Disubstituted amino acids and methods of preparation and use thereof
Inventors
Darlak, Krzysztof • Kawahata, Noriyuki • Athamneh, Sameer Ahmed
Assignees
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Publication Number
US-10669230-B2
Publication Date
2020-06-02
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 invention relates to crystalline solid forms of compounds of Formula (I), including crystalline salts and crystalline compositions derived therefrom. The compounds comprise a stereocenter (*), a chain-length parameter n that is an integer from 1 to 20, and R1 selected from C1-C3 alkyl, C1-C3 deuteroalkyl, or C1-C3 haloalkyl, with R2 and R3 specified as —H in some embodiments and R2 as 9-Fluorenylmethoxycarbonyl (Fmoc) and R3 as —H in other embodiments.
The disclosed crystalline forms emphasize isolable solid crystalline material rather than general solution forms. The subject matter includes deuterated and halogenated analogs, and the crystalline solids and crystalline compositions are characterized by chemical purity, optical purity, and enantiomeric excess. Additional crystalline outcomes are associated with salt formation, including an HCl salt, and with specified solvent systems used to form the solid crystalline materials.
The invention also links these crystalline building blocks to stapled macrocyclic peptide synthesis and stitched polypeptides. In this context, the α-methyl-α-amino-enoic acid framework and N-Fmoc-(R/S)-α-methyl-α-amino-enoic acids are described as crystalline solids used in peptide-related contexts and as precursors in downstream peptide macrocycle construction.
Claims Coverage
The claim coverage includes three independent claims that cover crystalline solid forms of Formula (I) materials. The inventive coverage centers on a crystalline salt, a crystalline composition containing an additional alkane or haloalkane component, and a crystalline compound obtained by crystallization from an alkane/haloalkane solvent system, with the structural constraints defined by R1, the stereocenter (*), n, and R2/R3.
Crystalline salt of a Formula (I) compound with defined substituents
A crystalline salt in solid form of a Formula (I) compound wherein R1 is C1-C3 alkyl, C1-C3 deuteroalkyl, or C1-C3 haloalkyl, * is a stereocenter, n is an integer from 1 to 20, R2 is —H, and R3 is —H.
Crystalline composition with a Formula (I) crystalline compound and alkane or haloalkane
A crystalline composition comprising a crystalline compound of Formula (I) in solid form wherein R1 is C1-C3 alkyl, C1-C3 deuteroalkyl, or C1-C3 haloalkyl, * is a stereocenter, n is an integer from 3 to 11, R2 is 9-Fluorenylmethoxycarbonyl (Fmoc), and R3 is —H, and wherein the crystalline composition further comprises an alkane or a haloalkane.
Crystalline Formula (I) compound obtained by crystallization from alkane or haloalkane
A crystalline compound of Formula (I) in solid form wherein R1 is C1-C3 alkyl, C1-C3 deuteroalkyl, or C1-C3 haloalkyl, * is a stereocenter, n is an integer from 3 to 11, R2 is 9-Fluorenylmethoxycarbonyl (Fmoc), and R3 is —H, wherein the crystalline compound is obtained by crystallization of a compound of Formula (I) with a solvent comprising an alkane and a haloalkane.
The claim coverage is focused on crystalline solid forms of Formula (I) α,α-disubstituted amino acid derivatives with terminal alkene side chains. The inventive features are the crystalline salt, the crystalline composition with an alkane or haloalkane component, and the crystalline compound obtained by crystallization from an alkane/haloalkane solvent system.
Stated Advantages
Crystalline solid forms rather than commercial solution forms.
Chemical purity, enantiomeric excess, and optical purity.
Isolable crystalline material.
Quantitative chiral-purity thresholds, including ≥95% for Fmoc-R8 vs Fmoc-S8, and a reported upgrade to approximately 97.8%.
Documented Applications
Stapled macrocyclic peptide synthesis.
Stitched polypeptides.
Peptide macrocycle construction.
Downstream Fmoc-protected products derived from the described aminoalkenoic acid derivatives.
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