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Preparation method for staurosporine medical intermediate

A cephalosporin and intermediate technology, applied in the field of pharmaceutical preparation, can solve the problems of inconvenient operation, inconvenience and safety, high irritation and the like of bromine, and achieve the effects of speeding up the reaction rate, reducing the production cost and high utilization rate

Active Publication Date: 2013-02-13
SHENZHEN SALUBRIS PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the latter stage of the bromination reaction is slow, and the reaction rate is not ideal even under reflux conditions.
[0012] In the above-mentioned preparation methods of aminothioxime acetic acid, bromine with high toxicity, strong corrosiveness and high irritation must be directly used as the bromination reagent, which brings great inconvenience and potential safety hazards to transportation, storage and use.
[0013] In order to solve problems such as inconvenient operation of directly using bromine in the prior art, the applicant has found the cephalosporin drug intermediate 4-bromo-2-(Z The preparation method of )-alkoxyimino acetoacetate, especially propose the present invention

Method used

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  • Preparation method for staurosporine medical intermediate
  • Preparation method for staurosporine medical intermediate
  • Preparation method for staurosporine medical intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1 Preparation of ethyl 4-bromo-2-(Z)-methoxyiminoacetoacetate

[0046] Add 20 mL of dichloromethane and 3.58 g (34.8 mmol) of sodium bromide into a 100 mL round bottom flask, and add dropwise 6.96 g (69.6 mmol) of sulfuric acid with a mass fraction of 98% under magnetic stirring. After the dropwise addition, 5.0 g (28.9 mmol) of ethyl 2-(Z)-methoxyiminoacetoacetate was added, followed by 6.1 g (8.7 mmol) of sodium sulfate-hydrogen peroxide-sodium chloride adduct. At room temperature, place the reaction container at a distance of 5 cm from a 25W fluorescent energy-saving lamp (color temperature 6400K) for irradiation. After the red-brown color of the reaction solution faded obviously, the remaining sodium sulfate-hydrogen peroxide-sodium chloride adduct was added in three batches, totaling 8.4g (12mmol), and the light was maintained. After 6 hours, the progress of the reaction was detected by HPLC, and the conversion of the raw materials was basically complete. ...

Embodiment 2

[0047] Example 2 Preparation of methyl 4-bromo-2-(Z)-ethoxyiminoacetoacetate

[0048] 12mL of dichloromethane and 2.47g (20.8mmol) of potassium bromide were added to a 100mL round bottom flask, and under magnetic stirring, 5.2g (52mmol) of sulfuric acid with a mass fraction of 98% was added dropwise. After dropping, 3.0 g (17.3 mmol) of methyl 2-(Z)-ethoxyiminoacetoacetate was added, and the reaction vessel was placed 5 cm away from a 50W metal halide lamp at room temperature for irradiation. A total of 7.20 g (10.4 mmol) of the sodium sulfate-hydrogen peroxide-sodium chloride adduct was subsequently added in four portions. The reaction solution was reddish brown, and the color gradually became lighter under light. Stop the light after 4 hours, add 10 mL of water, adjust the pH to 6~7 with sodium bicarbonate under vigorous stirring, and add an appropriate amount of sodium sulfite to make the reddish brown fade. After standing still, the layers were separated, and the organic...

Embodiment 3

[0049] Example 3 Preparation of ethyl 4-bromo-2-(Z)-ethoxyiminoacetoacetate

[0050] 20 mL of dichloromethane and 5.86 g (57.0 mmol) of sodium bromide were added to a 100 mL round bottom flask, and 11.4 g (114 mmol) of sulfuric acid with a mass fraction of 98% was added dropwise under magnetic stirring. After the dropwise addition, 5.0 g (28.5 mmol) of ethyl 2-(Z)-ethoxyiminoacetoacetate was added, followed by 9.9 g (14.3 mmol) of sodium sulfate-hydrogen peroxide-sodium chloride adduct. At room temperature, place the reaction container at a distance of 5 cm from a 25W fluorescent energy-saving lamp (color temperature 6400K) for irradiation. The reaction solution was reddish-brown, and the color gradually became lighter under the light, and then the remaining sodium sulfate-hydrogen peroxide-sodium chloride adduct was added in 2 batches, a total of 5.9g (8.5mmol), and the light was maintained. Stop the light after 4 hours, add 15 mL of water, adjust the pH to 6~7 with sodium b...

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Abstract

The invention relates to a preparation method for a staurosporine medical intermediate. The method comprises the step of: by adopting 2-alkoxy imido acetoacetic ester as a starting material, and bromide / sodium sulfate-hydrogen peroxide-sodium chloride adduct as a brominating reagent, reacting in an organic solvent under the conditions of an acidic reagent and illumination, so as to obtain the staurosporine medical intermediate. The novel preparation method for the staurosporine medical intermediate reduces the corrosion of the production equipment and the pollution of the environment during producing, and is mild and controllable in reaction conditions, and high in utilization rate of the brominating reagent; and the obtained product is high in purity and yield, and can be simply purifiedand then directly used in the follow-up ring-closure reaction, so that the production is reduced, and higher industrial value is brought.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to a preparation method of cephalosporin drug intermediate 4-bromo-2-(Z)-alkoxyiminoacetoacetate. Background technique [0002] Aminothioxime acetic acid, the chemical name is 2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetic acid, which is prepared such as: cefotaxime (cefotaxime), cefodizime ( Cefodizime), ceftriaxone, cefuzonam, cefetamet, cefepime, cefpirome and other third- and fourth-generation semi-synthetic cephalosporin antibiotics The essential intermediate of the drug. [0003] According to many current literature reports: the synthesis of acetoxime acetic acid, using methyl acetoacetate or ethyl acetoacetate as the starting material, is prepared through multi-step reactions such as nitrosation, etherification, bromination, cyclization and hydrolysis. Among them, 4-bromo-2-(Z)-methoxyiminoacetoacetate methyl (ethyl) ester synthesized by bromination reaction is an impo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C251/38C07C251/66C07C249/12
Inventor 谭端明赵晋
Owner SHENZHEN SALUBRIS PHARMA CO LTD