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

A process for the preparation of a compound with formula III

• wherein R′1 is an ester-group of the formula —O—C(O)—R7, wherein R7 represents hydrogen or an alkyl group having from 1 to 3 C atoms;
• R2 is hydrogen or an hydrocarbyl group;
• R′3 is a hydroxy group;
• R′4 is a nitrobenzophenone group;
• and R5 and R6 independently are hydrogen or a hydroxy- or hydrocarbyl group;
• from a compound of formula II
• wherein R1 is an hydroxy group;
• R2 is hydrogen or an hydrocarbyl group;
• R3 is hydrogen;
• R′4 is a nitrobenzophenone group;
• and R5 and R6 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.

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)—R7, wherein R7 represents hydrogen or an alkyl group having from 1 to 3 C atoms;
• R2 is hydrogen or an hydrocarbyl group;
• R′3 is a hydroxy group;
• R′4 is a nitrobenzophenone group;
• and R5 and R6 independently are a hydrogen or a hydroxy- or hydrocarbyl group;
• from a compound of formula II
• wherein R1 is an hydroxy group;
• R2 is hydrogen or an hydrocarbyl group;
• R3 is hydrogen;
• R′4 is a nitrobenzophenone group;
• and R5 and R6 independently are hydrogen or a hydroxy- or hydrocarbyl group;
• comprising
• a) esterification of the R1 hydroxy group in the compound of formula II by reacting said compound with an excess of an acid anhydride of the formula R7—C(O)—O—C(O)—R7, wherein R7 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)—R7, wherein R7 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)—R7, wherein R7 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)—R7, 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 R3 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)—R7, wherein R7 represents hydrogen or an alkyl group having from 1 to 3 C atoms, and optionally any residual water and/or organic peroxoic acid.

A process for the preparation of an 2-alkoxy-Δ1,3,5 (10)-estratriene-derivative with formula V

• wherein R1 is an hydroxy group;
• R2 is hydrogen or an hydrocarbyl group;
• R″3 is an alkoxy group;
• R4 is hydrogen;
• and R5 and R6 independently are hydrogen or a hydroxy- or hydrocarbyl group;
• from a compound of formula I
• wherein, R1, R2, R4, R5 and R6 are as defined above and R3 is hydrogen,
• wherein a compound of formula II
• wherein R1, R2, R3, R5 and R6 are as defined above and R′4 is a nitrobenzophenone group;
• is prepared from a compound of formula I
• wherein, R1, R2, R3R5 and R6 are as defined above and R4 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)—R7, wherein R7 represents hydrogen or an alkyl group having from 1 to 3 C atoms;
• R2, R′4, R5 and R6 are as defined above and R′3 is an hydroxy group;
• is prepared from a compound of formula II
• wherein R1, R2, R3, R′4, R5 and R6 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.

A complex of an alkanol and a compound of formula II

• wherein R1 and R2 independently are hydrogen or a hydroxy- or hydrocarbyl group;
• or wherein R1 and R2 together are a double bonded oxygen;
• R3 is hydrogen;
• R′4 is a nitrobenzophenone group;
• and R5 and R6 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.