benzofuran-6-carboxylic acid

Benzofuran-6-carboxylic acid (4 g, 0.024 mmol) was added to triethyl amine (7.5 g, 0.72 mmol) and 3-[bis(dimethylamino) mcthylium-ylJ-3/7-bcnzotriazol- 1 -oxide hexaflorophosphate (HBTU, 11.2 g, 0.029 mmol), then stirred for 15 minutes at 25- 35C in dimethyl formamide (40 ml, 10 volumes) and then stage-IV (16.1 g, 0.024 mmol) was added to the reaction mass at 25-35C and stirred at 35-45C for 5 hours. After completion of the reaction, DMF was distilled under vacuum at below 60C. The residue was dissolved in ethyl acetate and washed with about 5% sodium bicarbonate solution (40 ml) and water (40 ml). The organic layer was distilled under vacuum at below 50C to get the product. The obtained crude was stirred in hexane (20 ml) for 30 min at 25-35C, filtered the product and washed with hexane (10 ml). The compound was dried in vacuum oven at 50-55C.Benzofuran-6-carboxylic acid (50.0 g, 0.308 moles), toluene and a catalytic amount of dimethyl formamide (DMF) are added, in sequence, to a reactor in N2 atmosphere. The suspension is heated under stirring to 55±5C. SOCl2 (0.370 moles) dissolved in toluene is added slowly, maintaining the temperature at 55±5C until conversion is complete. The solution is then concentrated under vacuum until an almost solid yellow residue is obtained. Residue = 55.6 g, molar yield = quantitative. 'HNMR (300MHz, CDC13): d 8.32 (s, lH), 8.01 (dd, l H, J;=8.3 l Hz J2=l .34Hz), 7.87 (d, 1 H, =2.08 Hz), 7.69 (d, 1 H, J=8.31 Hz), 6.88 (br d, 1 H).[00142] The benzofuran carboxylic acid 18' was treated with oxalyl chloride (1.2 equivalents) and a catalytic amount of DMF, stirring for 5.5 hours until a clear solution was obtained. The solvent was removed under reduced pressure and the acid chloride of compound 18' was stored under argon until use, on the next day. The acid chloride, in methylene chloridewas added slowly to a methylene chloride solution of the compound of Formula 12 and diisopropylethylamine (DIPEA) which was cooled to 0-5 C. The reaction was not permitted to rise above 5C, and after completion of addition, was stirred at 5C for a further 0.5 hour. Upon aqueous workup and extraction with methylene chloride, the product, compound 19, was isolated in quantitative yield.To a solution of the compound benzofurancarboxylic acid (9) in THF was added dropwise oxalyl chloride (1.2 equivalents) and a small amount of DMF in 10 minutes. The reaction solution was stirred at 0 C until a clear solution was obtained. TLC and LCMS show that the starting material (9) is consumed and the solvent is removed under reduced pressure. The resulting acid chloride compound was dissolved in methylene chloride under argon and allowed to cool to 0-5 C. To a solution of the intermediate (8) and diisopropylethylamine (DIPEA) in dichloromethane was slowly added under cooling with ice. After completion of the addition, the mixture was stirred at 5 C for 0.5 hour. LCMS and TLC show that the intermediate reaction is complete. The reaction was quenched by addition of water, extracted with dichloromethane, and the combined organic phases were washed with water. Dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product. The crude product was purified by silica gel column chromatography (eluent MeOH: DCM = 1: 10) to give the product compound (10) in a yield of 70-90%.Benzofuran carboxylic acid (II) (1.0 g, 6.17 mmol, 1.0 equiv), DMF (0.01 eq) and THF (10 mL, 10 vol) is charged to a two-neck round bottom flask under nitrogen atmosphere. Oxalyl chloride (1.1 mL, 13.34 mmol, 2.0 equiv) is slowly added while keeping the temperature between 20 to 30 C. The resulting solution was stirred at 20-30 C. for over 2 hr. When the reaction was complete as determined by TLC analysis, the solvent was removed under reduced pressure and the acid chloride of compound of Formula II (Formula IIb) was stored under nitrogen.Benzofuran-6-carboxylic acid (compound of formula VII, 10 gm), acetonitrile (240 mL) and N, N-Dimethylformamide (1 mL) were charged into a 1000 mL RBF and the mixture was cooled to 0 C. Thionyl chloride (17.61 gm) was added slowly over a period of 30 minutes. The resulted mixture was stirred for 3 hours at 30 C. The reaction mixture was concentrated completely under vacuum and the resulted crude was dissolved in acetonitrile (15 mL). Compound of formula V-A (HCI salt, 17.43 gm) and N, N- Dimethylacetamide (50 mL) were charged into another RBF and stirred for 10 minutes. To the clear solution Hunig's base (DIPEA, 31 .9 gm) was added. The reaction mixture was cooled to 0 C and above acid chloride solution was added slowly over a period of 30 minutes and the reaction mixture was stirred for 30 minutes at 15 C. Water (100 mL) and aqueous hydrochloric acid were added and stirred for 10 minutes. Isopropyl alcohol (25 mL) was added and stirred for 2 hours. The precipitation was filtered and the solid was washed with water (50 mL). The wet solid and MTBE (80 mL) were charged into 500 mL RBF and stirred for 30 minutes. The precipitation was filtered and the solid was washed with MTBE (50 ml_). The wet solid and isopropyl alcohol (75 ml_) were charged into 500 ml_ RBF and stirred for 30 minutes. The precipitation was filtered and the solid was washed with isopropyl alcohol (30 ml_). The wet compound was dried under vacuum at 50 C for 3 hours to yield 19 gm of compound of formula VIII. Purity: 93.3 by HPLC. Example-5: Purification of compound of formula VIIIEthylacetate (80 ml_) and compound of formula VIII (18 gm) were charged into a 500 ml_ RBF and stirred for 10 minutes. 5% Sodium bicarbonate solution was charged into the mass and stirred for 10 minutes at 28 C. Layers were separated and the aqueous layer was washed with ethylacetate. The aqueous layer was treated with charcoal and filtered through a hyflow bed. The aqueous layer was charged into another 1000 ml_ RBF and aqueous hydrochloric acid was added slowly by stirring the aqueous layer. The resulted mixture was stirred for 1 hour at 28 C. The precipitation was filtered and washed with water. The wet compound was slurried in isopropyl alcohol and the suspension was filtered and washed with isopropyl alcohol. The wet compound was dried under vacuum at 60C. Dry weight: 17 g. Purity: 98.015% by HPLC.l-Benzofuran-6-carboxylic acid (VI) (50 gms , 0.3086 moles) was suspended in 250 ml MDC and cooled to l5-20C. 5 ml DMF was added at l5-20C followed by thionyl Chloride ( 34 ml , 0.4629 moles). The temperature was raised to 35-40C and the reaction mixture was further stirred for 2 hours. The solvent was removed under vacuum at 45C. The residue was stirred in 250 ml MDC and the solution was cooled to 5-l0C. The solution of 5, 7-dichloro-l, 2, 3, 4-tetrahydroisoquinoline- 6-carboxylic acid HC1 (V) ( 74.12 gms , 0.2623 moles) and tri ethyl amine ( 215 ml , 1.5432 moles) in 500 ml MDC , was cooled to 5-l0C. To this solution was added benzofuran-6-carboxylic chloride (VII) maintaining temperature at 5-l0C. The temperature was raised to 25-30C and the reaction mixture was further stirred for 2 hours. The reaction mixture was quenched in 500 ml of water. The organic layer was separated, washed with water and stirred with 2.5 gms of charcoal for 30 minutes. The reaction mixture was filtered over hyflo and the clear filtrate evaporated under vacuum at 40-45C. The residue was stirred in 250 ml ethyl acetate and stirred for an hour at 25-30C. The solid was isolated by filtration and dried to yield titled compound. Yield: 95-98%An oven-dried flask was charged with 2 (40 mg, 0.103 mmol), EDC.HCl (29.5 mg, 0.154 mmol), DMAP (18.8 mg, 0.154 mmol), and the appropriate acid (0.154 mmol). To the flask was added CH2CI2 (8 mL). After stirring overnight at RT the reaction was quenched with HC1 (1 M, 8 mL) and the organic layer rinsed sequentially with saturated NaHCCh (8 mL) and brine (8 mL) then dried over NarSOu The solvent was removed in vacuo and the resulting residue purified by flash column chromatography (?FCC?) eluting with 30-35% EtOAc/Pent. Compounds <95% pure as indicated by HPLC were further purified by reverse phase semi -preparatory HPLC.

Benzofuran-6-carboxylic Acid is a reagent in the development of potent LFA-1/ICAM antagonist SAR 118 as an opthalmic solution for treating dry eyes.
Benzofuran-6-carboxylic acid is also an important intermediate applied in organic synthesis.

Molecular Weight:162.14
XLogP3:1.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:162.031694049
Monoisotopic Mass:162.031694049
Topological Polar Surface Area:50.4
Heavy Atom Count:12
Complexity:190
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes