* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With manganese(IV) oxide In dichloromethane at 20℃; for 4 h;
A mixture of methyl 6-(hydroxymethyl)nicotinate (7 g , 37 mmol) and Mn02 (32,3 g , 372 mmol) in DCM ( 200 mL ) was stirred at 20 °C for 4 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE/EtOAc = 5/1) to afford methyl 6-formylnicotinate (6 g , 97percent).MS-ESI (m/z): 166.2 (M+l) + (LC-MS method C; Ret. time: 0.36 min).
97%
With manganese(IV) oxide In dichloromethane at 20℃; for 4 h;
(c) methyl 6-formylnicotinate A mixture of methyl 6-(hydroxymethyl)nicotinate (7 g, 37 mmol) and MnO2 (32.3 g, 372 mmol) in DCM (200 mL) was stirred at 20° C. for 4 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE/EtOAc=5/1) to afford methyl 6-formylnicotinate (6 g, 97percent). MS-ESI (m/z): 166.2 (M+1)+ (LC-MS method C; Ret. time: 0.36 min).
86%
With Dess-Martin periodane In dichloromethane at 20℃; Inert atmosphere
Dess-Martin periodinane (3.0 g, 7.2 mmol) was added slowly to the mixture of compound 38 (1.0 g,6.0 mmol) in DCM (10 mL). The resulting mixture continued to stir at room temperature overnight.The reaction was quenched with water. The aqueous phase was extracted with EtOAc. The combinedorganic phases were then processed in the usual way and chromatographed (3:1 petroleum ether/EtOAc)to yield compound 39 (0.85 g, 86percent).
85.6%
With Dess-Martin periodane In dichloromethane
The A solution of compound 25 (1.0 g, 6. Ommol)Dissolved in dichloromethane (10 mL)in,Add a Dess-Martin periodinane(3.0 g, 7.2 mmo 1)TLC to track the degree of completion of the assay,After the reaction is completed,Water extraction, ethyl acetate extraction,Concentration gave compound 26 (0.6 g, 85.6percent
Stage #1: With calcium chloride In tetrahydrofuran; ethanol for 0.5 h; Stage #2: With sodium tetrahydroborate; ethanol In tetrahydrofuran at 0℃;
Step 1. Synthesis of methyl 6-(hydroxymethyl)nicotinate (55):A mixture of dimethyl pyridine-2,5-dicarboxylate (54; 100.0 g, 0.51 mol), CaCl2 (227.4 g, 2.05 mol), THF (1100 mL) and EtOH (1200 mL) was stirred for 30 min, NaBH4 (48.6 g, 1.28 mol) was added portionwise at 0C. The mixture was stirred for 18 hours. Saturated NH4Cl solution (1.5 L) and water (2.0L) was added slowly, and the resulting mixture was extracted with dichloromethane (3 x 3.0 L). The combined organic solvent was dried over MgSO4 and concentrated to give methyl 6- (hydroxymethyl)nicotinate 55 (82.0 g, 96percent).
75%
With sodium tetrahydroborate; calcium chloride In tetrahydrofuran; ethanol at 0℃;
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 (75percent yield) of the crude product of 6-hydroxymethyl-nicotinic acid methyl ester. MS (m/z): 168.3 (M+1).
66%
With sodium tetrahydroborate; ethanol; calcium chloride In tetrahydrofuran for 0.5 h; Inert atmosphere; Cooling with ice
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).
58%
With sodium tetrahydroborate; calcium chloride In tetrahydrofuran; ethanol at 0℃; for 4 h; Inert atmosphere
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).
58.1%
With sodium tetrahydroborate; calcium chloride In tetrahydrofuran; ethanol at 20℃; for 0.5 h;
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)
3 g
With sodium tetrahydroborate; water In tetrahydrofuran at 0 - 20℃;
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].
Reference：
[1] Patent: WO2010/56549, 2010, A1, . Location in patent: Page/Page column 103
[2] Journal of Organic Chemistry, 2010, vol. 75, # 3, p. 650 - 659
[3] Inorganic Chemistry, 2015, vol. 54, # 22, p. 10542 - 10558
[4] Patent: US2010/16373, 2010, A1, . Location in patent: Page/Page column 16
[5] Patent: US2016/256578, 2016, A1, . Location in patent: Paragraph 0124; 0125
[6] Molecules, 2014, vol. 19, # 1, p. 102 - 121
[7] Patent: CN104418811, 2017, B, . Location in patent: Paragraph 0234-0236
[8] Russian Journal of Organic Chemistry, 2017, vol. 53, # 7, p. 963 - 970[9] Zh. Org. Khim., 2017, vol. 53, # 7, p. 951 - 958,8
[10] Angewandte Chemie - International Edition, 2012, vol. 51, # 24, p. 5852 - 5856
[11] Journal of Medicinal Chemistry, 2004, vol. 47, # 21, p. 5230 - 5234
[12] Tetrahedron, 2008, vol. 64, # 37, p. 8963 - 8973
[13] Patent: WO2009/36996, 2009, A2, . Location in patent: Page/Page column 85-86
[14] Patent: WO2011/26917, 2011, A1, . Location in patent: Page/Page column 107
[15] Patent: WO2011/26904, 2011, A1, . Location in patent: Page/Page column 107
[16] Patent: WO2012/101063, 2012, A1, . Location in patent: Page/Page column 180
[17] Patent: WO2012/101064, 2012, A1, . Location in patent: Page/Page column 223-224
[18] Patent: WO2013/177668, 2013, A1, . Location in patent: Page/Page column 60-61
[19] Journal of the American Chemical Society, 2014, vol. 136, # 29, p. 10450 - 10459
[20] Inorganic Chemistry, 2015, vol. 54, # 4, p. 1901 - 1911
[21] Patent: WO2015/74138, 2015, A1, . Location in patent: Page/Page column 82; 83
[22] Patent: WO2015/77866, 2015, A1, . Location in patent: Page/Page column 48; 49
[23] Patent: US2015/191473, 2015, A1, . Location in patent: Paragraph 0185
[24] Journal of the American Chemical Society, 2015, vol. 137, # 35, p. 11222 - 11225
[25] Patent: WO2015/180612, 2015, A1, . Location in patent: Page/Page column 75
[26] Patent: WO2016/106628, 2016, A1, . Location in patent: Page/Page column 74
[27] Patent: WO2016/109215, 2016, A1, . Location in patent: Page/Page column 58
[28] Patent: US2016/221948, 2016, A1, . Location in patent: Paragraph 0444-0446
[29] Patent: WO2018/140809, 2018, A1, . Location in patent: Paragraph 00409
3
[ 63362-34-5 ]
[ 56026-36-9 ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate In methanol at 20 - 40℃; for 2 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)+.
With trifluoroacetic anhydride In dichloromethane at 0℃; for 2 h; Reflux
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) + (LC-MS method C; Rt: 0.25 min).
58%
With trifluoroacetic anhydride In dichloromethane at 0℃; for 2 h; Reflux
(b) methyl 6-(hydroxymethyl)nicotinate 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 NaHCO3. 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+1)+ (LC-MS method C; Rt: 0.25 min).
Stage #1: With diisobutylaluminium hydride In tetrahydrofuran; toluene at -78℃; for 2.16667 h; Stage #2: With hydrogenchloride; ethanol; water In tetrahydrofuran; toluene
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 K2CO3 and extracted with ethyl acetate (2.x.). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. MeOH (15.0 mL) was added to the crude reaction mixture and cooled to 0° C. Sodium borohydride (0.280 g, 7.20 mmol) was added in two portions to the reaction mixture and stirred at 0° C. for 30 minutes. Additional sodium borohydride (0.136 g, 3.6 mmol) was added to the reaction mixture, warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane (75.0 mL), washed with water and saturated NaHCO3, dried (Na2SO4), filtered and evaporated to yield 6-hydroxymethyl-nicotinic acid methyl ester (0.400 g, 49percent yield) as a solid. 1H NMR (400 MHz, CDCl3) 3.94 (s, 3H), 4.81 (s, 2H), 7.34 (d, 1H), 8.29 (d, 2H), 9.14 (s, 1H).
With phosphorus tribromide In toluene at 0 - 20℃; Heating / reflux
Preparation 31 6-Bromomethyl-nicotinic acid methyl ester [0339] [CHEMMOL-00088] [0340] Phosphorus tribromide (1.4 g; 5.32 mmol) was added slowly to a cooled solution (ice/water/sodium chloride bath) of Preparation 30 (1 g, 5.7 mmol) in toluene (100 ml). The reaction mixture was allowed to warm to RT overnight and then refluxed for one hour. The reaction mixture was cooled to RT and DCM was added. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, then with water, dried over sodium sulfate, and concentrated under reduced pressure to yield an oil (m=0.99 g, yield 76percent) which was used without further purification. 1H NMR (CDCl3): 9.18 (1H, s); 8.35 (1H, d); 7.56 (1H, d); 4.62 (2H, s); 4.00 (3H,s)
With manganese(IV) oxide; In dichloromethane; at 20℃; for 4h;
A mixture of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (7 g , 37 mmol) and Mn02 (32,3 g , 372 mmol) in DCM ( 200 mL ) was stirred at 20 C for 4 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE/EtOAc = 5/1) to afford methyl 6-formylnicotinate (6 g , 97%).MS-ESI (m/z): 166.2 (M+l) + (LC-MS method C; Ret. time: 0.36 min).
97%
With manganese(IV) oxide; In dichloromethane; at 20℃; for 4h;
(c) methyl 6-formylnicotinate A mixture of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (7 g, 37 mmol) and MnO2 (32.3 g, 372 mmol) in DCM (200 mL) was stirred at 20 C. for 4 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE/EtOAc=5/1) to afford methyl 6-formylnicotinate (6 g, 97%). MS-ESI (m/z): 166.2 (M+1)+ (LC-MS method C; Ret. time: 0.36 min).
86%
With Dess-Martin periodane; In dichloromethane; at 20℃;Inert atmosphere;
Dess-Martin periodinane (3.0 g, 7.2 mmol) was added slowly to the mixture of compound 38 (1.0 g,6.0 mmol) in DCM (10 mL). The resulting mixture continued to stir at room temperature overnight.The reaction was quenched with water. The aqueous phase was extracted with EtOAc. The combinedorganic phases were then processed in the usual way and chromatographed (3:1 petroleum ether/EtOAc)to yield compound 39 (0.85 g, 86%).
85.6%
With Dess-Martin periodane; In dichloromethane;
The A solution of compound 25 (1.0 g, 6. Ommol)Dissolved in dichloromethane (10 mL)in,Add a Dess-Martin periodinane(3.0 g, 7.2 mmo 1)TLC to track the degree of completion of the assay,After the reaction is completed,Water extraction, ethyl acetate extraction,Concentration gave compound 26 (0.6 g, 85.6%
71.4%
To a solution of oxalyl chloride (2.0 M in dichloromethane, 8.97 mL) in dichloromethane (35 mL) at -78 C was added (methylsulfinyl)methane (2.55 mL, 35.9 mmol) dropwise. This mixture was allowed to stir at -78 C for 10 minutes then <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (2.0 g, 11.96 mmol, Combi-Blocks) was added. The mixture was allowed to stir for an additional 15 minutes and triethylamine (6.67 mL, 47.9 mmol) was added, and the mixture was stirred for an additional 15 minutes at -78 C. The dry ice-acetone bath was then replaced with an ice-water bath, and the mixture was allowed to stir for 20 minutes. The mixture was quenched with saturated, aqueous NaHC( (15 mL) and the layers were separated. The aqueous layer was extracted with dichlorome thane (3 x 10 mL), and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via column chromatography (Si(, 50% ethyl acetate/heptanes) to give the title compound (1.41 g, 8.54 mmol, 71.4% yield). MS (ESI+) m/z 166 (M+H)+.
With Dess-Martin periodane; In dichloromethane; for 3h;
Dess-Martin reagent (207 mg, 0.49 mmol) was added to a stirring solution of 6- hydroxymethyl-nicotinic acid methyl ester (55 mg, 0.33 mmol) in DCM (17 mL). After stirring for 3 h the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (elution with n-hexane/EA 4:1) to give the title compound.GCMS (m/z): 165.2
With manganese(IV) oxide; In dichloromethane; at 20℃; for 4h;
A mixture of methyl 6-( ydroxymethyi)nicotinate (7 g, 37 mmol) and Mn02 (32,3 g,372 mmoi) in DCM ( 200 mL ) was stirred at 20 Q for 4 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel(PE/EtOAc = 5/i) to afford methyl 6-formylnicotinate. MS-ESI (m/z): 166.2 (M+i) + (LC-.MSmethod D; Ret. time: 0.36 mm).
With manganese(IV) oxide; In dichloromethane; at 20℃;
Intermediate 11-14 Step 1 : methyl 6-formylnicotinate To a solution of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (30 g, 179.6 mmol) in DCM (500 mL) was added MnC>2 (93.8 g, 1077.8 mmol). The mixture was stirred at room temperture overnight. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel eluted with PE/EA = 10/1 to give methyl 6-formylnicotinate. XH NMR (400 MHz, CDC13) delta ppm 3.98 (d, J= 0.78 Hz, 3 H), 8.01 (d, J= 8.0 Hz, 1 H), 8.40 - 8.49 (m, 1 H), 9.29 - 9.38 (m, 1 H), 10.11 (s, 1 H).
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 5% HCl/ethanol and warmed to room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was taken up in saturated K2CO3 and extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. MeOH (15.0 mL) was added to the crude reaction mixture and cooled to 0 C. Sodium borohydride (0.280 g, 7.20 mmol) was added in two portions to the reaction mixture and stirred at 0 C. for 30 minutes. Additional sodium borohydride (0.136 g, 3.6 mmol) was added to the reaction mixture, warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane (75.0 mL), washed with water and saturated NaHCO3, dried (Na2SO4), filtered and evaporated to yield 6-hydroxymethyl-nicotinic acid methyl ester (0.400 g, 49% yield) as a solid. 1H NMR (400 MHz, CDCl3) 3.94 (s, 3H), 4.81 (s, 2H), 7.34 (d, 1H), 8.29 (d, 2H), 9.14 (s, 1H).
(3-[6-({(E)-(1S,3R,5S)-3,5-Bis-[(pyridin-2-ylmethyl)-amino]-cyclohexylimino}-methyl)-pyridine-3-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester[ No CAS ]
With triethylamine; In dichloromethane; at 0℃; for 2h;
[1158] A 100 ml flask containing <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (1.1 g, 6.4 mmol), triethylamine (2.7 ml, 19.2 mmol) and CH2Cl2 (25 ml) is cooled in an ice-bath to 0 C. Methanesulfonyl chloride (1.0 ml, 12.8 mmol) is added dropwise to the mixture and the mixture is allowed to stir at 0 C. for 2 h. The 2.0M Na2CO3 (25 ml) is added to the cool solution, and the mixture is diluted with methyl t-butyl ether (50 ml). The mixture is washed with 2.0M Na2CO3 (2×50 ml) and brine. The ether layer is dried (MgSO4), filtered, and concentrated under vacuum to give an off-white solid (1.5 g, 6.4 mmol, 100%) for methyl 6-[(methylsulfonyl)oxy]methyl}nicotinate. MS (ESI+) for C9H11O5S m/z 246.17 (M+H)+.
87%
With dmap; triethylamine; In dichloromethane; at -78℃; for 1h;Inert atmosphere;
Example 1-1Preparation of methyl 6-[(methylsulfonyl)oxylmethyl}pyridine-3-carboxylateIn a 50 mL round-bottomed flask, 4-(dimethylamino)pyridine (0.037 g, 0.30 mmol) and methyl 6-(hydroxymethyl)pyridine-3-carboxylate (0.5 g, 2.99 mmoll) were dissolved in DCM (20 mL) under argon. Triethylamine (0.625 mL, 4.49 mmol) was added and the mixture was cooled to -78 C. Methanesulfonyl chloride (0.301 mL, 3.89 mmol) was added dropwise and the mixture was stirred at low temperature. The reaction mixture was poured into ice-water after lh. The organics were extracted with DCM (3 x 50 mL). The combined organic phase was washed with water (1 x 100 mL), brine (1 x 100 mL), dried over anhydrous Na2S04, filtered, concentrated under reduced pressure and dried in vacuum at r.t. The title compound was obtained in 87% yield (635 mg) as a yellow solid.1H NMR (400 MHz, CDC13) delta ppm 3.14 (s, 3 H) 3.98 (s, 3 H) 5.40 (s, 2 H) 7.59 (dd, J=8.08, 0.51 Hz, 1 H) 8.38 (dd, J=8.08, 2.02 Hz, 1 H) 9.20 (d, J=1.52 Hz, 1 H).MS (APPI/APCI) m/z 245.9 [M+H+]
50%
Methyl-6-(hydroxymethyl)nicotinate (500 mg, 2.99 mmol) is added to an oven dried round-bottom flask under N2 followed by dichloromethane (20.0 mL). Triethylamine (2.85 mL, 20.93 mmol) is added and then the flask is kept in an ice bath for 50 min. Methanesulfonylchloride (0.81 mL, 10.47 mmol) is added drop-wise. The reaction is stirred for 45 min at low temperature and then stirred at room temperature overnight. The reaction mixture is then poured into ice water. The organics are extracted with dichloromethane. The combined organic layers are washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure. It is further dried on high vacuum to give to afford the title compound (365 mg, 50% yield).
Step 1.; Preparation of methyl 6-((methylsulfonyloxy)methyl)nicotinate; [0121] A Catalytic amount of DMPA (dimethylol propionic acid), triethylamine (2.Og, 19.7mmol) in 20 mL CH2C12, and methanesulfonyl chloride (1.95g, 17.0mmol) are added dropwise to a solution of 6-hydroxymethyl-nicotinic methyl ester 6 (2.2g, 13.1mmol), at -78C under argon. The mixture is stirred for 5 hours at -78C and then quenched with 30 mL saturated aqueous sodium bicarbonate. The organic layer is collected and the water phase extracted with CH2C12 (2x30mL). The organic phases are combined and washed with water. The CH2C12 solution is dried over MgSO4 and concentrated to give compound 7, which is used without further purification.
With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
Dissolving <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> in DCM (10 mL).Cool to 0 C,Triethylamine (2.43 g, 12 mmol) was added in sequenceAnd methanesulfonyl chloride (2.06 g, 18 mmol),Slowly warm to room temperature and react overnight.TLC monitors the reaction completely,Add saturated aqueous ammonium chloride solution (5 mL),Liquid separation,The aqueous phase was extracted with DCM (3×10 mL).Combine the organic phase,Washed (2 × 5mL),Dry over anhydrous sodium sulfate,filter,Concentrated6-((((methylsulfonyl)oxy)methyl)methyl nicotinate(3.2g crude).
With triethylamine;dmap; In dichloromethane; at -78℃; for 5h;
A Catalytic amount of DMAP (dimethylamine pyridine), triethylamine (2.Og, 19.7mmol) in 20 mL CH2Cl2, and methanesulfonyl chloride (1.95g, 17.0mmol) are added dropwise to a solution of 6-hydroxymethyl -nicotinic methyl ester 6 (2.2g, 13.1mmol), at -78C under argon. The mixture is stirred for 5 hours at -78C and then quenched with 30 mL saturated aqueous sodium bicarbonate. The organic layer is collected and the water phase extracted with CH2Cl2 (2x3 OmL). The organic phases are combined and washed with water. The CH2Cl2 solution is dried over MgSO4 and concentrated to give compound 7, which is used without further purification.
With potassium carbonate; In methanol; at 20 - 40℃; for 2h;
[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 (3×15 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, 89%) for methyl 6-(hydroxymethyl)nicotinate. This compound is used without further purification. MS (ESI+) for C8H9O3 m/z 168.2 (M+H)+.
With hydrogenchloride; methanol; for 48h;Inert atmosphere;
Intermediate 98. Methyl 6-(hydroxymethyl)nicotinate To a solution of methyl-6-(acetoxymethyl)nicotinate (Prepared according to the experimental procedure described in Dalton et. al. J. Heterocyclic. Chem. 1995, 32, 665; 4.0g, 19.2mmol) in methanol (20ml_) was added, under inert atmosphere, a solution of hydrochloric acid in methanol (20ml_ of a 1 .25M solution in methanol) and stirring was maintained for 2 days. The organic solvent was removed and 4% aqueous sodium bicarbonate solution was added until pH = 8 was reached. The aqueous phase was extracte with ethyl acetate (3 x 100ml_) and the combined organic phases were washed with brine and concentrated to yield the title compound (2.83g of a 90% purity, 80%) as a brown solid. LRMS (m/z): 168 (M+1 )+
With pyridine; thionyl chloride; In dichloromethane; at 0 - 20℃; for 2h;
2.119b. methyl 6-chloromethyl-nicotinate 1.06 mL (13 mmol) of pyridine added and slowly 1.08 mL (13 mmol) of thionyl chloride are added dropwise to a solution of 2.0 g (11.96 mmol) of methyl 6-hydroxymethyl-nicotinate in 100 mL CH2Cl2 cooled to 0 C. This is stirred for a further hour at 0 C. and then slowly heated to RT. To complete the reaction a further 1 mL (12 mmol) of thionyl chloride is added and the mixture is stirred for 1 h at RT. The reaction mixture water is added, the organic phase is separated off, washed with dilute NaHCO3 solution and water and dried over MgSO4. This is filtered through activated charcoal and the solvent is evaporated down in vacuo. The product obtained is further reacted without purification. Yield: 1.7 g (65.1% of theory); C8H8ClNO2 (M=185.61); calc.: molar peak (M+H)+: 186/188 fnd.: molar peak (M+H)+: 186/188; Retention time HPLC: 6.7 min (method A).
With thionyl chloride; In dichloromethane; at 0 - 20℃;
Preparation 114 6-Chloromethyl-nicotinic acid methyl ester Add <strong>[56026-36-9]6-hydroxymethyl-nicotinic acid methyl ester</strong> (9.6 g, 57.4 mmol) and dichloromethane (200 mL) to a flask and cool to 0 C. Add thionyl chloride (10.25 g, 86.14 mmol). Stir the mixture at room temperature for 1 hr. Concentrate the reaction mixture under reduce pressure to give the crude 6-chloromethyl-nicotinic acid methyl ester (13 g, 102% yield) as a yellow solid. MS (m/z): 223 (M+1).
Step 2. Synthesis of Methyl 6-(chloromethyl)nicotinate (56):To a solution of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (55; 83.0 g, 0.497 mol) in dichloromethane (400 mL) at 0ºC was added SOCl2 (119.0 g, 1.0 mol). The mixture was stirred at room temperature for 2 hours, concentrated, and the residue was neutralized with aqueous NaHCO3 (sat). The mixture was extracted with ethyl acetate (3 x 250 mL), dried over Na2SO4, concentrated and purified by chromatography on silica gel to give Methyl 6-(chloromethyl)nicotinate 56 (70.0 g)
With thionyl chloride; In dichloromethane; at 45℃; for 3h;
A mixture of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (250 mg, 1.496 mmol) and thionyl chloride (1 mL, 13.70 mmol) in dichloromethane (2 mL) was stirred at 45 C for 3 hrs and concentrated under reduced pressure. The residue was taken up in dichloromethane (25 mL), sonicated and concentrated under reduced pressure. This was repeated three times and the residue was dried in high vacuo providing of methyl 6- (chloromethyl)nicotinate (266 mg), which was used in the next reaction without further purification. LCMS (m/z): 186.0 [M+H]+; Rt = 0.63 min.
With thionyl chloride; In dichloromethane; at 45℃; for 3h;
A mixture of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (250 mg, 1.496 mmol) and thionyl chloride (1 mL, 13.70 mmol) in dichloromethane (2 mL) was stirred at 45 C for 3 hrs and concentrated under reduced pressure. The residue was taken up indichloromethane (25 mL), sonicated and concentrated under reduced pressure. This was repeated three times and the residue was dried in high vacuo providing of methyl 6- (chloromethyl)nicotinate (266 mg), which was used in the next reaction without further purification. LCMS (m/z): 186.0 [M+H]+; Rt = 0.63 min.
With thionyl chloride; In dichloromethane; at 45℃; for 3h;
A mixture of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (250 mg, 1 .496 mmol) and thionyl chloride (1 ml_, 13.70 mmol) in dichloromethane (2 mL) was stirred at 45 C for 3 hrs and concentrated under reduced pressure. The residue was taken up in dichloromethane (25 mL), sonicated and concentrated under reduced pressure. This was repeated three times and the residue was dried in high vacuo providing of methyl 6-(chloromethyl)nicotinate (266 mg), which was used in the next reaction without further purification. LCMS (m/z): 186.0 [M+H]+; Rt = 0.63 min.
With thionyl chloride; In dichloromethane; at 45℃; for 3h;
A mixture of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (250 mg, 1.496 mmol) and thionyl chloride (1 mL, 13.70 mmol) in dichloromethane (2 mL) was stirred at 45 C for 3 hrs and concentrated under reduced pressure. The residue was taken up in dichloromethane (25 mL), sonicated and concentrated under reduced pressure. This was repeated three times and the residue was dried in high vacuo providing of methyl 6- (chloro methyl )nicotinate (266 mg), which was used in the next reaction without further purification. LCMS (m/z): 186.0 [M+H]+; Rt = 0.63 min.
With thionyl chloride; In dichloromethane; at 20℃; for 1h;
To a solution of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (500 mg, 2.99 mmol) in dichloromethane (5 mL) at 20 C was added thionyl chloride (529 mg, 4.49 mmol). The residue was stirred for 1 h before solvent was removed under reduced pressure. The crude material was dissolved in methanol (15 mL) and sodium methoxide (1 mL) was added. The reaction solution was stirred at 75 C for 1 h. The volatiles were removed under reduced pressure and the crude product was purified by column chromatography (petroleum ether/ethyl acetate = 4/1 ) to offer methyl 6-(methoxymethyl)nicotinate (250 mg, 1 .38 mmol, 46%) as a yellow solid.
With phosphorus tribromide; In toluene; at 0 - 20℃;Heating / reflux;
Preparation 31 6-Bromomethyl-nicotinic acid methyl ester [0339] [CHEMMOL-00088] [0340] Phosphorus tribromide (1.4 g; 5.32 mmol) was added slowly to a cooled solution (ice/water/sodium chloride bath) of Preparation 30 (1 g, 5.7 mmol) in toluene (100 ml). The reaction mixture was allowed to warm to RT overnight and then refluxed for one hour. The reaction mixture was cooled to RT and DCM was added. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, then with water, dried over sodium sulfate, and concentrated under reduced pressure to yield an oil (m=0.99 g, yield 76%) which was used without further purification. 1H NMR (CDCl3): 9.18 (1H, s); 8.35 (1H, d); 7.56 (1H, d); 4.62 (2H, s); 4.00 (3H,s)
Methyl 2-(Dimethyl-t-butylsilyloxymethyl)pyridine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.32 g (100%)
In N,N-dimethyl-formamide;
PREPARATION 12 Methyl 2-(Dimethyl-t-butylsilyloxymethyl)pyridine-5-carboxylate To <strong>[56026-36-9]methyl 2-(hydroxymethyl)pyridine-5-carboxylate</strong> (0.77 g, 4.61 mmol) in 10 mL DMF was added dimethyl-t-butylsilyl chloride (0.77 g, 1.1 equivalents) and imidazole (0.47 g, 1.5 equivalents). After 1 hour, the reaction mixture was poured into 30 mL water and extracted 3*20 mL ether. The organic layers were combined, washed 2*20 mL water, dried (MgSO4) and stripped in vacuo to yield 1.32 g (100%) of present title product.
1.32 g (100%)
In N,N-dimethyl-formamide;
PREPARATION 12 Methyl 2-(Dimethyl-t-butylsilyloxymethyl)pyridine-5-carboxylate To <strong>[56026-36-9]methyl 2-(hydroxymethyl)pyridine-5-carboxylate</strong> (0.77 g, 4.61 mmol) in 10 mL DMF was added dimethyl-t-butylsilyl chloride (0.77 g, 1.1 equivalents) and imidazole (0.47 g, 1.5 equivalents). After 1 hour, the reaction mixture was poured into 30 mL water and extracted 3 x 20 mL ether. The organic layers were combined, washed 2 x 20 mL water, dried (MgSO4) and stripped in vacuo to yield 1.32 g (100%) of present title product.
methyl 6-[(2,2,2-trifluoroethoxy)methyl]nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h;
Reference Synthesis Example 115 (0762) Methyl 6-[(2,2,2-trifluoroethoxy)methyl]nicotinate (0763) To an N,N-dimethylformamide solution (10 mL) of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (500 mg, 2.99 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (518 muL, 3.59 mmol), sodium hydride (179 mg, 4.49 mmol) was added at 0 C. and the resultant mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain the title compound (171 mg, yield 23%).
To a solution of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (500 mg, 2.99 mmol) in tetrahydrofuran (30 mL) was added sodium hydride 60 % dispersion in mineral oil (126 mg, 3.14 mmol) and the reaction mixture was stirred at ambient temperature for 5 min. 2,2,2-trifiuoroethyl trifluoromethanesulphonate (729 mg, 3.14 mmol) was added and the reaction mixture was stirred at ambient temperature for 4 h. Additional sodium hydride (42 mg, 1.05 mmol) was added followed by 2,2,2-Trifluoroethyl trifluoromethanesulphonate (243 mg, 1.45 mmol) after 5 min. Water (20 mL) was added carefully followed by lithium hydroxide monohydrate (0.376 g, 8.97 mmol) and the formed reaction mixture was stirred at ambient temperature for 5.5 h. The solvent was partially removed in vacuo and IM hydrochloric acid added until an acidic pH was reached. The mixture was extracted with ethyl acetate (3x25 mL) and the combined organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography using a gradient of methanol in dichloromethane yielded 171 mg (24%) of the title compound; 1H NMR (400 MHz, DMSOtZ6) delta ppm 9.02 (dd, 1 H), 8.32 (dd, 1 H), 7.56 (dd, 1 H), 4.84 (s, 2 H), 4.26 (q, 2 H); MS (ESI) m/z 236 [M+H+].
With 1H-imidazole; dmap; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;
To a solution of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (2 g, 12 mmol), imidazole (2.44 g, 36 mmol) and 4-dimethylaminepyridine (0.020 g, 0.1 6 mmol) in dry A/,A/-dimethylformamide (30 ml_) was added dimethyl-ferf-butylchlorosilane (2.17 g, 14.4 mmol) under argon. The reaction mixture was stirred at room temperature for 16 h and diluted with ethyl acetate (150 ml_). The organic layer was washed with brine (50 ml_ x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude sample was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 ) to give methyl 6-((ferf-butyldimethylsilyloxy)methyl)nicotinate (3.37 g, 1 .19 mmol, 99%) as a colorless oil. LCMS (ESI) m/z: 282.1 [M+H]+.
66%
With 1H-imidazole; In dichloromethane; at 20℃; for 2h;Inert atmosphere;
Intermediate 85a: Methyl 6-(((tert-butyldimethylsilyl)oxy)methyl)nicotinate tert-Butylchlorodimethylsilane (3.97 g, 26.3 mmol) was added in one portion to <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (4.00 g, 23.9 mmol) and 1H-imidazole (1.79 g, 26.3 mmol) in DCM (40 mL) at 20 C. under nitrogen. The resulting cream suspension was stirred for 2 hours. The reaction mixture was diluted with DCM (100 mL), and washed with water (50 mL) and saturated brine (100 mL). The organic layer was dried with MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane to afford the title compound (4.47 g, 66%) as a colourless oil; 1H NMR (400 MHz, CDCl3, 30 C.) 0.13 (6H, s), 0.97 (9H, s), 3.95 (3H, s), 4.88 (2H, s), 7.61 (1H, d), 8.31 (1H, dd), 9.10 (1H, d); m/z: ES+ [M+H]+ 282.5.
With 1H-imidazole; In N,N-dimethyl-formamide; for 2h;
A solution of compound 9 (2.5 g, 14.96 mmol) in 25 DMF (10 mL) was treated with 26 imidazole (1.527 g, 22.43 mmol) and 27 t-butyldimethylsilyl chloride (TBS-Cl, 2.480 g, 16.45 mmol). After 2 h, LCMS showed completion of reaction. The reaction was washed with sat. aq. NaHCO3 and brine, and the organic layer was dried over Na2SO4. The crude 28 methyl 6-(((tert-butyldimethylsilyl)oxy)methyl)nicotinate (93% yield) was taken to next step without further purification.
With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 42h;
Example 63. Preparation of 3-(4-sec-butylphenyl)-2-(6-(hydroxymethyl)pyridin-3- yl)quinazolin-4(3H)-one; [0250] Methyl 6-(hydroxymethyl)nicotinate (1.0 g, 6.0 mmol), 2,3- dihydropyran (1.5 mL, 16.5 mmol), and p-TsOH (1.14 g, 6.0 mmol) were combined in CH2CI2 (100 mL) and stirred at room temperature for 18 hours. An additional 1 mL of 2,3-dihyropyran was added and the reaction was continued at room temperature for 24 hours. The reaction mixture was washed with water (200 mL), dried (MgSO4), filtered, and concentrated, to afford methyl 6-((tetrahydro-2/-/-pyran-2- yloxy)methyl)nicotinate (1.5 g, quantitative). [0251 ] Methyl 6-((tetrahydro-2H-pyran-2-yloxy)methyl)nicotinate (1.5 g, 6.0 mmol) was dissolved in THF (30 ml_) and cooled to 00C under nitrogen. DIBAL-H (1.0 M in THF, 21 ml_, 21 mmol) was added dropwise, via a syringe over 5 min, and stirred for 90 min. The reaction mixture was warmed to room temperature, and quenched with water (25 ml_), followed by saturated NH4CI (10 ml_). After stirring for 10 minutes, the mixture was basified with solid KOH, extracted with CH2CI2 (2 * 100 mL), washed with brine (100 ml_), dried (MgSO4), filtered, and concentrated, to afford (6-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-3-yl)methanol as a yellow oil (1.3 g, 97%).[0252] (6-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-3-yl)methanol (1.3 g, 6.0 mmol) was dissolved in CH2CI2 (80 mL) and NMO (0.846 g, 7.2 mmol) and TPAP (0.210 g, 0.6 mmol) were added. After stirring at room temperature for 20 minutes, the reaction mixture was filtered through Celite, and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel, eluting with 30% ethyl acetate/heptane to 75% ethyl acetate/heptane, afforded 6-((tetrahydro-2/-/- pyran-2-yloxy)methyl)nicotinaldehyde as a yellow oil (0.560 g, 42%).[0253] 2-amino-Lambda/-(4-sec-butylphenyl)benzamide (0.250 g, 0.92 mmol) and 6- ((tetrahydro-2/-/-pyran-2-yloxy)methyl)nicotinaldehyde (0.77 mmol) were mixed in anyhydrous EtOH (40 mL) and anyhydrous CuCI2 (0.310 g, 2.3 mmol) was added. After heating at reflux for 1.5 hours, and concentrating, ethyl acetate (150 mL) was added, the mixture was washed with water (2 * 125 mL), dried (MgSO4), filtered, and concentrated. Flash chromatograph on silica gel, eluting with 50% ethyl acetate/heptane to 100% ethyl acetate, plus re-chromatographing with 30% ethyl acetate/CH2CI2 to 100% ethyl acetate, afforded the title compound as a white solid (40%). 1H-NMR (300 MHz, DMSO-d6): delta 8.47 (d, J = 1.6 Hz, 1 H), 8.21 (d, J = 7.8 Hz, 1 H), 7.89-7.94 (m, 1H), 7.79 (d, J = 7.9 Hz, 1 H), 7.60-7.72 (m, 2H), 7.26-7.29 (m, 3H), 7.14-7.18 (m, 2H), 5.42 (t, J = 5.8 Hz, 1 H), 4.45 (d, J = 5.7 Hz1 2H), 2.55-2.64 (m, 1 H), 1.37-1.58 (m, 2H), 1.15 (d, J = 6.9 Hz, 3H), 0.64 (t, J = 7.3 Hz, 3H). MS (APCI) m/z: 386 (M+H)+.
90%
With toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃; for 16h;
To a stirred solution of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (0.5 g, 3.0 mmol) in DCM (50 mL), was added p-TsOH (0.63 g, 3.3 mmol) at 0 C. followed by 3,4-dihydro-2H-pyran (0.9 mL, 9.0 mmol) at same temperature. The mixture was allowed to warm to rt then stirred for 16 h. The reaction mixture was diluted with water (50 mL) and product was extracted using DCM (50 mL×3). The combined organic layer was dried over anhydrous sodium sulphate and vacuum evaporated and the crude product was purified by silica gel column chromatography (0-1% MeOH-DCM to give methyl 6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)nicotinate as a yellow semisolid (0.7 g, 90%); LC-MS (ESI+) m/z 252.3 (M+H)+.
79%
With pyridinium p-toluenesulfonate; In tetrahydrofuran; dichloromethane; at 50℃; for 2h;Inert atmosphere;
Intermediate 132. Methyl 6-[(tetrahydro-2H-pyran-2-yloxy)methyl]nicotinate To a solution of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (Intermediate 98, 505mg, 3.02mmol) in a mixture of dichloromethane (20ml_) and THF (10ml_) were added, under argon atmosphere, 3,4-dihydro-2H-pyran (640muIota_, 7.0mmol) and pyridinium p-toluene sulphonate (170mg, 0.68mmol), and the reaction mixture was heated to 50 C for 2h. The mixture was concentrated to dryness and the residue was purified by column chromatography over silica gel using a gradient of Hexane/Ethyl Acetate. The title compound was obtained (600mg, 79%) as a yellow solid. LRMS (m/z): 251 (M+1 )+
With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃;
Step 2: Intermediate 32-c To a solution of intermediate 32-b (1.70 g, 10.17 mmol) in dichloromethane (203 ml_) was added 3,4-dihydro-2H-pyran (4.28 g, 50.8 mmol) and PPTS (2.56 g, 10.17 mmol) and the reaction was stirred at room temperature overnight. Water was added and the organic layer was separated, washed with brine, dried over MgS04, filtered and concentrated under reduced pressure to provide intermediate 32-c as a white solid.
With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃;
To a solution of Intermediate 59-b (1.70 g, 10.17 mmol) in dichloromethane (203 mL) was added 3,4-dihydro-2H-pyran (4.28 g, 50.8 mmol), and PPTS (2.56 g, 10.17 mmol), and the reaction was stirred at room temperature overnight. Water was added and the organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to provide Intermediate 59-c as a white solid.
With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃;
To a solution of Intermediate 21-b (1.70 g, 10.17 mmol) n dichloromethane (203 mL) was added 3,4-dihydro-2H-pyran (4.28 g, 50.8 mmol) and PPTS (2.56 g, 10.17 mmol) and the reaction was stirred at room temperature overnight. Water was added and the organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to provide Intermediate 21-c as a white solid.
With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃;
Step 2: Intermediate 32-c [0186] To a solution of intermediate 32-b (1.70 g, 10.17 mmol) in dichloromethane (203 mL) was added 3,4-dihydro-2H-pyran (4.28 g, 50.8 mmol) and PPTS (2.56 g, 10.17 mmol) and the reaction was stirred at room temperature overnight. Water was added and the organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to provide intermediate 32-c as a white solid.
With toluene-4-sulfonic acid; In dichloromethane; for 18h;Cooling with ice;
To a methylene chloride solution (500 mE) of the compound 9(17.07 g, 94.21 mmol) and p-toluenesulphonic acid monohydrate (18.11 g, 94.21 mmol), 3,4-dihydro-2H- pyran (23.55 mE, 259.2 mmol) was added under ice-cooling, and the reaction solution was stirred for 18 hours. The organic layer was washed with saturated sodium bicarbonate water (500 mE) and saturated saline (500 mE) 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 liquid compound 10? (42.72 g, crude yield: 170.9%). The compound 10? was subjected to the subsequent step while the compound 10? was crude.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃;
Preparative Example 6 2.13 g oftert-butyl (2-hydroxy-4,5-dimethylphenyl)carbamate was dissolved in 44.9 mL of THF, and 1.50 g of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong>, 7.06 g of triphenylphosphine, and 11.7 g of diethyl azodicarboxylate were added thereto, followed by stirring overnight at room temperature. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was dissolved in 30.0 mL of ethyl acetate, and 60.0 mL of a 4 M hydrogen chloride/ethyl acetate solution was added thereto, followed by stirring for 1 hour. The resulting precipitate was collected by filtration, washed with ethyl acetate, and then dried under reduced pressure to obtain 1.76 g of methyl 6-[(2-amino-4,5-dimethylphenoxy)methyl]nicotinate hydrochloride.
With potassium tert-butylate; In tetrahydrofuran; toluene; at 20℃; for 12h;
Preparation of 6-f(prop-2-vn- l -yloxy)methyl)nicotinic acid (10). Methyl 6- (hydroxymethyl)nicotinate (9, 303 mg) was dissolved in THF. 0.28 mL of a 9 M solution of propargyl bromide in toluene was added to the reaction vessel at ambient temperature. After 12 hours, the reaction mixture was diluted with 50 mL of Et20 and washed once with 30 mL of a saturated solution of sodium bicarbonate. The organic layer was dried with MgSC*4, filtered, and concentrated to a residue, which was chromatographed on a silica gel column with ethyl acetate and hexanes to obtain an oil. TLC (ethyl acetate, uv): Rf = 0.64. NMR (400 MHz, CDC13): 9.16 (d, I H), 8.32 (dd, I H), 7.57 (d, I H), 4.80 (s, 2H), 4.33 (dd, 2H), 3.96 (s, 3H), 2.50 (t, I H).
To a solution of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (15.0 g, 89.7 mmol) in tetrahydrofuran (300 mL) was added NaH (4.7 g, 10.4 mmol, 60%) in one portion at 0 C . After 30 min, ethyl 2-bromoacetate (14.9mL, 134.6 mmol) was added to the reaction mixture. The reaction mixture was heated to 70 Covernight and quenched with saturated NaHC03 and extracted with ethyl acetate (150 mL><3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (EA: PE = 10%~70%) to give methyl 6-((2-ethoxy-2- oxoethoxy)methyl)nicotinate (12.0 g, 53.1% yield).1HNMR (400 MHz, CDC13): delta= 9.12 (d, J=1.5 Hz, IH), 8.29 (dd, J=8.2, 2.1 Hz, IH), 7.60 (d, J=8.0 Hz, IH), 4.79 (s, 2H), 4.20-4.25 (m, 4H), 3.93 (s, 3H), 1.25-1.30 ppm (m, 3H). MS (ESI): M/Z (M+1): 253.9.
53.1%
a) methyl 6-((2-ethoxy-2-oxoethoxy)methyl)nicotinate To a solution of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (15.0 g, 89.7 mmol) in tetrahydrofuran (300 mL) was added NaH (4.7 g, 10.4 mmol, 60%) in one portion at 0 C. After 30 min, ethyl 2-bromoacetate (14.9 mL, 134.6 mmol) was added to the reaction mixture. The reaction mixture was heated to 70 C. overnight and quenched with saturated NaHCO3 and extracted with ethyl acetate (150 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (EA: PE=10%?70%) to give methyl 6-((2-ethoxy-2-oxoethoxy)methyl)nicotinate (12.0 g, 53.1% yield). 1HNMR (400 MHz, CDCl3): delta=9.12 (d, J=1.5 Hz, 1H), 8.29 (dd, J=8.2, 2.1 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 4.79 (s, 2H), 4.20-4.25 (m, 4H), 3.93 (s, 3H), 1.25-1.30 ppm (m, 3H). MS (ESI): M/Z (M+1): 253.9.
53.1%
To a solution of <strong>[56026-36-9]methyl 6-(hydroxymethyl)nicotinate</strong> (15.0 g, 89.7 mmol) in tetrahydrofuran (300 mL) was added NaH (4.7 g, 10.4 mmol, 60%) in one portion at 0 C . After 30 min, ethyl 2-bromoacetate (14.9 mL, 134.6 mmol) was added to the reaction mixture. The reaction mixture was heated to 70 C overnight and quenched with saturated NaHC03 and extracted with ethyl acetate (150 mL><3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (EA: PE = 10%~70%) to give methyl 6-((2-ethoxy-2- oxoethoxy)methyl)nicotinate (12.0 g, 53.1% yield). 1HNMR (400 MHz, CDC13): delta= 9.12 (d, J=1.5 Hz, IH), 8.29 (dd, J=8.2, 2.1 Hz, IH), 7.60 (d, J=8.0 Hz, IH), 4.79 (s, 2H), 4.20-4.25 (m, 4H), 3.93 (s, 3H), 1.25-1.30 ppm (m, 3H). MS (ESI): M/Z (M+l): 253.9.
With trifluoroacetic anhydride; In dichloromethane; at 0℃; for 2h;Reflux;
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, 58%). MS-ESI (m/z): 168.2 (M+l) + (LC-MS method C; Rt: 0.25 min).
58%
With trifluoroacetic anhydride; In dichloromethane; at 0℃; for 2h;Reflux;
(b) methyl 6-(hydroxymethyl)nicotinate 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 NaHCO3. 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, 58%). MS-ESI (m/z): 168.2 (M+1)+ (LC-MS method C; Rt: 0.25 min).
With trifluoroacetic anhydride; In dichloromethane; at 0℃; for 2h;Reflux;
To a solution of 5-.(methoxycarbonyi)-.2-methylpyridine i-oxide (12 g, 72 mn:ioi) in DCM (So mL) was added TFAA (25 mL) dropwise at 0 C. The mixture was stirred at reflux for2 hours. The mixture was concentrated and the residue was adjusted to p1-1 9 with saturated
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1.5h;Inert atmosphere;
6-hydroxymethyl nicotinic acid methyl ester (11 ) (10.0 g, 59.8 mmol) was azeotroped with acetonitrile ( 2 x 100 mL) then dissolved in (0261) dichloromethane (alcohol free, 150 mL) and treated with (0262) diisopropylethylamine (12.5 mL, 71 .8 mmol) followed by 2-cyanoethyl-N,N- diisopropylchlorophosphoramidite (13.4g, 56.8 mmol). The reaction mixture was stirred at RT, under argon for 1 .5 hours. TLC (1 : 1 hexane: EtOAc, visualised by PMA/heat) showed reaction completion (SM Rf ~ 0.3, prod Rf ~ 0.5). (0263) The mixture was washed with sat. NaHC03(aq) (100 mL) and the layers were separated. The organic phase was washed with 100 mL sat. then dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to give a brown oil. This was triturated with pentane (2 x 150 mL). (0264) The crude material was purified by flash column chromatography on pre- equilibrated silica gel (1 : 1 EtOAc : pentane + 1 % NEt3) eluting with 1 : 1 EtOAc : pentane, the crude product was loaded in DCM. Product containing fractions were selected by TLC and concentrated in vacuo to give a colourless oil. This was azeotroped with MeCN and dried on the freeze-drier overnight to give 12 (6.55g, 30%).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
