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THF (125 mL; KF<200 ppm), TMEDA (24.40 mL; 1.1 eq.; KF<125 ppm) and <strong>[13529-27-6]2-furaldehyde diethyl acetal</strong> (24.80 mL) were added at room temperature to a 1 L round bottomed flask equipped with a thermocouple, an overhead stirrer, N2 inlet and an addition funnel. The solution was cooled to -40 C. over 15 min., and then n-BuLi (101 mL; 1.1 eq.) was added over 1 hour with the temperature maintained at less than -20 C. The mixture was stirred 15 min at -25 C., and then assayed via LC. The assay showed 96% deprotonation. The reaction mixture was then cooled to -35 C., and a slurry of 1.5M ZnCl2/THF (68.5 mL; 0.7 eq.; KF=680 ppm-dried by soxhlet distillation through molecular sieves for 3 days) was added over 1 h while maintaining the temperature at less than <-20 C. throughout the addition. The mixture was then stirred for 30 min at -25 C. and warmed to 25 C. over 60 min. Solid Pd(dppf)Cl2 (0.60 g; 0.5 mol %) was then added, followed by solid 2,5-dichloropyridine (23.91 g; 1.1 eq.), each in one portion. The mixture was then heated to 55 C. and aged for 3 h (95% conversion by NMR assay; 85% assay yield by LC), after which the mixture was allowed to cool to room temperature and stirred overnight. [00987] The reaction mixture was then cooled to 0 C. and quenched with 5 C. 5M AcOH (294 mL; 5 eq.) over 10 min with the temp. maintained less than 25 C. throughout. The mixture was agitated for 15 min at 23 C. and then allowed to settle for 2 h. The aqueous layer was removed and the organic layer was cooled to 0 C., followed by addition thereto of 5 C. 10% NaOH (250 mL; 5 mL/g) over 10 min with the temperature maintained <25 C. throughout. The mixture was agitated for 15 min at 23 C., allowed to settle for 2 h, the aqueous layer removed, followed by addition of sat'd brine (62.5 mL; 2.5 mL/g) over 2 min with the temp. maintained less than 25 C. The mixture was agitated for 15 min at 23 C., allowed to settle for 2 h, and the aqueous layer removed. [00988] The organic soln. was concentrated down to 5 mL/g (125 mL) under vacuum with the soln.'s temperature maintained between 25-35 C. The concentrated solution was then diluted to 10 mL/g (250 mL) with heptane. This was repeated twice more to solvent switch completely to heptane (THF<1%). Darco G-60 (12.5 g) was added to the solution, and the mixture was heated to 50 C. for 2 h, cooled to 23 C. over 1 h and aged at 23 C. for 15 h. The mixture was then filtered through solka floc (25 g) and the filtercake was washed with heptane (250 mL). [00989] The heptane solution of the acetal was then added to a 500 mL round bottomed flask equipped with a thermocouple, an overhead stirrer, an N2 inlet and a distillation setup, concentrated down to 340 mL, and then diluted up with THF (25 mL). One quarter of an acid charge consisting of HCl (5M; 3 mL=10 mol % based on starting acetal) diluted in 12.5 mL of THF was added to the acetal soln. over 1 min and aged for 5 min at room temperature. The batch was then seeded with aldehyde 0.25 g and aged at room temperature for 15 min upon which some of the aldehyde began to crystallize out. The remaining acid charge was then added over 5 min and the slurry was aged at room temperature for 2 h. After such time, the deprotection was only 90% complete as determined by LC assay, so an additional 0.3 mL of acid was added to the slurry. The slurry was aged for an additional 30 min with little change in the percentage of deprotected aldehyde. [00990] The slurry was constant volume batch concentrated at 350 mL with 200 mL of heptane being flushed through to remove the THF and the EtOH which formed upon deprotection. (The temperature of the slurry was maintained <35 C.). The slurry was diluted to 375 mL with heptane and cooled to 23 C. The deprotection was complete at this time, with only about 1% acetal remaining. The solid aldehyde was filtered and displacement washed with 250 mL of r.t. heptane and dried overnight under a stream of nitrogen. The aldehyde was then dried for 2 days at 40 C. and 200 torr.
2,5-dichloropyridine-4-carbaldehvde A solution of 2,5-dichloropyridine (27.0 g, 180 mmol) in THF (65 mL) was added via cannula to a cooled solution of LDA (100 mL of a 1 .8 M solution, 180 mmol) in THF (80 mL) at -78 C. The mixture was stirred at -78 C for 30 mins, then a solution of DMF (21.1 mL, 271 mmol) in THF (25 mL) was added slowly via syringe. The reaction was stirred at -78 C for 3 hours and was then warmed to R.T. gradually. The solution was poured into a mixture of ice (800 mL) and cone. HCI (150 mL) and stirred for 20 mins before being basified with NaOH (3.0 M) to pH 9-10, and extracted with Et20 (2 x 500 mL). The combined organic layers were dried over MgS04 and concentrated to give the crude product as pale yellow solid. This solid was suspended in n-hexane with trace EtOAc and boiled for 5 mins. The liquors were decanted and stripped to yield a yellow solid which was purified by Biotage flash chromatography (65i, loaded in DCM / EtOAc, eluted with heptane - 20 % EtOAc / heptane over 8 CV, then holding for 5 CV) to afford the title compound (17.9 g, 56 %) as a pale yellow solid, 1H NMR (400 MHz, DMSO-d6) delta 7.85 (s, 1 H) 8.76 (s, 1 H) 10.22 (s, 1 H).
With n-butyllithium;
2,5-Dichloropyridine-4-carboxaldehyde was prepared from 2.5-dichloropyridine using the procedure described in Eur. J. Org. Chem. 2001, 1371-1376 (E. Marzi, A. Bigi, M. Schlosser ) and converted to 2-(2,5-dichloro-pyridin-3-yl)-lH- benzoimidazole using the method in route 1 step 4. This was aminated as described for compound 34 and the aminopyridine converted to compound 38 using the method in route 1 step 1
Intermediate 8: 2, 5-Dichloro-4-pyridinecarbaldehyde; Diisopropylamine (7. 5ml) was dissolved in THF (47ml) and the solution was cooled to -35C. n-Butyl lithium (1.6M in hexanes, 44ml) was added slowly maintaining the temperature below-30C. After the addition the reaction mixture was cooled to-75C and a solution of 2, 5-dichloropyridine (8.9g) in THF (27ml) was added dropwise. The mixture was stirred at-75C for a further 30min and a solution of DMF (7. Oml) in THF (14ml) was added dropwise. The reaction mixture was stirred at-75C for 1.5h then allowed to warm to 10C over 2.5h. The solution was poured onto a mixture of ice (500ml) and concentrated hydrochloric acid (45ml) and stirred for 15min. The mixture was basified to pH8 with sodium hydroxide (2N), extracted with ether (x3) and the combined organic extracts were washed with brine, dried (magnesium sulfate) and reduced to dryness under vacuum. The resulting oil was applied to a silica column (50g) and eluted with cyclohexane/ethyl acetate (100: 0 to 80: 20) The product obtained was recrystallised from cyclohexane to give the title compound as beige needles (6.65g). NMR: [8H d6-DMSO] 10.20 (1H, s), 8.75 (1H, s), 7.83 (1H, s)
Preparation 44 Tert-Butyl 4-[(5-chloro-2-pyridyl)thio]-1-piperidinecarboxylate The title compound was obtained from <strong>[134464-79-2]tert-butyl 4-mercapto-1-piperidinecarboxylate</strong> and 2,5-dichloropyridine in the same manner as in Preparation 7. 1H-NMR (300 MHz, CDCl3) δ 8.38(dd, J=2,1 Hz, 1H), 7.45(dd, J=8,2 Hz, 1H), 7.10(dd, J=8,1 Hz, 1H), 4.01-3.85(m, 3H), 3.14-3.00(m, 2H), 2.10-1.98(m, 2H), 1.70-1.58(m, 2H), 1.46(s, 9H).
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