Preparation method of E-olopatadine

A technology of olopatadine and mass ratio, which is applied in the field of preparation of E-olopatadine, can solve the problems such as complex preparation process of E-olopatadine, and achieve the effect of reducing loss and reducing reaction steps

Pending Publication Date: 2021-03-09
重庆西南制药二厂有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a preparation method of E-olopatadine, aiming to solve the problem that the existing E-olopatadine preparation process is complicated

Method used

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  • Preparation method of E-olopatadine
  • Preparation method of E-olopatadine
  • Preparation method of E-olopatadine

Examples

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Embodiment 1

[0061] Under nitrogen protection, add 100g [3-(dimethylamino)propyl]triphenylphosphine bromide hydrobromide to the three-necked flask, then add 500g toluene, start stirring, control the temperature at about -8°C, and add it with a syringe Add 75ml of 1.3mol / L tert-butyllithium n-pentane solution, keep it warm for 1h after adding, and then slowly raise the temperature to 105~110℃. 50g of 6,11-dihydro-11-oxodibenzo( b,e ) The solution prepared by methyl oxazapine-2-acetate and 100g toluene was heated up to 105~110°C after dropping, stirred at 105~110°C for 3 hours, and then cooled to about 5°C. Control the temperature at about 5°C, slowly drop in 10g of methanol, then drop in 200g of 60% tetrahydrofuran aqueous solution, and finally add 800g of water. The aqueous layer of the reaction solution was adjusted to pH=6±0.2 with concentrated hydrochloric acid, then distilled to dryness under reduced pressure and evaporated to dryness to obtain a solid. The solid was passed through t...

Embodiment 2

[0065] Under nitrogen protection, add 120g [3-(dimethylamino)propyl]triphenylphosphine bromide hydrobromide to the three-necked flask, then add 500g toluene, start stirring, control the temperature at about -8°C, and add it with a syringe Add 83ml of 1.3mol / L tert-butyllithium n-pentane solution, keep it warm for 1.5h after adding, and then slowly raise the temperature to 105~110℃. 50g of 6,11-dihydro-11-oxodibenzo( b,e ) Oxazepine-2-acetic acid methyl ester and 100g of toluene, the temperature was raised to 105~110°C after dropping, stirred at 105~110°C for 3.5 hours, and then cooled to about 8°C. Control the temperature at about 8°C, slowly drop in 10g of methanol, then drop in 240g of 50% tetrahydrofuran aqueous solution, and finally add 750g of water. The aqueous layer of the reaction solution was adjusted to pH=6±0.2 with concentrated hydrochloric acid, then distilled to dryness under reduced pressure and evaporated to dryness to obtain a solid. The solid was passed thr...

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Abstract

The invention discloses a preparation method of E-olopatadine, which comprises the following steps: adding [3-(dimethylamino)propyl]triphenylphosphine bromide hydrobromide into a solvent, adding an n-pentane solution of tert-butyl lithium, carrying out heat preservation reaction for 0.5-2 hour, heating to 105-110 DEG C, dropwise adding a toluene solution of methyl 6, 11-dihydro-11-oxo-dibenzo(b, e)oxepine-2-acetate, heating to 105-110 DEG C, stirring for 2-5 hours at the temperature of 105-110 DEG C, then cooling to 0-15 DEG C, carrying out quenching reaction, adding concentrated hydrochloricacid to adjust the pH value to 6+ / -0.2, carrying out reduced pressure distillation to dryness to obtain a solid, enabling the solid to pass through a column to obtain an E-olopatadine methyl ester crude product, and carrying out purification. According to the preparation method of Eolopatadine provided by the invention, on the basis of the prior art, key steps are upgraded and transformed, so thatthe reaction steps can be reduced, and the loss is reduced.

Description

technical field [0001] The invention relates to the field of drug synthesis, and mainly relates to a preparation method of E-olopatadine. Background technique [0002] E-Olopatadine (E-Olopatadine), as an isomer of the antiallergic drug Olopatadine Hydrochloride, is usually used to calibrate the purity of impurities in Olopatadine. Its chemical name is: (E)-11-[3-(dimethylamino)propylene]-6,11-dihydrodibenzo[ b,e ] Oxapine-2-acetic acid, CAS: 113806-06-7. The structural formulas of it and Z-olopatadine are as follows: [0003] [0004] At present, the preparation of E-olopatadine is mainly based on chemical synthesis. Some manufacturers use isoket acid (CAS: 55453-87-7) or isoket acid with protective groups and 3,3-dimethylaminopropylmagnesium chloride (CAS: 19070-16-7) Grignard reaction, followed by deprotection by salt formation to obtain E-olopatadine. Some manufacturers use (3-dimethylaminopropyl)triphenylphosphine bromide (CAS: 18355-96-9) to prepare phosphine y...

Claims

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Application Information

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IPC IPC(8): C07D313/12
CPCC07D313/12C07B2200/09Y02P20/55
Inventor 邹浩胡训刚谭启宣
Owner 重庆西南制药二厂有限责任公司
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