CN116730832B - Preparation method of 2-propyl caproic acid - Google Patents

Preparation method of 2-propyl caproic acid Download PDF

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CN116730832B
CN116730832B CN202310370099.3A CN202310370099A CN116730832B CN 116730832 B CN116730832 B CN 116730832B CN 202310370099 A CN202310370099 A CN 202310370099A CN 116730832 B CN116730832 B CN 116730832B
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malonate
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CN116730832A (en
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胡艾希
刘宇阳
刘晨
易阳杰
李明芳
叶姣
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Hunan University
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    • 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

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Abstract

The invention relates to a chemical structural formula II which is characterized in that malonic acid diester is firstly butylated and then propylated in a solvent under the combined action of alkali and PTC to prepare 2-propyl-2-butyl malonic acid diester shown in a formula III; 2-propyl-2-butyl malonic acid diester is hydrolyzed and decarboxylated to prepare 2-propyl caproic acid shown as II; the preparation reaction is as follows: R 1 and R 2 are each selected from: benzyl, C1-C5 straight chain alkyl or C3-C5 branched alkyl; r 1 and R 2 are the same or different; the PTC is selected from: tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide or tetrapropylammonium iodide. The 2-propylhexanoic acid is used for qualitative and quantitative analysis of impurities in a novel process for producing sodium valproate.

Description

Preparation method of 2-propyl caproic acid
Technical Field
The invention relates to a preparation method of 2-propyl hexanoic acid (II), which is a trace impurity existing in a process for preparing valproic acid by a tetrabutylammonium halide phase transfer catalysis method.
Background
The intermediate, namely the dimethyl 2-butylmalonate and the diethyl 2-butylmalonate, is widely applied to the industries of electrochemistry products, spices, medicines, pesticides and the like, and has extremely broad market prospect. 2-butyl malonate is an intermediate of phenylbutazone, an antipyretic analgesic [ Shen Xiaojuan, gu Jianbo, wu Jing, teng Fei and Chen Xuelian ] a green process for the preparation of phenylbutazone, 201810059902.0, 2020.5.8; liao Ru Er A process for synthesizing phenylbutazone intermediate diethyl butylmalonate, CN201610815932.0, 2017.2.22. Use of diethyl 2-butylmalonate in the manufacture of a medicament for the treatment of obesity is described by Xuzhou university of medical science, england et al, diethyl butylmalonate in the manufacture of a medicament for the treatment of obesity. 2-butyl diethyl malonate can reduce weight and liver weight of obese mice, prevent lipid accumulation in liver tissues, enhance fatty acid oxidation of obese mice and increase energy consumption, thereby exerting weight-reducing effect; and can improve glucose tolerance and insulin resistance, and has the effect of correcting obesity-related metabolic disorder.
Huntington et al [ Biochemistry,2000, 39:4543-4551 dimethyl malonate and 1-iodobutane were selected and under the action of sodium methoxide, dimethyl 2-butylmalonate was prepared in a yield of 62%.
Rzayev et al [ Journal of Polymer SCIENCE PART A: polymer Chemistry,2002, 44 (7): 836-843], journal et al [ Journal of THE AMERICAN CHEMICAL Society,1972, 94 (21): 7469-7479] and Okimoto et al [ Synthesis,2002, (15): 2215-2219 dimethyl malonate and 1-bromobutane were selected, and sodium methoxide was used as a base to prepare dimethyl 2-butylmalonate in a yield of 72%.
Kristina et al J Org Chem 2004, 69 (11): 3746-3752] selected dimethyl malonate and 1-bromobutane, reacted sodium hydride with dimethyl malonate in a mixed solution of anhydrous THF and DMF to give the corresponding sodium salt, which was then reacted with 1-bromobutane to give dimethyl 2-butylmalonate.
The Shanghai application technology college [ Europa. A method for preparing n-butyl dimethyl malonate ], CN201410243733.8, 2014.9.10] selects dimethyl malonate, 1-chlorobutane, alkali and a phase transfer catalyst, and the reflux reaction is carried out to prepare the 2-butyl dimethyl malonate, and the yield is 82%.
Preparation method of diethyl 2-butylmalonate by Fangfang Crystal wetting chemical Co., ltd [ Guo Xinping, N-butylmalonate, CN201610102343.8, 2016.06.08] and Sun Changjun et al (theory and practice of pharmaceutical Synthesis, chemical industry Press, P217) describe that diethyl malonate reacts with bromobutane under the action of sodium ethoxide to prepare diethyl 2-butylmalonate with the yields of 76% and 82.4%, respectively:
The research on phase transfer catalytic hydrocarbylation reaction of diethyl malonate, chemical reagent, 2001, 23 (3): 132-133, 160] of university of Zhongshan et al [ Xie Wenlin, cost honest, select diethyl malonate to be butylated under the catalysis of quaternary ammonium salt (A-1) to prepare diethyl 2-butylmalonate; the yields of diethyl 2-butylmalonate were 77.9%,92.2% and 61.5%, respectively, with n-BuCl, n-BuBr and n-BuI as the butylating agent:
in 2020, reppe et al [ Chem Commun.2020, 56 (5): 711-714] selected diethyl 2-butylmalonate as the starting material, and reacted with 1-bromopropane under the action of NaH to obtain diethyl 2-propyl-2-butylmalonate; in the presence of LiCl, diethyl 2-propyl-2-butylmalonate is subjected to ethoxycarbonyl removal to obtain ethyl 2-propylhexanoate, and then 2-propylhexanoic acid (II) is obtained through hydrolysis, and the yield is 28%.
Cabrera-Rivera et al [ Green and Sustainable Chemistry,2017,7 (4): 270-280] selecting diethyl 2-propyl malonate as a raw material, reacting with 1-bromobutane under the action of NaH to obtain diethyl 2-propyl-2-butylmalonate, hydrolyzing the obtained 2-propyl-2-butylmalonate in dimethylbenzene, adding catalytic amount of pyridine, refluxing for 2h, and decarboxylating to obtain 2-propylhexanoic acid (II) with a yield of 37%; the 2-propyl-2-butyl malonic acid is heated and decarboxylated under the radiation of 200W to obtain 2-propyl caproic acid (II), and the yield is 98%.
2-Propylhexanoic acid (II) is also a tetrabutylammonium halide phase transfer catalysis method which is jointly developed by pharmaceutical limited company in Hunan province and Hunan university and adopts cyanoacetate and 1-chloropropane as raw materials [ a preparation method and application of 2-cyano-2-valproic acid, ZL2022101320389, 2023.3.17 authorization; a compound catalytic preparation method of 2-cyano-2-methyl valproate, ZL2022101320660, 2023.3.31 authorizes the impurities existing in the new process for preparing the valproic acid. Cyanoacetate is propylated under the catalysis of tetrabutylammonium halide (n-Bu 4 NX) with minimal production of butylated by-product (I):
The propylated product is catalyzed by sulfuric acid [ Shanghai Qingping pharmaceutical Co., ltd. ] a new method for preparing valproic acid, CN2021103366414, 2021.8.3; a method for preparing sodium valproate, CN2021103339474, 2021.8.3; a method for preparing valproic acid, CN 2021103366274, 2021.7.27 is hydrolyzed, decarboxylated and the like to prepare the valproic acid:
Wherein, in the synthesis process, the butyl byproduct (I) undergoes sulfuric acid catalytic hydrolysis, decarboxylation and other reactions in the same kettle, and simultaneously a trace of 2-propyl caproic acid (II) is produced as a byproduct:
2-propylhexanoic acid is an impurity which is easy to produce in the preparation process of sodium valproate bulk drug, and plays a key role in detecting and controlling related substances in the production of sodium valproate bulk drug. The 2-propylhexanoic acid can be used for qualitative and quantitative analysis of impurities in a novel process for producing sodium valproate, so that the quality standard of sodium valproate can be improved, and the method provides assistance for safe medication.
Disclosure of Invention
The invention aims to provide a preparation method of 2-propyl caproic acid shown in a chemical structural formula II: the preparation method is characterized in that malonic acid diester is subjected to butylation and then propylation in a solvent under the combined action of alkali and PTC to prepare 2-propyl-2-butylmalonic acid diester shown in a formula III; 2-propyl-2-butyl malonic acid diester is hydrolyzed and decarboxylated to prepare 2-propyl caproic acid shown as II; the preparation reaction is as follows:
wherein R 1 and R 2 are each selected from: benzyl, C1-C5 straight chain alkyl or C3-C5 branched alkyl; r 1 and R 2 are identical or different.
The alkylated PTC is selected from: tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide or tetrapropylammonium iodide.
The catalytic amount of the alkylation PTC is selected: malonic acid diester: catalyst ptc=1:0.001 to 0.15 molar ratio.
And (3) selecting an alkylation solvent: one or two of ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, DMF, DMC or DMSO.
Alkylation K 2CO3 selection: 100 mesh K 2CO3, 150 mesh K 2CO3, 200 mesh K 2CO3, 250 mesh K 2CO3, 300 mesh K 2CO3 or 350 mesh K 2CO3.
The alkylation reaction temperature is selected: 40-130 ℃; alkylation reaction time selection: 1.0 to 12.0 hours;
The dosage of alkylation material is selected: malonic diester 1-chlorobutane=1:1-2 molar ratio; malonic diester 1-chloropropane=1:1-2 molar ratio;
the dosage of the alkylation alkali is selected: malonic acid diester, K 2CO3 =1:1 to 3.0 molar ratio.
The malonic acid diester in the alkylation is selected from: dimethyl malonate, diethyl malonate, di-n-propyl malonate, diisopropyl malonate, di-n-butyl malonate, di-t-butyl malonate, dibenzyl malonate, ethyl malonate, propyl malonate, or propyl malonate.
The second aspect of the invention provides a preparation method of 2-propyl caproic acid shown in a chemical structural formula II: the preparation method is characterized in that malonic acid diester is firstly propylated and then butylated in a solvent under the combined action of alkali and PTC to prepare 2-propyl-2-butylmalonic acid diester shown in a formula III; 2-propyl-2-butyl malonic acid diester is hydrolyzed and decarboxylated to prepare 2-propyl caproic acid shown as II; the preparation reaction is as follows:
wherein R 1 and R 2 are each selected from: benzyl, C1-C5 straight chain alkyl or C3-C5 branched alkyl; r 1 and R 2 are identical or different.
The alkylated PTC is selected from: tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide or tetrapropylammonium iodide.
The catalytic amount of the alkylation PTC is selected: malonic acid diester: catalyst ptc=1:0.001 to 0.15 molar ratio.
And (3) selecting an alkylation solvent: one or two of ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, DMF, DMC or DMSO.
Alkylation K 2CO3 selection: 100 mesh K 2CO3, 150 mesh K 2CO3, 200 mesh K 2CO3, 250 mesh K 2CO3, 300 mesh K 2CO3 or 350 mesh K 2CO3.
The alkylation reaction temperature is selected: 40-130 ℃; alkylation reaction time selection: 1.0 to 12.0 hours;
The dosage of alkylation material is selected: malonic diester 1-chlorobutane=1:1-2 molar ratio; malonic diester 1-chloropropane=1:1-2 molar ratio;
the dosage of the alkylation alkali is selected: malonic acid diester, K 2CO3 =1:1 to 3.0 molar ratio.
The malonic acid diester in the alkylation is selected from: dimethyl malonate, diethyl malonate, di-n-propyl malonate, diisopropyl malonate, di-n-butyl malonate, di-t-butyl malonate, dibenzyl malonate, ethyl malonate, propyl malonate, or propyl malonate.
The third aspect of the invention aims to provide the application of the 2-propyl caproic acid shown in the chemical structural formula II in qualitative and quantitative analysis of impurities in a novel sodium valproate production process. The 2-propylhexanoic acid is used for qualitative and quantitative analysis of impurities in a novel process for producing sodium valproate, so that the quality standard of sodium valproate can be improved, and the method provides help for safe medication.
Compared with the prior art, the invention has the following advantages:
The preparation of 2-propylhexanoic acid by a novel process of malonic acid diester phase transfer catalysis, which selects 1-chloropropane and 1-chlorobutane as alkylating agents, is carried out as follows:
Detailed Description
The present invention will be described in further detail with reference to examples.
Example 1
Preparation of 2-propylhexanoic acid (II)
(1) Preparation of diethyl 2-propyl-2-butylmalonate
0.1Mol diethyl malonate, 2.0mmol tetrapropylammonium bromide, 13.8g K 2CO3 (200 meshes), 20ml ethylene glycol dimethyl ether or ethylene glycol diethyl ether, 0.18mol 1-chloropropane and 85 ℃ are added in sequence, stirred and reacted for 4.0h, and the 1-chloropropane and diethyl malonate are recovered by rectification; 9.2g K 2CO3 and 0.16mol of 1-chlorobutane are added into the residual liquid, the mixture is stirred at 90 ℃ for reaction for 5 hours, 100ml of water is added, the solid is dissolved, petroleum ether is extracted, sodium hydroxide solution is used for washing, anhydrous sodium sulfate is used for drying, suction filtration and rotary evaporation are carried out to recover petroleum ether, and 2-propyl-2-butyl diethyl malonate (colorless liquid) is obtained by rectification and is directly used for the next hydrolysis reaction.
(2) Preparation of 2-propyl-2-butylmalonic acid
Adding potassium hydroxide aqueous solution (KOH 15g, H 2 O40 g) into the diethyl 2-propyl-2-butylmalonate obtained in the step (1), hydrolyzing 5ml of ethanol at 95 ℃ for 3h, adjusting pH1 with concentrated hydrochloric acid, extracting with ethyl acetate, washing with dilute hydrochloric acid, drying with anhydrous sodium sulfate, suction filtering, rotary steaming to obtain white solid, adding dichloromethane for dissolving, adding 5 times of petroleum ether (calculated by dichloromethane), separating out solid, suction filtering, and drying to obtain white solid 2-propyl-2-butylmalonate, wherein mp.147-149 ℃; directly used for the next decarboxylation reaction.
1H NMR(DMSO-d6,400MHz)δ：0.88(t,J＝6.8Hz,3H,CH3),0.89(t,J＝6.8Hz,3H,CH3),1.08～1.17(m,4H,CH2CH2),1.26～1.32(m,2H,CH2),1.69～1.75(m,4H,CH2×2),12.61(s,2H,CO2H).
(3) Preparation of 2-propylhexanoic acid
The 2-propyl-2-butyl malonic acid obtained in the step (2) is heated to 180 ℃ and decarboxylated for 2 hours, and 2-propyl caproic acid (II) is obtained by rectification, and the yield is 83.0 percent (calculated by diethyl malonate).
1H NMR(DMSO-d6,400MHz)δ：0.87(t,J＝7.6Hz,6H,CH3+CH3),1.21～1.26(m,6H,CH2+CH2CH2),1.28～1.36(m,2H,CH2),1.41～1.53(m,2H,CH2),2.20～2.23(m,1H,CH),12.14(bs,1H,CO2H).
Example 2
Preparation of 2-propylhexanoic acid (II)
(1) Preparation of diethyl 2-propyl-2-butylmalonate
0.1Mol diethyl malonate, 3.0mmol tetrabutylammonium bromide, 13.8g K 2CO3 (100 meshes) and 5g potassium bromide are sequentially added, 20ml ethylene glycol dimethyl ether, 0.16mol 1-chlorobutane and stirred at 85 ℃ for 3.5 hours, and 1-chlorobutane and diethyl malonate are recovered by rectification; adding 9.3g K 2CO3 and 0.18mol of 1-chloropropane into the residual liquid, and stirring at 95 ℃ for reaction for 5.5 hours; adding 100ml of water, dissolving the solid, extracting with petroleum ether, washing with sodium hydroxide solution, drying with anhydrous sodium sulfate, suction filtering, recovering petroleum ether by rotary evaporation, and rectifying to obtain diethyl 2-propyl-2-butylmalonate (colorless liquid) which is directly used for the next hydrolysis reaction.
(2) Preparation of 2-propyl-2-butylmalonic acid
Adding potassium hydroxide aqueous solution (KOH 15g, H 2 O40 g) into the diethyl 2-propyl-2-butylmalonate obtained in the step (1), hydrolyzing 5ml of ethanol at 95 ℃ for 3h, adjusting pH1 with concentrated hydrochloric acid, extracting with ethyl acetate, washing with dilute hydrochloric acid, drying with anhydrous sodium sulfate, suction filtering, rotary steaming to obtain white solid, adding dichloromethane for dissolving, adding 5 times of petroleum ether (calculated by dichloromethane), separating out solid, suction filtering, and drying to obtain white solid 2-propyl-2-butylmalonate, wherein mp.147-149 ℃; directly used for the next decarboxylation reaction.
1H NMR(DMSO-d6,400MHz)δ：0.88(t,J＝6.8Hz,3H,CH3),0.89(t,J＝6.8Hz,3H,CH3),1.08～1.17(m,4H,CH2CH2),1.26～1.32(m,2H,CH2),1.69～1.75(m,4H,CH2×2),12.61(s,2H,CO2H).
(3) Preparation of 2-propylhexanoic acid
The 2-propyl-2-butyl malonic acid obtained in the step (2) is heated to 175-185 ℃ and decarboxylated for 2 hours, and 2-propyl caproic acid (II) is obtained by rectification, and the yield is 84.0 percent (calculated by diethyl malonate).
1H NMR(DMSO-d6,400MHz)δ：0.87(t,J＝7.6Hz,6H,CH3+CH3),1.21～1.26(m,6H,CH2+CH2CH2),1.28～1.36(m,2H,CH2),1.41～1.53(m,2H,CH2),2.20～2.23(m,1H,CH),12.14(bs,1H,CO2H).
Example 3
Preparation of 2-propylhexanoic acid (II)
(1) 0.1Mol of dimethyl malonate, 3.0mmol of tetrabutylammonium chloride, 13.0g of K 2CO3 (100 meshes) and 8g of potassium bromide are sequentially added, 20ml DMF,0.17mol1-chlorobutane are stirred at 90 ℃ for reaction for 3.5 hours, and 1-chlorobutane and dimethyl malonate are recovered by rectification; 9.2g K 2CO3 and 0.18mol of 1-chloropropane are added into the residual liquid, the mixture is stirred at 100 ℃ for reaction for 4 hours, 100ml of water is added, the solid is dissolved, petroleum ether is extracted, sodium hydroxide solution is used for washing, anhydrous sodium sulfate is used for drying, suction filtration and rotary evaporation are carried out to recover petroleum ether, and 2-propyl-2-butyl dimethyl malonate (colorless liquid) is prepared by rectification and is directly used for the next hydrolysis reaction.
(2) Preparation of 2-propyl-2-butylmalonic acid
Adding potassium hydroxide aqueous solution (KOH 15g, H 2 O40 g) into the dimethyl 2-propyl-2-butylmalonate obtained in the step (1), hydrolyzing 5ml of ethanol at 100 ℃ for 3h, adjusting pH1 with concentrated hydrochloric acid, extracting with ethyl acetate, washing with dilute hydrochloric acid, drying with anhydrous sodium sulfate, carrying out suction filtration, carrying out rotary evaporation to obtain white solid, adding dichloromethane for dissolving, adding 5 times of petroleum ether, precipitating solid, carrying out suction filtration, and drying to obtain white solid 2-propyl-2-butylmalonate, wherein the temperature is mp.147-149 ℃; directly used for the next decarboxylation reaction.
1H NMR(DMSO-d6,400MHz)δ：0.88(t,J＝6.8Hz,3H,CH3),0.89(t,J＝6.8Hz,3H,CH3),1.08～1.17(m,4H,CH2CH2),1.26～1.32(m,2H,CH2),1.69～1.75(m,4H,CH2×2),12.61(s,2H,CO2H).
(3) Preparation of 2-propylhexanoic acid
The 2-propyl-2-butyl malonic acid obtained in the step (2) is heated to 180 ℃ and decarboxylated for 2 hours, and 2-propyl caproic acid (II) is obtained by rectification, and the yield is 85.0 percent (calculated by dimethyl malonate).
1H NMR(DMSO-d6,400MHz)δ：0.87(t,J＝7.6Hz,6H,CH3+CH3),1.21～1.26(m,6H,CH2+CH2CH2),1.28～1.36(m,2H,CH2),1.41～1.53(m,2H,CH2),2.20～2.23(m,1H,CH),12.14(bs,1H,CO2H).
Example 4 (control)
Preparation of dimethyl 2-butylmalonate
The preparation is carried out as described in example 1 of the description of patent application at the Shanghai institute of technology [ European bloom. A process for the preparation of dimethyl n-butylmalonate, CN201410243733.8, 2014.9.10 ]: 264.22g (227.78 ml,2.0 mol) of dimethyl malonate, 231.43g (260.03 ml,2.5 mol) of 1-chlorobutane, 131.29g (0.95 mol) of anhydrous potassium carbonate powder, 438.55g (464.4 ml,6.0 mol) of DMF were added to a three-necked flask, equipped with a condensing reflux device, a thermometer, and heated and stirred at a reaction temperature of 110 to 120 ℃. After 2 hours of reaction, 185.14g (208.02 ml,2.0 mol) of 1-chlorobutane was added to the reaction mixture. Reflux was continued for 3h, and 2.58g (0.008 mol) of tetrabutylammonium bromide was slowly added over 0.5 h. After the addition of the phase transfer catalyst, the reaction was continued and followed by GC analysis, when the conversion of dimethyl malonate could reach 90% (GC analysis after about 6 hours). Distilling out 1-chlorobutane from the reaction mixture at 110-120 ℃, cooling, filtering, distilling out unreacted dimethyl malonate and solvent from the filtrate under reduced pressure, and collecting 2-butyl dimethyl malonate distilled out under the condition of 110 ℃/8mmHg, wherein the purity can reach more than 99%, and the yield is 82.0%.
1H NMR(200MHz,CDCl3)δ：3.71(s,6H,OCH3),3.34(t,J＝7.5Hz,1H,CH),1.80～1.97(m,2H,CH2),1.15～1.45(m,4H,CH2CH2),0.87(t,J＝7.2Hz,3H,CH3).
Example 5 (control)
Preparation of diethyl 2-butylmalonate
The preparation is carried out according to the method described in Zhongshan university et al [ Xie Wenlin, cost honest, phase transfer catalytic hydrocarbylation reaction of diethyl malonate, chemical reagent, 2001, 23 (3): 132-133, 160 ]. Into a 125mL three-necked flask were charged 19mL (0.125 mol) of diethyl malonate, 16.1mL (0.15 mol) of 1-bromobutane, 22.5g (0.1625 mol) of anhydrous K 2CO3 and 1.72g (3.75 mmol) of A-1 (quaternary ammonium salt), and the mixture was refluxed for 2 hours. Cooling, adding distilled water until K 2CO3 is completely dissolved. Layering, adding 36% hydrochloric acid into the organic layer to pH 5-7. Then, the mixture was washed with saturated brine (20 mL. Times.2). The organic layer was separated, dried over anhydrous MgSO 4, filtered, distilled at atmospheric pressure, and excess 1-BuBr recovered; and collecting 115-120 ℃/15mmHg distillate (diethyl 2-butylmalonate) by distillation, wherein the yield is 92.2 percent and the content is 90 percent. 1-chlorobutane was used in place of 1-bromobutane and diethyl 2-butylmalonate was obtained in 77.9% yield.
1H NMR(400MHz,CDCl3)δ：0.91(t,J＝7.2Hz,3H,CH3),1.27(t,J＝7.2Hz,6H,CH3×2),1.32～1.39(m,4H,CH2CH2),1.89(sext,J＝7.2Hz,7.2Hz,2H,3-CH2),3.32(t,J＝7.2Hz,1H,CH),4.20(q,J＝7.2Hz,4H,OCH2×2).
Example 6 (control)
Preparation of 2-propylhexanoic acid
Prepared as described in [ Chem Commun.2020, 56 (5): 711-714 ]: under the action of 1.4g of NaH, 5.0g of diethyl 2-butylmalonate reacts with 4.3g of 1-bromopropane to obtain diethyl 2-propyl-2-butylmalonate; liCl (3 eq) and H 2 O (1 eq) are then added into DMSO to react, and the mixture is purified by column chromatography (eluent: CHCl 3/hexane 1/1, V/V) to obtain ethyl 2-propylhexanoate; adding 0.1g/mL sodium hydroxide aqueous solution and ethanol, and acidifying with concentrated hydrochloric acid; finally, diethyl ether was used for extraction, and rotary evaporation gave 1.0g of 2-propylhexanoic acid in 28.0% yield.
1H NMR(CDCl3,400MHz)δ：0.88(t,J＝7.2Hz,3H,CH3),0.92(t,J＝7.2Hz,3H,CH3),1.25～1.37(m,6H,CH2+CH2CH2),1.38～1.48(m,2H,CH2),1.55～1.64(m,2H,CH2),2.30～2.37(m,1H,CH),11.4(bs,1H,CO2H).
Example 8
Application of 2-propylhexanoic acid
The 2-propylhexanoic acid is used for qualitative and quantitative analysis of impurities in a novel process for producing sodium valproate, so that the quality standard of sodium valproate can be improved, and the method provides help for safe medication.
In this specification, the invention has been described with reference to specific embodiments thereof. It will be apparent that various modifications and variations can 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 (9)

1. The preparation method of 2-propyl hexanoic acid shown in chemical structural formula II is characterized in that malonic acid diester is firstly propylated and then butylated in solvent under the combined action of alkali and PTC to prepare 2-propyl-2-butyl malonic acid diester shown in formula III; 2-propyl-2-butyl malonic acid diester is hydrolyzed and decarboxylated to prepare 2-propyl caproic acid shown as II; the preparation reaction is as follows:
R 1 and R 2 are each selected from: C1-C5 straight chain alkyl or C3-C5 branched alkyl; r 1 and R 2 are the same or different;
the alkylated PTC is selected from: tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide or tetrapropylammonium iodide;
And (3) selecting an alkylation solvent: one or two of ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, DMF, DMC or DMSO;
Alkylation K 2CO3 selection: 100 mesh K 2CO3, 150 mesh K 2CO3, 200 mesh K 2CO3, 250 mesh K 2CO3, 300 mesh K 2CO3 or 350 mesh K 2CO3;
the alkylation reaction temperature is selected: the alkylation reaction time is 1.0h to 12.0h at the temperature of 40 ℃ to 130 ℃.
2. The method for preparing 2-propylhexanoic acid according to claim 1, wherein the dosage is selected from the group consisting of: malonic diester 1-chloropropane=1:1-2 molar ratio.
3. The method for preparing 2-propylhexanoic acid according to claim 1, wherein the dosage is selected from the group consisting of: malonic diester 1-chlorobutane=1:1-2 molar ratio.
4. The method for preparing 2-propylhexanoic acid according to claim 1, wherein the amount of PTC is selected from the group consisting of: malonic acid diester: ptc=1:0.001 to 0.15 molar ratio.
5. The process for preparing 2-propylhexanoic acid according to claim 1, wherein the amount of the base is selected from the group consisting of: malonic acid diester, K 2CO3 =1:1 to 3.0 molar ratio.
6. The process for preparing 2-propylhexanoic acid as claimed in claim 1, wherein malonic acid diester is selected from the group consisting of: dimethyl malonate, diethyl malonate, di-n-propyl malonate, diisopropyl malonate, di-n-butyl malonate, di-t-butyl malonate, ethyl methyl malonate, propyl ethyl malonate, or propyl methyl malonate.
7. The process for preparing 2-propylhexanoic acid as claimed in claim 1, wherein malonic acid diester is selected from the group consisting of: dimethyl malonate or diethyl malonate.
8. The preparation method of the 2-propyl caproic acid shown in the chemical structural formula II is characterized by comprising the following preparation reaction:
(1) Preparation of diethyl 2-propyl-2-butylmalonate
0.1Mol diethyl malonate, 3.0mmol tetrabutylammonium bromide, 13.8g 100 mesh K 2CO3 g potassium bromide, 20ml ethylene glycol dimethyl ether, 0.16mol 1-chlorobutane and 85 ℃ are added in sequence to react for 3.5 hours under stirring, and 1-chlorobutane and diethyl malonate are recovered by rectification; adding 9.3g K 2CO3 and 0.18mol of 1-chloropropane into the residual liquid, and stirring at 95 ℃ for reaction for 5.5 hours; adding 100ml of water, dissolving the solid, extracting with petroleum ether, washing with sodium hydroxide solution, drying with anhydrous sodium sulfate, filtering, recovering petroleum ether by rotary evaporation, and rectifying to obtain colorless liquid diethyl 2-propyl-2-butylmalonate, which is directly used for the next hydrolysis reaction;
(2) Preparation of 2-propyl-2-butylmalonic acid
Adding 15g KOH and 40g H 2 O potassium hydroxide aqueous solution into the 2-propyl-2-butyl diethyl malonate obtained in the step (1), hydrolyzing for 3h at 95 ℃ with 5ml ethanol, adjusting pH with concentrated hydrochloric acid, extracting with ethyl acetate, washing with dilute hydrochloric acid, drying with anhydrous sodium sulfate, suction filtering, rotary steaming to obtain white solid, adding dichloromethane to dissolve, adding 5 times of dichloromethane petroleum ether to precipitate solid, suction filtering, and drying to obtain white solid 2-propyl-2-butyl malonic acid, wherein mp.147 ℃ to 149 ℃; directly used for the next decarboxylation reaction;
(3) Preparation of 2-propylhexanoic acid
And (2) heating the 2-propyl-2-butyl malonic acid obtained in the step (2) to 175-185 ℃, decarboxylating for 2 hours, and rectifying to obtain the 2-propyl hexanoic acid shown in the formula II, wherein the total yield is 84.0%.
9. The preparation method of the 2-propyl caproic acid shown in the chemical structural formula II is characterized by comprising the following preparation reaction:
(1) 0.1mol of dimethyl malonate, 3.0mmol of tetrabutylammonium chloride, 13.0g of 100-mesh K 2CO3 and 8g of potassium bromide are sequentially added, 20ml DMF,0.17mol 1-chlorobutane is stirred at 90 ℃ for reaction for 3.5 hours, and 1-chlorobutane and dimethyl malonate are recovered by rectification; adding 9.2g of K 2CO3 and 0.18mol of 1-chloropropane into the residual liquid, stirring at 100 ℃ for reaction for 4 hours, adding 100ml of water, dissolving solids, extracting petroleum ether, washing with sodium hydroxide solution, drying with anhydrous sodium sulfate, filtering, recycling petroleum ether by rotary evaporation, rectifying to obtain colorless liquid, namely 2-propyl-2-butyl dimethyl malonate, and directly using the colorless liquid in the next hydrolysis reaction;
(2) Preparation of 2-propyl-2-butylmalonic acid
Adding 15g KOH and 40g H 2 O potassium hydroxide aqueous solution into the 2-propyl-2-butyl dimethyl malonate obtained in the step (1), hydrolyzing for 3h at 100 ℃, adjusting pH to 1 with concentrated hydrochloric acid, extracting with ethyl acetate, washing with dilute hydrochloric acid, drying with anhydrous sodium sulfate, suction filtering, rotary steaming to obtain white solid, adding dichloromethane for dissolving, adding 5 times of petroleum ether, precipitating solid, suction filtering, and drying to obtain white solid 2-propyl-2-butyl malonic acid, wherein mp.147-149 ℃; directly used for the next decarboxylation reaction;
(3) Preparation of 2-propylhexanoic acid
And (2) heating the 2-propyl-2-butylmalonic acid obtained in the step (2) to 180 ℃, decarboxylating for 2 hours, and rectifying to obtain the 2-propylhexanoic acid shown in the formula II, wherein the total yield is 85.0%.
CN202310370099.3A 2023-04-10 2023-04-10 Preparation method of 2-propyl caproic acid Active CN116730832B (en)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
CN103183612A (en) * 2011-12-30 2013-07-03 北大方正集团有限公司 Dipropylmalonic acid diester preparation method
CN104030922A (en) * 2014-06-04 2014-09-10 上海应用技术学院 Method for preparing dimethyl n-butyl malonate
CN114763319A (en) * 2022-05-16 2022-07-19 湖南大学 Method for co-producing valproamide and sodium valproate

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Publication number Priority date Publication date Assignee Title
CN103183612A (en) * 2011-12-30 2013-07-03 北大方正集团有限公司 Dipropylmalonic acid diester preparation method
CN104030922A (en) * 2014-06-04 2014-09-10 上海应用技术学院 Method for preparing dimethyl n-butyl malonate
CN114763319A (en) * 2022-05-16 2022-07-19 湖南大学 Method for co-producing valproamide and sodium valproate

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