* 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 aluminium tetrahydride In tetrahydrofuran at 0℃; for 6.5 h;
To a stirred solution of ethyl 6-(tert-butoxycarbonylamino)nicotinate (100; 10.0 g, 27.3 mmol) in THF (40 mL) was added LA1H4 (1.92 g, 50.5 mmol) in THF (60 mL) over a period of 30 min at 0 0C. The resulting reaction mixture was stirred at 0 0C for 6 h. The reaction was then quenched by carefully adding water (1.0 ml) and 10percent NaOH solution (2.0 mL) at O0C. The resulting mixture was filtered and the filtrate was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (dichloromethane:methanol = 40:1) to afford tert-butyl 5- (hydroxymethyl)pyridin-2-ylcarbamate 101 (4.50 g, 74percent).
64%
With lithium aluminium tetrahydride In tetrahydrofuran at -10 - 20℃; for 3.5 h;
To a cooled (-10 °C) solution of Scheme 44 compound 2 (1.7 g, 6.4 mmol) in dry THF (200 mL) was added LiAlH4 (305 mg, 8.5 mmol) portion wise over a period of 30 min and the reaction mixture was slowly warmed to RT over 3 h. After TLC showed the starting material was completely consumed, the reaction mixture was quenched with saturated ammonium chloride (10 mL), passed through a pad of celite and washed with EtOAc (30 mL). The filtrate was washed with water (2 x 5 mL) and brine (2 x 5 mL), dried over Na2S04 and concentrated to give a residue which was purified by flash chromatography on silica gel (eluting with petroleum ether/EtOAc 100/0 gradually increasing to 60/40) to give Scheme 44 compound 3 (900 mg, 64 percent) as an off-white solid. MS [ESI, MH+] = 225.2.
0.85 g
With lithium aluminium tetrahydride In tetrahydrofuran at 5℃; Inert atmosphere
Lithium aluminiumhydride (251 mg, 6.61 mmol, 1.1 equiv) was added portion wise to a cold (5°C) solution of 6-tertbutoxycarbonylamino nicotinic acid ethyl ester (Step 8.4) (1.6 g, 6.01 mmol) in THF (25 mL), under an argon atmosphere. The reaction mixture was stirred for 1 h at 5°C and quenched by sequential addition of water (0.4 mL), 15 percent NaOH aqueous solution (0.4 mL) and water (1.2 mL). The resulting mixture was filtered through a pad of celite and concentrated. The residue was diluted with EtOAc and water and extracted with EtOAc. The organic phase was washed with water and brine, dried (Na2S04), filtered and concentrated. The residue was purified by trituration in Et20 to provide the title compound (0.85 g) as a solid. M/Z: 224.2, M+H: 225.4, tR = 0.63 min. (System 1)
Reference：
[1] Patent: WO2010/3048, 2010, A1, . Location in patent: Page/Page column 110
[2] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 5, p. 1151 - 1175
[3] Patent: WO2014/52365, 2014, A1, . Location in patent: Page/Page column 257-258
[4] Patent: US6046190, 2000, A,
[5] Patent: US5968942, 1999, A,
[6] Patent: WO2014/44846, 2014, A1, . Location in patent: Page/Page column 32
[7] Patent: WO2009/141386, 2009, A1, . Location in patent: Page/Page column 81
2
[ 1089330-72-2 ]
[ 169280-83-5 ]
Yield
Reaction Conditions
Operation in experiment
46%
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 6.5 h;
To a stirred solution of ethyl 6-(bis(tert-butoxycarbonyl)amino)nicotinate (300.0 g, 819 mmol) in THF (1.2 L) was added LiAlH4 (57.6 g, 1.51 mol) in THF (3 L) over a period of 30 min at 0 °C. The reaction mixture was stirred for 6 h, and H2O (30.0 mL) and 10percent NaOH solution (60.0 mL) were added. The solids were removed by filtration and the filtrate was dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (DCM : MeOH = 40 : 1) to give tert-butyl 5-(hydroxymethyl)pyridin-2- ylcarbamate (85.0 g, 46 percent yield)
46%
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 6.5 h;
To a stirred solution of ethyl 6-(bis(tert-butoxycarbonyl)amino)nicotinate (300.0 g, 819 mmol) in THF (1.2 L) was added LiAlH4 (57.6 g, 1.51 mol) in THF (3 L) over a period of 30 min at 0 °C. The reaction mixture was stirred for 6 h, and H2O (30.0 mL) and 10percent NaOH solution (60.0 mL) were added. The solids were removed by filtration and the filtrate was dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (DCM : MeOH = 40 : 1) to give tert-butyl 5-(hydroxymethyl)pyridin-2-ylcarbamate (85.0 g, 46 percent yield).
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 4.0h;
To a cooled (0 C) solution of Scheme 44 compound 3 (900 mg, 4.0 mmol) in dry CH2C12 (20 mL) were added TPP (1.1 g, 4.2 mmol) and CBr4 (2.2 g, 6.5 mmol) and the reaction mixture was stirred at RT for 4 h. After TLC showed the starting material was completely consumed, the reaction mixture was diluted with CH2C12 (20 mL), washed with water (2 x 10 mL) and brine (10 mL), dried over Na2S04 and concentrated to give a residue which was purified by flash chromatography on silica gel (eluting with petroleum ether/EtOAc 100/0 gradually increasing to 90/10) to give Scheme 44 compound 4 (800 mg, 72%) as a colorless liquid. MS [ESI, MH+] = 287.0.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 6.5h;
To a stirred solution of ethyl 6-(tert-butoxycarbonylamino)nicotinate (100; 10.0 g, 27.3 mmol) in THF (40 mL) was added LA1H4 (1.92 g, 50.5 mmol) in THF (60 mL) over a period of 30 min at 0 0C. The resulting reaction mixture was stirred at 0 0C for 6 h. The reaction was then quenched by carefully adding water (1.0 ml) and 10% NaOH solution (2.0 mL) at O0C. The resulting mixture was filtered and the filtrate was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (dichloromethane:methanol = 40:1) to afford tert-butyl 5- (hydroxymethyl)pyridin-2-ylcarbamate 101 (4.50 g, 74%).
64%
With lithium aluminium tetrahydride; In tetrahydrofuran; at -10 - 20℃; for 3.5h;
To a cooled (-10 C) solution of Scheme 44 compound 2 (1.7 g, 6.4 mmol) in dry THF (200 mL) was added LiAlH4 (305 mg, 8.5 mmol) portion wise over a period of 30 min and the reaction mixture was slowly warmed to RT over 3 h. After TLC showed the starting material was completely consumed, the reaction mixture was quenched with saturated ammonium chloride (10 mL), passed through a pad of celite and washed with EtOAc (30 mL). The filtrate was washed with water (2 x 5 mL) and brine (2 x 5 mL), dried over Na2S04 and concentrated to give a residue which was purified by flash chromatography on silica gel (eluting with petroleum ether/EtOAc 100/0 gradually increasing to 60/40) to give Scheme 44 compound 3 (900 mg, 64 %) as an off-white solid. MS [ESI, MH+] = 225.2.
With sodium hydroxide; magnesium sulfate; In tetrahydrofuran; diethyl ether; water;
Part C Preparation of 6-(tert-Butyloxycarbonylamino)-3-pyridylmethanol To 4.6 mL (4.6 mmol) of a 1M solution of lithium aluminum hydride in diethyl ether at -40 C. under a nitrogen atmosphere, was added a slution of 618 mg (2.3 mmol) of ethyl 6-(tert-butyloxycarbonylamino)nicotinate from part B in 40 mL of anhydrous tetrahydrofuran. After the addition, this was warmed to room temperature, stirred for 3 hours, cooled to 0 C., and 145 muL of water, 145 muL of 20% sodium hydroxide solution and 290 muL of water were successively added. To the resulting mixture was added 50 mL of tetrahydrofuran and stirring continued for 30 minutes. Anhydrous magnesium sulfate was added, the solids removed via filtration and the filtrate concentrated under reduced pressure to afford 460 mg of the desired product, m/e=224(M+), which was used directly in the next step.
0.85 g
With lithium aluminium tetrahydride; In tetrahydrofuran; at 5℃;Inert atmosphere;
Lithium aluminiumhydride (251 mg, 6.61 mmol, 1.1 equiv) was added portion wise to a cold (5C) solution of 6-tertbutoxycarbonylamino nicotinic acid ethyl ester (Step 8.4) (1.6 g, 6.01 mmol) in THF (25 mL), under an argon atmosphere. The reaction mixture was stirred for 1 h at 5C and quenched by sequential addition of water (0.4 mL), 15 % NaOH aqueous solution (0.4 mL) and water (1.2 mL). The resulting mixture was filtered through a pad of celite and concentrated. The residue was diluted with EtOAc and water and extracted with EtOAc. The organic phase was washed with water and brine, dried (Na2S04), filtered and concentrated. The residue was purified by trituration in Et20 to provide the title compound (0.85 g) as a solid. M/Z: 224.2, M+H: 225.4, tR = 0.63 min. (System 1)
Lithium aluminium hydride (1.6 g, 40.9 mmol, 1.1 equiv) was added portionwise to a cold (5C) solution of theta-tert-butoxycarbonylamino-nicotinic acid ethyl ester (Step 26.5) (9.9 g, 37.2 mmol) in THF (250 ml_), under an argon atmosphere. The reaction mixture was stired for 1 h at 5C and quenched by sequential addition of H2O (4 ml_), 15% NaOH aqueous solution (4 ml.) and H2O (12 ml_). The resulting mixture was filtered through a pad of celite and concentrated. The residue was diluted with EtOAc and H2O, and extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by trituration in Et2O to provide 5 g of the title compound as a white solid: ESI-MS: 223.0 [M-H]"; tR= 1.75 min (System 1 ).
(2S,3S,5S)-5-<N-<N-<<(6-amino-3-pyridinyl)methoxy>carbonyl>valinyl>amino>-2-<N-<<(3-pyridinyl)methoxy>carbonyl>amino>-1,6-diphenyl-3-hydroxyhexane[ No CAS ]
(5-{(S)-1-[(1S,3S,4S)-1-Benzyl-3-hydroxy-5-phenyl-4-(pyridin-3-ylmethoxycarbonylamino)-pentylcarbamoyl]-2-methyl-propylcarbamoyloxymethyl}-pyridin-2-yl)-carbamic acid tert-butyl ester[ No CAS ]
crude2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine[ No CAS ]
[ 169280-83-5 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; magnesium sulfate; In tetrahydrofuran; diethyl ether; water;
Part C. Preparation of 6-(tert-Butyloxycarbonylamino)-3-pyridylmethanol. To 4.6 mL(4.6 mmol) of a 1M solution of lithium aluminum hydride in diethyl ether at -40 C under a nitrogen atmosphere, was added a solution of 618 mg(2.3 mmol) of ethyl 6-(tert-butyloxycarbonylamino)nicotinate from part B in 40 mL of anhydrous tetrahydrofuran. After the addition, this was warmed to room temperature, stirred for 3 hours, cooled to 0 C, and 145 muL of water, 145 muL of 20% sodium hydroxide solution and 290 muL of water were successively added. To the resulting mixture was added 50 mL of tetrahydrofuran and stirring continued for 30 minutes. Anhydrous magnesium sulfate was added, the solids removed via filtration and the filtrate concentrated under reduced pressure to afford 460 mg of the desired product, m/e=224(M+), which was used directly in the next step.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; for 1.0h;
<strong>[169280-83-5]2-(Boc-amino)-5-pyridinemethanol</strong> (3.8 g, 17.1 mmol), TH-1152 (5 g, 11.4 mmol), and PPh3 (5.97 g, 22.8 mmol), were co-evaporated from anhydrous toluene and dried under high vacuume for 10 min. The residue was taken up in THF (50 mL), DIAD (4.5 mL, 0.91 mmol) was added, the reaction mixture was stirred for Ih, diluted with EtOAc, and washed <n="62"/>with water and brine. The organic layer was dried over Na2SO4 and volatiles removed. The residue was purified by column chromatography using 0-60% EtOAc/Hexanes to provide crude TH-1254.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 5℃;Inert atmosphere;
Methanesulfonic anhydride (0.490 g, 4.28 mmol, 1.21 equiv) was added portion wise to a cold (5C) mixture of (5-hydroxymethyl-pyridin-2-yl) carbamic acid tert-butyl ester (Step 8.3) (0.8 g, 3.5 mmol) and DIPEA (1.3 mL, 10.7 mmol, 3 equiv) in DCM (10 mL), under an argon atmosphere. The reaction mixture was allowed to stir for 1 h at 5C, diluted with EtOAc and water and extracted with EtOAc. The organic phase was washed with water and brine, dried (Na2S04), filtered and concentrated and used as such for the next step without further purification.
With triethylamine; In dichloromethane; at 5℃; for 1.0h;Inert atmosphere;
Methanesulfonic anhydride (0.854 g, 4.9 mmol, 1.1 equiv) was added portionwise to a cold (5C) mixture of (5-hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (Step 26.4) (1 g, 4.5 mmol) and triethylamine (0.75 ml_, 5.4 mmol, 1.2 equiv) in DCM (20 ml_), under an argon atmosphere. The reaction mixture was allowed to stir for 1 h at 5C, diluted with EtOAc and H2O, and extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated to provide 1.25 g of the title compound as a white solid: tR= 2.60 min (System 1 ).
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃;
To a mixture containing <strong>[169280-83-5]tert-butyl 5-(hydroxymethyl)pyridin-2-ylcarbamate</strong> (101; 4.5 g, 20.2 mmol) and DIPEA (16.0 g, 121 mmol) in THF (45 mL) was added MsCl (6.93 g, 60.5 mmol) over a period of 30 min at 0 C. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was then washed with water (2x5 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (10:1 petroleum ether/ethyl acetate) to afford (6-(tert- butoxycarbonylamino)pyridm-3-yl)methyl methanesulfonate 102 (3.0 g, 61%) .
With pyridine-SO3 complex; dimethyl sulfoxide; triethylamine; at 20℃;
Production Example 1 To a mixture of tert-butyl [5-(hydroxymethyl)pyridine-2-yl]carbamate (2.13 g), triethylamine (5.3 ml), and DMSO (15 ml), a sulfur trioxide-pyridine complex (3.02 g) in a DMSO solution (15 ml) was added dropwise, followed by stirring at room temperature for 4.5 hours. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2.00 g of tert-butyl (5-formylpyridin-2-yl)carbamate.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 6.5h;
To a stirred solution of ethyl 6-(bis(tert-butoxycarbonyl)amino)nicotinate (300.0 g, 819 mmol) in THF (1.2 L) was added LiAlH4 (57.6 g, 1.51 mol) in THF (3 L) over a period of 30 min at 0 C. The reaction mixture was stirred for 6 h, and H2O (30.0 mL) and 10% NaOH solution (60.0 mL) were added. The solids were removed by filtration and the filtrate was dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (DCM : MeOH = 40 : 1) to give tert-butyl 5-(hydroxymethyl)pyridin-2- ylcarbamate (85.0 g, 46 % yield)
46%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 6.5h;
To a stirred solution of ethyl 6-(bis(tert-butoxycarbonyl)amino)nicotinate (300.0 g, 819 mmol) in THF (1.2 L) was added LiAlH4 (57.6 g, 1.51 mol) in THF (3 L) over a period of 30 min at 0 C. The reaction mixture was stirred for 6 h, and H2O (30.0 mL) and 10% NaOH solution (60.0 mL) were added. The solids were removed by filtration and the filtrate was dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (DCM : MeOH = 40 : 1) to give tert-butyl 5-(hydroxymethyl)pyridin-2-ylcarbamate (85.0 g, 46 % yield).
With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 12.5h;
To a solution of <strong>[169280-83-5]tert-butyl 5-(hydroxymethyl)pyridin-2-ylcarbamate</strong> (85.0 g, 379 mmol) and diisopropylethylamine (296.0 g, 2.27 mol) in THF (850 mL) was added methanesulfonyl chloride (130.0 g, 1.14 mol) over a period of 30 min at 0 C. The mixture was stirred for 12 h at room temp then washed with H2O (2x 100 mL) and dried over Na2SO4. The mixture was concentrated and the crude residue was purified by flash chromatography (petroleum ether: ethyl acetate=10:l) to give tert-butyl 5-(chloromethyl)pyridin-2-ylcarbamate (30.0 g, 63 % yield)
63%
With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 12.5h;
To a solution of <strong>[169280-83-5]tert-butyl 5-(hydroxymethyl)pyridin-2-ylcarbamate</strong> (85.0 g, 379 mmol) and diisopropylethylamine (296.0 g, 2.27 mol) in THF (850 mL) was added methanesulfonyl chloride (130.0 g, 1.14 mol) over a period of 30 min at 0 C. The mixture was stirred for 12 h at room temp then washed with H2O (2×100 mL) and dried over Na2SO4. The mixture was concentrated and the crude residue was purified by flash chromatography (petroleum ether: ethyl acetate=10:1) to give tert-butyl 5-(chloromethyl)pyridin-2-ylcarbamate (30.0 g, 63 % yield).
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 6.0h;
0464-1 Methanesulfonyl chloride (0.14 mL) was added to a mixture of (<strong>[169280-83-5]tert-butyl (5-(hydroxymethyl)pyridin-2-yl)carbamate</strong> (133 mg), N,N-diisopropylethylamine (0.62 mL), and tetrahydrofuran (1.3 mL) at a temperature of from 0 C. to 5 C., followed by stirring at room temperature for 6 hours. After water and ethyl acetate were added to the reaction mixture, the organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining tert-butyl (5-(chloromethyl)pyridin-2-yl)carbamate (158 mg) as a pale brown solid. MS m/z (M+H): 243.
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