CN108239138A - - 16 α of -16 Beta-methyl of 5- pregnenes, -3 β -ol -20- ketone pharmaceutical intermediate synthetic methods of 17 beta epoxide - Google Patents
- 16 α of -16 Beta-methyl of 5- pregnenes, -3 β -ol -20- ketone pharmaceutical intermediate synthetic methods of 17 beta epoxide Download PDFInfo
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- CN108239138A CN108239138A CN201710835772.0A CN201710835772A CN108239138A CN 108239138 A CN108239138 A CN 108239138A CN 201710835772 A CN201710835772 A CN 201710835772A CN 108239138 A CN108239138 A CN 108239138A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
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Abstract
The invention discloses 5 pregnene, 16 β methyl, 16 α, 17 β epoxies, 3 β alcohol, 20 ketone pharmaceutical intermediate synthetic method includes the following steps：5 pregnene, 16 alpha methoxy, 16 β methyl, 17 bromine, 3 methoxyl group, 20 ketone, cycloheptane solution are added in reaction vessel, control solution temperature controls 410 440rpm of mixing speed to 35 42 DEG C, adds in aqueous solution, and lead tetraacetate reacts 90 130min；Then raising solution temperature adds in diethyl zinc powder to 50 55 DEG C, adds in potassium sulfate solution, control 230 260rpm of mixing speed, 4 5h are reacted, temperature is reduced to 5 10 DEG C, 30 50min is washed with sodium chloride solution, 60 90min are washed with ethylene oxide solution, it is recrystallized in 1,6 hexylene glycol solution, dehydrating agent dehydration, obtain 5 pregnene of finished product, 16 β methyl, 16 α, 17 β epoxies, 3 β alcohol, 20 ketone.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, belong to organic synthesis field more particularly to 5- pregnenes-
- 16 α of 16 Beta-methyl, -3 β -ol -20- ketone pharmaceutical intermediate synthetic methods of 17 beta epoxide.
Background technology
- 16 α of -16 Beta-methyl of 5- pregnenes, -3 β -ol -20- ketone of 17 beta epoxide are mainly used for synthesizing as hormone intermediate
Dexamethasone acetate.Dexamethasone acetate drug is mainly used for anti-inflammatory and antiallergy, suitable for rheumatoid arthritis and
Other collagenosis etc..Existing synthetic method uses -3 β -ol -20- ketone -3- vinegar of -16 Beta-methyl of 5,16- pregnen diethylenes mostly
Acid esters, methanol, sodium hydroxide, hydrogen peroxide are synthesized as reaction raw materials, the reaction raw materials methanol vapor that this synthetic method uses
There is intense stimulus effect to respiratory mucosa, the toxicity of methanol is related with the accumulation of its metabolite formaldehyde and formic acid, formaldehyde energy
Inhibit the oxidative phosphorylation process of retina, make that ATP cannot be synthesized in film, cell is denaturalized, and causes optic atrophy；Cause
This, can generate larger harm to production operation personnel health as reaction synthesis material using methanol, be unfavorable for keeping the safety in production.It adopts
Reaction raw materials sodium hydroxide has extremely strong corrosivity, and solution or dust splash on skin, especially splash mucous membrane, can produce
Raw soft scab, and deep tissues can be penetrated into；This danger coefficient that will increase building-up process is unfavorable for keeping the safety in production；And hydroxide
The strong corrosive of sodium will be more demanding to consersion unit rotproofness, increase consersion unit manufacture cost.These above-mentioned factors are all
It can lead to this synthetic method there are many deficiencies part, and 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 -16 Beta-methyl of 5- pregnenes -16 α, 17 β-ring
- 3 β -ol -20- ketone pharmaceutical intermediate synthetic methods of oxygen, include the following steps：
A:- 16 α of 5- pregnenes-bromo- 3- methoxyl groups -20- ketone of -16 Beta-methyl -17- of methoxyl group is added in reaction vessel,
Cycloheptane solution, control solution temperature is to 35-42 DEG C, control mixing speed 410-440rpm, addition aqueous solution, lead tetraacetate,
React 90-130min；
B:Then raising solution temperature adds in diethyl zinc powder to 50-55 DEG C, adds in potassium sulfate solution, control stirring
Speed 230-260rpm reacts 4-5h, reduces temperature to 5-10 DEG C, washs 30-50min with sodium chloride solution, use ethylene oxide
Solution wash 60-90min, recrystallized in 1,6- hexylene glycol solution, dehydrating agent dehydration, obtain -16 Beta-methyl of finished product 5- pregnenes -
16 α, -3 β -ol -20- ketone of 17 beta epoxide.
Preferably, cycloheptane liquid quality fraction is 15-21%.
Preferably, potassium sulfate solution mass fraction is 10-16%.
Preferably, sodium chloride solution mass fraction is 5-9%.
Preferably, ethylene oxide solution mass fraction is 40-46%.
Preferably, 1,6- hexylene glycols liquid quality fraction is 60-67%.
Entire building-up process can be used following net reaction to represent：
Compared to synthetic method disclosed in background technology, -16 α of -16 Beta-methyl of 5- pregnenes, 17 β-ring provided by the invention
- 3 β -ol -20- ketone pharmaceutical intermediate synthetic methods of oxygen do not need to do reaction raw materials using methanol, sodium hydroxide, avoid due to
Health hazard of the toxicity of methanol to production operation personnel；It also avoids that there is extremely strong corrosive sodium hydroxide to production equipment
The more demanding adverse effect of rotproofness, reduces reaction cost, reduces security risk, and reaction intermediate link reduces
Very much, the reaction time also shortens much, and reaction yield also improves, while the present invention provides a kind of new synthetic route, is
Reaction yield is further promoted to lay a good foundation.
Specific embodiment
Embodiment 1：
- 16 α of -16 Beta-methyl of 5- pregnenes, -3 β -ol -20- ketone pharmaceutical intermediate synthetic methods of 17 beta epoxide, including as follows
Step：
A:2mol 5- pregnenes -16 α-bromo- 3- methoxyl groups of -16 Beta-methyl -17- of methoxyl group-are added in reaction vessel
20- ketone, 900ml mass fractions are 15% cycloheptane solution, and control solution temperature controls mixing speed 410rpm, add to 35 DEG C
Enter 4mol aqueous solutions, 4mol lead tetraacetates react 90min；
B:Then raising solution temperature adds in 2mol diethyl zinc powder to 50 DEG C, and it is 10% to add in 700ml mass fractions
Potassium sulfate solution controls mixing speed 230rpm, reacts 4h, reduces temperature to 5 DEG C, is 5% sodium chloride solution with mass fraction
30min is washed, 60min is washed for 40% ethylene oxide solution with mass fraction, it is molten for 60%1,6- hexylene glycols in mass fraction
It being recrystallized in liquid, the dehydration of activated alumina dehydrating agent obtains -16 α of -16 Beta-methyl of finished product 5- pregnenes, -3 β -ol of 17 beta epoxide -
20- ketone 675.616g, yield 98.2%.
Embodiment 2：
- 16 α of -16 Beta-methyl of 5- pregnenes, -3 β -ol -20- ketone pharmaceutical intermediate synthetic methods of 17 beta epoxide, including as follows
Step：
A:2mol 5- pregnenes -16 α-bromo- 3- methoxyl groups of -16 Beta-methyl -17- of methoxyl group-are added in reaction vessel
20- ketone, 900ml mass fractions are 18% cycloheptane solution, and control solution temperature controls mixing speed 430rpm, add to 39 DEG C
Enter 5mol aqueous solutions, 5mol lead tetraacetates react 110min；
B:Then raising solution temperature adds in 3mol diethyl zinc powder to 53 DEG C, and it is 13% to add in 700ml mass fractions
Potassium sulfate solution controls mixing speed 240rpm, reacts 4.5h, reduces temperature to 8 DEG C, molten for 7% sodium chloride with mass fraction
Liquid washs 40min, and 80min is washed for 43% ethylene oxide solution with mass fraction, is 64%1,6- hexylene glycols in mass fraction
It being recrystallized in solution, the dehydration of activated alumina dehydrating agent obtains -16 α of -16 Beta-methyl of finished product 5- pregnenes, -3 β -ol of 17 beta epoxide -
20- ketone 678.363g, yield 98.6%.
Embodiment 3：
- 16 α of -16 Beta-methyl of 5- pregnenes, -3 β -ol -20- ketone pharmaceutical intermediate synthetic methods of 17 beta epoxide, including as follows
Step：
A:2mol 5- pregnenes -16 α-bromo- 3- methoxyl groups of -16 Beta-methyl -17- of methoxyl group-are added in reaction vessel
20- ketone, 900ml mass fractions are 21% cycloheptane solution, and control solution temperature controls mixing speed 440rpm, add to 42 DEG C
Enter 6mol aqueous solutions, 6mol lead tetraacetates react 130min；
B:Then raising solution temperature adds in 4mol diethyl zinc powder to 55 DEG C, and it is 16% to add in 700ml mass fractions
Potassium sulfate solution controls mixing speed 260rpm, reacts 5h, reduces temperature to 10 DEG C, is 9% sodium chloride solution with mass fraction
50min is washed, 90min is washed for 46% ethylene oxide solution with mass fraction, it is molten for 67%1,6- hexylene glycols in mass fraction
It being recrystallized in liquid, the dehydration of activated alumina dehydrating agent obtains -16 α of -16 Beta-methyl of finished product 5- pregnenes, -3 β -ol of 17 beta epoxide -
20- ketone 679.744g, yield 98.8%.
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 (7)
- - 16 α of -16 Beta-methyl of 1.5- pregnenes, -3 β -ol -20- ketone pharmaceutical intermediate synthetic methods of 17 beta epoxide, feature exist In including the following steps：A:- 16 α of 5- pregnenes-bromo- 3- methoxyl groups -20- ketone of -16 Beta-methyl -17- of methoxyl group, cycloheptyl are added in reaction vessel Alkane solution, control solution temperature control mixing speed 410-440rpm to 35-42 DEG C, add in aqueous solution, lead tetraacetate, reaction 90-130min；B:Then raising solution temperature adds in diethyl zinc powder to 50-55 DEG C, adds in potassium sulfate solution, controls mixing speed 230-260rpm reacts 4-5h, reduces temperature to 5-10 DEG C, washs 30-50min with sodium chloride solution, use ethylene oxide solution 60-90min to be washed, is recrystallized in 1,6- hexylene glycol solution, dehydrating agent dehydration obtains -16 α of -16 Beta-methyl of finished product 5- pregnenes, - 3 β -ol -20- ketone of 17 beta epoxide.
- 2. -16 α of -16 Beta-methyl of 5- pregnenes according to claim 1, -3 β -ol -20- ketone pharmaceutical intermediate of 17 beta epoxide closes Into method, which is characterized in that the cycloheptane liquid quality fraction is 15-21%.
- 3. -16 α of -16 Beta-methyl of 5- pregnenes according to claim 1, -3 β -ol -20- ketone pharmaceutical intermediate of 17 beta epoxide closes Into method, which is characterized in that the potassium sulfate solution mass fraction is 10-16%.
- 4. -16 α of -16 Beta-methyl of 5- pregnenes according to claim 1, -3 β -ol -20- ketone pharmaceutical intermediate of 17 beta epoxide closes Into method, which is characterized in that the sodium chloride solution mass fraction is 5-9%.
- 5. -16 α of -16 Beta-methyl of 5- pregnenes according to claim 1, -3 β -ol -20- ketone pharmaceutical intermediate of 17 beta epoxide closes Into method, which is characterized in that the ethylene oxide solution mass fraction is 40-46%.
- 6. -16 α of -16 Beta-methyl of 5- pregnenes according to claim 1, -3 β -ol -20- ketone pharmaceutical intermediate of 17 beta epoxide closes Into method, which is characterized in that 1, the 6- hexylene glycols liquid quality fraction is 60-67%.
- 7. -16 α of -16 Beta-methyl of 5- pregnenes according to claim 1, -3 β -ol -20- ketone pharmaceutical intermediate of 17 beta epoxide closes Into method, which is characterized in that include the following steps：A:- 16 α of 2mol 5- pregnenes-bromo- 3- methoxyl groups -20- ketone of -16 Beta-methyl -17- of methoxyl group is added in reaction vessel, 900ml mass fractions are 21% cycloheptane solution, and control solution temperature controls mixing speed 440rpm to 42 DEG C, adds in 6mol Aqueous solution, 6mol lead tetraacetates react 130min；B:Then raising solution temperature adds in 4mol diethyl zinc powder to 55 DEG C, and it is 16% sulfuric acid to add in 700ml mass fractions Potassium solution controls mixing speed 260rpm, reacts 5h, reduces temperature to 10 DEG C, is washed with mass fraction for 9% sodium chloride solution 50min washs 90min, in mass fraction is 67%1,6- hexylene glycol solution with mass fraction for 46% ethylene oxide solution Recrystallization, activated alumina dehydrating agent dehydration, obtains -16 α of -16 Beta-methyl of finished product 5- pregnenes, -3 β -ol -20- ketone of 17 beta epoxide.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710835772.0A CN108239138A (en) | 2017-09-16 | 2017-09-16 | - 16 α of -16 Beta-methyl of 5- pregnenes, -3 β -ol -20- ketone pharmaceutical intermediate synthetic methods of 17 beta epoxide |
| GBGB1719122.2A GB201719122D0 (en) | 2017-09-16 | 2017-11-20 | 5-pregneno-16ß-methyl-16a,17ß-epoxy-3ß-alcohol-20-ketone drug intermediates synthesis method |
| AU2018101142A AU2018101142A4 (en) | 2017-09-16 | 2018-08-12 | 5-pregneno-16β-methyl-16α,17β-epoxy-3β-alcohol-20-ketone drug intermediates synthesis method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710835772.0A CN108239138A (en) | 2017-09-16 | 2017-09-16 | - 16 α of -16 Beta-methyl of 5- pregnenes, -3 β -ol -20- ketone pharmaceutical intermediate synthetic methods of 17 beta epoxide |
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| Publication Number | Publication Date |
|---|---|
| CN108239138A true CN108239138A (en) | 2018-07-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710835772.0A Withdrawn CN108239138A (en) | 2017-09-16 | 2017-09-16 | - 16 α of -16 Beta-methyl of 5- pregnenes, -3 β -ol -20- ketone pharmaceutical intermediate synthetic methods of 17 beta epoxide |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN108239138A (en) |
| AU (1) | AU2018101142A4 (en) |
| GB (1) | GB201719122D0 (en) |
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2017
- 2017-09-16 CN CN201710835772.0A patent/CN108239138A/en not_active Withdrawn
- 2017-11-20 GB GBGB1719122.2A patent/GB201719122D0/en not_active Ceased
-
2018
- 2018-08-12 AU AU2018101142A patent/AU2018101142A4/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| AU2018101142A4 (en) | 2018-09-13 |
| GB201719122D0 (en) | 2018-01-03 |
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| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20180703 |
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| WW01 | Invention patent application withdrawn after publication |