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Step A: 2,6-Dichloronicotinic acid (30g, 156.3 mmol) was dissolved in methanol (300 mL) at room temperature. Sodium ethoxide (5.4 M in MeOH, 781.3 mmol, 145 mL) was added slowly at the same temperature. The reaction mixture was stirred at 70 C for 5 hours and cooled to room temperature. The precipitated solid from reaction mixture was filtered off and the mother liquor was concentrated under vacuum. All solid collected was dissolved in water (300 mL) and the solution was acidified with 6N HC1 solution to pH 6 at 0 C. The aqueous layer was extracted with ethyl acetate five times. The combined organic layers were dried over MgS04. The organic layer was filtered off and concentrated to give a 1 : 1 mixture of 6-chloro-2- methoxynicotinic acid and 2-chloro-6-methoxynicotinic acid (20.22g, 69%). MS m/z 188 [M+H]+. Step B: The mixture obtained above (11.48g, 61.2 mmol) was dissolved in THF (50 mL) and cooled to 0 C. Borane-THF complex (1.0 M in THF, 200 mL) was added slowly at 0 C. The reaction mixture was stirred at room temperature for 1 hour and cooled back to 0 C. Aqueous 6N HC1 (15 mL) was added very slowly at 0 C. The aqueous layer was neutralized with a saturated NaHC03 solution to pH 7. Dichloromethane was added and the aqueous layer was extracted. The combined organic layers were dried over K2C03, filtered and concentrated under vacuum to yield 10.6 g of corresponding alcohols. The residue can be used directly in the oxidation step or purified on silica gel with the mixture of ethyl acetate and hexane. TLC Rf 0.31 (30% EtOAc in hexane). MS m/z 174 [M+H]+.
(2-chloro-6-methoxypyridin-3-yl)methyl methanesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
In dichloromethane; at 0 - 20℃; for 3h;
[0568] Methanesulfonyl chloride (3.4 mL, 44.0 mmol) was added to a stirred solution of (2- chloro-6-methoxypyridin-3-yl)methanol (3.82 g, 22.0 mmol) in dichloromethane (90 mL) at 0 C, and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water (100 mL), affording a biphasic solution. The organic phase was collected and the aqueous phase extracted with dichloromethane (2 x 50 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give the desired product as an orange solid (4.26 g, 77%). UPLC-MS (Acidic Method, 2 mins): rt = 1.13 min, m/z 252.1 [M+Hf. NMR (400 MHz, CDCb) d ppm 7.65 (d, J= 8.2 Hz, 1H) 6.69 (d, J= 8.2 Hz, 1H) 4.64 (s, 2 H) 3.94 (s, 3 H) 3.14 (s, 3 H)
77%
In dichloromethane; at 0 - 20℃; for 3h;
Methanesulfonyl chloride (3.4 mL, 44.0 mmol) was added to a stirred solution of (2- chloro-6-methoxypyridin-3-yl)methanol (3.82 g, 22.0 mmol) in dichloromethane (90 mL) at 0 C, and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water (100 mL), affording a biphasic solution. The organic phase was collected and the aqueous phase extracted with dichloromethane (2 x 50 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give the desired product as an orange solid (4.26 g, 77%). UPLC-MS (Acidic Method, 2 mins): rt = 1.13 min, m/z 252.1 [M+H]+. NMR (400 MHz, CDC ) d ppm 7.65 (d, .7=8.2 Hz, 1 H) 6.69 (d, .7=8.2 Hz, 1 H) 4.64 (s, 2 H) 3.94 (s, 3 H) 3.14 (s, 3 H)
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 50℃;
[0567] To a solution of methyl 2-chloro-6-methoxynicotinate (5.0 g, 24.8 mmol) in THF (50 mL) at 0 C was added lithium aluminium hydride (1.88 g, 49.6 mmol) in a portion wise manner, taking care to keep the temperature below 10 C. Upon completion of the addition, the reaction mixture was stirred at 50 C for 3 h. The reaction mixture was then cooled to 0 C, before being quenched by the careful addition of a saturated solution of aqueous sodium sulphate (50 mL). The resulting suspension was stirred for 20 min, before being filtered through a pad of celite, washing with ethyl acetate (2 x 50 mL). The combined organics were dried over anhydrous sodium sulphate, filtered and evaporated to dryness to give the desired product as a yellow- orange oil (3.82 g, 89%). UPLC-MS (Acidic Method, 2 mins): rt = 0.83 min, m/z 174.0 [M+H]+. NMR (400 MHz, CDCb) d ppm 7.69 (d,.7=8.2 Hz, 1H) 6.69 (d, J=8.2 Hz, 1H) 4.70 (s, 2 H) 3.88 (s, 3 H)
89%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 50℃; for 3h;
To a solution of methyl 2-chloro-6-methoxynicotinate (5.0 g, 24.8 mmol) in THF (50 mL) at 0 C was added lithium aluminium hydride (1.88 g, 49.6 mmol) in a portion wise manner, taking care to keep the temperature below 10 C. Upon completion of the addition, the reaction mixture was stirred at 50 C for 3 h. The reaction mixture was then cooled to 0 C, before being quenched by the careful addition of a saturated solution of aqueous sodium sulphate (50 mL). (1917) The resulting suspension was stirred for 20 min, before being filtered through a pad of celite, washing with ethyl acetate (2 c 50 mL). The combined organics were dried over anhydrous sodium sulphate, filtered and evaporated to dryness to give the desired product as a yellow- orange oil (3.82 g, 89%). UPLC-MS (Acidic Method, 2 mins): rt = 0.83 min, m/z 174.0 [M+H]+. NMR (400 MHz, CDCb) d ppm 7.69 (d, .7=8.2 Hz, 1 H) 6.69 (d, .7=8.2 Hz, 1 H) 4.70 (s, 2 H) 3.88 (s, 3 H)
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