Method for preparing flumetasone, compound

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes the improved method for preparing flumetasone (6α,9α-difluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione), flumetazone 21-acetate or its 17-carboxyl-androstene analogue of the formula (I) . Method involves interaction of benzoyl chloride with compound of the formula (II) in pyridine medium of its mixture with N,N'-dimethylacetamide to prepare 3-enol ester of the formula (IIIa) and it's the following interaction with 1-(chloromethyl)-4-fluoro-1,4-diazonium-bicyclo[2.2.2]octane-bis(tetrafluoroborate) in acetonitrile medium and water to prepare compound of the formula (IIIb) and the following removing the protective group in compound of the formula (IIIb) at the position C3 in medium of aqueous metabisulfite and ammonia to prepare compound of the formula (IV) . After the fluorination reaction of 9,11-epoxy group in compound of the formula (IV) using HF flumetasone 21-acetate is prepared followed by the selective hydrolysis with KOH in methanol (CH3OH) medium in the presence or absence of H2O2 to prepare compound of the formula (I) or flumetasone, respectively.

EFFECT: improved preparing method.

3 cl, 5 ex

 

The present invention relates to a method for flumetazon, flumetazon 21-acetate and 17-carboxylesterase analog, as well as some of the initial substances for the implementation of this method.

Flumetazon, 6α,9α-debtor-16α-methylprednisolone was first described in 1962. Although this steroid has a high anti-inflammatory activity, it has not found wide application in clinical practice. Currently, cheap obtain this medication on an industrial scale is becoming more important because this substance is also an excellent feedstock for the production of new debtor-17-carboxyaniline, which are becoming increasingly important substances from a clinical point of view.

Flumetazon its receipt been the subject of several patents, including US patent 3499016 (1962) and the patent GB 902292 (1970). New synthetic technologies developed since 1970, allow more efficient production of flumetazon with a significantly higher yield compared with the outputs that have been achieved in earlier patents.

Developed a new method of obtaining flumetazon and receive 6α,9α-debtor-11β,17α-dihydroxy-16α-methyl-17β-carboxylate-1,4-Dien-3-one, also known as "hydroxycitrate" represents an excellent starting material for receiving fluticasone and other new anti-inflammatory compounds androsta-1,4-diene series. "Hydroxycitrate" was first described and claimed in patent US 3636010 priority (1968).

In the European patent 0610138 B1 (1994) describes a new synthetic method of obtaining the so-called "hydroxy acid". However, the present invention has a significant and unexpected advantages over the method described in the mentioned patent is:

- the reaction sequence is reduced by one stage through the elimination stage desolvatation 6α,9α-debtor-11β,17α-dihydroxy-16α-methyl-17β-methoxycarbonylamino-1,4-Dien-3-one, an additional stage of the process,

the method of the present invention eliminates the use of highly toxic reagent, dimethylsulfate,

- provides simultaneous deacetylation and oxidation degradation of the side chain Pregnana, resulting directly formed equivalent androstanolone derived,

- increased output hydroxy acid of high purity.

While all of the reaction stage of the present invention, except for the last stage, implemented in pregnanolone series that provides efficient retrieval flumetazon, the sequence of reactions according to EP 0610138 B1 converts traditional source material of both processes, for example, in the first stage, in connection androstane the first row.

In accordance with the present invention provides a method of obtaining flumetazon (6α,9α-debtor-11β,17α,21 trihydroxy-16α-methylpregna-1,4-diene-3,20-dione), flumetazon 21-acetate or its 17-carboxylesterase analogue of the formula:

moreover, such a method includes:

(a) reaction of compounds of formula (II)

c benzoyl chloride with the formation of 3-enol ether complex of the formula (IIIa)

b) reaction of roventine (IIIa) with an electrophilic fluorinating agent with the purpose of introducing fluorine in the C6 position with the formation of new compounds of the formula (IIIb)

(c) removing the protective group from position C3 in the compound (IIIb) with the formation of the compounds of formula (IV)

d) fluoridation 9,11-epoxypropyl compounds IV by reaction with hydrofluoric acid with the formation of flumetazon 21-acetate; and

e) optional hydrolysis flumetazon 21-acetate in the presence or in the absence of oxidizing agent, to form compound (I) or flumetazon respectively.

In addition, the present invention also provides compounds of formula (V)

where X represents a hydrogen or fluorine.

In stage d) of the method is formed flumetazon 21-acetate of the formula

ie 6α,9α-debtor-11β,17α,21 trihydroxy-16α-methylpregna-1,4-diene-3,20-dione, 21-acetate. As a result of hydrolysis of this compound, preferably with a solution of potassium hydroxide in methanol, formed flumetazon that does not contain alcohol.

On the other hand, as a result of hydrolysis of the acetate flumetazon, preferably with a solution of potassium hydroxide in methanol, and subsequent oxidation, preferably with a solution of hydrogen peroxide, are the so-called "gidrokshikislotu", corresponding to the formula

The present invention provides a direct conversion of acetate flumetazon in connection I.

Two new compounds IIIa and IIIb meet the General formula (V)shown in item 8.

Compound I may also be obtained in accordance with the patent US 3636010 as a result of oxidation flumetazon that does not contain alcohol.

The original material of the present invention is a commercially available product and is widely used for receiving corticosteroids such as dexamethasone and ecomarathon.

To introduce the fluorine in the C6 position in the electrophilic fluorination, you must first activate the C6 position. For this purpose, 3-ketogroup subjected enolizatsii using the acid chloride of carbon is th acid with the formation of the remainder of the enol ether complex of the formula-COR, in which R represents aryl or aracelio group. The preferred substance for enolizatsii is benzoyl chloride, the interaction with which is formed the substance of the formula IIIa in the presence of a tertiary amine such as pyridine. The preferred solvent is N,N'-dimethylacetamide, and the reaction is preferably carried out at a temperature of 80-85°With the resulting gain Δ3,5-inalberta. After this connection IIIa is reacted with an electrophilic fluorinating agent to obtain the corresponding C6-fluoro derivative. The preferred fluorinating agent is a 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate), Selectfluor®. For carrying out fluorination at position C6 preferred solvent is acetonitrile in the presence of water at the preferred temperature -5°+2°C. After fluorination at position C6 3-enol ester can be easily converted into 3-keto-1,4-diene system with the formation of compound IV. Elimination enol ether complex is preferably carried out using an aqueous solution of sodium metabisulfite in ammonia.

At the next stage, known per se manner at a temperature below 25°To carry out the reaction between 9,11-epoxypropoxy compounds IV and a concentrated aqueous solution of fluoric the hydrogen of the acid or a solution of hydrogen fluoride in N,N'-dimethylformamide. After the compound IV is almost completely reacted, the reaction mixture was poured into a mixture of ice with ammonia, which is sufficient to neutralize hydrofluoric acid and simultaneous deposition with high yield flumetazon 21-acetate with high purity. The resulting product can be recrystallized, for example, from methanol. Then, the obtained 21-acetate may be subjected to hydrolysis by any known means with the formation of flumetazon that does not contain alcohol. One of the preferred methods is carried out in degassed solution of potassium hydroxide in methanol at a temperature in the range of -15° - -5°C. After 1 hour by HPLC establish completion of the reaction, which is completed when the amount of starting compound is less than 1%.

In accordance with the known method, in order to conduct oxidative degradation, flumetazon suspended in tetrahydrofuran and add drops of the solution of oxidizing agent. First is the dissolution of the substrate with its subsequent deposition. The oxidation is preferably carried out at 20°using, for example, periodic acid. After 1 hour stirring the completion of the reaction is determined by HPLC. If the amount of unreacted flumetazon is less than 0.3%, the reaction is considered complete. Then p is a promotional mix containing compound I, precipitated by adding the reaction mixture an aqueous solution of sodium metabisulfite and ice.

In accordance with the present invention flumetazon 21-acetate can be simultaneously subjected to deacetylation and oxidation of the potassium hydroxide solution in methanol and an aqueous solution of hydrogen peroxide with the formation after completion of the reaction, the desired hydroxy acid, compound I, acidification of the reaction mixture with dilute hydrochloric acid solution to pH 2. This reaction is carried out at 10°+2°under stirring until it is completed.

The total stoichiometric output in the manner described in EP 0610138 B1, based on supercriticalities connection I is 48.9% of 9,11β-epoxy-17α,21-dihydroxypregna-1,4-diene-3,20-dione. In accordance with the present invention, according to the data given in examples 1b, 2 and 4, the total stoichiometric output is 62.4 per cent when using the 21-acetate as the starting substance. To conduct an informed comparison of the outputs of the source material EP 0610138 B1 first azetilirovanie exit 110% mass/mass and total stoichiometric yield was calculated on the basis of this value and the values obtained in examples 1b, 2 and 4, upon receiving the value of 61.7%.

The following examples are presented to illustrate this image is possible and not limit its scope.

EXAMPLE 1

9,11β-epoxy-6α-fluoro-17α,21-dihydroxy-16A-methylpregna-1,4-diene-3,20-dione, 21-acetate (formula V)

a) In an inert atmosphere, 50 g 9,11β-epoxy-17α,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione, 21-acetate was dissolved in 25 ml of N,N'-dimethylacetamide (DMA). Added 65 ml of pyridine and the reaction mixture was heated with stirring to a temperature of between 80 and 85°C.

After that, when the system protection from light was added 33 ml of benzoyl chloride. Stirring is continued for two to three hours at the same temperature. After completion of the reaction the mixture was cooled to 40°C. Then was added 75 ml of methanol and stirring was continued for 30 minutes at 40°C, after which the reaction mixture was cooled to 20-25°C. Next, the reaction mixture was added to 1000 ml of water containing of 57.5 ml of hydrochloric acid and 100 ml of dichloromethane. The phases were separated and the aqueous phase was additionally extracted with 100 ml dichloromethane. The organic phases were combined and washed with water and aqueous sodium hydroxide solution. Thus obtained dichloromethane solution was evaporated to dryness in vacuum with the formation of oil, representing 21 acetate 3-benzoyloxy-9,11β-epoxy-17α,21-dihydroxy-16α-methylpregna-1,3,5-triene-20-she (formula IIIa), which was treated with 150 ml of acetonitrile, cooled to -5 - 0°C. Then Astor of roventine was added to a suspension of 44,5 g of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), Selectfluor®in 175 ml of acetonitrile containing 5 ml of water.

After completion of the reaction of fluorination at position C6 (formula IIIb), the reaction mixture was poured into a solution containing 100 ml of water, 1.2 g of sodium metabisulfite, 5 ml of 25% ammonia and 200 ml of dichloromethane. the pH of the solution was brought to values in the range of 7-8 and the mixture was stirred for 30 minutes, after which the phases were separated and the organic phase is washed with ammonia solution (12.5 percent). Next, the organic phase is evaporated to dryness in vacuo and added to methanol. The target compound was led, and then it was filtered, and dried at 40-45°to obtain 40 g of the desired product with a purity of 90%, calculated from the peak areas determined by HPLC.

b) Repeating the procedure of example 1A, however, the resulting 3-inalberta not were extracted and isolated. To the reaction mixture obtained in example 1A, slowly and directly added to 44.5 g of crystals Selectfluor®conducting adding four portions. When the content of the source material in quantities less than 1% of the reaction mixture was poured into 100 ml of water containing 1.2 g of sodium metabisulfite. Then the pH is brought to values in the range of 7-7,5, the solution was stirred for 30 minutes and the resulting precipitate was filtered and washed. Next, the thus obtained product was washed by suspension in 150 ml of methanol when the AC is shivani. After stirring for 30 minutes the product was filtered and dried at a temperature of 40-45°to obtain 46 g of 21-acetate 9,11β-epoxy-6α-fluoro-17α,21-dihydroxy-1,4-diene-3,20-dione with a purity of 91.6%.

EXAMPLE 2

The 21-acetate of 6α,9α-debtor-11β,17α,21 trihydroxy-16α-methylpregna-1,4-diene-3,20-dione (21-acetate flumetazon).

36 g of the compound obtained in example 1 was dissolved in inert atmosphere in 360 ml of a complex of hydrogen fluoride and N,N'-dimethylformamide (˜64% mass/mass) at a temperature of 20±3°C. After stirring for three hours at this temperature, stir the product was poured into a mixture of 3000 ml of water, 1000 ml of ice and 800 ml of ammonia (25%), maintaining the temperature during the deposition on the value below 25°C. the pH was brought to values in the range of 4.5-5 with a solution of ammonia and stirring is continued for one hour. Then the precipitate was filtered and washed with water to neutral pH values. After drying, the compound was dissolved in a mixture of 333 ml of dichloromethane and 148 ml of methanol. The resulting solution was concentrated to a volume of 89 ml with the crystallization of the desired product. After filtration, the crystals were dried at a temperature of 40-45°obtaining 29,2 g 6α,9α-debtor-11β,17α,21 trihydroxy-16α-methylpregna-1,4-diene-3,20-dione, 21-acetate with a purity of 95%, particularly the second peak area, specific HPLC method.

EXAMPLE 3

6α,9α-debtor-11β,17α,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione (Flumetazon)1.4 g of potassium hydroxide was dissolved in 140 ml of degassed methanol under inert atmosphere and the resulting solution was cooled to 0 to -5°C. Then, with stirring, the solution was added to a suspension of 28 g of the compound obtained in the previous example, in 700 ml of degassed methanol. The resulting mixture was stirred for 1-2 hours at a temperature of -10°+2°C. After completion of the reaction, according to the HPLC system was added acetic acid to pH 7. Then the volume of the system was reduced in vacuo to ˜224 Jr. then were cooled to 10°and added 140 ml of cold water. After stirring for one hour at a temperature of between 5 and 10°the resulting material was filtered, washed with water and dried at 45°with the formation of 22.4 g of target compound with a purity of 96% according to the determination of the peak area by HPLC.

EXAMPLE 4

6α,9α-debtor-11β,17α-dihydroxy-16α-methyl-17β-carboxylate-1,4-Dien-3-one (formula I, "hydroxycitrate")

In an inert atmosphere, 2 g of potassium hydroxide was dissolved in a mixture of 100 ml methanol and 100 ml of water. After this was added 10 ml of an aqueous solution of hydrogen peroxide (130 volumes) and the reaction mixture was cooled to 10°+2°to to the th was added 5 g of 21-acetate flumetazon. The reaction mixture was stirred overnight at the same temperature, and after completion of the reaction, hydrochloric acid brought the pH to a value of 2. The precipitate was filtered off, washed with water until neutral pH and dried at 45°C. the Yield of the target compounds was 80% mass/mass, which corresponds to the stoichiometric yield of 91.3%.

EXAMPLE 5

6α,9α-debtor-11β,17α-dihydroxy-16α-methyl-17β-carboxylate-1,4-Dien-3-one

22 g flumetazon, not containing alcohol obtained in example 3 in an inert atmosphere suspended in 110 ml of tetrahydrofuran and cooled to 20°+2°C. With stirring was slowly added to 17.6 g period acid in 70 ml of water. After stirring at the same temperature the completion of the reaction was determined by HPLC. Has determined that the reaction is usually completed within two hours. After the reaction mixture was poured into a solution of 33 g of sodium metabisulfite in 770 ml of water and 330 ml of ice. The precipitated reaction product was filtered and washed with water until neutral pH, then dried at 40-45°to obtain 21 g of the target compound with a purity of 96% according to the determination of the peak area by HPLC. After recrystallization of the resulting compound in ethanol was obtained 6α,9α-debtor-11β,17α-dihydroxy-16α-methyl-17β-carboxy what androsta-1,4-Dien-3-one high purity, having the following analytical values:

optical rotation = +64,4° (C=1% in DMF);

- KF - 0,09%;

the purity determined by HPLC according to the peak area = 99,2%.

The product is characterized by a major absorption peaks in the infrared region at wavelengths 1698 cm-1, 1660 cm-1, 1614 cm-1and 1603 cm-1.

1. The method of obtaining flumetazon (6α,9α-debtor-11β,17α,21 trihydroxy-16α-methylpregna-1,4-diene-3,20-dione), flumetazon 21-acetate or its 17-carboxylesterase analogue of the formula:

including

(a) reaction of compounds of formula (II)

with benzoyl chloride to form a 3-enol ether complex of the formula (IIIa), in which the reaction medium is a pyridine or N,N'-dimethylacetamide and pyridine:

b) reaction of roventine (IIIa) with an electrophilic fluorinating agent, which is 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate) for the introduction of fluorine in the C6 position with the formation of the compounds of formula (IIIb), the reaction medium is a acetonitrile in the presence of water

(C) removing the protective group from a position NW of the compound (IIIb) with the formation of compounds is of formula (IV) using an aqueous solution of metabisulfite and ammonia:

(d) the fluoridation of 9,11-epoxypropyl compounds IV by reaction with hydrofluoric acid to obtain 21-acetate flumetazon, and optional

(e) hydrolysis of the 21-acetate flumetazon potassium hydroxide solution in methanol in the presence or in the absence of oxidizing agent, which is an aqueous solution of hydrogen peroxide, to obtain the compound (I) or flumetazon respectively.

2. The method according to claim 1, wherein the reaction temperature in stage (a) is from 80 to 85°and at the stage (b) (-5)±2°C.

3. The compound of formula (V):

in which X represents hydrogen or fluorine.



 

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