CN112851504B - Synthesis method of methyl isobutyrylacetate - Google Patents
Synthesis method of methyl isobutyrylacetate Download PDFInfo
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- CN112851504B CN112851504B CN202110174123.7A CN202110174123A CN112851504B CN 112851504 B CN112851504 B CN 112851504B CN 202110174123 A CN202110174123 A CN 202110174123A CN 112851504 B CN112851504 B CN 112851504B
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- methyl isobutyrylacetate
- isobutyrylacetate
- isobutyryl chloride
- acetonitrile
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- 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
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- 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
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- 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
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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 10-48h.
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 using amount 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 8-15h.
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 is further illustrated by 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 to be =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 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 invention relates to a synthesis method of methyl isobutyrylacetate, wherein 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 to be =1 by 1.5mol/L hydrochloric acid, adding 200mmol of methanol, reacting for 15h at 120 ℃, demixing after the reaction is finished, washing an organic layer by water, washing by saturated sodium bicarbonate, washing by water until the pH is =6.5-7.5, and cleaning and transparent feed liquid. Concentrating under reduced pressure at first under normal 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 of acetonitrile, 120mmol of sodium hydride and 12.318g of o-xylene are put into a flask, the reaction temperature is raised to 90 ℃, mechanical stirring is started, and 120mmol of isobutyryl chloride is slowly dropped for 2h. After the reaction is carried out for 10 hours, 1.5mol/L hydrochloric acid is used for adjusting the pH to be =1, 100mmol methanol is added, the reaction is carried out for 10 hours at 60 ℃, the layers are separated after the reaction is finished, an organic layer is washed by water, saturated sodium bicarbonate is washed by water, the organic layer is washed to be pH to be =6.5-7.5, and the feed liquid is clean and transparent. 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 of acetonitrile, 120mmol of sodium methoxide and 12.318g of o-xylene are put into a flask, the reaction temperature is raised to 100 ℃, mechanical stirring is started, and 100mmol of isobutyryl chloride is slowly dropped for 2 hours. After the reaction is carried out for 10 hours, the pH is adjusted to be =1 by 1.5mol/L hydrochloric acid, 100mmol of methanol is added, the reaction is carried out for 12 hours at 80 ℃, the layers are separated after the reaction is finished, an organic layer is washed by water, saturated sodium bicarbonate and water until the pH is =6.5-7.5, and the feed liquid is clean and transparent. Concentrating under reduced pressure at first under normal pressure, and obtaining the product methyl isobutyrylacetate after the concentration is finished, wherein the yield of the product is 80 percent, and the purity is more than 99 percent.
Example 5
The invention relates to a synthesis method of methyl isobutyrylacetate, wherein 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 the reaction is carried out for 10 hours, the pH is adjusted to be =1 by 1.5mol/L hydrochloric acid, 100mmol of methanol is added, the reaction is carried out for 10 hours at 60 ℃, the layers are separated after the reaction is finished, an organic layer is washed by water, saturated sodium bicarbonate and water until the pH is =6.5-7.5, and the feed liquid is clean and transparent. Concentrating under normal pressure and reduced pressure, and obtaining the product methyl isobutyrylacetate with the yield of 76% and the purity of 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 of acetonitrile, 120mmol of sodium methoxide and 12.318g of o-xylene are put into a flask, the reaction temperature is raised to 90 ℃, mechanical stirring is started, and 150mmol of isobutyryl chloride is slowly dropped for 2h. After the reaction is carried out for 10 hours, the pH is adjusted to be =1 by 1.5mol/L hydrochloric acid, 120mmol of methanol is added, the reaction is carried out for 10 hours at 60 ℃, the layers are separated after the reaction is finished, an organic layer is washed by water, saturated sodium bicarbonate and water until the pH is =6.5-7.5, and the feed liquid is clean and transparent. 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 solvent in the presence of alkali catalyst to obtain methyl isobutyrylacetate, regulating pH value to 1 with hydrochloric acid, adding methanol, hydrolysis-esterification, and ordinary-pressure distillation and vacuum distillation of organic phase.
2. The process of claim 1 wherein the molar ratio of acetonitrile to isobutyryl chloride is (1-2) to (1-3).
3. The method of 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 8-15h.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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| KR100850558B1 (en) * | 2008-01-02 | 2008-08-06 | 조동옥 | Process for preparing useful in synthesis of atorvastatin |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
|---|
| 阿托伐他汀钙中间体的合成工艺研究;饶历等;《武汉工程大学学报》;20101215(第12期);全文 * |
| 降血脂药瑞舒伐他汀钙重要中间体的合成工艺研究;张立光等;《化学试剂》;20171215(第12期);全文 * |
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