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Preparation method of prednisolone sodium phosphate intermediate

A technology for prednisolone sodium phosphate and prednisolone phosphate, which is applied in the preparation of pharmaceutical intermediates and the preparation field of prednisolone sodium phosphate intermediate prednisolone phosphate, can solve the problem of unfavorable quality of raw materials. , does not meet the problems of energy saving and environmental protection, serious environmental pollution, etc., to achieve the effect of more secure quality yield, avoid impurities, and reduce side reactions

Active Publication Date: 2019-05-10
HENAN LIHUA PHARMA
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  • Abstract
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  • Claims
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Problems solved by technology

[0003] The preparation method of traditional prednisolone sodium phosphate is carried out with reference to the technique of prednisolone sodium phosphate in "National Material Drug Process Compilation" (National Pharmaceutical Administration, 1980), specifically by formazan Obtained by sulfonylation, iodination, replacement, and salt formation. In the preparation of prednisolone phosphate, the reaction steps are tedious, and there are many side reactions, and the highly toxic reagent methanesulfonyl chloride and the high ammonia nitrogen reagent pyridine and piperazine acetate are used. etc., producing a large amount of waste water and causing serious environmental pollution
Chinese patents CN201510758961.3, CN201410133362.8, and CN200710061255.9 relate to the synthesis of the analogue dexamethasone sodium phosphate, in which the ester-forming reaction is carried out with tetrahydrofuran (THF) / pyrophosphoryl chloride system, compared with the aforementioned process. It has been greatly improved, but there are still many problems, including complex post-processing, the organic solvent THF has not been recycled and applied mechanically, and the acid products produced in the reaction have destructive effects, resulting in many side reactions and high impurity content, which do not meet energy conservation and environmental protection. The concept of development is also not conducive to the improvement of the quality of raw materials

Method used

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  • Preparation method of prednisolone sodium phosphate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] A. In the reaction bottle, add 50g of prednisolone and 500ml of MTHP under the protection of nitrogen, stir and cool down to -55~-60℃, slowly add 40ml of pyrophosphoryl chloride dropwise within 40min, after the addition is completed, keep warm for 1h, and detect by TLC No raw material points;

[0018] B. Add 100ml of purified water to quench the reaction, let it stand for 2 hours, and separate the layers;

[0019] C. The organic phase was extracted twice with 150ml of purified water each time, and then 2.5g of activated carbon was added to the organic phase for decolorization at 30°C for 1 hour;

[0020] D. Filter, concentrate under reduced pressure at 60°C to a paste, cool to below 0°C and discharge, vacuum-dry at 60°C to constant weight, HPLC99.5%, maximum simplex 0.2%, yield 115.2%.

Embodiment 2

[0022] A. In the reaction bottle, add 100g of prednisolone and 1000ml of MTHP under the protection of nitrogen, stir and cool down to -55~-60℃, slowly add 80ml of pyrophosphoryl chloride dropwise within 1 hour, after the addition is completed, keep it warm for 80min, and detect it by TLC No raw material points;

[0023] B. Add 200ml of purified water to quench the reaction, let it stand for 3 hours, and separate the layers;

[0024] C. The organic phase was extracted twice with 300ml of purified water each time, and then 5g of activated carbon was added to the organic phase for decolorization at 40°C for 1.5h;

[0025] D. Filtrate, concentrate under reduced pressure at 60°C to a paste, cool to below 0°C and discharge, vacuum-dry at 70°C to constant weight, HPLC99.4%, maximum simplex 0.25%, yield 116.3%, of which MTHP800ml was recovered.

Embodiment 3

[0027] A. In the reaction bottle, add 50g of prednisolone under the protection of nitrogen, recover 500ml of MTHP, stir and lower the temperature to -55~-60℃, slowly add 50ml of pyrophosphoryl chloride dropwise within 45min, after the addition is completed, keep warm for 1h, TLC Detect no raw material point;

[0028] B. Add 75ml of purified water to quench the reaction, let it stand for 3 hours, and separate the layers;

[0029] C. The organic phase was extracted twice with 200ml of purified water each time, and then 3g of activated carbon was added to the organic phase for decolorization at 40°C for 1.5h;

[0030] D. Filtrate, concentrate under reduced pressure at 60°C to a paste, cool to below 0°C and discharge, vacuum-dry at 60°C to constant weight, HPLC99.5%, maximum simplex 0.21%, yield 116.5%.

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Abstract

The invention discloses a preparation method of a prednisolone sodium phosphate intermediate. The prednisolone sodium phosphate intermediate is prednisolone phosphate as shown in a formula II, prednisolone is used as a raw material and reacts with diphosphoryl chloride, and reaction steps include: A adding a compound I into an organic solvent MTHP under nitrogen protection, stirring and dissolvingthe compound I, slowing dropping the diphosphoryl chloride at the temperature ranging from -50 DEG C to -60 DEG C and performing heat reaction; B adding purified water after reaction to terminate reaction and performing standing layering for 2-4 hours; C adding an organic phase into the purified water, performing extraction twice, adding activated carbon into the organic phase and performing heatinsulation discoloration at the heat insulation temperature of 30-50 DEG C for 1-2 hours; D performing filtration, vacuum concentration, cooling, discharging and vacuum drying to obtain a compound II. The preparation method is economical and environmentally friendly.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of prednisolone sodium phosphate intermediate prednisolone phosphate, which belongs to the field of medicinal chemistry. Background technique [0002] Prednisolone Sodium Phosphate (Prednisolone Sodium Phosphate), the chemical name is 11β, 17-dihydroxy-3,20-diketone pregna-1,4-diene-21-phosphate disodium, is an adrenal glucocorticoid A kind of medicine, mainly used for anti-inflammation, anti-allergy, anti-shock, currently recorded in Chinese, American and European Pharmacopoeias. [0003] The preparation method of traditional prednisolone sodium phosphate is carried out with reference to the technique of prednisolone sodium phosphate in "National Material Drug Process Compilation" (National Pharmaceutical Administration, 1980), specifically by formazan Obtained by sulfonylation, iodination, replacement, and salt formation. In the prep...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J51/00
Inventor 李合兴孟栋梁王海波
Owner HENAN LIHUA PHARMA
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