Scalable synthesis of dual-target inhibitor of cannabinoid-1 receptor and inducible nitric oxide synthase
Inventors
Alimardanov, Asaf Ragim • Huang, Junfeng
Assignees
US Department of Health and Human Services
Publication Number
US-12286405-B2
Publication Date
2025-04-29
Expiration Date
2040-04-30
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
A process for the preparation of racemic and optically active (1E,NE)-N-(1-aminoethylidene)-3-(4-chlorophenyl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide in high enantiomerical purity is provided.
Core Innovation
The invention provides an improved and scalable process for the synthesis of (S,1E,NE)-N-(1-aminoethylidene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide, a dual-target inhibitor acting on cannabinoid-1 receptor (CB1R) and inducible nitric oxide synthase (iNOS). The process allows preparation of both racemic and optically active forms in high enantiomeric purity, overcoming limitations of previous synthetic routes.
The problem addressed is that earlier syntheses of this compound were low-yielding, used hazardous materials and cryogenic conditions, and were difficult to apply on a large scale. The previously reported method employed hazardous reagents such as phosphorus pentachloride and chlorobenzene at high temperatures, and required expensive, low-throughput chiral separation techniques to isolate the desired enantiomer.
The invention solves these issues by providing improved synthetic steps involving more stable intermediates and safer reagents, such as ethyl chloroformate replacing methyl chloroformate, and phosphorus oxychloride with N,N-diisopropylethylamine instead of phosphorus pentachloride and chlorobenzene. This results in significantly increased yields and safer, more controllable reactions. An optically active resolution approach involving diastereomeric salt formation with an optically active acid like D-aspartic acid enables efficient isolation of the (S)-enantiomer with high optical purity, avoiding burdensome chromatographic separations.
Claims Coverage
The patent contains multiple independent claims covering processes for the preparation of the (S)-enantiomer and the racemic (1E,NE) compound, as well as the compound itself. The inventive features relate mainly to the synthetic steps, reagents, and purification methods described.
Process for preparation involving enantioselective resolution
A process comprising providing a compound, contacting it with an optically active isomer of an acid to form a diastereomeric salt, separating this salt by crystallization, converting it back to the free base, and subsequent conversion steps to yield the (S)-enantiomer of the target compound with high purity, including purification by recrystallization to achieve greater than 98.5% purity.
Improved synthesis using ethyl chloroformate and phosphorus oxychloride
A process comprising reacting 4-(trifluoromethyl)benzenesulfonamide with ethyl chloroformate to form a sulfonyl carbamate, coupling this with an intermediate compound to form a sulfonyl urea derivative, chlorination using phosphorus oxychloride with N,N-diisopropylethylamine to form an imidoyl chloride intermediate, and subsequent reaction with acetimidamide in an iso-propanol-dichloromethane solvent system to yield the racemic target compound in significantly improved yield and purity.
Alternative synthesis via isocyanate and dehydration pathway
A process involving initial reaction of a dihydro-1H-pyrazole derivative with an isocyanate agent forming a cyclic urea intermediate, dehydration with a dehydrating agent to form a nitrile intermediate, reaction with acetamidine salt to yield an intermediate compound, and final sulfonylation to obtain the racemic compound.
Compound of specific chemical structure with enantiomers
A compound represented by specific chemical formulae disclosed in the patent, including both racemic and optically active forms of (S,1E,NE)-N-(1-aminoethylidene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide.
The claims cover innovative synthetic routes improving yield, safety, and scalability using specific reagents and conditions, including novel enantioselective resolution methods to provide highly pure (S)-enantiomer. They also protect the compound itself.
Stated Advantages
Significant increase in synthetic yield and purity over previous methods.
Avoidance of hazardous reagents and conditions like phosphorus pentachloride and cryogenic temperatures.
Improved control and safer reaction conditions using phosphorus oxychloride and N,N-diisopropylethylamine.
Efficient enantioselective resolution enabling high optical purity (>95% ee) without costly chromatographic separation.
Reduced by-product formation and improved scalability for biological evaluation and clinical studies.
Documented Applications
Treatment of obesity, diabetes, and metabolic syndromes via CB1R antagonism.
Mitigation of fibrotic disorders through dual inhibition of CB1R and iNOS.
Potential therapy for Hermansky-Pudlak syndrome (HPS), a rare genetic disorder characterized by blood platelet dysfunction, visual impairment, and oculocutaneous albinism.
Interested in licensing this patent?