METHOD FOR THE PREPARATION OF 21-HYDROXY-6,19-OXIDOPROGESTERONE (21OH-6OP)

1 . A method of preparing 21-hydroxy-6,19-oxidoprogesterone (1) or an acyl or phosphate derivative thereof.

the method comprising the steps

a) providing 21-acetoxypregnenolone;

b) protecting the C-3 hydroxy group of 21-acetoxypregnenolone through formation of a labile ester;

c) obtaining the bromohydrin product thereof, by addition of a bromine and a hydroxy group onto the double bond of position of C5-C6 of the ester protected 21-acetoxy-pregnenolone;

d) performing an intramolecular cyclization with the C19 atom with the “Suarez-reagent” (diacetoxyiodobenzene) and iodine under irradiation, thus obtaining the 6,19 oxido-bridge within the scaffold;

e) performing a selective hydrolysis, followed by an oxidation, to obtain a bromo-ketone;

f) performing a hydrolysis of the bromoketone resulting from step e) to obtain 21-hydroxy-6,19-oxidoprogesterone (1); and optionally

g) reacting compound (I) with an acylating agent or phosphorylating agent.

2 . The method according to claim 1 , wherein the 21-acetate derivative is obtained by acetylating 21-hydroxy-6,19-oxidoprogesterone (1) of step f).

3 . The method according to claim 1 , wherein a C1-18 acyl derivative is obtained by esterifying 21-hydroxy-6,19-oxidoprogesterone with a C1-18 acid, anhydride, active ester or acyl chloride.

4 . The method according to claim 1 , wherein a 21-propionate, 21-hemisuccinate, 21-phosphate, 21-oleate derivative is obtained by esterifying 21-hydroxy-6,19-oxidoprogesterone (1) of step f) with propionic acid, succinic acid, oleic acid or their anhydrides or active esters or acid chlorides.

5 . The method according to claim 1 , wherein the 21-phosphate derivative is obtained by reacting oxidoprogesterone (1) of step (f) with a phosphorylating agent.

6 . The method according to any of the preceding claims wherein for step b) a formate ester is afforded.

7 . The method according to any of the preceding claims, wherein the intramolecular cyclisation step d) is performed in dichloromethane as solvent.

8 . The method according to any of the preceding claims, wherein the selective hydrolysis of step e) is performed with HCl in MeOH/dichloromethane as solvent.

9 . The method according to any of the preceding claims, wherein the oxidation in step e) is performed with pyridinium chlorochromate (PCC).

10 . The method according to any of the preceding claims, wherein the hydrolysis in step f) is performed with KOH in MeOH/dichloromethane as solvent.

11 . A method for preparing (6)

comprising the step of performing an intramolecular cyclisation between the 6-OH and the C 21 of the molecule (5)

12 . A method according to claim 11 , wherein the intramolecular cyclisation is carried out by photoreaction with DIAB and I 2 .

13 . A method according to claim 11 or 12 , wherein the intramolecular cyclisation is carried out in CH 2 Cl 2 .