CN109251230A - It is a kind of to prepare 16a, the method for 21- biacetyl oxygroup prednisolone - Google Patents
It is a kind of to prepare 16a, the method for 21- biacetyl oxygroup prednisolone Download PDFInfo
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- CN109251230A CN109251230A CN201811343103.2A CN201811343103A CN109251230A CN 109251230 A CN109251230 A CN 109251230A CN 201811343103 A CN201811343103 A CN 201811343103A CN 109251230 A CN109251230 A CN 109251230A
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- acid
- prednisolone
- organic solvent
- deshydroxy
- epoxy material
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0092—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by an OH group free esterified or etherified
Abstract
The present invention provide it is a kind of prepare 16a, the method for 21- biacetyl oxygroup prednisolone, including use 17a- deshydroxy prednisolone for raw material, first by starting material 17a- deshydroxy prednisolone in the first organic solvent, with organic peroxide acid in 16,17 generation epoxidation reactions, epoxy material is made；Again in a second organic solvent by the epoxy material, open loop is reacted under the catalysis of acid catalyst with glacial acetic acid, target product 16a, 21- biacetyl oxygroup prednisolone is made.Intermediate 16a, 21- the biacetyl oxygroup prednisolone of 16 alpha-hydroxy prednisonlones is prepared in a kind of method of efficient, environmental protection and par by the present invention.
Description
Technical field
The invention belongs to steroid hormone pharmaceutical intermediate fabricating technology, in particular to a kind of prepare 16a, the bis- second of 21-
The method of acyloxy prednisolone.
Background technique
16a- hydroxy prednisonlone (molecular formula C21H28O6), chemistry entitled 11b, 16a, 17a, 21- tetrahydroxy-pregnant steroid -1,
4- diene -3,20- diketone, be it is a kind of production how the key intermediate of moral class steroidal cortex hormone of aadrenaline drug, with its for original
Material, as soon as desonide is just made with the condensation reaction of acetone step, and the obtained budesonide of one step of n-butanal condensation, how moral class steroidal kidney
Upper gland corticosteroid drug is a kind of potent local anti-inflammatory agent, as budesonide is clinically mainly used for various rhinitis, urgency, slowly
The treatment of many diseases such as property bronchitis, side effect is low, and effect is good, wide market.The biography of 16a- hydroxy prednisonlone
System production method is using prednisolone as raw material, is eliminated through 17,21 double esterifications, 17-position ester, 16,17 double bonds oxidations, 21
The four-step reactions such as ester hydrolysis are made, which synthesizes 16a hydroxy prednisonlone, and synthesis total recovery is low, the main reason is that: on the one hand
When being with 16,17 double bonds of potassium permanganate oxidation, due to the strong 6a hydroxy prednisonlone oxidisability of potassium permanganate, it will lead to point
11 hydroxyls can be also oxidized in son, and 16 hydroxyls in product 16a hydroxacetic acid prednisolone molecule generated also can be by
Oxidation, causes impurity more, hardly possible purifying, so that it is low to aoxidize this step yield；It on the other hand is the 4th step 16a- hydroxacetic acid prednisone
When Long Yong such as sodium hydroxide or sodium carbonate highly basic or such as hydrochloric acid, sulfuric acid strong acid hydrolysis, open loop can be generated by D ring in the molecule
Rearrangement ring-enlarging reaction generates two very big impurity, the two impurity are also difficult to remove, the yield for causing the 4th one-step hydrolysis to react
Also very low.Therefore, 16a- hydroxy prednisonlone is produced with the method, the production cost is very high, and budesonide class drug is caused to be produced into
This is greatly improved with the market price, considerably increases drug cost when such Case treatment.
Such as Chinese patent application CN201610060609, CN201410455522 and CN201010106918 patent is all
16a hydroxy prednisonlone is produced using potassium permanganate oxidation method.
In addition, patent CN201010205878 provides a kind of synthetic method of 16 alpha-hydroxy prednisonlones, including walk as follows
It is rapid: advanced in structure in the acidic ion liquid as shown in formula (II) using structure prednisolone as shown in formula (I) as raw material
Row dehydration generates double bond, and aqueous hydrogen peroxide solution is then added and is reacted, and water sufficiently is added after reaction and further hydrolyzes,
Finally obtain 16 alpha-hydroxy prednisonlones；The synthetic method using acidic ion liquid not only as reaction medium but also
As the property of catalyst, by changing the process conditions such as reaction time and reaction temperature, realizing reduces cost, energy-saving and emission-reduction
Purpose, be suitable for industrialized production.And patent CN201210364257 also provides a kind of synthesis side of 16 alpha-hydroxy prednisonlones
Method.It using structure prednisolone as shown in formula (I) as raw material, the Gemini surface active agent as shown in formula (II) effect under into
Row dehydration generate double bond compound, then be added aqueous hydrogen peroxide solution further react, add water after reaction into
Row hydrolysis, obtains 16 alpha-hydroxy prednisonlone of purpose product, and the Gemini surface active agent is living for diphenyl-methane Shuangzi surface
Property agent.The invention after the completion of reaction, can be recycled by regarding Gemini surface active agent as reaction medium and catalyst simultaneously
And reuse, simple process, convenient post-treatment, obtained product production capacity height, excellent in efficiency, the three wastes are few, yield be up to 85% with
On, Gemini surface active agent repeats prednisolone and uses, and is economical and practical green environmental protection technique, is suitable for popularization and application.
Although however, avoided in above-mentioned patent using strong oxidizers such as potassium permanganate, wherein the use of prednisolone is raw material,
First dehydration generates object containing double bond, if the double bond object refers to 17- deshydroxy prednisolone, using 17- deshydroxy prednisolone as raw material,
It is hydrolyzed again with water after being reacted with hydrogen peroxide oxidation and the processes of 16 alpha-hydroxy prednisonlones is prepared is difficult to realize and repeats.
It does not also point out that substance the intermediary generated in reaction process is on earth in this two pieces patent, thus does not also know this two
The inventor of patent of invention obtains 16 alpha-hydroxy prednisonlones particular by which kind of approach and route, but can therefrom see
Out, it is unused acetic acid in this two patents, thus is not related to the process of acetic acid open loop completely wherein.
Therefore, generally speaking, in the prior art there is no a kind of " avoiding using strong oxidizers such as potassium permanganate " but energy
Efficiently, environmental protection and par prepare the technology of 16 alpha-hydroxy prednisonlones.This field is bold and vigorous it is necessary to develop a kind of 16 new Alpha-hydroxies
The preparation method of Ni Songlong and its intermediate.
Summary of the invention
16 alpha-hydroxy prednisonlones for high-efficiency environment friendly are prepared, is used in the present invention and first uses specific method system
Standby 16a, 21- biacetyl oxygroup prednisolone, then pass through 16a, the basic hydrolysis under given conditions of 21- biacetyl oxygroup prednisolone
Method obtain 16 alpha-hydroxy prednisonlones.
16a, the method for 21- biacetyl oxygroup prednisolone are prepared present invention firstly provides a kind of, including is taken off using 17a-
Hydroxyl prednisolone is raw material, and first starting material 17a- deshydroxy prednisolone exists in the first organic solvent with organic peroxide acid
Epoxy material is made in 16,17 generation epoxidation reactions；Again in a second organic solvent by the epoxy material, it is urged with glacial acetic acid in acid
Open loop is reacted under the catalysis of agent, target product 16a, 21- biacetyl oxygroup prednisolone is made.
In a kind of specific embodiment, first organic solvent be toluene, methylene chloride, chloroform, ethyl acetate,
One of DME, dioxane are a variety of, the organic peroxide acid be adjacent peroxide benzene first diacid, methyl benzoyl hydroperoxide,
One of chloroperoxybenzoic acid, Peracetic acid, Perbutyric Acid are a variety of.
In a kind of specific embodiment, first organic solvent is ethyl acetate, and the organic peroxide acid is neighbour
Peroxide benzene first diacid.
In a kind of specific embodiment, the epoxidation reaction temperature is 10--60 DEG C；17a- deshydroxy prednisolone:
Organic peroxide acid=1g:0.1~0.8g, 17a- deshydroxy prednisolone: the first organic solvent=1g:10~25ml.
In a kind of specific embodiment, the epoxidation reaction temperature is 25--30 DEG C；17a- deshydroxy prednisolone:
Organic peroxide acid=1g:0.3~0.5g, 17a- deshydroxy prednisolone: the first organic solvent=1g:13~17ml.
In a kind of specific embodiment, second organic solvent is methylene chloride, glacial acetic acid, chloroform, acetic acid second
One of ester, DME, THF, C4 and following low-carbon alcohols are a variety of, and the acid catalyst is hydrochloric acid, sulfuric acid, p-methyl benzenesulfonic acid, three
One of fluorine acetic acid is a variety of.
In a kind of specific embodiment, second organic solvent is methylene chloride, and the acid catalyst is to first
Benzene sulfonic acid.
In a kind of specific embodiment, ring-opening reaction temperature is 10--80 DEG C, and epoxy material in open loop step: acid is urged
Agent: glacial acetic acid=1g:0.02~0.20g:0.2~1.6g, and epoxy material: the second organic solvent=1g:2~15ml.
In a kind of specific embodiment, ring-opening reaction temperature is 40--45 DEG C, and epoxy material in open loop step: acid is urged
Agent: glacial acetic acid=1g:0.04~0.08g:0.8~1.2g, and epoxy material: the second organic solvent=1g:4~6ml.
16a, the method for 21- biacetyl oxygroup prednisolone product are prepared the present invention also provides a kind of, including uses 17a-
Deshydroxy prednisolone is raw material, first by starting material 17a- deshydroxy prednisolone in the first organic solvent, with organic peroxide acid
In 16,17 generation epoxidation reactions, epoxy material is made；Again in a second organic solvent by the epoxy material, with glacial acetic acid in acid
Open loop is reacted under the catalysis of catalyst, target product 16a, 21- biacetyl oxygroup prednisolone is made；Again by the 16a, 21- is bis-
Acetoxyl group prednisolone crude product is heated to reflux decoloration recrystallization through C4 or less low-carbon alcohols, obtains 16a, 21- biacetyl oxygroup sprinkles Buddhist nun
Loose dragon product.
In a kind of specific embodiment, the low-carbon alcohols are alcohol, and 16a, 21- biacetyl oxygroup prednisolone are thick
The amount ratio of product and alcohol is 1g:3.5~6ml.
The present invention also provides a kind of methods for preparing 16a- hydroxy prednisonlone, including use 17a- deshydroxy prednisolone for
Raw material, first by starting material 17a- deshydroxy prednisolone in the first organic solvent, with organic peroxide acid in 16,17 generation rings
Epoxy material is made in oxidation reaction；Again in a second organic solvent by the epoxy material, anti-under the catalysis of acid catalyst with glacial acetic acid
Open loop is answered, 16a, 21- biacetyl oxygroup prednisolone is made；Then by 16a, 21- biacetyl oxygroup prednisolone dissolves in third
In organic solvent, under the catalytic action of solid base catalyst, by the acetic acid ester hydrolysis on two positions, 16a- hydroxyl is prepared
Base prednisolone, the solid base catalyst are and carbonic acid to be adsorbed on carrier using aluminium oxide, silica gel or calcium carbonate as carrier
The catalyst of sodium or sodium hydroxide.
It further include pair before the hydrolysis of 21- biacetyl oxygroup prednisolone by 16a in a kind of specific embodiment
16a, 21- biacetyl oxygroup prednisolone crude product are heated to reflux the process of decoloration recrystallization and purification through C4 or less low-carbon alcohols, then
By the 16a after purification, 21- biacetyl oxygroup prednisolone product is for hydrolyzing preparation 16a- hydroxy prednisonlone.
In a kind of specific embodiment, in 16a, 21- biacetyl oxygroup prednisolone hydrolysis preparation 16a- hydroxyl sprinkles
During Ni Songlong, including first by 16a, 21- biacetyl oxygroup prednisolone dissolves in third organic solvent, stirs, and is added
Solid base catalyst heat preservation in 10~60 DEG C hydrolysis 6~12 hours, TLC confirms reaction end, after having reacted, nitrogen while hot
Then filters pressing, filter cake third organic solvent washing recycle solid base catalyst and apply；Filtrate merges with washing lotion, is concentrated under reduced pressure
Third organic solvent is recycled, after cooling plus water elutriation is, it is preferable to use tap water, centrifugation, it is organic that filtrate decompression recycles remaining third
Solvent, filter cake washing and drying obtain 16a- hydroxy prednisonlone crude product.
In a kind of specific embodiment, the third organic solvent be selected from toluene, chloroform, methylene chloride, acetone,
One of DMF, DME, dioxane, C4 and following low-carbon alcohols are a variety of, preferably toluene or chloroform；The preferred 40- of reaction temperature
45℃；And weight ratio is 16a in the step, 21- biacetyl oxygroup prednisolone: solid base catalyst=1:0.5~1.2,
It is preferred that 1:0.6~1.0；Proportion between reactant and solvent is 16a, 21- biacetyl oxygroup prednisolone: third organic solvent
=1g:10~25ml.
In a kind of specific embodiment, the solid base catalyst the preparation method comprises the following steps: by solid alkali sodium carbonate
Or sodium hydroxide is dissolved in the water, and support powder is added, and reacts 3~4 hours in 10~50 DEG C of stirring and adsorbings, after having reacted, subtracts
Pressure boils off water to close dry, dry solid base catalyst, moisture content 3~8% after taking-up；Weight proportion between reactant is,
Carrier: alkali: water=1:0.2~0.4:8~12.
The present invention also provides a kind of methods for preparing 16a- hydroxy prednisonlone product, including use 17a- deshydroxy prednisone
Dragon is raw material, first by starting material 17a- deshydroxy prednisolone in the first organic solvent, is sent out with organic peroxide acid at 16,17
Raw epoxidation reaction, is made epoxy material；Again in a second organic solvent by the epoxy material, with glacial acetic acid acid catalyst catalysis
16a, 21- biacetyl oxygroup prednisolone is made in lower reaction open loop；Then by 16a, 21- biacetyl oxygroup prednisolone dissolves in
In third organic solvent, under the catalytic action of solid base catalyst, the acetic acid ester hydrolysis on two positions is prepared
16a- hydroxy prednisonlone, the solid base catalyst are and to adsorb on carrier using aluminium oxide, silica gel or calcium carbonate as carrier
There is the catalyst of sodium carbonate or sodium hydroxide；The 16a- hydroxy prednisonlone crude product that finally solid phase alkali catalyzed hydrolysis is obtained is through C4
Following low-carbon alcohols are heated to reflux decoloration recrystallization, obtain 16a- hydroxy prednisonlone product.
In a kind of specific embodiment, the low-carbon alcohols for refining the 16a- hydroxy prednisonlone crude product are alcohol, and
The amount ratio of 16a- hydroxy prednisonlone crude product and alcohol is 1g:8~15ml.
That is, the purpose of the present invention is more, the synthesis for reaction impurities in the synthesis of above-mentioned 16a- hydroxy prednisonlone
The defects of yield low production cost is high, proposes a kind of new by synthesizing 16a, and 21- biacetyl oxygroup prednisolone is made indirectly
The synthetic method of standby 16a- hydroxy prednisonlone, i.e., using 17a- deshydroxy prednisolone as raw material, first in peroxide acid oxidase molecule
16,17 double bonds form epoxy material, and 16a is just made in epoxy material acid catalysis open loop in acetic acid, and 21- biacetyl oxygroup sprinkles Buddhist nun
Song Long.The 16a, 21- biacetyl oxygroup prednisolone use solid phase alkali catalyzed hydrolysis to prepare 16a- hydroxy prednisonlone again.It avoids
Using side reaction is more, impurity is more, miscellaneous brought by potassium permanganate oxidation in existing tradition 16a- hydroxy prednisonlone production method
The many difficulties such as matter difficulty purifying, substantially increase the synthesis total recovery of 16a- hydroxy prednisonlone, thus greatly reduce 16a-
The production cost of hydroxy prednisonlone.
The technical scheme is that the preparation method of a kind of 16a, 21- biacetyl oxygroup prednisolone, de- using 17a-
Hydroxyl prednisolone is raw material, it may be assumed that first by starting material 17a- deshydroxy prednisolone in the first organic solvent, with organic peroxide acid
In 16,17 generation epoxidation reactions, epoxy material is made；Again in a second organic solvent by the epoxy material, with glacial acetic acid in acid
Catalysis is lower to react open loop, and target product 16a, 21- biacetyl oxygroup prednisolone is made；
Further, 16a, 21- biacetyl oxygroup prednisolone preparation method specific steps are as follows:
A, it prepares epoxy material: being to dissolve in starting material 17a- deshydroxy prednisolone in the first organic solvent, 10~60
In the peracid solutions that dropwise addition organic peroxide acid and the first organic solvent are made into 2-2.5 hours at DEG C, then at 10~60 after dripping off
Continue insulation reaction 6-12 hours at DEG C, TLC confirms reaction end, after having reacted, neutralizes and destroys the acid and mistake for reacting generation
Then the peroxy acid of amount is concentrated under reduced pressure recycling 90-95% organic solvent, then cools down, tap water elutriation, filtering, filtrate row is added
Enter purification tank for liquid waste, filter cake washing and drying obtains 16,17a- epoxy group prednisolone, HPLC content 95.0-98.0%, and weight is received
Rate 95-100%；
B, 16a is prepared, 21- biacetyl oxygroup prednisolone: being that epoxy material prepared by above-mentioned steps A is dissolved in second to have
In solvent, be added glacial acetic acid and appropriate acid catalyst at room temperature, heat preservation in 10~80 DEG C reaction 2-3 hour, TLC confirms instead
Terminal is answered, after having reacted, excessive acetic acid and catalysis acid is neutralized, 90% organic solvent of recycling is then concentrated under reduced pressure, then cool down,
Tap water elutriation, filtering is added, filtrate is discharged into purification tank for liquid waste, filter cake washing and drying；Filtrate merges with washing lotion, is concentrated under reduced pressure back
The organic solvent for receiving 90-95%, then cools down, and tap water elutriation, centrifugation is added, and filtrate decompression recycles residual organic solvents, so
After be discharged into purification tank for liquid waste, filter cake washing and drying obtains 16a, 21- biacetyl oxygroup prednisolone crude product；
M, the crude product decolourizes to recrystallize through C4 or less low-carbon alcohols, obtains 16a, 21- biacetyl oxygroup prednisolone product.
99.0% or more HPLC content.
The beneficial effects of the present invention are: the present invention uses 17a- deshydroxy prednisolone for raw material, 17a- deshydroxy is first sprinkled into Buddhist nun
In the first organic solvent, with organic peroxide acid in 16,17 generation epoxidation reactions, epoxy material is made in Song Long；Again by the ring
Oxygen object reacts open loop under the catalysis of acid catalyst in a second organic solvent, with glacial acetic acid, and target is made by two-step reaction
Product 16a, 21- biacetyl oxygroup prednisolone；The 16a produced using the method for the present invention, 21- biacetyl oxygroup prednisolone,
Again in third organic solvent, with solid phase alkali catalyzed hydrolysis method, to produce 16a- hydroxy prednisonlone, not only production operation letter
Just, production technology is economic and environment-friendly for folk prescription, it is most important that, avoiding makes in existing tradition 16a- hydroxy prednisonlone production method
The many difficulties such as the side reaction brought by potassium permanganate oxidation is more, impurity is more, impurity difficulty is purified, so that synthesis greatly improved
Total recovery.Compared with the 16a- hydroxy prednisonlone preparation method described in the conventional production methods, the preparation cost of the method for the present invention is wanted
Reduce 10-15%.In addition, solvent used in this law production, can be recycled recycled, easily implement industrialized production.
In conclusion the present invention with it is a kind of efficiently, the method for environmental protection and par be prepared 16 alpha-hydroxy prednisonlones and
Wherein mesosome 16a, 21- biacetyl oxygroup prednisolone.
Detailed description of the invention
Fig. 1 is to prepare 16a in the present invention, 21- biacetyl oxygroup prednisolone and prepares 16a- hydroxy prednisonlone
Structure flow chart.
Specific embodiment
In order to more easily illustrate main points and spirit of the invention, citing is explained below:
Embodiment 1
The preparation of step A--- epoxy material:
In a 3000ml there-necked flask, addition 100g starting material 17a- deshydroxy prednisolone, 1000ml ethyl acetate,
Being stirred at room temperature is completely dissolved solid, and temperature control is added dropwise containing 40g neighbour's peroxide benzene first diacid and 500ml second at 25~30 DEG C
The peracid solutions that acetoacetic ester is made into, about 2-2.5 hour drip off, and it is small to continue insulation reaction 6-12 after dripping off at 25~30 DEG C
When, TLC confirms reaction end, after having reacted, 5% sodium hydroxide of 400ml is added and mixes with what 10% sodium sulfite of 100ml was made into
And solution, to neutralize and destroy the acid and excessive peroxy acid that react and generate, then 90-95% is recycled in 50 DEG C or less reduced pressures
Ethyl acetate, then it is down to room temperature, 500ml tap water is added, stirs elutriation 3-4 hours, filtering, filtrate is discharged into purification tank for liquid waste,
Filter cake washing, 60 DEG C or less dryings obtain 16,17a- epoxy group prednisolone 99.3g, HPLC content 97.8%, weight yield
99.3%.
The preparation of step B---16a, 21- biacetyl oxygroup prednisolone:
In a 1000ml there-necked flask, epoxy material prepared by 100g above-mentioned steps A, 500ml methylene chloride, room is added
The lower stirring of temperature makes it completely dissolved, and adds 100g glacial acetic acid and the agent of 6g Catalyzed by p-Toluenesulfonic Acid, heat preservation is reacted in 40~45 DEG C
2-3 hours, TLC confirmed reaction end, and after having reacted, the sodium bicarbonate solution of 200ml 10% is slowly added dropwise, neutralizes excessive
Acetic acid and catalysis acid, make system pH about 6-7, then the methylene chloride of 35 DEG C or less reduced pressure recycling 90-95%, then
5~10 DEG C are cooled to, 500ml tap water is added, is stirred elutriation 3-4 hours, filtering, filtrate is discharged into purification tank for liquid waste, filter cake water
It washes, 70 DEG C or less dryings, obtains 16a, 21- biacetyl oxygroup prednisolone crude product 127.8g.
The preparation of step M---16a, 21- biacetyl oxygroup prednisolone product:
The crude product obtained in step B is added into 500ml alcohol, 5g active carbon is added in decoloration, is then heated to reflux
1.0-1.5 hours, filters pressing while hot, with 100ml alcohol, foam washing Hou Song producer recycled filter cake in two times, subtracted after filtrate and washing lotion merging
Concentration and recovery 85-90% alcohol is pressed, -5-0 degree is cooled to, stirred crystallization 2-3 hours, filters, filtrate recovered alcohol and mother liquor material
Set is in lower batch of process for refining；Filter cake is rinsed with the cold alcohol of 5ml, and drying obtains 16a, 21- biacetyl oxygroup prednisolone fine work
103.3g, HPLC content 99.6%, weight yield 103.3%.
Step C, 16a- hydroxy prednisonlone is synthesized
In a 2000ml there-necked flask, the 16a prepared in 100g step M is added, 21- biacetyl oxygroup prednisolone is
Raw material, 1500ml toluene make it completely dissolved under stirring, add the solid base catalyst that 60g makes by oneself, heat preservation in 40~
45 DEG C stirring hydrolysis 6-8 hours, TLC confirm reaction end, after having reacted, nitrogen filters pressing while hot, filter cake 500ml toluene
Then foam washing in two times recycles solid base catalyst and applies；Filtrate merges with washing lotion, 95% toluene of recycling is concentrated under reduced pressure, then
Tap water elutriation is added in cooling, and centrifugation, remaining toluene is first recovered under reduced pressure in filtrate, then is discharged into purification tank for liquid waste, and filter cake washing is dry
It is dry, obtain 16a- hydroxy prednisonlone crude product 80.1g, HPLC content 98.5%, weight yield 80.1%；Above-mentioned 16a- hydroxyl is sprinkled
Ni Songlong crude product dissolves in 800ml alcohol, and 5g active carbon is added, is then heated to reflux 1.0-1.5 hours, filters pressing while hot, filter cake
With 100ml alcohol, foam washing Hou Song producer is recycled in two times, and 95% alcohol of recycling is concentrated under reduced pressure after filtrate and washing lotion merging, cooling
To -5-0 DEG C, stirred crystallization 2-3 hours, filtering, filter cake is rinsed with the cold alcohol of 5ml, and drying obtains 16a- hydroxy prednisonlone fine work
70.5g, HPLC content 99.6% refines weight yield 88.0%, prepares weight total recovery 70.5%；Filtrate recovered alcohol and mother
Liquid material set is used for lower batch of process for refining.
In addition, preparing solid base catalyst in the present embodiment step C, detailed process is as follows: in a 1000ml there-necked flask
In, the solution being made by 50g solid alumina, 300ml tap water, 200ml tap water and 15g sodium carbonate is added, in 25-30 DEG C
Stirring and adsorbing is reacted 3~4 hours, and after react, decompression boils off water to close dry, taking-up it is dry solid base catalyst 50.1g, water
Divide content 5.6%, weight yield 102%.
Embodiment 2
Step A: the preparation of epoxy material:
In a 3000ml there-necked flask, 100g starting material 17a- deshydroxy prednisolone, 1000ml chloroform, in room is added
The lower stirring of temperature is completely dissolved solid, and temperature control is added dropwise containing 40g metachloroperbenzoic acid and 500ml acetic acid second at 25~30 DEG C
The peracid solutions that ester is made into, about 2-2.5 hour drip off, and continue insulation reaction 6-12 hours at 25~30 DEG C after dripping off, TLC
Confirm reaction end, after having reacted, addition 5% sodium hydroxide of 400ml and the mixing that 10% sodium sulfite of 100ml is made into are molten
Liquid, to neutralize and destroy the acid and excessive peroxy acid that react and generate, then 90-95% chloroform is recycled in 50 DEG C or less reduced pressures
With the mixing solvent of ethyl acetate, then it is down to room temperature, 500ml tap water is added, stirred elutriation 3-4 hour, filtered, filtrate is discharged into
Purification tank for liquid waste, filter cake washing, 60 DEG C or less dryings obtain 16,17a- epoxy group prednisolone 98.2g, HPLC content 98.1%,
Weight yield 98.2%；
The preparation of step B:16a, 21- biacetyl oxygroup prednisolone:
In a 1000ml there-necked flask, epoxy material prepared by 100g above-mentioned steps A, 500ml ethyl acetate, room is added
The lower stirring of temperature makes it completely dissolved, and adds 100g glacial acetic acid and 6g concentrated sulfuric acid catalyst, keeps the temperature small in 40~45 DEG C of reaction 2-3
When, TLC confirm reaction end, after react, slowly be added dropwise 200ml 10% sodium bicarbonate solution, neutralize excessive acetic acid and
Catalysis acid, makes system pH about 6-7, then the solvent ethyl acetate of recycling 90-95% is concentrated under reduced pressure for 45 DEG C or less, then be cooled to
5~10 DEG C, 500ml tap water is added, stirs elutriation 3-4 hours, filtering, filtrate is discharged into purification tank for liquid waste, and filter cake is washed, and 70 DEG C
It dries below, obtains 16a, 21- biacetyl oxygroup prednisolone crude product 125.4g.
The preparation of step M---16a, 21- biacetyl oxygroup prednisolone product:
The crude product obtained in step B is recrystallized by method described in 1 step M of embodiment, obtains 16a, the bis- second of 21-
Acyloxy prednisolone fine work 101.2g, HPLC content 99.5%, weight yield 101.2%.
Step C, 16a- hydroxy prednisonlone is synthesized
In a 2000ml there-necked flask, the 16a prepared in 100g step M is added, 21- biacetyl oxygroup prednisolone is
Raw material, 1500ml alcohol make it completely dissolved under stirring, add the solid base catalyst that 60g makes by oneself, heat preservation in 40~
45 DEG C stirring hydrolysis 6-8 hours, TLC confirm reaction end, after having reacted, nitrogen filters pressing while hot, filter cake 500ml alcohol
Then foam washing in two times recycles solid base catalyst and applies；Filtrate merges with washing lotion, 95% alcohol of recycling is concentrated under reduced pressure, then
Tap water elutriation is added in cooling, and centrifugation, remaining alcohol is first recovered under reduced pressure in filtrate, then is discharged into purification tank for liquid waste, and filter cake washing is dry
It is dry, obtain 16a- hydroxy prednisonlone crude product 79.5g, HPLC content 98.6%, weight yield 79.5%；By 16a- hydroxyl prednisone
Imperial crude product is recrystallized according to step C the method in embodiment 1, obtains 16a- hydroxy prednisonlone fine work 68.9g, and HPLC contains
Amount 99.3% refines weight yield 86.7%, prepares weight total recovery 68.9%；Filtrate recovered alcohol and mother liquor material set are used for down
It criticizes in process for refining.
In addition, preparing solid base catalyst in the present embodiment step C, detailed process is as follows: in accordance with the above-mentioned embodiment 1
Aluminium oxide, is only changed into silica gel by the preparation method of solid base catalyst described in step C, and the solid phase alkali for making carrier with silica gel is made
Catalyst 49.8g, water content 6.8%.
Embodiment 3
The preparation of step A--- epoxy material:
In a 3000ml there-necked flask, 100g starting material 17a- deshydroxy prednisolone, 1000mlDME, in room is added
The lower stirring of temperature is completely dissolved solid, and the mistake being made into containing 40g Peracetic acid and 500mlDME is added dropwise in temperature control at 25~30 DEG C
Acid solution, about 2-2.5 hour drip off, and continue insulation reaction 6-12 hours at 25~30 DEG C after dripping off, and TLC confirmation reaction is eventually
After having reacted, the mixed solution that 5% sodium hydroxide of 400ml and 10% sodium sulfite of 100ml are made into is added in point, with neutralize with
The acid and excessive peroxy acid that reaction generates are destroyed, then 90-95%DME solvent is recycled in 50 DEG C or less reduced pressures, then is down to
500ml tap water is added in room temperature, stirs elutriation 3-4 hour, and filtering, filtrate is discharged into purification tank for liquid waste, and filter cake is washed, 60 DEG C with
Lower drying obtains 16,17a- epoxy group prednisolone 98.2g, HPLC content 97.2%, weight yield 98.2%；
The preparation of step B---16a, 21- biacetyl oxygroup prednisolone:
In a 1000ml there-necked flask, epoxy material prepared by addition 100g above-mentioned steps A, 500mlTHF, at room temperature
Stirring makes it completely dissolved, and adds 100g glacial acetic acid and 6g phosphoric acid catalyst, heat preservation in 40~45 DEG C reaction 2-3 hours, TLC
Confirm reaction end, after having reacted, the sodium bicarbonate solution of 200ml 10% is slowly added dropwise, neutralizes excessive acetic acid and catalysis is used
Acid makes system pH about 6-7, then the solvent THF of recycling 90-95% is concentrated under reduced pressure for 45 DEG C or less, then be cooled to 5~10 DEG C, adds
Entering 500ml tap water, stirs elutriation 3-4 hours, filtering, filtrate is discharged into purification tank for liquid waste, and filter cake is washed, 70 DEG C or less dryings,
Obtain 16a, 21- biacetyl oxygroup prednisolone crude product 128.9g.
The preparation of step M---16a, 21- biacetyl oxygroup prednisolone product:
The crude product obtained in step B is recrystallized by method described in 1 step M of embodiment, obtains 16a, the bis- second of 21-
Acyloxy prednisolone fine work 104.5g, HPLC content 99.7%, weight yield 104.5%.
Step C, 16a- hydroxy prednisonlone is synthesized
In a 2000ml there-necked flask, the 16a prepared in 100g step M is added, 21- biacetyl oxygroup prednisolone is
Raw material, 1500ml chloroform make it completely dissolved under stirring, add the alkaline carbonic acid calcium solid base catalyst that 60g makes by oneself,
Keep the temperature in 40~45 DEG C stirring hydrolysis 6-8 hours, TLC confirm reaction end, after having reacted, nitrogen filters pressing while hot, filter cake
With 500ml chloroform foam washing in two times, then recycles solid base catalyst and apply；Filtrate merges with washing lotion, and recycling is concentrated under reduced pressure
95% chloroform, then cools down, and tap water elutriation is added, centrifugation, remaining chloroform is first recovered under reduced pressure in filtrate, then is discharged into wastewater treatment
Pond, filter cake washing and drying obtain 16a- hydroxy prednisonlone crude product 79.8g, HPLC content 98.7%, weight yield 79.8%；It will
Above-mentioned 16a- hydroxy prednisonlone crude product is recrystallized by 1 step C the method for embodiment, obtains 16a- hydroxy prednisonlone essence
Product 70.3g, HPLC content 99.5% refines weight yield 88.1%, prepares weight total recovery 70.3%；Filtrate recovered alcohol with
Mother liquor material set is in lower batch of process for refining.
In addition, preparing solid base catalyst in the present embodiment step C, detailed process is as follows: in accordance with the above-mentioned embodiment 1
Aluminium oxide is only changed into calcium carbonate by the preparation method of solid base catalyst described in step C, and sodium carbonate changes sodium hydroxide into, system
It is able to the solid base catalyst 49.6g that calcium carbonate makees carrier, water content 4.8%.
The above content is combine specific preferred embodiment to the further description of the invention made, and it cannot be said that originally
The specific implementation of invention is only limited to these instructions.For those of ordinary skill in the art to which the present invention belongs, not
Under the premise of being detached from present inventive concept, several simple deductions and replacement can also be made, all shall be regarded as belonging to guarantor of the invention
Protect range.
Claims (9)
1. a kind of prepare 16a, the method for 21- biacetyl oxygroup prednisolone, which is characterized in that use 17a- deshydroxy prednisolone
Occur with organic peroxide acid at 16,17 first by starting material 17a- deshydroxy prednisolone in the first organic solvent for raw material
Epoxy material is made in epoxidation reaction；Again in a second organic solvent by the epoxy material, with glacial acetic acid under the catalysis of acid catalyst
Open loop is reacted, target product 16a, 21- biacetyl oxygroup prednisolone is made.
2. the method according to claim 1, wherein first organic solvent is toluene, methylene chloride, chlorine
One of imitative, ethyl acetate, DME, dioxane are a variety of, and the organic peroxide acid is adjacent peroxide benzene first diacid, methyl
One of benzoyl hydroperoxide, metachloroperbenzoic acid, Peracetic acid, Perbutyric Acid are a variety of.
3. according to the method described in claim 2, it is characterized in that, first organic solvent be ethyl acetate, it is described organic
Peroxy acid is adjacent peroxide benzene first diacid.
4. the method according to claim 1, wherein the epoxidation reaction temperature is 10--60 DEG C；17a- is de-
Hydroxyl prednisolone: organic peroxide acid=1g:0.1~0.8g, 17a- deshydroxy prednisolone: the first organic solvent=1g:10~
25ml。
5. according to the method described in claim 4, it is characterized in that, the epoxidation reaction temperature is 25--30 DEG C；17a- is de-
Hydroxyl prednisolone: organic peroxide acid=1g:0.3~0.5g, 17a- deshydroxy prednisolone: the first organic solvent=1g:13~
17ml。
6. the method according to claim 1, wherein second organic solvent is methylene chloride, glacial acetic acid, chlorine
One of imitative, ethyl acetate, DME, THF, C4 and following low-carbon alcohols are a variety of, and the acid catalyst is hydrochloric acid, sulfuric acid, to first
One of benzene sulfonic acid, trifluoracetic acid are a variety of.
7. according to the method described in claim 6, the acid is urged it is characterized in that, second organic solvent is methylene chloride
Agent is p-methyl benzenesulfonic acid.
8. the method according to claim 1, wherein ring-opening reaction temperature is 10--80 DEG C, and in open loop step
Epoxy material: acid catalyst: glacial acetic acid=1g:0.02~0.20g:0.2~1.6g, and epoxy material: the second organic solvent=1g:2
~15ml.
9. according to the method described in claim 8, it is characterized in that, ring-opening reaction temperature is 40--45 DEG C, and in open loop step
Epoxy material: acid catalyst: glacial acetic acid=1g:0.04~0.08g:0.8~1.2g, and epoxy material: the second organic solvent=1g:4
~6ml.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2789118A (en) * | 1956-03-30 | 1957-04-16 | American Cyanamid Co | 16-alpha oxy-belta1, 4-pregnadienes |
| CN104262440A (en) * | 2014-09-10 | 2015-01-07 | 江西赣亮医药原料有限公司 | Preparation method of 16alpha-hydroxyprednisolone |
-
2018
- 2018-11-13 CN CN201811343103.2A patent/CN109251230B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2789118A (en) * | 1956-03-30 | 1957-04-16 | American Cyanamid Co | 16-alpha oxy-belta1, 4-pregnadienes |
| CN104262440A (en) * | 2014-09-10 | 2015-01-07 | 江西赣亮医药原料有限公司 | Preparation method of 16alpha-hydroxyprednisolone |
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| Title |
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| BARNEY J. MAGERLEIN等: "A New Approach to l6α-Hydroxycorticoids", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| MILTON HELLER等: "16-Hydroxylated Steroids. XXI.1 The Preparation and Epimerization of 16β,21-Diacetoxy-9a-fluorocorticoids", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| TOSHIO NAMBARA等: "Rearrangements of the C-16,17 Ring-D Ketols of 14β-Steroids", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
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