CN106632561A - Method for preparing difluprednate - Google Patents
Method for preparing difluprednate Download PDFInfo
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- CN106632561A CN106632561A CN201611195527.XA CN201611195527A CN106632561A CN 106632561 A CN106632561 A CN 106632561A CN 201611195527 A CN201611195527 A CN 201611195527A CN 106632561 A CN106632561 A CN 106632561A
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- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—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 not substituted in position 16
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Abstract
The invention discloses a method for preparing difluprednate. The difluprednate is synthesized from a raw material hydrocortisone-21-acetate. The raw material is readily available and relatively low-cost. A synthesis line comprising eight steps is relatively short, cost is relatively low, reaction conditions are mild, yield is relatively high, and industrial production is convenient.
Description
Technical field
The present invention relates to field of medicinal compositions, is exactly a kind of preparation method of Difluprednate.
Background technology
Difluprednate is the bifluoride derivative of corticosteroid prednisolone, with stronger anti-inflammatory and analgesic effect.
He is the gel and creme of Pfizer companies exploitation originally, and 2006 by Sirion companies from Japanese Senju Pharma Co., Ltd
The mandate of the ophthalmic emulsion for obtaining.The Difluprednate eye-drops preparations of U.S.'s listing at present is that Sirion Therapeutics are public
Department's production, the 0.05% Difluprednate ophthalmic emulsion of trade name Durezol, for treating post-operation inflammatory and pain.Two
Fluorine sprinkles the III clinical trial phases of Buddhist nun's ester ophthalmic emulsion and obtains certainty result, and the medicine can quickly solve eye in this test
The postoperative inflammation of eye section of section, it is both effective and safe.The unique texture of the medicine is that drug ingedient can rapidly enter steroids cutin
Layer, can faster solve the inflammation and front waterproof flash of light problem of anterior chamber's cell.The medicine market prospects are very wide.
The preparation method of present either external Difluprednate or the preparation method of domestic Difluprednate, all
Shortcomings, need to be improved in technique.
The content of the invention
For drawbacks described above, present invention solves the technical problem that be that a kind of preparation method of Difluprednate is provided, it is former
Material hydrocortisone -21- acetates are easily obtained and price is relatively low, and synthetic route is shorter, and cost is relatively low, and reaction condition is gentle,
Yield is higher, is easy to industrial production.
In order to solve the technical problem of the above, the preparation method of the Difluprednate of the present invention comprises the steps：
Step one：Synthetic intermediate two
Hydrocortisone -21- acetates are added in container, DMF and pyridine is added, stirring, solid is insoluble, slow to heat up
To 40-60 DEG C, Fumette is added dropwise to, is in faint yellow turbid solution after finishing, be warming up to 60-100 DEG C, reactant liquor first becomes after clarification
Become cloudy, react 1-3h, monitoring reaction terminates, and stops heating, is down to room temperature, adds to crystallization in methyl alcohol, is cooled to -5-5 DEG C and stirs
Filter after mixing, obtain the solid intermediate two of white, the pregnant α of steroid -17 of 4,9 (11)-diene, 21- dihydroxy -3,20- diketone -21-
Acetic acid esters；
Step 2：Synthetic intermediate three
Intermediate two and DMAP, pyridine and acetonitrile are added in container, adds butyric anhydride, stirring to be warming up to 60-100
Reaction is monitored after DEG C reaction 20-30h to terminate, be down to room temperature, concentrate acetonitrile, be down to be stirred at room temperature after 0.5-2h and filter, with a small amount of
Solvent is washed, and obtains the solid intermediate three of white, the α of 4,9 (11)-diene -17,21- dihydroxy -3,20- diketone -21- acetic acid
The iophenoxic acid ester of ester 17
Step 3：Synthetic intermediate four
Intermediate three and dioxane are added in container, nitrogen displacement, add DDQ and tert-butyldimethylsilyl chloride silicon
Alkane, overnight, monitoring reaction terminates stirring reaction, concentrates dioxane, is dissolved with DCM, filters insoluble matter, then under room temperature condition
Washed with saturated sodium bicarbonate solution, saturated common salt water washing concentrates DCM after anhydrous sodium sulfate drying, obtain brown oil,
Column chromatography obtains the solid intermediate four of white, pregnant steroid-Isosorbide-5-Nitrae, 9 (11)-triolefin -3, the iophenoxic acid of 20- diketone -21- acetic acid esters -17
Ester；
Step 4：Synthetic intermediate five
Intermediate four and methylvinyl acetate are added in container, the concentrated sulfuric acid is slowly added dropwise, drop finishes after stirring 10-30min
60-100 DEG C of reaction 0.5-3h is warming up to, monitoring reaction terminates, and is cooled to 30-40 DEG C, adds triethylamine that reaction is quenched, and adds
Water, is extracted 2-6 time, saturated common salt water washing, anhydrous sodium sulfate with EA, and concentration EA obtains brown oil, obtains after column chromatography
The solid intermediate four of white, (11)-tetraene -3 of pregnant steroid 1,3,5,9,20- diketone -3, the iophenoxic acid ester of 21- diacetate esters -17；
Step 5：Synthetic intermediate six
Intermediate five and acetonitrile are added in container, -10-5 DEG C is cooled to, Selectfluor reagents is added with acetonitrile
Mixture, finishes, and insulated and stirred reaction 3-6h, monitoring reaction terminates, and adds water, EA extractions to separate EA layers, saturated common salt washing
Wash, anhydrous sodium sulfate drying, concentrate EA, obtain light brown yellow solid DL body；DL body and acetic acid are added in another container,
HCl gases are passed through, until solid is completely dissolved, continue stirring reaction 4-6h, monitoring reaction terminates, and adds elutriation brilliant, filters, and obtains
To the solid intermediate six of brown, pregnant steroid-Isosorbide-5-Nitrae, 9 (11)-triolefin -3, the fluoro- 17 iophenoxic acid esters of 20- diketone -21- acetic acid esters -6-；
Step 6：Synthetic intermediate seven
Intermediate six and dioxane are added in container, adds perchloric acid, stirring to be slowly added to NBS, solution clarification, room
3-8h is reacted under the conditions of temperature, monitoring reaction terminates, and reaction is quenched with sodium sulfite solution, adds water, EA extractions to separate EA layers,
Saturated common salt water washing, anhydrous sodium sulfate drying concentrates EA, obtains intermediate seven, 6 α-fluoro- 9 β-bromo- 11 beta-hydroxies-Isosorbide-5-Nitrae-two
Alkene-pregnant steroid -3, the iophenoxic acid ester of 20- diketone -21- acetic acid esters -17；
Step 7：Synthetic intermediate eight
Intermediate seven and acetone are added in container, sodium carbonate is added, back flow reaction is warming up to overnight, monitoring reaction knot
Beam, adds water, EA extractions to separate EA layers, and saturated common salt water washing, anhydrous sodium sulfate drying concentrates EA, obtains brown oil
Thing, column chromatography obtains the solid intermediate eight of white, 6 α-fluoro- 9 β, 11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid -3,20- diketone -21-
The iophenoxic acid ester of acetic acid esters -17；
Step 8：Synthesis Difluprednate
Intermediate eight and polytetrafluoroethylene (PTFE) are added in reaction bulb, -30--20 DEG C is cooled to, HF pyridine solutions are added, is protected
Warm stirring reaction 2-6h, monitoring reaction terminates, and with 20% sodium hydroxide solution pH to 7-8 is adjusted, then with pickling, saturated aqueous common salt
Wash, separate DCM layers, DCM is concentrated after anhydrous sodium sulfate drying, obtain the liquid of brown yellow oil, column chromatography obtains white solid
Finished product Difluprednate, 6 α, 9 α-fluoro- 11 beta-hydroxy -4- alkene-pregnant steroid -3,20- diketone -17- butyrate -20- acetic acid esters.
Preferably, in step one, the acetate of hydrocortisone -21 is added in three mouthfuls of reaction bulbs, adds DMF and pyrrole
Pyridine, stirring, solid is insoluble, is to slowly warm up to 50 DEG C, is added dropwise to mesyl chloride, is warming up to 80-85 DEG C, reacts 1-3h, TLC monitoring
Reaction terminates, and stops heating, is down to room temperature, is down to and adds to crystallization in methyl alcohol, is cooled to after 0 DEG C of stirring 1h and filters, and obtains white
Solid intermediate two, wherein, the molar equivalent of the acetate of hydrocortisone -21 and mesyl chloride is 1: 1.2-2.8, pyridine
Molar equivalent is 3-5, and DMF is 5ml/g-15ml/g.
Preferably, in step 2, intermediate two and DMAP, pyridine and acetonitrile are added in there-necked flask, adds butyric acid
Acid anhydride, stirring, after being warming up to 80-85 DEG C of reaction 22-25h, TLC monitoring reactions terminate, and are down to room temperature, concentrate acetonitrile, are down to room temperature
Filter after stirring 1h, washed with a small amount of acetonitrile, obtain the solid intermediate three of white, wherein, intermediate two rubs with butyric anhydride
Your ratio is catalytic amount for 1: 10-20, DMAP, and the molar equivalent of pyridine is 6-11, and acetonitrile equivalent is 5ml/g-10ml/g.
Preferably, in step 3, intermediate three and dioxane are added in there-necked flask, nitrogen displacement, add DDQ and
Tert-butyl chloro-silicane, overnight, TLC monitoring reactions terminate stirring reaction, concentrate dioxane, use DCM under room temperature condition
Dissolving, filters insoluble matter, is then washed with saturated sodium bicarbonate solution, and saturated common salt water washing is dense after anhydrous sodium sulfate drying
Contracting DCM, obtains brown oil, and column chromatography obtains the solid intermediate four of white, wherein, intermediate three：The molar ratio of DDQ
For 1: 1.2-3, tert-butyl chloro-silicane is catalytic amount.
Preferably, in step 4, intermediate four and methylvinyl acetate are added in there-necked flask, are slowly added dropwise the concentrated sulfuric acid,
80-85 DEG C of reaction 0.5-2h is warming up to after the complete stirring 15min of drop, TLC monitoring reactions terminate, and are cooled to 32-37 DEG C, add three second
Amine is quenched reaction, adds water, is extracted 3 times with EA, saturated common salt water washing, anhydrous sodium sulfate, and concentration EA obtains brown oil,
The solid intermediate five of white is obtained after column chromatography, wherein, intermediate four, methylvinyl acetate, the concentrated sulfuric acid and triethylamine rub
You are than being 1: 2-10: 0.05-1: 0.5-10.
Preferably, in step 5, intermediate five and acetonitrile are added in there-necked flask, is cooled to -10-5 DEG C, added
Selectfluor reagents and the mixture of acetonitrile, finish, and insulated and stirred reaction 4-6h, TLC monitoring reactions terminate, and add water, EA
Extraction, separates EA layers, and saturated common salt water washing, anhydrous sodium sulfate drying concentrates EA, obtains light brown yellow solid DL body；Will
DL body is added in another there-necked flask with acetic acid, is passed through HCl gases, until solid is completely dissolved, continues stirring reaction 4-6h,
TLC monitoring reactions terminate, and add elutriation brilliant, filter, and obtain the solid intermediate six of brown, wherein, intermediate five with
The molar equivalent of Selectfluor reagents is 1: 1.1-3, and DL body is 1: 5-10 with the molar equivalent of acetic acid.
Preferably, in step 6, intermediate six and dioxane are added in there-necked flask, adds perchloric acid, stir 5-
After 40min, NBS is slowly added to, 4-6h is reacted in solution clarification under room temperature condition, TLC monitoring reactions terminate, molten with sodium sulfite
Liquid is quenched reaction, adds water, EA extractions to separate EA layers, and saturated common salt water washing, anhydrous sodium sulfate drying concentrates EA, in obtaining
Mesosome seven, wherein, the molar equivalent of intermediate six, perchloric acid and NBS is 1: 0.5-1: 3-5.
Preferably, in step 7, intermediate seven and acetone are added in there-necked flask, adds sodium carbonate, be warming up to backflow anti-
Should overnight, TLC monitoring reactions terminate, and add water, EA extractions to separate EA layers, saturated common salt water washing, anhydrous sodium sulfate drying,
Concentration EA, obtains brown oil, and column chromatography obtains the solid intermediate eight of white, wherein, intermediate seven rubs with sodium carbonate
Your equivalent is 1: 2-5.
Preferably, in step 8, intermediate eight and polytetrafluoroethylene (PTFE) are added in reaction bulb, is cooled to -30--20 DEG C, plus
Enter HF pyridine solutions, insulated and stirred reaction 2-6h, TLC monitoring reactions terminate, with sodium hydroxide solution pH to 7-8 is adjusted, then with acid
Wash, saturated common salt washing separates DCM layers, and DCM is concentrated after anhydrous sodium sulfate drying, obtains the liquid of brown yellow oil, column chromatography
White solid finished product Difluprednate is obtained, wherein, intermediate eight is 1: 50-150 with the molar equivalent of fluorination reagent.
The present invention relates to certain some technical term it is as follows：
DCM：Dichloromethane；
DMF：DMF；
DMAP：Dimethylamino naphthyridine；
EA：Ethyl acetate；
Selectfluor reagents：Double (tetrafluoro boric acid) salt of the fluoro- ring 2.2.2 octanes of Isosorbide-5-Nitrae-diazotising two of 1- chloromethyl -4-；
DDQ：DDQ；
NBS：N-bromosuccinimide.
Compared with prior art, the preparation method of Difluprednate of the invention, raw material hydrocortisone -21- acetates
Easily it is obtained and price is relatively low, synthetic route is shorter, and cost is relatively low, reaction condition is gentle, and yield is higher, is easy to industrial life
Produce.
Specific embodiment
In order to those skilled in the art better understood when technical scheme provided by the present invention, with reference to concrete
Embodiment is illustrated.
This case can be illustrated by below example and is fully understood so that the personage for being familiar with this skill can be according to this
It is completed, the embodiment of right this case not can be by following and limited its and implement kenel.
The preparation method of the Difluprednate of the present embodiment is as follows：
The first step：Intermediate 2：The pregnant α of steroid -17 of 4,9 (11)-diene, 21- dihydroxy -3,20- diketone -21- acetic acid esters
The acetate of 20.2g hydrocortisones -21 is added in tri- mouthfuls of reaction bulbs of 250ml, 100mlDMF and 17.4g pyrroles are added
Pyridine, stirring, solid is insoluble, is to slowly warm up to 50 DEG C or so, is added dropwise to 14.9g mesyl chlorides, in faint yellow after being added completely into.Rise
To 82 DEG C, reactant liquor first becomes and become cloudy after clarification temperature, reacts 2h, and TLC monitoring reactions terminate, and stop heating, are down to room temperature, will be anti-
Answer liquid to add to crystallization in 300ml methyl alcohol, be cooled to after 0 DEG C or so stirring 1h and filter, obtain white solid 18.5g, yield
95.85%, purity >=98%.
Second step：Intermediate 3：The α of 4,9 (11)-diene -17,21- dihydroxy -3, the iophenoxic acid of 20- diketone -21- acetic acid esters 17
Ester
9.7g intermediates 2 and 0.97gDMAP, 14.8g pyridine and 50ml acetonitriles are added in 250ml there-necked flasks, is added
59.8g butyric anhydrides, stirring is warming up to TLC monitoring reactions after 83 DEG C of reaction 23h and terminates, and is down to room temperature, concentrates acetonitrile, is down to room
Filter after temperature stirring 1h, washed with a small amount of acetonitrile, obtain white solid 10.3g, yield 90%, purity >=98%.
3rd step：Intermediate 4：Pregnant steroid-Isosorbide-5-Nitrae, 9 (11)-triolefin -3, the iophenoxic acid ester of 20- diketone -21- acetic acid esters -17
9.1 intermediates 3 and 45ml dioxane are added in 100ml there-necked flasks, nitrogen displacement, add 6.8gDDQ and
The tert-butyl chloro-silicane of catalytic amount, overnight, TLC monitoring reactions terminate stirring reaction, concentrate dioxy six under room temperature condition
Ring, is dissolved with DCM, filters insoluble matter, is then washed with saturated sodium bicarbonate solution, saturated common salt water washing, anhydrous sodium sulfate
DCM is concentrated after drying, brown oil is obtained, column chromatography obtains white solid 7.7g, yield 85%, purity >=98%.
4th step：Intermediate 5：(11)-tetraene -3 of pregnant steroid 1,3,5,9,20- diketone -3, the iophenoxic acid of 21- diacetate esters -17
Ester
4.5g intermediates 4 and 36ml methylvinyl acetates are added in 100ml there-necked flasks, the 0.5ml concentrated sulfuric acids are slowly added dropwise,
85 DEG C of reaction 1h are warming up to after the complete stirring 15min of drop, TLC monitoring reactions terminate, and are cooled to 35 DEG C or so, add 2ml triethylamines
Reaction is quenched, water is added, is extracted 3 times with EA, saturated common salt water washing, anhydrous sodium sulfate, concentration EA obtains brown oil, post
White solid 4.0g, yield 80.65%, purity >=97% are obtained after chromatography.
5th step：Intermediate 6：Pregnant steroid-Isosorbide-5-Nitrae, 9 (11)-triolefin -3, fluoro- 17 iophenoxic acids of 20- diketone -21- acetic acid esters -6-
Ester
3.7g intermediates 5 and 20ml acetonitriles are added in 50ml there-necked flasks, -6 DEG C are cooled to, is added
3.2gSelectfluor reagents and the mixture of 6ml acetonitriles, finish, and insulated and stirred reaction 5h, TLC monitoring reactions terminate, and add
Water, EA extractions separate EA layers, and saturated common salt water washing, anhydrous sodium sulfate drying concentrates EA, obtains light brown yellow solid 3.2g
DL body；DL body and 16ml acetic acid are added in 100ml there-necked flasks, HCl gases are passed through, until solid is completely dissolved, is continued
Stirring reaction 5h, TLC monitoring reactions terminate, and add elutriation brilliant, filter, and obtain brown solid 3.0g, yield 80%, and purity >=
98%.
6th step：Intermediate 7：6 α-fluoro- 9 β-bromo- 11 beta-hydroxies-Isosorbide-5-Nitrae-diene-pregnant steroid -3,20- diketone -21- acetic acid
The iophenoxic acid ester of ester -17
2.4g intermediates 6 and 12ml dioxane are added in 50ml there-necked flasks, 0.5g perchloric acid is added, 15min is stirred
Afterwards, 2.85gNBS is slowly added to, 5h is reacted in solution clarification under room temperature condition, TLC monitoring reactions terminate, and use 10% sodium sulfite
Solution is quenched reaction, adds water, EA extractions to separate EA layers, and saturated common salt water washing, anhydrous sodium sulfate drying concentrates EA, obtains
Sterling 2.3g, yield 80%, purity purity >=98%.
7th step：Intermediate 8：6 α-fluoro- 9 β, 11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid -3,20- diketone -21- acetic acid esters -17
Iophenoxic acid ester
1.7g intermediates 7 and 17ml acetone are added in 50ml there-necked flasks, 0.6g sodium carbonate is added, back flow reaction is warming up to
Overnight, TLC monitoring reaction terminates, and adds water, EA extractions to separate EA layers, and saturated common salt water washing, anhydrous sodium sulfate drying is dense
Contracting EA, obtains brown oil, and column chromatography obtains white solid 1.2g, yield 82%, purity >=99.0%
8th step：Difluprednate：6 α, 9 α-fluoro- 11 beta-hydroxy -4- alkene-pregnant steroid -3,20- diketone -17- butyrate -20-
Acetic acid esters
200mg intermediates 8 and 5ml are added in 50ml polytetrafluoroethylene (PTFE) reaction bulbs, -25 DEG C are cooled to, the HF of 2ml is added
Pyridine solution, insulated and stirred reaction 4h, TLC monitoring reactions terminate, and pH is adjusted to 7.5 with 30% sodium hydroxide solution, then with acid
Wash, saturated common salt washing separates DCM layers, and DCM is concentrated after anhydrous sodium sulfate drying, obtains the liquid of brown yellow oil, column chromatography
Obtain 160mg white solids, yield 80%, purity >=99.0%.
The foregoing description of the disclosed embodiments, enables professional and technical personnel in the field to realize or using the present invention.
Various modifications to these embodiments will be apparent for those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.Therefore, the present invention
The embodiments shown herein is not intended to be limited to, and is to fit to and principles disclosed herein and features of novelty phase one
The most wide scope for causing.
Claims (9)
1. a kind of preparation method of Difluprednate, it is characterised in that comprise the steps：
Step one：Synthetic intermediate two
Hydrocortisone -21- acetates are added in reaction vessel, DMF and pyridine is added, stirring, solid is insoluble, slow to heat up
To 40-60 DEG C, mesyl chloride is added dropwise, is in faint yellow turbid solution after finishing, be warming up to 60-100 DEG C, reactant liquor first becomes and become after clarification
Brown is muddy, reacts 1-3h, and monitoring reaction terminates, and stops heating, is down to room temperature, adds to crystallization in methyl alcohol, is cooled to -5-5 DEG C
After stirring filter, obtain white solid intermediate two, the pregnant α of steroid -17 of 4,9 (11)-diene, 21- dihydroxy -3,20- diketone -
21- acetic acid esters；
Step 2：Synthetic intermediate three
Intermediate two and DMAP, pyridine and acetonitrile are added in reaction vessel, adds butyric anhydride, stirring to be warming up to 60-100
Reaction is monitored after DEG C reaction 20-30h to terminate, be down to room temperature, concentrate acetonitrile, be down to be stirred at room temperature after 0.5-2h and filter, with a small amount of
Solvent is washed, and obtains the solid intermediate three of white, the α of 4,9 (11)-diene -17,21- dihydroxy -3,20- diketone -21- acetic acid
The iophenoxic acid ester of ester 17
Step 3：Synthetic intermediate four
Intermediate three and dioxane are added in reaction vessel, nitrogen displacement, add DDQ and tert-butyldimethylsilyl chloride silicon
Alkane, overnight, monitoring reaction terminates stirring reaction, concentrates dioxane, is dissolved with DCM, filters insoluble matter, then under room temperature condition
Washed with saturated sodium bicarbonate solution, saturated common salt water washing concentrates DCM after anhydrous sodium sulfate drying, obtain brown oil,
Column chromatography obtains the solid intermediate four of white, pregnant steroid-Isosorbide-5-Nitrae, 9 (11)-triolefin -3, the iophenoxic acid of 20- diketone -21- acetic acid esters -17
Ester；
Step 4：Synthetic intermediate five
Intermediate four and methylvinyl acetate are added in reaction vessel, the concentrated sulfuric acid is slowly added dropwise, drop finishes after stirring 10-30min
60-100 DEG C of reaction 0.5-3h is warming up to, monitoring reaction terminates, and is cooled to 30-40 DEG C, adds triethylamine that reaction is quenched, and adds
Water, is extracted 2-6 time, saturated common salt water washing, anhydrous sodium sulfate drying with EA, and concentration EA obtains brown oil, after column chromatography
Obtain the solid intermediate four of white, (11)-tetraene -3 of pregnant steroid 1,3,5,9,20- diketone -3, the iophenoxic acid of 21- diacetate esters -17
Ester；
Step 5：Synthetic intermediate six
Intermediate five and acetonitrile are added in reaction vessel, -10-5 DEG C is cooled to, Selectfluor reagents is added with acetonitrile
Mixture, finishes, and insulated and stirred reaction 3-6h, monitoring reaction terminates, and adds water, EA extractions to separate EA layers, saturated common salt washing
Wash, anhydrous sodium sulfate drying, concentrate EA, obtain light brown yellow solid；Gained solid and acetic acid are added in another container, is passed through
HCl gases, until solid is completely dissolved, continue stirring reaction 4-6h, and monitoring reaction terminates, and adds elutriation brilliant, filters, and obtains palm fibre
The solid intermediate six of color, pregnant steroid-Isosorbide-5-Nitrae, 9 (11)-triolefin -3, the fluoro- 17 iophenoxic acid esters of 20- diketone -21- acetic acid esters -6-；
Step 6：Synthetic intermediate seven
Intermediate six and dioxane are added in reaction vessel, add perchloric acid, stirring to be slowly added to NBS, solution is clarified,
3-8h is reacted under room temperature condition, monitoring reaction terminates, and reaction is quenched with saturated sodium bisulfite solution, add water, EA extractions to separate
EA layers, saturated common salt water washing, anhydrous sodium sulfate drying concentrates EA, obtains intermediate seven, and 6 α-fluoro- 9 β-bromo- 11 beta-hydroxy-
Isosorbide-5-Nitrae-diene-pregnant steroid -3, the iophenoxic acid ester of 20- diketone -21- acetic acid esters -17；
Step 7：Synthetic intermediate eight
Intermediate seven and acetone are added in reaction vessel, natrium carbonicum calcinatum is added, back flow reaction is warming up to overnight, monitoring reaction
Terminate, add water, EA extractions to separate EA layers, saturated common salt water washing, anhydrous sodium sulfate drying concentrates EA, obtains brown oil
Thing, column chromatography obtains the solid intermediate eight of white, 6 α-fluoro- 9 β, 11 beta epoxides-Isosorbide-5-Nitrae-diene-pregnant steroid -3,20- diketone -21-
The iophenoxic acid ester of acetic acid esters -17；
Step 8：Synthesis Difluprednate
Intermediate eight and polytetrafluoroethylene (PTFE) are added in reaction bulb, -30-20 DEG C is cooled to, HF pyridine solutions, insulated and stirred is added
Reaction 2-6h, monitoring reaction terminates, and with 20% sodium hydroxide solution pH to 7-8 is adjusted, then with pickling, saturated common salt washing, separates
DCM layers, concentrate DCM after anhydrous sodium sulfate drying, obtain the liquid of brown yellow oil, and column chromatography obtains white solid finished product difluoro
Bold and vigorous Buddhist nun's ester, 6 α, 9 α-fluoro- 11 beta-hydroxy -4- alkene-pregnant steroid -3,20- diketone -17- butyrate -20- acetic acid esters.
2. the preparation method of Difluprednate according to claim 1, it is characterised in that in step one, can by hydrogenation
The acetate of pine -21 be added in three mouthfuls of reaction bulbs, add DMF and pyridine, stirring, solid is insoluble, is to slowly warm up to 50 DEG C, drop
Addition mesyl chloride, is warming up to 80-85 DEG C, reacts 1-3h, and TLC monitoring reactions terminate, and stop heating, are down to room temperature, are down to and add
The crystallization into methyl alcohol, is cooled to after 0 DEG C of stirring 1h and filters, and obtains the solid intermediate two of white, wherein, hydrocortisone -21
Acetate is 1: 1.2-2.8 with the molar equivalent of mesyl chloride, and the molar equivalent of pyridine is 3-5, and DMF is 5ml/g-15ml/g.
3. the preparation method of Difluprednate according to claim 2, it is characterised in that in step 2, by intermediate
Two and DMAP, pyridine and acetonitrile are added in there-necked flask, add butyric anhydride, stirring, after being warming up to 80-85 DEG C of reaction 22-25h,
TLC monitoring reactions terminate, and are down to room temperature, concentrate acetonitrile, are down to be stirred at room temperature after 1h and filter, and are washed with a small amount of acetonitrile, obtain white
The solid intermediate three of color, wherein, intermediate two is catalytic amount for 1: 10-20, DMAP with the molar ratio of butyric anhydride, pyridine
Molar equivalent is 6-11, and acetonitrile equivalent is 5ml/g-10ml/g.
4. the preparation method of Difluprednate according to claim 3, it is characterised in that in step 3, by intermediate three
Add in there-necked flask with dioxane, nitrogen displacement, add DDQ and tert-butyl chloro-silicane, stir under room temperature condition
Overnight, TLC monitoring reactions terminate, and concentrate dioxane, are dissolved with DCM, filter insoluble matter, then use saturated sodium bicarbonate for reaction
Solution is washed, and saturated common salt water washing concentrates DCM, obtains brown oil after anhydrous sodium sulfate drying, column chromatography obtains white
Solid intermediate four, wherein, intermediate three：The molar ratio of DDQ is 1: 1.2-3, and tert-butyl chloro-silicane is catalysis
Amount.
5. the preparation method of Difluprednate according to claim 4, it is characterised in that in step 4, by intermediate four
Add in there-necked flask with methylvinyl acetate, be slowly added dropwise the concentrated sulfuric acid, drop to finish and be warming up to 80-85 DEG C of reaction after stirring 15min
0.5-2h, TLC monitoring reaction terminates, and is cooled to 32-37 DEG C, adds triethylamine that reaction is quenched, and adds water, is extracted 3 times with EA, satisfies
And brine It, anhydrous sodium sulfate, concentrate EA and obtain brown oil, the solid intermediate five of white is obtained after column chromatography,
Wherein, the mol ratio of intermediate four, methylvinyl acetate, the concentrated sulfuric acid and triethylamine is 1: 2-10: 0.05-1: 0.5-10.
6. the preparation method of Difluprednate according to claim 5, it is characterised in that in step 5, by intermediate
Five add in there-necked flask with acetonitrile, are cooled to -10-5 DEG C, add the mixture of Selectfluor reagents and acetonitrile, finish, and protect
Warm stirring reaction 4-6h, TLC monitoring reactions terminate, and add water, EA extractions to separate EA layers, saturated common salt water washing, anhydrous slufuric acid
Sodium is dried, and concentrates EA, obtains light brown yellow solid；Gained solid and acetic acid are added in another there-necked flask, HCl gas is passed through
Body, until solid is completely dissolved, continues stirring reaction 4-6h, and TLC monitoring reactions terminate, and add elutriation brilliant, filter, and obtain brown
Solid intermediate six, wherein, the molar equivalent of intermediate five and Selectfluor reagents is 1: 1.1-3, DL body and acetic acid
Molar equivalent is 1: 5-10.
7. the preparation method of Difluprednate according to claim 6, it is characterised in that in step 6, by intermediate
Six add in there-necked flask with dioxane, add perchloric acid, after stirring 5-40min, are slowly added to NBS, solution clarification, room temperature bar
4-6h is reacted under part, TLC monitoring reactions terminate, and reaction is quenched with saturated sodium bisulfite solution, add water, EA extractions to separate EA
Layer, saturated common salt water washing, anhydrous sodium sulfate drying, concentrate EA, obtain intermediate seven, wherein, intermediate six, perchloric acid with
The molar equivalent of NBS is 1: 0.5-1: 3-5.
8. the preparation method of Difluprednate according to claim 7, it is characterised in that in step 7, by intermediate seven
Add in there-necked flask with acetone, add sodium carbonate, be warming up to back flow reaction overnight, TLC monitoring reactions terminate, add water, EA extractions
Take, separate EA layers, saturated common salt water washing, anhydrous sodium sulfate drying concentrates EA, obtains brown oil, and column chromatography obtains white
The solid intermediate eight of color, wherein, intermediate seven is 1: 2-5 with the molar equivalent of sodium carbonate.
9. the preparation method of Difluprednate according to claim 8, it is characterised in that in step 8, by intermediate eight
Add in reaction bulb with polytetrafluoroethylene (PTFE), be cooled to -30-20 DEG C, add HF pyridine solutions, insulated and stirred reaction 2-6h, TLC prisons
Control reaction terminates, and with sodium hydroxide solution pH to 7-8 is adjusted, then with pickling, saturated common salt washing, separates DCM layers, anhydrous sodium sulfate
DCM is concentrated after drying, the liquid of brown yellow oil is obtained, column chromatography obtains white solid finished product Difluprednate, wherein, it is middle
Body eight is 1: 50-150 with the molar equivalent of fluorination reagent.
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