Disubstituted amino acids and methods of preparation and use thereof
Inventors
Darlak, Krzysztof • Kawahata, Noriyuki • Athamneh, Sameer Ahmed
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9604919-B2
Publication Date
2017-03-28
Expiration Date
Abstract
Provided are crystalline α, α-disubstituted amino acids and their crystalline salts containing a terminal alkene on one of their side chains, as well as optionally crystalline halogenated and deuterated analogs of the α, α-disubstituted amino acids and their salts; methods of making these, and methods of using these.
Core Innovation
The disclosure provides crystalline salt forms of compounds of Formula (I) that include a stereocenter, where R1 is C1-C3 alkyl, C1-C3 deuteroalkyl, or C1-C3 haloalkyl, n is an integer from 1 to 20, R2 is 9-Fluorenylmethoxycarbonyl (Fmoc), and R3 is —H or a protecting/activating group. The salts are described as cyclic amine salt forms, and the disclosure includes HCl salts and addition salts, including cyclic amine salt formation.
A core aspect of the disclosure is crystallization and recrystallization to obtain and upgrade crystalline, chiral N-protected amino-alkenoic acids and crystalline α,α-disubstituted amino acids bearing a terminal alkene on a side chain, together with the corresponding cyclic amine salts. The preparation includes intermediate crystalline acid salt forms, final acid salts, and crystallization of metal complexes, with recrystallization documented for purification and chiral-purity upgrading. The disclosure further includes reported chemical purity, enantiomeric excess, optical purity, diastereomeric excess, and chiral-purity measurements.
The disclosure also includes generation of crude oils from Ni-BPB precursors and subsequent decomplexation with HCl to obtain BPB salts, followed by purification and recrystallization using solvents such as acetonitrile, MTBE, hexanes, and chloroform. Fmoc installation is described using Fmoc-OSu under controlled pH, and salt formation is described using cyclic amines such as cyclohexylamine. The document further describes methods of preparing polypeptides using one or more crystalline Formula (I) compounds or salts.
Claims Coverage
The independent claim coverage centers on crystalline cyclic amine salts of Formula (I) compounds. Across the consolidated independent and dependent coverage, the inventive features specify the Formula (I) structure, stereochemical configuration, selected n values, defined cyclic amines, purity-related ranges, and a peptide-making context with metal-catalyzed olefin metathesis.
Crystalline cyclic amine salt of a formula (I) compound
A crystalline salt of a compound of Formula (I) where R1 is C1-C3 alkyl, C1-C3 deuteroalkyl, or C1-C3 haloalkyl; the compound includes a stereocenter; n is an integer from 3 to 11; R2 is 9-Fluorenylmethoxycarbonyl (Fmoc); R3 is —H; and the salt is a cyclic amine salt.
Enantiomeric excess range for the crystalline salt
The crystalline salt is characterized by an enantiomeric excess of about 90% to 100%.
Absolute stereochemical configuration at the stereocenter
The crystalline salt is defined such that the stereocenter is specified as (S).
Discrete selection of the n parameter
The crystalline salt is defined where the value of n is either 3 or 6.
Cyclic amine selection for the salt
The cyclic amine is selected from cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, or cyclooctylamine.
Peptide crosslinking using metal-catalyzed olefin metathesis
In the peptide-making method, crosslinking is carried out using a metal-catalyzed olefin metathesis reaction.
Overall, the claim coverage centers on crystalline cyclic amine salts of Formula (I) compounds with an Fmoc group and a stereocenter, and further constrains the salts by enantiomeric-excess ranges, specific (S) stereochemistry, discrete n values, and selected cyclic amines. Dependent coverage also connects the crystalline salt context to polypeptides and peptide-making with crosslinking via metal-catalyzed olefin metathesis.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Polypeptides prepared using one or more crystalline Formula (I) compounds or salts.
Interested in licensing this patent?