Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-31
2003-07-01
Badio, Barbara P. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S044000, C540S076000, C549S200000
Reexamination Certificate
active
06586591
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the novel processes for the preparation of 9,11-epoxy steroid compounds, especially those of the 20-spiroxane series and their analogs, novel intermediates useful in the preparation of steroid compounds, and processes for the preparation of such novel intermediates. Most particularly, the invention is directed to novel and advantageous methods for the preparation of methyl hydrogen 9,11 &agr;-epoxy-17&agr;-hydroxy-3-oxopregn-4-ene-7&agr;,21-dicarboxylate, &ggr;-lactone (eplerenone; epoxymexrenone).
Methods for the preparation of 20-spiroxane series compounds are described in U.S. Pat. No. 4,559,332. The compounds produced in accordance with the process of the '332 patent have an open oxygen containing ring E of the general formula:
in which
—A—A— represents the group —CH
2
—CH
2
— or —CH═CH—,
R
1
represents an &agr;-oriented lower alkoxycarbonyl or hydroxycarbonyl radical.
—B—B— represents the group —CH
2
—CH
2
— or an &agr;- or &bgr;-oriented group
R
6
and R
7
being hydrogen
X represents two hydrogen atoms or oxo,
Y
1
and Y
2
together represent the oxygen bridge —O—, or
Y
1
represents hydroxy, and
Y
2
represents hydroxy, lower alkoxy or, if X represents H
2
, also lower alkanoyloxy,
and salts of such compounds in which X represents oxo and Y
2
represents hydroxy, that is to say of corresponding 17&bgr;-hydroxy-21-carboxylic acids.
U.S. Pat. No. 4,559,332 describes a number of methods for the preparation of epoxymexrenone and related compounds of Formula IA. The advent of new and expanded clinical uses for epoxymexrenone create a need for improved processes for the manufacture of this and other related steroids.
SUMMARY OF THE INVENTION
The primary object of the present invention is the provision of improved processes for the preparation of epoxymexrenone, other 20-spiroxanes and other steroids having common structural features. Among the particular objects of the invention are: to provide an improved process that produces products of Formula IA and other related compounds in high yield; the provision of such a process which involves a minimum of isolation steps; and the provision of such a process which may be implemented with reasonable capital expense and operated at reasonable conversion cost.
Accordingly, the present invention is directed to a series of synthesis schemes for epoxymexrenone; intermediates useful in the manufacture of eplerenone; and syntheses for such novel intermediates.
The novel synthesis schemes are described in detail in the Description of Preferred Embodiments. Among the novel intermediates of this invention are those described immediately below.
A compound of Formula IV corresponds to the structure:
wherein:
—A—A— represents the group —CHR
4
—CHR
5
— or —CR
4
═CR
5
—
R
3
R
4
and R
5
are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy carbonyl, cyano, aryloxy,
R
1
represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbonyl radical,
R
2
is an 11&agr;-leaving group the abstraction of which is effective for generating a double bond between the 9- and 11-carbon atoms;
—B—B— represents the group —CHR
6
—CHR
7
— or an alpha- or beta-oriented group:
where R
6
and R
7
are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano, aryloxy, and
R
8
and R
9
are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano, aryloxy, or R
8
and R
9
together comprise a carbocyclic or heterocyclic ring structure, or R
8
or R
9
together with R
6
or R
7
comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring.
A compound of Formula IVA corresponds to Formula IV wherein R
8
and R
9
together with the ring carbon to which they are attached form the structure:
where X, Y
1
, Y
2
and C(17) are as defined above.
A compound of Formula IVB corresponds to Formula IVA wherein R
8
and R
9
together form the structure of Formula XXXIII:
Compounds of Formulae IVC, IVD and IVE, respectively, correspond to any of Formula IV, IVA, or IVB wherein each of —A—A— and —B—B— is —CH
2
—CH
2
—, R
3
is hydrogen, and R
1
is alkoxycarbonyl, preferably methoxycarbonyl. Compounds within the scope of Formula IV may be prepared by reacting a lower alkylsulfonylating or acylating reagent, or a halide generating agent, with a corresponding compound within the scope of Formula V.
A compound of Formula V corresponds to the structure:
wherein —A—A—, —B—B—, R
1
, R
3
, R
8
and R
9
are as defined in Formula IV.
A compound of Formula VA corresponds to Formula V wherein R
8
and R
9
with the ring carbon to which they are attached together form the structure:
where X, Y
1
, Y
2
and C(17) are as defined above.
A compound of Formula VB corresponds to Formula VA wherein R
8
and R
9
together form the structure of Formula XXXIII:
Compounds of Formulae VC, VD and VE, respectively, correspond to any of Formula V, VA, or VB wherein each of —A—A— and —B—B— is —CH
2
—CH
2
—, R
3
is hydrogen, and R
1
is alkoxycarbonyl, preferably methoxycarbonyl. Compounds within the scope of Formula V may be prepared by reacting an alkali metal alkoxide with a corresponding compound of Formula VI.
A compound of Formula VI corresponds to the structure:
wherein —A—A—, —B—B—, R
3
, R
8
and R
9
are as defined in Formula IV.
A compound of Formula VIA corresponds to Formula VI wherein R
8
and R
9
together with the ring carbon to which they are attached form the structure:
where X, Y
1
, Y
2
and C(17) are as defined above.
A compound of Formula VIB corresponds to Formula VIA wherein R
8
and R
9
together form the structure of Formula XXXIII:
Compounds of Formulae VIC, VID and VIE, respectively, correspond to any of Formula VI, VIA, or VIB wherein each of —A—A— and —B—B— is —CH
2
—CH
2
—, and R
3
is hydrogen. Compounds of Formula VI, VIA, VIB and VIC are prepared by hydrolyzing a compound corresponding to Formula VII, VIIA, VIIB or VIIC, respectively.
A compound of Formula VII corresponds to the structure:
wherein —A—A—, —B—B—, R
3
, R
8
and R
9
are as defined in Formula IV.
A compound of Formula VIIA corresponds to Formula VII wherein R
8
and R
9
together with the ring carbon to which they are attached form the structure:
where X, Y
1
, Y
2
and C(17) are as defined above.
A compound of Formula VIIB corresponds to Formula VIIA wherein R
8
and R
9
together form the structure of Formula XXXIII:
Compounds of Formulae VIIC, VIID and VIIE, respectively, correspond to any of Formula VII, VIIA, or VIIB wherein each of —A—A— and —B—B— is —CH
2
—CH
2
—, and R
3
is hydrogen. A compound within the scope of Formula VII may be prepared by cyanidation of a compound within the scope of Formula VIII.
A compound of Formula VIII corresponds to the structure:
wherein —A—A—, —B—B—, R
3
, R
8
and R
9
are as defined in Formula IV.
A compound of Formula VIIIA corresponds to Formula VIII wherein R
8
and R
9
together with the ring carbon to which they are attached form the structure:
where X, Y
1
, Y
2
and C(17) are as defined above.
A compound of Formula VIIIB corresponds to Formula VIIIA wherein R
8
and R
9
together form the structure of Formula XXXIII:
Compounds of Formulae VIIIC, VIIID and VIIIE, respectively, correspond to any of Formula VIII, VIIIA, or VIIIB wherein each of —A—A— and —B—B— is —CH
2
—CH
2
—, and R
3
is hydrogen. Compounds within the scope of Formula VIII are prepared by oxidizing a substrate comprising a compound of Formula XXX as described hereinbelow by fermentation effective for introducing an 11-hydroxy group into the substrate in &agr;-orientation.
A compound of Formula XIV corresponds to the structure:
wherein —A—A—, —B—B—, R
3
, R
8
and R
9
are as defined in Formula IV.
A compound of Formula XIVA corresponds to Formula XIV wherein R
8
and
Anderson Dennis K.
Baez Julio A.
Erb Bernhard
Kunda Sastry A.
Lawson Jon P.
Badio Barbara P.
G.D. Searle & Co.
Senninger, Powers, Leavitt & Roedel
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