CN114380690A

CN114380690A - Novel preparation method of methyl cyclopropylformate

Info

Publication number: CN114380690A
Application number: CN202111639963.2A
Authority: CN
Inventors: 王可为; 蔡小川; 韩建国; 赵文武; 刘威; 唐培昆
Original assignee: China Haohua Dalian Research and Design Institute of Chemical Industry Coltd
Current assignee: China Haohua Dalian Research and Design Institute of Chemical Industry Coltd
Priority date: 2021-12-30
Filing date: 2021-12-30
Publication date: 2022-04-22

Abstract

The invention discloses a novel preparation method of methyl cyclopropyl formate, which takes methyl acrylate as a raw material and diazomethane in Pd (oAc)₂Under the action of a catalyst, performing denitrification cyclization reaction in a solvent to obtain a crude product of methyl cyclopropylformate, and performing acid washing, filtering and layering, and rectifying under normal pressure to obtain a pure product with the content of more than 98%, wherein the yield is more than 85%. The synthesis route has the advantages of simple process, mild conditions, high yield, environmental friendliness and high economic value.

Description

Novel preparation method of methyl cyclopropylformate

Technical Field

The invention relates to a novel synthesis method of methyl cyclopropyl formate, belonging to the technical field of synthesis of medical intermediates.

Background

Methyl cyclopropyl formate is also called methyl cyclopropanecarboxylate, and is an important medical synthetic intermediate; in the industrial production, methyl chlorobutyrate is mainly used as a raw material, and sodium methoxide, calcium methoxide and potassium methoxide are used as catalysts to synthesize methyl cyclopropanecarboxylate. Although the process is simple to operate, raw materials are easy to obtain, and the cost is low, a large amount of mixed gas of sulfur dioxide and hydrochloric acid is generated, the waste gas is treated by matching with an expensive tail gas absorption device, the gas tightness requirement of the absorption device on a reaction kettle is high, and hydrogen chloride and sulfur dioxide generated by gas leakage cause serious pollution to the air, so that the process is very unfavorable for environmental protection and production safety.

Disclosure of Invention

Aiming at the problems, the invention provides an improved synthesis route of methyl cyclopropyl formate, which adopts methyl acrylate as a raw material to denitrify and cyclize with diazomethane under the catalysis of palladium to prepare the methyl cyclopropyl formate, and the specific mechanism and the steps are as follows:

(1) the first step is that methyl acrylate is used as a starting material and reacts with diazomethane in a certain amount of solvent at a certain molar ratio and a certain reaction temperature under the action of a palladium catalyst to obtain a crude product of methyl cyclopropyl formate.

(2) And secondly, slowly adding a certain concentration of dilute acid into the reaction mother liquor, stirring for several hours, standing for layering, and rectifying the organic phase at normal pressure to obtain a methyl cyclopropyl formate finished product.

Further, in the above scheme, in the first step, the reaction solvent is at least one of ethanol, diethyl ether, toluene, benzene, ethanol, xylene, chlorobenzene, dichlorobenzene, acetonitrile, THF, DMF, ethyl acetate.

Further, in the above scheme, in the first step, the molar ratio of the methyl acrylate to the diazomethane, palladium catalyst is 1: 1-1.5: 0.005-0.01.

Further, in the scheme, in the first step, the reaction temperature is-10-125 ℃, and the reaction time is 10-25 h.

Further, in the above scheme, in the second step, the quenching agent is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and nitric acid.

Further, in the scheme, in the second step, the concentration of the quenching agent is 1-5%.

Advantageous effects of the invention

(1) The synthesis route has the advantages of simple process, mild reaction conditions, high yield and stable product quality.

(2) Avoids the generation of highly toxic waste gas, uses a catalyst and a solvent with low toxicity, almost does not generate waste water, is environment-friendly, and is suitable for large-scale industrial production.

Detailed description of the preferred embodiment

[ example 1 ] Synthesis of methyl Cyclopropylcarboxylate

The first step, in a 500ml four-neck flask, under the protection of nitrogen, 200ml toluene is added, the temperature is reduced to-10 ℃, 12.6 g (0.30mol) diazomethane and 0.67g (0.003mol) Pd (oAc) are added₂Starting stirring, slowly dropwise adding 21.5g (0.25mol) of methyl acrylate, reacting for 2 hours, heating up and refluxing, keeping the temperature for reacting for 6 to 8 hours, and cooling to-10 ℃ after TLC detection reaction.

And secondly, slowly dropwise adding 100g of 1% diluted hydrochloric acid into the reaction mother liquor, stirring for 0.5h, standing for liquid separation, and distilling the organic phase at normal pressure to obtain a light yellow product, namely methyl cyclopropylformate 22.6g, the purity of 98.5% and the yield of 90.5%.

[ example 2 ] Synthesis of methyl Cyclopropylcarboxylate

The first step, in a 500ml four-neck bottle, under the protection of nitrogen, 200ml benzene is added, the temperature is reduced to-10 ℃, and then 14.7g (0.35 mol) diazomethane and 0.89g (0.004mol) Pd (oAc) are added₂Stirring is started, 25.8g (0.30mol) of methyl acrylate is slowly dripped, the temperature is raised and the reflux is carried out after the reaction is carried out for 2 hours, the reaction is kept for 4 to 8 hours, and the temperature is reduced to minus 10 ℃ after the TLC detection reaction is finished.

And secondly, slowly dropwise adding 100g of 1% dilute sulfuric acid into the reaction mother liquor, stirring for 0.5h, standing for liquid separation, and distilling the organic phase at normal pressure to obtain 25.6g of a light yellow product, namely methyl cyclopropylformate, wherein the purity of the methyl cyclopropylformate is 99.2% and the yield of the methyl cyclopropylformate is 85.3%.

[ example 3 ] Synthesis of methyl Cyclopropylcarboxylate

Firstly, 200ml of chlorobenzene mixed solution is added into a 500ml four-mouth bottle under the protection of nitrogen, the temperature is reduced to-15 ℃, and then 12.6 g (0.30mol) of diazomethane and 0.67g (0.003mol) of Pd (oAc) are added₂Stirring is started, 26.75g (0.25mol) of liquid methyl acrylate is slowly dripped, the temperature is raised and the reflux is carried out after the reaction is carried out for 1.5h, the temperature is kept for reaction for 12h to 14h, and the temperature is reduced to minus 10 ℃ after the TLC detection reaction is finished.

And secondly, slowly dropwise adding 100g of 3% dilute hydrochloric acid into the reaction mother liquor, stirring for 1.0h, standing for liquid separation, and distilling the organic phase at normal pressure to obtain 21.88g of a light yellow product, namely methyl cyclopropylformate, wherein the purity of the product is 99.6% and the yield of the product is 87.5%.

Claims

1. A novel synthesis method of methyl cyclopropylformate is characterized by comprising the following two synthesis steps:

(1) using methyl acrylate as a starting material, and reacting with diazomethane in a certain amount of solvent at a certain molar ratio and a certain reaction temperature under the action of a palladium catalyst to obtain a crude product of methyl cyclopropylformate;

(2) slowly adding a certain concentration of dilute acid into the reaction mother liquor, stirring for several hours, standing for layering, and rectifying the organic phase at normal pressure to obtain a methyl cyclopropyl formate finished product.

2. The method as claimed in claim 1, wherein the reaction solvent in step (1) is at least one of dichlorobenzene, benzene, ethanol, acetonitrile, ethanol, diethyl ether, toluene, xylene, chlorobenzene, THF, DMF, and ethyl acetate.

3. The process according to claim 1, wherein the molar ratio of methyl acrylate to diazomethane and palladium catalyst in step (1) is 1: 1-1.8: 0.001 to 0.02.

4. The process according to claim 1, wherein the palladium catalyst in step (1) is Pd (oAc)₂、Pd(NO₃)₂、PdSO₄、Pdcl₂、Pd (TFA)₂At least one of them.

5. The novel synthesis method of methyl cyclopropylformate according to claim 1, wherein the reaction temperature in step (1) is-10 to 125 ℃ and the reaction time is 8 to 24 hours.

6. The method of claim 1, wherein the quenching agent in step (2) is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and nitric acid.

7. The novel synthesis method of methyl cyclopropylformate according to claim 1, wherein the concentration of the quencher in step (2) is 1-10%.