Trospium chloride synthesis process

Abstract

The invention provides a trospium chloride synthesis process which includes the steps: firstly, preparing benziloyl chloride; secondly, preparing nortropine; thirdly, preparing chloridized (3alpha-nortropine)-8-whorl-1-pyrrole ammonium salt; and fourthly, preparing the trospium chloride by condensing the benziloyl chloride and the chloridized (3alpha-nortropine)-8-whorl-1-pyrrole ammonium salt to obtain the trospium chloride. The trospium chloride synthesis process has the advantages that the reaction steps are short, atom economy is high, yield is high, production cost is low, catalysts can be repeatedly applied mechanically by a method for removing methyl through Pd / C catalytic hydrogenation, consumption of the catalysts is reduced, pollution is decreased, and complicated post-reaction treatment and the like are omitted.

Description

technical field

[0001] The invention relates to medicines and is a synthesis process of trospium chloride. Background technique

[0002] The chemical name of trospium chloride is -3-diphenylglycolyl nortropane-8-spiro-1-pyrrolidine chloride, which is mainly used to treat various detrusor muscle instability or detrusor hyperfunction. Frequent urination, urgency and urinary incontinence drugs, trospium chloride synthesis process currently mainly has two categories: one is: diphenylglycolic acid is activated with N,N-carbonyldiimidazole to prepare the intermediate diphenylglycoimidazole, to Metropine alcohol uses acetyl to protect the N atom, reacts with the intermediate diphenylglycol imidazole to form an ester, then deprotects it, and finally reacts with 1,4-dichlorobutane to prepare trospium chloride.

[0003] .

[0004] The other type is: diphenylglycol...

Examples

Embodiment 1

[0028] Embodiment 1: the concrete steps of a kind of trospium chloride synthetic technique of the present invention are as follows:

[0029] ①Preparation of diphenylglycol chloride: Add 50g of diphenylglycolic acid and 130g of thionyl chloride into the reaction flask, reflux for 5 hours, and recover unreacted SOCl under reduced pressure 2 , and then add n-hexane for recrystallization to obtain 49 g of diphenylglycolyl chloride, yield 93%;

[0030] ② Preparation of nortropine alcohol: In an autoclave, add 100 g of α-tropine alcohol, dissolve in 500 mL of methanol, add 1 g of 10% Pd / C, 50 g of hydrochloric acid, replace with nitrogen, then pass hydrogen to 1 atm, and heat up to 60 ℃, heat preservation reaction for 2 hours, lowered to room temperature, filtered out the catalyst after pressure relief, and evaporated the solvent under reduced pressure to obtain 33 g of nortropine alcohol, with a yield of 73%;

[0031] ③Preparation of (3α-nortropine alcohol)-8-spiro-1-pyrrole ammon...

Embodiment 2

[0033] Embodiment 2: the concrete steps of a kind of trospium chloride synthetic technique of the present invention are as follows:

[0034] ①Preparation of diphenylglycol chloride: Add 50g of diphenylglycolic acid and 150g mL of thionyl chloride into the reaction flask, reflux for 5 hours, and recover unreacted SOCl under reduced pressure 2 , and then add n-hexane for recrystallization to obtain 50 g of diphenylglycolyl chloride, with a yield of 93%;

[0035] ② Preparation of nortropine alcohol: In an autoclave, add 100 g of α-tropine alcohol, dissolve in 500 mL of methanol, add 1.5 g of 10% Pd / C, 50 g of hydrochloric acid, replace with nitrogen, then pass hydrogen to 1 atm, and heat up to 60°C, heat preservation reaction for 2 hours, lower to room temperature, filter out the catalyst after pressure relief, and evaporate the solvent to dryness under reduced pressure to obtain 30 g of nortropine alcohol, with a yield of about 66%;

[0036] ③ Preparation of (3α-nortropine alco...

technical field

[0001] The invention relates to medicines and is a synthesis process of trospium chloride. Background technique

[0002] The chemical name of trospium chloride is -3-diphenylglycolyl nortropane-8-spiro-1-pyrrolidine chloride, which is mainly used to treat various detrusor muscle instability or detrusor hyperfunction. Frequent urination, urgency and urinary incontinence drugs, trospium chloride synthesis process currently mainly has two categories: one is: diphenylglycolic acid is activated with N,N-carbonyldiimidazole to prepare the intermediate diphenylglycoimidazole, to Metropine alcohol uses acetyl to protect the N atom, reacts with the intermediate diphenylglycol imidazole to form an ester, then deprotects it, and finally reacts with 1,4-dichlorobutane to prepare trospium chloride.

[0003] .

[0004] The other type is: diphenylglycol...

Examples

Embodiment 1

[0028] Embodiment 1: the concrete steps of a kind of trospium chloride synthetic technique of the present invention are as follows:

[0029] ①Preparation of diphenylglycol chloride: Add 50g of diphenylglycolic acid and 130g of thionyl chloride into the reaction flask, reflux for 5 hours, and recover unreacted SOCl under reduced pressure 2 , and then add n-hexane for recrystallization to obtain 49 g of diphenylglycolyl chloride, yield 93%;

[0030] ② Preparation of nortropine alcohol: In an autoclave, add 100 g of α-tropine alcohol, dissolve in 500 mL of methanol, add 1 g of 10% Pd / C, 50 g of hydrochloric acid, replace with nitrogen, then pass hydrogen to 1 atm, and heat up to 60 ℃, heat preservation reaction for 2 hours, lowered to room temperature, filtered out the catalyst after pressure relief, and evaporated the solvent under reduced pressure to obtain 33 g of nortropine alcohol, with a yield of 73%;

[0031] ③Preparation of (3α-nortropine alcohol)-8-spiro-1-pyrrole ammon...

Embodiment 2

[0033] Embodiment 2: the concrete steps of a kind of trospium chloride synthetic technique of the present invention are as follows:

[0034] ①Preparation of diphenylglycol chloride: Add 50g of diphenylglycolic acid and 150g mL of thionyl chloride into the reaction flask, reflux for 5 hours, and recover unreacted SOCl under reduced pressure 2 , and then add n-hexane for recrystallization to obtain 50 g of diphenylglycolyl chloride, with a yield of 93%;

[0035] ② Preparation of nortropine alcohol: In an autoclave, add 100 g of α-tropine alcohol, dissolve in 500 mL of methanol, add 1.5 g of 10% Pd / C, 50 g of hydrochloric acid, replace with nitrogen, then pass hydrogen to 1 atm, and heat up to 60°C, heat preservation reaction for 2 hours, lower to room temperature, filter out the catalyst after pressure relief, and evaporate the solvent to dryness under reduced pressure to obtain 30 g of nortropine alcohol, with a yield of about 66%;

[0036] ③ Preparation of (3α-nortropine alco...