Combined synthesis route for desogestrel and etonogestrel

1. A process for the manufacture of a steroid derivative according to general formula IX

using a steroid derivative of general formula VI or VII

wherein in the steroid derivatives of general formula VI, VII and IX, R 1 and R 2 are the same and are selected from H and (1-4C)alkyl; or R 1 and R 2 , together with the sulphur atoms to which they are attached, form a 1,3-dithiolane or 1,3-dithiane, said dithiolane or dithiane being optionally substituted with one or more (1-4C)alkyl group; and

R 3 and R 4 are the same and are selected from H and (1-4C)alkyl; or R 3 and R 4 , together with the oxygen atoms to which they are attached, form a 1,3-dioxolane or 1,3-dioxane, said dioxolane or dioxane being optionally substituted with one or more (1-4C)alkyl group.

2. The process according to claim 1 comprising steps 1 through 6 according to the following scheme:

wherein,

in the steroid derivatives of general formula IV, V, VI, VII, VIII and IX, R 1 and R 2 are the same and are selected from H and (1-4C)alkyl; or R 1 and R 2 , together with the sulphur atoms to which they are attached, form a 1,3-dithiolane or 1,3-dithiane, said dithiolane or dithiane being optionally substituted with one or more (1-4C)alkyl group and in the steroid derivatives of general formula V, VI and VII, R 3 and R 4 are the same and are selected from H and (1-4C)alkyl; or R 3 and R 4 , together with the oxygen atoms to which they are attached, form a 1,3-dioxolane or 1,3-dioxane, said dioxolane or dioxane being optionally substituted with one or more (1-4C)alkyl group, wherein

in step 1, 13β-ethyl-11-hydroxygon-4-ene-3,17-dione, (1) is reacted with a thioalcohol or dithioalcohol into a 3-dithioacetal steroid derivative of general formula IV;

in step 2, the 3-dithioacetal steroid derivative of general formula IV is reacted with an alcohol or diol to obtain a 17-acetal,-3-dithioacetal steroid derivative of general formula V;

in step 3, the 11-hydroxy group in the 17-acetal-3-dithioacetal steroid derivative of general formula V is oxidized to obtain a 11-keto-17-acetal-3-dithioacetal steroid derivative of general formula VI;

in step 4, the 11-keto-17-acetal-3-dithioacetal steroid derivative of general formula VI is methylenylated to give a 11-methylene-17-acetal-3-dithioacetal steroid derivative of general formula VII;

in step 5, the 11-methylene-17-acetal-3-dithioacetal steroid derivative of general formula VII is hydrolysed to obtain a 11-methylene 3-dithioacetal steroid derivative of general formula VIII and

in step 6, the 11-methylene 3-dithioacetal steroid derivative of general formula VIII is ethynylated to give a 20-yn-11-methylene-3-dithioacetal steroid derivative of general formula IX.

3. The process according claim 2 , wherein in step 4, the 11-keto group is converted into a methylene group using Peterson reaction conditions and the 11-methylene 17-acetal, 3-dithioacetal steroid derivative of general formula VII is reacted without isolation.

4. The process according to claim 2 , wherein in step 4, the 11-keto group is converted into a 11-methylene group using Wittig reaction conditions.

5. A process for the manufacture of etonogestrel comprising steps 1 through 7, wherein etonogestrel is obtained from the 20-yn-11-methylene-3-dithioacetal steroid derivative of general formula IX by deprotection of the 3-dithioactetal

6. The process according to claim 5 , wherein in step 7 the 3-dithioacetal is converted into a carbonyl using stabilized 2-iodobenzoic acid (SIBX) and β-cyclodextrin (β-CD).

7. A process for the manufacture of desogestrel comprising steps 1 through 6 and further comprising an additional step 8, wherein desogestrel is obtained from the 20-yn-11-methylene-3-dithioacetal stereoid derivative of general formula IX by deprotection of the 3-dithioactetal followed by reduction of the resulting carbonyl group

8. The process according to claim 5 , wherein

R 1 and R 2 , together with the sulphur atoms to which they are attached, form a 1,3-dithiolane;

R 3 and R 4 , together with the oxygen atoms to which they are attached, form a 1,3-dioxolane;

in step 3, the 11-hydroxy group in the 17-acetal,-3-dithioacetal steroid derivative of general formula V is oxidised using pyridinium dichromate;

in step 4, the 11-keto-17-acetal-3-dithioacetal steroid derivative of general formula VI is methylenylated using Peterson reaction conditions followed by deprotection of the 17-diacetal (step 5) using hydrochloric acid without isolation of the 11-methylene-17-acetal-3-dithioacetal steroid derivative of general formula VII and

in step 7, the 3-dithioacetal is deprotected using periodic acid.

9. The process according to claim 7 , wherein

R 1 and R 2 , together with the sulphur atoms to which they are attached, form a 1,3-dithiolane;

R 3 and R 4 , together with the oxygen atoms to which they are attached, form a 1,3-dioxolane;

in step 3, the 11-hydroxy group in the 17-acetal,-3-dithioacetal steroid derivative of general formula V is oxidised using pyridinium dichromate;

in step 4, the 11-keto-17-acetal-3-dithioacetal steroid derivative of general formula VI is methylenylated using Peterson reaction conditions followed by deprotection of the 17-diacetal (step 5) using hydrochloric acid without isolation of the 11-methylene-17-acetal-3-dithioacetal steroid derivative of general formula VII; and

in step 7, the 3-dithioacetal is deprotected using periodic acid.

10. A steroid derivative of general formula VI or VII,

wherein,

R 1 and R 2 are the same and are selected from H and (1-4C)alkyl; or R 1 and R 2 , together with the sulphur atoms to which they are attached, form a 1,3-dithiolane or 1,3-dithiane, said dithiolane or dithiane being optionally substituted with one or more (1-4C)alkyl group and R 3 and R 4 are the same and are selected from H and (1-4C)alkyl; or R 3 and R 4 , together with the oxygen atoms to which they are attached, form a 1,3-dioxolane or 1,3-dioxane, said dioxolane or dioxane being optionally substituted with one or more (1-4C)alkyl group.

11. The steroid derivative according to claim 10 selected from:

13β-ethyl-cyclic-3-(1,2-ethanediyl dithioacetal)-cyclic-17-(1,2-ethanediyl acetal)-gon-4-ene-3,11,17-trione (6); and

13β-ethyl-11-methylene-cyclic-3-(1,2-ethanediyl dithioacetal)-cyclic-17-(1,2-ethanediyl acetal)-gon-4-ene-3,17-dione (7).