Synthetic method of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester

A technology of ethyl pyrrolecarboxylate and a synthetic method, applied in the direction of organic chemistry, etc., can solve the problems of difficult control of the hydrolysis process, harsh reaction conditions, cumbersome operation steps, etc., and achieve easy large-scale industrial production, mild reaction conditions, and simple operation steps Effect

CN103265468AInactive Publication Date: 2013-08-28LIANYUNGANG SHENGHE BIOTECH
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Publication Date
2013-08-28
Estimated Expiration
Not applicable · inactive patent

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Abstract

The invention relates to a synthetic method of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester. The synthetic method comprises the following steps of: carrying out bromination reaction on propionaldehyde and bromine at the temperature of 0-50 DEG C to obtain 2-bromopropanal, wherein the adopted solvent is a non-proton solvent; and carrying out ring-closure reaction on 2-bromopropanal, ethyl acetoacetate and ammonia water to obtain 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester. The synthetic method of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester has the advantages of mild reaction conditions, available raw materials, high conversion rate, simple operation steps and easy realization of large-scale industrialized production; the defects of too high cost and pollution of sodium nitrite to the environment and disadvantages on large-scale industrial production, which are caused by adoption of tert-butyl acetoacetate, can be avoided; available ethyl acetoacetate and ammonia water are adopted as raw materials, operation is easy, aftertreatment is simple, and large-scale industrial production is easy to realize; and the defects of unmanageable reaction process, high product impurity content and low yield during hydrolysis, which are caused as tert-butyl acetoacetate is adopted as a closed-loop reagent, can be avoided.
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Description

technical field

[0001] The invention relates to a method for synthesizing ethyl 2,4-dimethyl-3-pyrrolecarboxylate, and relates to the field of medicinal chemistry. Background technique

[0002] 2,4-dimethyl-3-pyrrole carboxylic acid ethyl ester, its structural formula is as follows:

[0003]

[0004] Ethyl 2,4-dimethyl-3-pyrrolecarboxylate is an important intermediate in the synthesis of sunitinib malate. Sunitinib, chemical name N-[2-(diethylamino)ethyl]-5-[(Z)-5-fluoro-1,2-dihydro-2-oxoindole- 3-enmethyl]-2,4-dimethyl-1H-pyrrole carboxamide, an oral multi-target receptor tyrosine kinase inhibitor launched in 2006, is clinically used for malignant gastrointestinal stromal tumors and metastasis treatment of renal cell carcinoma. Sunitinib has dual effects of anti-tumor growth and inhibition of angiogenesis. On January 26, 2006, it was approved by the US FDA for the treatment of ARCC and GIST.

[0005] The existing synthetic routes of 2,4-dimethyl-3-pyrrolecarboxylic ...

Examples

Embodiment 1

[0028] Embodiment 1, a kind of synthetic method of ethyl 2,4-dimethyl-3-pyrrolecarboxylate, the method comprises the following steps:

[0029] (1) Propionaldehyde and bromine undergo bromination reaction to obtain 2-bromopropionaldehyde; the reaction is carried out at 0°C~50°C; the solvent used is an aprotic solvent;

[0030] (2) 2-Bromopropionaldehyde, ethyl acetoacetate and ammonia water undergo a ring-closing reaction to obtain ethyl 2,4-dimethyl-3-pyrrolecarboxylate; the reaction is carried out under alkaline conditions at 0°C to 50°C.

Embodiment 2

[0031] Example 2, in the synthesis method described in Example 1: the aprotic solvent described in step (1) is selected from toluene, dichloromethane, N,N-dimethylformamide, N,N-dimethylformamide One or a mixture of amides and dimethyl sulfoxide.

Embodiment 3

[0032] Embodiment 3, in the synthetic method described in embodiment 1 or 2: its specific synthetic steps are as follows:

[0033] (1) Preparation of 2-bromopropionaldehyde: Add propionaldehyde to an appropriate amount of aprotic solvent, cool down to 0-10°C, add bromine dropwise, control the reaction temperature at 0°C-50°C during the dropwise addition, drop bromine After the addition is completed, react at 0°C~50°C for 3~5h, wait until the color of bromine fades, and concentrate to dryness to obtain 2-bromopropionaldehyde; the mass ratio of propionaldehyde to bromine is 1:2.5~3.5;

[0034] (2) Preparation of ethyl 2,4-dimethyl-3-pyrrolecarboxylate: put 2-bromopropionaldehyde and ethyl acetoacetate into the reaction vessel, cool down to 0~10°C, add ammonia water dropwise, and drop the temperature 0°C~50°C. After the dropwise addition, react at 0°C~50°C for 10-14 hours; Remove dichloromethane, freeze and crystallize for 2 days, take out the crystals and stir at 0°C, beat the ...