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Process for Preparation of 9, 11- Epoxy Steroids and Intermediates Useful Therein

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Process for Preparation of 9, 11- Epoxy Steroids and Intermediates Useful Therein Europäisches Patentamt *EP001148061A2* (19) European Patent Office Office européen des brevets (11) EP 1 148 061 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: C07J 1/00, C07J 21/00, 24.10.2001 Bulletin 2001/43 C07J 31/00, C07J 41/00, C07J 53/00, C07J 71/00, (21) Application number: 01111209.1 C12P 33/00, C12P 33/10, (22) Date of filing: 11.12.1997 C07D 301/12 (84) Designated Contracting States: • Pozzo, Marc J. AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL Chicago, Illinois 60680-9899 (US) PT SE • Sing, Yuen-Lung L. Chicago, Illinois 60680-9899 (US) (30) Priority: 11.12.1996 US 33315 P • Wang, Ping T. 11.06.1997 US 49388 P Chicago, Illinois 60680-9899 (US) • Yonan, Edward E. (62) Document number(s) of the earlier application(s) in Chicago, Illinois 60680-9899 (US) accordance with Art. 76 EPC: • Weier, Richard M. 97954126.5 / 0 944 644 Chicago, Illinois 60680-9899 (US) • Kowar, Thomas R. (71) Applicant: G.D. SEARLE & CO. Chicago, Illinois 60680-9899 (US) Chicago, IL 60680-5110 (US) • Baez, Julio A. Chicago, Illinois 60680-9899 (US) (72) Inventors: • Erb, Bernhard • Ng, John S. 5073 Gipf-Oberpfirch (CH) Chicago, Illinois 60680-9899 (US) • Liu, Chin (74) Representative: Beil, Hans Christoph, Dr. et al Chicago, Illinois 60680-9899 (US) Hansmann & Vogeser, • Anderson, Dennis K. Patent- und Rechtsanwälte, Chicago, Illinois 60680-9899 (US) Postfach 80 01 40 • Lawson, Jon P. 65901 Frankfurt (DE) Chicago, Illinois 60680-9899 (US) • Wieczorek, Joseph Remarks: Chicago, Illinois 60680-9899 (US) This application was filed on 14 - 05 - 2001 as a • Kunda, Sastry A. divisional application to the application mentioned Chesterfield, Missouri 63017 (US) under INID code 62. • Letendre, Leo J. Chicago, Illinois 60680-9899 (US) (54) Process for preparation of 9, 11- epoxy steroids and intermediates useful therein (57) Multiple novel reaction schemes, novel process steps and novel intermediates are provided for the synthesis of epoxymexrenone and other compounds of Formula I wherein: EP 1 148 061 A2 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 148 061 A2 -A-A- represents the group -CHR4-CHR5- or -CR4=CR5-R3R4and R5 are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano, aryloxy; R1 represents an alpha-oriented lower alkoxycarbonyl or hydroxyalkyl radical; -B-B- represents the group -CHR6-CHR7- or an alpha- or beta- oriented group: where R6 and R7 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy; and R8 and R9 are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy, or R8 and R9 together comprise a carbocyclic or heterocyclic ring structure, or R8 or R9 together with R6 or R7 comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring. 2 EP 1 148 061 A2 Description Background of the Invention 5 [0001] 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 9,11α-epoxy-17α-hydroxy-3-oxopregn-4-ene-7α,21-di- carboxylate, γ-lactone (also referred to as eplerenone or epoxymexrenone). 10 [0002] Methods for the preparation of 20-spiroxane series compounds are described in U.S. patent 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: 15 20 25 in which -A-A- represents the group -CH2-CH2- or -CH=CH-; R1 represents an α-oriented lower alkoxycarbonyl or hydroxycarbonyl radical; -B-B- represents the group -CH2-CH2- or an α- or β-oriented group; 30 35 R6 and R7 being hydrogen; X represents two hydrogen atoms or oxo; Y1 and Y2 together represent the oxygen bridge -O-, or 40 Y1 represents hydroxy, and 2 Y represents hydroxy, lower alkoxy or, if X represents H2, also lower alkanoyloxy; and salts of such compounds in which X represents oxo and Y2 represents hydroxy, that is to say of corresponding 17β-hydroxy-21-carboxylic acids. 45 [0003] U.S. patent 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 50 [0004] 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 55 of such a process which may be implemented with reasonable capital expense and operated at reasonable conversion cost. [0005] Accordingly, the present invention is directed to a series of synthesis schemes for epoxymexrenone; inter- mediates useful in the manufacture of epoxymexrenone; and syntheses for such novel intermediates. 3 EP 1 148 061 A2 [0006] 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. [0007] A compound of Formula IV corresponds to the structure: 5 10 15 wherein: -A-A- represents the group -CHR4-CHR5- or -CR4=CR5-; R3,R4and R5 are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower 20 alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy carbonyl, cyano and aryloxy; R1 represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbonyl radical; R2 is an 11α-leaving group the abstraction of which is effective for generating a double bond between the 9- and 25 11- carbon atoms; -B-B- represents the group -CHR6-CHR7- or an alpha-or beta- oriented group: 30 35 where R6 and R7 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy; and R8 and R9 are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy, or R8 and R9 40 together comprise a carbocyclic or heterocyclic ring structure, or R8 or R9 together with R6 or R7 comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring. [0008] A compound of Formula IVA corresponds to Formula IV wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 45 50 where X, Y1, Y2 and C(17) are as defined above. [0009] A compound of Formula IVB corresponds to Formula IV wherein R8 and R9 together form the structure of Formula XXXIII: 55 4 EP 1 148 061 A2 5 [0010] Compounds of Formulae IVC, IVD and IVE, respectively, correspond to any of Formula IV, IVA, or IVB wherein 3 1 each of -A-A- and -B-B- is -CH2-CH2-, R is hydrogen, and R is alkoxycarbonyl, preferably methoxycarbonyl. Com- pounds within the scope of Formula IV may be prepared by reacting a lower alkylsulfonylating or acylating reagent, or 10 a halide generating agent, with a corresponding compound within the scope of Formula V. [0011] A compound of Formula V corresponds to the structure: 15 20 wherein -A-A-, -B-B-, R1, R3, R8 and R9 are as defined in Formula IV. [0012] A compound of Formula VA corresponds to Formula V wherein R8 and R9 with the ring carbon to which they 25 are attached together form the structure: 30 where X, Y1, Y2 and C(17) are as defined above. [0013] A compound of Formula VB corresponds to Formula V wherein R8 and R9 together form the structure of 35 Formula XXXIII: 40 [0014] Compounds of Formulae VC, VD and VE, respectively, correspond to any of Formula V, VA, or VB wherein 3 1 each of -A-A- and -B-B- is -CH2-CH2-, R is hydrogen, and R is alkoxycarbonyl, preferably methoxycarbonyl. Com- 45 pounds within the scope of Formula V may be prepared by reacting an alkali metal alkoxide with a corresponding compound of Formula VI. [0015] A compound of Formula VI corresponds to the structure: 50 55 5 EP 1 148 061 A2 5 10 15 wherein -A-A-, -B-B-, R3, R8 and R9 are as defined in Formula IV. [0016] A compound of Formula VIA corresponds to Formula VI wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 20 25 where X, Y1, Y2 and C(17) are as defined above. [0017] A compound of Formula VIB corresponds to Formula VI wherein R8 and R9 together form the structure of Formula XXXIII: 30 35 [0018] Compounds of Formulae VIC, VID and VIE, respectively, correspond to any of Formula VI, VIA, or VIB wherein 3 each of -A-A- and -B-B- is -CH2-CH2-, and R 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. [0019] A compound of Formula VII corresponds to the structure: 40 45 50 wherein -A-A-, -B-B-, R3, R8 and R9 are as defined in Formula IV.
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