* 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 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.
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).
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