Claims
- 1 A process useful in synthesizing antipicornaviral compounds, comprising:
(a) performing cyanomethylation of a compound of formula V using bis(trimethysily)amide and bromoacetonitrile to yield a compound of formula VI; 29(b) performing reduction, then cyclization, and then deprotection of the compound of formula VI to yield a compound of formula VII; and 30(c) performing oxidation and olefination of the compound of formula VII by reacting the compound of formula VII with a SO3-pyridine complex to 31 yield a reaction mixture and reacting the reaction mixture with a compound for formula VIII to form a compound of formula IV: wherein R1 is H, F, an alkyl group, OH, SH, or an O-alkyl group; wherein each R41 is independently H or lower alkyl; wherein is any suitable protecting group for nitrogen and wherein Z and Z1 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R21, —CO2R21, CN, —C(O)NR21R22, —C(O)NR21OR22, —C(S)R21, —C(S)NR21R22, —NO2, —SOR21, —SO2R21, —SO2NR21R22, —SO(NR21)(OR22), —SONR21, —SO3R21, —PO(OR21)2, —PO(R21)(R22), —PO(NR21R22)(OR23), —PO(NR21R22)(NR23R24), —C(O)NR21NR22R23, or —C(S)NR21NR22R23, where R21, R2, R23, and R24 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where any of two of R21, R22, R23, and R24, together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z1 are not both H; or Z1 and R1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z1 and R1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group; or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group.
- 2. The process of claim 1, wherein the compound of formula V is prepared from N-Boc L glutanic acid γ-benzyl ester.
- 3. The process of claim 1, wherein X is a Boc group.
- 4. The process of claim 1, wherein R41 is H.
- 5. The process of claim 1, wherein Z is H.
- 6. The process of claim 1, wherein Z1 is —COOEt.
- 7. A process useful in synthesizing antipicornaviral compounds according to claim 1, further comprising the steps of:
(d) deprotecting the compound of formula IV to yield a compound of formula IVA: 32 ; and (e) subjecting a compound of formula II and the compound of formula IVA to an amide-forming reaction to yield a compound of formula IA: 33wherein each R41 is independently H or lower alkyl; R4 is 34R5 and R6 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and Z and Z1 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R21, —CO2R21, CN, —C(O)NR21R22, —C(O)NR21OR22, —C(S)R21, —C(S)NR21R22, —NO2, —SOR21, —SO2R21, —SO2NR21R22, —SO(NR21)(OR22), —SONR21, —SO3R21, —PO(OR21)2, —PO(R21)(R22), —PO(NR21R22)(OR23), —PO(NR21R22)(NR23R24), —C(O)NR21NR22R23, or —C(S)NR21NR22R23, where R21, R22, R23, and R24 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where any of two of R21, R22, R23, and R24, together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z1 are not both H; or Z1 and R1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z1 and R1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group; or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group.
- 8. The process of claim 7, wherein X is a Boc group.
- 9. The process of claim 7, wherein compound IV is
- 10. The process of claim 7, wherein the compound of formula II is
- 11. The process of claim 7, wherein the compound of formula IVA is
- 12. The process according to claim 7, wherein the compound of formula IA is
- 13. A process useful in synthesizing antipicornaviral compounds, comprising:
(a) performing dianionic alkylation of a compound of formula IX using bromoacetonitrile to prepare a compound of formula X; 39(b) performing hydrogenation of the compound of formula X to yield an amine of formula XI; 40(c) reacting the compound of formula XI with Et3N to yield a lactam ester of formula XII; 41(d) performing reduction of the lactam ester of formula XII to yield a compound of formula XIII: 42(e) performing oxidation and olefination of the compound of formula XIII to yield a compound of formula XIV by reacting it with a compound of formula 43wherein each R41 is independently H or lower alkyl; Z and Z1 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R21, —CO2R21, CN, —C(O)NR21R22, —C(O)NR21OR22, —C(S)R21, —C(S)NR1R22, —NO2, —SOR21, —SO2R21, —SO2NR21R22, —SO(NR21)(OR22), —SONR21, —SO3R21, —PO(OR21)2, —PO(R21)(R22), —PO(NR21R22)(OR23), —PO(NR21R23(NR23R24), —C(O)NR21NR22R23, or —C(S)NR21NR22R23, where R21, R22, R23, and R24 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where any of two of R21, R22, R23, and R24, together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z1 are not both H; or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group; and X is any suitable protecting group for nitrogen.
- 14. The process useful in synthesizing antipicornaviral compounds according to claim 13, further comprising:
preparing a compound of formula IV by converting the compound of formula XIV to yield the compound of formula Iv: 44wherein R1 is H, F, an alkyl group, OH, SH, or a O-alkyl group.
- 15. The process useful in synthesizing antipicornaviral compounds according to claim 14, further comprising:
Step A: deprotecting the compound of formula IV to yield a compound of formula IVA: 45Step B: subjecting a compound of formula II and the compound of formula IVA to an amide-forming reaction to yield a compound of formula IA: 46wherein each R4 is independently H or lower alkyl, R4 is 47R5 and R6 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and Z and Z1 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R21, —CO2R21, CN, —C(O)NR21R22, —C(O)NR21OR22, —C(S)R21, —C(S)NR21R22, —NO2, —SOR21, —SO2R21, —SO2NR21R22, —SO(NR21)(OR22), —SONR21, —SO3R21, —PO(OR21)2, —PO(R21)(R22), —PO(NR21R22)(OR23), —PO(NR21R22)(R23R24), —C(O)NR21NR22R23, or —C(S)NR21NR22R23, where R21, R22, R23, and R24 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where any of two of R21, R22, R23, and R24, together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z1 are not both H; or Z1 and R1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloallyl group, where Z1 and R1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group; or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group.
- 16. The process of claim 13, wherein X is a Boc group.
- 17. The process of claim 13, wherein R41 is H.
- 18. The process of claim 13, wherein Z is H.
- 19. The process of claim 13, wherein Z1 is —COOEt.
- 20. The process of claim 14, wherein R1 is H.
- 21. A process useful for the synthesis of a compound of formula IA′, and acid addition salts thereof:
- 22. The process of claim 21, wherein the compound of formula V is prepared from N-Boc L glutanic acid γ-benzyl ester.
- 23. A process useful in synthesizing antipicornaviral compounds, comprising:
(a) performing dianionic alkylation of a compound of formula IX′ using bromoacetonitrile to prepare a compound of formula X′; 54(b) performing hydrogenation of the compound of formula X′ to yield an amine of formula XI′; 55(c) reacting the compound of formula XI′ with Et3N to yield a lactam ester of formula XII′; (d) performing reduction of the lactam ester of formula XII′ to yield a compound of formula XIII′: 56(e) performing oxidation and olefination of the compound of formula XIII′ to yield a compound of formula XIV′ by reacting it with Ph3P═CHCO2Et; 57
- 24. The process useful in synthesizing antipicornaviral compounds according to claim 23, further comprising:
converting the compound of formula XIV′ to the compound of formula IV′; 58
- 25. The process useful in synthesizing antipicornaviral compounds according to claim 24, further comprising:
deprotecting the compound of formula IV′ to yield a compound of formula IVA′: 59 ; and subjecting a compound of formula II′ and the compound of formula IVA′ to an amide-forming reaction; 60
- 26. A compound having formula III, made by the process of claim 25.
- 27. A process for forming intermediate IV′, useful for synthesizing antipicornaviral compounds comprising
- 28. The process of claim 27 further comprising hydrogenating the compound of formula X′ to yield an amine of formula XI′
- 29. The process of claim 27 further comprising hydrogenating the compound of
- 30. The process of claim 28 further comprising reacting the compound of formula XI′ with Et3N to yield a lactam ester of formula XII′
- 31. The process of claim 29 further comprising reacting the compound of formula XI′A with Na2CO3 to yield a lactam ester of formula XII″
- 32. The process of claim 30 further comprising performing a reduction of the lactam ester of formula XII′ to yield a lactam alcohol of formula XIII′
- 33. The process of claim 31 further comprising performing a reduction of the
- 34. The process of claim 33 further comprising oxidizing the lactam alcohol of formula XIII′, then olefination by treating the oxidized lactam alcohol with Et3P, and BrCH2CO2Et in the presence of base to yield a compound of formula IV′
- 35. A process for forming intermediate IV′, useful for synthesizing antipicornaviral compounds comprising
- 36. The process of claim 35 further comprising reducing the lactam ester of formula XII′ to yield a lactam alcohol of formula XIII′
- 37. The process of claim 36 further comprising reacting the salt of the compound of formula XI′B with base to yield a lactam ester of formula XII′
- 38. The process of claim 37 further comprising hydrogenating the compound of formula X′ ti yield a compound of formula XI′B
- 39. The process of claim 38 further comprising performing dianionic alkylation of a compound of formula IX′ to prepare a compound of formula X′
RELATED APPLICATION DATA
[0001] This application relates to U.S. Provisional Patent Application Serial No. 60/150,358, filed on Aug. 24, 1999 and is a continuation-in-part of U.S. application Ser. No. 09/643,864, filed Aug. 23, 2000. The above-mentioned applications are relied upon and incorporated herein by reference.
[0002] This application also relates to U.S. Provisional Patent Application Serial No. 60/150,365 (Attorney Docket No. 0125.0027), also filed Aug. 24, 1999, entitled “Efficient Methods For The Preparation Of Rhinovirus Protease Inhibitors, Key Intermediates And A Continuous Membrane Reactor Useful For The Preparation Of The Same” having named as inventors: J. Tao, S. Babu, R. Dagnino, Jr., Q. Tian, T. Remarchuk, K. McGee, N. Nayyar, and T. Moran. The aforementioned application also relates to synthetic routes for the preparation of rhinovirus protease inhibitors, as well as key intermediates useful in their preparation.
Provisional Applications (2)
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Number |
Date |
Country |
|
60150358 |
Aug 1999 |
US |
|
60150365 |
Aug 1999 |
US |
Continuation in Parts (1)
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Number |
Date |
Country |
Parent |
09643864 |
Aug 2000 |
US |
Child |
09984555 |
Oct 2001 |
US |