Boc-N-methyl-L-valine

White powder

To a solution of N-BOC-valine 1 (217 mg, 1 mmol) and iodomethane(1.42 g, 10 mmol) in anhydrous tetrahydrofuran (THF, 20 mL) was added neat sodium hydride (240 mg, 10 mmol). Thereaction mixture was stirred at room temperature for 24 h. The mixture was then quenched with water (30 mL). The reaction mixturewas extracted with ethyl acetate (EtOAc, 2 15 mL) and theaqueous solution was acidified to pH 3, after which it wasextracted with EtOAc (3 20 mL). The combined organic phasewas dried over anhydrous Na2SO4 and evaporated to afford the corresponding N-methylated product 2 (thick colorless oil), 99percentyield.Preparation of compound Boc-N-Me-Val-OH To a solution of Boc-L-Val-OH (2.0(3 g, 9.2 mmol) and methyl iodide (5.74 mL, 92 mmol) in anhydrous THF (40 mL) was added sodium hydride (3.68 g, 92 mmol) at 0 'C. The reaction mixture was stirred at 0 Example 37. Preparation of compound Boc-N-Me-Val-OH To a solution of Boc-L-Vai-OH (2.00 g, 9.2 mmoi) and methyl iodide (5.74 mL, 92 mmol) in anhydrous THE (40 mL) was added sodium hydride (3.68 g, 92 mmol) at 0 °C.The reaction mixture was stirred at 0 °C for 1.5 h, then warmed to r.t, and stirred for 24 h, The reaction was quenched by ice water (50 mL). After addition of water (100 mL), the reaction mixture was washed with ethyl acetate (50 mL x 3) and the aqueous soIuion was acidified to pH 3 then extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over Na2SO4 and concentrated to afford Boc-N-Me-Val-OH (2.00 g, 94percentyield) as a white solid. ‘H NMR (500 MHz, CDC13) 4.10 (d, J = 10.0 Hz, 1H), 2.87 (s, 3H), 2.37 — 2.13 (m, 1H), 1.44 (d, J = 26.7 Hz, 9H), 1.02 (d, J = 6.5 Hz, 3H), 0.90 (t, J =8.6 Hz, 3H).To a solution of Boc-L-Val-OH (2.00 g, 9.2 mmol) and methyl iodide (5.74 mL, 92 mmol) in anhydrous THF (40 mL) was added sodium hydride (3.68 g, 92 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 h, then warmed to r.t. and stirred for 24 h. The reaction was quenched by ice water (50 mL). After addition of water (100 mL), the reaction mixture was washed with ethyl acetate (3 × 50 mL) and the aqueous solution was acidified to pH 3 then extracted with ethyl acetate (3 × 50 mL). The combined organic phase was dried over NaGeneral procedure: (S)-2-(Tert-butoxycarbonyl(methyl)amino)-3-hydroxypropanoic acid(6a) Gummy substance (This compound was prepared byadding neat sodium hydride (10 equiv.) in portion wiseover a period of 2.0 h to a cooled (0 °C) solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (1equiv.) and iodomethane (10 equiv.) in dry THF under astream of nitrogen. The reaction mixture was stirred at room temperature for 24 h under nitrogen atmosphere andthen diluted with ether (20 mL) and quenched with water(30 mL). The layers were separated and the aqueous layerwas extracted with ether (2 x9 15 mL), acidified to pH 3with a 20 percent aqueous solution of citric acid and extractedwith EtOAc (3 x 20 mL). The combined organic phasewas dried over Na2SO4 and evaporated to afford thecorresponding N-methylated product in 90 percent yield asGummy substance.)(2S)-2-[[(tert-butoxy)carbonyl] amino] -3 -methylbutanoic acid (63 g, 289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before addingsodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form of a yellow oil.(2S)-2-[[(tert-butoxy)carbonyl] amino] -3 -methylbutanoic acid (63 g, 289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before addingsodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form of a yellow oil.(2S)-2-[[(tert-butoxy)carbonyl] amino] -3 -methylbutanoic acid (63 g, 289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before addingsodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form of a yellow oil.Compound 1ZA: (2S)—2—[ [(tert—butoxy)carbonyl] (methyl)amino]—3—methyl butanoic acid (2S)—2—[[Qert—butoxy)carbonyl]amino]—3—methylbutanoic acid (63 g, 289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before adding sodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitationcontinued for 18 hours. The reaction was neutralised with 200 mL of water and thenconcentrated under reduced pressure. The residual aqueous phase was diluted with 4litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3times with 1.2 L of EtOAc. The organic phases were combined, dried over sodiumsulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form ofa yellow oil.Compound 1ZA: (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-methyl butanoic acid (2S)-2-[[(tert-butoxy)carbonyl]amino]-3-methylbutanoic acid (63 g, 289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before adding sodium hydride (1 16 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3 and 4 with a IN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound IZA in the form of a yellow oil.(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-methylbutanoic acid (63 g, 289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before adding sodium hydride (1 16 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3 and 4 with a IN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound IZA in the form of a yellow oil.Compound 1ZA: (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-methyl butanoic acid (2S)—2—[ [Qert—butoxy)carbonyl] amino]—3—methylbutanoic acid (63 g, 289.97 mmo 1, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence ofiodomethane (181 mL). The solution was cooled to 0°C before adding sodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residualaqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3 and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form of a yellow oil.Na

Molecular Weight:231.29
XLogP3:2.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:5
Exact Mass:231.14705815
Monoisotopic Mass:231.14705815
Topological Polar Surface Area:66.8
Heavy Atom Count:16
Complexity:268
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes