ETHYL 5-METHYLINDOLE-2-CARBOXYLATE

7.2 g (0.104 mol) of sodium nitrite dissolved in 40 ml of water are added, at 5 C., to a mixture of 10.7 g (0.1 mol) of 4-methylaniline, 74 ml of 12 N hydrochloric acid and 140 ml of water. The reaction mixture is stirred for 15 minutes at 5 C. and is neutralized by addition of 8.1 g of sodium acetate. 12.33 g (0.085 mol) of ethyl a-methyl acetoacetate and 80 ml of ethanol are introduced into a three-necked Uask, followed, at 0 C., by 4.8 g (0.085 mol) ofpotassium hydroxide dissolved in 20ml ofwater and 100 g of ice. The diazonium solution prepared above is added dropwise, at 0 C., to this reaction mixture and the resulting mixture is left for 18 hours at 0 C. The aqueous phase is extracted 4 times with 50 ml of ethyl acetate and the organic phases are combined and dried over anhydrous sodium sulphate. The residue is taken up in 100 ml of toluene and 16.3 g (0.085 mol) of para-toluene sulphonic acid monohy drate. The mixture is then heated slowly to 110 C. and maintained at this temperature for S hours. After cooling and then addition of saturated sodium carbonate solution, the insoluble material is removed by ltration and the organic phase is separated out after settling has taken place, dried over anhydrous sodium sulphate and concentrated. The residue is chromatographed on a column of silica gel, eluent:30/70 (v/v) dichloromethane/cyclohexane, to give beige coloured crystals; m.p.=94 C.; yield=25percent.Ethyl 5-methylindole-2-carboxylate in 1percent yield (2 steps), mp 157-158°; NMR delta(CD3SOCD3) 1.3 (t, 3H), 2.35 (s, 3H), 4.3 (q, 2H), 7.05 (m, 2H), 7.35 (m, 2H), 11.7 (bs, 1H); M/z (+) 203 (M+).B. 5-Methyl-1H-indole-2-carboxylic acid, ethyl ester The title A compound (2.095 g, 9.51 mmol, 1.0 eq) was dissolved in absolute ethanol (9.8 ml, 1M) and hydrochloric acid gas was bubbled through the reaction until it showed no starting material (45 minutes). The reaction solution was then concentrated, dissolved in ethyl acetate, and washed once with aqueous saturated sodium hydrogen carbonate. The organic phase was then dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on silica gel (60 g) eluding with toluene followed by chloroform:hexane (1:4) followed by ether:hexane (2:3) to give the title B compound (1.5187 g).b Ethyl 5-methylindole-2-carboxylate 130 g of P2 O5 are added to 111 ml of orthophosphoric acid. After cooling, 37 g of the compound from a) are added, and the mixture is heated to 80° C. After the reaction starts, the temperature rises to 130° C. The mixture is cooled and then poured into ice-water and extracted with ethyl acetate. The organic phase is washed with NaHCO3 (1N), H2 O and saturated NaCl solution, dried with Na2 SO4 and concentrated. The product is recrystallized from n-hexane/EtOAc. 11.7 g of product of melting point 158° C. are obtained.

Reactant for synthesis of oxazino[4,3-a]indoles via cascade addition-cyclization reactions 1 Reactant for preparation of indolecarboxamides as cannabinoid CB1 receptor antagonists 2 Reactant for preparation of indole-3-propionic acids as antiinflammatory and analgesic agents 3 Reactant for Friedel-Crafts acylation with nitrobenzoyl chloride 4 Reactant for oximation reactions 5

Molecular Weight:203.24
XLogP3:3.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:203.094628657
Monoisotopic Mass:203.094628657
Topological Polar Surface Area:42.1
Heavy Atom Count:15
Complexity:242
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes