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Method for synthesizing 4-(4-carbomethoxyphenyl) butyraldehyde

一种基苯基、甲酯的技术，应用在合成4-丁醛领域，能够解决步骤繁琐、试剂昂贵、需要柱层析等问题，达到工艺操作简单、来源易得、试剂价廉的效果

Active Publication Date: 2009-12-02
SHANGHAI ACEBRIGHT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are mainly three kinds of reports about its synthetic method: one is J.Org.Chem., 1990,55:3222-7 report adopts 3-butyn-1-alcohol and p-bromobenzoic acid methyl ester to condense, and then through palladium carbon Hydrogenation reduction, PCC oxidation alcohol to obtain product, this method steps is loaded down with trivial details, and reagent is expensive; The second is Tetrahedron Letters, 1989,30:6629-32 report adopts 3-buten-1-alcohol and p-bromobenzoic acid methyl ester to condense, through Column chromatography separates and obtains pure product, and this method needs column chromatography, is not suitable for suitability for suitability for industrialized production; The 3rd is Chemical Industry Times Magazine, 2006, 20:54-55. It is reported that 3-buten-1-alcohol and p-bromobenzoic acid methyl The 4-(4-methoxyphenyl) butyraldehyde crude product obtained by ester condensation reacts with sodium bisulfite to form a sulfonate, and then treats it with hydrochloric acid to obtain a pure product. The product obtained by this method has high purity, but the total yield is only 38%

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Dissolve methyl p-bromobenzoate (85.0g, 0.395mol) in 1L DMF, add 45.0g lithium acetate dihydrate, 50.0g lithium chloride, 60.0g tetrabutylammonium bromide, blow nitrogen for 5 minutes, and then add 3-buten-1-ol (34.0 g, 0.472 mol) and 2.3 g of palladium acetate were stirred and reacted at 60° C. for 10 hours. Cool to 25°C, add 1 L of water, extract 3 times with 300 ml of a mixed solution of cyclohexane and ethyl acetate (6:1, volume ratio), combine the organic layers, adjust the pH of the organic layer to 8 with saturated sodium bicarbonate solution, and then Wash with water (4 x 500ml). Add 80 g of silica gel and stir for half an hour to decolorize. The obtained pale yellow solution is evaporated to dryness under reduced pressure at 40° C. to obtain 70.0 g of 4-(4-methoxyphenyl)butyraldehyde, with a yield of 86.0% and a purity of 96.3% by GC.

Embodiment 2

[0019] Dissolve methyl p-bromobenzoate (10.8g, 0.050mol) in 150ml of DMF, add 5.7g of lithium acetate dihydrate, 6.4g of lithium chloride, 7.6g of tetrabutylammonium bromide, blow nitrogen for 5 minutes, and then add 3-buten-1-ol (4.3 g, 0.060 mol), palladium acetate 0.3 g, stirred and reacted at 60° C. for 10 hours. Cool to 25°C, add 200ml of water, extract 3 times with 100ml of a mixed solution of petroleum ether (60-90°C) and ethyl acetate (7:1, volume ratio), combine the organic layers, and adjust the organic layers with saturated sodium bicarbonate solution. After the pH reached 7, it was washed with water (5 x 50ml). Add 10 g of silica gel and stir for half an hour to decolorize. The obtained light yellow solution is evaporated to dryness under reduced pressure at 40° C. to obtain 8.4 g of 4-(4-methoxyphenyl)butyraldehyde, with a yield of 81.6% and a purity of 96.1% by GC.

Embodiment 3

[0021] Dissolve methyl p-bromobenzoate (10.8g, 0.050mol) in 150ml of DMF, add 5.7g of lithium acetate dihydrate, 6.4g of lithium chloride, 7.6g of tetrabutylammonium bromide, blow nitrogen for 5 minutes, and then add 3-buten-1-ol (4.3 g, 0.060 mol), palladium acetate 0.3 g, stirred and reacted at 60° C. for 10 hours. Cool to 25°C, add 200ml of water, extract 3 times with 100ml of a mixed solution of isopropyl ether and ethyl acetate (9:1, volume ratio), combine the organic layers, adjust the pH of the organic layer to 7.5 with saturated sodium bicarbonate solution, It was washed again with water (5 x 50ml). Add 10 g of silica gel and stir for half an hour to decolorize. The obtained pale yellow solution is evaporated to dryness under reduced pressure at 40° C. to obtain 8.0 g of 4-(4-methoxyphenyl)butyraldehyde, with a yield of 77.7% and a purity of 95.2% by GC.

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PUM

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Abstract

The invention provides a method for synthesizing 4-(4-carbomethoxyphenyl) butyraldehyde, which comprises the following steps: condensing methyl 4-bromobenzoate and3-buten-1-ol; extracting the condensation product by organic solvent during post processing; adding silica gel to decolorize the product; removing the organic solvent by evaporation and then obtaining the 4-(4-carbomethoxyphenyl) butyraldehyde. A product obtained by the method has the yield of more than 80 percent and the GC detecting purity of more than 95 percent and can be directly used for the following brominating reaction for synthesizing pemetrexed disodium without any refinement. The method has the advantages of simple technological operation and low cost and easy acquisition of the used reagent and is suitable for industrial production.

Description

technical field [0001] The present invention relates to a method for synthesizing 4-(4-methoxyphenyl)butyraldehyde. Background technique [0002] 4-(4-Methoxyphenyl)butyraldehyde is a key intermediate in the synthesis of antineoplastic drug pemetrexed disodium. There are mainly three kinds of reports about its synthetic method: one is J.Org.Chem., 1990,55:3222-7 report adopts 3-butyn-1-alcohol and p-bromobenzoic acid methyl ester to condense, and then through palladium carbon Hydrogenation reduction, PCC oxidation alcohol to obtain product, this method steps is loaded down with trivial details, and reagent is expensive; The second is Tetrahedron Letters, 1989,30:6629-32 report adopts 3-buten-1-alcohol and p-bromobenzoic acid methyl ester to condense, through Column chromatography separates and obtains pure product, and this method needs column chromatography, is not suitable for suitability for suitability for industrialized production; The 3rd is Chemical Industry Times Ma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/76C07C67/343
CPCC07D487/04C07C67/343C07C69/76
Inventor 李金亮赵楠
Owner SHANGHAI ACEBRIGHT PHARMA CO LTD
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