ZA200407492B

ZA200407492B - C-17 spirolactonization and 6,7 oxidation of steroids

Info

Publication number: ZA200407492B
Application number: ZA200407492A
Authority: ZA
Inventors: Paula C Miller; Mark J Pozzo; Shine K Chou; Pearlman Bruce Allen; Padilla Amphlett Greg; Jeffrey L Havens; Sonja S Makey; Wu Haifeng
Original assignee: Pharmacia Corp
Priority date: 2002-03-22
Filing date: 2003-03-21
Publication date: 2006-11-29
Also published as: ZA200407607B; CN101492487A

Description

c-17 SPTROLACTONIZATION AND 6,7 OXIDATION OF STEROIDS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. provisional

Application gerial No. 60/425,596, filed November 12, 2002,

U.S. Provisional Application gerial No. 60/411,874, filed

September 19, 2002 and U.S. Provisional Application Serial

No. 60/366,784, filed March 22, 2002. The texts of U.S.

Provisional Application gerial No. 60/425,596, U.S.

Provisional Application Serial No. 60/411,874 and U.S. provisional Application Serial No. 60/366,784 are hereby incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

This invention generally relates to processes for preparing steroid compounds, and more particularly, to processes for the C-17 spirolactonization and 6,7 oxidation of steroid compounds. Most particularly, the invention relates to processes for the C-17 gpirolactonization and 6,7 oxidation of steroid compounds which are ugeful in the preparation of methyl hydrogen 9,110-epoxy-17a-hydroxy-3- oxopregn-4-ene-7d, 21-dicarboxylate, y-lactone (otherwise referred to as eplerenone Or epoxymexrenone) .

Methods for the preparation of 9,11 epoxy steroids in general, and eplerenone in particular, are described in

International Publication Wo 98/25948 and U.S. Patent No. 6,331,622, U.S. Patent No. 6,180,780 and U.S. Patent No. 5,981,744, the entire texts of which are hereby incorporated herein by reference. Further methods for preparing 9,11 epoxy steroids, and eplerenone in particular, are described in co-assigned U.S. Patent Application Serial No. , entitled "Processes To Prepare Eplerenone which wae filed on even date herewith and the text of which is hereby incorporated herein by reference in its entirety.

SUMMARY OF THE INVENTION

This invention provides for, in part, improved processes for the Cc-17 gpirolactonization and 6,7 oxidation of steroid compounds. Among the objects of certain preferred embodiments of the invention are the provision of such a process wherein high purity spirolactone steroid compounds are produced in high yield; the provision of such a process wherein a broad range of substrates may be used; and the provision of such a process which may be implemented with reasonable capital expense and operated at reasonable conversion cost.

Accordingly, in a first embodiment, the present jnvention is directed to a process for the preparation of a steroid compound corresponding the Formula II: rR? )

A G B x + i

D BE L

Ree” ~p” pa (II) wherein:

R®* is alkyl;

R!? is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl,

acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy;

A-A represents the group -CHR!-CHR?*- or -CR}=CR?-, where

R! and R? are independently gelected from the group consisting of hydrogen, halo, hydroxy. alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano. nitro, thioalkyl, aryl and aryloxy;

B-B represents the group -CHR!S-CHR!*- or an o-oriented or R-oriented cyclic group:

RS 16

R

N /

Pr ——CH—CH,—CH—— where RY and R'¢ are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy;

G-J represents the group: aie or aun where R° and RY! are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thiocalkyl, aryl and aryloxy;

D-D represents the group:

CH—CHR*— or Fo where R* is gelected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thiocalkyl, aryl and aryloxy;

E-E represents the group: a. or baum where RS is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; and

L-M represents the group:

HR AN or — =A where R? is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, 5 alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl, aryloxy, heteroaryl, heterocyclyl, furyl and gubstituted furyl.

The process comprises contacting a steroid substrate with a base and a solvent medium containing a gulfonium salt to produce a product mixture comprising the compound of Formula 11 above, wherein the steroid substrate comprises a compound corresponding to Formula I:

R!? o)

A G B x Su (I)

D E L

Ro” ~p~ ~~ wherein the substituents R?, R?, A-A, B-B, D-D. E-E, G-J and 1,-M are as defined in Formula II above.

In another embodiment, the invention is directed to a process for the preparation of a steroid compound corresponding to the Formula III: ° 0

R12 0

OR¥

A G B nd L Ny | (IIT) ro” ~p~ pe 5 wherein:

R? and R* are independently selected from the group consisting of alkyl;

R*? ig selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; :

A-A represents the group -CHR-CHR?*- or -CR!'=CR?*-, where

R! and R? are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy;

B-B represents the group -CHR!-CHR*¢- or an o-oriented or B-oriented cyclic group:

R'® R16

AN J

1 ——CH——CH,—CH— where R} and R'® are independently gelected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thiocalkyl, aryl and aryloxy:

G-J represents the group:

Sew —omi~ or Yo where R® and R!! are independently selected from the group consisting of hydrogen, halo. hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thiocalkyl, aryl and aryloxy:

D-D represents the group:

J or ST where R* is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy;

E-E represents the group:

Neca or ST where R¢ is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; and

L-M represents the group: omRl— / /

HR NN or TERT where R’ is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl, aryloxy, heteroaryl, heterocyclyl, furyl and substituted furyl.

The process comprises contacting a steroid substrate with a malonic acid diester and a base in the presence of a solvent to produce a product mixture comprising the compound of

Formula III, wherein the steroid substrate comprises a compound corresponding to the Formula II above. The process ig further characterized in that the product mixture is treated to remove or sequester base.

In another embodiment, the invention ig directed to a process for preparing a steroid compound of Formula III as described immediately above. The process comprises contacting a steroid substrate of Formula II described above with diethyl malonate and sodium ethoxide to produce a product mixture comprising the steroid compound corresponding to Formula III.

In still another embodiment, the invention is further directed to a process for preparing a asteroid compound corresponding to the Formula VI:

Rr? Rr! 7

R18

A G B x Su

F py o) E (VI) 4 wherein:

R* and R*? are independently gelected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy;

RY and R!® are independently selected from the group consisting of hydrogen, alkyl, hydroxy, alkenyl and alkynyl; or RY and R* together form a ketal or keto group; or RY and R*® together with the Cy, carbon to which they are attached form the a-oriented or B- oriented cyclic structure:

0] 0 0 0} { or { or* or | /

C

Civ 17 Cig where R* is alkyl;

A-A represents the group -CHR'-CHR?- or -CR!'=CR?-, where

R* and R?® are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy;

B-B represents the group -CHRY-CHR*- or an d-oriented or B-oriented cyclic group:

RS 16

R

AN ys 1 ——CH——CH,—CHE—— where R!® and RY are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy;

G-J represents the group:

Sow—omt' or bau where R® and RY are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy:;

E-L represents the group -CHRS-CHR’- or -CR®=CR’-, where

RS and R? are independent, R¢ being selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; and R’ being selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl, aryloxy, heteroaryl, heterocyclyl, furyl and substituted furyl; and

M-G represents the group: nN or STN where R° is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl,

alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy.

The process comprises oxidizing an enol ether steroid substrate corresponding to Formula V to produce a product mixture comprising the steroid compound of Formula VI, wherein the enol ether steroid substrate corresponds to a compound of Formula V:

RY? RY’

R18

I B

P id Y 7

R%0 ~~” (V)

Ré wherein:

R® is alkyl:

E-E represents the group:

JE or Yor where R® is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy;

Claims

What Is Claimed:

1. A process for the preparation of a steroid compound corresponding to the Formula II: R'? 0 I A G B ae ~ D E L (11) pig” Np Ng wherein: R® is alkyl; R!? ig selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; A-A represents the group -CHR!-CHR?- or -CR!=CR?-, where R! and R? are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; B-B represents the group -CHR!-CHR'- or an o-oriented or PB-oriented cyclic group: R AN ys L ——CH——CH,~—CH——

where RY and R*® are independently gelected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; G-J represents the group: Sor —cnmt- or SE where R® and R* are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; D-D represents the group: J or ba where R* is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thiocalkyl, aryl and aryloxy; E-E represents the group: JT or ban where R® is selected from the group consisting of hydrogen, halo, hydroxy. alkyl. alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, 40 alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; and L-M represents the group: — CHR — / / NN or REN . where R? is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl,

45 hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl, aryloxy, heteroaryl, heterocyclyl, furyl and gubstituted furyl,

the process comprising: 50 contacting a steroid substrate corresponding to the Formula I:

RY? 0) i A G B ~V 7 D E L (1) od ~~ ~g wherein the substituents R?, R'?, A-A, B-B, D-D, E-E, G-J and L-M are as defined in Formula II, with a base and a 55 solvent medium containing a gulfonium salt to produce a product mixture comprising the compound of Formula II.

2. A process as set forth in claim 1, wherein the product mixture comprises the B-oriented oxirane compound of Formula II in preference to the o-oriented oxirane compound of Formula II, said B-oriented oxirane compound of Formula II corresponding to the compound of Formula II-B: R12 on oo A G B ~~ i ae D E L (II-B) ro” ~~ pa wherein the substituents R?, RZ, A-A, B-B, D-D, E-E, G-J and L-M are as defined in Formula II.

3. A process as get forth in claim 2, wherein the solvent medium, the base and the reaction conditions are gelected to yield said B-oriented oxirane compound in a ratio to the corresponding o-oriented oxirane compound of at least about 70:30.

4. A process as set forth in claim 2, wherein the solvent medium, the base and the reaction conditions are gelected to yield said B-oriented oxirane compound in a ratio to the corresponding o-oriented oxirane compound of at 5 least about 90:10.

5. A process as set forth in claim 2, wherein the solvent medium, the base and the reaction conditions are selected to yield said R-oriented oxirane compound in a ratio to the corresponding a-oriented oxirane compound of at 5 least about 95:5.

6. A process as set forth in claim 1, wherein the process further comprises: preparing a substrate pre-mixture comprising the steroid substrate and the base in a solvent medium; and 5 contacting the substrate pre-mixture with the solvent medium containing the sulfonium salt.

7. A process as set forth in claim 6 wherein the substrate pre-mixture is maintained at a temperature of less than about 15°C before being contacted with the solvent medium containing the sulfonium salt.

8. A process as set forth in claim 6 wherein the substrate pre-mixture is maintained at a temperature of less than about 10°C before being contacted with the solvent medium containing the sulfonium salt.

9. BA process as set forth in claim 6 wherein the substrate pre-mixture is maintained at a temperature of less than about 5°C before being contacted with the solvent medium containing the sul fonium salt.

10. A process as set forth in claim 6, wherein the solvent medium of the substrate pre-mixture comprises a golvent selected from the group consisting of dimethylsulfoxide, diethyl ether, dioxanes, diglyme, triglyme, dimethylformamide, tetrahydrofuran, dimethylacetamide, acetonitrile and mixtures thereof.

11. A process as get forth in claim 6, wherein the : solvent medium containing the sulfonium salt comprises a solvent selected from the group consisting of dimethylsulfoxide, diethyl ether, dioxanes, diglyme, 5 triglyme, dimethylformamide, tetrahydrofuran, dimethylacetamide, acetonitrile and mixtures thereof.

12. A process as set forth in claim 6, wherein the solvent medium containing the sul fonium salt and the solvent medium of the substrate pre-mixture are independently gelected from the group consisting of dimethylsulfoxide, 5 diethyl ether, dioxanes, diglyme, triglyme, dimethylformamide, tetrahydrofuran, dimethylacetamide, acetonitrile and mixtures thereof.

13. A process as set forth claim 12, wherein the sul fonium salt comprises a trimethylsulfonium salt.

14. A process as set forth in claim 13, wherein the gulfonium salt comprises trimethylsulfonium methyl sulfate.

15. A process as set forth in claim 13, wherein the solvent medium containing the gulfonium salt comprises dimethylsulfoxide.

16. A process as set forth in claim 15, wherein the solvent medium of the substrate pre-mixture comprises tetrahydrofuran.

17. A process as set forth in claim 6, wherein the process further comprises preparing the solvent medium containing the sulfonium salt.

18. A process as set forth in claim 17, wherein the solvent medium containing the sul fonium salt is prepared by contacting dimethyl sulfide with an alkanizing agent in the presence of the golvent medium.

19. A process as set forth in claim 18, wherein the alkanizing agent is selected from the group consisting of dimethyl sulfate or dimethyl iodide.

20. A process as set forth in claim 19, wherein the alkanizing agent comprises dimethyl sulfate.

21. A process as set forth in claim 18, wherein the golvent medium is selected from the group consisting of dimethylsulfoxide, diethyl ether, dioxanes, diglyme, triglyme, dimethylformamide, dimethylacetamide and mixtures thereof.

22. A process as set forth in claim 21, wherein the solvent medium comprises dimethylsulfoxide.

23. A process as set forth in claim 21, wherein the solvent medium containing the gulfonium salt comprises trimethylsulfonium methyl sulfate in dimethylsulfoxide.

24. A process as get forth in claim 21, wherein the solvent selected as the solvent medium containing the sulfonium salt and the solvent gelected as the solvent medium of the substrate pre-mixture are independent, the solvent medium of the steroid substrate pre-mixture being selected from the group consisting of dimethylsulfoxide, diethyl ether, dioxanes, diglyme, triglyme, dimethyl formamide, tetrahydrofuran, dimethylacetamide, acetonitrile and mixtures thereof.

25. A process as set forth in claim 24, wherein the solvent medium of the substrate pre-mixture comprises tetrahydrofuran.

26. A process as set forth in claim 6, wherein the base is selected from the group consisting of alkali metal hydroxides, alkali metal hydrides, t-butyl alkali metal alkoxides and alkaline earth metal hydroxides.

27. A process as set forth in claim 26, wherein the base is selected from the group consisting of KOH, NaOH, LiOH, KH, NaH, LiH and mixtures thereof.

28. A process as set forth in claim 27, wherein the base comprises a solid particulate.

29. A process as set forth in claim 28, wherein the base comprises potassium hydroxide.

30. A process as set forth in claim 6, wherein the molar ratio of base to gsulfonium salt is from about 0.75:1 to about 1.5:1.

31. A process as set forth in claim 6, wherein the molar ratio of base to sulfonium salt is from about 0.9:1 to about 1.1:1.

32. A process as set forth in claim 6, wherein the process further comprises removing solvent from the product mixture by distillation.

33. A process as set forth in claim 6, wherein the process further comprises recovering a steroid product from the product mixture by precipitation, gaid recovered steroid product comprising the compound of Formula II.

34. A process as set forth in claim 33, wherein said precipitation comprises contacting the product mixture with water.

35. A process as set forth in claim 33, wherein the process further comprises washing the recovered steroid product.

36. A process as set forth in claim 35, wherein the recovered steroid product is washed by contacting said steroid product with water.

37. A process as set forth in claim 36, wherein the recovered steroid product is washed by contacting said steroid product with water at a temperature of at least about 25°C.

38. A process as set forth in claim 36, wherein the recovered steroid product is washed by contacting said steroid product with water at a temperature of at least about 40°C.

39. A process as set forth in claim 36, wherein the recovered steroid product is further washed by contacting said steroid product with an alcohol.

40. A process as set forth in claim 39, wherein the recovered steroid product is washed by contacting gaid steroid product with alcohol at a temperature of from about 15°C to about 30°C.

41. A process as set forth in claim 39, wherein the recovered steroid product is washed by contacting said steroid product with alcohol at a temperature of about 20°C.

42. A process as set forth in claim 39, wherein said alcohol is selected from the group consisting of methanol, ethanol, isopropanol, t-butanol and mixtures thereof.

43. A process as set forth in claim 39, wherein said alcohol comprises methanol.

44. A process a set forth in claim 33, wherein the process further comprises drying the recovered steroid product.

45. A process as get forth in claim 44, wherein drying the recovered steroid product comprises contacting the steroid product with air or nitrogen.

46. A process as get forth in claim 45, wherein the steroid product is contacted with nitrogen at a temperature of from about 20°C to about 80°C.

47. A process as set forth in claim 45, wherein the steroid product is contacted with nitrogen at a temperature of from about 60°C to about 75°C.

48. A process as set forth in claim 45, wherein the steroid product is contacted with nitrogen at a temperature of about 70°C.

49. A process as set forth in claim 1, wherein the process comprises: preparing a steroid substrate pre-mixture comprising the steroid substrate and the solvent medium containing the sulfonium salt; and contacting the base with the steroid substrate pre- mixture.

50. A process as set forth in claim 49, wherein the steroid substrate pre-mixture is prepared by contacting the steroid substrate, the sulfonium salt and a solvent medium.

51. A process as set forth in claim 50, wherein the solvent medium is selected from the group consisting of dimethylsulfoxide, diethyl ether, dioxanes, diglyme, triglyme dimethyl formamide, tetrahydrofuran, 5 dimethylacetamide, acetonitrile and mixtures thereof.

52. A process as set forth in claim 49, wherein the page is selected from the group consisting of alkali metal hydroxides, alkali metal hydrides, t-butyl alkali metal alkoxides and alkaline earth metal hydroxides.

53. A process as set forth in claim 52, wherein the base comprises a t-butyl alkali metal alkoxide selected from the group consisting of potassium t-butoxide, sodium t- butoxide, lithium t-butoxide and mixtures thereof.

54. A process as set forth in claim 53, wherein the base comprises potassium t~-butoxide.

55. A process as set forth in claim 54, wherein the sul fonium salt comprises a trimethylsulfonium salt.

56. A process as set forth in claim 55, wherein the sulfonium salt comprises trimethylsulfonium methyl sulfate.

57. A process as set forth in claim 54, wherein the solvent medium is selected from the group consisting of dimethylsulfoxide, diethyl ether, dioxanes, diglyme, triglyme dimethylformamide, tetrahydrofuran, dimethylacetamide, acetonitrile and mixtures thereof.

58. A process as set forth in claim 57, wherein the solvent medium comprises tetrahydrofuran.

59. A process as set forth in claim 57, wherein the solvent medium comprises dimethylsulfoxide.

60. A process as set forth in claim 49, wherein the molar ratio of base to sulfonium salt ig from about 0.75:1 to about 1.5:1.

61. A process as set forth in claim 49, wherein the molar ratio of base to sulfonium salt is from about 0.9:1 to about 1.1l:1.

62. A process as set forth in claim 49, wherein the process further comprises removing solvent from the product mixture by distillation.

63. A process as get forth in claim 49, wherein the process further comprises recovering a steroid product from the product mixture by precipitation, gaid recovered steroid product comprising the compound of Formula II.

64. A process as set forth in claim 63, wherein said precipitation comprises contacting the product mixture with water.

65. A process as set forth in claim 63, wherein the process further comprises washing the recovered steroid product.

66. A process as set forth in claim 65, wherein the recovered steroid product is washed by contacting said steroid product with water. :

67. A process as set forth in claim 66, wherein the recovered steroid product is washed by contacting said steroid product with water at a temperature of at least about 25°C.

68. A process as set forth in claim 66, wherein the recovered steroid product is washed by contacting said steroid product with water at a temperature of at least about 40°C.

69. A process as set forth in claim 66, wherein the recovered steroid product is further washed by contacting said steroid product with an alcohol.

70. A process as set forth in claim 69, wherein the recovered steroid product is washed by contacting said steroid product with alcohol at a temperature of from about 15°C to about 30°C.

71. A process as set forth in claim 69, wherein the recovered steroid product is washed by contacting said steroid product with alcohol at a temperature of about 20°C.

72. A process as set forth in claim 69, wherein said alcohol is selected from the group consisting of methanol, ethanol, isopropanol, t-butanol and mixtures thereof.

73. A process as set forth in claim 69, wherein said alcohol comprises methanol.

74. A process a set forth in claim 63, wherein the : process further comprises drying the recovered steroid : product.

75. A process as set forth in claim 74, wherein drying the recovered steroid product comprises contacting the steroid product with air or nitrogen.

76. A process as set forth in claim 74, wherein the steroid product is contacted with nitrogen at a temperature of from about 20°C to about 80°C.

77. A process as set forth in claim 74, wherein the steroid product is contacted with nitrogen at a temperature of from about 60°C to about 75°C.

78. A process as set forth in claim 74, wherein the steroid product is contacted with nitrogen at a temperature of about 70°C.

79. A process as set forth in claim 1, wherein the steroid substrate is a compound corresponding to the Formula I-A: 0 AGE (I-A) CH,O

80. A process as set forth in claim 79, wherein the product mixture comprises a compound corresponding to the Formula II-A: 0) (11-3) CH,0

81. A process as set forth in claim 80, wherein the product mixture comprises the B-oriented oxirane compound of Formula II-A in preference to the o-oriented oxirane compound of Formula II-A, said P-oriented oxirane compound of Formula II-A corresponding to the compound of Formula II- C: \ <

82. A process for the preparation of a steroid compound corresponding to the Formula III: 0) 0 RZ o OR* A G B pd + Nu L | (III) R%0 yd ~p yd “Ng yd wherein R* and R* are independently alkyl; R}2 ig selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thiocalkyl, aryl and aryloxy; A-A represents the group _CHR!-CHR?*- or -CR!=CR?-, where R! and R? are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; B-B represents the group -CHR!S-CHR- or an oa-oriented or P-oriented cyclic group:

RS R16

1 ——CH——CH,—CH where R!® and R!¢ are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl. hydroxyalkyl, alkoxyalkyl, hydxoxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; G-J represents the group: Ser —om= or pa where R® and RY are independently gelected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy:; D-D represents the group: J or ain where R* is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy;

E-E represents the group: Semen or ST where R¢ is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl,

40 hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; and L-M represents the group:

HR NN or REE where R’ is selected from the group consisting of

45 hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl, aryloxy, heteroaryl, heterocyclyl, furyl and substituted furyl, 50 the process comprising: contacting a steroid substrate corresponding to the Formula II:

R'? 0 A G B ~N i ¥ AP Pa Pe (11) R*0 D E wherein the substituents R®, R%, R}2, A-A, B-B, D-D, 55 E-E, G-J and L-M of the steroid substrate are as defined in Formula III, with a malonic acid diester and a base in the presence of a solvent to produce a product mixture comprising the compound of Formula III; and treating the product mixture to remove or sequester 60 base.

83. A process as set forth in claim 82, wherein the product mixture comprises a compound of the Formula III-B: 0 0) R12 0 OR* win I B A G ro” Sp Ng (III-B)

wherein R?®, R*, R?, A-A, B-B, D-D, E-E, G-J and 1-M are as defined in Formula III.

84. A process as set forth in claim 82, wherein said treatment of the product mixture comprises removing base from the product mixture.

85. A process as set forth in claim 84, wherein said treatment of the product mixture comprises neutralizing base within the product mixture.

86. A process as set forth in claim 85, wherein the product mixture ig treated by contacting gaid product mixture with an acid.

87. A process as get forth in claim 82, wherein the process comprises: preparing a steroid substrate pre-mixture comprising the steroid substrate, solvent and the malonic acid diester; 5 and contacting the base and the steroid substrate pre- mixture.

gg. A process as set forth in claim 82 wherein the malonic acid diester comprises an alkyl malonate.

89. A process as set forth in claim 88 wherein the malonic acid diester comprises dimethyl malonate or diethyl malonate.

90. A process as set forth in claim 88, wherein the malonic acid diester comprises diethyl malonate.

91. A process as set forth in claim 82, wherein the base comprises an alkali metal alkoxide.

92. A process as set forth in claim 91 wherein the base comprises sodium methoxide or sodium ethoxide.

93. A process as set forth in claim 82 wherein the malonic acid diester comprises diethyl malonate and the base comprises sodium ethoxide.

94. A process as set forth in claims 82, wherein the solvent is selected from the group consisting of an anhydrous alcohol, dimethylformamide, dimethylsulfoxide, dimethylacetamide and mixtures thereof.

95. A process as set forth in claim 94 wherein the solvent comprises an anhydrous alcohol.

96. A process as set forth in claim 95 wherein the solvent comprises anhydrous ethanol.

97. A process as set forth in claim 82, wherein the product mixture is treated by contact with an acid and said acid is selected to be soluble within the medium of the product mixture.

98. A process as set forth in claim 82, wherein the product mixture is treated by contact with an acid selected from the group consisting of acetic acid, formic acid, propionic acid, sulfuric acid, phosphoric acid and hydrochloric acid.

99. A process as set forth in claim 98, wherein said acid comprises acetic acid.

100. A process as set forth in claim 98, wherein said product mixture ig contacted with from about 0.75 to about

1.5 molar equivalents of acid.

101. A process as set forth in claim 98, wherein the product mixture is contacted with about 0.85 to about 1.05 molar equivalents of acid.

102. A process as set forth in claim 82, wherein the process further comprises cooling the product mixture prior to removing or sequestering base within the product mixture.

103. A process as set forth in claim 102, wherein the product mixture is cooled to a temperature of from about 40° to about 75°C prior to removing or sequestering base within the product mixture. 104, A process as set forth in claim 82, wherein the process further comprises recovering a gteroid product from the product mixture, gaid recovered steroid product comprising the compound of Formula III.

105. A process as set forth in claim 104, wherein the steroid product is recovered from the product mixture by precipitation.

106. A process as set forth in claim 104, wherein the process further comprises washing the recovered steroid product.

107. A process as set forth in claim 106, wherein the recovered steroid product is washed by contacting said steroid product with water.

108. A process as set forth in claim 106, wherein the recovered steroid product ig washed by contacting said steroid product with alcohol.

109. A process as set forth in claim 106, wherein the recovered steroid product is washed by contacting said steroid product with a mixture of water and alcohol.

110. A process as get forth in claim 109, wherein said mixture of water and alcohol comprises from about 10% to about 50% by weight alcohol.

111. A process as set forth in claim 109, wherein said mixture of water and alcohol comprises from about 25% to about 35% by weight alcohol.

112. A process as set forth in claim 109, wherein said mixture of alcohol and water comprises about 30% by weight alcohol.

113. A process a set forth in claim 104, wherein the process further comprises drying the recovered steroid product.

114. A process as set forth in claim 113, wherein drying the recovered steroid product comprises contacting the steroid product with air or nitrogen.

115. A process as set forth in claim 113, wherein the steroid product is contacted with nitrogen at a temperature of from about 20°C to about 70°C.

116. A process as set forth in claim 113, wherein the steroid product is contacted with nitrogen at a temperature of about 60°C.

117. A process as set forth in claim 82, wherein the process comprises: preparing a pre-mixture comprising the base, the malonic acid diester and the solvent; and contacting the steroid substrate with said pre-mixture to produce the product mixture.

118. A process as set forth in claim 82 wherein the steroid substrate is a compound corresponding to the Formula IT-A: 0 (11-3)

119. A process as set forth in claim 118 wherein the product mixture comprises a compound corresponding to the Formula III-A: 0 0 0} OR* : (III-A) CH,O0 wherein R* is alkyl.

120. A process as set forth in claim 118, wherein the product mixture comprises a compound corresponding to the Formula III-C: 0) 0 o AA nm (ITI-C) CH,0 5 wherein R* is alkyl.

121. A process for the preparation of a steroid compound corresponding to the Formula VI: Rr? rt’ R18 A G B x” oY L JF o) E (VI) rR: wherein

R* and RY are independently gelected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy;

RY and RY are independently selected from the group consisting of hydrogen, alkyl, hydroxy, alkenyl and alkynyl or RY and R}® together form a ketal or keto group or RY and R* together with the Cy, carbon to which they are attached form the o-oriented or R-oriented cyclic structure:

0 0 0 o 0) \ or \ OR* or | / c C 17 17 C1q where R* is alkyl;

A-A represents the group -CHR}-CHR?- or -CR'=CR?-, where R! and R? are independently gelected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl. aryl and aryloxy: B-B represents the group -CHR!5-CHR}®- or an o-oriented or B-oriented cyclic group: RS 16 R AN ys rl ——CH—CH,—CH——

where R' and R are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy;

G-J represents the group:

orto or Yr where R°® and R! are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl,

alkoxy, acyl, hydroxyalkyl, alkoxyalkyl,

hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, 40 nitro, thioalkyl, aryl and aryloxy;

E-L represents the group —-CHRS-CHR’- or -CR®=CR’-, where

R¢ and R’ are independent, R® being selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl,

45 hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy, and R’ being gelected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl,

50 acyloxyalkyl, cyano, nitro, thioalkyl, aryl, aryloxy, heteroaryl, heterocyclyl, furyl and substituted furyl; and M-G represents the group:

ETTORE or S>=L_ where R® is selected from the group congisting of 55 hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy,

the process compriging: 60 oxidizing a steroid substrate corresponding to a compound of the Formula V: RY? RY’ R18 I A | B Ng 2g hi E L R%0 NNT (Vv) 4 wherein R®* is alkyl; 65 E-E represents the group: CH—CHR®— or et where R® is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thiocalkyl, 70 aryl and aryloxy; 1L-M represents the group: , J —CHR "NN or w= where R’ is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, 75 alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl, aryloxy, heteroaryl, heterocyclyl, furyl and substituted furyl, and the substituents R*, R?, RY, R'®, A-A, B-B, and G-J are as defined in Formula VI.

122. A process as set forth in claim 121, wherein the steroid substrate corresponds to a compound of Formula V-A: [o] r*? o vd Ny py | v » B L R®0 AS ~~ wherein the substituents R®*, E-E and L-M are as defined in Formula V and the substituents RY, R'?, A-A, B-B and G-J are as defined in Formula VI.

123. A process as set forth in claim 122, wherein the product mixture comprises a steroid compound corresponding to a compound of Formula VI-A: . [o] Rr*? o A (e] B vd Ny VI-A G A ( )

[0] E wherein the substituents R*, R'?, A-A, B-B, G-J, BE-L and M-G are as defined in Formula VI.

124. A process as set forth in claim 122, wherein the product mixture comprises a gteroid compound corresponding to a compound of Formula VI-B:

[0] R32 A nnn A G B X yd NN PF p (VI-B) [o] E 5 wherein the substituents R*, R?, A-A, B-B, G-J, E-L and M-G are as defined in Formula VI.

125. A process as set forth in claim 121, wherein the process comprises contacting the steroid substrate of Formula V with an oxidizing agent in the presence of water to produce a product mixture comprising the steroid compound of Formula VI.

126. A process as get forth in claim 125, wherein the oxidizing agent is gelected from the group consisting of o- chloranil, p-chloranil, dichlorodicyanobenzogquinone and mixtures thereof.

127. A process as set forth in claim 125, wherein the oxidizing agent comprises p-chloranil.

128. A process as set forth in claim 125, wherein the steroid substrate is contacted with an amount of oxidizing agent which is in excess of the stoichiometric amount of oxidizing agent required for the oxidation of the steroid 5 substrate.

129. A process as set forth in claim 128, wherein the steroid substrate is contacted with about 1.01 to about 1.50 molar equivalents of oxidizing agent.

130. A process as set forth in claim 128, wherein the steroid substrate is contacted with about 1.01 to about 1.25 molar equivalents of oxidizing agent.

131. A process as set forth in claim 128, wherein the steroid substrate is contacted with about 1.01 to about 1.05 molar equivalents of oxidizing agent.

132. A process as get forth in claim 125, wherein the steroid substrate and the oxidizing agent are contacted in the presence of a solvent.

133. A process as set forth in claim 132, wherein the process comprises: introducing the steroid substrate and the oxidizing agent into a reaction zone; and thereafter contacting said steroid substrate and said oxidizing agent in said reaction zone with said solvent and water.

134. A process as set forth in claim 132, wherein the process comprises: preparing a gubstrate pre-mixture comprising the asteroid substrate and the oxidizing agent; and 5 contacting the substrate pre-mixture with said solvent and water.

135. A process as set forth in claim 132, wherein the process comprises: contacting the steroid substrate and the oxidizing agent with a premixed reaction medium comprising said 5 solvent and water.

136. A process as set forth in claim 132, wherein the golvent is selected from the group consisting of dimethylformamide, acetonitrile, methanol, acetone, methylene chloride and mixtures thereof.

137. A process as set forth in claim 132, wherein the golvent comprises methylene chloride.

138. A process as set forth in claim 132, wherein the solvent comprises a mixture of methylene chloride and methanol.

139. A process as set forth in claim 132, wherein the solvent and water are mixed prior to contacting the steroid substrate and the oxidizing agent.

140. A process as set forth in claim 125, wherein the process further comprises isolating the steroid compound of Formula VI from the product mixture.

141. A process as set forth in claim 125, wherein the process further comprises contacting the product mixture with a reducing agent.

142. A process as set forth in claim 141, wherein the reducing agent is gelected from the group consisting of gulfite, metabisulfite, and mixtures thereof.

143. A process as set forth in claim 125, wherein the product mixture further comprises a substituted dihydroquinone byproduct.

144. A process as set forth in claim 143 wherein the process further comprises removing the substituted dihydroquinone byproduct from the product mixture and recovering the steroid compound of Formula VI.

145. A process as set forth in claim 144 wherein removing said substituted dihydroquinone by-product from the product mixture comprises contacting the product mixture with a base.

146. A process as set forth in claim 145 wherein said product mixture is contacted with a base under essentially anhydrous conditions.

147. A process as set forth in claim 145, wherein the base comprises an alkali metal hydroxide selected from the group consisting of NaOH, LiOH, KOH, and mixtures thereof.

148. A process as set forth in claim 147, wherein the base comprises a solid particulate.

149. A process as set forth in claim 148, wherein the base comprises potassium hydroxide.

150. A process as set forth in claim 121, wherein the oxidation process comprises contacting the steroid substrate with a source of a halogen in the presence of water to produce a halogenated steroid intermediate; and dehydrohalogenating the halogenated steroid intermediate with a base to produce a product mixture comprising the steroid product of Formula VI.

151. A process as set forth in claim 121, wherein the steroid substrate is gelected from the group consisting of o} CH,0’ : “ ] : CH,0 0) 0 0 OR™ CH,0

0] e) CH,0 OH Va ~f CH,0 and OH C——=CH CH,07 3 wherein R* is alkyl.

152. A process as set forth in claim 121, wherein the steroid substrate is gelected from the group consisting of NY < 0 0 % xX OR mim CH,0 0 NN ul CH,0™ _ .

0} - ] : CH,0 OH V4 CH, unniCH CH,0 and OH 1IC=—=CH CH,0 wherein R* is alkyl.

152. A process as set forth in claim 121, wherein the steroid product of Formula VI is selected from the group consisting of 0 Z ) 0} Z i

0 0 e= ) Oo Z S : o OH J CH o and OH 0] wherein R* is alkyl.

154. A process as set forth in claim 121, wherein the steroid product of Formula VI is selected from the group consisting of 0] 2 j :

0 S santitll 0) es = : 0 0 0 8 OR" nin oF J wcy 0 and OH <= (0) wherein R* is alkyl.

155. A process for the preparation of a steroid compound corresponding to the Formula VI: Rr? RY R8 A G B I'd x L 0 = 8 (VI) r:

wherein R* and RY? are independently gelected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxyi RY and R!?® are independently gelected from the group consisting of hydrogen, alkyl, hydroxy, alkenyl and alkynyl or RY and R!® together form a ketal or keto group or RY and R!® together with the ¢,, carbon to which they are attached form the a-oriented or R-oriented cyclic structure: 0 0] 0 0 \ or \ OR" or J Cc Cc 17 17 Cyy where R* is alkyl; A-A represents the group _CHR!-CHR?- or -CR!=CR?-, where R! and R? are independently gelected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; B-B represents the group -CHRYS-CHR**- or an o-oriented or B-oriented cyclic group: rR 16 R AN / 1 ——CH——CH,—CHE—

where R®* and R® are independently gelected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxyi G-J represents the group: Sera or ro where R® and RY are independently gelected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano,

nitro, thioalkyl, aryl and aryloxy;

E-L represents the group -CHRS-CHR’- or -CRS=CR’-, where R® and R’ are independent, R¢ being selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl,

40 hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy, and R’ being selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl,

45 acyloxyalkyl, cyano, nitro, thioalkyl, aryl, aryloxy, heteroaryl, heterocyclyl, furyl and substituted furyl; and M-G represents the group:

where R® is selected from the group congisting of 50 hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl. alkoxyalkyl, hydroxycarbonyl , alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy, the process comprising: 55 contacting a steroid gubstrate corresponding to a compound of the Formula V: p12 rY? R'® A G B Nd ag E L R%0 Ve (V) RY wherein R* is alkyl; 60 E-E represents the group: J or ba where RS is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, 65 aryl and aryloxy; L-M represents the group: —CHR N or = where R’ is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, 70 alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thiocalkyl, aryl, aryloxy, heteroaryl, heterocyclyl, furyl and substituted furyl, and the substituents R*, R}¥, RY", R'®, A-A, B-B, and G-J are as defined in Formula VI, 75 with an oxidizing agent in the presence of water to produce a product mixture comprising the steroid compound of Formula Vi; and contacting the product mixture with a base.

156. A process as set forth in claim 155, wherein the product mixture is contacted with a base under essentially anhydrous conditions.

157. A process as set forth in claim 155, wherein the pase comprises an alkali metal hydroxide selected from the group consisting of NaOH, LiOH, KOH, and mixtures thereof.

158. A process as set forth in claim 157, wherein the base comprises a solid particulate.

159. A process as set forth in claim 158, wherein the base comprises potassium hydroxide.

160. A process as set forth in claim 155, wherein the process further comprises contacting the product mixture with a reducing agent prior to contacting the product mixture with a base.

161. A process as set forth in claim 160, wherein the reducing agent is selected from the group consisting of sulfite, metabisulfite, and mixtures thereof.

162. A process as set forth in claim 155, wherein the process further comprises recovering the steroid compound of Formula VI from the product mixture.

163. A process as set forth in claim 162, wherein the steroid compound of Formula VI ig recovered from the product mixture by precipitation.

164. A process as set forth in claim 155, wherein the oxidizing agent is selected from the group consisting of o- chloranil, p-chloranil, dichlorodicyancbenzoquinone and mixtures thereof.

165. A process as set forth in claim 155, wherein the oxidizing agent comprises p-chloranil.

166. A process as set forth in claim 155, wherein the gteroid substrate is contacted with an amount of oxidizing agent which is in excess of the stoichiometric amount of oxidizing agent required for oxidizing the steroid substrate.

167. A process as set forth in claim 166, wherein the steroid substrate is contacted with about 1.01 to about 1.50 molar equivalents of oxidizing agent.

168. A process as set forth in claim 166, wherein the steroid substrate is contacted with about 1.01 to about 1.25 molar equivalents of oxidizing agent.

169. A process as set forth in claim 166, wherein the steroid substrate is contacted with about 1.01 to about 1.05 molar equivalents of oxidizing agent.

170. A process as set forth in claim 155, wherein the steroid substrate and the oxidizing agent are contacted in the presence of a solvent.

171. A process as get forth in claim 170, wherein the process comprises: introducing the gteroid substrate and the oxidizing agent into a reaction zone; and thereafter contacting gaid steroid substrate and said oxidizing agent in gaid reaction zone with said solvent and water.

172. A process as get forth in claim 170, wherein the process comprises: preparing a substrate pre-mixture comprising the steroid substrate and the oxidizing agent; and 5 contacting the substrate pre-mixture with said solvent and water.

173. A process as get forth in claim 170, wherein the process comprises: contacting the ateroid substrate and the oxidizing agent with a pre-mixed reaction medium comprising said 5 solvent and water.

174. A process as set forth in claim 170, wherein the solvent is selected from the group consisting of dimethylformamide, acetonitrile, methanol, acetone, methylene chloride and mixtures thereof.

175. A process as set forth in claim 170, wherein the solvent comprises methylene chloride.

176. A process as set forth in claim 170, wherein the solvent comprises a mixture of methylene chloride and methanol.

177. A process as set forth in claim 170, wherein the solvent and water are mixed prior to contacting the steroid aubstrate and the oxidizing agent.

178. A process as get forth in claim 155, wherein the steroid substrate corresponds to a compound of Formula V-A: 0 Rl? J B A x Ny (V-3) R® A ~~ wherein the substituents R®, E-E and L-M are as defined in Formula V and the substituents RY, RZ?, A-A, B-B and G¢-J are as defined in Formula VI.

179. A process as set forth in claim 178, wherein the product mixture comprises a gteroid compound corresponding to a compound of Formula VI-A: [o} rR}? o A G B R yd ~N, = | (VI-A) [o] ee wherein the substituents R*, R*?, A-A, B-B, G-J, E-L and M-G are as defined in Formula VI.

180. A process as get forth in claim 178, wherein the product mixture cowprises a asteroid compound corresponding to a compound of Formula VI-B:

[0] RY? AN Nn A G B

~~. PZ p (VI-B) [o] E 5 wherein the substituents RY, R¥?, A-A, B-B, G-J, E-L and M-G are as defined in Formula VI.

181. A process as set forth in claim 155, wherein the steroid substrate is gelected from the group consisting of 0] CH,0” i :

“ ]

CH,O

0

0 0 es ) CH,O OH Y CH, Sl CH,0

OH C——=CH CH,0™ 8 . 0 CH,0” 3 ! wherein R* is alkyl.

182. A process as set forth in claim 155, wherein the steroid substrate is selected from the group consisting of I < CH,0

[o] Q 0 @) CH,0 Q xX OR Hun CH,0 0} AN LLLLLLLL CH,0™ $ ’

OH Vas bl CH,O and CH mune =——CH CH,O~ g ) : wherein R* is alkyl.

183. A process as get forth in claim 155, wherein the steroid product of Formula VI is gelected from the group consisting of: 0 Z ] : 0) CH,0” } :

0 0} pe=h 0] Z% _ : 0] OH Va CH and OH <= 0 wherein R* is alkyl.

184. A process as set forth in claim 155, wherein the steroid product of Formula VI is selected from the group consisting of 0 Z ] :

0 AN < 0] 0 > SN 0) Q 0 AA mann

/082894 PCT/US03/07792

OH Vas WINCH o J J and OH we =—=CH 0] S wherein R* is alkyl.

185. A process for the preparation of a steroid compound corresponding to Formula VI-A: 0] rR? © A G B JOS (VI-A) F L o z wherein:

rR? ig selected from the group congisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy;

A-A represents the group —CHR!-CHR?- or -CR'=CR?-, where rR! and R? are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl,

is aryl and aryloxy;

B-B represents the group -CHR-CHR!¢- or an a-oriented or P-oriented cyclic group: RS 16 R AN / 1 ——(CH———CH,——CH——

where R! and R* are independently selected from the group consisting of hydrogen, halo, hydroxy. alkyl,

alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy;

G-J represents the group: orem or ba where R® and R!! are independently gelected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; E-L represents the group -CHRS-CHR’- or -CR®=CR’-, where RS and R’ are independent, R® being selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; and R’ being gelected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl, aryloxy, heteroaryl, heterocyclyl, furyl and gubstituted furyl; 40 and M-G represents the group:

pe or ARN where R° is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, 45 alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy, the process comprising: contacting a steroid substrate corresponding to a compound of Formula I: rR? 0 y:N G B + ~ 50 D E L (1) vd ~~ Ng wherein: R* is alkyl;

D-D represents the group: Noi or ban where R* is selected from the group consisting of 55 hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; E-E represents the group: Jahan or Jet 60 where RS is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thioalkyl, aryl and aryloxy; 65 L-M represents the group: / ya aR NN or BERN where R’ is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, nitro, thiocalkyl,

70 aryl, aryloxy, heteroaryl, heterocyclyl, furyl and substituted furyl; and the substituents R'?, A-A, B-B and G-J are as defined in Formula VI-A, with a base and a solvent medium containing a sulfonium salt 75 to produce an oxirane intermediate steroid compound of Formula 11: R'? o) 9 A G B ~N i + D E L (II) rio” ~~ ~~ wherein the substituents R?, R2, A-A, B-B, G-J, D-D, E-E and

1.-M are as defined in Formula I; 80 contacting the oxirane intermediate compound of Formula ITI with a malonic acid diester and a base in the presence of a solvent to produce a dicarboxylate intermediate steroid compound corresponding to Formula III: 0] jo) R12 0 OR* A G x Su (III) D BE L R20” py” Ng

85 wherein R* is alkyl and the substituents R®, R!?, A-A, B-B, G- J, D-D, E-E and L-M are as defined in Formula I; decarboxylating the dicarboxylate intermediate compound of Formula III to produce an enol ether steroid compound of Formula V-A: [¢] Rr? 0 A vd 0S 90 py | (V-A) R%0 AN ~N wherein the substituents R*, RY, A-A, B-B, G-J, E-E and L-M are as defined in Formula I; and oxidizing the enol ether steroid compound of Formula V- A to produce the steroid compound of Formula VI-A.

186. A process for the preparation of a steroid compound corresponding to Formula VI-C: 0 2 nn (VI-C) of the process comprising:

contacting a steroid substrate corresponding to Formula I-A: 0 prio (1-3) CH,O with a base and a solvent medium containing a sulfonium salt to produce an oxirane intermediate compound of Formula II-C: ANG > (II-C) CH,0 contacting the oxirane intermediate compound of Formula II-C with a malonic acid diester and a base in the presence of a solvent to produce a dicarboxylate intermediate steroid compound corresponding to Formula III-C: 0] 0 AA {nnn (III-C) CH,0 decarboxylating the dicarboxylate intermediate compound of Formula III-C to produce an enol ether steroid compound of Formula IV-C: 0 o Hm (IV-C) CH;0 and oxidizing the enol ether steroid compound of Formula IV-C to produce the steroid compound of Formula VI-C.

187. A process for the preparation of a compound corresponding to Formula X: 0] A 0 111} CO) OMe a2 o iT 0] the process comprising: contacting a steroid substrate of Formula I-A: 0] eo CH,0 with a base and a solvent medium containing a sulfonium salt to produce an oxirane intermediate steroid compound of Formula II-C: \ a (II-C) CH,0 contacting the oxirane intermediate steroid compound of Formula II-C with a malonic acid diester and a base in the presence of a solvent to produce a dicarboxylate intermediate steroid compound of Formula III-C: 0 0) 0 OR* nn (III-C) CH,0 wherein R* is alkyl; decarboxylating the dicarboxylate intermediate steroid compound of Formula III-C to produce an enol ether steroid compound of Formula IV-C: 0 o nnn (IV-C) CH,0 oxidizing the enol ether steroid compound of Formula IV-C to produce a dienone steroid compound of Formula VI-C:

lo] o unm (VI-C) 10) contacting the dienone steroid compound of Formula VI-C with an alkyl furan and a Lewis acid to produce a 7a-furyl intermediate steroid compound of Formula VII: 0 A oO = of (VII) preparing a 7o-methoxycarbonyl intermediate steroid compound of Formula IX from the 7a-furyl intermediate steroid compound of Formula VII, said compound of Formula IX comprising:

0] A, U1 (1X) Io) K and; 0] converting the 7a-methoxycarbonyl intermediate steroid 35 compound of Formula IX to the steroid compound of Formula X.

188. A steroid compound corresponding to Formula X: 0) A, CT O 0 (g Me (X) 6] prepared by a process comprising: contacting a steroid substrate of Formula I-A: 0] pies ee CH;0 with a base and a solvent medium containing a sulfonium salt to produce an oxirane intermediate steroid compound of Formula II-C:

SN ow (11-C) CH30 contacting the oxirane intermediate steroid compound of Formula II-C with a malonic acid diester and a base in the presence of a solvent to produce a dicarboxylate steroid compound of Formula III-C: 0 0 0 OR* (III-C) CH;0 i5 wherein R* is alkyl; decarboxylating the dicarboxylate steroid compound of Formula III-C to produce an enol ether steroid compound of Formula IV-C:

0 o LIL (IV-C) CH;0 oxidizing the enol ether steroid compound of Formula IV-C to produce a dienone steroid compound of Formula vVi-C: (0) o dll (VI-C) 0] contacting the dienone steroid compound of Formula VI-A with an alkyl furan and a Lewis acid to produce a 7a-furyl intermediate steroid compound of Formula VII:

0 A il! Oo Ke 04 (VII) preparing a 70-methoxycarbonyl intermediate steroid compound of Formula IX from the 7a-furyl intermediate steroid compound of Formula VII, said compound of Formula IX comprising: 0] A, oll GS yy re (IX) 0) and; converting the 70-methoxycarbonyl intermediate steroid compound of Formula IX to the steroid compound of Formula X.