KR800000405B1 - Process for preparation of d-homosteroids - Google Patents

Abstract

D-homosteroids(I, R6 = H, F, Cl, Br, Me; R11 = F, Cl, OH; R17a= OH, acyloxy) useful as anti-inflammatory agent, were prepd. by halogenating 21-position of compd. II(R20 =Me, MeOH). Thus, 590mg 9-fluoro-11β, 17a, 21-trihyihydroxy-D-homopregna-1,4-diene-3, 20-dione and 590mg triphenylphosphine were dissolved in 6ml DMF, and added 0.5ml CCl4. The mixt. was treated for 1 hr, and extracted to give 405ml 21-chloro-9-fluoro-11β, 17a-dihydroxy-D- homopregna-1,4-diene-30,20-dione.

Description

Preparation method of D-homosteroid

The present invention relates to a method for preparing D-homosteroid of the following structural formula (I).

In the above structural formula

R ⁶ represents a hydrogen, fluorine, chlorine, bromine or methyl group

R ¹¹ represents fluorine or chlorine or a hydroxyl group

R ⁹ represents hydrogen, fluorine, chlorine or bromine when R ¹¹ is a hydroxy group, chlorine or bromine when R ¹¹ is fluorine or chlorine and R ²¹ represents halogen

R ^1a is a hydroxyl group or an acyloxy group,

Dotted lines at 1,2-positions indicate any bond.

As used herein, the term halogen refers to fluorine, chlorine, bromine, iodine and acyloxy groups can be derived from saturated or unsaturated aliphatic monocarboxylic acids, alicyclic or araliphatic or aromatic mono carboxylic acids containing up to 15 carbon atoms. . Examples of such acids are formic acid, acetic acid, pivalic acid, propionic acid, butyric acid, keproic acid, enanthic acid, undecylenic acid, oleic acid, cyclopentyl propionic acid, cyclohexylpropionic acid, phenylacetic acid and benzoic acid, with particular preferred acyl oxide groups having 1 To alkanoyl oxy groups containing from 7 to 7.

Structural formula (I) compounds in the text include D homosteroids of the following structural formulas (I-1) and (I-2).

In the above structural formula

R ⁶ represents a hydrogen, fluorine, chlorine, bromine or methyl group,

R ⁹¹ represents hydrogen, fluorine, chlorine or bromine,

R ⁹² represents chlorine or bromine,

^L10 R is fluorine or chlorine,

R ²¹ is a halogen atom,

R ^1a represents a hydroxy or acyloxy group,

Dotted lines at 1,2-positions indicate any bond.

The 6α-isomer is commonly used among the 6-position substituted D-homosteroids represented by the above structural formula.

By the method of the present invention, D-homosteroid, which is a compound of formula (I), is prepared by the following method.

That is, it is prepared by halogenating the 21-position of the D-homosteroid of the following formula (II).

In the above structural formula

The dashed lines in R ⁶ , R ⁹ , R ¹¹ , R ^17a and 1,2-positions are as described above and R ²⁰ is a methyl or hydroxymethyl group.

A method of halogenating the 21-position of the D-homosteroid of formula (II) is provided that R ²⁰ is a methyl group and the 3-kero-Δ ⁴ or 3-kero-Δ ^1,4 -system is protected (eg 3-ri In the form of 3-enaminium salts such as rolidinium-enamine) D-homosteroid of formula (II) is reacted with chlorine, bromine or iodine in an acidic solution. Halogenation also involves the reaction of D-homosteroids having a hydroxy group in the 21-position (preferably via mesylate or tosylate) with sodium fluoride, sodium chloride or lithium chloride in triphenylpodpine / dimethylformamide, or It may also be carried out by reacting with carbon chloride.

Of the starting materials used in the reaction, the method for producing the same is not described in the main body or may be prepared by a known method.

The above-mentioned D-homosteroid of formula (I) has an effect on the endocrine system and in particular has an anti-inflammatory effect. In addition, these compounds have a selective action, so the 9,11-dihalo-D-homosteroid has a weak phylogenetic effect but strong local action.

The D-homosteroid of formula (I) may be used in the form of a pharmaceutical formulation containing a suitable pharmaceutical carrier, and the carrier is an organic or inorganic inert carrier suitable for oral, dermal or subcutaneous administration. . Water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycol, petroleum jelly and the like. Pharmaceutical formulations may be in solid form (tablets, dragees, suppositories or capsules, etc.), semisolid forms (such as ointments), or in liquid form (liquids, suspensions or emulsifiers). Such pharmaceutical preparations may be sterilized, or preservatives, stabilizers, wetting agents, emulsifiers, salts, etc. may be added to change osmotic pressure or pH, and pharmaceutically effective substances other than the D-homosteroid of the present invention may be added. It may contain.

Generally, in the case of topical pharmaceutical preparations, the dosage range may be about 0.01 to 1% and in the case of systemic therapy the formulation may contain about 0.1 to 10 mg per dosage unit. .

The pharmaceutical preparations may be prepared by mixing the D-homosteroid of formula (I) with known carriers in a nontoxic solid or liquid carrier material suitable for administration, in the form of a desired pharmaceutical dose if necessary.

Next, examples of the present invention are illustrated.

Example 1

590 mg of 9-fluoro-Uβ, 17a, 21-trihydroxy-D-homopregna-1,4-diene-3,20-dione and 590 mg of triphenylphosphine were dissolved in 6 m1 of dimethylformamide and carbon tetrachloride. Treat it to 0.5m1.

After stirring for 1 hour at room temperature, it is poured into water and extracted with methylene chloride. The oil obtained by evaporating the extract is dissolved in toluene and evaporated again. The remaining residue was chromatographed on silica gel to give 21-chloro-fluoro-11β, 17a-dihydroxy-D-homopregnna-1,4-diene-3,20- at a melting point of 259 ° to 260 ° C. (decomposition). 405 mg of dione is obtained.

[α] _D = + 110 ° (at C = 0.1% dioxane)

UV: ε ₂₄₀ = 15,050.

Example 2

0.4 m1 of pyrrolidone was added to a solution in which 1 l of 11β, 17α-dihydroxy-D-homopregna-4-ene-3,20 dione was dissolved in 100 m1 of methanol under an argon atmosphere at 60 ° C., and the solution was cooled. Let's do it. The separated enamine is suction filtered and dried. 1 g of this enamine is dissolved in 50 ml of anhydrous alcohol containing 0.8 g of hydrogen bromide, and a solution of 0.18 ml of bromine in 10 ml of alcohol is added dropwise to the solution over 30 minutes.

The mixture was evaporated to yield l.3 g of bromide of 21-bromo-11β, 17α-dihydroxy-3- (N-pyrrolidinium) -fre-4-ene-20, which was dissolved in 100 ml of ethanol and this solution Was treated with a solution of 1 g of potassium carbonate dissolved in 20 ml of water, followed by stirring at room temperature for 1.5 hours. The mixture is poured into water and extracted with methylene chloride. The methylene chloride extract is washed with water, dehydrated over sodium sulfate, evaporated and crystallized with acetone-hexane to give 2l-bromo-11β, 17a-dihydroxy-D-hompreg-4-ene-3,20-dione. do.

U.V: ε242 = 6,100

The starting material is prepared as follows.

3β, 11β-dihydroxy-D-homoanthros-5-ene-17a-one is reacted with sodium hydride and triphenylethylphosphonium bromide in dimethylsulfoxide to have a melting point of 172 to 173 ° C. Dihydroxy-D-homopregna-5,17a (20) -diene is obtained.

[α] _D = 137 ° (in C = 1.04% dioxane)

Oxidation of the diene by the Offenauer reaction yields 11β-hydroxy-D-homopregna-4,17a (2o) -dien-3-one having a melting point of 160 to 161 ° C. ([α] _D = + 96 °, C = 0.102% in dioxane, ε243 = 15,000), which is 11β, 17a-dihydroxy-D having a melting point of 213 to 215 ° C. when oxidized to osmium tetraoxide and N-methyl-morpholine oxide / hydrogen peroxide. It is converted to homopreg-4-ene-3,20 dione.

[α] _D = + 104 ° (in C = 0.102% dioxane)

ε242 = 16,250

Example 3

21-chloro-11β having a melting point of 248 ° to 249 ° C. from 11β, 17a, 21-trihydroxy-D-homopregnna-1,4-diene-3,20-dione by the method described in Example 1, 17a-dihydroxy-D-homopregna-1,4-diene-3,20-dione is obtained.

[α] ²⁵ _D = + 125 ° (in C = 0.1% dioxane)

U.V: ε 243 = 14,650.

Claims (1)

A method of preparing the D-homosteroid of the following formula (I) by halogenating the 21 position of the D-homosteroid of the formula (II).

In the above structure, R ⁶ represents hydrogen, fluorine, chlorine or bromine or methyl group, R ¹ represents fluorine or chlorine or a hydroxy group, and R ⁹ represents hydrogen, fluorine, chlorine or bromine when R ¹¹ represents a hydroxy group, ^{When 11} is fluorine or chlorine, it represents chlorine or bromine, R ²¹ represents a halogen atom, R ^17a represents a hydroxyl group or an acyloxy group, the 1,2-position dotted line represents an arbitrary bond, and R ²⁰ represents Methyl or hydroxymethyl group is shown.