4-Chloropyridine-3-carboxaldehyde

White to light yellow powder

A solution (50 ml) of 4-chloropyridine (25.0 g, 0.22 mol) in tetrahydrofuran was added dropwise to a tetrahydrofuran solution (300 ml) of lithium diisopropylamide prepared from a solution (179 ml, 0.29 mol) of 1.6 M n-butyllithium in hexane and diisopropylamine (33.4 g, 0.33 mol) under an argon atmosphere at -78 DEG C. After stirring for 30 min., DMF (19.3 g, 0.26 mol) was added and the mixture was gradually heated to room temperature. The reaction mixture was extracted with ethyl acetate (200 ml) - 5percent NH4Cl aq. (300 ml). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give a crude title compound (27 g, 86percent) as an oil.<1>H-NMR (200Hz, CDCl3) delta : 7.45 (1H, d, J = 5.0 Hz), 8.69 (1H, d, J = 5.0Hz), 9.05 (1H, s), 10.51 (1H, S).4-Chloropyridine 1 is obtained by neutralization of 4-chloropyridine hydrochloride with 10percent NaOH as described in SCHMID WOLKOFF (Canadian Journal of Chemistry, vol. 50, p. 1181-1187, 1972). 4-Chloropyridine 1 (15 mmol) is reacted in THF (250 ml) at -78° C. (nitrogen atmosphere) with 1.2 equivalents of lithium diisopropylamide (1.5 M solution in hexanes containing one equivalent of THF, ALDRICH) (THRASHER et al., Heterocycles, vol. 67, p. 543-547, 2006).Reaction of the resulting anion with either an excess of anhydrous DMF or an excess of methyl formate allows the formation of 4-chloropyridine-3-carboxaldehyde 2, isolated in the form of a colorless solid (60-70percent).To a solution of diisopropylamine (18.2 mL, 0.13 mol) in THF (200 mL, 0.5 M) at - 78°C was added n-butyl lithium (2.5 M in hexane, 52 mL, 0.13 mol) dropwise. After 30 min, 4-chloropyridine from Step A in THF (10 mL) was added and the reaction mixture was stirred at-78°C for 1 h. To the resulting reddish-brown solution AT-78 °C was added N, N-DIMETHYLFORMAMIDE (12.4 mL, 0.16 mol). The reaction mixture was allowed to warm slowly to room temperature over a 15 h period, and then the reaction was quenched with water (150 mL). The THF was removed in vacuo and the aqueous layer was extracted with isopropyl acetate (3 x 150 mL). The organic layers were combined, dried over sodium sulfate, filtered and the solvent was removed in vacuo to give the crude product as a brown oil. This residue was purified by silica gel chromatography (using 5percent ETOH in EtOAc) to afford 3.97 g of the title intermediate as a yellow solid (RF = 0.6, 28percent yield).35.8 ml of n-BuLi (1.6 M in hexane; 57 mmol, 1 eq.) is added to a solution of 7.5 ml of N, N-diisopropylamine in 100 ml of tetrahydrofuran at -60° C. in nitrogen. The mixture is then left under stirring at 0° C. for 45 min before being cooled to -90° C. To this solution, a solution of 6.5 g of 4-chloropyridine (57 mmol, 1 eq.) in 25 ml of tetrahydrofuran is added drop by drop such that the temperature remains between -70 and -60° C. The mixture is left under stirring at -70° C. for 3 hrs. Then, a solution of 5.1 ml of ethylformate (63 mmol, 1.1 eq.) in 10 ml of tetrahydrofuran is added. The mixture is left under stirring for 1 hr at -65/-70° C. and the reaction mixture is then returned to -10° C. and hydrolysed with water. The organic phase is separated and the aqueous phase is extracted 3 times with ethyl acetate. The combined organic phases are dried on NaExample 18; Preparation of ter?-butyl-2-((4-mercaptopyridin-3-yl)methylthio)ethyl carbamate; ), DMF ) c HStep 1: LDA (0.11 mmol) was added to 4-chloropyridine 1 (15 g, 0.1 mol) in THF (250 mL) dropwise at -60°C and stirred at this temperature for 1 h. Then, DMF (9.3 mL, 0.12 mol) was added and stirred at room temperature overnight. The product was extracted with EA from water. The combined organic layer was dried(NaSaturated NaHCO3 was added to a suspension of 4-chloropyridinium hydrochloride (10 g, 67 mmol) in diethyl ether (100 mL).The biphasic mixture was stirred for 1 h, then separated. The aqueous layer was extracted with diethyl ether (3 x 50 mL). Combined organic layers were dried over Na2SO4 andconcentrated. The resulting oil was purified by distillation to afford pure 4-chloropyridine.A -78 °C solution of 2 M lithium diisopropylamide (LDA) in heptane/tetrahydrofuran (THF)(19 mL, 38.04 mmol, 1.2 equiv.) was diluted in THF (60 mL) and treated with the dropwiseaddition of a solution of 4-chloropyridine (3.6 g, 31.7 mmol, 1 equiv.) in THF (10 mL). Themixture was slowly warmed to -40 °C and stirred 1 h before returning to -78 °C. Dimethylformamide (DMF, 3.0 mL, 38.04 mmol, 1.2 equiv.) was added, and the reaction was stirred 2 h at -78 °C, then warmed to RT as ice bath expired and stirred 16 h. The reaction was cooled to -10 °C and quenched with sat. NH4C1 (5 mL). The reaction wasdiluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude red oil was purified by silica gel chromatography (30percent EtOAc/hexanes) to afford the title compound as a yellow tinted oil which crystalized to clear needles under argon (1.6 g, 36percent yield). Spectra matched the literature reports. ‘H-NIVIR (400 IVIHz, CDC13): = 10.51 (s, 1 H); 9.05 (s, 1 H); 8.68 (d, J5.76 Hz, 1 H); 7.43 (d, J 5.4 Hz, 1 H).Manganese dioxide (1.53 g) was added to a solution of (4-chloro pyridin-3-yl)methanol (630 mg) in ethyl acetate (15 mL), followed by refluxing for 2 hours. Manganese dioxide (382 mg) was added thereto, followed by refluxing for 2 hours. The reaction mixture was cooled to room temperature, the insoluble materials were filtered off, and the solvent was distilled off under reduced pressure. The obtained residues were purified by silica gel column chromatography (hexane:ethyl acetate=7:3→3:7), whereby 4-chloronicotinic aldehyde (480 mg) was obtained as a white solidEXAMPLE 21 Step 3 7-[1-(3-Formylpyridin-4-yl)piperidin-4-ylmethoxy]-1, 2, 3, 4-tetrahydroisoquinoline-2-carboxylic Acid tert-Butyl Ester To a solution of 7-(piperidin-4-ylmethoxy)-1, 2, 3, 4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (442 mg) in ethanol (3 ml) were added triethylamine (0.3 ml) and 4-chloro-3-formylpyridine (Journal of Heterocyclic Chemistry, vol. 25, p. 81 (1988)) (150 mg), and the mixture was stirred under reflux for 27 hours. After completion of the reaction, tetrahydrofuran and diethyl ether were added and insoluble material was removed. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1) and dried under reduced pressure to give the title compound (430 mg). 1H-NMR (delta ppm, CDCl3) 1.49 (s, 9H), 1.60-1.70 (m, 2H), 1.95-2.15 (m, 3H), 2.76 (m, 2H), 3.07 (m, 2H), 3.60-3.65 (m, 4H), 3.86 (d, 2H), 4.54 (s, 2H), 6.65 (1H), 6.73 (1H), 6.84 (d, J=6.0 Hz, 1H), 7.05 (1H), 8.42 (d, J=6.0 Hz, 1H), 8.74 (s, 1H), 10.02 (s, 1H).[0146] A solution (50 ml) of 4-chloropyridine (25.0 g, 0.22 mol) in tetrahydrofuran was added dropwise to a tetrahydrofuran solution (300 ml) of lithium diisopropylamide prepared from a solution (179 ml, 0.29 mol) of 1.6 M n-butyllithium in hexane and diisopropylamine (33.4 g, 0.33 mol) under an argon atmosphere at -78 DEG C. After stirring for 30 min., DMF (19.3 g, 0.26 mol) was added and the mixture was gradually heated to room temperature. The reaction mixture was extracted with ethyl acetate (200 ml) - 5% NH4Cl aq. (300 ml). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give a crude title compound (27 g, 86%) as an oil.<1>H-NMR (200Hz, CDCl3) delta : 7.45 (1H, d, J = 5.0 Hz), 8.69 (1H, d, J = 5.0Hz), 9.05 (1H, s), 10.51 (1H, S).4-Chloropyridine 1 is obtained by neutralization of 4-chloropyridine hydrochloride with 10% NaOH as described in SCHMID & WOLKOFF (Canadian Journal of Chemistry, vol. 50, p. 1181-1187, 1972). 4-Chloropyridine 1 (15 mmol) is reacted in THF (250 ml) at -78 C. (nitrogen atmosphere) with 1.2 equivalents of lithium diisopropylamide (1.5 M solution in hexanes containing one equivalent of THF, ALDRICH) (THRASHER et al., Heterocycles, vol. 67, p. 543-547, 2006).Reaction of the resulting anion with either an excess of anhydrous DMF or an excess of methyl formate allows the formation of To a solution of diisopropylamine (18.2 mL, 0.13 mol) in THF (200 mL, 0.5 M) at - 78C was added n-butyl lithium (2.5 M in hexane, 52 mL, 0.13 mol) dropwise. After 30 min, 4-chloropyridine from Step A in THF (10 mL) was added and the reaction mixture was stirred at-78C for 1 h. To the resulting reddish-brown solution AT-78 C was added N, N-DIMETHYLFORMAMIDE (12.4 mL, 0.16 mol). The reaction mixture was allowed to warm slowly to room temperature over a 15 h period, and then the reaction was quenched with water (150 mL). The THF was removed in vacuo and the aqueous layer was extracted with isopropyl acetate (3 x 150 mL). The organic layers were combined, dried over sodium sulfate, filtered and the solvent was removed in vacuo to give the crude product as a brown oil. This residue was purified by silica gel chromatography (using 5% ETOH in EtOAc) to afford 3.97 g of the title intermediate as a yellow solid (RF = 0.6, 28% yield).Synthesis of stilbene (olefin) compounds; 4-Chloropyridme 1 is obtained by neutralization of 4-chloropyridme hydrochloride with 10% NaOH as described in SCHMID & WOLKOFF (Canadian Journal of Chemistry, vol. 50, p. 1181-1187, 1972) . 4- Chloropyridme 1 (15 mmol) is reacted in THF (250 ml) at -78 0C (nitrogen atmosphere) with 1.2 equivalents of lithium diisopropylamide (1.5 M solution m hexanes containing one equivalent of THF, ALDRICH) (THRASHER et al., Heterocycles, vol. 67, p. 543-547, 2006) .Reaction of the resulting anion with either an excess of anhydrous DMF or an excess of methyl formate allows the formation of 4-chloropyridme-3- 15 g of diisopropylamine was dissolved in 50 mL of tetrahydrofuran to prepare a solution A; 10 g of n-butyllithium was dissolved in 50 mL of n-hexane to prepare a solution B; The solution A and the solution B were fed into the multi-module temperature-controlled silicon carbide microchannel reactor with a reaction temperature of -10 C through a tetrafluoro pump at the same flow rate of 100 mL/min. The material is uniformly mixed in the microreactor, And the residence time is 0.5 min, and the collected material is solution C; 11.5 g of 4-chloropyridine dissolved in 100 mL of tetrahydrofuran, configured as solution D; The solution C and the solution D were fed into the silicon carbide reactor at a reaction temperature of -10 C through a tetrafluoro pump at the same flow rate of 100 mL/min. The material is uniformly mixed in the microreactor, And the residence time is 1 min, and the collected material after the reaction is solution E; 40 mL of solution E and N, N-dimethylformamide were fed into a silicon carbide reactor at a reaction temperature of -10 C by a tetrafluoro pump at flow rates of 100 mL/min and 20 mL/min, respectively. The material is uniformly mixed in the microreactor, And its residence time is 2min, Collect the reacted materials, pour into 600 mL of ice water, slowly add dilute hydrochloric acid solution at 0 C, adjust the pH of the reaction solution to neutral. Then, the reaction liquid was extracted several times with dichloromethane, and the reaction liquid was concentrated, and then a mixed solution of toluene and n-hexane (V toluene: V n-hexane = 1:2) was recrystallized to obtain 3-aldehyde-4-chloropyridine 12 g.At -50 C, 8 g (0.12 mol) of n-butyllithium was dissolved in 30 mL of tetrahydrofuran, and 10 g (0.1 mol) of diisopropylamine was slowly added dropwise.Keep the temperature not exceeding -40 C, After the addition is completed, the temperature is slowly added and dissolved.4-chloropyridine (0.1 mol) was dissolved in 100 mL of tetrahydrofuran.After the addition is completed, the temperature is lowered to -60 C.Keep the temperature constant, N, N-dimethylformamide 16 mL (0.2 mol) was slowly added dropwise, and after the addition, Maintain -60 C reaction for 20 min, The reaction was heated to -40 C for 20 min, Finally, it is raised to 0 C for 30 min.Finally, pour into ice water 100mL, At 0 C, Slowly add dilute hydrochloric acid solution, Adjust the pH of the reaction solution to neutral, Then extract the reaction solution several times with dichloromethane.The reaction solution was concentrated to give 3-aldehyde-4-chloropyridine.8 g (0.12 mol) of n-butyllithium was dissolved in tetrahydrofuran 30 mL at -50 C.Then slowly add 10 g (0.1 mol) of diisopropylamine.Keep the temperature not exceeding -40 C, After the completion of the dropwise addition, the temperature was slowly added dropwise, and 11.3 g of 4-chloropyridine was dissolved in tetrahydrofuran 100 mL.After the addition is completed, the temperature is lowered to -20 C.Keep the temperature constant, N, N-dimethylformamide 16 mL (0.2 mol) was added dropwise slowly. After the addition was completed, the reaction was kept at -20 C for 20 min. The reaction was heated to 0 C for 20 min, and finally poured into ice water 100 mL.In the case of 0 C, slowly add dilute hydrochloric acid solution, adjust the pH of the reaction solution to neutral, and then extract the reaction solution with dichloromethane. After several times, the reaction liquid was concentrated to obtain 11 g of 3-aldehyde-4-chloropyridine.To a mixture of To a mixture of To a solution of PI-62a (0.8 g, 3.82 mmol, 1.0 eq) in DMF (40 mL) was added To a solution of PI-61c (600 mg, 2.58 mmol, 1.0 eq) in THF (20 mL) was added NaH (103 mg, 2.58 mmol, 1 eq, 60%) at 0C. under nitrogen atmosphere. The mixture was stirred at 0C. for 1 h. Then To a solution of PI-57b (230 mg, 1 mmol, 1.0 eq) in DMF (10 mL) was added To a solution of PI-56a (5 g, 22.19 mmol, 1.0 eq) in DMF (40 mL) was added To a solution of

Molecular Weight:141.55
XLogP3:0.9
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:140.9981414
Monoisotopic Mass:140.9981414
Topological Polar Surface Area:30
Heavy Atom Count:9
Complexity:107
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes