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Synthesis method of 4'-halogenated methylbiphenyl-2-formic aid alkyl ester

A technology of halomethylbiphenyl and alkyl formate, which is applied in the preparation of carboxylic acid esters, chemical instruments and methods, and the preparation of organic compounds, can solve the problem that p-tolueneboronic acid is expensive, unsuitable for industrialization, difficult Recycling and other issues to achieve the effect of low cost, less environmental pollution and mild conditions

Active Publication Date: 2016-02-17
常州博世伟业生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this process route, p-tolueneboronic acid is expensive, and a large amount of heavy metal catalysts are used in the coupling reaction, which is difficult to recycle and pollutes the environment, so this route is not suitable for industrialization

Method used

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  • Synthesis method of 4'-halogenated methylbiphenyl-2-formic aid alkyl ester
  • Synthesis method of 4'-halogenated methylbiphenyl-2-formic aid alkyl ester

Examples

Experimental program
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Effect test

Embodiment 1

[0036] In a three-necked flask equipped with mechanical stirring and a thermometer, add 19.8g (0.1mol) of biphenyl-2-carboxylic acid, 200ml of methanol and 2g (0.02mol) of concentrated sulfuric acid, and heat to reflux for 6h. Cooling, crystallization, after recovering 3 / 4 of the solvent from the mother liquor, continue cooling and crystallization. The two crystals were combined and dried to obtain 20.5 g of the finished product of methyl biphenyl-2-carboxylate, with a yield of 96.7%.

[0037] In a four-necked reaction flask, add 15g (70.7mmol) of methyl biphenyl-2-carboxylate, 2.4g (80mmol) of paraformaldehyde and 80g of carbon tetrachloride, and add the catalyst zinc bromide at a temperature of 25-30°C. 8g (36mmol), stirred for 20min. Add PBr slowly 3 11.5g (43mmol), the dropwise addition time is about 1h, after the dropwise addition is completed, HPLC sampling and analysis of raw material reaction is complete, about 3-4h. Cool down to 10°C, wash the oil layer with ice wa...

Embodiment 2

[0039] The preparation technology of biphenyl-2-methyl carboxylate is the same as in Example 1.

[0040] In a four-necked reaction flask, add 15g (70.7mmol) of methyl biphenyl-2-carboxylate, 2.4g (80mmol) of paraformaldehyde and 80g of carbon tetrachloride, and add the catalyst zinc chloride at a temperature of 25-30°C. 4.9g (36mmol), stirred for 20min. Slowly add PCl dropwise 3 5.82g (43mmol), the dropwise addition time is about 1h, the dropwise addition is completed, HPLC sampling analysis raw material reaction is complete, about 3 ~ 4h. The temperature was lowered to 10°C, the oil layer was washed with ice water three times, dried, and carbon tetrachloride was recovered to obtain a crude product. After the crude product was recrystallized, 15 g of pure 4'-chloromethylbiphenyl-2-methyl carboxylate was obtained, with a yield of 81.4%.

Embodiment 3

[0042] In a three-neck flask equipped with mechanical stirring and a thermometer, add 19.8g (0.1mol) of biphenyl-2-carboxylic acid, 200ml of ethanol and 2g (0.02mol) of concentrated sulfuric acid, and heat to reflux for 6h. Cooling, crystallization, after recovering 3 / 4 of the solvent from the mother liquor, continue cooling and crystallization. The two crystals were combined and dried to obtain 21.5 g of ethyl biphenyl-2-carboxylate, with a yield of 95.1%.

[0043] In a four-necked reaction flask, add 16g (70.7mmol) of ethyl biphenyl-2-carboxylate, 2.75g (91.7mmol) of paraformaldehyde and 100g of dichloromethane, and add the catalyst zinc bromide at a temperature of 30-35°C. 12g (53.3mmol), stirred for 20min. Add PBr slowly 314.4g (53.2mmol), the dropwise addition time is about 1h, after the dropwise addition is completed, HPLC sampling and analysis of raw material reaction is complete, about 2-3h. The temperature was lowered to 10°C, the oil layer was washed with ice wate...

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Abstract

The invention discloses a synthesis method of a 4'-halogenated methylbiphenyl-2-formic acid alkyl ester compound, and belongs to the technical field of organic synthesis. The method includes the following steps that 1, biphenyl-2-formic acid (I) and low alkyl alcohol are subjected to an esterification reaction under an acid catalyst to prepare biphenyl-2-formic acid alkyl ester (II); 2, the temperature in a four-mouth bottle containing biphenyl-2-formic acid alkyl ester (II), paraformaldehyde and a solvent is controlled to be within 20-50 DEG C, zinc halide is added, a dehydrating agent is added drop by drop, liquid chromatography monitoring is performed till the raw materials disappear about 2-5 h later, the reaction is finished, the temperature is lowered to the room temperature, an oil layer is washed, crystallization is performed to prepare 4'-halogenated methylbiphenyl-2-formic acid alkyl ester (III), and recrystallization purification is performed to prepare a pure product of 4'-halogenated methylbiphenyl-2-formic acid alkyl ester (III). According to the method, with biphenyl-2-formic acid as the starting raw material, the sartan drug intermediate 4'-halogenated methylbiphenyl-2-formic acid alkyl ester is prepared; the process is simple, conditions are easy to control, the raw materials are cheap and easy to get, production cost is low, environmental pollution is small, and the method is suitable for industrial production.

Description

【Technical field】 [0001] The invention relates to the technical field of fine chemicals, in particular to a synthetic method of 4'-halogenated methyl biphenyl-2-alkyl carboxylate. 【Background technique】 [0002] Telmisartan is an antihypertensive drug with a novel mechanism of action, definite curative effect, long-lasting and small side effects, and belongs to a new type of antihypertensive drug. Alkyl 4'-halomethylbiphenyl-2-carboxylate is a key intermediate in the synthesis of telmisartan. [0003] ArchivderPharmazie (Weinheim, Germany), 2011, 344 (9): 617-626; Medicinal Chemistry Research, 2009, 18 (8): 611-628; Organic Process Research & Development, 2007, 11 (1): 81-85; Bioorganic & Medicinal Chemistry Letters, 2005, 15 9): 2385-2388; CN102557987, WO2006044754, US20040044041, US20040034064 reported that 4'-methylbiphenyl-2-methyl carboxylate was used as raw material to obtain 4'-bromomethylbiphenyl-2 through one-step bromination reaction -The technological yield of m...

Claims

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Application Information

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IPC IPC(8): C07C67/343C07C69/76
CPCC07C67/08C07C67/343C07C69/76
Inventor 王钟毓张权青
Owner 常州博世伟业生物科技有限公司
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