“…Then, deprotection of 24 with trifluoroacetic acid (Mu 2001) followed by acylation of the resulting compound 25 afforded the compounds 26a – 26c . Finally, the amides 24 and 26a – 26c were cyclized in the presence of POCl 3 and pyridine in refluxing dichloroethane (Cookson et al 1986), resulting in the generation of the target derivatives 27a – 27d , respectively.Scheme 3Reagents and conditions: ( a ) CH 3 NO 2 , KOH, DMSO, RT; ( b ) SnCl 2 , conc. HCl, EtOH, reflux; ( c ) acetic anhydride, reflux; ( d ) DCC, DMAP, anhydrous CH 2 Cl 2 , RT; ( e ) POCl 3 , benzene, reflux; ( f ) NaOH, THF/H 2 O, RT; ( g ) R 4 Cl, TEA, DMAP, anhydrous CH 2 Cl 2 , RT, or R 5 Cl, K 2 CO 3 , acetone, reflux.…”
In this study, a series of fused-heterocyclic derivatives were systematically designed and synthesized using an efficient route, and evaluated in terms of GLP-1R agonist activity. We employed short synthetic steps and reactions that are tolerant of the presence of various functional groups and suitable for parallel operations to enable the rapid generation of libraries of diverse and structurally complex small molecules. Of the compounds synthesized, 3-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a] pyridin-2-yl)phenyl methanesulfonate (8e) was the most potent agonist with an EC50 of 7.89 μM, and thus is the compound with the greatest potential for application. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1R agonists that can be administered orally.Electronic supplementary materialThe online version of this article (doi:10.1007/s12272-013-0253-9) contains supplementary material, which is available to authorized users.
“…Then, deprotection of 24 with trifluoroacetic acid (Mu 2001) followed by acylation of the resulting compound 25 afforded the compounds 26a – 26c . Finally, the amides 24 and 26a – 26c were cyclized in the presence of POCl 3 and pyridine in refluxing dichloroethane (Cookson et al 1986), resulting in the generation of the target derivatives 27a – 27d , respectively.Scheme 3Reagents and conditions: ( a ) CH 3 NO 2 , KOH, DMSO, RT; ( b ) SnCl 2 , conc. HCl, EtOH, reflux; ( c ) acetic anhydride, reflux; ( d ) DCC, DMAP, anhydrous CH 2 Cl 2 , RT; ( e ) POCl 3 , benzene, reflux; ( f ) NaOH, THF/H 2 O, RT; ( g ) R 4 Cl, TEA, DMAP, anhydrous CH 2 Cl 2 , RT, or R 5 Cl, K 2 CO 3 , acetone, reflux.…”
In this study, a series of fused-heterocyclic derivatives were systematically designed and synthesized using an efficient route, and evaluated in terms of GLP-1R agonist activity. We employed short synthetic steps and reactions that are tolerant of the presence of various functional groups and suitable for parallel operations to enable the rapid generation of libraries of diverse and structurally complex small molecules. Of the compounds synthesized, 3-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a] pyridin-2-yl)phenyl methanesulfonate (8e) was the most potent agonist with an EC50 of 7.89 μM, and thus is the compound with the greatest potential for application. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1R agonists that can be administered orally.Electronic supplementary materialThe online version of this article (doi:10.1007/s12272-013-0253-9) contains supplementary material, which is available to authorized users.
“…We then turned our attention to the preparation of the ketone (23), starting from the ester (9). The racemic ketone (23) has been transformed into an intermediate (31), used in the synthesis of carbocyclic nucleoside analogues, by Cookson ct al. 23 Hydrogenation of the ester (9) over Pd gave the saturated ester (24) in 92"" yield (Scheme 4).…”
“…The observation that in some runs of the reaction of 5 with benzamidine the yields of 6d were significantly lower than the usual 38% led us to isolate from these reaction mixtures a side product, in 16% yield, that on the basis of 1 H and 13 C NMR spectroscopy and mass spectrometry was identified as (±)-2-endo-5-exo-6-exo-5,6-(isopropylidenedioxy)bicyclo[2.2.1]heptan-2-ol (7) ( Figure 2). 16 The formation of this product is tentatively attributed to retrocondensation promoted by traces of water under basic conditions, followed by reduction of the resulting ketone (possibly by released formiate), as this erratic behavior ceased when strictly anhydrous conditions were adhered to.…”
Cyclocondensation of (±)-exo,exo-5,6-(Isopropylidenedioxy)-3-(pyrrolidinomethylene)bicyclo[2.2.1]heptan-2-one with N-C-N Dinucleophiles (±)-2-P h e n y l-6 , 7-d i h y d r o-5 H-c y c l o p e n t a [ d ] p y r i m i d i n e-5 , 7-d i m e t h a n o l
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