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Preparation method of olopatadine hydrochloride

A technology of olopatadine hydrochloride and hydrobromide, which is applied in the field of drug synthesis and can solve the problems of long reaction routes and low yields

Pending Publication Date: 2021-11-09
SICHUAN ZIREN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, in the prior art, p-hydroxyphenylacetic acid and phthalide are used as raw materials to prepare olopatadine hydrochloride through nucleophilic substitution, dehydration ring closure, Wittig reaction, and salification. The yield is low and the reaction route is long.

Method used

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  • Preparation method of olopatadine hydrochloride
  • Preparation method of olopatadine hydrochloride
  • Preparation method of olopatadine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] A, under nitrogen protection conditions, at first in 60.0kg massfraction is 10% THF, add 30.76kg (60.40mol) [3-(dimethylamino) propyl group] triphenylphosphine bromide hydrobromide, Control the temperature at 10°C, then add 3.65kg (152.12mol) of sodium hydride solution with a mass fraction of 60% and 3.96kg of dimethyl sulfoxide with a mass fraction of 0.66%, keep stirring at 20°C for 1 hour, then raise the temperature to 45 ℃, continue to stir for 2h, finally add 6.00kg (22.37mol) 11-oxo-6,11-dihydrodibenzo[b,e]oxazepine-2-acetic acid, continue to stir for 15h, until the reaction system turns black The reaction of the brown turbid liquid is finished, and the reaction liquid is quenched by a mixed solution of 77.94kg purified water and 2.44kg mass fraction of 10% tetrahydrofuran, and the aqueous phase is treated with a mixed solvent of 5kg hydrochloric acid and 87.4kg n-butanol, and the obtained aqueous solution is passed through Concentrate under reduced pressure, and ...

Embodiment 2

[0028] A, under nitrogen protection condition, at first in 52.34kg massfraction is 10% tetrahydrofuran, add 18.31kg (44.74mol) [3-(dimethylamino) propyl group] triphenyl phosphorus bromide hydrobromide, Control the temperature at 15°C, then add 2.59kg (107.71mol) of sodium hydride solution with a mass fraction of 60% and 3.12kg of dimethyl sulfoxide with a mass fraction of 0.66%, keep stirring at 23°C for 2 hours, and then heat up to 48°C , continue to stir for 2h, and finally add 6.00kg (22.37mol) of 11-oxo-6,11-dihydrodibenzo[b,e]oxazepine-2-acetic acid, continue to stir for 18h, until the reaction system turns dark brown The reaction of the turbid liquid is completed, and the reaction solution is quenched with a mixed solution of 62.41kg purified water and 1.83kg mass fraction of 10% tetrahydrofuran, and the aqueous phase is treated with a mixed solvent of 3.1kg hydrochloric acid and 64.23kg n-butanol, and the obtained aqueous solution is passed through Concentrate under re...

Embodiment 3

[0033] A, under nitrogen protection condition, at first in 68.25kg massfraction is 10% tetrahydrofuran, add 34.17kg (67.11mol) [3-(dimethylamino) propyl group] triphenyl phosphorus bromide hydrobromide, Control the temperature at 20°C, then add 4.118kg (173.99mol) of sodium hydride solution with a mass fraction of 60% and 5.12kg of dimethyl sulfoxide with a mass fraction of 0.66%, keep stirring at 30°C for 2 hours, and then heat up to 48°C , continue to stir for 2h, and finally add 6.00kg (22.37mol) of 11-oxo-6,11-dihydrodibenzo[b,e]oxazepine-2-acetic acid, continue to stir for 20h, until the reaction system turns dark brown The reaction of the turbid liquid is finished, and the reaction solution is quenched by a mixed solution of 93.12kg purified water and 3.67kg mass fraction of 10% tetrahydrofuran, and the aqueous phase is treated with a mixed solvent of 8kg hydrochloric acid and 98.12kg n-butanol, and the aqueous solution obtained is then subjected to reducing Concentrate ...

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Abstract

The invention relates to the field of drug synthesis, in particular to a preparation method of olopatadine hydrochloride, which comprises the following steps: adding [3-(dimethylamino) propyl] triphenylphosphonium bromide hydrobromide into tetrahydrofuran, sodium hydride and dimethyl sulfoxide, keeping the temperature, stirring, adding 11-oxo-6, 11-dihydrodibenzo [b, e] oxepin-2-acetic acid, stirring until a reaction system becomes black brown turbid liquid, and ending the reaction; quenching the reaction liquid by using a mixed solution of purified water and tetrahydrofuran, post-treating a water phase by using a mixed solvent of hydrochloric acid and n-butyl alcohol, carrying out vacuum concentration on a post-treated aqueous solution, crystallizing a concentrated solution by using n-butyl alcohol, filtering and drying to obtain a crude olopatadine hydrochloride product, separating out a solid in water and a sodium hydroxide solution, and filtering and drying to obtain olopatadine; and adding the olopatadine into hydrochloric acid while stirring by acetone to form white turbid liquid, continuously stirring, filtering and drying to obtain the olopatadine hydrochloride. The prepared olopatadine hydrochloride is high in yield, and short in reaction path.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of olopatadine hydrochloride. Background technique [0002] Olopatadine hydrochloride, the molecular formula is C 21 h 23 NO 3 .HCl, molecular weight 373.87, its chemical name is (Z)-11-[3-(dimethylamino)propylene]-6,11-dihydrodibenzo[b,e]oxazepine-2 - Acetic hydrochloride, CAS: 140462-76-6. Its structural formula is as follows: [0003] [0004] Olopatadine hydrochloride is an anti-allergic drug developed and marketed by Kyowa Hakko Corporation in Japan. It has been listed in Europe, the United States, Japan and other countries successively. It belongs to the h1 receptor antagonist. The main clinical effects and effects are antihistamine and antiallergic For the treatment of allergic rhinitis, allergic conjunctivitis, allergic asthma, insect bite dermatitis, skin diseases (eczema, dermatitis, prurigo, pruritus, psoriasis vulgaris, erythema multiforme) ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D313/12
CPCC07D313/12
Inventor 李昌华
Owner SICHUAN ZIREN PHARMA
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