CN1159336C

CN1159336C - Technological process of producing Fludrocortisone 6 alpha F

Info

Publication number: CN1159336C
Application number: CNB00136586XA
Authority: CN
Inventors: 李金禄; 王福军; 付锡珍
Original assignee: TIANJIN PHARMACEUTICAL INDUSTRY GROUP CORP Ltd
Current assignee: TIANJIN PHARMACEUTICAL INDUSTRY GROUP CORP Ltd
Priority date: 2000-12-27
Filing date: 2000-12-27
Publication date: 2004-07-28
Anticipated expiration: 2020-12-27
Also published as: CN1361110A

Abstract

The present invention relates to a method of the production technology of fluocinolone acetonide 6 alphaF. An intermediate body, namely enol ester, is used as raw material. Perchloryl fluoride is used for fluorination reaction, 40% to 70% of Na2HPO4 water solutions are added into reaction liquid for neutralizing acidic material after reaction, the pH value of the reaction liquid is stable and is maintained between 6 and 8; after the reaction is finished, the reaction liquid is concentrated and crystallized, is diluted by lots of water, is filtered, and is dried; the reaction liquid is recrystallized, is refined, and is dissolved by the solvent of 7 parts of chloroform and 3 parts of methanol; methanol is poured at the later period of concentration, the reaction liquid is recrystallized in the methanol, and 6 alphaF substances are obtained through filtration and dryness. The technology can enhance the yield and the quality of the 6 alphaF substances, and decrease impurity content in the 6 alphaF substances.

Description

The producing and manufacturing technique of fluocinonide 6 α F

Technical field:

The present invention relates to the production technique of fluocinonide 6 α F (6-α F ketenes ester).

Background technology:

The production technique of traditional fluocinonide 6-α F ketenes ester is a raw material with the intermediate enol ester; Carry out fluoride reaction with perchloryl fluoride, after reaction finished, the reaction solution condensing crystal passed through big water gaging dilution, filtration, drying successively; Carrying out recrystallizing and refining again, is that 7: 3 chloroform and methanol mixed solvent dissolves with volume ratio; Concentrate, the later stage is poured methyl alcohol; Carry out recrystallization in methyl alcohol, filter, drying gets 6-α F ketenes ester thing.Its shortcoming is that pH value progressively reduces in reaction process, causes reaction unstable, and quality and yield are not high.

Summary of the invention:

The present invention is directed to the problem that prior art exists, a kind of producing and manufacturing technique of fluocinonide 6-α F ketenes ester is provided, is raw material with the intermediate enol ester; Carry out fluoride reaction with perchloryl fluoride,

In reaction solution, add 40～70% Na ₂HPO ₄The acidic substance of the aqueous solution after with neutralization reaction make the pH value of reaction solution stable, maintain between 6～8, react.Because pH value is stable in the reaction process, and product quality and yield are improved.

In order to realize purpose of the present invention, the invention provides following technical scheme:

With the intermediate enol ester is raw material; Carry out fluoride reaction with perchloryl fluoride, in reaction solution, add 40～70% Na ₂HPO ₄The acidic substance of the aqueous solution after with neutralization reaction make the pH value of reaction solution stable, maintain between 6～8, and after reaction finished, the reaction solution condensing crystal passed through big water gaging dilution, filtration, drying successively; Carrying out recrystallizing and refining again, is that 7: 3 chloroform and methanol mixed solvent dissolves with volume ratio; Concentrate, the later stage is poured methyl alcohol; Carry out recrystallization in methyl alcohol, filter, drying gets 6-α F ketenes ester thing.

Excellent beneficial effect of the present invention can be confirmed by following experiment effect.

Table 1: the production technique of fluocinonide 6-α F ketenes ester thing of the present invention and prior art effect are relatively

Numbering	Enol ester is criticized charging capacity kg	Production method	6-α F ketenes ester produce amount kg	Yield %	Improve yield %	Content %	Improve content %
Numbering	Enol ester is criticized charging capacity kg	Production method	6-α F ketenes ester produce amount kg	Yield %	Improve yield %	Content %	Improve content %	1	30	Prior art	23.4	78.0	0	88	0
2	30	Add 15kg Na ₂HPO ₄	24.9	83.0	6.4	90	2.3	1	30	Prior art	23.4	78.0	0	88	0
2	30	Add 15kg Na ₂HPO ₄	24.9	83.0	6.4	90	2.3	3	30	Add 18kg Na ₂HPO ₄	25.1	83.7	7.2	91	3.4
4	30	Add 21kg Na ₂HPO ₄	25.1	83.7	7.2	90	2.3	3	30	Add 18kg Na ₂HPO ₄	25.1	83.7	7.2	91	3.4

Annotate: yield %=6-α F ketenes ester produce amount ÷ enol ester is criticized charging capacity * 100%

Improve yield %=(6-α F ketenes ester produce amount-contrast 6-α F ketenes ester produce amount) ÷ contrast 6-α F ketenes ester produce amount * 100%

Improve content %=(6-α F ketenes ester thing content-contrast 6-α F ketenes ester thing content) ÷ contrast 6-α F ketenes ester thing content * 100%

Above sample is that 7: 3 benzene and ethyl ester mixed solvent made developping agent with volume ratio through the chromatography chromatogram relatively, clearly adds Na ₂HPO ₄The impurity of product be less than and do not add Na ₂HPO ₄Product.

As can be seen from the above table: the Na of adding 40～70% ₂HPO ₄The aqueous solution can make 6-α F ketenes ester thing yield content obviously improve, simultaneously when adding Na ₂HPO ₄It is little that the aqueous solution is lower than 40% o'clock increase rate, adds Na ₂HPO ₄The aqueous solution 40～70% increase rates are basic identical.

This shows that excellent beneficial effect of the present invention is:

Embodiment:

Embodiment 1:

Use enol ester 30kg; Add 400kg acetone, carry out fluoride reaction with the 24kg perchloryl fluoride, after reaction finished, the reaction solution condensing crystal passed through big water gaging dilution, filtration, drying successively; Carrying out recrystallizing and refining again, is that 7: 3 chloroform and methanol mixed solvent dissolves with volume ratio; Concentrate, the later stage is poured methyl alcohol; Carry out recrystallization in methyl alcohol, filter, drying gets 6-α F ketenes ester thing 23.4kg, content 88%.

Embodiment 2:

Use enol ester 30kg; Add 400kg acetone, carry out fluoride reaction, in reaction solution, add 15kgNa with the 24kg perchloryl fluoride ₂HPO ₄The acidic substance of the aqueous solution after with neutralization reaction are surveyed pH value=6.5, and after reaction finished, the reaction solution condensing crystal passed through big water gaging dilution, filtration, drying successively; Carrying out recrystallizing and refining again, is that 7: 3 chloroform and methanol mixed solvent dissolves with volume ratio; Concentrate, the later stage is poured methyl alcohol; Carry out recrystallization in methyl alcohol, filter, drying gets 6-α F ketenes ester thing 24.9kg, content 90%.

Embodiment 3:

Use enol ester 30kg; Add 400kg acetone, carry out fluoride reaction, in reaction solution, add 18kgNa with the 24kg perchloryl fluoride ₂HPO ₄The acidic substance of the aqueous solution after with neutralization reaction are surveyed pH value=7.0, and after reaction finished, the reaction solution condensing crystal passed through big water gaging dilution, filtration, drying successively; Carrying out recrystallizing and refining again, is that 7: 3 chloroform and methanol mixed solvent dissolves with volume ratio; Concentrate, the later stage is poured methyl alcohol; Carry out recrystallization in methyl alcohol, filter, drying gets 6-α F ketenes ester thing 25.1kg, content 91%.

Embodiment 4:

Use enol ester 30kg; Add 400kg acetone, carry out fluoride reaction, in reaction solution, add 21kgNa with the 24kg perchloryl fluoride ₂HPO ₄The acidic substance of the aqueous solution after with neutralization reaction are surveyed pH value=7.0, and after reaction finished, the reaction solution condensing crystal passed through big water gaging dilution, filtration, drying successively; Carrying out recrystallizing and refining again, is that 7: 3 chloroform and methanol mixed solvent dissolves with volume ratio; Concentrate, the later stage is poured methyl alcohol; Carry out recrystallization in methyl alcohol, filter, drying gets 6-α F ketenes ester thing 25.1kg, content 90%.

Claims

1. the producing and manufacturing technique of a fluocinonide 6-α F ketenes ester, it is characterized in that: with the intermediate enol ester is raw material, carries out fluoride reaction with perchloryl fluoride, adds 40～70% Na in reaction solution ₂HPO ₄The acidic substance of the aqueous solution after with neutralization reaction make the pH value of reaction solution stable, maintain between 6～8, and after reaction finished, the reaction solution condensing crystal passed through big water gaging dilution, filtration, drying successively; Carrying out recrystallizing and refining again, is that 7: 3 chloroform and methanol mixed solvent dissolves with volume ratio; Concentrate, the later stage is poured methyl alcohol; Carry out recrystallization in methyl alcohol, filter, drying gets 6-α F ketenes ester thing.