16-Methyl-9α-halo steroid esters, ethers and preparation thereof

Claim 2

A process for the preparation of 16-methyl-9α-chloro or fluoro steroid compounds of high topical and/or protracted activity of the formula ##STR4## wherein X is chlorine or fluorine, R 1 and R 2 are hydroxyl or esterified hydroxyl provided at least one of R 1 and R 2 is esterified hydroxyl, R 3 is hydrogen, hydroxy or an esterified hydroxy group, comprising (A) selectively protecting the 11α-hydroxy of a compound of the formula ##STR5## wherein X is chlorine or fluorine, with a tetrahydropropyranyl group to obtain a compound of the formula ##STR6## wherein Y is said tetrahydropyanyl group; and therafter (B) esterifying the 17α-hydroxyl group; whereby an 11α-protected 17α-monoester is obtained.

Claim 3

The process of claim 1 wherein said tetrahydropyanyl group of the 17α-esterified steroid produced in step (B) is removed by hydrolysis,

Claim 4

The process of claim 2 wherein the hydrolyzed steroid is esterified at 11α, whereby an 11α,17α-diester is obtained.

Claim 5

The process of claim 2 wherein the 21 group of the 11α,17α-diester whereby an 11β,17α,21-triester is obtained.

Claim 6

The process of claim 2 wherein said hydrolozyed steroid is esterified at the 11β-position by contact with an excess of a 1-16 carbon atom carboxylic acid or anhydride thereof in the presence of an acid catalyst.

Claim 7

The process of claim 2 wherein said tetrahydropyranyl and group is removed by contact with (a) ethanol or ethanol containing para-toluene-sulfonic acid, dilute aqueous organic acid, aqueous magnesium sulfate, or silica gel.

Claim 8

The process of claim 1 wherein the 21 group is acyloxylated subsequent to step (B) whereby an 11β-tetrahydropyanyl 17α,21-diester is obtained.

Claim 9

The process of claim 7 wherein said tetrahydropyanyl group of the 17α-esterified steroid produced in step (B) is removed by hydrolysis, whereby an 11β-hydroxy 17α,21-diester is obtained.

Claim 10

The process of claim 7 wherein the 21-ester group is converted to a hydroxyl group by weak akaline hydrolysis, whereby a 21-hydroxy, 11β-tetrahydropyanyl 17α-ester is obtained.

Claim 11

The process of claim 9 wherein the 11β-tetrahydropyanyl group is converted into a hydroxyl group by a solvolysis, whereby an 11β,21-dihydroxy 17α-ester is obtained.

Claim 12

The process of claim 7 wherein said 11β-tetrahydropyranyl 17α,21-diester is heated in a lower carboxylic acid to convert said tetrahydropyranyl group into an ester group, whereby an 11β17α,21-triester is obtained.

Claim 13

The process of claim 7 wherein said tetrahydropyranyl group is cleaved from said 11β-protected 21-esterified hydroxy, 17α-monoester by solvolysis, whereby an 11β,21-dihydroxy 17α-monoester is obtained.

Claim 14

The process of claim 9 wherein the conversion of the 21-ester group to a hydroxyl group is effected by contacting the 11β-tetrahydropyranyl 17α,21-diester with methanol or ethanol containing perchloric acid or aqueous sodium bicarbonate.

Claim 15

The process of claim 1 wherein step (A) is effected by contacting said compound of formula IV with an excess of 2,3-dihydropyran in the presence of an acid catalyst, at 0°-80° C. for 1-40 hours.

Claim 16

The process of claim 1 wherein step (B) is effected by contacting said compound of formula V with an excess of a 1-16 carbon atom carboxylic acid or anhydride thereof in the presence of an acid catalyst.

Claim 17

The process of claim 1 wherein R 1 is an esterified hydroxyl group of 1-16 carbon atoms, R 2 is hydroxy or an esterified hydroxyl group of 1-8 carbon atoms or a tetrahydropyran-2'yloxy group, R 3 is hydrogen and X is chlorine.

Claim 18

The process of claim 1 wherein R 1 is an esterified hydroxyl group of 5-16 carbon atoms, R i is hydroxy or an esterified hydroxyl group of 1-8 carbon atoms or a tetrahydropyran-2'yloxy group, R 3 is hydrogen and X is fluorine.

Claim 19

A process for the preparation of a 16-methyl-9α-chloro or fluoro steroid 11β-monoester of high topical and/or protracted activity of the formula ##STR7## wherein X is chlorine or fluorine, R 1 is hydroxyl, and R 2 is an esterified hydroxyl group comprising selectively protecting the 11β-hydroxyl of a compound of the formula ##STR8## wherein X is chloro or fluoro with a a tetrahydropyranyl to obtain a compound of the formula ##STR9## wherein Y is said tetrahydropyranyl group, and thereafter heating said protected steroid in a lower carboxylic acid.

Claim 20

A process for the preparation of a 16-methyl-9α-chloro or fluoro steroid 11β-monoester of high topical and/or protracted activity of the formula ##STR7## wherein X is chlorine or fluorine, R 1 is hydroxyl, and R 2 is an esterified hydroxyl group comprising selectively protecting the 11β-hydroxyl of a compound of the formula ##STR8## wherein X is chloro or fluoro with a a tetrahydropyranyl to obtain a compound of the formula ##STR9## wherein Y is said tetrahydropyranyl group, and thereafter heating said protected steroid in a lower carboxylic acid.

Claim 21

A process for the preparation of 16-methyl-9α-chloro or fluoro steroid compounds of high topical and/or protracted activity of the formula ##STR10## wherein X is chlorine or fluorine, R 1 and R 2 are hydroxyl or esterified hydroxyl provided at least one of R 1 and R 2 is esterified hydroxyl, R 3 is hydrogen, hydroxy or an esterified hydroxy group, comprising (A) selectively protecting the 11β-hydroxy of a compound of the formula ##STR11## wherein X is chlorine or fluorine or fluorine, with a di, trichloro or fluoroacetyl group or tetrahydropyranyl group to obtain a compound of the formula ##STR12## wherein Y is said protecting group; (B) esterifying the 17α-hydroxyl group, whereby an 11β-protected 17α-monoester is obtained: (C) removing said protecting group of the 17α-esterified steroid produced in step (B) by hydrolysis; (D) esterifying the hydrolyzed steroid at 11β, whereby an 11β, 17α-diester is obtained; and (E) contacting the 11β, 17α-diester with iodine in the presence of calcium oxide or calcium chloride and the 21-oido derivative thus obtained is reacted with a salt of a carboxylic acid, phosphoric acid or sulfuric acid.

Claim 22

A process for the preparation of 16-methyl-9α-chloro or fluoro steroid compounds of high topical and/or protracted activity of the formula ##STR10## wherein X is chlorine or fluorine, R 1 and R 2 are hydroxyl or esterified hydroxyl provided at least one of R 1 and R 2 is esterified hydroxyl, R 3 is hydrogen, hydroxy or an esterified hydroxy group, comprising (A) selectively protecting the 11β-hydroxy of a compound of the formula ##STR11## wherein X is chlorine or fluorine or fluorine, with a di, trichloro or fluoroacetyl group or tetrahydropyranyl group to obtain a compound of the formula ##STR12## wherein Y is said protecting group; (B) esterifying the 17α-hydroxyl group, whereby an 11β-protected 17α-monoester is obtained: (C) removing said protecting group of the 17α-esterified steroid produced in step (B) by hydrolysis; (D) esterifying the hydrolyzed steroid at 11β, whereby an 11β, 17α-diester is obtained; and (E) contacting the 11β, 17α-diester with iodine in the presence of calcium oxide or calcium chloride and the 21-oido derivative thus obtained is reacted with a salt of a carboxylic acid, phosphoric acid or sulfuric acid.

Claim 23

A process for the preparation of 16-methyl-9α-chloro or fluoro steroid compounds of high topical and/or protracted activity of the formula ##STR13## wherein X is chlorine or fluorine, R 1 and R 2 are hydroxyl or esterified hydroxyl provided at least one of R 1 and R 2 is esterified hydroxyl, R 3 is hydrogen, hydroxy or an esterified hydroxy group, comprising (A) selectively protecting the 11β-hydroxy of a compound of the formula ##STR14## wherein x is chlorine or fluorine, with a di, trichloro or fluoroacetyl group to obtain a compound of the formula ##STR15## wherein Y is said protecting group; (B) esterifying the 17α-hydroxyl group, whereby an 11β-protected 17α-monoester is obtained; and (C) removing said protecting group by (a) contact with activated silica gel employing as the solvent, a member of the group consisting of dichloromethane, trichloromethane, tetrachloromethane, tetrahydrofuran, dioxane, benzene, ethylacetate and mixtures thereof, or (b) contact with an aqueous sodium bicarbonate solution and methanol.

Claim 24

A process for the preparation of 16-methyl-9α-chloro or fluoro steroid compounds of high topical and/or protracted activity of the formula ##STR13## wherein X is chlorine or fluorine, R 1 and R 2 are hydroxyl or esterified hydroxyl provided at least one of R 1 and R 2 is esterified hydroxyl, R 3 is hydrogen, hydroxy or an esterified hydroxy group, comprising (A) selectively protecting the 11β-hydroxy of a compound of the formula ##STR14## wherein x is chlorine or fluorine, with a di, trichloro or fluoroacetyl group to obtain a compound of the formula ##STR15## wherein Y is said protecting group; (B) esterifying the 17α-hydroxyl group, whereby an 11β-protected 17α-monoester is obtained; and (C) removing said protecting group by (a) contact with activated silica gel employing as the solvent, a member of the group consisting of dichloromethane, trichloromethane, tetrachloromethane, tetrahydrofuran, dioxane, benzene, ethylacetate and mixtures thereof, or (b) contact with an aqueous sodium bicarbonate solution and methanol.

Claim 25

A process for the preparation of 16-methyl-9α-chloro or fluoro steroid compounds of high topical and/or protracted activity of the formula ##STR16## wherein X is chlorine or fluorine, R 1 and R 2 are hydroxyl or esterified hydroxyl provided at least one or R 1 and R 2 is esterified hydroxyl, R 3 is hydrogen, hydroxy or an esterified hydroxy group, comprising (A) selectively protecting the 11β-hydroxy of a compound of the formula ##STR17## wherein X is chlorine or fluorine, with a di, trichloro or fluoroacetyl group or tetrahydropyranyl group to obtain a compound of the formula ##STR18## wherein Y is said protecting group; (B) esterifying the 17α-hydroxyl group, whereby an 11β-protected 17α-monoester is obtained; (C) introducing an esterified hydroxyl group at 21 by contacting the 11β-protected 17α-monoester with iodine in the presence of calcium oxide or calcium chloride, and the 21-iodo derivative thus obtained is contacted with a salt of a carboxylic acid, phosphoric acid or sulphuric acid; and (D) removing said protecting group by hydrolysis whereby an 11β-hydroxy 17α,21-diester is obtained.

Claim 26

A process for the preparation of 16-methyl-9α-chloro or fluoro steroid compounds of high topical and/or protracted activity of the formula ##STR16## wherein X is chlorine or fluorine, R 1 and R 2 are hydroxyl or esterified hydroxyl provided at least one or R 1 and R 2 is esterified hydroxyl, R 3 is hydrogen, hydroxy or an esterified hydroxy group, comprising (A) selectively protecting the 11β-hydroxy of a compound of the formula ##STR17## wherein X is chlorine or fluorine, with a di, trichloro or fluoroacetyl group or tetrahydropyranyl group to obtain a compound of the formula ##STR18## wherein Y is said protecting group; (B) esterifying the 17α-hydroxyl group, whereby an 11β-protected 17α-monoester is obtained; (C) introducing an esterified hydroxyl group at 21 by contacting the 11β-protected 17α-monoester with iodine in the presence of calcium oxide or calcium chloride, and the 21-iodo derivative thus obtained is contacted with a salt of a carboxylic acid, phosphoric acid or sulphuric acid; and (D) removing said protecting group by hydrolysis whereby an 11β-hydroxy 17α,21-diester is obtained.

Claim 27

A process for the preparation of 16-methyl-9α-chloro or fluoro steroid compounds of high topical and/or protracted activity of the formula ##STR19## wherein X is chlorine or fluorine, R 1 and R 2 are hydroxyl or esterified hydroxyl provided at least one of R 1 and R 2 is esterified hydroxyl, R 3 is hydrogen, hydroxy or an esterified hydroxy group, comprising (A) selectively protecting the 11β-hydroxy of a compound of the formula ##STR20## wherein X is chlorine or fluorine, with a di, trichloro or fluoroacetyl group to obtain a compound of the formula ##STR21## wherein Y is said protecting group (B) esterifying the 17α-hydroxyl group, whereby an 11β-protected 17α-monoester is obtained: (2) acyloxylating the 11β-protected 17α-monoester at 21 whereby an 11β-protected 17α,21-diester is obtained; (D) converting the 21-ester group to a hydroxy group by weak alkaline hydrolysis, whereby a 21-hydroxy, 11β-protected, 17α-ester is obtained; and (E) converting the 11β-haloacetyl group into a hydroxyl group by contact with activated silica gel, whereby an 11β,21-dihydroxy 17α-ester is obtained.

Claim 28

A process for the preparation of 16-methyl-9α-chloro or fluoro steroid compounds of high topical and/or protracted activity of the formula ##STR19## wherein X is chlorine or fluorine, R 1 and R 2 are hydroxyl or esterified hydroxyl provided at least one of R 1 and R 2 is esterified hydroxyl, R 3 is hydrogen, hydroxy or an esterified hydroxy group, comprising (A) selectively protecting the 11β-hydroxy of a compound of the formula ##STR20## wherein X is chlorine or fluorine, with a di, trichloro or fluoroacetyl group to obtain a compound of the formula ##STR21## wherein Y is said protecting group (B) esterifying the 17α-hydroxyl group, whereby an 11β-protected 17α-monoester is obtained: (2) acyloxylating the 11β-protected 17α-monoester at 21 whereby an 11β-protected 17α,21-diester is obtained; (D) converting the 21-ester group to a hydroxy group by weak alkaline hydrolysis, whereby a 21-hydroxy, 11β-protected, 17α-ester is obtained; and (E) converting the 11β-haloacetyl group into a hydroxyl group by contact with activated silica gel, whereby an 11β,21-dihydroxy 17α-ester is obtained.

Claim 29

A process for the preparation of 16-methyl-9α-chloro or fluoro steroid compounds of high topical and/or protracted activity of the formula ##STR22## wherein X is chlorine or fluorine, R 1 and R 2 are hydroxyl or esterified hydroxyl provided at least one of R 1 and R 2 is esterified hydroxyl, R 3 is hydrogen, hydroxy or an esterified hydroxy group, comprising (A) selectively protecting the 11β-hydroxy of a compound of the formula ##STR23## wherein X is chlorine or fluorine, with a di, trichloro or fluoroacetyl group of tetrahydropyranyl group to obtain a compound of the formula ##STR24## wherein Y is said protecting group; (B) esterifying the 17α-hydroxyl group, whereby an 11β-protected 17α-monoester is obtained; (C) contacting the 11β-protected 17α-monoester with iodine in the presence of calcium chloride in methanol, whereby the 2t-monoiodo and 2-diiodo derivatives are obtained; (D) contacting the 21-iodo derivatives with a salt of a carboxylic acid, phosphoric acid or sulfuric acid, whereby a 21-esterified compound by pouring the reaction mixture rapidly into iced water.

Claim 30

A process for the preparation of 16-methyl-9α-chloro or fluoro steroid compounds of high topical and/or protracted activity of the formula ##STR22## wherein X is chlorine or fluorine, R 1 and R 2 are hydroxyl or esterified hydroxyl provided at least one of R 1 and R 2 is esterified hydroxyl, R 3 is hydrogen, hydroxy or an esterified hydroxy group, comprising (A) selectively protecting the 11β-hydroxy of a compound of the formula ##STR23## wherein X is chlorine or fluorine, with a di, trichloro or fluoroacetyl group of tetrahydropyranyl group to obtain a compound of the formula ##STR24## wherein Y is said protecting group; (B) esterifying the 17α-hydroxyl group, whereby an 11β-protected 17α-monoester is obtained; (C) contacting the 11β-protected 17α-monoester with iodine in the presence of calcium chloride in methanol, whereby the 2t-monoiodo and 2-diiodo derivatives are obtained; (D) contacting the 21-iodo derivatives with a salt of a carboxylic acid, phosphoric acid or sulfuric acid, whereby a 21-esterified compound by pouring the reaction mixture rapidly into iced water.

Claim 31

A process for the preparation of 16-methyl-9α-chloro or fluoro steroid compounds of high topical and/or protracted activity of the formula ##STR25## wherein X is chlorine or fluorine, R 1 and R 2 are hydroxyl or esterified hydroxyl provided at least one of R 1 and R 2 is esterified hydroxyl, R 3 is hydrogen, hydroxy or an esterified hydroxy group, comprising (A) selectively protecting the 11β-hydroxy of a compound of the formula ##STR26## wherein X is chlorine or fluorine, with a di, trichloro or fluoroacetyl group of tetrahydropyranyl group to obtain a compound of the formula ##STR27## wherein Y is said protecting group; (B) esterifying the 17α-hydroxyl group, whereby an 11β-protected 17α-monoester is obtained; (C) contacting the 11β-protected 17α-monoester with iodine in the presence of calcium oxide or calcium chloride whereby the 21-iodo derivative is obtained; (D) contacting the 21-iodo derivative with a salt of a carboxylic acid, phosphoric acid or sulfuric acid, whereby a 21-esterified compound is obtained; and (E) precipitating the resulting 2-esterified compound by slowly adding water to the reaction mixture.

Claim 32

A process for the preparation of 16-methyl-9α-chloro or fluoro steroid compounds of high topical and/or protracted activity of the formula ##STR25## wherein X is chlorine or fluorine, R 1 and R 2 are hydroxyl or esterified hydroxyl provided at least one of R 1 and R 2 is esterified hydroxyl, R 3 is hydrogen, hydroxy or an esterified hydroxy group, comprising (A) selectively protecting the 11β-hydroxy of a compound of the formula ##STR26## wherein X is chlorine or fluorine, with a di, trichloro or fluoroacetyl group of tetrahydropyranyl group to obtain a compound of the formula ##STR27## wherein Y is said protecting group; (B) esterifying the 17α-hydroxyl group, whereby an 11β-protected 17α-monoester is obtained; (C) contacting the 11β-protected 17α-monoester with iodine in the presence of calcium oxide or calcium chloride whereby the 21-iodo derivative is obtained; (D) contacting the 21-iodo derivative with a salt of a carboxylic acid, phosphoric acid or sulfuric acid, whereby a 21-esterified compound is obtained; and (E) precipitating the resulting 2-esterified compound by slowly adding water to the reaction mixture.

Claim 33

The process of claim 1 wherein the 11β-tetrahydropyranyl 17α-monoester is contacted with iodine in the presence of calcium chloride in methanol; the 21-monoiodo and 21-diiodo derivatives thus obtained are contacted with a salt of a carboxylic acid, phosphoric acid or sulfuric acid; the resultant 21-esterified compound is precipitated by pouring the reaction mixture rapidly into iced water; and wherein the 11β-tetrahydropyranyl group is removed from the 11β-tetrahydropyranyl 17α,21-di-ester by contact with activated silica gel employing as the solvent a member of the group consisting of dichloromethane, trichloromethane, tetrachloromethane, tetrahydrofuran, dioxane, benzene, ethyl acetate and mixtures thereof.

Claim 34

16-methyl-9α-fluoro-21-desoxyprednisolone 11β-propionate,17α-valerate.

Claim 35

16-methyl-9α-fluoro-21-desoxyprednisolone 11β-propionate,17α-valerate.

Claim 36

16β-methy-9α-fluoro-prednisolone 11β, 17α-dipropionate, 21-acetate.

Claim 37

16β-methy-9α-fluoro-prednisolone 11β, 17α-dipropionate, 21-acetate.

Claim 38

16-methyl-9α-halo-11β-(tetrahydropyran-2'yloxy)-21-desoxyprednisolone, wherein halo is fluoro or chloro.

Claim 39

16-methyl-9α-halo-11β-(tetrahydropyran-2'yloxy)-21-desoxyprednisolone, wherein halo is fluoro or chloro.

Claim 40

16-methyl-9α-halo-11β-(tetrahydropyran-2'yloxy)-prednisolone wherein halo is fluoro or chloro.

Claim 41

16-methyl-9α-halo-11β-(tetrahydropyran-2'yloxy)-prednisolone wherein halo is fluoro or chloro.

Claim 42

An ester of 16-methyl-9α-chloro-11β(tetrahydropyran-2'yloxy) prednisolone selected from the group consisting of 17-propionate, 17-valerate, 17,21-dipropionate and 17,21-divalerate.

Claim 43

An ester of 16-methyl-9α-chloro-11β(tetrahydropyran-2'yloxy) prednisolone selected from the group consisting of 17-propionate, 17-valerate, 17,21-dipropionate and 17,21-divalerate.