“…Malonic esters 33 were also alkylated (R 2 I, NaH, DMF) to afford compounds 38 , which on treatment with KOH/EtOH underwent simultaneous hydrolysis and decarboxylation to give the α-alkylated carboxylic acids 35g − j , l − m . The trifluoromethyl derivative 35k was obtained by hydrolysis of 39 , which was prepared by treatment of 33 with dibromodifluoromethane in the presence of sodium hydride followed by simultaneous desethoxycarboxylation and replacement of the bromine atom by fluorine by heating with potassium fluoride in DMSO at 170 °C 3 …”
Section: Chemistrymentioning
confidence: 99%
“…The trifluoromethyl derivative 35k was obtained by hydrolysis of 39, which was prepared by treatment of 33 with dibromodifluoromethane in the presence of sodium hydride followed by simultaneous desethoxycarboxylation and replacement of the bromine atom by fluorine by heating with potassium fluoride in DMSO at 170 °C. 24 Compounds 35a-e were racemic mixtures, whereas 35f-n consisted of equimolar mixtures of four diastereoisomers. The two pairs of enantiomers of the most active compounds (35g-i) were separated by flash chromatography to yield a faster (36g-i) and a slower (37g-i) eluting component (Table 3).…”
The synthesis and pharmacological evaluation of a new series of potent AT1 selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the alpha-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the reference compound losartan but faster onset of action and somewhat greater oral activity, presumably due to its improved bioavailability.
“…Malonic esters 33 were also alkylated (R 2 I, NaH, DMF) to afford compounds 38 , which on treatment with KOH/EtOH underwent simultaneous hydrolysis and decarboxylation to give the α-alkylated carboxylic acids 35g − j , l − m . The trifluoromethyl derivative 35k was obtained by hydrolysis of 39 , which was prepared by treatment of 33 with dibromodifluoromethane in the presence of sodium hydride followed by simultaneous desethoxycarboxylation and replacement of the bromine atom by fluorine by heating with potassium fluoride in DMSO at 170 °C 3 …”
Section: Chemistrymentioning
confidence: 99%
“…The trifluoromethyl derivative 35k was obtained by hydrolysis of 39, which was prepared by treatment of 33 with dibromodifluoromethane in the presence of sodium hydride followed by simultaneous desethoxycarboxylation and replacement of the bromine atom by fluorine by heating with potassium fluoride in DMSO at 170 °C. 24 Compounds 35a-e were racemic mixtures, whereas 35f-n consisted of equimolar mixtures of four diastereoisomers. The two pairs of enantiomers of the most active compounds (35g-i) were separated by flash chromatography to yield a faster (36g-i) and a slower (37g-i) eluting component (Table 3).…”
The synthesis and pharmacological evaluation of a new series of potent AT1 selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the alpha-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the reference compound losartan but faster onset of action and somewhat greater oral activity, presumably due to its improved bioavailability.
“…Among the approaches to trifluoromethylated organic compounds, halogen exchange reaction [3] and trifluoromethylation [4] are possible methods, but these suffer from low reactivity and selectivity. As a convenient strategy for the preparation and application of trifluoromethylated building blocks [5], Qing et al reported a new method for the synthesis of ethyl (Z)-3-iodo-4,4,4-trifluoro-2-butenoate 2 and its alkynylation by the Sonogashira reaction [6]; Gildas et al [7] described a stereoselective access to functional dienes containing the trifluoromethyl group via the Stille coupling of the compound 2.…”
The Suzuki-type cross-coupling reaction of arylboronic acids 3 with ethyl (Z)-3-iodo-4,4,4-trifluoro-2-butenoate 2, which was generated by hydroiodination of available ethyl 4,4,4-trifluoro-2-butynoate 1, to afford ethyl (E)-3-aryl-4,4,4-trifluoro-
Afacile synthetic procedure for the preparation of atrifluoromethyl carboxylic acids and esters was achieved through multicomponent coupling reactions between gemdifluoroalkenes,c esium fluoride,a nd carbon dioxide.T he products were generated in moderate to excellent yields,a nd the synthetic utility of this method was demonstrated through the preparation of trifluoromethylated versions of popular nonsteroidal anti-inflammatory drugs (NSAIDs). Scheme 1. Synthesis of a-trifluoromethyl carboxylic acids.
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