* 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.
Reference:
[1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 15, p. 2155 - 2163
2
[ 112418-19-6 ]
[ 185692-85-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With lithium borohydride In tetrahydrofuran at 20℃; for 2.5 h; Stage #2: With ammonium chloride In tetrahydrofuran; water
To a solution of the product of Step 3 (16.5 g, 45.6 mmol) in THF (150 ml) wasadded 2M lithium borohydride in THF (37.1 ml) slowly. The mixture was stirred at RTfor 2.5 h. The reaction was quenched with saturated NH4CI and extracted with EtOAc(2x250 ml). The combined organic layer was washed with saturated NH4CI (100 ml),saturated sodium bicarbonate, and brine, dried, and concentrated to give the product(14.5 g, 100percent). MS m/e 306 (M+H)+
100%
With lithium borohydride In tetrahydrofuran at 20℃; for 2.5 h;
To a solution of the product of Step 3 (16.5 g, 45.6 mmol) in THF (150 ml) wasadded 2M lithium borohydride in THF (37.1 ml) slowly. The mixture was stirred at RTfor 2.5 h. The reaction was quenched with saturated NH4CI and extracted with EtOAc(2x250 ml). The combined organic layer was washed with saturated NH4CI (100 ml),saturated sodium bicarbonate, and brine, dried, and concentrated to give the product(14.5 g, 100percent). MS m/e 306 (M+H)+
Reference:
[1] Patent: WO2006/14762, 2006, A1, . Location in patent: Page/Page column 42
[2] Patent: WO2006/14944, 2006, A1, . Location in patent: Page/Page column 32
[3] European Journal of Organic Chemistry, 2013, # 31, p. 7145 - 7151
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4204 - 4219
[5] Patent: WO2008/86122, 2008, A2, . Location in patent: Page/Page column 68
3
[ 95715-85-8 ]
[ 185692-85-7 ]
Reference:
[1] European Journal of Organic Chemistry, 2013, # 31, p. 7145 - 7151
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4204 - 4219
4
[ 18162-48-6 ]
[ 185692-85-7 ]
Reference:
[1] European Journal of Organic Chemistry, 2013, # 31, p. 7145 - 7151
Step C; OH OTBS O OTBSNHBOC NHBOC13-3 13-4 <n="70"/>To a solution of oxalyl chloride (1.4 eq.) in anhydrous methylene chloride at -78C was added DMSO (2.2 eq.) followed by stirring for 10 minutes. A solution of alcohol 13-3 (1 eq.) in methylene chloride was then introduced drop wise and allowed to react for 5 minutes. Triethylamine (5 eq.) was then introduced slowly and upon complete addition, the reaction stirred for 10 min at -78 0C followed by 30 minutes at room temperature. Upon complete conversion, the reaction was diluted with EtOAc and washed with sodium bicarbonate (saturated aq.) three times. Organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified on silica gel with 0-100% EtOAc/Hexane gradient elution to provide compound 13-4.
To a solution of the product of Step 3 (16.5 g, 45.6 mmol) in THF (150 ml) wasadded 2M lithium borohydride in THF (37.1 ml) slowly. The mixture was stirred at RTfor 2.5 h. The reaction was quenched with saturated NH4CI and extracted with EtOAc(2x250 ml). The combined organic layer was washed with saturated NH4CI (100 ml),saturated sodium bicarbonate, and brine, dried, and concentrated to give the product(14.5 g, 100%). MS m/e 306 (M+H)+
100%
With lithium borohydride; In tetrahydrofuran; at 20℃; for 2.5h;
To a solution of the product of Step 3 (16.5 g, 45.6 mmol) in THF (150 ml) wasadded 2M lithium borohydride in THF (37.1 ml) slowly. The mixture was stirred at RTfor 2.5 h. The reaction was quenched with saturated NH4CI and extracted with EtOAc(2x250 ml). The combined organic layer was washed with saturated NH4CI (100 ml),saturated sodium bicarbonate, and brine, dried, and concentrated to give the product(14.5 g, 100%). MS m/e 306 (M+H)+
Step B; 13-2 13-3To a solution of BOC-L-serine methyl ester 13-2 in toluene was added DIBAL-H (3 eq. of 2.5 M in toluene) at 0 0C. Reaction was allowed to warm to room temperature and stir until complete conversion was observed. After this time, reaction was treated with methanol and concentrated. To this residue was added 2M potassium sodium tartrate solution (sat. aqueous) and stirred vigorously for 30 minutes. The resulting residue was partitioned between EtOAc and water, layers were separated and aqueous was extracted with EtOAc three times. The combined organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified on silica gel with 0-100% EtOAc/Hexane gradient elution to provide compound 13-3.
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; acetonitrile; at 0 - 20℃; for 48h;
To an ice-cold solution of triphenylphosphine (13.95 g, 53.19 mmol) in THF(400 ml) and CH3CN (50 ml) was added DIAD (10.76 g, 53.21 mmol). The mixturewas stirred for 15 min and a solution of the product of Step 4 (8.20 g, 26.2 mmol) inTHF (100 ml) was added over 15 min. After the addition was complete, the ice-waterbath was removed and the mixture was stirred at RT for 2 d. The mixture wasconcentrated and purified by column chromatography (gradient EtOAc/Hexanes 0-5%) to give the product (3.75 g, 50%). MS m/e 288 (M+H)+
50%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; acetonitrile; at 0 - 20℃; for 48.5h;
To an ice-cold solution of triphenylphosphine (13.95 g, 53.19 mmol) in THF(400 ml) and CH3CN (50 ml) was added DIAD (10.76 g, 53.21 mmol). The mixturewas stirred for 15 min and a solution of the product of Step 4 (8.20 g, 26.2 mmol) inTHF (100 ml) was added over 15 min. After the addition was complete, the ice-waterbath was removed and the mixture was stirred at RT for 2 d. The mixture wasconcentrated and purified by column chromatography (gradient EtOAc/Hexanes 0-5%) to give the product (3.75 g, 50%). MS m/e 288 (M+H)+
5-[5-((2S)-1-tert-Butoxycarbonyl-aziridin-2-ylmethoxy)-pyridin-3-yl]-3-methyl-indazole-1-carboxylic Acid Tert-Butyl Ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5-[5-((2R)-1-tert-Butoxycarbonyl-aziridin-2-ylmethoxy)-pyridin-3-yl]-3-methyl-indazole-1-carboxylic Acid Tert-Butyl Ester The desired product was prepared by substituting <strong>[185692-85-7](S)-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester</strong> for (R)-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester in Example 273D. MS (APCI) m/z 481 (M+1)+.
tert-butyl (4R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1H-imidazole; thionyl chloride In dichloromethane at 0 - 20℃; for 1h;
39.C Step C: Tert-butyl (R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3-oxathiazolidine-3- carboxylate 2,2-dioxide
To a solution of imidazole (1.18 g, 17.28 mmol) in DCM (20 mL) was slowly added a solution of SOCl2 (685.2 mg, 5.76 mmol) in DCM (10 mL) at 0 °C. Then the mixture was warmed up to RT and stirred over 1 h. After cooled to 0 °C, a solution of tert-butyl (S)-(1-((tert- butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)carbamate (0.88 g, 2.88 mmol) in DCM (5 mL) was added to the mixture above. Upon completion, the resulting mixture was allowed to warm up to RT and stirred for 1 h. The resulting mixture was cooled to 0 °C, quenched with ice-water (50 mL), stirred for 10 min, extracted with DCM (4*50 mL), washed with sat. citric acid (100 mL) and brine (100 mL*2). The organic layer was separated, dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to give the crude product tert-butyl (4R)-4-(((tert- butyldimethylsilyl)oxy)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (950 mg) as a yellow oil which was directly used in the next step without further purification.