2',3'-O-carbonyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine synthesis method

Abstract

The invention discloses a 2',3'-O-carbonyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine synthesis method. According to the method, 2,3-di-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine is adopted as a raw material, and is dissolved by using an organic solvent; organic alkali is added; CO2 is delivered in; and a reaction is allowed under a reaction temperature controlled at 0-50 DEG C and a reaction time controlled at 1-24h. According to the method, an intermediate of a capecitabine production process is used for preparing capecitabine impurity C2',3'-O-carbonyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine. The raw materials are easier to obtain, and the method is more simplified.

Description

technical field

[0001] The present invention relates to a synthesis method of capecitabine impurity C (2',3'-O-carbonyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine nucleoside) , belonging to the field of medical technology. Background technique

[0002] Capecitabine (Capecitabine) is an anti-metabolite fluoropyrimidine deoxynucleoside carbamate drug that can be converted into 5-FU in the body. It is developed by Roche and its trade name is Xeloda. It can inhibit cell division and interfere with RNA and protein synthesis. With the widespread promotion of capecitabine, more and more people pay attention to the research on its impurities.

[0003] Capecitabine impurity C, chemical name: 2',3'-O-carbonyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine, CAS number: 921769-65 -5, molecular formula: C 16 h 20 N 3 o 7 F, molecular weight: 385.3443. Its chemical structural formula is shown below.

[0004]

[0005] The synthetic method of the impurity C of existi...

Examples

example 1

[0023] Example 1: Using dichloromethane as a solvent and pyridine as an organic base.

[0024] Take 20g of 2,3-di-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine nucleoside into a 500ml four-necked bottle, add 200ml of dichloromethane and 20ml of pyridine , start stirring, control the reaction temperature at 25°C, and slowly introduce CO 2 After 5 hours, add 150ml of purified water to wash for 30 minutes, static layering, after separating the organic layer, add 150ml of purified water and wash for 30 minutes, static layering, after separating the organic layer, concentrate the organic layer under reduced pressure, the temperature of the water bath is 40°C, concentrated to dryness under reduced pressure to obtain a white solid, and then added 60ml of isopropanol to recrystallize to obtain 10.9g of a white solid with a purity of 99.2% and a yield of 62.7%.

example 2

[0025] Example two: using dichloromethane as a solvent and triethylamine as an organic base.

[0026] Take 20g of 2,3-di-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine nucleoside into a 500ml four-necked bottle, add 200ml of dichloromethane, triethyl Amine 28ml, start stirring, control the reaction temperature 25°C, slowly feed CO 2 After 5 hours, add 150ml of purified water to wash for 30 minutes, static layering, after separating the organic layer, add 150ml of purified water and wash for 30 minutes, static layering, after separating the organic layer, concentrate the organic layer under reduced pressure, the temperature of the water bath is 40°C, concentrated to dryness under reduced pressure to obtain a white solid, and then added 60ml of isopropanol for recrystallization to obtain 9.1 g of an off-white solid with a purity of 97.8% and a yield of 52.6%.

example 3

[0027] Example three: using toluene as a solvent and pyridine as an organic base.

[0028] Take 20g of 2,3-di-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine nucleoside into a 500ml four-necked bottle, add 200ml of toluene and 20ml of pyridine, and open Stir, control the reaction temperature at 25°C, and slowly introduce CO 2 After 5 hours, add 150ml of purified water to wash for 30 minutes, static layering, after separating the organic layer, add 150ml of purified water and wash for 30 minutes, static layering, after separating the organic layer, concentrate the organic layer under reduced pressure, the temperature of the water bath is 40°C, concentrated to dryness under reduced pressure to obtain a white solid, and then added 60ml of isopropanol to recrystallize to obtain 10.2g of a white solid with a purity of 98.6% and a yield of 58.9%.

technical field

[0001] The present invention relates to a synthesis method of capecitabine impurity C (2',3'-O-carbonyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine nucleoside) , belonging to the field of medical technology. Background technique

[0002] Capecitabine (Capecitabine) is an anti-metabolite fluoropyrimidine deoxynucleoside carbamate drug that can be converted into 5-FU in the body. It is developed by Roche and its trade name is Xeloda. It can inhibit cell division and interfere with RNA and protein synthesis. With the widespread promotion of capecitabine, more and more people pay attention to the research on its impurities.

[0003] Capecitabine impurity C, chemical name: 2',3'-O-carbonyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine, CAS number: 921769-65 -5, molecular formula: C 16 h 20 N 3 o 7 F, molecular weight: 385.3443. Its chemical structural formula is shown below.

[0004]

[0005] The synthetic method of the impurity C of existi...

Examples

example 1

[0023] Example 1: Using dichloromethane as a solvent and pyridine as an organic base.

[0024] Take 20g of 2,3-di-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine nucleoside into a 500ml four-necked bottle, add 200ml of dichloromethane and 20ml of pyridine , start stirring, control the reaction temperature at 25°C, and slowly introduce CO 2 After 5 hours, add 150ml of purified water to wash for 30 minutes, static layering, after separating the organic layer, add 150ml of purified water and wash for 30 minutes, static layering, after separating the organic layer, concentrate the organic layer under reduced pressure, the temperature of the water bath is 40°C, concentrated to dryness under reduced pressure to obtain a white solid, and then added 60ml of isopropanol to recrystallize to obtain 10.9g of a white solid with a purity of 99.2% and a yield of 62.7%.

example 2

[0025] Example two: using dichloromethane as a solvent and triethylamine as an organic base.

[0026] Take 20g of 2,3-di-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine nucleoside into a 500ml four-necked bottle, add 200ml of dichloromethane, triethyl Amine 28ml, start stirring, control the reaction temperature 25°C, slowly feed CO 2 After 5 hours, add 150ml of purified water to wash for 30 minutes, static layering, after separating the organic layer, add 150ml of purified water and wash for 30 minutes, static layering, after separating the organic layer, concentrate the organic layer under reduced pressure, the temperature of the water bath is 40°C, concentrated to dryness under reduced pressure to obtain a white solid, and then added 60ml of isopropanol for recrystallization to obtain 9.1 g of an off-white solid with a purity of 97.8% and a yield of 52.6%.

example 3

[0027] Example three: using toluene as a solvent and pyridine as an organic base.

[0028] Take 20g of 2,3-di-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine nucleoside into a 500ml four-necked bottle, add 200ml of toluene and 20ml of pyridine, and open Stir, control the reaction temperature at 25°C, and slowly introduce CO 2 After 5 hours, add 150ml of purified water to wash for 30 minutes, static layering, after separating the organic layer, add 150ml of purified water and wash for 30 minutes, static layering, after separating the organic layer, concentrate the organic layer under reduced pressure, the temperature of the water bath is 40°C, concentrated to dryness under reduced pressure to obtain a white solid, and then added 60ml of isopropanol to recrystallize to obtain 10.2g of a white solid with a purity of 98.6% and a yield of 58.9%.

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