CN109796515A - A method of preparing the reduction rear center body of Aclovate - Google Patents
A method of preparing the reduction rear center body of Aclovate Download PDFInfo
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Abstract
The present invention provides a kind of method of reduction rear center body for preparing Aclovate; including using 16a- methyl table hydrocortisone as raw material; through 21 propionates; 7; 11 dual oxides are at diketone, 17 propionates, 3 enolization etherification protections; 7,11 diketone reduction and sour water solution are deprotected the reduction rear center body of totally five steps reaction synthesis Aclovate.Many advantages, such as present invention reacts the reduction rear center body of synthesis Aclovate through five steps using 16a- methyl table hydrocortisone as raw material, and present invention process has synthetic route short, process economics environmental protection, production operation is easy, and product yield is high；Recycled can be recycled in solvent used in production, easily implementation industrialized production.
Description
Technical field
The invention belongs to the fabricating technologies of steroid hormone drug, and in particular to prepare Aclovate to a kind of
The method for restoring rear center body.
Background technique
Aclovate (molecular formula C28H37ClO7), the entitled chloro- 16a- methyl-1 1- hydroxyl of the 7a--pregnant steroid -1 of chemistry,
4- diene -3,20- diketone -17,21- double propionate is a kind of potent steroidal corticosteroid drug, have potent local anti-inflammatory,
Antipruritic and pressor effect is clinically mainly used for eczema, atopic dermatitis, psoriasis and other dermopathic controls
It treats, side effect is low, and effect is good, wide market.The conventional production methods of Aclovate are to fill in removing fluorine acetic acid
Meter Song Wei raw material, through DDQ6 dehydrogenations, 21 alkali catalyzed hydrolysis, 17,21 triethyl orthopropionate cyclic esters, acid catalysis cyclic ester water
It solves, 21 propyl ester, the chemical reaction of six steps such as 7a-Cl, is made Aclovate, technique in 6,7 HCl gas additions
Route is shown in attached drawing 1.The synthetic method, synthetic route is long, and synthesis total recovery only has 2.678%, especially final step 6, and 7
HCl gas addition reaction, synthesis yield is less than 20%, and since synthesis total recovery is low, multistep synthesis chemical reaction side reaction is more, produces
Raw impurity level is big, and purification purification is difficult, while it is also more to generate the three wastes, and not easy to handle, environment easy to pollute so that double propionic acid Ah
Chlorine rice pine production cost is very high with the market price, has aggravated the medication burden of such patient.
Therefore, this field needs a kind of preparation method of new Aclovate.
Summary of the invention
The present invention provides a kind of method of reduction rear center body for preparing Aclovate.
The technical scheme is that a method of the reduction rear center body of Aclovate is prepared, it is described
Method includes using 16a- methyl table hydrocortisone as raw material, and through 21 propionates, 7,11 dual oxides are at diketone, and 17 third
Esterification, 3 enolization etherification protections, simultaneously the reaction of totally five steps synthesizes double propionic acid Ah chlorine to the deprotection of sour water solution for 7,11 diketone reduction
The reduction rear center body of meter Song Yong, specific steps include:
A, carboxylate is synthesized, is using 16a- methyl table hydrocortisone as raw material, by it with third in the first organic solvent
Under acid catalyst catalysis, esterification occurs acid anhydrides for 21 hydroxyls, obtains carboxylate: 16a- methyl table hydrocortisone -21
Propionic ester；
B, synthesis oxide, be by carboxylate containing acid the second organic solvent in oxidant with 11a hydroxyl in molecule
7,11 oxidation reactions occur with 7 active hydrogens, obtain oxide: 16a- methyl-17 a- hydroxyl -21- propionyloxy-pregnant steroid -4
Alkene -3,7,11,20- tetrone；
C, synthesize dibasic acid esters object, be by oxide in third organic solvent with propionic andydride acid catalyst catalysis under, 17a-
Hydroxyl occurs esterification and generates dibasic acid esters object: the pregnant Gona-4-ene-3 of the bis- propionyloxies-of 16a- methyl-17 a, 21-, 7,11,20- tetra-
Ketone；
D, synthesize etherate, be by dibasic acid esters object in the 4th organic solvent with triethyl orthoformate acid catalyst catalysis under
The reaction of enol form etherification protection occurs with the ketone group in the 3- ketone -4- alkene structure in molecule, obtains etherate: 3- vinyl alcohol ether -
Pregnant steroid -3,5- diene -7,11,20- the triketone of the bis- propionyloxies-of 16a- methyl-17 a, 21-；
E, reduzate is synthesized, is to send out etherate in molecule 7,11 ketone groups with reducing agent in the 5th organic solvent
Raw reduction reaction, and be deprotected under acid catalysis, obtain the reduction rear center body of the i.e. Aclovate of reduzate: 16a- first
The pregnant Gona-4-ene-3 of the base bis- propionyloxies-of -7,11- dihydroxy -17a, 21-, 20- diketone.
Further, the method specific steps are as follows:
A, it synthesizes carboxylate: being that 16a- methyl table hydrocortisone is dissolved in the first organic solvent, in 10~50 DEG C
Lower addition propionic andydride, acid catalyst catalysis lower reaction 6~8 hours, TLC confirmed reaction end, after having reacted, adds alkali neutralization, subtracts
Receipts organic solvent is pushed back, is then crystallized with ethanol water, dry carboxylate: -21 propionic acid of 16a- methyl table hydrocortisone
Ester, HPLC content 97.0~98.5%, weight yield 110~115%；
B, synthesis oxide: being to dissolve in above-mentioned carboxylate in the second organic solvent, at 10~50 DEG C, in 2~3 hours
Oxidant is slowly added dropwise, keeps the temperature in 10~50 DEG C that the reaction was continued 1~2 hour after dripping off again, TLC confirms reaction end, has reacted
Afterwards, suitable sodium hydrosulfite is added to remove excessive oxidant, 90~95% organic solvents of recycling are concentrated under reduced pressure, then temperature lowering water
Analysis, centrifugation, filtrate are discharged into purification tank for liquid waste, and filtration cakes torrefaction obtains oxide, HPLC content 95.0~98.5%, weight yield 95
~100%；
C, it synthesizes dibasic acid esters object: being to dissolve in above-mentioned oxide in third organic solvent, heat preservation is added third at 10~80 DEG C
Acid anhydrides, acid catalyst catalysis lower reaction 6~8 hours, TLC confirmed reaction end, after having reacted, is cooled to 25~30 DEG C, is added
Suitable alkali neutralization cools after the organic solvent of recycling 90~95% is concentrated under reduced pressure to 10 to pH6.5~7.5 of solution
~25 DEG C, pure water is added, stirring and crystallizing 1.5~2.5 hours, centrifugation, filtrate was discharged into purification tank for liquid waste, and Washing of Filter Cake is dry, obtained
Dibasic acid esters object: the pregnant Gona-4-ene-3 of the bis- propionyloxies-of 16a- methyl-17 a, 21-, 7,11,20- tetrones, HPLC content 98.0~
99.0%, weight yield 110~115%；
D, it synthesizes etherate: being to dissolve in above-mentioned dibasic acid esters object in the 4th organic solvent, triethyl orthoformate is added and acid is urged
Agent, heat preservation are reacted 3~4 hours in 10~80 DEG C, and TLC confirms reaction end, and after having reacted, suitable alkali neutralization is added to molten
PH6.5~7.5 of liquid cool after the organic solvent of recycling 90~95% is concentrated under reduced pressure to 10~25 DEG C, and pure water is added,
Stirring and crystallizing 1.5~2.5 hours, centrifugation, filtrate was discharged into purification tank for liquid waste, and Washing of Filter Cake is dry, obtained etherate: 3- ethylene alcohol ether
Pregnant steroid -3, the 5- diene -7,11 of the bis- propionyloxies-of base -16a- methyl-17 a, 21-, 20- triketone, HPLC content 97.0~
99.0%, weight yield 100~105%；
E, it synthesizes reduzate: being that above-mentioned etherate is dissolved in the 5th organic solvent, keep the temperature at 10~80 DEG C, slowly
Be added reducing agent, add within 1.5~2.5 hours, then then at 10~80 DEG C continuations insulation reaction 1~2 hour, TLC confirmation reacts
Terminal after having reacted, is slowly added dropwise suitable acid catalyst aqueous solution, makes system pH to 2~3, then at 10~80 DEG C of continuation water
Solution reaction 2~3 hours, TLC confirms reaction end, and after having reacted, slowly plus appropriate bases are neutralized to system pH to 6~7, then subtract
90~95% organic solvent of concentration and recovery is pressed, then is cooled down, pure water elutriation is slowly added into, is centrifuged, filtrate is discharged into purification tank for liquid waste, filters
Biscuit is dry, obtains the reduction rear center body of Aclovate: the bis- propionyl oxygen of 16a- methyl -7,11- dihydroxy -17a, 21-
The pregnant Gona-4-ene-3 of base-, 20- diketone.
Further, in the specific steps:
A, synthesize the first organic solvent described in carboxylate be propionic andydride, toluene, propionic acid, chloroform, DME, in dioxane
One kind；The acid catalyst of reaction is one of inorganic acid sulfuric acid, hydrochloric acid or organic acid p-methyl benzenesulfonic acid；Between reactant
Weight proportion be 16a- methyl table hydrocortisone: propionic andydride: acid catalyst=1g:0.3~0.5g:0.01~0.15g；
Proportion between reactant and solvent is 16a- methyl table hydrocortisone: the first organic solvent=1g:1~5ml；
B, the second organic solvent described in synthesis oxide is toluene, acetone, chloroform, DME, tetrahydrofuran, DMSO, dioxy
One of six rings, glacial acetic acid；The oxidant is one of chromium oxide, PPC, hypohalogenous acids sodium；Weight between reactant is matched
Than being, carboxylate: oxidant=1g:0.2~0.8g；Proportion between reactant and solvent is carboxylate: the second organic solvent=
1g:3~10ml；
C, synthesize third organic solvent described in dibasic acid esters object be propionic andydride, toluene, propionic acid, chloroform, DME, in dioxane
One kind；The acid catalyst of reaction is one of inorganic acid sulfuric acid, hydrochloric acid or organic acid p-methyl benzenesulfonic acid；Between reactant
Weight proportion be oxide: propionic andydride: acid catalyst=1g:0.3~0.5g:0.05~0.25g；Between reactant and solvent
Proportion be oxide: third organic solvent=1g:1~8ml；
D, synthesize etherate described in the 4th organic solvent be toluene, methylene chloride, chloroform, tetrahydrofuran, dioxane,
One of DME, C4 or less lower alcohol；The acid catalyst of reaction is inorganic acid sulfuric acid, hydrochloric acid or organic acid to toluene sulphur
One of acid, trifluoroacetic acid；Weight proportion between reactant is dibasic acid esters object: triethyl orthoformate: acid catalyst=1g:0.6
~1.2ml:0.05~0.25g；Proportion between reactant and solvent is dibasic acid esters object: four organic solvents=1g:2~8ml.
Further, in the specific steps:
A, synthesizing the first organic solvent described in carboxylate is propionic acid；Reaction temperature is 25~30 DEG C；The acid catalysis of reaction
Agent is p-methyl benzenesulfonic acid；Weight proportion between reactant is 16a- methyl table hydrocortisone: propionic andydride: acid catalyst=1g:
0.4g:0.05g；Proportion between reactant and solvent is 16a- methyl table hydrocortisone: the first organic solvent=1g:2ml；
B, the second organic solvent described in synthesis oxide is glacial acetic acid；Reaction temperature is 20~25 DEG C；The oxidant
It is chromium oxide；Weight proportion between reactant is carboxylate: oxidant=1g:0.4g；Proportion between reactant and solvent is,
Carboxylate: the second organic solvent=1g:5ml；
C, synthesizing third organic solvent described in dibasic acid esters object is propionic acid；Reaction temperature is 30~35 DEG C；The acid catalysis of reaction
Agent is p-methyl benzenesulfonic acid；Weight proportion between reactant is oxide: propionic andydride: acid catalyst=1g:0.4g:0.1g；Reaction
Proportion between object and solvent is oxide: third organic solvent=1g:3ml；
D, synthesizing the 4th organic solvent described in etherate is methylene chloride；The acid catalyst of reaction is p-methyl benzenesulfonic acid；
Reaction temperature is 20~25 DEG C；Weight proportion between reactant is dibasic acid esters object: triethyl orthoformate: acid catalyst=1g:
0.9ml:0.10g；Proportion between reactant and solvent is dibasic acid esters object: four organic solvents=1g:6ml.
Further, in the specific steps:
D, synthesizing antacid alkali in etherate is inorganic base sodium hydroxide, in sodium carbonate or organic base pyridine, triethylamine
One kind；
E, synthesizing the acid catalyst of hydrolysis in reduzate is inorganic acid sulfuric acid, hydrochloric acid or organic acid to toluene sulphur
One of acid.
Further, in the specific steps:
D, synthesizing antacid alkali in etherate is triethylamine；
E, synthesizing the acid catalyst of hydrolysis in reduzate is hydrochloric acid.
Further, in the specific steps:
E, synthesizing the 5th organic solvent described in reduzate is toluene, methylene chloride, chloroform, tetrahydrofuran, C4 or less low
One of carbon alcohol；The reducing agent is one of sodium borohydride, potassium borohydride, calcium borohydride；Weight between reducing agents
Amount proportion is etherate: reducing agent=1g:0.12~0.24g；Weight proportion between hydrolysis reactant is etherate: acid catalysis
Agent=1g:0.2~0.5g；Proportion between reactant and solvent is etherate: five organic solvents=1g:8~16ml.
Further, in the specific steps:
E, synthesizing the 5th organic solvent described in reduzate is methanol；The reducing agent is sodium borohydride；Reduction reaction and
The temperature of hydrolysis is 25~30 DEG C；Weight proportion between reducing agents is etherate: reducing agent=1g:0.16g；
Weight proportion between hydrolysis reactant is etherate: acid catalyst=1g:0.3g；Proportion between reactant and solvent is to be etherified
Object: five organic solvents=1g:12ml.
The beneficial effect comprise that
The present invention is using 16a- methyl table hydrocortisone as raw material, through five step such as esterification, oxidation, double esterification, etherificate, reduction
The reduction rear center body of reaction synthesis Aclovate, present invention process have synthetic route short, process economics environmental protection,
Many advantages, such as production operation is easy, and product yield is high；Solvent used in production can be recycled recycled, easily implement industry
Metaplasia produces.
Detailed description of the invention
Fig. 1 is traditional Aclovate synthetic route chart.
Fig. 2 is Aclovate synthetic route chart of 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 carboxylate: in a 1000ml there-necked flask, being added 100g16a- methyl table hydrocortisone,
200ml propionic acid, 40g propionic andydride, 5g p-methyl benzenesulfonic acid react 6~8 hours in 20~25 DEG C, and TLC confirms reaction end, reaction
After complete, reaction solution is slowly added dropwise to equipped with 2000ml molar concentration be 5% sodium hydroxide solution 5000ml there-necked flask in, in
0~5 DEG C stirring and crystallizing 4~5 hours, filtering, filtrate is discharged into purification tank for liquid waste, and it is 20% that filter cake, which is added to 600ml molar concentration,
Ethanol water in, stirred 5~6 hours at 30~35 DEG C, then be cooled to 0~5 DEG C of stirring and crystallizing 5~6 hours, filter,
Filtrate set is used for lower batch of process for refining, and Washing of Filter Cake is dry, obtains carboxylate: -21 propionic ester of 16a- methyl table hydrocortisone
112g, HPLC content 97.4%, weight yield 112%；
B, in a 1000ml there-necked flask, carboxylate prepared by the above-mentioned A of 100g, 500ml the preparation of oxide: is added
Glacial acetic acid, stirring are allowed to complete molten, and then at 20~25 DEG C of temperature control, it is molten that the oxidant that 40g chromium oxide and 80g water are made into slowly is added dropwise
Liquid, drips off in about 2.5~3 hours, keeps the temperature in 20~25 DEG C that the reaction was continued 1~2 hour after dripping off again, and TLC determines reaction end,
After having reacted, the sodium hydrosulfite of 10g is added to remove excessive oxidant, the glacial acetic acid of recycling about 90% is then concentrated under reduced pressure, then
Be cooled to 20~30 DEG C, 500ml pure water be added, in 0~5 DEG C stirring and crystallizing 3~4 hours, filtering, filtrate is discharged into wastewater treatment
Pond, Washing of Filter Cake is dry, obtains oxide 98g, HPLC content 97.5%, weight yield 98%；
C, in a 1000ml there-necked flask, oxide prepared by the above-mentioned B of 100g, 300ml the preparation of dibasic acid esters object: is added
Propionic acid, 40g propionic andydride, 10g p-methyl benzenesulfonic acid, heat preservation are reacted 6~8 hours at 30~35 DEG C, and TLC confirms reaction end, instead
After having answered, 25~30 DEG C are cooled to, reaction solution is slowly added dropwise to equipped with 2000ml molar concentration is 5% sodium hydroxide solution
In 5000ml there-necked flask, in 0~5 DEG C stirring and crystallizing 4~5 hours, filtering, filtrate is discharged into purification tank for liquid waste, and filter cake washing is done
It is dry, obtain dibasic acid esters object: pregnant -4 alkene -3,7 of steroid of the bis- propionyloxies-of 16a- methyl-17 a, 21-, 11,20- tetrone 113.6g, HPLC contents
98.5%, weight yield 113.6%；
D, in a 1000ml there-necked flask, dibasic acid esters object prepared by the above-mentioned C of 100g, 600ml the preparation of etherate: is added
After methylene chloride, 90ml triethyl orthoformate and 10g p-methyl benzenesulfonic acid, heat preservation are reacted 3~4 hours in 20~25 DEG C, TLC confirmation
Reaction end, after having reacted, it is 6.5~7.5 that suitable triethylamine, which is added, and is neutralized to the pH of solution, reduced pressure recycling 90~
It after 95% methylene chloride, cools to 20~25 DEG C, 500ml pure water is added, it is small in 0~5 DEG C of stirring and crystallizing 1.5~2.5
When, filtering, filtrate is discharged into purification tank for liquid waste, and Washing of Filter Cake is dry, obtain etherate: 3- vinyl alcohol ether -16a- methyl-17 a,
Pregnant steroid -3, the 5- diene -7,11 of the bis- propionyloxies-of 21-, 20- triketone 104g, HPLC content 97.6%, weight yield 104%；
E, the preparation of reduzate: in a 2000ml there-necked flask, being added etherate prepared by the above-mentioned D of 100g,
1200ml methanol is kept the temperature at 25~30 DEG C, and stirring dissolves solid all, then is slowly added into 16g sodium borohydride reduction agent, about
Add within 1.5~2.5 hours, then then at 25~30 DEG C continuation insulation reaction 1~2 hour, TLC confirm reaction end, reacted
Afterwards, the aqueous hydrochloric acid solution that 100g molar concentration is 30% is slowly added dropwise, makes system pH to 2~3, continues to hydrolyze then at 25~30 DEG C
Reaction 2~3 hours, TLC confirm reaction end, and after having reacted, slowly plus appropriate bases are neutralized to system pH to 6~7, then depressurize
90~95% organic solvent methanol of concentration and recovery, then cool down, it is slowly added into 600ml pure water elutriation, is filtered, filtrate is discharged at waste water
Pond is managed, Washing of Filter Cake is dry, obtains reduzate crude product, which is tied again with the alcohol water blend that 500ml molar concentration is 50%
Crystalline substance obtains reduzate: the bis- propionyloxies of 16a- methyl -7,11- dihydroxy -17a, 21--pregn-4-ene-3,20-dione 74.2g,
HPLC content 98.8%, weight yield 74.2%；
F, the preparation of 1- dehydrogen substance: in a 2000ml there-necked flask, being added reduzate prepared by the above-mentioned E of 100g,
1200ml dioxane, 80gDDQ dehydrogenating agent, stirring make it completely dissolved, and are warming up to 75~80 DEG C of insulation reactions 6~10 hours,
TLC confirms reaction end, after having reacted, filters out the quinhydrones that reaction generates, adds suitable solution of sodium bisulfite and destroyed
Then the DDQ of amount is concentrated under reduced pressure 90~95% organic solvent dioxane of recycling, then cools down, be slowly added into 600ml pure water water
Analysis, centrifugation, filtrate are discharged into purification tank for liquid waste, and Washing of Filter Cake is dry, obtain 1- dehydrogen substance crude product, and crude product 500ml is contained 20%
The aqueous solution of 10% caustic soda of alcohol recrystallizes, and obtains 1- dehydrogen substance: the bis- propionyloxies-of 16a- methyl -7,11- dihydroxy -17a, 21-
Pregnant steroid-Isosorbide-5-Nitrae-diene -3,20- diketone 63.8g, HPLC content 98.2%, weight yield 63.8%；
G, in a 2000ml there-necked flask, it is de- that 1- prepared by the above-mentioned F of 100g the preparation of Aclovate: is added
Hydrogen object, 800ml toluene, 200g pyridine add 80g phosphorus trichloride chlorinating agent after heating stirring dissolves solid all, keep the temperature
It is stirred to react in 40~45 DEG C 4~6 hours, TLC confirms reaction end, and after having reacted, it is 30% that 500g molar concentration, which is added,
It is 6~7 that 2 neutralizations of soda bath point, which are washed to aqueous layer pH, after the organic solvent toluene of recycling 90~95% is concentrated under reduced pressure,
Cool to 20~25 DEG C, be added 600ml pure water, in 0~5 DEG C stirring and crystallizing 1.5~2.5 hours, filtering, filtrate is discharged into useless
Water treating pond, Washing of Filter Cake is dry, obtains Aclovate crude product, and crude product 600ml alcohol and 5g active carbon are flowed back
Decoloration 1 hour, filtering, Washing of Filter Cake, filtrate and washing lotion merge the alcohol of concentration 80%, small in 0~5 DEG C of stirred crystallization 3~4
When, processing obtained solid again with methanol-acetone-isopropyl ether=2:1:3 mixed solvent recrystallization obtains Aclovate:
Pregnant steroid-the Isosorbide-5-Nitrae of the chloro- 16a- methyl-1 1- hydroxyl-of 7a--diene -3,20- diketone -17,21- double propionate 64.2g, fusing point: 214~
216 DEG C, HPLC content 99.4%, weight yield 64.2%.
Embodiment 2
A, the preparation of carboxylate: in a 1000ml there-necked flask, being added 100g16a- methyl table hydrocortisone,
500ml chloroform, 40g propionic andydride, 8g p-methyl benzenesulfonic acid react 6~8 hours in 20~25 DEG C, and TLC confirms reaction end, reaction
After complete, it is 50% sodium hydroxide solution that 20ml molar concentration, which is slowly added dropwise, divides the chloroform of reduced pressure recycling 90~95% after water,
Then 500ml pure water is added, in 0~5 DEG C stirring and crystallizing 4~5 hours, filtering, filtrate is discharged into purification tank for liquid waste, filter cake be added to
In the ethanol water that 600ml molar concentration is 20%, stirred 5~6 hours at 30~35 DEG C, then be cooled to 0~5 DEG C of stirring
Crystallization 5~6 hours, filtering, filtrate set was used for lower batch of process for refining, and Washing of Filter Cake is dry, obtained carboxylate: 16a- methyl-table hydrogen
Change -21 propionic ester 109.5g, HPLC content 97.8% of cortisone, weight yield 109.5%；
B, in a 1000ml there-necked flask, carboxylate prepared by the above-mentioned A of 100g, 600ml the preparation of oxide: is added
Acetone, stirring are allowed to complete molten, and then at 20~25 DEG C of temperature control, it is molten that the oxidant that 40g chromium oxide and 80g pure water are made into slowly is added dropwise
Liquid, drips off in about 2.5~3 hours, keeps the temperature in 20~25 DEG C that the reaction was continued 1~2 hour after dripping off again, and TLC confirms reaction end,
After having reacted, the sodium hydrosulfite of 10g is added to remove excessive oxidant, the acetone of recycling about 90% is then concentrated under reduced pressure, then drops
500ml pure water is added to 20~30 DEG C in temperature, in 0~5 DEG C stirring and crystallizing 3~4 hours, filtering, filtrate is discharged into purification tank for liquid waste,
Washing of Filter Cake is dry, obtains oxide 97.4g, HPLC content 96.6%, weight yield 97.4%；
C, in a 1000ml there-necked flask, oxide prepared by the above-mentioned B of 100g, 300ml the preparation of dibasic acid esters object: is added
Chloroform, 40g propionic andydride, 10g p-methyl benzenesulfonic acid, heat preservation are reacted 6~8 hours at 50~55 DEG C, and TLC confirms reaction end, instead
After having answered, 25~30 DEG C are cooled to, it is 30% sodium hydroxide solution that 50ml molar concentration is slowly added dropwise into reaction solution, divides and goes
Water layer, then it is primary with 50ml pure water, divide water to the greatest extent, the solvent chloroform of recycling 90~95% is then concentrated under reduced pressure, adds after cooling
Enter 500ml pure water, in 0~5 DEG C stirring and crystallizing 4~5 hours, filtering, filtrate is discharged into purification tank for liquid waste, filter cake washing, dry, obtains
Dibasic acid esters object: the pregnant Gona-4-ene-3 of the bis- propionyloxies-of 16a- methyl-17 a, 21-, 7,11,20- tetrone 112.2g, HPLC contents
97.8%, weight yield 112.2%；
D, the preparation of etherate: in a 1000ml there-necked flask, being added dibasic acid esters object prepared by the above-mentioned C of 100g,
600mlTHF, 90ml triethyl orthoformate and the 10g concentrated sulfuric acid, heat preservation are reacted 3~4 hours in 20~25 DEG C, and TLC confirmation reaction is eventually
Point after having reacted, is added PH6.5~7.5 that suitable sodium carbonate solid is neutralized to solution, recycling 90~95% is concentrated under reduced pressure
After THF, cool to 20~25 DEG C, be added 500ml pure water, in 0~5 DEG C stirring and crystallizing 1.5~2.5 hours, filtering, filtrate
It is discharged into purification tank for liquid waste, Washing of Filter Cake is dry, obtains etherate: the bis- propionyloxies-of 3- vinyl alcohol ether -16a- methyl-17 a, 21-
Pregnant steroid -3,5- diene -7,11,20- triketone 101.8g, HPLC content 96.4%, weight yield 101.8%；
E, the preparation of reduzate: in a 2000ml there-necked flask, being added etherate prepared by the above-mentioned D of 100g,
1200mlDME is kept the temperature at 25~30 DEG C, and stirring dissolves solid all, then is slowly added into 18g sodium borohydride reduction agent, about
Add within 1.5~2.5 hours, then then at 25~30 DEG C continuation insulation reaction 1~2 hour, TLC confirm reaction end, reacted
Afterwards, the aqueous hydrochloric acid solution that 120g molar concentration is 30% is slowly added dropwise, makes system PH to 2~3, continues to hydrolyze then at 25~30 DEG C
Reaction 2~3 hours, TLC confirm reaction end, and after having reacted, slowly plus appropriate bases are neutralized to system PH to 6~7, then depressurize
90~95% organic solvent DME of concentration and recovery, then cool down, it is slowly added into 600ml pure water elutriation, is filtered, filtrate is discharged at waste water
Pond is managed, Washing of Filter Cake is dry, obtains reduzate crude product, which is tied again with the alcohol water blend that 500ml molar concentration is 50%
Crystalline substance obtains reduzate: the bis- propionyloxies of 16a- methyl -7,11- dihydroxy -17a, 21--pregn-4-ene-3,20-dione 72.6g,
HPLC content 97.2%, weight yield 72.6%；
F, the preparation of 1- dehydrogen substance: in a 2000ml there-necked flask, being added reduzate prepared by the above-mentioned E of 100g,
1200ml toluene, 80gDDQ dehydrogenating agent, stirring make it completely dissolved, and are warming up to 75~80 DEG C of insulation reactions 6~10 hours, TLC
Confirm reaction end, after having reacted, filter out the quinhydrones that reaction generates, it is excessive to add suitable solution of sodium bisulfite destruction
Then DDQ is concentrated under reduced pressure 90~95% organic solvent toluenes of recycling, then cools down, be slowly added into 600ml pure water elutriation, is centrifuged, filter
Liquid is discharged into purification tank for liquid waste, and Washing of Filter Cake is dry, obtains 1- dehydrogen substance crude product, which is burnt with 500ml containing 20% alcohol 10%
The aqueous solution of alkali recrystallizes, and obtains 1- dehydrogen substance: the pregnant steroid-Isosorbide-5-Nitrae-of the bis- propionyloxies-of 16a- methyl -7,11- dihydroxy -17a, 21-
Diene -3,20- diketone 61.5g, HPLC content 97.8%, weight yield 61.5%；
G, in a 2000ml there-necked flask, it is de- that 1- prepared by the above-mentioned F of 100g the preparation of Aclovate: is added
Hydrogen object, 800ml chloroform, 200g triethylamine add 80g phosphorus trichloride chlorinating agent after heating stirring dissolves solid all, protect
Temperature is stirred to react 4~6 hours in 40~45 DEG C, and TLC confirms reaction end, and after having reacted, it is 30% that 500g molar concentration, which is added,
Soda bath point 2 neutralization washing to aqueous layer PH6~7, after the organic solvents, chloroform for recycling 90~95% is concentrated under reduced pressure,
Cool to 20~25 DEG C, be added 600ml pure water, in 0~5 DEG C stirring and crystallizing 1.5~2.5 hours, filtering, filtrate is discharged into useless
Water treating pond, Washing of Filter Cake is dry, obtains Aclovate crude product, which is tied again by G the method in embodiment 1
Crystalline substance obtains Aclovate: pregnant steroid-Isosorbide-5-Nitrae-diene -3, the 20- diketone -17,21- bis- third of the chloro- 16a- methyl-1 1- hydroxyl-of 7a-
Acid esters 61.6g, fusing point: 214~215.5 DEG C, HPLC content 99.3%, weight yield 61.6%.
Embodiment 3
A, the preparation of carboxylate: in a 1000ml there-necked flask, being added 100g16a- methyl table hydrocortisone,
500ml toluene, 40g propionic andydride, 6g trifluoroacetic acid react 6~8 hours in 20~25 DEG C, and TLC confirms reaction end, have reacted
Afterwards, 20ml molar concentration is slowly added dropwise is 50% sodium hydroxide solution, divides the toluene of reduced pressure recycling 90~95% after water, so
500ml pure water is added afterwards, in 0~5 DEG C stirring and crystallizing 4~5 hours, filtering, filtrate is discharged into purification tank for liquid waste, filter cake be added to
In the ethanol water that 600ml molar concentration is 20%, stirred 5~6 hours at 30~35 DEG C, then be cooled to 0~5 DEG C of stirring
Crystallization 5~6 hours, filtering, filtrate set was used for lower batch of process for refining, and Washing of Filter Cake is dry, obtained carboxylate: 16a- methyl-table hydrogen
Change -21 propionic ester 106.8g, HPLC content 97.2% of cortisone, weight yield 106.8%；
B, in a 1000ml there-necked flask, carboxylate prepared by the above-mentioned A of 100g, 600ml the preparation of oxide: is added
Chloroform, stirring are allowed to complete molten, and then at 20~25 DEG C of temperature control, it is molten that the oxidant that 40g chromium oxide and 80g pure water are made into slowly is added dropwise
Liquid, drips off in about 2.5~3 hours, keeps the temperature in 20~25 DEG C that the reaction was continued 1~2 hour after dripping off again, and TLC confirms reaction end,
After having reacted, the sodium hydrosulfite of 10g is added to remove excessive oxidant, the chloroform of recycling about 90% is then concentrated under reduced pressure, then drops
500ml pure water is added to 20~30 DEG C in temperature, in 0~5 DEG C stirring and crystallizing 3~4 hours, filtering, filtrate is discharged into purification tank for liquid waste,
Washing of Filter Cake is dry, obtains oxide 98.2g, HPLC content 97.5%, weight yield 98.2%；
C, in a 1000ml there-necked flask, oxide prepared by the above-mentioned B of 100g, 300ml the preparation of dibasic acid esters object: is added
Toluene, 40g propionic andydride, 12g phosphoric acid, heat preservation are reacted 6~8 hours at 50~55 DEG C, and TLC confirms reaction end, after having reacted,
Be cooled to 25~30 DEG C, be slowly added dropwise into reaction solution 80ml molar concentration be 30% sodium hydroxide solution, branch vibration layer, then
Primary with 50ml pure water, then point most water is concentrated under reduced pressure the solvent toluene of recycling 90~95%, 500ml is added after cooling
Pure water, in 0~5 DEG C stirring and crystallizing 4~5 hours, filtering, filtrate is discharged into purification tank for liquid waste, filter cake washing, dry, obtain dibasic acid esters object:
The pregnant Gona-4-ene-3 of the bis- propionyloxies-of 16a- methyl-17 a, 21-, 7,11,20- tetrone 111.8g, HPLC contents 98.2%, weight
Yield 111.8%；
D, in a 1000ml there-necked flask, dibasic acid esters object prepared by the above-mentioned C of 100g, 600ml the preparation of etherate: is added
Ethyl alcohol, 90ml triethyl orthoformate and 10g trifluoroacetic acid, heat preservation are reacted 3~4 hours in 20~25 DEG C, and TLC confirmation reaction is eventually
Point after having reacted, is added PH6.5~7.5 that suitable pyridine solid is neutralized to solution, the second of recycling 90~95% is concentrated under reduced pressure
After alcohol, cool to 20~25 DEG C, be added 500ml pure water, in 0~5 DEG C stirring and crystallizing 1.5~2.5 hours, filtering, filtrate
It is discharged into purification tank for liquid waste, Washing of Filter Cake is dry, obtains etherate: the bis- propionyloxies-of 3- vinyl alcohol ether -16a- methyl-17 a, 21-
Pregnant steroid -3,5- diene -7,11,20- triketone 102.6g, HPLC content 96.8%, weight yield 102.6%；
E, the preparation of reduzate: in a 2000ml there-necked flask, being added etherate prepared by the above-mentioned D of 100g,
1200mlTHF is kept the temperature at 25~30 DEG C, and stirring dissolves solid all, then is slowly added into 18g potassium borohydride reduction agent, about
Add within 1.5~2.5 hours, then then at 25~30 DEG C continuation insulation reaction 1~2 hour, TLC confirm reaction end, reacted
Afterwards, the aqueous sulfuric acid that 100g molar concentration is 50% is slowly added dropwise, makes system pH to 2~3, continues to hydrolyze then at 25~30 DEG C
Reaction 2~3 hours, TLC confirm reaction end, and after having reacted, slowly plus appropriate bases are neutralized to system pH to 6~7, then depressurize
90~95% organic solvent THF of concentration and recovery, then cool down, it is slowly added into 600ml pure water elutriation, is filtered, filtrate is discharged at waste water
Pond is managed, Washing of Filter Cake is dry, obtains reduzate crude product, which is tied again with the alcohol water blend that 500ml molar concentration is 50%
Crystalline substance obtains reduzate: the bis- propionyloxies of 16a- methyl -7,11- dihydroxy -17a, 21--pregn-4-ene-3,20-dione 70.8g,
HPLC content 97.6%, weight yield 70.8%；
F, the preparation of 1- dehydrogen substance: in a 2000ml there-necked flask, being added reduzate prepared by the above-mentioned E of 100g,
1200ml ethyl acetate, 85gDDQ dehydrogenating agent, stirring make it completely dissolved, and are warming up to 75~80 DEG C of insulation reactions 6~10 hours,
TLC confirms reaction end, after having reacted, filters out the quinhydrones that reaction generates, adds suitable solution of sodium bisulfite and destroyed
Then the DDQ of amount is concentrated under reduced pressure 90~95% organic solvent ethyl acetate of recycling, then cools down, be slowly added into 600ml pure water water
Analysis, centrifugation, filtrate are discharged into purification tank for liquid waste, and Washing of Filter Cake is dry, obtain 1- dehydrogen substance crude product, and crude product 500ml is contained 20%
The aqueous solution of 10% caustic soda of alcohol recrystallizes, and obtains 1- dehydrogen substance: the bis- propionyloxies-of 16a- methyl -7,11- dihydroxy -17a, 21-
Pregnant steroid-Isosorbide-5-Nitrae-diene -3,20- diketone 62.4g, HPLC content 97.2%, weight yield 62.4%；
G, in a 2000ml there-necked flask, it is de- that 1- prepared by the above-mentioned F of 100g the preparation of Aclovate: is added
Hydrogen object, 800ml toluene, 200g pyridine add 80g thionyl chloride chlorinating agent after heating stirring dissolves solid all, keep the temperature
It is stirred to react in 40~45 DEG C 4~6 hours, TLC confirms reaction end, and after having reacted, it is 30% that 500g molar concentration, which is added,
2 neutralizations of soda bath point washing is cold after the organic solvent toluene of recycling 90~95% is concentrated under reduced pressure to aqueous layer PH6~7
But be cooled to 20~25 DEG C, 600ml pure water be added, in 0~5 DEG C stirring and crystallizing 1.5~2.5 hours, filtering, filtrate is discharged into waste water
Processing pond, Washing of Filter Cake is dry, obtains Aclovate crude product, which is recrystallized by G the method in embodiment 1,
Obtain Aclovate: the double propionic acid of the chloro- 16a- methyl-1 1- hydroxyl of 7a--pregnant steroid -1,4- diene -3,20- diketone -17,21-
Ester 62.8g, fusing point: 214~215.5 DEG C, HPLC content 99.2%, weight yield 62.8%.
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 (8)
1. it is a kind of prepare Aclovate reduction rear center body method, which is characterized in that the method includes with
16a- methyl table hydrocortisone is raw material, and through 21 propionates, 7,11 dual oxides are at diketone, 17 propionates, 3
Enolization etherification protection, 7,11 diketones restore and sour water solution is deprotected totally five steps reaction and synthesizes going back for Aclovate
Former rear center body, specific steps include:
A, synthesize carboxylate, be using 16a- methyl table hydrocortisone as raw material, by its in the first organic solvent with propionic andydride
Under acid catalyst catalysis, esterification occurs for 21 hydroxyls, obtains carboxylate: -21 propionic acid of 16a- methyl table hydrocortisone
Ester；
B, synthesis oxide, be by carboxylate containing acid the second organic solvent in oxidant with 11a hydroxyl in molecule and 7
7,11 oxidation reactions occur for active hydrogen, obtain oxide: 16a- methyl-17 a- hydroxyl -21- propionyloxy--4 alkene -3,7 of pregnant steroid,
11,20- tetrone；
C, synthesize dibasic acid esters object, be by oxide in third organic solvent with propionic andydride acid catalyst catalysis under, 17a- hydroxyl
Esterification occurs and generates dibasic acid esters object: the pregnant Gona-4-ene-3 of the bis- propionyloxies-of 16a- methyl-17 a, 21-, 7,11,20- tetrone；
D, synthesize etherate, be by dibasic acid esters object in the 4th organic solvent with triethyl orthoformate acid catalyst catalysis under with point
The reaction of enol form etherification protection occurs for the ketone group in the 3- ketone -4- alkene structure in son, obtains etherate: 3- vinyl alcohol ether -16a-
Pregnant steroid -3,5- diene -7,11,20- the triketone of the bis- propionyloxies-of methyl-17 a, 21-；
E, reduzate is synthesized, is that etherate occurs also with reducing agent in molecule 7,11 ketone groups in the 5th organic solvent
Original reaction, and be deprotected under acid catalysis, obtain the reduction rear center body of the i.e. Aclovate of reduzate: 16a- methyl-
The pregnant Gona-4-ene-3 of the bis- propionyloxies-of 7,11- dihydroxy -17a, 21-, 20- diketone.
2. the method according to claim 1, wherein the method specific steps are as follows:
A, it synthesizes carboxylate: being that 16a- methyl table hydrocortisone is dissolved in the first organic solvent, add at 10~50 DEG C
Enter propionic andydride, acid catalyst catalysis lower reaction 6~8 hours, TLC confirmed reaction end, after having reacted, adds alkali neutralization, depressurizes back
Organic solvent is received, is then crystallized with ethanol water, dry carboxylate: -21 propionic ester of 16a- methyl table hydrocortisone,
HPLC content 97.0~98.5%, weight yield 110~115%；
B, synthesis oxide: being to dissolve in above-mentioned carboxylate in the second organic solvent, at 10~50 DEG C, in 2~3 hours slowly
Oxidant is added dropwise, keeps the temperature in 10~50 DEG C that the reaction was continued 1~2 hour after dripping off again, TLC confirms reaction end, after having reacted, adds
Enter suitable sodium hydrosulfite to remove excessive oxidant, 90~95% organic solvents of recycling are concentrated under reduced pressure, then cool down elutriation, from
The heart, filtrate are discharged into purification tank for liquid waste, filtration cakes torrefaction, obtain oxide, HPLC content 95.0~98.5%, and weight yield 95~
100%；
C, it synthesizing dibasic acid esters object: being to dissolve in above-mentioned oxide in third organic solvent, propionic andydride is added at 10~80 DEG C in heat preservation,
Acid catalyst catalysis lower reaction 6~8 hours, TLC confirmed reaction end, after having reacted, is cooled to 25~30 DEG C, is added suitable
Alkali neutralization cools after the organic solvent of recycling 90~95% is concentrated under reduced pressure to 10~25 DEG C to pH6.5~7.5 of solution,
Pure water is added, stirring and crystallizing 1.5~2.5 hours, centrifugation, filtrate was discharged into purification tank for liquid waste, and Washing of Filter Cake is dry, obtain dibasic acid esters object:
The pregnant Gona-4-ene-3 of the bis- propionyloxies-of 16a- methyl-17 a, 21-, 7,11,20- tetrones, HPLC content 98.0~99.0%, weight
Yield 110~115%；
D, it synthesizes etherate: being to dissolve in above-mentioned dibasic acid esters object in the 4th organic solvent, triethyl orthoformate and acid catalyst is added,
It keeps the temperature and is reacted 3~4 hours in 10~80 DEG C, TLC confirms reaction end, and after having reacted, suitable alkali neutralization is added to solution
PH6.5~7.5 cool after the organic solvent of recycling 90~95% is concentrated under reduced pressure to 10~25 DEG C, and pure water, stirring is added
Crystallization 1.5~2.5 hours, centrifugation, filtrate was discharged into purification tank for liquid waste, and Washing of Filter Cake is dry, obtained etherate: 3- vinyl alcohol ether-
Pregnant steroid -3, the 5- diene -7,11 of the bis- propionyloxies-of 16a- methyl-17 a, 21-, 20- triketone, HPLC content 97.0~99.0%, weight
Measure yield 100~105%；
E, it synthesizes reduzate: being that above-mentioned etherate is dissolved in the 5th organic solvent, keep the temperature at 10~80 DEG C, be slowly added into
Reducing agent adds for 1.5~2.5 hours, then then at 10~80 DEG C continuation insulation reaction 1~2 hour, TLC confirm reaction end,
After having reacted, suitable acid catalyst aqueous solution is slowly added dropwise, makes system pH to 2~3, then at 10~80 DEG C of continuation hydrolysis
2~3 hours, TLC confirmed reaction end, and after having reacted, slowly plus appropriate bases are neutralized to system pH to 6~7, are then concentrated under reduced pressure
90~95% organic solvents are recycled, then are cooled down, pure water elutriation is slowly added into, are centrifuged, filtrate is discharged into purification tank for liquid waste, and filter cake is dry
Dry, obtain the reduction rear center body of Aclovate: the bis- propionyloxies-of 16a- methyl -7,11- dihydroxy -17a, 21- are pregnant
Gona-4-ene-3,20- diketone.
3. method according to claim 1 or 2, which is characterized in that in the specific steps:
A, synthesizing the first organic solvent described in carboxylate is propionic andydride, toluene, propionic acid, chloroform, DME, one in dioxane
Kind；The acid catalyst of reaction is one of inorganic acid sulfuric acid, hydrochloric acid or organic acid p-methyl benzenesulfonic acid；Weight between reactant
Amount proportion is 16a- methyl table hydrocortisone: propionic andydride: acid catalyst=1g:0.3~0.5g:0.01~0.15g；Reaction
Proportion between object and solvent is 16a- methyl table hydrocortisone: the first organic solvent=1g:1~5ml；
B, the second organic solvent described in synthesis oxide is toluene, acetone, chloroform, DME, tetrahydrofuran, DMSO, dioxy six
One of ring, glacial acetic acid；The oxidant is one of chromium oxide, PPC, hypohalogenous acids sodium；Weight proportion between reactant
It is carboxylate: oxidant=1g:0.2~0.8g；Proportion between reactant and solvent is carboxylate: the second organic solvent=
1g:3~10ml；
C, synthesizing third organic solvent described in dibasic acid esters object is propionic andydride, toluene, propionic acid, chloroform, DME, one in dioxane
Kind；The acid catalyst of reaction is one of inorganic acid sulfuric acid, hydrochloric acid or organic acid p-methyl benzenesulfonic acid；Weight between reactant
Amount proportion is oxide: propionic andydride: acid catalyst=1g:0.3~0.5g:0.05~0.25g；Matching between reactant and solvent
Than being, oxide: third organic solvent=1g:1~8ml；
D, synthesize etherate described in the 4th organic solvent be toluene, methylene chloride, chloroform, tetrahydrofuran, dioxane, DME,
One of C4 or less lower alcohol；The acid catalyst of reaction is inorganic acid sulfuric acid, hydrochloric acid or organic acid p-methyl benzenesulfonic acid, three
One of fluoroacetic acid；Weight proportion between reactant is dibasic acid esters object: triethyl orthoformate: acid catalyst=1g:0.6~
1.2ml:0.05~0.25g；Proportion between reactant and solvent is dibasic acid esters object: four organic solvents=1g:2~8ml.
4. according to the method described in claim 3, it is characterized in that, in the specific steps:
A, synthesizing the first organic solvent described in carboxylate is propionic acid；Reaction temperature is 25~30 DEG C；The acid catalyst of reaction is
P-methyl benzenesulfonic acid；Weight proportion between reactant is 16a- methyl table hydrocortisone: propionic andydride: acid catalyst=1g:
0.4g:0.05g；Proportion between reactant and solvent is 16a- methyl table hydrocortisone: the first organic solvent=1g:2ml；
B, the second organic solvent described in synthesis oxide is glacial acetic acid；Reaction temperature is 20~25 DEG C；The oxidant is oxygen
Change chromium；Weight proportion between reactant is carboxylate: oxidant=1g:0.4g；Proportion between reactant and solvent is to be esterified
Object: the second organic solvent=1g:5ml；
C, synthesizing third organic solvent described in dibasic acid esters object is propionic acid；Reaction temperature is 30~35 DEG C；The acid catalyst of reaction is
P-methyl benzenesulfonic acid；Weight proportion between reactant is oxide: propionic andydride: acid catalyst=1g:0.4g:0.1g；Reactant with
Proportion between solvent is oxide: third organic solvent=1g:3ml；
D, synthesizing the 4th organic solvent described in etherate is methylene chloride；The acid catalyst of reaction is p-methyl benzenesulfonic acid；Reaction
Temperature is 20~25 DEG C；Weight proportion between reactant is dibasic acid esters object: triethyl orthoformate: acid catalyst=1g:0.9ml:
0.10g；Proportion between reactant and solvent is dibasic acid esters object: four organic solvents=1g:6ml.
5. according to the method described in claim 2, it is characterized in that, in the specific steps:
D, synthesizing antacid alkali in etherate is inorganic base sodium hydroxide, one in sodium carbonate or organic base pyridine, triethylamine
Kind；
E, synthesizing the acid catalyst of hydrolysis in reduzate is in inorganic acid sulfuric acid, hydrochloric acid or organic acid p-methyl benzenesulfonic acid
One kind.
6. according to the method described in claim 5, it is characterized in that, in the specific steps:
D, synthesizing antacid alkali in etherate is triethylamine；
E, synthesizing the acid catalyst of hydrolysis in reduzate is hydrochloric acid.
7. method according to claim 1 or 2, which is characterized in that in the specific steps:
E, synthesizing the 5th organic solvent described in reduzate is toluene, methylene chloride, chloroform, tetrahydrofuran, C4 or less low-carbon alcohols
One of；The reducing agent is one of sodium borohydride, potassium borohydride, calcium borohydride；Weight between reducing agents is matched
Than being, etherate: reducing agent=1g:0.12~0.24g；Weight proportion between hydrolysis reactant is etherate: acid catalyst=
1g:0.2~0.5g；Proportion between reactant and solvent is etherate: five organic solvents=1g:8~16ml.
8. the method according to the description of claim 7 is characterized in that in the specific steps:
E, synthesizing the 5th organic solvent described in reduzate is methanol；The reducing agent is sodium borohydride；Reduction reaction and hydrolysis
The temperature of reaction is 25~30 DEG C；Weight proportion between reducing agents is etherate: reducing agent=1g:0.16g；Hydrolysis
Weight proportion between reactant is etherate: acid catalyst=1g:0.3g；Proportion between reactant and solvent is etherate:
Five organic solvents=1g:12ml.
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