A new method for preparing 2-ethylbutyraldehyde

Abstract

The invention belongs to the field of chemical pharmaceutical synthesis technology, and more particularly to a novel method for preparing 2-ethylbutyraldehyde, comprising the following steps: slowly dropping alkyl methoxyacetate into a tetrahydrofuran solution of ethyl magnesium halide, stirring the reaction at room temperature to obtain 3-methoxymethyl-3-pentanol; adding malonic acid to the obtained 3-methoxymethyl-3-pentanol, stirring and warming the reaction to obtain 2-ethylbutyraldehyde. The synthetic route of the present invention is simple, the raw materials are cheap and easy to obtain, the reaction conversion rate is high, the by-products are few, the product is easy to purify, and the yield is high; tetrahydrofuran and malonic acid can be recycled, waste discharge is reduced, and cost is reduced. The novel process provided by the present invention has good application prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical pharmaceutical synthesis, and in particular relates to a new method for preparing 2-ethylbutyraldehyde. Background Art

[0002] Peramivir, with the English name Peramivir, was developed by Biocryst Pharmaceuticals, USA, as a third-generation anti-influenza virus neuramidase inhibitor with the advantages of small toxic and side effects and good patient tolerance. It has been listed in many countries and has huge market demand potential. 2-Ethylbutyraldehyde is an important intermediate for the preparation of Peramivir. The synthetic methods reported so far are relatively few, and the raw material cost is high, not easy to obtain, or there are many by-products and low yield. Patent CN106892804A reports a method for obtaining 2-ethylbutyraldehyde by coupling reaction and deprotection reaction of halogenated acetal and Grignard reagent. In this method, halogenated acetal is not easy to obtain, the reaction steps are complicated, and the yield is low. In the traditional synthesis process, butyraldehyde and acetaldehyde are condensed by aldol, and then hydrogenation reduction is performed to obtain 2-ethylbutyraldehyde. This method is simple to react, but because aldol condensation reaction is also prone to occur between butyraldehyde and butyraldehyde, and between acetaldehyde and acetaldehyde, there are many by-products and a large proportion, and the boiling point is close to 2-ethylbutyraldehyde, the separation is difficult, the overall yield is low, and the production cost is high. Summary of the invention

[0003] In order to solve the above technical problems, the present invention provides a new method for preparing 2-ethylbutyraldehyde, using methoxy alkyl acetate and ethyl magnesium halide as raw materials to prepare 3-methoxymethyl-3-pentanol intermediate, and then 3-methoxymethyl-3-pentanol undergoes rearrangement reaction under malonic acid conditions to obtain 2-ethylbutyraldehyde. The synthesis process provided by the present invention is simple, the raw materials are cheap and easy to obtain, the solvent and malonic acid can be recycled, the reaction conversion rate is high, the by-products are few, easy to separate and purify, and the product yield is high.

[0004] The present invention is implemented by the following technical scheme: a new method for preparing 2-ethylbutyraldehyde, which comprises the following specific steps: the first step: slowly dripping alkyl methoxyacetate into a tetrahydrofuran solution of ethyl magnesium halide, stirring at room temperature for reaction after dripping; after the reaction is completed, evaporating the solvent, extracting, washing, drying and desolventizing the organic phase to obtain 3-methoxymethyl-3-pentanol. The second step: adding malonic acid to 3-methoxymethyl-3-pentanol, stirring and heating for reaction; after the reaction is completed, cooling, filtering, and distilling the filtrate under reduced pressure to obtain 2-ethylbutyraldehyde.

[0005] Furthermore, in the first step of the above technical solution, the halogen in the ethyl magnesium halide is selected from any one of Cl, Br, and I, wherein Cl is preferred.

[0006] Furthermore, in the first step of the above technical solution, the alkyl group in the methoxyacetic acid alkyl ester is selected from methyl or ethyl.

[0007] Furthermore, in the first step of the above technical solution, the molar ratio of the alkyl methoxyacetate to the ethyl magnesium halide is 1:(2.0-2.4), preferably 1:2.1.

[0008] Furthermore, in the first step of the above technical solution, the reaction time at room temperature is 1-10 hours, preferably 2 hours.

[0009] Furthermore, in the second step of the above technical solution, the molar ratio of 3-methoxymethyl-3-pentanol to malonic acid is 1:(1.0-3.0), preferably 1:2.0.

[0010] Furthermore, in the second step of the above technical solution, the reaction temperature is 90-120°C, preferably 110°C.

[0011] Furthermore, in the second step of the above technical solution, the reaction time is 2-8 hours, preferably 3 hours.

[0012] The novel method for preparing 2-ethylbutyraldehyde provided by the present invention has the following beneficial effects compared with the prior art: the synthetic route is simple, the raw materials are cheap and easy to obtain, and the problems of the original reported complex process and high raw material prices are solved; the reaction conversion rate is high, the by-products are few, the product is easy to purify, and the yield is high, and the problems of the traditional process with many by-products and a high proportion, difficult to purify, and low yield are solved; tetrahydrofuran and malonic acid can be recycled, reducing waste discharge and reducing costs. Therefore, the novel process provided by the present invention has good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 It is the gas chromatogram of 2-ethylbutyraldehyde in Example 1. DETAILED DESCRIPTION

[0014] The present invention is further described below in conjunction with specific examples. The examples here are only used to explain the present invention and do not limit the scope of protection of the present invention. Depending on the amount of feed, the specific reaction temperature and reaction time are different. In the technical scheme provided by the present invention, the first step reaction time is 1-10 hours, preferably 2 hours; the second step reaction temperature is 90-120°C, preferably 110°C; the second step reaction time is 2-8 hours, preferably 3 hours. The technical effects achieved in the following examples can be achieved within the reaction time range or reaction temperature range provided by the present invention.

[0015] Example 1

[0016] Step 1: Add 500 mL of ethylmagnesium chloride tetrahydrofuran solution (2.0 M) to the reaction bottle, and add 50 g of methyl methoxyacetate dropwise under stirring at room temperature; after the addition is complete, stir and react at room temperature for 2 hours; after the reaction is complete, evaporate tetrahydrofuran under reduced pressure; quench the remaining reaction solution with 250 mL of water, then add 100 mL×3 dichloromethane for extraction, combine the organic phases, dry, and desolventize to obtain 59 g of 3-methoxymethyl-3-pentanol, with a yield of 92.9%.

[0017] Step 2: Add 40g of the above 3-methoxymethyl-3-pentanol and 63g of malonic acid to the reaction bottle in sequence, stir and heat to 110°C, and react for 3 hours; after the reaction is completed, cool down, filter and recover malonic acid; the filtrate is distilled under reduced pressure to obtain 25g of 2-ethylbutyraldehyde, with a yield of 82.5% and a purity of 96.1%.

[0018] Example 2

[0019] Step 1: Add 10 L of ethylmagnesium chloride tetrahydrofuran solution (2.0 M) to the reactor, and add 950 g of methyl methoxyacetate dropwise under stirring at room temperature; after the addition is complete, stir and react at room temperature for 3 hours; after the reaction is complete, evaporate tetrahydrofuran under reduced pressure; quench the remaining reaction solution with 4 L of water, then add 1500 mL×3 of dichloromethane for extraction, combine the organic phases, dry, and desolventize to obtain 1135 g of 3-methoxymethyl-3-pentanol, with a yield of 94.1%.

[0020] Step 2: add 500g of the above 3-methoxymethyl-3-pentanol and 790g of malonic acid to the reaction bottle in sequence, stir and heat to 110°C, and react for 4 hours; after the reaction is completed, cool down, filter and recover malonic acid; the filtrate is distilled under reduced pressure to obtain 319g of 2-ethylbutyraldehyde, with a yield of 84.2% and a purity of 95.8%.

[0021] It can be seen from the above embodiments that the synthesis process of the present invention is simple, the raw materials are cheap and easy to obtain; the reaction conversion rate is high, the by-products are few, the product purity is good, and the yield is greatly improved compared with the prior art; the solvent and reagent recovery rate is high, the cost is low, the market competitiveness is strong, and the industrialization potential is great.

Claims

1. A method for preparing 2-ethylbutyraldehyde, characterized in that: Add 500 mL of 2.0 M tetrahydrofuran solution of ethyl magnesium chloride to the reaction bottle, and add 50 g of methyl methoxyacetate dropwise under stirring at room temperature; after the addition is complete, stir at room temperature for 2 hours; after the reaction is complete, remove tetrahydrofuran under reduced pressure; quench the remaining reaction solution with 250 mL of water, then add 100 mL × 3 of dichloromethane for extraction, combine the organic phases, dry, and desolventize to obtain 59 g of 3-methoxymethyl-3-pentanol, with a yield of 92.9%; To the reaction flask, 40 g of the above-mentioned 3-methoxymethyl-3-pentanol and 63 g of malonic acid were added in sequence, the temperature was raised to 110° C. with stirring, and the reaction was carried out for 3 hours. After the reaction was completed, the temperature was lowered, the malonic acid was filtered off, and the filtrate was distilled under reduced pressure to obtain 25 g of 2-ethylbutyraldehyde, with a yield of 82.5% and a purity of 96.1%.

2. A method for preparing 2-ethylbutyraldehyde, characterized in that: Add 10L of 2.0M tetrahydrofuran solution of ethyl magnesium chloride to the reaction kettle, and add 950g of methyl methoxyacetate dropwise under stirring at room temperature; after the addition is complete, stir and react at room temperature for 3 hours; after the reaction is complete, remove tetrahydrofuran under reduced pressure; quench the remaining reaction solution with 4L of water, then add 1500mL×3 of dichloromethane for extraction, combine the organic phases, dry, and desolventize to obtain 1135g of 3-methoxymethyl-3-pentanol, with a yield of 94.1%; To the reaction flask, 500 g of the above-mentioned 3-methoxymethyl-3-pentanol and 790 g of malonic acid were added in sequence, the temperature was raised to 110° C. with stirring, and the reaction was carried out for 4 hours. After the reaction was completed, the temperature was lowered, the mixture was filtered off, and the malonic acid was recovered. The filtrate was distilled under reduced pressure to obtain 319 g of 2-ethylbutyraldehyde, with a yield of 84.2% and a purity of 95.8%.

Images