	US 12,129,274 B2
	Modular synthesis of aminoglycosides
Andrew Antony Calabrese, Cockeysville, MD (US); Timothy Robert Kane, San Diego, CA (US); Darin Hildebrandt, San Diego, CA (US); Michael Lopez, Petaluma, CA (US); Nikolai Evdokimov, San Diego, CA (US); Frederick Cohen, San Diego, CA (US); Malken Bayrakdarian, Montreal (CA); Sanijia Xu, Montreal (CA); Samuel Desjardins, Montreal (CA); and Olivier Soueidan, Montreal (CA)
Assigned to Revagenix, Inc., San Francisco, CA (US)
Filed by REVAGENIX, INC., San Francisco, CA (US)
Filed on Dec. 21, 2022, as Appl. No. 18/085,645.
Application 18/085,645 is a division of application No. 17/044,960, granted, now 11,673,907, previously published as PCT/US2018/047993, filed on Aug. 24, 2018.
Claims priority of provisional application 62/652,169, filed on Apr. 3, 2018.
Prior Publication US 2023/0167148 A1, Jun. 1, 2023
Int. Cl. C07H 7/04 (2006.01); C07H 5/06 (2006.01); C07H 17/02 (2006.01)

CPC C07H 7/04 (2013.01) [C07H 5/06 (2013.01); C07H 17/02 (2013.01)]

5 Claims

1. A process for preparing a compound of formula ABC-1′:

or a salt thereof,

wherein:

R^1aand R^1bare independently selected from the group consisting of H, C₁-C₁₂alkyl, C₁-C₆cycloalkyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³, —OSF₂NR¹⁴R¹⁵, NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵and R¹⁶is independently H or alkyl; or

R^1aand R^1b, together with the atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group, wherein the cycloalkyl group or heterocycloalkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²², —SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶is independently H or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, NR¹⁴R¹⁵and —OR¹⁶;

R^2a, R^2b, R^3aand R^3bare independently selected from the group consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄cycloalkyl, and C₁-C₆alkyl, wherein each R²⁷, R²⁸, and R²⁹is independently H, alkyl, amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of aryl, halogen, —OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³and R³⁴is independently H or alkyl substituted with one or more substituents independently selected from the group consisting of halogen, cyano, NR¹⁴R¹⁵and —OR¹⁶; or

R^2aand R^2bform an oxo or imino group substituted with C₁-C₆alkyl;

R^3aand R^3bform an oxo or imino group substituted with C₁-C₆alkyl;

R^4aaand R^4bbare, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², or halogen;

wherein each R⁴⁰, R⁴¹, and R⁴²are independently H, alkyl, —CONH₂, or —COCH₃; wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^5aais H, —CN, —CONH₂or C₁-C₃alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^6aand R^6bare, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy, —OC(O)CH₃, or -OPg^2m; wherein Pg^2mis a hydroxyl protecting group;

N^1sis N₃or —NR^8aR^8b;

R⁸is H, C₁-C₆alkyl, an amino protecting group, or

wherein

Q¹is NH, O, or S;

z is an integer from 0 to 4,

R^35zis H or C₁-C₃alkyl;

each R^36zand R^37zis independently selected from the group consisting of H, alkyl, halogen, and —OH, and

R^38zis H, alkyl, or —C(═NH)NR^39zR^40zwherein R^39zand R^40zare independently H or C₁-C₃alkyl; or

R^35zand R^38z, together with the atoms to which they are attached, form a heterocycloalkyl group comprising at least one N;

R^8bis H or C₁-C₃alkyl;

N^1eis —OH, protected hydroxyl group, —NHPg^1eor N₃, wherein Pg^1eis an amino protecting group;

N^1fis —NHPg^1for N₃, wherein Pg^1fis an amino protecting group;

X⁷is H, —NH₂, —N₃, protected amino group, —OH, protected hydroxyl group, or halogen;

m is zero, 1, or 2;

n is zero, 1, or 2;

wherein m+n is 1, 2 or 3;

is zero, 1, or 2;

p is zero, 1, or 2;

wherein o+p is 1, 2 or 3;

R^7a, R^7b, and R^7care independently H, NH₂, OH, —OR⁷¹or -OPg^2r;

wherein R⁷¹is alkyl; wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

wherein Pg^2ris a hydroxyl protecting group;

R^9aand R^9bare independently H, OH, or —OR⁹¹,

wherein R⁹¹is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl, and alkynyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^10aand R^10bare independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl, or alkynyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

Pg^2fis a hydroxyl protecting group;

q is zero, 1, or 2;

r is zero, 1, or 2; and

wherein q+r is 1, 2 or 3;

the process comprising:

(a) contacting a compound of formula A-9′:

wherein LVG³is a leaving group,

with a compound of formula B-12:

to yield a compound of formula AB-1′

where Pg²e is a hydroxyl protecting group;

(b) selectively deprotecting the compound of formula AB-1′ by removing the Pg²e group to yield a compound of formula AB-3′:

or a salt thereof, and

or a salt thereof,

where LVG⁴is a leaving group, to yield the compound of formula ABC-1′ or salt thereof.