Synthesis in the R2 methyl analog 17b was achieved by reductive a

Synthesis of the R2 methyl analog 17b was accomplished by reductive amination on the commercially available 4 trifluoromethoxyacetophenone 9b. Imidizolium ylide created from Nbenzylimidazole employing diisopropylcarbamyl chloride and diisopropylethylamine was taken care of with trifluoromethoxybenzaldehyde in refluxing CH3CN to produce the carbamate, which on hydrolysis afforded the benzylic alcohol . Ndebenzylation using Pd/C followed by mesylation within the benzylic alcohol and subsequent reaction with amine seven in THF inside the presence of NaH at room temperature created the last item like a mixture of diastereomers. The 3 alkyl derivatives were all prepared in moderate yield by alkylation of amine 7, by using the corresponding bromides 15a?c, as illustrated in Scheme two.
Addition of ethyl and npropyl Grignard reagents to 4trifluoromethoxybenzaldehyde afforded read the article the corresponding benzylic alcohols even though 1 phenyl)butan1ol was prepared by the addition of nBuLi to trifluoromethoxybenzaldehyde. Alcohols 14a?c had been converted to their corresponding bromides 15a?c) applying PBr3 in ether and handled with amine in DMF in the presence of K2CO3/KI at 90 ?C to provide the required compounds 17d?f as a mixture of diastereomers. Synthesis of carboxamide derivative 17g was achieved by nucleophilic addition of TMSCN to your imine formed concerning the amine 7 and 4trifluoromethoxybenzaldehyde at one hundred ?C and subsequent hydrolysis in ethanolic HCl. Response of four phenyl)oxirane 18 with 4trifluoromethoxybenzyl alcohol in presence of KOtBu at 60 ?C afforded alcohol 19. Additional oxidation of the ring opened product, followed by elimination in the pmethoxybenzyl group by using TBDMSOTf afforded 2hydroxy1 phenyl)ethanone .
3Hydroxy1kinase phenyl)propan1one was synthesized from 13 in 3 methods involving a Reformatsky reaction with ethylbromoacetate in presence of Zn, LiAlH4 mediated reduction within the ester group to yield 21, and lastly oxidation from the benzylic selleckchem ATP-competitive VEGFR inhibitor to alcohol by using MnO2 to provide the hydroxy ketone 22. Reductive amination of 20 and 22 with amine 7 afforded nitroimidazooxazines 17h?i respectively. R3 modifications R3 modified nitroimidazooxazines were synthesized through the reductive amination of substituted trifluoromethoxybenzaldehydes with amine . Many of these aldehydes had been not readily available commercially and have been synthesized as described in Schemes 3, four and 5. Consequently 2hydroxy4trifluoromethoxybenzoic acid 19 was used as being a key intermediate in the synthesis of 2hydroxy bearing analogs as well as corresponding ether derivatives .
Esterification of with ethyl alcohol followed by alkylation with BnBr and cyclopropylmethylbromide gave the respective ether derivatives in outstanding yields. Protection of phenolicOH group of 24 as its Omethoxymethyl ether was carried out applying MOMCl/DIPEA to afford 27a.