KR800001381B1 - Process for preparing d-homosteroids - Google Patents

Abstract

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Description

Preparation method of D-homosteroid

The present invention relates to a method for preparing D-homosteroid, the following structural formula (I) having anti-inflammatory action.

In the above structural formula

The dashed line at position 1,2 is any carbon bond,

R ⁶ is hydrogen, fluorine or chlorine or methyl group,

R ⁹ is hydrogen, fluorine or chlorine,

R ^17a is hydroxy or acyloxy.

Provided that R ⁶ in the 11, 17a-dihydroxy compound is hydrogen or fluorine in the 11, 17a-dihydroxy-4-ene compound, R ⁹ must be fluorine or chlorine.

The acyloxy group can be derived preferably from saturated or unsaturated aliphatic carboxylic acids, alicyclic, araliphatic or aromatic carboxylic acids having 1 to 15 carbon atoms. Examples of such acids are fric acid, acetic acid, trifluoroacetic acid, pivalic acid, propionic acid, butyric acid, caproic acid, oenant acid, undecylenic acid, oleic acid, cyclopentylpropionic acid, cyclohexylpropionic acid, phenylacetic acid and benzoic acid. Particularly preferred acyloxy groups are alkanoyloxy groups having 1 to 7 carbon atoms.

Preferred structural formula (I), D-homosteroid, is a double bond at position 1,2.

Examples of D-homosteroids of formula (I) prepared according to the present invention are as follows.

17a-butyryloxy-11β-hydroxy-D-homopregna-1,4-diene-3,20-dione,

6α-fluoro-11β, 17a-dihydroxy-D-homopregnna-1,4-diene-3,20-dione,

6α-chloro-11β, 17a-dihydroxy-D-homopregnna-1,4-diene-3,20-dione,

17a-butyryloxy-6α-fluoro-11β-hydroxy-D-homopregna-1,4-diene-3,20-dione,

17a-bararoyloxy-6α-chloro-11β-hydroxy-D-homopregnna-1,4-diene-3,20-dione,

9-fluoro-11β, 17a-dihydroxy-D-homopregna-1,4-diene-3,20-dione,

9-chloro-11β, 17a-dihydroxy-D-homopregna-1,4-diene-3,20-dione,

9-fluoro-17a-hydroxy-11β-propionyloxy-D-homopregnna-1,4-diene-3,20-dione,

17a-butyryloxy-9-fluoro-11β-propionyloxy-D-homopregnna-1,4-diene-3,20-dione,

17a-butyryloxy-9-fluoro-11β-hydroxy-D-homopregnna-1,4-diene-3,20-dione,

9-chloro-11β-hydroxy-17a-propionyloxy-D-homopregnna-1,4-diene-3,20-dione,

11β, 17a-dihydroxy-6α-methyl-D-homopregna-4-diene-3,20-dione,

17a-butyryloxy-11β-hydroxy-6α-methyl-D-homopregna-4-diene-3,20-dione,

11β, 17a-hydroxy-6α-methyl-D-homopregna-1,4-diene-3,20-dione,

17a-butyryloxy-11β-hydroxy-6α-methyl-D-homopregnna-1,4-diene-3,20-dione,

9-fluoro-11β, 17a-dihydroxy-6α-methyl-D-homopregna-4-diene-3,20-dione,

17a-butyryloxy-9-fluoro-11β-hydroxy-6α-methyl-D-homopregna-4-diene-3,20-dione,

9-fluoro-11β, 17a-dihydroxy-6α-methyl-D-homopregnna-1,4-diene-3,20-dione,

9-fluoro-11β-hydroxy-6α-methyl-17a-bararoyloxy-D-homopregnna-1,4-diene-3,20-dione,

9-chloro-6α-fluoro-11β, 17a-dihydroxy-D-homopregnna-1,4-diene-3,20-dione,

6α, 9-difluoro-11β, 17a-dihydroxy-D-homopregnna-1,4-diene-3,20-dione,

6α, 9-difluoro-11β-hydroxy-17a-propionyloxy-D-homopregnna-1,4-diene-3,20-dione,

According to the present invention, the D-homosteroid of formula (I) is prepared by replacing the iodine atom of the D-homosteroid of formula (II) with a hydrogen atom.

R ⁶ , R ⁹ and R ¹⁷ a in the above formula are as defined in the above formula (I).

Substitution reaction of iodine by hydrogen of D-homosteroid of structural formula (II) according to the present invention may be progressed by treatment with a reducing agent such as sodium hydrogen sulfite.

The reaction for the 1,2-dehydrogenation of the 1,2-saturated D-homosteroid of formula (I) is carried out according to the known method, for example, using a microorganism or using iodine, periodic acid, and selenium dioxide. Dehydrogenating agents such as 2,3-dichloro-5,6-dicyanobenzoquinone, chloranyl or red tetraacetate.

Microorganisms suitable for 1,2-dehydrogenation reactions are the same as Schizomycetes, especially Arthro bacter (e.g. A. Simplex ATTC 6946), Bacillus (e.g. B. lentus ATTC 13805 And B. Sphaericus ATTC 7055), PsEudomonas (e.g. Pseudomonas aeruginosa IFO 3505), Flavoacterium (e.g. F. flavescens IFO 3058), Lactobacillus (e.g. L. brevis IFO 3345) and Nocardia (eg N. Opaca ATTC 4276) are preferred.

The fluorination or chlorination reaction of the 6-position of the D-homosteroid of structural formula (I) is carried out according to a known method. The 6,7-saturated D-homosteroid of structure (I) is reacted with a fluorinating agent or chlorinating agent such as N-chloroamide or amide (e.g., N-chlorosuccinimide) or elemental chlorine to fluorinate or chlorinate You can. [Reference: J. Am. Chem. Soc. 72, 4534 (1950)] This reaction converts 6,7-saturated D-homosteroids of formula (I) to 3-enol esters or 3-enol ethers (e.g., enol acetates) and 3-enol esters or 3 Enol ethers are chlorine [J. Am Chem. Soc. 82, 1230 (1960)], N-chloroimides [J. Am. Chem. Soc. 82, 1230 (1960); 77, 3827 (1955)] or perchloroyl fluoride [J. Am. Chem. Soc. 81, 5259 (1959); Chem. and Ind. 1959, 1317]. Trifluoromethylhypofluoride can also be used as fluorinating agent.

If the above-mentioned fluorination or chlorination reaction yields an isomer mixture (e.g. a mixture of 6α and 6β- (fluor or chloro) -D-homosteroids), the mixture is separated into pure isomers according to known methods such as chromatography. Can be. The acylation reaction of 17a-hydroxy group of D-homosteroid of structure (I) is carried out according to known methods, for example, in the presence of an acid binder (e.g. pyridine or triethylamine) with a suitable catalyst or a strong acid catalyst ( Example: P-fluene sulfonic acid) is treated with an acylating agent such as acyl chloride or acid anhydride. As a solvent of the acylating agent, an organic solvent containing no hydroxy group (for example, a hydrocarbon such as methylene chloride or benzene) may be used. Structural formula (I), a D-homosteroid, has anti-inflammatory action and can therefore be used for the treatment of inflammatory conditions such as eczema.

In general, the oral medicine may contain 0.01% to 5.0% of D-homosteroid, which is a structural formula (OI). The daily dose is between 0.05 and 10.0 mg depending on the condition of treatment and the duration of treatment desired. Generally, the amount of D-homosteroid, structural formula (I), used in topical medicines is 0.0001% to 5% (weight ratio), preferably 0.001% to 0.5% (weight ratio), preferably 0.01% to 0.25% (weight ratio) )to be.

Example 1

4.g is 9-fluoro-11β, 17a-dihydroxy-21-urido-D-homopregna-1,4-diene-3,20-dione, 80 ml ether, 80 ml benzene, 40 ml water And 40 ml of saturated sodium hydrogen sulfite solution are stirred at 25 ° C. for 30 hours. The mixture is diluted with ethyl acetate. The aqueous layer is separated and extracted twice with ethyl acetate. The ethyl acetate solution is washed twice with sodium chloride solution, dehydrated with sodium sulfate and evaporated. Filtration with silica gel and crystallization with acetone / hexanes yields 9-fluoro-11β, 17a-dihydroxy-D-homopregna-1,4-diene-3,20-dione. Melting Point: 268 ° to 269 ° C

UV: ε ₃₂₉ = 15200;

[α] _D = + 67 ° (C = 0.1% in methanol)

Starting materials were 9-fluoro-D-homoprednisolone [melting point: 241 ° to 246 ° C .; [α] _D = + 101 ° (C = 0.1% in dioxane); UV: ε ₂₃₈ = 14540] was reacted with methanesulfonyl chloride in pyridine to give 9-fluoro-11β, 17a-dihydroxy-21-methanefonyloxy-D-homopregna-1,4-diene-3 Obtain 20-dione and react with sodium iodide in acetone to 9-fluoro-11β, 17a-dihydroxy-21-iod-D-homopregna-1,4-diene-3,20-dione Get Melting point: 190 ° C. (decomposition); [α] _D = + 118 °

(C = 0.1% in dioxane); UV: ε ₂₃₈ = 15750

In a similar manner, 6α-fluoro-11β, 17a-dihydroxy-2-iod-D-homopregna-1,4-diene-3,20-dione [melting point: 175 ° C to 177 ° C; UV: epsilon ₂₃₈ = 115830; [α] _D = + 121 ° (C = 0.1% in dioxane)] 6α-fluoro-11β, 17a-dihydroxy-D-homopregna-1,4-diene-3,20- Dione was obtained [melting point: 183 ° C to 184 ° C; UV: epsilon ₂₄₂ = 14400; [α] _D = + 56 ° (C = 0.1% in dioxane), 6α, 9-difluoro-11β, 17a-dihydroxy-21-urido-D-homopregnna-1,4-diene -3,20-dione [melting point: 189 ° C to 190 ° C; UV: ε ₂₃₈ = 16750; 6α, 9-difluoro-11β, 17a-dihydroxy-D-homopregna-1,4-diene-3 from [α] _D = + 118 ° (C = 0.1% in dioxane)] Obtain 20-Dion. Melting point: 230 ° C to 231 ° C; UV: ε ₂₃₈ = 16000; [a] _D = + 57 ° (C = 0.1% in dioxane).

The following compounds were prepared according to the method of Example 1.

17a-butyryloxy-11β-hydroxy-D-homopregna-1,4-diene-3,20-dione,

ε ₂₄₄ = 13940; [α] _D = + 22 ° (C = 0.1% in dioxane)

17a-butyryloxy-9-fluoro-11β-hydroxy-D-homopregna-1,4-diene-3,20-dione, melting point: 187-188 ° C.

17a-butyryloxy-6α, 9-difluoro-11β-hydroxy-D-homopregna-1,4-diene-3,20-dione, melting point: 224 to 225 ° C

17a-butyryloxy-6α-fluoro-11β-hydroxy-D-homopregna-1,4-diene-3,20-dione, melting point: 168-169 ° C.

17a-acetoxy-9-fluoro-D-homopregna-1,4-diene-3,20-dione, melting point: 232 to 233 ° C

9-fluoro-11β-hydroxy-17a-propionyloxy-D-homopregnna-1,4-diene-3,20-dione,

Melting Point: 204-205 ℃

9-fluoro-11β-hydroxy-17a-barroyloxy-D-homopregna-1,4-diene-3,20-dione, melting point: 144 to 146 ° C

9-chloro-11β, 17a-dihydroxy-D-homopregna-1,4-diene-3,20-dione, melting point: 265 to 270 ° C

11β-17a-hydroxy-6α-methyl-D-homopregna-4-ene-3,20-dione, melting point: 223 to 225 ° C

17aα-acetoxy-11β-hydroxy-D-homo-4-pregene-3,20-dione, melting point: 134 ° / 235 ° to 237 ° C

17aα-acetoxy-11β-hydroxy-D-homo-4-pregnadiene-3,20-dione, melting point: 218 ° / 219 ° to 220 ° C.

Claims (1)

Method for producing a D-homosteroid of the following formula (I) characterized by substituting a hydrogen atom of the iodine atom of the D-homosteroid of the formula (II).

The dotted line at position 1, 2 in the above formula is any carbon bond, R⁶Is hydrogen, fluorine or chlorine or methyl group, R⁹Is hydrogen, fluorine or chlorine, R^17aIs hydroxy or acyloxy. Provided that R in 11, 17a-dihydroxy compound⁶Is hydrogen or R in the 11, 17a-dihydroxy-4-ene compound⁶Is R if fluorine⁹Must be fluorine or chlorine.