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CAS No. : | 13865-19-5 | MDL No. : | MFCD00082185 |
Formula : | C5H8O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DLZVZNAPRCRXEG-UHFFFAOYSA-N |
M.W : | 116.12 | Pubchem ID : | 83779 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.6 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 27.63 |
TPSA : | 43.37 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) : | -7.38 cm/s |
Log Po/w (iLOGP) : | 1.25 |
Log Po/w (XLOGP3) : | -0.52 |
Log Po/w (WLOGP) : | 0.14 |
Log Po/w (MLOGP) : | -0.09 |
Log Po/w (SILICOS-IT) : | 0.49 |
Consensus Log Po/w : | 0.25 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.03 |
Solubility : | 125.0 mg/ml ; 1.08 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 0.08 |
Solubility : | 139.0 mg/ml ; 1.2 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.66 |
Solubility : | 25.4 mg/ml ; 0.219 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.17 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P210-P264-P280-P302+P352-P305+P351+P338-P332+P313-P337+P313-P370+P378-P403+P235-P501 | UN#: | N/A |
Hazard Statements: | H227-H315-H319 | 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 |
---|---|---|
76% | With 2,6-dimethylpyridine; hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; at 20℃; under 1200.12 Torr; for 7h; | 2,6-Lutidine (158 g, 1.48 mol) and 10% palladium on carbon (15 g) were added to a solution of methyl 4-CHLORO-4-OXOBUTANOATE (220 g, 1.46 mol) in tetrahydrofuran (3600 ml). The mixture was stirred under a hydrogen atmosphere at 1.6 bar for 7 hours at ambient temperature. The reaction mixture was filtered through glass fibre paper washing with diethyl ether. The filtrate was concentrated under reduced pressure and the residue purified by vacuum distillation (72 C, 13MMHG) to yield methyl 4-OXOBUTANOATE (130.8 g, 76 % yield) as an oil: 1H-NMR (DMSO D6) : 9.60 (s, 1H), 3.60 (s, 3H), 2.70 (t, 2H), 2.50 (t, 2H) |
55% | With 2,6-dimethylpyridine; palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; under 2068.65 Torr; for 6h; | A 500-mL Parr bottle was charged with methyl 4-chloro-4-oxobutyrate (20.0 g, 133 mmol), 2,6-lutidine (15.6 mL, 134 mmol) and 10% palladium on carbon (1.4 g) in tetrahydrofuran (250 mL). This mixture was vigorously shaken under H2 (40 psi) for 6h. The mixture was then filtered through celite and the filtrate concentrated under reduced pressure. The residue was distilled under vacuum (130 C/10 mm) to afford the title compound (8.52 g, 55%) as a colorless oil. MW = 116.12. ]H NMR (CDC13, 300 MHz) delta 9.82 (s, 1H), 3.70 (s, 3H), 2.81 (t, / = 6.6 Hz, 2H), 2.64 (t, / = 6.3 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With bromine; In 1,4-dioxane; diethyl ether; at 20℃; for 4h; | Bromine (180 g, 1.12 mol) was added, over 3 hours, to a solution of methyl 4- oxobutanoate (123.6 g, 1.07 mol) in diethyl ether (1000 ml) and 1,4-dioxane (9.10 ml) and the reaction mixture stirred for one hour at ambient temperature. The reaction mixture was poured into dichloromethane (1000 ml) and calcium carbonate (250g, 2.50 mol) and sodium hydrogen carbonate (80 g, 0.95 mol) were added before the mixture was stirred for 21 hours at ambient temperature. The inorganic solids were removed by suction filtration and the filtrate was concentrated under reduced pressure to yield methyl 3-bromo-4-oxobutanoate (208 g, quantitative yield) as a brown oil: 'H-NMR (DMSO D6) : 9. 55 (s, 1H), 4.45 (t, 1H), 3.70 (s, 3H), 3.22 (M, 1H), 2.95 (M, 1H) |
100% | A 500-mL round bottom flask was charged with <strong>[13865-19-5]methyl 4-oxobutanoate</strong> (8.52 g, 73.3 mmol), dioxane (0.7 mL) in diethyl ether (70 mL). Bromine (3.94 mL, 77.0 mmol) was added at room temperature over 1.5 h. After this time, the mixture was diluted with dichloromethane (250 mL) and solid sodium bicarbonate (13.6 g, 161 mmol) was added. After stirring for 2h the mixture was filtered and the filtrate concentrated under reduced pressure to afford the title compound (15.3 g, 100%) as a colorless oil. MW = 195.01. ]H NMR (CDCI3, 300 MHz) delta 9.54 (s, 1H), 4.68 (dd, J = 6.9, 6.6 Hz, 1H), 3.74 (s, 3H), 3.25 (dd, 7 = 17.4, 7.2 Hz, 1H), 2.94 (dd, / = 17.1, 6.6 Hz, 1H). | |
100% | With bromine; In dichloromethane; at 0 - 20℃; | Bromine (10.2 mL, 199 mmol, 1 equiv) was added dropwise to a solution of (2) (23.1 g, 199 mmol, 1 equiv.) in dichloro-methane (1 L) at 0 C. The rate of addition was adjusted to maintain the temperature below 5 C. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure to give (3) (40 g, quantitative yield, 95% purity) as a light brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With water; for 2h;Reflux; | A solution of (1) (49 g, 300 mmol) in water (150 mL) was refluxed for two hours. The reaction was cooled to room temperature and diluted with dichloromethane (300 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (3*300 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give (2) (24.2 g, 50% yield) as a colorless oil. |
4.00 g (99%) | With hydrogenchloride; | (a) 4-Oxo-butyric acid methyl ester. A solution of 4,4-dimethoxy-butyric acid methyl ester (5.00 g, 30.8 mmol), ether (25.0 mL) and 1.2 N HCl (12.0 mL) was stirred at room temperature for 1 h. The reaction was diluted with water (50 mL), extracted with dichloromethane (3*60 mL), dried over Na2SO4 and the solvent was removed by rotary evaporation to give 4.00 g (99%) of the title compound as an oil that was carried forward to the next reaction. |
With water; trifluoroacetic acid; In dichloromethane; at 20℃; for 16h; | Trifluoroacetic acid (6.0 ml_, 81 mmol) was added slowly drop-wise to a stirred solution of methyl 4,4-dimethoxybutyrate (5.0 g, 31 mmol) in dichloromethane (125 ml_) and water (13 ml_). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was then washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-oxo-butyhc acid methyl ester (3.03 g, 85%) as a light yellow oil. The crude product was used in subsequent reactions without further purification. 1H NMR (300 MHz, CDCI3) delta 9.81 (s, 1 H), 3.69 (s, 3 H), 2.80 (t, 2 H, J = 6.64 Hz), 2.63 (t, 2 H, J = 6.64 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With ozone; 4-methylmorpholine N-oxide; In dichloromethane; at 0℃; for 0.833333h; | A modified procedure of Dussault was used (Schwartz, C. et al., Org. Lett. 8, 3199-3201 (2006)). A stirred solution of methyl pent-4-enoate SI-1 (1.00 g, 8.76 mmol) and N-methylmorpholine-A/-oxide (NMO) (3.08 g, 26.3 mmol) in CH2CI2 (50 ml) was cooled to 0 C. A stream of ozone was passed through the reaction mixture for 50 min. The reaction mixture was washed successively with 1 M HCl (30 ml), water (30 ml), saturated Na2CO3 solution (30 ml), and brine (30 ml) before being dried (MgSO4), filtered, and concentrated to give the aldehyde 16 (854 mg, 83%) as a clear, colourless oil. The H and 13C spectra matched data reported by Ley (Sedelmeier, J. etal., Org. Lett. 12, 3618-3621 (2010)) and IR data was consistent with that reported by both Miller (Lotz, B. T. et al., J. Org. Chem. 58, 618-625 (1993)) and Gannett (Gannett, P. M. et al., J. Org. Chem. 53, 1064-1071 (1988)). Rf = 0.29 (heptane/EtOAc, 1:1) vmax (film)/cm 1 2956, 2845, 2735, 1732 (br.), 1438, 1367, 1205, 1172 *H NMR (400 MHz; CDCl3) deltaEta = 2.61 (2 H, t, J = 6.6 Hz, CH2), 2.79 (2 H, t, J = 6.6 Hz, CH2), 3.67 (3 H, s, CH3), 9.79 (1 H, t, J = 0.6 Hz, CH) 13C NMR (100 MHz; CDCl3) 5C = 26.2 (CH2), 38.4 (CH2), 51.8 (CH3), 172.6 (C=0), 199.9 (C=0) |
83% | With ozone; 4-methylmorpholine N-oxide; In dichloromethane; at 0℃; for 0.833333h; | 8A(b) Methyl 4-oxobutanoate, 16 A modified procedure of Dussault was used (Schwartz, C. et al., Org. Lett. 8, 3199-3201 (2006)). A stirred solution of methyl pent-4-enoate SI-1 (1.00 g, 8.76 mmol) and N-methylmorpholine-N-oxide (NMO) (3.08 g, 26.3 mmol) in CH2Cl2 (50 ml) was cooled to 0 C. A stream of ozone was passed through the reaction mixture for 50 min. The reaction mixture was washed successively with 1 M HCl (30 ml), water (30 ml), saturated Na2CO3 solution (30 ml), and brine (30 ml) before being dried (MgSO4), filtered, and concentrated to give the aldehyde 16 (854 mg, 83%) as a clear, colourless oil. The 1H and 13C spectra matched data reported by Ley (Sedelmeier, J. et al., Org. Lett. 12, 3618-3621 (2010)) and IR data was consistent with that reported by both Miller (Lotz, B. T. et al., J. Org. Chem. 58, 618-625 (1993)) and Gannett (Gannett, P. M. et al., J. Org. Chem. 53, 1064-1071 (1988)). Rf=0.29 (heptane/EtOAc, 1:1) numax (film)/cm-1 2956, 2845, 2735, 1732 (br.), 1438, 1367, 1205, 1172 1H NMR (400 MHz; CDCl3) deltaH=2.61 (2H, t, J=6.6 Hz, CH2), 2.79 (2H, t, J=6.6 Hz, CH2), 3.67 (3H, s, CH3), 9.79 (1H, t, J=0.6 Hz, CH) 13C NMR (100 MHz; CDCl3) deltaC=26.2 (CH2), 38.4 (CH2), 51.8 (CH3), 172.6 (C=O), 199.9 (C=O) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Example 65; Methyl 4-oxobutanoate 32 (Scheme 9)To a stirred solution of DMSO (2.9 mL., 4.4 eq) in 10 mL of DCM anhydrous at -75 C. was added drop by drop a solution of oxalyl chloride (1.7 mL, 2.2 eq). After 1 hour of reaction, methyl 4-hydroxybutanoate (1.1 g, 0.0093 mol.) in 10 mL of DCM was added. After the addition was completed, the reaction mixture was stirred for 1 hour, warm-up to -45 C. and then triethylamine (7.7 mL, 6 eq)) was added. The reaction mixture was stirred for 18 hours. The progress of the reaction was monitored by thin layer chromatography (TLC). After the reaction was complete, saturated sodium bicarbonate was added and extracted with DCM. The Organic layer was dried over Na2SO4 and concentrated on rotavap to give methyl 4-oxobutanoate which was purified by silica gel chromatography using gradient of hexane and ethyl acetate.Colorless oil (0.57 g, 53% yield). 1HNMR (400 MHz, CDCl3): delta 2.60 (t, J=6.8 Hz, 2H); 2.77 (t, J=6.8 Hz, 2H); 3.66 (s, 3H); 9.78 (s, 1H). | |
50% | With pyridinium chlorochromate; In dichloromethane; at 20℃; for 12h; | [0082] Methyl 4-hydroxybutyrate (120 g, 1.02 mol) was added to a dichloromethane solution (1.2 L), then pyridiniumchlorochromate (330 g, 1.53 mol) was added to the above reaction solution, and the reaction was carried out at roomtemperature for 12 hours. Thin layer chromatography (petroleum ether:ethyl acetate = 3:1) was used to detect that thereaction was completed. The reaction solution was filtered through celite and rotary dried to give methyl 4-oxobutyrate(60 g, 50%, as a yellow liquid), which was used directly in the next step. |
With pyridinium chlorochromate; In dichloromethane; | EXAMPLE 136 Methyl-4-oxobutanoate STR133 To 10.3 g (86 mmol) methyl 4-hydroxybutanoate in 100 ml dry dichloromethane was added 20 g (93 mmol) pyridinium chlorochromate. After 4 hours this was filtered through a pad of florisil and concentrated in vacuo. Kugelrohr distillation gave 3.95 g colourless liquid. Boiling point: 50 C. 0.5 mbar. Yield: 39% of theory. NMR (CDCl3, 60 MHz): 2.4[2] m, 2.6[2] m, 3.65[3] s, 9.72[1] s. |
3.4 g | With pyridinium chlorochromate; In dichloromethane; at 20℃; for 1.5h; | To asolution of gamma-butyrolactone (5.00 g, 58.67 mmol) in MeOH (30 mL) was addedtriethylamine (29.7 g, 293.37 mmol) and stirred at room temperature forovernight. Then the reaction mixture was concentrated under vacuum to affordalcohol 2. The resulting crudemethyl gamma-hydroxyester 2 was taken upin CH2Cl2 (80 mL) and PCC (18.9 g, 87.68 mmol) was added.After being stirred at room temperature for 1.5 h, Et2O (200 mL) wasadded, the reaction mixture was filtered through Celite, washed with Et2Oand the filtrate was concentrated in vacuo. The residue was purified bysilica gel (n-hexane : Et2O: EtOAc = 2:0.5:1) to afford 3.40 g (29.27 mmol, 50%) of the title compound 3 as a colorless oil: Rf= 0.47 (n-hexane : Et2O :EtOAc = 2:1:1); 1H NMR (400 MHz, CDCl3) delta 9.82 (1H, s), 3.70 (3H, s),2.82 (2H, t, J = 6.8 Hz), 2.64 (2H, t, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3)delta 199.8, 172.3, 51.3, 38.0, 25.8; IR (neat, cm-1) 2956, 1737,1439, 1210, 1164. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Concentrated H2SO4 (0.5 mL) was added to a solution of gamma-butyrolactone (10 g, 0.117 mol) in MeOH (40 mL). The mixture was refluxed for 12 h, and then cooled to room temperature. The solvent was evaporated, and the residue was dissolved in dry CH2Cl2 (200 mL). PCC (30.0 g, 0.136 mol) was added and stirring was continued for 5 h. The mixture was diluted with ether and filtered through celite. Evaporation of the solvent and flash chromatography of the residue over silica gel, using 2:1 PE-ether, gave 4-oxobutanoic acid methyl ester as colorless oil (9.9 g, yield 73 %). 1H NMR (400 MHz, CDCl3) delta 9.82 (s, 1H), 3.69 (s, 3H), 2.80 (t, J = 6.8 Hz, 2H), 2.63 (t, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) delta 200.0, 172.8, 51.9, 38.6, 26.2. | |
50% | In a nitrogen-substituted round flask, & lt; RTI ID = 0.0 & gt; y-butyrolactone(? -butyrolactone, 5.00 g, 58.67 mmol) was dissolved in 30 mL of methanol, Triethylamine (29.7 g, 293.37 mmol) was added dropwise at room temperature.The reaction solution was stirred at room temperature for 12 hours and then concentrated under reduced pressure to give crude (crude, crude compound)To the 80 mL of dichloromethane distilled from the methyl [gamma] -hydroxy ester, PCC (18.9 g, 87.68 mmol) was added dropwise.The reaction solution was stirred at room temperature for 1.5 hours,200 mL of ethyl ether was added. The reaction solution was filtered through a pad of celite and washed with ethyl ether.This residue was concentrated under reduced pressure to give 4-oxobutylic acid methyl ester (3.40 g, 29.27 mmol, 50%) as a clear liquid by performing column chromatography (eluent: n-hexane / ethyl acetate = 2: 1 v / ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | A solution of 16.32 g (52.5 mmol) of (S)-2-(tert-butyldiphenylsilyloxy)-1-(methyl)ethylamine (part A), 6.70 g (57.8 mmol) of methyl 3-formylpropionate and 11.0 mL of TEA in 100 mL of MeOH was stirred at ambient temperature for 2 h, concentrated in vacuo, reconstituted in 100 mL of MeOH, and treated with 3.05 g (78.8 mmol) of NaBH4 in portions. The reaction mixture was heated to 50 C. overnight, diluted with 300 mL of H2O, and extracted with EtOAc (3×300 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 21.6 g of an oil. Purification by flash chromatography (SiO2; 5% MeOH in CH2Cl2) afforded 11.6 g (30.2 mmol; 57%)of the title ether as an oil. FDMS 382 (M+1); Anal. calcd for C23H31NO2Si: C, 72.40; H, 8.19; N, 3.67. Found: C, 72.28; H, 8.12; N, 3.78. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With hydrogenchloride; water; sodium cyanoborohydride; In N,N-dimethyl-formamide; at 20℃; for 18h; | Example 14. Synthesis of N, N-Di- (methyl-4-butanoate) -AmB (15):; To a solution of methyl-4-oxobutanoate (520 mg, 4.50 mmol) and AmB (1) (820 mg, 0.890 mmol) in DMF (5.00 mL) was added NaBH3CN (280 mg, 4.50 mmol) followed by a drop of cone. HCl. After 18 h at room temperature, Amberlite IRA-743 (800 mg) was added and the mixture was stirred for an hour. After filtration, the solution was concentrated down and added dropwise to diethyl ether (250 mL) . The yellow precipitate was filtered and purified by flash chromatography (40-8-1 CHCl3-MeOH-H2O) providing the desired compound 15 as a yellow solid (450 mg, 45%). Rf 0.30 (40-8- 1 CHCl3-MeOH-H2O), 1H NMR (500 MHz, DMSO-de) delta 6.46-6.06 (m, 13H), 5.95 (dd, J = 15, 9 Hz, IH), 5.82 (s, IH), 5.45 (dd, J = 15, 10 Hz, IH), 5.32 (s, IH), 5.21-5.19 (m, IH), 4.80-4.74 (m, 2H), 4.62 (s, IH), 4.43-4.36 (m, IH), 4.32 (s, IH), 4.25-4.17 (m, 2H), 4.06-3.96 (m, 2H), 3.75 (s, IH), 3.58 (s, 6H), 3.55-3.35 (m, OH), 3.11-3.08 (m, IH), 2.78-2.72 (m, IH), 2.64-2.59 (m, IH), 2.31 (t, J = I Hz, 4H), 2.17 (d, J = 6 Hz, IH), 1.98-1.23 (m, 21H), 1.18 (d, J = beta Hz, 3H), 1.11 (d, J = 6 Hz, 3H), 1.04 (d, J = 6 Hz, 3H), 0.92 (d, J = I Hz, 3H), 13C NMR (125 MHz, <n="73"/>DMSO-d6) delta 173.6, 173.2, 170.5, 136.9, 136.7, 133.8, 133.6, 133.5, 133.1, 132.4, 132.3, 132.1, 132.0, 131.8, 131.6, 131.1, 128.7, 97.4, 97.1, 80.3, 77.1, 76.3, 75.7, 74.4, 73.8, 73.7, 73.5, 69.4, 69.2, 68.9, 67.9, 67.6, 66.2, 65.4, 63.9, 56.9, 51.0, 50.2, 46.2, 44.6, 44.2, 42.3, 42.0, 35.0, 31.0, 29.0, 24.0, 18.4, 18.2, 16.9, 12.0; MALDI-TOF calcd for C55H85NO2I [M+H+]+: 1124.6005. Found: 1124.5600. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.21 g (>100%) | With sodium tris(acetoxy)borohydride; sodium hydrogencarbonate; In acetic acid; | (b) 4-(2-Chloro-5-cyano-phenylamino)-butyric acid methyl ester. To a stirring solution of <strong>[53312-79-1]3-amino-4-chloro-benzonitrile</strong> (1.19 g, 7.83 mmol), glacial acetic acid (1.8 mL, 31 mmol), 4-oxo-butyric acid methyl ester (4.00 g, 31 mmol) and dichloroethane (150 mL) was added sodium triacetoxyborohydride (6.74 g, 31.8 mmol) and the reaction mixture was stirred at room temperature for 15 h. The solvent was removed by rotary evaporation and the residue was diluted with EtOAc (100 mL) and water (50 mL). Saturated NaHCO3 was added until the aqueous layer was neutralized and then the organic layer was collected, dried over Na2SO4, and the solvent was removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel, elution with EtOAc:hexanes, 1:3.5), to give 2.21 g (>100%) of the title compound as a mixture. 1H NMR (CDCl3): 7.32 (d, 1H, J=8.0 Hz), 6.90 (dd, 1H, J=8.0 and 1.9 Hz), 4.64 (br s, 1H), 3.71 (s, 3H), 3.25 (q, 2H, J=7.0 Hz), 2.47 (t, 2H, J=7.0 Hz), 2.04 (q, 2H, J=7.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | zirconium(IV) chloride; In PEG-400; at 50℃; for 44.0h; | A mixture of <strong>[117719-17-2]5-bromo-3-morpholin-4-yl-pyrazin-2-ylamine</strong> (0.3 g, 1 eq), methyl 4- oxobutanoate (182 mu, 1.5 eq), 1 , 1 ,3,3-tetramethylbutyl isocyanide (305 mu, 1 .5 eq) and ZrCL, (54 mg, 0.2 eq) in PEG-400 (3 mL) was heated at 50 C under open air for 20 h and 24 h more. On cooling, H20 (60 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The organics were dried, filtered and evaporated and the residue was purified by automated chromatography (Biotage, eluent: 20% to 40% EtOAc in Cyclohexane) to give the expected product 1-14 (155 mg, 26% yield) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | To a solution of 3-[(R)-2-amino-2-(2-hydroxy-phenyl)-ethyl]-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione (15-1) (67 mg, 0.100 mmol) in 1,2-dicholoroethane (2 mL) were 4-oxo-butyric acid methyl ester (17 mg, 0.150 mmol) and sodium triacetoxyborohydride (42 mg, 0.200 mmol) in the order, followed by stirring at room temperature for 1.5 hrs. The solution was neutralized with an aqueous saturated sodium bicarbonate solution to separate an organic layer. After concentration of the organic layer, the residue was purified using silica gel chromatography(eluent: dichloromethane/methanol, 30/1)and dried in a vacuum to afford 40 mg of the compound as a colorless oil (yield 53%). 1H NMR (300MHz, CDCl3) delta 1.79 (2H, m), 2.20-2.33 (4H, m), 2.32 (3H, s), 2.48 (2H, m), 2.60 (2H, t), 2.80 (2H, m), 3.58 (2H, m), 3.61 (2H, s), 3.63 (3H, s), 4.06-4.15 (2H, m), 4.42 (1H, dd), 5.42 (2H, dd), 6.30 (1H, d), 6.72-6.78 (3H, m), 7.06-7.15 (2H, m), 7.26 (1H, m), 7.41 (1H, m), 7.55 (1H, d) | |
53% | With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 1.5h; | Step A. 4-[(R)-2-{3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-5-[4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-3,6-dihydro-2H-pyrimidin-1-yl}-1-(2-hydroxy-phenyl)-ethylamino]-butyric acid methyl ester To a solution of 3-[(R)-2-amino-2-(2-hydroxy-phenyl)-ethyl]-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione (15-1) (67 mg, 0.100 mmol) in 1,2-dicholoroethane (2 mL) were 4-oxo-butyric acid methyl ester (17 mg, 0.150 mmol) and sodium triacetoxyborohydride (42 mg, 0.200 mmol) in the order, followed by stirring at room temperature for 1.5 hrs. The solution was neutralized with an aqueous saturated sodium bicarbonate solution to separate an organic layer. After concentration of the organic layer, the residue was purified using silica gel chromatography(eluent: dichloromethane/methanol, 30/1) and dried in a vacuum to afford 40 mg of the compound as a colorless oil (yield 53%). 1H NMR (300 MHz, CDCl3) delta 1.79 (2H, m), 2.20-2.33 (4H, m), 2.32 (3H, s), 2.48 (2H, m), 2.60 (2H, t), 2.80 (2H, m), 3.58 (2H, m), 3.61 (2H, s), 3.63 (3H, s), 4.06-4.15 (2H, m), 4.42 (1H, dd), 5.42 (2H, dd), 6.30 (1H, d), 6.72-6.78 (3H, m), 7.06-7.15 (2H, m), 7.26 (1H, m), 7.41 (1H, m), 7.55 (1H, d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Example 66; General Procedure for Compounds 13 (Scheme 9)Methyl 4-((1-(1-(4-ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)butanoate 13a (Scheme 9)A solution of 1-(1-(4-ethoxyphenyl))cyclobutyl)-3-methylbutan-1-anamine (0.619 g, 0.0023 mol) and <strong>[13865-19-5]methyl 4-oxobutanoate</strong> (0.25 g, 0.0021 mol) in methanol anhydrous (10 mL) was stirred for 15 hour at reflux. The reaction mixture was cooled down to 0 C., And then NaBH4 (0.4 g, 5 eq) was added. The reaction mixture was stirred from 0 C. to room temperature for 4 hours. The progress of the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the reaction mixture was concentrated under reduce pressure. The residue was taken with Ethyl acetate and then washed with NaHCO3 solution. dried over Na2SO4 and evaporated under reduced pressure to give methyl 4-((1-(1-(4-ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)butanoate which was purified by silica gel column chromatography using gradient of hexane and ethyl acetate, isolated as a (0.55 g, 73% yield).1HNMR (400 MHz, CDCl3): delta 0.59-0.66 (m, 1H); 0.80 (d, J=6.8 Hz, 3H); 0.85 (d, J=6.8 Hz, 3H); 1.02-1.08 (m, 1H); 1.39 (t, J=6.8 Hz, 3H); 1.59-1.63 (m, 1H); 1.67-1.76 (m, 3H); 1.79-1.85 (m, 1H); 2.10-2.14 (m, 1H); 2.24-2.34 (m, 3H); 2.36-2.40 (m, 2H); 2.66 (dd, J=2.8 Hz; 10 Hz, 1H); 2.74 (t, J=6.8 Hz, 2H); 3.65 (s, 3H); 4.01 (q, J=7.2 Hz, 2H); 6.82 (d, J=8.8 Hz, 2H); 7.12 (d, J=8.8 Hz, 2H). MS (ESI): m/z=362.3 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃;Inert atmosphere; | Example 112, step b: methyl 4-(benzyl(1-ethoxy-1-oxopropan-2-yl)amino)butanoate To a solution of the product of Example 112, step a (794 mg, 3.8 mmol) in DCE (10 mL) was added methyl-4-oxobutanoate (0.891 mL, 7.7 mmol) followed by Na(OAc)3BH (1.6 g, 7.7 mmol). The mixture was stirred at room temperature overnight and then quenched by the addition of saturated aqueous NaHCO3 solution. The layers were separated and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 column eluting with EtOAc/Hex afforded the desired compound as a colorless liquid (1.11 g, 95%). MS (ESI) mass calcd. C17H25NO4, 307.2. m/z found 308.2 [M+H]+. 1H NMR (500 MHz, CDCl3) delta 7.35-7.20 (m, 5H), 4.22-4.12 (m, 2H), 3.86-3.80 (m, 1H), 3.67-3.60 (m, 4H), 3.52-3.45 (m, 1H), 2.69-2.56 (m, 2H), 2.41-2.26 (m, 2H), 1.80-1.71 (m, 2H), 1.33-1.24 (m, 6H). |
84.29% | With sodium tris(acetoxy)borohydride; triethylamine; In 1,2-dichloro-ethane; at 20℃;Inert atmosphere; | Methyl 4-[benzyl(1-ethoxy-1-oxopropan-2-yl)amino]butanoate To a stirred solution of ethyl 2-(benzylamino)propanoate (8 g, 38.596 mmol, 1 equiv.) and <strong>[13865-19-5]methyl 4-oxobutanoate</strong> (4.48 g, 38.596 mmol, 1.00 equiv.) in DCE (120 mL, 1515.779 mmol, 39.27 equiv.) was added TEA (3.91 g, 38.596 mmol, 1 equiv.) and NaBH(OAc)3 (16.36 g, 77.193 mmol, 2 equiv.) in portions at room temperature under nitrogen atmosphere. The mixture was stirred at rt overnight. Desired product could be detected by LCMS. The resulting mixture was extracted with DCM (2*150 mL). The combined organic layers were washed with brine (1*90 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 4-[benzyl(1-ethoxy-1-oxopropan-2-yl)amino]butanoate (10 g, 84.29%) as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With titanium tetrachloride; In tetrahydrofuran; dichloromethane; at 20℃; for 20h; | Example 12d (443 mg, 0.100 mmol) and me 4-oxobutanoate (33.1 mg, 0.300 mmol) were comb ined in f l rtiL). To this suspensionwas added 1M titaniumilV) chloride in d i Ho lo m_ thane (0.200 mL, 0.200 mmol). The reaction mixture was stirred at amb ent temperature for 20 hours, and partitioned with ethyl acetate and water. The oigarric layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, filtered, and concentrated . The residue was purified by flash chromatography (silica gel, 2-4% methanol in dkhlo-Omethane) to afford the title compound (38 mg, 70%). 1 H HM (300 MHz, DMS Q-dt) delta 11 91 (d, 3= 2.14 Hz. 1 H) 7.S3 (d, J= 1.S3 Hz, 1 H) 7.69 (s, 1 H) 724 (dd, /=824, 1.S3 Hz, 1 H) 7.04 - 7.13 (m, 2 H) 6 SI - 7.02 (m, 3 H) 5.03 (t, HZ, 1 H) 4.3S - 4.63 (m, 2 H) 3.64 (s. 3 H) 3.53 (s, 3 H) 2.93 (s, 3 H) 235 - 2.46 (m, 2 H) 1.82 - 2.03 Cm, 1 H) 1.34 - 1 .61 (m, 1 Eta). MuXi (EpsilonXiIota+) mfe 542 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With copper(I) bromide; In toluene; at 25℃; for 24h; | To a stirred suspension of chiral piperazine 1 or 2 (0.210 g,1 mmol), CuBr (0.014 g, 0.1 mmol), and 1-alkyne 3 (1.1 mmol) in toluene (3 mL), freshly distilled aldehyde 4 (1 mmol) was addedat 25 C. The contents were stirred at 25 C for 24 h. Toluene was then removed after which water (5 mL) and DCM (15 mL) were added. The DCM layer was washed with saturated NaCl solution, dried (Na2SO4), and concentrated. The residue was purified by column chromatography using hexane and ethyl acetate (9:1) as eluent to isolate the propargyl amines 6. 4.1.22 4-(4,5,9,9-Tetramethyl-octahydro-5,8-methano-quinazolin-1-yl)-tetradec-5-ynoic acid methyl ester 6ng Brown liquid; Rf = 0.6 (silica gel, hexane/EtOAc 90:10); yield: 0.412 g, 93%, [alpha]D25 = -45.5(c 0.62, CHCl3); IR(neat) 2947, 2931, 2854, 1655, 1473, 1391, 1358, 1249, 1090, 1002, 936, 843, 772 cm-1; 1H NMR (400 MHz, CDCl3, delta ppm) 3.64 (s, 3H), 3.59-3.57 (t, J = 8.0 Hz, 1H), 2.83-2.80 (m, 2H), 2.74-2.71 (m, 1H), 2.58-2.54 (m, 1H), 2.41-2.38 (t, J = 12.0 Hz, 2H), 2.26 (s, 3H), 1.86-1.81 (q, J = 20.0 Hz, 6H), 1.67-1.59 (m, 2H), 1.48-1.38 (m, 5H), 1.27 (s, 9H), 1.22 (s, 3H), 0.97 (s, 3H), 0.88-0.85 (t, J = 20.0 Hz, 4H), 0.75 (s, 3H); 13C NMR (100 MHz, CDCl3, delta ppm) 174.0, 84.8, 78.1, 64.7, 54.4, 52.9, 51.4, 50.0, 48.3, 47.8, 47.0, 41.7, 37.1, 31.8, 30.7, 29.3, 29.0, 28.7, 25.9, 22.6, 22.0, 20.7, 18.5, 14.4, 14.1; HRMS (ESI): m/z calcd for C28H48N2O2: 444.3716, [M+H+]; found: 445.3785. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | A solution of S2 (12.0 g, 84.3 mmol) in the 5:1 mixture of CH2Cl2 and MeOH (total 120 mL) was stirred under O3 bubbling for 30 minutes at -78 C. Then the reaction mixture was bubbled with argon gas to purge off unreacted O3, and triphenyl phosphine (26.5 g, 101 mmol) was added at -78 C. The resulting mixture was stirred at room temperature for 3 hours. Then the reaction mixture was concentrated by distillation. The resulting residue was purified by distillation (75 C, 15 mmHg) to afford 51 (8.46 g, 86%) as a colorless oil. | |
86% | A solution of 11 (12.0 g, 84.3 mmol) in a 5:1 mixture of CH2Cl2 and MeOH (total 120 mL) was stirred under O3 bubbling for 30 min at -78 C. The reaction mixture was then bubbled with argon gas to purge the unreacted O3, and triphenylphosphine (26.5 g, 101 mmol) was added at -78 C. The resulting mixture was stirred at r.t. for 3 h, then concentrated by distillation. The resulting residue was purified by distillation (75 C, 15 mmHg) to afford 8 (8.46 g, 86%) as a colorless oil. IR (film): 2957, 1717, 1738 cm-1. 1H NMR (500 MHz, CDCl3): delta = 9.81 (s, 1 H), 3.69 (s, 3 H), 2.81 (t, J =6.9 Hz, 2 H), 2.63 (t, J = 6.9 Hz, 2H). 13C NMR (125 MHz, CDCl3): delta = 199.9, 172.7, 51.9, 38.5, 26.3. HRMS (ESI): m/z [M+Na]+ calcd for C5H8O3Na: 139.0371; found: 139.0365. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 0.5h;Inert atmosphere; | To a solution of (R)- 1 -(2-fluorophenyl)ethanamine(278 mg, 2.0 mmol, Kingston) in DCM (3.0 mE) was addedmethyl 4-oxobutanoate (232 mg, 2.0 mmol, Aldrich). Thereaction mixture was stirred at room temperature for 30 mm, and Na(OAc)3BH (636 mg, 3.00 mmol) and i-PrOH (2.0 mE) were then added. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with MeOH (2.0 mE) and sat. aq. K2HPO4 (2.0 mE) and then diluted with DCM (50 mE). The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative HPEC to provide the desired product (239 mg, 50%) as a white solid. ?H NMR (CDC13) oe 7.37 (td, J=7.5, 1.8 Hz, 1H), 7.21-7.14 (m, 1H), 7.12-7.07 (m, 1H), 6.98 (ddd, J=10.6, 8.1, 1.1 Hz, 1H), 4.09 (q, J=6.6 Hz, 1H),3.62 (s, 3H), 2.58-2.50 (m, 1H), 2.48-2.40 (m, 1H), 2.33 (td, J=7.4, 3.3 Hz, 2H), 1.81-1.73 (m, 2H), 1.35 (d, J=6.6 Hz, 3H); MS(ESI) m/z 240.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium tris(acetoxy)borohydride; In ethyl acetate; at 20℃; | Sodium triacetoxyborohydride (313 mg, 1.48 mmol) was added to a solution of (R)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (96 mg, 0.25 mmol) and <strong>[13865-19-5]methyl 4-oxobutanoate</strong> (0.077 mL, 0.74 mmol) in ethyl acetate (4 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0?75% ethyl acetate/hexane) to give the title compound (93 mg, 0.189 mmol, 77%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With boron trifluoride diethyl etherate; In chloroform; at -78℃; for 0.5h;Inert atmosphere; | Aldehyde 13 (4.6 mmol) and borom trifluoride etherate(0.51 ml, 4.1 mmol) were added successively to the solution of12 in chloroform obtained above. The reaction mixture was stirredat 78 C, under an argon atmosphere for 30 min, neutralized witha saturated solution of sodium bicarbonate and extracted withdichloromethane. The organic layer was washed with water anddried with sodium sulphate. Evaporation of the solvent followedby flash chromatography (ethyl acetate-hexane 5:95) gave steroid14 as a mixture of epimers (7:3) at C-22 (620 mg, 61%). From theflash chromatografhy an analitical sample of the major epimerwas obtained and characterized: [a]D20 = +26,5 (c = 0,7, methanol);IR (KBr) tmax: 3466, 2935, 2859, 1731, 1704, 1645, 1381, 1256 cm1; 1H NMR (500.13 MHz): 5.31 (1H, bs, H-6), 4.05 (1H, m,H-22), 3.68 (3H, s, 25-COOCH3), 3.48 (1H, m, H-3), 2.57 (1H, dd,J = 17.7 and 2.8 Hz, H-21a), 2.52 (1H, t, J = 8.3 Hz, H-17), 2.51 (1H,m, H-21b), 2.50 (2H, m, H-24), 2.27 (1H, m, H-4b), 2.18 (2H, m,H-4a and H-16a), 2.04 (1H, m, H-12b), 2.00 (1H, m, H-7b), 1.81(1H, m, H-1b), 1.77 (2H, m, H-23), 1.74 (1H, m, H-2a), 1.70 (1H,m, H-15a), 1.66 (1H, m, H-16b), 1.62 (1H, m, H-11a), 1.57 (1H,m, H-7a), 1.54 (1H, m, H-2b), 1.48 (1H, m, H-8), 1.46 (1H, m, H-11b), 1.42 (1H, m, H-12a), 1.25 (1H, m, H-15b), 1.15 (1H, m, H-14), 1.06 (1H, m, H-1a), 1.00 (3H, s H-19), 0.97 (1H, m, H-9), 0.89(9H, s, 3-(CH3)3Si), 0.63 (3H, s, H-18), 0.06 (6H, s, 3-(CH3)2Si); 13CNMR (125.77 MHz): 212.6 (C-20), 174.1 (C-25), 141.5 (C-5), 120.7(C-6), 72.5 (C-3), 66.7 (C-22), 63.4 (C-17), 57.0 (C-14), 51.6(COOCH3), 50.7 (C-21), 50.0 (C-9), 44.5 (C-13), 42.7 (C-4), 38.8(C-12), 37.3 (C-1), 36.6 (C-10), 32.0 (C-2), 31.83 (C-7), 31.75 (C-8), 31.2 (C-23), 30.1 (C-24), 25.9 ((CH3)3CSi), 24.5 (C-15), 22.6 (C-16), 21.0 (C-11), 19.4 (C-19), 18.2 (C-Si), 13.2 (C-18), -4.6 (CH3CSi);HR MS-ESI: calculated for C32H55O5Si 547.38133, found 547.38192 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | The triethyl 2-fluoro-2-phosphonoacetate 2 (58g, 0.24 mmol) and 0.8 ml of anhydrous tetrahydrofuran were added to a separate constant pressure dropping funnel. In a Low temperature thermometer and nitrogen filled three-way 2-liter three-necked flask, cooled to minus 78 degrees Celsius, then n-butyllithium (101 mL, 0.25 mmol) was added dropwise from the constant pressure dropping funnel to a three-necked flask. After completion of the dropwise addition, keep the reaction at minus 78 degrees Celsius for 1 hour. 3-methoxycarbonyl propionaldehyde 8 (27.8 g, 0.24 mmol) was dissolved in 100 ml of anhydrous tetrahydrofuran and then dropped into the reaction flask at minus 78 C. After completion of the dropwise addition, keep the reaction at minus 78 degrees Celsius for 2 hours. The reaction was quenched with 500 ml of saturated aqueous ammonium chloride and extracted twice with 500 ml of ethyl acetate and combine the organic phases. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was separated by column chromatography to give 35 g of (E) - 1- ethyl -6- methyl -3-fluoro-hex-2-ene diester 9, yield 71%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With (S)-2-(diphenyl((triethylsilyl)oxy)methyl)pyrrolidine; benzoic acid; In toluene; at 25℃; for 24h; | Take a clean 10mL small test tube,The diaryl proline siloxane catalyst (vii) (0.0294 g, 0.08 mmol) was added,Cocatalyst benzoic acid (0.0098 g, 0.08 mmol)(E) -alpha, beta-unsaturated o-trifluoroacetylamino nitroolefin (0.104 g, 0.4 mmol)Solvent Toluene (2.0 mL),Add a small magnet,A solution of methyl 3-aldehyde propionate (0.139 g,1.2 mmol),25 reaction 24h,Using ethyl acetate: petroleum ether = 1: 4 mixed solvent as eluent;200-300 column column chromatography silica gel as filler,Column chromatography The purified product was dissolved in CH2Cl2 (5 mL) in a 10 mL flask,PCC (0.431 g, 2 mmol) was combined with anhydrous sodium acetate (0.164 g, 2 mmol)The reaction was carried out at 35 C for 24 hours,Washed with distilled water (10 mL)Ethyl acetate (3 x 10 mL)Organic phase decompression,Using ethyl acetate: petroleum ether = 1: 3 mixed solvent as eluent; 200-300 mesh column chromatography silica gel as filler,The resulting product was purified by column chromatography (0.0756 g,Yield 68%dr value> 99: 1,Ee value> 99%), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With ammonium chloride; In ethanol; at 60℃; for 3.0h;Inert atmosphere; | General procedure: To a solution of 2-aminothiophen carboxyamide (1.37 mmol, 250 mg) and aldehyde (1.4 equiv., 219 mg) in EtOH (4.5 mL) was added ammonium chloride (1.2 equiv., 88 mg) in portions at 60 C under N2 and the solution was kept at 60 C for 3 h. The reaction was monitored with TLC (DCM/(DCM/CH3OH 10%) 1:1). The mixture was concentrated under vacuum and the residue was suspended in H2O and sonicated for 3 min. The solid material was filtered off and washed with H2O. The crude solid was dried under high vacuum, dissolved in DMSO and purified by HPLC (A: 0.75% HCOOH in H2O, B: 0.75% HCOOH in CH3CN, 10?60% B over 25 min afforded diastereomeric mixture. Another run with 10?50% B over 35 min afforded pure diastereoisomer, while the other diasteroisomer was not isolated pure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With sulfuric acid; In water; at 20℃; for 0.0833333h;Green chemistry; | General procedure: To the stirred mixture of the appropriate indole (3.1-6.7 mmol) and the appropriate aldehyde (1.5-3.3 mmol, 0.5 equiv.) dissolved in water (5 mL) concentrated sulfuric acid (1 equiv.) was added. The progress of the reaction was monitored immediately after the addition of H2SO4 by TLC using ethyl acetate: petroleum ether (20:80). After completion of the reaction as indicated by TLC, the aqueous mixture was dissolved in ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The resulting crude product was purified by recrystallization with an appropriate solvent system or by washing it with nonpolar solvents. Few compounds were purified by silica gel column chromatography using non-chlorinated solvent systems such as ethyl acetate: petroleum ether (b.p.42?62 °C) mixtures (10:90 to 20:80) as eluent to afford the pure diindolylmethane derivatives. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30%; 70% | With acetic acid; In dichloromethane; at 0 - 20℃; for 10h;Inert atmosphere; Molecular sieve; | General procedure: Compounds 35 and 37 were prepared from 33 and 36, respectively, following the previously reported procedures.26,27 The Nb-alkylated D-tryptophan derivative 33 (1.5 g, 3.51 mmol) was dissolved in dry CH2Cl2 (50 mL) in a 100-mL round bottom flask equipped with a magnetic stirrer bar. To this solution, the aldehyde41 34 (612 mg, 5.27 mmol) and AcOH (633 mg, 603 muL, 10.55 mmol), as well as 4 A MS (0.7 g) were added at 0 C. The solution, which resulted, was stirred at rt for 10 h (TLC monitoring for the consumption of 33 and appearance of a non-polar spot by UV and CAN stain). The mixture was diluted with CH2Cl2 (50 mL) and water (50 mL) and brought to pH 8-9 with cold 1M aq NaOH. The organic layer was separated and washed with water (2 × 50 mL) and brine (3 × 100 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to give 35 as a light yellow colored oil. The residue [LRMS (M + H)+ = 525, Rf = 0.3 (silica gel, 20% EtOAc/hexanes + NH4OH)] was purified by column chromatography (silica gel, 10-20% EtOAc/hexanes) to furnish the pure cis-diester 35 (1.52 g, 83%) as a colorless oil as the sole product. By following the same procedure performed at rt, 3626,27 (2.0 g, 4.69 mmol) gave cis-diesters 37 (1.72 g, 70%) [LRMS (M + H)+ = 525; Rf = 0.6 (silica gel, 30% EtOAc/hexanes)] accompanied by the trans-diester (0.73 g, 30%) [Rf = 0.7 ( silica gel, 30% EtOAc/hexanes)], which resulted in a quantitative overall isolated yield. Both 35 and 37 were used for the next transformation without further characterization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.8% | With sodium tris(acetoxy)borohydride; acetic acid; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 12h; | To a solution of methyl 4-[2-{4-.[[24[3-{(2,2dimethyipiperazin.- I yi)methyljbenzoyljamino]-4, 5,6, 7tetrahydrobenzothiophene-3 .carbonyl 1aminoi-2,6difluoro--phenyl1ethy1ibenzoate dihydrochioiide (148.4 ing, 01688 rnrnol), DIPEA (60 iL, 034 mmoi) and 4 oxobutanoic acid methyl ester (40 mg, 0.34 mmoi) in 4 mnL of DCM is added AcOH (0.01 mL), followed by sodium triacetoxyborohydride (0.073 g, 0.34 mmol). The resulting reaction mixture is allowed to stir at RT for 12 hr. The reaction mixture is diluted with amixture of 5% aqueous Na}1C03 (75 mE) and [)CM (25 mE), The layers are separated, and the aqueous layer is washed with additional DCM (2 x 25 mL). The organic extracts are combined, washed with saturated aqueous NaC1 (25 mE), dried over hydrous Na2O., filtered, and concentrated under reduced pressure. The resulting residue is purified by chromnatography over silica, using a gradient of 35-40% of a mixture of 9:1 EtOF1IDCM inhexane, to afford the desired product as a light yellow solid (132.1 mg, 91.8% yield) after solvent evaporation. ?HNMR (400.1 MHz, DMSO-d6) 6 1.09 (s, 611), 1.70-1.58 (m, 2H), 1.87-1.70 (m, 4H), 220-209 (in, 21:4), 2.36-2.27 (m, 4H), 2.63-2.54 (rn, 21:1), 2.75-2.64 (in, 4H), 2.92 (s, 4H), 3.30-3.28 (in, 2H), 3.65-3.53 (m, 5H), 3,84 (s, 3H), 732 (d, J= 8.3 Hz, 2H), 7.58-7.37 (m, 4H), 7.72-7.69 (m, IH), 7.91-7.83 (m, 3H), 9.99 (s, 1H), 11.45 (s, 1H).IL-ES/MS (m/z) 801 [M+i j, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With acetic acid; In dichloromethane; at 0 - 20℃; for 10h;Inert atmosphere; Molecular sieve; | Compounds 35 and 37 were prepared from 33 and 36, respectively, following the previously reported procedures.26,27 The Nb-alkylated D-tryptophan derivative 33 (1.5 g, 3.51 mmol) was dissolved in dry CH2Cl2 (50 mL) in a 100-mL round bottom flask equipped with a magnetic stirrer bar. To this solution, the aldehyde41 34 (612 mg, 5.27 mmol) and AcOH (633 mg, 603 muL, 10.55 mmol), as well as 4 A MS (0.7 g) were added at 0 C. The solution, which resulted, was stirred at rt for 10 h (TLC monitoring for