Preparation method of pregnenolone phosphate derivatives and their salts

A technology of pregnenone phosphate and pregnenone sodium phosphate, applied in the field of preparation of pregnenone phosphate derivatives and their salts, can solve the problem that the clarity and color of the solution may not meet the requirements, cumbersome, impurity Extraction and other problems, to achieve strong impurity removal capabilities, reduce equipment requirements, and improve efficiency

Inactive Publication Date: 2015-07-01
CHONGQING HUAPONT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method requires multiple extractions with organic solvents, which is very cumbersome, and even so, it is difficult to extract impurities from the product well, and the clarity and color of the product solution may not meet the requirements

Method used

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  • Preparation method of pregnenolone phosphate derivatives and their salts
  • Preparation method of pregnenolone phosphate derivatives and their salts
  • Preparation method of pregnenolone phosphate derivatives and their salts

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Take 0.3kg of dexamethasone (formula III, R1 is a methyl group, and the 18th carbon is an R configuration) in a dry and clean reaction kettle, add 6kg of tetrahydrofuran, stir to disperse, turn on the refrigerant to cool down to -10°C, and add pyrophosphoryl chloride dropwise 0.55kg, after reacting at -12°C to -9°C for 1 hour, add 6kg of water, rise to room temperature, stir well, evaporate THF under reduced pressure, and filter to obtain dexamethasone phosphate (formula I, R1 is methyl, 18 carbon is R configuration) crude product. Disperse the obtained product in purified water, add sodium carbonate to adjust the pH value to 6-8, filter, collect the filtrate, and obtain the crude product aqueous solution of dexamethasone sodium phosphate (formula II, R1 is methyl, 18-position carbon is R configuration) 4.5 kg.

[0052]Take 500ml of the above crude dexamethasone sodium phosphate aqueous solution, add 100ml of chloroform to obtain a two-phase system, then adjust the pH ...

Embodiment 2

[0055] Take 120g of prednisolone (formula III, R1 is hydrogen) in a dry and clean reaction kettle, add 3000g of tetrahydrofuran, stir to disperse, turn on the refrigerant to cool down to -12°C, add 380g of pyrophosphoryl chloride dropwise, at -10°C to -5 After reacting at ℃ for 3 hours, add 2000 g of water, rise to room temperature, stir well, distill off THF under reduced pressure, and filter the crude product of prednisolone phosphate (formula III, R1 is hydrogen). Disperse the obtained product in purified water, add sodium bicarbonate to adjust the pH value to 6.5-7.0, filter, collect the filtrate, and obtain 1800 g of an aqueous solution of the crude product of prednisolone sodium phosphate (formula III, R1 is hydrogen).

[0056] Take 1000ml of the above crude prednisolone sodium phosphate aqueous solution, add 300ml of cyclohexane to obtain a two-phase system, then use hydrochloric acid to adjust the pH value to 3.5-4.0, leave it to crystallize, filter, and dry to obtain p...

Embodiment 3

[0059] Get 800ml of the crude product aqueous solution of dexamethasone sodium phosphate in Example 1, add 1600ml of n-hexane to obtain a two-phase system, then adjust the pH value to 0.2 to 0.4 with hydrochloric acid, place to crystallize, filter, and dry to obtain dexamethasone phosphate ester.

[0060] Dissolve the obtained dexamethasone phosphate in methanol, adjust the pH value to 9-12 with sodium hydroxide, crystallize, filter and dry to obtain the refined product of dexamethasone sodium phosphate.

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PUM

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Abstract

The invention relates to a method for preparing pregnenolone phosphate shown in the formula I from sodium pregnenolone phosphate as a raw material. The method utilizes a two-phase acidification crystallization method and comprises the following steps of 1, preparing an aqueous solution of a compound shown in the formula II, 2, adding a hydrophobic organic solvent into the aqueous solution to obtain a two-phase system comprising water and the organic solvent, and 3, adjusting pH of the two-phase system to less than 7 so that the compound shown in the formula I is precipitated. The product has good quality, less impurities, and solution clarification degree and color satisfying pharmacopeia requirements. The method is efficient, can remove water-soluble impurities and fat-soluble impurities by one step, improves efficiency, has simple processes, is free of reworking, realizes one-step production of the high-quality qualified product, has low energy consumption and reduces a cost.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a preparation method of pregnenone phosphate derivatives and salts thereof. Background technique [0002] Pregnenone is a class of compounds with pregnane as the core and containing ketone groups and carbon-carbon double bonds. The 16-position carbon of the pregnane core may have a stereo configuration. The phosphate derivative of pregnenone refers to the ester formed by the 21-position hydroxyl group of pregnenone and phosphoric acid. Specific compounds include dexamethasone phosphate (formula III), prednisolone phosphate (formula IV), betamethasone phosphate (formula V) and the like. [0003] [0004] Pregnenone phosphate derivatives and pharmaceutically acceptable salts thereof are used as adrenal corticosteroid drugs, and the clinical dosage forms are mainly injections. Therefore, the country has higher quality requirements for raw materials for the preparat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
CPCC07J5/0053C07J5/0076
Inventor 熊伟
Owner CHONGQING HUAPONT PHARMA
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