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Belinostatsynthesis method suitable for industrial production

A synthetic method, the technology of belistat, applied in the direction of organic chemistry, sulfonamide preparation, etc., can solve the problems of easy decomposition and deterioration, long production cycle, easy to catch fire, etc., and achieve the goal of shortening the process cycle, simplifying the operation, and shortening the time Effect

Inactive Publication Date: 2015-04-01
深圳万乐药业有限公司
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0008] This method uses the highly controlled drug phosphorus oxychloride in the acid chlorination process, which greatly increases the cost of procurement, transportation and management, and if phosphorus oxychloride is used in a large amount in industrial production, dangerous accidents may occur. PCC pyridinium chlorochromate is used in the oxidation process, and the yield of the oxidation reaction is not high. The chromium ions produced after use are likely to cause heavy metal chromium pollution. The selected alkali for the Wittig-Horner reaction forming a double bond is sodium hydride, potassium hydride, Lithium diisopropylamide, these alkalis are easy to decompose and deteriorate, and are easy to catch fire when exposed to oxygen, so there is a big safety hazard in production
This method has many operation steps and a long production cycle, so it is necessary to further improve to obtain a method more suitable for industrial production

Method used

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  • Belinostatsynthesis method suitable for industrial production
  • Belinostatsynthesis method suitable for industrial production
  • Belinostatsynthesis method suitable for industrial production

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The preparation of embodiment 1 compound IV

[0031]Add compound III, sodium m-carboxybenzenesulfonate (224g), methanol (3000ml) and hydrochloric acid (20g) into a 5L reaction flask, heat to reflux for 3h, cool down to room temperature, and concentrate to dryness to obtain compound IV, which is directly carried out to the next step.

Embodiment 2

[0032] The preparation of embodiment 2 compound V

[0033] Put the crude compound IV (2kg) into the reaction kettle, then add pyridine (6L), stir to dissolve, add thionyl chloride (1.2kg) dropwise, control the temperature at 40-50°C for 2-3h, add acetonitrile (6L) Dilute, lower the temperature to 0°C, add aniline (940g) dropwise, control the temperature below 30°C and react for 2 hours. After the reaction is completed, add it to a 50L reactor with 30L ice water, stir rapidly for 1h, filter, wash the filter cake with water, and then Wash with an appropriate amount of methyl tert-butyl ether / petroleum ether (1 / 2), suck dry, and dry at 50°C for 8 hours to obtain 1.75 kg of compound V with a yield of 71.5%.

Embodiment 3

[0034] The preparation of embodiment 3 compound VI

[0035] Add lithium chloride (848g) and potassium borohydride (1080g) into the reaction flask, add THF (12.5L) and stir to dissolve, heat at 50°C and stir for 30min, add the THF solution of compound V (3kg) dropwise, after the reaction is complete, add Add 4 L of ethyl acetate to 5.5 L of ice water, stir for 30 min, separate the liquid, separate the organic phase, dry, and concentrate to obtain the crude compound V; then recrystallize with toluene, and dry the solid at 50°C for 6 hours to obtain 2453 g of white crystalline compound VI , yield 90.5%.

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Abstract

The invention provides an improved belinostatsynthesis method. According to the method, sodium m-carboxyl benzenesulfonate is taken as a starting material, and belinostat is prepared through six steps of esterification, acylation and aniline condensation, reduction, oxidation, Wittig-Horner condensation and hydrolysis as well as acylation and hydroxylamine condensation. With the adoption of the method, the production time is shortened, the reaction yield is increased, the production safety is enhanced, the environmental pollution is reduced, and the method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to an industrial production method of Belinostat, a drug for relapsed and refractory peripheral T-cell lymphoma. Background technique [0002] Belinostat (compound of formula I, Belinostat, PXD101) is a histone deacetylase inhibitor (HDACi) developed by Topotarget AS in Denmark, which can directly act on the link of abnormal gene expression, thereby inhibiting and correcting For the excessive proliferation and abnormal differentiation of tumor cells, it can also be used in combination with drugs with other mechanisms of action for common drug resistance problems. HDACi can effectively inhibit the proliferation of solid tumor cells such as colon cancer, lung cancer, ovarian cancer, and myeloma, and also has therapeutic effects on malignant tumors of the blood system such as leukemia and lymphoma. Its chemical name is N-hydroxy-3-(3-phenylaminosulfonylphenyl)a...

Claims

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Application Information

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IPC IPC(8): C07C311/21C07C303/40
Inventor 罗锦李瑞远李昌希雷光华苏云淡陈其阳
Owner 深圳万乐药业有限公司
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