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CAS No. : | 7579-36-4 | MDL No. : | MFCD00426620 |
Formula : | C16H14O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZYZXGWGQYNTGAU-UHFFFAOYSA-N |
M.W : | 270.28 | Pubchem ID : | 82058 |
Synonyms : |
|
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 72.89 |
TPSA : | 52.6 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.54 cm/s |
Log Po/w (iLOGP) : | 2.61 |
Log Po/w (XLOGP3) : | 3.39 |
Log Po/w (WLOGP) : | 2.17 |
Log Po/w (MLOGP) : | 2.65 |
Log Po/w (SILICOS-IT) : | 3.09 |
Consensus Log Po/w : | 2.78 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.63 |
Solubility : | 0.0629 mg/ml ; 0.000233 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.17 |
Solubility : | 0.0181 mg/ml ; 0.000067 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -5.1 |
Solubility : | 0.00213 mg/ml ; 0.00000789 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.02 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
EXAMPLE 7 The autoclave is charged with 104 grams of benzyl alcohol, 1.85 grams of Pd(CO)(PPh3)3 and 1.0 gram of triethylamine hydrobromide. The autoclave is heated at 120 C. for 4 hours under a pressure of carbon monoxide of 50 kgs/sq.cm. There are obtained 3.5 grams of dibenzyl oxalate. | ||
After the completion of the addition of the halide, the suspension was held at ~55 C. to complete the formation of the Grignard reagent. While the Grignard reagent was forming, a suspension of dibenzyl oxalate (5.1 g, 19 mmol) was prepared in a mixture of ether (50 mL), and THF (15 mL). This suspension was cooled to <-70 C. (internal monitoring) and then treated with the Grignard solution prepared previously at a rate sufficient to keep the internal temperature below -70 C. After stirring for 3 hours at <-70 C., the reaction was quenched by the addition of saturated aqueous NH4Cl, followed by addition of 1 N HCl (25 mL). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; for 3h;Heating / reflux; | To a solution of the indole product in Example 38 (150 mg, 0.572 mmol) and <strong>[7579-36-4]dibenzyl oxalate</strong> (170 mg, 0.63 mmol) in DMF (5 mL), potassium tert-butoxide (71 mg, 0.63 mmol) was added in one portion at room temperature under nitrogen. The reaction mixture was warmed to reflux under nitrogen for 3 h and then was cooled down to room temperature. The mixture was diluted with water (50 mL) and extracted (3*) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, EtOAc/hexanes, 1:1) to afford the N-benzyl-indole product, Example 39, (161 mg, 80%): 1H NMR (500 MHz, CDCl3) delta7.09-7.29 (m, 11H), 7.01 (d, J=8.5 Hz, 1H), 6.67 (d, J=8.5 Hz, 1H), 6.48 (dd, J=3.1, <1 Hz, 1H), 5.26 (s, 2H), 4.34 (t, J=8.1, 5.4 Hz, 1H), 4.00 (d, J=15.1 Hz, 1H), 3.86 (d, J=15.1 Hz, 1H), 3.06 (dd, J=11.3, 5.4 Hz, 1H), 2.67 (dd, J=11.3, 8.1 Hz, 1H), 2.50 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A suspension of 90 g. (1.0 mole) of anhydrous oxalic acid in 224 g. (ca. 2.02 moles) of benzyl alcohol and 400 ml. of benzene is stirred while 0.25 g. of concentrated H2 SO4 are added. The mixture is refluxed with stirring for about four hours using a Dean-Stark water trap to remove the H2 O formed. About 38 ml. of H2 O is collected. About 210 ml. of benzene is removed by distillation. The resulting concentrated benzene solution yields a silvery precipitate on cooling to room temperature overnight. The precipitate is filtered, washed with benzene and dried in vacuo. Wt. =118.6 g. M.P.=83-84. An additional 42.5 g. of dibenzyl oxalate is recovered from the filtrate and washes. Total yield=161.1 g. (ca. 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.2% | To a cooled (ice bath) stirred solution of 0.0625 mol of sodium hydride, in 100 mL of dry toluene was added <strong>[7579-36-4]dibenzyl oxalate</strong> 13.5 g (0.05 mol) and after stirring for 15 min solution of 8.4 g (0.05 mol) of benzyl fluoroacetaterefPreviewPlaceHolder2refPreviewPlaceHolder[4] in 15 mL of dry toluene was added dropwise. The mixture was stirred an additional 2-3 h allowed to come to room temperature and then heated under reflux for 15 min and left for a night at room temperature. The solution was cooled the next day (ice bath) and to it was added 5 mL of ethanol to the mixture, and then, 0.0625 mol of 10% HCl solution. The toluene layer was separated, dried on MgSO4 and after evaporation of the toluene and benzyl alcohol the residue was mixed with hexanes and cooled on dry ice. The solid material was separated at room temperature and excess of hexanes was evaporated giving 15.05 g (91.2%) of mixture of d,l-dibenzyl 2-fluoro-3-oxosuccinate 7. Attempts to distill the product led to decomposition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Oxalyl chloride (1 mL) was cooled to 0 C, and anhydrous benzyl alcohol (1.4 mL) added dropwise over 15 min. After the addition of the alcohol was completed, the reaction mixture was warmed up to room temperature and stirred for 1.5 h. The resulting mixture was analysed by 1H and 13C NMR spectroscopyand found to be a mixture of the oxalic acidmonobenzyl ester monochloride and the dibenzyl oxalate in a 5:1 molar ratio. The mixture was used in the next step immediately without further purification. 1H NMR (300 MHz, 297 K,CDCl3, delta, ppm) 7.47-7.42 (m, 5H), 7.42-7.38 (m, 1.75 H), 5.38(s, 2H), 5.32 (s, 0.72 H); 13C NMR (75 MHz, 297 K, CDCl3, delta,ppm) 160.95, 157.57, 155.53, 134.18, 133.33, 129.35, 128.91,128.78, 128.74, 70.38, 68.63. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | at 160℃; for 7.5h; | 14a (57 mg, 0.27 mmol) and <strong>[7579-36-4]dibenzyl oxalate</strong> (0.32 g, 1.2 mmol) was stirred at 160C for 7.5 h. Purification of the reaction mixture by column chromatography (silica gel, AcOEt/MeOH=10/1, CHCl3/MeOH=10/1) gave 6 (65 mg, 77%) as red crystals. A small amount of the compound was recrystallized to give an analytical sample. Mp 223-231C (decomp.) (hexane/CH2Cl2); 1H NMR:(400 MHz, DMSO-d6) delta 8.44 (d, J=8.0 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.12 (d, J=6.8 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.60 (d, J=6.8 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.37 (t, J=7.6 Hz, 2H), 7.29 (t, J=7.6 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 5.95 (s, 2H), 3.51 (s, 3H); 13C NMR: (125 MHz, DMSO-d6): delta 165.4, 157.2, 139.5, 138.7, 137.5, 132.9, 132.8, 130.3, 128.8, 127.6, 126.0, 126.0, 125.8, 124.8, 122.9, 122.7, 116.1, 105.2, 59.2, 58.3; HRMS (ESI) calcd for C22H17N2O3 (M+H)+ 357.1234. Found 357.1227. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | at 160℃; for 7.5h; | General procedure: 14a (57 mg, 0.27 mmol) and <strong>[7579-36-4]dibenzyl oxalate</strong> (0.32 g, 1.2 mmol) was stirred at 160C for 7.5 h. Purification of the reaction mixture by column chromatography (silica gel, AcOEt/MeOH=10/1, CHCl3/MeOH=10/1) gave 6 (65 mg, 77%) as red crystals. A small amount of the compound was recrystallized to give an analytical sample. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | at 160℃; for 7.5h; | General procedure: 14a (57 mg, 0.27 mmol) and <strong>[7579-36-4]dibenzyl oxalate</strong> (0.32 g, 1.2 mmol) was stirred at 160C for 7.5 h. Purification of the reaction mixture by column chromatography (silica gel, AcOEt/MeOH=10/1, CHCl3/MeOH=10/1) gave 6 (65 mg, 77%) as red crystals. A small amount of the compound was recrystallized to give an analytical sample. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | General procedure: A mixture of ammonium thiocyanate (1.5 mmol), HPA (0.1 mmol), and oxalate source (1.5 mmol) in 2 cm3 i-PrOH was stirred at 85 C for 30 min. A solution of amine(1.0 mmol) in 1 cm3 i-PrOH was then added to initial mixture in one portion. The resulting mixture was heated for an additional 8-11 h. After completion of reaction, the mixture was diluted with 5 cm3 EtOAc and subsequently 5 cm3 sat. NH4Cl solution was added. The mixture was stirred for additional 30 min, and two layers were separated. The aqueous layer was extracted with EtOAc(7 cm3 *3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was washed with ether and then recrystallized from CH2-Cl2/acetone to give the pure desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With urea; at 140℃; for 2h;Green chemistry; | General procedure: A 10-mL test-tube was equipped with magnetic stirring bar and charged with 1 mmol cinnamic acid and 6 mL DES, heated at 140 C in a preheated oil bath for 2 hours, then the mixture was cooled to room temperature, extracted with ethyl acetate (3*15 mL), combined and evaporated under vacuum. Pure product was obtained by silica gel column chromatography with petroleum ether and ethyl acetate. All the compounds, after purification, were weighted and characterized by MS, 1H NMR, 13C NMR, and then compared them with the spectral data of authentic samples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | General procedure: To a solution of 2-bromoaniline (1.0 equiv.) and N,N-diisopropylethylamine (2.4 equiv.) in toluene was added cis-1,4-dichlorobut-2-ene (1.8 equiv.). The mixture was stirred at reflux until complete consumption monitored by TLC. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with saturated NaCl solution and dried over Na 2 SO 4 . The solvents were removed under reduced pressure, purified by flash chromatography to give the pure or crude desired product 3. The product 3 was dissolved in anhydrous THF, then was cooled to -78 oC, n-BuLi (1.2 equiv., 2.5 mol/L in n-hexane) was added dropwise to the mixture and keep temperature no more than -50 oC, the mixture was stirred for 30 minutes, (COOR3) 2 (1.0-1.2 equiv.) in THF was added dropwise at -78 oC and stirred at -78 oC for 2 h. The reaction was warmed to room temperature slowly, then quenched with saturated NH 4 Cl solution, and extracted with EtOAc. The combined organic layers were washed with saturated NaCl solution and dried over Na 2 SO 4 . The solvents were removed under reduced pressure, purified by flash chromatography to give the desired product 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium tert-butoxide; In tetrahydrofuran; for 1h;Cooling with ice; Inert atmosphere; | To a solution of 1-(3-fluoro-5-(trifluoromethoxy)phenyl)ethan-1-one (5 g) and <strong>[7579-36-4]dibenzyloxalate</strong> (6.69 g) in THF (50 mL) was added litium tert-butoxide (1.982 g) under ice cooling under argon atmosphere. The reaction mixture was stirred under ice cooling for 1 hour. To the reaction mixture were added 2N hydrochloric acid (12.5 mL), ethyl acetate, and water under ice cooling. The mixture was separated. The obtained organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated to give a crude product of the title compound (11.7 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In benzene; for 5h;Reflux; | Preparation method of pyrroquinoline quinone:Combine 4-methyl-5-nitro-2-fluoroaniline (2) (170.14 g, 1.00 mol), benzene (1.00 L),Dibenzyl 4-oxo-2-enoglutarate (324.33 g, 1.00 mol) and methanesulfonic acid (9.61 g, 0.1mol) are placed in a three-necked bottle,Heat to reflux for 5 h, and wait for the reaction to coolWash, separate, dry,A benzene solution of 6-methyl-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dibenzyl ester (3) is obtained;Put compound 3 in benzene solution,Dibenzyl oxalate (270.28 g, 1.00 mol) and sodium hydroxide (40.00 g, 1.00 mol) were placed in a three-necked bottle and heated to reflux for 5 h,After the reaction is cooled, the solvent is recovered under reduced pressure,The crude product 6-(2-benzyloxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dibenzyl ester (5);Put compound 5, 20% platinum carbon (5 g) and ethanol (1.00 L) in the autoclave, fill with hydrogen, and maintain a pressure of 5 atmospheres,After heating to 50 for 12 h, the solvent was recovered under reduced pressure to obtain crude 5-fluoro-1H-pyrrole[2,3-f]quinoline-2,7,9-tricarboxylic acid tribenzyl ester (6);Put compound 6, sodium carbonate (212.00 g, 2.00 mol) and methanol (1.00 L) in a three-necked flask, and stir at 25 for 24 h,Rotate the solvent under reduced pressure, then add dilute hydrochloric acid to acidify to pH 5.0,Extract with benzene, wash with water, dry, filter,A benzene solution of 5-methoxy-1H-pyrrole[2,3-f]quinoline-2,7,9-tricarboxylic acid (7) was obtained;Put the benzene solution of compound 7 and cerium ammonium nitrate (548.22 g, 1.00 mol) in a three-necked flask and stir at 25 for 24 h,After filtration, the mother liquor was recovered under reduced pressure to obtain pyrroloquinoline quinone (58.00 g, total yield 17.56%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.8% | In tert-butyl methyl ether at 20℃; for 16h; Inert atmosphere; Large scale; | 3.a Step (a): Preparation of 2,3,4,6,7,9,10,11-octahydropyrazine [1,2-a:4,3-a']bipyrimidine of formula 3 Maintain a slight positive pressure of nitrogen,Sequentially add to the 200L reactor100L tert-butyl methyl ether,17.43 kg Formula 1 compound 1,4,8,11-tetraazaundecaneAnd 30.14kg of dibenzyl oxalate compound of formula 2,After adding, stir well;The reaction solution is reacted at room temperature for 16 hours,The reaction is complete.The reaction liquid is distilled to recover tert-butyl methyl ether and benzyl alcohol,The residue is recrystallized with appropriate amount of xylene to obtain 17.66kg2,3,4,6,7,9,10,11-octahydropyrazine [1,2-a:4,3-a']bipyrimidine as a yellow solid.The yield was 91.8%,HPLC purity 98.2% |