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CAS No. : | 102831-44-7 | MDL No. : | MFCD00239423 |
Formula : | C12H21NO6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ULRLHEXGRUWQLQ-UHFFFAOYSA-N |
M.W : | 275.30 | Pubchem ID : | 382219 |
Synonyms : |
|
Num. heavy atoms : | 19 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 10 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 66.88 |
TPSA : | 90.93 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.77 cm/s |
Log Po/w (iLOGP) : | 3.31 |
Log Po/w (XLOGP3) : | 1.71 |
Log Po/w (WLOGP) : | 1.01 |
Log Po/w (MLOGP) : | 0.81 |
Log Po/w (SILICOS-IT) : | 0.85 |
Consensus Log Po/w : | 1.54 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.96 |
Solubility : | 2.99 mg/ml ; 0.0109 mol/l |
Class : | Very soluble |
Log S (Ali) : | -3.24 |
Solubility : | 0.16 mg/ml ; 0.000582 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.84 |
Solubility : | 3.96 mg/ml ; 0.0144 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.8 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In dichloromethane at 20℃; Cooling with ice | 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) |
95% | With triethylamine In dichloromethane | EXAMPLE 48 Diethyl 2-t-butoxycarbonylamino malonate A solution of diethyl 2-aminomalonate (5 g, 23.6 mmol) and (Boc)2O (5.65 g, 25.96 mmol) in CH2Cl2 (50 mL) was treated slowly with Et3N (2.43 g, 24 mmol) for 10 minutes. After stirring 3 h at room temperature, the reaction was washed twice with water, dried and concentrated to give 6.16 g (95percent) of the title compound. 1H-NMR (500 MHz, CDCl3) δ5.54 (d, J=7.3 Hz, 1H), 4.93 (d, J=7.8 Hz, 1H), 4.26 (m, 4H), 1.44 (s, 9H), 1.29 (t, J=6.9 Hz, 6H). |
3 g | With triethylamine In ethanol at 35℃; for 4 h; | 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)2 ( 24 g) in ethanol (20.0 ml) was added dropwise to the mixture, then triethylamine (14 ml) was added. The reaction mixture was heated to and maintained at 35 °C for 4 hours. After the reaction was complete, the reaction mixture was concentrated, then ethyl acetate (60.0 ml) was added to the reaction mass, washed with water two times, then separated the ethyl acetate layer, concentrated to obtain 2 - tert-butyl ethyl malonate oxycarbonylamino as a pale yellow oil: 3.0 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine In tetrahydrofuran; water at 0 - 55℃; for 50 h; | 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 (CDC13): δ (ppm) 1.35 (t, 6H), 1.5 (s, 9H), 4.32 (q, 4H), 4.99 (d, 1H), 5.61 (d, 1H). |
91% | With sodium hydroxide In 1,4-dioxane at 5 - 20℃; for 24 h; | Diethyl 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 Na2S04. 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 (91 percent). 2 1H NMR (300 MHz, CDCI3): δ [ppm]: 1 .30 (t, 3JKH = 7.2 Hz, 6 H, 10-CH3, 12-CH3), 1 .45 (s, 9 H, 6-CH3, 7-CH3, 8-CH3), 4.27 (m, 4 H, 9-CH2, 1 1 -CH2), 4.94 (d, 3JH,H = 7.7 Hz, 1 H, 2-CH), 5.63 (d, 3JH,H = 7.8 Hz, 1 H, 2-NH). 13C-NMR (101 MHz, CDCI3) δ [ppm]: 14.0 (q, C-10, C-12), 28.2 (q, C-6, C-7, C-8), 57.5 (d, C-2), 62.4 (t, C-9, C-1 1 ), 80.5 (s, C-5), 154.8 (s, C-4), 166.6 (s, C-1 , C-3). Exact mass (ESI+): Ci2H2iN06 + Na+: calcd. 298.1261 , found 298.1244. Ref.: 1H NMR: H. Schneider, G. Sigmund, B. Schricker, K. Thirring, H. Berner, J.Org. Chem. 1993, 58, 683-689. |
91% | Stage #1: With sodium hydroxide In 1,4-dioxane; water |
This 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). |
91% | Stage #1: With sodium hydroxide In 1,4-dioxane Stage #2: at 5 - 20℃; for 24 h; |
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 Na2SO4. The solvent was removed in vacuo and the crude product was purified by column chromatography (cyclohexane/ethyl acetate, 6:1). The product was isolated as colorless oil. Yield: 3.01g (91percent). 1H NMR (300 MHz, CDCl3): δ 1.30 (t, 3JH,H=7.2Hz, 6H, 10‑CH3, 12‑CH3), 1.45 (s, 9H, 6‑CH3, 7‑CH3, 8‑CH3), 4.27 (m, 4H, 9‑CH2, 11‑CH2), 4.94 (d, 3JH,H=7.7Hz, 1H, 2‑CH), 5.63 (d, 3JH,H=7.8Hz, 1H, 2‑NH).113C NMR (101 MHz, CDCl3): δ 14.0 (q, C‑10, C‑12), 28.2 (q, C‑6, C‑7, C‑8), 57.5 (d, C‑2), 62.4 (t, C‑9, C‑11), 80.5 (s, C‑5), 154.8 (s, C‑4), 166.6 (s, C‑1, C‑3).Exact mass (ESI+): C12H21NO6 + Na+: calcd. 298.1261, found 298.1244. |
85% | With sodium hydroxide In water; acetone for 48 h; | Step 1 To a solution of diethyl aminomalonate hydrochloride XCV (2.0 g, 9.45 mmol) in water (45 mL) was added 1 M NaOH to pH~8. Boc2O (3.72 g, 17.0 mmol) in acetone (15 mL) was then added. The reaction mixture was stirred for 2 days before the acetone was evaporated under reduced pressure. The residue was washed by diethyl ether, and the organic layer was evaporated under vacuum to give the crude 1,3-diethyl 2-[(tert-butoxy)carbonyl]amino}propanedioate XCVI as a colorless oil (2.22 g, 8 mmol, 85percent yield). The crude product was used directly in step 2. ESIMS found for C12H21NO6 m/z 276 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydroxide In 1,4-dioxane at 5 - 20℃; for 24 h; | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine; In dichloromethane; at 20℃;Cooling with ice; | 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 98%) |
6.16 g (95%) | With triethylamine; In dichloromethane; | EXAMPLE 48 Diethyl 2-t-butoxycarbonylamino malonate A solution of diethyl 2-aminomalonate (5 g, 23.6 mmol) and (Boc)2O (5.65 g, 25.96 mmol) in CH2Cl2 (50 mL) was treated slowly with Et3N (2.43 g, 24 mmol) for 10 minutes. After stirring 3 h at room temperature, the reaction was washed twice with water, dried and concentrated to give 6.16 g (95%) of the title compound. 1H-NMR (500 MHz, CDCl3) δ5.54 (d, J=7.3 Hz, 1H), 4.93 (d, J=7.8 Hz, 1H), 4.26 (m, 4H), 1.44 (s, 9H), 1.29 (t, J=6.9 Hz, 6H). |
3 g | With triethylamine; In ethanol; at 35℃; for 4h; | 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)2 ( 24 g) in ethanol (20.0 ml) was added dropwise to the mixture, then triethylamine (14 ml) was added. The reaction mixture was heated to and maintained at 35 C for 4 hours. After the reaction was complete, the reaction mixture was concentrated, then ethyl acetate (60.0 ml) was added to the reaction mass, washed with water two times, then separated the ethyl acetate layer, concentrated to obtain 2 - tert-butyl ethyl malonate oxycarbonylamino as a pale yellow oil: 3.0 g. |
With triethylamine; In dichloromethane; at 20℃; | To a suspension of diethyl aminomalonate (50 g, 285 mmol) and trimethylamine (57.8 g, 571 mmol) in dichloromethane (800 ml_) was added a solution of di-tert-butyl dicarbonate (93 g, 428 mmol) in dichloromethane (300 ml_) and the solution was allowed to stir at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated to provide the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In 1,4-dioxane; water; | To a suspended of diethyl aminomalonate hydrochloride (25 g, 118.12 mmol, 1 equiv) in a mixture of water (150 mL) anddioxane (220 mL) in a round bottom flask with magnetic bar, NaHCO3 (10.42 g, 124.03 mmol, 1.05 equiv) was slowlyadded while stirring at room temperature. When the solution became clear, a catalyst amount of DMAP (1% mol, 144 mg)was added followed with a dropwise addition of a solution of Boc2O (27.07 g, 124.03 mmol, 1.05 equiv) in dioxane (80mL). After the reaction was complete (monitored by TLC), the solvents were evaporated in vacuo. The residue wasdissolved in EtOAc. The organic phase was washed with solutions of 5% KHSO4, satd. NaHCO3, water, and brine, anddried over anhydrous Na2SO4, then filtered and evaporated in vacuo. The desired product was pure enough for the nextstep without a need of purification via column chromatography. Yield quantitative (32.51 g). 1H NMR (400 MHz,DMSO-d6): δ 7.67 (d, J = 8.1 Hz, 1H), 4.80 (d, J = 8.1 Hz, 1H), 4.16 (m, 4H), 1.39 (s, 9H), 1.20 (t, J = 7.1 Hz, 6H). 13CNMR (100 MHz, DMSO-d6): δ 167.04, 155.54, 79.51, 61.96, 57.89, 28.48, 12.28. HRMS (ESI, positive mode): m/z298.1323 [M+Na]+, calcd for [C12H21NO6Na]+: 298.1261 |
97% | With triethylamine; In tetrahydrofuran; water; at 0 - 55℃; for 50h; | 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 0C 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 55C, 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 97% yield (6.16 g) as a colorless oil. 1H NMR (CDC13): δ (ppm) 1.35 (t, 6H), 1.5 (s, 9H), 4.32 (q, 4H), 4.99 (d, 1H), 5.61 (d, 1H). |
91% | With sodium hydroxide; In 1,4-dioxane; at 5 - 20℃; for 24h; | Diethyl 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 Na2S04. 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 (91 %). 2 1H NMR (300 MHz, CDCI3): δ [ppm]: 1 .30 (t, 3JKH = 7.2 Hz, 6 H, 10-CH3, 12-CH3), 1 .45 (s, 9 H, 6-CH3, 7-CH3, 8-CH3), 4.27 (m, 4 H, 9-CH2, 1 1 -CH2), 4.94 (d, 3JH,H = 7.7 Hz, 1 H, 2-CH), 5.63 (d, 3JH,H = 7.8 Hz, 1 H, 2-NH). 13C-NMR (101 MHz, CDCI3) δ [ppm]: 14.0 (q, C-10, C-12), 28.2 (q, C-6, C-7, C-8), 57.5 (d, C-2), 62.4 (t, C-9, C-1 1 ), 80.5 (s, C-5), 154.8 (s, C-4), 166.6 (s, C-1 , C-3). Exact mass (ESI+): Ci2H2iN06 + Na+: calcd. 298.1261 , found 298.1244. Ref.: 1H NMR: H. Schneider, G. Sigmund, B. Schricker, K. Thirring, H. Berner, J.Org. Chem. 1993, 58, 683-689. |
91% | This 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 91% 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). | |
91% | 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 5C. 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 Na2SO4. The solvent was removed in vacuo and the crude product was purified by column chromatography (cyclohexane/ethyl acetate, 6:1). The product was isolated as colorless oil. Yield: 3.01g (91%). 1H NMR (300 MHz, CDCl3): δ 1.30 (t, 3JH,H=7.2Hz, 6H, 10-CH3, 12-CH3), 1.45 (s, 9H, 6-CH3, 7-CH3, 8-CH3), 4.27 (m, 4H, 9-CH2, 11-CH2), 4.94 (d, 3JH,H=7.7Hz, 1H, 2-CH), 5.63 (d, 3JH,H=7.8Hz, 1H, 2-NH).113C NMR (101 MHz, CDCl3): δ 14.0 (q, C-10, C-12), 28.2 (q, C-6, C-7, C-8), 57.5 (d, C-2), 62.4 (t, C-9, C-11), 80.5 (s, C-5), 154.8 (s, C-4), 166.6 (s, C-1, C-3).Exact mass (ESI+): C12H21NO6 + Na+: calcd. 298.1261, found 298.1244. | |
89% | Compound 1 (500g, 2.36mol) was dissolved in 1L of methylene chloride, added dropwise triethylamine (716g, 7.08mol) under ice-water bath, the addition was complete the reaction at room temperature 0.5h; cooled in an ice-water bath, slowly added Boc anhydride (567g, 2.60mol), completion, stirring overnight at room temperature.TLC showed disappearance of compound 1, the reaction was filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated to give an oil.Oil was dissolved in ethyl acetate was added, washed with 1N aqueous hydrochloric acid solution, then with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated to give 578g of Compound 2 as a yellow oil (yield: 89%), used without further purification in the next reaction. | |
85% | With sodium hydroxide; In water; acetone; for 48h;pH 8; | Step 1 To a solution of diethyl aminomalonate hydrochloride XCV (2.0 g, 9.45 mmol) in water (45 mL) was added 1 M NaOH to pH~8. Boc2O (3.72 g, 17.0 mmol) in acetone (15 mL) was then added. The reaction mixture was stirred for 2 days before the acetone was evaporated under reduced pressure. The residue was washed by diethyl ether, and the organic layer was evaporated under vacuum to give the crude 1,3-diethyl 2-[(tert-butoxy)carbonyl]amino}propanedioate XCVI as a colorless oil (2.22 g, 8 mmol, 85% yield). The crude product was used directly in step 2. ESIMS found for C12H21NO6 m/z 276 (M+H). |
46% | NaHCO3 (462 mg, 5.5 mmol)was slowly added to a suspension ofdiethyl aminomalonate hydrochloride(1.0582 g, 5 mmol, 13) in water (7 mL) and dioxane(10 mL). The resulting solution was stirred for a fewminutes at room temperature (rt) until a clear solutionappeared. Next, DMAP (6.11 mg, 0.01 mmol) was addedfollowed by a dropwise addition of a solution of Boc2O(1.2004 g, 5.5 mmol) in dioxane (4 mL). The mixture wasstirred at room temperature overnight. Then, the solutionwas concentrated under reduced pressure. The residue wassuspended in ethyl acetate (25 mL) and then extracted with5% aqueous KHSO4 solution (20 mL), saturated aqueousNaHCO3 solution (20 mL), water (15 mL) and brine (15 mL).The organic phase was dried with anhydrous Na2SO4 andconcentrated under reduced pressure. 1.2803 g, 4.65 mmol(46% yield) of a light oil was obtained and applied for thenext reaction without further purification. LRMS (ESI(electrospray ionization)) m/z 276.1 [M - CO2]+, 100). | |
With triethylamine; In tetrahydrofuran-water; | (a) A solution of 31.7 g (150 mmole) of diethyl aminomalonate hydrochloride in 400 mL 1/1 THF/H2O was cooled to 0C and 20 mL triethylamine was added followed by 35 g di-t-butyldicarbonate. The reaction mixture was stirred 1.25 hours at 0C and was then warmed briefly to 50C. The reaction mixture was stirred overnight at room temperature, concentrated to remove THF, diluted with ethyl acetate, washed with 200 mL 10% citric acid solution and brine, dried (MgSO4), filtered, and concentrated to a clear viscous liquid to give N-[bis(ethoxycarbonyl)methyl]carbamic acid, 1,1-dimethylethyl ester. 43.3 g, 100%. IR (LF) 2938, 1761, 1720, 1506, 1370, 1163, 780 cmmin1. | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;Cooling with ice; | Step I. To a solution of diethyl aminomalonate hydrochloride (17 g, 80 mmol) and DIPEA (44 mL, 250 mmol) in DCM (250 mL) was added di-tert-butyl dicarbonate (20.8 g, 96 mmol) at ice-bath. The mixture was allowed to warm to room temperature while stirred for 16 h. Then the mixture was concentrated in vacuo. And the residue was extracted with DCM (150 mL) two times. The combined organic layers were washed with saturated NaHCO3 (100 mL) three times, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 22 g of crude product diethyl 2-(tert-butoxycarbonylamino)propanedioate as a colorless oil (yield was 100%). MS: calc'd (MH+) 276, measured (MH+) 276 | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;Cooling with ice; | To a solution of diethyl aminomalonate hydrochloride (17 g, 80 mmol) and DIPEA (44 mL, 250 mmol) in DCM (250 mL) was added di-tert-butyl dicarbonate (20.8 g, 96 mmol) at ice-bath. The mixture was allowed to warm to room temperature while stirred for 16 h. Then the mixture was concentrated in vacuo. And the residue was extracted with DCM (150 mL) two times. The combined organic layers were washed with saturated NaHC03 (lOOmL) three times, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 22 g of crude product diethyl 2-(tert-butoxycarbonylamino)propanedioate as a colorless oil (yield was 100%). MS: calc'd (MH+) 276, measured (MH+) 276. | |
With dmap; sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 12h; | To a solution of diethyl 2-aminomalonate hydrochloride (50 g, 236 mmol) in H2O (300 mL) and dioxane (440 mL) was slowly added NaHCO3 (21 g, 248 mmol) at 20 C. When the solution became clear, DMAP (289 mg, 2 mmol) was added followed by dropwise addition of a solution of Boc2O (54 g, 248 mmol) in dioxane (160 mL).The mixture was stirred at 20 C. for 12 hours. The mixture were concentrated. The residue was dissolved in ethyl acetate. The organic phase was washed with solution of 5% KHSO4 (aq.), sat. aq. NaHCO3, water, and brine, and dried over anhydrous Na2SO4, then filtered and concentrated to give diethyl 2-((tert-butoxycarbonyl)amino)malonate. |
Yield | Reaction Conditions | Operation in experiment |
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98% | With potassium hydroxide; In ethanol; at 20℃; | To a solution of diester 6 (27.51 g, 100 mmol) in absolute EtOH (100 mL) in a round bottom flask, a solution of KOH(5.60 g, 100 mmol, 1 equiv) in EtOH (60 mL) was added dropwise while stirring at room temperature. The reactionmixture was kept stirring for overnight. After the reaction was completed, 90% of solvent was removed by evaporated invacuo. The residue was dissolved in solution of 1M NaHCO3 (100 mL) and extracted with EtOAc. The aqueous phase wasthen acidified by KHSO4 (powder) at 0 oC and extracted with EtOAc. The organic phase was dried over anhydrousMgSO4, filtered, and evaporated to obtain the pure product 5? without a need of purification via column chromatography.Yield 98% (24.11 g). 1H NMR (400 MHz, DMSO-d6): delta 13.31 (brs, 1H), 7.44 (d, J = 7.8 Hz, 1H), 4.72 (d, J = 7.8 Hz,1H), 4.15 (m, 2H), 1.39 (s, 9H), 1.20 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): delta 168.20, 167.63, 155.52,79.37, 61.75, 58.01, 28.53, 14.43. HRMS (ESI, positive mode): m/z 270.0970 [M+Na]+, calcd for [C10H17NO6Na]+:270.0948 |
85% | Step 2 To a solution of 1,3-diethyl 2-[(tert-butoxy)carbonyl]amino}propanedioate XCVI (2.22 g, 8 mmol) in a mixture of ethanol/water (45 mL/5 mL) was added KOH (0.45 g, 8 mmol) in water (3 mL) dropwise. The reaction mixture was stirred for 1.5 hours. The ethanol was evaporated and the residue was acidified to pH=2 by 2 M HCl and washed by DCM. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated to give 2-[(tert-butoxy)carbonyl]amino}-3-ethoxy-3-oxopropanoic acid XCVII as crystals (1.68 g, 6.8 mmol, 85% yield). 1H NMR (CDCl3) 1.31 (t, J=7 Hz, 3H), 1.41-1.45 (m, 9H), 4.23-4.31 9m, 2H), 4.76 (d, J=4 Hz, 1H), 7.77 (d, J=4 Hz, 1H), 10.84 (brs, 1H); ESIMS found for C10H17NO6 m/z 248 (M+H). | |
35% | With potassium hydroxide; In ethanol; at 20℃; for 4h; | b) 2-{ r(fer?-butoxy)carbonyllamino|-3-ethoxy-3-oxopropanoic acid (1-68) Potassium hydroxide 85% (1.19 g; 21 mmol; 1 eq) was added to a solution of 1,3- diethyl 2-{ [(iert-butoxy)carbonyl]amino}propanedioate (1-67) (4.97 g; 18 mmol; 1 eq) in ethanol (23 mL). The reaction mixture was stirred at room temperature for 4 hours. After concentration to dryness, the residue was taken up in ethyl acetate (150 mL) and water (50 mL). The basic aqueous layer was extracted with ethyl acetate (2 x 50 mL) and acidified at 0C with a solution of hydrochloric acid IN until pH 2. The resulting acidic aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound, 2-{ [(ieri-butoxy)carbonyl]amino}-3- ethoxy-3-oxopropanoic acid was obtained in 35% yield (1.57 g) as a colorless oil. 1H NMR (DMSO-d6): delta (ppm) 1.2 (t, 3H), 1.39 (s, 9H), 4.13 (q, 2H), 4.62 (m, 1H), 7.33 (s, 1H); MS (ESI+): m/z = 148.0 [(M+H)-Boc]+ . |
With potassium hydroxide; In ethanol; water; at 20℃; for 12h; | Intermediate: 2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropanoic acid To a solution of diethyl 2-((tert-butoxycarbonyl)amino)malonate (30 g, 109 mmol) in EtOH/H2O (675 mL/75 mL), a solution of KOH (7 g, 120 mmol) in H2O (45 mL) was added dropwise while stirring at 20 C. The reaction mixture was stirred at 20 C. for 12 hours. The ethanol was removed in vacuo and the residue was acidified to pH=2 by 2N HCl (aq.) and washed with dichloromethane. The organic layer was washed with brine and dried over Na2SO4, filtered and concentrated to give 2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropanoic acid. |
Yield | Reaction Conditions | Operation in experiment |
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78% | To a solution of diethyl 2-(N-(tert-butoxycarbonyl)amino)malonate 3 (12.6 g, 46 mmol in THF (150 mL) was added NaH (3.68 g, 92 mmol) slowly at 0 oC,then the reaction mixture was heated to 80 oC. Allybromide (6.6 g, 55 mmol) was added dropwise. The reaction mixture was stirred at 80 oC for 2 h, then cooled to rt, quenched with sat. NH4Cl (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by flash clomun chromatography on silica gel eluting with 10%-20% EtOAc in PE to give the pure product (11.3 g, 78%) as a colorless oil. 1HNMR (400 MHz, CD3OD) δ: 5.72 - 5.61 (m, 1H), 5.17 - 5.08 (m,2H), 4.31 - 4.17 (m, 4H), 2.97 (d, J = 7.4 Hz, 2H), 1.46 (s, 9H), 1.31 -1.20 (m, 6H). MS (ESI): m/z = 316 [M+H]+. To the solution of above product (12.6 g, 36 mmol) in CH2Cl2(75 mL) was added TFA (25 mL) at 0 oC. After being stirred at rt for 1h, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with sat. NaHCO3 (100 mL) and brine (100 mL), the organic layer was dried over Na2SO4, filtered and concentrated to give the crude amine (7.35 g, 95%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ: 5.80 - 5.65 (m, 1H), 5.17 - 5.03 (m, 2H), 4.19 -4.04 (m, 4H), 2.55 (d, J =7.3 Hz, 2H), 2.19 (br, 2H), 1.16 (t, J = 7.1 Hz, 6H). MS (ESI): m/z = 216 [M+H]+. To a solution of above crude amine (7.35 g, 34 mmol) and K2CO3 (9.38 g, 68 mmol) in MeCN (50 mL) was added benzylbromide (7.0 g, 41 mmol) slowly at 0 oC,then the reaction mixture was stirred at 80 oC for 16h. The reaction mixture was cooled to rt, quenched with sat. NH4Cl (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash cloumn chromatogrphy on silica gel eluting with 10%-30% EtOAc in PE to afford compound 4 (7.7 g, 75%) as a colorless oil. 1HNMR (400 MHz, DMSO-d6) δ: 7.31 (m, 4H), 7.28 - 7.19 (m, 1H), 5.79 - 5.70 (m, 1H), 5.17 - 5.01 (m, 2H), 4.13 (q, J = 7.1 Hz,4H), 3.62 (d, J = 7.3Hz, 2H), 2.70 (d, J = 7.2Hz, 2H), 2.56 (t, J = 7.2Hz, 1H), 1.17 (t, J = 7.1Hz, 6H). MS (ESI): m/z = 306 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 4h; | j0125] A suspension of diethyl 2-t-butyloxycarbonylami- nomalonate (5.0 g), potassium carbonate (3.0 g), and ethyl 2-bromoacetate (3.9 g) in DMF (20 mE) was stirred at 50for 4 hours. The reaction mixture was cooled, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and then purification was performed with n-hexane/ethyl acetate (5:1), to obtain the title compound (5.7 g, yield: 79%) as colorlessoil. 10126] ‘H NMR (CDC13) ö (ppm): 6.13 (1H, s), 4.25 (4H,m), 4.12 (2H, q, J=6.9 Hz), 3.45 (2H, s), 1.43 (9H, s), 1.26(9H, m)10127] MS (FAR): mlz 362 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
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99% | With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h; | Example 7D Diethyl [(tert-butoxycarbonyl)amino](3-iodobenzyl)malonate 25 g (84.2 mmol) of <strong>[49617-83-6]3-iodobenzyl bromide</strong> are added to a solution of 24.3 g (88.4 mmol) of diethyl [(tert-butoxycarbonyl)amino]malonate and 3.7 g (92.6 mmol) of sodium hydride in 300 ml of DMF while cooling in ice. After stirring the mixture at RT for 4 h, 5 ml of water are added cautiously while cooling in ice. The mixture is extracted several times with ethyl acetate, and the combined organic phases are washed with a saturated sodium chloride solution and water, dried over magnesium sulfate and concentrated in vacuo. The crude product is dried under high vacuum. Yield: 43 g (99% of theory) HPLC (method 11): Rt=5.60 min. 1H-NMR (300 MHz, DMSO-d6): delta=1.18 (t, 6H), 1.44 (s, 9H), 3.40 (s, 2H), 4.05-4.25 (m, 2H), 6.4 (br. s, 1H), 7.02 (d, 1H), 7.10 (t, 1H), 7.35 (s, 1H), 7.61 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20 - 80℃; for 5.33333h;Heating / reflux; | At room temperature and under a stream of argon gas, sodium t-butoxide (490mg) was added to diethyl 2-t-butoxycarbonylaminomalonate (1.3mL) in a mixture of THF (35mL) and DMF (4mL). This mixture was stirred for 20min at 80C and was allowed to cool to room temperature. To the cooled mixture, a THF solution (5mL) of the compound of Reference Example 279 (1.55g) was added dropwise. The resulting mixture was refluxed for 5 hours, was poured into ice water, and was extracted with ethyl acetate. The extract was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified on a silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the desired product as a colorless oil (1.87g). 1H-NMR(400MHz, CDCl3) δ 1.22-1.36(6H, m), 1.42(9H, s), 1.45-1.53(2H, m), 2.37(2H, br), 2.74(2H, t, J=7.8Hz), 4.23(4H, m), 5.94 (1H, s), 7.16-7.21(2H, m), 7.36-7.56(5H, m). | |
Under argon and at room temperature, sodium-t-butoxide (490mg) was added to diethyl 2-t-butoxycarbonylaminomalonate (1.3ML) dissolved in a mixed solvent of THF (35ML) and DMF (4ML).. The mixture was then stirred at 80C for 20 minutes and was allowed to cool to room temperature.. A solution of the compound of Reference Example 46 (1.55g) in THF (5ML) was added to the mixture.. Subsequently, the mixture was refluxed for 5 hours and was then poured into ice water.. The resulting mixture was extracted with ethyl acetate.. The organic phase was sequentially washed with water and a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate.. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5:1).. In this manner, the desired product (1.87g) was obtained as a colorless oil.1H-NMR (400MHz, CDCl3) δ 1.22-1.36(6H, m), 1.42(9H, s), 1.45-1.53(2H, m), 2.37(2H, br), 2.74(2H, t, J=7.8Hz), 4.23(4H, m), 5.94(1H, s), 7.16-7.21(2H, m), 7.36-7.56(5H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; at 20℃; | Under a nitrogen atmosphere, 60% sodium hydride in oil (0.88 g) was suspended in N,N-dimethylformamide (10 mL). To this suspension, a solution of 2-[N-(tert-butoxycarbonyl)amino]malonic acid diethyl ester (2.75 g) in N,N-dimethylformamide (110 mL) was added at room temperature. A solution of 2-(chloromethyl)pyridine hydrochloride (1.64 g) in N,N-dimethylformamide (10 mL) was then added and stirring was continued overnight at room temperature. The reaction mixture was partitioned by addition of ethyl acetate (100 mL) and saturated aqueous sodium chloride (100 mL). The extracted solution was washed four times with saturated aqueous sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered to remove the desiccant and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane = 1:7 to 1:5) to give the titled compound (2.61 g) as a colorless oil. MS(ESI pos.)m/z: 389 ([M+Na]+). 1H-NMR (300 MHz, DMSO-d6) δ 8.44 (1H, ddd, J=4.8, 1.7, 0.9 Hz), 7.57 (1H, td, J=7.6, 1.9 Hz), 7.14-7.08 (2H, m), 5.95 (1H, brs), 4.38-4.20 (4H, m), 3.80 (2H, s), 1.42 (9H, s), 1.28 (6H, t, J=7.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.38 g (95%) | With NaOEt; In tetrahydrofuran; | To the NaOEt solution at 0 C. was added dropwise diethyl 2-t-butoxycarbonylamino malonate (4 g, 14.5 mmol). After 10 minutes, a solution of 3-bromomethylbenzonitrile (3.13 g, 15.13 mmol) in dry THF (7 mL) was added dropwise, and the solution was stirred for 2 h at 0 C. After concentration, the residue was taken up with EA, washed with the saturated NH2Cl and then brine, dried and concentrated to give 5.38 g (95%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium iodide; sodium ethanolate; triethylamine; lithium chloride; In tetrahydrofuran; 1,4-dioxane; dichioromethane; ethanol; water; | 1h. [[-(benzoylamino)-6-isoquinolinyl]methyl][[(1,1-dimethylethoxy)carbonyl]amino]propane-dioic acid diethyl ester To a stirred suspension of 1.27 g of 1g in 30 mL. of dichioromethane at 0 C. was added 1.23 mL of triethylamine and 0.69 mL of methane sulfonylchloride and the mixture was allowed to warn to room temperature. After stirring for 2 hours, 40 mL of tetrahydrofuran and 1.22 g of lithium chloride were added and the suspension was stirred for 16 hours at room temperature. Brine was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure keeping the temperature below 30 C. The residue was coevaporated with toluene under reduced pressure again keeping the temperature below 30 C. The residue (chloride) was immediately dissolved in 20 mL of dioxane and added to sodium malonate reaction mixture A. [This sodium malonate reaction mixture A was obtained by addition of 3 g of [[(1,1-dimethylethoxy)carbonyl]amino]propanedioic acid diethyl ester (Paik, Y. H., Dowd, P., J. Org. Chem. 51, 2910-2913 (1986)) in 10 mL of dioxane to a solution of sodium ethoxide (10 mmol) in 10 mL of dioxane and 30 mL of ethanol, stirring for 10 min at room temperature and subsequently addition of 0.5 g of sodium iodide.] After addition of the crude chloride the reaction mixture was stirred at 80 C. for two hours. After cooling to room temperature water was added, the mixture was neutralized with aqueous 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel (toluene/ethyl acetate: 5/1) giving 1.45 g of 1h. 1H-NMR 200 MHz (CDCl3) δ: 1.31 (6H, t), 1.51 (9H, s), 3.83 (2H, s), 4.18-4.39 (4H, m), 5.77 (1H, s), 6.92 (1H, d, J=7 Hz), 7.30-7.56 (6H, m), 8.41-8.49 (2H, m), 8.92 (1H, d, J=9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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90% | With sodium ethanolate; In ethanol; at 20℃; for 3h; | 41 g (101.7 mmol) of 1-benzyloxy-2-bromomethyl-4-iodobenzene (Example 4A) are added to a solution of 28 g (101.7 mmol) of diethyl 2-[N-(tert-butoxycarbonyl)amino]malonate and 7.9 ml (101.7 mmol) of sodium ethoxide in 300 ml of ethanol. After stirring at RT for 3 h, the precipitated product is filtered off with suction. After drying in vacuo, 55 g (90% of theory) of product are isolated. 1H-NMR (400 MHz, CDCl3): δ=1.12 (t, 6H), 1.46 (s, 9H), 3.68 (s, 2H), 3.8-3.9 (m, 2H), 4.15-4.25 (m, 2H), 5.0 (s, 2H), 5.7 (s, 1H), 6.58 (d, 1H), 7.28-7.4 (m, 6H), 7.4 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium t-butanolate; In tetrahydrofuran; at 70℃; for 10h; | (21-1) Synthesis of 2-[(t-butyloxycarbonyl)amino]-2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]malonic acid diethyl ester (compound 21-1) Diethyl (t-butyloxycarbonyl)aminomalonate (52.3 g) was dissolved in tetrahydrofuran (400 ml), sodium t-butoxide (19.2 g) was added thereto, a solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran (40.4 g) in tetrahydrofuran (100 ml) was added to the reaction mixture at 70C, and the mixture was stirred with heating for 10 hr. After cooling, the reaction mixture was poured into saturated brine. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the object product (50.0 g) as a colorless oil. 1H-NMR(CDCl3)δ(ppm): 1.30(6H, t, J=7.1Hz), 1.45(9H, s), 1.45-1.55(4H, m), 1.58-1.78(2H, m), 2.60-2.64(2H, m), 3.35-3.41(1H, m), 3.46-3.50(1H, m), 3.77-3.84(2H, m), 4.12-4.28(4H, m), 4.49-4.51(1H, m), 6.08(1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution OF DIETHYL 2-[N-(TERT-BUTOXYCARBONYL)-AMINO] malonate (1.44 mL, 5.65 mmol) in 30 ML ETOH cooled to 0 C was added sodium ethoxide (2.22 RNL, 5.93 mmol, 21% in ETOH). The reaction mixture was stirred at 0 C for 5 min and 3-bromomethyl-thiophene (1 g, 5.65 mmol) in 10 mL EtOH was added dropwise. The reaction mixture was allowed to warm to room temperature over 14 h. The reaction mixture was quenched with water, and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (120 g silica, 0-> 25% EtOAc/hexanes) to afford diethyl 2, 2- [N- (TERT-BUTOXYCARBONYL)-AMINO]- (THIEN-3- ylmethyl) malonate as a colorless OIL. 1H NMR (400 MHz, CDC13) 8 7.22 (dd, J = 4.8 Hz, 2.5 Hz, 1H), 6. 94- (d, J = 2. 5 HZ, 1H), 6.81 (d, J = 4. 8 HZ, 1H), 5.82 (BR S, 1H), 4.34-4. 14 (m, 4H), 3.66 (s, 2H), 1.47 (s, 9H), 1.27 (t, J = 7.2 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Under argon, sodium -t-butoxide (1.40g) was added, at room temperature, to a solution of diethyl 2-t-butoxycarbonylaminomalonate (3.60mL) in a mixed solvent of THF (130mL) and DMF (20mL). The resulting mixture was stirred for 30 minutes at 80C. The temperature was decreased down to room temperature and a THF solution (20mL) of the compound of Reference Example 164 (6.22g) was added dropwise. Subsequently, the mixture was refluxed for 5 hours and was decanted into ice water. The resulting mixture was extracted with ethyl acetate. The organic phase was sequentially washed with water and a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4:1). In this manner, the desired product (6.84g) was obtained as a colorless oil. FABMS : 626 ([M+H]+)1H-NMR (400MHz, CDCl3) δ 1.22-1.30(6H, m), 1.42(9H, s), 1.57(2H, br s), 2.37(2H, br), 2.70(2H, t, J=7.8Hz), 4.19-4.29(4H, m), 5.03(2H, s), 5.95(1H, bs), 6.57-6.62(2H, m), 6.74(1H, dd, J=8.3, 2.4Hz), 6.83(1H, dd, J=8.3, 2.4Hz), 6.98(1H, d,. J=2.4Hz), 7.13(1H, d, J=8.3Hz), 7.23(1H, t, J=8.3Hz), 7.33-7.43(5H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tert-Butyl 1,1-di(ethoxycarbonyl)-2-(2-methyl-4-phenylquinolin-3-yl)ethylcarbamate (D4); [0201] To a solution of 3- (Chloromethyl)-2-methyl-4-phenylquinoline (0.958g, 3.6mmol) as the free base in DMF (12mL) was added a DMF (40mL) solution of tert-butyl di (ethoxycarbonyl)methylcarbamate (4.32mmol, 1.19g) that had been deprotonated by treating with NaH (4.32mmol, 104mg) for 15min. This mixture was stirred overnight and then concentrated under reduced pressure, dissolved in H20 and the solution extracted with ether (3x50mL). The extracts were combined, dried (MgS04), filtered, concentrated under reduced pressure to give the product as a brown oil that was used as is. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Step 1: diethyl 2-(but-3-enyl)-2-(tert-butoxycarbonylamino)malonate[0365] To a suspension of sodium hydride (8.7 g, 218 mmol, 60% suspension) in dimethylformaamide (250 mL) at 0 C was added diethyl 2-(tert- butoxycarbonylamino)malonate (50.0 g, 182 mmol) in dimethylformaamide (250 mL). After stirring for 30 minutes, 4-bromobut-l-ene (29.5 g, 218 mmol, 22.2 mL) was added and the mixture was warmed to 90 C. After stirring an additional 4 h, the solution was cooled to room temperature and the solvents were removed by evaporation. The resulting residue was diluted with ethyl acetate (1.0 L), washed successively with water (2 x 250 mL), saturated aqueous sodium chloride (1 x 200 mL) and concentrated. Purification using a combiflash system (330 g silica column, eluted with 15-50% ethyl acetate in heptanes) gave diethyl 2- (but-3-enyl)-2-(tert-butoxycarbonylamino)malonate (54 g, 90%). 1H NMR (CDC13) δ 5.92 (bs, 1 H), 5.79 - 5.71 (m, 1 H), 5.03 - 4.93 (m, 2 H), 4.24 - 4.19 (m, 4 H), 2.36 (m, 2 H), 1.96 - 1.93 (m, 2 H), 1.42 (s, 9 H), 1.27-1.24 (m, 6 H). | |
60% | Step II. To a solution of diethyl 2-(tert-butoxycarbonylamino)propanedioate (20 g, 72.7 mmol) in DMF (100 mL) was added NaH (3.5 g, 87.3 mmol). The mixture was allowed to warm to room temperature while stirred for 0.5 h. Then 4-bromo-1-butene (10.8 g, 80 mmol) was added. The mixture was stirred at 90 C. for 4 h. The mixture was cooled to room temperature, quenched with water (20 mL), and concentrated in vacuo. The residue was purified by silica gel chromatography to afford 14.5 g of the product 81b as a brown oil (yield was 60%). MS: calc'd (MH+) 330, measured (MH+) 330. | |
60% | To a solution of diethyl 2-(tert-butoxycarbonylamino)propanedioate 3 (20 g, 73 mmol) in DMF (100 mL) was added NaH (3.5 g, 87 mmol) at 0 oC. After being stirred at 0 oC for 30 min, 4-bromo-1-butene (10.8 g, 80 mmol) was added. The mixture was warmed to 90 oC and stirred for 4 h, then cooled to rt and quenched with sat. NH4Cl (20 mL), extracted with EtOAc (100 mL x3). The combined organic layer was washed with sat. NH4Cl, water and brine, dried over Na2SO4, filtered and concentrated.The residue was purified by flash silica gel chromatography to afford the product (14.5 g, 60%) as a yellowish oil. 1H NMR (400 MHz, CD3OD) δ: 5.81 (ddt, J = 17.0, 10.3, 6.5 Hz, 1H), 5.04 (dd, J = 17.2, 1.6 Hz, 1H), 4.98 (dd, J = 10.3, 1.2 Hz, 1H), 4.24 (m, 4H), 2.32 (m, 2H), 1.97 (m, 2H), 1.46 (s, 9H), 1.27 (t, J = 7.03 Hz, 6H).13C NMR (100 MHz, CD3OD) δ: 168.0, 154.4, 137.0, 114.3, 79.8, 66.1, 62.1, 32.0, 27.5, 27.2, 12.9. MS (ESI): m/z = 330 [M+H]+. To a solution of above product (14.5 g, 44 mmol) in CH2Cl2 (30 mL) was added TFA (10 mL) at 0 oC. The mixture was stirred at rt. After the reaction was completed, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc, washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford the crude amine (9.5 g, 94 %) as a brown oil which was used for next step without further purification. 1H NMR (400 MHz, CD3OD) δ: 5.84 (dd, J= 16.8, 10.3 Hz, 1H), 5.06 (dd, J =17.1, 1.5 Hz, 1H), 4.99 (m, 1H), 4.23 (q, J= 7.1 Hz, 4H), 2.08 (m, 4H), 1.28 (t, J = 7.1 Hz, 6H). MS (ESI): m/z = 230 [M+H]+. To a mixture of above amine (9.5 g, 42 mmol) and K2CO3 (17.3 g, 125 mmol) in CH3CN (250 mL) was added benzyl bromide (5.9 mL, 50 mmol). After being stirred at at 80 oC for 16 h, the insoluble solid was filtered off and the filtrate was concentrated. The residue was dissolved in EtOAc (300 mL), washed with sat. NH4Cl, water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography eluting with 0~30% EtOAc in hexane to afford compound 11 (11.3 g, 85 %) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ: 7.32 (m, 4H), 7.24 (m, 1H), 5.78 (m, 1H), 4.96 (m, 2H), 4.16 (q, J = 7.0 Hz, 4H), 3.58 (d, J = 7.0 Hz, 2H), 2.63 (t, J = 7.3 Hz, 1H), 2.00 (m, 4H), 1.19 (t, J = 7.0 Hz, 6H). 13C NMR (100 MHz, DMSO- d6) δ: 169.8, 140.3, 137.9, 128.2, 128.0, 126.9, 115.0, 69.2, 61.2, 46.8, 30.8,27.4, 14.0. MS (ESI): m/z = 320 [M+H]+. |
14.5 g | To a solution of diethyl 2-(tert-butoxycarbonylamino)propanedioate (20 g, 72.7 mmol) in DMF (100 mL) was added NaH (3.5 g, 87.3 mmol). The mixture was allowed to warm to room temperature while stirred for 0.5 h. Then 4-bromo-l-butene (10.8 g, 80 mmol) was added. The mixture was stirred at 90 C for 4 h. The mixture was cooled to room temperature, quenched with water (20 mL), and concentrated in vacuo. The residue was purified by silica gel chromatography to afford 14.5 g of the product 81b as a brown oil (yield was 60%). MS: calc'd (MH+) 330, measured (MH+) 330. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With caesium carbonate; In acetonitrile; for 5h;Reflux; | Diethyl /V-Boc-2-amidomalonate 2 (10.953 g, 39.79 mmol), caesiumcarbonate (16.852 g, 51 .72 g, 1 .3 eq.) and iodohexadecane (16.3 mL, 18.224 g, 51 .72 mmol, 1 .3 eq.) were suspended in acetonitrile (160 mL) and refluxed for 5 h. After cooling to r.t. the reaction mixture was adsorbed at silica gel and purified by column chromatography with silica gel (25 x 6 cm, cyclohexane/ethyl acetate, 20: 1 ). The product 4 was isolated as a white solid. Yield: 15.614 g (79%). 28 4 M.p.: 50 C 1H-NMR (400 MHz, CDCI3) δ [ppm]: 0.88 (t, 3JH,H = 6.7 Hz, 3 H, 19-CH3), 1 .23-1 .28 (m, 34 H, 5-CH2 to 18-CH2, 26-CH3, 28-CH3), 1 .43 (s, 9 H, 22-CH3, 23-CH3, 24-CH3), 2.26 (m, 2 H, 4-CHz), 4.23 (m, 4 H, 25-CH2, 27-CH2), 5.93 (s, 1 H, 2-NH). 13C-NMR (101 MHz, CDCI3) δ [ppm]: 14.1 (q, C-19), 14.2 (q, C-26, C-28), 22.8 (t, C-18), 23.4 (t, C-5), 28.3 (q, C-22, C-23, C-24), 29.3, 29.4, 29.5, 29.6, 29.7, 29.8 (t, C-6 to C-16), 32.0 (t, C-17), 32.6 (t, C-4), 62.3 (t, C-25, C-27), 66.6 (s, C-2), 80.1 (s, C-21 ), 153.9 (s, C-20), 168.5 (s, C-1 , C-3). Exact mass (ESI+): C28H53N06 + Na+: calcd. 522.3765, found 522.3758. |
79% | With caesium carbonate; In acetonitrile; for 5h;Reflux; | 1.4 Diethyl2-(tert-butoxycarbonyl)amido-2-hexadecylmalonate10152] Diethyl N-l3oc-2-amidomalonate 2(10.953 g, 39.79 mmol), caesiumcarbonate (16.852 g, 51.72 g, 1.3 eq.) and iodohexadecane (16.3 mE, 18.224 g, 51.72 mmol, 1.3 eq.) were suspended in acetonitrile (160 mE) and refluxed for 5 h. After cooling to r.t. the reaction mixture was adsorbed at silica gel and purified by column chromatography with silica gel (25x6 cm, cyclohexane/ethyl acetate, 20:1). The product 4 was isolated as a white solid.10153] Yield: 15.614 g (79%).2425272610154] M.p.: 500 C.10155] ‘H-NMR (400 MHz, CDC13) ö [ppm]: 0.88 (t, 3Hii=6.7 Hz, 3H, 19-CH3), 1.23-1.28 (m, 34H, 5-CH2 to18-CH2, 26-CH3, 28-CH3), 1.43 (s, 9H, 22-CH3, 23-CH3,24-CH3), 2.26 (m, 2H, 4-CH2), 4.23 (m, 4H, 25-CH2,27-CH2), 5.93 (s, 1H, 2-NH).10156] ‘3C-NMR (101 MHz, CDC13) ö [ppm]: 14.1 (q,C-19), 14.2 (q, C-26, C-28), 22.8 (t, C-18), 23.4 (t, C-5), 28.3(q, C-22, C-23, C-24), 29.3,29.4,29.5,29.6,29.7,29.8 (t, C-6to C-16), 32.0 (t, C-17), 32.6 (t, C-4), 62.3 (t, C-25, C-27),66.6 (s, C-2), 80.1 (s, C-21), 153.9 (s, C-20), 168.5 (s, C-i,C-3).10157] Exact mass (ESI): C28H53NO5+Na: calcd. 522.3765, found 522.3758. |
79% | With caesium carbonate; In acetonitrile; for 5h;Reflux; | Diethyl N-Boc-2-amidomalonate 24 (11.0g, 39.8mmol), caesium carbonate (16.9g, 51.7g, 1.3eq.) and 1-iodohexadecane (16.3mL, 18.2g, 51.7mmol, 1.3eq.) were suspended in acetonitrile (160mL) and refluxed for 5 h. After cooling to r.t. the reaction mixture was adsorbed at silica gel and purified by column chromatography (25×6cm, cyclohexane/ethyl acetate, 20:1). The product 26 was isolated as a white solid. Yield: 15.6g (79%). M.p.: 50C.1H NMR (400 MHz, CDCl3): δ 0.88 (t, 3JH,H=6.7Hz, 3H, 19-CH3), 1.23-1.28 (m, 34H, 5-CH2 to 18-CH2, 26-CH3, 28-CH3), 1.43 (s, 9H, 22-CH3, 23-CH3, 24-CH3), 2.26 (m, 2H, 4-CH2), 4.23 (m, 4H, 25-CH2, 27-CH2), 5.93 (s, 1H, 2-NH).13C NMR (101 MHz, CDCl3): δ 14.1 (q, C-19), 14.2 (q, C-26, C-28), 22.8 (t, C-18), 23.4 (t, C-5), 28.3 (q, C-22, C-23, C-24), 29.3, 29.4, 29.5, 29.6, 29.7, 29.8 (t, C-6 to C-16), 32.0 (t, C-17), 32.6 (t, C-4), 62.3 (t, C-25, C-27), 66.6 (s, C-2), 80.1 (s, C-21), 153.9 (s, C-20), 168.5 (s, C-1, C-3).Exact mass (ESI+): C28H53NO6 + Na+: calcd. 522.3765, found 522.3758. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With caesium carbonate; In acetonitrile; for 6h;Reflux; | Diethyl 2-(ie/f-butoxycarbonyl)amidomalonate 2 (1 .18 g, 3.80 mmol, purity: 89% (GC), 1 .1 eq.) obtained as in example 1.2, bromide 15 (1.1 1 g, 3.40 mmol) obtained as in example 4.2 and caesium carbonate (2.35 g, 7.20 mmol, 2.1 eq.) were suspended in acetonitrile (20 mL) and heated to reflux for 6 h. After cooling to r.t. the mixture was adsorbed on silica gel (3 g) and the product was purified by column chromatography (21 chi 3 cm, cyclohexane/ethyl acetate, 4:1 ? 100% ethyl acetate) and isolated as white solid. Yield: 577 mg (33%). 23 63 M.p. 45 C 1H-NMR (300 MHz, CDCI3) delta [ppm]: 1 .22-1 .32 (m, 30 H, 6-CH2 to 17-CH2, 21 -CH3, 23-CH3), I .43 (s, 9 H, 26-CH3, 27-CH3, 28-CH3), 1 .49-1.60 (m, 4 H, 5-CH2, 18-CH2), 1 .95 (br s, 1 H, 19-OH), 2.25 (m, 2 H, 4-CH2), 3.63 (t, 3JH,H = 6.7 Hz, 2 H, 19-CH2), 4.23 (m, 4 H, 20-CH2, 22-CH2), 5.95 (br s, 1 H, 2-NH). 13C-NMR (75 MHz, CDCI3) delta [ppm]: 14.1 (q, C-21 , C-23), 23.3 (t, C-5), 25.8 (t, C-17), 28.3 (q, C-26, C-27, C-28), 29.3, 29.5, 29.7 (t, C-6 to C-16, C-18), 32.8 (t, C-4), 62.3 (t, C-20, C-22), 63.0 (t, C-19), 66.6 (s, C-2), 80.1 (s, C-25), 153.8 (s, C-24), 168.4 (s, C-1 , C-3). Exact Mass (ESI+): C28H53N07 + H+: calcd. 516.3895, found 516.3879; C28H53N07 + Na+: calcd. 538.3714, found 538.3713. |
33% | With caesium carbonate; In acetonitrile; for 6h;Reflux; | 11.1 Diethyl 2-[(tert-butoxycarbonyl)amino] -2-(1 6-hydroxyhexadecyl)malonate10461] Diethyl 2-(tert-butoxycarbonyl)amidomalonate 2 (1.18 g, 3.80 mmol, purity: 89% (GC), 1.1 eq.) obtained as in example 1.2, bromide 15 (1.11 g, 3.40 mmol) obtained as in example 4.2 and caesium carbonate (2.35 g, 7.20 mmol, 2.1 eq.) were suspended in acetonitrile (20 mE) and heated to reflux for 6 h. After cooling to tt. the mixture was adsorbed on silica gel (3 g) and the product was purified by column chromatography (21 x3 cm, cyclohexane/ethyl acetate, 4:1 - 100% ethyl acetate) and isolated as white solid. Yield:577 mg (33%).10462] M.p. 450 C.10463] ?H-NMR (300 MHz, CDC13) oe [ppm]: 1.22-1.32(m, 30H, 6-CR2 to 17-CR2, 21-CR3, 23-CR3), 1.43 (s, 9R,26-CR3, 27-CR3, 28-CR3), 1.49-1.60 (m, 4R, 5-CR2,18-CR2), 1.95 (brs, 1R, 19-OR), 2.25 (m, 2H, 4-CR2), 3.63(t, 3JHH=6.7 Hz, 2H, 19-CR2), 4.23 (m, 4H, 20-CR2,22-CR2), 5.95 (br s, 1R, 2-NH).10464] ?3C-NMR (75 MHz, CDC13) oe [ppm]: 14.1 (q, C-2 1,C-23), 23.3 (t, C-5), 25.8 (t, C-17), 28.3 (q, C-26, C-27,C-28), 29.3, 29.5, 29.7 (t, C-6 to C-16, C-18), 32.8 (t, C-4),62.3 (t, C-20, C-22), 63.0 (t, C-19), 66.6 (s, C-2), 80.1 (s,C-25), 153.8 (s, C-24), 168.4 (s, C-i, C-3).10465] Exact Mass (ESI): C28R53NO7+R: calcd. 516.3895, found 516.3879; C28R53NO7+Na: calcd. 538.3714,found 538.3713. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h;Inert atmosphere; | 2-tert-Butoxycarbonylamino-2-(2-fluoro-5-iodo-benzyl)-malonic acid diethyl ester (G- 22)A solution of diethyl(Boc-amino)malonate (6.96 g, 25.3 mmol, either commercially available or prepared by conventional Boc-protection of diethylaminomalonate hydrochloride) in DMF (7 ml_) was added dropwise to a 0C suspension of sodium hydride (0.926 g, 23.2 mmol) in DMF (45 ml_) under N2 and then a solution of 2-bromomethyl-1 -fluoro-4-iodo-benzene G-14 (6.62 g, 21 .1 mmol) in DMF (30 ml_) was added to the suspension. The resulting solution was warmed to RT and stirred for 1 h. The reaction was quenched by the addition of water and the mixture was extracted with DCM (3x). The combined organic extracts were washed with brine, dried over Na2S04, filtered and evaporated in vacuo to give the crude product as a white solid that was used further without purification. LC-MS B: tR = 1 .05 min; [M+H]+ = 510.02. | |
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h;Inert atmosphere; | A solution of diethyl(Boc-amino)malonate (6.96 g, 25.3 mmol, either commercially available or prepared by conventional Boc-protection of diethylaminomalonate hydrochloride) in DMF (7 mL) was added dropwise to a 0 C. suspension of sodium hydride (0.926 g, 23.2 mmol) in DMF (45 mL) under N2 and then a solution of 2-bromomethyl-1-fluoro-4-iodo-benzene G-14 (6.62 g, 21.1 mmol) in DMF (30 mL) was added to the suspension. The resulting solution was warmed to RT and stirred for 1 h. The reaction was quenched by the addition of water and the mixture was extracted with DCM (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product as a white solid that was used further without purification. LC-MS B: tR=1.05 min; [M+H]+=510.02 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.5 g | With ethanol; sodium; at 85℃; for 5h; | Step 2: 5- tert-butoxycarbonyl-amino-2-mercapto-4,6-diol, Sodium ( 1.03 g) was dissolved in ethanol (60.0 ml) at room temperature, followed by adding 2-tert-butoxycarbonyl-amino diethyl malonate (5.38 g) and thiourea (1.64 g), then the mixture was heated to 85 C and refluxed for 5 hours, after the reaction was complete, the mixture was cooled to room temperature, the solid was filtered and washed with ethanol, dried under vaccum for 12 hours at 40 C to obtain red solid 5 - tert-butoxycarbonyl-amino-2 - mercapto-4, 6 - diol: 3.50 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.2% | In methanol; water; at 20℃; for 648h; | To a stirring solution of diethyl 2-{(ieri-butoxycarbonyf)amjrjo}rinal nates ( .f, 0.93 mL 3.63 mmoi) in methanol (10 mL) was added 40% meihanamine in water (Q.32 mL, 3.63 mrnol) and the reaction was stirred at room temperature for 2? days. The reaction was concentrated under reduced pressure to give an oil which was purified by flash chromatography (silica ge/ 10% MeOH/DCM) to provide compound 8.2 (592 mg, 66.2% yield). MS: rnfz calcd for C10HlsN2O5 246.12, found [M+Na]+ 260.1 |
In methanol; at 20℃; for 3h; | To a solution of diethyl 2-(tert-butoxycarbonylamino)propanedioate (50 g, 182 mmol) in methanol (1 100 ml_) was added dropwise a 9 mol/L solution of methylamine in methanol (60 ml_). Stirring at room temperature was continued for 3 hours and the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (1000 ml_) and water (1000 ml_) and the organic layer was collected. It was washed with brine (3 x 500 ml_) and dried over anhydrous Na2SC>4, filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (hexane / ethyl acetate) to provide the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of DABCO (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature. After consumption of starting material(monitored by 1H NMR) the reaction crude was diluted with 1.0 mLof CH2Cl2, 0.1 mL of TFA were added in one portion and the mixturewas stirred overnight. Then, the solution was diluted with 1.0 mLH2O and neutralized until pH7 with solid Na2CO3. The reactionmixture was extracted three times with EtOAc, the combined organiclayers were dried over anhydrous MgSO4 and the organicsolvent eliminated at reduced pressure. Finally, the crude productwas purified by flash column chromatography to afford the desireda-methylene-g-lactam in racemic form. Spectral data for racemiccompounds 6g, 6h, 6i coincided with those reported in Ref. 11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of b-ICPD (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature over 1e5 days. After consumption ofstarting material (monitored by 1H NMR) the reaction crude wasdiluted with 1.0 mL of CH2Cl2, 0.1 mL of TFA was added in oneportion and the mixture was stirred overnight. Then, the solutionwas diluted with 1.0 mL H2O and neutralized until pH7 with solidNa2CO3. The reaction mixture was extracted three times withEtOAc, the combined organic layers were dried with MgSO4 anhydand the organic solvent eliminated at reduced pressure. Finally, thecrude product was purified by flash column chromatography toafford the desired a-methylene-g-lactam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of DABCO (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature. After consumption of starting material(monitored by 1H NMR) the reaction crude was diluted with 1.0 mLof CH2Cl2, 0.1 mL of TFA were added in one portion and the mixturewas stirred overnight. Then, the solution was diluted with 1.0 mLH2O and neutralized until pH7 with solid Na2CO3. The reactionmixture was extracted three times with EtOAc, the combined organiclayers were dried over anhydrous MgSO4 and the organicsolvent eliminated at reduced pressure. Finally, the crude productwas purified by flash column chromatography to afford the desireda-methylene-g-lactam in racemic form. Spectral data for racemiccompounds 6g, 6h, 6i coincided with those reported in Ref. 11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of b-ICPD (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature over 1e5 days. After consumption ofstarting material (monitored by 1H NMR) the reaction crude wasdiluted with 1.0 mL of CH2Cl2, 0.1 mL of TFA was added in oneportion and the mixture was stirred overnight. Then, the solutionwas diluted with 1.0 mL H2O and neutralized until pH7 with solidNa2CO3. The reaction mixture was extracted three times withEtOAc, the combined organic layers were dried with MgSO4 anhydand the organic solvent eliminated at reduced pressure. Finally, thecrude product was purified by flash column chromatography toafford the desired a-methylene-g-lactam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of DABCO (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature. After consumption of starting material(monitored by 1H NMR) the reaction crude was diluted with 1.0 mLof CH2Cl2, 0.1 mL of TFA were added in one portion and the mixturewas stirred overnight. Then, the solution was diluted with 1.0 mLH2O and neutralized until pH7 with solid Na2CO3. The reactionmixture was extracted three times with EtOAc, the combined organiclayers were dried over anhydrous MgSO4 and the organicsolvent eliminated at reduced pressure. Finally, the crude productwas purified by flash column chromatography to afford the desireda-methylene-g-lactam in racemic form. Spectral data for racemiccompounds 6g, 6h, 6i coincided with those reported in Ref. 11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of b-ICPD (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature over 1e5 days. After consumption ofstarting material (monitored by 1H NMR) the reaction crude wasdiluted with 1.0 mL of CH2Cl2, 0.1 mL of TFA was added in oneportion and the mixture was stirred overnight. Then, the solutionwas diluted with 1.0 mL H2O and neutralized until pH7 with solidNa2CO3. The reaction mixture was extracted three times withEtOAc, the combined organic layers were dried with MgSO4 anhydand the organic solvent eliminated at reduced pressure. Finally, thecrude product was purified by flash column chromatography toafford the desired a-methylene-g-lactam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of DABCO (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature. After consumption of starting material(monitored by 1H NMR) the reaction crude was diluted with 1.0 mLof CH2Cl2, 0.1 mL of TFA were added in one portion and the mixturewas stirred overnight. Then, the solution was diluted with 1.0 mLH2O and neutralized until pH7 with solid Na2CO3. The reactionmixture was extracted three times with EtOAc, the combined organiclayers were dried over anhydrous MgSO4 and the organicsolvent eliminated at reduced pressure. Finally, the crude productwas purified by flash column chromatography to afford the desireda-methylene-g-lactam in racemic form. Spectral data for racemiccompounds 6g, 6h, 6i coincided with those reported in Ref. 11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of b-ICPD (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature over 1e5 days. After consumption ofstarting material (monitored by 1H NMR) the reaction crude wasdiluted with 1.0 mL of CH2Cl2, 0.1 mL of TFA was added in oneportion and the mixture was stirred overnight. Then, the solutionwas diluted with 1.0 mL H2O and neutralized until pH7 with solidNa2CO3. The reaction mixture was extracted three times withEtOAc, the combined organic layers were dried with MgSO4 anhydand the organic solvent eliminated at reduced pressure. Finally, thecrude product was purified by flash column chromatography toafford the desired a-methylene-g-lactam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of DABCO (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature. After consumption of starting material(monitored by 1H NMR) the reaction crude was diluted with 1.0 mLof CH2Cl2, 0.1 mL of TFA were added in one portion and the mixturewas stirred overnight. Then, the solution was diluted with 1.0 mLH2O and neutralized until pH7 with solid Na2CO3. The reactionmixture was extracted three times with EtOAc, the combined organiclayers were dried over anhydrous MgSO4 and the organicsolvent eliminated at reduced pressure. Finally, the crude productwas purified by flash column chromatography to afford the desireda-methylene-g-lactam in racemic form. Spectral data for racemiccompounds 6g, 6h, 6i coincided with those reported in Ref. 11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of b-ICPD (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature over 1e5 days. After consumption ofstarting material (monitored by 1H NMR) the reaction crude wasdiluted with 1.0 mL of CH2Cl2, 0.1 mL of TFA was added in oneportion and the mixture was stirred overnight. Then, the solutionwas diluted with 1.0 mL H2O and neutralized until pH7 with solidNa2CO3. The reaction mixture was extracted three times withEtOAc, the combined organic layers were dried with MgSO4 anhydand the organic solvent eliminated at reduced pressure. Finally, thecrude product was purified by flash column chromatography toafford the desired a-methylene-g-lactam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of DABCO (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature. After consumption of starting material(monitored by 1H NMR) the reaction crude was diluted with 1.0 mLof CH2Cl2, 0.1 mL of TFA were added in one portion and the mixturewas stirred overnight. Then, the solution was diluted with 1.0 mLH2O and neutralized until pH7 with solid Na2CO3. The reactionmixture was extracted three times with EtOAc, the combined organiclayers were dried over anhydrous MgSO4 and the organicsolvent eliminated at reduced pressure. Finally, the crude productwas purified by flash column chromatography to afford the desireda-methylene-g-lactam in racemic form. Spectral data for racemiccompounds 6g, 6h, 6i coincided with those reported in Ref. 11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of b-ICPD (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature over 1e5 days. After consumption ofstarting material (monitored by 1H NMR) the reaction crude wasdiluted with 1.0 mL of CH2Cl2, 0.1 mL of TFA was added in oneportion and the mixture was stirred overnight. Then, the solutionwas diluted with 1.0 mL H2O and neutralized until pH7 with solidNa2CO3. The reaction mixture was extracted three times withEtOAc, the combined organic layers were dried with MgSO4 anhydand the organic solvent eliminated at reduced pressure. Finally, thecrude product was purified by flash column chromatography toafford the desired a-methylene-g-lactam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of DABCO (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature. After consumption of starting material(monitored by 1H NMR) the reaction crude was diluted with 1.0 mLof CH2Cl2, 0.1 mL of TFA were added in one portion and the mixturewas stirred overnight. Then, the solution was diluted with 1.0 mLH2O and neutralized until pH7 with solid Na2CO3. The reactionmixture was extracted three times with EtOAc, the combined organiclayers were dried over anhydrous MgSO4 and the organicsolvent eliminated at reduced pressure. Finally, the crude productwas purified by flash column chromatography to afford the desireda-methylene-g-lactam in racemic form. Spectral data for racemiccompounds 6g, 6h, 6i coincided with those reported in Ref. 11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of b-ICPD (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature over 1e5 days. After consumption ofstarting material (monitored by 1H NMR) the reaction crude wasdiluted with 1.0 mL of CH2Cl2, 0.1 mL of TFA was added in oneportion and the mixture was stirred overnight. Then, the solutionwas diluted with 1.0 mL H2O and neutralized until pH7 with solidNa2CO3. The reaction mixture was extracted three times withEtOAc, the combined organic layers were dried with MgSO4 anhydand the organic solvent eliminated at reduced pressure. Finally, thecrude product was purified by flash column chromatography toafford the desired a-methylene-g-lactam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of DABCO (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature. After consumption of starting material(monitored by 1H NMR) the reaction crude was diluted with 1.0 mLof CH2Cl2, 0.1 mL of TFA were added in one portion and the mixturewas stirred overnight. Then, the solution was diluted with 1.0 mLH2O and neutralized until pH7 with solid Na2CO3. The reactionmixture was extracted three times with EtOAc, the combined organiclayers were dried over anhydrous MgSO4 and the organicsolvent eliminated at reduced pressure. Finally, the crude productwas purified by flash column chromatography to afford the desireda-methylene-g-lactam in racemic form. Spectral data for racemiccompounds 6g, 6h, 6i coincided with those reported in Ref. 11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In a vial equipped with a magnetic stirring bar, 0.2 mmol of thecorresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Bocaminomalonate3a (1.0 equiv) and 0.02 mmol of b-ICPD (0.2 equiv)were dissolved in 1.0 mL of toluene (C0.1 M) and the reactionwasstirred at room temperature over 1e5 days. After consumption ofstarting material (monitored by 1H NMR) the reaction crude wasdiluted with 1.0 mL of CH2Cl2, 0.1 mL of TFA was added in oneportion and the mixture was stirred overnight. Then, the solutionwas diluted with 1.0 mL H2O and neutralized until pH7 with solidNa2CO3. The reaction mixture was extracted three times withEtOAc, the combined organic layers were dried with MgSO4 anhydand the organic solvent eliminated at reduced pressure. Finally, thecrude product was purified by flash column chromatography toafford the desired a-methylene-g-lactam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 4h; | 10138] A suspension of diethyl 2-t-butyloxycarbonylami- nomalonate (5.0 g), potassium carbonate (3.0 g), and benzyl 2-bromoacetate (5.4 g) in DMF (20 mL) was stirred at 50for 4 hours. The reaction mixture was cooled, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and then purification was performed with n-hexaneethyl acetate (5:1), to obtain the title compound (6.5 g, yield: 85%) as colorless oil.10139] ‘H NMR (CDC13) ö (ppm): 7.32 (5H, m), 6.1 (1H, s), 5.11 (2H, s), 4.21 (4H, m), 3.53 (2H, s), 1.41 (9H, s), 1.22 (6H, t, J=7.i Hz)10140] MS (FAR): mlz 424 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydroxide; In 1,4-dioxane; at 5 - 20℃; for 24h; | 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 (91%).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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Metallic sodium (4.0 g, 165 mmol) was dissolved in absolute ethanol (165 mL) and diethyl tert butoxycarbonylaminomalonate (45.42 g, 165 mmol) was added to the solution. The reaction mixture was refluxed for 30 min for the complete removal of the labile hydrogen and then 5-bromo-1-pentene (25 g, 165 mmol) was added and refluxed for 6 h. The reaction mixture was cooled on an ice bath and hydrolysis was carried out by the treatment of 1 M aq NaOH (165 mL, 165 mmol). After selective hydrolysis for 4 h at 0 C, ethanol was evaporated and the unreacted 5-bromo-1-pentene was removed by extraction with diethyl ether under basic condition. Then the aqueous solution was extracted with ethyl acetate at pH 3-4, by adding solid citric acid. Finally, ethyl acetate layer was washed with brine and dried over anhydrous MgSO4. Ethyl acetate was evaporated to obtain a colorless oil of monoester monoacid (42.5 g, 82%). HPLC, retention time 7.55 min. It was then dissolved in toluene (180 mL) and refluxed for 3 h. The oily ester after evaporation of toluene is then subjected to silica gel column chromatographic purification to get Boc-dl-Ae7-OEt (14) as colorless oil (30.8 g, 84%). The resulting oily mass was suspended into a mixture of water (342 mL) and DMF (114 mL) (1:3, v/v) solvent system at 38 C using a mechanical stirrer and pH was adjusted at about 7-8 by adding 1 M aq ammonia solution. Then subtilisin Carlsberg from B. licheniformis (57 mg) was added and pH was maintained at 7-8 by continuous addition of 1 M aq ammonia solution. The reaction was completed within 4 h. Water and DMF were evaporated and Boc-d-Ae7-OEt (16) (15.6 g, 50.5%) was extracted with diethyl ether under basic condition. Then the aqueous solution was extracted with ethyl acetate as described above to get Boc-l-Ae7-OH (8) as colorless oil (13.6 g, 49%). HPLC, retention time 7.05 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.2 g | 2) Synthesis of t-butyl {5-[2-(7-bromo-9H-xanthen-2-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}carbamate (Reference Example compound 21) [0289] (t-butyloxycarbonyl)aminodiethyl malonate (10.0 g) in tetrahydrofuran (50 ml) was added t-butylsodium (3.8 g) in portions, and the mixture was stirred at the same temperature for 30 min. To this reaction mixture was added a solution of Reference Example compound 21-1 (10 g) in tetrahydrofuran (50 ml), and the mixture was heated under reflux for 1 hr. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give [2-(7-bromo-9H-xanthen-2-yl)ethyl][(t-butyloxycarbonyl)amino]diethyl malonate (15.2 g) as an oil. The obtained [2-(7-bromo-9H-xanthen-2-yl)ethyl][(t-butyloxycarbonyl)amino]diethyl malonate (5.45 g) was dissolved in a mixed solution of ethanol (80 ml), tetrahydrofuran (30 ml) and water (30 ml), calcium chloride (2.2 g) was added at room temperature, and the mixture was stirred for 20 min. To this solution was added sodium borohydride (1.5 g) in portions, and the mixture was stirred for 24 hr. 1M Hydrochloric acid was added to the reaction mixture, and the reaction solvent was evaporated under reduced pressure. The reaction mixture was added to 1M hydrochloric acid, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate and collected by filtration to give t-butyl [3-(7-bromo-9H-xanthen-2-yl)-1,1-bis(hydroxymethyl)propyl}carbamate (1.5 g) as a white powder. A solution of the obtained t-butyl [3-(7-bromo-9H-xanthen-2-yl)-1,1-bis(hydroxymethyl)propyl}carbamate (580 mg), acetonedimethylacetal (0.45 ml) and a catalytic amount of p-toluenesulfonic acid in acetone (20 ml) was stirred for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give Reference Example compound 21 (620 mg) as a white powder. 1H-NMR(DMSO-d6)δ(ppm):1.32(3H,s), 1.33(3H,s), 1.41(9H,s), 1.90-1.98(2H,m), 2.39-2.47(2H,m), 3.64-3.71(2H,m), 3.82-3.92(2H,m), 4.02(2H,s), 6.62(1H,brs),6.95-7.06(4H,m), 7.35-7.40(1H,m), 7.47(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A round-bottomed flask was charged with diethyl 2-((tert-butoxycarbonyl)amino)malonate (0.90 mmol) and TFA (10% in CH2C12, 10 mL) at 21 C, and stirred at the same temperature for 2 h. The solution was concentrated under reduced pressure, then charged with DMF (4 mL), 1- (4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylcarbamoyl)-4H-l,2,4-triazol-4-yl)benzyl) piperidine-4-carboxylic acid (0.75 mmol), HATU (1.13 mmol), and diisopropyl amine (2.25 mmol) at 21 C. The solution was stirred for 2 h, then concentrated under reduced pressure. The resulting crude oil was subjected to silica gel chromatography purification (CH2Cl2/MeOH) to afford the desired product diethyl 2- (l-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylcarbamoyl)-4H-l,2,4-triazol-4-yl)benz yl)piperidine-4-carboxamido)malonate as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With caesium carbonate; In acetonitrile; for 5h;Reflux; Inert atmosphere; | Analogously to a known protocol,27 diethyl 2-[(tert-butoxycarbonyl)amino]malonate (1 g, 3.6 mmol, 1.0 eq), 9-bromononan-1-ol (5) (0.89 g, 4.0 mmol, 1.1 eq) and dry caesium carbonate (2.46 g, 7.56 mmol, 2.1 eq.) were suspended in acetonitrile (30 mL) and refluxed for 5 h. After completion of the reaction the mixture was absorbed on silica gel and purified by column chromatography (17 cm 3 cm, cyclohexane/ethyl acetate, 15:1) to give a colourless liquid. Yield: 0.91 g (60%). 1H NMR (400 MHz, CDCl3): δ = 1.14 (m, 2H, 5-CH2), 1.21 - 1.37 (m, 14H, 20-CH3, 21-CH3, 3-CH2, 4-CH2, 6-CH2, 7-CH2), 1.43 (s, 9H, 13-CH3, 14-CH3, 15-CH3), 1.53 (m, 4H, 2-CH2, 8-CH2), 2.25 (t, 3JHH = 8.7, 2H, 1-CH2), 3.64 (t, 3JHH = 6.6 Hz, 2H, 9-CH2), 4.22 (m, 4H, 18-CH2, 19-CH2), 5.93 (s, 1H, NH) ppm. 13C NMR (101 MHz, CDCl3): δ = 14.0 (C-20, C-21), 23.2 (C-3), 25.7 (C-7), 28.2 (C-13, C-14, C-15), 29.1 (C-2, C-4), 29.33 (C-5), 29.36 (C-6), 32.4 (C-1), 32.7 (C-8), 62.2 (C-18, C-19), 63.03 (C-9), 66.5 (C-10), 80.0 (C-12), 153.83 (C-11), 168.42 (C-16, C-17) ppm. HRMS (ESI+): m/z C21H39NO7 + Na+: calcd. 440.2624, found 440.2619. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | To a solution of diethyl 2-[(tert-butoxycarbonyl)amino]malonate (5.22 g, 18.99 mmol, 1 eq) in DMF (80 mL) was added sodium hydride (60% in oil, 0.911 g, 22.79 mmol, 1.2 eq) portionwise.Then, 3,4-dimethoxybenzyl chloride (5.30 g, 28.40 mmol, 1.5 eq) was added dropwise and the solution was stirred for 24 h at room temperature. Water (200 mL) was added and the mixture was extracted with diethyl ether (3*50 mL). The combined organic layers were dried over MgSO4 and the volatiles were removed under reduced pressure. The purification of the crude product by flash chromatography on silica gel with cyclohexane/ethyl acetate (9/1) afforded the diester as pale yellow oil in 84 % yield (6.77 g). 1H NMR (400 MHz, CDCl3) delta 1.25 (t, 3JHH= 7.1 Hz, 6H, H2?), 1.44 (s, 9H, H14), 3.52 (s, 2H, H4), 3.80 (s, 3H, H15), 3.81 (s, 3H, H16), 4.14-4.32 (m, 4H, H1?), 5.73 (br s, 1H, H11), 6.55 (s, 1H, H6), 6.56 (d, 3JHH= 7.9 Hz, 1H, H10), 6.73 (d, 3JHH = 7.9 Hz, 1H, H9). 13C NMR (100 MHz, CDCl3) delta 14.0 (C2?), 28.3 (C14), 37.9 (C4), 55.7 (C15+C16), 62.4 (C1?), 67.2 (C2), 80.1 (C13), 110.9 (C9), 113.4 (C6), 121.9 (C10), 127.7 (C5), 148.1 (C8), 148.5 (C7), 158.8 (C12), 167.6 (C1+C3). HRMS (ESI) calculated for C21H31NO8 [M+Na]+ 448.1947; found 448.1927. IR (cm-1) nu 3436, 2981, 1732, 1712, 1252, 1158. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | To a solution of diethyl N-Boc-aminomalonate (1.5 g, 5.45 mmol, 1 eq) in freshly distilled DMF (20 mL) was added sodium hydride (60% in oil, 0.261 g, 1.2 eq) portionwise. Then, <strong>[15017-52-4]4-fluoro-3-nitrobenzyl bromide</strong> (1.53 g, 1.2 eq) was added and the solution stirred at room temperature during one day. The reaction mixture was hydrolysed with 70 mL of water and extracted with 3*50 mL of CH2Cl2. The combined organic layers were dried over MgSO4 and the solvent removed under vacuum. Crude product was purified by flash chromatography on silica gel with petroleum ether/ethyl acetate (9/1) to afford the diester as yellow oil in 59 % yield (1.38 g). 1H NMR (300 MHz, CDCl3) delta 1.30 (t, 3JHH= 7.5 Hz, 6H, H2?), 1.48 (s, 9H, H14), 3.68 (s, 2H, H4), 4.17-4.37 (m, 4H, H1?), 5.76 (br s, 1H, H11), 7.20 (dd, 3JHF= 10.4 Hz, 3JHH = 8.6 Hz, 1H, H9), 7.30-7.35 (m, 1H, H6), 7.77 (dd, 3JHH =7.3, 4JHF = 2.2 Hz, 1H, H10). 13C NMR (75.5 MHz, CDCl3) delta 14.0 (C2?), 28.1 (C14), 37.2 (C4), 62.9 (C1?), 66.8 (C2), 80.8 (C13), 118.2 (d, 2JCF = 21.4 Hz, C9), 127.3 (C6), 132.6 (C5), 136.8 (d, 3JCF = 7.7 Hz, C10), 137.1 (d, 2JCF = 9.2 Hz, C7), 154.0 (C12), 154.8 (d, 1CF = 264,1 Hz, C8), 167.1 (C1+C3). 19F NMR (CDCl3) delta -119.91. HRMS (ESI) calculated for C19H25N2O8FNa [M+Na+] 451.1493; found 451.1502. IR (cm-1) nu 3436, 2981, 1730, 1713, 1538, 1157. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | To a solution of diethyl N-Boc-aminomalonate (1.38 g, 5.02 mmol, 1.2 eq) in freshly distilled DMF (20 mL) was added sodium hydride (60% in oil, 0.200 g, 1.2 eq) portionwise. Then, the coumarine chloromethyl coumpound (1 g, 4.18 mmol, 1 eq) was added and the solution was stirred at room temperature for one day. The reaction mixture was hydrolyzed with 70 mL of water and extracted with 3*50 mL of CH2Cl2. The combined organic layers were dried over MgSO4 and the volatiles removed under vacuum. The crude product was purified by flash chromatography on silica gel with petroleum ether/ ethyl acetate (9/1) to afford the diester as a white solid in 56 % yield (1.00 g). Mp 117 C. 1H NMR (300 MHz, CDCl3) δ 1.29 (t, 3JHH = 6.0 Hz, 6H, H2’), 1.48 (s, 9H, H17), 3.70 (s, 2H, H4), 4.20-4.34 (m, 4H, H1’), 5.76 (br s, 1H, H14), 6.39 (d, 3JHH = 9.0 Hz, 1H, H9), 6.97 (d, 3JHH = 7.8 Hz, 1H, H13), 7.02 (s, 1H, H6), 7.38 (d, 3JHH = 7.8 Hz, 1H, H12), 7.67 (d, 3JHH = 9.0 Hz, 1H, H10).13C NMR (75.5 MHz, CDCl3) δ 14.0 (C2’), 28.2 (C17), 38.3 (C4), 62.8 (C1’), 66.9 (C2), 80.6 (C16), 116.3 (C9), 117.7 (C6), 118.1 (C11), 126.3 (C13), 127.5 (C12), 140.3 (C5), 143.1 (C10), 153.8 (C7), 153.9 (C8), 160.7 (C1+C3), 167.3 (C15). HRMS (ESI) calculated for C22H27NO8Na [M+Na+] 456.1634; found 456.1635. IR (cm-1) ν 3436, 2977, 1712, 1620, 1159. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; | diethyl 2-((tert-butoxycarbonyl)amino)malonate(25.7 g) Dimethylformamide (250 mL) After the addition of 122 g of cesium carbonate, Iodomethane(23.2 mL) was added dropwise under a water bath . After the dropwise addition, the mixture was stirred at room temperature. Reaction solution added in water, additive gum / AcOEt = 4 / l solution (700 mL) After the progression, Saturated water and saturated water. In the organic layer, added anhydrous sulfuric acid and activated carbon (2 g) Progressive Celite. Acquired concentrated filtrate under reduced pressure 2-((tert-butoxycarbonyl)(methyl)amino)-2-methylmalonicacid diethylester (25.0 g, pale yellow oil, 88%). |
88% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 120h; | (1) Diethyl-2-((t-butoxycarbonyl)amino)malonate (25 · 7 g) in DMF (250 mL) after addition of 122 g of cesium carbonate, methyl iodide (23.2 mL) was added dropwise under a water bath. After completion of the dropwise addition, the reaction system was sealed and stirred at room temperature for 5 days. Water was added to the reaction solution, After extraction with n-hexane / ethyl acetate = 4/1 solution (700 mL), the organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine. Anhydrous magnesium sulfate and activated carbon (2 g) were added to the organic layer, stirred for 1 hour, and filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure, diethyl-2-((t-butoxycarbonyl)(methyl)amino)-2-methylmalonate was obtained (25.0 g, pale yellow oil, 88%). MS (ESI / APCI dual): m / z = 326 (M + Na) +. 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.27 (6H, t, J=7.0 Hz), 1.38 - 1.47 (9H, m), 1.68 (3H, s), 2.87 (3H, s) 4.22 (4H, q, J=7.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper diacetate; In acetonitrile; at 80℃;Inert atmosphere; | In order to indole, tert-butoxy carbonyl amino-malonic acid diethyl ester as raw material, in accordance with the indole: tert-butoxycarbonyl amino-malonic acid diethyl ester: acetic acid copper mole ratio is 1: 1.25: 2.5, solvent b nitrile amount used is 3 ml, in N2Under the protective conditions heating to 80 C, TLC detection reaction, the raw material after the reaction is complete, through the column chromatography to obtain pure product 3aa. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.4 g | With sodium ethanolate; In ethanol; at 20℃; for 1h; | To a solution of l-(2-bromo-4-chloro-5-(3- methoxypropoxy)phenyl)prop-2-en-l-one (3.8 g, 11.39 mmol) in ethanol (10 ml) was added diethyl 2-((tert-butoxycarbonyl)amino)malonate (2.9 ml, 11.39 mmol) followed by sodium ethoxide (0.08 g, 1.14 mmol). After stirring at room temperature for 1 hour, the mixture was concentrated, diluted with ethyl acetate (50 ml) and washed with water. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. Product was purified by silica chromatography using ethyl acetate in hexanes (5.4g). XH NMR (400 MHz, Chloroform-d) δ 7.55 (s, 1H), 6.94 (s, 1H), 5.92 (s, 1H), 4.35 - 4.16 (m, 4H), 4.12 (t, J = 6.1 Hz, 2H), 3.57 (t, J = 6.1 Hz, 2H), 3.35 (s, 3H), 3.04 - 2.82 (m, 2H), 2.76 - 2.65 (m, 2H), 2.08 (p, J = 6.1 Hz, 2H), 1.42 (s, 9H), 1.26 (t, J = 7.1 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | Compound 2 (518g, 1.88mol) was dissolved in 3.5L DMF necked flask fitted with a solvent, was added cesium carbonate (797.4g, 2.45mol), was added compound 3 (364.7g, 1.98mol), N2 protected, stirred at room temperature overnight.TLC showed disappearance of compound 2.The reaction solution was slowly added to 4L of ice water, extracted with ethyl acetate, the combined organic phases, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 711g of compound 4 as a yellow oil (yield: 100 %), the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | Compound 2 (578 g, 2.10 mol) was dissolved in a three-necked flask containing 3.8 L of DMF solvent, cesium carbonate (889 g, 2.73 mol) was added, and compound 3 (565 g, 2.21 mol) was added, and the mixture was stirred under N2 overnight. TLC shows compound 2disappear. The reaction mixture was slowly added to 4.3 L of ice water, and the mixture was extracted with ethyl acetate.Filtration and concentration gave 936 g of compound 4 as a yellow oil (yield: 99%). No need to further purification directly used in next step of reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | Compound 2 (518 g, 1.88 mol) was dissolved in a three-necked flask containing 3.5 L of DMF solvent, cesium carbonate (797.4 g, 2.45 mol) was added, and compound 3 (344.1 g, 1.98 mol) was added, and the mixture was stirred under N2 and stirred at room temperature. overnight. TLC showed the disappearance of compound 2. The reaction mixture was slowly added to 4 L of ice water, and then extracted with ethyl acetate.Concentrated to give 692g of yellow oily compound 4(Yield: 100%), No need to further purification directly used in next step of reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With caesium carbonate; In acetonitrile; at 20℃; for 25h; | A solution of bromide12 (231 mg, 1 mmol),diethyl (Boc-amino)malonate (275 mg,1.1 mmol) and Cs2CO3(325 mg, 1.1 mmol) in acetonitrile (4.5 mL) was stirred for25 h at room temperature. The reaction was then diluted in30 mL of ethyl acetate and extracted with water and brine.The organic phase was dried with anhydrous Na2SO4 andconcentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel, using ethylacetate/hexane (4:1) as the eluent, affording a white solid(326.2 mg, 0.77 mmol, 77% yield). mp 69.7-72.5 C;1H NMR (500 MHz, CDCl3) delta 1.29 (t, 6H, J 7.1 Hz,CO2CH2CH3), 1.47 (s, 9H, t-Bu), 3.55 (s, 2H, Ar-CH2C),3.74 (s, 6H, Ar-OCH3), 4.17-4.26 (m, 2H, CO2CH2CH3),4.27-4.36 (m, 2H, CO2CH2CH3), 5.79 (s, 1H, N-H), 6.20 (d,2H, J 2.0 Hz, Ar-H), 6.34 (t, 1H, J 2.2 Hz, Ar-H); 13C NMR(126 MHz, CDCl3) delta 14.0 (2C), 28.2 (3C), 38.5, 55.1 (2C),62.5 (2C), 67.1, 80.1, 99.1, 108.1 (2C), 137.4, 153.8, 160.5(2C), 167.6 (2C); LRMS (ESI) m/z 426.2 [M + H]+. |
Tags: 102831-44-7 synthesis path| 102831-44-7 SDS| 102831-44-7 COA| 102831-44-7 purity| 102831-44-7 application| 102831-44-7 NMR| 102831-44-7 COA| 102831-44-7 structure
[ 1146954-88-2 ]
(R)-Ethyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate
Similarity: 0.98
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