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US 5,981,744 AGranted
Processes for preparation of 9,11-epoxy steroids and intermediates useful therein
AssigneeG. D. Searle & Co.
InventorsJohn S. Ng, Ping T. Wang, Julio A. Baez, Chin Liu, Dennis K. Anderson, Jon P. Lawson, Bernhard Erb, Joseph Wieczorek, Sastry A. Kunda, Leo J. Letendre, Mark J. Pozzo, Yuen-Lung L. Sing, Edward E. Yonan
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Abstract
Multiple reaction schemes, process steps and intermediates are provided for the synthesis of epoxymexrenone, useful as a diuretic, and other 9,11-epoxy-steroids.
Claims26
A process for the preparation of a compound of Formula II:
- ##STR131## wherein --A--A-- represents the group --CHR.sup.4 --CHR.sup.5 -- or --CR.sup.4 .dbd.CR.sup.5 --
- R.sup.3, R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy carbonyl, cyano, aryloxy,
- R.sup.1 represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbonyl radical,
- --B--B-- represents the group --CHR.sup.6 --CHR.sup.7 -- or an alpha- or beta-oriented group:
- ##STR132## where R.sup.6 and R.sup.7 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano, aryloxy, and
- R.sup.8 and R.sup.9 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano, aryloxy, or R.sup.8 and R.sup.9 together comprise a carbocyclic or heterocyclic ring structure, or R.sup.8 or R.sup.9 together with R.sup.6 or R.sup.7 comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring;
- the process comprising:
- removing an 11.alpha.-leaving group from a compound of Formula IV:
- ##STR133## wherein --A--A--, R.sup.1, R.sup.3, --B--B--, R.sup.8, and R.sup.9 are as defined above, and R.sup.2 is a leaving group the abstraction of which is effective for generating a double bond between the 9- and 11-carbon atoms.
6 more elements
A process for the preparation of a compound of Formula IV:
- ##STR139## wherein --A--A-- represents the group --CHR.sup.4 --CHR.sup.5 -- or --CR.sup.4 .dbd.CR.sup.5 --
- R.sup.3, R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy carbonyl, cyano, aryloxy,
- R.sup.1 represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbonyl radical,
- --B--B-- represents the group --CHR.sup.6 --CHR.sup.7 -- or an alpha- or beta-oriented group:
- ##STR140## where R.sup.6 and R.sup.7 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano, aryloxy, and
- R.sup.8 and R.sup.9 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano, aryloxy or R.sup.8 and R.sup.9 together comprise a carbocyclic or heterocyclic ring structure, or R.sup.8 or R.sup.9 together with R.sup.6 or R.sup.7 comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring, and
- R.sup.2 is lower alkylsulfonyloxy or acyloxy or a halide
- the process comprising:
- reacting a lower alkylsulfonylating or acylating reagent or a halide generating agent with a compound of Formula V ##STR141## wherein --A--A--, R.sup.1, R.sup.3, --B--B--, R.sup.8, and R.sup.9 are as defined above.
6 more elements
A process for the preparation of a compound of Formula V:
- ##STR147## wherein --A--A-- represents the group --CHR.sup.4 --CHR.sup.5 -- or --CR.sup.4 .dbd.CR.sup.5 --
- R.sup.3, R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano, aryloxy,
- R.sup.1 represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbonyl radical,
- --B--B-- represents the group --CHR.sup.6 --CHR.sup.7 -- or an alpha- or beta-oriented group:
- ##STR148## where R.sup.6 and R.sup.7 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano, aryloxy, and
- R.sup.8 and R.sup.9 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano, aryloxy, or R.sup.8 and R.sup.9 together comprise a carbocyclic or heterocyclic ring structure, or R.sup.8 or R.sup.9 together with R.sup.6 or R.sup.7 comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring;
- the process comprising:
- reacting a compound of Formula VI with an alkali metal alkoxide corresponding to the formula R.sup.10 OM wherein M is alkali metal and R.sup.10 O-- corresponds to the alkoxy substituent of R.sup.1, said compound of Formula VI having the structure:
- ##STR149## wherein --A--A--, R.sup.3, --B--B--, R.sup.8, and R.sup.9 are as defined above.
6 more elements
A process for the preparation of a compound corresponding to Formula II:
- wherein:
- --A--A-- represents the group --CHR.sup.4 --CHR.sup.5 -- or --CR.sup.4 .dbd.CR.sup.5 --
- R.sup.3, R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano, aryloxy,
- R.sup.1 represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbonyl radical,
- --B--B-- represents the group --CHR.sup.6 --CHR.sup.7 -- or an alpha- or beta-oriented group:
- ##STR155## where R.sup.6 and R.sup.7 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano, aryloxy, and
- R.sup.8 and R.sup.9 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano, aryloxy, or R.sup.8 and R.sup.9 together comprise a carbocyclic or heterocyclic ring structure,
- the process comprising:
- preparing a compound of Formula V ##STR156## wherein --A--A--, R.sup.1, R.sup.3, --B--B--, R.sup.8, and R.sup.9 are as defined above by reacting a compound of Formula VI with an alkali metal alkoxide corresponding to the formula R.sup.10 OM wherein M is alkali metal and R.sup.10 O-- corresponds to the alkoxy substituent of R.sup.1, said compound of Formula VI having the structure:
- ##STR157## wherein --A--A--, R.sup.3, --B--B--, R.sup.8, and R.sup.9 are as defined above;
- without isolating said compound of Formula V in purified form, reacting said compound of Formula V with a lower alkylsulfonylating or acylating reagent or a halide generating agent to produce a compound of Formula IV ##STR158## wherein --A--A--, R.sup.1, R.sup.3, --B--B--, R.sup.8, and R.sup.9 are as defined above, and R.sup.2 is alkylsulfonyloxy, acyloxy leaving group or halide;
- without isolating said compound of Formula IV in purified form, removing the 11.alpha.-leaving group therefrom by reaction with a reagent for abstraction thereof to produce said compound of Formula II.
9 more elements
Dependencies are inferred from the claim text.