* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With potassium permanganate In water for 3 h; Heating / reflux
A mixture of the 5.9 g of product from step a) above, (42 mmol, 1 eq.) with 6.6 g of potassium permanganate (42 mmol, 1 eq.) in 200 ml of water is reflux heated for 3 hrs. The mixture is then hot-filtered and the residue is washed with 500 ml of hot water. The combined filtrate is concentrated to 50 ml, the pH is adjusted to 3 with 1N HCl and the solution is reconcentrated. This solution is placed at 4° C. for the crystallization of the product which is filtered and dried. 3.71 g (56percent) of the desired acid is obtained. NMR (1H, CDCl3/DMSO-d6): 7.67 (d, J=4.8 Hz; 1H), 8.66 (d, J=4.8 Hz; 1H), 8.86 (s; 1H), 14.23 (large; 2H).
Reference：
[1] Patent: US2005/80085, 2005, A1, . Location in patent: Page/Page column 8
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5781 - 5788
2
[ 114077-82-6 ]
[ 189449-41-0 ]
Yield
Reaction Conditions
Operation in experiment
42%
With sodium borohydrid; acetic acid In tetrahydrofuran; methanol
Example 5 4-chloro-3-hydroxymethylpyridine To a solution of 4-chloro-3-pyridyl carboxyaldehyde (140 mg, 1.0 mmol) in THF (1 mL) at 0° C. was added methanol (1 mL) followed by portionwise addition of sodium borohydride (75 mg, 2.0 mmol). After 1 hr, acetic acid (0.15 ml) was added and the reaction mixture was evaporated to dryness with rotary evaporator at room temperature. The solid residue was chromatographed on silica gel column (1percent MeOH/dichloromethane) to afford 60 mg (42percent) of the title compound. 1H NMR (CDCl3) δ4.30 (br s, 1H), 4.80 (s, 2H), 7.30 (d, 1H, J=5), 8.34 (d, 1H, J=5), 8.62 (s, 1H).
42%
With sodium borohydrid; acetic acid In tetrahydrofuran; methanol
Example 5 4-chloro-3-hydroxymethylpyridine To a solution of 4-chloro-3-pyridyl carboxyaldehyde (140 mg, 1.0 mmol) in THF (1 mL) at 0° C. was added methanol (1mL) followed by portionwise addition of sodium borohydride (75 mg, 2.0 mmol). After 1 hr, acetic acid (0.15 ml) was added and the reaction mixture was evaporated to dryness with rotary evaporator at room temperature. The solid residue was chromatographed on silica gel column (1percent MeOH/dichloromethane) to afford 60 mg (42percent) of the title compound. 1H NMR (CDCl3) δ4.30 (br s, 1H), 4.80 (s, 2H), 7.30 (d, 1H, J=5), 8.34 (d, 1H, J=5), 8.62 (s, 1H).
42%
With sodium borohydrid; acetic acid In tetrahydrofuran; methanol
Example 5 4-chloro-3-hydroxymethylpyridine To a solution of 4-chloro-3-pyridyl carboxyaldehyde (140 mg, 1.0 mmol) in THF (1 mL) at 0° C. was added methanol (1 mL) followed by portionwise addition of sodium borohydride (75 mg, 2.0 mmol). After 1 hr, acetic acid (0.15 ml) was added and the reaction mixture was evaporated to dryness with rotary evaporator at room temperature. The solid residue was chromatographed on silica gel column (1percent MeOH/dichloromethane) to afford 60 mg (42percent) of the title compound. 1H NMR (CDCl3) δ 4.30 (br s, 1H), 4.80 (s, 2H), 7.30 (d, 1H, J=5), 8.34 (d, 1H, J=5), 8.62 (s, 1H).
42 %
With sodium borohydrid; acetic acid In tetrahydrofuran; methanol
Example 5 4-chloro-3-hydroxymethylpyridine To a solution of 4-chloro-3-pyridyl carboxyaldehyde (140 mg, 1.0 mmol) in THF (1 mL) at 0 °C was added methanol (1mL) followed by portionwise addition of sodium borohydride (75 mg, 2.0 mmol). After 1 hr, acetic acid (0.15 ml) was added and the reaction mixture was evaporated to dryness with rotary evaporator at room temperature. The solid residue was chromatographed on silica gel column (1percent MeOH / dichloromethane) to afford 60 mg (42 percent) of the title compound. 1H NMR (CDCl3) δ 4.30 (br s, 1H), 4.80 (s, 2H), 7.30 (d, 1H, J=5), 8.34 (d, 1H, J=5), 8.62 (s, 1H).
Reference：
[1] Synthesis, 1999, # 8, p. 1294 - 1296
[2] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 20, p. 5841 - 5863
[3] Tetrahedron, 2006, vol. 62, # 10, p. 2240 - 2246
[4] Journal of Medicinal Chemistry, 2002, vol. 45, # 13, p. 2832 - 2840
[5] Patent: US6025352, 2000, A,
[6] Patent: US6030965, 2000, A,
[7] Patent: US6057312, 2000, A,
[8] Patent: US6066630, 2000, A,
[9] Patent: US6087355, 2000, A,
[10] Patent: US5859256, 1999, A,
[11] Patent: EP1059293, 2000, A1,
[12] Synlett, 2013, vol. 24, # 1, p. 49 - 52
[13] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5781 - 5788
3
[ 124-41-4 ]
[ 114077-82-6 ]
[ 82257-15-6 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1988, vol. 25, p. 81 - 87
4
[ 626-61-9 ]
[ 68-12-2 ]
[ 114077-82-6 ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at 20℃;
[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) - 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).
70%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; Inert atmosphere
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).
28%
With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 20℃; for 16 h;
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).
Reference：
[1] Patent: EP1348706, 2003, A1, . Location in patent: Page/Page column 37
[2] Patent: US2011/53975, 2011, A1, . Location in patent: Page/Page column 60
[3] Journal of the American Chemical Society, 2013, vol. 135, # 40, p. 14916 - 14919
[4] Patent: WO2018/152329, 2018, A1, . Location in patent: Page/Page column 44
[5] Patent: WO2004/41806, 2004, A2, . Location in patent: Page 88-89
[6] Synthesis, 1999, # 8, p. 1294 - 1296
[7] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 20, p. 3521 - 3525
[8] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 20, p. 5841 - 5863
[9] Journal of Medicinal Chemistry, 2002, vol. 45, # 13, p. 2832 - 2840
[10] Patent: WO2009/87238, 2009, A2, . Location in patent: Page/Page column 97-98
5
[ 626-61-9 ]
[ 109-94-4 ]
[ 114077-82-6 ]
Yield
Reaction Conditions
Operation in experiment
73%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -60 - 0℃; for 0.75 h; Stage #2: at -90 - -60℃;
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 Na2SO4 and the solvent is evaporated. 5.91 g (73percent) of formylated product is obtained. NMR (1H, CDCl3/DMSO-d6): 7.46 (d, J=5.6 Hz; 1H), 8.69 (d, J=5.6 Hz; 1H), 9.05 (s; 1H), 10.51 (s; 1H).
Reference：
[1] Patent: US2005/80085, 2005, A1, . Location in patent: Page/Page column 8
[2] Journal of Heterocyclic Chemistry, 1988, vol. 25, p. 81 - 87
6
[ 7379-35-3 ]
[ 68-12-2 ]
[ 114077-82-6 ]
Yield
Reaction Conditions
Operation in experiment
65%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran Stage #2: at 20℃;
Example 18; Preparation of ter?-butyl-2-((4-mercaptopyridin-3-yl)methylthio)ethyl carbamate; ), DMF ) c H3OH h; Step 1 : LDA (0.11 mmol) was added to 4-chloropyridine 1 (15 g, 0.1 mol) in THF (250 mL) dropwise at -6O0C and stirred at this temperature for 1 hr. Then, DMF (9.3 mL, 0.12 mol) was added and stirred at rt overnight. The product was extracted with ethyl acetate from water. The combined organic layer was dried(Na2SO4), filtered and concentrated. The residue was purified by column chromatography (PE:EA = 10:1) to afford 4.6 g white solid, yield 65percent. 1H NMR (400 MHz, CDCl3):10.51 (s, IH), 9.05 (s, IH), 8.08 (d, IH), 7.45 (d, IH).
65%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Stage #2: at 20℃;
Step 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(Na2SCU), filtered and concentrated. The residue was purified by column <n="90"/>chromatography (P.E/EA 10:1) to afford 4.6 g white solid, yield 65percent. 1HNMR (400MHz, CDCl3): 10.51 (s, 1H), 9.05 (s, 1H), 8.08 (d, 1H), 7.45 (d, 1H).
36%
Stage #1: With sodium hydrogencarbonate In diethyl ether for 1 h; Stage #2: With lithium diisopropyl amide In tetrahydrofuran at -78 - -40℃; for 1 h; Stage #3: at -78 - 20℃; for 18 h;
Saturated 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).
With manganese(IV) oxide In ethyl acetate for 4 h; Reflux
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 solid
With diisopropylamine In tetrahydrofuran; sodium hydrogencarbonate
EXAMPLE 21 N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]thieno[3,2-c]pyridine-2-carboxamide Dihydrochloride Preparation of the Acid: 4-Chloropyridine hydrochloride (15 g, 99.9 mmol) is free-based by stirring in 1000 mL 1:1 saturated NaHCO3/ether for 1 h. The layers are allowed to separate, the aqueous layer is extracted with ether (2*175 mL), and the combined organic layer is dried over MgSO4, filtered, and concentrated to an oil. THF (300 mL) is chilled to -70° C. in a dry flask. N-butyllithium (105.1 mL, 168.2 mmol) is added drop-wise, and the mixture is placed in an ice bath. Diisopropylamine (23.6 mL. 168.4 mmol) in THF (50 mL) is added drop-wise, the yellow solution is stirred for 30 min, and the reaction is cooled to -70° C. The free-based 4-chloropyridine oil (9.55 g, 84.1 mmol) is dissolved in THF (50 mL) and added drop-wise to the chilled yellow solution, that turned dark red after the addition. The reaction is stirred at -70° C. for 2 h. Ethyl formate (13.6 mL, 168.3 mmol) in THF (25 mL) is then added drop-wise to the dark solution at -70° C. After 2 hours, the reaction is warmed to -10° C. and quenched with water (450 mL). The layers are allowed to separate, and the aqueous layer is extracted with ether (3*200 mL). The combined organic layer is dried over MgSO4, filtered, and concentrated in vacuo to an oil. The crude material is chromatographed over 320 g slurry-packed silica eluding with 30percent EtOAc/hexane. The fractions with the desired compound are collected and concentrated to an orange oil which solidified under vacuum, affording 4-chloropyridine-3-carboxaldehyde (C140) as an orange solid (21percent yield).
Reference：
[1] Patent: US2003/45540, 2003, A1,
10
[ 626-61-9 ]
[ 7379-35-3 ]
[ 114077-82-6 ]
Reference：
[1] Patent: US2002/193596, 2002, A1,
11
[ 626-61-9 ]
[ 2591-86-8 ]
[ 114077-82-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 3, p. 662 - 667
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 Na2SO4 and the solvent is evaporated. 5.91 g (73%) of formylated product is obtained. NMR (1H, CDCl3/DMSO-d6): 7.46 (d, J=5.6 Hz; 1H), 8.69 (d, J=5.6 Hz; 1H), 9.05 (s; 1H), 10.51 (s; 1H).
With hydrogenchloride; dihydrogen peroxide; In water; for 6h;Heating;
Following the procedure described in MARSAIS et al. (J. Het. Chem., vol. 25, p. 81-87, 1988), compound 2 is heated for 6 h in an aqueous solution of 3 N HCl containing several drops of 3% H2O2, in order to obtain 4-hydroxypyridine-3-carboxaldehyde 4 as a colorless solid (>80%) .
> 80%
With hydrogenchloride; dihydrogen peroxide; In water; for 6h;
Following the procedure described in MARSAIS et al. (J. Het. Chem., vol. 25, p. 81-87, 1988), compound 2 is heated for 6 h in an aqueous solution of 3 N HCl containing several drops of 3% H2O2, in order to obtain 4-hydroxypyridine-3-carboxaldehyde 4 as a colorless solid (>80%).
With palladium diacetate; potassium carbonate; triphenylphosphine; In 1,2-dimethoxyethane; water; at 85℃; for 18h;
3-formyl-4-(4-trifluorophenyl)benzonitrile In a 50 mL pear flask, magnetic stirrer, <strong>[114077-82-6]4-chloronicotinaldehyde</strong> (500 mg, 3.53 mmol), 4-trifluoromethyl)phenylboronic acid (671 mg, 3.53 mmol), triphenylphosphine (55.6 mg, 0.212 mmol), palladium(II) acetate (47.6 mg, 0.212 mmol) and potassium carbonate (976 mg, 7.06 mmol) were added successively followed by 1,2-dimethoxyethane (10 mL) and water (2.5 mL). The reaction mixture was stirred and heated at 85C for 18 hours (LC/MS showed no starting material). 20 mL of water and 20 mL of ethyl acetate were added. The mixture was filtered over Celite and the cake rinsed with 20 mL of ethyl acetate. Organic phases were washed twice with brine, dried over sodium sulfate, filtered and the solvent was removed to give 890 mg of an oil. The crude oil was purified by flash chromatography on Si02, eluted with 100% dichloromethane then 95/5 dichloromethane/acetone to give 370 mg of a grey solid (Yield: 42%) APCI-MS: (M+H)+ =252 1H NMR (300 MHz, DMSO-d6) delta ppm: 10.00 (s, 1H), 9.08 (s, 1H), 8.90 (d, / = 5.1 Hz, 1H), 7.92 (d, / = 8.1 Hz, 2H), 7.78 (d, / = 8.0 Hz, 2H), 7.61 (dd, / = 5.1, 0.6 Hz, 1H)
Example 18; Preparation of ter?-butyl-2-((4-mercaptopyridin-3-yl)methylthio)ethyl carbamate; ), DMF ) c H3OH h; Step 1 : LDA (0.11 mmol) was added to 4-chloropyridine 1 (15 g, 0.1 mol) in THF (250 mL) dropwise at -6O0C and stirred at this temperature for 1 hr. Then, DMF (9.3 mL, 0.12 mol) was added and stirred at rt overnight. The product was extracted with ethyl acetate from water. The combined organic layer was dried(Na2SO4), filtered and concentrated. The residue was purified by column chromatography (PE:EA = 10:1) to afford 4.6 g white solid, yield 65%. 1H NMR (400 MHz, CDCl3):10.51 (s, IH), 9.05 (s, IH), 8.08 (d, IH), 7.45 (d, IH).
65%
Step 1: LDA (0.11 mmol) was added to 4-chloropyridine 1 (15 g, 0.1 mol) in THF (250 mL) dropwise at -60C 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(Na2SCU), filtered and concentrated. The residue was purified by column <n="90"/>chromatography (P.E/EA 10:1) to afford 4.6 g white solid, yield 65%. 1HNMR (400MHz, CDCl3): 10.51 (s, 1H), 9.05 (s, 1H), 8.08 (d, 1H), 7.45 (d, 1H).
36%
Saturated 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 (30% EtOAc/hexanes) to afford the title compound as a yellow tinted oil which crystalized to clear needles under argon (1.6 g, 36% 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).
The title compound can be prepared starting from 4-chloropyridine hydrochloride by published methods (Bioorg. Med. Chem. Lett. 17 (2007), 662-667).
(S)-2-[(5-{(E)-2-[4-(3,5-Difluoro-benzyloxy)-pyridin-3-yl]-vinyl}-2'-methyl-biphenyl-2-carbonyl)-amino]-4-methylsulfanyl-butyric acid methyl ester[ No CAS ]
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 50℃; for 1.5h;
4-Chloronicotinaldehyde [prepared according to D. Albanese, M. Penso, M. Zenoni, Synthesis 1999,1294-1296] (500 mg, 3.5 mmol), 4-methylsulfanyl-benzenethiol (606 mg, 3.88 mmol) potassium carbonate (586 mg, 4.24 mmol) and DMF (7 mL) were combined, the mixture was heated together at 50C for 1.5 h and then stirred at room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and 10% aqueous K2CO3 (100 mL). The organic layer was dried (MgS04) and evaporated to give the title compound (1.05 g) as a yellow oil. The'H NMR spectrum showed the material to be of sufficient purity (90-95%) to be used without further purification; delta H (CDCl3, 400 MHz) 2.54 (3H, s), 6.69 (1 H, d), 7.35 (2H, d), 7.47 (2H, d), 8.35 (1 H, d), 8.87 (1 H, s), 10.24 (1 H, s); MS m/z (TS+) 262 (MH+).
To a solution of NaSMe (9.5 g, 135 rnmol) in MeOH (250 mL) was added the <strong>[114077-82-6]4-chloronicotinaldehyde</strong> (13.5 g, 94.4 rnmol) of Step 1 in MeOH (250 mL). The reaction mixture was maintained at 60C. for 15 min. The reaction mixture was poured over NH4Cl and EtOAc.The organic phase was separated, washed with H2O and dried over Na2SO4. The compound was then purified over silica gel with 50% EtOAc in Hexanes to provide the title compound.
In methanol; at 60℃; for 0.25h;
Step 2 4-(Methylthio)nicotinaldehydeTo a solution of NaSMe (9.5 g, 135 mmol) in MeOH (250 mL) was added the 4- chloronicotinaldehyde (13.5 g, 94.4 mmol) of Step 1 in MeOH (250 mL). The reaction mixture was maintained at 600C for 15 min. The reaction mixture was poured over NH4CI and EtOAc. The organic phase was separated, washed with H2O and dried over Na2SO4. The compound was then purified over silica gel with 50% EtOAc in Hexanes to provide the title compound
In methanol; at 60℃; for 0.25h;
To a solution of NaSMe (9.5 g, 135 mmol) in MeOH (250 mL) was added the 4- chloronicotinaldehyde (13.5 g, 94.4 mmol) of Step 1 in MeOH (250 mL). The reaction mixture was maintained at 6O0C for 15 min. The reaction mixture was poured over NH4CI and EtOAc. The organic phase was separated, washed with H2O and dried over Na2SOphi The compound was then purified over silica gel with 50% EtOAc in Hexanes to provide the title compound.
In methanol; at 60℃; for 0.25h;
Step 2; 4-(Methylthio)nicotmaldehvde To a solution of NaSMe (9.5 g, 135 mmol) in MeOH (250 mL) was added the 4- chloronicotinaldehyde (13.5 g, 94.4 mmol) of Step 1 in MeOH (250 mL). The reaction mixture was maintained at 600C for 15 min. The reaction mixture was poured over NH4CI and EtOAc. The organic phase was separated, washed with H2O and dried over Na2SO4. The compound was then purified over silica gel with 50% EtOAc in Hexanes to provide the title compound.
In methanol; at 60℃; for 0.25h;
To a solution of NaSMe (9.5 g, 135 mmol) in MeOH (250 mL) was added the <strong>[114077-82-6]4-chloronicotinaldehyde</strong> (13.5 g, 94.4 mmol) of Step 1 in MeOH (250 mL). The reaction mixture was maintained at 60 C. for 15 min. The reaction mixture was poured over NH4Cl and EtOAc. The organic phase was separated, washed with H2O and dried over Na2SO4. The compound was then purified over silica gel with 50% EtOAc in Hexanes to provide the title compound.
In methanol; at 60℃; for 0.25h;
To a solution of NaSMe (9.5 g, 135 mmol) in MeOH (250 mL) was added the A- chloronicotinaldehyde (13.5 g, 94.4 mmol) of Step 1 in MeOH (250 mL). The reaction mixture was maintained at 600C for 15 min. The reaction mixture was poured over NH4CI and EtOAc. The organic phase was separated, washed with H2O and dried over Na2SO4. The compound was then purified over silica gel with 50% EtOAc in Hexanes to provide the title compound.
In methanol; at 60℃; for 0.25h;
Step 2 4-(Methylthio)nicotinaldehyde To a solution of NaSMe (9.5 g, 135 mmol) in MeOH (250 mL) was added the 4- chloronicotinaldehyde (13.5 g, 94.4 mmol) of Step 1 in MeOH (250 mL). The reaction mixture was maintained at 600C for 15 min. The reaction mixture was poured over NH4CI and EtOAc. The organic phase was separated, washed with H2O and dried over Na2SO4. The compound was then purified over silica gel with 50% EtOAc in Hexanes to provide the title compound
A solution of 4-{N-[7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1- yl) hept-1-yl]-N-(isopropyl)amino}piperidine (0.56 g, 1.085 mmol) and 4-chloropyridine- 3-carboxaldehyde (169 mg, 1.19 mmol) in 1,2-dichloroethane (11 ML, 0.1 M) was stirred at room temperature for 2 h. Acetic acid (75 muL, 1.30 mmol) was added and then sodium triacetoxyborohydride (299 mg, 1.41 mmol) was added. After 64 h, the reaction was quenched by adding aqueous 10% sodium carbonate (10 mL). The layers were separated and the aqueous layer was made basic by adding aqueous 1N sodium hydroxide until the pH was about 13 to 14. The aqueous layer was then extracted with dichloromethane (2 x 15 mL) and the organic layers were combined, dried over sodium sulfate, filtered and the solvent was removed in vacuo. The resulting residue (a yellow oil) was purified by silica gel chromatography (using CH2CL2/CH3OH/AQUEOUS NH40H = 84/15/1) to afford 0.46 g of the title intermediate as a very light yellow thick oil (Rf= 0.2 ; 66 % yield). Analytical Date: LCMS m/z 644.3 (expected 644.34 for C39H54CIN5O).
With potassium permanganate; In water; for 3h;Heating / reflux;
A mixture of the 5.9 g of product from step a) above, (42 mmol, 1 eq.) with 6.6 g of potassium permanganate (42 mmol, 1 eq.) in 200 ml of water is reflux heated for 3 hrs. The mixture is then hot-filtered and the residue is washed with 500 ml of hot water. The combined filtrate is concentrated to 50 ml, the pH is adjusted to 3 with 1N HCl and the solution is reconcentrated. This solution is placed at 4 C. for the crystallization of the product which is filtered and dried. 3.71 g (56%) of the desired acid is obtained. NMR (1H, CDCl3/DMSO-d6): 7.67 (d, J=4.8 Hz; 1H), 8.66 (d, J=4.8 Hz; 1H), 8.86 (s; 1H), 14.23 (large; 2H).
General procedure: Preparatio example 411·' 3-chloroi son i cot inaldehyde To a 250 ml round-bottomed flask, LDA (11ml, 22.02mmol) was added to 3- chloropyr icli edg, 8.80mmol) in THF(20 ml) dropwise at -78 C and stirred at same temperature for l~2hr. Then DMF(822//.P, , 10.56mmol )was added and stirred at room temperature for Ihr. EA (Ethyl acetate) and water were added to the reaction mixture, and after the separation of the layers, the aqueous phase was further extracted with the organic solvent. The combined organic extracts were dried over anhydrous Sodium sulfate (Na2S04), filtered and concentrated under vacuum. The crude compound was purified by. a silica gel column, to produce the title compound (0.33g, 30~65%) NMR (400MHz, CDC 13 ) delta 7.73 (d, J = 8.0, 1H) 8.71 (cl, J = 4.0, 1H) 8.81 (s, 1H) 10.52 (s, 1H)
a 4-Chloro-3-formyl-pyridine In a flame-dried 3-necked 100 ml r.b. flask fitted with internal thermometer was prepared LDA at -78 using diisopropyl amine (2.8 ml, 19.9 mmol) and 2.5 M n-BuLi (8.32 ml, 20.8 mmol) in dry THF (15 ml). After stirring for 20 min, 4-chloropyridine (2.26 g, 19.9 mmol) in THF (5 ml) was added via a syringe pump at 0.15 ml/min over about 30 min. The mixture was stirred for 1 h, then dry DMF (4.8 ml, 62 mmol) was added via a syringe pump so that the temperature remained at -78. After complete addition, the mixture was stirred 30 min then allowed to warm to -40 and hydrolyzed with 5% NaHCO3. The mixture was extracted twice with t-butyl methyl ether and washed with 5% NaHCO3, brine, dried (MgSO4), and concentrated. Chromatography (flash silica gel, 1:1 t-butyl methyl ether/hexanes) afforded the title compound as a white solid. (1.55 g, 55%).
EXAMPLE 4 STR14 a) 4-Chloro-3-formyl-pyridine In a flame-dried 3-necked 100 ml r.b. flask fitted with internal thermometer was prepared LDA at -78 using diisopropyl amine (2.8 ml, 19.9 mmol) and 2.5 M n-BuLi (8.32 ml, 20.8 mmol) in dry THF (15 ml). After stirring for min, 4-chloropyridine (2.26 g, 19.9 mmol) in THF (5 ml) was added via a syringe pump at 0.15 ml/min over about 30 min. The mixture was stirred for 1 h, then dry DMF (4.8 ml, 62 mmol) was added via a syringe pump so that the temperature remained at -78. After complete addition, the mixture was stirred 30 min then allowed to warm to -40 and hydrolyzed with 5% NaHCO3. The mixture was extracted twice with t-butyl methyl ether and washed with 5% NaHCO3, brine, dnred (MgSO4), and concentrated. Chromatography (flash silica gel, 1:1 t-butyl methyl ether/hexanes) afforded the title compound as a white solid. (1.55 g, 55%).
54
[ 114077-82-6 ]
[ 947371-37-1 ]
Yield
Reaction Conditions
Operation in experiment
With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃;
Step B; 4-Chloro-3-difluoromethylpyridine; To a solution of <strong>[114077-82-6]4-chloro-3-pyridinecarboxaldehyde</strong> (3.7 g, 26 mmol) in 15 mL of dichloromethane at -78was added (dimethylamino)sulfur trifluoride (15 mL, 0.15 mol), and the reaction was allowed to warm up to room temperature overnight. The reaction was quenched by carefully transferring into a mixture of ice (100 g) and sodium sulfite (10 g). The product was extracted with ether (100 mL x 2), and the combined extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluting with 0 to 10% ether in hexane to give the title compound. *H NMR (500 MHz, CD3OD): delta 8.59 (s, IH), 7.84 (d, IH), 7.48 (d, IH), 6.74 (t, IH).
4-Chloro-pyridine-3-carbaldehyde (10.0 g, 71 mmol) was dissolved in EtOH (12 ml). H2O (30 ml), ice (30 g) and hydroxylamine hydrochloride (5.40 g, 78 mmol) were added. To the resulting mixture was added over a period of 2 min a solution of 2 N NaOH (88.3 ml, 177 mmol). The resulting yellowish solution was stirred 2.5 h at r.t. before neutralisation with AcOH (pH=6). White crystals precipitated, were collected by filtration and washed with H2O (30 ml). The product was dried 1 h at 50 C. on the high vacuum to yield 9.25 g (84%) of a off white solid. m/z=157.1 ([M-H]-).
With hydroxylamine hydrochloride; sodium acetate; In methanol; at 20℃; for 2h;
Reference Example 10 4-chloronicotinonitrile (20) The compound (19) (27.0 g, 0.19 mol), hydroxylamine hydrochloride (13.01 g, 0.19 mol) and sodium acetate (15.6 g, 0.19 mol) were suspended in methanol (100 ml) and the mixture was stirred at room temperature for 2 hrs. The solvent was evaporated and the residue was dissolved in chloroform (100 ml). Phosphorus oxychloride (125 g) was added and the mixture was heated under reflux for 3 hrs. The solvent was evaporated and the residue was added to water (200 ml), which was adjusted to pH=7 with sodium carbonate. The mixture was extracted with ethyl acetate (200 ml x 2) and the organic layer was dried (MgSO4). The solvent was evaporated under reduced pressure to give the title compound (18 g, 68%). 1H-NMR (200Hz, CDCl3) delta: 7.52 (1H, d, J = 5.0 Hz), 8.72 (1H, d, J = 5.0Hz), 8.87 (1H, s).
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]thieno[3,2-c]pyridine-2-carboxamide Dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium carbonate; In water; N,N-dimethyl-formamide;
C140 (2.53 g, 17.9 mmol) is dissolved in DMF (20 mL) and water (2 mL). K2CO3 (2.97 g, 21.5 mmol) and methyl thioglycolate (1.92 mL, 21.5 mmol) are added portionwise. The reaction is stirred at 45 C. for 24 h, then quenched with cold water (100 mL), and the flask is placed on ice to enhance precipitation. The precipitate is isolated by filtration and dried, affording methyl thieno[3,2-c]pyridine-2-carboxylate (C141) as a white solid (92% yield). MS (EI) for C9H7NO2S, m/z: 193 (M)+.
With diisopropylamine; In tetrahydrofuran; sodium hydrogencarbonate;
EXAMPLE 21 N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]thieno[3,2-c]pyridine-2-carboxamide Dihydrochloride Preparation of the Acid: 4-Chloropyridine hydrochloride (15 g, 99.9 mmol) is free-based by stirring in 1000 mL 1:1 saturated NaHCO3/ether for 1 h. The layers are allowed to separate, the aqueous layer is extracted with ether (2*175 mL), and the combined organic layer is dried over MgSO4, filtered, and concentrated to an oil. THF (300 mL) is chilled to -70 C. in a dry flask. N-butyllithium (105.1 mL, 168.2 mmol) is added drop-wise, and the mixture is placed in an ice bath. Diisopropylamine (23.6 mL. 168.4 mmol) in THF (50 mL) is added drop-wise, the yellow solution is stirred for 30 min, and the reaction is cooled to -70 C. The free-based 4-chloropyridine oil (9.55 g, 84.1 mmol) is dissolved in THF (50 mL) and added drop-wise to the chilled yellow solution, that turned dark red after the addition. The reaction is stirred at -70 C. for 2 h. Ethyl formate (13.6 mL, 168.3 mmol) in THF (25 mL) is then added drop-wise to the dark solution at -70 C. After 2 hours, the reaction is warmed to -10 C. and quenched with water (450 mL). The layers are allowed to separate, and the aqueous layer is extracted with ether (3*200 mL). The combined organic layer is dried over MgSO4, filtered, and concentrated in vacuo to an oil. The crude material is chromatographed over 320 g slurry-packed silica eluding with 30% EtOAc/hexane. The fractions with the desired compound are collected and concentrated to an orange oil which solidified under vacuum, affording 4-chloropyridine-3-carboxaldehyde (C140) as an orange solid (21% yield).
With diisopropylamine; In tetrahydrofuran; dichloromethane; sodium hydrogencarbonate; ethyl acetate;
4-Chloropyridine-3-carboxaldehyde 4-Chloropyridine (3.1 g, 27.3 mmol, after drying over Na2SO4) was extracted from a mixture of 4-chloropyridine hydrochloride in 5% NaHCO3 with methylene chloride, dissolved in THF (50 mL), and cooled to -78 C. under dry nitrogen, followed by addition of LDA (1.5 in cylclohexane, 18.2 mL). After 4 hours at -78 C., excess ethyl formate was added quickly. After 3 hours at -78 C., the reaction was allowed to warm to ambient temperature overnight. The reaction was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, chromatographed (20% EtOAc in hexanes), and dried under high vacuum to give 1.47 g of the aldehyde. MS m/e 142 (M+H)+. 1H NMR (CDCl3, 300 MHz) delta 7.44 (d, 1H, J=6 Hz), 8.69 (d, 1H, J=6 Hz), 9.06 (s, 1H), 10.51 (s, 1H).
3-[[4-(pyrrolidin-1-yl)pyridin-3-yl]methylidene]-1-pyrroline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; dichloromethane;
(i) A mixture of <strong>[114077-82-6]4-chloropyridine-3-carboxaldehyde</strong> (10 g, prepared according to the method described in J. Het. Chem, 25, 81), pyrrolidine (25 ml) and ethanol (100 ml) was heated under reflux for 5 hours, then concentrated. The residue was purified by flash column chromatography (grade II alumina) eluding first with dichloromethane and then with methanol/dichloromethane (1:200) to give 3-[[4-(pyrrolidin-1-yl)pyridin-3-yl]methylidene]-1-pyrroline (900 mg) as a white solid. NMR (d6 DMSO): delta 1.8(4H,m); 2.5(2H,m); 3.3(4H,m); 3.95(2H,m); 6.6(1H,d); 7.0(1H,t), 7.9(1H,t), 8.0(1H,d); 8.15(1H,s); m/e 228(M+H)+; calculated for C14 H17 N3: C, 74.0; H, 7.5; N, 18.5; found C, 74.1; H, 7.7; N, 18.4%.
Step 2 4-(Methylthio)nicotinaldehyde To a solution of NaSMe (9.5 g, 135 mmol) in MeOH (250 mL) was added the <strong>[114077-82-6]4-chloronicotinaldehyde</strong> (13.5 g, 94.4 mmol) of Step 1 in MeOH (250 mL). The reaction mixture was maintained at 60 C. for 15 min. The reaction mixture was poured over NH4Cl and EtOAc. The organic phase was separated, washed with H2O and dried over Na2SO4. The compound was then purified over silica gel with 50% EtOAc in Hexanes to provide the title compound.
Step A: 1 ,1-Dimethylethyl(4-r(3-formyl-4-pyridinyl)oxyiphenyl)carbamate; 4-Chloro-3-pyridinecarbaldehyde was prepared 4-chloropyridine (commercially available, for example, from Sigma-AIdrich) according to Synthesis 1999, delta, 1294. A mixture of 4-chloro-3-pyridinecarbaldehyde (680 mg, 4.8 mmol), 1 ,1-dimethylethyl-(4- hydroxyphenyl)carbamate (commercially available, for example, from Sigma-AIdrich) (1 g, 4.8 mmol) and potassium carbonate (1.28 g, 9.4 mmol) in N, N- dimethylformamide was stirred at 80 0C for 1 h. After cooling to room temperature, aqueous ammonium chloride solution was added, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting solid was collected by filtration, washed with dichloromethaneiota and dried in vacuo to give the title compound (1.4 g, 93 %). 1H NMR (400 MHz, DMSO-cf6) ppm 1.49 (s, 9H), 6.71 (d, 1 H, J = 5.8 Hz), 7.17-7.23 (m, 2H), 7.56-7.62 (m, 2H), 8.58 (d, 1 H, J = 5.8 Hz), 8.85 (s, 1 H), 9.54 (br, 1 H), 10.47 (s, 1 H).
5.1.102 EXAMPLE 102 : SYNTHESIS OF 2-(4-CHLOROPYRIDIN- 3-YL)-8-OXO-9-(2-(TRIFLUOROMETHYL)PHENYL)-8,9-DIHYDRO-7H-PURINE-6-CARBOXAMIDE; [00455] A. 2-(4-Chloropyridin-3-yI)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9- dihydro-7H-purine-6-carboxamide. (Z)-l-(2-Amino-l,2-dicyanovinyl)-3-(2- (trifluoromethyl)phenyl)urea {See Example 50.A) (0.15 g, 0.51 mmol), 4- chloronicotinaldehyde (0.14 g, 0.99 mmol), and triethylamine (0.10 ml, 0.72 mmol) were combined in ethanol (7.0 mL) and stirred at room temperature overnight. Excess solvent was removed under reduced pressure and the resulting residue was purified by silica gel EPO <DP n="143"/>Biotage chromatography (0-20% methanol in dichloromethane). Clean fractions were combined and solvent removed under reduced pressure. The resulting material was dried under house vacuum to provide the product as an off white solid (0.075 g, 0.17 mmol, 34% yield). 1H NMR (400 MHz, DMSO-betafc) delta 12.1 1 (s, IH), 8.93 (s, IH), 8.56 (d, J=5.3, IH), 8.25 (bs, IH), 8.06 (bs, IH), 8.01 (d, J= 7.8, IH), 7.93 (m, IH), 7.82 (m, 2H), 7.61 (d, J=J. 73, IH); MS (ESI) m/z 435.0 [M+l]+; mp 244-248 C (dec).
With potassium carbonate; In N,N-dimethyl-formamide; for 12h;Product distribution / selectivity;
Step 2: The mixture of <strong>[114077-82-6]4-chloronicotinaldehyde</strong> 2 (4.6 g, 32.6 mmol), 2- methyl-2-propanethiol (4.4 mL, 32.6 mmol), K2CO3 (9.0 g, 65.2 mmol) and DMF (70 mL) was stirred at 1000C for 12 hrs until TLC indicate no <strong>[114077-82-6]4-chloronicotinaldehyde</strong> was existed. The reaction mixture was diluted with water, extracted with ethyl acetate and the organic layer was concentrated. The residue was purified by column chromatography (PE:EA = 12:1) to afford 6.3 g clear oil, yield 99%. 1H NMR (400 MHz, CDCl3): 10.63 (s, IH), 9.03 (s, IH), 8.65 (d, IH), 7.50 (d, IH), 1.40 (s, 9H).
99%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
Step 2: The mixture of <strong>[114077-82-6]4-chloronicotinaldehyde</strong> 2 (4.6 g, 32.6 mmol), 2- methyl-2-propanethiol (4.4 mL, 32.6 mmol), K2CO3 (9.0 g, 65.2 mmol) and DMF (70 mL) was stirred at 100C for 12 h until TLC indicate no <strong>[114077-82-6]4-chloronicotinaldehyde</strong> was existed. The reaction mixture was diluted with water, extracted with EA and the organic layer was concentrated. The residue was purified by column chromatography (P.E/EA 12: 1) to afford 6.3 g clear oil, yield 99%. 1HNMR (400 MHz, CDCl3): 10.63 (s, 1H), 9.03 (s, 1H), 8.65 (d, 1H), 7.50 (d, 1H), 1.40 (s, 9H).
(2E)-ethyl 3-(4-chloropyridin-3-yl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
Triethyl phosphonoacetate (0.075 ml, 0.00038 mol) was added dropwise to a mixture of sodium hydride (10.6 mg, 0.00044 mol) in THF (5 ml) at room temperature under argon. The mixture was stirred at room temperature for 20 minutes, then a solution of <strong>[114077-82-6]4-chloro-3-pyridinecarboxaldehyde</strong> (50 mg, 0.00035 mol) in THF (3 ml) was added dropwise. The mixture was stirred at room temperature for 16 hours, then poured out into water and extracted twice with EtOAc. The organic layer was separated, washed EPO <DP n="55"/>with brine, dried (MgSO4), filtered, and the solvent was evaporated, yielding 77 mg (88%) of intermediate 43
86%
A solution of ethyl 2-(diethoxyphosphoryl)acetate (10.0 mL, 50.40 mmol) in THF (10 mL) was added dropwise over a few min to a suspension of NaH (60% dispersion in oil, 1.84 g, 45.9 mmol) in THF (40 mL) at 0 C, and stirring continued at 0 C for 60 min. To this solution was then added a solution of <strong>[114077-82-6]4-chloronicotinaldehyde</strong> (5, 5.06 g, 35.7 mmol) in DMF (35 mL) dropwise over 10 min at 0 C. The resulting solution was stirred at rt for 4 h. The reaction was concentrated under vacuum, and water (50 mL) and EtOAc (50 mL) added. The layers were separated, and the aqueous layer extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (2 × 50 mL) and brine (2 × 50 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 5-40% EtOAc/hexane) to yield 6 (6.47 g, 86%) as a white solid. 1H NMR (300 MHz, DMSO-d6) delta 1.28 (3H, t, J = 7.1 Hz), 4.23 (2H, q, J = 7.1 Hz), 6.90 (1H, d, J = 16.2 Hz), 7.65 (1H, d, J = 5.4 Hz), 7.82 (1H, d, J = 16.2 Hz), 8.55 (1H, d, J = 5.4 Hz), 9.09 (1H, s). MS (API): m/z 211.9 (M + H)+.
6.47 g
To a mixture of 60% sodium hydride (1.836 g) and THF (40 mL), a solution of ethyl 2-(diethoxyphosphoryl)acetate (10 mL) in THF (10 mL) was added with ice cooling under nitrogen atmosphere, and the resulting mixture was stirred at the same temperature for 1 hour. A mixture of <strong>[114077-82-6]4-chloronicotinaldehyde</strong> (5.056 g) and DMF (35 mL) was added dropwise to the reaction mixture under ice cooling, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, then water (50 mL) and ethyl acetate (50 mL) were added to the residue at room temperature, and the aqueous layer was extracted with ethyl acetate. The extract was washed with water and brine and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (6.47 g). MS: [M+H]+ 211.9.
6.47 g
In a nitrogen atmosphere, Ice cold, In 60% sodium hydride (1.836 g) And THF (40 mL) was added a solution of ethyl 2- (diethoxyphosphoryl) acetate (10 mL) in THF (10 mL) The resulting mixture was stirred at the same temperature for 1 hour. A mixture of <strong>[114077-82-6]4-chloronicotinaldehyde</strong> (5.056 g) and DMF (35 mL) was added dropwise to the reaction mixture under ice-cooling, The resulting mixture was stirred at the same temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, To the residue was added water (50 mL) and ethyl acetate (50 mL) at room temperature, And the aqueous layer was extracted with ethyl acetate. The extract was washed with water and brine, Dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (6.47 g).
Step A; 4-Chloro-3-pyridinecarboxaldehyde; To a solution of 2-chloro-5-iodopyridine (18 g, 75 mmol) in ether (100 mL) and tetrahydrofuran (100 mL) at -78C was added tert-butyllithium (1.7 M in pentane, 60 mL, 100 mmol). After stirring at - 78C for 30 min, DMF (11 mL, 150 mmol) was added, and the reaction was allowed to warm up to 00C over 30 min, and was poured into a stirred mixture of ice (200 g), concentrated hydrochloric acid (20 mL) and ether (200 mL). The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluting with 0 to 10% ether in hexane/dichloromethane (1:1) to give the title compound. 1H NMR (500 MHz, CD3OD): 10.18 (s, IH), 8.90 (s, IH), 8.17 (d, IH), 7.55(d, IH).
With potassium carbonate; In water; N,N-dimethyl-formamide; at 45℃;
To a solution of <strong>[114077-82-6]4-chloropyridine-3-carboxaldehyde</strong> (D-1) (1 .4 g, 10 mmol) dissolved in DMF (10 mL) and water (1 mL) were added K2C03 (1 .66 g, 12 mmol) and methyl thioglycolate (1.07 mL, 12 mmol) portion-wise. The reaction mixture was stirred at 45C overnight and then quenched with cold water. The flask was placed on ice to enhance precipitation. The precipitate was collected by filtration and air-dried to afford the title compound (1.23 g). MS (m/z): 194 (M+1 )
With potassium carbonate; In water; N,N-dimethyl-formamide; at 45℃;
Methyl thieno[3,2-c]pyridine-2-carboxylate (D-2) To a solution of <strong>[114077-82-6]4-chloropyridine-3-carboxaldehyde</strong> (D-1) (1.4 g, 10 mmol) dissolved in DMF (10 mL) and water (1 mL) were added K2CO3 (1.66 g, 12 mmol) and methyl thioglycolate (1.07 mL, 12 mmol) portion-wise. The reaction mixture was stirred at 45 C. overnight and then quenched with cold water. The flask was placed on ice to enhance precipitation. The precipitate was collected by filtration and air-dried to afford the title compound (1.23 g). MS (m/z): 194 (M+1)+.
With triethylamine; In N,N-dimethyl-formamide; at 80℃; for 12h;
Ethyl 2-(5-bromo-2-hydroxyphenyl)acetate (4.29 g, 16.6 mmol) and <strong>[114077-82-6]4-chloronicotinaldehyde</strong> (2.34 g, 16.6 mmol) were diluted with DMF (40 mL), followed by the addition of TEA (2.31 mL, 16.6 mmol; d. 0.726). The reaction was heated to 80C and stirred for 12 hours. The reaction was allowed to cool and diluted with ethyl acetate and water. The layers were separated, and the organics were dried over MgS04, filtered and concentrated. The material was purified on silica gel, eluting with 10-70% ethyl acetate/hexanes to yield ethyl 8-bromobenzo[6,7]oxepino[3,2-c]pyridine-10-carboxylate (1.4 g, 4.04 mmol, 24.4% yield).
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