Claims
- 1. A process for the preparation of the racemic mixture of compounds of Formula (1): wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom;R1 is where R3 and R4 are independently H, OH, C1-8alkoxy, F,CF3 or C1-6alkyl and R5 is —OCH2CO2H;R2 is where R3 and R4 are as indicated above andZ is H, OH, or C1-5alkoxy; or a pharmaceutically acceptable salt thereof, which comprises the steps of:(1) treating a compound of Formula (10): where A, B, C and D are as described above; and R is H, OH, C1-5alkyl of a protected oxy group, in an activation reaction to form a compound of formula (11): where A, B, C, D and R are as described above and R7 is Br, I, —OSO2CF3 or —OSO2F;(2) reacting the product of step (1) with an acid chloride to form a compound of the formula where A, B, C, D, R and R7 are as defined above;and a compound of the Formula: where R3 and R4 are as described above, R6 is OH or protected OH and R8 is MgBr or H, to form a compound of Formula (12): where A, B, C, D, R, R3, R4 and R6 as defined above and R7 is Br, I, —OSO2CF3 or —OSO2F;(3) reacting the product of step (2) with the compound wherein Xc is an achiral group;in the presence of a catalyst to form a compound of formula (13): where A, B, C, D, R, R3, R4, R6 and Xc are as defined above;(4) treating the product of step (3) with a compound of the formula: where R3 and R4 are as defined above, with copper complex to form a compound of the Formula: where A, B, C, D, R, R3, R4, R6 and Xc are as defined above:(5) treating the product of step (4) with sodium methoxide in methanol to form a compound of the Formula: where A, B, C, D, R, R3, R4 and R6 are as defined above;(6) treating the product of step (5) under acidic conditions to form a compound of the Formula: where A, B, C, D, R, R3, R4 and R6 are as defined above;(7) hydrogenating the product of step (6) over palladium to form a compound of Formula (29): where A, B, C, D, R, R3 and R4 are as defined above;(8) treating the product of step (7) with methyl bromoacetate, potassium carbonate in acetone/methanol, followed by saponification with lithium hydroxide monohydrate and acidic workup to form a compound of the Formula: where A, B, C, D, R, R3 and R4 are as defined above;(9) treating the product of step (8) with sodium hydroxide to form the final product, the compound where A, B, C, D, R, R3 and R4 are as defined above.
- 2. A process for the preparation of the racemic mixture of compounds of Formula (1): wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom;R1 is where R and R4 are independently H, OH, C1-8alkoxy, F,CF3 or C1-6alkyl and R5 is —OCH2CH2OH;R2 is where R3 and R4 are as indicated above andZ is H, OH, or C1-5alkoxy; or a pharmaceutically acceptable salt thereof, which comprises the steps of:(1) reacting the compound (11): where A, B, C and D are as described above, R is H, OH, C1-5alkyl of a protected oxy group and R7 is Br, I, —OSO2CF3 or —OSO2F;with an acid chloride to form a compound of the formula where A, B, C, D, R and R7 are as defined above;and a compound of the formula: where R3 and R4 are as described above, R6 is OH or protected OH and R8 is MgBr, to form a compound of Formula (21) where A, B, C, D, R, R3, R4 and R6 are as described above and R7 is Br, I, —OSO2CF3 or —OSO2F;(2) reacting the product of step (1) with the compound wherein Xc is an achiral group;in the presence of a catalyst to form a compound of formula (22): where A, B, C, D, R, R3, R4, R6 and Xc are as defined above;(3) treating the product of step (2) with a compound of the formula: where R3 and R4 are as defined above, with copper complex to form a compound of the Formula: where A, B, C, D, R, R3, R4, R6 and Xc are as defined above;(4) treating the product of step (3) with sodium methoxide in methanol to form a compound of the Formula: where A, B, C, D, R, R3, R4 and R6 are as defined above;(5) treating the product of step (4) under acidic conditions to form a compound of the Formula: where A, B, C, D, R, R3, R4 and R6 are as defined above;(6) hydrogenating the product of step (5) over palladium to form a compound of Formula: where A, B, C, D, R, R3 and R4 are as defined above;(7) treating the product of step (6) with lithium hydroxide monohydrate to effect saponification and epimerization followed by acidic workup to form a compound of the Formula: where A, B, C, D, R, R3 and R4 are as defined above;(8) treating the product of step (7) with ethylene diamine to form the final product, the compound where A, B, C, D, R, R3 and R4 are as defined above.
- 3. A process of claim 1 for the preparation of a compound of the Structure (k) comprising the steps of(1) treating a compound of the formula where R is as defined in claim 1, in an activation reaction to form a compound of the formula where R and R7 is as defined in claim 1;(2) treating the product of step (1) with an acid chloride to form a compound of the formula; where R and R7 is as defined in claim 1;(3) reacting the product of step (2) in an acylation reaction with a compound of the formula where R8 is MgBr and R6 is benzyl or R8 is H and R6 OMe, to form a compound of the formula where R and R7 are as defined in claim 1;(4) reacting the product of step (3) with the compound wherein Xc is in the presence of a palladium catalyst to form a compound of the formula where R is as defined in claim 1 and Xc is as indicated above;(5) treating the product of step (4) with 3,4-(methylenedioxy)phenylmagnesium bromide and a copper complex to form a compound of the formula where R is as defined in claim 1;(6) treating the product of step (5) with sodium methoxide in methanol to form a compound of the formula where R is as defined in claim 1;(7) treating the product of step (6) under acidic conditions to form a compound of the formula where R is as defined in claim 1;(8) hydrogenating the product of step (7) over pallidium on carbon to form the compound where R is as defined in claim 1;(9) treating the product of step (8) with methyl bromoacetate, potassium carbonate in acetone/methanol, followed by saponification with lithium hydroxide monohydrate and acidic workup to form the compound (10) treating the product of step (9) with sodium hydroxide to form the final product, the compound
- 4. A process of claim 2 for the preparation of a compound of the Structure (s) comprising the steps of(1) reacting the a compound of the formula where R and R7 are as described in claim 3, with the compound to form the compound (2) reacting the product of step (1) with the compound wherein Xc is in the presence of a palladium catalyst to form a compound of the formula where R is as described in claim 1;(3) treating the product of step (2) with 3,4-(methylenedioxy)phenylmagnesium bromide and a copper complex to form a compound of the formula where R is as described in claim 1;(4) treating the product of step (3) with sodium methoxide in methanol to form a compound of the formula where R is as described in claim 1;(5) treating the product of step (4) under acidic conditions to form a compound of the formula where R is as described in claim 1;(6) hydrogenating the product of step (5) over palladium to form a compound of the formula where R is as described in claim 1;(7) treating the product of step (6) with lithium hydroxide monohydrate, followed by the acidic workup to form the compound (8) treating the product of step (7) with ethlenediamine to form the final product, the compound
- 5. A process of claim 1 for the preparation of compounds of Formula (19): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom,R1 is where R3 and R4 are independently H, OH, C1-8alkoxy, F, CF3 orC1-6alkyl and R5 is —OCH2CO2H; R2 is where R3 and R4 are as indicated above andZ is H, OH, or C1-5alkoxy; or a pharmaceutically acceptable salt thereof, which comprises the steps of:(1) treating a compound of Formula (10): where A, B, C and D are as described above; and R is H, OH, C1-5alkyl of a protected oxy group, in an activation reaction to form a compound of the formula: where A, B, C, D and R are as described above and R7 is Br, I, —OSO2CF3 or —OSO2F;(2) reacting the product of step (1) with an acid chloride to form a compound of the formula where A, B, C, D, R and R7 are as defined above,and a compound of Formula (t): where R3 and R4 are as described above, R6 is OH or protected OH and R8 is MgBr or H, to form a compound of Formula (12): where A, B, C, D, R, R3, R4 and R6 as defined above and R7 is Br, I, —OSO2CF3 or —OSO2F;(3) reacting the product of step (2) with the compound wherein Xc is in the presence of a palladium catalyst to form a compound of the formula: where A, B, C, D, R, R3, R4, R6 and Xc are as defined above;(4) treating the product of step (3) with a compound of the formula: where R3 and R4 are as defined above, with copper complex to form a compound of the Formula (14): where A, B, C, D, R, R3, R4, R6 and Xc are as defined above;(5) treating the product of step (4) with sodium methoxide in methanol to form a compound of the Formula (15): where A, B, C, D, R, R3, R4 and R6 are as defined above;(6) treating the product of step (5) under acidic conditions to form a compound of the Formula (16): where A, B, C, D, R, R3, R4 and R6 are as defined above;(7) hydrogenating the product of step (6) over palladium to form a compound of Formula (20): where A, B, C, D, R, R3 and R4 are as defined above;(8) treating the product of step (7) with methyl bromoacetate, potassium carbonate in acetone/methanol, followed by saponification with lithium hydroxide monohydrate and acidic workup to form a compound of the Formula: where A, B, C, D, R, R3 and R4 are as defined above;(9) treating the product of step (8) with sodium hydroxide to form the final product, the compound where A, B, C, D, R, R3 and R4 are as defined above, predominantly as the single enantiomer depicted.
- 6. A process of claim 2 for the preparation of compounds of Formula (19): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom;R1 is where R3 and R4 are independently H, OH, C1-8alkoxy, F,CF3 or C1-6alkyl and R5 is —OCH2CH2OH;R2 is where R3 and R4 are as indicated above andZ is H, OH, or C1-5alkoxy; or a pharmaceutically acceptable salt thereof, which comprises the steps of:(1) reacting the compound (11): where A, B, C and D are as described above, R is H, OH, C1-5alkyl or a protected oxy group and R7 is Br, I, —OSO2CF3 or —OSO2F;with an acid chloride to form a compound of the formula where A, B, C, D, R and R7 are as defined above;and a compound of the formula: where R3 and R4 are as described above, R6 is OH or protected OH and R8 is MgBr, to form a compound of Formula (21) where A, B, C, D, R, R3, R4 and R6 are as described above and R7 is Br, I, —OSO2CF3 or —OSO2F,(2) reacting the product of step (1) with the compound wherein Xc is in the presence of a catalyst to form a compound of formula (22): where A, B, C, D, R, R3, R4, R6 and Xc are as defined above;(3) treating the product of step (2) with a compound of the formula: where R3 and R4 are as defined above, with copper complex to form a compound of the Formula (23): where A, B, C, D, R, R3, R4, R6 and Xc are as defined above;(4) treating the product of step (3) with sodium methoxide in methanol to form a compound of the Formula (24): where A, B, C, D, R, R3, R4 and R6 are as defined above;(5) treating the product of step (4) under acidic conditions to form a compound of the Formula (25): where A, B, C, D, R, R3, R4 and R6 are as defined above;(6) hydrogenating the product of step (5) over palladium to form a compound of Formula (26): where A, B, C, D, R, R3, R4 and R6 are as defined above;(7) treating the product of step (6) with lithium hydroxide monohydrate to effect saponification and epimerization followed by an acidic workup to form a compound of the Formula: where A, B, C, D, R, R3 and R4 are as defined above;(8) treating the product of step (7) with ethylene diamine to form the final product, the compound where A, B, C, D, R, R3 and R4 are as defined above, predominantiy as the single enantiomer depicted.
- 7. A process for the preparation of a compound as described in claim 1, step (8), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4, R6 and Xc are as described in claim 1, into a compound as described in claim 1, step (8), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 8. A process for the preparation of a compound as described in claim 1, step (8), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4 and R6 are as described in claim 1, into a compound as described in claim 1, step (8), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 9. A process for the preparation of a compound as described in claim 1, step (8), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4 and R6 are as defined in claim 1, into a compound as described in claim 1, step (8), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 10. A process for the preparation of a compound as described in claim 2, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4, R6 and Xc are as defined in claim 2, into a compound as described in claim 2, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 11. A process for the preparation of a compound as described in claim 2, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4 and R6 are as defined in claim 2, into a compound as described in claim 2, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 12. A process for the preparation of a compound as described in claim 2, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4 and R6 are as defined in claim 2, into a compound as described in claim 2, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 13. A process for the preparation of a compound of formula (j), as described in claim 3, step (9), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the structure, predominantly as the single diastereomer depicted, into a compound of formula (j), as described in claim 3, step (9), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 14. A process for the preparation of a compound of formula (j), as described in claim 3, step (9), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the structure, predominantly as the single enantiomer depicted, into a compound of formula (j), as described in claim 3, step (9), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 15. A process for the preparation of a compound of formula (j), as described in claim 3, step (9), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the structure, predominantly as the single enantiomer depicted, into a compound of formula (j), as described in claim 3, step (9), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 16. A process for the preparation of a compound of formula (r), as described in claim 4, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the structure, predominantly as the single enantiomer depicted, into a compound of formula (r), as described in claim 4, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 17. A process for the preparation of a compound of formula (r), as described in claim 4, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the structure, predominantly as the single enantiomer depicted, into a compound of formula (r), as described in claim 4, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 18. A process for the preparation of a compound of formula (r), as described in claim 4, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the structure, predominantly as the single enantiomer depicted, into a compound of formula (r), as described in claim 4, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 19. A process for the preparation of a compound as described in claim 5, step (8), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4, R6 and Xc are as defined in claim 5, predominantly as the single enantiomer depicted into a compound as described in claim 5, step (8), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 20. A process for the preparation of a compound as described in claim 5, step (8), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4 and R6 are as defined in claim 5, predominantly as the single enantiomer depicted into a compound as described in claim 5, step (8), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 21. A process for the preparation of a compound as described in claim 5, step (8), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4 and R6 are as defined in claim 5, predominantly as the single enantiomer depicted into a compound as described in claim 5, step (8), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 22. A process for the preparation of a compound as described in claim 6, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4, R6 and Xc are as defined in claim 6, predominantly as the single enantiomer depicted, into a compound as described in claim 6, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 23. A process for the preparation of a compound as described in claim 6, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4 and R6 are as defined in claim 6, predominantly as the single enantiomer depicted, into a compound as described in claim 6, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 24. A process for the preparation of a compound as described in claim 6, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4 and R6 are as defined in claim 6, predominantly as the single enantiomer depicted, into a compound as described in claim 6, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 25. A process for the preparation of a compound as defined in claim 2, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4, R6 and Xc are described in claim 2 into a compound as described in claim 2, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 26. A process for the preparation of a compound as described in claim 2, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4 and R6 are as defined in claim 2 into a compound as described in claim 2, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 27. A process for the preparation of a compound as described in claim 2, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4 and R6 are as defined in claim 2 into a compound as described in claim 2, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 28. A process for the preparation of a compound of formula (r), as described in claim 4, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the structure, predominantly as the single diastereomer depicted, into a compound of formula (r), as described in claim 4, step (7), and therafter optionally forming a pharmaceutically acceptable salt thereof.
- 29. A process for the preperation of a compound of a formula (r), as described in claim 4, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the structure, predominantly as the single enantiomer depicted, into a compound of formula (r), as described in claim 4, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 30. A process for the preperation of a compound of formula (r), as described in claim 4, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the structure, predominantly as the single enantiomer depicted, into a compound of formula (r), as described in claim 4, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 31. A process for the preparation of a compound as described in claim 6, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4, R6 and Xc are as defined in claim 6, predominantly as the single enantiomer depicted, into a compound as described in claim 6, step (7), and thereafter optionally forming, a pharmaceutically acceptable salt thereof.
- 32. A process for the preparation of a compound as described in claim 6, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4 and R6 are as defined in claim 6, predominantly as the single enantiomer depicted, into a compound as described in claim 6, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
- 33. A process for the preparation of a compound as described in claim 6, step (7), or a pharmaceutically acceptable salt thereof, which comprises converting a compound of the formula, wherein A, B, C, D, R, R3, R4 and R6 are as defined in claim 6, predominantly as the single enantiomer depicted, into a compound as described in claim 6, step (7), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
Parent Case Info
This is a divisional of application Ser. No. 09/068,581 filed May 8, 1998, now U.S. Pat. No. 6,147,232 which is a 371 of PCT/US96/18846, filed Nov. 8, 1996 and claims benefit of No. 60/006,345 Nov. 8, 1995.
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