Asolution of 35g (0.16 mol) of 2-(2-ethyl-3-benzofuranyl)-propionamide in 500mlof toluene was refuxed for 18 hours in the presence of P2O5. The organic phase was decanted off and theresidue was carefully decomposed with ice-water and extracted with ether. The organic phase was washed with water,dried over sodium sulphate and added to the toluenic phase. The solvent was evaporated off under reducedpressure and the residue was fractionated to give 23.8g of2-(2-ethyl-3-benzofuranyl)-propionitrile (yield 74.4%, boiling point: 105.deg.C. at0.2 mmHg).
Reference: US4124710 A1 (1978/11/07)
A mixture of2-chloro-1,3,4-thiadiazole-5-carboxamide (1.4 g) in 17 ml of POCl3 is heated atreflux for 18 hours. The reactionmixture is concentrated and the residue is suspended in 25 ml of ethyl acetate. The suspension is cooled in an ice bath andneutralized with saturated, aqueous NaHCO3 (to pH 7). The phases are separated and the aqueousphase is extracted with 20 ml of ethyl acetate. The combined organic phases are dried over MgSO4, filteredand concentrated. The residue ispurified by column chromatography (using 30 percent ethyl acetate / hexane aseluent) to afford 0.832 g of 2-cyano-5-chloro-1,3,4-thiadiazole. MP: 65-67. deg.C
Reference: Patent; EP883611 B1 (2002/07/31)
A solution of thionyl chloride (7.70 g, 0.065 mol)in dry DMF (10 ml) was added dropwise to a stirred solution of compound 13 (4.20g, 0.013 mol) in dry DMF (25 ml) at room temperature. The stirred mixture was heated at 120C for 3h and poured into ice–water. The product was extracted into ether (twice) and thecombined ethereal extracts were washed with water, saturated sodium hydrogencarbonate solution, water, and dried (MgSO4). The solvent was removedin vacuo and the residue was purified by column chromatography (silicagel–light petroleum (bp 40–60 8C) with the gradual introduction ofdichloromethane) to yield a colourless solid. Yield 2.88 g (68%);
Reference: J. Chem. Soc.,Perkin Trans. 1, 1998,3479–3484
4-Oxo-4H-9-oxa-1,4a-diaza-fluorene-3-carboxylic acidamide (4.58 g, 20 mmol) wassuspended in 150 ml of anhydrous DMF, PC15 (5.0 g, 24 mmol) wasadded, and the mixture was stirred for 2 h at 40-50 oC. The reaction mixture was poured into 600 mlice-water to yield a solid, which was collected by filtration. The solid was washed thoroughly (first withsaturated aqueous NaHCO3, then with water) and dried to give 4-oxo-4H-9-oxa-1,4a-diaza-fluorene-3-carbonitrile.
Ref: J . Med. Chem. 1983, 26,608-611
To a solution of 2-tetrazol-1-yl-benzamide(1.5 g, 7.9 mmol) in tetrahydrofuran (50 ml) was added Et3N+SO2N-COOMe(2.8 g, 11.8 mmol) in three portions over 1.5 h. Water was added and the reaction mixture was extracted with ethylacetate. The combined organic layers were washed with brine and water.After drying and filtration, the solvent was evaporated to give 2-tetrazol-1-yl-benzonitrile.
Reference: J. Med.Chem. 47, 12, 2004, 2995-3008.
Preparation of Bugess reagent:
将无水甲醇19.2g (0.6 mol) 和无水苯40mL的混合物在30-40分钟内，滴入ClSO2NCO 85g(52.3 mL, 0.6 mol)和无水苯200mL的混合物中，控温10-15℃。加毕，室温搅拌2小时。然后加入1000mL无水苯稀释后，小心滴入190mL无水三乙胺和250mL无水苯的混合物中，控温10-15℃，约40分钟左右加完。加毕，室温搅拌2小时，析出大量固体。反应毕，过滤，固体用无水苯200mL、无水THF200mL洗后，滤液浓缩后，（控温<30℃），加入无水THF溶解后，重结晶得123g, 收率86%。注：整个操作温度要低于30℃。
To a mixture of compound amide (287 mg, 1 mmol), Et3N (470 mg, 4.5 mmol) in anhydrous DCM (4 mL) was added TFAA (0.44 g, 2 mmol) at 0℃ with stirring. The resulting mixture was warmed to room temperature and stirred for 12 h. The reaction was monitored by TLC (Hexane:AcOEt = 1:1) until its completion. The organic layer was washed with brine and water, dried and concentrated to give the desired product (~80% yield).
A solution of (COCl)2(67 μL, 0.77 mmol) in CH2Cl2 (0.5 mL) was addedto the solution of 3-carbamoyl-piperidine-1-carboxylic acid tert-butylester (142.0 mmol) and DMSO (78 μL, 1.1 mol) in CH2Cl2(1.5 mL) at -78 oC. Afterstirring for 15 min at -78 oC, Et3N (0.23 mL, 1.65 mmol)was added dropwise to the mixture. Afterthe reaction mixture was stirred for 15 min. at -78 oC, the mixturewas quenched by addition of water (5 mL). After this mixture was warmed to room temperature, the aqueous layer wasextracted with EtOAc (3×10 mL). The combined organiclayers were washed with brine, dried and filtered. Concentration after filtration in vaccuofollowed by purification by column gave 3-cyano-piperidine-1-carboxylic acid tert-butyl ester (123.3 mg, 93%).
Reference: T. L. 38, 12,1997, 2099-2102
6-(3-Methoxy-2-propyl-phenyl)-hexanoic acid amide (7.2g, 27.2 mmol) was cooled to 0 oC and added methane-sulfonyl chloride(18.5 mL, 239 mmol) dropwise over 5 min. The mixture was stirred overnight while slowlywarming to 25 oC. Thereaction mixture was then poured into 3 volumes of ice water. The aqueous mixture was repeatedly extractedwith ethyl acetate. The combined organicextracts were washed with dilute HC1 and brine, then dried over MgSO4. After evaporation of the solvent, a brownoily residue was obtained. The crudenitrile was purified by bulb-to-bulb distillation (bp 133-137"C (0.02mmHg)), which was pure enough for further transformation (5.50 g, 83 %).
Reference: J. Med. Chem. 1988, 31, 172-175
Toa solution of CCl4 (110 μL, 1.17 mmol) and THF (6 mL) at 0 oC wasadded TiCl4 (58 μL, 0.52mmol). After 5 min, 5,11-diethyl-8-methoxy-5,6,11,12-tetrahydro-chrysene-2-carboxylic acid amide (47 mg, 0.13 mmol) in THF (14 mL) and Et3N(72μL, 0.52 mmol) was added to thisyellow heterogeneous solution, and stirring was continued at room temperature untilno starting material remained. Diethylether and water were added, and the organic layer was washed with brine, driedover MgSO4, and concentrated. Repeated recrystallization from diethyl ether gave 5,11-diethyl-8-methoxy-5,6,11,12-tetrahydro-chrysene-2-carbonitrile (45 mg, 99%).
Reference: J. Org. Chem. 1992, 1262-1271