Efficient Synthesis of a GABA_A α_2,3-Selective Allosteric Modulator via a Sequential Pd-Catalyzed Cross-Coupling Approach

Abstract

A practical synthesis of 2-[3-(4-fluoro-3-pyridin-3-yl-phenyl)-imidazo[1,2-a]pyrimidin-7-yl]-propan-2-ol (1), an oral GABA(A) alpha(2/3)-selective agonist, is described. The five-step process, which afforded 1 in 40% overall yield, included imidazopyrimidine 2 and pyridine boronic acid 4 as key fragments. The synthesis is highlighted by consecutive Pd-catalyzed coupling steps to assemble the final free base 1 in high yield and regioselectivity. A novel method for Pd removal in the final step is also described.

Further delineation of hydrophobic binding sites in dopamine D2/D3 receptors for N-4 substituents on the piperazine ring of the hybrid template 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol

“…Commercially available 1-(4-iodophenyl)piperazine was treated with Boc-anhydride to make mono Boc protected intermediate which was then exposed to Suzuki coupling reaction21, 22 with 3- or 4- pyridinyl boronic acid to give 17a and 17b . Pyridinyl boronic acid was made from pyridinyl bromides using the reported procedure 21.…”

“…Commercially available 1-(4-iodophenyl)piperazine was treated with Boc-anhydride to make mono Boc protected intermediate which was then exposed to Suzuki coupling reaction21, 22 with 3- or 4- pyridinyl boronic acid to give 17a and 17b . Pyridinyl boronic acid was made from pyridinyl bromides using the reported procedure 21. The amine protecting group, Boc was removed using trifluoroacetic acid and subjected to N-amidation reaction with Chloroacetylchloride to get intermediates 19a and 19b which was then treated with either racemic or enantiomerically pure 7-methoxy or 5-methoxy 2-amino tetralin in standard N-alkylation reaction condition to produce corresponding amides 20a–d which after LAH reduction gave the amines 21a–d .…”

Transition metals in organic synthesis: Highlights for the year 2005

“…Synthetic targets included, prodigiosines [198], chartelline alkaloids [199], eupomatilone-3 [200], 9,10-deoxytridachione [201], hamigeran B [202], leprapinic acid and calycin [203], dehydrocoelenterazine analogs [204], gymnocin A (Eq. (11)) [205], murrastifoline A [206], styelsamine C and norsegoline [207], trispheridine [208], dragmacin F [209], ningalin D [210], eupomatilones [211], lucilactaene [47], epoxyquinols A-C and epoxytwinol A [212], mukonine [213], cepharanone [214], ␣ v ␤ 3 antagonist [215], alternariol [216], core of roseophilin [21], (−)-callystatin A [217], dibenzo[c,p]chrysene [218], GABA agonist [219,220], diazonamide A [221], dityrosine, trityrosine, pulcherosine [222], lamellarin D [223], integramycin [224], (+)-discodermolide and analogues [225,226], AB-ring system of hexacyclinic acid [227], ␦-trans-tocotrienoloic acid [135], spirofungins [228], kwakhurin [229], toward (+)-and (−)-deplanchein [230], combretastatin analogs [231], diazonamide A [75], cadiolide B [232], pukeleimide A [233], toward apoptolidin [234], polycitone A and B …”

“…The palladium-catalyzed intramolecular variation ("aromatic-Heck") using aromatic rings in place of alkenes in couplings with organic and halides and triflates [392][393][394] was used to prepare benanomicin B [395], cavicularin and riccardin C [396], 5,6-dihydro-4H,8H-pyrido[3,2,1-de]phenanthridin-8-one [397], GABA agonist [219,220], lamellarin D and lamellarin analogs [223,240], allocolchicinoid [341], rhazinilam [398], givocarcin M [399], isoneocryptolepine [400], graphislactones A-D [401] and fused benzazepinones [402].…”

Synthesis, central nervous system activity, and structure–activity relationship of 1-aryl-6-benzyl-7-hydroxy-2,3-dihydroimidazo[1,2-a]pyrimidine-5(1H)-ones

“…2 as well as the model for serotoninergic activity depicted in Fig. 3; (b) the designed series is aimed to determine the effect of the second aromatic moiety on the antinociceptive activity; (c) the designed compounds were expected to have favorable values of lipohilicity and ADMET parameters for the activity in central nervous system; (d) the imidazo[1,2-a]pyrimidine scaffold is present in many biologically active compounds which have been reported to exhibit not only central nervous system activity (Blackaby et al , 2006; Goodacre et al , 2006; Jensen et al, 2005; Matosiuk, et al , 1996; Tully et al , 1991) but also anti-inflammatory and analgesic (Abignente et al , 1994; Freeman et al, 1978; Sacchi et al , 1997; Vidal et al, 2001), antibacterial (Al-Tel and Al-Qawasmeh, 2010; Moraski et al, 2012; Rival et al , 1992; Steenackers et al , 2011a, b), antiviral (Gueiffier et al , 1996), antifungal (Rival et al , 1991, 1993), insecticidal, acaricidal and nematocidal (Dehuri et al , 1983), hormonal (Sasaki et al , 2002), mutagenic (Turner et al , 1978), anticancer (Guo et al , 2011; Lin et al , 2012; Linton et al, 2011), and cardiovascular (Okabe et al , 1983) activity; (e) the set of substituents was similar to those in previously reported series (Fig. 1) which turned out to exhibit the expected profile of pharmacological activity.…”