CN108218951A - A kind of high-purity fluorine easily preparation method - Google Patents
A kind of high-purity fluorine easily preparation method Download PDFInfo
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- CN108218951A CN108218951A CN201810181914.0A CN201810181914A CN108218951A CN 108218951 A CN108218951 A CN 108218951A CN 201810181914 A CN201810181914 A CN 201810181914A CN 108218951 A CN108218951 A CN 108218951A
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
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Abstract
The present invention provides a kind of high-purity fluorine easily preparation method, includes the following steps：（1）Reaction is hydrolyzed in 11 β hydroxyls 16 α, 17 [(1 methyl ethylidene) bis- (oxygen)] 21 (acetoxyl group) 6 α, 9 two pregna-fluoride, 1,4 diene, 3,20 diketone；（2）11 β, 21 couples of hydroxyl 16 α, 17 [(1 methyl ethylidene) bis- (oxygen)] 6 α, 9 two pregna-fluorides 1,4 diene 3,20 diketone crude products obtain 11 β, 21 couples of 16 α of hydroxyl by refining, 17 [(1 methyl ethylidene) bis- (oxygen)] 6 α, 9 two 3,20 diketone of pregna-fluoride Isosorbide-5-Nitrae diene I is brilliant；（3）11 β, 21 couples of hydroxyl 16 α, 17 [(1 methyl ethylidene) bis- (oxygen)] 6 α, 9 two 3,20 diketone of pregna-fluoride Isosorbide-5-Nitrae diene, I crystalline substance are refining to obtain fluocinolone acetonide finished product.
Description
Technical field
The present invention relates to pharmaceutical technology field, in particular it relates to a kind of high-purity fluorine easily preparation method.
Background technology
Black spot or chloasma are a kind of common pigments illnesss that women is mainly influenced during the childbearing age.It is dark, miscellaneous
The spot of color (hyperpigmentation) can be seen in face and neck, particularly in cheek and frons.Black spot usually by gestation or
Caused by hormonal activity caused by pill.Therefore, which is referred to as " mask of pregnancy ".When excessive melanin deposition exists
When in epidermis and dermal cell, there is the illness.Black spot can continue long time, and usually in subsequent gestation
It reappears.
It is yellowish-brown for treating (containing quinhydrones, Tretinoin and fluocinolone acetonide) that foreign countries list a kind of compound topical external preparation for 2004
Spot is known as the most effective drug for the treatment of chloasma so far.Fluocinolone acetonide plays in this compound preparation offsets Tretinoin to skin
The stimulation allergic reaction of thinning effect and mitigation compound to skin.It is domestic to there is no the fluocinolone acetonide production for meeting medicinal requirements at present.
In addition, the fluocinolone acetonide for meeting medicinal requirements is alternatively arranged as the topical preparations such as fluocinolone acetonide ointment and Fluocet (for allergy
Property dermatitis, atopic dermatitis, connect solution property dermatitis, seborrhea, eczema, cutaneous pruritus, psoriasis, neurodermatitis etc.)
Raw material.
Entitled 11 β of chemistry of fluocinolone acetonide, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis-
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone, No. CAS is 67-73-2, chemistry entitled -16 α of 11 beta-hydroxy, 17- of Fluocinonide
- 6 α of [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group), bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, No. CAS
For 356-12-7.
Fluocinolone acetonide is a kind of synthesis fluorinated corticosteroid for local skin, and there is stronger anti-inflammatory and antiallergy to make
With being classified as anti-inflammatory agent in the treatment.It is a kind of white crystalline powder, and tasteless and chance light is stablized.
The present invention provides a kind of high-purity fluorine easily preparation method, and by-product is few, high income, single miscellaneous is less than
0.10%th, it is always miscellaneous to be less than 0.50%.
Invention content
To solve the above-mentioned problems, easily preparation method, the high-purity fluorine are light for a kind of high-purity fluorine of present invention offer
The preparation method of pine includes the following steps：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetyl oxygen is added in into reaction kettle
Base) -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent are passed through inert gas, stir；It is cooled to 0-5
DEG C, hydrolysing agent is added in, insulation reaction 4-10h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 35-45 DEG C, subtracts
Pressure is concentrated into the 10-35% of solution weight before concentration, and purified water, the insulated and stirred 1-3h under the conditions of 5-15 DEG C is added dropwise；Filtering is used
Mass fraction is that the ethyl alcohol of 30-70% is eluted, and 60 DEG C are dried under reduced pressure, and obtain 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl
Ethylidene)-bis- (oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；
(2) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reaction kettle
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, mixed solvent, are warming up to 30-40 DEG C, and 1h is kept the temperature after stirring and dissolving, and decompression is dense
The 40-60% of solution weight before concentrating is reduced to, is cooled to 5-15 DEG C, insulated and stirred 1-3h, filtering with eluent methylene chloride, obtains
To 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- bis-
Ketone I is brilliant；
(3) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reactor
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent, is warming up to 40-50 DEG C, 1h is kept the temperature after stirring and dissolving, then
Slow cooling to 25-35 DEG C, be added dropwise purified water, be added dropwise it is rear 10-25 DEG C heat preservation 0.5-2h, 5-15 DEG C heat preservation 1h, 0-10 DEG C
1h is kept the temperature, filtering, 80 DEG C are dried under reduced pressure filter cake, obtain 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-it is bis-
(oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone II is brilliant, i.e. fluocinolone acetonide finished product.
In one embodiment, first organic solvent is one in absolute methanol, absolute ethyl alcohol, tetrahydrofuran
Kind.
In one embodiment, 11 beta-hydroxy -16 α, 17- described in the step (1) [(1- methyl ethylidene)-bis-
(oxygen)] -6 α of -21- (acetoxyl group), bis- pregna-fluoride -1,4- diene -3,20- diketone of 9- tries with first organic solvent, hydrolysis
The weight ratio of agent is 1：(10-20)：(0.1-0.13).
In one embodiment, 11 beta-hydroxy -16 α, 17- described in the step (1) [(1- methyl ethylidene)-bis-
(oxygen)] -6 α of -21- (acetoxyl group), the weight ratio of bis- pregna-fluoride -1,4- diene -3,20- diketone of 9- and the purified water is 1：
(6-10)。
In one embodiment, the hydrolysing agent is selected from hydrazine hydrate, ammonium hydroxide, sodium hydroxide, potassium hydroxide, hydronium(ion)
It is a kind of in lithia.
In one embodiment, the mixed solvent is selected from absolute methanol, absolute ethyl alcohol, dichloromethane, acetone, tetrahydrochysene
Two or more in furans, acetonitrile.
In one embodiment, the mixed solvent be selected from absolute methanol and dichloromethane, and the absolute methanol with
The volume ratio of the dichloromethane is 1：(0.7-2).
In one embodiment, 11 β described in the step (2), the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl Asia second
Base)-bis- (oxygen)] -6 α, 9- bis- the weight ratio of pregna-fluoride -1,4- diene -3,20- diketone crude product and the mixed solvent be 1：(5-
10)。
In one embodiment, second organic solvent is one in absolute ethyl alcohol, acetone, tetrahydrofuran, acetonitrile
Kind.
In one embodiment, 11 β described in the step (3), the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl Asia second
Base)-bis- (oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone of -6 α, 9- I is brilliant with second organic solvent, the purified water
Weight ratio be 1：(8-15)：(15-25).
The above-mentioned of the application and other features, aspect and advantage is more readily understood with reference to following detailed description.
Specific embodiment
The detailed description for preferred implementation method of the invention below of participating in the election of and including embodiment this hair can be more easily understood
Bright content.Unless otherwise defined, all technologies used herein and scientific terminology have common with fields of the present invention
The normally understood identical meaning of technical staff.When there is a conflict, the definition in this specification shall prevail.
As used herein term " by ... prepare " it is synonymous with "comprising".Term "comprising" used herein, " comprising ",
" having ", " containing " or its any other deformation, it is intended that cover including for non-exclusionism.For example, the combination comprising listed elements
Object, step, method, product or device are not necessarily limited to those elements, but can include not expressly listed other elements or
Such composition, step, method, product or the intrinsic element of device.
Conjunction " Consists of " excludes any element do not pointed out, step or component.If in claim, this
Phrase will make claim be closed, it be made not include the material in addition to the material of those descriptions, but relative normal
Except rule impurity.When being rather than immediately following after theme in the clause that phrase " Consists of " appears in claim main body,
It is only limited to the element described in the clause；Other elements are not excluded except the claim as a whole.
Equivalent, concentration or other values or parameter are excellent with range, preferred scope or a series of upper limit preferred values and lower limit
During the Range Representation that choosing value limits, this, which should be understood as, specifically discloses by any range limit or preferred value and any range
All ranges that any pairing of lower limit or preferred value is formed, regardless of whether the range separately discloses.For example, when open
During range " 1 to 5 ", described range should be interpreted as including range " 1 to 4 ", " 1 to 3 ", " 1 to 2 ", " 1 to 2 and 4 to
5 ", " 1 to 3 and 5 " etc..When numberical range is described herein, unless otherwise stated, otherwise range intention includes its end
Value and all integers and score in the range.
Singulative includes plural number and object is discussed, unless the context clearly dictates otherwise." optional " or it is " arbitrary
It is a kind of " refer to that the item described thereafter or event may or may not occur, and the description include situation that event occurs and
The situation that event does not occur.
Approximate term in specification and claims is used for modifying quantity, represents specific the present invention is not limited to this
Quantity further includes the modified part of the acceptable change without lead to related basic function close to the quantity.Phase
It answers, modifies a numerical value with " about ", " about " etc., mean that the present invention is not limited to the exact numericals.In some examples, it is approximate
Term likely corresponds to the precision of the instrument of measured value.In present specification and claims, range limits can be with
It combines and/or exchanges, these ranges include all subranges contained therebetween if not stated otherwise.
In addition, indefinite article " one kind " before element of the present invention or component and "one" quantitative requirement to element or component
(i.e. occurrence number) unrestriction.Therefore "one" or " one kind " should be read as including one or at least one, and odd number
The element or component of form also include plural form, unless the apparent purport of the quantity refers to singulative.
In order to solve the above technical problem, the present invention provides a kind of high-purity fluorine easily preparation method, the high-purities
The preparation method of fluocinolone acetonide includes the following steps：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetyl oxygen is added in into reaction kettle
Base) -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent are passed through inert gas, stir；It is cooled to 0-5
DEG C, hydrolysing agent is added in, insulation reaction 4-10h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 35-45 DEG C, subtracts
Pressure is concentrated into the 10-35% of solution weight before concentration, and purified water, the insulated and stirred 1-3h under the conditions of 5-15 DEG C is added dropwise；Filtering is used
Mass fraction is that the ethyl alcohol of 30-70% is eluted, and 60 DEG C are dried under reduced pressure, and obtain 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl
Ethylidene)-bis- (oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；
(2) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reaction kettle
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, mixed solvent, are warming up to 30-40 DEG C, and 1h is kept the temperature after stirring and dissolving, and decompression is dense
The 40-60% of solution weight before concentrating is reduced to, is cooled to 5-15 DEG C, insulated and stirred 1-3h, filtering with eluent methylene chloride, obtains
To 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- bis-
Ketone I is brilliant；
(3) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reactor
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent is warming up to 40-50 DEG C, 1h is kept the temperature after stirring and dissolving, then
Slow cooling to 25-35 DEG C, be added dropwise purified water, be added dropwise it is rear 10-25 DEG C heat preservation 0.5-2h, 5-15 DEG C heat preservation 1h, 0-10 DEG C
1h is kept the temperature, filtering, 80 DEG C are dried under reduced pressure filter cake, obtain 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-it is bis-
(oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone II is brilliant, i.e. fluocinolone acetonide finished product.
In one embodiment, first organic solvent is one in absolute methanol, absolute ethyl alcohol, tetrahydrofuran
Kind；Preferably, first organic solvent is absolute ethyl alcohol.
In one embodiment, the inert gas is a kind of in nitrogen, argon gas, helium；Preferably, the inertia
Gas is nitrogen.
In one embodiment, 11 beta-hydroxy -16 α, 17- described in the step (1) [(1- methyl ethylidene)-bis-
(oxygen)] -6 α of -21- (acetoxyl group), bis- pregna-fluoride -1,4- diene -3,20- diketone of 9- tries with first organic solvent, hydrolysis
The weight ratio of agent is 1：(10-20)：(0.1-0.13)；Preferably, 11 beta-hydroxy -16 α, 17- [(1- described in the step (1)
Methyl ethylidene)-bis- (oxygen)] and -6 α of -21- (acetoxyl group), bis- pregna-fluoride -1,4- diene -3,20- diketone of 9- and described first
Organic solvent, hydrolysing agent weight ratio be 1：16：0.105.
In one embodiment, 11 beta-hydroxy -16 α, 17- described in the step (1) [(1- methyl ethylidene)-bis-
(oxygen)] -6 α of -21- (acetoxyl group), the weight ratio of bis- pregna-fluoride -1,4- diene -3,20- diketone of 9- and the purified water is 1：
(6-10)；Preferably, 11 beta-hydroxy -16 α, 17- described in the step (1) [(1- methyl ethylidene)-bis- (oxygen)] -21- (second
Acyloxy) -6 α, 9- bis- the weight ratio of pregna-fluoride -1,4- diene -3,20- diketone and the purified water be 1：8.
In one embodiment, the hydrolysing agent is selected from hydrazine hydrate, ammonium hydroxide, sodium hydroxide, potassium hydroxide, hydronium(ion)
It is a kind of in lithia；Preferably, the hydrolysing agent is hydronium(ion) lithia.
In one embodiment, the mixed solvent is selected from absolute methanol, absolute ethyl alcohol, dichloromethane, acetone, tetrahydrochysene
Two or more in furans, acetonitrile.
In one embodiment, the mixed solvent be selected from absolute methanol and dichloromethane, and the absolute methanol with
The volume ratio of the dichloromethane is 1：(0.7-2)；Preferably, the volume ratio of the absolute methanol and the dichloromethane is 1：
1。
In one embodiment, 11 β described in the step (2), the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl Asia second
Base)-bis- (oxygen)] -6 α, 9- bis- the weight ratio of pregna-fluoride -1,4- diene -3,20- diketone crude product and the mixed solvent be 1：(5-
10)；Preferably, 11 β described in the step (2), the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α,
The weight ratio of bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of 9- and the mixed solvent is 1：6.
In one embodiment, second organic solvent is one in absolute ethyl alcohol, acetone, tetrahydrofuran, acetonitrile
Kind；Preferably, second organic solvent is absolute ethyl alcohol.
In one embodiment, 11 β described in the step (3), the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl Asia second
Base)-bis- (oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone of -6 α, 9- I is brilliant with second organic solvent, the purified water
Weight ratio be 1：(8-15)：(15-25)；Preferably, 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- described in the step (3)
Methyl ethylidene)-bis- (oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone of -6 α, 9- I is brilliant with second organic solvent, institute
The weight ratio for stating purified water is 1：10：20.
In the present invention, methanol and fluocinolone acetonide molecule easily form solvate, i.e., solvent methanol molecules by hydrogen bond or its
He interacts and is bonded on fluocinolone acetonide molecule, collectively forms multi-component crystal structure, fluocinolone acetonide is made to be formed with methanol molecules
A kind of crystal structure of stabilization；Although methanol solvate can be good at the impurity generated except dereaction, high-purity fluocinolone acetonide is obtained,
But methanol easily forms solvate with fluocinolone acetonide molecule, structure is more stable, and methanol is not easy to remove during drying, leads
Cause dissolvent residual is excessively high, and product is unqualified.
The determination condition of HPLC：
Pillar：4.6 × 250mm of C18 chromatographic columns, 5 μm；
Mobile phase：
Mobile phase A：Acetonitrile, buffer solution (acetonitrile：Buffer solution=28:72, V/V)；
Mobile phase B：Water, acetonitrile (water：Acetonitrile=40:60, V/V)；
Buffer solution：5.68g Anhydrous Disodium Phosphate and 3.63g potassium dihydrogen phosphates are dissolved in water, are diluted with water to
1000.0mL。
Flow velocity：1.0mL/min；
Column temperature：Room temperature；
Detection：The high performance liquid chromatography of 238nm.
Related substance examination criteria：Impurity K≤0.3%；Impurity D≤0.15%；Impurity J≤0.15%；Impurity H≤
0.15%；Impurity I≤0.15%；Other it is single it is miscellaneous≤0.10%；Always miscellaneous≤0.7%.
The control of impurity in drug：A, B, C, E, F, G, L, M, concrete structure formula are as follows：
Impurity A structural formula is as follows：
Impurity B structural formula is as follows：
Impurity C structure formulas are as follows：
Impurity D structural formulas are as follows：
Impurity E structural formula is as follows：
Impurity F structural formula is as follows：
Impurity G structural formulas are as follows：
Impurity H structure formula is as follows：
Impurity I structural formulas are as follows：
Impurity J structural formulas are as follows：
Impurity K structure formula is as follows：
Impurity L structural formulas are as follows：
Impurity M structure formula is as follows：
Fluocinonide of the present invention is hydrolyzed under the action of hydrolysing agent hydronium(ion) lithia, passes through Multiple factors
Synergistic effect, obtains fluocinolone acetonide in high yield, high-purity.
If raw materials used to be all commercially available in addition, without other explanations, it is purchased from traditional Chinese medicines chemical reagent.
Embodiment 1
Easily preparation method includes the following steps the high-purity fluorine：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetyl oxygen is added in into reaction kettle
Base) -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent are passed through inert gas, stir；It is cooled to 2
DEG C, hydrolysing agent is added in, insulation reaction 6h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 40 DEG C, is concentrated under reduced pressure
Purified water, the insulated and stirred 2h under the conditions of 10 DEG C is added dropwise in the 30% of solution weight before to concentration；It filters, is with mass fraction
50% ethyl alcohol is eluted, and 60 DEG C are dried under reduced pressure, and obtains 11 β, the bis- hydroxy-16 alphas of 21-, and 17- [(1- methyl ethylidene)-it is bis-
(oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；First organic solvent is absolute ethyl alcohol；It is described lazy
Property gas be nitrogen；- 16 α of 11 beta-hydroxy, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, 9-
The weight ratio of two pregna-fluoride -1,4- diene -3,20- diketone and first organic solvent, hydrolysing agent is 1：16：0.105；Institute
State 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, bis- pregna-fluoride -1,4- two of 9-
The weight ratio of alkene -3,20- diketone and the purified water is 1：8；The hydrolysing agent is hydronium(ion) lithia；
(2) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reaction kettle
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, mixed solvent, are warming up to 35 DEG C, 1h are kept the temperature after stirring and dissolving, be concentrated under reduced pressure into
The 50% of solution weight before concentration, is cooled to 10 DEG C, insulated and stirred 2h, and filtering with eluent methylene chloride, obtains 11 β, 21- is bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I are brilliant；It is described
Mixed solvent is selected from absolute methanol and dichloromethane；The volume ratio of the absolute methanol and the dichloromethane is 1：1；Described 11
The bis- hydroxy-16 alphas of β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone are thick
The weight ratio of product and the mixed solvent is 1：6；
(3) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reactor
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent, is warming up to 45 DEG C, 1h, Ran Houhuan are kept the temperature after stirring and dissolving
Slowly 30 DEG C are cooled to, purified water is added dropwise, after being added dropwise, 20 DEG C of heat preservation 1h, 10 DEG C of heat preservation 1h, 5 DEG C keep the temperature 1h, filter, 80 DEG C
Filter cake is dried under reduced pressure, obtains 11 β, the bis- hydroxy-16 alphas of 21-, bis- pregna-fluorides of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- -
Isosorbide-5-Nitrae-diene -3,20- diketone II is brilliant, i.e. fluocinolone acetonide finished product；Second organic solvent is absolute ethyl alcohol；11 β, 21- are bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I it is brilliant with it is described
Second organic solvent, the purified water weight ratio be 1：10：20.
Embodiment 2
Easily preparation method includes the following steps the high-purity fluorine：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetyl oxygen is added in into reaction kettle
Base) -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent are passed through inert gas, stir；It is cooled to 2
DEG C, hydrolysing agent is added in, insulation reaction 6h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 40 DEG C, is concentrated under reduced pressure
Purified water, the insulated and stirred 2h under the conditions of 10 DEG C is added dropwise in the 30% of solution weight before to concentration；It filters, is with mass fraction
50% ethyl alcohol is eluted, and 60 DEG C are dried under reduced pressure, and obtains 11 β, the bis- hydroxy-16 alphas of 21-, and 17- [(1- methyl ethylidene)-it is bis-
(oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；First organic solvent is absolute ethyl alcohol；It is described lazy
Property gas be nitrogen；- 16 α of 11 beta-hydroxy, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, 9-
The weight ratio of two pregna-fluoride -1,4- diene -3,20- diketone and first organic solvent, hydrolysing agent is 1：16：0.1；It is described
- 6 α of 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group), bis- pregna-fluoride -1,4- diene of 9- -
The weight ratio of 3,20- diketone and the purified water is 1：8；The hydrolysing agent is hydronium(ion) lithia；
(2) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reaction kettle
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, mixed solvent, are warming up to 35 DEG C, 1h are kept the temperature after stirring and dissolving, be concentrated under reduced pressure into
The 50% of solution weight before concentration, is cooled to 10 DEG C, insulated and stirred 2h, and filtering with eluent methylene chloride, obtains 11 β, 21- is bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I are brilliant；It is described
Mixed solvent is selected from absolute methanol and dichloromethane；The volume ratio of the absolute methanol and the dichloromethane is 1：1；Described 11
The bis- hydroxy-16 alphas of β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone are thick
The weight ratio of product and the mixed solvent is 1：6；
(3) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reactor
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent, is warming up to 45 DEG C, 1h, Ran Houhuan are kept the temperature after stirring and dissolving
Slowly 30 DEG C are cooled to, purified water is added dropwise, after being added dropwise, 20 DEG C of heat preservation 1h, 10 DEG C of heat preservation 1h, 5 DEG C keep the temperature 1h, filter, 80 DEG C
Filter cake is dried under reduced pressure, obtains 11 β, the bis- hydroxy-16 alphas of 21-, bis- pregna-fluorides of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- -
Isosorbide-5-Nitrae-diene -3,20- diketone II is brilliant, i.e. fluocinolone acetonide finished product；Second organic solvent is absolute ethyl alcohol；11 β, 21- are bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I it is brilliant with it is described
Second organic solvent, the purified water weight ratio be 1：10：20.
Embodiment 3
Easily preparation method includes the following steps the high-purity fluorine：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetyl oxygen is added in into reaction kettle
Base) -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent are passed through inert gas, stir；It is cooled to 2
DEG C, hydrolysing agent is added in, insulation reaction 6h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 40 DEG C, is concentrated under reduced pressure
Purified water, the insulated and stirred 2h under the conditions of 10 DEG C is added dropwise in the 30% of solution weight before to concentration；It filters, is with mass fraction
50% ethyl alcohol is eluted, and 60 DEG C are dried under reduced pressure, and obtains 11 β, the bis- hydroxy-16 alphas of 21-, and 17- [(1- methyl ethylidene)-it is bis-
(oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；First organic solvent is absolute ethyl alcohol；It is described lazy
Property gas be nitrogen；- 16 α of 11 beta-hydroxy, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, 9-
The weight ratio of two pregna-fluoride -1,4- diene -3,20- diketone and first organic solvent, hydrolysing agent is 1：16：0.12；Institute
State 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, bis- pregna-fluoride -1,4- two of 9-
The weight ratio of alkene -3,20- diketone and the purified water is 1：8；The hydrolysing agent is hydronium(ion) lithia；
(2) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reaction kettle
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, mixed solvent, are warming up to 35 DEG C, 1h are kept the temperature after stirring and dissolving, be concentrated under reduced pressure into
The 50% of solution weight before concentration, is cooled to 10 DEG C, insulated and stirred 2h, and filtering with eluent methylene chloride, obtains 11 β, 21- is bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I are brilliant；It is described
Mixed solvent is selected from absolute methanol and dichloromethane；The volume ratio of the absolute methanol and the dichloromethane is 1：1；Described 11
The bis- hydroxy-16 alphas of β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone are thick
The weight ratio of product and the mixed solvent is 1：6；
(3) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reactor
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent, is warming up to 45 DEG C, 1h, Ran Houhuan are kept the temperature after stirring and dissolving
Slowly 30 DEG C are cooled to, purified water is added dropwise, after being added dropwise, 20 DEG C of heat preservation 1h, 10 DEG C of heat preservation 1h, 5 DEG C keep the temperature 1h, filter, 80 DEG C
Filter cake is dried under reduced pressure, obtains 11 β, the bis- hydroxy-16 alphas of 21-, bis- pregna-fluorides of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- -
Isosorbide-5-Nitrae-diene -3,20- diketone II is brilliant, i.e. fluocinolone acetonide finished product；Second organic solvent is absolute ethyl alcohol；11 β, 21- are bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I it is brilliant with it is described
Second organic solvent, the purified water weight ratio be 1：10：20.
Embodiment 4
Easily preparation method includes the following steps the high-purity fluorine：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetyl oxygen is added in into reaction kettle
Base) -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent are passed through inert gas, stir；It is cooled to 2
DEG C, hydrolysing agent is added in, insulation reaction 6h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 40 DEG C, is concentrated under reduced pressure
Purified water, the insulated and stirred 2h under the conditions of 10 DEG C is added dropwise in the 30% of solution weight before to concentration；It filters, is with mass fraction
50% ethyl alcohol is eluted, and 60 DEG C are dried under reduced pressure, and obtains 11 β, the bis- hydroxy-16 alphas of 21-, and 17- [(1- methyl ethylidene)-it is bis-
(oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；First organic solvent is absolute ethyl alcohol；It is described lazy
Property gas be nitrogen；- 16 α of 11 beta-hydroxy, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, 9-
The weight ratio of two pregna-fluoride -1,4- diene -3,20- diketone and first organic solvent, hydrolysing agent is 1：16：0.105；Institute
State 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, bis- pregna-fluoride -1,4- two of 9-
The weight ratio of alkene -3,20- diketone and the purified water is 1：8；The hydrolysing agent is hydronium(ion) lithia；
(2) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reaction kettle
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, mixed solvent, are warming up to 35 DEG C, 1h are kept the temperature after stirring and dissolving, be concentrated under reduced pressure into
The 50% of solution weight before concentration, is cooled to 10 DEG C, insulated and stirred 2h, and filtering with eluent methylene chloride, obtains 11 β, 21- is bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I are brilliant；It is described
Mixed solvent is selected from absolute methanol and dichloromethane；The volume ratio of the absolute methanol and the dichloromethane is 1：0.7；It is described
The bis- hydroxy-16 alphas of 11 β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone
The weight ratio of crude product and the mixed solvent is 1：6；
(3) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reactor
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent, is warming up to 45 DEG C, 1h, Ran Houhuan are kept the temperature after stirring and dissolving
Slowly 30 DEG C are cooled to, purified water is added dropwise, after being added dropwise, 20 DEG C of heat preservation 1h, 10 DEG C of heat preservation 1h, 5 DEG C keep the temperature 1h, filter, 80 DEG C
Filter cake is dried under reduced pressure, obtains 11 β, the bis- hydroxy-16 alphas of 21-, bis- pregna-fluorides of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- -
Isosorbide-5-Nitrae-diene -3,20- diketone II is brilliant, i.e. fluocinolone acetonide finished product；Second organic solvent is absolute ethyl alcohol；11 β, 21- are bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I it is brilliant with it is described
Second organic solvent, the purified water weight ratio be 1：10：20.
Embodiment 5
Easily preparation method includes the following steps the high-purity fluorine：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetyl oxygen is added in into reaction kettle
Base) -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent are passed through inert gas, stir；It is cooled to 2
DEG C, hydrolysing agent is added in, insulation reaction 6h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 40 DEG C, is concentrated under reduced pressure
Purified water, the insulated and stirred 2h under the conditions of 10 DEG C is added dropwise in the 30% of solution weight before to concentration；It filters, is with mass fraction
50% ethyl alcohol is eluted, and 60 DEG C are dried under reduced pressure, and obtains 11 β, the bis- hydroxy-16 alphas of 21-, and 17- [(1- methyl ethylidene)-it is bis-
(oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；First organic solvent is absolute ethyl alcohol；It is described lazy
Property gas be nitrogen；- 16 α of 11 beta-hydroxy, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, 9-
The weight ratio of two pregna-fluoride -1,4- diene -3,20- diketone and first organic solvent, hydrolysing agent is 1：16：0.105；Institute
State 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, bis- pregna-fluoride -1,4- two of 9-
The weight ratio of alkene -3,20- diketone and the purified water is 1：8；The hydrolysing agent is hydronium(ion) lithia；
(2) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reaction kettle
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, mixed solvent, are warming up to 35 DEG C, 1h are kept the temperature after stirring and dissolving, be concentrated under reduced pressure into
The 50% of solution weight before concentration, is cooled to 10 DEG C, insulated and stirred 2h, and filtering with eluent methylene chloride, obtains 11 β, 21- is bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I are brilliant；It is described
Mixed solvent is selected from absolute methanol and dichloromethane；The volume ratio of the absolute methanol and the dichloromethane is 1：2；Described 11
The bis- hydroxy-16 alphas of β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone are thick
The weight ratio of product and the mixed solvent is 1：6；
(3) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reactor
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent, is warming up to 45 DEG C, 1h, Ran Houhuan are kept the temperature after stirring and dissolving
Slowly 30 DEG C are cooled to, purified water is added dropwise, after being added dropwise, 20 DEG C of heat preservation 1h, 10 DEG C of heat preservation 1h, 5 DEG C keep the temperature 1h, filter, 80 DEG C
Filter cake is dried under reduced pressure, obtains 11 β, the bis- hydroxy-16 alphas of 21-, bis- pregna-fluorides of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- -
Isosorbide-5-Nitrae-diene -3,20- diketone II is brilliant, i.e. fluocinolone acetonide finished product；Second organic solvent is absolute ethyl alcohol；11 β, 21- are bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I it is brilliant with it is described
Second organic solvent, the purified water weight ratio be 1：10：20.
Comparative example 1
Easily preparation method includes the following steps the high-purity fluorine：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetyl oxygen is added in into reaction kettle
Base) -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent are passed through inert gas, stir；It is cooled to 2
DEG C, hydrolysing agent is added in, insulation reaction 6h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 40 DEG C, is concentrated under reduced pressure
Purified water, the insulated and stirred 2h under the conditions of 10 DEG C is added dropwise in the 30% of solution weight before to concentration；It filters, is with mass fraction
50% ethyl alcohol is eluted, and 60 DEG C are dried under reduced pressure, and obtains 11 β, the bis- hydroxy-16 alphas of 21-, and 17- [(1- methyl ethylidene)-it is bis-
(oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；First organic solvent is absolute ethyl alcohol；It is described lazy
Property gas be nitrogen；- 16 α of 11 beta-hydroxy, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, 9-
The weight ratio of two pregna-fluoride -1,4- diene -3,20- diketone and first organic solvent, hydrolysing agent is 1：16：0.105；Institute
State 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, bis- pregna-fluoride -1,4- two of 9-
The weight ratio of alkene -3,20- diketone and the purified water is 1：8；The hydrolysing agent is sodium hydroxide；
(2) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reaction kettle
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, mixed solvent, are warming up to 35 DEG C, 1h are kept the temperature after stirring and dissolving, be concentrated under reduced pressure into
The 50% of solution weight before concentration, is cooled to 10 DEG C, insulated and stirred 2h, and filtering with eluent methylene chloride, obtains 11 β, 21- is bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I are brilliant；It is described
Mixed solvent is selected from absolute methanol and dichloromethane；The volume ratio of the absolute methanol and the dichloromethane is 1：1；Described 11
The bis- hydroxy-16 alphas of β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone are thick
The weight ratio of product and the mixed solvent is 1：6；
(3) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reactor
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent, is warming up to 45 DEG C, 1h, Ran Houhuan are kept the temperature after stirring and dissolving
Slowly 30 DEG C are cooled to, purified water is added dropwise, after being added dropwise, 20 DEG C of heat preservation 1h, 10 DEG C of heat preservation 1h, 5 DEG C keep the temperature 1h, filter, 80 DEG C
Filter cake is dried under reduced pressure, obtains 11 β, the bis- hydroxy-16 alphas of 21-, bis- pregna-fluorides of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- -
Isosorbide-5-Nitrae-diene -3,20- diketone II is brilliant, i.e. fluocinolone acetonide finished product；Second organic solvent is absolute ethyl alcohol；11 β, 21- are bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I it is brilliant with it is described
Second organic solvent, the purified water weight ratio be 1：10：20.
Comparative example 2
Easily preparation method includes the following steps the high-purity fluorine：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetyl oxygen is added in into reaction kettle
Base) -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent are passed through inert gas, stir；It is cooled to 2
DEG C, hydrolysing agent is added in, insulation reaction 6h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 40 DEG C, is concentrated under reduced pressure
Purified water, the insulated and stirred 2h under the conditions of 10 DEG C is added dropwise in the 30% of solution weight before to concentration；It filters, is with mass fraction
50% ethyl alcohol is eluted, and 60 DEG C are dried under reduced pressure, and obtains 11 β, the bis- hydroxy-16 alphas of 21-, and 17- [(1- methyl ethylidene)-it is bis-
(oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；First organic solvent is absolute ethyl alcohol；It is described lazy
Property gas be nitrogen；- 16 α of 11 beta-hydroxy, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, 9-
The weight ratio of two pregna-fluoride -1,4- diene -3,20- diketone and first organic solvent, hydrolysing agent is 1：16：0.105；Institute
State 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, bis- pregna-fluoride -1,4- two of 9-
The weight ratio of alkene -3,20- diketone and the purified water is 1：8；The hydrolysing agent is hydronium(ion) lithia；
(2) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reaction kettle
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, mixed solvent, are warming up to 35 DEG C, 1h are kept the temperature after stirring and dissolving, be concentrated under reduced pressure into
The 50% of solution weight before concentration, is cooled to 10 DEG C, insulated and stirred 2h, and filtering with eluent methylene chloride, obtains 11 β, 21- is bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I are brilliant；It is described
Mixed solvent is selected from absolute ethyl alcohol and dichloromethane；The volume ratio of the absolute ethyl alcohol and the dichloromethane is 1：1；Described 11
The bis- hydroxy-16 alphas of β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone are thick
The weight ratio of product and the mixed solvent is 1：6；
(3) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reactor
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent, is warming up to 45 DEG C, 1h, Ran Houhuan are kept the temperature after stirring and dissolving
Slowly 30 DEG C are cooled to, purified water is added dropwise, after being added dropwise, 20 DEG C of heat preservation 1h, 10 DEG C of heat preservation 1h, 5 DEG C keep the temperature 1h, filter, 80 DEG C
Filter cake is dried under reduced pressure, obtains 11 β, the bis- hydroxy-16 alphas of 21-, bis- pregna-fluorides of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- -
Isosorbide-5-Nitrae-diene -3,20- diketone II is brilliant, i.e. fluocinolone acetonide finished product；Second organic solvent is absolute ethyl alcohol；11 β, 21- are bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I it is brilliant with it is described
Second organic solvent, the purified water weight ratio be 1：10：20.
Comparative example 3
Easily preparation method includes the following steps the high-purity fluorine：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetyl oxygen is added in into reaction kettle
Base) -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent are passed through inert gas, stir；It is cooled to 2
DEG C, hydrolysing agent is added in, insulation reaction 6h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 40 DEG C, is concentrated under reduced pressure
Purified water, the insulated and stirred 2h under the conditions of 10 DEG C is added dropwise in the 30% of solution weight before to concentration；It filters, is with mass fraction
50% ethyl alcohol is eluted, and 60 DEG C are dried under reduced pressure, and obtains 11 β, the bis- hydroxy-16 alphas of 21-, and 17- [(1- methyl ethylidene)-it is bis-
(oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；First organic solvent is absolute ethyl alcohol；It is described lazy
Property gas be nitrogen；- 16 α of 11 beta-hydroxy, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, 9-
The weight ratio of two pregna-fluoride -1,4- diene -3,20- diketone and first organic solvent, hydrolysing agent is 1：16：0.105；Institute
State 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, bis- pregna-fluoride -1,4- two of 9-
The weight ratio of alkene -3,20- diketone and the purified water is 1：8；The hydrolysing agent is hydronium(ion) lithia；
(2) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reaction kettle
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, absolute methanol, are warming up to 35 DEG C, 1h are kept the temperature after stirring and dissolving, be concentrated under reduced pressure into
The 50% of solution weight before concentration, is cooled to 10 DEG C, insulated and stirred 2h, and filtering with eluent methylene chloride, obtains 11 β, 21- is bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I are brilliant；It is described
The bis- hydroxy-16 alphas of 11 β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone
The weight ratio of crude product and the mixed solvent is 1：6；
(3) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reactor
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent, is warming up to 45 DEG C, 1h, Ran Houhuan are kept the temperature after stirring and dissolving
Slowly 30 DEG C are cooled to, purified water is added dropwise, after being added dropwise, 20 DEG C of heat preservation 1h, 10 DEG C of heat preservation 1h, 5 DEG C keep the temperature 1h, filter, 80 DEG C
Filter cake is dried under reduced pressure, obtains 11 β, the bis- hydroxy-16 alphas of 21-, bis- pregna-fluorides of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- -
Isosorbide-5-Nitrae-diene -3,20- diketone II is brilliant, i.e. fluocinolone acetonide finished product；Second organic solvent is absolute ethyl alcohol；11 β, 21- are bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I it is brilliant with it is described
Second organic solvent, the purified water weight ratio be 1：10：20.
Comparative example 4
Easily preparation method includes the following steps the high-purity fluorine：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetyl oxygen is added in into reaction kettle
Base) -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent are passed through inert gas, stir；It is cooled to 2
DEG C, hydrolysing agent is added in, insulation reaction 6h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 40 DEG C, is concentrated under reduced pressure
Purified water, the insulated and stirred 2h under the conditions of 10 DEG C is added dropwise in the 30% of solution weight before to concentration；It filters, is with mass fraction
50% ethyl alcohol is eluted, and 60 DEG C are dried under reduced pressure, and obtains 11 β, the bis- hydroxy-16 alphas of 21-, and 17- [(1- methyl ethylidene)-it is bis-
(oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；First organic solvent is absolute ethyl alcohol；It is described lazy
Property gas be nitrogen；- 16 α of 11 beta-hydroxy, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, 9-
The weight ratio of two pregna-fluoride -1,4- diene -3,20- diketone and first organic solvent, hydrolysing agent is 1：16：0.105；Institute
State 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, bis- pregna-fluoride -1,4- two of 9-
The weight ratio of alkene -3,20- diketone and the purified water is 1：8；The hydrolysing agent is hydronium(ion) lithia；
(2) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reaction kettle
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, mixed solvent, are warming up to 35 DEG C, 1h are kept the temperature after stirring and dissolving, be concentrated under reduced pressure into
The 50% of solution weight before concentration, is cooled to 10 DEG C, insulated and stirred 2h, and filtering with eluent methylene chloride, obtains 11 β, 21- is bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I are brilliant；It is described
Mixed solvent is selected from absolute methanol and dichloromethane；The volume ratio of the absolute methanol and the dichloromethane is 1：1；Described 11
The bis- hydroxy-16 alphas of β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone are thick
The weight ratio of product and the mixed solvent is 1：6；
(3) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reactor
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent, is warming up to 45 DEG C, 1h, Ran Houhuan are kept the temperature after stirring and dissolving
Slowly 30 DEG C are cooled to, purified water is added dropwise, after being added dropwise, 20 DEG C of heat preservation 1h, 10 DEG C of heat preservation 1h, 5 DEG C keep the temperature 1h, filter, 80 DEG C
Filter cake is dried under reduced pressure, obtains 11 β, the bis- hydroxy-16 alphas of 21-, bis- pregna-fluorides of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- -
Isosorbide-5-Nitrae-diene -3,20- diketone II is brilliant, i.e. fluocinolone acetonide finished product；Second organic solvent is absolute methanol；11 β, 21- are bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I it is brilliant with it is described
Second organic solvent, the purified water weight ratio be 1：10：20.
Comparative example 5
Easily preparation method includes the following steps the high-purity fluorine：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetyl oxygen is added in into reaction kettle
Base) -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent are passed through inert gas, stir；It is cooled to 2
DEG C, hydrolysing agent is added in, insulation reaction 6h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 40 DEG C, is concentrated under reduced pressure
Purified water, the insulated and stirred 2h under the conditions of 10 DEG C is added dropwise in the 30% of solution weight before to concentration；It filters, is with mass fraction
50% ethyl alcohol is eluted, and 60 DEG C are dried under reduced pressure, and obtains 11 β, the bis- hydroxy-16 alphas of 21-, and 17- [(1- methyl ethylidene)-it is bis-
(oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；First organic solvent is absolute ethyl alcohol；It is described lazy
Property gas be nitrogen；- 16 α of 11 beta-hydroxy, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, 9-
The weight ratio of two pregna-fluoride -1,4- diene -3,20- diketone and first organic solvent, hydrolysing agent is 1：16：0.105；Institute
State 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, bis- pregna-fluoride -1,4- two of 9-
The weight ratio of alkene -3,20- diketone and the purified water is 1：8；The hydrolysing agent is hydronium(ion) lithia；
(2) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reaction kettle
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, mixed solvent, are warming up to 35 DEG C, 1h are kept the temperature after stirring and dissolving, be concentrated under reduced pressure into
The 50% of solution weight before concentration, is cooled to 10 DEG C, insulated and stirred 2h, and filtering with eluent methylene chloride, obtains 11 β, 21- is bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I are brilliant；It is described
Mixed solvent is selected from absolute methanol and dichloromethane；The volume ratio of the absolute methanol and the dichloromethane is 1：1；Described 11
The bis- hydroxy-16 alphas of β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone are thick
The weight ratio of product and the mixed solvent is 1：6；
(3) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reactor
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent, is warming up to 45 DEG C, 1h, Ran Houhuan are kept the temperature after stirring and dissolving
Slowly 30 DEG C are cooled to, purified water is added dropwise, after being added dropwise, 20 DEG C of heat preservation 1h, 10 DEG C of heat preservation 1h, 5 DEG C keep the temperature 1h, filter, 80 DEG C
Filter cake is dried under reduced pressure, obtains 11 β, the bis- hydroxy-16 alphas of 21-, bis- pregna-fluorides of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- -
Isosorbide-5-Nitrae-diene -3,20- diketone II is brilliant, i.e. fluocinolone acetonide finished product；Second organic solvent is acetone；The bis- hydroxyls of 11 β, 21--
Bis- pregna-fluoride -1,4- diene -3,20- diketone of 16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9-, I crystalline substance and described second
Organic solvent, the purified water weight ratio be 1：10：20.
Comparative example 6
Easily preparation method includes the following steps the high-purity fluorine：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetyl oxygen is added in into reaction kettle
Base) -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent are passed through inert gas, stir；It is cooled to 2
DEG C, hydrolysing agent is added in, insulation reaction 6h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 40 DEG C, is concentrated under reduced pressure
Purified water, the insulated and stirred 2h under the conditions of 10 DEG C is added dropwise in the 30% of solution weight before to concentration；It filters, is with mass fraction
50% ethyl alcohol is eluted, and 60 DEG C are dried under reduced pressure, and obtains 11 β, the bis- hydroxy-16 alphas of 21-, and 17- [(1- methyl ethylidene)-it is bis-
(oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；First organic solvent is absolute ethyl alcohol；It is described lazy
Property gas be nitrogen；- 16 α of 11 beta-hydroxy, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, 9-
The weight ratio of two pregna-fluoride -1,4- diene -3,20- diketone and first organic solvent, hydrolysing agent is 1：16：0.105；Institute
State 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, bis- pregna-fluoride -1,4- two of 9-
The weight ratio of alkene -3,20- diketone and the purified water is 1：8；The hydrolysing agent is hydronium(ion) lithia；
(2) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reaction kettle
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, mixed solvent, are warming up to 35 DEG C, 1h are kept the temperature after stirring and dissolving, be concentrated under reduced pressure into
The 50% of solution weight before concentration, is cooled to 10 DEG C, insulated and stirred 2h, and filtering with eluent methylene chloride, obtains 11 β, 21- is bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I are brilliant；It is described
Mixed solvent is selected from absolute methanol and dichloromethane；The volume ratio of the absolute methanol and the dichloromethane is 1：1；Described 11
The bis- hydroxy-16 alphas of β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone are thick
The weight ratio of product and the mixed solvent is 1：6；
(3) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reactor
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent, is warming up to 45 DEG C, 1h, Ran Houhuan are kept the temperature after stirring and dissolving
Slowly 30 DEG C are cooled to, purified water is added dropwise, after being added dropwise, 20 DEG C of heat preservation 1h, 10 DEG C of heat preservation 1h, 5 DEG C keep the temperature 1h, filter, 80 DEG C
Filter cake is dried under reduced pressure, obtains 11 β, the bis- hydroxy-16 alphas of 21-, bis- pregna-fluorides of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- -
Isosorbide-5-Nitrae-diene -3,20- diketone II is brilliant, i.e. fluocinolone acetonide finished product；Second organic solvent is acetonitrile；The bis- hydroxyls of 11 β, 21--
Bis- pregna-fluoride -1,4- diene -3,20- diketone of 16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9-, I crystalline substance and described second
Organic solvent, the purified water weight ratio be 1：10：20.
Comparative example 7
Easily preparation method includes the following steps the high-purity fluorine：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetyl oxygen is added in into reaction kettle
Base) -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent are passed through inert gas, stir；It is cooled to 2
DEG C, hydrolysing agent is added in, insulation reaction 6h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 40 DEG C, is concentrated under reduced pressure
Purified water, the insulated and stirred 2h under the conditions of 10 DEG C is added dropwise in the 30% of solution weight before to concentration；It filters, is with mass fraction
50% ethyl alcohol is eluted, and 60 DEG C are dried under reduced pressure, and obtains 11 β, the bis- hydroxy-16 alphas of 21-, and 17- [(1- methyl ethylidene)-it is bis-
(oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；First organic solvent is absolute ethyl alcohol；It is described lazy
Property gas be nitrogen；- 16 α of 11 beta-hydroxy, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, 9-
The weight ratio of two pregna-fluoride -1,4- diene -3,20- diketone and first organic solvent, hydrolysing agent is 1：16：0.105；Institute
State 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 α, bis- pregna-fluoride -1,4- two of 9-
The weight ratio of alkene -3,20- diketone and the purified water is 1：8；The hydrolysing agent is hydronium(ion) lithia；
(2) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reaction kettle
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, mixed solvent, are warming up to 35 DEG C, 1h are kept the temperature after stirring and dissolving, be concentrated under reduced pressure into
The 50% of solution weight before concentration, is cooled to 10 DEG C, insulated and stirred 2h, and filtering with eluent methylene chloride, obtains 11 β, 21- is bis-
Hydroxy-16 alpha, bis- pregna-fluoride -1,4- diene -3,20- diketone of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- I are brilliant；It is described
Mixed solvent is selected from absolute methanol and dichloromethane；The volume ratio of the absolute methanol and the dichloromethane is 1：1；Described 11
The bis- hydroxy-16 alphas of β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone are thick
The weight ratio of product and the mixed solvent is 1：6；
(3) 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- bis- are added in into reactor
Pregna-fluoride-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent, is warming up to 45 DEG C, 1h, Ran Houhuan are kept the temperature after stirring and dissolving
It is slow to be cooled to 30 DEG C, purified water is added dropwise, after being added dropwise, 5 DEG C of heat preservation 3h, filtering, 80 DEG C are dried under reduced pressure filter cake, obtain 11 β,
The bis- hydroxy-16 alphas of 21-, bis- pregna-fluoride -1,4- diene -3,20- diketone II of 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9-
Crystalline substance, i.e. fluocinolone acetonide finished product；Second organic solvent is absolute ethyl alcohol；The bis- hydroxy-16 alphas of 11 β, 21-, 17- [(1- methyl
Ethylidene)-bis- (oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone of -6 α, 9- I it is brilliant with second organic solvent, it is described pure
The weight ratio for changing water is 1：10：20.
Performance test：
The determination condition of HPLC：
Pillar：4.6 × 250mm of C18 chromatographic columns, 5 μm；
Mobile phase：
Mobile phase A：Acetonitrile, buffer solution (acetonitrile：Buffer solution=28:72, V/V)；
Mobile phase B：Water, acetonitrile (water：Acetonitrile=40:60, V/V)；
Buffer solution：5.68g Anhydrous Disodium Phosphate and 3.63g potassium dihydrogen phosphates are dissolved in water, are diluted with water to
1000.0mL；Flow velocity：1.0mL/min；Column temperature：Room temperature；Detection：The high performance liquid chromatography of 238nm.
Wherein, ND representatives do not detect.
It is seen from the above data that a kind of high-purity fluorine provided by the invention easily preparation method, by-product is few,
High income single miscellaneous be less than 0.10%, total miscellaneous be less than 0.50%.
Above-mentioned example is merely illustrative, some features of feature for explaining the present invention.Appended claim
The range as wide as possible that requirement is contemplated that is intended to, and embodiments as presented herein is only according to all possible embodiment
Combination selection embodiment explanation.Therefore, the purpose of applicant is that appended claim is not illustrated the present invention
Feature exemplary selectional restriction, and the progress in science and technology will not formed due to the inaccuracy that language is expressed and not
The possible equivalent or son being presently considered are replaced, and these variations also should in the conceived case be interpreted by appended
Claim covers.
Claims (10)
1. a kind of high-purity fluorine easily preparation method, which is characterized in that the high-purity fluorine easily preparation method include with
Lower step：
(1) 11 beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group) -6 is added in into reaction kettle
Bis- pregna-fluorides of α, 9--Isosorbide-5-Nitrae-diene -3,20- diketone, the first organic solvent, are passed through inert gas, stirring；0-5 DEG C is cooled to, is added
Enter hydrolysing agent, insulation reaction 4-10h after reaction with vinegar acid for adjusting pH value to 6-7, is warming up to 35-45 DEG C, is concentrated under reduced pressure
Purified water, the insulated and stirred 1-3h under the conditions of 5-15 DEG C is added dropwise in the 10-35% of solution weight before to concentration；Filtering, with quality point
Number is eluted for the ethyl alcohol of 30-70%, and 60 DEG C are dried under reduced pressure, and obtain 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl Asia second
Base)-bis- (oxygen)] bis- pregna-fluoride -1,4- diene -3,20- diketone crude products of -6 α, 9-；
(2) 11 β are added in into reaction kettle, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- difluoros are pregnant
Steroid-Isosorbide-5-Nitrae-diene -3,20- diketone crude product, mixed solvent, are warming up to 30-40 DEG C, keep the temperature 1h after stirring and dissolving, be concentrated under reduced pressure into
The 40-60% of solution weight before concentration, is cooled to 5-15 DEG C, insulated and stirred 1-3h, and filtering with eluent methylene chloride, obtains 11
The bis- hydroxy-16 alphas of β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone I
It is brilliant；
(3) 11 β are added in into reactor, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, 9- difluoros are pregnant
Steroid-Isosorbide-5-Nitrae-diene -3,20- diketone I is brilliant, the second organic solvent, is warming up to 40-50 DEG C, 1h is kept the temperature after stirring and dissolving, then slowly
25-35 DEG C is cooled to, purified water is added dropwise, rear 10-25 DEG C of heat preservation 0.5-2h, 5-15 DEG C of heat preservation 1h, 0-10 DEG C of heat preservation is added dropwise
1h, filtering, 80 DEG C are dried under reduced pressure filter cake, obtain 11 β, the bis- hydroxy-16 alphas of 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α,
Bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone II is brilliant, i.e. fluocinolone acetonide finished product.
2. high-purity fluorine easily preparation method according to claim 1, which is characterized in that first organic solvent is selected from
It is a kind of in absolute methanol, absolute ethyl alcohol, tetrahydrofuran.
3. high-purity fluorine easily preparation method according to claim 1, which is characterized in that 11 described in the step (1)
- 6 α of beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group), bis- pregna-fluoride -1,4- diene -3 of 9-,
The weight ratio of 20- diketone and first organic solvent, hydrolysing agent is 1：(10-20)：(0.1-0.13).
4. high-purity fluorine easily preparation method according to claim 1, which is characterized in that 11 described in the step (1)
- 6 α of beta-hydroxy -16 α, 17- [(1- methyl ethylidene)-bis- (oxygen)] -21- (acetoxyl group), bis- pregna-fluoride -1,4- diene -3 of 9-,
The weight ratio of 20- diketone and the purified water is 1：(6-10).
5. high-purity fluorine easily preparation method according to claim 1, which is characterized in that the hydrolysing agent is selected from hydration
It is a kind of in hydrazine, ammonium hydroxide, sodium hydroxide, potassium hydroxide, hydronium(ion) lithia.
6. high-purity fluorine easily preparation method according to claim 1, which is characterized in that the mixed solvent is selected from anhydrous
Two or more in methanol, absolute ethyl alcohol, dichloromethane, acetone, tetrahydrofuran, acetonitrile.
7. high-purity fluorine easily preparation method according to claim 6, which is characterized in that the mixed solvent is selected from anhydrous
Methanol and dichloromethane, and the volume ratio of the absolute methanol and the dichloromethane is 1：(0.7-2).
8. high-purity fluorine easily preparation method according to claim 1, which is characterized in that 11 described in the step (2)
The bis- hydroxy-16 alphas of β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone are thick
The weight ratio of product and the mixed solvent is 1：(5-10).
9. high-purity fluorine easily preparation method according to claim 1, which is characterized in that second organic solvent is selected from
It is a kind of in absolute ethyl alcohol, acetone, tetrahydrofuran, acetonitrile.
10. high-purity fluorine easily preparation method according to claim 1, which is characterized in that 11 described in the step (3)
The bis- hydroxy-16 alphas of β, 21-, 17- [(1- methyl ethylidene)-bis- (oxygen)] -6 α, bis- pregna-fluorides of 9--Isosorbide-5-Nitrae-diene -3,20- diketone I
The brilliant weight ratio with second organic solvent, the purified water is 1：(8-15)：(15-25).
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| CN110759962A (en) * | 2019-11-19 | 2020-02-07 | 湖南新合新生物医药有限公司 | Preparation method of high-purity fluocinolone acetonide |
| CN112142820A (en) * | 2019-06-29 | 2020-12-29 | 天津药业研究院股份有限公司 | Synthetic method of triamcinolone acetonide |
| CN114213495A (en) * | 2021-12-09 | 2022-03-22 | 河南利华制药有限公司 | Method for refining fluorometholone |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292292A (en) * | 2014-09-10 | 2015-01-21 | 新乡恒久远药业有限公司 | Refining technology of fluocinonide crude product |
| WO2018037423A1 (en) * | 2016-08-25 | 2018-03-01 | Coral Drugs Pvt. Ltd. | Novel process for preparation of corticosteroids |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292292A (en) * | 2014-09-10 | 2015-01-21 | 新乡恒久远药业有限公司 | Refining technology of fluocinonide crude product |
| WO2018037423A1 (en) * | 2016-08-25 | 2018-03-01 | Coral Drugs Pvt. Ltd. | Novel process for preparation of corticosteroids |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112142820A (en) * | 2019-06-29 | 2020-12-29 | 天津药业研究院股份有限公司 | Synthetic method of triamcinolone acetonide |
| CN110759962A (en) * | 2019-11-19 | 2020-02-07 | 湖南新合新生物医药有限公司 | Preparation method of high-purity fluocinolone acetonide |
| CN110759962B (en) * | 2019-11-19 | 2022-06-24 | 湖南新合新生物医药有限公司 | Preparation method of high-purity fluocinolone acetonide |
| CN114213495A (en) * | 2021-12-09 | 2022-03-22 | 河南利华制药有限公司 | Method for refining fluorometholone |
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