1-(Phenylmethyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate

Viscous Oil

General procedure: To a solution of 1 or 7 (78.7 g, 600 mmol) and NaHCOGeneral procedure: The (S)-amino acid (10.0 g) was dissolved in HTypical procedure for the preparation of (2S, 4R)-1-benzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid (10): A solution of 2 (6.56 g, 0.05 mol) in HTrans-4-OH-proline (5.0 g, 38.1mmol) wasadded at 0 A stirrer, a dropping funnel, a Dimroth condenser, a thermometer, 4-neck flask 2000 ml with apH meter fitted, L- hydroxyproline 132.0 g (1.0 mol), 48percent aqueous sodium hydroxide solution 86g (1.03 mol ), was charged with water 655g, and the mixture was stirred at room temperature.While maintaining the pH at 11.5 to 12.0, was added dropwise benzyloxycarbonyl chloride 179 g(1.05 mol) and 48percent aqueous sodium hydroxide solution 84g alternately. Toluene 300g Afterstirring After completion of the dropwise addition, 1.5 hours added to remove the toluene layerwas separated. CPME600g was added to the aqueous layer, it was added 95percent sulfuric acid 63.8gstirring. Stirring was stopped, after removing the aqueous layer was separated and subjected tovacuum concentration at 40 kPa. The aqueous layer of the distillate was separated and removed, subjected to vacuum concentrated again to return the upper layer to the flask, trans - to give aCPME solution 888g, including benzyloxycarbonyl-4-hydroxy-proline (trans - benzyloxycarbonyl-4 - 26percent by weight as hydroxyproline, 229.6g (0.87 mol, 86.6percent yield) containing). The yield ofthis step was 86.6percent.In ice bath, benzyl chloroformate (24 mmol, 4.09 g) was added dropwise to a mixture of l-4-hydroxyproline (20 mmol, 2.62 g) and NaHCO(2S, 4R)-N-(Benzyloxycarbonyl)-2-carboxy-4-hydroxy-pyrrolidine (4).; A solution of benzyl chloroformate (50 mL, 0.35 mol) in EtaO (160 mL) was added dropwise, during 10 min, to a rapidly stirred mixture of trans-4-hydroxy-L-proline (39.8 g, 0.308 mol), NaHCO3 (63.7 g, 0.758 mol) and H20 (660 mL). The reaction mixture was stirred at room temperature for 20 h. The layers were separated, and the aqueous layer was washed with Et2O (4 x 200 mL), cooled, and then acidified to pH 1-2 with concentrated hydrochloric acid. The resulting emulsion was extracted with EtOAc (5 x 200 mL). Combined EtOAc extracts were washed in succession with H20 (3 x 500 mL) and brine (3 x 500 mL), dried over MgSO4, and then concentrated in vacuo to give intermediate (4) as a colorless foam (62.7 g, 78percent). Additional reactions were carried out to give a total of 284 g of product suitable for further transformationSodium hydrogencarbonate (16 O g, 191 mmol) was added to a stirred solution of frans-4-hydroxy-L-prolιne (105a) (10 0 g, 76 mmol) in water (8 7 mL) at 0(2S, 4R)-N-(Benzoxycarbonyl)-2-carboxy-4-hydroxypyrrolidine (45) To a 3 L flask were added (25, 4R)-4-hydroxypyrrolidine-2-carboxylic acid (87.0 g, 663.46 mmol, 1.0 eq.), water (1500 ml), Na2CO3 (141.0 g, 1330 mmol, 2.0 eq.) andNaHCO3 (55.7 g, 663 mmol, 1.0 eq.). Acetone (250 ml) was added to the solution which was then cooled in an ice-water bath. To the mixture was slowly added Cbz-Cl (141.0 g, 829 mmol, 1.25 eq.). After addition, the reaction mixture was warmed gradually to 22 °C and was stirred for 15 h. The reaction mixture was washed with MTBE (600 ml x 2). To the aqueous phase was slowly added aqueous 1 N HCI until pH—2 was achieved. The resulting mixture was extracted with EtOAc (1 L x 3) and the combined organic layer was dried over MgSO4, filtered and concentrated underreduced pressure to provide 190 g of the title compound as an oil, which was taken to the next step without further purification. LCMS: MS = 287.8 (M+H).

A competitive inhibitor of porcine kidney prolidase.

Molecular Weight:265.26
XLogP3:0.8
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:265.09502258
Monoisotopic Mass:265.09502258
Topological Polar Surface Area:87.1
Heavy Atom Count:19
Complexity:340
Undefined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes