CN112851504A - Synthesis method of methyl isobutyrylacetate - Google Patents
Synthesis method of methyl isobutyrylacetate Download PDFInfo
- Publication number
- CN112851504A CN112851504A CN202110174123.7A CN202110174123A CN112851504A CN 112851504 A CN112851504 A CN 112851504A CN 202110174123 A CN202110174123 A CN 202110174123A CN 112851504 A CN112851504 A CN 112851504A
- Authority
- CN
- China
- Prior art keywords
- reaction
- methyl isobutyrylacetate
- isobutyrylacetate
- isobutyryl chloride
- acetonitrile
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
-
- 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
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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 belongs to the technical field of medicine preparation, and particularly relates to a synthesis method of methyl isobutyrylacetate. The raw material acetonitrile used in the synthetic method of methyl isobutyrylacetate is cheaper and has low boiling point, is easy to separate from the product, and can realize product purification only by a reduced pressure distillation mode after the reaction is finished, so that the energy consumption is low.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a synthetic method of methyl isobutyrylacetate.
Background
With the rapid development of global economy and the change of human life style, the development situation of cardiovascular diseases such as atherosclerosis and the like is increasingly prominent among people under the influence of hypertension, hyperlipidemia and hyperglycemia. Among the drugs for treating cardiovascular and cerebrovascular diseases, atorvastatin, which is currently the most effective statin lipid-regulating drug, has the greatest effect of lowering low-density lipoprotein (LDL-C) and the strongest effect of lowering triglyceride, and can raise the level of high-density lipoprotein cholesterol (HDI-C), is the only statin drug that has been proven to be superior to revascularization. Methyl isobutyrylacetate is a key intermediate for synthesizing atorvastatin and has irreplaceability.
The synthesis of methyl isobutyrylacetate by the conventional process uses methyl acetoacetate to react with isobutyryl chloride. Because the boiling points of the product methyl isobutyrylacetate and the raw material methyl acetoacetate are close, the product is difficult to separate, and the methyl isobutyrylacetate with higher purity can be obtained only by rectification, so that the three wastes are high, the environmental protection pressure is high, and the energy consumption is high. Therefore, it is very necessary to develop a process for producing methyl isobutyrylacetate with high yield and simple post-treatment.
Disclosure of Invention
The invention aims to provide a method for synthesizing methyl isobutyrylacetate with high yield and simple post-treatment.
The synthesis process of methyl isobutyrylacetate includes the reaction of acetonitrile and isobutyryl chloride in the presence of alkali catalyst in the solvent to prepare methyl isobutyrylacetate, regulating pH value to 1 with hydrochloric acid, adding methanol, hydrolysis and esterification, and normal pressure distillation and reduced pressure distillation of the organic phase to separate product.
The molar ratio of acetonitrile to isobutyryl chloride is (1-2) to (1-3).
The alkali catalyst is one of sodium methoxide, sodium amide and sodium hydride.
The reaction solvent is one of o-xylene, p-xylene, mesitylene and tetrahydrofuran.
In the process of preparing methyl isobutyrylacetate by reacting acetonitrile and isobutyryl chloride, the reaction temperature is 80-120 ℃, and the reaction time is 10-48 h.
The dosage of the alkali catalyst is 1.1 to 2 times of the molar weight of the acetonitrile.
The dosage of the organic solvent is 2-6 times of the mass of the isobutyryl chloride.
The dosage of the methanol is 0.8 to 2 times of the molar weight of the isobutyryl chloride.
The temperature of the hydrolysis esterification reaction is 40-120 ℃, and the reaction time is 8-15 h.
Compared with the prior art, the invention has the beneficial effects that: the raw material acetonitrile used in the synthetic method of methyl isobutyrylacetate is cheaper and has low boiling point, is easy to separate from the product, and can realize product purification only by a reduced pressure distillation mode after the reaction is finished, so that the energy consumption is low.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
The synthesis method of methyl isobutyrylacetate of the invention is characterized in that catalytic reaction is carried out in a two-neck flask with the volume of 500mL and a mechanical stirrer is arranged. The procedure for the catalytic test was as follows: 100mmol acetonitrile, 120mmol sodium methoxide and 8.21g p-xylene are put into a flask, the reaction temperature is raised to 80 ℃, mechanical stirring is started, and 120mmol isobutyryl chloride is slowly dropped for 2 hours. After 10h of reaction, adjusting the pH value to 1 by 1.5mol/L hydrochloric acid, adding 100mmol of methanol, reacting at 40 ℃ for 8h, demixing after the reaction is finished, washing an organic layer by water, washing by saturated sodium bicarbonate, washing by water until the pH value is 6.5-7.5, and cleaning and transparent the feed liquid. Concentrating under normal pressure and reduced pressure, and obtaining the product methyl isobutyrylacetate with the yield of 80 percent and the purity of more than 99 percent after the concentration is finished.
Example 2
The synthesis method of methyl isobutyrylacetate of the invention is characterized in that catalytic reaction is carried out in a two-neck flask with the volume of 500mL and a mechanical stirrer is arranged. The procedure for the catalytic test was as follows: 100mmol acetonitrile, 100mmol sodium methoxide and 49.27 o-xylene are put into a flask, the reaction temperature is raised to 120 ℃, mechanical stirring is started, 100mmol isobutyryl chloride is slowly dropped, and the dropping time is 2 hours. After 48h of reaction, adjusting the pH value to 1 by 1.5mol/L hydrochloric acid, adding 200mmol of methanol, reacting at 120 ℃ for 15h, demixing after the reaction is finished, washing an organic layer by water, washing by saturated sodium bicarbonate, washing by water until the pH value is 6.5-7.5, and cleaning and transparent the feed liquid. Concentrating under normal pressure and reduced pressure, and obtaining the product methyl isobutyrylacetate after the concentration is finished, wherein the yield of the product is 83 percent, and the purity is more than 99 percent.
Example 3
The synthesis method of methyl isobutyrylacetate of the invention is characterized in that catalytic reaction is carried out in a two-neck flask with the volume of 500mL and a mechanical stirrer is arranged. The procedure for the catalytic test was as follows: 100mmol acetonitrile, 120mmol sodium hydride and 12.318g o-xylene are put into a flask, the reaction temperature is raised to 90 ℃, mechanical stirring is started, and 120mmol isobutyryl chloride is slowly dropped for 2 hours. After reaction for 10h, adjusting pH to 1 with 1.5mol/L hydrochloric acid, adding 100mmol methanol, reacting at 60 ℃ for 10h, demixing after the reaction is finished, washing an organic layer with water, washing with saturated sodium bicarbonate, washing with water until pH is 6.5-7.5, and cleaning and transparent the feed liquid. Concentrating under normal pressure and reduced pressure, and obtaining the product methyl isobutyrylacetate after the concentration is finished, wherein the yield of the product is 82 percent, and the purity is more than 99 percent.
Example 4
The synthesis method of methyl isobutyrylacetate of the invention is characterized in that catalytic reaction is carried out in a two-neck flask with the volume of 500mL and a mechanical stirrer is arranged. The procedure for the catalytic test was as follows: 100mmol acetonitrile, 120mmol sodium methoxide and 12.318g o-xylene are put into a flask, the reaction temperature is raised to 100 ℃, mechanical stirring is started, 100mmol isobutyryl chloride is slowly dropped, and the dropping time is 2 hours. After 10h of reaction, adjusting the pH value to 1 by 1.5mol/L hydrochloric acid, adding 100mmol of methanol, reacting at 80 ℃ for 12h, demixing after the reaction is finished, washing an organic layer by water, washing by saturated sodium bicarbonate, washing by water until the pH value is 6.5-7.5, and cleaning and transparent the feed liquid. Concentrating under normal pressure and reduced pressure, and obtaining the product methyl isobutyrylacetate with the yield of 80 percent and the purity of more than 99 percent after the concentration is finished.
Example 5
The synthesis method of methyl isobutyrylacetate of the invention is characterized in that catalytic reaction is carried out in a two-neck flask with the volume of 500mL and a mechanical stirrer is arranged. The procedure for the catalytic test was as follows: 100mmol acetonitrile, 120mmol sodium methoxide and 12.318g o-xylene are put into a flask, the reaction temperature is raised to 90 ℃, mechanical stirring is started, 100mmol isobutyryl chloride is slowly dropped, and the dropping time is 2 hours. After reaction for 10h, adjusting pH to 1 with 1.5mol/L hydrochloric acid, adding 100mmol methanol, reacting at 60 ℃ for 10h, demixing after the reaction is finished, washing an organic layer with water, washing with saturated sodium bicarbonate, washing with water until pH is 6.5-7.5, and cleaning and transparent the feed liquid. Concentrating under normal pressure and reduced pressure, and obtaining the product methyl isobutyrylacetate after the concentration is finished, wherein the yield of the product is 76%, and the purity is more than 99%.
Example 6
The synthesis method of methyl isobutyrylacetate of the invention is characterized in that catalytic reaction is carried out in a two-neck flask with the volume of 500mL and a mechanical stirrer is arranged. The procedure for the catalytic test was as follows: 100mmol acetonitrile, 120mmol sodium methoxide and 12.318g o-xylene are put into a flask, the reaction temperature is raised to 90 ℃, mechanical stirring is started, and 150mmol isobutyryl chloride is slowly dropped for 2 hours. After reaction for 10h, adjusting pH to 1 with 1.5mol/L hydrochloric acid, adding 120mmol methanol, reacting for 10h at 60 ℃, demixing after the reaction is finished, washing an organic layer with water, washing with saturated sodium bicarbonate, washing with water until pH is 6.5-7.5, and cleaning and transparent feed liquid. Concentrating under normal pressure and reduced pressure, and obtaining the product methyl isobutyrylacetate after the concentration is finished, wherein the yield of the product is 76%, and the purity is more than 99%.
Claims (9)
1. A process for synthesizing methyl isobutyrylacetate includes such steps as reaction between acetonitrile and isobutyryl chloride in reaction solvent in the presence of alkali catalyst to obtain methyl isobutyrylacetate, regulating pH value to 1 by hydrochloric acid, addition of methanol, hydrolysis-esterification, and ordinary-pressure distillation and vacuum distillation of organic phase to separate out product.
2. The process of claim 1 wherein the molar ratio of acetonitrile to isobutyryl chloride is (1-2) to (1-3).
3. The method for synthesizing methyl isobutyrylacetate according to claim 1, wherein the base catalyst is one of sodium methoxide, sodium amide and sodium hydride.
4. The method of claim 1, wherein the reaction solvent is one of o-xylene, p-xylene, mesitylene, and tetrahydrofuran.
5. The method for synthesizing methyl isobutyrylacetate according to claim 1, wherein the reaction temperature is 80-120 ℃ and the reaction time is 10-48h in the process of preparing methyl isobutyrylacetate by reacting acetonitrile and isobutyryl chloride.
6. The method for synthesizing methyl isobutyrylacetate according to claim 1 or 3, wherein the amount of the base catalyst is 1.1 to 2 times of the molar amount of the acetonitrile.
7. The method for synthesizing methyl isobutyrylacetate according to claim 1 or 4, wherein the amount of the organic solvent is 2 to 6 times of the mass of the isobutyryl chloride.
8. The method of claim 1, wherein the amount of methanol is 0.8 to 2 times the molar amount of isobutyryl chloride.
9. The method for synthesizing methyl isobutyrylacetate according to claim 1, wherein the temperature of the hydrolysis esterification reaction is 40-120 ℃ and the reaction time is 8-15 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110174123.7A CN112851504B (en) | 2021-02-09 | 2021-02-09 | Synthesis method of methyl isobutyrylacetate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110174123.7A CN112851504B (en) | 2021-02-09 | 2021-02-09 | Synthesis method of methyl isobutyrylacetate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112851504A true CN112851504A (en) | 2021-05-28 |
| CN112851504B CN112851504B (en) | 2022-10-14 |
Family
ID=75989322
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110174123.7A Active CN112851504B (en) | 2021-02-09 | 2021-02-09 | Synthesis method of methyl isobutyrylacetate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112851504B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115246772A (en) * | 2021-12-07 | 2022-10-28 | 浙江科技学院 | Preparation method of methyl isobutyrylacetate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110112309A1 (en) * | 2008-01-02 | 2011-05-12 | Dong-Ock Cho | Preparation process useful in synthesis of atorvastatin |
| WO2012074068A1 (en) * | 2010-12-01 | 2012-06-07 | 日産化学工業株式会社 | Method for producing hematopoietic stem cells using pyrazole compound |
| CN104059024A (en) * | 2014-06-16 | 2014-09-24 | 浙江大学 | Preparation method of rosuvastatin intermediate and intermediate compound |
-
2021
- 2021-02-09 CN CN202110174123.7A patent/CN112851504B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110112309A1 (en) * | 2008-01-02 | 2011-05-12 | Dong-Ock Cho | Preparation process useful in synthesis of atorvastatin |
| WO2012074068A1 (en) * | 2010-12-01 | 2012-06-07 | 日産化学工業株式会社 | Method for producing hematopoietic stem cells using pyrazole compound |
| CN104059024A (en) * | 2014-06-16 | 2014-09-24 | 浙江大学 | Preparation method of rosuvastatin intermediate and intermediate compound |
Non-Patent Citations (2)
| Title |
|---|
| 张立光等: "降血脂药瑞舒伐他汀钙重要中间体的合成工艺研究", 《化学试剂》 * |
| 饶历等: "阿托伐他汀钙中间体的合成工艺研究", 《武汉工程大学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115246772A (en) * | 2021-12-07 | 2022-10-28 | 浙江科技学院 | Preparation method of methyl isobutyrylacetate |
| CN115246772B (en) * | 2021-12-07 | 2024-02-02 | 浙江科技学院 | Preparation method of isobutyryl methyl acetate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112851504B (en) | 2022-10-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102653443B1 (en) | Preparation method of artificially synthesized racemic nicotine salt | |
| CN101830821B (en) | Chemical synthesis method of N-alcoxyloxalyl alanine ester | |
| KR20130027568A (en) | Method for preparing rosuvastatin calcium intermediate | |
| CN108623456B (en) | Preparation method of butylphthalide and pharmaceutical intermediate thereof | |
| CN112851504B (en) | Synthesis method of methyl isobutyrylacetate | |
| CN102336723A (en) | Preparation method of L-chloperastine fendizoic acid | |
| CN112479938B (en) | Preparation method of N-cyclohexyl-2-aminoethanesulfonic acid | |
| CN116178136B (en) | Preparation method of 2-hexyl decanoic acid | |
| CN102285957B (en) | Method for preparing glycerol carbonate | |
| CN101481335B (en) | Rivastigmine intermediate preparation | |
| CN102976940A (en) | Method for synthesizing (R)-beta-hydroxytetradecanoate | |
| CN110396072B (en) | Method for producing(s) -3-hydroxytetrahydrofuran | |
| CN104151283B (en) | One catalyzes and synthesizes the method for 12-aryl-8,9,10,12-tetrahydro benzo [α] xanthene-11-ketone derivatives | |
| CN113262822A (en) | N-heterocyclic carbene metal palladium complex catalyst, and synthesis method and application thereof | |
| CN101274886A (en) | Preparation for 6,8-dicloro caprylate | |
| CN115536517B (en) | Preparation method of 4-hydroxymethylphenylacetic acid | |
| CN103420871B (en) | Method for preparing (5R)-6-cyanogroup-5-hydroxy-3-oxocaproic acid tert-butyl ester | |
| CN118530108B (en) | Preparation method of 3-oxo-cyclobutanecarboxylic acid | |
| CN115872887B (en) | Preparation method of agomelatine | |
| CN103193679A (en) | Preparation method of rivastigmine intermediate (R)-N-ethyl-N-methyl carbamic acid-3-(1-hydroxyethyl) phenyl ester | |
| US9040739B2 (en) | Catalyst and method for synthesis of lactic acid and its derivatives | |
| CN107382723B (en) | Chemical synthesis method of 1, 2-diglyceride | |
| CN112724076A (en) | Improved synthesis method of 6-methyl-2-ethyl-3-hydroxypyridine | |
| CN114517215A (en) | Demethylation method of aryl methyl ether and preparation method of desvenlafaxine or salt thereof | |
| CN105111136A (en) | Method for preparing 3-mehtyl-1-phenethyl piperidine-4-ketone or 1-phenethyl piperidine-4-ketone |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |