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Pyrrolecarboxylic acid derivative synthesis method

A technology for pyrrole carboxylic acid and synthesis method, which is applied in the field of synthesis of pyrrole carboxylic acid derivatives, can solve the problems of many by-products, unsuitability for scale-up production, and low yield, and achieve easy scale-up production, good operability, and yield high rate effect

Inactive Publication Date: 2019-10-22
上海毕得医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] However, there are many by-products in this route, and the yield is very low, so it is not suitable for industrialized scale-up production

Method used

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  • Pyrrolecarboxylic acid derivative synthesis method
  • Pyrrolecarboxylic acid derivative synthesis method
  • Pyrrolecarboxylic acid derivative synthesis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] A kind of synthetic method of pyrrole carboxylic acid derivative, the steps are as follows:

[0065] Step 1: Under the protection of argon, add 10 g of 2-acetylthiophene (1-1) into anhydrous tetrahydrofuran (100 ml), control the temperature below 10 degrees Celsius, and slowly add sodium hydride (60%, 6.3 g , 2eq), after the addition, the temperature was raised to 40 degrees Celsius, and ethyl acetate (14g, 2eq) was slowly added dropwise, and the drop was completed, kept at 40 degrees Celsius, stirred and reacted for 1h, after TLC detected that the reaction was complete, slowly added ice water (200ml) and ethyl acetate Ester (100ml), separated, the aqueous phase was extracted with ethyl acetate (100ml*5), all organic phases were combined, washed with saturated brine (200ml), concentrated under reduced pressure until almost no liquid flowed out, and a brown liquid 1 was obtained -(2-Thienyl)-1,3-butanedione (1-2) (17 g, crude).

[0066] The synthetic route is as follows...

Embodiment 2

[0078] A kind of synthetic method of pyrrole carboxylic acid derivative, the steps are as follows:

[0079] Step 1: Add 1-(4-fluoro-phenyl)-butane-1,3-dione (2-1) (26g) to glacial acetic acid (250ml), add diethyl aminomalonate Acetate (85.5g, 2.4eq) and sodium acetate (112.4g, 5eq) were heated and refluxed for overnight reaction. After TLC detected that the reaction was complete, ice water (400ml) and ethyl acetate (200ml) were added, and then adjusted with solid sodium carbonate. pH value to 8-9. After the adjustment, stir for 30min and separate layers. The aqueous layer was extracted with ethyl acetate (200ml*3). All organic layers were combined and washed with saturated brine (500ml). Concentrate under reduced pressure until almost no liquid flows out, add silica gel to spin dry, and obtain white solid compound 5-(4-fluorophenyl)-3-methyl- 1H-Pyrrole-2-carboxylic acid ethyl ester (2-2) (24.6 g, yield 67%, UPLC purity: 99%).

[0080] The synthetic route is as follows: ...

Embodiment 3

[0089] A kind of synthetic method of pyrrole carboxylic acid derivative, the steps are as follows:

[0090] Step 1: Add acetylcyclohexane (3-1) (30g) into tetrahydrofuran (300ml), slowly add sodium hydrogen (19.02g, 2eq) at 10°C, drop ethyl acetate (41.9g, 2eq), reacted at 40°C for 1h, after the completion of the reaction as detected by TLC, poured into ice water, extracted the aqueous layer with ethyl acetate (200ml*3), combined all organic layers, and washed with saturated brine (500ml). Concentrate under reduced pressure until almost no liquid flows out, add silica gel to spin dry, and pass column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain the white solid compound 1-cyclohexylbutane-1,3-dione (3 -2) (36.2 g, yield: 90.5%, UPLC purity: 99%).

[0091] The synthetic route is as follows:

[0092]

[0093] Step 2: Add 1-cyclohexylbutane-1,3-dione (3-2) (36.2g) to glacial acetic acid (360ml), add diethyl aminomalonate hydrochloride (109.3g, 2.4eq) and ...

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Abstract

The invention discloses a pyrrolecarboxylic acid derivative synthesis method, which comprises: obtaining a group substituted formylacetone derivative by using a group substituted acetyl derivative andethyl acetate as raw materials; carrying out cyclization with diethyl aminomalonate hydrochloride to generate a pyrrolecarboxylic acid derivative ethyl ester; and carrying out a hydrolysis reaction to obtain the target product pyrrolecarboxylic acid derivative. According to the present invention, the method has characteristics of mild reaction conditions, simple purification, high yield and highproduct purity, and is suitable for process amplification and mass production.

Description

technical field [0001] The invention relates to the technical field of synthesis of organic chemical intermediates, in particular to a synthesis method of pyrrole carboxylic acid derivatives. Background technique [0002] Pyrrole derivatives are widely used as raw materials for organic synthesis, pharmaceuticals, pesticides, spices, rubber vulcanization accelerators, epoxy resin curing agents, etc., used as standard substances for chromatographic analysis, and also used in organic synthesis and pharmaceutical industries. [0003] Heteroaryl-substituted pyrrole derivatives due to their excellent inhibitory activity against the production of pro-inflammatory cytokines such as interleukin (IL)-1, IL-6 and IL-8 and tumor necrosis factor (TNF) , especially IL-1β and TNFα, therefore have antipyretic, analgesic, antiviral and anti-inflammatory activities, and can be used for the synthesis of prevention and treatment of autoimmune diseases such as chronic rheumatism, bone diseases s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/34C07D409/04
CPCC07D207/34C07D409/04
Inventor 涂强郦荣浩
Owner 上海毕得医药科技股份有限公司
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