Methyl 6-(hydroxymethyl)nicotinate

Step 1. Synthesis of methyl 6-(hydroxymethyl)nicotinate (55):A mixture of dimethyl pyridine-2, 5-dicarboxylate (54; 100.0 g, 0.51 mol), CaClPreparation 113 Calcium chloride (29.92 g, 269.6 mmol), ethanol(390 mE), and THF (390 mE) were input into a reactor in anAr atmosphere, and subsequently sodium borohydride (20.40g, 539.2 mmol) was introduced into the reactor under ice- cooling in portions. Afier introduction of sodium borohydride, the reaction solution was stirred under ice-cooling for 2.5 hours. A compound T (30.09 g, 134.8 mmol) was introduced into the reaction solution under ice-cooling in portions, and the reaction solution was stirred under ice-cooling for 30 minutes. The reaction solution was poured into ice water (1.5 L), and then ammonium chloride (300 g) was added to the reaction solution while being stirred. A target compound was extracted with ethyl acetate (1 Lx2). The organic layer was washed with water (1 L) and saturated saline (1 L) sequentially. The organic layer was dried over magnesium sulfate, and then a solvent in the organic layer was distilled off under reduced pressure to obtain a light yellowish brown solid compound 9(16.12 g, yield: 66.0percent).NaBH4 (2.4 g, 64 mmol) wasadded dropwise to the mixture of compound 37 (5 g, 25.6 mmol) and CaCl2 (11.4 g, 102.6 mmol) inTHF (25 mL)/EtOH (25 mL) at 0 °C. After completion, the reaction was quenched with water. Theaqueous phase was extracted with EtOAc. The combined organic phases were then processed in theusual way and chromatographed (1:1 petroleum ether/EtOAc) to yield compound 38 (2.5 g, 58percent).Compound 24 (5 g, 25.6 mmol)And calsium chloride | beggar (11.4g, 102.6mmol)Was added to THF (25 mL) and ethanol(25 mL) in a mixed solution, Stirring at room temperature for 30 minutes, Then cool down to 0 ° C, Sodium borohydride (2.4 g, 64 mmol) was added in portions, TLC to track the degree of completion of the assay, After the completion of the reaction, Ethyl acetate extraction, concentrate, Column chromatography to give compound 25 (2.5 g, 58.1percent)Description 118Methyl 6-(hydroxymethyl)nicotinate (D118)HONLL(O0A solution of dimethyl pyridine-2, 5-dicarboxylate (5 g) in T1{F (50 mL) was cooled to 0°C and then NaBH4 (1.454 g) was added in several portions. The reaction mixture was stirred at RTovernight, aq NII4C1 solution (50 mL) was added and the mixture was extracted with EtOAc (3 x20mL). The combined organic layer was dried over Na2SO4, Filtered, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleumether/EtOAc = 5:1) to afford the title compound (3 g) as white solid. MS (ESI): C8H9N03 requires 167; found 168 [M+H].[1157] A 50 ml flask containing methyl 6-[(acetyloxy)methyl]nicotinate (1.5 g, 7.2 mmol) in CH3OH (7.5 ml) is heated to 40° C. until the solid completely dissolves. To this solution, K2CO3 (0.03 g, 0.2 mmol) is added, and the reaction mixture is stirred at rt for 2 h. The reaction mixture is extracted with CH2Cl2 (3.x.15 ml) and the combined organic layers are dried (NaSO4), filtered, and concentrated under vacuum to give a white solid (1.1 g, 6.4 mmol, 89percent) for methyl 6-(hydroxymethyl)nicotinate. This compound is used without further purification. MS (ESI+) for C8H9O3 m/z 168.2 (M+H)+.To a solution of 5-(methoxycarbonyl)-2-methylpyridine 1 -oxide (12 g, 72 mmol) in DCM (50 mL) was added TFAA (25 mL) dropwise at 0 °C. The mixture was stirred at reflux for 2 hours. The mixture was concentrated and the residue was adjusted to pH 9 with saturated aqueous NaHCCh. The resulting mixture was extracted with EA. The solvent was removed and the residue was purified by column chromatography on silica gel (PE/EtOAc = 1/1) to afford methyl 6-(hydroxymethyl)nicotinate(7 g, 58percent). MS-ESI (m/z): 168.2 (M+l) (b) 4B. 6-Hydroxymethyl-nicotinic acid methyl ester Diisobutylaluminum hydride (1.5 M solution in toluene, 9.82 mL) was added dropwise to a solution of 6-(methoxy-methyl-carbamoyl)-nicotinic acid methyl ester (1.1 g, 4.91 mmol) in THF (50 mL) at -78° C. over 10 minutes. The reaction mixture was stirred for 2 hours at -78° C., quenched with 5percent HCl/ethanol and warmed to room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was taken up in saturated KStep 1. Synthesis of To a solution of dimethyl pyridine-2, 5-dicarboxylate 8 (CAS Reg. No. 881-86-7, 5 g, 25.6 mmol) in THF (50 mL)/MeOH (100 mL) was added calcium chloride (11.37 g, 102 mmol). The reaction mixture was sonicated for 5 min and cooled to 0 C. Sodium borohydride (2.423 g, 64.0 mmol) powder was added slowly (gas evolution). The mixture was stirred at 0 C. for 2 h, after which LCMS showed completion of the reaction. The reaction was quenched by addition of ice and extracted with CHCl3 and dried over Na2SO4 to provide compound 9 as an off-white solid (93% yield). LCMS ESI: calculated for C8H9NO3=167.05 (M+H+), found 168.0 (M+H+).Preparation 113 6-Hydroxymethyl-nicotinic acid methyl ester Add 2, 5-pyridinedicarboxylic acid dimethyl ester (15 g, 76.8 mmol), calcium chloride (34.12 g, 307.4 mmol), ethanol (100 mL) and tetrahydrofuran (100 mL) into a reaction flask. Cool the mixture to 0 C. Add sodium borohydride (3.49 g, 92.3 mmol) slowly to the reaction mixture. Maintain the temperature of the reaction mixture at 0 C. and stir the mixture for 7 hrs. Remove the solid by filtration. Pour the mixture onto ice. Extract with dichloromethane (100 mL*4). Combine organic layers and dry with sodium sulfate. Remove solvent under reduced pressure to give 9.6 g (75% yield) of the crude product of Calcium chloride (29.92 g, 269.6 mmol), ethanol(390 mE), and THF (390 mE) were input into a reactor in anAr atmosphere, and subsequently sodium borohydride (20.40g, 539.2 mmol) was introduced into the reactor under ice- cooling in portions. Afier introduction of sodium borohydride, the reaction solution was stirred under ice-cooling for 2.5 hours. A compound T (30.09 g, 134.8 mmol) was introduced into the reaction solution under ice-cooling in portions, and the reaction solution was stirred under ice-cooling for 30 minutes. The reaction solution was poured into ice water (1.5 L), and then ammonium chloride (300 g) was added to the reaction solution while being stirred. A target compound was extracted with ethyl acetate (1 Lx2). The organic layer was washed with water (1 L) and saturated saline (1 L) sequentially. The organic layer was dried over magnesium sulfate, and then a solvent in the organic layer was distilled off under reduced pressure to obtain a light yellowish brown solid compound 9(16.12 g, yield: 66.0%).NaBH4 (2.4 g, 64 mmol) wasadded dropwise to the mixture of compound 37 (5 g, 25.6 mmol) and CaCl2 (11.4 g, 102.6 mmol) inTHF (25 mL)/EtOH (25 mL) at 0 C. After completion, the reaction was quenched with water. Theaqueous phase was extracted with EtOAc. The combined organic phases were then processed in theusual way and chromatographed (1:1 petroleum ether/EtOAc) to yield compound 38 (2.5 g, 58%).Compound 24 (5 g, 25.6 mmol)And calsium chloride | beggar (11.4g, 102.6mmol)Was added to THF (25 mL) and ethanol(25 mL) in a mixed solution, Stirring at room temperature for 30 minutes, Then cool down to 0 C, Sodium borohydride (2.4 g, 64 mmol) was added in portions, TLC to track the degree of completion of the assay, After the completion of the reaction, Ethyl acetate extraction, concentrate, Column chromatography to give compound 25 (2.5 g, 58.1%)Sodiumborhydride (0.51 g, 13.5 mmol) was added portionwise at O0C to a stirring suspension of pyridine-2, 5-dicarboxylic acid dimethyl ester (1.05 g, 5.38 mmol) and calcium choride (2.39 g, 21.5 mmol) in THF/methanol 1:2 (33 mL). After stirring overnight at O0C 20 mL water were added and the solvent was removed in vacuo. The aqueous residue was extraxted with DCM (3 x 30 mL), the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 1 :1) to give the title compound. MS (m/z): 167.9 [M+H*]To a mixture of dimethyl pyridine-2, 5-dicarboxylate (3.08 g, 15.78 mmol) and calcium chloride (7.01 g, 63.1 mmol) in tetrahydrofuran (33 mL) and EtOH (67 mL) was added sodium borohydride (1.493 g, 39.5 mmol) in portions at 0 C. The reaction mixture was stirred at 0 C for 12 hrs. The mixture was poured into ice/water, was diluted with dichloromethane (400 mL) and stirred vigorously for 15 minutes. The separated organic layer was dried over magnesium sulfate, filtered off and concentrated under reduced pressure providing To a mixture of dimethyl pyridine-2, 5-dicarboxylate (3.08 g, 15.78 mmol) and calcium chloride (7.01 g, 63.1 mmol) in tetrahydrofuran (33 ml_) and EtOH (67 ml_) was added sodium borohydride (1.493 g, 39.5 mmol) in portions at 0 C. The reaction mixture was stirred at 0 C for 12 hrs. The mixture was poured into ice/water, was diluted with dichloromethane (400 ml_) and stirred vigorously for 15 minutes. The separated organic layer was dried over magnesium sulfate, filtered off and concentrated under reduced pressure providing To a mixture of dimethyl pyridine-2, 5-dicarboxylate (3.08 g, 15.78 mmol) and calcium chloride (7.01 g, 63.1 mmol) in tetrahydrofuran (33 mL) and EtOH (67 mL) was added sodium borohydride (1 .493 g, 39.5 mmol) in portions at 0 C. The reaction mixture was stirred at 0 C for 12 hrs. The mixture was poured into ice/water, was diluted with dichloromethane (400 ml.) and stirred vigorously for 15 minutes. The separated organic layer was dried over magnesium sulfate, filtered off and concentrated under reduced pressure providing Step 1: Intermediate 32-b To a solution of dimethyl pyridine-2, 5-dicarboxylate (13.0 g, 66.6 mmol) in a mixture of THF (110 mL) and ethanol (110 mL) was added calcium chloride (29.6 g, 266 mmol). After stirring at room temperature for 30 minutes the reaction was cooled to 0C and sodium borohydride (3.78 g, 100 mmol) was added portion wise. After the addition was completed the reaction was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride and dichloromethane were added, the organic layer was separated and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure to provide intermediate 32- b as a yellow solid.To a solution of dimethyl pyridine-2, 5-dicarboxylate 59-a (13.0 g, 66.6 mmol) in a mixture of THF (110 mL) and ethanol (110 mL) was added calcium chloride (29.6 g, 266 mmol). After stirring at room temperature for 30 minutes, the reaction was cooled to 0C, and sodium borohydride (3.78 g, 100 mmol) was added portion wise. After the addition was completed the reaction was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride and dichloromethane were added, the organic layer was separated and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to provide Intermediate 59-b as a yellow solid.To a solution of dimethyl pyridine-2, 5-dicarboxylate 21-a (13.0 g, 66.6 mmol) in a mixture of THF (110 mL) and ethanol (110 mL) was added calcium chloride (29.6 g, 266 mmol). After stirring at room temperature for 30 minutes, the reaction was cooled to 0C, and sodium borohydride (3.78 g, 100 mmol) was added portion wise. After the addition was completed the reaction was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride and dichloromethane were added, the organic layer was separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to provide Intermediate 21-b as a yellow solid.Step 1: Intermediate 32-b [0185] To a solution of dimethyl pyridine-2, 5-dicarboxylate (13.0 g, 66.6 mmol) in a mixture of THF (110 mL) and ethanol (110 mL) was added calcium chloride (29.6 g, 266 mmol). After stirring at room temperature for 30 minutes the reaction was cooled to 0 C. and sodium borohydride (3.78 g, 100 mmol) was added portion wise. After the addition was completed the reaction was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride and dichloromethane were added, the organic layer was separated and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to provide intermediate 32-b as a yellow solid.Description 118Methyl 6-(hydroxymethyl)nicotinate (D118)HONLL(O0A solution of dimethyl pyridine-2, 5-dicarboxylate (5 g) in T1{F (50 mL) was cooled to 0C and then NaBH4 (1.454 g) was added in several portions. The reaction mixture was stirred at RTovernight, aq NII4C1 solution (50 mL) was added and the mixture was extracted with EtOAc (3 x20mL). The combined organic layer was dried over Na2SO4, Filtered, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleumether/EtOAc = 5:1) to afford the title compound (3 g) as white solid. MS (ESI): C8H9N03 requires 167; found 168 [M+H].The mixture of dimethyl pyridine2, 5dicarhoxylate (200 g, 1.03 mol) in MeOH (2400ml) and THF (2200 ml) was added CaC12 (455 g, 4.iOmoi) and NaB1-14 (97 g, 2.56 mol) below10 d. The mixture was stirred below 0 C for 3 hours. The mixture was added NH4CI (15%, 2000 ml), and the temperature maintain below 5 C. Then, the solution was extracted with B A(500 ml x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated togive the crude product. The crude product was washed with PE: DCM=5:1 to give methyl 6(hydroxymethyl) nicotinate as a solid. 'H NMR:400 MFIz CDC13: oe . 052 (s, 11-i), 8.3i58.29()(in, 1H), 7.381-7.359 (m, 1H), 4.845 (s, 2H), 3.969 (s, 3H) ppm.Step 2. Methyl 6-(hydroxymethyl)nicotinate The mixture of dimethyl pyridine-2, 5-dicarboxylate (200 g, 1.03 mol) in MeOH (2400 ml) and THF (2200 ml) was added CaCl2 (455 g, 4.10mol) and NaBH4 (97 g, 2.56 mol) below -10 C. The mixture was stirred below 0 C for 3 hours. The mixture was added NH4C1 (15%, 2000 ml), and the temperature maintain below 5 C. Then, the solution was extracted with EA (500 ml x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated to give the crude product. The crude product was washed with PE: DCM=5: 1 to give methyl 6-(hydroxymethyl) nicotinate as a solid. 1H NMR: 400 MHz CDC13: delta 8.052 (s, 1H), 8.315-8.290 (m, 1H), 7.381-7.359 (m, 1H), 4.845 (s, 2H), 3.969 (s, 3H) ppm.To a methanol (68 mL)-THF (34 mL) solution of methyl 6-methoxycarbonylnicotinate (3.00 g, 15.4 mmol), potassium chloride (6.82 g, 61.5 mmol) was added. Then, the reaction solution was cooled to 0 C., and sodium borohydride (1.46 g, 38.4 mmol) was added. After stirred for 7 hours at 0 C., water (100 mL) was added to the reaction solution, and the product was extracted with chloroform (100 mL) three times. The obtained organic layer was washed with water (100 ml) three times, and dried with sodium sulfate. The solvent was removed under reduced pressure to give a crude crystal of methyl 6-hydroxymethylnicotinate (2.01 g; crude yield, 78%). The product was used for the next reaction without further purification.To a mixture of dimethyl pyridine-2, 5-dicarboxylate (3.08 g, 15.78 mmol) and calcium chloride (7.01 g, 63.1 mmol) in tetrahychofuran (33 mL) and EtOH (67 mL) was added sodium borohydride (1.493 g, 39.5 mmol) in portions at 0 C. The reaction mixture was stirred at 0 C for 12 hrs. The mixture was poured into ice/water, was diluted with dichloromethane (400 mL) and stirred vigorously for 15 minutes. The separated organic layer was dried over magnesium sulfate, filtered off and concentrated under reduced pressure providing

Molecular Weight:167.16
XLogP3:-0.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:167.058243149
Monoisotopic Mass:167.058243149
Topological Polar Surface Area:59.4
Heavy Atom Count:12
Complexity:160
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes