METHOD OF PREPARING 21-ALKYLATED PREGNA-1,4,16-TRIEN-3,20-DIONES

Abstract: Methods for preparing intermediates for 21-alkylated corticosteroids are discloded. Pregna-1,4,16-trien-3,20-diones are contacted with a base and an alkylating agent to produce corresponding 21-alkylated pregna-1,4,16-trien-3,20-diones.

Description: METHOD OF PREPARING 21-ALKYLATED PREGNA-1 ,4,16-TRIEN-3.20- DIONES FIELD OF THE INVENTION The present invention relates to methods of synthesizing intermediates which are used to prepare pharmaceutically active steroids. In particular, the present invention relates to methods of preparing 21-alkylated pregna-1 ,4,16- trien-3,20-diones. BACKGROUND OF THE INVENTION Pregna-1 , 4, 16-trien-3,20-diones of Formula I can be obtained using methods known in the art, for example, methods described in U.S. Patent Nos. 2,874,172; 3,033,873; 3,082,219; 3,281 ,415; 3,842,105; 4,012,510; and 4,216,159; Vitali et al., Gazz. Chem. Ital., 96:1115 (1966); Hofmeister et al., Chem. Ber., 109: 185 (1976) and Kovendi et al., Rev. Chim. (Bucharest), 27:467 (1976). wherein X is OSiR 3 R 4 R 5 or OC(=O)R 6 ; R 3 , R 4 , and R 5 are independently C 1 - C 4 alkyl; R 6 is H or C T - C 4 alkyl; Y is H, F, or CI; or X and Y taken together are a covalent bond; and Q is H or CH 3 . These pregna-1 ,4, 16-trien-3,20-diones are useful for making pharmaceutically valuable corticosteroids. U.S. Patent Nos. 3,947,478 and 3,862,194 disclose the preparation of pharmaceutically valuable 21-alkylated corticosteroids starting with a 16- pregnen-20-one in which the oxygen functional group at carbon 3 is present in the form of a ketal, enol ether, or protected hydroxyl group. Functional groups are then appended at positions 16 and 17. In a subsequent step, the 21 -alkyl group is introduced by, for example, Mannich condensation or ketone alkylation reactions. The 3-keto group is unmasked at a later stage in the synthesis. Alternative methods of preparing 21-alkylated corticosteroids are desired. SUMMARY OF THE INVENTION According to the present invention, pregna-1 , 4, 16-trien-3,20-diones are contacted with a base and an alkylating agent in a ketone alkylation reaction to produce corresponding 21-alkylated pregna-1 ,4, 16-trien-3,20-diones. The 21-alkylated products can be converted into pharmaceutically valuable 21- alkylated corticosteroids using techniques known in the art. Among other factors, the present invention is based upon the finding that 21-alkylated pregna-1 ,4,16-trien-3,20-dione intermediates can be readily obtained from pregna-1 ,4, 16-trien-3,20-diones, providing convenient access to pharmaceutically valuable 21-alkylated corticosteroids. Among other factors, the present invention is also based upon the finding that certain ketone alkylation reactions are highly selective for the 16- en-20-one grouping in the presence of a 1 ,4-dien-3-one grouping. DETAILED DESCRIPTION OF THE INVENTION Ketone alkylation reactions are known in the art. For a discussion of the general chemical methodology employed in such reactions, see d'Angelo, Tetrahedron, 32:2979 (1976). According to the methods of the present invention, ketone alkylation reactions are used to convert pregna-1 , 4,16-trien- 3,20-diones of Formula I above into the corresponding 21-alkylated pregna- 1 ,4,16-trien-3,20-diones of Formula II below. wherein R 1 and R 2 are independently H or C, - C 4 alkyl (optionally unsaturated); X is OSiR 3 R 4 R 5 or OC(=O)R 6 ; R 3 , R 4 , and R 5 are independently C-, - C 4 alkyl; R 6 is H or d - C 4 alkyl; Y is H, F, or CI; or X and Y taken together are a covalent bond; and Q is H or CH 3 . Preferred compounds of Formula II are those where R 1 , R 2 , Y, and Q are H; X is OSiR 3 R 4 R 5 ; and R 3 , R 4 , and R 5 are CH 3 . According to the present invention, a compound of Formula I is dissolved in a suitable solvent. Suitable solvents generally include, but are not limited to, tetrahydrofuran (THF), glyme, hexamethyiphosphoramide (HMPA), 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (DMPU), diethyl ether, methyl t-butyl ether, and combinations thereof. Generally, it is desirable to cool the solution to increase the yield of the intended alkylated product. Appropriate temperatures will be determined by those skilled in the art, but will typically range from 0 to -100 °C. In most instances, it is expected that temperatures ranging from -20 to -80 °C will be sufficient for the ketone . alkylation reaction to selectively produce the intended product. Once the solution of the compound of Formula I reaches the chosen temperature, approximately one molar equivalent of base is added. Though other ratios of base to the compound of Formula I could be employed, they are generally not desirable. If an excess of base is used, the chances for side reactions are increased. (An excess of base can form the extended enolate of the A-ring dienone; see Barton et al., J. Chem. Soc, Perkin Trans. I, p. 1075 (1977) and Barton et al., Chem. Comm., p. 1497 (1969)). On the other hand, if less than one equivalent of base is used, the yield is limited. Suitable bases include lithium diethylamide; lithium diisopropylamide; lithium dicyciohexylamide; lithium isopropylcyclohexylamide; lithium 2,2,6,6- tetramethylpiperidide; lithium hexamethyldisilazide; sodium hexamethyldisilazide; and potassium hexamethyldisilazide. The preferred base is lithium hexamethyldisilazide. After approximately one equivalent of base has been added to the cooled solution of the compound of Formula I, at least one equivalent of an alkylating agent is added. Suitable alkylating agents are those having the formula R 1 R 2 CHZ, wherein R 1 and R 2 are as defined above; and Z is selected from the group consisting of Br, CI, and I. Z is preferably Br or I. As one skilled in the art will readily appreciate, it may be necessary or desirable to allow the reaction temperature to increase after adding the alkylating agent in order to improve the yield. The following examples are presented to illustrate further various aspects of the present invention, but are not intended to limit the scope of the invention in any respect. EXAMPLE 1 Preparation of Pregna-1 ,4,16-trien-11β-ol-3,20-dione. a) The method of Kovendi et al., Rev. Chim. (Bucharest), 27:467 (1976) was modified. Semicarbazide hydrochloride (7.1 mL of a 5% aq. solution, 3.2 mmol) was added to a stirred, 50 °C solution of 21-deoxyprednisolone (1.82 g, 5.29 mmol) [see U.S. Patent No. 3,033,873 and Vitali et al., Gazz. Chim. Ital., 96:1115 (1966)] in acetic acid (60 mL) under Ar. The solution was heated to 75-80 °C (internal). After 2.7 h, another 4.7 mL of 5% aq. semicarbazide hydrochloride (2.1 mmol) was added. After 5.5 h at 75 °C, water (50 mL) was added and the solution was heated to 75 °C for 10 h and then to 90 °C for 1.5 h. The solution was cooled to room temperature, poured into 600 mL of water, stirred for 1 h, diluted with water to 1 L, stirred for 0.5 h and filtered on a fritted Buchner funnel. The solid was dried at 80 °C for 3-4 h to a constant weight of 1.00 g (58%, nominal) of crude product, C21 H26O3. Proton NMR (CDCI3): d 1.22 (s, 3H, I8-H3); 1.48 (s, 3H, 19-H3), 2.27 (s, 3H, 21-H3); 1.0-2.7 (m, 12H); 4.38 (br q, 1 H, J=2.5, H-11); 6.00 (s, 1 H, H-4); 6.25 (dd, 1 H, J=10 and 2, H-2); 6.66 (q, 1 H, J=2, H-16); 7.32 (d, 1 H, J=10, H-1). This material was converted in 75% yield to the known trimethylsilyl derivative, 11 β-(trimethylsiloxy)-pregna-1 ,4,16-trien-3,20-dione (Formula I where X = OSi(CH 3 ) 3 ; Y = Q = H), as described in U.S. Patent No. 4,012, 510. SUBSTITUTE SHEET (RULE 25) b) The method of Kovendi et al., Rev. Chim. (Bucharest), 27:467 (1976) was modified. Semicarbazide hydrochloride (4.75 mL of a 5.0 % aq. solution, 2.14 mmol) was added to a stirred solution of 21-deoxyprednisolone (2.15 g, 6.25 mmol) [see U.S. Patent No. 3,033,873 and Vitali et al., Gazz. Chim. Ital., 96:1115 (1966)] in acetic acid (72 mL) under Ar. The solution was heated to 80-85 °C (bath) for 4.2 h. Water (75 mL) was added and heating (85 °C bath) was continued for 5.5 h. The solution was cooled to 23 °C over 11 h, poured into water (850 mL), cooled in ice (to 7 °C) and filtered on a fritted Buchner funnel. The solid was dried under vacuum to give 1.40 g (69%, nominal) of crude product, C21H26O3. Proton NMR (CDCI3): d 1.22 (s, 3H, I8-H3); 1.48 (s, 3H, 19-H3), 2.27 (s, 3H, 21-H3); 1.0-2.7 (m, 12H); 4.38 (br q, 1 H, J=2.5, H-11); 6.00 (s, 1 H, H-4); 6.25 (dd, 1 H, J=10 and 2, H-2); 6.66 (q, 1 H, J=2, H-16); 7.32 (d, 1 H, J=10, H-1). This material was converted in 83% yield to the known trimethylsilyl derivative, 11 β-(trimethylsiloxy)-pregna-1 ,4,16-trien-3,20-dione (Formula I where X = OSi(CH 3 ) 3 ; Y = Q = H), as described in U.S. Patent No. 4,012, 510. EXAMPLE 2 Preparation of 21 -Methy 1-11 β-(trimethy lsiloxy)-pregna-1 ,4,16-trien-3,20- dione. Lithium hexamethyldisilazide (estimated 0.9 M in THF, 2.1 mL, 1.9 mmol) was added over 8 min. to a stirred, cooled (-60 to -65 °C internal) solution of 11 β- (trimethylsiloxy)-pregna-1 ,4,16-trien-3,20-dione (0.73 g, 1.83 mmol) in THF (12.0 mL) and HMPA (3.0 mL) under Ar. After a further 2 min, the cloudy pale-orange mixture was quenched rapidly with iodomethane (2.5 mL, 40 mmol) whereupon the temperature rose to -57 °C and the suspension cleared. The solution was warmed over 2 min to 10 °C, quenched with sat. KH2PO4, and partitioned with EtOAc. The organic solution was dried (MgSO4), filtered and concentrated. The residue (1.9 g) was purified by chromatography (80 g silica, 25% to 50% EtOAc-hexanes) to give 0.62 g (82%) of the product, C25H36θ3Si, as an off-white solid, m.p. 178 - 182 °C (dec). [α] 23 D + 144° (c = 0.05, CHCI 3 ). .-1 IR(KBr) 1660, 1060, 840 cm " Anal, calcd: C, 72.76, H, 8.79. Found: C, 72.57, H, 8.73. MS (CI, Me3CH): 413 (m+1)(100), 323 ((m-Me3SiOH)+1)(10). Proton NMR (CDCI3): d 0.24 (s, 9H, Me3Si); 1.05 (t, 3H, J=7.3, Me-21); 1.18 (s, 3H, I8-H3); 1.41 (s, 3H, 19-H3); 1.0 - 2.8 (m, 11 H); 2.6 (q, 2H, 21-H2); 4.37 (br q, 1 H, J=2.5, H-11); 5.99 (s, 1 H, H-4); 6.25 (dd, 1 H, J=10 and 2, H- 2); 6.64 (q, 1 H, J=2, H-16); 7.12 (d, 1H, J=10, H-1). The invention has been described by reference to certain preferred embodiments; however, it should be understood that it may be embodied in other specific forms or variations thereof without departing from its spirit or essential characteristics. The embodiments described above are therefore considered to be illustrative in all respects and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description. SUBSTITUTE SHEET (RULE 25)

Claims: WHAT IS CLAIMED IS: A method of preparing a compound of the formula wherein R 1 and R 2 are independently H or C 1 - C 4 alkyl (optionally unsaturated); X is OSiR 3 R R 5 or OC(=O)R 6 ; R 3 , R 4 , and R 5 are independently C - C 4 alkyl; R 6 is H or C 1 - C 4 alkyl; Y is H, F, or CI; or X and Y taken together are a covalent bond; and Q is H or CH 3 ; comprising dissolving a compound of the formula wherein X, Y, and Q are as defined above, SUBSTITUTE SHEET (RULE 25) in a solvent to form a solution and contacting the solution with a base and an alkylating agent. 2. The method of Claim 1 wherein the base is selected from the group consisting of lithium diethylamide; lithium diisopropylamide; lithium dicyclohexylamide; lithium isopropylcyclohexylamide; lithium 2,2,6,6- tetramethylpiperidide; lithium hexamethyldisilazide; sodium hexamethyldisilazide; and potassium hexamethyldisilazide. 3. The method of Claim 2 wherein the base is lithium hexamethyldisilazide. 4. The method of Claim 1 wherein the alkylating agent has the formula R R 2 CHZ, wherein R 1 and R 2 are independently selected from the group consisting of hydrogen and C 1 - C 4 alkyl (optionally unsaturated); and Z is selected from the group consisting of Br, CI, and I. 5. The method of Claim 4 wherein R 1 and R 2 are H; and Z is selected from the group consisting of Br and I. 6. The method of Claim 1 wherein the solvent is selected from the group consisting of tetrahydrofuran; glyme; hexamethylphosphoramide; 1 ,3- dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone; diethyl ether; methyl t-butyl ether; and combinations thereof. SUBSTITUTE SHEET (RULE 25) 7. A method of preparing a compound of the formula wherein R 1 and R 2 are independently H or C - C 4 alkyl (optionally unsaturated); X is OSiR 3 R 4 R 5 or OC(=O)R 6 ; R 3 , R 4 , and R 5 are independently C 1 - C 4 alkyl; R 6 is H or d - C 4 alkyl; Y is H, F, or CI; or X and Y taken together are a covalent bond; and Q is H or CH 3 ; comprising a) dissolving a compound of the formula wherein X, Y and Q are as defined above, in a solvent to obtain a solution; b) cooling the solution of step (a) to a temperature from about 0 to about -100 °C; c) adding approximately one equivalent of a base selected from the group consisting of lithium diethylamide; lithium diisopropylamide; lithium s dicyclohexylamide; lithium isopropylcyclohexylamide; lithium 2,2,6,6- tetramethylpiperidide; lithium hexamethyldisilazide; sodium hexamethyldisilazide; and potassium hexamethyldisilazide to the cooled solution of step (b); and d) adding at least one equivalent of an alkylating agent of the formula o R 1 R 2 CHZ, wherein R 1 and R 2 are as defined above; and Z is selected from the group consisting of Br, CI, and I to the solution of step (c). 8. The method of Claim 7 wherein R 1 , R 2 , Y, and Q are H; X is s OSiR 3 R 4 R 5 ; and R 3 , R 4 , and R 5 are CH 3 . 9. The method of Claim 7 wherein the base is lithium hexamethyldisilazide. o 10. The method of Claim 7 wherein R 1 and R 2 are H; and Z is selected from the group consisting of Br and I. 11. The method of Claim 7 wherein the solvent is selected from the group consisting of tetrahydrofuran; glyme; hexamethylphosphoramide; 1 ,3- 5 dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; diethyl ether; methyl t-butyl ether; and combinations thereof. 12. The method of Claim 7 wherein the solution of step (a) is cooled to a temperature ranging from about -20 to about -80 °C in step (b). 11 SUBSTITUTE SHEET (RULE 25) 13. A method of preparing a compound of the formula wherein R 1 and R 2 are independently H or Ci - C 4 alkyl (optionally unsaturated); and Q is H or CH 3 ; comprising dissolving a compound of the formula wherein Q is as defined above, in a solvent to form a solution and contacting the solution with a base and an alkylating agent. 12 SUBSTITUTE SHEET (RULE 25) 14. The method of Claim 13 wherein the base is selected from the group consisting of lithium diethylamide; lithium diisopropylamide; lithium dicyclohexylamide; lithium isopropylcyclohexylamide; lithium 2,2,6,6- tetramethylpiperidide; lithium hexamethyldisilazide; sodium hexamethyldisilazide; and potassium hexamethyldisilazide. 15. The method of Claim 13 wherein the alkylating agent has the formula R 1 R 2 CHZ, wherein R 1 and R 2 are independently selected from the group consisting of hydrogen and C, - C 4 alkyl (optionally unsaturated); and Z is selected from the group consisting of Br, CI, and I. 16. The method of Claim 13 wherein the solvent is selected from the group consisting of tetrahydrofuran; glyme; hexamethylphosphoramide; 1 ,3- dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; diethyl ether; methyl t-butyl ether; and combinations thereof. 13 SUBSTITUTE SHEET (RULE 25)

Inventors: CONROW RAYMOND E, CONROW, RAYMOND, E.
Applicants: ALCON LAB INC, CONROW RAYMOND E, ALCON LABORATORIES, INC., CONROW, RAYMOND, E.
Application year: 1997
Main classification: C07J13
IPC codes: C07J13, C07J51, C07J71