(4-CHLORO-PYRIDIN-2-YL)-CARBAMIC ACID TERT-BUTYL ESTER

To a solution of LHMDS (1M in THF, 17.11 mL, 17.11 mmol) in THF (5 mL) at -5 °C was added a solution of 4-chloropyridin-2-amine (1 g, 7.78 mmol) in THF (5 mL) and the mixture was stirred for 5 min. To this mixture was added a solution of BocTo a solution of LHMDS (1M in THF, 17.11 mL, 17.11 mmol) in THF (5 mL) at -5 °C was added a solution of 4-chloropyridin-2-amine (1 g, 7.78 mmol) in THF (5 mL) and the mixture was stirred for 5 min. To this mixture was added a solution of BOC2O (1.898 mL, 8.18 mmol) in THF (5 mL). The mixture was stirred at 0 °C for 2 h and quenched by addition of aqueous NH4Cl. The pH of the solution was adjusted to 6 by addition of 1.5N HCl and extracted with ethyl acetate (3x15 mL). The combined organic extracts were washed with sodium bicarbonate (15 mL), water (15 mL) and brine (15 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate, petroleum ether gradient) to yield tert-butyl (4-chloropyridin-2-yl)carbamate (1.435 g, 6.28 mmol, 81percent yield).To a solution of 4-chloropyridin-2-amine (4.00 g, 31.1 mmol) in THF (60 mL) was added lithium bis(trimethylsilyl)amide in THF (1.0 M, 65.3 ml, 65.3 mmol) at -5 °C under Ar atmosphere. After 10 minutes, di-tert-butyl dicarbonate was added (7.22 ml, 31 .1 mmol) and stirring was continued for lh. Sat. NHIn a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, dissolve 20.6 g (0.158 mol) of 2-amino-4- chloropyridine in tert-butanol, add 38.5 g (0.175 mol) of BOC anhydride. Stir the mixture for 5 hours at 40 °. Remove excess solvent by distillation in a rotary evaporator at 40 °; treat the residue with hexane. Cool the resulting suspension to 0 °, and filter the precipitate. Yield: 28 g (77percent).The 4-chloro-N-methyl-pyridin-2-amine used as starting material was made as follows: General procedure: To a solution of2-amino-4-chloropyridine 2b (3.5g, 27.2 mmol) in t-BuOH (40 mL) warmedat 40°C was added BocIntermediate 1 tert-Butyl (4-chloropyridin-2-yl)carbamate [0039] A 500 mL round bottom flask was charged with 4-chloropyridin-2-amine (9.15 g, 71.2 mmol) which was dissolved in DCE (225 mL). To that stirring solution was added di-tert-butyl dicarbonate (16.31 g, 74.7 mmol) followed by slow addition of DMAP (1.739 g, 14.23 mmol). Vigorous bubbling persisted for about 20 min after which the reaction was analyzed by LCMS which showed clean and complete consumption of the starting material to a large peak with the desired mass (m/z=174[M-55]) Methanol/Water/TFA Phenomenex Luna C18, 30×2 mm, 3u ES+/−). The contents of the flask were transferred into a separatory funnel and the organic was washed twice with a sat'd sodium bicarbonate, and brine. The aqueous was back extracted with EtOAc and discarded. The combined organics were washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. The crude solid was diluted with ethanol and the resulting solid was collected by filtration and washed with ethanol. Compound 10 (4-chloropyridin-2-amine, 128g, lmol) was dissolved in DCM (3.0L), to which was added TEA (121g, 1.2mol) and DMAP (9.76g, 0.08mol) with stirring. After themixture was stirred at 15°C-20°C for several minutes, to which the reaction mixture was slowly added (Boc )20 (229g) in DCM ( 500ml) at 15 DC -20 DC. The reaction was continued below 25 DCuntil completion. The precipitate was collected by filtration and washed with DCM (500ml). Thefinal compound 11 was purified by recrystallization with ethyl acetate to yield compound 11(160g).Example 2.4: Preparation of 3-Hydroxy-8-morpholin-4-yl-4-oxo-4//-pyrido[l, 2- α]pyrimidine-2-carboxylic acid methyl ester; rt t-Butanol 2-Picolinic acid was reacted with thionyl chloride and methanol to provide methyl 4- chloro-2-picolinate which was hydrolysed and the hydrochloride salt and subjected to a Curtius rearrangement. Cleavage of the Boc protecting group afforded 2-amino-4- chloropyridine. The procedure described in W02006040520 was adapted to introduce the morpholine at position 4. This was cyclised to the intermediate ester using an adaptation of the procedure described in where the reaction was performed at 60° C.A stirred solution of 4-chloropicolinic acid (0.2 g, 1.269 mmol), DPPA (0.351 g, 1.269 mmol) and TEA (0.354 mL, 2.54 mmol) in tert-butanol (15 mL) was purged with nitrogen for 5 min and the reaction mixture was heated at 100° C. for 12 h. A stirred solution of 4-chioropicolinic acid (0.2 g, 1.269 mmol), DPPA (0.35 1 g, 1.269 mmol) and TEA (0.354 mL, 2.54 mmol) in tert-butanol (15 mL)was purged with nitrogen for 5 mm and the reaction mixture was heated at 100 °C for 12 h. The mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3X1 5 mL). The combined organic extracts were washed with brine (11 mL), dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel chromatography(15percent Ethyl acetate in hexane) to yield tert-butyl (4-chloropyridin-2-yl)carbamate(0.17 g, 0.743 mmol, 59percent yield) as a yellow solid. ‘H NMR (400 MHz, CD3OD)8.23 (d, J 5.2 Hz, 1H), 7.88 (d, J 5.2 Hz, 1H), 7.16 (m, 1H), 1.48 (s, 9 H).

Molecular Weight:228.67
XLogP3:2.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:228.0665554
Monoisotopic Mass:228.0665554
Topological Polar Surface Area:51.2
Heavy Atom Count:15
Complexity:228
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes