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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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 he

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

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Example Embodiment

[0030] Example 1 Preparation of Compound IV

[0031] Compound III, sodium m-carboxybenzene sulfonate (224g), methanol (3000ml) and hydrochloric acid (20g) were added to a 5L reaction flask, heated to reflux for 3h, cooled to room temperature, and concentrated to dryness to obtain compound IV and proceed directly to the next reaction.

Example Embodiment

[0032] Example 2 Preparation of Compound V

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

Example Embodiment

[0034] Example 3 Preparation of Compound VI

[0035] Put lithium chloride (848g) and potassium borohydride (1080g) into the reaction flask, add THF (12.5L) and stir to dissolve, heat at 50℃ and stir for 30min, add dropwise the THF solution of compound V (3kg), add after the reaction is complete Add 4L ethyl acetate to 5.5L ice water, stir for 30min, separate the liquids, separate the organic phase, dry and concentrate to obtain the crude compound V; then recrystallize with toluene and dry the solid at 50℃ for 6 hours to obtain white crystal compound VI2453g , The yield is 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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