A kind of preparation method of hydrocortisone acetate

Abstract

The invention belongs to the field of preparation of steroid drugs and particularly relates to a preparation method of hydrocortisone acetate. The preparation method comprises steps as follows: a bromohydroxy compound is synthesized from a compound C5 as a raw material through a bromohydroxy reaction, a crude hydrocortisone acetate product is produced through a debromination reaction, and finally, a refined hydrocortisone acetate product is obtained through refining, wherein alkali halide is added as a catalyst of the bromohydroxy reaction and a feeding mass ratio of the compound C5 to alkali halide is 1:(0.08-0.1). The preparation method of hydrocortisone acetate has the advantages as follows: alkali halide is adopted as the catalyst of the bromohydroxy reaction, so that the key of the problem that the reaction is incomplete in the bromohydroxy reaction process is solved, and one novel preparation method of hydrocortisone acetate with stable product quality and higher yield is provided.

Description

technical field

[0001] The invention belongs to the technical field of organic chemical synthesis, and relates to a preparation method of steroid medicines, in particular to a preparation method of hydrocortisone acetate. Background technique

[0002] Hydrocortisone acetate has important physiological activities, such as anti-inflammatory, anti-viral, anti-allergic, anti-shock, reducing inflammatory exudation, etc. It is often used clinically for allergic, non-infectious skin diseases and some proliferative skin diseases. Such as dermatitis, eczema, neurodermatitis, seborrheic dermatitis and pruritus.

[0003] There are many production processes for hydrocortisone acetate, and the common methods are biological fermentation and chemical synthesis. In biological fermentation, the 11-position beta-hydroxyl group is generally directly added to the 11-position beta-hydroxyl by M. arhicephala. This method is non-specific, and RS products are generated. It is characterized by a sh...

Examples

Embodiment 1

[0034] A preparation method of hydrocortisone acetate, comprising:

[0035] (1) Bromo-hydroxyl reaction: The mass ratio of feeding is compound C5: catalyst: solvent: brominating agent: 2% perchloric acid=1:0.08:25:0.8:3. The process is: compound C5 (3g) is dropped into bromohydrin reaction tank, then add acetone (75ml), when stirring and cooling to 0°C, add 2% perchloric acid aqueous solution (9ml), then add 10% sodium iodide aqueous solution ( 2.4ml), put NBS (2.4g) into the reaction tank three times at about 0°C, and it takes about 60 minutes. After the injection, continue to react at 0°C-20°C for 4 hours, start sampling, TLC detects that the reaction is complete, and the reaction is complete Finally, lower the temperature and add 10% sodium sulfite aqueous solution to adjust the pH value to about 7, then carry out vacuum concentration and distill off acetone. Let it stand for 2 hours, filter tap water, wash and blot dry, and dry to obtain the bromohydroxyl compound. Based ...

Embodiment 2

[0038] A preparation method of hydrocortisone acetate, comprising:

[0039](1) Bromo-hydroxyl reaction: The mass ratio of feeding is compound C5: catalyst: solvent: brominating agent: 2% perchloric acid=1:0.09:24:0.9:2. The process is: put compound C5 into bromohydrin reaction tank, then add tetrahydrofuran, stir and cool down to 0°C, then add 2% perchloric acid aqueous solution, then add 10% sodium iodide aqueous solution, and put NBS into the reaction three times at about 0°C In the tank, it takes about 60 minutes. After the injection, continue to react at 0°C-20°C for 4 hours, start sampling, and TLC detects that the reaction is complete. Concentrate under pressure to remove tetrahydrofuran. The concentration temperature should not exceed 55°C. After recovering tetrahydrofuran under reduced pressure, add water to dilute under stirring. After cooling down to 20°C, let stand for 2 hours, filter tap water, wash and dry, and dry to obtain bromohydroxyl compound , based on comp...

Embodiment 3

[0042] A preparation method of hydrocortisone acetate, comprising:

[0043] (1) Bromo-hydroxyl reaction: The mass ratio of feeding is compound C5: catalyst: solvent: brominating agent: 2% perchloric acid=1:0.1:25:0.6:3. The process is: put compound C5 (20g) into bromohydrin reaction tank, add acetone (500ml) again, when stirring and cooling down to 0°C, add 2% perchloric acid aqueous solution (60ml), then add 10% potassium iodide aqueous solution (20ml) , put dibromohydantoin (12g) into the reaction tank three times at about 0°C, and it takes about 60 minutes. After the throwing, continue to react at 0°C-20°C for 4 hours, start sampling, TLC detects that the reaction is complete, after the reaction is completed , lower the temperature and add 10% sodium sulfite aqueous solution to adjust the pH value to about 7, then carry out vacuum concentration and distill off acetone. Placed for 2 hours, centrifuged, washed with tap water, dried, and dried to obtain the bromohydroxyl comp...

technical field

[0001] The invention belongs to the technical field of organic chemical synthesis, and relates to a preparation method of steroid medicines, in particular to a preparation method of hydrocortisone acetate. Background technique

[0002] Hydrocortisone acetate has important physiological activities, such as anti-inflammatory, anti-viral, anti-allergic, anti-shock, reducing inflammatory exudation, etc. It is often used clinically for allergic, non-infectious skin diseases and some proliferative skin diseases. Such as dermatitis, eczema, neurodermatitis, seborrheic dermatitis and pruritus.

[0003] There are many production processes for hydrocortisone acetate, and the common methods are biological fermentation and chemical synthesis. In biological fermentation, the 11-position beta-hydroxyl group is generally directly added to the 11-position beta-hydroxyl by M. arhicephala. This method is non-specific, and RS products are generated. It is characterized by a sh...

Examples

Embodiment 1

[0034] A preparation method of hydrocortisone acetate, comprising:

[0035] (1) Bromo-hydroxyl reaction: The mass ratio of feeding is compound C5: catalyst: solvent: brominating agent: 2% perchloric acid=1:0.08:25:0.8:3. The process is: compound C5 (3g) is dropped into bromohydrin reaction tank, then add acetone (75ml), when stirring and cooling to 0°C, add 2% perchloric acid aqueous solution (9ml), then add 10% sodium iodide aqueous solution ( 2.4ml), put NBS (2.4g) into the reaction tank three times at about 0°C, and it takes about 60 minutes. After the injection, continue to react at 0°C-20°C for 4 hours, start sampling, TLC detects that the reaction is complete, and the reaction is complete Finally, lower the temperature and add 10% sodium sulfite aqueous solution to adjust the pH value to about 7, then carry out vacuum concentration and distill off acetone. Let it stand for 2 hours, filter tap water, wash and blot dry, and dry to obtain the bromohydroxyl compound. Based ...

Embodiment 2

[0038] A preparation method of hydrocortisone acetate, comprising:

[0039](1) Bromo-hydroxyl reaction: The mass ratio of feeding is compound C5: catalyst: solvent: brominating agent: 2% perchloric acid=1:0.09:24:0.9:2. The process is: put compound C5 into bromohydrin reaction tank, then add tetrahydrofuran, stir and cool down to 0°C, then add 2% perchloric acid aqueous solution, then add 10% sodium iodide aqueous solution, and put NBS into the reaction three times at about 0°C In the tank, it takes about 60 minutes. After the injection, continue to react at 0°C-20°C for 4 hours, start sampling, and TLC detects that the reaction is complete. Concentrate under pressure to remove tetrahydrofuran. The concentration temperature should not exceed 55°C. After recovering tetrahydrofuran under reduced pressure, add water to dilute under stirring. After cooling down to 20°C, let stand for 2 hours, filter tap water, wash and dry, and dry to obtain bromohydroxyl compound , based on comp...

Embodiment 3

[0042] A preparation method of hydrocortisone acetate, comprising:

[0043] (1) Bromo-hydroxyl reaction: The mass ratio of feeding is compound C5: catalyst: solvent: brominating agent: 2% perchloric acid=1:0.1:25:0.6:3. The process is: put compound C5 (20g) into bromohydrin reaction tank, add acetone (500ml) again, when stirring and cooling down to 0°C, add 2% perchloric acid aqueous solution (60ml), then add 10% potassium iodide aqueous solution (20ml) , put dibromohydantoin (12g) into the reaction tank three times at about 0°C, and it takes about 60 minutes. After the throwing, continue to react at 0°C-20°C for 4 hours, start sampling, TLC detects that the reaction is complete, after the reaction is completed , lower the temperature and add 10% sodium sulfite aqueous solution to adjust the pH value to about 7, then carry out vacuum concentration and distill off acetone. Placed for 2 hours, centrifuged, washed with tap water, dried, and dried to obtain the bromohydroxyl comp...

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