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Preparation method of o-hydroxyl Olopatadine

A technology of o-hydroxyisoket acid and o-hydroxy, which is applied in the field of medicine, can solve problems such as no synthetic method reports, and achieve the effects of good yield, stable product quality, and easy operation

Active Publication Date: 2014-09-10
BEIJING JIALIN PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, the way to obtain this impurity basically depends on chromatographic separation technology, and there are no reports on related synthesis methods

Method used

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  • Preparation method of o-hydroxyl Olopatadine
  • Preparation method of o-hydroxyl Olopatadine
  • Preparation method of o-hydroxyl Olopatadine

Examples

Experimental program
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Effect test

Embodiment 1

[0045] Preparation of 2-hydroxy-2-(11-oxa-6,11-dihydrodibenzo[b,e]oxepin)-2-acetic acid.

[0046]

[0047] Prepare with reference to the preparation method disclosed in US4417063 Example 1-4:

[0048] Add ethyl 2-bromomethylbenzoate (100g), p-hydroxybenzaldehyde (52.5g), potassium carbonate (241g), potassium iodide (2.1g), DMF (500ml) in a 2L glass reactor (mechanical stirring), The system was heated to reflux for about 18 hours. TLC detected that the reaction was substantially complete and dropped to room temperature. After filtration, the filtrate was concentrated under reduced pressure to obtain an oil. Add 800ml of ethyl acetate to dissolve, and wash with saturated sodium carbonate solution and brine successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain an oil. Add 500ml of ethyl acetate and n-heptane mixed solution (1:12), heat to reflux, crystallize at 0-5°C, filter to ob...

Embodiment 2

[0052] Preparation of 2-benzyloxy-2-(11-oxa-6,11-dihydrodibenzo[b,e]oxepin)-2-acetic acid

[0053] 2-Hydroxy-2-(11-oxa-6,11-dihydrodibenzo[b,e]oxepin-2-acetic acid (284 g) in ethanol was added to a 2 L glass reactor (mechanically stirred) (1200ml), potassium carbonate (200g), stir at room temperature until no gas is produced, add benzyl chloride (127g), potassium iodide (8g), heat up to reflux, keep warm for 8-10 hours, TLC detection reaction is basically complete, cool to room temperature , filter.The filtrate is concentrated, add 1000ml of water, adjust to a pH value of less than 3 with 1N hydrochloric acid, add ethyl acetate for extraction, the organic phase is dried with anhydrous sodium sulfate, filter.Filter and concentrate under reduced pressure to obtain an oil, add 600ml of ethyl acetate Mix solution with n-heptane (1:10), heat to reflux, crystallize at 0-5°C, filter to obtain 2-benzyloxy-2-(11-oxa-6,11-dihydrodibenzo[b, e] oxheptin-2-acetic acid (275g). The yield is...

Embodiment 3

[0055] Preparation of (Z)-11-[3-(dimethylamino)propenyl]-6,11-dihydrodibenzo[b,e]oxepin-2-benzyloxy-2-acetic acid

[0056] Add [3-(dimethylamino)propyl]triphenylphosphine bromide hydrobromide (230g) and anhydrous tetrahydrofuran (1200ml) into a 3L glass reactor (mechanical stirring), cool to below -10°C , dropwise add butyllithium solution (2.5N, 250ml), the reaction exotherm is obvious, keep the temperature below -10°C, keep stirring for 1-2 hours, add dropwise 2-benzyloxy-2-(11-oxa- 6,11-Dihydrodibenzo[b,e]oxepin)-2-acetic acid (37.4g) in anhydrous tetrahydrofuran solution (200ml), the reaction exotherm is obvious, keep the temperature below -5 ° C, keep stirring After 1-2 hours, slowly rise to room temperature, continue stirring for 4-5 hours, and slowly add deionized water (200ml) dropwise to destroy excess butyllithium. The reaction solution was concentrated to dryness under reduced pressure, added water (1200ml) to dissolve, added methyl tert-butyl ether for extraction ...

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Abstract

The invention discloses a preparation method of o-hydroxyl Olopatadine. The preparation method comprises the following steps: (1) performing a hydroxyl protection reaction on o-hydroxyl Isoxepac to obtain a compound shown in the general formula (I); (2) performing a Wittig reaction between the compound shown in the general formula (I) and [3-(dimethylamino)propyl]triphenylphosphine bromide hydrobromide to obtain a compound shown in the general formula (II); and (3) performing a protecting group removal reaction on the compound shown in the general formula (II) to obtain the o-hydroxyl Olopatadine, wherein the definition of R1 is specified in the specification. Moreover, the invention also discloses an intermediate compound for preparing o-hydroxyl Olopatadine.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of o-hydroxy olopatadine, which is an impurity of the antihistamine drug olopatadine hydrochloride (Olopatadine Hydrochloride), and an intermediate compound thereof. Background technique [0002] Histamine is an active substance that exists in the body itself. It mainly forms complexes with polysaccharide sulfate, heparin or chondroitin sulfate and acidic proteins and exists in the granules of mast cells and basophils, especially in the lungs. , skin mucous membrane, bronchial mucous membrane, gastric mucosa and gastric parietal cells. When the tissue is stimulated by immune response or physical or chemical, it can cause mast cells to degranulate and release histamine, and the released histamine binds to histamine receptors, resulting in a pathophysiological response. Olopatadine hydrochloride is a safe and effective new type of histamine H1 rec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D313/12
CPCY02P20/55C07D313/12
Inventor 周泽建杨爽
Owner BEIJING JIALIN PHARM INC
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