the consumption of 33 and appearance of a non-polar spot by UV and CAN stain). The mixture was diluted with CH2Cl2 (50 mL) and water (50 mL) and brought to pH 8-9 with cold 1M aq NaOH. The organic layer was separated and washed with water (2 × 50 mL) and brine (3 × 100 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to give 35 as a light yellow colored oil. The residue [LRMS (M + H)+ = 525, Rf = 0.3 (silica gel, 20% EtOAc/hexanes + NH4OH)] was purified by column chromatography (silica gel, 10-20% EtOAc/hexanes) to furnish the pure cis-diester 35 (1.52 g, 83%) as a colorless oil as the sole product. By following the same procedure performed at rt, 3626,27 (2.0 g, 4.69 mmol) gave cis-diesters 37 (1.72 g, 70%) [LRMS (M + H)+ = 525; Rf = 0.6 (silica gel, 30% EtOAc/hexanes)] accompanied by the trans-diester (0.73 g, 30%) [Rf = 0.7 ( silica gel, 30% EtOAc/hexanes)], which resulted in a quantitative overall isolated yield. Both 35 and 37 were used for the next transformation without further characterization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With Candida antarctica lipase B; sodium hydrogencarbonate; In tetrahydrofuran; at -18℃; for 192h;Sealed tube; Molecular sieve; | General procedure: In a typical experiment, a reaction mixture of 1 (11 uL, 0.1 mmol), methyl 2-sulfanylacetate 5 (27.6 uL, 0.3 mmol), NaHCO3 (14 mg, 0.1 mmol) in dry toluene (0.5 mL) were added to a sealed-cap vial (1.75 mL) containing Candida antarctica lipase B (CALB, Sigma-Aldrich, L4777, 20 mg) together with 200 mg 4 A molecular sieves. The reaction mixture was kept at -18 C for 8 days, at which time the reaction mixture was filtered and washed with saturated NH4Cl and brine. The solvent was dried over Na2SO4 and removed under vacuum. The crude product was purified by column chromatography: PE : EtOAc = 10 : 1, affording 7 (14 mg) as a colorless oil; yield: 65 %; ee: 97 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With Candida antarctica lipase B; triethylamine; In toluene; at 0℃; for 96h;Sealed tube; Molecular sieve; | General procedure: In a typical experiment, a reaction mixture of 1 (11 uL, 0.1 mmol), methyl 2-sulfanylacetate 5 (27.6 uL, 0.3 mmol), NaHCO3 (14 mg, 0.1 mmol) in dry toluene (0.5 mL) were added to a sealed-cap vial (1.75 mL) containing Candida antarctica lipase B (CALB, Sigma-Aldrich, L4777, 20 mg) together with 200 mg 4 A molecular sieves. The reaction mixture was kept at -18 C for 8 days, at which time the reaction mixture was filtered and washed with saturated NH4Cl and brine. The solvent was dried over Na2SO4 and removed under vacuum. The crude product was purified by column chromatography: PE : EtOAc = 10 : 1, affording 7 (14 mg) as a colorless oil; yield: 65 %; ee: 97 %. 5-(butylthio)dihydrofuran-2(3H)-one 4 The general procedure was followed. Yield: 66 %; Enantiomeric excess: 92 %, determined by HPLC analysis: Chiral OJ Hex : iPrOH = 99 : 1, 0.5 mL/min, detection 210 nm, tR: 17.196 min, 38.405 min; Colorless oil; 1H NMR (400 MHz, CDCl3) delta 5.68 (dd, J = 6.8 Hz, 5.2 Hz, 1H), 2.79-2.51 (m, 5H), 2.16-2.03 (m, 1H), 1.68-1.59 (m, 2H), 1.44-1.36 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) delta 176.2, 84.7, 31.7, 31.4, 28.9, 28.6, 21.9, 13.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With Candida antarctica lipase B; sodium hydrogencarbonate; In toluene; at -18℃; for 192h;Sealed tube; Molecular sieve; | In a typical experiment, a reaction mixture of 1 (11 uL, 0.1 mmol), methyl 2-sulfanylacetate 5 (27.6 uL, 0.3 mmol), NaHCO3 (14 mg, 0.1 mmol) in dry toluene (0.5 mL) were added to a sealed-cap vial (1.75 mL) containing Candida antarctica lipase B (CALB, Sigma-Aldrich, L4777, 20 mg) together with 200 mg 4 A molecular sieves. The reaction mixture was kept at -18 C for 8 days, at which time the reaction mixture was filtered and washed with saturated NH4Cl and brine. The solvent was dried over Na2SO4 and removed under vacuum. The crude product was purified by column chromatography: PE : EtOAc = 10 : 1, affording 7 (14 mg) as a colorless oil; yield: 65 %; ee: 97 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With Candida antarctica lipase B; sodium hydrogencarbonate; In tetrahydrofuran; at -18℃; for 192h;Sealed tube; Molecular sieve; | General procedure: In a typical experiment, a reaction mixture of 1 (11 uL, 0.1 mmol), methyl 2-sulfanylacetate 5 (27.6 uL, 0.3 mmol), NaHCO3 (14 mg, 0.1 mmol) in dry toluene (0.5 mL) were added to a sealed-cap vial (1.75 mL) containing Candida antarctica lipase B (CALB, Sigma-Aldrich, L4777, 20 mg) together with 200 mg 4 A molecular sieves. The reaction mixture was kept at -18 C for 8 days, at which time the reaction mixture was filtered and washed with saturated NH4Cl and brine. The solvent was dried over Na2SO4 and removed under vacuum. The crude product was purified by column chromatography: PE : EtOAc = 10 : 1, affording 7 (14 mg) as a colorless oil; yield: 65 %; ee: 97 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Compounds 40 and 42 were prepared from 39 and 41, respectively according to the previously published procedure.[26,27] The Nb-alkylated L-tryptophan derivative 41 (1.0 g, 2.34 mmol) was dissolvedin dry CH2Cl2 (40 mL) in a 100-mL round bottom flask equipped with a magnetic stirrer bar. To this solution, the aldehyde 34 (408 mg, 3.51 mmol) and AcOH (422 mg, 402 muL, 7.03 mmol), as well as 4 A MS (0.5g) were added at rt. The solution, which resulted, was stirred at rt for10 h [TLC (silica gel) monitoring for the consumption of 41 and appearance of a non-polar spot by UV and CAN stain]. The mixture was diluted with CH2Cl2 (50 mL) and water (50 mL) and brought to pH 8-9 with cold 1 M aq NaOH. The organic layer was separated and washed with water (2 × 50 mL) and brine (3 × 100 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to give a light yellow oil. The residue was subjected to a short wash column (silica gel) to remove any baseline material. The solvent was removed under reduced pressure and the residue, which resulted, was dissolved in dry CH2Cl2 (30 mL). To this solution, TFA (267 mg, 180 muL, 2.34 mmol) was added at rt and the reaction, which resulted, was stirred at rt until complete conversion. After the reaction was complete, the reaction was brought to pH 8-9 with cold 1 M aq NaOH. The organic layer was separated and the aqueous layer was extracted with additional CH2Cl2 (2 × 10 mL). The combined organic layers were washed with brine (3 × 100mL) and dried (Na2SO4). The solvent was removed under reduced pressure to give a light yellow oil that was purified by column chromatography (silica gel, 0-20% EtOAc/hexanes) to furnish pure trans-diester 42 (1.05 g, 85%) as a colorless oil as the sole product [LRMS (M + H)+ = 525]. By following the same procedure with 39 (1.0 g, 2.34 mmol), this process furnished the trans-diester 40 (1.06 g, 86%) as the sole product [LRMS (M + H)+ = 525]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | General procedure: Compounds 40 and 42 were prepared from 39 and 41, respectively according to the previously published procedure.[26,27] The Nb-alkylated L-tryptophan derivative 41 (1.0 g, 2.34 mmol) was dissolvedin dry CH2Cl2 (40 mL) in a 100-mL round bottom flask equipped with a magnetic stirrer bar. To this solution, the aldehyde 34 (408 mg, 3.51 mmol) and AcOH (422 mg, 402 muL, 7.03 mmol), as well as 4 A MS (0.5g) were added at rt. The solution, which resulted, was stirred at rt for10 h [TLC (silica gel) monitoring for the consumption of 41 and appearance of a non-polar spot by UV and CAN stain]. The mixture was diluted with CH2Cl2 (50 mL) and water (50 mL) and brought to pH 8-9 with cold 1 M aq NaOH. The organic layer was separated and washed with water (2 × 50 mL) and brine (3 × 100 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to give a light yellow oil. The residue was subjected to a short wash column (silica gel) to remove any baseline material. The solvent was removed under reduced pressure and the residue, which resulted, was dissolved in dry CH2Cl2 (30 mL). To this solution, TFA (267 mg, 180 muL, 2.34 mmol) was added at rt and the reaction, which resulted, was stirred at rt until complete conversion. After the reaction was complete, the reaction was brought to pH 8-9 with cold 1 M aq NaOH. The organic layer was separated and the aqueous layer was extracted with additional CH2Cl2 (2 × 10 mL). The combined organic layers were washed with brine (3 × 100mL) and dried (Na2SO4). The solvent was removed under reduced pressure to give a light yellow oil that was purified by column chromatography (silica gel, 0-20% EtOAc/hexanes) to furnish pure trans-diester 42 (1.05 g, 85%) as a colorless oil as the sole product [LRMS (M + H)+ = 525]. By following the same procedure with 39 (1.0 g, 2.34 mmol), this process furnished the trans-diester 40 (1.06 g, 86%) as the sole product [LRMS (M + H)+ = 525]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium tris(acetoxy)borohydride; triethylamine; In dichloromethane; at 20℃; for 18h;Inert atmosphere; | A solution of methyl 2-amino-2-methylpropanoate (500 mg, 3.25 mmol) in dichloroethane was stirred at room temperature, then triethylamine (1.6 equiv., 5.2 mmol), Na(OAc)3BH (2.5 equiv., 8.1 mmol) and Methyl 4-oxobutanoate (0.9 equiv., 2.9 mmol) were added under N2 and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with NaHCOs solution for 30 minutes then aqueous solution was extracted twice with DCM. The organic solution was dried over Na2SC>4 and evaporated under reduced pressure. The crude was purified by column chromatography on silica gel using ethyl acetate in hexane as mobile phase to give Methyl 4-((l-methoxy-2-methyl-l-oxopropan-2-yl)amino)butanoate (0.466 g, 74%) as a yellowish oil. UPLC-MS (Basic Method, 2 min): rt 0.84 min, m/z 218.2 [M+H]+ (0528) iH NMR (DMSO-c/6) d ppm: 3.60 (s, 3H), 3.57 (s, 3H), 2.29-2.39 (m, 4H), 1.54-1.64 (m, 2H), 1.17 (t, J=7.0 Hz, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39 % | Stage #1: 4-oxobutanoic acid methyl ester; N,N-dimethyl-1,5-pentanediamine In dichloromethane at 20℃; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; | 37 Synthesis of 39-1: methyl 4-[5-(dimethylamino)pentyl-(4-methoxy-4-oxo- butyl)amino]butanoate A mixture of 5 -(dimethyl amino)amyl amine (3.10 g, 23.80 mmol, 1 equiv.) and methyl 4-oxobutanoate (8.29 g, 71.41 mmol, 3.0 equiv.) in DCM (60 mL, 20V) was stirred for 30 min at room temperature. To the above mixture, sodium tri acetoxyb or ohydri de (STAB, 25.22 g, 119.02 mmol, 5.0 equiv.) was added in portions at room temperature. The mixture was stirred overnight at room temperature. The reaction was quenched by the addition of sat. aqueous ISfeCCh solution (60 mL) at room temperature. The resulting mixture was extracted with DCM (2 x 60 mL), the combined organics were washed with brine (120 mL), dried over anhydrous ISfeSCU, and filtered. To the filtrate, 6 g silica gel (type: ZCX-2, 100-200 mesh, 2.00 w./w.) was added, after concentration to dryness, the residue was purified on a 30 g of silica gel column, using a combi- flash purification system. The column was eluted with DCM/MeOH (95:5) and the eluent was collected in fractions. After TLC analysis (DCM:MeOH = 8: 1), pure product fractions were combined and concentrated in vacuo to afford 39-1 (3.1 g, 39%) as light-yellow oil. ELSD A: water/0.05% TFA: B: CH3CN/0.05% TFA, 95:5 to 5:95 A/B, RT 0.49 min), m/z (Calcd.) 330.3, (found) 331.5 [M+H], |
39 % | Stage #1: 4-oxobutanoic acid methyl ester; N,N-dimethyl-1,5-pentanediamine In dichloromethane at 20℃; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; | 37 Synthesis of 39-1: methyl 4-[5-(dimethylamino)pentyl-(4-methoxy-4-oxo- butyl)amino]butanoate A mixture of 5 -(dimethyl amino)amyl amine (3.10 g, 23.80 mmol, 1 equiv.) and methyl 4-oxobutanoate (8.29 g, 71.41 mmol, 3.0 equiv.) in DCM (60 mL, 20V) was stirred for 30 min at room temperature. To the above mixture, sodium tri acetoxyb or ohydri de (STAB, 25.22 g, 119.02 mmol, 5.0 equiv.) was added in portions at room temperature. The mixture was stirred overnight at room temperature. The reaction was quenched by the addition of sat. aqueous ISfeCCh solution (60 mL) at room temperature. The resulting mixture was extracted with DCM (2 x 60 mL), the combined organics were washed with brine (120 mL), dried over anhydrous ISfeSCU, and filtered. To the filtrate, 6 g silica gel (type: ZCX-2, 100-200 mesh, 2.00 w./w.) was added, after concentration to dryness, the residue was purified on a 30 g of silica gel column, using a combi- flash purification system. The column was eluted with DCM/MeOH (95:5) and the eluent was collected in fractions. After TLC analysis (DCM:MeOH = 8: 1), pure product fractions were combined and concentrated in vacuo to afford 39-1 (3.1 g, 39%) as light-yellow oil. ELSD A: water/0.05% TFA: B: CH3CN/0.05% TFA, 95:5 to 5:95 A/B, RT 0.49 min), m/z (Calcd.) 330.3, (found) 331.5 [M+H], |
Tags: 13865-19-5 synthesis path| 13865-19-5 SDS| 13865-19-5 COA| 13865-19-5 purity| 13865-19-5 application| 13865-19-5 NMR| 13865-19-5 COA| 13865-19-5 structure
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