3-Cyano-4-fluorobenzoic acid

To a stirred solution of 15.0 g (97, 6 mmol) 2-fluoro-5-formyl-benzonitrile (Aldrich), 150 ml dest. water and 630 ml t-butanol are added 40.8 g (361 mmol) sodium chlorite and 35.9 g (230 mmol) sodium hydrogen phosphate dihydrate. The reaction mixture is stirred over night and poured into a diluted aqueous hydrogen chloride solution (pH=3.5). The pH value is readjusted to pH=3.5 by aqueous hydrogen chloride. The aqueous solution is extracted trice with dichloromethane/isopropanol (10:1). The combined organic phases are dried (sodium sulphate) and concentrated. The residue is purified by extraction with sodium hydrogen carbonate solution and dichloromethane, acidification with aqueous solution and subsequent filtering. The solid crude product 2a is obtained in 90percent yield (14.5 g, 87.8 mmol) and is used for the next step without purification. MS-ESI: 166 (MExample BPreparation of X~ NA 1 L flask was charged with 5-fluoro-2-fonnylbenzonitrile (10.0 g, 67.0 mmol, 1eq), water (100 mL) and tert-butanol (450 mL). After 10 mm, sodium phosphate monobasic hydrate (21.8 g, 158.0 mmol, 2.36 eq) and sodium chlorite (28.0 g, 248.0 mmol, 3.7 eq) were introduced successively in one portion under vigorous stirring. The colorless suspension rapidly turned orange and an orange gas formed. After 18 h, the reaction mixture has turned yellow and concentrated hydrochloric acid was added at 0 °C until the white solid was entirely dissolved. The tert-butanol was evaporated under reduced pressure in a well- ventilated fume-hood (caution: a yellow gas escaped) and the resulting suspension was diluted to 500 mL with water, filtered and washed with water (1 L). The white solid obtained was dissolved in ethyl acetate (80 mL), washed with brine (2 x 30 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the product (7.14 g, 43.2 mmol, 65percent) as a white powder. ‘H NMR (400 MHz, DMSO-d6) 13.57 (s, 1H), 8.35 (dd, J = 6.3, 2.2 Hz, 1H), 8.26 (ddd, J = 8.8, 5.3, 2.2 Hz, 1H), 7.61 (t, J = 9.0 Hz, 1H). ‘3C NMR(100 MHz, DMSO-d6) 164.9, 164.9 (d, JCF = 261.5 Hz), 137.0 (d, JCF = 10.2 Hz), 135.2 (d, JCF = 1.2 Hz), 128.5 (d, JCF = 3.3 Hz), 117.1 (d, JCF = 20.3 Hz), 113.3, 101.0 (d, JCF= 16.1 Hz).a Compound 1 (180 mg, 1.21 mmol) H2O (1 mL) after dissolving in ACN (2 mL)KH2PO4 (99 mg, 0.73 mmol, 0.6 eq.) Dissolved inWith hydrogen peroxide (30% in water) (0.23 mL)Added.The mixture was brought to 0 C. and NaClO 2 (241 mg in 2 mL of water, 80% technical grade) was added slowly.After stirring until the oxygen production stops, Na 2 SO 3 (190 mL in 0.6 mL of water) was added and stirred at room temperature for 2 hours.1N HCl was added to the obtained residue, followed by extraction several times with EA. The combined organic layers were washed with water and brine, dried over MgSO 4, and concentrated under reduced pressure in vacuo to yield the title compound in a yield of 98%.To a stirred solution of 15.0 g (97, 6 mmol) 2-fluoro-5-formyl-benzonitrile (Aldrich), 150 ml dest. water and 630 ml t-butanol are added 40.8 g (361 mmol) sodium chlorite and 35.9 g (230 mmol) sodium hydrogen phosphate dihydrate. The reaction mixture is stirred over night and poured into a diluted aqueous hydrogen chloride solution (pH=3.5). The pH value is readjusted to pH=3.5 by aqueous hydrogen chloride. The aqueous solution is extracted trice with dichloromethane/isopropanol (10:1). The combined organic phases are dried (sodium sulphate) and concentrated. The residue is purified by extraction with sodium hydrogen carbonate solution and dichloromethane, acidification with aqueous solution and subsequent filtering. The solid crude product 2a is obtained in 90% yield (14.5 g, 87.8 mmol) and is used for the next step without purification. MS-ESI: 166 (M+ +1, 77), Elementary analysis: Calculated: C 58.19% H 2.44% F 11.51% N 8.48% Determined: C 58.81% H 2.42% F 11.41% N 8, 47%Example BPreparation of X~ N+(R1)(R2)(R3)-(CfiH4(-G))-L-OH 5 (-G = -CN)a) Synthesis of 3-Cvano-4-fluoro-benzoic acid:To a stirred solution of 15.0 g (97, 6 mmol) 2-fluoro-5-formyl-benzonitrile (Aldrich), 150 ml dest. water and 630 ml t-butanol were added 40.8 g (361 mmol) sodium chlorite and 35.9 g (230 mmol) sodium hydrogen phosphate dihydrate. The reaction mixture was stirred over night and poured into a diluted aqueous hydrogen chloride solution (pH=3.5). The pH value was readjusted to pH=3.5 by aqueous hydrogen chloride. The aqueous solution was extracted trice with dichloromethane/isopropanol (10:1). The combined organic phases were dried (sodium sulfate) and concentrated. The residue was purified by extraction with sodium hydrogen carbonate solution and dichloromethane, acidification with aqueous A 1 L flask was charged with 5-fluoro-2-fonnylbenzonitrile (10.0 g, 67.0 mmol, 1eq), water (100 mL) and tert-butanol (450 mL). After 10 mm, sodium phosphate monobasic hydrate (21.8 g, 158.0 mmol, 2.36 eq) and sodium chlorite (28.0 g, 248.0 mmol, 3.7 eq) were introduced successively in one portion under vigorous stirring. The colorless suspension rapidly turned orange and an orange gas formed. After 18 h, the reaction mixture has turned yellow and concentrated hydrochloric acid was added at 0 C until the white solid was entirely dissolved. The tert-butanol was evaporated under reduced pressure in a well- ventilated fume-hood (caution: a yellow gas escaped) and the resulting suspension was diluted to 500 mL with water, filtered and washed with water (1 L). The white solid obtained was dissolved in ethyl acetate (80 mL), washed with brine (2 x 30 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the product (7.14 g, 43.2 mmol, 65%) as a white powder. 'H NMR (400 MHz, DMSO-d6) 13.57 (s, 1H), 8.35 (dd, J = 6.3, 2.2 Hz, 1H), 8.26 (ddd, J = 8.8, 5.3, 2.2 Hz, 1H), 7.61 (t, J = 9.0 Hz, 1H). '3C NMR(100 MHz, DMSO-d6) 164.9, 164.9 (d, JCF = 261.5 Hz), 137.0 (d, JCF = 10.2 Hz), 135.2 (d, JCF = 1.2 Hz), 128.5 (d, JCF = 3.3 Hz), 117.1 (d, JCF = 20.3 Hz), 113.3, 101.0 (d, JCF= 16.1 Hz).EXAMPLE 105 3-(4-(2-(3-Cyano-4-cYanomethoxyphenyl)-lss3n4-thiadiazol-5-yl)-3-methylphenyl) propanoic acid; Step A: 3-Cyano-4-fluorobenzoic acid Chromium oxide (14.77 mmol; 1.48 g) was dissolved in a solution of sulfuric acid (1.1 mL) and water (3.4 mL) at 0C. To this solution was added to a mixture of 3-cyano-4- fluorobenzaldehyde (13.4 mmol; 2.0 g) in acetone (17 mL) at 0C. The reaction mixture was warmed to rt and stirred for 6 h. The reaction was then quenched with methanol (20 mL) and water (50 mL) and the product was extracted with EtOAc (2 x 50 mL). The combined organics were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to yield 2.25 g of product :'H NMR (500 MHZ, CDCl3) 8 8.39 (d, J = 5.0, 1H), 8.28-8. 29 (m, 1H), 7.64 (t, J = 8. 9, 1H).STEP A: 3-Cvano-4-fluoro-benzoic acid. To a solution of 2-fluoro-5-formyl-benzonitrile (2.57 g) in fBuOH (110 ml_) was added 2-methyl-2-butene (86 ml_) followed by a mixture of NaCIO2 (14 g) and NaH2PO4 (14 g) in H2O (140 ml_) dropwise via an addition funnel at O0C. The resulting mixture was allowed to warm to room temperature and the volatiles removed in vacuo. The remaining residue was diluted with H2O and washed 3X with hexanes. The aqueous layer was acidified to pH 3 with 4 N HCI and extracted with CH2CI2 and EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to yield the title compound as a white solid.MS (electrospray): exact mass for C8H4FNO2, 165.02; found m/z 166.1 [M+H]+.Preparation of BB5: 3-Cyano-4-fluoro-benzoic acid; To a solution of the 2-fluoro-5-formyl-benzonitrile BB4 in mixed solvent of H20/t-BuOH (48 mL/201 mL), the NaC102 (28.2 g, 223.5 mmol) and NaH2P04 (22.2 g, 142.6 mmol) was added. The mixture was stirred vigorously at about 25 C and stood overnight. The analysis by TLC indicated the complete consumption of the starting material. The solution was adjusted to pH=3.5 by addition of 1 N aqueous HC1 and extracted with DCM/i-Propanol (10:1, 200 mL x 3). The combined organic layer was dried over Na2S04 and concentrated in vacuum. The residue was redissolved in aqueous NaHC03 and extracted with DCM. The aqueous layer was acidified; the white precipitate was extracted with DCM, dried over Na2S04 and concentrated under reduced pressure to afford 3-Cyano-4-fluoro-benzoic acid as white solid (BB5, 9.5 g).3-cyano-4-fluorobenzoic acid To a solution of 3-cyano-4-fluorobenzaldehyde (45 g, 301 mmol) in CH3CN (450 mL) was added potassium phosphate monobasic (24 g, 176 mmol) in water (225 mL) and 30% hydrogen peroxide in water (30 mL). The reaction mixture was cooled to 0 C. and sodium chlorite (60 g, 663 mmol) in water (450 mL) was added dropwise over 2 h. The resulting yellow suspension was stirred at room temperature until production of oxygen ceased (4 h). Sodium sulfite (30 g, 238 mmol) in water (100 mL) was added and the reaction mixture stirred for 1 h. The reaction was quenched with 2N HCl (500 mL) and the resulting solid was filtered and washed with water. The aqueous phase was extracted with EA (2*500 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, concentrated, and combined with the collected solid to produce a total of 48.5 g (97%) of crude 3-cyano-4-fluorobenzoic acid as a white solid. LCMS-ESI (m/z) calculated for C8H4FNO2: 165.0. found 166.1 [M+H]+, tR=2.54 min. 1H NMR (400 MHz, DMSO) delta 13.60 (s, 1H), 8.41 (dd, J=6.3, 2.1 Hz, 1H), 8.30 (ddd, J=8.8, 5.3, 2.2 Hz, 1H), 7.66 (t, J=9.0 Hz, 1H).Sodium chlorite (1 .819 g, 20.12 mmol) and potassium dihydrogen phosphate (0.228 g, 1.676 mmol) in water (20.00 ml) was added to 2-fluoro-5-formylbenzonitrile (Aldrich; 1 g, 6.71 mmol) in f-butanol (20 ml), followed by 2-methyl-2-butene (10.06 ml, 20.12 mmol). The resulting mixture was stirred at room temperature for 2 hrs. A solution of 4.5 g of sodium disulfite in water (100 ml) was then added carefully. DCM (150 ml) was added and phases were separated. The aqueous layer was then extracted once more with DCM (150 ml). The combined organic extracts were passed through a phase separation cartridge, concentrated under vacuum and dried in a vacuum oven to give the title compound as a white solid (1.09 g). MS: m/z 164 [M-H].A mixture of 2-fluoro-5-formylbenzonitrile (9.22g) and pyridinium dichromate (46.52g)in dimethylformamide (90mL) was stirred at room temperature overnight. The reactionmixture was then extracted into ethyl acetate, washed with water, dried (MgSO4) and thesolvent removed in vacuo to yield 3-cyano-4-fluoro-benzoic acid (8.21g)To 3-cyano-4-fluoro-benzoic acid (8.21g) in methanol (80mL) was added acetyl chloride(14mL) and the reaction mixture was stirred at room temperature for 2 days. The solutionwas reduced in vacuo yielding a precipitate which was collected by filtration to yield 3-cyano-4-fluoro-benzoic acid methyl ester as a white solid (7.25g)A mixture of 3-cyano-4-fluoro-benzoic acid methyl ester (7.25g), glycine ethyl esterhydrochloride (5.94g) and potassium carbonate (14g) in acetonitrile (70mL) was heatedto reflux for 24 hours. After cooling, the reaction mixture was extracted intodichloromethane, washed with water, dried (MgSC>4) and the solvent removed in vacuo toyield crude product which was purified using flash chromatography to yield the 3-cyano-4-(ethoxycarbonyhnethyl-amino)-benzoic acid methyl ester (4.49mg).A mixture of 3-cyano-4-(ethoxycarbonylmethyl-amino)-benzoic acid methyl ester(SOOmg), triethylamine (0.27mL), di-tert-butyl dicarbonate (502mg) and 4-dimethylaminopyridine (20mg) was stirred in dichloromethane (5mL) at roomtemperature overnight. The reaction mixture was then extracted into dichloromethane, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield the titlecompound (476mg).3, 4, 5-trimethoxyphenyl-2, 4-diaminoquinazoline-6-carboxylate (Compound No. 31)STEP-I: To a solution of 3-cyano 4-fluro benzoic acid (2 g, 0.012 mol) in dry MeOH (20 ml) was added thionyl chloride (1.2 ml, 0.018 mol) at 0 0C and heated to reflux for 3 hours. The reaction mixture was concentrated under vacuum to afford the step-1 product (2 g, 95 %) as white solid. This was used as such for the next step. Rf = 0.5 (CHCI3: MeOH, 9:1).To a solution of To a stirred suspension of 16.0 g (96, 9 mmol) 2.3.1.a and 161 ml methanol are added 30.4 g (387, 6 mmol) acetyl chloride drop wisely at 0C. The reaction mixture is stirred over night, filtered and concentrated. The residue is diluted with dichloromethane, washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The residue is purified by column chromatography (hexane : ethylacetate). The desired product 2.3.1.b is obtained in 78, 1% yield (13.5 g; 75.7 mmol) MS-ESI: 180 (M+ +1, 57), Elementary analysis: Calculated: C 60.34% H 3.38% F 10.60% N 7.82% Determined: C 60.51% H 3.39% F 10.57% N 7, 80%b) Synthesis of 3-Cvano-4-fluoro-benzoic acid methyl ester 2:To a stirred suspension of 16.0 g (96, 9 mmol) 1 and 161 ml methanol were added 30.4 g (387, 6 mmol) acetyl chloride drop wisely at 00C. The reaction mixture was stirred over night, filtered and concentrated. The residue was diluted with dichloromethane, washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The residue was purified by column chromatography (hexane : ethylacetate). The desired product 2 was obtained in 78, 1% yield (13.5 g; 75.7 mmol) MS-ESI: 180 (M+ +1 , 57), Elementary analysis:Calculated: C 60.34% H 3.38% F 10.60% N 7.82% Determined: C 60.51% H 3.39% F 10.57% N 7, 80%A mixture of Description 5: Methyl 3-cyano-4-fluorobenzoate A mixture of A mixture of 2-fluoro-5-formylbenzonitrile (9.22g) and pyridinium dichromate (46.52g)in dimethylformamide (90mL) was stirred at room temperature overnight. The reactionmixture was then extracted into ethyl acetate, washed with water, dried (MgSO4) and thesolvent removed in vacuo to yield Compound 2 (2.2 g, 13.32 mmol) was dissolved in DMF (25 mL), followed by DMAP (325 mg, 2.66 mmol, 0.2 eq.), Benzyl amine (2.18 mL, 19.98 mmol, 1.5 eq.), EDC-HCl (5.11 g, 26.64 mmol, 2.0 eq.) Was added.The reaction mixture was stirred at room temperature for 12 hours, then extracted with EA and water and washed with sodium hydrogen carbonate. The organic layer was then dried over MgSO 4, concentrated under reduced pressure in vacuo and purified by silica gel column chromatography to yield the title compound in 76% yield.General procedure: To the solution of carboxylic acid (1eq.) in thionyl chloride were added one drop DMF. The mixture was heated to reflux temperature and stirred for 3 h. The solvent was removed and the crude material dissolved in DCM. To this solution were added the amine (1eq.) and triethylamine (1.5eq). The mixture was stirred for 3 h at room temperature under argon. Afterwards the DCM was removed. The crude material was dissolved in ethyl acetate and washed with water and brine. The resulting organic layer was dried over MgSO4, and the solvent was removed by evaporation. The obtained residue was purified by flash chromatography (CH2Cl2/MeOH).

Molecular Weight:165.12
XLogP3:1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:165.02260653
Monoisotopic Mass:165.02260653
Topological Polar Surface Area:61.1
Heavy Atom Count:12
Complexity:233
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes