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A kind of preparation method that uses oxygen as oxidant to prepare dioxpromazine hydrochloride

A technology of dioxpromazine hydrochloride and oxidant, applied in the direction of organic chemistry, etc., can solve the problems of increased difficulty in processing work, poor production safety, complicated production process, etc., and achieve the effects of reduced production cost, low cost, and improved experimental safety

Active Publication Date: 2018-10-26
大连万福制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the oxidation step of this method, strong corrosive or toxic liquids such as concentrated sulfuric acid and hydrogen peroxide need to be used, the production safety is poor and the difficulty of waste liquid post-treatment is greatly increased, and the production process is relatively complicated, which increases the production cost. Therefore, the process The major oxidation process steps in the

Method used

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  • A kind of preparation method that uses oxygen as oxidant to prepare dioxpromazine hydrochloride
  • A kind of preparation method that uses oxygen as oxidant to prepare dioxpromazine hydrochloride
  • A kind of preparation method that uses oxygen as oxidant to prepare dioxpromazine hydrochloride

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Embodiment 1: the synthesis of intermediate B

[0016]

[0017] In a 250ml three-neck flask, add 100ml of weighed pure water and 2.0g of promethazine hydrochloride A in sequence, and stir on a magnetic stirrer for 10min until all the materials are dissolved. After complete dissolution, slowly add the prepared lye ((600g sodium hydroxide + 1400g drinking water)) to adjust the pH to 12, the temperature is controlled at 25°C, the liquid dropping rate is 60 drops per minute, and the stirring is continued until the pH is stable. Add 20ml of dichloromethane to extract the promethazine in the reaction solution, repeat the washing and extraction operation 3 times, after drying over anhydrous magnesium sulfate, extract the solvent, and the thick product is purified by column chromatography to obtain 1.69g of white solid promethazine. Process yield: 95.1%. MS(EI):m / z:284.1349([M] + ).

Embodiment 2

[0018] Embodiment 2: the synthesis of intermediate C

[0019]

[0020] Take by weighing substrate 1.78g promethazine, 0.28g palladium acetate, 2.65g sodium carbonate, in dry 250ml two-necked flask, add 100ml anhydrous toluene as reaction solvent, feed oxygen (flow velocity is 8m / s, tube diameter area 9×10 -6 m 2 ), be heated to 80 ℃ of reaction 18 hours; Described substrate promethazine: triphenylphosphine: the mol ratio of anhydrous sodium carbonate is 1:0.5:4, and the consumption of described palladium acetate is that of substrate promethazine 2mol%, after the reaction is over, after the solvent is extracted under reduced pressure, the reaction solution is extracted three times with dichloromethane, the extracts are combined and dried with anhydrous magnesium sulfate, the solvent is spin-dried, and dried; the crude product is purified by column chromatography to obtain the target product C1 .78g, the yield of this process was 90.2. MS(EI):m / z:316.1245([M] + ).

Embodiment 3

[0021] Embodiment 3: the synthesis of target product dioxetazine hydrochloride D

[0022]

[0023] In a 500ml three-necked flask, add 1.78g of promethazine, add acetone as a solvent, and stir on a magnetic stirrer until all the materials are dissolved. After feeding, the temperature was lowered to 20°C. (keep the liquid temperature at 20°C, slowly pass 300g of hydrochloric acid gas into 500ml of acetone for use), slowly add the pre-prepared acetone hydrogen chloride solution dropwise (keep the liquid temperature at 20°C, slowly pass 300g of hydrochloric acid gas ( Pass through for about 1 hour) into 900g of acetone for later use) to pH = 4, stir until the pH is stable, and obtain an off-white suspension of dioxpromazine hydrochloride acetone solution, add activated carbon, stir for 35 minutes to decolorize, after the decolorization is completed, filter In addition to activated carbon, the activated carbon filter cake was rinsed with 200ml acetone, and the washing liquid wa...

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Abstract

The invention discloses a green technology for preparing dioxopromethazine hydrochloride by using oxygen as an oxidant, and belongs to the technical field of medical intermediates. The green technology is characterized in that a target product-the dioxopromethazine hydrochloride can be obtained through a series of reaction by using the oxygen as the oxidant and adopting palladium acetate as a catalyst, and a production process is greatly simplified; compared with a method of using hydrogen peroxide as the oxidant, the yield of an intermediate is much higher, a whole oxidation process requires no addition of sulfuric acid or the hydrogen peroxide, a final product is powder which is white to yellowish or crystalline powder, and the final product is odorless and is bitter in taste and very high in purity. By adopting an improved synthesis path, the green technology disclosed by the invention has multiple advantages that the yield is increased to a large extent, the cost is reduced, safety is increased, energy is saved, and the like, and modern chemical industry production requirements of green reaction are met.

Description

technical field [0001] The invention relates to a method for preparing dioxpromazine hydrochloride by using oxygen as an oxidizing agent, which belongs to the technical field of pharmaceutical intermediates. Background technique [0002] Dioxetazine hydrochloride has antitussive and antiasthma, expectorant, anticholaminergic and local anesthetic effects, and the antitussive effect is strong, which is equivalent to codeine. Clinically used for antitussive, expectorant, acute and chronic bronchitis and cough caused by various diseases. At present, the main production route of the drug is to use promethazine hydrochloride as the starting raw material to obtain the finished product through alkalization, oxidation, salt formation, decolorization, pressure filtration, crystallization separation, vacuum drying, crushing, sieving, mixing, internal packaging, and external packaging. (Dioxpromazine Hydrochloride API). However, in the oxidation step of this method, strong corrosive o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D279/34
CPCC07D279/34
Inventor 孙庆发
Owner 大连万福制药有限公司
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