CN1142176C - Halcinonide producing process - Google Patents
Halcinonide producing process Download PDFInfo
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- CN1142176C CN1142176C CNB001365878A CN00136587A CN1142176C CN 1142176 C CN1142176 C CN 1142176C CN B001365878 A CNB001365878 A CN B001365878A CN 00136587 A CN00136587 A CN 00136587A CN 1142176 C CN1142176 C CN 1142176C
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- Prior art keywords
- fluoride
- reaction
- halcinonide
- fluorine
- methyl alcohol
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Abstract
The present invention provides a Halcinonide producing process which uses a ring reduction object of an intermediate body as a raw material; 54 to 62% of HF/D. M. F (hydrogen fluoride/dimethylformamide solution) is used for fluorine reaction; after the reaction is finished, a large amount of water is used for dilution, ammonia water is neutralized, and filtration and drying are carried out; then, recrystallization refinement is carried out; the solvent with the ratio of chloroform to methanol of 7 to 3 is used for dissolution; the solvent is then concentrated, and methanol is flushed at the later stage; after recrystallization, filtration and drying are carried out in the methanol, and accordingly, the fluorine object is obtained. The process can increase the yield and the quality of the fluorine object, and the content of the impurities in the fluorine object is reduced.
Description
Technical field:
The present invention relates to the production technique of fluorine on the halcinonide.
Background technology:
The production technique of fluorine on traditional halcinonide is a raw material with halcinonide intermediate ring shrinking material, and the aqueous hydrogen fluoride solution with 60% carries out fluoride reaction, after reaction finishes, and big water gaging dilution, ammoniacal liquor neutralization, filtration, drying; 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; In methyl alcohol, carry out recrystallization, filter, the dry fluoride that gets.Its shortcoming is that water is cooked solvent, and solvent polarity is strong, and the selectivity of reaction is not high, and hydrolysis easily takes place in the 21-position in reaction process, causes reaction unstable, and quality and yield are not high.
The ring shrinking material fluoride
Summary of the invention:
The present invention is directed to existing technical problem, the production technique of fluorine on a kind of halcinonide is provided, is raw material with halcinonide intermediate ring shrinking material; Hydrogen fluoride with 54%～62% and dimethyl formamide mixing solutions carry out fluoride reaction, after reaction finishes, and big water gaging dilution, ammoniacal liquor neutralization, filtration, drying; 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; In methyl alcohol, carry out recrystallization, filter, the dry fluoride that gets.Owing to do solvent with dimethyl formamide, make the polarity of solvent reduce, the selectivity of reaction strengthens, and has reduced the possibility of the hydrolysis of 21-position, thereby has improved the yield and the quality of fluoride, reduces the content of impurity in the fluoride.
In order to realize purpose of the present invention, the invention provides following technical scheme:
With halcinonide intermediate ring shrinking material is raw material; Carry out fluoride reaction with 54%～62% hydrogen fluoride and dimethyl formamide mixing solutions, after reaction finishes, with the frozen water dilution, ammoniacal liquor neutralization, filtration, the drying that are equivalent to 100 times of ring shrinking material weight; 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; In methyl alcohol, carry out recrystallization, filter, the dry fluoride that gets.
Excellent beneficial effect of the present invention can be confirmed by following result.
Table 1: the production technique of halcinonide fluoride of the present invention and prior art effect are relatively
| Numbering | Ring shrinking material is criticized charging capacity kg | Production method | Fluoride output kg | Yield % | Improve yield % | Fusing point ℃ |
| 1 | 12 | Prior art | 8.4 | 70.0 | 0 | 220 |
| 2 | 12 | Add concentration 54% hydrogen fluoride and dimethyl formamide | 8.9 | 74.2 | 6.0 | 226 |
| 3 | 12 | Add concentration 58% hydrogen fluoride and dimethyl formamide | 9 | 75.0 | 7.1 | 228 |
| 4 | 12 | Add concentration 62% hydrogen fluoride and dimethyl formamide | 8.9 | 74.2 | 6.0 | 227 |
Annotate: yield=fluoride output ÷ ring shrinking material is criticized charging capacity * 100%
Improve yield %=(fluoride output-contrast fluoride output) ÷ contrast fluoride output * 100%
Above sample is that 8: 2 mixing solutions is made developping agent with volume ratio through the chromatography chromatogram relatively, clearly is less than the product of fluorine on usefulness hydrogen fluoride/aqueous solution with the impurity of the product of fluorine on hydrogen fluoride and the dimethyl formamide mixing solutions.
As can be seen from the above table: fluoride yield quality is obviously improved with fluorine on 54%～62% hydrogen fluoride and the dimethyl formamide mixing solutions.
This shows: excellent beneficial effect of the present invention is:
Carry out fluoride reaction with 54%～62% hydrogen fluoride and dimethyl formamide mixing solutions, owing to do solvent with dimethyl formamide, make the polarity of solvent reduce, the selectivity of reaction strengthens, reduced the possibility of the hydrolysis of 21-position, thereby improved the yield and the quality of fluoride, reduced the content of impurity in the fluoride.
Embodiment:
Embodiment 1:
With halcinonide intermediate ring shrinking material 12kg; The aqueous hydrogen fluoride solution that adds 60kg60% carries out fluoride reaction, after reaction finishes, is diluted in the 1200L frozen water, ammoniacal liquor neutralization, filtration, drying; 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; In methyl alcohol, carry out recrystallization, filter, dry fluoride 8.4kg, 220 ℃ of the fusing points of getting.
Embodiment 2:
With halcinonide intermediate ring shrinking material 12kg; The hydrogen fluoride and the dimethyl formamide mixing solutions that add 60kg54% carry out fluoride reaction, after reaction finishes, are diluted in the 1200L frozen water, ammoniacal liquor neutralization, filtration, drying; 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; In methyl alcohol, carry out recrystallization, filter, dry fluoride 8.9kg, 226 ℃ of the fusing points of getting.
Embodiment 3:
With halcinonide intermediate ring shrinking material 12kg; The hydrogen fluoride and the dimethyl formamide mixing solutions that add 60kg58% carry out fluoride reaction, after reaction finishes, are diluted in the 1200L frozen water, ammoniacal liquor neutralization, filtration, drying; 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; In methyl alcohol, carry out recrystallization, filter, dry fluoride 9kg, 228 ℃ of the fusing points of getting.
Embodiment 4:
With halcinonide intermediate ring shrinking material 12kg; The hydrogen fluoride and the dimethyl formamide mixing solutions that add 60kg62% carry out fluoride reaction, after reaction finishes, are diluted in the 1200L frozen water, ammoniacal liquor neutralization, filtration, drying; 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; In methyl alcohol, carry out recrystallization, filter, dry fluoride 8.9kg, 228 ℃ of the fusing points of getting.
Claims (1)
1. the production technique of fluorine on the halcinonide is a raw material with halcinonide intermediate ring shrinking material; Carry out fluoride reaction with 54%～62% hydrogen fluoride and dimethyl formamide mixing solutions, after reaction finishes, with the frozen water dilution, ammoniacal liquor neutralization, filtration, the drying that are equivalent to 100 times of ring shrinking material weight; 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, the dry fluoride that gets is characterized in that: when carrying out fluoride reaction, use 54%～62% hydrogen fluoride and dimethyl formamide mixing solutions.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB001365878A CN1142176C (en) | 2000-12-27 | 2000-12-27 | Halcinonide producing process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB001365878A CN1142176C (en) | 2000-12-27 | 2000-12-27 | Halcinonide producing process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1361112A CN1361112A (en) | 2002-07-31 |
| CN1142176C true CN1142176C (en) | 2004-03-17 |
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ID=4597373
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB001365878A Expired - Fee Related CN1142176C (en) | 2000-12-27 | 2000-12-27 | Halcinonide producing process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1142176C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107778341A (en) * | 2016-08-30 | 2018-03-09 | 天津太平洋制药有限公司 | A kind of preparation method of Halcinonide |
| CN109206471B (en) * | 2017-06-30 | 2022-07-12 | 天津药业研究院股份有限公司 | Preparation method of halcinonide |
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2000
- 2000-12-27 CN CNB001365878A patent/CN1142176C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CN1361112A (en) | 2002-07-31 |
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Granted publication date: 20040317 Termination date: 20111227 |