1,4-Dihydro-2,6-dimethyl-4-(2',3'-dichlorophenyl)-5-carboxy methyl-3-pyridinecarboxylic acid

Take 400g of intermediate II plus 2L isopropanol in three-necked flask and dissolved, and then followed by adding 30g potassium hydroxide and 10g of triethylbenzylammonium bromide, stirred and heated to reflux for 80°C 5 to 6 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure to dryness. The residue was added 2L of methylene chloride and 2L of water, stirred for 10 minutes, standing layer, the aqueous phase was added dropwise under ice-cooling dilute hydrochloric acid to adjust pH = 4.5, was stirred for one hour ice bath, suction filtered and the filter cake washed with purified water to pH = 7, after the cake was dried to give 260g, tested, HPLC purity of 96.11percent. (See Fig. 3). A mixture of 2, 3-dichlorobenzaldehyde (0.9 kg, 5.14 mol), methyl acetoacetate (0.6 kg, 5.14 mol) and cyanoethyl 3-aminocrotonate (0.88 kg, 5.71 mol) Mol), pyridine (22g, 0.28mol) was added to isopropanol (15 L) and reacted at 80 ° C for 10 h. Cooling the temperature, filtering to obtain solid, the obtained solid by adding isopropyl alcohol (5L) recrystallization, filtration to get compound 3-(2-cyanoethyl) 5-methyl 4-(2', 3'-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate (1.8kg, 4.37mol). Compound III (1.8kg, 4.37mol) Was dissolved in isopropanol (20L) 1M Bu4NI 5.24L (5.2mol) solution was added at room temperature Stir for 4 h, The solvent was evaporated and addedWater (18 L), dilute hydrochloric acid(1M) at 20 ° C adjusted PH5-6, And stirred at this temperature for 2h, a yellow precipitate formation, Filtration was solid 1. 43kg, Yield: 78.0percent (based on 2, 3-dichlorobenzaldehyde).The 3-amino-crotonic acid cyanogen ethyl ester 1.0 kg (6.49mol) inputs 5.5L isopropanol, inputs under stirring 2, 3- two chlorine Asia phenmethyl acetyl methyl acetate 2.0 kg (7.32mol), heating to reflux reaction 6-8h, after the reaction is ended cooling to 35-45°C, inputs potassium hydroxide 550.0g (9.80mol), preserving heat and stirring 2-4h, subsequently inputs 60.0g activated carbon decolourizations 5-15min, filtering, filtrates in 30-40 °C dropwise 1mol/L hydrochloric acid solution to adjust pH value to 5-6, filtering, 40-50 °C decompression drying to obtain the intermediate-4 - (2, 3-dichlorophenyl) - 1, 4-dihydro -2, 6-dimethyl-5-methoxy carbonyl-3-pyridine carboxylic acid 2.11 kg, yield 91.32percent.To about 1.03g 2.8mmol S13 compound prepared above was dissolved in 15mL of methanol was added Into approximately 260mg of 1.14mmol TEBAc a concentration of 40percent NaOH 2.5mL, at 70 ° C Under stirring at reflux, the reaction overnight, the methanol was removed by rotary evaporation, diluted with water, 2mol / L hydrochloric PH is 2-3 to the reaction system in the precipitated solid was filtered to give the product S14200mg, yield To 20percent, 4-(2, 3-dichlorophenyl)-1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylate-(tert-butyl) methylester(1) (412 mg, 1mmol) dissolved in dichloromethane (10 ml), by adding trifluoroacetic acid (1.5mmol), 20 °C stirring 2.5h, turns on lathe does solvent, cyclohexane and a small amount of ethyl acetate is added, solid precipitation, filtration, a small amount of cold ethyl acetate filter cake washing, drying, the obtained product (IV) 267 mg, yield 75.2percent (to 1 parts).

Molecular Weight:356.2
XLogP3:3.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:355.0378133
Monoisotopic Mass:355.0378133
Topological Polar Surface Area:75.6
Heavy Atom Count:23
Complexity:585
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes