CN115477593B - Synthesis method of cooling agent N,2, 3-trimethyl-2-isopropyl butyramide - Google Patents
Synthesis method of cooling agent N,2, 3-trimethyl-2-isopropyl butyramide Download PDFInfo
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- 239000002826 coolant Substances 0.000 title claims abstract description 19
- 238000001308 synthesis method Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- 239000011259 mixed solution Substances 0.000 claims abstract description 57
- 239000000243 solution Substances 0.000 claims abstract description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 39
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 30
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 16
- 235000019270 ammonium chloride Nutrition 0.000 claims abstract description 13
- 238000004817 gas chromatography Methods 0.000 claims abstract description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 13
- 238000010791 quenching Methods 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 230000035484 reaction time Effects 0.000 claims abstract description 8
- -1 N-methylpropanamide-tetrahydrofuran Chemical compound 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 230000000171 quenching effect Effects 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 claims description 14
- QJQAMHYHNCADNR-UHFFFAOYSA-N n-methylpropanamide Chemical compound CCC(=O)NC QJQAMHYHNCADNR-UHFFFAOYSA-N 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 11
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- 239000003929 acidic solution Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- RWAXQWRDVUOOGG-UHFFFAOYSA-N N,2,3-Trimethyl-2-(1-methylethyl)butanamide Chemical compound CNC(=O)C(C)(C(C)C)C(C)C RWAXQWRDVUOOGG-UHFFFAOYSA-N 0.000 abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 231100000086 high toxicity Toxicity 0.000 abstract description 2
- 238000007344 nucleophilic reaction Methods 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 22
- 238000000605 extraction Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- ZMRCOHMOBLASFC-UHFFFAOYSA-N 2,3-dimethylbutanenitrile Chemical compound CC(C)C(C)C#N ZMRCOHMOBLASFC-UHFFFAOYSA-N 0.000 description 2
- YLJJHNOCQAERGL-UHFFFAOYSA-N 4-methyl-3-propan-2-ylpentan-2-one Chemical compound CC(C)C(C(C)C)C(C)=O YLJJHNOCQAERGL-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 238000006237 Beckmann rearrangement reaction Methods 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- OWEMTCOXFULTNW-UHFFFAOYSA-N 2,3-dimethyl-2-propan-2-ylbutanoic acid Chemical compound CC(C)C(C)(C(C)C)C(O)=O OWEMTCOXFULTNW-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 231100000862 numbness Toxicity 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
Abstract
The invention relates to a synthesis method of a cooling agent N,2, 3-trimethyl-2-isopropyl butyramide, which comprises the following specific steps: n-butyllithium is dropwise added into the N-methylpropanamide-tetrahydrofuran mixed solution under the protection of nitrogen at the temperature of-40 to-60 ℃ to react for 0.5 to 1 hour at the same temperature, so as to obtain a mixed solution A; adding a 2-bromopropane-tetrahydrofuran mixed solution into the mixed solution A obtained in the step 1, and performing a reaction at the same temperature for 1-1.5 hours to obtain a mixed solution B; and after the reaction is detected by utilizing gas chromatography, adding an ammonium chloride solution into the mixed solution B for quenching reaction, adding an acid solution to adjust the pH to 6-7, extracting by ethyl acetate, and removing the solvent under reduced pressure to obtain the target product. The invention replaces the Litt reaction with the carbanion nucleophilic reaction to prepare WS-23, and simultaneously avoids the complex steps of the traditional preparation method and the influence of high pollution and high toxicity on safety and environment caused by reagents, simplifies the post-treatment procedure, shortens the reaction time and improves the purity of the product.
Description
Technical Field
The invention relates to the technical field of synthesis of cooling agents, in particular to a synthesis method of cooling agent N,2, 3-trimethyl-2-isopropyl butyramide with short synthesis reaction time, high purity and high recovery rate.
Background
The cooling agent WS-23 has the chemical name: n,2, 3-trimethyl-2-isopropyl butyramide has a molecular formula: c (C) 10 H 21 NO, molecular weight: 171.16, cas number: 51115-67-4 is a non-menthol amide type cooling agent with very wide application, has higher cooling activity without side effects such as burning, numbness and irritation, and is mainly used as a cooling agent in candy, oral care and medicine. The known synthesis method of WS-23 is to react propionitrile with 2-bromopropane at alpha carbon position, and react nitrile alcoholysis or acyl hydrogenation with monomethylamine to obtain N,2, 3-trimethylAnd (3) base-2-isopropyl butyramide.
Wherein patent US4230688 takes 2, 2-isopropyl propionitrile (DIPPN) as a starting material, firstly hydrolyzes to generate diisopropyl propionic acid, then reacts with thionyl chloride to generate corresponding acyl chloride, and finally reacts with methylamine to prepare WS-23. The process has the defects of more three wastes, poor safety, longer synthesis steps and complex operation, and has certain requirements on large-scale industrial production devices.
Patent US6482983 uses 2, 2-isopropyl propionitrile (DIPPN) as a starting material and uses concentrated sulfuric acid or chlorosulfonic acid as a catalyst to react with methanol in one step to obtain WS-23. The reaction uses methanol as an N-alkylating reagent, the methanol is used as primary alcohol, the stability of carbocation is low, the reaction time is long, the purity of a product is low, and a large amount of neutralized brine is generated in the post-treatment process of concentrated acid.
The Chinese patent No. CN107954888A discloses a method for synthesizing a cooling agent N,2, 3-trimethyl-2-isopropyl butyramide, which comprises the following steps: (1) Methyl acetoacetate reacts with 2-bromopropane under the condition of strong alkali to obtain 3, 3-diisopropyl methyl acetoacetate; (2) The obtained 3, 3-diisopropyl acetoacetic acid methyl ester reacts with ethylene glycol to protect ketocarbonyl, then ester is hydrolyzed into hydroxyl under the action of a reducing agent, then the hydroxyl reacts with p-toluenesulfonyl chloride, and p-toluenesulfonate is removed to obtain 3-isopropyl-4-methyl-2-pentanone; (3) 3-isopropyl-4-methyl-2-pentanone is reacted with hydroxylamine hydrochloride and then subjected to Beckmann rearrangement under acid conditions to obtain N,2, 3-trimethyl-2-isopropyl butyramide. The method for synthesizing the cooling agent in multiple steps is adopted, but a large amount of strong acid, corrosive byproducts and the like are generated through Beckmann rearrangement and other steps in the synthesis process, so that the problems of environmental pollution, equipment corrosion and the like are caused.
Disclosure of Invention
First, problems to be solved
In order to solve the problems, the invention provides a synthesis method of a cooling agent N,2, 3-trimethyl-2-isopropyl butyramide, which aims to solve the problems of complex synthesis process steps, low product purity, large pollution of post-treatment pollution byproducts and the like of the existing cooling agent, and solves the defects in the prior art.
(II) technical scheme
The invention provides a synthesis method of WS-23 (N-2, 3-trimethyl-2-isopropyl butyramide), which comprises the following specific preparation steps:
(1) N-butyllithium is dropwise added into the N-methylpropanamide-tetrahydrofuran mixed solution under the protection of nitrogen at the temperature of-40 ℃ to-60 ℃ to react for 0.5 to 1 hour at the same temperature, so as to obtain a mixed solution A;
(2) Adding a 2-bromopropane-tetrahydrofuran mixed solution into the mixed solution A obtained in the step 1, and performing a reaction at the same temperature for 1-1.5 hours to obtain a mixed solution B;
(3) And after the reaction is detected by utilizing gas chromatography, adding an ammonium chloride solution into the mixed solution B for quenching reaction, adding an acid solution to adjust the pH to 6-7, extracting by ethyl acetate, and removing the solvent under reduced pressure to obtain the target product.
As a further improvement of the invention, the mass ratio of the materials is N-methylpropionamide: 2-bromopropane: n-butyllithium=1: 2:3-3.05.
As a further improvement of the present invention, the reaction temperature maintained during the preparation is-40 ℃. A step of
As a further improvement of the present invention, the reaction time in the step (1) is 1 hour.
As a further improvement of the present invention, the reaction time in the step (2) is 1 hour.
As a further improvement of the present invention, the pH is adjusted to 7 in the step (3).
As a further improvement of the present invention, the acidic solution in the step (3) is one or a mixture of hydrochloric acid and sulfuric acid.
The synthetic process route diagram of the invention is as follows:
(III) beneficial effects
Compared with the prior art, the invention has the beneficial effects that: the invention replaces the Litt reaction with the carbanion nucleophilic reaction to prepare WS-23, and simultaneously avoids the complex steps of the traditional preparation method and the influence of high pollution and high toxicity on safety and environment caused by reagents, simplifies the post-treatment procedure, shortens the reaction time and improves the purity of the product.
Drawings
FIG. 1 is a gas chromatogram of a mixed solution B according to the first embodiment of the present invention.
Detailed Description
For a clearer understanding of technical features, objects and effects of the present invention, a specific embodiment of the present invention will be described with reference to the accompanying drawings, but the scope of the present invention is not limited to the following.
Example 1
Referring to the gas chromatogram of the mixed solution B of fig. 1.
(1) 1mol of N-methylpropanamide (87.12 g) is added into a dry three-necked flask at the temperature of-40 ℃, 600ml of dry tetrahydrofuran solution is added into the mixture solution of the two under the protection of nitrogen, 1.2L of N-butyllithium (2.5 mol/L) is added dropwise into the mixture solution, and the mixture solution is reacted at the same temperature for 1 hour after the dropwise addition to obtain a mixed solution A;
(2) Adding 2mol of 2-bromopropane (243 g) -tetrahydrofuran mixed solution into the mixed solution A obtained in the step 1, and carrying out a reaction at the same temperature for 1 hour to obtain a mixed solution B;
(3) After the reaction was completed by gas chromatography, 1.5L of ammonium chloride solution (1 mol/L) was added to the mixed solution B to quench the reaction, hydrochloric acid solution (1 mol/L) was added to adjust the pH of the reaction system to 7, followed by extraction with 3L of ethyl acetate, and the solvent was removed under reduced pressure to give 163g of a white solid, with a yield of 95% and a purity of 97%.
Example two
(1) 2mol of N-methylpropanamide (174.24 g) is added into a dry three-necked flask at the temperature of minus 40 ℃, 1300ml of dry tetrahydrofuran solution is added into the reaction system dropwise with 2.4L of N-butyllithium (2.5 mol/L) under the protection of nitrogen, and the mixture solution A is obtained after the dropwise reaction at the same temperature for 1 hour;
(2) Adding 4mol of 2-bromopropane (486 g) -tetrahydrofuran mixed solution into the mixed solution A obtained in the step (1), and performing a isothermal reaction for 1.5 hours;
(3) After the reaction was completed by gas chromatography, 3L of ammonium chloride solution (1 mol/L) was added to the reaction system to quench the reaction, hydrochloric acid solution (2 mol/L) was added to adjust the pH of the reaction system to 7, followed by extraction with 6L of ethyl acetate, and the solvent was removed under reduced pressure to obtain 327g of a white solid, with a yield of 95% and a purity of 97%.
Example III
(1) 1mol of N-methylpropanamide (87.12 g) is added into a dry three-necked flask at the temperature of-50 ℃, 600ml of dry tetrahydrofuran solution is added into the mixture solution of the two under the protection of nitrogen, 1.2L of N-butyllithium (2.5 mol/L) is added dropwise into the mixture solution, and the mixture solution is reacted at the same temperature for 1 hour after the dropwise addition to obtain a mixed solution A;
(2) Adding 2mol of 2-bromopropane (243 g) -tetrahydrofuran mixed solution into the mixed solution A obtained in the step 1, and carrying out a isothermal reaction for 1.5 hours to obtain a mixed solution B;
(3) After the reaction was completed by gas chromatography, 1.5L of an ammonium chloride solution (1 mol/L) was added to the mixed solution B to quench the reaction, a hydrochloric acid solution (1.5 mol/L) was added to adjust the pH of the reaction system to 7, followed by extraction with 3L of ethyl acetate, and the solvent was removed under reduced pressure to give 156g of a white solid, with a yield of 93% and a purity of 95%.
Example IV
(1) 2mol of N-methylpropanamide (174.24 g) is added into a dry three-necked flask at the temperature of minus 60 ℃, 1300ml of dry tetrahydrofuran solution is added into the reaction system dropwise with 2.4L of N-butyllithium (2.5 mol/L) under the protection of nitrogen, and the mixture solution A is obtained after the dropwise reaction at the same temperature for 1 hour;
(2) Adding 4mol of 2-bromopropane (486 g) -tetrahydrofuran mixed solution into the mixed solution A obtained in the step (1), and performing a isothermal reaction for 1.5 hours;
(3) After the reaction was completed by gas chromatography, 3L of ammonium chloride solution (1 mol/L) was added to the reaction system to quench the reaction, hydrochloric acid solution (2 mol/L) was added to adjust the pH of the reaction system to 7, followed by extraction with 6L of ethyl acetate, and the solvent was removed under reduced pressure to obtain 300g of a white solid, yield 92% and purity 94%.
Example five
(1) 2mol of N-methylpropanamide (174.24 g) is added into a dry three-necked flask at the temperature of minus 40 ℃, 1300ml of dry tetrahydrofuran solution is added into the reaction system dropwise with 2.44L of N-butyllithium (2.5 mol/L) under the protection of nitrogen, and the mixture solution A is obtained after the dropwise reaction at the same temperature for 1 hour;
(2) Adding 4mol of 2-bromopropane (486 g) -tetrahydrofuran mixed solution into the mixed solution A obtained in the step (1), and performing a reaction at the same temperature for 1 hour;
(3) After the reaction was completed by gas chromatography, 3L of ammonium chloride solution (1 mol/L) was added to the reaction system to quench the reaction, hydrochloric acid solution (2 mol/L) was added to adjust the pH of the reaction system to 7, followed by extraction with 6L of ethyl acetate, and the solvent was removed under reduced pressure to obtain 325g of a white solid, with a yield of 94% and a purity of 97%.
Example six
(1) 1mol of N-methylpropanamide (87.12 g) is added into a dry three-necked flask at the temperature of minus 60 ℃, 600ml of dry tetrahydrofuran solution is added into the mixture solution of the two under the protection of nitrogen, 1.22L of N-butyllithium (2.5 mol/L) is added dropwise, and the mixture solution A is obtained after the reaction at the same temperature for 1 hour;
(2) Adding 2mol of 2-bromopropane (243 g) -tetrahydrofuran mixed solution into the mixed solution A obtained in the step 1, and carrying out a isothermal reaction for 1.5 hours to obtain a mixed solution B;
(3) After the reaction was completed by gas chromatography, 1.5L of ammonium chloride solution (1 mol/L) was added to the mixed solution B to quench the reaction, hydrochloric acid solution (1 mol/L) was added to adjust the pH of the reaction system to 7, followed by extraction with 3L of ethyl acetate, and the solvent was removed under reduced pressure to give 160g of a white solid with a yield of 94% and a purity of 95%.
Example seven
(1) 2mol of N-methylpropanamide (174.24 g) is added into a dry three-necked flask at the temperature of minus 40 ℃, 1300ml of dry tetrahydrofuran solution is added into the reaction system dropwise with 2.4L of N-butyllithium (2.5 mol/L) under the protection of nitrogen, and the mixture solution A is obtained after the dropwise reaction at the same temperature for 0.5 hour;
(2) Adding 4mol of 2-bromopropane (486 g) -tetrahydrofuran mixed solution into the mixed solution A obtained in the step (1), and performing a isothermal reaction for 1.5 hours;
(3) After the reaction was completed by gas chromatography, 3L of ammonium chloride solution (1 mol/L) was added to the reaction system to quench the reaction, hydrochloric acid solution (2 mol/L) was added to adjust the pH of the reaction system to 7, followed by extraction with 6L of ethyl acetate, and the solvent was removed under reduced pressure to obtain 320g of a white solid, with a yield of 93% and a purity of 95%.
Example eight
(1) 1mol of N-methylpropanamide (87.12 g) is added into a dry three-necked flask at the temperature of-50 ℃, 600ml of dry tetrahydrofuran solution is added into the mixture solution of the two under the protection of nitrogen, 1.22L of N-butyllithium (2.5 mol/L) is added dropwise into the mixture solution, and the mixture solution is reacted at the same temperature for 1 hour after the dropwise addition to obtain a mixed solution A;
(2) Adding 2mol of 2-bromopropane (243 g) -tetrahydrofuran mixed solution into the mixed solution A obtained in the step 1, and carrying out a reaction at the same temperature for 1 hour to obtain a mixed solution B;
(3) After the reaction was completed by gas chromatography, 1.5L of ammonium chloride solution (1 mol/L) was added to the mixed solution B to quench the reaction, a diluted sulfuric acid solution (1 mol/L) was added to adjust the pH of the reaction system to 7, followed by extraction with 3L of ethyl acetate, and the solvent was removed under reduced pressure to give 160g of a white solid with a yield of 94% and a purity of 96%.
Example nine
(1) 1mol of N-methylpropanamide (87.12 g) is added into a dry three-necked flask at the temperature of-40 ℃, 600ml of dry tetrahydrofuran solution is added into the mixture solution of the two under the protection of nitrogen, 1.2L of N-butyllithium (2.5 mol/L) is added dropwise into the mixture solution, and the mixture solution is reacted at the same temperature for 1 hour after the dropwise addition to obtain a mixed solution A;
(2) Adding 2mol of 2-bromopropane (243 g) -tetrahydrofuran mixed solution into the mixed solution A obtained in the step 1, and carrying out a reaction at the same temperature for 1 hour to obtain a mixed solution B;
(3) After the reaction was completed by gas chromatography, 1.5L of ammonium chloride solution (1 mol/L) was added to the mixed solution B to quench the reaction, a diluted sulfuric acid solution (1 mol/L) was added to adjust the pH of the reaction system to 6.5, followed by extraction with 3L of ethyl acetate, and the solvent was removed under reduced pressure to obtain 158g of a white solid with a yield of 94% and a purity of 96%.
Examples ten
(1) 1mol of N-methylpropanamide (87.12 g) is added into a dry three-necked flask at the temperature of-50 ℃, 600ml of dry tetrahydrofuran solution is added into the mixture solution of the two under the protection of nitrogen, 1.22L of N-butyllithium (2.5 mol/L) is added dropwise into the mixture solution, and the mixture solution is reacted at the same temperature for 0.5 hour after the dropwise addition to obtain a mixed solution A;
(2) Adding 2mol of 2-bromopropane (243 g) -tetrahydrofuran mixed solution into the mixed solution A obtained in the step 1, and carrying out a isothermal reaction for 1.5 hours to obtain a mixed solution B;
(3) After the reaction was completed by gas chromatography, 1.5L of ammonium chloride solution (1 mol/L) was added to the mixed solution B to quench the reaction, a diluted sulfuric acid solution (1.5 mol/L) was added to adjust the pH of the reaction system to 6.8, followed by extraction with 3L of ethyl acetate, and the solvent was removed under reduced pressure to give 160g of a white solid with a yield of 94% and a purity of 96%.
The foregoing disclosure is merely illustrative of the preferred embodiments of the present invention and is not intended to limit the scope of the claims herein, as equivalent changes may be made in the claims herein without departing from the scope of the invention.
Claims (7)
1. A method for synthesizing a cooling agent N,2, 3-trimethyl-2-isopropyl butyramide is characterized by comprising the following specific preparation steps:
(1) N-butyllithium is dropwise added into the N-methylpropanamide-tetrahydrofuran mixed solution under the protection of nitrogen at the temperature of-40 to-60 ℃ to react for 0.5 to 1 hour at the same temperature, so as to obtain a mixed solution A;
(2) Adding a 2-bromopropane-tetrahydrofuran mixed solution into the mixed solution A obtained in the step (1), and performing a reaction at the same temperature for 1-1.5 hours after dripping to obtain a mixed solution B;
(3) And after the reaction is detected by utilizing gas chromatography, adding an ammonium chloride solution into the mixed solution B for quenching reaction, adding an acid solution to adjust the pH to 6-7, extracting by ethyl acetate, and removing the solvent under reduced pressure to obtain the target product.
2. The method for synthesizing the cooling agent N,2, 3-trimethyl-2-isopropyl butyramide according to claim 1, wherein the mass ratio of the materials is N-methyl propionamide: 2-bromopropane: n-butyllithium=1: 2:3-3.05.
3. The method for synthesizing the cooling agent N,2, 3-trimethyl-2-isopropyl butyramide according to claim 1, wherein the reaction temperature maintained in the preparation process is-40 ℃.
4. The method for synthesizing a cooling agent N,2, 3-trimethyl-2-isopropyl butyramide according to claim 1, wherein the reaction time in the step (1) is 1 hour.
5. The method for synthesizing a cooling agent N,2, 3-trimethyl-2-isopropyl butyramide according to claim 1, wherein the reaction time in the step (2) is 1 hour.
6. The method for synthesizing cooling agent N,2, 3-trimethyl-2-isopropyl butyramide according to claim 1, wherein the pH is adjusted to 7 in the step (3).
7. The method for synthesizing the cooling agent N,2, 3-trimethyl-2-isopropyl butyramide according to claim 1, wherein the acidic solution in the step (3) is hydrochloric acid or sulfuric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211067359.1A CN115477593B (en) | 2022-09-01 | 2022-09-01 | Synthesis method of cooling agent N,2, 3-trimethyl-2-isopropyl butyramide |
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Citations (4)
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| GB1421744A (en) * | 1972-04-18 | 1976-01-21 | Wilkinson Sword Ltd | Aliphatic n-substituted tertiary amides possessing physiological cooling activity |
| CN102273733A (en) * | 2010-06-08 | 2011-12-14 | 湖北中烟工业有限责任公司 | Sustained-release pellet capsule of sweet cooling agent for cigarette with filter plug |
| CN103274959A (en) * | 2013-06-20 | 2013-09-04 | 安徽科技学院 | Synthetic method of cooling agent N-, 2, 3-trimethyl-2-isopropyl butyrylamide |
| CN107954888A (en) * | 2017-11-27 | 2018-04-24 | 昆山亚香香料股份有限公司 | A kind of synthetic method of coolant agent N, 2,3- trimethyl -2- butanamides |
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| US6303817B1 (en) * | 2000-08-10 | 2001-10-16 | International Flavors & Fragrances Inc. | Method for making amides |
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| GB1421744A (en) * | 1972-04-18 | 1976-01-21 | Wilkinson Sword Ltd | Aliphatic n-substituted tertiary amides possessing physiological cooling activity |
| CN102273733A (en) * | 2010-06-08 | 2011-12-14 | 湖北中烟工业有限责任公司 | Sustained-release pellet capsule of sweet cooling agent for cigarette with filter plug |
| CN103274959A (en) * | 2013-06-20 | 2013-09-04 | 安徽科技学院 | Synthetic method of cooling agent N-, 2, 3-trimethyl-2-isopropyl butyrylamide |
| CN107954888A (en) * | 2017-11-27 | 2018-04-24 | 昆山亚香香料股份有限公司 | A kind of synthetic method of coolant agent N, 2,3- trimethyl -2- butanamides |
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