Diastereoselective synthesis of trans-2-(1-triphenylmethyl-1H-imidazol-4-yl)cyclopropanecarboxylic acids: Key intermediates for the preparation of potent and chiral histamine H3 receptor agents

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 23, 1997, Pages 3017-3022

  Khan, M Amin ^a   Yates, Stephen L ^a   Tedford, Clark E ^a   Kirschbaum, Kristin ^b   Phillips, James G ^a  

^a GUILFORD PHARMACEUTICALS INC   (United States)

^b UNIVERSITY OF TOLEDO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (1 TRIPHENYLMETHYL 1H IMIDAZOL 4 YL)CYCLOPROPANECARBOXYLIC ACID; CYCLOPROPANE DERIVATIVE; HISTAMINE H3 RECEPTOR; HISTAMINE H3 RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG;

ANIMAL TISSUE; ARTICLE; BRAIN MEMBRANE; CONTROLLED STUDY; DRUG SYNTHESIS; ENANTIOMER; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IN VITRO STUDY; MASS SPECTROMETRY; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; RAT; REACTION ANALYSIS; RECEPTOR AFFINITY; RECEPTOR BINDING; STEREOCHEMISTRY; X RAY CRYSTALLOGRAPHY;

EID: 0030662588     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)10137-8     Document Type: Article

References (21)

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18. The ratio of diastereoisomers 9 and 10 was determined by HPLC analysis. Using a chiralcel OD column, Regis Technologies serial # 01 12201, and an eluent of 95:5 0.1 hexanes:isopropyl alcohol:DEA, flow rate 1 mL/ min, 9 had a retention time of 29.46 min, whereas 10 had a retention time of 33.57 min.
19. The optical purities of the carboxylic acids 6 and 7, prepared by LiOH hydrolysis of cyclopropylsultams 9 and 10, respectively, were 96% and 97%, respectively, and were determined by conversion of the acids to their n-butyl esters. The enantiomers (1R,2R)-trans-butyl 2-[1-triphenylmethyl-1H-imidazol-4-yl)cyclopropanecarboxylate 12 and (1S,2S)-trans-butyl 2-[1-triphenylmethyl-1H-imidazol-4-yl)cyclopropanecarboxylate 13 could be separated on a multigram scale using chiral column technology. Using a chiralcel OD column, Regis Technologies serial # 0112201, and an eluent of 90:10 hexanes:isopropyl alcohol, flow rate 1 mL/ min, 12 had a retention time of 5.787 min, whereas 13 had a retention time of 7.815 min. These esters 12 and 13 were independently converted to carboxylic acids 6 and 7, respectively.
20. 2, 1 atm, rt, in methanol); and trityl deprotection using 2N HCl (90 °C, 30 min).
21. 1H NMR (300 MHz) and mass spectral data for 4 and 5 were consistent with data reported in 4. Selected experimental and analytical data: (5R)-trans-4-Aza-10,10-dimethyl-3-thia-4-(3-(1H-imidazol-4-yl)prop-2-enoyl) tricyclo[5.2.1.0<1,5>]decane-3,3-dione 11. To a suspension of urocanic acid (1.38 g, 10.0 mmol) in anhydrous dimethylformamide (20 mL) at rt under nitrogen was added 1,1′-carbonyldimidazole (1.62 g, 10.0mmol). The reaction mixture was stirred for 1