* 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 tetrahydroborate In methanol; water at 0 - 20℃; for 1.5 h; Inert atmosphere
Methyl-6-methoxypyridine-2-carboxylate (2 g, 11.96 mmol) in anhydrous methanol (20 mL) was cooled to 0° C. under nitrogen and sodium borohydride (1.36 g, 35.89 mmol) was slowly added to the solution. The reaction was left stirring at 0° C. for 30 minutes, then allowed to warm up to room temperature for 1 hour. The reaction was quenched with water and concentrated on the rotovap. The reaction was diluted with brine (100 mL) and extracted with dichloromethane/2-propanol solution (2:1) (3*, 150 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap to afford (6-methoxypyridin-2-yl)methanol (500 mg, 30percent) as an oil. MS M+H calculated 140.1. Found 140.1.
30%
at 0 - 20℃; for 1.5 h; Inert atmosphere
Example 75a (6-Methoxypyridin-2-yl)methanol Methyl-6-methoxypyridine-2-carboxylate (2 g, 11.96 mmol) in anhydrous methanol (20 mL) was cooled to 0° C. under nitrogen and sodium borohydride (1.36 g, 35.89 mmol) was slowly added to the solution. The reaction was left stirring at 0° C. for 30 minutes, then allowed to warm up to room temperature for 1 hour. The reaction was quenched with water and concentrated on the rotovap. The reaction was diluted with brine (100 mL) and extracted with dichloromethane/2-propanol solution (2:1) (3*, 150 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap to afford (6-methoxypyridin-2-yl)methanol (500 mg, 30percent) as an oil. MS M+H calculated 140.1. found 140.1.
10%
With lithium aluminium tetrahydride In diethyl ether at 20℃; for 4 h;
To a solution of the compound (730 mg, 4.37 mmol) prepared in step 1) in diethylether was dropwise added lithium aluminum hydride (175 mg, 4.37 mmol), followed by stirring at room temperature for 4 hrs. Celite (1.5 g) and sodium sulfate decahydrate (0.8 g) were dropwise added to the reaction mixture, and stirred for 10 min at room temperature. The reaction mixture was filtered, and extracted with diethylether. The organic layers were pooled and 'subjected to vacuum filtration and vacuum distillation. The residue was purified using column chromatography (ethyl acetate :hexane = 1 :3) to obtain the desired compound (55 mg, 10percent).
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: With water; rochelle salt In tetrahydrofuran at 20℃; for 1 h;
Step A: Preparation of (6-methoxypyridin-2-yl)methanol: A cold solution of6-methoxypicolinic acid (1.8 g, 11.8 mmol) in tetrahydrofuran (0.3M, 40 mL) was treated with lithium aluminum hydride (11.8 mL, 11.8 mmol) at 0 °C. This mixture was stirred at 0 °C for 30 minutes, poured into a beaker containing aqueous saturated Rochelle's salt and stirring at ambient temperature continued for 1 hour. The product was extracted from EtO Ac, dried (phase separator silicone treated filter paper) paper, concentrated (1.13 g, 69percent yield) as a clear oil.
With thionyl chloride; In Dichlorofluoromethane; at 0 - 50℃; for 2h;Inert atmosphere;
Synthesis of 2-(chloromethyl)-6-methoxypyridine:To a stirred solution of <strong>[63071-12-5](6-methoxypyridin-2-yl)methanol</strong> (0.7 g 5.03 mmol) in CH2CI2 (20 mL) was added SOCl2 (2 mL) at 0 C under inert atmosphere. The resultant reaction mixture was heated up to 50 C and stirred for 2 h. After completion of starting material (by TLC), the volatiles were evaporated under reduced pressure. The residue was quenched with ice cold water and saturated NaHC03 and extracted with EtOAc. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford 2- (chloromethyl)-6-methoxypyridine (180 mg, 24%) as a liquid. 1H-NMR (DMSO d6, 500 MHz): delta 7.72 (t, 1H), 7.12 (d, 1H), 6.87 (d, 1H), 4.64 (s, 2H), 3.82 (s, 3H); LC-MS: 98.62%; 158.0 (M++l); (column; X-select C-18, (50x3.0 mm, 3.5mu); RT 4.12 min. 5mM NH4OAc in water: ACN; 0.50 ml/min); TLC: 10% EtOAc/Hexane (Rf: 0.6).
180 mg
With thionyl chloride; In dichloromethane; at 0 - 50℃;Inert atmosphere;
[0529] Synthesis of 2-(chlorometh -6-methoxypyridine: [0530] To a stirred solution of <strong>[63071-12-5](6-methoxypyridin-2-yl)methanol</strong> (0.7 g 5.03 mmol) in CH2CI2 (20 mL) was added SOCl2 (2 mL) at 0 C under inert atmosphere. The resultant reaction mixture was heated up to 50 C and stirred for 2 h. After completion of starting material (by TLC), the volatiles were evaporated under reduced pressure. The residue was quenched with ice cold water and saturated NaHC03 and extracted with EtOAc. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford 2-(chloromethyl)-6-methoxypyridine (180 mg, 24%) as a liquid. 1H-NMR (DMSO d6, 500 MHz): delta 7.72 (t, 1H), 7.12 (d, 1H), 6.87 (d, 1H), 4.64 (s, 2H), 3.82 (s, 3H); LC-MS: 98.62%; 158.0 (M++l); (column; X- select C-18, (50x3.0 mm, 3.5mu); RT 4.12 min. 5mM NH4OAc in water: ACN; 0.50 ml/min); TLC: 10% EtOAc/Hexane (Rf: 0.6).
With thionyl chloride; at 20℃; for 2h;
The compound (55 mg, 0.40 mmol) obtained in step 2) was dissolved in thionyl chloride (1 mL) and stirred at room temperature for 2 hrs. The resulting reaction mixture was filtered and distilled in a vacuum. The residue thus obtained was used in the subsequent step without purification.
With methanesulfonyl chloride; triethylamine; In dichloromethane; at 20℃; for 18h;
A solution of <strong>[63071-12-5](6-methoxy-pyridin-2-yl)-methanol</strong> (334 mg, 2.40 mmol) and Et3N (0.50 ml, 3.60 mmol) in CH2CI2 (10 mL) is added dropwise MsCI (0.22 mL, 2.88 mmol) at 0C. The reaction mixture is warmed to rt abd stirred for 18h before it is diluted with CH2CI2 and extracted with H2O. The organic phase is dried over MgSO4, filterated and evaporated to leave a residue, which is purified by flash chromatography on silica gel (eluting: EtOAc:Hexane 3:7) to give the titled compound as a yellow oil.; ES-MS: M+H =167; HPLC (Condition-B): tR = 1.16 min.
With tributylphosphine; In tetrahydrofuran; methanol; hexane; water; ethyl acetate; acetonitrile;
Example 10-75 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-((6-methoxypyridin-2-yl)methyl)imidazolidine-2,4-dione 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (100 mg, 0.4 mmol), <strong>[63071-12-5](6-methoxy-pyridin-2-yl)-methanol</strong> (example 10-75a) (101 mg, 0.7 mmol), tributylphosphine (147 mg, 0.7 mmol), and 1,1""-azobis(N,N-dimethylformamide) (125 mg, 0.7 mmol) were dissolved in THF (5 mL) and stirred at room temperature for 15 hours. The reaction was diluted with brine (100 mL) and extracted with ethyl acetate (2*, 100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap. The residue was taken up in methanol (5 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O:25 minute gradient). The pure fractions were combined, concentrated then re-dissolved in ethyl acetate/hexane (1:9). The solution was cooled at 5 C. for 15 hrs, where a white solid formed. The precipitate was collected to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-((6-methoxypyridin-2-yl)methyl)imidazolidine-2,4-dione (5 mg, 4%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): delta2.11 (s, 3H), 2.37 (s, 3H), 3.74 (s, 3H), 4.17 (s, 2H), 4.54 (s, 2H), 5.17 (s, 2H), 6.69 (d, J=7.6 Hz, 1H), 6.96 (d, J=6.8 Hz, 1H), 7.67 (d, J=6.8 Hz, 1H), 7.76 (s, 1H), 8.17 (s, 1H). MS M+H calculated 397.2. found 397.2.
Example 10-75a (6-methoxypyridin-2-yl)methanol Methyl-6-methoxypyridine-2-carboxylate (2 g, 11.96 mmol) in anhydrous methanol (20 mL) was cooled to 0 C. under nitrogen and sodium borohydride (1.36 g, 35.89 mmol) was slowly added to the solution. The reaction was left stirring at 0 C. for 30 minutes, then allowed to warm up to room temperature for 1 hour. The reaction was quenched with water and concentrated on the rotovap. The reaction was diluted with brine (100 mL) and extracted with dichloromethane/2-propanol solution (2:1) (3*, 150 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap to afford (6-methoxypyridin-2-yl)methanol (500 mg, 30%) as an oil. MS M+H calculated 140.1. found 140.1.
30%
With sodium tetrahydroborate; In methanol; water; at 0 - 20℃; for 1.5h;Inert atmosphere;
Methyl-6-methoxypyridine-2-carboxylate (2 g, 11.96 mmol) in anhydrous methanol (20 mL) was cooled to 0 C. under nitrogen and sodium borohydride (1.36 g, 35.89 mmol) was slowly added to the solution. The reaction was left stirring at 0 C. for 30 minutes, then allowed to warm up to room temperature for 1 hour. The reaction was quenched with water and concentrated on the rotovap. The reaction was diluted with brine (100 mL) and extracted with dichloromethane/2-propanol solution (2:1) (3*, 150 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap to afford (6-methoxypyridin-2-yl)methanol (500 mg, 30%) as an oil. MS M+H calculated 140.1. Found 140.1.
30%
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1.5h;Inert atmosphere;
Example 75a (6-Methoxypyridin-2-yl)methanol Methyl-6-methoxypyridine-2-carboxylate (2 g, 11.96 mmol) in anhydrous methanol (20 mL) was cooled to 0 C. under nitrogen and sodium borohydride (1.36 g, 35.89 mmol) was slowly added to the solution. The reaction was left stirring at 0 C. for 30 minutes, then allowed to warm up to room temperature for 1 hour. The reaction was quenched with water and concentrated on the rotovap. The reaction was diluted with brine (100 mL) and extracted with dichloromethane/2-propanol solution (2:1) (3*, 150 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap to afford (6-methoxypyridin-2-yl)methanol (500 mg, 30%) as an oil. MS M+H calculated 140.1. found 140.1.
10%
With lithium aluminium tetrahydride; In diethyl ether; at 20℃; for 4h;
To a solution of the compound (730 mg, 4.37 mmol) prepared in step 1) in diethylether was dropwise added lithium aluminum hydride (175 mg, 4.37 mmol), followed by stirring at room temperature for 4 hrs. Celite (1.5 g) and sodium sulfate decahydrate (0.8 g) were dropwise added to the reaction mixture, and stirred for 10 min at room temperature. The reaction mixture was filtered, and extracted with diethylether. The organic layers were pooled and 'subjected to vacuum filtration and vacuum distillation. The residue was purified using column chromatography (ethyl acetate :hexane = 1 :3) to obtain the desired compound (55 mg, 10%).
To methyl 6- methoxypicolinate (4.65 g, 27.8 mmol) in Et20 (100 mL) was added LAH (1.06 g). The reaction mixture was stirred for 4 hours. Celite (10 g) was added, followed by sodium sulfate-decahydrate (5 g). The reaction mixture was filtered and concentrated to provide the desired product (3.36 g).
With sodium tetrahydroborate; In ethanol; at 0 - 20℃; for 3h;
Synthesis of (6-methoxypyridin-2-yl)methanol:To a stirred solution of methyl 6-methoxypicolinate (1.2 g, 7.18 mmol) in ethanol (30 mL) was added NaBH4 (409 mg, 10.77 mmol) portion wise at 0 C and stirred for 3 h at RT. Progress of the reaction was monitored by TLC. Volatiles were evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc (2 x 25 mL). Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to afford crude (6-methoxypyridin-2-yl)methanol (0.7 g). LC-MS: 52.48%>; 139.5 (M++l); (column; X-select C-18, (50x3.0 mm, 3.5mu); RT 2.55 min. 5mM NH4OAc in water: ACN; 0.50 ml/min); TLC: 20% EtOAc/Hexane (Rf: 0.2).
With sodium tetrahydroborate; ethanol; at 0 - 20℃;
[0527] Synthesis of (6-methoxypyridin-2-yl)methanol: [0528] To a stirred solution of methyl 6-methoxypicolinate (1.2 g, 7.18 mmol) in ethanol (30 mL) was added NaBH4 (409 mg, 10.77 mmol) portion wise at 0 C and stirred for 3 h at RT. Progress of the reaction was monitored by TLC. Volatiles were evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc (2 x 25 mL). Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to afford crude (6-methoxypyridin-2-yl)methanol (0.7 g). LC-MS: 52.48%; 139.5 (M++l); (column; X-select C-18, (50x3.0 mm, 3.5mu); RT 2.55 min. 5mM NH4OAc in water: ACN; 0.50 ml/min); TLC: 20% EtOAc/Hexane (Rf: 0.2).
Bromopyridine 4 (5.7 g, 30.3 mmol) was dissolved in 28.5 mL of THF in a 250 mL flask. The solution was cooled to -65C. n-Hexyllithium (14.50 mL of 2.3M solution, 33.3 mmol) was added while maintaining the temperature below -60C. After addition, the solution was aged for 5 minutes at -65C. LC analysis showed complete reaction. DMF (2.82 ml, 36.4 mmol) was added dropwise while maintaining the temperature below -60C. After 5 minutes age, LC showed presence of the aldehyde product. The mixture was warmed to -30C. Methanol (22.80 mL) was added. The low temperature bath was replaced with an ice bath. NaBl¾ (0.688 g, 18.19 mmol) was added. The temperature increased to 12C, then dropped again. LC analysis showed that no aldehyde remained. The solution was concentrated to a final volume of -25 mL and was then diluted with MTBE and water. 3N HC1 was added to quench the excess NaBH4 and bring the pH to 8. The layers were separated. The organic layer was dried with MgS04- The solvent was removed by evaporation. The product 5 was left under vacuum for the weekend. The product (4.4 g) was used directly in the next step without purification.
In a 1000 ml flask, the pyridine compound 5 (23.3 g, 147 mmol) was dissolved in CH2C12 (233 ml). The solution was cooled to -20C. Bromine (8.30 ml, 161 mmol) was added dropwise. The solution was warmed slowly to room temperature, and then 350 mL of 7% NaHCC<3 solution was added. The solution was aged at RT for lh. The reaction was then complete. Sodium thiosulfate (1 g) was added to decolorize the product. The layers were separated, and the organic layer was washed with 100 mL of 7% NaHCC>3 solution and dried with MgSC>4. The solvent was removed, yielding a yellow oil (32 g), which was used directly in the next step without further purification.
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 0.666667h;Inert atmosphere;
General procedure: To a flame-dried flask were added an arylmethyl alcohol (1.0 eq.), anhydrous DCM (1.94 mL/mmol) and CBr4 (1.1 eq.), followed by addition of PPh3 (1.1 eq.) in portions under argon. The resulting reaction mixture was stirred at room temperature for 40 min and was then filtered through a short pad of celite. Upon the evaporation of the solvent, the residue was purified through flash chromatography on silica gel (9:1 or 2:1 hexane/EtOAc) to provide the desired product.2-(bromomethyl)-6-methoxypyridine. Reaction of <strong>[63071-12-5](6-methoxypyridin-2-yl)methanol</strong> (Procedure A) yielded the title product as a colorless liquid (73%). 1 H NMR (400 MHz, CDCI3) d 7.53 (t, J = 8.4 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.45 (s, 2H), 3.93 (s, 3H). 13C NMR (lOOMHz, CDCl3) d 163.8, 154.2, 139.2, 115.9, 110.4, 53.5, 34.1. LC-MS (ESI) calcd for: C7H9BrNO (MH+): 202.0, found 202.0.
With carbon tetrabromide; triphenylphosphine; In dichloromethane; for 1h;
To (6- methoxypyridin-2-yl)methanol (3.36 g, 24.1 mmol) in DCM (30 mL) was added perbromomethane (12.0 g, 36.2 mmol) and triphenylphosphine (9.50 g, 36.2 mmol). The reaction mixture was stirred for 1 hour, concentrated and silica gel chromatography (EtOAc/Hexane 1 :5) to provide the desired product (4.23 g).
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0℃; for 2h;
To a 100-mL round-bottomed flask was added 6-methoxy-2- pyridinyl)methanol (1.1 g, 7.91 mmol), triphenylphosphine (2.28 g, 8.70 mmol, Aldrich, St. Louis, MO) and tetrabromomethane (0.84 mL, 8.70 mmol, Aldrich, St. Louis, MO) in DCM (20 mL). The reaction mixture was stirred at 0 C for 2 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 10% EtOAc/hexanes to give 2-(bromomethyl)-6- methoxypyridine (1.33 g) as a colorless oil.
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