CN109575097A - A kind of new preparation method of 16a- hydroxy prednisonlone product - Google Patents
A kind of new preparation method of 16a- hydroxy prednisonlone product Download PDFInfo
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- 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
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Abstract
A kind of new preparation method of 16a- hydroxy prednisonlone product is dissolved in organic solvent using 17- deshydroxy prednisone acetate as raw material, aoxidizes 16 under acid catalysis; oxide is made in 17 double bonds; the oxide is dissolved in organic solvent again, adds acetone, acid catalyzed reaction obtains protection；Then protection is dissolved in organic solvent; reducing agent is added to restore 11 ketone; and direct acid adding aqueous hydrolysis is deprotected to obtain 16a- hydroxacetic acid prednisolone after reduction reaction; it is dissolved in organic solvent again; under solid phase base catalysis; 21 acetic acid ester hydrolysis are obtained into 16a- hydroxy prednisonlone crude product, the crude product is finally heated to reflux decoloration through low-carbon alcohols and recrystallizes to obtain 16a- hydroxy prednisonlone product.Although increasing protection and deprotection reaction, each reaction yield that walks is high, simple to operate, and synthesis total recovery greatly improved, and preparation cost of the invention reduces by 20~25% than conventional method in process economics environmental protection.
Description
Technical field
The invention belongs to the fabricating technologies of steroid hormone pharmaceutical intermediate, and in particular to one kind with 17- deshydroxy vinegar
Sour prednisone is raw material, is reacted through 4 steps to synthesize the key intermediate 16a- hydroxyl of cortex hormone of aadrenaline drug budesonide
The fabricating technology of prednisolone product.
Background technique
16a- hydroxy prednisonlone (molecular formula C21H28O6), chemistry entitled 11b, 16a, 17a, 21- tetrahydroxy-pregnant steroid-
Isosorbide-5-Nitrae-diene -3,20- diketone, be it is a kind of production how the key intermediate of moral class steroidal cortex hormone of aadrenaline drug, be with it
Raw 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
Cortex hormone of aadrenaline drug is a kind of potent local anti-inflammatory agent, as budesonide is clinically mainly used for various rhinitis, urgency
The treatment of many diseases such as chronic bronchitis, side effect is low, and effect is good, wide market.16a- hydroxy prednisonlone
Conventional production methods are using prednisolone as raw material, are eliminated through 17,21 double esterifications, 17-position ester, 16,17 double bond oxidations, 21
The four-step reactions such as position ester hydrolysis are made, and wherein 16a- hydroxacetic acid prednisolone is prepared in first three step, and specific steps are shown in figure
1,16a- hydroxy prednisonlone is prepared by 16a- hydroxacetic acid prednisolone in the 4th step.The method synthesizes 16a- hydroxyl prednisone
Dragon, synthesis total recovery is low, the main reason is that: when being on the one hand with 16,17 double bonds of potassium permanganate oxidation, due to permanganic acid
The strong oxidizing property of potassium, will lead to 11 hydroxyls in molecule can also be oxidized, the product 16a- hydroxacetic acid prednisolone generated
16 hydroxyls in molecule can be also oxidized, and cause impurity more, hardly possible purifying, so that it is low to aoxidize this step yield；It on the other hand is the
Four step 16a- hydroxacetic acid prednisolones are with such as sodium hydroxide or sodium carbonate highly basic or such as hydrochloric acid, sulfuric acid strong acid hydrolysis
When, open loop rearrangement ring-enlarging reaction can be generated by D ring in the molecule, generate two very big impurity, the two impurity are also difficult to remove,
The yield for causing the 4th one-step hydrolysis to react is also very low.Therefore, 16a- hydroxy prednisonlone is produced with the method, the production cost is very high,
Cause budesonide class pharmaceutical market price very high, considerably increases drug cost when such Case treatment.
The patent CN201710765122.3 of the applicant's earlier application provides a kind of preparation of 16a- hydroxy prednisonlone
Method is to dissolve in 16a- hydroxacetic acid prednisolone in organic solvent, and the inert solid carrier conduct for having adsorbed highly basic is added
16a- hydroxy prednisonlone crude product is made in 21 acetic acid ester hydrolysis by hydrolysis solid base catalyst；Crude product is low through C4 or less
Carbon alcohol recrystallization, obtains 16a- hydroxy prednisonlone fine work.Above-mentioned solid carrier is selected from aluminium oxide or silica gel or calcium carbonate；Base catalysis
Sodium carbonate is selected in agent；Organic solvent is selected from toluene or chloroform etc..This method is compared with the traditional method, and production operation is simple and convenient,
The impurity generated in traditional mode of production can be greatly reduced, synthesis total recovery is greatly improved.
That is, above-mentioned prepared the defect of 16a- hydroxy prednisonlone step by 16a- hydroxacetic acid prednisolone
It is greatly improved, but final step in above-mentioned Fig. 1 (i.e. above-mentioned third step reaction) is by 16- alkene -17- deshydroxy-prednisone acetate
Dragon aoxidized under potassium permanganate generate 16a- hydroxacetic acid prednisolone the step of do not improved.Such as patent
CN201410455522 is also the side using 16,17 double bonds with potassium permanganate oxidation prednisolone structure similar in Fig. 1
Method produces 16a hydroxy prednisonlone, this also results in 11 hydroxyls and is oxidized.
Therefore, this field needs the preparation side of a kind of new 16a- hydroxacetic acid prednisolone and 16a- hydroxy prednisonlone
Method.
Patent CN201010106918.6 is related to a kind of synthetic method of 16 alpha-hydroxy prednisonlones.The invention uses strong
Pine is starting material, is made by elimination, oxidation, condensation, reduction and hydrolysis five steps reaction.The intermediate compound I of the patent and centre
Body II is respectively 17- deshydroxy prednisone acetate and its oxide 16a- hydroxacetic acid prednisone, and 16a- hydroxacetic acid sprinkles Buddhist nun thereafter
16 alpha-hydroxy prednisonlones are prepared by condensation, reduction and hydrolysis in pine, but wherein need using condensing agent hydrochloric acid amido urea
It is hydrolyzed with nitrite aqueous solution.The program still has that environmental protection pressure is big and what yield was not high thus at high cost lacks
It falls into.Therefore, Buddhist nun is sprinkled there is still a need for new synthesis 16a- hydroxy prednisonlone and its intermediate 16a- hydroxacetic acid is developed in this field
The preparation method of Song Long.
Summary of the invention
Therefore, the present invention is for oxygen in tradition 16a- hydroxy prednisonlone and 16a- hydroxacetic acid prednisolone production technology
Change reaction side reaction it is more, the low problem of the more yields of impurity, for high-efficiency environment friendly be prepared 16a- hydroxy prednisonlone and
16a- hydroxacetic acid prednisolone using first first preparing 16a- hydroxacetic acid prednisolone with ad hoc approach in the present invention, then leads to
The method for crossing the basic hydrolysis under given conditions of 16a- hydroxacetic acid prednisolone obtains 16a- hydroxy prednisonlone.
The present invention provides a kind of new preparation method of 16a- hydroxy prednisonlone product, which comprises
It first using 17- deshydroxy prednisone acetate as raw material, is dissolved in the first organic solvent, with oxidation under acid catalysis
Agent aoxidizes 16,17 double bonds, and oxide: 16a- hydroxacetic acid prednisone is made；
Above-mentioned obtained 16a- hydroxacetic acid prednisone is dissolved in the second organic solvent again, acetone is added, acid is urged
Change and reacts to obtain the protection protected by acetone of 16,17 hydroxyls；
Then protection obtained above is dissolved in third organic solvent, it is hydroxyl that reducing agent, which is added, and restores 11 ketone
Base, and aqueous acid is directly added into as acid catalyst after reduction reaction, the acetone protection of 16,17 hydroxyls is taken off in hydrolysis,
16a- hydroxacetic acid prednisolone crude product is made；The 16a- hydroxacetic acid prednisolone crude product is heated back through C4 or less low-carbon alcohols
Stream decoloration recrystallization, obtains 16a- hydroxacetic acid prednisolone product；
Finally 16a- hydroxacetic acid prednisolone is dissolved in the 4th organic solvent, in the catalytic action of solid base catalyst
Under, by 21 acetic acid ester hydrolysis, 16a- hydroxy prednisonlone crude product is prepared, the solid base catalyst is to have adsorbed by force
The inert solid carrier of alkali；And the 16a- hydroxy prednisonlone crude product is heated to reflux decoloration recrystallization through C4 or less low-carbon alcohols,
Obtain 16a- hydroxy prednisonlone product.
In a specific embodiment, which comprises
A, the preparation of oxide:
It is that 17- deshydroxy prednisone acetate is dissolved in the first organic solvent, acid catalyst, stirring, temperature control to 10 is added
It~50 DEG C, in oxidant potassium permanganate aqueous solution is added dropwise in 1~1.5 hour, after dripping off, then reacts 1~2 hour, TLC control is anti-
Terminal is answered, after having reacted, vacuum distillation recovered solvent, residue is cooled to room temperature, and pure water elutriation is added, and oxidation is made in filtering
Object: 16a- hydroxacetic acid prednisone crude product；The crude product is recrystallized with alcohol water blend, obtains 16a- hydroxacetic acid prednisone；
B, the preparation of protection:
Above-mentioned oxide is dissolved in the second organic solvent, is stirred, acetone and acid catalyst is added, keep the temperature lower reaction 6~
12 hours, TLC confirmed reaction end, after having reacted, suitable alkali neutralization acid was added, then having for recycling 90~95% is concentrated under reduced pressure
Then solvent is cooled to room temperature, pure water elutriation, filtering is added, and filtrate is discharged into purification tank for liquid waste, and filter cake washing and drying must be protected
Protect object；
C, the preparation of 16a- hydroxacetic acid prednisolone product:
Protection prepared by above-mentioned B is dissolved in third organic solvent, is stirred, under heat preservation slowly in 1~1.5 hour
Reducing agent is added, the reaction was continued 3~4 hours after adding, and TLC confirms reaction end, slow in 0.5~1.0 hour after having reacted
The aqueous acid of slow dropwise addition 5~10% after adding, continues hydrolysis 3~4 hours, and TLC confirms hydrolysis terminal, reaction
After complete, the organic solvent of recycling 90~95% is concentrated under reduced pressure, is then cooled to room temperature, pure water elutriation, filtering is added, filtrate is discharged into
Purification tank for liquid waste, filter cake washing and drying obtain 16a- hydroxacetic acid prednisolone crude product；The 16a- hydroxacetic acid prednisolone is thick
Product are heated to reflux decoloration recrystallization through active carbon in C4 or less low-carbon alcohols, obtain 16a- hydroxacetic acid prednisolone product；
D, the preparation of 16a- hydroxy prednisonlone product:
16a- hydroxacetic acid prednisolone product prepared by above-mentioned C is dissolved in the 4th organic solvent, is stirred, is added solid
The heat preservation of phase base catalyst in 10~60 DEG C hydrolysis 6~12 hours, TLC confirms reaction end, after having reacted, nitrogen pressure while hot
Then filter, the 4th organic solvent washing of filter cake recycle solid base catalyst and apply；Filtrate merges with washing lotion, is concentrated under reduced pressure back
The 4th organic solvent is received, after cooling plus pure water elutriation, centrifugation, filtrate decompression recycle remaining 4th organic solvent, and filter cake washing is dry
It is dry, obtain 16a- hydroxy prednisonlone crude product；By the 16a- hydroxy prednisonlone crude product in C4 or less low-carbon alcohols active carbon decoloring
Recrystallization, obtains 16a- hydroxy prednisonlone product.
In a specific embodiment, in the A oxide prepare first organic solvent be acetone, toluene,
One or both of chloroform, ethyl acetate, THF, DME；Oxidant potassium permanganate concentration is 1~10%；Acid catalyst is salt
One of acid, sulfuric acid, phosphoric acid, p-methyl benzenesulfonic acid, acetic acid and formic acid；Weight proportion between reactant is starting material: oxidation
Agent: acid catalyst=1g:0.2~0.8g:0.05~0.25g, the proportion between reactant and solvent are starting materials: first has
Solvent=1g:10~30ml.
In a specific embodiment, first organic solvent for preparing of oxide is acetone in the A；Oxidant
Concentration is 3~5%；Acid catalyst is formic acid；Oxidizing reaction temperature is 20~25 DEG C；Weight proportion between reactant is to originate
Raw material: oxidant: acid catalyst=1g:0.45g:0.1g, the proportion between reactant and solvent are starting materials: first is organic
Solvent=1g:20ml.
In a specific embodiment, in the B protection prepare second organic solvent be acetone, toluene,
One or both of chloroform, ethyl acetate, THF, DME；Acid catalyst is hydrochloric acid, sulfuric acid, phosphoric acid, p-methyl benzenesulfonic acid, acetic acid
Or one of formic acid；Protecting reaction temperature is 10~60 DEG C；Weight proportion between reactant is oxide: acetone: acid catalysis
Agent=1g:0.4~1.2g:0.01~0.20g, the proportion between reactant and solvent are oxides: the second organic solvent=1g:2
~10ml.
In a specific embodiment, second organic solvent for preparing of protection is acetone in the B；Acid catalysis
Agent is p-methyl benzenesulfonic acid；Protecting reaction temperature is 25~30 DEG C；Weight proportion between reactant is oxide: acetone: acid catalysis
Agent=1g:0.6g:0.05g, the proportion between reactant and solvent are oxides: the second organic solvent=1g:5ml.
In a specific embodiment, third described in the preparation of 16a- hydroxacetic acid prednisolone is organic molten in the C
Agent is toluene, methylene chloride, acetone, chloroform, THF, DME, dioxane or C4 and following low-carbon alcohols；Reducing agent is hydroboration
One of sodium, potassium borohydride, Lithium Aluminium Hydride；Reduction reaction temperature is 10~60 DEG C；Acid in the sour water of hydrolysis is salt
One of acid, sulfuric acid, phosphoric acid, p-methyl benzenesulfonic acid, acid or glacial acetic acid；Hydrolysising reacting temperature is 10~60 DEG C；Reduction reaction is anti-
Answering the weight proportion between object is protection: reducing agent=1g:0.06~0.20g；Weight proportion between hydrolysis reactant
It is protection: acid catalyst=1g:0.20~0.40g；Proportion between reactant and solvent is protection: third organic solvent
=1g:5~15ml.
In a specific embodiment, third described in the preparation of 16a- hydroxacetic acid prednisolone is organic molten in the C
Agent is alcohol；Reducing agent is sodium borohydride or potassium borohydride；Reduction reaction temperature is 20~25 DEG C；The acid of hydrolysis is salt
Acid；Hydrolysising reacting temperature is 40~45 DEG C；Weight proportion between reduction reaction reactant is protection: reducing agent=1g:
0.08g；Weight proportion between hydrolysis reactant is protection: acid=1g:0.28g；Proportion between reactant and solvent
It is protection: third organic solvent=1g:10ml.
In a specific embodiment, the solid base catalyst the preparation method comprises the following steps: solid alkali is dissolved in water
In, the strong inert solid carrier powder of adsorption capacity is added, is reacted 3~4 hours in 10~50 DEG C of stirring and adsorbings, after having reacted,
Decompression boils off water to close dry, dry solid base catalyst, moisture content 3~8% after taking-up；Weight proportion between reactant
It is carrier: alkali: water=1:0.2~0.4:8~12.
In a specific embodiment, the 4th organic solvent described in the preparation of 16a- hydroxy prednisonlone is in the D
Toluene, methylene chloride, acetone, chloroform, DMF, DME, dioxane or C4 and following low-carbon alcohols；The solid carrier is selected from oxygen
Change aluminium or silica gel or calcium carbonate；Base catalyst is selected from one of sodium carbonate, caustic soda, potassium hydroxide, sodium bicarbonate, potassium fluoride；
Reaction temperature is 40~45 DEG C；And weight ratio is in the step, 16a- hydroxacetic acid prednisolone: solid base catalyst=
1g:0.1~0.8g；Proportion between reactant and solvent is 16a- hydroxacetic acid prednisolone: four organic solvents=1g:10
~25ml.
The beneficial effect comprise that
The present invention uses 17- deshydroxy prednisone acetate for raw material, is first dissolved in the first organic solvent, in acid catalysis
It is lower to obtain 16,17 pairs of hydroxyl objects with 16,17 double bonds of potassium permanganate oxidation；Again in a second organic solvent by above-mentioned 16,17 pairs of hydroxyl objects,
Double hydroxyls are protected under acid catalysis with acetone；Then 11 ketone are restored with reducing agent in third organic solvent again, and directly added
The deprotection of sour water solution, three steps, which operate, is made 16a- hydroxacetic acid prednisolone；The 16a- hydroxyl vinegar produced using the method for the present invention
Sour prednisolone, then in the 4th organic solvent, 16a- hydroxy prednisonlone is produced with solid phase alkali catalyzed hydrolysis method.This hair
Although increasing protection, deprotection two-step reaction in the bright production technology for preparing 16a- hydroxy prednisonlone, each step unit is anti-
High income is answered, reduction and deprotection reaction can treat different things alike, and production operation is simple and convenient, and production technology is economic and environment-friendly, and significantly
Reduce in 16a- hydroxacetic acid prednisolone traditional processing technology that oxidation reaction side reaction is more, impurity is more, and impurity difficulty refines
The problem of, the total recovery of synthesis 16a- hydroxy prednisonlone, the side with traditional mode of production 16a- hydroxy prednisonlone greatly improved
Method is compared, and the preparation cost of the method for the present invention will reduce by 20~25%.In addition, solvent used in this law production, recyclable to follow
Ring set is used, easily implementation industrialized production.
In conclusion the present invention is few with a kind of intermediate product impurity, and the method for efficient, environmental protection and par is prepared
16a- hydroxy prednisonlone and its intermediate 16a- hydroxacetic acid prednisolone.
Detailed description of the invention
Fig. 1 is the synthetic route chart of tradition 16a- hydroxacetic acid prednisolone.
Fig. 2 is the synthetic route chart that 16a- hydroxy prednisonlone is produced in the present invention.
Specific embodiment
In order to which main points and spirit of the invention are described in more detail, name several embodiments and be explained.
Embodiment 1
A, the preparation of oxide:
In a 5000ml there-necked flask, addition 100g17- deshydroxy prednisone acetate, 2000ml acetone, 12.5g80%'s
Formic acid, stirring are completely dissolved solid, and temperature control is to 20~25 DEG C, in the potassium permanganate water that 900g5% is added dropwise in 1~1.5 hour
Solution after dripping off, reacts 1~2 hour again at 20~25 DEG C, and TLC controls reaction end, after having reacted, 35 DEG C or less decompressions
The solvent acetone set for being distilled to recover 90~95% is used for lower batch of oxidation reaction, and residue is cooled to room temperature, and 1000ml pure water is added
Oxide: 16a- hydroxacetic acid prednisone crude product is made in elutriation, filtering；The alcohol water blend weight of crude product 1000ml50%
Crystallization, obtains 16a- hydroxacetic acid prednisone 93.8g, HPLC content 97.5%, weight yield about 93.8%；
B, the preparation of protection:
In a 1000ml there-necked flask, oxide prepared by the above-mentioned A of 100g is added, 500ml acetone, 5g is to toluene sulphur
Acid, stirring are completely dissolved solid, and heat preservation is reacted 8~12 hours in 25~30 DEG C, and TLC confirms reaction end, after having reacted, add
Enter 5ml triethylamine neutralizing acid, then the solvent acetone of recycling 90~95% is concentrated under reduced pressure, be then cooled to room temperature, it is pure that 500ml is added
Water elutriation, filtering, filtrate are discharged into purification tank for liquid waste, and filter cake is washed to neutrality, and 70 DEG C or less dryings obtain protection 16,17- acetone
Contracting -16a- hydroxacetic acid prednisone 109.2g, HPLC content 97.5%, weight yield 109.2%；
C, the preparation of 16a- hydroxacetic acid prednisolone:
In a 2000ml there-necked flask, protection prepared by the above-mentioned B of 100g, 1000ml alcohol is added, stirring makes solid
Body is completely dissolved, and keeps the temperature in 20~25 DEG C, 8g sodium borohydride is slowly added in about 1~1.5 hour, and it is anti-to add subsequent continuation of insurance temperature
It answers 3~4 hours, TLC confirms reaction end, and after having reacted, the hydrochloric acid water of 280g10% is slowly added dropwise in 0.5~1.0 hour
Solution, after adding, continue 40~45 DEG C hydrolysis 3~4 hours, TLC confirm hydrolysis terminal, after having reacted, 60 DEG C
The alcohol set that recycling 90~95% is concentrated under reduced pressure below is reacted for this step, and residue is cooled to room temperature, and 500ml pure water water is added
Analysis, filtering, filtrate are discharged into purification tank for liquid waste, and filter cake washing and drying obtains 16a- hydroxacetic acid prednisone crude product 95g, by the 16a-
Prednisone acetate crude product is dissolved in 500ml50% alcohol, and 5g active carbon is added, and reflux decoloration 1~1.5 hour is filtered while hot,
100ml alcohol washes charcoal, and filter cake send producer to recycle, and filtrate and washing lotion merging are concentrated into extraction raffinate body about 120~150ml, is cooled to -5
~0 DEG C crystallizes 4~5 hours, and filtering, disposing mother liquor is applied, and 70 DEG C of filter cake or less drying obtain 16a- hydroxacetic acid prednisone
89.6g, HPLC content 98.5%, weight yield 89.6%.
D, the preparation of 16a- hydroxy prednisonlone
In a 2000ml there-necked flask, it is raw material that the 16a- hydroxacetic acid prednisolone prepared in 100g step C, which is added,
1500ml toluene makes it completely dissolved under stirring, adds the solid base catalyst that 30g makes by oneself, keeps the temperature in 40~45 DEG C
Stirring hydrolysis 6-8 hours, TLC confirm reaction end, and after having reacted, nitrogen filters pressing while hot, filter cake is divided to two with 500ml toluene
Then secondary foam washing recycles solid base catalyst and applies；Filtrate merges with washing lotion, and 95% toluene of recycling is concentrated under reduced pressure, then cools down,
Pure water elutriation is added, centrifugation, remaining toluene is first recovered under reduced pressure in filtrate, then is discharged into purification tank for liquid waste, and filter cake washing and drying obtains
16a- hydroxy prednisonlone crude product 88.2g, HPLC content 98.8%, weight yield 88.2%；By above-mentioned 16a- hydroxyl prednisone
Imperial crude product dissolves in 800ml alcohol, be added 5g active carbon, be then heated to reflux 1.0-1.5 hours, filters pressing while hot, filter cake with
Foam washing Hou Song producer recycles 100ml alcohol in two times, and 95% alcohol of recycling is concentrated under reduced pressure after filtrate and washing lotion merging, be cooled to-
5-0 DEG C, stirred crystallization 2-3 hours, filtering, filter cake was rinsed with the cold alcohol of 5ml, and drying obtains 16a- hydroxy prednisonlone fine work
78.9g, HPLC content 99.4% refines weight yield 89.5%, prepares weight total recovery 78.9%；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 D, detailed process is as follows: in a 1000ml there-necked flask
In, the solution being made by 50g solid alumina, 300ml pure water, 200ml pure water and 15g sodium carbonate is added, is stirred in 25-30 DEG C
Adsorption reaction 3~4 hours, after having reacted, decompression boiled off water and does to close, took out dry that solid base catalyst 50.1g, moisture contain
Amount 5.6%, weight yield 102%.
Embodiment 2
A, the preparation of oxide:
In a 5000ml there-necked flask, 100g17- deshydroxy prednisone acetate, 1500ml chloroform, the phosphorus of 15g20% is added
Acid, stirring are completely dissolved solid, and temperature control is water-soluble in the potassium permanganate that 1500g3% is added dropwise in 1~1.5 hour to 20~25 DEG C
Liquid after dripping off, reacts 1~2 hour again at 20~25 DEG C, and TLC controls reaction end, and after having reacted, 35 DEG C or less decompressions are steamed
The solvent chloroform set of recycling 90~95% is evaporated for lower batch of oxidation reaction, and residue is cooled to room temperature, and 1000ml pure water water is added
Oxide: 16a- hydroxacetic acid prednisone crude product is made in analysis, filtering；The crude product is tied again with the alcohol water blend of 1000ml50%
Crystalline substance obtains 16a- hydroxacetic acid prednisone 91.6g, HPLC content 98.0%, weight yield about 91.6%；
B, the preparation of protection:
In a 1000ml there-necked flask, oxide prepared by the addition above-mentioned A of 100g, 50ml acetone, 500ml chloroform,
5g p-methyl benzenesulfonic acid, stirring are completely dissolved solid, and heat preservation is reacted 8~12 hours in 25~30 DEG C, and TLC confirms reaction end,
After having reacted, 5ml triethylamine neutralizing acid is added, then the solvent chloroform of recycling 90~95% is concentrated under reduced pressure, is then cooled to room temperature,
500ml pure water elutriation, filtering is added, filtrate is discharged into purification tank for liquid waste, and filter cake is washed to neutrality, and 70 DEG C or less dryings must be protected
Object 16,17- acetone contracting -16a- hydroxacetic acid prednisone 105.2g, HPLC content 97.8%, weight yield 105.2%；
C, the preparation of 16a- hydroxacetic acid prednisolone:
In a 2000ml there-necked flask, protection prepared by the above-mentioned B of 100g, 1000ml methanol is added, stirring makes solid
Body is completely dissolved, and keeps the temperature in 20~25 DEG C, 8g potassium borohydride is slowly added in about 1~1.5 hour, and it is anti-to add subsequent continuation of insurance temperature
It answers 3~4 hours, TLC confirms reaction end, and after having reacted, the sulfuric acid water of 280g10% is slowly added dropwise in 0.5~1.0 hour
Solution, after adding, continue 40~45 DEG C hydrolysis 3~4 hours, TLC confirm hydrolysis terminal, after having reacted, 40 DEG C
The methanol set that recycling 90~95% is concentrated under reduced pressure below is reacted for this step, and residue is cooled to room temperature, and 500ml pure water water is added
Analysis, filtering, filtrate are discharged into purification tank for liquid waste, and filter cake washing and drying obtains 16a- hydroxacetic acid prednisone crude product 95g, by the 16a-
Prednisone acetate crude product obtains 16a- hydroxacetic acid prednisone 86.8g, HPLC contains by the recrystallization of method described in the embodiment 1C
Amount 98.7%, weight yield 86.8%.
D, the preparation of 16a- hydroxy prednisonlone:
In a 2000ml there-necked flask, it is raw material that the 16a- hydroxacetic acid prednisolone prepared in 100g step C, which is added,
1500ml alcohol makes it completely dissolved under stirring, adds the solid base catalyst that 30g makes by oneself, keeps the temperature in 40~45 DEG C
Stirring hydrolysis 6-8 hours, TLC confirm reaction end, and after having reacted, nitrogen filters pressing while hot, filter cake is divided to two with 500ml alcohol
Then secondary foam washing recycles solid base catalyst and applies；Filtrate merges with washing lotion, and 95% alcohol of recycling is concentrated under reduced pressure, then cools down,
Pure water elutriation is added, centrifugation, remaining alcohol is first recovered under reduced pressure in filtrate, then is discharged into purification tank for liquid waste, and filter cake washing and drying obtains
16a- hydroxy prednisonlone crude product 87.8g, HPLC content 98.6%, weight yield 87.8%；16a- hydroxy prednisonlone is thick
Product are recrystallized according to step C the method in embodiment 1, obtain 16a- hydroxy prednisonlone fine work 77.6g, HPLC content
99.5%, weight yield 88.4% is refined, weight total recovery 77.6% is prepared；Filtrate recovered alcohol and mother liquor material set are used for lower batch
In process for refining.
In addition, preparing solid base catalyst in the present embodiment step D, 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 D, and the solid phase alkali for making carrier with silica gel is made
Catalyst 49.8g, water content 6.8%.
Embodiment 3
A, the preparation of oxide:
In a 5000ml there-necked flask, 100g17- deshydroxy prednisone acetate, the vinegar of 1500mlDME, 50g20% is added
Acid, stirring are completely dissolved solid, and temperature control is water-soluble in the potassium permanganate that 900g5% is added dropwise in 1~1.5 hour to 20~25 DEG C
Liquid after dripping off, reacts 1~2 hour again at 20~25 DEG C, and TLC controls reaction end, and after having reacted, 35 DEG C or less decompressions are steamed
The solvent DME set of recycling 90~95% is evaporated for lower batch of oxidation reaction, and residue is cooled to room temperature, and 1000ml pure water water is added
Oxide: 16a- hydroxacetic acid prednisone crude product is made in analysis, filtering；The crude product is tied again with the alcohol water blend of 1000ml50%
Crystalline substance obtains 16a- hydroxacetic acid prednisone 92.5g, HPLC content 97.6%, weight yield about 92.5%；
B, the preparation of protection:
In a 1000ml there-necked flask, oxide prepared by the above-mentioned A of 100g, 50ml acetone, 500mlTHF, 5g is added
Sulfuric acid, stirring are completely dissolved solid, and heat preservation is reacted 8~12 hours in 25~30 DEG C, and TLC confirms reaction end, after having reacted,
5ml triethylamine neutralizing acid is added, then the solvent THF of recycling 90~95% is concentrated under reduced pressure, is then cooled to room temperature, 500ml is added
Pure water elutriation, filtering, filtrate are discharged into purification tank for liquid waste, and filter cake is washed to neutrality, and 70 DEG C or less dryings obtain protection 16,17- third
Ketone contracting -16a- hydroxacetic acid prednisone 106.7g, HPLC content 97.6%, weight yield 106.7%；
C, the preparation of 16a- hydroxacetic acid prednisolone:
In a 2000ml there-necked flask, protection prepared by the above-mentioned B of 100g, 1000mlDME is added, stirring makes solid
It is completely dissolved, keeps the temperature in 20~25 DEG C, 6g Lithium Aluminium Hydride is slowly added in about 1~1.5 hour, adds subsequent continuous insulation reaction
3~4 hours, TLC confirm reaction end, after having reacted, be slowly added dropwise in 0.5~1.0 hour 350g10% to toluene sulphur
Aqueous acid, after adding, continue 40~45 DEG C hydrolysis 3~4 hours, TLC confirm hydrolysis terminal, after having reacted,
40 DEG C or less the DME sets that recycling 90~95% is concentrated under reduced pressure are reacted for this step, and residue is cooled to room temperature, and it is pure that 500ml is added
Water elutriation, filtering, filtrate are discharged into purification tank for liquid waste, and filter cake washing and drying obtains 16a- hydroxacetic acid prednisolone crude product 96g, will
The 16a- hydroxacetic acid prednisolone crude product obtains 16a- hydroxacetic acid prednisone by the recrystallization of method described in the embodiment 1C
Imperial 86.2g, HPLC content 98.4%, weight yield 86.2%.
D, the preparation of 16a- hydroxy prednisonlone:
In a 2000ml there-necked flask, it is raw material that the 16a- hydroxacetic acid prednisolone prepared in 100g step C, which is added,
1500ml chloroform makes it completely dissolved under stirring, adds the alkaline carbonic acid calcium solid base catalyst that 30g makes by oneself, heat preservation
In 40~45 DEG C stirring hydrolysis 6-8 hours, TLC confirm reaction end, after react, nitrogen filters pressing while hot, filter cake use
Then 500ml chloroform foam washing in two times recycles solid base catalyst and applies；Filtrate merges with washing lotion, and recycling 95% is concentrated under reduced pressure
Then chloroform cools down, tap water elutriation is added, and centrifugation, remaining chloroform is first recovered under reduced pressure in filtrate, then is discharged into purification tank for liquid waste,
Filter cake washing and drying obtains 16a- hydroxy prednisonlone crude product 88.2g, HPLC content 98.9%, weight yield 88.2%；It will be above-mentioned
16a- hydroxy prednisonlone crude product is recrystallized by 1 step D the method for embodiment, obtains 16a- hydroxy prednisonlone fine work
78.2g, HPLC content 99.3% refines weight yield 88.7%, prepares weight total recovery 78.2%；Filtrate recovered alcohol and mother
Liquid material set is in lower batch of process for refining.
In addition, preparing solid base catalyst in the present embodiment step D, 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 D, 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 (10)
1. a kind of new preparation method of 16a- hydroxy prednisonlone product, which is characterized in that the described method includes:
First using 17- deshydroxy prednisone acetate as raw material, it is dissolved in the first organic solvent, with oxidant oxygen under acid catalysis
Change 16,17 double bonds, oxide: 16a- hydroxacetic acid prednisone is made；
Above-mentioned obtained 16a- hydroxacetic acid prednisone is dissolved in the second organic solvent again, acetone is added, acid catalysis is anti-
The protection that deserved 16,17 hydroxyls are protected by acetone；
Then protection obtained above is dissolved in third organic solvent, it is hydroxyl that reducing agent, which is added, and restores 11 ketone, and
Aqueous acid is directly added into after reduction reaction as acid catalyst, the acetone protection of 16,17 hydroxyls is taken off in hydrolysis, is made
16a- hydroxacetic acid prednisolone crude product；The 16a- hydroxacetic acid prednisolone crude product is heated to reflux through C4 or less low-carbon alcohols de-
Color recrystallization, obtains 16a- hydroxacetic acid prednisolone product；
Finally 16a- hydroxacetic acid prednisolone is dissolved in the 4th organic solvent, under the catalytic action of solid base catalyst,
By 21 acetic acid ester hydrolysis, 16a- hydroxy prednisonlone crude product is prepared, the solid base catalyst is to have adsorbed highly basic
Inert solid carrier；And the 16a- hydroxy prednisonlone crude product is heated to reflux decoloration recrystallization through C4 or less low-carbon alcohols, it obtains
16a- hydroxy prednisonlone product.
2. the method according to claim 1, wherein the described method includes:
A, the preparation of oxide:
It is that 17- deshydroxy prednisone acetate is dissolved in the first organic solvent, acid catalyst, stirring, temperature control to 10~50 is added
DEG C, it in oxidant potassium permanganate aqueous solution is added dropwise in 1~1.5 hour, after dripping off, then reacts 1~2 hour, TLC control reaction is eventually
Point, after having reacted, vacuum distillation recovered solvent, residue is cooled to room temperature, and pure water elutriation is added, and oxide is made in filtering:
16a- hydroxacetic acid prednisone crude product；The crude product is recrystallized with alcohol water blend, obtains 16a- hydroxacetic acid prednisone；
B, the preparation of protection:
Above-mentioned oxide is dissolved in the second organic solvent, is stirred, acetone and acid catalyst is added, it is small to keep the temperature lower reaction 6~12
When, TLC confirms reaction end, after having reacted, suitable alkali neutralization acid is added, then the organic molten of recycling 90~95% is concentrated under reduced pressure
Then agent is cooled to room temperature, pure water elutriation, filtering is added, and filtrate is discharged into purification tank for liquid waste, and filter cake washing and drying obtains protection；
C, the preparation of 16a- hydroxacetic acid prednisolone product:
Protection prepared by above-mentioned B is dissolved in third organic solvent, stirs, is slowly added in 1~1.5 hour under heat preservation
Reducing agent, the reaction was continued 3~4 hours after adding, and TLC confirms reaction end, after having reacted, slowly drips in 0.5~1.0 hour
The aqueous acid for adding 5~10% after adding, continues hydrolysis 3~4 hours, and TLC confirms hydrolysis terminal, after having reacted,
The organic solvent of recycling 90~95% is concentrated under reduced pressure, is then cooled to room temperature, pure water elutriation, filtering is added, filtrate is discharged into waste water
Processing pond, filter cake washing and drying obtain 16a- hydroxacetic acid prednisolone crude product；The 16a- hydroxacetic acid prednisolone crude product is passed through
Active carbon is heated to reflux decoloration recrystallization in C4 or less low-carbon alcohols, obtains 16a- hydroxacetic acid prednisolone product；
D, the preparation of 16a- hydroxy prednisonlone product:
16a- hydroxacetic acid prednisolone product prepared by above-mentioned C is dissolved in the 4th organic solvent, is stirred, solid phase alkali is added
Catalyst heat preservation in 10~60 DEG C hydrolysis 6~12 hours, TLC confirm reaction end, after having reacted, nitrogen filters pressing while hot,
Then the 4th organic solvent washing of filter cake recycles solid base catalyst and applies；Filtrate merges with washing lotion, and recycling the is concentrated under reduced pressure
Four organic solvents, after cooling plus pure water elutriation, centrifugation, filtrate decompression recycle remaining 4th organic solvent, and filter cake washing and drying obtains
16a- hydroxy prednisonlone crude product；By the 16a- hydroxy prednisonlone crude product, active carbon decoloring is tied again in C4 or less low-carbon alcohols
Crystalline substance obtains 16a- hydroxy prednisonlone product.
3. according to the method described in claim 2, it is characterized in that, oxide prepares first organic solvent in the A
It is one or both of acetone, toluene, chloroform, ethyl acetate, THF, DME；Oxidant potassium permanganate concentration is 1~10%；
Acid catalyst is one of hydrochloric acid, sulfuric acid, phosphoric acid, p-methyl benzenesulfonic acid, acetic acid and formic acid；Weight proportion between reactant is,
Starting material: oxidant: acid catalyst=1g:0.2~0.8g:0.05~0.25g, the proportion between reactant and solvent are to rise
Beginning raw material: the first organic solvent=1g:10~30ml.
4. according to the method described in claim 3, it is characterized in that, oxide prepares first organic solvent in the A
It is acetone；Oxidant concentration is 3~5%；Acid catalyst is formic acid；Oxidizing reaction temperature is 20~25 DEG C；Weight between reactant
Amount proportion is starting material: oxidant: acid catalyst=1g:0.45g:0.1g, the proportion between reactant and solvent are to originate
Raw material: the first organic solvent=1g:20ml.
5. according to the method described in claim 2, it is characterized in that, protection prepares second organic solvent in the B
It is one or both of acetone, toluene, chloroform, ethyl acetate, THF, DME；Acid catalyst be hydrochloric acid, sulfuric acid, phosphoric acid, to first
One of benzene sulfonic acid, acid or glacial acetic acid；Protecting reaction temperature is 10~60 DEG C；Weight proportion between reactant is oxide:
Acetone: acid catalyst=1g:0.4~1.2g:0.01~0.20g, the proportion between reactant and solvent are oxides: second has
Solvent=1g:2~10ml.
6. according to the method described in claim 5, it is characterized in that, protection prepares second organic solvent in the B
It is acetone；Acid catalyst is p-methyl benzenesulfonic acid；Protecting reaction temperature is 25~30 DEG C；Weight proportion between reactant is to aoxidize
Object: acetone: acid catalyst=1g:0.6g:0.05g, the proportion between reactant and solvent are oxides: the second organic solvent=
1g:5ml.
7. according to the method described in claim 2, it is characterized in that, in the C 16a- hydroxacetic acid prednisolone preparation in institute
Stating third organic solvent is toluene, methylene chloride, acetone, chloroform, THF, DME, dioxane or C4 and following low-carbon alcohols；Also
Former agent is one of sodium borohydride, potassium borohydride, Lithium Aluminium Hydride；Reduction reaction temperature is 10~60 DEG C；The acid of hydrolysis
Acid in water is one of hydrochloric acid, sulfuric acid, phosphoric acid, p-methyl benzenesulfonic acid, acid or glacial acetic acid；Hydrolysising reacting temperature is 10~60
℃；Weight proportion between reduction reaction reactant is protection: reducing agent=1g:0.06~0.20g；Hydrolysis reactant
Between weight proportion be protection: acid catalyst=1g:0.20~0.40g；Proportion between reactant and solvent is protection:
Third organic solvent=1g:5~15ml.
8. the method according to the description of claim 7 is characterized in that in the C 16a- hydroxacetic acid prednisolone preparation in institute
Stating third organic solvent is alcohol；Reducing agent is sodium borohydride or potassium borohydride；Reduction reaction temperature is 20~25 DEG C；Hydrolysis is anti-
The acid answered is hydrochloric acid；Hydrolysising reacting temperature is 40~45 DEG C；Weight proportion between reduction reaction reactant is protection: reduction
Agent=1g:0.08g；Weight proportion between hydrolysis reactant is protection: acid=1g:0.28g；Between reactant and solvent
Proportion be protection: third organic solvent=1g:10ml.
9. preparation method according to claim 2, which is characterized in that the solid base catalyst the preparation method comprises the following steps: will
Solid alkali is dissolved in the water, and the strong inert solid carrier powder of adsorption capacity is added, in 10~50 DEG C of stirring and adsorbings reactions 3~
4 hours, after having reacted, decompression boiled off water to close dry, dry solid base catalyst, moisture content 3~8% after taking-up；Reaction
Weight proportion between object is carrier: alkali: water=1:0.2~0.4:8~12.
10. according to the method described in claim 2, it is characterized in that, in the D the described in the preparation of 16a- hydroxy prednisonlone
Four organic solvents are toluene, methylene chloride, acetone, chloroform, DMF, DME, dioxane or C4 and following low-carbon alcohols；It is described solid
Body carrier is selected from aluminium oxide or silica gel or calcium carbonate；Base catalyst is selected from sodium carbonate, caustic soda, potassium hydroxide, sodium bicarbonate, fluorination
One of potassium；Reaction temperature is 40~45 DEG C；And weight ratio is in the step, 16a- hydroxacetic acid prednisolone: solid phase
Base catalyst=1g:0.1~0.8g；Proportion between reactant and solvent is that 16a- hydroxacetic acid prednisolone: the 4th is organic molten
Agent=1g:10~25ml.
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