3-CYANO-4-ETHOXYBENZOIC ACID synthesis

Yield:1201447-07-5 79%

Reaction Conditions:

Stage #1: 3-cyano-4-(ethyloxy)benzoic acidwith benzotriazol-1-ol;1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in N,N-dimethyl-formamide at 20; for 0.333333 h;
Stage #2: N',1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide in N,N-dimethyl-formamide at 20 - 130; for 1.08333 h;Microwave irradiation;

Steps:

2-ethoxy-5-(3-(l-hydroxy-2,3-dihydro-lH-inden-4-yl)-l,2,4-oxadiazol-5- yl)benzonitrileIn a microwave vial, a stirring solution of 3-cyano-4-ethoxybenzoic acid (200mg, 1.05mmol) in DMF was treated with HOBt (185mg, 1.36mmol) and EDCI (260mg, 1.36mmol) at room temperature. The reaction was stirred for 20 min followed by addition, in a single portion, of iV,l-dihydroxy-2,3-dihydro-lH- indene-4-carboximidamide (261mg, 1.36mmol). The reaction was stirred for additional 30 min at room temperature and then heated to 130 °C for 35 min in the initiator. The reaction was diluted using a saturated solution of NaCl and extracted with EtOAc (80ml X3). The organic phase was dried over Na₂SO₄ anhydrous and concentrated under reduced pressure. The product was purified by column chromatography using CH₂Cl₂IMeOH (9:1) to offer the product as pale yellow solid in 79% yield (274mg).¹H NMR (300 MHz, CDCl₃-CH₃OD): δ 8.31 (d, J= 2.1 Hz, IH), 8.25 (dd, Jl = 2.1 Hz, J2 = 8.7 Hz, IH), 7.96 (d, J= 7.5 Hz, IH), 7.46 (d, J= 7.5 Hz, IH), 7.29 (t, J= 7.8 Hz, IH), 7.06 (d, J= 9.0 Hz, IH), 5.16 (t, J= 6.0 Hz, IH), 4.18 (q, J = 6.9 Hz, 2H), 3.40-3.30 (m, IH), 3.10-2.93 (m, IH), 2.46-2.39 (m, IH), 1.94-1.87 (m, IH), 1.43 (t, J= 6.9 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃-CH₃OD): δ 172.91, 167.05, 161.92, 145.72, 142.08, 133.24, 132.83, 127.38, 126.16, 126.10, 121.85, 115.98, 111.76, 101.85, 74.36, 64.55, 34.08, 30.18, 13.20. MS (EI) m/z 348 (M⁺), HRMS (EI) for C₂₃H₂₇N₃O₃ (M⁺): calcd 348.1343, found 348.1345.

References:

WO2009/151529,2009,A1 Location in patent:Page/Page column 167-168