Modular synthesis of aminoglycosides
Inventors
Calabrese, Andrew • Kane, Timothy Robert • Hildebrandt, Darin • Lopez, Michael • Evdokimov, Nikolai • Cohen, Frederick • Bayrakdarian, Malken • XU, Sanjia • DESJARDINS, SAMUEL • SOUEIDAN, Olivier
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Assignees
Intellisyn R&d • Revagenix Inc
Member
Revagenix, IncRevagenix is a precision-therapeutics company specializing in the discovery and development of targeted medicines for serious chronic diseases, with a primary focus on respiratory conditions such as non-cystic fibrosis bronchiectasis. Leveraging a biology-driven, first-principles approach, the company engineers therapies optimized for disease biology, patient need, and real-world delivery requirements. The team brings experience spanning the entire drug lifecycle from discovery through commercialization and collaborates closely with public and private partners to accelerate advancement from early-stage science to clinical development.
Revagenix is a precision-therapeutics company specializing in the discovery and development of targeted medicines for serious chronic diseases, with a primary focus on respiratory conditions such as non-cystic fibrosis bronchiectasis. Leveraging a biology-driven, first-principles approach, the company engineers therapies optimized for disease biology, patient need, and real-world delivery requirements. The team brings experience spanning the entire drug lifecycle from discovery through commercialization and collaborates closely with public and private partners to accelerate advancement from early-stage science to clinical development.
Publication Number
US-11673907-B2
Publication Date
2023-06-13
Expiration Date
Abstract
The present disclosure relates to novel methods for preparing antibacterial aminoglycoside compounds and the compounds used in such preparations.
Core Innovation
The invention relates to preparing compounds of formula A-5 and A-5a, and salts thereof, via defined intermediate structures and substituent transformations controlled by chiral auxiliary groups and leaving groups. A compound of formula A-1 is contacted with a chiral auxiliary reagent to yield a compound of formula A-2, followed by contacting A-2 with a Grignard or organolithium reagent to yield A-3.
A compound of formula A-3 is then contacted with a halogen reagent in the presence of a nucleophile reagent Nuc-1 to yield A-4, and the chiral auxiliary group is exchanged for an amino protecting group reagent to yield A-5. In a related sequence, the process converts OH in a compound of formula A-7 to R3a to yield A-8, and then contacts A-8 with a halogen reagent in the presence of a nucleophile reagent Nuc-2 to yield A-5a.
The disclosed content further includes conversion of X1 or X2 to X, where X is NH2, N3, a protected amino group, OH, or a protected hydroxyl group. The scope also includes related intermediates and substituent variables, including protected amino and hydroxyl forms and leaving-group-based substitution patterns.
Claims Coverage
The consolidated claims coverage includes two independent process claims, one for preparing a compound of formula A-5 and one for preparing a compound of formula A-5a. Across the independent claims, there are eight inventive features centered on chiral auxiliary use, Grignard or organolithium conversion, halogen reagent chemistry with LVG-based nucleophiles, amino protecting group exchange, OH-to-R3a conversion, and conversion of X substituents to specified amino or hydroxyl forms.
Chiral auxiliary reagent to prepare A-2
A compound of formula A-1 is contacted with a chiral auxiliary reagent to yield a compound of formula A-2, wherein Xc is a chiral auxiliary group.
Grignard or organolithium reagent conversion to prepare A-3
The compound of formula A-2 is contacted with a Grignard or organolithium reagent to yield a compound of formula A-3.
Halogen reagent with LVG1-M nucleophile to prepare A-4
The compound of formula A-3 is contacted with a halogen reagent in the presence of a nucleophile reagent Nuc-1 to yield a compound of formula A-4, wherein X1 is F, Cl, Br, or I, and Nuc-1 is LVG1-M.
Exchange of chiral auxiliary for an amino protecting group to prepare A-5
The chiral auxiliary group in A-4 is exchanged for an amino protecting group by reaction with an amino protecting group reagent to yield A-5.
Conversion of X1 in A-5 to amino or hydroxyl forms
X1 in the compound of formula A-5 is converted to X to yield a compound of formula A-6, or a salt thereof, where X is NH2, N3, a protected amino group, OH, or a protected hydroxyl group.
Conversion of OH in A-7 to R3a to prepare A-8
The OH group in a compound of formula A-7 is converted to R3a to yield a compound of formula A-8, or a salt thereof.
Halogen reagent with LVG2-M nucleophile to prepare A-5a
The compound of formula A-8 is contacted with a halogen reagent in the presence of a nucleophile reagent Nuc-2 to yield a compound of formula A-5a, wherein X2 is F, Cl, Br, or I, and Nuc-2 is LVG2-M.
Conversion of X2 in A-5a to amino or hydroxyl forms
X2 in the compound of formula A-5a is converted to X to yield a compound of formula A-6a, or a salt thereof, where X is NH2, N3, a protected amino group, OH, or a protected hydroxyl group.
The claims cover two related multi-step preparation routes: an A-5 route that uses a chiral auxiliary, Grignard or organolithium chemistry, halogen/nucleophile contact, and exchange to an amino protecting group; and an A-5a route that converts OH to R3a and then uses halogen reagent chemistry with an LVG2-M nucleophile. The claims also define dependent conversions of X1 or X2 to amino, azido, hydroxyl, or protected forms.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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