CN108239133A - The synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes - Google Patents
The synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes Download PDFInfo
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- CN108239133A CN108239133A CN201710526846.2A CN201710526846A CN108239133A CN 108239133 A CN108239133 A CN 108239133A CN 201710526846 A CN201710526846 A CN 201710526846A CN 108239133 A CN108239133 A CN 108239133A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
- C07J7/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa substituted in position 16
- C07J7/0055—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses the synthetic methods of 4 pregnene, 16 α methyl, 17 α alcohol, 3,20 diketone drug, include the following steps：2 bromine, 4 amino, 5 pregnene, 16 α methyl, 3 β, 17 α glycol, 20 ketone are added in reaction vessel, 1.5L potassium nitrate solutions control mixing speed, increase solution temperature, the reaction was continued；Methyl butyrate solution is added in, increases solution temperature, reaction a period of time, then four (triethyl phosphites) are added in and close nickel by powder, reflux reduces solution temperature, oxalic acid solution is added in, is stood, solution layering, it is washed repeatedly with Klorvess Liquid, the washing of 2 butylene Isosorbide-5-Nitrae diacid solutions is multiple, the washing of paraxylene solution is multiple, is recrystallized in dimethyl sulfone solution, dehydrating agent dehydration, obtain 4 pregnene of finished product, 16 α methyl, 17 α alcohol, 3,20 diketone.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, belong to organic synthesis field more particularly to 4- pregnenes-
The synthetic method of -17 α -ol -3,20- diketone drugs of 16 Alpha-Methyl.
Background technology
- 17 α -ol -3,20- diketone of -16 Alpha-Methyl of 4- pregnenes is mainly used for synthesizing mainly as hormonal medicaments intermediate
Dexamethasone acetate.The affiliated cortex hormone of aadrenaline of dexamethasone acetate and Actrope, available for resisting
Mucocutaneous various inflammation and allergic reaction；Eye ointment can be used for treating various ophthalmias.Existing synthetic method uses chromium oxide mostly
Mixed solution with sulfuric acid configuration is as one of reactant, and since chromium oxide environmental pollution is larger, sulfuric acid is as reactant meeting
Increase the danger coefficient of reaction process, and entire building-up process technics comparing is complicated, it is therefore necessary to propose a kind of new conjunction
Into method.
Invention content
Technical problems based on background technology, the present invention propose -17 α -ol -3,20- of -16 Alpha-Methyl of 4- pregnenes
The synthetic method of diketone drug, includes the following steps：
A：Addition bromo- -3 β of -16 Alpha-Methyl of 4- amino -5- pregnenes of 2- in reaction vessel, 17 salmefamol -20- ketone,
1.5L potassium nitrate solutions control mixing speed 110-150rpm, and raising solution temperature is to 40-47 DEG C, the reaction was continued 60-80min；
B：Methyl butyrate solution is added in, raising solution temperature reacts 30-40min to 50-56 DEG C, then adds in four (phosphorous
Triethylenetetraminehexaacetic acid ester) nickel by powder is closed, flow back 30-50min, reduces solution temperature to 30-36 DEG C, adds in oxalic acid solution, stands 1-2h, molten
Liquid is layered, and is washed repeatedly with Klorvess Liquid, 2- butene-1s, and the washing of 4- diacid solutions is multiple, and the washing of paraxylene solution is multiple,
It is recrystallized in dimethyl sulfone solution, dehydrating agent dehydration obtains -17 α -ol -3,20- diketone of -16 Alpha-Methyl of finished product 4- pregnenes.
Preferably, potassium nitrate solution mass fraction is 10-16%.
Preferably, methyl butyrate liquid quality fraction is 35-39%.
Preferably, Klorvess Liquid mass fraction is 15-19%.
Preferably, 2- butene-1s, 4- diacid solutions mass fraction are 50-56%.
Preferably, paraxylene liquid quality fraction is 60-65%.
Preferably, dimethyl sulfone liquid quality fraction is 80-87%.
Entire building-up process can be represented with following reaction formula：
Compared to synthetic method disclosed in background technology, -17 α -ol -3 of -16 Alpha-Methyl of 4- pregnenes provided by the invention,
The synthetic method of 20- diketone drugs does not need to the mixed solution of chromium oxide and sulfuric acid configuration as reactant, avoids chromium oxide
Pollution to environment, also avoid sulfuric acid leads to the increased risk of reaction process danger coefficient as reactant, reacts intermediate ring
Section reduces very much, and the reaction time also shortens much, and reaction yield also improves, while the present invention provides a kind of new synthesis
Route is laid a good foundation further to promote reaction yield.
Specific embodiment
Embodiment 1：
The synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes, includes the following steps：
A：3mol 2- bromo- -3 β of -16 Alpha-Methyl of 4- amino -5- pregnenes, 17 salmefamol -20- are added in reaction vessel
Ketone, 1.5L mass fractions are 10% potassium nitrate solution, control mixing speed 110rpm, and raising solution temperature continues to 40 DEG C
React 60min；
B：The methyl butyrate solution that 6mol mass fractions are 35% is added in, raising solution temperature reacts 30min to 50 DEG C,
Then it adds in 2mol tetra- (triethyl phosphite) and closes nickel by powder, flow back 30min, reduces solution temperature to 30 DEG C, it is molten to add in oxalic acid
Liquid stands 1h, and solution layering is washed 3 times with the Klorvess Liquid that mass fraction is 15%, and mass fraction is 50% 2- fourths
Alkene-Isosorbide-5-Nitrae-diacid solution is washed 5 times, and the paraxylene solution washing that mass fraction is 60% is 6 times more, is 80% in mass fraction
Dimethyl sulfone solution in recrystallize, anhydrous sodium sulfate dehydrating agent dehydration, obtain -17 α -ol -3 of -16 Alpha-Methyl of finished product 4- pregnenes,
20- diketone 895.23g, yield 87%.
Embodiment 2：
The synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes, includes the following steps：
A：3mol 2- bromo- -3 β of -16 Alpha-Methyl of 4- amino -5- pregnenes, 17 salmefamol -20- are added in reaction vessel
Ketone, 1.5L mass fractions are 13% potassium nitrate solution, control mixing speed 130rpm, and raising solution temperature continues to 45 DEG C
React 70min；
B：The methyl butyrate solution that 6.5mol mass fractions are 37% is added in, raising solution temperature is to 53 DEG C, reaction
Then 35min adds in 2.5mol tetra- (triethyl phosphite) and closes nickel by powder, flow back 40min, reduces solution temperature to 34 DEG C, adds
Enter oxalic acid solution, stand 1.5h, solution layering is washed 4 times with the Klorvess Liquid that mass fraction is 17%, and mass fraction is
54% 2- butene-1s, 4- diacid solutions are washed 6 times, and the paraxylene solution that mass fraction is 63% washs 8 times, in quality point
Number for 82% dimethyl sulfone solution in recrystallize, dead plaster dehydrating agent dehydration, obtain -16 Alpha-Methyl of finished product 4- pregnenes -
17 α -ol -3,20- diketone 936.39g, yield 91%.
Embodiment 3：
The synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes, includes the following steps：
A：3mol 2- bromo- -3 β of -16 Alpha-Methyl of 4- amino -5- pregnenes, 17 salmefamol -20- are added in reaction vessel
Ketone, 1.5L mass fractions are 16% potassium nitrate solution, control mixing speed 150rpm, and raising solution temperature continues to 47 DEG C
React 80min；
B：The methyl butyrate solution that 7mol mass fractions are 39% is added in, raising solution temperature reacts 40min to 56 DEG C,
Then it adds in 3mol tetra- (triethyl phosphite) and closes nickel by powder, flow back 50min, reduces solution temperature to 36 DEG C, it is molten to add in oxalic acid
Liquid stands 2h, and solution layering is washed 5 times with the Klorvess Liquid that mass fraction is 19%, and mass fraction is 56% 2- fourths
Alkene-Isosorbide-5-Nitrae-diacid solution is washed 7 times, and the paraxylene solution washing that mass fraction is 65% is 9 times more, is 87% in mass fraction
Dimethyl sulfone solution in recrystallize, Anhydrous potassium carbonate dehydrating agent dehydration, obtain -17 α -ol -3 of -16 Alpha-Methyl of finished product 4- pregnenes,
20- diketone 956.97g, yield 93%.
It described in above example, is merely preferred embodiments of the present invention, but protection scope of the present invention not office
Be limited to this, any one skilled in the art in the technical scope disclosed by the present invention, the technique according to the invention
Scheme and its inventive concept are subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (8)
- The synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 1.4- pregnenes, which is characterized in that including walking as follows Suddenly：A：Bromo- -3 β of -16 Alpha-Methyl of 4- amino -5- pregnenes of 2-, 17 salmefamol -20- ketone, 1.5L nitre are added in reaction vessel Sour potassium solution controls mixing speed 110-150rpm, and raising solution temperature is to 40-47 DEG C, the reaction was continued 60-80min；B：Methyl butyrate solution is added in, raising solution temperature reacts 30-40min to 50-56 DEG C, then adds in four (phosphorous acid three Ethyl ester) nickel by powder is closed, flow back 30-50min, reduces solution temperature to 30-36 DEG C, adds in oxalic acid solution, stands 1-2h, solution point Layer, is washed repeatedly, 2- butene-1s with Klorvess Liquid, and the washing of 4- diacid solutions is multiple, and the washing of paraxylene solution is multiple, two It is recrystallized in methyl sulfolane solution, dehydrating agent dehydration obtains -17 α -ol -3,20- diketone of -16 Alpha-Methyl of finished product 4- pregnenes.
- 2. the synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes according to claim 1, special Sign is that the potassium nitrate solution mass fraction is 10-16%.
- 3. the synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes according to claim 1, special Sign is that the methyl butyrate liquid quality fraction is 35-39%
- 4. the synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes according to claim 1, special Sign is that the Klorvess Liquid mass fraction is 15-19%.
- 5. the synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes according to claim 1, special Sign is that the 2- butene-1s, 4- diacid solutions mass fraction is 50-56%.
- 6. the synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes according to claim 1, special Sign is that the paraxylene liquid quality fraction is 60-65%.
- 7. the synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes according to claim 1, special Sign is that the dimethyl sulfone liquid quality fraction is 80-87%.
- 8. the synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes according to claim 1, special Sign is, includes the following steps：A：Addition 3mol bromo- -3 β of -16 Alpha-Methyl of 4- amino -5- pregnenes of 2- in reaction vessel, 17 salmefamol -20- ketone, 1.5L mass fractions are 16% potassium nitrate solution, control mixing speed 150rpm, raising solution temperature is to 47 DEG C, and the reaction was continued 80min；B：The methyl butyrate solution that 7mol mass fractions are 39% is added in, raising solution temperature reacts 40min, then to 56 DEG C It adds in 3mol tetra- (triethyl phosphite) and closes nickel by powder, flow back 50min, reduces solution temperature to 36 DEG C, adds in oxalic acid solution, quiet Put 2h, solution layering wash 5 times with the Klorvess Liquid that mass fraction is 19%, and mass fraction is 56% 2- butene-1s, 4- Diacid solution is washed 7 times, and the paraxylene solution washing that mass fraction is 65% is 9 times more, in the diformazan that mass fraction is 87% It is recrystallized in base sulfolane solution, the dehydration of Anhydrous potassium carbonate dehydrating agent obtains -17 α -ol -3,20- bis- of -16 Alpha-Methyl of finished product 4- pregnenes Ketone.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710526846.2A CN108239133A (en) | 2017-06-30 | 2017-06-30 | The synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes |
| GBGB1713386.9A GB201713386D0 (en) | 2017-06-30 | 2017-08-21 | 4-pregnene-16a-methyl-17a-mellow-3, 20-diketone drug synthesis method |
| AU2018100817A AU2018100817A4 (en) | 2017-06-30 | 2018-06-19 | 4-pregnene-16α-methyl-17α-mellow-3, 20-diketone drug synthesis method |
| IES20180212 IES20180212A2 (en) | 2017-06-30 | 2018-06-26 | 4-pregnene-16α-methyl-17α-mellow-3, 20-diketone drug synthesis method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710526846.2A CN108239133A (en) | 2017-06-30 | 2017-06-30 | The synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes |
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| Publication Number | Publication Date |
|---|---|
| CN108239133A true CN108239133A (en) | 2018-07-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710526846.2A Pending CN108239133A (en) | 2017-06-30 | 2017-06-30 | The synthetic method of -17 α -ol -3,20- diketone drugs of -16 Alpha-Methyl of 4- pregnenes |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN108239133A (en) |
| AU (1) | AU2018100817A4 (en) |
| GB (1) | GB201713386D0 (en) |
| IE (1) | IES20180212A2 (en) |
-
2017
- 2017-06-30 CN CN201710526846.2A patent/CN108239133A/en active Pending
- 2017-08-21 GB GBGB1713386.9A patent/GB201713386D0/en not_active Ceased
-
2018
- 2018-06-19 AU AU2018100817A patent/AU2018100817A4/en not_active Ceased
- 2018-06-26 IE IES20180212 patent/IES20180212A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU2018100817A4 (en) | 2018-08-02 |
| IES20180212A2 (en) | 2019-11-13 |
| GB201713386D0 (en) | 2017-10-04 |
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Application publication date: 20180703 |
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