Preparation method of 2-bromothiophene

Abstract

The invention discloses a preparation method of 2-bromothiophene, relates to a method for improving thiophene 2-site substitution selectivity and reducing the generation amount of 3-bromothiophene, and belongs to the technical field of preparation of fine chemical products such as medicines. The method is characterized in that thiophene is converted into 2-bromothiophene in the presence of L-valine methyl ester. The preparation method comprises the steps of adding sodium bromide, L-valine methyl ester and water, adding sulfuric acid, adding thiophene, and adding hydrogen peroxide. The reactionformula is shown in the attached drawing. The method has the advantages of being high in thiophene 2-sit substitution selectivity, small in 3-bromothiophene generation amount, environmentally friendly and low in cost.

Description

technical field

[0001] A method for preparing 2-bromothiophene relates to a method for improving the 2-position substitution selectivity of thiophene and reducing the amount of 3-bromothiophene produced, and belongs to the technical field of preparation of fine chemical products such as medicine. Background technique

[0002] 2-bromothiophene has important uses in the field of medicine and chemical industry: 2-thiophenethanol can be synthesized by using 2-bromothiophene as raw material through Grignard reaction and Grignard reagent conversion. 2-Thiphenethanol is an important intermediate in the synthesis of clopidogrel bisulfate.

[0003] The most critical impurity of 2-bromothiophene is 3-bromothiophene. Such as figure 1 Shown: 3-bromothiophene can be transferred to the raw material drug clopidogrel bisulfate through the related reactions of the synthesis of clopidogrel bisulfate. The impurity B of the European Pharmacopoeia of clopidogrel bisulfate is transferred from ...

Examples

Embodiment 1

[0028] Add 52.8g (0.513mol) of commercially available sodium bromide, 7.4g (0.056mol) of commercially available L-valine methyl ester, and 340ml of water into a 500ml reaction bottle. Sulfuric acid 64.3g (0.642mol), after dropwise addition, cool down to 5-10°C, add 45.0g (0.535mol) of thiophene, then add 62.4g (0.642mol) of 35% hydrogen peroxide dropwise at 5-10°C, about 1-10°C 2 hours to drip. After dropping, control the temperature at 5-10°C for 18 hours, let stand, and separate layers. The organic layer was steam distilled to obtain 2-bromothiophene, wherein the content of 3-bromothiophene was 0.12%, see Figure 4 .

Embodiment 2

[0030] Drop into 400g of valsartan waste water in the 500ml reaction bottle, contain sodium bromide 52.8g (0.513mol), L-valine methyl ester 7.4g (0.056mol) in the waste water, control feed liquid temperature ≤ 40 ℃ under stirring, drop Add 64.3g (0.642mol) of concentrated sulfuric acid, after the dropwise addition, cool down to 5-10°C, add 45.0g (0.535mol) of thiophene, and then add 62.4g (0.642mol) of 35% hydrogen peroxide dropwise at 5-10°C, approx. 1 to 2 hours to drop. After dropping, control the temperature at 5-10°C for 18 hours, let stand, and separate layers. The organic layer was steam-distilled to obtain 2-bromothiophene, wherein the content of 3-bromothiophene was 0.14%, see Figure 5 .

technical field

[0001] A method for preparing 2-bromothiophene relates to a method for improving the 2-position substitution selectivity of thiophene and reducing the amount of 3-bromothiophene produced, and belongs to the technical field of preparation of fine chemical products such as medicine. Background technique

[0002] 2-bromothiophene has important uses in the field of medicine and chemical industry: 2-thiophenethanol can be synthesized by using 2-bromothiophene as raw material through Grignard reaction and Grignard reagent conversion. 2-Thiphenethanol is an important intermediate in the synthesis of clopidogrel bisulfate.

[0003] The most critical impurity of 2-bromothiophene is 3-bromothiophene. Such as figure 1 Shown: 3-bromothiophene can be transferred to the raw material drug clopidogrel bisulfate through the related reactions of the synthesis of clopidogrel bisulfate. The impurity B of the European Pharmacopoeia of clopidogrel bisulfate is transferred from ...

Examples

Embodiment 1

[0028] Add 52.8g (0.513mol) of commercially available sodium bromide, 7.4g (0.056mol) of commercially available L-valine methyl ester, and 340ml of water into a 500ml reaction bottle. Sulfuric acid 64.3g (0.642mol), after dropwise addition, cool down to 5-10°C, add 45.0g (0.535mol) of thiophene, then add 62.4g (0.642mol) of 35% hydrogen peroxide dropwise at 5-10°C, about 1-10°C 2 hours to drip. After dropping, control the temperature at 5-10°C for 18 hours, let stand, and separate layers. The organic layer was steam distilled to obtain 2-bromothiophene, wherein the content of 3-bromothiophene was 0.12%, see Figure 4 .

Embodiment 2

[0030] Drop into 400g of valsartan waste water in the 500ml reaction bottle, contain sodium bromide 52.8g (0.513mol), L-valine methyl ester 7.4g (0.056mol) in the waste water, control feed liquid temperature ≤ 40 ℃ under stirring, drop Add 64.3g (0.642mol) of concentrated sulfuric acid, after the dropwise addition, cool down to 5-10°C, add 45.0g (0.535mol) of thiophene, and then add 62.4g (0.642mol) of 35% hydrogen peroxide dropwise at 5-10°C, approx. 1 to 2 hours to drop. After dropping, control the temperature at 5-10°C for 18 hours, let stand, and separate layers. The organic layer was steam-distilled to obtain 2-bromothiophene, wherein the content of 3-bromothiophene was 0.14%, see Figure 5 .

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