Process for the synthesis of (s) 3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid
Inventors
Silverman, Richard B. • MOSCHITTO, Matthew
Assignees
Publication Number
US-12331006-B2
Publication Date
2025-06-17
Expiration Date
2039-05-28
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Provided herein are processes, compounds and compositions for making (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid. Also provided herein a pharmaceutical compositions containing (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid.
Core Innovation
(S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid is a potent inhibitor of γ-aminobutyric acid aminotransferase (GABA-AT) with demonstrated potential as a treatment for epilepsy, addiction, and hepatocellular carcinoma. Previous methods for synthesizing this compound required lengthy, inefficient processes involving hazardous reagents such as tert-butyllithium and selenium, resulting in hazardous waste, poor scalability, and low yields.
This patent discloses novel processes, compounds, and compositions for preparing (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, including pharmaceutical compositions containing it. The disclosed processes utilize starting materials such as ((1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one) and ethyl-cyclopent-3-ene-carboxylate, incorporating improved methodologies like elimination of a leaving group from the β-position, thereby avoiding isomer mixtures and hazardous reagents, and enabling a reduction in total synthesis steps and an increase in overall yield.
These improved synthetic routes yield (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its salts with scalable, high-yield steps that do not require selenium or tert-butyllithium, while minimizing hazardous environmental waste. Additionally, the patent provides compositions and pharmaceutical dosage forms containing the claimed compound or intermediates, enabling efficient large-scale manufacture and formulation for therapeutic application.
Claims Coverage
The patent contains one independent claim, which covers a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, in combination with specific intermediates or derivatives.
Pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid and specific intermediates or their salts
The main inventive feature is a pharmaceutical composition which includes: - (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (or a pharmaceutically acceptable salt thereof) - One or more compounds selected from the group consisting of: - (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (2) - (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3) - (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4) - (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25) - (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) - (1R,4R,7R)-7-bromo-6-(difluoromethylene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) - (1R,4R,7R)-7-bromo-6-(difluoromethylene)-2-azabicyclo[2.2.1]heptan-3-one (7) - (1R,4R,7R)-7-bromo-6-(difluoromethylene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) - methyl (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylate (9) - ethyl (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylate (15) - (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid (19) - And/or a pharmaceutically acceptable salt of any of these specified compounds. This inventive feature broadly covers the combination of the therapeutic agent with key synthetic intermediates or their salts in a single pharmaceutical product.
The inventive feature is a pharmaceutical composition combining (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its salt with at least one of a specific set of synthetic intermediates or their pharmaceutically acceptable salts.
Stated Advantages
The processes are scalable and high yielding compared to the existing technique.
The synthesis avoids the use of hazardous reagents such as selenium and tert-butyllithium.
The process avoids forming multiple isomers from an α-elimination.
The number of synthesis steps is reduced from fourteen to nine compared to the existing technique.
Yield is increased from 3.7% (prior art) to 8.1% using the disclosed process.
The process reduces hazardous environmental waste and increases manufacturing efficiency.
Documented Applications
Treatment of epilepsy, addiction, and hepatocellular carcinoma.
Formulation of pharmaceutical compositions containing (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its intermediates.
Preparation of ophthalmic or parenteral pharmaceutical formulations suitable for administration by injection, infusion, instillation, or implantation.
Preparation of oral, rectal, nasal, ophthalmic, pulmonary, vaginal, sublingual, transdermal, intravenous, intraarterial, intramuscular, intraperitoneal, and subcutaneous dosage forms.
Interested in licensing this patent?