* 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 sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium chloride In aq. phosphate buffer; water; acetonitrile at 35℃;
[00108] 2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO, 2.3 g, 15 mmol) was added to a mixture of compound 1_5_4 (33.0 g, 150 mmol) in acetonitrile (750 mL) and sodium phosphate buffer (600 mL, 0.7 M solution, pH 6-7) and the resulting mixture was heated to 35°C. The mixture was then treated by a simultaneous addition of a sodium chlorite solution (34.2 g in 150 mL of water) and 60 drops of a very dilute sodium hypochlorite solution (3 mL of commercial solution in 100 mL of water). The mixture was stirred at 35°C overnight, cooled to room temperature, treated with citric acid (-15 g, pH 3), saturated with sodium chloride and extracted with ethyl acetate (3 x 2 L). The organic extracts were combined and concentrated under reduced pressure. The residue was dissolved in 1.5 L of a 2 M sodium carbonate solution and washed with ethyl acetate (2 x 2 L). The aqueous layer was cooled to 0°C, the pH was adjusted to 3.0 using a 2 M solution of H3P04 and the solution was saturated with sodium chloride. The resulting mixture was extracted with ethyl acetate (3 x 2 L), the organic phases were combined, dried, filtered and concentrated under reduced pressure to give compound 1_5_5 (28.4 g, 81 percent) as a colorless solid. [00109] NMR (400 MHz, DMSO-d6): δ = 1.15 (s, 3 H), 1.17 (s, 3 H), 1.39 (s, 9 H), 3.86 (d, / = 8.6 Hz, 1 H) 6.52 (d, / = 8.9 Hz, 1 H).
Reference：
[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 5, p. 1168 - 1170
[2] Journal of Organic Chemistry, 2018, vol. 83, # 13, p. 6977 - 6994
[3] Patent: WO2013/110643, 2013, A1, . Location in patent: Paragraph 00108; 00109
[4] Chemical Communications, 2017, vol. 53, # 40, p. 5549 - 5552
[5] Nature Chemistry, 2010, vol. 2, # 4, p. 280 - 285
3
[ 288159-36-4 ]
[ 102507-13-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 3996 - 4003
[2] Synthesis, 2000, # 5, p. 634 - 636
[3] Angewandte Chemie - International Edition, 2011, vol. 50, # 5, p. 1168 - 1170
4
[ 75-16-1 ]
[ 95715-85-8 ]
[ 102507-13-1 ]
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 1, p. 177 - 179
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-methylbutanoic acid (XXXVII) (851 mg, 3.65 mmol) in anhydrous THF (20 mL) was added HOBT (493 mg, 3.65 mmol). The reaction mixture was cooled in a salt/ice bath to -10 C. which was followed by addition of DCC (752 mg, 3.65 mmol). The reaction mixture was stirred at 0 C. for 40 min before adding a solution of O-benzylhydroxylamine (XXXVIII) (538 mg, 4.37 mmol) in THF (5 mL). Stirring continued 0 C. followed by warming to room temperature for 1.5 h. To the reaction mixture was added hexane (20 mL), the precipitate was filtered and the filtrate was concentrated under vacuum. To the oily residue was chromatographed on silica gel (1:1 EtOAc/hexane) followed by recrystallization from MTBE to produce (S)-tert-butyl 1-(benzyloxyamino)-3-hydroxy-3-methyl-1-oxobutan-2-ylcarbamate (XXXIX) (1.002 g, 2.96 mmol, 81.1% yield). ESIMS found C17H26N2O5 m/z 339 (M+H).
81.1%
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-methylbutanoic acid (XXXVII) (851 mg, 3.65 mmol) in anhydrous THF (20 mL) was added HOBT (493 mg, 3.65 mmol). The reaction mixture was cooled in a salt/ice bath to -10 C. which was followed by addition of DCC (752 mg, 3.65 mmol). The reaction mixture was stirred at 0 C. for 40 min before adding a solution of O-benzylhydroxylamine (XXXVIII) (538 mg, 4.37 mmol) in THF (5 mL). Stirring continued 0 C. followed by warming to room temperature for 1.5 h. To the reaction mixture was added hexane (20 mL), the precipitate was filtered and the filtrate was concentrated under vacuum. To the oily residue was chromatographed on silica gel (1:1 EtOAc/hexane) followed by recrystallization from MTBE to produce (S)-tert-butyl 1-(benzyloxyamino)-3-hydroxy-3-methyl-1-oxobutan-2-ylcarbamate (XXXIX) (1.002 g, 2.96 mmol, 81.1% yield). ESIMS found C17H26N2O5 m/z 339 (M+H).
methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride[ No CAS ]
[ 102507-13-1 ]
(1R,2S,5S)-3-((S)-2-tert-Butoxycarbonylamino-3-hydroxy-3-methyl-butyryl)-6,6-dimethyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid methyl ester[ No CAS ]
(E)-(S)-4-({(S)-2-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-3-phenyl-butyrylamino]-3-hydroxy-3-methyl-butyryl}-methyl-amino)-2,5-dimethyl-hex-2-enoic acid[ No CAS ]
(E)-(S)-4-({(S)-2-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-3-phenyl-butyrylamino]-3-hydroxy-3-methyl-butyryl}-methyl-amino)-2,5-dimethyl-hex-2-enoic acid ethyl ester[ No CAS ]
2-[(S)-1-((S)-2-Amino-3-hydroxy-3-methyl-butyrylamino)-2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-oxazole-4-carboxylic acid methyl ester[ No CAS ]
2-[(S)-1-{(S)-2-[((S)-3-Benzyloxycarbonyl-2,2-dimethyl-oxazolidine-4-carbonyl)-amino]-3-hydroxy-3-methyl-butyrylamino}-2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-oxazole-4-carboxylic acid[ No CAS ]
2-({2-[1-{2-[2-amino-3-(<i>tert</i>-butyl-dimethyl-silanyloxy)-propionylamino]-3-hydroxy-3-methyl-butyrylamino}-2-(<i>tert</i>-butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-oxazole-4-carbonyl}-amino)-3-(<i>tert</i>-butyl-diphenyl-silanyloxy)-propionic acid methyl ester[ No CAS ]
2-({2-[1-[2-(2-benzyloxycarbonylamino-3-hydroxy-propionylamino)-3-hydroxy-3-methyl-butyrylamino]-2-(<i>tert</i>-butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-oxazole-4-carbonyl}-amino)-3-(<i>tert</i>-butyl-diphenyl-silanyloxy)-propionic acid methyl ester[ No CAS ]
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 14h;
Product from step 5 HO-T-- of example 11 Compound 89 To a solution of the product from step 5 of example 11 (66.0 mg, 0.123 mmol), DIEA (63.7 mg, 0.492 mmol) and HATU (70.0, 0.184 mmol) was added 2S-tertbutoxycarbonylamino-3-hydroxy-3-methyl-butyric acid (34.0 mg, 0.147 mmol). After stirring at rt for 14 hr, the reaction mixture was washed with 5% aqueous NaHC03 (1 mL). The aqueous layer was extracted with 2x2mL DCM. The combined organic layer was washed with 5% aqueous citric acid (2 mL), brine, dried overMg04, concentrated and purified by reversed phase prep-HPLC to give Compound 89 (36.1 mg, 41% yield):'H NMR (CD30D, 500 MHz)
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium chloride; In aq. phosphate buffer; water; acetonitrile; at 35℃;pH 6 - 7;
[00108] 2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO, 2.3 g, 15 mmol) was added to a mixture of compound 1_5_4 (33.0 g, 150 mmol) in acetonitrile (750 mL) and sodium phosphate buffer (600 mL, 0.7 M solution, pH 6-7) and the resulting mixture was heated to 35C. The mixture was then treated by a simultaneous addition of a sodium chlorite solution (34.2 g in 150 mL of water) and 60 drops of a very dilute sodium hypochlorite solution (3 mL of commercial solution in 100 mL of water). The mixture was stirred at 35C overnight, cooled to room temperature, treated with citric acid (-15 g, pH 3), saturated with sodium chloride and extracted with ethyl acetate (3 x 2 L). The organic extracts were combined and concentrated under reduced pressure. The residue was dissolved in 1.5 L of a 2 M sodium carbonate solution and washed with ethyl acetate (2 x 2 L). The aqueous layer was cooled to 0C, the pH was adjusted to 3.0 using a 2 M solution of H3P04 and the solution was saturated with sodium chloride. The resulting mixture was extracted with ethyl acetate (3 x 2 L), the organic phases were combined, dried, filtered and concentrated under reduced pressure to give compound 1_5_5 (28.4 g, 81 %) as a colorless solid. [00109] NMR (400 MHz, DMSO-d6): delta = 1.15 (s, 3 H), 1.17 (s, 3 H), 1.39 (s, 9 H), 3.86 (d, / = 8.6 Hz, 1 H) 6.52 (d, / = 8.9 Hz, 1 H).
76%
With Iron(III) nitrate nonahydrate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium chloride; oxygen; In 1,2-dichloro-ethane; at 20℃; for 48h;Inert atmosphere;
TEMPO (156.3mg, 1.0mmol), Fe (NO3)3·9H2O (404.0mg, 1.0mmol) and KCl (74.6mg, 1.0mmol) were added to a stirred solution of (2R)-2-N-(Boc) amino-3-methyl- 1,3-butanediol 43 (2.19g, 10.0mmol) under O2 atmosphere in 100ml anhydrous DCE. The reaction was then stirred at room temperature until completion of the reaction as monitored by TLC (48h). The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (DCM/MeOH=20: 1), affording 41 (1.80g, 76% yield) as a yellowish solid. The spectroscopic data are consistent with those reported in literature [18a].
With N-ethyl-N,N-diisopropylamine; HATU; In methanol; N,N-dimethyl-formamide; at 20℃;Cooling with ice;
To a solution of N- (tert-butoxycarbonyl) -3-hydroxy-L- valine (1.00 g) , 2 dimethylamine methanol solution (2.14 mL) and N-ethyl-N- (1-methylethyl) propan-2-amine (1.11 g) in DMF (10 mL) was added 0- (7-azabenzotriazol-l-yl) -Nu,Nu,Nu' ,Nu' - tetramethyluronium hexafluorophosphate (1.63 g) at room temperature. The reaction mixture was stirred at roomtemperature overnight. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (670 mg) .1H NMR (300 MHz, DMS0-d6) delta 1.06 (3H, s) , 1.12 (3H, s) , 1.37 (9H, s), 2.84 (3H, s) , 3.07 (3H, s) , 4.44 (1H, d, J = 9.3 Hz), 4.72 (1H, s), 6.46 (1H, d, J = 9.2 Hz).
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere;
To a solution of 18 (0.503 g, 2.16 mmol) in DMF (10 mL) at room temperature under argon were sequentially added NaHCO3 (0.362 g, 4.31 mmol) and allyl bromide (0.28 mL, 3.23 mmol) and the mixture was stirred until the starting material had been consumed (TLC). The mixture was diluted with EtOAc and the solution was washed with H2O, brine and dried by (MgSO4) and then filtered and the filtrate concentrated. The resulting residue was purifiedby silica gel column chromatography (EtOAc/hexanes; from 1:10 to 1:2) to afford a white foam (0.35 g, 60%). This was dissolved in a 1 M solution of HCl in Et2O (12.44 mL, 12.44 mmol) and the reaction mixture stirred at room temperature (3 h). The solvent was then removed by evaporation and the residue was dissolved in a solution of THF/H2O (12 mL:12 mL, 1:1 v/v) and cooled in anice bath. Sodium bicarbonate (0.21 g, 2.49 mmol) and Fmoc-OSu (0.63 g, 1.87 mmol) were added and the mixture was stirred at room temperature (10 h). The THF was then removed by evaporation and the aqueous phase was extracted with EtOAc and the combined organic layer was washed with brine and dried (Na2SO4), then filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/hexanes; from 1:10 to 1:2) to yield product 19 (0.42 g) as a foam (85% for two steps).
[00110] Dicyclohexylcarbodiimide (DCC, 19.5 g, 94.3 mmol) was added to a solution of compound 1_5_5 (20.0 g, 85.7 mmol) in Nu,Nu-dimethylformamide at room temperature followed by 1-hydroxybenzotriazole (HOBt, 12.7 g, 94.3 mmol). The resulting mixture was stirred at room temperature for 30 min, and O-benzyl- hydroxylamine hydrochloride (15.1 g, 94.3 mmol) was added followed by sodium bicarbonate (18.0 g, 214.3 mmol). The reaction mixture was stirred at room temperature for 24 h and filtered through a celite bed, washed with ethyl acetate (2 x 50 mL), and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 30-40 % ethyl acetate in hexane to give compound 1_5_6 (24.5 g, 84.5 %) as a colorless solid. [00111] NMR (400 MHz, DMSO-rf6): delta = 1.05 (s, 3 H), 1.08 (s, 3 H), 1.26 (s, 9 H), 3.74 (d, / = 9.3 Hz, 1 H), 4.62 (br. s, 1 H), 4.72 (s, 2 H), 6.42 (d, / = 8.9 Hz, 1 H), 7.26 - 7.47 (m, 5 H), 11.03 (br. s, 1 H).
Example 102 (1 R)-1 -Amino- 1 -(5-fe/f-butyl-1 H-benzimidazol-2-yl)-2-methylpropan-2-ol A solution of 4-ferf-butyl-1 ,2-diaminobenzene (1 g, 6 mmol), N-boc-3-hydroxy-L-valine (1 .4 g, 6 mmol) and triethylamine (1 .5 mL, 15.1 mmol) in dioxane (50 mL) was stirred at 0°C for 15 minutes. T3P (50percent w/w in EtOAc, 4.6 mL, 7.3 mmol) was added dropwise and the reaction continued stirring at this temperature for 30 minutes. The reaction was then heated to reflux for 5 hours before cooling and diluting with EtOAc. The solution was washed with saturated aqueous sodium carbonate solution twice, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-50percent EtOAc in heptanes. The residue was dissolved in dioxane (10 mL) at 0°C and treated with 4M HCI in dioxane (10 mL). The reaction was stirred at room temperature for 2 hours before concentrating in vacuo. The residue was washed with EtOAc and pentane before basifying with saturated aqueous NaOH solution and extracting into EtOAc. The organic layer was collected, dried over Na2SO4, concentrated in vacuo and triturated with 10percent EtOH in pentane (5 mL) to afford the title compound (25 mg, 2percent). 1H NMR (400MHz, DMSO-d6): delta ppm 1 .08-1 .1 (m, 6H), 1 .21 -1 .39 (m, 9H), 2.17-2.27 (m, 2H), 3.81 (s, 1 H), 4.87 (s, 1 H), 7.18-7.21 (m, 1 H), 7.41 (m, 2H), 1 1 .9 (br s, 1 H). MS m/z 262 [M+H]+
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
