DIETHYL (BOC-AMINO)MALONATE

Colourless Oil

Ice bath, Amino malonic acid diethyl ester (17.5 g, 0.1 mol)And triethylamine (20 g, 0.2 mol)250 ml of dichloromethane, Di-tert-butyl dicarbonate (26 g, 0.12 mil) was added to a three-necked flask, gradually raised to room temperature and stirred at that temperature, TLC monitoring reaction ends. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with dichloromethane (200 ml of X). The resulting organic phase was dried over anhydrous magnesium sulfate, Concentrated to give diethyl 2-Boc-aminomalonic acid as a colorless oil27g (yield 98percent)EXAMPLE 48 Step 1 : 2-tert-butoxycarbonyl amino malonate, Diethyl aminomalonate (21.2g) and ethanol (80.0 ml) were added to a flask at room temperature, (t-Boc)a) 1, 3-diethyl 2-{ r(fe/t-butoxy)carbonyl1 amino jpropanedioate (T67) Di-ie/t-butyl dicarbonate (5.3 g; 24 mmol; 1 eq) and triethylamine (3 mL) at 0°C were added to a solution of 1, 3-diethyl 2-aminopropanedioate hydrochloride (5 g; 23 mmol; 1 eq) in tetrahydrofuran/water (1: 1, 60 mL). The reaction mixture was stirred at room temperature for 2 days and, at 55°C, 2 hours. After concentration to dryness, the residue was taken up in ethyl acetate (150 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with saturated ammonium chloride (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound, 1, 3-diethyl 2- { [(ieri-butoxy)carbonyl] amino Jpropanedioate was obtained in 97percent yield (6.16 g) as a colorless oil. 1H NMR (CDC1Diethyl 2-aminomalonate hydrochloride (2.535 g, 12.0 mmol) was dissolved in a mixture of 1 M NaOH (12 mL) and 1 , 4-dioxane (10 mL) and a solution of Boc-anhydride (2.54 g, 12.0 mmol, 1.0 eq.) in 1 , 4-dioxane (5 mL) was added dropwise at 5 °C. Subsequently, the mixture was stirred at r.t. for 24 h. Dioxane was removed in vacuo and the residue was dissolved in ethyl acetate. After phase separation, the organic layer was washed with 1 M HCI (3 x 50 mL) and dried over NaThis compound was synthetized according to the procedure describedby Berner and co-workers.21 To a solution of 10.0 g of diethylaminomalonate hydrochloride (47.3 mmol, 1.008 equiv) in 80.0 mLof dioxane, 1.89 g of NaOH in water (1.01 equiv, 47.4 mmol, 1.0 M)were added. After complete dissolution of the salt, a solution of10.3 g of (Boc)2O (1.0 equiv, 46.8 mmol) in 20.0 mL of dioxane wasadded dropwise and reacted overnight. Once the reaction wasfinished the solvents were removed at reduced pressure, the crudesolid was redissolved with EtOAc, washed with solutions of 1 N HCland saturated NaCl, dried over MgSO4 anhyd and the solvent of thecombined organic phases was removed at reduced pressure. Finally, the crude product was purified by flash column chromatography(Hexane/EtOAc 3:1) to afford the desired product as a whitesolid in 91percent yield. 1H NMR (400 MHz, CDCl3) d5.54 (br s, 1H), 4.93(d, J7.8 Hz, 1H), 4.35e4.15 (m, 4H), 1.44 (s, 9H), 1.29 (t, J7.1 Hz, 6H).Diethyl 2-aminomalonate hydrochloride (2.54 g, 12.0 mmol) was dissolved in a mixture of 1M NaOH (12 mL) and 1, 4-dioxane (10 mL) and a solution of Boc-anhydride (2.54 g, 12.0 mmol, 1.0e q.) in 1, 4-dioxane (5 mL) was added dropwise at 5°C. Subsequently, the mixture was stirred at r.t. for 24 h. Dioxane was removed in vacuo and the residue was dissolved in ethyl acetate. After phase separation, the organic layer was washed with 1M HCl (3×50mL) and dried over NaStep 1 1.2 Diethyl 2-(tert-butoxycarbonyl)amidomalonate10141] Diethyl 2-aminomalonate hydrochloride (2.535 g, 12.0 mmol) was dissolved in a mixture of 1 M NaOR (12 mL) and 1, 4-dioxane (10 mL) and a solution of Soc-anhydride (2.54 g, 12.0 mmol, 1.0 eq.) in 1 , 4-dioxane (5 mL) was added dropwise at 5° C. Subsequently, the mixture was stirred at tt. for 24 h. Dioxane was removed in vacuo and the residue was dissolved in ethyl acetate. Afier phase separation, the organic layer was washed with 1 M RC1 (3x50 mL) and dried over Na2504. The solvent was removed in vacuo and the crude product was purified by column chromatography with silica gel (cyclohexane/ethyl acetate, 6:1). The product was isolated as a colourless oil. Yield: 3.009 g (91percent).0 01112 10010142] ‘RNMR (300 MRz, CDC13): ö [ppm]: 1.30 (t, 3H ii=7.2 Rz, 6R, 10-CR3, 12-CR3), 1.45 (s, 9R, 6-CR3, 7-CR3, 8-CR3), 4.27(m, 4R, 9-CR2, 11-CR2), 4.94 (d, Rz, 1R, 2-CR), 5.63 (d, 3JHJI=7.8 Rz, 1R, 2-NR).10143] ‘3C-NMR (101 MRz, CDC13) ö [ppm]: 14.0 (q, C-b, C-12), 28.2 (q, C-6, C-7, C-8), 57.5 (d, C-2), 62.4 (t, C-9, C-li), 80.5 (s, C-5), 154.8 (s, C-4), 166.6 (s, C-i, C-3).10144] Exact mass (ESIj: C12R21NO5+Na: calcd. 298.1261, found 298.1244.10145] Ref.: ‘R NMR: R. Schneider, G. Sigmund, S.Schricker, K. Thirring, R. Serner, J. Org. Chem. 1993, 58, 683-689.

Molecular Weight:275.30
XLogP3:1.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:9
Exact Mass:275.13688739
Monoisotopic Mass:275.13688739
Topological Polar Surface Area:90.9
Heavy Atom Count:19
Complexity:316
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes