O-DIPHENYLPHOSPHINYLHYDROXYLAMINE

Light yellow or white powder solid

A 5 L 4-neck round bottom flask (rbf) fitted with an overhead stirrer a thermocouple was charged with; (1) a solution of NaOH (60.85 g, 1.52 mol, 2.4 eq) in 180 mL water, (2) a solution of hydroxylamine-HCl (110.12 g, 1.58 mol, 2.5 eq) in 180 mL water and (3) 180 mL dioxane. The mixture was cooled in an ice/acetone bath to to 0 °C. 150 g of ice was added, followed by a precooled (to about 10 °C) solution of diphenylphosphinic chloride (150.0 g, 0.634 mol, 1 eq) in 180 mL dioxane (added all at once). The reaction became very thick with a white precipitate, requiring vigorous stirring. The internal temperature rose to 22 0C. After 5 additional minutes stirring (10 minutes maximum) , the reaction mixture was diluted with 2.5 L of ice cold water and filterered thru a large fritted funnel (15 cm diameter). The crude material was left on the frit to drain for one hour, then transfered back into the 5 L rbf. The solid was suspended in 500 mL ice cold 0.25N NaOH solution and vigorously stirred for five minutes (no more than 10 min), then filterered again, washing 2x with ice cold water and left to dry overnight on the fritted filter. The partially dried material was dried for 12 h in a vacuum oven (50 °C, 0.1 torr) and then well crushed with a mortar pestal. An additional 16 h of drying in the vacuum oven afforded 122 g (82 percent) the above compound as a white powder.Using a variation of the Knoevenagel procedure described for the preparation of 50, ethyl 2-pyridylacetate (500 mg, 3.02 mmol) was dissolved in anhydrous THF (8 mL) and the solution cooled to -78° C. under a nitrogen atmosphere. Lithium bis(trimethylsilyl)amide (1M in THF, 3.00 mL, 3.00 mmol) was added via syringe over 10 min followed by 3-furaldehyde (290 mg, 3.02 mmol) and the yellow solution allowed to warm to -40° C., with further stirring at this temperature for 2 h. Acetic anhydride (616 mg, 6.04 mmol) was added and the reaction allowed to warm to rt. Triethylamine (610 mg, 6.04 mmol) was added and the solution stirred overnight at rt and then at 55° C. for 3 h or until elimination was complete (as determined by LCMS). The solvent was evaporated and the brown solid chromatographed on silica (eluent 30percent EtOAc in DCM) to afford the title compound as mixture of regioisomers which were separately isolated during the chromatography step; combined yield 540 mg, 73percent); MS m/e 244 (MH)To a solution of hydroxylamine hydrochloride (7.3 g, 106 mmol, 2.5 eq) in water (12 mL) and dioxane (12 mL) was added a solution of NaOH (4.07 g, 102 mmol, 2.4 eq) in water (12 mL), and the mixture was cooled to −5° C. in an ice/salt bath. A solution of diphenylphosphinic chloride (10 g, 42 mmol, 1 eq) in dioxane (12 mL), precooled to below 10° C., was rapidly added to the above solution in an ice/salt bath under vigorous stirring. After completion of the addition, the mixture was stirred for additional 5 minutes in an ice/salt bath, then diluted with ice water (150 mL) and filtered. The filtration cake was washed with ice water, and lyophilized to give o-(diphenylphosphoryl)hydroxylamine (6.0 g, yield 61percent) as a white solid. MS (ES+) requires: 233. found 234 [M+H]Example 17A O-(diphenylphosphoryl)hydroxylamineTo a stirred solution of hydroxylamine hydrochloride (9.5 g, 137 mmol) in HTo a suspension of hydroxylamine hydrochloride (735 g, ‘LOS mol) in dichloromethane (500 mL) was added DIPEA (136 g, t05 mol) over 15 minutes at 30 C under a nitrogen atmosphere. A white precipitate formed upon the addition. After stirring for one hour at that temperature, a solution of diphenylphosphinic chloride A (50 g, 02 mol) in dichloromethane (100 mL) was added over 60 minutes, The mixture reaction was warmed to 0 °C over 1 hour with stirring. The reaction was quenched by adding water (200 mL) over 10 minutes. After stirring the mixture for 05 hour, the precipitate was coHected by filtration and washed with water (100 mL x 2). Then the solid was dried under reduced pressure to afford a crude product. The crude product was triturated in EtOH to afford compound B (27 g, 56percent yield) as a whitesolid, 1HNMR (400 MHz, CD3OD): 677, 91479 (rn, SF1), 7, 62-7.50 (m, 7H). MS Calcd, : 233; MS Found: 234 ([M+Hj4’).To hydroxylamine hydrochloride (15.86 g, 228.2 mmol) in H20 (35 mL) cooled in an ice-salt bath was added 7.1 N NaOH (27.4 mL, 194.4 mmol) followed by 1, 4-dioxane (100 mL). The solution was vigorously stirred for 15 min and then chlorodiphenylphosphine oxide (20.00 g, 84.52 mmol) was added as a solution in 1, 4-dioxane (100 mL). The solution was stirred an additional 15 min as a white precipitate formed which was filtered. The solid was suspended in 0.25 N NaOH (250mL) while stirring in an ice-salt bath for 1 h. The solid was then collected, washed with H20 (100 mL), and thoroughly dried under vacuum to afford 7.09 g of the above compound as a white powder (30.4 mmol, yield 36percent). (at)H-NMR (DMSO- d6) No. 7.72 to 7.67 (m, 4H), 7.50 to 7.40 (m, 6H) ; To hydroxylamine hydrochloride (15.86 g, 228.2 mmol) in water (35 mL) cooled in an ice- salt bath was added 7.1 N aqueous sodium hydroxide (27.4 mL, 194.4 mmol) followed by 1 , 4-dioxane (100 mL). The solution was vigorously stirred for 15 min and then chlorodiphenylphosphine oxide (20.00 g, 84.52 mmol) was added as a solution in 1, 4- dioxane (100 mL). The solution was stirred an additional 15 min as a white precipitate formed. The precipitate was collected and then suspended in cold (0 °) 0.25 N aqueous sodium hydroxide (250 mL). The mixture was stirred for 1 h and then the solid was collected, washed with water (100 mL), and thoroughly dried under vacuum to afford the desired intermediate (7.09 g, 36percent) as a white solid. PREPARATION 2 N-aminoindole To a suspension of 177.72 g of ground potassium hydroxide in 1.3 litres of DMF there are added 21.85 g of indole and then, all at once, 72.5 g of a suspension of the compound of Preparation 1 in 1.3 litres of DMF. The thick mixture is heated at between 60 and 70 C. for 3 hours 30 minutes with mechanical stirring and then, whilst hot, is poured into 3.5 litres of ice-cold water.Step 4: Preparation of ethyl 1-amino-2, 4-dimethyl-1H-imidazole-5-carboxylate LiHMDS (8.5 mL, 1M in THF) was added dropwise into a mixture of ethyl 2, 4-dimethyl-1H-imidazole-5-carboxylate (1.3 g, 7.73 mmol) and N, N-dimethylformamide (200 mL) with stirring at -10 C. in a dry ice bath under nitrogen. The resulting solution was stirred for 30 min at -10 C. To this was added amino diphenylphosphinate (2.2 g, 9.43 mmol) in portions at 0 C. The resulting solution was allowed to react, with stirring, for an additional 12 h at room temperature. The resulting solution was diluted with of water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column eluting with dichloromethane/methanol (10/1) to afford the title compound (1.0 g, 71%) as a light yellow solid. LCMS [M+H+] 184.To a solution of cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (12.4 g, 42.8 mmol) in N, N-dimethylformamide (400 mL) was slowly added sodium hydride (60%, 2.6 g, 64.1 mmol) at 0 C. After addition, the mixture was stirred at 0 C. for 20 min and subsequently O-(diphenylphosphoryl)hydroxylamine (14.9 g, 64.1 mmol) was added. The reaction mixture was stirred at 25 C. for 16 h and then filtered. The filtrate was concentrated under reduced pressure to afford the crude cis-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one as a yellow oil (9.5 g, 73%), used in the next step without further purification. LCMS RT=0.877 min, m/z=307.0 [M+H]+.LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.877 mm, ESI+ found [M+H]=307.0.To a cooled (-10 C.) solution of ethyl 4-isopropyl-2-methyl-1H-imidazole-5-carboxylate (3.72 g, 19.0 mmol) in DMF (30 mL) was added a solution of LiHMDS (lithium hexamethyldisilazide) (1 M in THF, 20.86 mL). The mixture was stirred at -10 C. for 30 minutes. Then a solution of (aminooxy)diphenylphosphine oxide (5.31 g, 22.8 mmol) in DMF (20 mL) was added dropwise. The mixture was stirred at -10 C. for 1 hour. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL*2). The organic layer was washed with water (50 mL*3), brine (50 mL), dried over Na2SO4, filtered and concentrated to give ethyl 1-amino-4-isopropyl-2-methyl-1H-imidazole-5-carboxylate (3.07 g).To a solution of 5-(1, 1-difluoroethyl)pyrrolidin-2-one (60 mg, 0.4 mmol) in N, N-dimethylformamide (5 mL) was added sodium hydride (60%, 24 mg, 0.6 mmol) at 0 C. After addition, the mixture was stirred at 0 C. for 30 min and O-(diphenylphosphoryl)hydroxylamine (141 mg, 0.6 mmol) was added. The reaction mixture was stirred at 25 C. for 16 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (100% ethyl acetate in petroleum ether, Rf=0.4) to afford 1-amino-5-(1, 1-difluoroethyl)pyrrolidin-2-one (30 mg, 45%) as a yellow oil. LCMS RT=0.716 min, m/z=165.1 [M+H]+.A synthesis of this compound has also been reported by Yamawaki et al (Bioorg. Med. Chem. 15 (2007), 6716).To a stirred mixture of benzhydryl 1-hydroxycyclopropane-1-carboxylate(2.00 kg, 7.46 mol, 1 eq) and (aminooxy)diphenylphosphine oxide (2.08 kg, 8.93 mol, 1.2 eq) in THF (20 L) was added sodiumtert-butoxide (0.86 kg, 8.96 mol, 1.2 eq) at 0-10under nitrogen. The resulting mixture was stirred at 0-10for 60 min.5% aq. NaCl (12 L) was added and the mixture was stirred at 15-25for 30 min. The precipitate was removed by filtration and washed with EtOAc (4 L). The filtrate was stirred for 5 min and the phases were separated. The aqueous layer was extracted with EtOAc (2x 10 L). The combined organic phases were washed with 5% aq. NaCl (2x 6 L) to give a solution of benzhydryl 1-(aminooxy)cyclopropane-1-carboxylate in THF/EtOAc (39.75 kg, 68.9% purity) which was used in the next step directly without further purification.To a solution of compound 3H-lmidazole-4-carboxylic acid methyl ester 32 (30.0 g0, 24 mol) in THF (1, 0 L)was dropwise added LiHMDS (239 mL, 1OM in THF, 2, 4 mol) over 2 hours at -78 0C Then the reaction mixture was stirred at -78 C for another two hours and allowed to warm to 10 C. Compound B (60.0 g, 0.26 mol) was added at this temperature. Then the mixture reaction was stirred at ambient temperature overnight. After quenching with water (250 mL), the reaction mixture was concentrated. The crude product was purified by column chromatography on silica gel(DCM/MeOH= 20/1) to afford compound 46 (24 g, 73% yield) as a solid.1H NMR (400 MHz, DMSO-d6): 57.82 (s, IH), 7.51 (s, 1H), 6.20 (s, 2H), 3.79 (5, 3H). MS Calcd.: 382; MS Found: 383 ([M+Hfl. MS Calcd.: 141; MS Found: 142 ([M+Hfl.To the solution of thus obtained 2-amino-3, 6-dimethylpyrazine (4.0 g, 32.5 mmol) in drydichloromethane (150 mL), 6.89 g (29.5 mmol) of

Efficient reagent for direct conversion of aldehydes to nitriles in the presence of alcohol, ketone, ester, or amine functionality.

Molecular Weight:233.20
XLogP3:1.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:233.06056562
Monoisotopic Mass:233.06056562
Topological Polar Surface Area:52.3
Heavy Atom Count:16
Complexity:236
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes