* 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 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
2
[ 37831-62-2 ]
[ 189449-41-0 ]
Reference：
[1] Journal of Antibiotics, 2000, vol. 53, # 11, p. 1272 - 1281
[2] Patent: US2006/25433, 2006, A1, . Location in patent: Page/Page column 94
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 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) delta4.30 (br s, 1H), 4.80 (s, 2H), 7.30 (d, 1H, J=5), 8.34 (d, 1H, J=5), 8.62 (s, 1H).
60 mg (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) delta4.30 (br s, 1H), 4.80 (s, 2H), 7.30 (d, 1H, J=5), 8.34 (d, 1H, J=5), 8.62 (s, 1H).
60 mg (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) delta 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).
60 mg (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) delta 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).
With lithium aluminium tetrahydride; In diethyl ether; for 1.16667h;
To a solution of 4-chloro-nicotinic acid ethyl ester (1.5 g, 8.1 mmol) in ether (15 mL) was added lithium aluminum hydride (0.31 g, 8.2 mmol) in ether (10 mL) over 10 min while cooling. The reaction mixture was stirred for 1 h and quenched with water (2 mL) and 15percent NaOH (0.5 mL). The reaction mixture was filtered and the residue on the filter was washed with ether. The combined filtrate was dried over anhydrous Na2SO4 and concentrated in vacuo to afford 0.75 g of (4-chloro-pyridin-3-yl)-MeOH as a yellowish solid.
With sodium hydroxide; water; for 24h;Heating / reflux;
To a solution of <strong>[189449-41-0]4-chloro-3-(hydroxymethyl)pyridine</strong> (2.33 g, 16.2 mmol) in water (25 ml) was added sodium hydroxide (5.20 g, 130 mmol), and the mixture was refluxed for 24 hours. After cooling, the reaction mixture was neutralized with concentrated hydrochloric acid and concentrated under reduced pressure. The residue obtained was dissolved into N,N-dimethylformamide (20 ml), then ethyl 3-ethoxy-7-fluoro-6-nitroquinoxaline-2-carboxylate (500 mg, 1.62 mmol) was added, and the mixture was stirred for 4 hours at 110° C. The reaction mixture was poured into ice water, which was extracted with ethyl acetate. After dried over anhydrous sodium sulfate, solvent was distilled off. The residue obtained was purified by means of silica gel column chromatography [ethyl acetate] to obtain 410 mg of the title compound as yellow powder. Yield 61percent. 1H-NMR(CDCl3,delta):1.47(3H,t,J=7.1 Hz),1.54(3H,t,J=7.1 Hz), 4.56(2H,q,J=7.2 Hz),4.59(2H,s),4.68(2H,q,J=7.2 Hz), 6.52(1H,d,J=8.0 Hz),7.41(1H,dd,J=7.3,2.4 Hz),7.45(1H,d,J=2.4 Hz), 8.20(1H,s),8.57(1H,s).
With diphenyl phosphoryl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene; In toluene; at 20℃; for 3h;
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (0.69 mL, 4.5 mmol) was added to a solution of the above (4-chloro-pyridin-3-yl)-MeOH (0.51 g, 3.6 mmol) and diphenylphosphoryl azide (DPPA) (0.92 mL, 4.3 mmol) in toluene (8 mL). The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using 1:4 EtOAc:hexanes to afford 0.47 g (79%) of 3-azidomethyl-4-chloro-pyridine.
3-chloromethyl-4-chloropyridine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
813 mg (84%)
With thionyl chloride; In N,N-dimethyl-formamide;
Example 21 3-chloromethyl-4-chloropyridine hydrochloride Thionyl chloride (0.714 mL, 9.78 mmol) was added at room temperature to dry DMF (7 mL). After 30 min the above solution was cannulated into the solution of <strong>[189449-41-0]3-hydroxymethyl-4-chloropyridine</strong> (700 mg, 4.89 mmol) in DMF (3 mL). After 45 min, the product was precipitated by addition of dry ether (100 ml), washed with ether, and dried in vacuum to yield 813 mg (84percent) of the title compound. 1H NMR (CD3 OD) delta 5.00 (s, 2H), 8.31 (d, 1H, J=S), 8.99 (d, 1H, J=5), 9.18 (s, 1H).
813 mg (84%)
With thionyl chloride; In N,N-dimethyl-formamide;
Example 21 3-chloromethyl-4-chloropyridine hydrochloride Thionyl chloride (0.714 mL, 9.78 mmol) was added at room temperature to dry DMF (7 mL). After 30 min the above solution was cannulated into the solution of <strong>[189449-41-0]3-hydroxymethyl-4-chloropyridine</strong> (700 mg, 4.89 mmol) in DMF (3 mL). After 45 min, the product was precipitated by addition of dry ether (100 ml), washed with ether, and dried in vacuum to yield 813 mg (84percent) of the title compound. 1H NMR (CD3 OD) delta5.00 (s, 2H), 8.31 (d, 1H, J=5), 8.99 (d, 1H, J=5), 9.18 (s, 1H).
813 mg (84%)
With thionyl chloride; In N,N-dimethyl-formamide;
Example 21 3-chloromethyl-4-chloropyridine hydrochloride Thionyl chloride (0.714 mL, 9.78 mmol) was added at room temperature to dry DMF (7 mL). After 30 min the above solution was cannulated into the solution of <strong>[189449-41-0]3-hydroxymethyl-4-chloropyridine</strong> (700 mg, 4.89 mmol) in DMF (3 mL). After 45 min, the product was precipitated by addition of dry ether (100 ml), washed with ether, and dried in vacuum to yield 813 mg (84percent) of the title compound. 1H NMR (CD3 OD) delta 5.00 (s, 2H), 8.31 (d, 1H, J=5), 8.99 (d, 1H, J=5), 9.18 (s, 1H).
813 mg (84%)
With thionyl chloride; In N,N-dimethyl-formamide;
Example 21 3-chloromethyl-4-chloropyridine hydrochloride Thionyl chloride (0.714 mL, 9.78 mmol) was added at room temperature to dry DMF (7 mL). After 30 min the above solution was cannulated into the solution of <strong>[189449-41-0]3-hydroxymethyl-4-chloropyridine</strong> (700 mg, 4.89 mmol) in DMF (3 mL). After 45 min, the product was precipitated by addition of dry ether (100 ml), washed with ether, and dried in vacuum to yield 813 mg (84percent) of the title compound. 1H NMR (CD3OD) delta 5.00 (s, 2H), 8.31 (d, 1H, J=5), 8.99 (d, 1H, J=5), 9.18 (s, 1H).
Synthetic Example 2 Synthesis of [4-(piperazin-1-yl)pyridin-3-yl]methanol hydrochloride 4-Chloro-3-hydroxymethylpyridine ( ) (143 mg, 1 mmol), 1- (tert-butoxycarbonyl)piperazine (186 mg, 1 mmol) and triethylamine (1 ml, 7 mmol) were dissolved in ethanol(3 ml), and the mixture was stirred overnight in a threaded test tube at 130°C. The solvent was evaporated and work-up according to a conventional method gave a crude product. The obtained crude product was dissolved in a dioxane solution (5 ml) containing 4 N hydrogen chloride, and the mixture was stirred for 2 hr. The solvent was evaporated to give the title compound, which was used for the synthesis of C-22 and C-37.
With manganese(IV) oxide; In ethyl acetate; for 4h;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
1.37 g
With manganese(IV) oxide; In dichloromethane; at 50℃; for 12h;
After dissolving (4-chloropyridin-3-yl)methanol (2.6 g, 18.0 mmol) synthesized in Step 1 in dichloromethane (26 mL), manganese(IV) oxide (23.5 g, 270.5 mmol) was introduced thereto, and the result was stirred for 12 hours at 50°C. After terminating the reaction, the result was extracted by introducing water thereto. The organic layer was dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain an intermediate (1.37 g). 1H NMR spectrum (300 MHz, CDCl3) delta 10.51(s, 1H), 9.05(s, 1H), 8.67(s, 1H), 7.42(s, 1H).
A 1.0 mol/L borane-tetrahydrofuran complex tetrahydrofuran solution (30 mL) was added to a solution of 4-chloronicotinic acid (1.58 g) in tetrahydrofuran (20 mL), followed by refluxing for 1.5 hours. 2.0 mol/L hydrochloric acid (10 mL) was added thereto, followed by refluxing for 1 hour. The reaction mixture was cooled to room temperature, and extracted with ethyl acetate. The organic layer was washed sequentially with a sodium carbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residues were purified by silica gel column chromatography (ethyl acetate:methanol=1:0?9:1), whereby (4-chloro pyridin-3-yl)methanol (630 mg) was obtained as a white solid. (0954) MS(ESI m/z): 144 (M+H) (0955) RT(min): 0.77
2.6 g
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 1h;
After dissolving 4-chloronicotinic acid (7.0 g, 44.4 mmol) in tetrahydrofuran (500 mL), lithium aluminum hydride (1.68 g, 44.4 mmol) was introduced thereto, and the result was stirred for 1 hour at room temperature. After terminating the reaction, the reaction solution was removed under vacuum, and the result was extracted by introducing ethyl acetate and water thereto. The organic layer was dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain an intermediate (2.6 g). 1H NMR spectrum (300 MHz, CDCl3) delta 8.62(s, 1H), 8.42(s, 1H), 7.48(s, 1H), 7.53(s, 2H).
N-(2,3-dimethylphenyl)-4-hydroxybenzamide[ No CAS ]
4-(4-chloropyridin-3-ylmethoxy)-N-(2,3-dimethylphenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22.9%
To a stirred solution of Triphenyl phosphine (122 mg, 0.467 mmol) in THF (5 ml) was added DIAD (94 mg, 0.467 mmol) at 0°C and the reaction mixture was stirred at 0°C for 15 minutes. Then N-(2,3-Dimethyl-phenyl)-4-hydroxy-benzamide (3) (75 mg, 0.311 mmol) was added to the reaction mixture and stirred for 10 minutes. (2-Methoxy-pyridin-3-yl)- methanol (19) (43 mg, 0.311 mmol) was then added and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was then evaporated to dryness and purified by column chromatography in 100-200 silica using Hexane/EtOAc (5: 1) as eluent followed by Prep HPLC on Waters auto purification instrument. Column name:- YMC Prep C18 (100Chi30iotatauiotaiotaeta,5mu) is operating at ambient temperature and flow rate of 30.0 ml/min. A=20mM H4HCO3 in H20, B=Acetonitrile. Mobile phase initial from 90 percent of 20mM H4HC03 in H20 and 10 percent acetonitrile composition then 60percent 20mM H4HCO3 in H20 and 40percent acetonitrile in 1.00 min, then 20percent of 20mM H4HCO3 in H20 and 80percent acetonitrile in 15.00 min to 5percent of 20mM NH4HCO3 in H20 and 95 percent acetonitrile in 16.0min, held in this composition up to 17.0 min, then returned to initial composition in 18.0 min to afford Compound 66 (25 mg, 22.9percent) as white solid.
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