Methods for converting quinolone esters into quinolone amides

1. A method for preparing a compound having formula 2,

comprising contacting an ester having formula 4, an amine with formula NHR 1 R 2, and a Lewis acid having formula ML n , wherein L is a halogen atom or an alkyl group, n is 3-5, and M is a group III elemental atom, a group IV elemental atom, As, Sb, vanadium, or Fe,

wherein A, V, and X are independently H, halo, azido, R 2, CH 2 R 2, SR 2, OR 2 or NR 1 R 2 ;

wherein in NR 1 R 2 , R 1 and R 2 may form an optionally substituted ring; Z is O, S, or NR 1 ;

Z 5 , Z 6 , Z 7 , and Z 8 are C;

each R 1 is H or a C 1-6 alkyl;

each R 2 is a C 1-10 alkyl or C 2-10 alkenyl optionally containing one or more non-adjacent heteroatoms selected from N, O, and S, and optionally substituted with a carbocyclic or heterocyclic ring; or R 2 is an optionally substituted carbocyclic ring, heterocyclic ring, aryl or heteroaryl;

each W is an optionally substituted aryl or heteroaryl, which may be monocyclic, or fused with a single or multiple ring and optionally containing a heteroatom;

and each R 5 is a substituent at any position on W; and is H, OR 2 , NR 1 R 2 , C 1-6 alkyl, C 2-6 alkenyl, each optionally substituted by halo, C═O or one or more heteroatoms; or two adjacent R 5 are linked to obtain a 5-6 substituted or unsubstituted carbocyclic or heterocyclic ring, optionally fused to an additional substituted or unsubstituted carbocyclic or heterocyclic ring.

2. The method of claim 1 , wherein said ester, amine, and Lewis acid are contacted at room temperature.

3. The method of claim 1 , comprising contacting said ester and amine in an organic solvent to form a solution, and contacting said solution with Lewis acid.

4. The method of claim 3 , wherein said organic solvent is methylene chloride.

5. The method of claim 1 , wherein an excess of amine in relation to the ester is used.

6. The method of claim 5 , wherein the ratio of the ester to the amine is 1:2; 1:1.5; or 1:1.25.

7. The method of claim 1 , wherein an equimolar amount of Lewis acid to the amine is used.

8. The method of claim 1 , further comprising isolating the compound having formula 2, and optionally purifying said isolated compound having formula 2.

9. The method of claim 8 , wherein said isolated compound is purified through column chromatography, recrystallization, or both.

10. The method of claim 9 , wherein the purity of the isolated compound is between 90 and 99%.

11. The method of claim 10 , wherein the purity of the isolated compound is between 90 and 95%.

12. The method of claim 1 , wherein W in any compound having formula 1-4 is selected from the group consisting of:

wherein each Q, Q 1, Q 2, and Q 3 is independently CH or N; Y is independently O, CH, C═O or NR 1; and R5 as defined in claim 1 .

13. The method of claim 1 , wherein X in any compound having formula 2 or formula 4 is SR 2, where R 2 is a C 1-10 alkyl or C 2-10 alkenyl optionally substituted with a heteroatom, a carbocyclic ring, a heterocyclic ring, an aryl or a heteroaryl.

14. The method of claim 1 , wherein X and A in any compound having formula 2 or formula 4 may independently be halo or NR 1 R 2 ,

wherein R 1 is H;

R 2 is a C 1-10 alkyl optionally substituted with a heteroatom, a C 3-6 cycloalkyl, aryl or a 5-14 membered heterocyclic ring containing one or more N, O or S;

or R 1 and R 2 together with N in NR 1 R 2 may form an optionally substituted heterocyclic ring containing one or more N, O or S.

15. The method of claim 14 , wherein R 2 is a C 1-10 alkyl substituted with morpholine, thiomorpholine, imidazole, aminodithiadiazole, pyrrolidine, piperazine, pyridine or piperidine; or wherein R 1 and R 2 together with N form piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, imidazole, or aminodithiazole.

16. The method of claim 14 , wherein said optionally substituted heterocyclic ring is tetrahydrofuran, 1 ,3-dioxolane, 2,3-dihydrofuran, tetrahydropyran, benzofuran, isobenzofuran, 1 ,3-dihydro-isobenzofuran, isoxazole, 4,5 -dihydroisoxazole, piperidine, pyrrolidine, pyrrolidin-2-one, pyrrole, pyridine, pyrimidine, octahydro-pynolo [3 ,4-b]pyridine, piperazine, pyrazine, morpholine, thiomorpholine, imidazole, aminodithiadiazole, imidazolidine-2,4-dione, benzimidazole, 1 ,3-dihydrobenzimidazol-2-one, indole, thiazole, benzothiazole, thiadiazole, thiophene, tetrahydro-thiophene 1,1-dioxide, diazepine, triazole, guanidine, diazabicyclo [2.2.1 ]heptane, 2,5 -diazabicyclo [2.2.1 ]heptane, or 2,3 ,4,4a,9,9a-hexahydro- 1 H-β-carboline.

17. The method of claim 14 , wherein X has the formula

NR 1 −(CR 1 2 ) n NR 3 R 4   (5)

wherein R 1 is H; n is 1-6; and R 3 and R 4 together with N in NR 3 R 4 form an optionally substituted ring.

18. The method of claim 17 , wherein n is 2 or 3.

19. The method of claim 1 , wherein each optionally substituted moiety in any compound having formula 2 or formula 4 may be substituted with one or more halo, OR 2 , NR 1 R 2, carbamate, C 1-10 alkyl, C 2-10 alkenyl, each optionally substituted by halo, C═O, aryl or one or more heteroatoms; aryl, carbocyclic or a heterocyclic ring.

20. The method of claim 1 , wherein said compound having formula 2 is

21. The method of claim 1 , wherein said Lewis acid is BL 3, AlL 3, FeL 3, GaL 3 , SbL 5 , InL 3 , ZrL 4 , SnL 4 , TiL 4 , TiL 3 , AsL 3 , or SbL 3 , wherein L is halo or alkyl.

22. The method of claim 21 , wherein said Lewis acid is aluminum chloride.

23. The method of claim 1 , wherein in —NR 1 R 2 , R 2 is C 1-10 alkyl or C 2-10 alkenyl substituted with a carbocyclic or heterocyclic ring.

24. The method of claim 23 , wherein in —NR 1 R 2 , R 2 is C 1-10 alkyl substituted with a heterocyclic ring,

where said heterocyclic ring is selected from tetrahydrofuran, 1 ,3-dioxolane, 2,3-dihydrofuran, pyran, tetrahydropyran, benzofuran, isobenzofuran, 1,3 -dihydro-isobenzofuran, isoxazole, 4,5 -dihydroisoxazole, piperidine, pyffolidine, pyrrolidin-2-one, pyrrole, pyridine, pyrimidine, octahydro-pyrrolo [3 ,4-b]pyridine, piperazine, pyrazine, morpholine, thiomorpholine, imidazole, imidazolidine-2,4-dione, 1 ,3-dihydrobenzimidazol-2-one, indole, thiazole, benzothiazole, thiadiazole, thiophene, tetrahydro-thiophene 1,1-dioxide, diazepine, triazole, guanidine, diazabicyclo [2.2.1 ]heptane, 2,5 -diazabicyclo [2.2.1 ]heptane, 2,3 ,4,4a,9,9a-hexahydro- 1 H-β-carboline, oxirane, oxetane, tetrahydropyran, dioxane, lactones, aziridine, azetidine, piperidine, and lactams.

25. The method of claim 1 , wherein the amine of formula NHR 1 R 2 is 2-(2- aminoethyl)- 1-methyl pyffolidine or 1 -(2-aminoethyl) pyrrolidine.

26. The method of claim 1 , wherein the amine of formula NHR 1 R 2 is 2-(2- aminoethyl)- 1-methyl pyffolidine.

27. The method of claim 1 , wherein in —NR 1 R 2, R 2 is an optionally substituted carbocyclic ring, heterocyclic ring, aryl or heteroaryl.

28. The method of claim 1 , wherein NHR 1 R 2 is an amine of the formula:

29. The method of claim 28 , which produces a compound of formula (2), wherein said compound of formula (2) is: