Method of producing highly functionalized 1,3-diamino-propan-2-ols from solid support

A method of synthesizing a hydroxyethylamino amide of Formula (I):

• wherein:
• R1 is C5-14heteroaryl;
• wherein said C5-14heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of C6-14aryloxy, diC1-8alkanylamino, C1-8alkanylamino, C1-8alkanyl, C6-14aryl, C1-8alkanyloxy, C1-8alkanylcarbonyl, perhaloC1-6alkanyl, halo, C5-14heteroaryl, C1-8alkanyl, C1-8alkanylthio, oxoC5-8cyclicheteroalkenyl, C6-14arylalkynyl, C1-8alkanylsulfonyl, C6-14arylC1-8alkanyl, C1-8alkanyloxy, C6-14arylC1-8alkanyloxy, C6-14arylC1-8alkanyloxycarbonylamino, and C1-8alkanylcarbonylamino;
• R2 is C1-8alkanyl, C1-8alkenyl, hydrogen, or N-linked-C1-8alkanylcarbonylamino, wherein said C1-8alkanyl and C1-8alkenyl are optionally substituted with one or two substituents independently selected from the group consisting of C1-8alkanylC6-14aryl, C1-8alkanyloxyC6-14aryl, C5-14heteroaryl, and C6-14aryl;
• R3 is C1-8alkanyl wherein said C1-8alkanyl is optionally and independently substituted with one or two substituent selected from the group consisting of (C1-8alkanylthio)(aminocarbonyl), C1-8alkanylaminocarbonyl, (C6-14aryl)(C1-8alkanylaminocarbonyl), amino, aminosulfonylC6-14aryl, C1-8alkanylC3-8cyclicheteroalkanyl, C1-8alkanyloxycarbonylamino, C1-8alkanylC6-14arylamino, C1-8alkanylC6-14aryl, C1-8alkanyloxyC6-14aryl, C3-8cyclicheteroalkanyl, C6-14aryl, C6-14arylC1-8alkanyloxycarbonylamino, C6-14aryloxy, C6-14aryloxyC6-14aryl, diC1-8alkanyloxyC6-14aryl, dihaloC6-14aryl haloC6-14aryl, and oxoC3-8cyclicheteroalkanyl;
• C6-14aryl wherein said aryl is optionally and independently substituted with a substituent selected from the group consisting of C1-8alkanyl, C6-14aryloxy;
• C1-8alkanylC3-8cyclicheteroalkanyl;
• C5-14heteroaryl;
• C6-14arylC1-8alkanylheteroalkanyl;
• and C3-8cyclicheteroalkanyl;
• and an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, the method comprising:
• (a) preparing a epoxymethylated support of formula (Ia)
• wherein (support) is selected from the group consisting of amine based polystyrene resins;
• (b) reacting the support of formula (Ia) with an R1 carboxylic acid or substituent of the formula R1COY wherein Y is OH, Cl, Br, OC1-3alkanyl or OOCR1 to generate an epoxymethylated amido support of formula (Ib)
• (c) reacting the epoxymethylated amido support of formula (Ib) with an R2 amine of the formula R2NH2 to generate a hydroxyethylamino amido support of formula (Ic)
• (d) reacting the hydroxyethylamino amido support of formula (Ic) with an R3 aldehyde of the formula R3CHO to generate a hydroxyethlamino amido support of formula (Id)
• and
• (e) cleaving the hydroxyethylamino amide of formula (I) from the hydroxyethlamino amido support of formula (Id).

A method of synthesizing a hydroxyethylamino amide of Formula (I):

• wherein:
• R1 is heteroaryl(C2-8)alkenyl, or heteroaryl(C2-8)alkynyl;
• wherein said heteroaryl(C2-8)alkenyl, and heteroaryl(C2-8)alkynyl are optionally substituted with one to two substituents independently selected from the group consisting of C6-14aryloxy, diC1-8alkanylamino, C1-8alkanylamino, C1-8alkanyl, C6-14aryl, C1-8alkanyloxy, C1-8alkanylcarbonyl, perhaloC1-6alkanyl, halo, C5-14heteroaryl, C1-8alkanyl, C1-8alkanylthio, oxoC5-8cyclicheteroalkenyl, C6-14arylalkynyl, C1-8alkanylsulfonyl, C6-14arylC1-8alkanyl, C1-8alkanyloxy, C6-14arylC1-8alkanyloxy, C6-14arylC1-8alkanyloxycarbonylamino, and C1-8alkanylcarbonylamino;
• R2 is C1-8alkanyl, C2-8alkenyl, C1-8alkoxy(C2-8)alkenyl, C2-8alkynyl, C1-8alkanyloxy(C2-8)alkynyl, heteroaryl(C2-8)alkenyl, heteroaryl(C2-8)alkynyl, or hydrogen, wherein the C1-8alkanyl, C1-8alkenyl C2-8alkynyl portions of R2 are optionally substituted with one or two substituents independently selected from the group consisting of C1-8alkanylC6-14aryl, C1-8alkanyloxyC6-14aryl, C5-14heteroaryl, and C6-14aryl;
• or taken together with the nitrogen atom to which they are attached, R2 and R3 form a 4-7 membered cyclicheteroalkanyl wherein the cyclicheteroalkanyl optionally has in addition to the nitrogen atom one or 2 additional heteroatoms selected from the group consisting of N, O and S, and wherein the cyclicheteroalkanyl is optionally substituted with C1-8alkanyl, C2-8alkenyl, C1-8alkoxy(C2-8)alkenyl, C2-8alkynyl, C1-8alkanyloxy(C2-8)alkynyl, heteroaryl(C2-8)alkenyl, heteroaryl(C2-8)alkynyl, or hydrogen, wherein the C1-8alkanyl, C1-8alkenyl C2-8alkynyl portions of cyclicheteroalkanyl substitution are optionally substituted with one or two substituents independently selected from the group consisting of C1-8alkanylC6-14aryl, C1-8alkanyloxyC6-14aryl, C5-14heteroaryl, C6-14aryl, or C6-14aryl;
• R3 is C1-8alkanyl, C2-8alkenyl, C1-8alkoxy(C2-8)alkenyl, C2-8alkynyl, C1-8alkoxy(C2-8)alkynyl, heteroaryl(C2-8)alkenyl, heteroaryl(C2-8)alkynyl, C1-8alkanyl, cyclicC1-8alkanyl, C6-14aryl, or C5-14heteroaryl;
• wherein said C1-8alkanyl, cyclicC1-8alkanyl, C6-14aryl, and C5-14heteroaryl is optionally and independently substituted with one or two substituent selected from the group consisting of (C1-8alkanylthio)(aminocarbonyl), C1-8alkanylaminocarbonyl, (C6-14aryl)(C1-8alkanylaminocarbonyl), amino, aminosulfonylC6-14aryl, C1-8alkanylC3-8cyclicheteroalkanyl, C1-8alkanyloxycarbonylamino, C1-8alkanylC6-14arylamino, C1-8alkanylC6-14aryl, C1-8alkanyloxyC6-14aryl, C3-8cyclicheteroalkanyl, C6-14aryl, C6-14arylC1-8alkanyloxycarbonylamino, C6-14aryloxy, C6-14aryloxyC6-14aryl, diC1-8alkanyloxyC6-14aryl, dihaloC6-14aryl haloC6-14aryl, and oxoC3-8cyclicheteroalkanyl;
• C6-14aryl wherein said aryl is optionally and independently substituted with a substituent selected from the group consisting of C1-8alkanyl, C6-14aryloxy;
• C1-8alkanylC3-8cyclicheteroalkanyl;
• C5-14heteroaryl;
• C6-14arylC1-8alkanylheteroalkanyl;
• and C3-8cyclicheteroalkanyl;
• and
• an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, the method comprising:
• (a) preparing a epoxymethylated support of formula (Ia)
• wherein (support) is a Rink-AM resin;
• (b) reacting the support of formula (Ia) with an R1 carboxylic acid or substituent of the formula R1COY wherein Y is OH, Cl, Br, OC1-3alkanyl or OOCR1 to generate an epoxymethylated amido support of formula (Ib)
• (c) reacting the epoxymethylated amido support of formula (Ib) with an secondary amine of the formula R2R3NH to generate a hydroxyethylamino amido support of formula (Ic)
• and
• (e) cleaving the hydroxyethylamino amide of formula (I) from the hydroxyethylamino amido support of formula (Id).