2-(Chloromethyl)-4-methylquinazoline

White to yellow powder

In 150 mL of tetrahydrofuran, 6.05 g (45 mmol) of o-aminoacetophenone and 4.68 g (50 mmol) of 2-chloroacetamide were added, and 0.45 g (4.5 mmol) of catalyst cuprous chloride and 9.11 g (90 mmol) of triethylamine were present. Next, pass in oxygen and stir under reflux for 12 hours.The progress of the reaction was monitored by TLC. After the reaction was completed, the solvent was removed under reduced pressure. After column chromatography, 7.61 g (39.5 mmol) of the compound 2-chloromethyl-4-methylquinazoline was obtained with a yield of 88%.General procedure: To the solution of compound 3 (1 equiv) in MeCN was addedNaH (3 equiv) and the Benzyl chloride derivatives (1.5 equiv) atroom temperature. The reaction mixture was stirred at roomtemperature for 4 h. The mixture was extracted with ethyl acetate, washed with brine, dried (Na2SO4), and filtered. The filtrate wasconcentrated in vacuo, and the residue was purified by columnchromatography (silica gel, ethyl acetate/Petroleum ether) to givethe desired product.Compound B 27 g (0.09 mol), compound F'' 15.7 g (0.1 mol), potassium carbonate 25 g (0.181 mol), potassium iodide 0.3 g (0.02 mol) were added to a 1 L reaction flask, followed by the addition of 125 ml of NMP.Stir the mixture to 60-70 C and stir for 2-3 h.After completion of the TLC reaction, 18.3 g (0.095 mol) of Compound E was added and the reaction was continued for 3-4 h.After the TLC test (DCM: MeOH = 20:1), the reaction was stopped and the mixture was cooled to room temperature. Work-up: 250 ml of dichloromethane and 500 ml of water were added and stirred until the solid dissolved.The liquid layer was separated, and the aqueous layer was extracted with 125 ml*2DCM, and the organic phase was combined; the mixture was washed once with 300 ml of 5% aqueous acetic acid solution, and washed twice with saturated sodium chloride (200 ml) to obtain an organic phase.The organic phase was evaporated to dryness to a pale yellow solid, then 150 ml of ethanol was added, and the mixture was heated to reflux to dissolve, cooled to 20-30 C, 150 ml of methyl tert-butyl ether was added dropwise, stirred for 2 h, then cooled to 0-10 C, stirred for 1 h. .After suction filtration, the filter cake was rinsed with 20 ml of a solution of absolute ethanol: MTBE = 1:1. Dry at 60-70 C for 5-6 h.Intermediate D'' 40.5 g yield 85%, HPLC > 96.0%.Compound B 27 g (0.09 mol), Compound F '46 g (0.1 mol), potassium carbonate 25 g (0.181 mol), potassium iodide 0.3 g (0.02 mol) were added to a 1 L reaction flask, followed by the addition of 125 ml of NMP.Stir the mixture to 50-60 C and stir for 2-3 h.After completion of the TLC reaction, Compound E 18.3 g (0.095 mol) was added and the reaction was continued for 3-4 h.After the TLC test (DCM: MeOH = 20:1), the reaction was stopped and the mixture was cooled to room temperature. Work-up: 250 ml of dichloromethane and 500 ml of water were added and stirred until the solid dissolved.The liquid layer was separated, and the aqueous layer was extracted with 125 ml*2DCM, and the organic phase was combined;The mixture was washed once with 300 ml of 1% aqueous acetic acid solution and once with 200 ml of saturated sodium chloride to obtain an organic phase.The organic phase was evaporated to dryness to a pale yellow solid, then 150 ml of ethanol was added, and the mixture was heated to reflux to dissolve, cooled to 20-30 C, stirred for 2 h, then cooled to 0-10 C and stirred for 1 h.Filter by suction and the filter cake was washed with 10 ml of anhydrous ethanol. Dry at 60-70 C for 5-6 h.Intermediate D' 49.8 g yield 91%, HPLC purity 99.0%.The compound 8-[(R)-3-amino-piperidin-1-yl]-3, 7-dihydro-3-methyl-7-(2-butynyl)-1H-indole-2, 6 -dione 100 mmol, 4-methyl-2-chloro-methylquinazoline150mmol and 160mmol of potassium carbonate and 200ml of N, N-dimethylformamide were added to the reactor and stirred.The temperature was raised to 80 C for 10 hours, after the reaction was completed, Cool down, add 1200ml water, precipitate solids, filter, The obtained solid was added to 500 ml of dichloromethane and 500 ml of water, and the layers were stirred.The organic layer was evaporated to dryness, and 400 mL of ethanol was added to the residue.The temperature was raised to 70-75 C, and the solid was completely dissolved and kept for 0.5 h.Then slowly cool to room temperature and crystallize, after stirring at room temperature for 4 h, Add 300 mL of methyl tert-butyl ether and cool to 5 C.Stir for 2 hours with heat. Filter and filter the cake with 100 mL of methyl tert-butyl ether.Drying gave linagliptin in a yield of 94.8% and a purity of 99.9%.1 g of compound e, 1.8 g of compound d and 0.7 g of sodium bicarbonate were added to 10 mL of N-methylpyrrolidone, Stirring heated to 90 reaction, TLC monitoring, the reaction is complete, Cooling to 20 , The reaction mixture was poured into 50mL of water, Precipitation of the solid, filter, The resulting solid was added to 20 mL of methylene chloride and 20 mL of water, Stirring 1h, liquid separation, The organic layer was evaporated to dryness to give linagliptin, which had a mass of 1.8 g;

Liraglitine intermediates

Molecular Weight:192.64
XLogP3:1.9
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:192.0454260
Monoisotopic Mass:192.0454260
Topological Polar Surface Area:25.8
Heavy Atom Count:13
Complexity:174
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes