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Post-treatment purification method of olopatadine hydrochloride

A technology of olopatadine hydrochloride and a purification method, which is applied in the field of drug purification, can solve problems such as affecting product yield, loss of target product, and difficulty in removing bromide ion impurities, so as to improve preparation yield and product purity, and reduce production cost , The effect of reducing the risk of bromide ion residues

Active Publication Date: 2021-02-19
GUANGZHOU JOINCARE RESPIRATORY DRUG ENG TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Yet there are following defects in these methods: (1) still contain a small amount of bromide ion impurity to be difficult to remove in the post-treatment, purified product; (2) part target product can be lost when extracting olopatadine free alkali, influences product yield; (3) The final product contains more inorganic salts, which greatly affects the preparation yield and product quality of olopatadine hydrochloride
However, the inventor found after repeated repetitions according to the method disclosed in CN110343086A that in the process of preparing olopatadine free base by using the crude product, although inorganic salts and bromide ions can be removed, the free base has a high solubility in water and is not easy to crystallize. Seriously affect the yield of olopatadine hydrochloride

Method used

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  • Post-treatment purification method of olopatadine hydrochloride
  • Post-treatment purification method of olopatadine hydrochloride
  • Post-treatment purification method of olopatadine hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0047] The preparation of embodiment 1 olopatadine hydrochloride crude product

[0048] Weigh [3-(dimethylamino)propyl]triphenylphosphine bromide hydrobromide (231.6g) and tetrahydrofuran (915ml) into a reaction flask, nitrogen protection, then stir in a cooling bath at -10°C ; Add BuLi (284.5g) dropwise to the system, keeping the temperature of the system at -10-10°C. After the drop is complete, stir for 2h; add dropwise a solution of isoket acid (61g) in tetrahydrofuran (305ml), and heat up to 55-60°C , Reaction 4h.

[0049] The reaction solution system was lowered to room temperature, and water (305ml) was added dropwise to quench the reaction; then NaCl (91.5g), NaOH (37g), and water (183ml) were added, and the temperature was raised to 55-60°C and stirred for 2h; the phases were separated, and the organic phase was reserved. Add 25% (w / w) sodium chloride solution (305ml) for washing, stir at 35-40°C for 30min, let stand to separate the phases, and keep the organic phas...

Embodiment 2

[0051] The preparation of embodiment 2 olopatadine hydrochloride crude product

[0052] Weigh [3-(dimethylamino)propyl]triphenylphosphine bromide hydrobromide (231.6g) and tetrahydrofuran (915ml) into a reaction flask, nitrogen protection, then stir in a cooling bath at -10°C ; Add BuLi (284.5g) dropwise to the system, keeping the temperature of the system at -10-10°C. After the drop is complete, stir for 2h; add dropwise a solution of isoket acid (61g) in tetrahydrofuran (305ml), and heat up to 55-60°C , Reaction 4h.

[0053] The reaction solution system was lowered to room temperature, and water (305ml) was added dropwise to quench the reaction; then NaCl (91.5g), NaOH (37g), and water (183ml) were added, and the temperature was raised to 55-60°C and stirred for 2h; the phases were separated, and the organic phase was reserved. Add 27% (w / w) sodium chloride solution (305ml) for washing, stir at 45-50°C for 30min, let stand to separate the phases, and keep the organic phas...

Embodiment 3

[0055] The preparation of embodiment 3 olopatadine hydrochloride crude product

[0056] Weigh [3-(dimethylamino)propyl]triphenylphosphine bromide hydrobromide (231.6g) and tetrahydrofuran (915ml) into a reaction flask, nitrogen protection, then stir in a cooling bath at -10°C ; Add BuLi (284.5g) dropwise to the system, keeping the temperature of the system at -10-10°C. After the drop is complete, stir for 2h; add dropwise a solution of isoket acid (61g) in tetrahydrofuran (305ml), and heat up to 55-60°C , Reaction 4h.

[0057] The reaction solution system was lowered to room temperature, and water (305ml) was added dropwise to quench the reaction; then NaCl (91.5g), NaOH (37g), and water (183ml) were added, and the temperature was raised to 55-60°C and stirred for 2h; the phases were separated, and the organic phase was reserved. Add 20% (w / w) sodium chloride solution (305ml) for washing, stir at 35-40°C for 30min, let stand to separate the phases, and keep the organic phas...

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Abstract

The invention provides a post-treatment purification method of olopatadine hydrochloride. The method comprises the steps of 1) washing a reaction liquid crude product with a sodium chloride solution to remove bromide ions so as to obtain an olopatadine hydrochloride salt-containing crude product; (2) dissolving the olopatadine hydrochloride salt-containing crude product prepared in the step (1) into a mixed solvent of dichloromethane, glacial acetic acid, acetic acid and alcohols, and carrying out desalting treatment so as to obtain an olopatadine hydrochloride crude product; and (3) recrystallizing the olopatadine hydrochloride crude product obtained in the step (2), wherein a solvent adopted for recrystallization is a mixed solvent of dimethyl sulfoxide and isopropyl ether. The target product olopatadine hydrochloride obtained through the method is extremely low in inorganic salt content, meanwhile, the preparation yield and the product purity of olopatadine hydrochloride are greatlyimproved, the production cost is reduced, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine purification, and in particular relates to a post-treatment purification method of olopatadine hydrochloride. Background technique [0002] Olopatadine hydrochloride, the chemical name is (Z)-11-[3-(dimethylamino)propylene]-6,11-dihydrodibenzo[b,e]oxazepine-2-ethane Hydrochloride is a third-generation powerful and safe anti-allergic drug developed by Kyowa Hakka, which can inhibit tachykinin and other chemical transmitters, such as histamine, arachidonic acid, and thrombosis The release of hormones, leukotrienes, etc., for H with higher selectivity 1 It has dual inhibitory effects on receptors, less side effects, no central inhibition and cardiotoxicity, and is a commonly used anti-allergic drug in clinical practice. Its structural formula is as follows: [0003] [0004] There are multiple methods for synthesizing olopatadine hydrochloride at present, wherein, [3-(dimethylamino) propyl gro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D313/12
CPCC07D313/12
Inventor 俞雄骆健明肖杜政陈与华
Owner GUANGZHOU JOINCARE RESPIRATORY DRUG ENG TECH CO LTD
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