Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Stage #2: at 20℃;
The reaction kettle is added compound XVI (190g, 1.0 µM), anhydrous THF (1L) dissolved, cooling to -78 °C, slowly adds by drops positively BuLi (2.5M, 0 . 5L), to maintain the temperature of the reaction 2 hours after DMF slowly adds by drops anhydrously (95g, 1.3 µM), the reaction temperature to room temperature slowly to the disappearance of the raw material, to join the semi-saturated ammonium chloride quenching, ethyl acetate after extracting the concentrated white solid, petroleum ether ethyl acetate system beating shall be required compound XII (179g, 82percent).
80%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; Inert atmosphere Stage #2: for 2 h;
Take 3,5-dichlorobenzoic acid (191mg, 1mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, and argon protection, followed by cooling to -78 .At this temperature, slowly added dropwise 2N lithium diisopropylamide (LDA) in tetrahydrofuran (0.6 mL, 1.2mmol).Stirring was continued for 0.5 ~ 1h after addition was complete.It was then slowly added dropwise a solution of 0.5mL DMF 2mL of tetrahydrofuran, was added after the reaction was continued for 2h, TLC detection, reaction was almost completed. The residue was quenched with 1N dilute hydrochloric acid and evaporated to dryness. The residue was purified by column chromatography using ethyl acetate and water and the ethyl ester layer to give the title compound 3,5-dichloro-4-formylbenzoic acid (175 mg , 80percent).
Reference：
[1] Patent: CN106565625, 2017, A, . Location in patent: Paragraph 0073-0074
[2] Patent: CN104341316, 2017, B, . Location in patent: Paragraph 0379; 0381; 0382
2
[ 153203-78-2 ]
[ 153203-80-6 ]
Reference：
[1] Patent: CN106565625, 2017, A, . Location in patent: Paragraph 0067-0068
With thionyl chloride; In N-methyl-acetamide; toluene;
f) Preparation of 4-formyl-3,5-dichlorobenzoyl chloride A mixture of <strong>[153203-80-6]4-formyl-3,5-dichlorobenzoic acid</strong> (15.0 g, 0.06 moles), thionyl chloride (12.1 g, 0.107 moles), and dimethylformamide (5 ml) in toluene (100 ml) was slowly warmed to 70 C. and stirred at that temperature for 2 hours. The toluene was eliminated in the rotavap to yield 16.5 g of 4-formyl-3,5-dichlorobenzoyl chloride used in the next step as such.
Triethylphosphonopropionate (4.5 g) was dissolved in THF (15 mL), sodium hydride (1.59 g) was added under ice-cooling, and the mixture was stirred for 30 minutes. To the solution was added a solution obtained by dissolving <strong>[153203-80-6]3,5-dichloro-4-formyl-benzoic acid</strong> (3.9 g) in THF (10 mL), and the mixture was further stirred for 1 hour and 20 minutes. The reaction solution was extracted with ethyl acetate, and a solvent was distilled off until a weight including a weight of the solvent became 11.7 g. The precipitated crystal was filtered off, and washed with a mixed solvent of ethyl acetate and n-heptane (1 : 2) to obtain 3 (E)-3,5-dichloro-4-(2-ethyloxycarbonylphenylpropyl)benzoic acid (13, 3.98 g). Melting point: 145C NMR (CDCl3) delta ppm: 8.07 (s, 2H), 7.47 (s, 1H), 4.32 (q, 2H, J = 7.0 Hz), 1.79 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz)
With 4-methylmorpholine N-oxide; In acetonitrile;Reflux;
The compound XIII (750 g, crude) was added to the reaction vessel, dissolved in anhydrous MeCN, and 4-methylmorpholine-N-oxidation(410 g, 3.50 mol), added, refluxed to TLC to show the disappearance of the starting material. After cooling to room temperature, slowly saturate with saturated sodium thiosulfate. After washing with Mu1EpsilonEpsilon, the mixture was washed with water and dried over anhydrous sodium sulfate. The compound XII (371 g, two steps, 68%) was concentrated and the reaction was further carried out.
3,5-dichloro-4-(2-ethoxycarbonylpropenyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃; for 2h;
NaH (60% in oil, 72 g, 1.8 mol) was added to the reaction kettle and anhydrous THF was added.Ethyl 2- (dimethoxyphosphoryl) propionate was slowly added dropwise. After completion of the reaction at room temperature for 2 hours, a solution of compound XII (371 g, 1.7 mol) in dry THF was slowly added dropwise. Reaction to TLC indicated that the starting material disappeared. Add 2N hydrochloric acid quenching reaction, ethyl acetate extraction, washing, saturated brine, anhydrousDried over sodium sulfate, and the concentrated petroleum ether ethyl acetate system was beaten to obtain the desired compound II
The reaction kettle is added compound XVI (190g, 1.0 muM), anhydrous THF (1L) dissolved, cooling to -78 C, slowly adds by drops positively BuLi (2.5M, 0 . 5L), to maintain the temperature of the reaction 2 hours after DMF slowly adds by drops anhydrously (95g, 1.3 muM), the reaction temperature to room temperature slowly to the disappearance of the raw material, to join the semi-saturated ammonium chloride quenching, ethyl acetate after extracting the concentrated white solid, petroleum ether ethyl acetate system beating shall be required compound XII (179g, 82%).
80%
Take 3,5-dichlorobenzoic acid (191mg, 1mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, and argon protection, followed by cooling to -78 .At this temperature, slowly added dropwise 2N lithium diisopropylamide (LDA) in tetrahydrofuran (0.6 mL, 1.2mmol).Stirring was continued for 0.5 ~ 1h after addition was complete.It was then slowly added dropwise a solution of 0.5mL DMF 2mL of tetrahydrofuran, was added after the reaction was continued for 2h, TLC detection, reaction was almost completed. The residue was quenched with 1N dilute hydrochloric acid and evaporated to dryness. The residue was purified by column chromatography using ethyl acetate and water and the ethyl ester layer to give the title compound 3,5-dichloro-4-formylbenzoic acid (175 mg , 80%).
To the product of step (219mg, 1mmol) was dissolved in 10mL of methanol was added 2 drops of concentrated sulfuric acid was heated to reflux, the reflux temperature of the reaction 4 ~ 5h, TLC detection reaction was almost complete.Evaporated to dryness and methanol, treated with ethyl acetate and saturated sodium hydrogen carbonate solution stratification, the organic layer was evaporated to dryness, the next step directly administered.
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