Pyridine intermediate compound

Disclosed are novel 2-(5-halopyridyl) and 2-(5-halopyrimidinyl) magnesium halides, processes of making and their use in the efficient synthesis in their respective 5-halo-2- substituted pyridines and pyrimidines.

SYNTHETIC EXAMPLES 
 Example 1 
 Synthesis of 5-bromo-2-iodopyridine from 2.5-dibromopyridine 2,5-Dibromopyridine (100 g) was suspended in acetonitrile (500 mL) at rt. NaI (94 g) and AcCl (45 mL) were added and the reaction was then gently refluxed for 3 h. An aliquot was analyzed by 1 H NMR and MS and the reaction was about 80% complete. The reaction was cooled to rt and quenched with a few mL of water and then K 2 CO 3 aqueous solution to pH 8. EtOAc (1.5 L) was added to extract the organic materials. The organic layer was washed with saturated NaHSO 3 solution, the brine, and then dried over MgSO 4 . Concentration gave crude material that was subjected to the same conditions for about 3 h at which time 1 H NMR showed that the reaction was greater than 97% complete. The same workup provided the crude material. The crude crystals were washed twice with CH 3 CN and dried in the oven. The yield was 95 g. 1 H NMR (CDCl 3 , 400 MHz) 67 8.44 (s, 1H), 7.60 (d, J&equals;8.26 Hz, 1H), 7.44 (d, J&equals;8.25 Hz, 1H). 
 Example 2 
 Synthesis of 5-bromo-2-formylpyridine from 5-bromo-2-iodopyridine via the Grignard Intermediate In a 22 L 3-neck round bottomed flask equipped with a mechanical stirrer, 1 kg (3.52 mol) of 2-iodo-5-bromopyridine was dissolved in 5 L of THF. The solution was cooled to about −15 to −10° C. 1.9 L (2 M, 380 mol, 1.08 eq) of 1 PrMgCl was added at a rate to keep the internal temperature below 0° C. The reaction mixture became a brown suspension. After the reaction mixture was stirred between −15 to 0° C. for 1 h, 400 mL (5.16 mol, 1.5 eq) of DMF was added at a rate to keep the internal temperature below 0° C. After stirring at this temperature for 30 min, the cooling bath was removed and the reaction was allowed to warm to room temperature over 1 h. The reaction mixture was then cooled to 0° C. and 4.0 L (7.74 mol, 2.2 eq) of 2 N HCl was added at a rate to keep the internal temperature below 25° C. The mixture was stirred for 30 min, then pH was raised from 1 to a pH 6-7 by adding about 150 mL of 2 N NaOH. The layers were separated and the THF layer was concentrated to give dark brown wet solids. The aqueous layer was extracted with 3 L of CH 2 Cl 2 . The CH 2 C 2 layer was used to dissolve the residue obtained from the THF layer, the resulting solution was washed with water (2×2 L), dried by stirring with MgSO 4 (400 g) for 30 min, and filtered. Concentration of the filtrate to dryness gave 583 g of the desired aldehyde as brownish-yellow solids (89% yield after air drying). 1 H NMR (CDCl 3 , 400 MHz) 67 10.04 (d, J&equals;0.68 Hz, 1H), 8.86 (t, J&equals;0.52 Hz, 1H), 8.02 (dt, J&equals;8.20, 0.68 Hz, 1H), 7.85 (d, J&equals;8.48 Hz, 1H). 
 Example 3 
 Synthesis of 5-bromo-2-(4-morpholinylmethyl)pyridine from 5-bromo-2-iodopyridine via the Grignard Intermediate To a solution of bis(1-morpholinyl)methane (130 mg) in THF (3 mL) at rt was added acetyl chloride (45 mL). The reaction was stirred for 1 h and cooled to 0° C. In another flask, 5-bromo-2-iodopyridine (130 mg) was dissolved in THF (3 mL) at −40° C. The solution was treated with 1 PrMgCl (2 M in THF, 0.39 mL) at the same temperature for 15 min. Then the Grignard solution was cannulated into the immonium salt suspension generated above at 0° C. After the addition, the reaction mixture was stirred at rt for 1 h and quenched with saturated NH 4 Cl solution. Extraction with CH 2 Cl 2 , drying over MgSO 4 , filtration and concentration gave a crude oil. This was further purified by column chromatography to afford the product in about 50 % yield. 1 H NMR (CDCl 3 , 400 MHz) 67 8.60 (s, 1H), 7.76 (d, J&equals;8.24 Hz, 1H), 7.32 (d, J&equals;8.64 Hz, 1H), 3.72 (m, 4H), 3.59 (s, 2H), 2.48 (m, 4H). 
 Example 4 
 Synthesis of 5-bromo-2-(4-morpholinyl)methylpyridine from 5-bromo-2-formylpyridine To a solution of 500 g (2.688 moles) aldehyde in a 5 L of 1,2- dichloroethane at room temperature was added morpholine (1.15 eq, 3.09 moles, 269 ml) in one portion. The reaction temperature went up to 29° C. After stirring the reaction mixture for 15 min, acetic acid (2.1 eq, 5.6 moles, 323 mL) was added in one portion. The temperature rose to 31° C. It was stirred for 1.5 h at room temperature. Sodium triacetoxyborohydride (1.06 eq, 2.85 moles, 604 g ) was added in 100 g portions every 10 min. The temperature was maintained between 35° C. and 46° C. by gentle cooling. It was stirred for an additional 2 h. The reaction mixture was quenched with 4 N HCl keeping the temperature below 15° C. At the end of addition, the pH of aqueous phase was between 0 and 1 (˜2200 mL). The organic phase was separated and discarded. The aqueous phase was basified with 9 N NaOH (˜740 g NaOH) to pH ˜9.5 keeping the internal temperature below 15° C. The product was extracted with methylene chloride. Evaporation of the solvent gave pure amine (660 g, 2.57 moles). 
 Example 5 
 Synthesis of 5-Bromo-3-methyl-2-pyridinecarboxaldehyde An example of the synthesis of a compound of formula (F) in which W is CR 3 (R 3 &equals;methyl), and subsequent reaction with an electrophile is provided below and illustrated in Scheme VIII. 31 2,5-Dibromo-3-picoline is commercially available or may be prepared from 2-amino-5-bromo-3-methylpyridine by standard diazotization followed by bromination in Br 2 /HBr. Acetyl chloride (0.68 mol, 52.7 mL) was added to a stirring solution of 2,5-dibromo-3-picoline (0.45 mol, 113 g) in acetonitrile (600 mL) followed by sodium iodide (1.66 mol, 250 g) and the reaction mixture was gently refluxed for 18 h. The cooled reaction mixture was filtered and the solid was washed with acetonitrile until colorless. It was suspended in methylene chloride and treated with aq. Na 2 CO 3 until the pH was 10-11. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to give a brown oil. It was subjected to iodination a second time as above (reflux time 6 h). A dark brown oil was obtained using the same work-up as above. A solution of this oil in hexane was treated with charcoal, filtered and concentrated to give a light brown oil. It slowly solidified on standing to give 5-bromo-2-iodo-3-methylpyridine as a light brown solid (95.0 g, 0.32 mol). Yield: 70%. 2-Iodo-5-bromo-3-methylpyridine (250 mg) was dissolved in THF (4.0 mL). The solution was cooled to 0° C. 0 PrMgCl (2 M in THF, 0.5 mL) was added at a rate to keep the internal temperature below 5° C. After the reaction mixture was stirred at 0° C. for 1 h, DMF (0.13 mL) was added at 0° C. After stirring at this temperature for 30 min, the cooling bath was removed and the reaction was allowed to warm to room temperature over 1 h. The reaction mixture was hydrolyzed by a saturated aqueous NH 4 Cl solution. Then the aqueous layer was extracted with CH 2 Cl 2 . The CH 2 Cl 2 layer was dried over MgSO 4 and concentrated to give the desired aldehyde as a brownish-yellow solid (80% yield).