl-2-propyl malonic acid (II) by ethanol aqueous solution or methanol aqueous solution to obtain dipropyl malonic acid (IIa); the aqueous ethanol (filtrate) or aqueous methanol (filtrate) recovery jacket is used for the hydrolysis of the 2-alkyl-2-propylmalonic acid diester.
R 3 Selected from methyl, ethyl, propyl, butyl or isopropyl;
the invention also provides a method for preparing 2-alkyl valeric acid (III) by decarboxylation of 2-alkyl-2-propyl malonic acid (II):
R 3 selected from methyl, ethyl, propyl, butyl or isopropyl.
The invention aims to provide a preparation method of 2-alkyl-2-propyl malonic acid diester, which comprises the following steps: the method is characterized in that dimethyl malonate and 1-chloropropane (containing a trace amount of 1-chlorobutane and 2-chloropropane) are subjected to catalytic dialkylation under the action of alkali to prepare 2-alkyl-2-propyl malonic acid diester shown in a formula I-1:
R 3 selected from methyl, propyl, butyl or isopropyl; r is R 2 Selected from methyl or propyl;
the 2-alkyl-2-propylmalonic acid diester represented by I-1 is selected from the following compounds:
the catalyst in the catalytic dialkylation reaction consists of PTC and molecular sieve; the molecular sieve is selected from: ZSM-12, ZSM-23 zeolite molecular sieve;
the PTC is selected from tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), tetraethylammonium fluoride, tetraethylammonium chloride (TEAC), tetraethylammonium bromide (TEAB), tetraethylammonium iodide (TEAI), tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetrapropylammonium chloride (TPAC), tetrapropylammonium iodide (TPAI) or tetrapropylammonium bromide (TPAB).
The solvent in the dialkylation reaction is one or two selected from THF, DMF, DEF (N, N-diethylformamide), DMC, DMSO, acetonitrile, propionitrile, butyronitrile, 1, 4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether.
The base in the dialkylation reaction is selected from: solid MOH or solid M 2 CO 3 Wherein m=na or K; the solid MOH is selected from granular or powdery MOH; solid M 2 CO 3 Selecting particles M 2 CO 3 Or in powder form M 2 CO 3 The method comprises the steps of carrying out a first treatment on the surface of the Where m=na or K.
Powdery M 2 CO 3 Selected from 100 mesh M 2 CO 3 M of 150 meshes 2 CO 3 200 mesh M 2 CO 3 250 mesh M 2 CO 3 300 mesh M 2 CO 3 Or 350 mesh M 2 CO 3 Where m=na or K.
The invention also provides a method for preparing 2-alkyl-2-propyl malonic acid (II) by hydrolyzing 2-alkyl-2-propyl malonic acid dimethyl ester (I-1):
R 3 selected from methyl, propyl, butyl or isopropyl; 2-alkyl-2-propylmalonic acid (II) is selected from the following compounds:
the invention also provides a method for obtaining dipropylmalonic acid (IIa) by recrystallizing the crude product of 2-alkyl-2-propylmalonic acid (II) in ethanol aqueous solution or methanol aqueous solution. An aqueous ethanol solution (filtrate) or an aqueous methanol solution (filtrate) is used for the hydrolysis of the 2-alkyl-2-propylmalonic acid diester.
The invention also provides a method for preparing 2-alkyl valeric acid (III) by decarboxylation of 2-alkyl-2-propyl malonic acid (II):
R 3 selected from methyl, propyl, butyl or isopropyl; 2-alkyl valeric acid (III) is selected from the following compounds:
2-methyl valeric acid (L), 2-propyl caproic acid (X) or 2-isopropyl valeric acid (C) are process impurities for preparing valproic acid P by a dimethyl malonate method (a method for preparing valproic acid by taking dimethyl malonate as a raw material).
The invention aims to provide a preparation method of 2-alkyl-2-propyl malonic acid diester (I-2): the method is characterized in that diethyl malonate and 1-chloropropane (containing a trace amount of 1-chlorobutane and 2-chloropropane) are subjected to catalytic dialkylation under the action of alkali to prepare 2-alkyl-2-propyl malonic acid diester shown in the formula I-2:
R 2 selected from ethyl or propyl; r is R 3 Selected from ethyl, propyl, butyl or isopropyl; the 2-alkyl-2-propylmalonic acid diester represented by I-2 is selected from the following compounds:
the catalyst in the catalytic dialkylation reaction consists of PTC and molecular sieve; the molecular sieve is selected from: ZSM-12, ZSM-23 zeolite molecular sieve;
the PTC is selected from tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), tetraethylammonium fluoride, tetraethylammonium chloride (TEAC), tetraethylammonium bromide (TEAB), tetraethylammonium iodide (TEAI), tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetrapropylammonium chloride (TPAC), tetrapropylammonium iodide (TPAI) or tetrapropylammonium bromide (TPAB).
The solvent in the dialkylation reaction is selected from THF, DMF, DEF (N, N-diethylformamide), DMC, DMSO, acetonitrile, propionitrile, butyronitrile, 1, 4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether.
The base in the dialkylation reaction is selected from: solid MOH or solid M 2 CO 3 Wherein m=na or K; the solid MOH is selected from granular or powdery MOH; solid M 2 CO 3 Selecting particles M 2 CO 3 Or in powder form M 2 CO 3 The method comprises the steps of carrying out a first treatment on the surface of the Where m=na or K.
Powdery M 2 CO 3 Selected from 100 mesh M 2 CO 3 M of 150 meshes 2 CO 3 200 mesh M 2 CO 3 250 mesh M 2 CO 3 300 mesh M 2 CO 3 Or 350 mesh M 2 CO 3 Where m=na or K.
The invention also provides a method for preparing 2-alkyl-2-propyl malonic acid (II) by hydrolyzing 2-alkyl-2-propyl malonic acid diester (I-2): recrystallizing the 2-alkyl-2-propyl malonic acid (II) by ethanol aqueous solution or methanol aqueous solution to obtain dipropyl malonic acid (IIa); the aqueous ethanol (filtrate) or aqueous methanol (filtrate) recovery jacket is used for the hydrolysis of 2-alkyl-2-propylmalonic acid diester:
R 3 selected from ethyl, propyl, butyl or isopropyl; 2-alkyl-2-propylmalonic acid (II) is selected from the following compounds:
Ⅱa
the invention also provides a method for obtaining dipropylmalonic acid (IIa) by recrystallizing the crude product of 2-alkyl-2-propylmalonic acid (II) in ethanol aqueous solution or methanol aqueous solution. An aqueous ethanol solution (filtrate) or an aqueous methanol solution (filtrate) is used for the hydrolysis of the 2-alkyl-2-propylmalonic acid diester.
The invention also provides a method for preparing 2-alkyl valeric acid (III) by decarboxylation of 2-alkyl-2-propyl malonic acid (II):
R 3 selected from ethyl, propyl, butyl or isopropyl; 2-alkyl valeric acid (III) is selected from the following compounds:
2-ethyl valeric acid (B), 2-propyl caproic acid (X) or 2-isopropyl valeric acid (C) are process impurities for preparing valproic acid P by diethyl malonate method (method for preparing valproic acid by using diethyl malonate as raw material).
Compared with the prior art, the invention has the following advantages:
1. in the invention, a method for carrying out composite catalysis and dialkylation on malonic acid diester and 1-chloropropane is adopted: the 1-chloropropane is sufficient in supply, rich in source, low in cost and low in production cost.
And recrystallizing the 2-alkyl-2-propyl malonic acid (II) crude product by adopting ethanol aqueous solution or methanol aqueous solution to obtain dipropyl malonic acid (IIa). The intermediate and the product have high purity and are simple to separate; an aqueous ethanol solution (filtrate) or an aqueous methanol solution (filtrate) is used for the hydrolysis of the 2-alkyl-2-propylmalonic acid diester (I); the process is green and environment-friendly, and the valproic acid product has good quality; has good social benefit and economic benefit.
Detailed Description
The present invention will be described in further detail with reference to examples.
Example 1
Preparation and hydrolysis of diethyl dipropylmalonate
(1) 16.02g diethyl malonate, 4.83g TBAB, 2g ZSM-12 zeolite molecular sieve, 41.46g K 2 CO 3 (300 meshes), 55ml of ethylene glycol dimethyl ether and 27.49g of 1-chloropropane (containing 1-chlorobutane and 2-chloropropane) are stirred and reacted for 16 hours at 75 ℃, 250ml of water is added to dissolve solid, ZSM-12 zeolite molecular sieve is recovered by filtration, filtrate is extracted by petroleum ether, washed by water, dried by anhydrous sodium sulfate, filtered by suction, steamed by rotation and dried to obtain light yellow transparent liquid.
The pale yellow liquid was 90% dipropylmalonic acid diethyl ester by HPLC (HPLC), and the dipropylated by-products were the following compounds (HPLC detection):
2-ethyl-2-propylmalonic acid diethyl ester: 1 H NMR(CDCl 3 ，400MHz):δ0.81(t，J＝7.6Hz，3H，CH 3 )，0.92(t，J＝7.2Hz，3H，CH 3 )，1.11～1.19(m，2H，CH 2 )，1.24(t，J＝7.2Hz，6H，2×CH 3 )，1.81～1.87(m，2H，CH 2 )，1.92(q，J＝7.6Hz，2H，CH 2 )，4.17(q，J＝7.2Hz，4H，2×OCH 2 )。
2-propyl-2-butylmalonic acid diethyl ester: 1 H NMR(CDCl 3 ，400MHz):δ0.87～0.94(m，6H，2×CH 3 )，1.24～1.36(m，12H，CH 2 +CH 2 CH 2 ，2×CH 3 )，1.82～1.89(m，4H，2×CH 2 )，4.17(q，J＝7.1Hz，4H，2×OCH 2 )。
2-isopropyl-2-propylmalonic acid diethyl ester: 1 H NMR(CDCl 3 ，400MHz):δ0.91(t，J＝7.2Hz，3H，CH 3 )，0.97(d，J＝7.2Hz，6H，2×CH 3 )，1.16～1.27(m，8H，CH 2 ，2×CH 3 )，1.82～1.87(m，2H，CH 2 )，4.17(sep，J＝7.2Hz，1H，CH)，4.18(q，J＝7.2Hz，4H，2×OCH 2 )。
(2) To the thus-obtained diethyl dipropylmalonate pale yellow liquid (crude product), 50ml of 30% aqueous potassium hydroxide ethanol solution was added, and the mixture was hydrolyzed at 82℃for 3 hours, followed by rotary evaporation to obtain a solid. Adding 50ml of water to dissolve solid, regulating pH to 1-1.5 with concentrated hydrochloric acid, precipitating solid, filtering, recrystallizing in ethanol water solution to obtain 17.0g of dipropylmalonic acid (IIa), melting point 157-158 ℃, yield 90.4% (calculated by diethyl malonate), 1 H NMR(400MHz，DMSO-d 6 )δ:12.56(s，2H，COOH×2)，1.74–1.65(m，4H，CH 2 ×2)，1.19–1.07(m，4H，CH 2 ×2)，0.87(t，J＝7.3Hz，6H，CH 3 x 2). The filtrate (aqueous ethanol) was recovered and used for hydrolysis of diethyl dipropylmalonate.
Byproducts of hydrolysis are the following compounds:
2-propyl-2-butylmalonic acid: mp.157-159 ℃; 1 H NMR(DMSO-d 6 ，400MHz):δ0.88(t，J＝6.8Hz，3H，CH 3 )，0.89(t，J＝6.8Hz，3H，CH 3 )，1.08～1.17(m，4H，CH 2 CH 2 )，1.26～1.32(m，2H，CH 2 )，1.69～1.75(m，4H，CH 2 ×2)，12.61(s，1H，CO 2 H)。
example 2
Preparation and hydrolysis of diethyl dipropylmalonate
(1) 16.02g diethyl malonate, 1.33g TPAB, 2.0g ZSM-23 zeolite molecular sieve, 41.46. 41.46g K 2 CO 3 (300 meshes), 55ml of N, N-diethyl formamide and 27.49g of 1-chloropropane (containing 1-chlorobutane and 2-chloropropane) are stirred and reacted for 11 hours at 85 ℃, 250ml of water is added to dissolve solid, ZSM-12 zeolite molecular sieve is recovered by filtration, filtrate is extracted by petroleum ether, washed by water, dried by anhydrous sodium sulfate, filtered by suction, steamed by rotation and dried to obtain light yellow transparent liquid.
The pale yellow liquid was 93% dipropylmalonic acid diethyl ester by HPLC (HPLC detection), and the dipropylated by-products were the following compounds (HPLC detection):
2-ethyl-2-propylmalonic acid diethyl ester: 1 H NMR(CDCl 3 ，400MHz):δ0.81(t，J＝7.6Hz，3H，CH 3 )，0.92(t，J＝7.2Hz，3H，CH 3 )，1.11～1.19(m，2H，CH 2 )，1.24(t，J＝7.2Hz，6H，2×CH 3 )，1.81～1.87(m，2H，CH 2 )，1.92(q，J＝7.6Hz，2H，CH 2 )，4.17(q，J＝7.2Hz，4H，2×OCH 2 )。
2-propyl-2-butylmalonic acid diethyl ester: 1 H NMR(CDCl 3 ，400MHz):δ0.87～0.94(m，6H，2×CH 3 )，1.24～1.36(m，12H，CH 2 +CH 2 CH 2 ，2×CH 3 )，1.82～1.89(m，4H，2×CH 2 )，4.17(q，J＝7.1Hz，4H，2×OCH 2 )。
2-isopropyl-2-propylmalonic acid diethyl ester: 1 H NMR(CDCl 3 ，400MHz):δ0.91(t，J＝7.2Hz，3H，CH 3 )，0.97(d，J＝7.2Hz，6H，2×CH 3 )，1.16～1.27(m，8H，CH 2 ，2×CH 3 )，1.82～1.87(m，2H，CH 2 )，4.17(sep，J＝7.2Hz，1H，CH)，4.18(q，J＝7.2Hz，4H，2×OCH 2 )。
(2) To the thus-obtained diethyl dipropylmalonate pale yellow liquid (crude product), 50ml of 30% aqueous potassium hydroxide ethanol solution or an aqueous ethanol solution (filtrate) recovered by recrystallization was added, and the mixture was hydrolyzed at 85℃for 3 hours, followed by rotary evaporation to obtain a solid. Adding 50ml of water to dissolve solid, regulating pH to 1-1.5 with concentrated hydrochloric acid, precipitating solid, filtering, washing with petroleum ether to obtain white solid, recrystallizing in ethanol water solution, and drying to obtain 17.7g of dipropylmalonic acid (IIa), with melting point of 157-158 ℃ and yield of 94.0% (calculated by diethyl malonate); 1 H NMR(400MHz，DMSO-d 6 )δ:12.56(s，2H，COOH×2)，1.74–1.65(m，4H，CH 2 ×2)，1.19–1.07(m，4H，CH 2 ×2)，0.87(t，J＝7.3Hz，6H，CH 3 x 2). The filtrate (aqueous ethanol) was recovered and used for hydrolysis of diethyl dipropylmalonate.
Byproducts of hydrolysis are the following compounds:
2-propyl-2-butylmalonic acid: mp.157-159 ℃; 1 H NMR(DMSO-d 6 ，400MHz):δ0.88(t，J＝6.8Hz，3H，CH 3 )，0.89(t，J＝6.8Hz，3H，CH 3 )，1.08～1.17(m，4H，CH 2 CH 2 )，1.26～1.32(m，2H，CH 2 )，1.69～1.75(m，4H，CH 2 ×2)，12.61(s，1H，CO 2 H)。
example 3
Preparation and hydrolysis of dimethyl dipropylmalonate
Dimethyl malonate is selected as a raw material, TPAB is used as a catalyst, and the operation is performed according to the method of example 2 to obtain dipropyldimethyl malonate; hydrolyzing the crude dimethyl dipropylmalonate in methanol aqueous solution by KOH catalysis; recrystallizing the methanol aqueous solution to obtain dipropylmalonic acid (IIa). The filtrate (aqueous methanol) was recovered and used for hydrolysis of dimethyl dipropylmalonate.
The dipropylated by-products are the following compounds:
byproducts of hydrolysis are the following compounds:
2-propyl-2-butylmalonic acid: mp.157-159 ℃; 1 H NMR(DMSO-d 6 ，400MHz):δ0.88(t，J＝6.8Hz，3H，CH 3 )，0.89(t，J＝6.8Hz，3H，CH 3 )，1.08～1.17(m，4H，CH 2 CH 2 )，1.26～1.32(m，2H，CH 2 )，1.69～1.75(m，4H，CH 2 ×2)，12.61(s，1H，CO 2 H)。
example 4
Preparation and hydrolysis of propyl methyl dipropylmalonate
Methyl propyl malonate is selected as a raw material, TPAB is used as a catalyst, and the method is carried out according to the method of the example 2 to obtain dipropyl methyl propyl malonate; the latter is hydrolyzed in aqueous methanol by KOH catalysis; recrystallizing the aqueous methanol solution to obtain dipropylmalonic acid (IIa), wherein the melting point is 157-158 ℃, and the yield is 92.0% (calculated by methyl propyl malonate). 1 H NMR(400MHz，DMSO-d 6 )δ:12.56(s，2H，COOH×2)，1.74–1.65(m，4H，CH 2 ×2)，1.19–1.07(m，4H，CH 2 ×2)，0.87(t，J＝7.3Hz，6H，CH 3 X 2). The filtrate (aqueous methanol) was recovered and used for hydrolysis of propyl methyl dipropylmalonate.
Example 5
Preparation and hydrolysis of ethyl propyl dipropylmalonate
Ethyl propyl malonate is selected as a raw material, TBAI is used as a catalyst, and dipropyl ethyl propyl malonate is prepared by operating the method of example 2; the latter is hydrolyzed in ethanol aqueous solution by KOH catalysis; recrystallizing the ethanol water solution to obtain dipropylmalonic acid (IIa). 1 H NMR(400MHz，DMSO-d 6 )δ:12.56(s，2H，COOH×2)，1.74–1.65(m，4H，CH 2 ×2)，1.19–1.07(m，4H，CH 2 ×2)，0.87(t，J＝7.3Hz，6H，CH 3 X 2). The filtrate (aqueous ethanol) was recovered and used for hydrolysis of ethyl propyl dipropylmalonate. .
Example 6
Preparation of valproic acid (P)
The dipropylmalonic acid (IIa) is decarboxylated for 2 hours at 160-180 ℃ to obtain valproic acid (P), the yield is more than 85.0% (calculated by malonic acid diester), and the content is more than 99.85% (GC). 1 H NMR(400MHz,DMSO-d 6 )δ:11.99(s，1H，COOH)，2.24–2.18(m，1H，CH)，1.53–1.44(m，2H，CH 2 )，1.39–1.34(m，2H，CH 2 )，1.32–1.22(m，4H，CH 2 ×2)，0.86(t，J＝7.2Hz，6H，CH 3 ×2)。
Example 7
Preparation of 2-methylpentanoic acid (L)
2-methyl-2-propyl malonic acid is decarboxylated for 2 hours at 160-180 ℃ to prepare 2-methyl valeric acid (L). 1 H NMR(DMSO-d 6 ，400MHz)δ：11.95(brs，1H，CO 2 H)，2.37～2.21(m，1H，CH)，1.62～1.42(m，1H，1/2CH 2 )，1.38～1.16(m，3H，1/2CH 2 +CH 2 )，1.03(d，J＝7.0Hz，3H，CH 3 )，0.85(t，J＝7.2Hz，3H，CH 3 )。
Example 8
Preparation of 2-ethylvaleric acid (B)
Decarboxylation of 2-ethyl-2-propyl malonic acid at 160-180 ℃ for 2h to obtain 2-ethyl valeric acid (B). 1 H NMR(CDCl 3 ，400MHz)δ：0.91(t，J＝7.2Hz，3H，CH 3 )，0.93(t，J＝7.2Hz，3H，CH 3 )，1.25～1.79(m，6H，CH 2 CH 2 +CH 2 )，2.25～2.36(m，1H，CH)，11.5(brs，1H，CO 2 H)。
Example 9
Preparation of 2-methylpentanoic acid (C)
Decarboxylating 2-isopropyl-2-propyl malonic acid at 160-180 ℃ for 2 hours to obtain 2-isopropyl valeric acid (C). 1 H NMR(DMSO-d 6 ，400MHz)δ：11.78(brs，1H，CO 2 H)，2.16～2.11(m，1H，CH)，1.92～1.86(m，1H，CH)，1.64～1.45(m，2H，CH 2 )，1.42～1.25(m，2H，CH 2 )，0.97(d，J＝7.2Hz，6H，CH 3 ×2)，0.91(t，J＝7.2Hz，3H，CH 3 )。
Example 10
Preparation of 2-propylhexanoic acid (X)
Decarboxylating 2-propyl-2-butyl malonic acid at 160-180 ℃ for 2 hours to obtain 2-propyl caproic acid (X). 1 H NMR(DMSO-d 6 ，400MHz)δ：0.87(t，J＝7.6Hz，6H，CH 3 +CH 3 )，1.21～1.26(m，6H，CH 2 +CH 2 CH 2 )，1.28～1.36(m，2H，CH 2 )，1.41～1.53(m，2H，CH 2 )，2.20～2.23(m，1H，CH)，12.14(bs，1H，CO 2 H)。
Example 11 (control 1)
Crystallization of 2, 2-dipropylmalonic acid
The crystallization of 2, 2-dipropylmalonic acid was authorized according to the method of the crystallization of ZL 20110457073. X,2015.8.12 by North Dakuang group Co., ltd. [ ceramic, lin Songwen, zhong Xuechao, deng Xiaobing ]]The crystallization process of example 1 is operated: 10g of crude 2, 2-dipropylmalonic acid was added to 180ml of a mixed solvent of ethyl acetate and cyclohexane (V Acetic acid ethyl ester And V Cyclohexane =1:5). Heating to 70-80 ℃, stirring until the 2, 2-dipropylmalonic acid is completely dissolved, filtering while the solution is hot, standing, naturally cooling to normal temperature, crystallizing, filtering, drying to constant weight, and obtaining 7.23g of 2, 2-dipropylmalonic acid, the recovery rate is 72.3%, and the purity is 99.78%.
In this specification, the invention has been described with reference to specific embodiments thereof. It will be apparent, however, that various modifications and changes may be made without departing from the spirit and scope of the invention. The description is thus to be regarded as illustrative instead of limiting.

Claims (10)

1. A method for preparing 2-alkyl-2-propyl malonic acid diester shown in a formula I: the method is characterized in that malonic diester and 1-chloropropane (containing 1-chlorobutane and 2-chloropropane) are catalyzed and dialkylated under the action of alkali to prepare 2-alkyl-2-propyl malonic diester:
R 1 ，R 2 selected from benzyl, C1-C5 straight chain alkyl or C3-C5 branched alkyl; r is R 1 And R is 2 The same or different; r is R 3 Selected from methyl, ethyl, propyl, butyl or isopropyl;
the catalyst in the catalytic dialkylation reaction consists of PTC and molecular sieve; the molecular sieve is selected from: ZSM-12, ZSM-23 zeolite molecular sieve; PTC is selected from tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), tetraethylammonium fluoride, tetraethylammonium chloride (TEAC), tetraethylammonium bromide (TEAB), tetraethylammonium iodide (TEAI), tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetrapropylammonium chloride (TPAC), tetrapropylammonium iodide (TPAI) or tetrapropylammonium bromide (TPAB);
the solvent in the dialkylation reaction is selected from THF, DMF, DEF (N, N-diethylformamide), DMC, DMSO, acetonitrile, propionitrile, butyronitrile, 1, 4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether;
the base in the dialkylation reaction is selected from: solid MOH or solid M 2 CO 3 Wherein m=na or K; the solid MOH is selected from granular or powdery MOH; solid M 2 CO 3 Selecting particles M 2 CO 3 Or in powder form M 2 CO 3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein m=na or K; powdery M 2 CO 3 Selected from 100 mesh M 2 CO 3 M of 150 meshes 2 CO 3 200 mesh M 2 CO 3 250 mesh M 2 CO 3 300 mesh M 2 CO 3 Or 350 mesh M 2 CO 3 Where m=na or K.
2. The process for the preparation of 2-alkyl-2-propylmalonic acid diester according to claim 1, wherein the 2-alkyl-2-propylmalonic acid diester of formula i is hydrolyzed to obtain 2-alkyl-2-propylmalonic acid (ii):
R 3 selected from methyl, ethyl, propyl, butyl or isopropyl.
3. The process according to claim 2, wherein 2-alkyl-2-propylmalonic acid (II) is decarboxylated to 2-alkylpentanoic acid (III):
R 3 selected from methyl, ethyl, propyl, butyl or isopropyl.
4. The process for the preparation of a 2-alkyl-2-propylmalonic acid diester according to claim 1, wherein dimethyl malonate is catalyzed by a base with 1-chloropropane (comprising 1-chlorobutane and 2-chloropropane) to obtain a 2-alkyl-2-propylmalonic acid diester of formula i-1:
R 3 selected from methyl, propyl, butyl or isopropyl; r is R 2 Selected from methyl or propyl;
the 2-alkyl-2-propylmalonic acid diester represented by I-1 is selected from the following compounds:
the catalyst, solvent and base in the dialkylation reaction are defined in claim 1.
5. The process according to claim 4, wherein dimethyl 2-alkyl-2-propylmalonate (I-1) is hydrolyzed to obtain 2-alkyl-2-propylmalonate (II):
R 3 selected from methyl, propyl, butyl or isopropyl.
6. The process according to claim 5, wherein 2-alkyl-2-propylmalonic acid (II) is decarboxylated to 2-alkylpentanoic acid (III):
R 3 selected from methyl, propyl, butyl or isopropyl; the structural formula of the compound selected from the group consisting of 2-alkyl valeric acid (III) is as follows:
2-methyl valeric acid (L), 2-propyl caproic acid (X) or 2-isopropyl valeric acid (C) are process impurities for preparing valproic acid P by a dimethyl malonate method.
7. The process for the preparation of a 2-alkyl-2-propylmalonic acid diester according to claim 1, wherein diethyl malonate is catalytically dialkylated with 1-chloropropane (containing 1-chlorobutane and 2-chloropropane) under the action of a base to give a 2-alkyl-2-propylmalonic acid diester of the formula i-2:
R 2 selected from ethyl or propyl; r is R 3 Selected from ethyl, propyl, butyl or isopropyl; the 2-alkyl-2-propylmalonic acid diester represented by I-2 is selected from the following compounds:
the catalyst, solvent and base in the dialkylation reaction are defined in claim 1.
8. The process according to claim 7, wherein the 2-alkyl-2-propylmalonic acid diester (I-2) is hydrolyzed to obtain 2-alkyl-2-propylmalonic acid (II):
R 3 selected from ethyl, propyl, butyl or isopropyl.
9. The process according to claim 8, wherein 2-alkyl-2-propylmalonic acid (II) is decarboxylated to 2-alkylpentanoic acid (III):
R 3 selected from ethyl, propyl, butyl or isopropyl; the structural formula of the compound selected from the group consisting of 2-alkyl valeric acid (III) is as follows:
2-ethyl valeric acid (B), 2-propyl caproic acid (X) or 2-isopropyl valeric acid (C) are process impurities for preparing valproic acid P by diethyl malonate method.
10. The process according to any one of claims 2, 5 and 8, wherein 2-alkyl-2-propylmalonic acid (ii) is recrystallized from an aqueous ethanol solution or an aqueous methanol solution to give dipropylmalonic acid (iia); an aqueous ethanol solution (filtrate) or an aqueous methanol solution (filtrate) recovery jacket is used for the hydrolysis of the 2-alkyl-2-propylmalonic acid diester;
decarboxylation of dipropylmalonic acid (IIa) to valproic acid (P):
the yield of valproic acid (P) is greater than 85.0% (calculated as malonic diester), and the content is greater than 99.85% (GC).
CN202311398306.2A 2023-10-26 2023-10-26 Preparation and hydrolysis method of 2-alkyl-2-propyl malonic acid diester Pending CN117430509A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202311398306.2A CN117430509A (en) 2023-10-26 2023-10-26 Preparation and hydrolysis method of 2-alkyl-2-propyl malonic acid diester

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202311398306.2A CN117430509A (en) 2023-10-26 2023-10-26 Preparation and hydrolysis method of 2-alkyl-2-propyl malonic acid diester

Publications (1)

Publication Number Publication Date
CN117430509A true CN117430509A (en) 2024-01-23

Family

ID=89552868

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202311398306.2A Pending CN117430509A (en) 2023-10-26 2023-10-26 Preparation and hydrolysis method of 2-alkyl-2-propyl malonic acid diester

Country Status (1)

Country Link
CN (1) CN117430509A (en)

Similar Documents

Publication Publication Date Title
CN114763319A (en) Method for co-producing valproamide and sodium valproate
CN108623455B (en) Intermediate of anti-heart failure medicine
CN114763328B (en) Preparation method and application of 2-cyano-2-valproic acid
CN117430509A (en) Preparation and hydrolysis method of 2-alkyl-2-propyl malonic acid diester
CN114790151B (en) Composite catalytic preparation method of 2-cyano-2-methyl valproate
JP2001081065A (en) Method for producing [bis-(trifluoromethyl)-phenyl]- acetic acid, its alkyl ester and dialkyl bis-(trifluoromethyl)-phenyl]-malonate
EP1310486A1 (en) Process for producing 5-fluorooxyindole and for producing intermediate therefor
US10562834B2 (en) Process for preparing substituted crotonic acids
JP2023532362A (en) Method for producing phenylisoxazoline compound
CN109988070B (en) Intermediate of trans-1-hydroxy-1- (trifluoromethyl) -3-aminocyclobutane hydrochloride, preparation method and application
CN116768697B (en) Method for preparing dipropylmalonic acid by using chloropropane as alkylating agent and application of dipropylmalonic acid
US20040199002A1 (en) Process for producing(2-nitrophenyl)acetonitrile derivative and intermediate therefor
KR20030005394A (en) Process for the preparation of trifluoroethoxy-substituted benzoic acids
CN111056997A (en) Synthetic method of benzamide compound
JPH10237016A (en) Production of optically active compound
CN115636764B (en) Synthesis method of benzamide compound
EP0652213B1 (en) Method for producing alkyl 3-phthalidylideneacetate
CN110862318B (en) Preparation method of tert-butyl substituted hydroxybenzoate
JP2804559B2 (en) Method for producing 2-chloro-5-chloromethylpyridine
JP2004018422A (en) Alicyclic spiro acid dianhydride and method for producing the same
CN117430527A (en) Preparation method of 2-alkyl-2-cyano valerate
JP3869531B2 (en) Production method of biphenyl derivatives
JP4030289B2 (en) Process for producing β-ketonitriles
EP2848612B1 (en) Method for producing a substituted benzoic acid compound
EP0970952B1 (en) Processes for preparing 2-omega-alkoxycarbonylalkanoyl)-4-butanolides, omega-hydroxy-omega-3)-keto fatty esters, and derivatives thereof

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