New process for synthesizing salbutamol and sulfate of salbutamol

Abstract

The invention discloses a new process for synthesizing salbutamol. The process comprises the steps that (1) chloromethylation reaction: reactants namely p-hydroxy benzaldehyde and paraformaldehyde react under an acidic condition to generate a compound 1; (2) hydrolysis reaction: the compound 1 is subjected to hydrolysis reaction under a weakly alkaline condition to generate a compound 2; (3) propylidene protective reaction: dihydroxy of a reactant 2 is subjected to propylidene protection under catalysis of concentrated sulfuric acid; (4) epoxidation reaction: a reactant 3 reacts to obtain a compound 4 by using the effect of strong base under the effects of a ylide reagent and a phase transfer catalyst; (5) aminolysis ring-opening reaction: the compound 4 is heated and refluxed in tert-butylamine, and is subjected to aminolysis ring-opening reaction to obtain a compound 5; (6) hydrolysis de-protective reaction: the compound 5 is subjected to hydrolysis reaction under the acidic condition to obtain salbutamol. The new process disclosed by the invention is mild in reaction condition, easy in purification, and simple and easily-available in raw materials; the total molar yield of the process reaches up to 45%, and the product quality reaches up to more than 99.5%.

Description

technical field

[0001] The invention relates to the field of chemical synthesis, in particular to a new method for synthesizing albuterol and sulfate thereof. Background technique

[0002] Salbutamol (salbutamol), trade name: albuterol, is a b-receptor agonist, its action is strong but slow. It was discovered by British scholars in 1962 and developed by the British Glaxo company. It was first listed in 1968, registered in my country in 1988, and produced in China in 1975. Although this is an old drug, it still plays an irreplaceable role. In recent years, its sales in the world pharmaceutical market have ranked before the top 20. The formulations of albuterol include tablets, capsules, aerosols and injections.

[0003] Due to the rapid economic development and rapid population increase, my country's smog weather has increasingly become a problem that cannot be ignored. Respiratory diseases caused by smog weather have been a problem that everyone has been paying attention t...

Examples

Embodiment 1

[0053] (1) Preparation of Compound 1

[0054] Add 40ml of concentrated hydrochloric acid, 10g of p-hydroxybenzaldehyde, and 4.8g of paraformaldehyde into the reaction bottle, stir and react at 25-30°C for 8 hours, filter, and wash the obtained filter cake with 20ml of water, and 14g of the obtained red tide product is directly used for Next reaction.

[0055] (2) Preparation of Compound 2

[0056] Add 30 ml of water, 45 ml of tetrahydrofuran, and 14 g of compound (1) to the reaction bottle, add 6.4 g of sodium bicarbonate under stirring, stir and react at 25-30 ° C for 8 hours, let stand to separate layers, and continue to use the upper layer of tetrahydrofuran Wash with 20ml of water, dry and concentrate, and 10g of the obtained concentrated raffinate is directly used in the next reaction

[0057] (3) Preparation of compound 3

[0058] Add 70ml of acetone, 0.4ml of concentrated sulfuric acid, 10g of compound (2) to the reaction flask, stir and react at 25-30°C for 8 ...

Embodiment 2

[0068] (1) Preparation of Compound 1

[0069] Add 60ml of concentrated hydrochloric acid, 15g of p-hydroxybenzaldehyde, and 7.2g of paraformaldehyde into the reaction bottle, stir and react at 20-25°C for 10 hours, filter, and wash the obtained filter cake with 20ml of water, and 22g of the obtained red tide product is directly used for Next reaction.

[0070] (2) Preparation of Compound 2

[0071] Add 45 ml of water, 45 g of tetrahydrofuran, and 22 g of compound (1) in the reaction bottle, add 9.6 g of sodium bicarbonate under stirring, stir and react at 25-30 ° C for 10 hours, let stand to separate layers, and the upper layer of tetrahydrofuran layer continues Wash with 30ml of water, dry and concentrate, and 16g of the obtained concentrated residue is directly used in the next reaction

[0072] (3) Preparation of compound 3

[0073] Add 110ml of acetone, 0.7ml of concentrated sulfuric acid, and 16g of compound (2) into the reaction flask, stir and react at 25-30°C ...

Embodiment 3

[0083] (1) Preparation of Compound 1

[0084] Add 80ml of concentrated hydrochloric acid, 20g of p-hydroxybenzaldehyde, and 9.6g of paraformaldehyde into the reaction bottle, stir and react at 20-25°C for 12 hours, filter, and wash the obtained filter cake with 20ml of water, and 25g of the obtained red tide product is directly used for Next reaction.

[0085] (2) Preparation of Compound 2

[0086] Add 50 ml of water, 50 ml of tetrahydrofuran, and 25 g of compound (1) in the reaction bottle, add 6.8 g of sodium carbonate under stirring, stir and react at 25-30 ° C for 12 hours, let stand to separate layers, and continue to use 20 ml of tetrahydrofuran for the upper layer Washed with water, dried and concentrated, and 20 g of the obtained concentrated raffinate was directly used in the next step reaction

[0087] (3) Preparation of compound 3

[0088] Add 80ml of acetone, 1ml of concentrated sulfuric acid, and 20g of compound (2) into the reaction flask, stir and react...

technical field

[0001] The invention relates to the field of chemical synthesis, in particular to a new method for synthesizing albuterol and sulfate thereof. Background technique

[0002] Salbutamol (salbutamol), trade name: albuterol, is a b-receptor agonist, its action is strong but slow. It was discovered by British scholars in 1962 and developed by the British Glaxo company. It was first listed in 1968, registered in my country in 1988, and produced in China in 1975. Although this is an old drug, it still plays an irreplaceable role. In recent years, its sales in the world pharmaceutical market have ranked before the top 20. The formulations of albuterol include tablets, capsules, aerosols and injections.

[0003] Due to the rapid economic development and rapid population increase, my country's smog weather has increasingly become a problem that cannot be ignored. Respiratory diseases caused by smog weather have been a problem that everyone has been paying attention t...

Examples

Embodiment 1

[0053] (1) Preparation of Compound 1

[0054] Add 40ml of concentrated hydrochloric acid, 10g of p-hydroxybenzaldehyde, and 4.8g of paraformaldehyde into the reaction bottle, stir and react at 25-30°C for 8 hours, filter, and wash the obtained filter cake with 20ml of water, and 14g of the obtained red tide product is directly used for Next reaction.

[0055] (2) Preparation of Compound 2

[0056] Add 30 ml of water, 45 ml of tetrahydrofuran, and 14 g of compound (1) to the reaction bottle, add 6.4 g of sodium bicarbonate under stirring, stir and react at 25-30 ° C for 8 hours, let stand to separate layers, and continue to use the upper layer of tetrahydrofuran Wash with 20ml of water, dry and concentrate, and 10g of the obtained concentrated raffinate is directly used in the next reaction

[0057] (3) Preparation of compound 3

[0058] Add 70ml of acetone, 0.4ml of concentrated sulfuric acid, 10g of compound (2) to the reaction flask, stir and react at 25-30°C for 8 ...

Embodiment 2

[0068] (1) Preparation of Compound 1

[0069] Add 60ml of concentrated hydrochloric acid, 15g of p-hydroxybenzaldehyde, and 7.2g of paraformaldehyde into the reaction bottle, stir and react at 20-25°C for 10 hours, filter, and wash the obtained filter cake with 20ml of water, and 22g of the obtained red tide product is directly used for Next reaction.

[0070] (2) Preparation of Compound 2

[0071] Add 45 ml of water, 45 g of tetrahydrofuran, and 22 g of compound (1) in the reaction bottle, add 9.6 g of sodium bicarbonate under stirring, stir and react at 25-30 ° C for 10 hours, let stand to separate layers, and the upper layer of tetrahydrofuran layer continues Wash with 30ml of water, dry and concentrate, and 16g of the obtained concentrated residue is directly used in the next reaction

[0072] (3) Preparation of compound 3

[0073] Add 110ml of acetone, 0.7ml of concentrated sulfuric acid, and 16g of compound (2) into the reaction flask, stir and react at 25-30°C ...

Embodiment 3

[0083] (1) Preparation of Compound 1

[0084] Add 80ml of concentrated hydrochloric acid, 20g of p-hydroxybenzaldehyde, and 9.6g of paraformaldehyde into the reaction bottle, stir and react at 20-25°C for 12 hours, filter, and wash the obtained filter cake with 20ml of water, and 25g of the obtained red tide product is directly used for Next reaction.

[0085] (2) Preparation of Compound 2

[0086] Add 50 ml of water, 50 ml of tetrahydrofuran, and 25 g of compound (1) in the reaction bottle, add 6.8 g of sodium carbonate under stirring, stir and react at 25-30 ° C for 12 hours, let stand to separate layers, and continue to use 20 ml of tetrahydrofuran for the upper layer Washed with water, dried and concentrated, and 20 g of the obtained concentrated raffinate was directly used in the next step reaction

[0087] (3) Preparation of compound 3

[0088] Add 80ml of acetone, 1ml of concentrated sulfuric acid, and 20g of compound (2) into the reaction flask, stir and react...

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