A post-treatment purification method for olopatadine hydrochloride

A technology of olopatadine hydrochloride and a purification method, applied in the field of pharmaceutical purification, can solve the problems of affecting product yield, difficult to remove bromide ion impurities, loss of target product, etc., so as to improve the preparation yield and product purity, and reduce the bromide ion Residual risks, the effect of reducing production costs

Active Publication Date: 2022-02-22
GUANGZHOU JOINCARE RESPIRATORY DRUG ENG TECH CO LTD
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  • Abstract
  • Description
  • Claims
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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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  • A post-treatment purification method for olopatadine hydrochloride
  • A post-treatment purification method for olopatadine hydrochloride
  • A post-treatment purification method for olopatadine hydrochloride

Examples

Experimental program
Comparison scheme
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 of the present invention comprises the following steps: step 1): washing the crude product of the reaction solution through sodium chloride solution to remove bromide ions, and obtaining the crude product of olopatadine hydrochloride containing salt; step 2): washing the crude product of olopatadine hydrochloride obtained in step 1) The salt-containing crude product is dissolved in a mixed solvent of dichloromethane, glacial acetic acid and alcohols for desalination treatment to obtain the crude product of olopatadine hydrochloride; step 3): the crude product of olopatadine hydrochloride obtained in step 2) The product is recrystallized, wherein the solvent used for recrystallization is a mixed solvent of dimethyl sulfoxide and isopropyl ether. The target product olopatadine hydrochloride obtained by the method of the present invention has extremely low inorganic salt content, and at the same time greatly improves the preparation yield and product purity of the olopatadine hydrochloride, reduces production costs, and 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 Patents(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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