CN104387433A - Preparation method of clobetasol and preparation method of clobetasol propionate - Google Patents
Preparation method of clobetasol and preparation method of clobetasol propionate Download PDFInfo
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- CN104387433A CN104387433A CN201410718532.9A CN201410718532A CN104387433A CN 104387433 A CN104387433 A CN 104387433A CN 201410718532 A CN201410718532 A CN 201410718532A CN 104387433 A CN104387433 A CN 104387433A
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- 0 CC(*)(*1)OCC1=O Chemical compound CC(*)(*1)OCC1=O 0.000 description 1
- QSZNJOAWOAJLSN-BKDHPRRPSA-N CCC(CCC(C1(C)C=C2)=CC2=O)[C@H]1F Chemical compound CCC(CCC(C1(C)C=C2)=CC2=O)[C@H]1F QSZNJOAWOAJLSN-BKDHPRRPSA-N 0.000 description 1
- MUTZCUJBSWGGMT-CZGJZSLRSA-N C[C@@H](CC(C(CCC([C@]1(C)C=C2)=CC2=O)C(C)[C@@]1([C@H](C1)O)F)[C@]11[O]=C2CO)[C@@]12O Chemical compound C[C@@H](CC(C(CCC([C@]1(C)C=C2)=CC2=O)C(C)[C@@]1([C@H](C1)O)F)[C@]11[O]=C2CO)[C@@]12O MUTZCUJBSWGGMT-CZGJZSLRSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
- C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom
Abstract
The invention discloses a preparation method of clobetasol and the preparation method of clobetasol propionate. The preparation method of the clobetasol comprises the following steps: by taking a compound I, namely 1,4,9(11)-triene androstane-3,17-diketone as an initial raw material, performing a methylation reaction, a cyan substitution reaction, a siloxy protection reaction, an intramolecular nucleophilic substitution reaction, a bromoepoxy reaction and a fluorination reaction to prepare a compound VII which is clobetasol. The compound VII is subjected to a propyl esterification reaction to prepare a compound VIII which is clobetasol propionate. According to the preparation method disclosed by the invention, since relatively basic initial raw materials which are cheap are used, each step of reaction is relatively easy to implement and high yield is achieved; the operation of multi-step protection and deprotection is simplified; moreover, 21 sites of fluorine are directly arranged in one step during arrangement of a side chain, and multiple steps of reaction for arranging the 21 sites of fluorine in the prior art are directly avoided, so that the synthetic route is greatly shortened, the total yield is increased, the product quality is improved and the production cost is greatly lowered.
Description
Technical field
The present invention relates to a kind of chemical synthesis process of medicine, be specifically related to a kind of preparation method of clobetasol and the preparation method of clobetasol propionate.
Background technology
Clobetasol propionate, has another name called chlorine Betamethasone third acetic acid, Clobetasol Propionate, English name ClobetasolPropionate, the chloro-9-of chemical name: 21-fluoro-11 beta-hydroxyl-17s-propionic ester-16 Beta-methyl pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone, and its structural formula is as follows:
Clobetasol propionate is the efficient local topical glucocorticoid medicine of synthetic.Have stronger anti-inflammatory, antipruritic and capillary vessel contraction, its anti-inflammatory action is about 112.5 times of hydrocortisone, 2.3 times of betamethasone sodium phosphate, 18.7 times of fluocinolone acetonide.There is the mitotic effect of T suppression cell simultaneously, effectively can penetrate into keratoderma and be used for the treatment of the symptoms such as neurodermatitis, contact dermatitis, eczema, discoid lupus erythematosus.Always in very great demand on world market, occupy hormones first.
The preparation of clobetasol propionate is mainly raw starting material at present with Betamethasone Valerate, and through cyclic ester reaction, hydrolysis reaction, (sulfonation reaction) and chlorination reaction are obtained.Application publication number is the manufacture method that the Chinese patent of CN1923842A discloses a kind of clobetasol propionate, take Betamethasone Valerate as raw starting material, through cyclic ester reaction, and hydrolysis reaction, sulfonation reaction and chlorination reaction obtain; Application publication number is a kind of method that the Chinese patent of CN101812107A discloses synthesizing clobetasol propionate intermediate, take Betamethasone Valerate as raw starting material, and through cyclic ester reaction, hydrolysis reaction and chlorination reaction obtain; Its operational path is as follows:
The starting raw material Betamethasone Valerate of these two kinds of methods is expensive, and for upper 21 chlorine have carried out polystep reaction, influence factor is many, and the side reaction of generation is also many.And the solvent contamination used is comparatively large, be difficult to reclaim.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of chemical synthesis process of compound, be specifically related to a kind of preparation method of clobetasol and the preparation method of clobetasol propionate, it uses relatively cheap starting raw material, and each step reaction is relatively easy to be realized, and yield is higher; Simplify the operation of multistep protection and deprotection; and while upper side chain, just settled directly 21 chlorine at one go; directly having cut current technology is the polystep reaction that upper 21 chlorine carries out; substantially reduce synthetic route; improve total recovery and quality; greatly reduce production cost, be more suitable for industrial production.
The present invention adopts following technical scheme to realize: a kind of preparation method of clobetasol, and with Compound I and Isosorbide-5-Nitrae, 9 (11)-triolefin androstane-3,17-diketone are starting raw material, comprise the following steps:
A) methylation reaction: Compound I added and methylate in solvent, protects 16 α hydrogen with the first organic bases and oxalic acid diethyl ester, then carries out methyl substituted with methylating reagent to 16 β hydrogen, be finally hydrolyzed to obtain Compound II per to protection;
B) cyano group substitution reaction: added by Compound II per in cyaniding solvent, reacts with cyanating reagent, obtains compound III under the first catalyst action;
C) silicon alkoxyl group protective reaction: compound III is added in protection solvent, with silicon alkoxyl group reagent react under the second organic bases exists, obtain compound IV;
D) intramolecular nucleophilic substitution reaction: compound IV is added and replaces in solvent, with alkali amide reagent react, obtain compound V;
E) Brominated Epoxy reaction: compound V is added in epoxy solvent, under the second catalyst action, react with bromizating agent and mineral alkali, obtain compound VI;
F) fluoride reaction: compound VI added in hydrofluoric acid solution and carry out upper fluorine, reacts to obtain compound VI I, i.e. clobetasol.
Further, the solvent that methylates described in is one or more in THF, methylene dichloride, chloroform, acetone and dioxane; Described first organic bases is one or more in sodium methylate, sodium ethylate and potassium tert.-butoxide; Described methylating reagent is one or more in methyl iodide, monobromethane and methyl-sulfate; The temperature of reaction of described methylation reaction is 0 ~ 70 DEG C.
Further, described cyaniding solvent is one or more in methyl alcohol, ethanol, n-propyl alcohol, Virahol, acetone and water; Described cyanating reagent is one or more in acetone cyanohydrin, potassium cyanide, sodium cyanide; When cyanating reagent is acetone cyanohydrin, described first catalyzer is one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium-acetate, Potassium ethanoate; When cyanating reagent be potassium cyanide and/or sodium cyanide time, described first catalyzer is one or more in Glacial acetic acid, hydrochloric acid, phosphoric acid; The temperature of reaction of described cyano group substitution reaction is 0 ~ 50 DEG C.
Further, described protection solvent is one or more in methylene dichloride, trichloromethane, tetracol phenixin, benzene, rudimentary aromatic hydrocarbon and acetone; Described second organic bases is one or more in DMAP, imidazoles, triethylamine, DBU; Described silicon alkoxyl group reagent is one or more in CMDMCS chloromethyl dimethyl chlorosilane, chloromethyl dimethyl bromo-silicane, chloromethyl dimethyl iodine silane; The temperature of reaction of described silicon alkoxyl group protective reaction is 0 ~ 60 DEG C.
Further, described replacement solvent is one or more in tetrahydrofuran (THF), dimethyl-tetrahydrofuran, hexanaphthene, ether, benzene, rudimentary aromatic hydrocarbon; Described alkali amide reagent is lithium diisopropyl amido; The temperature of reaction of described intramolecular nucleophilic substitution reaction is-10 ~ 50 DEG C.
Further, described epoxy solvent is one or more in acetone, dimethyl formamide, tetrahydrofuran (THF), dioxane; Described second catalyzer is one or more in organic acid, inorganic acid; Described bromizating agent is one or more in N-bromo-succinimide, phosphorus pentabromide, bromination dimethyl bromo sulphur, C5H6Br2N2O2, bromination ketone, Sodium Bromide, Potassium Bromide; Described mineral alkali is one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood; Described epoxy reactive temperature of reaction is-10 ~ 60 DEG C.
Further, described hydrofluoric acid solution is one or both in hydrofluoric acid dimethyl formamide solution, hydrofluoric acid aqueous solution; The temperature of reaction of described fluoride reaction is-40 ~ 60 DEG C.
The present invention also provides a kind of preparation method of clobetasol propionate, comprise the Overall Steps of the preparation method of above-mentioned arbitrary described clobetasol, step g third esterification is also comprised: added by compound VI I in the third esterified solvent after step f, under the 3rd catalyst action, by propyl ester agent, the third esterification is carried out to 17 ɑ hydroxyls obtain compound VI II, be i.e. clobetasol propionate.
Its operational path is as follows:
Further, described third esterified solvent is one or more in rudimentary alkyl chloride; Described propyl ester agent is propionic anhydride or propionyl chloride; When propyl ester agent is propionic anhydride, described 3rd catalyzer is one or more in organic acid, inorganic acid; When propyl ester agent is propionyl chloride, described 3rd catalyzer is one or more in organic bases; The temperature of reaction of described esterification is 0 ~ 80 DEG C.
Compared with present technology, the present invention has following beneficial effect: the present invention uses relatively cheap starting raw material, and each step reaction is relatively easy to be realized, and yield is higher, make production more economically, safety, be more suitable for industrial production.
The present invention, by the design optimization of circuit, avoids the operation of multistep protection and deprotection.
The present invention, by the design optimization of circuit, has just settled directly 21 chlorine at one go while upper side chain.
The present invention is optimized by line design, and directly having cut current technology is the polystep reaction that upper 21 chlorine carries out, and substantially reduces synthetic route, reduces integral production cost.
Embodiment
Below in conjunction with specific embodiment, the preparation method of a kind of clobetasol of the present invention and the preparation method of clobetasol propionate are described in further detail.
Embodiment 1
Get three mouthfuls of reaction flasks, pass into nitrogen protection, add 100g Compound I that is 1; 4,9 (11)-triolefin androstane-3,17-diketone; add 400ml THF; system is cooled to 0 DEG C, adds 60ml oxalic acid diethyl ester and 30g sodium methylate subsequently, and temperature control 0 ~ 5 DEG C stirs 1h; add 20g Anhydrous potassium carbonate and 28ml methyl iodide subsequently; be warming up to back flow reaction 12h, reaction is finished, and is evaporated near dry.Add 400ml anhydrous methanol, be cooled to 0 ~ 5 DEG C; Add 12g sodium methylate subsequently, temperature control 0 ~ 5 DEG C stirs 2h, and sampling detects to be existed without intermediate.Glacial acetic acid adjusts PH 7 ~ 8, adds 2000ml water, and system temperature control 0 ~ 5 DEG C stirs 2h, suction filtration, and washing filter cake is to neutral, dry, obtain Compound II per 95g, i.e. 16 Beta-methyls-Isosorbide-5-Nitrae, 9 (11)-triolefin androstane-3,17-diketone, mass yield: 95%, HPLC purity: 97%.
In clean four mouthfuls of reaction flasks, add 200ml methyl alcohol, 100ml acetone cyanohydrin, 200g Compound II per successively, after stirring, add the wet chemical 200ml of 10wt%, system temperature control detects raw material in 40 ~ 50 DEG C of reactions 30h, TLC no longer to be reduced.Reaction system is dropped in 4000ml water, stir 2h.Suction filtration, washing filter cake, to neutral, in 50 DEG C of oven dry after draining, obtains compound III 210g, i.e. 16 Beta-methyl-17 beta-cyano-17 Alpha-hydroxy androstane-Isosorbide-5-Nitraes, 9 (11)-triolefin-3-ketone, mass yield: 105%, HPLC purity: 97.8%.
250ml trichloromethane, 100g compound III, 52g imidazoles is added successively in four mouthfuls of reaction flasks of a clean dried, after stirring, temperature control to 30 ~ 40 DEG C, slow dropping 210g chloromethyl dimethyl bromo-silicane, 3 ~ 4h dropwises, and insulation reaction 0.5h, TLC detect without starting material left.In reaction system, drip 200ml water, stir 0.5h, separatory.Trichloromethane layer is evaporated to dry, add 500ml water, dispersed with stirring, suction filtration, washing filter cake is to neutral, in 50 DEG C of oven dry after draining, obtain compound IV 130g, i.e. 16 Beta-methyl-17 β cyano group-17 Alpha-hydroxy androstanes-1,4,9 (11)-triolefin-3-ketone-17-(chloromethyl) dimethyl-silicon ethers, mass yield: 130%, HPLC purity: 97.1%.
Under nitrogen protection; 600ml tetrahydrofuran (THF), 100g compound IV is added successively in a clean dried four mouthfuls of reaction flasks; after stirring; system temperature control is to-10 ~ 0 DEG C; the lithium diisopropyl amido of slow dropping 358ml 2mol/L; about 4 ~ 6h dropwises, and insulation reaction 0.5h, TLC detect without starting material left.Temperature control T≤10 DEG C, drop in 200ml concentrated hydrochloric acid by reaction system, stir 5h.System 10wt% aqueous sodium hydroxide solution adjusts PH=6 ~ 7, and temperature control T≤50 DEG C are concentrated into without obvious cut, in residue system, drip 500ml water, stir 1h, suction filtration, washing filter cake is to neutral, in 50 DEG C of oven dry after draining, obtain compound V 81g, the i.e. pregnant steroid-Isosorbide-5-Nitrae of chloro-17 Alpha-hydroxy of 16 Beta-methyl-21-, 9 (11)-triolefins-3,20-diketone, mass yield: 81.0%, HPLC purity: 97.0%.
Acetone 1000ml is added in three mouthfuls of reaction flasks, stir lower logical nitrogen 10min, drop into compound V50g, be cooled to about 0 DEG C, add bromination dimethyl bromo sulphur 50g, continue to stir 10min, drip 3wt% aqueous sulfuric acid 200ml, 30min drips off, insulation reaction is about 3h, react complete, add 10wt% sodium sulfite aqueous solution 100ml, then 10wt% aqueous sodium carbonate 600ml is added, stirring at room temperature reaction 10h, reaction is finished, slowly adding Glacial acetic acid adjusts PH to be about 7, negative pressure is concentrated into without acetone, add water 1000ml, stir loose crystallization, filtering drying obtains compound VI 48.5g, i.e. 16 Beta-methyl-21-chloro-9, the pregnant steroid-1 of 11-epoxy-17 Alpha-hydroxy, 4-diene-3, 20-diketone, mass yield: 97%, HPLC purity: 95%.
58wt% hydrofluoric acid dimethyl formamide solution 550ml is dropped in polytetrafluoro reaction flask, stir, be cooled to less than-10 DEG C, drop into compound VI 50g, in-10 ~-5 DEG C of constant temperature stirring reaction 15h, reaction is finished, reaction solution being joined 3500ml is cooled in the frozen water of 0 DEG C in advance, drip ammoniacal liquor and adjust PH=6.5 ~ 7, filtering drying, compound VI I crude product 48.5g, i.e. clobetasol, above-mentioned crude product is put into methyl alcohol 500ml, in the mixed solvent of trichloromethane 130ml, heat up clearly molten, add gac 4.9g, backflow 30min, suction filtration, filtrate negative pressure is concentrated into about 50ml volume,-10 ~ 0 DEG C of freezing crystallization 3h, filter, solid, a small amount of ice methanol rinses, dry, obtain clobetasol finished product 43g, mass yield: 86%, HPLC purity: more than 99%.
Compound VI I 100g is dropped into, trichloromethane 500ml, propionic anhydride 250ml and tosic acid 5g in three mouthfuls of reaction flasks, stirring is warming up to backflow, insulation reaction 14 ~ 16h, and reaction is finished, cool to about 25 DEG C, drip water 200ml termination reaction, be evaporated to and gradually do, add water 1000ml, stir 30min, filtered water is washed till neutrality, dries to obtain compound VI II crude product 112g, i.e. clobetasol propionate; Above-mentioned crude product is put into methyl alcohol 1120ml, in the mixed solvent of trichloromethane 250ml, heats up clearly molten, add gac 4.9g, backflow 30min, suction filtration, filtrate negative pressure is concentrated into about 150ml volume ,-10 ~ 0 DEG C of freezing crystallization 3h, filters, solid, a small amount of ice methanol rinses, dries, obtains clobetasol propionate finished product 104g, mass yield: 104%, HPLC purity: more than 99%.
Embodiment 2
Get three mouthfuls of reaction flasks, pass into nitrogen protection, add 100g Compound I that is 1; 4,9 (11)-triolefin androstane-3,17-diketone; add 600ml dioxane, system is cooled to 0 DEG C, adds 60ml oxalic acid diethyl ester and 40g sodium ethylate subsequently; temperature control 0 ~ 5 DEG C stirs 1h; add 20g Anhydrous potassium carbonate subsequently, pass into 60g monobromethane, be warming up to 60 ~ 70 DEG C of reaction 10h; reaction is finished, and is evaporated near dry.Add 400ml anhydrous methanol, be cooled to 0 ~ 5 DEG C; Add 14g sodium ethylate subsequently, temperature control 0 ~ 5 DEG C stirs 2h, and sampling detects to be existed without intermediate.Glacial acetic acid adjusts PH 7 ~ 8, adds 2000ml water, and system temperature control 0 ~ 5 DEG C stirs 2h, suction filtration, and washing filter cake is to neutral, dry, obtain Compound II per 93g, i.e. 16 Beta-methyls-Isosorbide-5-Nitrae, 9 (11)-triolefin androstane-3,17-diketone, mass yield: 93%, HPLC purity: 97%.
In a clean dried four mouthfuls of reaction flasks, add 300ml acetone, 120ml acetone cyanohydrin, 200g Compound II per successively, after stirring, add the sodium carbonate solution 150ml of 10wt%, system temperature control detects raw material in 40 ~ 50 DEG C of reactions 20h, TLC no longer to be reduced.In reaction system, drip 1000ml water, stir 2h.Suction filtration, washing filter cake, to neutral, in 50 DEG C of oven dry after draining, obtains compound III 208g, i.e. 16 Beta-methyl-17 beta-cyano-17 Alpha-hydroxy androstane-Isosorbide-5-Nitraes, 9 (11)-triolefin-3-ketone, mass yield: 104%, HPLC purity: 97.5%.
600ml toluene, 100g compound III, 54g triethylamine is added successively in a clean dried four mouthfuls of reaction flasks, after stirring, temperature control to 50 ~ 60 DEG C, slow dropping 70g CMDMCS chloromethyl dimethyl chlorosilane, about 4h dropwises, and insulation reaction 1h, TLC detect without starting material left.Drip 200ml water to reaction system, stir 1h.Separatory, toluene layer is concentrated into dry, adds 500ml water, dispersed with stirring, suction filtration, washing filter cake is extremely neutral, in 50 DEG C of oven dry after draining, obtain compound IV 131g, i.e. 16 Beta-methyl-17 β cyano group-17 Alpha-hydroxy androstane-Isosorbide-5-Nitraes, 9 (11)-triolefin-3-ketone-17-(chloromethyl) dimethyl-silicon ethers, mass yield: 131%, HPLC purity: 97.4%.
Under nitrogen protection; 700ml dimethyl-tetrahydrofuran, 100g compound IV is added successively in a clean dried four mouthfuls of reaction flasks; after stirring; system temperature control to 10 ~ 15 DEG C; slow dropping 358ml 2mol/L lithium diisopropyl amido; about 5h dropwises, and insulation reaction 0.5h, TLC detect without starting material left.Temperature control T≤20 DEG C, drop in 200ml concentrated hydrochloric acid by reaction system, stir 5h.System 10wt% aqueous sodium hydroxide solution adjusts PH=6 ~ 7, and temperature control T≤50 DEG C are concentrated into without obvious cut, in residue system, drip 500ml water, stir 1h, suction filtration, washing filter cake is to neutral, in 50 DEG C of oven dry after draining, obtain compound V 82g, the i.e. pregnant steroid-Isosorbide-5-Nitrae of chloro-17 Alpha-hydroxy of 16 Beta-methyl-21-, 9 (11)-triolefins-3,20-diketone, mass yield: 82.0%, HPLC purity: 97.3%.
Dimethyl formamide 250ml is added in three mouthfuls of reaction flasks, stir lower logical nitrogen 10min, drop into compound V 50g, be cooled to about-5 DEG C, add C5H6Br2N2O2 45g, continue to stir 10min, drip 2wt% high chloro acid solution 100ml, 30min drips off, insulation reaction is about 3h, react complete, add 20wt% sodium sulfite aqueous solution 50ml, then 20wt% aqueous sodium carbonate 200ml is added, 15 ~ 20 DEG C of reaction 20h, reaction is finished, slowly adding Glacial acetic acid adjusts PH to be about 7, add water 2000ml, stir loose crystallization, filtering drying obtains compound VI 47g, i.e. 16 Beta-methyl-21-chloro-9, the pregnant steroid-1 of 11-epoxy-17 Alpha-hydroxy, 4-diene-3, 20-diketone, mass yield: 94%, HPLC purity: 97%.
70wt% hydrofluoric acid aqueous solution 450ml is dropped in polytetrafluoro reaction flask, stir, be cooled to less than-5 DEG C, drop into compound VI 50g, in-10 ~ 0 DEG C of constant temperature stirring reaction 20h, reaction is finished, reaction solution being joined 3500ml is cooled in the frozen water of 0 DEG C in advance, drip ammoniacal liquor and adjust PH=6.5 ~ 7, filtering drying, obtain VII crude product 49g, i.e. clobetasol, above-mentioned crude product is put into methyl alcohol 490ml, in the mixed solvent of trichloromethane 130ml, heat up clearly molten, add gac 4.9g, backflow 30min, suction filtration, filtrate negative pressure is concentrated into about 50ml volume,-10 ~ 0 DEG C of freezing crystallization 3h, filter, solid, a small amount of ice methanol rinses, dry, obtain clobetasol finished product 44g, mass yield: 88%, HPLC purity: more than 99%.
Compound VI I 100g is dropped into three mouthfuls of reaction flasks, ethylene dichloride 600ml, propionic anhydride 250ml and vitriol oil 4ml, stirring is warming up to 80 DEG C, insulation reaction 14 ~ 16h, reaction is finished, cool to about 25 DEG C, drip water 200ml termination reaction, be evaporated to and gradually do, add water 1000ml, stir 30min, filtered water is washed till neutrality, dry to obtain compound VI II 115g, i.e. clobetasol propionate, above-mentioned crude product is put into methyl alcohol 1150ml, in the mixed solvent of trichloromethane 230ml, heat up clearly molten, add gac 11g, backflow 30min, suction filtration, filtrate negative pressure is concentrated into about 150ml volume,-10 ~ 0 DEG C of freezing crystallization 3h, filter, solid, a small amount of ice methanol rinses, dry, obtain clobetasol propionate finished product 105g, mass yield: 105%, HPLC purity: more than 99%.
Embodiment 3
Get three mouthfuls of reaction flasks, pass into nitrogen protection, add 100g Compound I that is 1; 4,9 (11)-triolefin androstane-3,17-diketone; add 700ml methylene dichloride, system is cooled to 0 DEG C, adds 60ml oxalic acid diethyl ester and 50g potassium tert.-butoxide subsequently; temperature control 0 ~ 5 DEG C stirs 1h; add 20g Anhydrous potassium carbonate subsequently, pass into 50g methyl chloride, be warming up to 40 ~ 45 DEG C of reaction 30h; reaction is finished, and is evaporated near dry.Add 400ml anhydrous methanol, be cooled to 0 ~ 5 DEG C; Add 16g potassium tert.-butoxide subsequently, temperature control 0 ~ 5 DEG C stirs 2h, and sampling detects to be existed without intermediate.Glacial acetic acid adjusts PH 7 ~ 8, adds 2000ml water, and system temperature control 0 ~ 5 DEG C stirs 2h, suction filtration, and washing filter cake is to neutral, dry, obtain Compound II per 90g, i.e. 16 Beta-methyls-Isosorbide-5-Nitrae, 9 (11)-triolefin androstane-3,17-diketone, mass yield: 90%, HPLC purity: 96%.
In clean four mouthfuls of reaction flasks, add 200ml methyl alcohol, 160g sodium cyanide, 200g Compound II per successively, system temperature control, in 0 ~ 10 DEG C, after stirring, is added dropwise to 128ml Glacial acetic acid, and system temperature control detects raw material in 10 ~ 20 DEG C of reactions 40h, TLC no longer to be reduced.Reaction system is dropped in 4000ml water, stir 2h.Suction filtration, washing filter cake, to neutral, in 50 DEG C of oven dry after draining, obtains compound III 210g, i.e. 16 Beta-methyl-17 beta-cyano-17 Alpha-hydroxy androstane-Isosorbide-5-Nitraes, 9 (11)-triolefin-3-ketone, mass yield: 105%, HPLC purity: 97.8%.
300ml methylene dichloride, 100g compound III, 100ml DBU is added successively in four mouthfuls of reaction flasks of a clean dried, after stirring, temperature control to 0 ~ 10 DEG C, slow dropping 300g chloromethyl dimethyl iodine silane, 3 ~ 4h dropwises, and insulation reaction 0.5h, TLC detect without starting material left.In reaction system, drip 200ml water, stir 0.5h, separatory.Dichloromethane layer is evaporated to dry, add 500ml water, dispersed with stirring, suction filtration, washing filter cake is to neutral, in 50 DEG C of oven dry after draining, obtain compound IV 128.0g, i.e. 16 Beta-methyl-17 β cyano group-17 Alpha-hydroxy androstanes-1,4,9 (11)-triolefin-3-ketone-17-(chloromethyl) dimethyl-silicon ethers, mass yield: 128%, HPLC purity: 97.1%.
Under nitrogen protection; 800ml hexanaphthene, 100g compound IV is added successively in a clean dried four mouthfuls of reaction flasks; after stirring; system temperature control to 40 ~ 50 DEG C; slow dropping 358ml 2mol/L lithium diisopropyl amido; about 4 ~ 6h dropwises, and insulation reaction 0.5h, TLC detect without starting material left.Temperature control T≤10 DEG C, drop in 200ml concentrated hydrochloric acid by reaction system, stir 5h.System 10wt% aqueous sodium hydroxide solution adjusts PH=6 ~ 7, and temperature control T≤50 DEG C are concentrated into without obvious cut, in residue system, drip 500ml water, stir 1h, suction filtration, washing filter cake is to neutral, in 50 DEG C of oven dry after draining, obtain compound V 79g, the i.e. pregnant steroid-Isosorbide-5-Nitrae of chloro-17 Alpha-hydroxy of 16 Beta-methyl-21-, 9 (11)-triolefins-3,20-diketone, mass yield: 79.0%, HPLC purity: 96.0%.
Tetrahydrofuran (THF) 250ml is added in three mouthfuls of reaction flasks, stir lower logical nitrogen 10min, drop into compound V 50g, be cooled to 10 ~ 20 DEG C, add N-bromo-succinimide 45g, continue to stir 10min, drip 2wt% tosic acid aqueous solution 100ml, 30min drips off, insulation reaction is about 3h, react complete, add 20wt% sodium sulfite aqueous solution 50ml, then 20wt% wet chemical 200ml is added, 15 ~ 20 DEG C of stirring reaction 20h, reaction is finished, slowly adding Glacial acetic acid adjusts PH to be about 7, add water 2000ml, stir loose crystallization, filtering drying obtains compound VI 47g, i.e. 16 Beta-methyl-21-chloro-9, the pregnant steroid-1 of 11-epoxy-17 Alpha-hydroxy, 4-diene-3, 20-diketone, mass yield: 94%, HPLC purity: 97%.
40wt% hydrofluoric acid dimethyl formamide solution 500ml is dropped in polytetrafluoro reaction flask, stir, be cooled to less than 10 DEG C, drop into compound VI 50g, in 15 ~ 20 DEG C of constant temperature stirring reaction 5h, reaction is finished, reaction solution being joined 3500ml is cooled in the frozen water of 0 DEG C in advance, drip ammoniacal liquor and adjust PH=6.5 ~ 7, filtering drying, obtain compound VI I crude product 48g, i.e. clobetasol, above-mentioned crude product is put into methyl alcohol 500ml, in the mixed solvent of trichloromethane 130ml, heat up clearly molten, add gac 4.9g, backflow 30min, suction filtration, filtrate negative pressure is concentrated into about 50ml volume,-10 ~ 0 DEG C of freezing crystallization 3h, filter, solid, a small amount of ice methanol rinses, dry, obtain clobetasol finished product 41g, mass yield: 82%, HPLC purity: more than 99%.
Compound VI I 100g is dropped into, methylene dichloride 500ml, propionyl chloride 110ml and pyridine 100ml in three mouthfuls of reaction flasks, stirring is warming up to 40 DEG C, insulation reaction 2 ~ 4h, and reaction is finished, cool to about 25 DEG C, drip water 100ml termination reaction, be evaporated to and gradually do, add water 1000ml, stir 30min, filtered water is washed till neutrality, dries to obtain compound VI II crude product 113g, i.e. clobetasol propionate; Above-mentioned crude product is put into methyl alcohol 1130ml, in the mixed solvent of trichloromethane 230ml, heats up clearly molten, add gac 11g, backflow 30min, suction filtration, filtrate negative pressure is concentrated into about 150ml volume ,-10 ~ 0 DEG C of freezing crystallization 3h, filters, solid, a small amount of ice methanol rinses, dries, obtains clobetasol propionate finished product 102g, mass yield: 102%, HPLC purity: more than 99%.
Embodiment 4
Get three mouthfuls of reaction flasks, pass into nitrogen protection, add 100g Compound I that is 1; 4,9 (11)-triolefin androstane-3,17-diketone; add 900ml chloroform, system is cooled to 0 DEG C, adds 60ml oxalic acid diethyl ester and 30g sodium methylate subsequently; temperature control 0 ~ 5 DEG C stirs 1h; add 20g Anhydrous potassium carbonate subsequently, add 100ml methyl-sulfate, be warming up to 55 ~ 60 DEG C of reaction 12h; reaction is finished, and is evaporated near dry.Add 400ml anhydrous methanol, be cooled to 0 ~ 5 DEG C; Add 16g sodium methylate subsequently, temperature control 0 ~ 5 DEG C stirs 2h, and sampling detects to be existed without intermediate.Glacial acetic acid adjusts PH 7 ~ 8, adds 2000ml water, and system temperature control 0 ~ 5 DEG C stirs 2h, suction filtration, and washing filter cake is to neutral, dry, obtain Compound II per 94g, i.e. 16 Beta-methyls-Isosorbide-5-Nitrae, 9 (11)-triolefin androstane-3,17-diketone, mass yield: 94%, HPLC purity: 95%.
In a clean dried four mouthfuls of reaction flasks, add 300ml ethanol, 180g potassium cyanide, 200g Compound II per successively, system temperature control, in 0 ~ 5 DEG C, after stirring, is added dropwise to 80ml phosphoric acid, and system temperature control detects raw material in 10 ~ 20 DEG C of reactions 20h, TLC no longer to be reduced.Drip in 1000ml water to reaction system, stir 2h.Suction filtration, washing filter cake, to neutral, in 50 DEG C of oven dry after draining, obtains compound III 204g, i.e. 16 Beta-methyl-17 beta-cyano-17 Alpha-hydroxy androstane-Isosorbide-5-Nitraes, 9 (11)-triolefin-3-ketone, mass yield: 102%, HPLC purity: 97.5%.
600ml benzene, 100g compound III, 100ml DMAP is added successively in a clean dried four mouthfuls of reaction flasks, after stirring, temperature control to 40 ~ 45 DEG C, slow dropping 70g CMDMCS chloromethyl dimethyl chlorosilane, about 4h dropwises, and insulation reaction 1h, TLC detect without starting material left.In reaction system, drip 200ml water, stir 1h.Separatory, benzene layer is concentrated into dry, adds 500ml water, dispersed with stirring, suction filtration, washing filter cake is extremely neutral, in 50 DEG C of oven dry after draining, obtain compound IV 128g, i.e. 16 Beta-methyl-17 β cyano group-17 Alpha-hydroxy androstane-Isosorbide-5-Nitraes, 9 (11)-triolefin-3-ketone-17-(chloromethyl) dimethyl-silicon ethers, mass yield: 128%, HPLC purity: 96.4%.
Under nitrogen protection, in a clean dried four mouthfuls of reaction flasks, add 800ml toluene, 100g compound IV successively, after stirring; system temperature control to 10 ~ 15 DEG C, slowly drip 358ml 2mol/L lithium diisopropyl amido, about 5h dropwises; insulation reaction 0.5h, TLC detect without starting material left.Temperature control T≤20 DEG C, drop in 200ml concentrated hydrochloric acid by reaction system, stir 5h.System 10wt% aqueous sodium hydroxide solution adjusts PH=6 ~ 7, and temperature control T≤50 DEG C are concentrated into without obvious cut, in residue system, drip 500ml water, stir 1h, suction filtration, washing filter cake is to neutral, in 50 DEG C of oven dry after draining, obtain compound V 82g, the i.e. pregnant steroid-Isosorbide-5-Nitrae of chloro-17 Alpha-hydroxy of 16 Beta-methyl-21-, 9 (11)-triolefins-3,20-diketone, mass yield: 82.0%, HPLC purity: 97.3%.
Dioxane 250ml is added in three mouthfuls of reaction flasks, stir lower logical nitrogen 10min, drop into compound V 50g, be cooled to about-10 DEG C, add phosphorus pentabromide 45g, continue to stir 10min, drip 2wt% high chloro acid solution 100ml, 30min drips off, insulation reaction is about 3h, react complete, add 20wt% sodium sulfite aqueous solution 50ml, then 1wt% potassium hydroxide aqueous solution 200ml is added, stirring at room temperature reaction 10h, reaction is finished, slowly adding Glacial acetic acid adjusts PH to be about 7, add water 2000ml, stir loose crystallization, filtering drying obtains compound VI 47.5g, i.e. 16 Beta-methyl-21-chloro-9, the pregnant steroid-1 of 11-epoxy-17 Alpha-hydroxy, 4-diene-3, 20-diketone, mass yield: 95%, HPLC purity: 97%.
70wt% hydrofluoric acid aqueous solution 500ml is dropped in polytetrafluoro reaction flask, stir, be cooled to less than-5 DEG C, drop into compound VI 50g, in-10 ~ 0 DEG C of constant temperature stirring reaction 20h, reaction is finished, reaction solution being joined 3500ml is cooled in the frozen water of 0 DEG C in advance, drip ammoniacal liquor and adjust PH=6.5 ~ 7, filtering drying, obtain compound VI I crude product 49g, i.e. clobetasol, above-mentioned crude product is put into methyl alcohol 500ml, in the mixed solvent of trichloromethane 130ml, heat up clearly molten, add gac 4.9g, backflow 30min, suction filtration, filtrate negative pressure is concentrated into about 50ml volume,-10 ~ 0 DEG C of freezing crystallization 3h, filter, solid, a small amount of ice methanol rinses, dry, obtain clobetasol finished product 44g, mass yield: 88%, HPLC purity: more than 99%.
Compound VI I 100g is dropped in three mouthfuls of reaction flasks, methylene dichloride 300ml, propionyl chloride 100ml and imidazoles 30g, stirring is warming up to backflow, insulation reaction 14 ~ 16h, reaction is finished, cool to about 25 DEG C, drip water 200ml termination reaction, be evaporated to and gradually do, add water 1000ml, stir 30min, filtered water is washed till neutrality, dry to obtain compound VI II crude product 115g, i.e. clobetasol propionate, above-mentioned crude product is put into methyl alcohol 1150ml, in the mixed solvent of trichloromethane 230ml, heat up clearly molten, add gac 11g, backflow 30min, suction filtration, filtrate negative pressure is concentrated into about 150ml volume,-10 ~ 0 DEG C of freezing crystallization 3h, filter, solid, a small amount of ice methanol rinses, dry, obtain clobetasol propionate finished product 104g, mass yield: 104%, HPLC purity: more than 99%.
The foregoing is only preferred embodiment of the present invention; not in order to limit the present invention; anyly be familiar with those skilled in the art in the technical scope that the present invention discloses, the change that can expect easily or replacement, all should be encompassed in protection scope of the present invention.Therefore, the protection domain that protection scope of the present invention should define with claim is as the criterion.
Claims (9)
1. a preparation method for clobetasol, is characterized in that, with Compound I and Isosorbide-5-Nitrae, 9 (11)-triolefin androstane-3,17-diketone are starting raw material, and the chemical formula of Compound I is:
Comprise the following steps:
A) methylation reaction: Compound I is added and methylates in solvent; with the first organic bases and oxalic acid diethyl ester, 16 α hydrogen are protected; carry out methyl substituted with methylating reagent to 16 β hydrogen again, be finally hydrolyzed to obtain Compound II per to protection, the chemical formula of Compound II per is:
B) cyano group substitution reaction: added by Compound II per in cyaniding solvent, reacts with cyanating reagent, obtains compound III under the first catalyst action, and the chemical formula of compound III is:
C) silicon alkoxyl group protective reaction: compound III added in protection solvent, with silicon alkoxyl group reagent react under the second organic bases exists, obtain compound IV, the chemical formula of compound IV is:
D) intramolecular nucleophilic substitution reaction: compound IV added and replace in solvent, with alkali amide reagent react, obtain compound V, the chemical formula of compound V is:
E) Brominated Epoxy reaction: added by compound V in epoxy solvent, under the second catalyst action, react, obtain compound VI with bromizating agent and mineral alkali, the chemical formula of compound VI is:
F) fluoride reaction: compound VI added in hydrofluoric acid solution and carry out upper fluorine, reacts to obtain compound VI I, i.e. clobetasol, and the chemical formula of compound VI I is:
2. the preparation method of clobetasol according to claim 1, is characterized in that, described in the solvent that methylates be one or more in THF, methylene dichloride, chloroform, acetone and dioxane; Described first organic bases is one or more in sodium methylate, sodium ethylate and potassium tert.-butoxide; Described methylating reagent is one or more in methyl iodide, monobromethane and methyl-sulfate; The temperature of reaction of described methylation reaction is 0 ~ 70 DEG C.
3. the preparation method of clobetasol according to claim 1, is characterized in that, described cyaniding solvent is one or more in methyl alcohol, ethanol, n-propyl alcohol, Virahol, acetone and water; Described cyanating reagent is one or more in acetone cyanohydrin, potassium cyanide, sodium cyanide; When cyanating reagent is acetone cyanohydrin, described first catalyzer is one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium-acetate, Potassium ethanoate; When cyanating reagent be potassium cyanide and/or sodium cyanide time, described first catalyzer is one or more in Glacial acetic acid, hydrochloric acid, phosphoric acid; The temperature of reaction of described cyano group substitution reaction is 0 ~ 50 DEG C.
4. the preparation method of clobetasol according to claim 1, is characterized in that, described protection solvent is one or more in methylene dichloride, trichloromethane, tetracol phenixin, benzene, rudimentary aromatic hydrocarbon and acetone; Described second organic bases is one or more in DMAP, imidazoles, triethylamine, DBU; Described silicon alkoxyl group reagent is one or more in CMDMCS chloromethyl dimethyl chlorosilane, chloromethyl dimethyl bromo-silicane, chloromethyl dimethyl iodine silane; The temperature of reaction of described silicon alkoxyl group protective reaction is 0 ~ 60 DEG C.
5. the preparation method of clobetasol according to claim 1, is characterized in that, described replacement solvent is one or more in tetrahydrofuran (THF), dimethyl-tetrahydrofuran, hexanaphthene, ether, benzene, rudimentary aromatic hydrocarbon; Described alkali amide reagent is lithium diisopropyl amido; The temperature of reaction of described intramolecular nucleophilic substitution reaction is-10 ~ 50 DEG C.
6. the preparation method of clobetasol according to claim 1, is characterized in that, described epoxy solvent is one or more in acetone, dimethyl formamide, tetrahydrofuran (THF), dioxane; Described second catalyzer is one or more in organic acid, inorganic acid; Described bromizating agent is one or more in N-bromo-succinimide, phosphorus pentabromide, bromination dimethyl bromo sulphur, C5H6Br2N2O2, bromination ketone, Sodium Bromide, Potassium Bromide; Described mineral alkali is one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood; Described epoxy reactive temperature of reaction is-10 ~ 60 DEG C.
7. the preparation method of clobetasol according to claim 1, is characterized in that, described hydrofluoric acid solution is one or both in hydrofluoric acid dimethyl formamide solution, hydrofluoric acid aqueous solution; The temperature of reaction of described fluoride reaction is-40 ~ 60 DEG C.
8. the preparation method of a clobetasol propionate, it is characterized in that, comprise the Overall Steps of the preparation method of the arbitrary described clobetasol of claim 1 to 7, step g third esterification is also comprised: added by compound VI I in the third esterified solvent after step f, under the 3rd catalyst action, by propyl ester agent, the third esterification is carried out to 17 ɑ hydroxyls obtain compound VI II, i.e. clobetasol propionate, the chemical formula of compound VI II is:
9. the preparation method of clobetasol propionate according to claim 8, is characterized in that, described third esterified solvent is one or more in rudimentary alkyl chloride; Described propyl ester agent is propionic anhydride or propionyl chloride; When propyl ester agent is propionic anhydride, described 3rd catalyzer is one or more in organic acid, inorganic acid; When propyl ester agent is propionyl chloride, described 3rd catalyzer is one or more in organic bases; The temperature of reaction of described esterification is 0 ~ 80 DEG C.
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