BOC-GLYCINE N,O-DIMETHYLHYDROXAMIDE

White powder

To a stirred solution of (tert-butoxycarbonyl)glycine (HN, 5.0 g, 28.57 mmol) and triethylamine (4.1 mL, 31.42 mmol) in DCM (80 mL) was added N, 0-dimethylhydroxylamine (3.0 g, 31.42 mmol) followed by DCC (6.5 g, 31.42 mmol) in DCM (20 mL) and the reaction mixture was stirred at RT for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and washed with DCM. The filtrate was concentrated under reduced pressure to yield the crude compound which was purified by silica gel column chromatography using 10percent EtOAc/hexane to afford compound HO (6.0 g, 97.0percent) as an off-white solid. 1H NMR (400 MHz, CDC13): _ 5.27 (brs, 1H), 4.08 (brs, 2H), 3.72 (s, 3H), 3.21 (s, 3H), 1.46 (s, 9H).General procedure: This procedure has been carried out according to the following article: J. Am. Chem. Soc., 1999, 121 (13), pp 2974–2986.To a stirred solution of the corresponding Boc-protected amino acid (Boc-D-Ala-OH, Boc-LAla-OH or Boc-Gly-OH) (1.00 equiv) in anhydrous dichloromethane (0.3 M) at 0°C wasadded 1, 1’-carbonyldiimidazole (1.40 equiv). After 30 min at 0°C, Et3N (1.40 equiv) and N, Odimethylhydroxylamine(1.40 equiv) were added. After 30 min, the reaction was stirred at r.tovernight. Et2O (for each 1.00 mmol of protected amino acid, add 6.70 mL of Et2O) wasadded and the organic layer was washed (x3) with a solution of HCl (1N) (for each 1.00mmol of protected amino acid, wash with 2.50 mL of HCl 1N), saturated solution of NaHCO3, brine and dried over MgSO4, filtered and concentrated to give the desired product ascolorless solid yield without further purification.N-Boc-Gly-OH (10.5 g, 60.0 mmol), N, O-dimethylhydroxylamine hydrochloride (11.1 g, 120 mmol) and DIEA (31.2 g, 240 mmol) were dissolved in 1:1 1 CH2C12/DMF (500 mL) and cooled to 0 °C. 1-Hydroxy-1H- benzotriazole (HOBt, 11.0 g, 72.0 mmol), DCC (14.9 g, 72.0 mmol) and DMAP (ca. 100 mg) were added and the reaction was stirred for 24 h. The reaction was filtered to remove dicyclohexylurea and concentrated. The resulting slurry was diluted with 500 mL ethyl acetate and washed with NH4C1 (2 x 100 mL), NaHC03 (2 x 100 mL) and brine (100 mL). The organic layer was dried on MgS04 and concentrated. Chromatography on silica with 20percent EtOAc in hexane gave 12.6 g (96percent) of 4 as a colorless plate-like crystal. m.p. 101-102 °C. To a solution of Boc-Gly-OH (4250g, 24.26 mol), Ν, Ο-dimethylhydroxylamine- HCl(2839g, 29.10 mol) and DMAP(297g, 2.43 mol) in dichloromethane(36 L), is added triethylamine (5.54 L) at 0 °C over a period of 90 min followed by the addition of EDC hydrochloride (5674g, 29.60 mol). The mixture is stirred at 0 °C for lh then warmed to room temp for 24 h. The reaction mixture is cooled to 0 °C and quenched with 1.0M HC1 to pH 3 to 4, stirred at room temp for 20 min, then allowed to stand and separate. The organic phase is washed successively with 1.0M HC1 (15L), water (15.0 L) and brine (8.0 L), dried over NaBoc-glycine was coupled with N, O-dimethyl hydroxylamine hydrochloride, 1 equivalent, in DMF/CHStep 1: To a suspension of /V-(ie f-butoxycarbonyl)glycine (4.0 g, 23 mmol), Ν, Ο- dimethylhydroxylamine hydrochloride (3.0 g, 31 mmol) and /V, /V-dimethylpyridin-4-amine (300 mg, 2.5 mmol) in dry CHPreparation Example 15fe -Butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate (45)To a mixture of N-Boc-glycine 44 (10.0 g, 57.1 mmol), Ν, Ο- dimethylhydroxylamine hydrochloride (6.68 g, 68.5 mmol), EDCI (13.1 g, 68.5 mmol), and HOBt (9.26 g, 68.5 mmol) in CHExample 54 - Synthesis of Compound 49 tert-butyl 2-(methoxy(methyl)amino)-2- oxoethylcarbamate (Boc-Gly Weinreb amide)49 tert-butyl 2-(methoxy(methyl)amino)- 2-oxoethylcarbamateTo a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 ml_, 1 14.1 mmol) and BOP (50.5 g, 1 14.1 mmol) in DCM (20 ml.) was added a pre-mixed solution of N, O- dimethylhydroxylamine hydrochloride (11.2 g, 1 14.1 mmol) and DIPEA (19.8 ml_, 114.1 mmol) in DCM (20 ml.) at room temperature. The resulting mixture was stirred for 16 h then washed with 1 N HCI (3 x 120 ml_), HTo a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL, 1 14.1 mmol) and BOP (50.5 g, 1 14.1 mmol) in DCM (20 mL) was added a pre-mixed solution of N, O- dimethylhydroxylamine hydrochloride (11.2 g, 1 14.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred for 16 h then washed with 1 N HCI (3 x 120 mL), HTo a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL, 114.1 mmol) and BOP (50.5 g, 114.1 mmol) in DCM (20 mL) was added a pre-mixed solution of N, O-dimethylhydroxylamine hydrochloride (11.2 g, 114.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at room temperature.N-Boc-Gly-OH (20 mmol) was dissolved in CH2Cl2(100 mL) and cooled to 25 °C. NMM (44 mmol) and isobutyl chloroformate(22 mmol) were added. After stirring for 30 min, N, O-dimethylhydroxylaminehydrochloride (22 mmol) was added at 25 °C. After 5 h, the reaction mixturewas washed with 10percent KHSO4 (2 100 mL), sat. NaHCO3 (2 100 mL) and H2O(1 100 mL), dried over Na2SO4 and evaporated. The obtained yellowish solidwas purified by column chromatography using CH2Cl2/EtOAc (1+1) to give 1 asa white solid (80percent). mp 102–104 C (lit. 102–103 C);36 1H NMR (500 MHz, DMSO-d6) d 1.37 (s, 9H), 3.08 (s, 3H), 3.66 (s, 3H), 3.81 (d, 3J = 6.0 Hz, 2H), 6.79(t, 3J = 6.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) d 28.31, 32.23, 40.95, 61.21, 78.05, 156.00, one carbon signal (CH2CO) is missing; LC-MS (ESI) (90percent H2O to100percent MeOH in 10 min, then 100percent MeOH for 10 min, DAD 200.0–400.0 nm): tr =8.16 min, 96percent purity, m/z= 219.2 ([M+H]+).Example 33 (Compound 46) Step 1; N-tert-Butoxycarboxylglycine (10.0 g, 57.1 mmol) was dissolved in THF (100 mL). To the solution was added CDI (14.3 g, 59.0 mmol) at room temperature, and the mixture was stirred for 30 minutes. To the reaction mixture was added N, O-dimethylhydroxylamine hydrochloride (6.2 g, 64.0 mmol), and the mixture was further stirred at room temperature for 12 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give [(methoxymethylcarbamoyl)methyl]carbamic acid tert-butyl ester (9.55 g, yield: 77percent). APCI-MS m/z: 218 [M+H]Intermediate 83, [(teit-butoxycarbonyl)amino]acetic acid (5.00 g, 28.5 mmol), DIPEA (14.75 g, 104 mmol) and Intermediate 84, N-methoxymethanamine hydrochloride (5.60 g, 57.0 mmol)were dissolved in DCM (100 mL) and DMF (100 mL) and Intermediate 85, EDC hydrochloride (6.56 g, 34.0 mmol) was added. The reaction mixture was stirred under nitrogen at 0 °C for 1 h, then Intermediate 86, HOBt (4.63 g, 34.0 mmol) and DMAP (100 mg) were added portionwise and the resulting mixture was stirred for 16 h at room temperature. The reaction mixture was partitioned between H20 (250 mL) and DCM (100 mL), and the aqueous layer was furtherextracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4), filteredand the solvent was removed in vacuo. The residue was purified by column chromatography(Normal-Phase Silica, 0 to 3 percent methanol in DCM) to give tert-butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate (4.50 g, 72 percent) as a solid.LCMS (Method F): mlz 219 (M+H) (ES), at 1 .77 mi UV active.2-(tert-Butoxycarbonylamino)acetic acid (800 mg, 4.57 mmol), N, O-dimethylhydroxylamine hydrochloride (535 mg, 5.48 mmol), EDCI (1.05 g, 5.48 mmol) and HOBt (740 mg, 5.48 mmol) were dissolved in DCM (25 mL), to which NMM (2.77 g, 27.42 mmol) was added at room temperature. The reaction mixture was stirred overnight. After the reaction was completed, DCM was evaporated in vacuo. The residue was dissolved in MeOH, filtered through a syringe filter, and then purified by reverse-phase preparative HPLC to provide the desired product (705 mg, 71percent) as a white solidA mixture of Boc-glycine (8.75g, 50mmol, 1 equiv), EDCI (11.5g, 60mmol) and HOBt (7.43g, 55mmol) in DCM (100ml) was stirred in an ice bath for 15min to give a clear solution. Then N, O-Dimethylhydroxylamine hydrochloride (5.1g, 52.5mmol) and triethylamine (5.85ml, 55mmol) were added and the mixture was stirred for 2h at room temperature. Water (100ml) was added and the solution was stirred tempestuously. The precipitate so formed was filtered off and the filtrate was transferred into a separating funnel. The organic phase was separated and the aqueous phase was extracted with CHA mixture of l3oc-glycine (8.75 g, 50 mmol, 1 equiv), EDCI (11.5 g, 60 mmol) and HOSt (7.43 g, 55 mmol) in DCM (100 ml) was stirred in an ice bath for 15 mm to give a clear solution. Then N, O-Dimethylhydroxylamine hydrochloride (5.1 g, 52.5 mmol) and triethylamine (5.85 ml, 55 mmol) were added and the mixture was stirred for 2 h at room temperature. Water (100 ml) was added and the solution was stirred tempestuously. The precipitate so formed was filtered off and the filtrate was transferred into a separating funnel. The organic phase was separated and the aqueous phase was extracted with CH2C12 once again. The combined organic phase was washed with brine (X2), dried over MgSO4 and concentrated. The residue was recrystallized from PE-EA to give Fl (6.0 g) as a crystal.To a solution of 2-((tert-butoxycarbonyl)(methyl)amino)acetic acid (25.0 g, 132.0 mmol) in 300 mL of anhydrous THF under NTo a well stirred solution of Boc-Gly (21.02 g, 0.12 mole) and BOP (53.10 g, 0.12 mole) in 300 ml of DCM, was added DIEA (20.88 mi, 0.12 mole). After 10 min, a solution of O, N-dimethylhydroxylamine hydrochloride (14.05 g, 0.144 mole) and DIEA (31.32 ml, 0.18 mole) in 100 ml of DCM was added to above stirred solution. The reaction was monitored by TLC (silica gel, hexane-EtOAc =2:1). After 20 min, 200 ml of DCM was added to the reaction solution. The DCM solution was washed successively with 1 N aqueous hydrochloric acid solution (500 ml.x.4), saturated aqueous sodium bicarbonate solution (500 ml.x.3), and saturated aqueous sodium chloride solution (500 ml). The organic solution was dried with 5 g of magnesium sulfate overnight, filtered, and concentrated under reduced pressure. The residue was dissolved in a minimal volume of DCM, followed by addition of hexane until the solution became cloudy. The solution was warmed until it became clear and then kept to stay at room temperature to give colorless needles of 19 (21 g). Yield: 80percent. TLC R

α-Amino Weinreb amide.

Molecular Weight:218.25
XLogP3:0.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:5
Exact Mass:218.12665706
Monoisotopic Mass:218.12665706
Topological Polar Surface Area:67.9
Heavy Atom Count:15
Complexity:235
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes