Methyl 2-chloro-6-methoxyisonicotinate → 2-Cyclopentyl-6-methoxy-isonicotinic acid methyl ester

Participants

Reaction Conditions

Reaction Steps

Under argon, Pd(dppf) (2.00 g, 2.4 mmol) is added to a solution of 2-chloro-6-methoxy-isonicotinic acid methyl ester (32.0 g, 0.159 mol) in THF (100 mL). A 0.5 M solution of cyclopentylzincbromide in THF (330 mL) is added via dropping funnel. Upon complete addition, the mixture is heated to 85° C. for 3 h before it is cooled to rt. The reaction mixture is concentrated, diluted with 1 N aq. HCl (275 mL) and extracted with TBME (275 mL). The org. extract is washed with 1 N aq. HCl (275 mL), filtered over Celite and washed with water (275 mL). The org. extract is concentrated and dried to give crude 2-cyclopentyl-6-methoxy-isonicotinic acid methyl ester (34.8 g) as a brown oil. This material is dissolved in ethanol (180 mL), water (45 mL) and 32% aq. NaOH solution (45 mL). The mixture is stirred at 90° C. for 30 min before it is cooled to rt. The ethanol is evaporated and the remaining solution is diluted with water (150 mL) and extracted with DCM (200 mL). The aq. phase is acidified by adding 32% aq. HCl (45 mL) and then extracted twice with DCM (2×100 mL). The org. extracts are combined and concentrated. The crude product is purified by crystallisation from hot acetonitrile (174 mL). The crystalline material is collected and dried at 50° C. under HV. From the mother liquor a second crop of crystalline material can be obtained. The two crops are combined to give 2-cyclopentyl-6-methoxy-isonicotinic acid (24.1 g) as a pale grey crystalline powder; LC-MS: tR=0.93 min, [M+1]+=222.02; 1H NMR (CDCl3): δ1.68-1.77 (m, 2H), 1.81-1.90 (m, 4H), 2.03-2.12 (m, 2H), 3.15-3.25 (m, 1H), 3.99 (s, 3H), 7.18 (d, J=1.0 Hz, 1H), 7.35 (d, J=0.8 Hz, 1H).

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