Process for the production of 3-oxo-pregn-4-ene-21, 17-carbolactones by the metal-free oxidation of 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes
This invention relates to processes for the production of 3-oxo-pregnane-21,17-carbolactones of formula II as well as 3-oxo-pregn-4-ene-21,17-carbolactones of formula III by the metal-free oxidation of 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes of formula I In addition, the invention relates to the dichioromethane hemisolvate of 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregnan-5β-ol-21,17-carbolactone (IV) as such as well as to a process for the production of drospirenone.
1 . Process for the production of 3-oxo-pregnane-21,17-carbolactones of formula II
in which
R 5 is hydrogen, hydroxy;
R 6a is hydrogen, together with R 5 a double bond, or together with R 7a a —CH 2 group;
R 6b is hydrogen, together with R 7b a —CH 2 group or a double bond;
R 7a is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -thioacyl or together with R 6a a —CH 2 group,
R 7b is hydrogen, or together with R 6b a —CH 2 group;
R 9 is hydrogen, together with R 11 a double bond, or together with R 11 an epoxy group -O-;
R 10 is hydrogen, methyl, or ethyl;
R 11 is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group -O-;
R 13 is hydrogen, methyl or ethyl;
R 15 is hydrogen, C 1 -C 4 -alkyl, together with R 16 a —CH 2 group or a double bond;
R 16 is hydrogen, together with R 15 a —CH 2 group or a double bond;
comprising the reaction of compounds of formula I
with at least 3 molar equivalents of an organic or inorganic hypochlorite as oxidizing agent in the presence of catalytic amounts of a 2,2,6,6-tetramethylpiperidine -N-oxide derivative at a pH of at least 8.0.
2 . Process according to claim 1 for the production of 3-oxo-17α-pregnane-21,17-carbolactones of formula IIa
in which
R 6a is hydrogen or together with R 7a a —CH 2 group:
R 6b is hydrogen, together with R 7b a —CH 2 group, or a double bond;
R 7a is hydrogen, C 1 -C 4 -alkoxycarbonyl, or C 1 -C 4 -thioacyl;
R 7b is hydrogen, or together with R 6b a —CH 2 group,
R 9 is hydrogen, together with R 11 a double bond or together with R 11 an epoxy group —O—;
R 10 is hydrogen, or methyl;
R 11 is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group -O-;
R 15 is hydrogen, together with R 16 a —CH 2 group or a double bond;
R 16 is hydrogen, together with R 15 a —CH 2 group or a double bond;
wherein compounds of formula Ia
are reacted.
3 . Process according to claim 1 for the production of the compound of formula IIb,
whereby the compound of formula Ib
is used as a starting material.
4 . Process for the production of 3-oxo-pregn-4-ene-21,17-carbolactones of formula III
in which
R 6a is hydrogen, together with R 5 a double bond, or together with R 7a a —CH 2 group;
R 6b is hydrogen, together with R 7b a —CH 2 group or a double bond;
R 7a is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -thioacyl or together with R 6a a —CH 2 group,
R 7b is hydrogen, or together with R 6b a —CH 2 group;
R 9 is hydrogen, together with R 11 a double bond, or together with R 11 an epoxy group -O-;
R 10 is hydrogen, methyl, or ethyl;
R 11 is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group -O-;
R 13 is hydrogen, methyl or ethyl;
R 15 is hydrogen, C 1 -C 4 -alkyl, together with R 16 a —CH 2 group or a double bond,
R 16 is hydrogen, together with R 15 a —CH 2 group or a double bond; comprising the following steps:
a) the reaction of compounds of general formula I
in which
R 5 is hydroxy;
R 6a , R 6b , R 7a , R 7b , R 10 , R 11 , R 13 , R 15 , R 16 have the same meaning as in formula III,
with at least 3 molar equivalents of an organic or inorganic hypochlorite as an oxidizing agent in the presence of 1-5mol % of a 2,2,6,6-tetramethyl-piperidine-N-oxide derivative at a pH of at least 8.0 and at a temperature of 0-15° C., in dichloromethane or in a two-phase dichloromethane-water mixture,
to form the compounds of formula II
b) subsequent elimination of water at pH<5, optionally in the presence of an acid.
5 . Process for the production of 3-oxo-pregn-4-ene-21,17-carbolactones of formula III
in which
R 6a is hydrogen, together with R 5 a double bond, or together with R 7a a —CH 2 group;
R 6b is hydrogen, together with R 7b a —CH 2 group or a double bond;
R 7a is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -thioacyl or together with R 6a a —CH 2 group,
R 7b is hydrogen, or together with R 6b a —CH 2 group; R 9 is hydrogen, together with R 11 a double bond, or together with R 11 an epoxy group -O-;
R 10 is hydrogen, methyl, or ethyl;
R 11 is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group —O—;
R 13 is hydrogen, methyl or ethyl;
R 15 is hydrogen, C 1 -C 4 -alkyl, together with R 16 a —CH 2 group or a double bond,
R 16 is hydrogen, together with R 15 a —CH 2 group or a double bond;
comprising the following steps:
a) the reaction of compounds of general formula I
in which
R 5 is hydroxy;
R 6a , R 6b , R 7a , R 7b , R 10 , R 11 , R 13 , R 15 , R 16 have the same meaning as in formula III, with at least 3 molar equivalents of an organic or inorganic hypochlorite as an oxidizing agent in the presence of catalytic amounts of a 2,2,6,6-tetramethyl-piperidine-N-oxide derivative at a pH of at least 8.0, in dichloromethane or in a two-phase dichloromethane-water mixture;
to form the compounds of formula II
b) the isolation of compounds of formula II
c) subsequent elimination of water at pH<5, optionally in the presence of an acid.
6 . Process according to claim 4 for the production of 3-oxo-17α-pregn-4-ene-21,17-carbolactones of formula IIa
in which
R 6a is hydrogen or together with R 7a a —CH 2 group;
R 6b is hydrogen, together with R 7b a —CH 2 group, or a double bond;
R 7a is hydrogen, C 1 -C 4 -alkoxycarbonyl, or C 1 -C 4 -thioacyl;
R 7b is hydrogen, or together with R 6b a —CH 2 group,
R 9 is hydrogen, together with R 11 a double bond or together with R 11 an epoxy group -O-;
R 10 is hydrogen, or methyl;
R 11 is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group -O-;
R 15 is hydrogen, together with R 16 a —CH 2 group or a double bond;
R 16 is hydrogen, together with R 15 a —CH 2 group or a double bond,
wherein the compounds of formula Ia
are reacted.
7 . Process according to claim 4 for the production of a compound of formula IIIb
whereby the compound of formula Ib
is used as a starting material.
8 . Process for the production of dichloromethane hemisolvate IV:
comprising the following steps:
a) the reaction of compounds of general formula Ib
with at least 3 molar equivalents of an organic or inorganic hypochlorite as an oxidizing agent in the presence of catalytic amounts of a 2,2,6,6-tetramethyl-piperidine-N-oxide derivative at a pH of at least 8.0, in dichloromethane or in a two-phase dichloromethane-water mixture;
b) the isolation of compounds of formula II
9 . Process according to claim 5 , wherein 1-5 mol % of the 2,2,6,6-tetramethylpiperidine-N-oxide derivative is used.
10 . Process according to claim 5 , wherein 1-1.5 mol % of 2,2,6,6-tetramethylpiperidine-N-oxide is used.
11 . Process according to claim 1 , wherein 3-6 molar equivalents of alkali hypochlorite are used.
12 . Process according to claim 1 , wherein 3-4 molar equivalents of sodium hypochlorite are used.
13 . Process according to claim 1 , wherein the pH of the reaction solution is between 8.5 and 10.0.
14 . Process according to claim 1 , wherein the pH of the reaction solution is set with potassium bicarbonate.
15 . Process according to claim 1 , wherein the reaction temperature is 0 to 15° C.
16 . Process according to claim 1 , wherein after the oxidation reaction is completed, a reducing agent for quenching excess hypochlorite reagent is added to the reaction mixture.
17 . Process according to claim 16 , wherein the reducing agent is added with the addition of a base or a basic buffer at a pH of more than 5.
18 . Process according to claim 16 , wherein an aqueous alkali hydrogen sulfite solution is used as a reducing agent.
19 . Process according to claim 16 , wherein as a reducing agent, sodium hydrogen sulfite or potassium hydrogen sulfite is used in the form of the aqueous solution of sodium disulfite or potassium disulfite.
20 . Process according to claim 17 , wherein sodium phosphate (Na 3 PO 4 ) is used as a base or a basic buffer.
21 . 6β,7β; 15β, 16β-dimethylene-3-oxo-17α-pregnan-5β-ol-21,17-carbolactone-dichloromethane hemisolvate.
22 . Process for the production of drospirenone comprising reacting 6β,7β; 15β, 16β-dimethylene-3-oxo-17α-pregnan-5β-ol-21,17-carbolactone-dichloromethane hemisolvate with an acid.
23 . Process according to claim 22 , wherein the acid is sulfuric acid, hydrochloric acid or para-toluenesulfonic acid.
24 . The compound of claim 21 in isolated form.
25 . The process of claim 22 wherein said hemisolvate was previously isolated.
26 . The process of claim 1 further comprising isolating said compound of formula II.
27 . The process of claim 2 further comprising isolating said compound of formula IIa.
28 . The process of claim 3 further comprising isolating said compound of formula IIb.
29 . A process of claim 1 wherein said number of molar equivalents is 3.0-3.5.
30 . A process of claim 4 wherein said number of molar equivalents is 3.0-3.5.
31 . A process of claim 5 wherein said number of molar equivalents is 3.0-3.5.