BOC-SER(ME)-OH

White to off-white crystals

To 2.0 g (17 mmol) of C606-1 were added 35 ml of a IN aqueous sodium hydroxide solution and 35 ml of THF. A solution of di-tert- butyl dicarbonate (4.03 g, 18.5 mmol) in THF (15 mL) was then added with stirring at 0°C. The reaction mixture was stirred overnight at room temperature and concentrated by evaporation under reduced pressure. The aqueous phase was acidified to pH 4-5 with 10percent aqueous citric acid and extracted with ethyl acetate. The extract was washed with brine, dried (MgS0A. (S)-2-(tert-Butoxycarbonylamino)-3-methoxypropanoic acid A sodium methanolate (NaOMe) solution was prepared by slowly adding MeOH (50 mL) to a suspension of sodium hydride (60percent in mineral oil, 28 g, 0.71 mol) in dry THF (1.2 L) at 0° C. The resulting mixture was stirred at RT for 2 h. A portion of the NaOMe solution (320 mL) was added to (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (36 g, 175 mmol) in dry THF (1.6 L), and the mixture was stirred at RT for 1 h. Methyl iodine (16 mL) was then added and the mixture was stirred at RT for 1 h. Another aliquot of NaOMe solution (540 mL) was added and the reaction mixture stirred at RT for 1 h. Additional methyl iodine (38 mL) in THF (200 mL) was added and the reaction mixture was stirred at RT for 36 h. Following reaction, the mixture was concentrated and the residue was dissolved in water and washed with diethyl ether (2.x.100 mL). The aqueous layer was acidified to pH 2 by the addition of solid citric acid and was extracted with EtOAc (3.x.200 mL) and dried over NaSynthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-methoxypropanoic acid (0033) (0034) 45percent 4 NaOH (746.3 kg; 8.40 kmoles) and DMS (1053.8 kg; 8.36 kmoles) were added to the reaction mixture below 10° C. over 38 h and for an additional 6 h to complete the reaction. 20percent 9 NHN, N-Diisopropylethylamine (0.082 ml_, 0.47 mmol) was added to a stirred solution of COMU (220 mg, 0.51 mmol), (2R, 4R)-2-benzyl 1 -tert-butyl 4-amino-2-(4-(4, 4, 5, 5-tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)butyl)pyrrolidine-1 , 2-dicarboxylate (Intermediate 30, 235 mg, 0.47 mmol) and N-Boc-O-methyl-L-serine (108 mg, 0.49 mmol) in DMF (3 mL) at room temperature. The reaction was stirred for 2 h then diluted with water (60 mL) and DCM (15 mL). The phases were separated and the aqueous phase was extracted with DCM (2 x 20 mL). The combined organics were washed with saturated aqueous NaHCC>3 (30 mL), saturated aqueous NaCI (2 x 10 mL), dried over MgSC , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexanes/EtOAc) to afford (2R, 4R)-2-benzyl 1 -tert- butyl 4-((S)-2-(tert-butoxycarbonylamino)-3-methoxypropanamido)-2-(4-(4, 4, 5, 5- tetramethyl-1 , 3, 2-dioxaborolan-2-yl)butyl)pyrrolidine-1 , 2-dicarboxylate (Intermediate 47, 145 mg, 44% yield) as colorless dry film and as a mixture of rotamers. 1 H NMR (500MHz, CDCI3) d 0.78 (2H, t), 1 .18 (1 H, br dd), 1 .22 - 1 .26 (13H, m), 1 .33 (6H, s), 1 .44 (5H, br s), 1 .46 (9H, s), (0612) 1 .57 - 1 .74 (1 H, m), 1 .74 - 1 .85 (1 H, m), 1 .94 (0.4H, d), 2.01 (0.6H, d), 2.18 - 2.27 (0.6H, m), 2.32 - 2.47 (1 AH, m), 3.32 (3H, s), 3.39 - 3.46 (1 H, m), 3.49 - 3.55 (0.4H, m), 3.60 (1 H, dd), 3.65 - 3.76 (1 .6H, m), 4.15 (1 H, br d), 4.51 - 4.64 (1 H, m), 5.06 - 5.22 (2H, m), 5.23 - 5.34 (1 H, m), 7.32 - 7.39 (5H, m); m/z (ES+) [M+H]+ = 704.To a solution of N-(tert-butoxycarbonyl)-O-methyl-l-serine 18a (2.19'g, 10.0'mmol) in DCM (30'mL) were added HOBt (162'g, 12.0'mmol) and EDCI (2.88'g, 15.0'mmol) at 0?. The reaction mixture was stirred for 30'min. Then compound 13a (2.47'mg, 10.5'mmol) and diisopropylethylamine (6.61'mL) were added. After stirring at room temperature for another 5'h, the resulting mixture was washed with aqueous NaHCO3 solution (30'mL?*?3), brine (30'mL?*?3) and dried over Na2SO4. The organic layer was evaporated in vacuo and the crude product was purified on silica gel to afford the compound 19a as a white solid (3.61'mg, 82%). 1 H NMR (500'MHz, CDCl3) delta 7.39 (d, J?=?6.5'Hz, 1H), 7.36-7.29 (m, 5H), 5.80-5.70 (m, 1H), 5.43 (d, J?=?5.0'Hz, 1H), 5.26-5.21 (m, 1H), 5.21-5.16 (m, 1H), 5.16-5.11 (m, 2H), 4.74 (dt, J?=?8.0, 3.0'Hz, 1H), 4.31-4.24 (m, 1H), 3.94-3.87 (m, 3H), 3.77 (dd, J?=?9.0, 4.0'Hz, 1H), 3.65 (dd, J?=?9.5, 3.0'Hz, 1H), 3.43 (dd, J?=?9.0, 7.0'Hz, 1H), 3.33 (s, 3H), 1.44 (s, 9H); ESI-MS: m/z = 437 [M+H]+.

Molecular Weight:219.23
XLogP3:0.4
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:6
Exact Mass:219.11067264
Monoisotopic Mass:219.11067264
Topological Polar Surface Area:84.9
Heavy Atom Count:15
Complexity:233
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes