CN107793460A

CN107793460A - A kind of preparation method of fluocortolone

Info

Publication number: CN107793460A
Application number: CN201610768046.7A
Authority: CN
Inventors: 宋德成
Original assignee: Tianjin Pacific Pharmaceutical Co Ltd
Current assignee: Tianjin Pacific Pharmaceutical Co Ltd
Priority date: 2016-08-30
Filing date: 2016-08-30
Publication date: 2018-03-13

Abstract

The present invention relates to a kind of method for preparing fluocortolone, and it passes through the grignard reaction of compound of formula I, production II fluocortolone.The present invention prepares the method simple in circuits of fluocortolone, and easy to operate, raw material is easy to get, and production cost and industrialized condition substantially reduce.

Description

A kind of preparation method of fluocortolone

Technical field

The present invention relates to the preparation method of steroidal compounds, more particularly, to the preparation of fluocortolone.

Background technology

Fluocortolone and its ester are the fluorine-containing corticosteroid medications for topical application, have anti-inflammatory activity, often with ointment Or the form of emulsifiable paste is widely used in multiple dermatosis problem, such as：Product Ultralan is fluocortolone and fluocortolone butyrate Compound preparation, for treat contact dermatoses, eczema, occupational eczema, ichthyosis, neurodermatitis, eczema of anus, A variety of skin problems such as dyshidrotic eczema.Schering AG have listed a kind of trade name Ultraproct product, are Using fluocortolone pivalate and anaesthetic Lignocaine as compound, the low distending pains and anal orifice being led to by hemorrhoid of Neng You Xiao Di Minus The redness on periphery.

Fluocortolone is obtained by Schering Corp (ScheringAG) exploitation earliest, and the main document that synthesizes sees United States Patent (USP) US3232839.The patent is with 16 Alpha-Methyls-Δ⁵- pregnant the β of steroid -3,21- glycol -20- ketone -21- acetates are that starting material passes through Br- F additions obtain the α of 16- methyl-5-bromo- 6 β-fluoro- 3,21 glycol-20- ketone-21- acetates, are then aoxidized by chromic anhydride by 3 hydroxyls Base is converted into carbonyl, then sloughs bromine, is in acid condition α conformations by β Conformation transitions by 6 fluorine, then makees in microorganism Under, hydroxyl is introduced at 11, while saponification occurs, 21 ester hydrolysis are finally first bit esterified by 21, then in microorganism Lower 1,2 dehydrogenations of effect, while 21 saponification, obtain fluocortolone.

Above-mentioned patent system is although feasible for the route of fluocortolone, but it introduces beta-hydroxy and 1,2 dehydrogenations at 11 The microbe fermentation method being respectively adopted, inventory are only 0.025%, low production efficiency, low yield, add production cost, no Beneficial to industrialized production.In addition, 3 hydroxyls are converted into carbonyl makees oxidant with chromic anhydride, contaminative is strong, is brought to cleaning procedure It is difficult.

The content of the invention

For the deficiency in fluocortolone synthetic method in history, we have explored the work of new synthesis fluocortolone and its ester Skill route：

Compound of formula I passes through grignard reaction, production II fluocortolone.

It is preferred that compound of formula I obtains its ethyl esterified formula III compound by the esterification of routine on its 21；

The compound of formula III again with grignard reagent reacting, production IV compound；

The compound hydrolysis production II of formula IV compound：

Specifically：

Step 1：Esterification

The acetic anhydride matched by compound of formula I and in right amount is added in organic solvent, and after reaction terminates, reaction solution is diluted in In water, solid is filtered out after water dilution, obtains ethyl esterified formula III compound.

Step 2：Grignard reaction：

Formula III compound is added in the solvent of such as tetrahydrofuran, add grignard reaction catalyst cuprous chloride or iodine Change sub- ketone, under nitrogen atmosphere, add RMgBr CH3Mgl and grignard reaction occurs, react and obtain formula IV through processing after terminating Compound.

Step 3：

By in the compound of formula IV and the organic solvent matched in right amount input reactor, lead to nitrogen, addition prepares in advance Organic solvent aqueous slkali, reaction terminate after, using acetic acid regulation pH value arrive 6.5-7.5, concentrate, crystallized, i.e. product formula II fluocortolone.

More specifically：

The esterification of step 1, the organic solvent of selection includes lower aliphatic alcohols, such as methanol or ethanol；Ketone, such as third Ketone；Halogenated hydrocarbons, such as chloroform；Ethers, such as ether, tetrahydrofuran etc.；Basic solvent, such as pyridine, pyrimidine.From these organic solvents In one or more.It is preferred that tetrahydrofuran, pyridine, more preferably pyrimidine, pyridine and pyrimidine.Reaction temperature is 10 DEG C to backflow, It is preferred that 30~60 DEG C.

The grignard reaction of step 2, the more preferably preferred dioxane of organic solvent or tetrahydrofuran of selection, tetrahydrofuran. The preferred cuprous chloride of grignard reaction catalyst, iodate Asia ketone.The preferred CH3Mgl of RMgBr.The addition temperature of RMgBr for- 50~20 DEG C, preferably -20~5 DEG C.Reaction temperature is maintained at -20~10 DEG C, preferably -10~5 DEG C.After reaction terminates, acid is used Neutralize, acid is organic acid, preferably acetic acid.Dilution buck can be conventional inorganic base, preferably ammoniacal liquor, aqueous ammonium chloride solution.

The organic solvent that the hydrolysis of step 3 is selected includes lower aliphatic alcohols, such as methanol or ethanol；Ketone, such as acetone； Halogenated hydrocarbons, such as chloroform；Ethers, such as ether, tetrahydrofuran etc.；From the one or more in these organic solvents；It is preferred that methanol, Acetone, chloroform and dichloromethane and its two or more mixed solvents, more preferably methanol and chloroform mixed solvent.Organic solvent alkali Solution refers mainly in polar solvent plus alkali, and polar solvent includes lower aliphatic alcohols, such as methanol or ethanol；Ketone, such as acetone；Ether Class, such as ether, tetrahydrofuran etc.；It is preferred that methanol and ethanol；Alkali refers mainly to inorganic base, preferably sodium hydroxide and potassium hydroxide.Instead The temperature answered is -10~40 DEG C, preferably -5~20 DEG C.Reaction terminates after neutralizing, and concentration is refined.

The present invention prepares the method simple in circuits of fluocortolone, and easy to operate, raw material is easy to get, production cost and industrialized condition Substantially reduce.

Embodiment

Below will by embodiment, the invention will be further described, these description be not present invention is made into The restriction of one step.It should be understood by those skilled in the art that the equivalent substitution made to the technical characteristic of the present invention, or change accordingly Enter, still fall within protection scope of the present invention.

The preparation of the formula III compound of embodiment 1

By in 3.61g compound of formula I and 15ml pyridines input tri- mouthfuls of reaction bulbs of 50ml, stirring and dissolving, 5ml acetic acid is added Acid anhydride, it is warming up to back flow reaction 0.5 hour, is diluted in water, stir 2 hours, stand 1 hour, filtering, is washed to neutrality (PH= 6.5-7), discharge, dry, obtain 3.99g product formula III compounds.The compound is directly used in reacts in next step, MS points of test Son amount：402.18；Mol.Wt：402.46.

The preparation of the formula IV compound of embodiment 2

By 50ml THF, 0.1g cuprous chlorides and 3.99g formula IIIs compound add tri- mouthfuls of reaction bulbs of 100ml, lead to nitrogen, Stirring, cools to less than -5 DEG C, adds the RMgBr CH3Mgl prepared, be incubated at -10 ± 2 DEG C 2 hours, adds 0.5ml Acetic acid, reaction solution is diluted in the ammonium chloride water of 300ml 15% prepared, 0~5 DEG C is stirred 1 hour, stands 1 hour, filtering, Discharging, dry, obtain 4.01g formula IV compounds, test MS molecular weight：418.23；Mol.Wt：418.51.

The preparation of the Formula II compound of embodiment 3

By in 4.01g formula IVs compound and 30ml methanol input tri- mouthfuls of reaction bulbs of 100ml, lead to nitrogen, stirring and dissolving, keep Temperature adds 1ml 2%NaOH/ ethanol solutions at 0-5 DEG C, reacts 1.5 hours, adjusts pH value to 6.5-7.5 using acetic acid, subtracts Pressure concentration, less than 5 DEG C are cooled to after concentration, are maintained at 0-5 DEG C and are stood 1 hour, filter, dry, and are recrystallized to give 3.2g productions The fluocortolone of thing Formula II.

Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should It is considered as protection scope of the present invention.

Claims

1. a kind of method for preparing fluocortolone, its route are：

2. preparation method according to claim 1, it is characterised in that：

Compound of formula I obtains its ethyl esterified formula III compound by the esterification of routine on its 21；

The compound hydrolysis production II of formula IV compound：

3. the method according to claim 1 or 2 for preparing fluocortolone, it is characterised in that：

Step 1：Esterification

The acetic anhydride matched by compound of formula I and in right amount is added in organic solvent, and after reaction terminates, reaction solution is diluted in into water In, solid is filtered out after water dilution, obtains ethyl esterified formula III compound；

Step 2：Grignard reaction：

Formula III compound is added in the solvent of such as tetrahydrofuran, add grignard reaction catalyst cuprous chloride or iodate is sub- Ketone, under nitrogen atmosphere, add RMgBr CH3Mgl and grignard reaction occurs, react and obtain the chemical combination of formula IV through processing after terminating Thing；

Step 3：

By in the compound of formula IV and the organic solvent matched in right amount input reactor, lead to nitrogen, what addition prepared in advance has Solvent aqueous slkali, after reaction terminates, pH value is adjusted to 6.5-7.5 using acetic acid, concentrates, is recrystallized to give the fluorine of product Formula II Can dragon.

4. preparation method according to claim 3, it is characterised in that：

The esterification of step 1, the organic solvent of selection is pyridine；Reaction temperature is backflow；

The grignard reaction of step 2, the organic solvent of selection is tetrahydrofuran, and grignard reaction catalyst is cuprous chloride, and grignard is tried Agent is CH3Mgl, and the addition temperature of RMgBr is -5 DEG C, and reaction temperature is maintained at -10 ± 2, after reaction terminates, uses acetic acid Neutralize, and diluted with aqueous ammonium chloride solution；

The organic solvent that the hydrolysis of step 3 is selected is methanol, and organic solvent aqueous slkali is NaOH/ ethanol solutions, reaction Temperature is 0-5 DEG C.