Process for the preparation of estrone and/or estradiol-derivatives

1. A process for the preparation of a compound of formula II

wherein R 1 and R 2 independently are hydrogen or a hydroxy- or hydrocarbyl group; or wherein R 1 and R 2 together are a double bonded oxygen; R 3 is hydrogen; R′ 4 is a nitrobenzophenone group; and R 5 and R 6 independently are hydrogen or a hydroxy- or hydrocarbyl group;

from a compound of formula I

wherein, R 1 , R 2 , R 3 , R 5 and R 6 are as defined above and R 4 is hydrogen;

wherein the compound of formula I is reacted under alkaline conditions with 2-chloro-5-nitrobenzophenone in the presence of an alkanolic solvent and the compound of formula II is directly crystallized from this alkanolic solvent.

2. The process according to claim 1 , wherein in the compound of formula I and in the compound of formula II R 1 is an hydroxy group and R 2 is hydrogen; or wherein R 1 and R 2 together are a double bonded oxygen; and wherein R 5 and R 6 are hydrogen groups.

3. A process according to claim 1 , wherein the alkanol is a C2-C6 mono-alkanol.

4. The process according to claim 1 , wherein the compound of formula II is crystallized from the alkanolic solvent as an alkanolic complex.

5. A process according to claim 2 , wherein the alkanol is a C2-6 mono-alkanol.

6. The process according to claim 2 , wherein the compound of formula II is crystallized from the alkanolic solvent as an alkanolic complex.

7. The process according to claim 3 , wherein the compound of formula II is crystallized from the alkanolic solvent as an alkanolic complex.

8. The process according to claim 5 , wherein the compound of formula II is crystallized from the alkanolic solvent as an alkanolic complex.

9. A process for the preparation of a compound with formula III

wherein R′ 1 is an ester-group of the formula —O—C(O)—R 7 , wherein R 7 represents hydrogen or an alkyl group having from 1 to 3 C atoms; R 2 is hydrogen or an hydrocarbyl group; R′ 3 is a hydroxy group; R′ 4 is a nitrobenzophenone group; and R 5 and R 6 independently are hydrogen or a hydroxy- or hydrocarbyl group; from a compound of formula II

wherein R 1 is an hydroxy group; R 2 is hydrogen or an hydrocarbyl group; R 3 is hydrogen; R′ 4 is a nitrobenzophenone group; and R 5 and R 6 independently are hydrogen or a hydroxy- or hydrocarbyl group;

wherein the compound of formula II is supplied as an alkanolic complex; and comprising the steps of acetylation and oxidation.

10. A one-pot process for the preparation of a compound with formula III

wherein R′ 1 is an ester-group of the formula —O—C(O)—R 7 , wherein R 7 represents hydrogen or an alkyl group having from 1 to 3 C atoms; R 2 is hydrogen or an hydrocarbyl group; R′ 3 is a hydroxy group; R′ 4 is a nitrobenzophenone group; and R 5 and R 6 independently are a hydrogen or a hydroxy- or hydrocarbyl group; from a compound of formula II

wherein R 1 is an hydroxy group; R 2 is hydrogen or an hydrocarbyl group; R 3 is hydrogen; R′ 4 is a nitrobenzophenone group; and R 5 and R 6 independently are hydrogen or a hydroxy- or hydrocarbyl group; comprising

a) esterification of the R 1 hydroxy group in the compound of formula II by reacting said compound with an excess of an acid anhydride of the formula R 7 —C(O)—O—C(O)—R 7 , wherein R 7 represents hydrogen or an alkyl group having from 1 to 3 C atoms, in the presence of a first acid, selected from phosphoric acid, sulphuric acid, hydrogen halides, sulphonic acids, and halogenated carboxylic acids, which first acid is soluble in the acid anhydride; yielding a reaction mixture containing the first acid, the 17β-ester-derivative of the compound of formula II, an acid of the formula HO—C(O)—R 7 , wherein R 7 represents hydrogen or an alkyl group having from 1 to 3 C atoms, and residual acid anhydride;

b) addition of a sufficient amount of water to convert the residual acid anhydride to an acid of the formula HO—C(O)—R 7 , wherein R 7 represents hydrogen or an alkyl group having from 1 to 3 C atoms; yielding a reaction mixture containing the first acid, the 17β-ester-derivative of the compound of formula II, the acid of formula HO—C(O)—R 7 , and optionally any residual water;

c) addition of a second acid, yielding a reaction mixture containing a complex of said second acid and the 17β-ester-derivative of the compound of formula II; and

d) oxidation of the R 3 hydrogen group in the 17β-ester-derivative by addition of an, optionally prepared in-situ, organic peroxoic acid, within a time period of 30 minutes; yielding a mixture comprising the compound of formula III, an acid of the formula HO—C(O)—R 7 , wherein R 7 represents hydrogen or an alkyl group having from 1 to 3 C atoms, and optionally any residual water and/or organic peroxoic acid.

11. A process for the preparation of an 2-alkoxy-Δ 1,3,5 (10) -estratriene-derivative with formula V

wherein R 1 is an hydroxy group; R 2 is hydrogen or an hydrocarbyl group; R″ 3 is an alkoxy group; R 4 is hydrogen; and R 5 and R 6 independently are hydrogen or a hydroxy- or hydrocarbyl group; from a compound of formula I

wherein, R 1 , R 2 , R 4 , R 5 and R 6 are as defined above and R 3 is hydrogen,

wherein a compound of formula II

wherein R 1 , R 2 , R 3 , R 5 and R 6 are as defined above and R′ 4 is a nitrobenzophenone group;

is prepared from a compound of formula I

wherein, R 1 , R 2 , R 3 R 5 and R 6 are as defined above and R 4 is hydrogen;

wherein the compound of formula I is reacted under alkaline conditions with 2-chloro-5-nitrobenzophenone in the presence of an alkanolic solvent and the compound of formula II is directly crystallized from this alkanolic solvent;

and wherein the compound with formula III

wherein R′ 1 is an ester-group of the formula —O—C(O)—R 7 , wherein R 7 represents hydrogen or an alkyl group having from 1 to 3 C atoms; R 2 , R′ 4 , R 5 and R 6 are as defined above and R′ 3 is an hydroxy group;

is prepared from a compound of formula II

wherein R 1 , R 2 , R 3 , R′ 4 , R 5 and R 6 are as defined above;

wherein the compound of formula II is supplied as an alkanolic complex; and comprising the steps of acetylation and oxidation;

and wherein

the compound of the formula III is alkylated and hydrolysed.

12. A process according to claim 11 for the preparation of a 2-alkoxy-derivate of 3,17β-estradiol (formula V) comprising the steps of

a) reacting 3,17β-estradiol (formula I) to 17β-hydroxy-Δ 1,3,5 (10) -estratriene 3-(2-benzoyl-4-nitro)-phenyl ether (formula II);

and

b) reacting the 17β-hydroxy-Δ 1,3,5 (10) -estratriene 3-(2-benzoyl-4-nitro)-phenyl ether (formula II) to a 2-alkoxy-derivate of 3,17β-estradiol (formula V).

13. A complex of an alkanol and a compound of formula II

wherein R 1 and R 2 independently are hydrogen or a hydroxy- or hydrocarbyl group; or wherein R 1 and R 2 together are a double bonded oxygen; R 3 is hydrogen; R′ 4 is a nitrobenzophenone group; and R 5 and R 6 independently are hydrogen or a hydroxy- or hydrocarbyl group;

obtainable from a process comprising crystallization of the compound of formula II from a solution of said alkanol.

14. The complex according to claim 13 , wherein in the compound of formula II, R 1 is an hydroxy group and R 2 is hydrogen; or wherein R 1 and R 2 together are a double bonded oxygen; and wherein R 5 and R 6 are hydrogen groups.

15. The complex according to claim 13 , wherein the alkanol is a C2-C6 mono-alkanol.

16. A complex of 17β-hydroxy-Δ 1,3,5 (10) -estratriene 3-(2-Benzoyl-4-nitro)-phenyl ether and a C2-C6 mono-alkanol.

17. The complex according to claim 14 , wherein the alkanol is a C2-6 mono-alkanol.