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Industrialized preparation method for 5 - formoxyl - 3 - ester thiohenic acid

A technology of thiophene carboxylate and formyl, which is applied in the field of industrial preparation of 5-formyl-3-thiophene carboxylate, can solve the problems of harsh reaction conditions, low reaction yield, and difficult availability of raw materials, and avoid low temperature Simple reaction and synthetic route, avoiding the use of organometallic reagents

Active Publication Date: 2012-03-07
SHANGHAI STA PHARMA R&D CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The purpose of the present invention is to provide a kind of synthetic technique of the 5-formyl-3-thiophene carboxylate of industrial production, overcome existing synthetic method route is long, raw material is difficult to obtain, reaction yield is low, reaction condition is harsh, and organic metal is used Disadvantages such as reagents

Method used

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  • Industrialized preparation method for 5 - formoxyl - 3 - ester thiohenic acid
  • Industrialized preparation method for 5 - formoxyl - 3 - ester thiohenic acid
  • Industrialized preparation method for 5 - formoxyl - 3 - ester thiohenic acid

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Effect test

Embodiment 1

[0019] Synthesis of methyl 5-formyl-3-thiophenecarboxylate via palladium-catalyzed carbonylation of tetrakistriphenylphosphine

[0020]

[0021] Under nitrogen protection, a mixed solution of 4-bromo-2-thiophenecarbaldehyde (100g, 588moml), triethylamine (115g, 1138mml), tetrakistriphenylphosphopalladium (5g, 4.3mmol), methanol (660mL) was prepared at 80 -85°C, 5 atmospheres of carbon monoxide atmosphere, reacted for 14 hours, then cooled to room temperature, concentrated to dryness, added water (400mL) and ethyl acetate (900mL), stirred until completely dissolved, stood to separate the layers, and the organic layer was washed with 2N Hydrochloric acid (300mL), 5% sodium bicarbonate (300mL), and water (300mL) were washed once each; then concentrated, and the crude product was recrystallized with petroleum ether to obtain 78g of the product, with a yield of 88%.

[0022] 1 H NMR (CDCl 3 ): .3.81(s, 3H), 8.33(s, 1H), 8.79(s, 1H), 9.94(s, 1H); MS(m / z): 171

Embodiment 2

[0024] Synthesis of 5-formyl-3-thienylmethanol by palladium acetate+1,3-bis(diphenylphosphino)propane catalyzed carbonylation reaction methyl ester

[0025]

[0026] Palladium acetate (2.25g, 10mmol) and 1,3-bis(diphenylphosphino)propane (8.3g, 20mmol) were added to 4-bromo-2-thiophenecarbaldehyde (80.5g, 0.50mol) and triethylamine ( 242.2g, 2.22mol) of dimethylformamide (4L)-methanol (1L) solution. 70°C, under normal pressure, reacted under carbon monoxide atmosphere for two days. The catalyst was removed by filtration, concentrated and recrystallized by n-hexane to obtain 72 g (yield: 85%).

Embodiment 3

[0028] Synthesis of 5-formyl-3- Ethyl thiophenecarboxylate

[0029]

[0030] Palladium chloride (18.4g, 0.104mol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (27.6g, 0.044mol) were added to 4-bromo-2-thiophenecarbaldehyde ( 80.5g, 0.50mol) and triethylamine (242.2g, 2.22mol) in methanol (4L)-acetonitrile (2L) solution. 100°C, under normal pressure, reacted under carbon monoxide atmosphere for two days. The catalyst was removed by filtration and the reactant was concentrated and then recrystallized from petroleum ether to obtain 75 g (yield: 82%).

[0031] 1 H NMR (CDCl 3 ): .1.21(t, 3H), 4.20(q, 2H), 8.31(s, 1H), 8.76(s, 1H), 9.96(s, 1H); MS(m / z): 185

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Abstract

This invention relates to an industrial production method for 5-formyl-3-thiophenecarboxylate. The method comprises: performing carbonylation reaction on 4-bromo-thiophene-2-carbaldehyde and alcohol in the presence of Pd catalyst and reaction promoter to obtain 5-formyl-3-thiophenecarboxylate in one step. The method has such advantages as simple route, reasonable process, no need for organic metal reagent, no need for low-temperature reaction, and high synthesis efficiency, and is suitable for mass production. Pd catalyst can be recovered and recycled, which can reduce the cost. The method solves the problems of long synthesis route, dew raw materials, low reaction yield, rigorous reaction conditions and organic metal reagent faced by the present synthesis method.

Description

[0001] Technical field: the present invention relates to a kind of industrialized preparation method of 5-formyl-3-thiophene carboxylate. Background technique: [0002] 5-formyl-3-thiophene carboxylate and its derivatives are relatively useful organic synthesis intermediates (see literature US5498755; US5840917; US2003 / 0166668; WO2003 / 76440; Bull.Chem.Soc.Jpn.1988, 2031; Bioorg.Med.Chem.; 2004, 4511-4532, etc.) [0003] For the synthesis of 5-formyl-3-thiophenecarboxylate, there are two methods reported in the literature at present: the one is to combine 5-bromo-3-thiophenecarboxylic acid with dimethylformamide after being treated with organometallic reagents at low temperature The corresponding 5-formyl-3-thiophenecarboxylic acid is obtained through the reaction, and the 5-formyl-3-thiophenecarboxylic acid ester is obtained through esterification (synthetic route 1, US5840917). The raw material of this process is not easy to obtain, while the first step is low temperature an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/38B01J31/24
Inventor 张峰胡伟峰沙春波马汝建唐苏翰李革
Owner SHANGHAI STA PHARMA R&D CO LTD
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