Tempo

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(7-fluoro-1H-benzimidazol-1-yl)ethanol (706 mg, 3.92 mmol) is suspended in 20 mL of acetonitrile and 15 mL of sodium phosphate buffer 1M (pH 6.5). The mixture is heated to 35° C. TEMPO (43 mg, 0.27 mmol) is added, followed by NaClO2 (80%, 887 mg, 7.84 mmol) dissolved in 4 mL of water and diluted bleach (2 ml of a 0.4% aqueous solution). The reaction mixture turns red-brown after the bleach addition. To drive the reaction to completion, if needed, more TEMPO (22 mg), NaClO2 (440 mg in 2 mL of water) and diluted bleach (1 mL) are added and the mixture stirred 6 hours at 35° C. After cooling at room temperature, the reaction is quenched by addition of saturated aqueous Na2SO3 (5 mL). The brown-red color disappears. The pH is adjusted to 8-9 by addition of NaOH 2M and the mixture is washed with ethyl acetate (2×). The organic layer is discarded and the aqueous phase is acidified with HCl 1M (up to pH 3). The desired product is crystallized in the aqueous phase as a white solid (537 mg, 70%). TLC: dichloromethane/methanol 10:1+5% triethylamine, Rf=0.33 (s.m.: Rf=0.56) after the bleach addition the reaction to completion are added After cooling at room temperature the reaction is quenched by addition of saturated aqueous Na2SO3 (5 mL) The pH is adjusted to 8-9 by addition of NaOH 2M the mixture is washed with ethyl acetate (2×) The desired product is crystallized in the aqueous phase as a white solid (537 mg, 70%)

Conditions: temp:42.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(6,7-difluoro-1H-benzimidazol-1-yl)ethanol (2.96 g, 15 mmol) is taken into 75 ml of MeCN and sodium phosphate buffer (56 ml, 0.67 M, pH 6.8) and the mixture is heated to 42° C. TEMPO (165 mg, 1.05 mol) is added followed by the simultaneous dropwise addition of a solution of NaClO2 (3.38 g, 80% pure, 30 mmol in 15 ml water) and a solution of bleach (350 μL of 6% NaOCl in 7.5 mL water) over 1.5 hours. After 48 hrs, the same quantities of NaClO2 and bleach are added. After a further 24 hours, TEMPO (165 mg, 1.05 mol) is added and the reaction is stirred for 72 hrs. The darkened reaction is allowed to cool to room temperature followed by the dropwise addition of 30 ml of a saturated solution of Na2SO3 (exothermic). The reaction becomes almost colourless. Using 2 N NaOH, the pH is raised to 9.2 and the reaction is extracted 4 times with ethyl acetate. The pH is then lowered to 3.8 with 2 N HCl and the solution allowed to stand for 48 hours. 1.98 grams of white crystalline material is recovered. The mother liquor is reduced to half the volume and allowed to stand. A further 260 mg is collected. (Combined yield 2.23 g, 70%) After a further 24 hours The darkened reaction to cool to room temperature the pH is raised to 9.2 the reaction is extracted 4 times with ethyl acetate to stand for 48 hours 1.98 grams of white crystalline material is recovered A further 260 mg is collected

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: ,A mixture of 4-ethylacetophenone (23 g), 2,2,6,6-tetramethylpiperidine-1-oxyl (10,7 g) and molybdenum(VI)oxide (0,67 g) are purged with Argon for one hour. The mixture is then heated up to 70° C. and the solution prepared under A) is added drop wise under stirring within 5 minutes. Pressure is reduced to 300 mbar and the mixture is heated for 18 hours at 70° C. After the+reaction is completed the mixture is cooled to room temperature and the pressure is allowed to raise to normal pressure. Ethylacetate and water is added. The water phase is separated and extracted three times with ethylacetate. The organic phases are combined, washed with water, dried over Magnesium sulfate and concentrated. Excessive amounts of 2-(4-ethyl-phenoxymethyl)-oxirane are removed at 40° C./0,2 mbar. The raw product is subsequently chromatographically purified on silica with petrolether/ethylacetate=95/5 as eluent. A white+powder is obtained after recrystalization from pentane, corresponding to the compound of formula (104), having a melting point of 61.5-63° C. are purged with Argon for one hour the solution prepared under A) is added drop wise the mixture is heated for 18 hours at 70° C After the+reaction is cooled to room temperature to raise to normal pressure The water phase is separated extracted three times with ethylacetate washed with water dried over Magnesium sulfate concentrated Excessive amounts of 2-(4-ethyl-phenoxymethyl)-oxirane are removed at 40° C./0,2 mbar The raw product is subsequently chromatographically purified on silica with petrolether/ethylacetate=95/5 as eluent A white+powder is obtained after recrystalization from pentane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of bleach (100 ml), containing sodium bicarbonate (7.34 g), was added dropwise to a rapidly stirred mixture of 3-hydroxy-4-benzyloxycarbonylamino-tetrahydrofuran (21 g, 88 mmol), sodium bromide (9.4 g), TEMPO (50 mg) in EtOAc (140 ml), toluene (140 ml) and water (40 ml). After a persistant orange colour developed the mixture was extracted with EtOAc and the combined organic layers were washed with saturated sodium bicarbonate, brine and dried (MgSO4). Evaporation under reduced pressure and purification of the residue by column chromatography afforded the title compound as white crystals, 18 g, 87%. was extracted with EtOAc the combined organic layers were washed with saturated sodium bicarbonate, brine dried (MgSO4) Evaporation under reduced pressure and purification of the residue by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Fe(NO3)3.9H2O (16.1607 g, 40.0 mmol), TEMPO (6.2510 g, 40.0 mmol), NaCl (2.3377 g, 40.0 mmol) and DCE (400 mL) were added to a 2 L-three-necked flask, and were stirred for 10 mins at room temperature under oxygen atmosphere. 1-Phenyl ethanol (488.64 g, 4.0 mol) was then added dropwise to the reaction solution. The reaction was exothermic, and the reaction temperature was kept below 50° C. The reaction was monitored by TLC till it was complete. The reaction solvent DCE was recovered after distillation under atmospheric pressure (350 mL, recovery of 88%) and acetophenone was obtained after further distillation under reduced pressure (b.p. 98˜100° C./20 mmHg, 436.6414 g, 91%). was kept below 50° C The reaction solvent DCE was recovered after distillation under atmospheric pressure (350 mL, recovery of 88%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A dichloromethane (dehydrated, 5 mL) solution of 946 mg (4.07 mmol) of the compound of the formula 3 was cooled to −5° C., 14.0 mg (0.090 mmol) of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), 102.0 mg (1.21 mmol) of sodium hydrogen carbonate, and 2.0 mL of water were added in sequence, and 3.86 g (5.19 mmol) of a 10% sodium hypochlorite aqueous solution was then added while keeping the internal temperature between −5° C. and 0° C. After stirring at −5° C. to 0° C. for 1 hour, the mixture was separated. The organic layer was washed with 1 mL of water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 899 mg of the compound of the formula 4 was obtained as an oily substance with yellow color. was then added the internal temperature between −5° C. and 0° C the mixture was separated The organic layer was washed with 1 mL of water dried over anhydrous sodium sulfate After concentration under reduced pressure, 899 mg of the compound of the formula 4 was obtained as an oily substance with yellow color

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (4S,5R)-4-benzyl-5-hydroxymethyloxazolidin-2-one obtained in the same manner as in Example 3 (4.68 g) were added acetonitrile (46.8 ml) and water (46.8 ml), and then sodium hydrogencarbonate (4.68 g), TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy (0.0468 g) and potassium bromide (2.69 g) were added. The mixture was stirred and 12% aqueous sodium hypochlorite solution (35.0 g) was added dropwise at room temperature over 30 min. The mixture was stirred at room temperature for 7 hr, and 12% aqueous sodium hypochlorite solution (14.0 g) was further added. The mixture was stirred for 12 hr and 12% aqueous sodium hypochlorite solution (7.0 g) was further added, which was followed by stirring for 3 hr. The reaction was quenched by adding sodium hydrogensulfite (2.84 g). The reaction mixture was analyzed by HPLC to confirm that (4S,5R)-4-benzyl-2-oxo-5-oxazolidinecarboxylic acid (4.67 g, yield 93%) was obtained. The mixture was extracted twice with dichloromethane (50 ml, 50 ml) and the solvent of the organic layer was removed under reduced pressure. The obtained oil was analyzed by HPLC to confirm that (4S,5R)-4-benzyl-2-oxo-5-oxazolidinecarboxylic acid (4.00 g, yield 80%) was obtained. The mixture was stirred at room temperature for 7 hr The mixture was stirred for 12 hr by stirring for 3 hr The reaction was quenched by adding sodium hydrogensulfite (2.84 g)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound is prepared by oxidation of the product of Step h with a suitable oxidizing reagent such as Dess-Martin periodinane or TEMPO and sodium hypochlorite. Specifically, in a flask containing 1.31 g of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide in 40 mL of dichloromethane is added at room temperature 1.06 g of Dess-Martin periodinane. After 2 hours of stirring, 50 mL of sodium bisulfite (1N) is added, and the mixture is stirred for 30 minutes. The 2 phases are separated, the organic is washed with water twice, brine and dried over Na2SO4. The crude product was purified by chromatography on silica (ethyl acetate 20-100% in Hexanes) to give the title compound. The diastereoisome ratio is determined by chiral HPLC normal phase. the mixture is stirred for 30 minutes The 2 phases are separated the organic is washed with water twice brine and dried over Na2SO4 The crude product was purified by chromatography on silica (ethyl acetate 20-100% in Hexanes)

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.0 eq.) in isopropyl acetate (5 vol) was cooled to 0° C. and TEMPO (0.05 eq.) was added. A solution of bleach (12.5 wt %, 1.2 eq., 2.6 vol) was then slowly added over 1 hour while maintaining the temperature at 0-5° C. The mixture was stirred and monitored by HPLC for completion, then aqueous 10% KHSO4 (2.5 vol) was added, stirred for 10 minutes, and then the phases were separated. The organic phase was washed with aqueous 5% Na2SO3 (2 vol) then brine (1 vol) then dried azeotropically and concentrated to afford the title compound as a solid. The solid was triturated with acetonitrile (1.0 vol) to remove residual color and impurities. 1H-NMR (400 MHz, DMSO): δ 4.54 (m, 1H), 3.82 (m, 1H), 3.67 (m, 1H); 3.15 (m, 1H); ≈2.50 (m, 1H, coincides with DMSO); 1.42 and 1.39 (2 s rotamers, 9H). A solution of bleach (12.5 wt %, 1.2 eq., 2.6 vol) was then slowly added over 1 hour stirred for 10 minutes the phases were separated The organic phase was washed with aqueous 5% Na2SO3 (2 vol) brine (1 vol) then dried azeotropically concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 0.32 g(0.94 mmoles) of N-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninol in 2.8 mL of toluene was added 2.4 mg (0.015 mmoles) of 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO), 0.1 g (0.97 mmoles) of sodium bromide, 2.8 mL of ethyl acetate and 0.34 mL of water. The mixture was cooled to 0° C. and an aqueous solution of 4.2 mL of 5% household bleach containing 0.23 g (3.0 mL, 2.738 mmoles) of sodium bicarbonate was added slowly over 30 minutes. The mixture was stirred at 0° C. for 10 minutes. Three more additions (0.4 mL each) of bleach was added followed by stirring for 10 minutes after each addition to consume all the starting material. The two phase mixture was allowed to separate. The aqueous layer was extracted twice with 8 mL of toluene. The combined organic layer was washed with 1.25 mL of a solution containing 0.075 g of potassium iodide, sodium bisulfate(0.125 g) and water(1.1 mL), 1.25 mL of 10% aqueous sodium thiosulfate solution, 1.25 mL of pH 7 phosphate buffer and 1.5 mL of brine solution. The organic solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.32 g (100% yield) of N-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninal. was added slowly over 30 minutes Three more additions (0.4 mL each) of bleach was added by stirring for 10 minutes after each addition to consume all the starting material to separate The aqueous layer was extracted twice with 8 mL of toluene The combined organic layer was washed with 1.25 mL of a solution containing 0.075 g of potassium iodide, sodium bisulfate(0.125 g) and water(1.1 mL), 1.25 mL of 10% aqueous sodium thiosulfate solution, 1.25 mL of pH 7 phosphate buffer and 1.5 mL of brine solution The organic solution was dried over magnesium sulfate filtered concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A vigorously stirred solution of 5-phenylpentanol (10 g), sodium bromide (6.45 g) and TEMPO, 2,2,6,6-tetramethyl-1-piperidinyloxy, (0.095 g) in a mixture of ethyl acetate, toluene and water (258 ml, 7:7:1, v/v/v), at 0° C., was treated with aqueous sodium hypochlorite solution (571 ml, 0.35M) saturated with sodium bicarbonate (43.85 g) in five portions separated by 10 minute intervals. The reaction mixture was treated with ethanol (20 ml) then partitioned between water (500 ml) and ethyl acetate (500 ml). The aqueous layer was extracted twice with ethyl acetate (500 ml). The combined organic phases were washed with aqueous sodium thiosulphate (500 ml, 5%), then with water (200 ml), then with brine (200 ml), then dried over magnesium sulphate and then evaporated to give the title compound as an orange oil, which was used without further purification. NMR (CDCl3): δ1.65 (m,4H), 2.35 (m,2H), 2.60 (t,2H), 7.10-7.30 (m,5H), 9.75 (s,1H). separated by 10 minute intervals The reaction mixture was treated with ethanol (20 ml) then partitioned between water (500 ml) and ethyl acetate (500 ml) The aqueous layer was extracted twice with ethyl acetate (500 ml) The combined organic phases were washed with aqueous sodium thiosulphate (500 ml, 5%) with water (200 ml), then with brine (200 ml), then dried over magnesium sulphate evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a well-stirred mixture of 4-bromo-3-fluorobenzyl alcohol (as described in Example 9, Step B) (10.25 g, 0.05 mol), TEMPO (0.781 g, 0.005 mol) and tetrabutylammonium fluoride (1.39 g, 0.005 mol) in CH2Cl2 (200 mL) and a solution of 0.5M NaHCO3/0.05M K2CO3 (200 mL) was added N-chlorosuccinimide (9.35 g, 0.07 mol). After 6 hrs, the layers were separated, the aqueous layer back-washed with CH2Cl2 (2×50 mL), the organics combined and dried (Na2SO4). The solution was filtered, concentrated to half its volume, then chromatographed (silica gel, CH2Cl2) to give the title compound. the layers were separated the aqueous layer back-washed with CH2Cl2 (2×50 mL) dried (Na2SO4) The solution was filtered concentrated to half its volume chromatographed (silica gel, CH2Cl2)