CN112094311B

CN112094311B - Process for preparing dexamethasone sodium phosphate by one-step method

Info

Publication number: CN112094311B
Application number: CN202011112167.9A
Authority: CN
Inventors: 王培文; 刘伟; 李娜; 蒲飞飞; 张恒
Original assignee: Xi'an Guokang Ruijin Pharmaceutical Co ltd
Current assignee: Xi'an Guokang Ruijin Pharmaceutical Co ltd
Priority date: 2020-10-16
Filing date: 2020-10-16
Publication date: 2022-04-08
Anticipated expiration: 2040-10-16
Also published as: CN112094311A

Abstract

The invention provides a process for producing dexamethasone sodium phosphate by a one-step method, which comprises the following steps: the method is characterized in that dexamethasone is used as a starting raw material, and the dexamethasone is subjected to (1) pyrophosphoryl chloride esterification, (2) purified water hydrolysis, (3) toluene extraction and purification, sodium hydroxide alkalization treatment, (4) activated carbon decolorization, and (5) acetone crystallization to obtain a high-purity dexamethasone sodium phosphate product with high yield.

Description

Process for preparing dexamethasone sodium phosphate by one-step method

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a preparation process for producing dexamethasone sodium phosphate by a one-step method.

Background

Dexamethasone sodium phosphate is called as fluorometholone sodium phosphate, has the chemical name of 1, 4-pregnadiene-9 alpha-fluoro-16 alpha-methyl-11 beta, 17 alpha, 21-triol-3, 20-diketone-21-phosphate disodium salt, belongs to adrenocortical hormone medicines, and is widely applied to the fields of anti-inflammation, antianaphylaxis, rheumatism resistance, immunosuppression and the like.

In the dexamethasone sodium phosphate product on the market at present, the production process must pass through a dexamethasone phosphate intermediate, CN104744543A and CN101397320A, and research on the synthesis process of dexamethasone sodium phosphate (periu) in the academic paper is to alkalize and acidify the dexamethasone phosphate and then alkalize the dexamethasone phosphate again to obtain a refined dexamethasone sodium phosphate product. In view of the situation, the dexamethasone phosphate intermediate liquid is directly subjected to extraction, alkalization sodium conversion and crystallization through technological innovation to obtain the product, and the batch production result shows that the product quality is stable, the process time is shortened, the use of equipment and a solvent is reduced, the production cost is greatly reduced, and the method has a good industrial application prospect.

Disclosure of Invention

The invention aims to provide a process for preparing dexamethasone sodium phosphate by a dexamethasone one-step method, the product obtained by the process has high yield, high purity and stable quality, the use of equipment and solvents is reduced, the method is simple and convenient, the production cost is greatly reduced, and the process is more suitable for industrial large-scale production.

The technical scheme adopted by the invention is as follows:

the method comprises the following operation steps:

esterification:

adding solvent anhydrous tetrahydrofuran into a reaction tank, adding raw material dexamethasone, cooling, dropwise adding pyrophosphoryl chloride, reacting for 1 hour, sampling and detecting dexamethasone residue (less than or equal to 1.0%, namely, the conversion rate is more than or equal to 99.0%);

(II) hydrolysis:

after the reaction liquid is detected to be qualified, adding purified water for hydrolysis;

(III) extraction and purification:

adding toluene after hydrolysis, standing for phase splitting, collecting an oil phase, dropwise adding a sodium hydroxide solution into the oil phase to adjust the pH value to 8-12, standing for phase splitting, and collecting a water phase;

(IV) decoloring:

adding activated carbon into the water phase, decoloring, and pumping the liquid into a clean area;

(V) crystallization:

after all the liquid is stirred, acetone is dripped for crystallization, crystal growth, centrifugation and drying are carried out, and dexamethasone sodium phosphate is obtained.

The reagents used in the invention are all the existing reagents, and since pyrophosphoryl chloride is decomposed into phosphoric acid and hydrochloric acid when meeting water, anhydrous tetrahydrofuran is required to be used for reducing the generation of byproducts. The method for preparing the dexamethasone sodium phosphate product has the advantages of high yield, high purity and simplicity, and is more suitable for industrial large-scale production.

The molar ratio of dexamethasone to pyrophosphoryl chloride in the step (I) is 1: 2-7, preferably 1: 3-6, more preferably 1: 4-5, most preferably 1: 5;

cooling to-50 to-60 ℃;

the reaction time of the step (I) is 1-4h, preferably 1-3h, more preferably 1-2h, and most preferably 1 h;

the volume ratio of the purified water added in the step (II) to the anhydrous tetrahydrofuran in the step (I) is 1:1-1:3, and the preferred volume ratio is 1: 2;

adding sodium hydroxide solution to adjust the pH to 8-12, preferably to 9-11, more preferably to 10, wherein the concentration of the added sodium hydroxide is 10% -40%;

the volume ratio of the toluene added in the step (III) to the purified water added in the step (II) is 0.5-4:1, preferably 1-3:1, and more preferably 1.5: 1;

and (4) the volume ratio of the acetone dropwise added in the step (five) to the sodium hydroxide solution dropwise added in the step (three) is 3:1, preferably 2:1, and most preferably 1: 1.

Detailed Description

The invention is further described below by way of examples, which are not intended to limit the present invention further. It will be understood by those skilled in the art that equivalent substitutions and corresponding modifications of the technical features of the present invention can be made and still fall within the scope of the present invention.

Example 1

Adding 2000ml of anhydrous tetrahydrofuran into a reaction tank, adding 392g (1.0mol) of dexamethasone, stirring and dispersing, cooling to-50 ℃, dropwise adding 755g (3.0mol) of pyrophosphoryl chloride, keeping the temperature unchanged, reacting for 1h after the addition is finished, sampling and detecting that the residue of dexamethasone is less than or equal to 1.0%, adding 1000ml of purified water for hydrolysis, slowly heating to room temperature, and fully stirring. Adding 1500ml of toluene after hydrolysis, standing for phase splitting, collecting an oil phase, dropwise adding a sodium hydroxide solution into the toluene oil phase to adjust the pH value to 10, standing for phase splitting, collecting a water phase, adding activated carbon into the water phase for decoloring for 30 minutes, filtering, completely pumping the liquid into a clean area, adding acetone with the same volume as that of the sodium hydroxide solution for crystallization, growing crystals, centrifuging, and drying to obtain 415g of dexamethasone sodium phosphate, wherein the yield is 80.4%, the purity is 99.0%, and the MP: 232 ℃ and 235 ℃.

Example 2

Adding 2000ml of anhydrous tetrahydrofuran into a reaction tank, adding 392g (1.0mol) of dexamethasone, stirring and dispersing, cooling to-50 ℃, dropwise adding 1007g (4.0mol) of pyrophosphoryl chloride, keeping the temperature unchanged, reacting for 1h after the addition is finished, sampling and detecting that the residue of dexamethasone is less than or equal to 1.0%, adding 1000ml of purified water for hydrolysis, slowly heating to room temperature, and fully stirring. Adding 1500ml of toluene after hydrolysis, standing for phase splitting, collecting an oil phase, dropwise adding a sodium hydroxide solution into the toluene oil phase to adjust the pH value to 10, standing for phase splitting, collecting a water phase, adding activated carbon into the water phase for decoloring for 30 minutes, filtering, completely pumping the liquid into a clean area, adding acetone with the same volume as that of the sodium hydroxide solution for crystallization, growing crystals, centrifuging and drying to obtain 445g of dexamethasone sodium phosphate, wherein the yield is 86.2%, the purity is 99.2%, and the MP: 232 ℃ and 235 ℃.

Example 3

Adding 2000ml of anhydrous tetrahydrofuran into a reaction tank, adding 392g (1.0mol) of dexamethasone, stirring and dispersing, cooling to-50 ℃, dropwise adding 1259g (5.0mol) of pyrophosphoryl chloride, keeping the temperature unchanged, reacting for 1h after the addition is finished, sampling and detecting that the dexamethasone residue is less than or equal to 1.0%, adding 1000ml of purified water for hydrolysis, slowly heating to room temperature, and fully stirring. Adding 1500ml of toluene after hydrolysis, standing for phase splitting, collecting an oil phase, dropwise adding a sodium hydroxide solution into the toluene oil phase to adjust the pH value to 10, standing for phase splitting, collecting a water phase, adding activated carbon into the water phase for decoloring for 30 minutes, filtering, completely pumping the liquid into a clean area, adding acetone with the same volume as that of the sodium hydroxide solution for crystallization, growing crystals, centrifuging and drying to obtain 482g of dexamethasone sodium phosphate, wherein the yield is 93.4%, the purity is 99.5%, and the MP: 233-.

Examples 5-10 the experiment of example 3 was repeated with the following equal volumes of solvent in place of toluene:

examples 5-10 the experiment of example 3 was repeated with equal volumes of solvent replacing toluene, but the product yield was lower when methylene chloride and xylene solvents were used, the product yield and purity were lower when ethyl acetate, petroleum ether and acetone solvents were used, and the separation was not possible by miscibility when ethanol was used as the solvent, as can be seen from the experimental results: in the technology for preparing dexamethasone sodium phosphate by a dexamethasone one-step method, only a toluene solvent can obtain a high-purity product with high yield.

Examples 11-15 the experiment of example 3 was repeated with varying amounts of toluene:

examples	Toluene (ml)	Yield of	Purity of
				11	500	81.7％	99.6％
12	1000	90.8％	99.4％
				13	2000	93.9％	98.2％
14	2500	94.5％	98.0％
				15	3000	95.9％	96.2％

Examples 11-15 the experiment of example 3 was repeated with the amount of toluene varied, and the yield was lower when the amount of toluene was 500ml, although the purity of the product was higher, and the yield and purity of the dexamethasone sodium phosphate product were higher when the amount of toluene was between 1000 and 3000ml, i.e. the volume ratio of toluene to purified water was 1-3:1, to achieve satisfactory results.

It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.

Claims

1. The process for preparing dexamethasone sodium phosphate by using the one-step method is characterized by comprising the following operation steps:

esterification:

adding solvent anhydrous tetrahydrofuran into a reaction tank, adding raw material dexamethasone, cooling, dropwise adding pyrophosphoryl chloride, reacting for 1 hour, sampling and detecting that dexamethasone residue is less than or equal to 1.0 percent, namely the conversion rate is more than or equal to 99.0 percent;

(II) hydrolysis:

(III) extraction and purification:

adding toluene after hydrolysis, standing for phase separation, collecting oil phase, adding sodium hydroxide solution dropwise into the oil phase to adjust pH to 10,

standing for phase separation, and collecting a water phase;

(IV) decoloring:

(V) crystallization:

after all the liquid is stirred, dropwise adding acetone for crystallization, growing crystals, centrifuging and drying to obtain dexamethasone sodium phosphate;

wherein, the molar ratio of the dexamethasone and the pyrophosphoryl chloride in the step (I) is 1: 5, cooling to-50 to-60 ℃;

the volume ratio of the purified water added in the step (II) to the anhydrous tetrahydrofuran in the step (I) is 1: 2;

the concentration of the sodium hydroxide added in the step (III) is 10-40%, and the volume ratio of the toluene added in the step (III) to the purified water added in the step (II) is 1.5: 1;

the volume ratio of the acetone dripped in the step (five) to the sodium hydroxide solution dripped in the step (three) is 1:1,

the dexamethasone phosphate intermediate liquid is directly subjected to extraction, alkalization sodium conversion and crystallization to obtain the product, so that the use of equipment and a solvent is reduced, and the method is suitable for industrial large-scale production.