Methyl 4-chloropicolinate

Brown Solid

Preparation of (R)-4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-(1-(hydroxyamino)-1-oxopropan-2-yl)picolinamide (Compound 1)Step 1a. Methyl 4-chloropicolinate (Compound 102); Anhydrous DMF (10 mL) was slowly added to SOCl77 Kg of chlorobenzene, 50 Kg of 2-picolinic acid, 6.7 Kg of sodium bromide, 360 g of water, Stirring the temperature to 72 ° C and control the temperature at60 ~ 72 ° C between the sulfide sulfone 270Kg dripping, slowly warming to reflux, the reaction 16 hours, most of the distillation of thionyl chloride under reduced pressure, adding 160Kg toluene, evaporated under reduced pressure thionyl chloride. Cooled to 10 ° C, 70 Kg of methanol was added dropwise, and the mixture was refluxed for 1 hour. The methanol was evaporated under reduced pressure and filtered to give a yellow solid. Add 150Kg of water dissolved, stirring slowly into the sodium carbonate solid neutralization to ρΗ7, filtered to obtain a yellow solid. The solid was recrystallized from water and air dried at 40 ° C to give a white crystal of 49.5 kg, yield 71.0 ο Μ 40 ^ 42 ° C, HPLC 99.6percent 0Example 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 mixture of picolinic acid (10.0 g, 81.0 mmol, 1 equiv.) and sodium bromide (16.7 g, 162.0 mmol, 2 equiv.) in thionyl chloride (41 mL) was refluxed for 5 h at 80° C. After that, the solvent was removed under the vacuum at 85° C. to afford the brown residue. 80 mL of anhydrous methanol was slowly added into the residue and the mixture was stirred at room temperature for half an hour. The solvent was evaporated, and the residue was taken up in the saturated sodium bicarbonate and extracted with ethyl acetate (three times). The organic layers were combined, washed with saturated brine, dried over anhydrous NaTo a cooled (0 °C) solution of picolinic acid (5.0 g, 40.6 mmol) in SOCl60 mi Thionylchloride are heated to a temperature of 45 °C under a nitrogen atmosphere and 1.83 mi DIMETHYLFORMAMIDE is added slowly. 20 g Pyridin-2-carboxylic acid is added to the solution in portions, the reaction mixture is stirred another 15 min at 45 °C and then heated to 80 °C for 24 hrs. The reaction mixture is evaporated and the resulting residue treated with dry toluene as a carrier and then evaporated. This procedure is repeated several times. The resulting oil is dissolved in toluene, cooled to 0 °C, slowly treated with methanol and stirred for one hour. The resulting precipitate is filtered by suction, washed with toluene and recrystallised from acetone. Yield : 15 g (44 percent) 1, colourless crystals1) Synthesis of (4-Chloropvridine-2-carboxylic acid)-methvlamide (2) ci I 1. SOC12 CH NH DMF MgClz _ O \ THF O 2. MeOH N N Toluene 1 60 ml of thionylchloride are heated to 45 °C under a N2 atmosphere, and slowly mixed with 1.83 ml dimethyl formamide. To this solution, 20 g of pyridine-2-carboxylic acid are added portion wise. The reaction mixture is stirred for another 15 min at 45 °C and subsequently kept at 80 °C for 24 hours. The reaction mixture is evaporated to dryness, the residue is stripped several times with water free toluene. The oil obtained by this procedure is dissolved in toluene, chilled to 0 °C, slowly mixed with methanol and stirred for 1 hour. The precipitated solid is separated by suction filtration, washed with toluene and recrystallized from acetone. Yield : 15 g (44 percent) of 1, colorless crystalsAnhydrous DMF (1 mL) was slowly added to sulfurous di chloride (30 mL) at 45 °C. The solution was stirred at room temperature for 10 min, and then picolinic acid (10 g, 81 mmol) was added over 30 min. The resulting solution was heated at 72 °C for 16 hours to generate a yellow solid. The mixture was cooled to room temperature, diluted with toluene (50 mL) and concentrated to 20 mL. The toluene addition/ concentration process was repeated twice. The resulted solid was added into 20 mL methanol at ice bath to keep the internal temperature below 55 °C. The mixture was stirred at room temperature for 45 min, cooled to 5 °C and treated with ethyl ether (20 mL) dropwise. The resulted solid was filtered, washed with ethyl ether (20 mL) and dried under 35 °C to provide a white yellow solid. After the solid was solvated with hot water (50 mL, 45 °C), sodium bicarbonate aqueous solution was added to adjust pH to 8-9. The mixture was extracted with ethyl acetate (2 x 30 mL) and the organic phase was concentrated to give desired compound (5.5 g, yield: 39.6percent) as a off-white solid.To 150 g of thionyl chloride, 38 g of a mixture of 2-pyridinecarboxylic acid hydrochloride and methyl 2-pyridinecarboxylate hydrochloride and 3 g of sodium bromide were added, Slowly warmed to reflux and then maintained at reflux for 16 h. After cooling down to 40 ° C, 200 g of toluene was added, the thionyl chloride was distilled off under reduced pressure, the temperature was lowered to 10 ° C, and 50 g of methanol was added dropwise and refluxed for 2 h. And then cooled to 0 ° C. The filtrate was washed with toluene and suspended in 10 ° C water. Sodium carbonate was added to precipitate a pale yellow solid. The solid was filtered off, recrystallized from water and dried at room temperature for 18 hours to obtain 25 g of white needle crystals.Step 1 [0216] To a suspension of 4-chloropyridine-2-carboxylic acid (4.5 g, 29.0 mmol) in methylene chloride (120 mL) was added oxalyl chloride (3.0 mL, 1.2 eq) under Ar2. The reaction was cooled to 0° C., added 500 uL of DMF. A large amount of gas was generated in situ. The reaction was stirred at room temperature for 1.5 h then concentrated. Dry MeOH (50 mL) was added to the crude acyl chloride residue. The reaction was stirred at room temperature for 0.5 h then quenched with NaHCO3 (5percent) to neutral, extracted with EtOAc, and washed with brine. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give 5.0 g of crude solid which was triturated with 5percent EtOAc/hexane to give the desired intermediate methyl ester as a light yellow solid (4.5 g, 90percent).Compound 5 was prepared according to a modified procedure (WO2013/057253). To a suspension of the commercially available 4-chloro-pyridine-2-carboxylic acid 4 (5.0 g, 31.84 mmol) in dichloromethane (135 ml) at 0 °C was added oxalyl chloride (4.8 g, 38.21 mmol), followed by a slow addition of catalytic amount of dimethylformamide (0.55 ml). The resulting mixture was stirred at room temperature for 2 h. After this time, the mixture was concentrated to dryness under reduced pressure. The solid residue was solubilized in methanol (55 ml) and was stirred at room temperature for another 16 h. The mixture was concentrated to dryness under reduced pressure, and the residue re-suspended with 5percent aq. NaHCC>3. The product was extracted with EtOAc (2 x 20 ml). The combined organic layer was washed with brine (2 [00091] 4-Chloropicolinic acid methyl ester (CYD-1-1). A mixture of picolinic acid (10.0 g, 81.0 mmol, 1 equiv.) and sodium bromide (16.7 g, 162.0 mmol, 2 equiv.) in thionyl chloride (41 mL) was refluxed for 5 h at 80°C. After that, the solvent was removed under the vacuum at 85°C to afford the brown residue. 80 mL of anhydrous methanol was slowly added into the residue and the mixture was stirred at room temperature for half an hour. The solvent was evaporated, and the residue was taken up in the saturated sodium bicarbonate and extracted with ethyl acetate (three times). The organic layers were combined, washed with saturated brine, dried over anhydrous NaTo a solution of picolinic acid (150 g, 1.22 mol) and sodium bromide (20.1 g, 0.197 mol) in chlorobenzene (200 mL), thionyl chloride (355 mL, 4.88 mol) was added slowly at room temperature. The reaction mixture was stirred at 50 °C for 30 min, and heated to 85 °C and stirred for another 20 h. The completion of reaction was determined by TLC, at which point the solvent was removed under reduced pressure to give a brown oil, which was immediately dissolved in toluene (300 mL). Then anhydrous methanol (80 mL) was added dropwise in an ice-bath. The mixture was stirred at 15 °C for 1.5 h. The precipitate was filtered out and dissolved in CH(Production Example 21) Methyl 4-chloropyridine-2-carboxylate 60 ml Thionylchloride are heated to a temperature of 45 °C under a nitrogen atmosphere and 1.83 ML Dimethylformamide is added slowly. 20 g Pyridin-2-carbonic acid is added to the solution in portions, the reaction mixture is stirred another 15 min at 45 °C and then heated to 80 °C for 24 hrs. The reaction mixture is evaporated and the resulting residue treated with dry toluene as a carrier and then evaporated. This procedure is repeated several times. The resulting oil is dissolved in toluene, cooled to 0 °C, slowly treated with methanol and stirred for one hour. The resulting precipitate is filtered by suction, washed with toluene and recrystallised from acetone. Yield : 15 g (44 percent) 10, colourless crystals 60 ML thionyl chloride are heated to 45 °C under a nitrogen atmosphere and treated slowly with 1.83 ML DIMETHYLFORMAMIDE. To this solution, 20 g pyridine-to-carbonic acid are added in portions and the reaction mixture stirred another 45 minutes at the same temperature and then heated to 80 °C for 24 hours. The reaction mixture is evaporated and the resulting residue treated with dry toluene as a carrier and then evaporated. This procedure is repeated several times. The resulting oil is dissolved in toluene, cooled to 0 °C, slowly treated with methanol and stirred for one hour. The resulting precipitate is filtered by suction, washed with toluene and recrystallised from acetone. Yield : 15 G (45percent) of compound 17, colourless crystals4-Chloro-pyridine-2-carboxylic acid methyl ester (according to a modified procedure described by Varlet, D. et al, Heterocycles, 2000, 53(4), 797): A green suspension of 2-picolinic acid (50.0 g, 406 mmol) in thionyl chloride (200 mL) was warmed to reflux. After 41 h, the clear, red-orange solution was cooled to rt and the excess thionyl chloride was removed via rotary evaporation to obtain a red-orange liquid containing a small amount of solid. Dichloroethane (200 mL) was added, and the reaction was concentrated. The above process was repeated a second time to obtain an orange residue. Diethyl ether (1.4 L) was added to obtain a suspension and the reaction mixture was cooled to 0Method P Method P EXAMPLE 21 69A: 4-Chloropicolinic acid (200 mg, 1.27 mmol) was dissolved in a mixture of 2 mL of THF and 600 of methanol and cooled to 0°C. Trimethylsilyldiazomethane (552 L, 1.1 mmol) were added dropwise (strong gas evolution). The solution was stirred for 3 hours at 0°C, then overnight at room temperature. After that time, a few drops of acetic acid were added, followed by water. The aqueous solution was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Compound 69A was obtained as a white crystalline solid (210 mg, 96percent yield). NMR (ppm, CDC1A mixture of picolinic acid (Aldrich) (20 g, 162 mmol, [1] equiv) and sodium bromide (33.43 g, 325 mmol, 2 equiv) in thionyl chloride (81 mL) was refluxed for 5 h. The solvent was removed under vacuum. Absolute methanol (160 mL) was added and the mixture was stirred at rt for 30 minutes. The solvent was evaporated, and the residue was taken up in 5percent sodium bicarbonate and extracted with ethyl acetate (3x). The organic layers were combined and dried over [MGS04] and evaporated. The residue was purified by chromatography to give 4- chloropicolinic acid methyl ester as a white solid (19.9 g, 72percent) [: 1H] NMR (300 MHz, [CDC13)] 8 8.63 (d, J= 5.4, 1), 8.13 (d, J= 2.1, 1), 7.48 (dd, J= 2.0, 5.3, 1), 4.00 (s, 3). [[0217]] A mixture of 4-chloropicolinic acid methyl ester (2.4 g, 14.1 mmol), 57percent hydroiodic acid (13.3 mL) and 50percent aqueous hypophosphorous acid (0.66 mL) was stirred at 85 [°C] for 2 h and then was stirred at [107 °C] overnight. The mixture was cooled to 95 [°C.] At this temperature over 30 minutes 10 M sodium hydroxide aqueous solution (4.2 mL) was added, followed by the addition of water (15.2 mL). The mixture was cooled to rt and stirred at rt for [LH.] The precipitate was filtered, washed with cold water and dried under high vacuum overnight to give 4-iodopipecolinic acid 13a (3.5 g, [66percent) : 1H] NMR (300 MHz, DMSO d6) 8 8. [39] (d, [J=] 5.1, 1), [8. 35] (d, [J= 1.] 8, 1), 8.07 (dd, [J= 1.] 7, 5. 2, [1) ;] MS (ESPOS): 250.2 [M + H] [+.] [[0218]] To a mixture of 7-Me MTL HCl salt 2b [(RAPOS;=ME, ] R2=Me) (200 mg, 0.69 mmol, [1] equiv) in dry DMF (1.8 mL) at [0 °C] was added triethylamine (0.50 mL, 3.61 mmol, 5.2 equiv), followed by the addition of BSTFA (0.28 mL, 1.04 mmol, 1.5 equiv). The reaction mixture was stirred at [0 °C] for 10 minutes, and then was stirred at rt for 50 minutes. To the reaction mixture was added the acid 13a (341 mg, 0.90 mmol, 1.3 equiv) and HATU (423 mg, 1.11 mmol, 1.6 equiv). The reaction mixture was stirred at rt for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate, washed with water [(1] x), sat. [NAHC03] [(1] x) and brine. The organic layer was dried over [NA2S04] and evaporated to give a yellow residue which was dissolved in methanol (20 mL) to which was added dry Dowex resin (250 mg). The reaction mixture was stirred at rt for 1 h. The resin was removed by filtration and the crude product eluted with 2M ammonia in methanol. The methanolic eluent was evaporated, and the resulting residue was purified by chromatography to provide a white solid 13b (Rl=Me, R2= Me, [R3=H)] (250 mg, 75percent) [: LH NMR] (300 MHz, CD30D) 8 8.46 (d, [J= 1.] 8, 1), 8.30 (d, J= 5.4, 1), 7.98 (dd, J= 1.8, 5.1, 1), 5.25 (d, J= 6.0, 1), 4.32-4. 23 (m, 2), 4.09 (dd, J= 5.7, 10.2, 1), 3.87 (d, J= 3.0, 1), 3.54 (dd, J= 3.3, 10.2, 1), 2.24-2. 15 (m, 1), 2.11 (s, 3), 0.99-0. 96 (m, 6); MS (ESPOS): [483.] 5 [M + [H] +] ; MS (ESNEG): 481.4 [[M-H]-.] [0219] To a dry flask was added 13b [(RL=ME, ] R2= Me, R3=H) (133.9 mg, [0.] 28 mmol, 1 equiv), triphenylphosphine (46.7 mg, 0.18 mmol, 0.64 equiv), copper (I) iodide [(33.] 9 mg, 0.18 mmol, 0.64 equiv), palladium acetate (20 mg, 0.09 mmol, 0.32 equiv) and triethylamine (1.6 mL). The mixture was deaerated with nitrogen, followed by addition of 3-prop-2-ynyl- cyclopentane (120 mg, [1.] 11 mmol, 4 equiv). The mixture was stirred at 50 oC overnight. The solvent was removed under vacuum to give a dark residue. The residue was purified by chromatography to give 13c (Rl=Me, R9'= 3-cyclopentyl-prop-1-ynyl, R2= Me, R3=H) as a yellow solid (106 mg, 83percent): 1H NMR (300 [MHZ, CD30D) 6] 8.55 (d, J= 4.8, 1), 7.98 (s, 1), 7.47 [(DD, ] [J=] 1.7, 5.0, 1), 5.26 (d, [J=] 5.4, [1), ] 4. [33-4.] 22 (m, 2), 4.10 (dd, [J=] 5.5, 10.4, 1), 3.86 (d, J= 3.3, 1), 3.55 (dd, J= 3.3, 10.5, 1), 2.49 (d, J= 6.9, 2), 2.26-2. 12 (m, 2), 2.11 (s, 3), 1.93- 1.82 (m, 2), 1.73-1. 55 (m, 4), 1.43-1. 31 (m, 2), 1.00-0. 