(2R,4R)-N-Boc-4-hydroxypyrrolidine-2-carboxylic acid

White solid

cis-4-Hydroxy-l-proline hydrochloride 14 (0.50 g, 3.0 mmol) was dissolved in 6 mL of THF/HAt room temperature, A solution of sodium hydroxide (4.73 g, 118.14 mmol) in water (41 mL) was added dropwise to a solution of 3A (9.0 g, 53.70 mmol) in tetrahydrofuran (90 mL)A mixture of di-tricarbonate (17.58 g, 80.55 mmol)Was added to the reaction solution, and the reaction was stirred at room temperature overnight.(2.15 g, 53.70 mmol), di-n-tri-n-butyl ester (9.38 g, 42.96 mmol) was added and stirring was continued at room temperature for 5 hours.Tetrahydrofuran was removed by distillation under reduced pressure, and the impurities were extracted with ethyl acetate (50 mL x 2).The aqueous phase was adjusted to pH 3 with 3 mol / L hydrochloric acid solution and extracted with ethyl acetate (50 mL x 3)The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give colorless liquid 15a (8.7 g, yield 70.1percent).[001 76j 1 C. (2R, 4R)- 1 -(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid:A solution of (2R, 4R)-4-hydroxypyrrolidine-2-carboxylic acid hydrochloride (50.0 g, 298mmol) in a 2:1 mixture of THF/water (750 mL) was treated first with a solution of NaOH(32.0 g, 800 mmol) in water (160 mL) and then with Boc2O (98.0 g, 448 mmol). The reaction mixture was stirred at 25 °C for 13 h and then the THF was removed in vacuo. The residue was adjusted to pH 2 by the addition of 10percent aq. KHSO4. The acidic solution was extracted with EtOAc (5x). The combined organic extracts were washed with waterand brine, dried over anhydrous Na2SO4, and concentrated to give 1C (62.0 g, 268 mmol, 90percent yield) as a white solid. LC-MS Anal. Calc’d for C10H17N05: 231.11, found [M+H]232. ‘HNMR(400 MHz, DMSO-d6) ö 4.16-4.25 (m, 1H), 4.06-4.14 (m, 1H), 3.45-3.54 (m, 1H), 3.07 - 3.14 (m, 1H), 2.25 - 2.39 (m, 1H), 1.78 - 1.86 (m, 1H), 1.32 - 1.44 (s, 9H).A 5 L, 3-necked flask was charged with (i?, /?)-4-hydroxy-pyrrolidine-2- carboxylic acid (300 g, 2.228 mol), di-tert-butyl dicarbonate (499.3 g, 2.228 mol), 50percent (w/w) NaOH (118 mL, 2.228 mol), THF (2 L) and HStep 1 : Preparation of (2R, 4R)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (14b) To a solution of (2R, 4R)-4-hydroxypyrrolidine-2-carboxylic acid (14a) (10 g, 76 mmol) in THFiH^O (125 mL, 2: 1) was added 2.5 M aqueous sodium hydroxide (42.1 mL, 105 mmol) followed by a solution of di-tert-butyl dicarbonate (22.80 g, 104 mmol) in THF: H2O (125 mL, 2: 1) and stirred at room temperature for 32 h. The mixture was concentrated in vacuum to remove the THF and aqueous layer was added acidified with 10percent aqueous potassium hydrogen sulfate solution (150 mL). The resulting mixture was extracted with ethyl acetate, washed with water, brine, dried, filtered, and evaporated to dryness. The resulting semi-solid was crystallized from hot ethyl acetate to afford (2R, 4R)-l-(tert- butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (14b) (13.58 g, 58.7 mmol, 77 percent yield) as a white solid; Step C (1): Step A (1): (2R, 4R)-l-(tert-butoxycarbonyl)-4-hydroxvpyrrolidine-2- carboxylic acid.; To a suspension of H-D-Cis-Hyp-OH (purchased from Aldrich, 10.0 g, 76.3 mmol) in 2:1 THF:HStep 1: A)

Molecular Weight:231.25
XLogP3:0.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:231.11067264
Monoisotopic Mass:231.11067264
Topological Polar Surface Area:87.1
Heavy Atom Count:16
Complexity:296
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes