Betamethasone fluorination production process

Abstract

The invention discloses a betamethasone fluorination production process, and belongs to the field of chemical synthesis methods of medicines. The process comprises the following steps: S1, preparing a reaction solution, S2, preparing a standby solution, S3, obtaining a betamethasone crude product wet product, and S4, obtaining a betamethasone fine product, wherein in the step 1, acetone can be replaced by recycled acetone, and a hydrofluoric acid-potassium fluoride solution is a solution obtained after potassium fluoride is slowly added into hydrofluoric acid to be dissolved, in the step S2, the feeding ratio of betamethasone epoxide to drinking water to potassium hydroxide is 1:(0.5-1):(0.2-0.6), and in the step S4, acetone can also be replaced by recycled acetone. According to the invention, the betamethasone fluorination production process is more scientific and reasonable, has higher controllability and operability, is milder in reaction and higher in yield and quality, reduces the risk of harm to operators, reduces the discharge of fluorine-containing wastewater, reduces the environmental pollution, is greener in reaction, improves the yield and quality, and has better application prospects.

Description

technical field

[0001] The invention relates to the field of pharmaceutical chemical synthesis methods, in particular to a process for producing fluorine on betamethasone. Background technique

[0002] Betamethasone, the chemical name is 9-fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione. The glucose metabolism and anti-inflammatory effect of betamethasone is stronger than that of hydrocortisone, which is 15 times that of hydrocortisone, but the sodium retention effect is more than 100 times that of hydrocortisone. In primary adrenal hypofunction, May be used in combination with glucocorticosteroids for alternative therapy. It is also suitable for orthostatic hypotension caused by low renin and low aldosterone syndrome and autonomic neuropathy.

[0003] The fluoride synthesis method of traditional betamethasone mostly adopts the aqueous solution of hydrogen fluoride or the dimethylformamide solution of hydrogen fluoride to add betamethasone epoxy (common n...

Examples

Embodiment 1

[0027] see figure 1 , a process for producing fluorine on betamethasone, comprising the following steps:

[0028] S1: Under the protection of nitrogen, add 30g of betamethasone epoxy and 150ml of acetone into the reaction flask, stir and cool down, keep the temperature at -5~0℃, control the temperature <5℃, add hydrofluoric acid-fluorination Potassium solution (0.18g of potassium fluoride dissolved in 3.3g of hydrofluoric acid), after the dropwise addition, was kept at 0-10°C for 2.5h to obtain a reaction solution;

[0029] S2: Preparation of reserve solution: Add 30ml of drinking water to a beaker, slowly add 12g of potassium hydroxide, stir evenly, exotherm violently during the preparation process, cool to 0-5°C for use, and obtain a reserve solution.

[0030] S3: TLC detects that the reaction of the raw material betamethasone epoxy is complete, slowly dilute it in 450ml of water, then add the reserve solution dropwise, control the temperature not to exceed 20°C, add dropwi...

Embodiment 2

[0033] see figure 1 , a process for producing fluorine on betamethasone, comprising the following steps:

[0034] S1: Under the protection of nitrogen, add 30g of betamethasone epoxy and 150ml of acetone into the reaction flask, stir and cool down to make the temperature -5~0°C, control the temperature <5°C, add dropwise hydrofluoric acid solution (0.15 g of potassium fluoride dissolved in 3 g of hydrofluoric acid), after the dropwise addition is completed, the temperature is kept at 0-10° C. for 3 hours to obtain a reaction solution;

[0035] S2: Preparation of reserve solution: add 30ml of drinking water to a beaker, slowly add 12g of potassium hydroxide, stir evenly, exotherm violently during the preparation process, cool to 0-5°C for use, and obtain a reserve solution;

[0036] S3: TLC detects that the reaction of the raw material betamethasone epoxy is complete, slowly dilute it in 450ml of water, then add the reserve solution dropwise, control the temperature not to exc...

Embodiment 3

[0039] see figure 1 , a process for producing fluorine on betamethasone, comprising the following steps:

[0040] S1: Under the protection of nitrogen, add 30g of betamethasone epoxy and 120ml of recovered acetone into the reaction flask, stir and cool down to make the temperature -5 ~ 0°C; control the temperature <5°C, add dropwise hydrofluoric acid solution ( Dissolve 0.3g of potassium fluoride in 4.5g of hydrofluoric acid), after the dropwise addition, keep warm at 0-10°C for 1.5h to obtain a reaction solution.

[0041] S2: Preparation of reserve solution: add 30ml of drinking water to a beaker, slowly add 12g of potassium hydroxide, stir evenly, exotherm violently during the preparation process, cool to 0-5°C for use, and obtain a reserve solution;

[0042] S3: TLC detects that the raw material betamethasone epoxy reacts completely, slowly dilute it in 360ml of water, then add the reserve solution dropwise, control the temperature not to exceed 20°C, add dropwise until th...

technical field

[0001] The invention relates to the field of pharmaceutical chemical synthesis methods, in particular to a process for producing fluorine on betamethasone. Background technique

[0002] Betamethasone, the chemical name is 9-fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione. The glucose metabolism and anti-inflammatory effect of betamethasone is stronger than that of hydrocortisone, which is 15 times that of hydrocortisone, but the sodium retention effect is more than 100 times that of hydrocortisone. In primary adrenal hypofunction, May be used in combination with glucocorticosteroids for alternative therapy. It is also suitable for orthostatic hypotension caused by low renin and low aldosterone syndrome and autonomic neuropathy.

[0003] The fluoride synthesis method of traditional betamethasone mostly adopts the aqueous solution of hydrogen fluoride or the dimethylformamide solution of hydrogen fluoride to add betamethasone epoxy (common n...

Examples

Embodiment 1

[0027] see figure 1 , a process for producing fluorine on betamethasone, comprising the following steps:

[0028] S1: Under the protection of nitrogen, add 30g of betamethasone epoxy and 150ml of acetone into the reaction flask, stir and cool down, keep the temperature at -5~0℃, control the temperature <5℃, add hydrofluoric acid-fluorination Potassium solution (0.18g of potassium fluoride dissolved in 3.3g of hydrofluoric acid), after the dropwise addition, was kept at 0-10°C for 2.5h to obtain a reaction solution;

[0029] S2: Preparation of reserve solution: Add 30ml of drinking water to a beaker, slowly add 12g of potassium hydroxide, stir evenly, exotherm violently during the preparation process, cool to 0-5°C for use, and obtain a reserve solution.

[0030] S3: TLC detects that the reaction of the raw material betamethasone epoxy is complete, slowly dilute it in 450ml of water, then add the reserve solution dropwise, control the temperature not to exceed 20°C, add dropwi...

Embodiment 2

[0033] see figure 1 , a process for producing fluorine on betamethasone, comprising the following steps:

[0034] S1: Under the protection of nitrogen, add 30g of betamethasone epoxy and 150ml of acetone into the reaction flask, stir and cool down to make the temperature -5~0°C, control the temperature <5°C, add dropwise hydrofluoric acid solution (0.15 g of potassium fluoride dissolved in 3 g of hydrofluoric acid), after the dropwise addition is completed, the temperature is kept at 0-10° C. for 3 hours to obtain a reaction solution;

[0035] S2: Preparation of reserve solution: add 30ml of drinking water to a beaker, slowly add 12g of potassium hydroxide, stir evenly, exotherm violently during the preparation process, cool to 0-5°C for use, and obtain a reserve solution;

[0036] S3: TLC detects that the reaction of the raw material betamethasone epoxy is complete, slowly dilute it in 450ml of water, then add the reserve solution dropwise, control the temperature not to exc...

Embodiment 3

[0039] see figure 1 , a process for producing fluorine on betamethasone, comprising the following steps:

[0040] S1: Under the protection of nitrogen, add 30g of betamethasone epoxy and 120ml of recovered acetone into the reaction flask, stir and cool down to make the temperature -5 ~ 0°C; control the temperature <5°C, add dropwise hydrofluoric acid solution ( Dissolve 0.3g of potassium fluoride in 4.5g of hydrofluoric acid), after the dropwise addition, keep warm at 0-10°C for 1.5h to obtain a reaction solution.

[0041] S2: Preparation of reserve solution: add 30ml of drinking water to a beaker, slowly add 12g of potassium hydroxide, stir evenly, exotherm violently during the preparation process, cool to 0-5°C for use, and obtain a reserve solution;

[0042] S3: TLC detects that the raw material betamethasone epoxy reacts completely, slowly dilute it in 360ml of water, then add the reserve solution dropwise, control the temperature not to exceed 20°C, add dropwise until th...

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