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[ CAS No. 102831-44-7 ] {[proInfo.proName]}

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Chemical Structure| 102831-44-7
Chemical Structure| 102831-44-7
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Product Details of [ 102831-44-7 ]

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 :

Calculated chemistry of [ 102831-44-7 ]      Expand+

Physicochemical Properties

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 ?2

Pharmacokinetics

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

Lipophilicity

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

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

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

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.8

Safety of [ 102831-44-7 ]

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:

Application In Synthesis of [ 102831-44-7 ]

* 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.

  • Downstream synthetic route of [ 102831-44-7 ]

[ 102831-44-7 ] Synthesis Path-Downstream   1~12

  • 1
  • [ 6829-40-9 ]
  • [ 24424-99-5 ]
  • [ 102831-44-7 ]
YieldReaction ConditionsOperation 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.

  • 2
  • [ 24424-99-5 ]
  • [ 13433-00-6 ]
  • [ 102831-44-7 ]
YieldReaction ConditionsOperation 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.

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  • 3
  • [ 102831-44-7 ]
  • 2-[(tert-butoxy)carbonyl]amino}-3-ethoxy-3-oxopropanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
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): δ 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): δ 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): δ (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.

  • 4
  • [ 102831-44-7 ]
  • [ 106-95-6 ]
  • [ 135722-55-3 ]
YieldReaction ConditionsOperation in experiment
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]+.
  • 6
  • [ 37746-78-4 ]
  • [ 102831-44-7 ]
  • [ 192636-66-1 ]
  • 7
  • [ 102831-44-7 ]
  • Carbonic acid 2-ethoxy-allyl ester ethyl ester [ No CAS ]
  • [ 185383-06-6 ]
  • 8
  • [ 102831-44-7 ]
  • [ 105-36-2 ]
  • [ 192636-68-3 ]
YieldReaction ConditionsOperation 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) ? (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)
  • 9
  • [ 102831-44-7 ]
  • [ 1129-28-8 ]
  • [ 192636-77-4 ]
  • 10
  • [ 102831-44-7 ]
  • sodium; <i>tert</i>-butoxycarbonylamino-ethoxycarbonyl-acetate [ No CAS ]
  • 11
  • [ 100-39-0 ]
  • [ 102831-44-7 ]
  • [ 518314-53-9 ]
YieldReaction ConditionsOperation in experiment
88% Examples for the synthesis of compounds according to the invention according to process FDiethyl-2-(tert-butoxycarbonylamino)malonate is commercionally availible or may be synthesized by conventional boc-protection of diethylaminomalonate hydrochloride.1. Diethyl 2-benzyl-2-(tert-butoxycarbonylamino)malonateoHN4.3 g (190 mmol) of sodium are dissolved in 600 ml of dry ethanol and slowly treated with a solution of 47 g (170 mmol) of diethyl-2-(tert-butoxycarbonylamino)malonate in 200 ml ethanol. After stirring for 30 min 29.2 g (170 mmol) of benzylbromide are added dropwise at room temperature. The reaction mixture is refluxed for 12 h followed by addition of aeq. HC1 (pH 6-7), evaporation of the solvent and subsequent extraction with dichloromethane / water. The combined organic layers are dried over MgSO4 and the solvent is evaporated to yield the pure product in 88% yield (55 g).1H-NMR{400 MHz, DMSO-d6}: 1.18 (t, 3JHH= 7 Hz, 6H, CH3); 1.42 (s, 9H, CH3); 3.44 (s, 2H, CH2); 4.18 (m, 4H, CH2); 6.2 (b, 1H, NH); 7.01 (b, 2H, Ph-H); 7.26 (b, 3H, Ph-H).LC: 87% purity, MS: 266 (M-boc)
80% With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 5h;Cooling with ice; Ice bath,A mixture of diethyl 2-Boc-aminomalonic acid (27.5 g, 0 mol)DMF (200 ml) was added to a three-necked flask,And then sodium hydride (4.8 g, 0.12 mol) was added in portions with stirring,The mixture was then raised to room temperature,Bromobenzyl (19 g, 0.1 lmol) was added,The reaction solution was stirred at room temperature for 5 hours,TLC was added to the reaction. After completion of the reaction, saturated aqueous sodium bicarbonate solution (100 ml) was added and extracted with diethyl ether (150 ml x 2). The organic phases were combined, dried over anhydrous magnesium sulfate,Concentrated target production2- (N- (tert-butoxycarbonyl) amino) -2-benzylmalonic acid diethyl ester29.5 g (yield 80%).
68% To a solution of diethyl 2-[(tert-butoxycarbonyl)amino]malonate (1.0 g, 3.63 mmol, 1 eq) in DMF (50 mL) was added sodium hydride (60% in oil, 0.113 g, 8.61 mmol, 1.3 eq) portionwise. Then, benzyl bromide (0.932 g, 9.94 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 colorless oil in 68 % yield (662 mg). 1H NMR (400 MHz, CDCl3) δ 1.28 (t, 3JHH= 7.1 Hz, 6H, H2’), 1.48 (s, 9H, H14), 3.62 (s, 2H, H4), 4.17-4.35 (m, 4H, H1’), 5.74 (br s, 1H, H11), 7.04-7.06 (m, 2H, H6+H10), 7.21-7.30 (m, 3H, H7+H8+H9). 13C NMR (100 MHz, CDCl3) δ 14.0 (C2’), 28.2 (C14), 38.3 (C4), 62.5 (C1’), 67.1 (C2), 80.17 (C13), 127.1 (C8), 128.2 (C7+C9), 130.0 (C6+C10), 135.3 (C5), 153.8 (C12), 167.6 (C1+C3). HRMS (ESI) calculated for C19H28NO6 MH+ 366.1917; found 366.1916. IR (cm-1) ν 3434, 1740, 1714, 1484, 1158, 700.
With sodium ethanolate; In ethanol; for 6h; EXAMPLE 7 (Si^-Benzyl-S -(3 ,4-dihydroisoquinolin-2( 1 H)-yl-carbonyl)-3 - [( 1 R)- 1 -phenylethyl]imidazolidine- 2,4-dione (Compound 23) Step A: Diethylbenzyl[(tert -butoxycarbonyDaminolpropanedioate To diethyl[(tert-butoxycarbonyl)amino]propanedioate (5.56 mL, 21.79 mmol) in ethanol (30ml) was added sodium ethoxide (9.76 ml, 26.2 mmol) followed by benzyl bromide (2.59 mL, 21.79 mmol). The mixture was stirred for 6 h, and the solvent was removed in vacuo. Saturated aqueous sodium hydrogen carbonate (50 mL) was added and the mixture was extracted with ethyl acacate (3 x 50 mL). The combined organic fractions were washed with saturated aqueous brine (1 x 50 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo to afford the title compound as a colorless amorphous solid. LC/MS 366.1 (M+l).
With sodium ethanolate; In ethanol; for 6h; To diethyl[(/ert-butoxycarbonyl)amino]propanedioate (5.56 mL, 21.79 mmol) in ethanol (30ml) was added sodium ethoxide (9.76 ml, 26.2 mmol) followed by benzyl bromide (2.59 mL, 21.79 mmol). The mixture was stirred for 6 h, and the solvent was removed in vacuo. Saturated aqueous sodium hydrogen carbonate (50 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed with saturated aqueous brine (1 x 50 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo to afford the title compound as a colorless amorphous solid. LC/MS 366.1 (M+l).
With sodium ethanolate; In ethanol; for 6h;Inert atmosphere; To diethyl[(tert-butoxycarbonyl)amino]propanedioate (5.56 mL, 21.79 mmol) in ethanol (30ml) was added sodium ethoxide (9.76 ml, 26.2 mmol) followed by benzyl bromide (2.59 mL, 21.79 mmol). The mixture was stirred for 6 h, and the solvent was removed in vacuo. Saturated aqueous sodium hydrogen carbonate (50 mL) was added and the mixture was extracted with ethyl acacate (3 x 50 mL). The combined organic fractions were washed with saturated aqueous brine (1 x 50 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo to afford the title compound as a colorless amorphous solid. LC/MS 366.1 (M+l).

  • 12
  • [ 102831-44-7 ]
  • [ 49617-83-6 ]
  • [ 856222-40-7 ]
YieldReaction ConditionsOperation in experiment
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 3-iodobenzyl bromide 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): δ=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).
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