Methods for the synthesis of ceragenins

A method of making a compound of Formula (I), comprising the steps of:

• (a) reacting a compound of Formula (1) and R1R2—NH
• to form a compound of Formula (2):
• (b) reducing a compound of Formula (2) to form a compound of Formula (3):
• (c) protecting the compound of Formula (3) with an amine protecting group (PG) to form a compound of Formula (4):
• where R2 is a hydrogen and is replaced with the amine protecting group,
• (d) reacting the compound of Formula (4) with a compound of Formula (A)
• to form a compound of Formula (5):
• (e) subjecting the compound of Formula (5) to hydroboration and oxidation conditions, followed by reaction with a compound of Formula (B)
• R3—SO2Cl (B)
• to form a compound of Formula (6) having three terminal sulfonate groups:
• (f) reacting a compound of Formula (6) and R4R5—NH to thereby directly replace the three terminal sulfonate groups with amino groups, followed by deprotection to form a compound of Formula (I):
• wherein:
• X is independently selected from the group consisting of —F, —Cl, —Br, —I, tosylate, brosylate, nosylate, mesylate, and triflate;
• n is an integer from 1 to 25;
• R1, R2, R4, and R5 are independently selected from the group consisting of hydrogen, optionally substituted C1-C24 alkyl, optionally substituted C2-C24 alkenyl, optionally substituted C2-C24 alkynyl, optionally substituted C6 or C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heterocyclyl, optionally substituted C7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C1-C6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C4-10 (carbocyclyl)alkyl, optionally substituted (5 to 10 membered heterocyclyl)-C1-C6 alkyl, an amine protecting group, and an optionally substituted amide;
• and
• R3 is selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C2-C24 alkenyl, optionally substituted C2-C24 alkynyl, optionally substituted C6 or C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heterocyclyl, optionally substituted C7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C1-C6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C4-10 (carbocyclyl)alkyl, optionally substituted amido, and optionally substituted (5 to 10 membered heterocyclyl)-C1-C6 alkyl,
• wherein if substituted, R1, R2, R3, R4 and/or R5 include a substitution selected from the group consisting of C1-C24 alkyl, C1-C24 alkenyl, C1-C24 alkynyl, C1-C24 heteroalkyl, C3-C10 carbocyclyl, C3-C10-carbocyclyl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, aryl, aryl(C1-C6)alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl(C1-C6)alkyl, halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl, halo(C1-C6)alkoxy, C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (═O), and
• wherein if one or more of R1, R2, R3, R4, or R5 includes a heterocyclyl, the heterocyclyl is selected from the group consisting of azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazol idinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

A method of making a compound of Formula (III), comprising the steps of:

• (a) reacting a compound of Formula (1) and R1R2—NH
• to form a compound of Formula (2):
• (b) optionally protecting a compound of Formula (2) with an amine protecting group (PG) to form a compound of Formula (10):
• where R2 is a hydrogen and is replaced with the amine protecting group;
• (c) reacting a compound of Formula (2) or Formula (10) with a compound of Formula (A) to form a compound of Formula (11a) or (11b):
• (d) subjecting a compound of Formula (11a) or (11b) to hydroboration and oxidation conditions, followed by reaction with a compound of Formula (B) to form a compound of Formula (12a) or (12b) having three terminal sulfonate groups:
• (e) reacting a compound of Formula (12a) or (12b) and R4R5—NH to thereby directly replace the tree terminal sulfonate groups with amino groups, followed by optional deprotection to form a compound of Formula (III):
• wherein:
• X is independently selected from the group consisting of —F, —Cl, —Br, —I, tosylate, brosylate, nosylate, mesylate, and triflate;
• n is an integer from 1 to 25;
• R1, R2, R4, and R5 are independently selected from the group consisting of hydrogen, optionally substituted C1-C24 alkyl, optionally substituted C2-C24 alkenyl, optionally substituted C2-C24 alkynyl, optionally substituted C6 or C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heterocyclyl, optionally substituted C7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C1-C6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C4-10 (carbocyclyl)alkyl, optionally substituted (5 to 10 membered heterocyclyl)-C1-C6 alkyl, an amine protecting group, and an optionally substituted amide;
• and
• R3 is selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C2-C24 alkenyl, optionally substituted C2-C24 alkynyl, optionally substituted C6 or C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heterocyclyl, optionally substituted C7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C1-C6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C4-10 (carbocyclyl)alkyl, optionally substituted amido, and optionally substituted (5 to 10 membered heterocyclyl)-C1-C6 alkyl
• wherein if substituted, R1, R2, R3, R4 and/or R5 include a substitution selected from the group consisting of C1-C14 alkyl, C1-C24 alkenyl, C1-C24 alkynyl, C1-C24 heteroalkyl, C3-C10 carbocyclyl, C3-C10-carbocyclyl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, aryl, aryl(C1-C6)alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl(C1-C6)alkyl, halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl, halo(C1-C6)alkoxy, C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (═O), and
• wherein if one or more of R1, R2, R3, R4, or R5 includes a heterocyclyl, the heterocyclyl is selected from the group consisting of azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazol idinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.