CN109734766B

CN109734766B - Preparation method of prednisolone sodium phosphate intermediate

Info

Publication number: CN109734766B
Application number: CN201910010072.7A
Authority: CN
Inventors: 李合兴; 孟栋梁; 王海波
Original assignee: Henan Lihua Pharmaceutical Co ltd
Current assignee: Henan Lihua Pharmaceutical Co ltd
Priority date: 2019-01-07
Filing date: 2019-01-07
Publication date: 2020-09-04
Anticipated expiration: 2039-01-07
Also published as: CN109734766A

Abstract

A preparation method of a prednisolone sodium phosphate intermediate is characterized in that the prednisolone sodium phosphate intermediate is prednisolone phosphate shown in formula II, prednisolone is adopted as a raw material to react with pyrophosphoryl chloride, and the reaction steps are as follows: A. under the protection of nitrogen, adding a compound I into an organic solvent MTHP, stirring and dissolving, slowly dropwise adding pyrophosphoryl chloride at-50 to-60 ℃, and carrying out heat preservation reaction; B. after the reaction is finished, adding purified water to stop the reaction, standing and layering; wherein, the standing and layering time is 2-4 h; C. adding purified water into the organic phase for extraction twice, then adding activated carbon into the organic phase, and carrying out heat preservation and decoloration; wherein the heat preservation temperature is 30-50 ℃, and the decoloring time is 1-2 h; D. filtering, concentrating under reduced pressure, cooling, discharging, and vacuum drying to obtain compound II. The preparation method is economical and environment-friendly.

Description

Preparation method of prednisolone sodium phosphate intermediate

Technical Field

The invention relates to a preparation method of a drug intermediate, in particular to a preparation method of a prednisolone sodium phosphate intermediate prednisolone phosphate, and belongs to the field of pharmaceutical chemistry.

Background

Prednisolone Sodium Phosphate (Prednisonone Sodium Phosphate) with the chemical name of 11 beta, 17-dihydroxy-3, 20-diketone pregna-1, 4-diene-21-disodium Phosphate is one of glucocorticoid medicaments, is mainly used for anti-inflammation, anti-allergy and anti-shock, and is currently accepted by China, United states, European pharmacopoeia and the like.

The traditional preparation method of prednisolone sodium phosphate is carried out by taking the process of prednisolone sodium phosphate in the national pharmaceutical product technology assembly (national institute of medicine and drug administration, nineteen and eighty percent) as reference, and is specifically obtained by mesylation, iodination, replacement and salt formation, wherein in the preparation of prednisolone phosphate, the reaction steps are complicated, the side reactions are more, and virulent reagents of methanesulfonyl chloride, high ammonia nitrogen reagents of pyridine, piperazine acetate and the like are used, so that a large amount of wastewater is generated, and the environmental pollution is serious. Chinese patents CN201510758961.3, CN201410133362.8, and CN200710061255.9 relate to the synthesis of dexamethasone sodium phosphate analog, wherein the ester formation reaction is performed by Tetrahydrofuran (THF)/pyrophosphate chloride system, which is a great improvement over the foregoing processes, but still have many problems, including complex post-treatment, recycling of organic solvent THF, destruction of acid multi-product produced during the reaction, which results in many side reactions and high impurity content, and the like, and are not in accordance with the concept of energy saving, environmental protection, and green development, and are not in favor of the improvement of quality of raw material medicine.

Disclosure of Invention

The invention aims to overcome the problems of the prior prednisolone phosphate and provide a preparation method of prednisolone phosphate as an intermediate of prednisolone sodium phosphate.

In order to realize the purpose of the invention, the following technical scheme is adopted: a preparation method of a prednisolone sodium phosphate intermediate is characterized in that the prednisolone sodium phosphate intermediate is prednisolone phosphate shown in a formula II, prednisolone shown in a formula I is adopted as a raw material to react with pyrophosphoryl chloride, and the reaction formula is as follows:

the reaction steps are as follows:

A. under the protection of nitrogen, adding a compound I into an organic solvent MTHP, stirring and dissolving, slowly dropwise adding pyrophosphoryl chloride at-50 to-60 ℃, and carrying out heat preservation reaction; wherein, the dropping time of the pyrophosphoryl chloride is 30 min-1 h, and the reaction is carried out for 50 min-2 h under the condition of heat preservation;

B. after the reaction is finished, adding purified water to stop the reaction, standing and layering; wherein, the standing and layering time is 2-4 h;

C. adding purified water into the organic phase for extraction twice, then adding activated carbon into the organic phase, and carrying out heat preservation and decoloration; wherein the heat preservation temperature is 30-50 ℃, and the decoloring time is 1-2 h;

D. filtering, concentrating under reduced pressure, cooling, discharging, and vacuum drying to obtain compound II; in the step, the temperature of decompression concentration is 50-80 ℃, and the temperature of vacuum drying is 50-80 ℃;

further, the method comprises the following steps of; the feed ratio in the step A is compound I, MTHP and pyrophosphoryl chloride =1: 10-15: 0.8-1.0 (w/v/v), and the feed ratio in the step B is compound II, purified water =1: 1-2 (w/v); and C, adopting a compound II, purified water and activated carbon =1: 3-6: 0.05-0.1 (w/v/w).

The invention has the positive and beneficial technical effects that: the preparation method adopts a novel reagent MTHP (4-methyl-tetrahydropyran) to replace tetrahydrofuran for reaction, fully utilizes the advantages that MTHP has high solubility and high stability which are comparable to THF, and compared with THF and water, MTHP and water phase have smaller mutual solubility, after the reaction is finished and water is added for quenching reaction, excessive pyrophosphate and water react to generate acid substances which enter the water phase, so that the target product and the acid substances are effectively separated, the prednisolone phosphate is prevented from being damaged by a strong acid system, the occurrence of side reactions is reduced, the generation of impurities in the product is avoided, the MTHP can be recovered and reused after the reaction, and the existing THF system patent technology cannot realize the efficient recovery and reuse of THF due to the water-miscible solvent; it is also evident from the reaction steps. The invention has simple and efficient reaction post-treatment, avoids numerous complex post-treatments and ensures the quality and yield. The HPLC content of the product prepared by the preparation method is not lower than 99.4 percent through tests, and the yield is more than 110 percent; meanwhile, the discharge of waste water is reduced, the purposes of energy conservation and environmental protection are achieved, and the method has incomparable advantages from the technical, economic, generation efficiency and environmental protection perspectives.

Detailed Description

In order to more fully explain the implementation of the present invention, examples of the implementation of the present invention are provided. These examples are merely illustrative of the process and do not limit the scope of the invention.

The raw material prednisolone used in the invention can be directly obtained from the market, wherein the solid material is measured by g (grams), the material (g) is used as a metering medium, the liquid material is measured by ml (milliliters), the material (ml) is used as a metering medium, the material ratio w/v refers to g: ml, w/w refers to g: g, TLC refers to thin-layer chromatography, and HPLC refers to high performance liquid chromatography. In the present invention, MTHP means 4-methyl-tetrahydropyran, cas: 4717-96-8.

Example 1:

A. adding 50g of prednisolone and MTHP500ml into a reaction bottle under the protection of nitrogen, cooling to-55-60 ℃ under stirring, slowly adding 40ml of pyrophosphoryl chloride dropwise within 40min, keeping the temperature for reaction for 1h after the addition is finished, and detecting by TLC to obtain no raw material point;

B. adding 100ml of purified water to quench the reaction, standing for 2 hours, and layering;

C. extracting the organic phase twice with 150ml of purified water each time, and then adding 2.5g of activated carbon into the organic phase, and keeping the temperature at 30 ℃ for decoloring for 1 h;

D. filtering, concentrating under reduced pressure at 60 deg.C to paste, cooling to below 0 deg.C, discharging, vacuum drying at 60 deg.C to constant weight, HPLC99.5%, maximum single impurity 0.2%, and yield 115.2%.

Example 2:

A. adding 100g of prednisolone and MTHP1000ml into a reaction bottle under the protection of nitrogen, cooling to-55-60 ℃ under stirring, slowly adding 80ml of pyrophosphoric chloride dropwise within 1h, keeping the temperature for 80min after the addition is finished, and detecting by TLC to obtain no raw material point;

B. adding 200ml of purified water to quench the reaction, standing for 3 hours, and layering;

C. extracting the organic phase twice with 300ml of purified water, and adding 5g of activated carbon into the organic phase, and keeping the temperature at 40 ℃ for decoloring for 1.5 h;

D. filtering, concentrating under reduced pressure at 60 deg.C to paste, cooling to below 0 deg.C, discharging, vacuum drying at 70 deg.C to constant weight, HPLC99.4%, maximum single impurity 0.25%, and yield 116.3%, wherein MTHP800ml is recovered.

Example 3:

A. adding 50g of prednisolone into a reaction bottle under the protection of nitrogen, recovering MTHP500ml, cooling to-55-60 ℃ under stirring, slowly adding 50ml of pyrophosphoric chloride dropwise within 45min, keeping the temperature for reaction for 1h after the addition is finished, and detecting by TLC to obtain no raw material point;

B. adding 75ml of purified water to quench the reaction, standing for 3 hours, and layering;

C. extracting the organic phase twice with 200ml of purified water, and adding 3g of activated carbon into the organic phase, and keeping the temperature at 40 ℃ for decoloring for 1.5 h;

D. filtering, concentrating under reduced pressure at 60 deg.C to paste, cooling to below 0 deg.C, discharging, vacuum drying at 60 deg.C to constant weight, HPLC99.5%, maximum single impurity 0.21%, and yield 116.5%.

Example 4:

A. adding 50g of prednisolone and MTHP500ml into a reaction bottle under the protection of nitrogen, cooling to-55-60 ℃ under stirring, slowly adding 45ml of pyrophosphoric chloride dropwise within 40min, keeping the temperature for reaction for 1h after the addition is finished, and detecting by TLC (thin layer chromatography) that no raw material point exists;

C. extracting the organic phase twice with 150ml of purified water each time, and then adding 2.5g of activated carbon into the organic phase, and keeping the temperature at 50 ℃ for decoloring for 1 h;

D. filtering, concentrating under reduced pressure at 60 deg.C to paste, cooling to below 0 deg.C, discharging, vacuum drying at 65 deg.C to constant weight, HPLC99.6%, maximum single impurity 0.24%, and yield 116.7%.

Although the invention has been described and illustrated in some detail by the inventor, it should be understood that modifications, adaptations, and alternatives thereof may become apparent to one skilled in the art without departing from the spirit of the invention.

Claims

1. A preparation method of a prednisolone sodium phosphate intermediate is characterized in that the prednisolone sodium phosphate intermediate is prednisolone phosphate shown in a formula II, and prednisolone shown in a formula I is adopted as a raw material to react with pyrophosphoryl chloride, and the preparation method is characterized in that: the reaction formula is as follows:

the reaction steps are as follows:

D. filtering, concentrating under reduced pressure, cooling, discharging, and vacuum drying to obtain compound II; in the step, the temperature of decompression concentration is 50-80 ℃, and the temperature of vacuum drying is 50-80 ℃; in the step A, a compound I, MTHP and pyrophosphoryl chloride =1: 10-15: 0.8-1.0 is adopted in the feeding ratio, and the unit is as follows: w/v/v, wherein the feeding ratio in the step B adopts a compound II to purified water =1: 1-2, and the unit is as follows: w/v; in the step C, a compound II, purified water and active carbon =1: 3-6: 0.05-0.1 is adopted in the feeding ratio, and the unit is as follows: w/v/w.