Preparation method of 5-(piperazine-1-group) benzofuran-2-carboxylic acid ethyl ester

Abstract

The invention relates to a preparation method of 5-(piperazine-1-group) benzofuran-2-carboxylic acid ethyl ester. 5-(piperazine-1-group) benzofuran-2-carboxylic acid ethyl ester is an important intermediate for synthetizing hydrochloric vilazodone. Under the existence of alkali and phase transfer catalyst, 5-amino-benzofuran-2-carboxylic acid ethyl ester and N, N-di (2-chlorine ethyl) amine hydrochloride are reacted in solvent, reaction time is 2-6 hours, and reaction temperature ranges from room temperature to backflow temperature of the solvent. By the preparation method, reaction time is shortened, and yield rate and purity of products are improved. The preparation method is simple, reliable and low in production cost and has higher implement value and social and economic benefits.

Description

technical field

[0001] The invention relates to a preparation method of ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate, which is an important intermediate for synthesizing vilazodone hydrochloride. Background technique

[0002] Vilazodone hydrochloride was approved by the US Food and Drug Administration in January 2011 for the treatment of moderate to severe depression in adults. Clinical trial data show that its curative effect is significantly better than that of placebo, with good tolerance and less adverse reactions.

[0003] 5-(piperazin-1-yl) ethyl benzofuran-2-carboxylate is the key intermediate of synthetic vilazodone hydrochloride, and a kind of its synthetic method is announced in U.S. Patent No. 5,723,614 as follows:

[0004]

[0005] In this method, ethyl 5-aminobenzofuran-2-carboxylate is used as raw material and N,N-bis(2-chloroethyl)amine to react with stirring for 10 hours to prepare 5-(piperazin-1-yl)benzo Ethyl furan-2-carboxylate, but did not give a...

Examples

Embodiment 1

[0025] 1 Add 50g of ethyl 5-aminobenzofuran-2-carboxylate, 50g of N,N-bis(2-chloroethyl)amine hydrochloride, 60g of anhydrous sodium carbonate, and tetrabutylammonium bromide into the reaction flask 4g, 500ml of n-butanol, heated and refluxed for 5 hours, filtered with suction, washed the filter cake with water to remove inorganic salts, and dried under reduced pressure at 40-50°C to obtain 60g of off-white solid with a yield of 89% and a purity of 98.6%. HPLC profile such as figure 1 shown. See Table 1 for specific data.

[0026] Table 1 Specific data of each spectrum

[0027] peak Retention time (min) Types of Peak width (min) Peak area (mAU*s) Peak height (mAU) Peak area% 1 5.146 MM 0.0938 8861.20703 1573.71216 98.6491 2 5.533 MM 0.0645 41.95242 10.83328 0.4670 3 7.042 MM 0.1209 79.38930 10.94166 0.8838 total 8982.54875 1595.48709

Embodiment 2

[0029] 1 Add 50g of ethyl 5-aminobenzofuran-2-carboxylate, 50g of N,N-bis(2-chloroethyl)amine hydrochloride, 57g of triethylamine, and 4g of tetrabutylammonium bromide into the reaction flask , toluene 500ml, heat up and react for 2 hours, filter with suction, wash the filter cake with water to remove inorganic salts, dry under reduced pressure at 40-50°C to obtain 56g of off-white solid, yield 84%, purity 99.1%. HPLC profile such as figure 2 shown. See Table 2 for specific data.

[0030] Table 2 Specific data of each spectrum

[0031] peak Retention time (min) Types of Peak width (min) Peak area (mAU *s) Peak height (mAU) Peak area% 1 5.111 MM 0.1124 1.58444e4 2349.64648 99.1588 2 5.416 MM 0.0589 44.65551 12.63103 0.2795 3 6.599 MM 0.1049 89.75358 14.26618 0.5617 total 1.59788e4 2376.54369

Embodiment 3

[0033] 1 Add 50g of ethyl 5-aminobenzofuran-2-carboxylate, 50g of N,N-bis(2-chloroethyl)amine hydrochloride, 4g of tetrabutylammonium chloride, and 500ml of distilled water into the reaction flask, and divide Add 60 g of anhydrous sodium carbonate in 5 batches, with an interval of 30 minutes between each batch. After the addition, raise the temperature and reflux for 3 hours, filter with suction, and dry the filter cake under reduced pressure at 40-50°C to obtain 54 g of off-white solid, with a yield of 81% and a purity of 98%. HPLC profile such as image 3 . See Table 3 for specific data.

[0034] Table 3 Specific data of each spectrum

[0035] peak Retention time (min) Types of Peak width (min) Peak area (mAU *s) Peak height (mAU) Peak area% 1 5.111 MM 0.1176 1.65750e4 2349.26392 98.0743 2 5.531 MM 0.0692 105.01313 25.28586 0.6214 3 7.063 MM 0.0989 220.43629 37.15370 1.3043 total 1.69005e4...

technical field

[0001] The invention relates to a preparation method of ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate, which is an important intermediate for synthesizing vilazodone hydrochloride. Background technique

[0002] Vilazodone hydrochloride was approved by the US Food and Drug Administration in January 2011 for the treatment of moderate to severe depression in adults. Clinical trial data show that its curative effect is significantly better than that of placebo, with good tolerance and less adverse reactions.

[0003] 5-(piperazin-1-yl) ethyl benzofuran-2-carboxylate is the key intermediate of synthetic vilazodone hydrochloride, and a kind of its synthetic method is announced in U.S. Patent No. 5,723,614 as follows:

[0004]

[0005] In this method, ethyl 5-aminobenzofuran-2-carboxylate is used as raw material and N,N-bis(2-chloroethyl)amine to react with stirring for 10 hours to prepare 5-(piperazin-1-yl)benzo Ethyl furan-2-carboxylate, but did not give a...

Examples

Embodiment 1

[0025] 1 Add 50g of ethyl 5-aminobenzofuran-2-carboxylate, 50g of N,N-bis(2-chloroethyl)amine hydrochloride, 60g of anhydrous sodium carbonate, and tetrabutylammonium bromide into the reaction flask 4g, 500ml of n-butanol, heated and refluxed for 5 hours, filtered with suction, washed the filter cake with water to remove inorganic salts, and dried under reduced pressure at 40-50°C to obtain 60g of off-white solid with a yield of 89% and a purity of 98.6%. HPLC profile such as figure 1 shown. See Table 1 for specific data.

[0026] Table 1 Specific data of each spectrum

[0027] peak Retention time (min) Types of Peak width (min) Peak area (mAU*s) Peak height (mAU) Peak area% 1 5.146 MM 0.0938 8861.20703 1573.71216 98.6491 2 5.533 MM 0.0645 41.95242 10.83328 0.4670 3 7.042 MM 0.1209 79.38930 10.94166 0.8838 total 8982.54875 1595.48709

Embodiment 2

[0029] 1 Add 50g of ethyl 5-aminobenzofuran-2-carboxylate, 50g of N,N-bis(2-chloroethyl)amine hydrochloride, 57g of triethylamine, and 4g of tetrabutylammonium bromide into the reaction flask , toluene 500ml, heat up and react for 2 hours, filter with suction, wash the filter cake with water to remove inorganic salts, dry under reduced pressure at 40-50°C to obtain 56g of off-white solid, yield 84%, purity 99.1%. HPLC profile such as figure 2 shown. See Table 2 for specific data.

[0030] Table 2 Specific data of each spectrum

[0031] peak Retention time (min) Types of Peak width (min) Peak area (mAU *s) Peak height (mAU) Peak area% 1 5.111 MM 0.1124 1.58444e4 2349.64648 99.1588 2 5.416 MM 0.0589 44.65551 12.63103 0.2795 3 6.599 MM 0.1049 89.75358 14.26618 0.5617 total 1.59788e4 2376.54369

Embodiment 3

[0033] 1 Add 50g of ethyl 5-aminobenzofuran-2-carboxylate, 50g of N,N-bis(2-chloroethyl)amine hydrochloride, 4g of tetrabutylammonium chloride, and 500ml of distilled water into the reaction flask, and divide Add 60 g of anhydrous sodium carbonate in 5 batches, with an interval of 30 minutes between each batch. After the addition, raise the temperature and reflux for 3 hours, filter with suction, and dry the filter cake under reduced pressure at 40-50°C to obtain 54 g of off-white solid, with a yield of 81% and a purity of 98%. HPLC profile such as image 3 . See Table 3 for specific data.

[0034] Table 3 Specific data of each spectrum

[0035] peak Retention time (min) Types of Peak width (min) Peak area (mAU *s) Peak height (mAU) Peak area% 1 5.111 MM 0.1176 1.65750e4 2349.26392 98.0743 2 5.531 MM 0.0692 105.01313 25.28586 0.6214 3 7.063 MM 0.0989 220.43629 37.15370 1.3043 total 1.69005e4...

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