KR820001643B1 - Process for the preparation of 6-halo-pregrnanes - Google Patents

Abstract

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Description

Improved Manufacturing of 6-Halo-Pregnanes

The present invention relates to a process for the preparation of 6α-halo-3-metho-Δ ¹ , ⁴ -pregnadiene derivative of the following formula (III).

의 그룹을 나타내며, w는 수소 또는 하이드록시 또는 메틸이고, X는 할로겐, 특히 불소 및 염소이다.Wherein R and Z are hydrogen, hydroxy, or acyloxy derived from a carboxylic acid of up to 9 carbon atoms, or when Z is hydroxy and w is hydroxy

And w is hydrogen or hydroxy or methyl and X is halogen, in particular fluorine and chlorine.

The present invention reacts a 3-keto-9β, 11β-oxido-Δ ¹ , ⁴ -pregnadiene derivative with a suitable acylating or ethering agent to give the corresponding 3-enol derivative and reacts with a suitable halogenating agent to halogenate it. by 6α- halo-3-keto -Δ ^{1, 4} - the synthesis of a steroid compound having a strong activity such as program derivative 6α- fluoro regeuna diene-frame that Nadi yen derivative particularly Δ ^{1, 4} -3-keto It is about a method.

These derivatives are Δ ⁴ -3-keto steroid of Δ ^{3, 5} derived from-the fact that conventional manufacturing processes with the diene 3-ol esters or ethers of halogenated parent E reagent is already known. Wiri has been found that it is possible to carry out the reaction successfully through the same reaction route starting from Δ ^{1, 4} -3- keto compound.

11 that the keto group to be having on the nolhwa Δ ^{1, 4} -3- keto group of a limited group known to the literature (U.S. Patent 3.50665 million and U.S. Patent No. 3,629,299), the large 11-keto group is more active 11β The process of converting to a hydroxy compound (which may or may not have a p-halo substituent) is very complicated.

We surprisingly react the 9β, 11β-oxido-steroids with suitable acylating or etherifying agents such as acyl anhydride, isopropenyl acetate, trialkylorthoformates, etc., under well controlled conditions of 3-enol- The derivatives are halogenated with a suitable halogenating agent such as N-haloamide perchlor, lauryl fluoride and the like to form 3-enol derivatives of 9β, 11β-oxido-Δ ^{1, 4} -prognadien-3-ones, that is, 9β, 11β- It has been found that oxido-Δ ^1,3,5 -pregnatrien-3-ol 3-esters or 3-ethers can be produced in high yield.

The halogenation reaction is carried out in advance of the 3-enol-derivatives or directly in the enolation reaction mixture. In this case, after completion of the enolation reaction, most of the solvent or reactants are removed under vacuum and the residue is dissolved in the solvent in the next step.

An object of the present invention is to provide novel steroid intermediates such as 9β, 11β-3-oxido-Δ ¹ , ⁴ -keto-steroids.

A further object of the present invention to provide a simplified process for forming a 6-halo, derivatives of Δ ^{1, 4} -3- keto steroids.

An advantage of the present invention is the fact that the resulting 6-halo derivatives are generally mixtures in which the a-orientation epimer is at least an α-epimer superior.

Conventional manner with a halo-6α- -Δ ^{1, 4} -3- keto-high activity corresponding to when the ring-opening of the epoxy ring of the derivative with a halo genistein deureu acid 6α, 9α- hydroxy -Δ ^{1, 4} -11β- a dihalo -Pregnadiene-3-ones are easily obtained. If the desired end product is a 6α-fluoro-derivative without substituents at the 9-position, the epoxides are ring-opened with halogenideric acid other than hydrofluoric acid. The resulting 9-halo derivative is then dehalogenated by a known method.

The method according to the invention can be represented by the following scheme.

R in the above formula is hydrogen or hydroxy or acyloxy,

R 'is acyl or alkyl,

Z is hydrogen or hydroxy or acyloxy,

w is hydrogen, hydroxy or methyl,

X is halogen,

Y is hydrogen or halogen.

In the starting material (I), when Z is hydroxy and w is α-direction hydroxy, these cis-diols are condensed with a single molecule of ketone or aldehyde to form 16α, 17α-acetan, or ketan group; When the R or Z or w of orientation present in the α- hydroxy in formula (Ⅰ) a compound Δ ^1, nolhwa the reaction of ^4-3-ketone belongs in the enol esterification reaction wherein the group is acylated by the following structural formula (Ⅱ In the compounds of (III) and (IV) are present as acyloxy groups with the same acyl moiety as the enol esterification agent used in the reaction.

Such acyloxy group may be removed by a conventional method or may be preserved as it is in order to obtain a free hydroxy derivative.

The following examples illustrate the invention.

Example 1

a) 9β, 11β-oxido-16α, 17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione 16,17-acetonide 21-acetate (10 g) and p-toluene sulfone A solution of isopropenyl acetate (100 ml) of phonic acid monohydrate (1.5 g) is sometimes distilled for 10 hours while adding isopropenyl acetate to maintain the volume at 100 ml. The solution is cooled to room temperature and 10 g of solid sodium hydrogen carbonate is added.

The remaining reactant is distilled off under vacuum, the residue is shaken with ether and water, the layers are separated and the aqueous layer is extracted twice with ether. The extracts are combined, washed with water and then with sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the residue was crystallized from methanol to give 3,2-diacetoxy-9β, 11β-oxide-16α, 17α-dihydroxy-pregna-1,3,5-trien-20-one -16,17-acetonide (10 g) is obtained. Melting Point: 182 ℃

[α] _D -195 ° (dioxane)

b) Perchloryl fluoride is passed through a solution of compound (9.5 g) in 400 ml tetrahydrofuran (containing 20% water) for 45 minutes. Nitrogen gas is removed from the mixture for 30 minutes to remove excess reactants and distilled under reduced pressure to remove most of the solvent. The residue is extracted with ether, the extracts are combined, washed with 5% sodium hydrogen carbonate and then washed with water. After drying over anhydrous sodium sulfate, the solvent was removed under vacuum and the residue was treated with methanol to give 6α-fluoro-9β, 11β-oxido-16α, 17α 21-trihydroxypregna-1,4-diene-3,20 Dion 16,17-acetonide 21-acetate (7.0 g) is obtained.

[α] _D + 59 ° (dioxane)

Treatment of the compound with hydrogen fluoride in a conventional manner yields fluorinide, which, if necessary, deacylated yields fluorocinolone acetonide. It has the same physical and chemical properties as the compound prepared according to the known method.

Example 2

5 g of 9β, 11β-oxido-17α, 21-dihydroxypregna-1,4-diene-3,20-dione are reacted with isopropenyl acetate as in Example 1a. The reaction mass was removed and the residue was dissolved in aqueous tetrahydrofuran (200 ml) and treated with perchloryl fluoride according to Example 1b to 6α-fluoro-9β11β-oxido-17α, 21-dihydroxypreg -1,4-diene-3,20-dione-17,21-diacetate (3,4 g) is obtained. Melting Point 224 ° C (Decomposition)

[α] _D + 3.14 ° (dioxane)

Treatment of the compound by conventional methods yields 6α, 9α-difluoro-prednisolone diacetate. Alkaline deacylation gives 6α, 9α-difluoroprednisolone, which has the same physicochemical properties as the compound prepared according to a known method.

Example 3

12 g of 9β, 11β-oxido-16α-methyl-17α, 21-dihydroxypregna-1,4-diene-3,20-dione was treated as in Example 2 and crude 6α-fluoro- 9β, 11β-Oxydo-16α-methyl-17α, 21-dihydroxypregna 1,4-diene-3,20-dione 17,21-diacetate (8.7 g) is suspended in a mixture of methylene chloride-methanol It is then treated with a catalytic amount of metallic potassium hydroxide for 90 minutes at room temperature under nitrogen gas.

After neutralization with aqueous acetic acid, the solution was concentrated under reduced pressure and the residue was crystallized from methanol to give 6αfluoro-9β, 11β-oxido-16α-methyl-17α, 21-dihydroxypregna-1,4-diene- 3,20-dione (6.5 g) is obtained. Melting Point: 268 ℃ (Decomposition)

[α] _D + 31 ° (DMF)

Treatment of the compound with hydrogen fluoride in a conventional manner yields flumethasone, which has the same physical-chemical properties as the compound prepared according to known methods.

Example 4

2 g of the 6α-fluoro derivative prepared in Example 1b was added dropwise to 10 ml of aqueous hydrobromic acid (48%) (precooled to 15 DEG C) with stirring, and left at 0 DEG C for 2 hours, followed by excess sodium carbonate. Pour into ice solution. Extracted with methylene chloride and crystallized from methylene chloride-methanol gave 6α-fluoro-9α-bromo-11β, 16α, 17α, 21-tetra hydroxypregna-1,4-diene-3, 20-dione 16,17 Acetonide 21-acetate (2.15 g) is obtained. Melting Point: 218 ° C (Decomposition)

[α] _D + 106.4 ° (dioxane)

9-debromination of the compound according to known procedures freezes 21-acetate of flunisolid.

Example 5

a) Tetrahydrofuran (50 ml) of 9β, β-oxido-16α, 17α, 21-trihydroxypregna-1,4-diene-3,20-dione 16,17-acetide 21-acetate (10 g) Methylorthoformate (10 ml), methanol (20 ml) and p-toluene-sulfonic acid (400 mg) are added to the suspension, followed by stirring at room temperature.

The starting material is dissolved and the reaction mixture is stirred for a total of 6 hours. Pyridine (1 ml) was added and the solution was distilled off under reduced pressure and the residue was crystallized from methanol to give 3-methoxy-9, β, 11β-oxide-16α, 17α, 21-trihydroxypregni-1,3, 5-triene-20-one-16,17-acetonide 21-acetate (5 g) is obtained.

Melting point 172 ℃

[α] _D -164 ° C (dioxane)

b) After passing through perchloryl fluoride for 10 minutes to a pyridine (60 ml) solution of the compound (3 g), the excess reactant is removed from the solution through a gaseous gas, and ice is poured into water. The crystalline solid was filtered, washed well with water, dried and crystallized from methanol to give 6α-fluoro-9β, 11β-oxide-16α, 17α, 21-trihydroxypregna-1,4-diene-3, 20- Dion 16,17-acetonide 21-acetate (2 g) is obtained. (Same as the product of Example 1b)

c) Acetone (40 ml) solution of 3-methyl-enol ether (2 g) obtained in a) was treated with anhydrous sodium acetate (0.4 g) water (6 ml), N-chlorosuccinimide (1.0 kg), and this mixture After stirring overnight, pour in ice water. The precipitate was collected by filtration, washed well with water, dried and treated with methanol to give 6α-fluoro-9β, 11β-oxide-16α, 17α, 21-trihydroxypregna-1,4-diene-3, 20 Dion 16,17-acetide 21-acetate (1.5 g) is obtained. Melting Point: 199 ℃

[α] _D +53 (dioxane).

Example 6

According to Example 5a, 9β, 11β-oxido-16α-methyl-21-hydroxypregna-1,4-diene-3,20-dione was reacted with methyl orthoformate and most of the solvent was removed under reduced pressure. The residue was then dissolved in pyridine and treated with perchloryl fluoride as in Example 5b to give 6α-fluoro-9β, 11β-oxide-16α-methyl-21-hydroxypregna-1,4-diene- 3, 20-dione-21-acetate is obtained. Melting Point: 178 ℃

[α] _D + 87 ° (dioxane)

The compound is converted to 21-acetate of difluorocopolone by reaction with hydrogen fluoride in a conventional manner.

Example 9

It is obtained by proceeding in the same manner as in Example 2 using 9β, 11β-oxido-16β-methyl-17α-hydroxypregna-1,4-diene-3,20-dione (5 g) as a starting material. 6α-fluoro-9β, 11β-oxide-16α-methyl-17α-hydroxy-pregna-1,4-diene-3, 20-dione (3.5 g) has a melting point of 212 ° C. (decomposition).

[α] _D + 41.2 ° (dioxane)

The conventional method is used to introduce 21-hydroxylated functional groups, ring-opening 9β, 11β-oxidos with hydrogen fluoride and converting the compound to diplason. It has the same physical and chemical properties as the compound prepared according to known methods.

Claims (1)

The 3-keto-Δ ¹ , ⁴ -pregnadiene derivative of the following structural formula (I) is preferably acyl anhydride, isopropenyl acetate, trialkyl ortho formate, or other suitable acylating or etherifying agent and p-toluenesulfonic acid. Reaction in the presence of an acid catalyst yields the corresponding 3-enol-derivative of formula (II), which is reacted with a suitable halogenating agent such as N-halo-amide, perchloryl fluoride to form 6α-halo of formula (III) Method for preparing 3-keto-Δ ¹ , ⁴ -pregnadiene-derivatives.

In the above structural formula R and Z are hydrogen, hydroxy or acyloxy derived from a carboxylic acid of up to 9 carbon atoms, or Z is hydroxy, When w is hydroxy the α-orientator is

Represents a group w is hydrogen, hydroxy or methyl and X is halogen, in particular fluorine and chlorine.