Novel method for preparing olopatadine hydrochloride by using high-activity organic zinc reagent

A technology of olopatadine and high-activity zinc, which is applied in the field of preparing olopatadine hydrochloride with high-activity organozinc reagent, can solve the problems of complicated post-processing, long process steps, etc., and achieves simplified post-processing process, simple operation and product high purity effect

Active Publication Date: 2014-03-26
北京华禧联合科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the process steps are long and the post-processing is complicated

Method used

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  • Novel method for preparing olopatadine hydrochloride by using high-activity organic zinc reagent
  • Novel method for preparing olopatadine hydrochloride by using high-activity organic zinc reagent
  • Novel method for preparing olopatadine hydrochloride by using high-activity organic zinc reagent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of Highly Active Organozinc Reagent

[0036] Under the protection of nitrogen, add 3-bromo-N,N-dimethylpropanamine (5.0g, 30mmol) and 32ml of anhydrous tetrahydrofuran to the reaction flask, stir and cool to 10-20℃, add activated zinc powder (3.9 g, 60mmol), after the addition, the temperature was controlled at 20-30°C and stirred for 0.5h, heated to reflux (65-70°C), and stirred for 5-6h. The resulting reaction solution is a highly active organic zinc reagent.

[0037] Preparation of Crude Olopatadine

[0038] Dissolve isoket acid (4.0g, 15mmol) in 12ml of tetrahydrofuran, stir, dissolve and clarify, then drop into the above-mentioned highly active organic zinc reagent at a temperature of 0-10°C, after about 0.5h, raise the temperature to 20-25°C and stir to react After 16 hours, HPLC tracked the end point of the reaction, and the purity was 37.6%.

[0039] Cool the above reaction solution, add 25ml of water for extraction, adjust the pH of the water pha...

Embodiment 2

[0043] Preparation of lithium naphthalene reagent

[0044] Under the protection of nitrogen, lithium metal (0.4 g, 60 mmol) was added to anhydrous naphthalene (2.6 g, 20 mmol), and the temperature was controlled at 20-25° C. and stirred for 2 h to obtain lithium naphthalene reagent.

[0045] Preparation of Highly Active Organozinc Reagent

[0046] Under the protection of nitrogen, add 3-bromo-N,N-dimethylpropanamine (5.0g, 30mmol) and 32ml of anhydrous tetrahydrofuran to the reaction flask, stir and cool to 10-20℃, add zinc bromide (13.5 g, 60 mmol), stirred for 10 min, added dropwise the above-mentioned naphthalene lithium reagent, after the reaction temperature was stabilized, heated to reflux (65-70°C), and stirred for 5-6 h. The resulting reaction solution is a highly active organic zinc reagent.

[0047] Preparation of Crude Olopatadine

[0048] Dissolve isoket acid (4.0g, 15mmol) in 12ml of tetrahydrofuran, stir to dissolve and clarify, then drop into the above-mentio...

Embodiment 3

[0053] Preparation of Highly Active Organozinc Reagent

[0054] Under the protection of nitrogen, add 3-bromo-N,N-dimethylpropylamine (5.0g, 30mmol), zinc bromide (13.5g, 60mmol) and 32ml of anhydrous tetrahydrofuran into the reaction flask, stir and cool to 10-20 ℃, add metal lithium (0.4g, 60mmol) in batches, after the reaction temperature stabilizes, heat to reflux (65-70℃), and stir for 5-6h. The obtained reaction solution is the highly active organic zinc reagent.

[0055] Preparation of Crude Olopatadine

[0056]Dissolve isoket acid (4.0g, 15mmol) in 12ml of tetrahydrofuran, stir, dissolve and clarify, then drop into the above-mentioned highly active organic zinc reagent at a temperature of 0-10°C, after about 0.5h, raise the temperature to 20-25°C and stir to react After 16 hours, HPLC tracked the end point of the reaction, and the purity was 75.2%.

[0057] Cool the above reaction solution, add 25ml of water for extraction, adjust the pH of the water phase to 4.0-4....

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Abstract

The invention discloses a novel method for preparing olopatadine hydrochloride. The method comprises the steps as follows: (1) high-activity zinc and 3-bromo-N,N-dimethylpropylamine form an organic zinc reagent (I); (2) the organic zinc reagent is eliminated after electrophilic substitution with isoxepac (II) to form olopatadine (III); (3) the olopatadine with higher purity is obtained through recrystalization of the olopatadine, wherein structural formulas of the organic zinc reagent (I), the isoxepac (II) and the olopatadine (III) are as follows.

Description

technical field [0001] The invention relates to a new method for preparing olopatadine hydrochloride with a highly active organic zinc reagent. technical background [0002] Olopatadine hydrochloride (IV) [(Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin- 2-acetate hydrochloride] is a selective antagonist of histamine H1 receptors, used for the treatment of typical ocular symptoms of seasonal allergic conjunctivitis. It is also used in the symptomatic treatment of allergic rhinitis and allergic urticaria, and in the treatment of eczema and dermatitis. It is administered as a solid oral dosage form or as an ophthalmic solution. [0003] [0004] Olopatadine and its pharmaceutically acceptable salts are described in patents EP0214779, US4871865, EP0235496 and US5116863. There are mainly two methods for preparing olopatadine, which are described in EP0214779: one uses Witting reaction, and the other uses Grignard reagent and dehydration reaction for prep...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D313/12
CPCC07D313/12
Inventor 田力文谢晓东毕华
Owner 北京华禧联合科技发展有限公司
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