* 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 lithium borohydride; ethanol In tetrahydrofuran at 20℃; for 15 h;
Step 2 To 33 (4.03 g, 20 mmol) in THF (50 mL) in a water bath was added LiBH4 (1.31 g, 60 mmol). Ethanol ( 10 mL) was added to the reaction mixture dropwise and the reaction mixture was stirred at room temperature for 15 h. Excess aqueous IN NaOH was added and the mixture was extracted with EtOAc. The combined organics were washed with water and brine, dried (MgS04), filtered, and concentrated in vacuo to provide 34 (3.43 g, 99percent).
Stage #1: With borane-THF In tetrahydrofuran for 3 h; Heating / reflux Stage #2: With water; sodium carbonate In tetrahydrofuranHeating / reflux
BH3. DMS (1.0 mL, 10.66 mmol) was refluxed in THF (20 mL) for 30 min (formation of BH3. THF). At RT, Example 17 (2.0 g, 10.66 mmol in 10 mL THF) was added dropwise, and then the reaction mixture was heated to reflux for 3 h. The solution was allowed to cool to ambient temperature, solid sodium carbonate (0.5 g) and water (5 mL). The resulting mixture was heated for a short while and poored in water (50 mL). Extraction with ethyl acetate (3 x 50 mL), drying of the combined organic layers (Na2SO4) and evaporation in vacuo gave a 1: 1 mixture of starting material and product. Purification by flash column chromatography over silica gel eluting with ethyl acetate gave 780 mg (42 percent) of an off-white solid. IH NMR (400 MHz, CDC13) 8 3.92 (s, 3H) 4.66 (s, 2H) 6.64 (s, 1H) 6.89 (s, 1H).
2 g
With borane-THF In tetrahydrofuran at 0 - 20℃; for 20.5 h; Inert atmosphere
To a solution of 2-chloro-6-methoxyisonicotinic acid (2.5 g) in dry tetrahydrofuran (50 ml) at 0°C under nitrogen was added dropwise a solution of borane- tetrahydrofuran complex (1.0M solution in tetrahydrofuran; 40 ml) over fifteen minutes. After the addition was complete, the cooling bath was removed and the mixture allowed to warm to room temperature. After three hours, the mixture was cooled to 0°C and borane-tetrahydrofuran complex (1.0M solution in tetrahydrofuran; 40 ml) was addedover fifteen minutes. After the addition was complete, the cooling bath was removed and the mixture allowed to warm to room temperature and stirred for seventeen hours. The reaction mixture was cooled to 0°C, quenched with 1.0M aqueous sodium hydroxide solution (30 ml), diluted with saturated aqueous ammonium chloride solution (50 ml) and extracted with diethyl ether (2 x 100 ml), the combined organic layer washed with brine then dried (Na2SC"4) and evaporated. The residue was triturated with hexane and filtered to afford (2-chloro-6-methoxypyridin-4-yl)methanol (2.0 g) as a white solid. LCMS: Rt 1.16 min, m/z 174/176 [M+H]+. 1H-NMR (400 MHz, CDC13) δ (ppm): 1.96 (t, 1 H) 3.94 (s, 3 H) 4.67 (d, J=3.67 Hz, 2 H) 6.65 (d, J=0.86 Hz, 1 H) 6.91 (s, 1 H)
Reference：
[1] European Journal of Organic Chemistry, 2003, # 22, p. 4445 - 4449
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 9, p. 2673 - 2676
[3] Organic Letters, 2000, vol. 2, # 22, p. 3421 - 3423
[4] Patent: WO2004/63156, 2004, A1, . Location in patent: Page 36
[5] Tetrahedron, 2002, vol. 58, # 34, p. 6951 - 6963
[6] Patent: WO2014/13076, 2014, A1, . Location in patent: Page/Page column 62; 63
3
[ 101990-69-6 ]
[ 193001-91-1 ]
Yield
Reaction Conditions
Operation in experiment
28%
With sodium hydroxide In methanol
The starting material was prepared as follows: A mixture of 2,6-dichloro-4-hydroxymethylpyridine (1.72 g, 16 mmol) and 40percent aqueous sodium hydroxide solution (5 ml) in methanol (50 ml) was heated at reflux for 24 hours. The mixture was allowed to cool and the volatiles removed by evaporation. The residue was extracted with ethyl acetate and the solvent removed from the extracts by evaporation. The residue was recrystallized from ethyl acetate/hexane to give 2-chloro-4-hydroxymethyl-6-methoxypyridine (490 mg, 28percent). 1 H NMR Spectrum: (DMSOd6) 3.80(s, 3H); 4.45(d, 2H); 5.45(t, 1H); 6.70(s, 1 H); 6.98(s, 1 H)
Reference：
[1] Patent: US5962458, 1999, A,
[2] Patent: US6362336, 2002, B1, . Location in patent: Example 61
With boron trifluoride diethyl etherate; In dichloromethane; at 0 - 20℃; for 4.25h;Inert atmosphere;
2-Chloro-6-methoxy-4-[(methoxymethoxy)methyl]pyridine (10). Boron trifluoride etherate (9.32 mL, 75.81 mmol) was added dropwise under argon during 15 min at 0 C. to a solution of dimethoxymethane (38.22 mL, 431.5 mmol) and <strong>[193001-91-1](2-chloro-6-methoxy-pyridin-4-yl)-methanol</strong> (9), (10.700 g, 61.64 mmol) in dry dichloromethane (80 mL). After the addition, the reaction mixture was stirred at room temperature for 4 h, cooled to 0 C. and quenched by dropwise addition of water. Diluted with dichloromethane and the organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate and evaporated. The crude product was purified using silica gel column chromatography (10% EtOAc/Hexane) to afford 12.820 g, (95%) of the protected alcohol 10. 1H NMR (CDCl3, 400 MHz): delta 6.91 (s, 1H), 6.65 (d, 1H, J=0.7 Hz), 4.72 (s, 2H), 4.54 (s, 2H), 3.95 (s, 3H), 3.42 (s, 3H). 13C NMR (CDCl3, 100 MHz): 163.7, 152.3, 148.1, 114.1, 106.5, 95.7, 66.5, 55.2, 53.7.
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 2h;
(a) 2-Chloro-4-([(l,l-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-(methyloxy)pyridineA solution of <strong>[193001-91-1][2-chloro-6-(methyloxy)-4-pyridinyl]methanol</strong> (for a synthesis see Adamczyk, M.; Akireddy, S. R.; Reddy, Rajarathnam E. Tetrahedron 2002, 58(34), 6951)(8.02 g, 46.22 mmol) in dry DMF (100 ml) was treated with tert-butyldimethylsilyl chloride (8.36 g, 55.46 mmol) and imidazole (3.77 g, 55.46 mmol) and stirred at rt for 2h. The reaction mixture was treated with water extracted three times with dichloromethane, <n="75"/>dried (magnesium sulphate), evaporated and chromatographed on silica gel (100 g), eluting with 1 :4 ethyl acetate-hexane to give the desired product (12.38g, 93%). MS (+ve ion electrospray) m/z 288/290 (MH+).
93%
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 2h;
(a) 2-Chloro-4-([(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-(methyloxy)pyridine A solution of <strong>[193001-91-1][2-chloro-6-(methyloxy)-4-pyridinyl]methanol</strong> (for a synthesis, see Adamczyk, M.; Akireddy, S. R.; Reddy, Rajarathnam E. Tetrahedron 2002, 58(34), 6951)(8.02 g, 46.22 mmol) in dry dimethylformamide (100 ml) was treated with tert-butyldimethylsilyl chloride (8.36 g, 55.46 mmol) and imidazole (3.77 g, 55.46 mmol) and stirred at room temperature for 2 hours. The reaction mixture was treated with water extracted 3* with dichloromethane, dried (magnesium sulphate), evaporated and chromatographed on silica gel (100 g), eluding with 1:4 ethyl acetate-hexane to give the desired product (12.38 g, 93%). MS (+ve ion electrospray) m/z 288/290 (MH+).
[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-2-pyrazinyl](4-[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-2-pyrazinyl]methyl}-6-methoxy-2-pyridinyl)methanone[ No CAS ]
The starting material was prepared as follows: A mixture of 2,6-dichloro-4-hydroxymethylpyridine (1.72 g, 16 mmol) and 40% aqueous sodium hydroxide solution (5 ml) in methanol (50 ml) was heated at reflux for 24 hours. The mixture was allowed to cool and the volatiles removed by evaporation. The residue was extracted with ethyl acetate and the solvent removed from the extracts by evaporation. The residue was recrystallized from ethyl acetate/hexane to give 2-chloro-4-hydroxymethyl-6-methoxypyridine (490 mg, 28%). 1 H NMR Spectrum: (DMSOd6) 3.80(s, 3H); 4.45(d, 2H); 5.45(t, 1H); 6.70(s, 1 H); 6.98(s, 1 H)
2-chloro-4-(chloromethyl)-6-methoxypyridine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With thionyl chloride; In toluene;
Thionyl chloride (1.0 ml) was added to a solution of <strong>[193001-91-1]2-chloro-4-hydroxymethyl-6-methoxypyridine</strong> (0.9 g, 5.2 mmol) in toluene (10 ml) and the mixture stirred at ambient temperature for 1 hour. The volatiles were removed by evaporation, the residue was azeotroped with toluene and dried under vacuum to give 2-chloro-4-chloromethyl-6-methoxypyridine hydrochloride (0.88 g, 74%). 1 H NMR Spectrum: (DMSOd6) 3.85(s, 3H); 4.70(s, 2H); 6.90(s, 1H); 7.15(s, 1H)
With thionyl chloride; In dichloromethane; for 3h;
A solution of <strong>[193001-91-1](2-chloro-6-methoxypyridin-4-yl)methanol</strong> (0.050 g, 0.288 mmol) in dichloromethane (5 mL) was treated with thionyl chloride (0.126 mL, 1.728 mmol) and stirred for 3 hours. The reaction was concentrated, then dried under vacuum pump for 30 minutes to afford the product as a clear viscous oil, which was used immediately in the following reaction.
With pyridinium chlorochromate; In dichloromethane;
2-Chloro-6-methoxyisonicotinaldehyde (15-2) To a solution of <strong>[193001-91-1](2-chloro-6-methoxypyridin-4-yl)methanol</strong> (1.73 g, 9.97 mmole) from the protocol immediately above in CH2Cl2 (40 mL) was added PCC (2.58 g, 11.96 mmole) all at once at RT. After 60 hr the mixture was diluted with Et2O and filtered through a plug of Celite. The filtrate was concentrated to give the titled compound as a tan-yellow solid which was sufficiently pure for use in the next step. 1H-NMR (500 MHz, CDCl3) delta 9.96 (s, 1 H), 7.32 (s, 1 H), 7.06 (s, 1 H), 4.00 (s, 3 H).
With lithium borohydride; ethanol; In tetrahydrofuran; at 20℃; for 15h;
Step 2 To 33 (4.03 g, 20 mmol) in THF (50 mL) in a water bath was added LiBH4 (1.31 g, 60 mmol). Ethanol ( 10 mL) was added to the reaction mixture dropwise and the reaction mixture was stirred at room temperature for 15 h. Excess aqueous IN NaOH was added and the mixture was extracted with EtOAc. The combined organics were washed with water and brine, dried (MgS04), filtered, and concentrated in vacuo to provide 34 (3.43 g, 99%).
In tetrahydrofuran; water;
(2-Chloro-6-methoxypyridin-4-yl)methanol To a solution of methyl (2-chloro-6-methoxypyridin-4-yl)carboxylate (15-1, 2.0 g, 9.92 mmole) in dry THF (40 mL) was added LiBH4 (7.4 mL, 2 M in THF, 14.88 mmole) then the mixture was heated to reflux. After 18 hr the mixture was cooled to RT and quenched by slow addition of H2O. The layers were separated and the aqueous layer extracted with EtOAc (2*). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the titled compound a white solid which was sufficiently pure for use in the next step. 1H-NMR (500 MHz, CDCl3) delta 6.90 (s, 1 H), 6.65 (s, 1 H), 4.67 (m, 2 H), 3.94 (s, 3 H).
(a) 2-Chloro-4-([(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-(methyloxy)pyridine A solution of <strong>[193001-91-1][2-chloro-6-(methyloxy)-4-pyridinyl]methanol</strong> (for a synthesis, see)(8.02 g, 46.22 mmol) in dry dimethylformamide (100 ml) was treated with tert-butyldimethylsilyl chloride (8.36 g, 55.46 mmol) and imidazole (3.77 g, 55.46 mmol) and stirred at room temperature for 2 hours. The reaction mixture was treated with water extracted 3x with dichloromethane, dried (magnesium sulphate), evaporated and chromatographed on silica gel (100 g), eluding with 1:4 ethyl acetate-hexane to give the desired product (12.38 g, 93%). MS (+ve ion electrospray) m/z 288/290 (MH+).
To a stirred ICEBATH-COOLED solution of triphenylphosphine (1.36 g, 5.19 mmol) in DCM (75 mL) was added bromine (0.83 g, 5.19 mmol) dropwise. Stirring of the resulting colorless solution was continued for 30 min after which time the ice-bath was removed. Example 18 (0.75 g, 4.32 mmol) was added portion-wise and the reaction mixture was stirred for another 2 h. DCM (75 mL) was added and the organic phase was washed with water (100 mL) and brine (100 mL). Drying (NA2S04) of the DCM-layer and evaporation in vacuo gave A solid residue that was purified by flash column chromatography over silica gel eluting with DCM giving 350 mg (34 %) of a white solid. 'H NMR (400 MHz, CDCL3) 8 3.93 (s, 3H) 4.27 (s, 2H) 6.64 (s, 1H) 6.92 (s, 1H).
Step 3 To 34 (3.43 g, 19.8 mmol) in DMF (30 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil, 1.19 g, 29.6 mmol). The solution was stirred at room temperature for 30 minutes and iodomethane (6.1 mL, 98.8 mmol) was added. The reaction vvas stirred at room temperature for 18 h. Water was added and the mixture was extracted with EtOAc. The organic layers were combined, washed with water and brine, dried ( gS04), filtered, and concentrated in vacuo to provide 35 (2.71 g, 73%).
0.112 g
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
To a solution of <strong>[193001-91-1](2-chloro-6-methoxypyridin-4-yl)methanol</strong> (0.25 g) in dry DMF (1.25 ml) at room temperature was added potassium carbonate (0.6 g) and methyl iodide (0.18 ml) and the reaction mixture stirred overnight. The reaction mixture was diluted with ethyl acetate (25 ml) and washed with water (3 x 10 ml) then dried (Na2SC"4) and evaporated. The residue was purified by silica gel column chromatography (gradient from 0 to 20% ethyl acetate / hexane) to afford the title compound (0.112 g) as a colourless oil. LCMS: Rt 1.52 min, m/z 188/190 [M+H]+.
1-methanesulfonyl-N-[6-(methylcarbamoyl)-2-oxo-1,2-dihydropyridin-4-yl]methyl}-3-[(3-pentanoyl-1Hindol-5-yl)oxy]methyl}-1H-indole-5-carboxamide[ No CAS ]
3-(((1H-indol-5-yl)oxy)methyl)-N-((6-((2-(3-methyl-3H-diazirin-3-yl)ethyl)carbamoyl)-2-oxo-1,2-dihydropyridin-4-yl)methyl)-1-(methylsulfonyl)-1H-indole-5-carboxamide[ No CAS ]
1-methanesulfonyl-3-[({3-[3-(3-methyl-3H-diazirin-3-yl)propanoyl]-1H-indol-5-yl}oxy)methyl]-N-[6-(methylcarbamoyl)-2-oxo-1,2-dihydropyridin-4-yl]methyl}-1H-indole-5-carboxamide[ No CAS ]
[6‐(methylcarbamoyl)‐2‐oxo‐1,2‐dihydropyridin‐4‐yl]methyl 3‐([(tertbutoxy)carbonyl](methyl)amino}methyl)‐1‐methanesulfonyl‐1H‐indole‐5‐carboxylate[ No CAS ]
tert‐butyl N‐cyclohexyl‐N‐[1‐methanesulfonyl‐5‐([6‐(methylcarbamoyl)‐2‐oxo‐1,2‐dihydropyridin‐4‐yl]methyl}carbamoyl)‐1H‐indol‐3‐yl]methyl}carbamate[ No CAS ]
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