96 (m, 6); MS (ESPOS): 463.6 [M [+ H] +] ; MS (ESNEG): 461.5 [M-H]-.Anhydrous DMF (1 mL) was slowly added to sulfurous dichloride (30 mL) at 45 °C. The solution was stirred at room temperature for 10 mm, and then picolinic acid (10 g, 81 mmol) was added over 30 mm. The resulting solution was heated at 72 °C for 16 hours to generate yellow solid. The mixture was cooled to room temperature, diluted with toluene (50 mL) and concentrated to 20 mL. The toluene addition/concentration process was repeated twice. Theresulting solution and solid was added into 20 mL methanol at ice bath to keep the internal temperature below 55 °C. The mixture was stirred at room temperature for 45 mm, cooled to 5°C and treated with ethyl ether (20 mL) dropwisely. The resulting solid was filtered, washed with ethyl ether (20 mL) and dried under 35 °C to provide a white yellow solid. After the solid were solvated to hot water (50 mL, 45 °C), sodium bicarbonate aqueous solution was added to adjustpH to 89. The mixture was extracted with ethyl acetate (2 x 30 mL) and the organic phase was concentrated to give desired compound (5.5 g, yield: 3 9.6percent) as off-white solid.2-Picolinic acid (15 g, 0.122 mol) was slowly added to thionyl chloride (50 mL) at a temperature range of 45-50 °C under stirring. Then the solution was heated to 72 °C, and kept refluxing for about 14 h. After cooled to room temperature, the mixture was diluted with toluene (100 mL), and concentrated to near dryness in vacuo. To the obtained oily residue, methanol (40 mL) was added. The contents were stirred for 2 h at 30 °C. After filtration, the filter cake was added 15percent NaStep 1 Picolinic acid (1) (30.84g, 250mmol) was added dropwise to the stirring thionyl chloride (50mL). The resulting mixture was heated at reflux for 3 days giving a clear orange solution. After cooling to ambient temperature, the solution was concentrated to small volume and the residue coevaporated with toluene (2×20mL). The residue was dissolved in toluene (40mL) and cooled to 0–5°C. Methanol (16mL) was then added dropwise to the cold reaction mixture and stirred for 1h giving a white precipitate. This precipitate was collected by filtration, washed with toluene (3×10mL), and dried at 40°C for 24h to give compound methyl 4-chloropicolinate (2) as a white crystal [25]. Yield: 32.49g, 76percent. mp:131–132°C. 112.5 mL of thionyl chloride was added to a 250 mL reaction flask and 2-picolinic acid (34 g, 0.275 mol) was added in portions at 45 ° C with constant stirring, The reaction heated at reflux for 14h.Stop the reaction, Cooled to room temperature, Adding 200 mL of toluene, Recovery of toluene by distillation under reduced pressure, A yellow solid-liquid mixture was obtained.Add 60 mL of methanol, The reaction was stirred at room temperature (20-30 ) for 2h, Filter, neutralize, dry, To give 36.9 g of a pale yellow solid, Yield 78.5percentMp: 52-54 ° C, Content of 98.8percent (HPLC)..) a) 750 ml of thionyl chloride were heated to 45°C under an N2 atmosphere, and 23 mi of DMF were added dropwise. 250 g (2.031 mol) of pyridine-2-carboxylic acid were subsequently added in portions, and the reaction mixture was stirred at 45°C for a further 15 minutes and at 80°C for 24 hours. The yellow suspension was evaporated, and the residue was entrained a number of times with toluene. The oily residue was dissolved in 180 ml of toluene, the solution was cooled to 0°C, and 110 ml of methanol were added dropwise. The suspension was stirred for a further hour, and the precipitated solid was filtered off with suction and rinsed with toluene. The resultant crude product was recrystallised a number of times from acetone and dried in a vacuum drying cabinet. Yield : 140 g (33percent) of 7, pale crystals

Molecular Weight:171.58
XLogP3:1.7
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:171.0087061
Monoisotopic Mass:171.0087061
Topological Polar Surface Area:39.2
Heavy Atom Count:11
Complexity:151
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes