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CAS No. : | 85-42-7 | MDL No. : | MFCD00064863 |
Formula : | C8H10O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MUTGBJKUEZFXGO-UHFFFAOYSA-N |
M.W : | 154.16 | Pubchem ID : | 85689 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 37.83 |
TPSA : | 43.37 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.4 cm/s |
Log Po/w (iLOGP) : | 1.36 |
Log Po/w (XLOGP3) : | 1.18 |
Log Po/w (WLOGP) : | 0.88 |
Log Po/w (MLOGP) : | 1.39 |
Log Po/w (SILICOS-IT) : | 1.55 |
Consensus Log Po/w : | 1.27 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.54 |
Solubility : | 4.45 mg/ml ; 0.0289 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.69 |
Solubility : | 3.17 mg/ml ; 0.0206 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.14 |
Solubility : | 11.2 mg/ml ; 0.0726 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.62 |
Signal Word: | Danger | Class: | N/A |
Precautionary Statements: | P261-P272-P280-P285-P302+P352-P304+P341-P305+P351+P338-P310-P333+P313-P342+P311-P363-P501 | UN#: | N/A |
Hazard Statements: | H317-H318-H334 | 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 |
---|---|---|
75% | Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 60℃; Stage #2: With water In tetrahydrofuran |
A solution of hexahydrophthalic anhydride (mixture of isomers, 5.00 g, 32.0 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise to a 0 °C cooled suspension of lithium aluminium hydride (4.21 g, 110 mol) in anhydrous tetrahydrofuran (200 mL). The reaction mixture was heated to 60 °C for 2 h. The reaction mixture was cooled to 0 °C, and crushed ice was carefully added to neutralize the excess of lithium aluminium hydride. The precipitate was filtered, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and evaporated. The crude residue was triturated in diethyl ether to give 54. Yield 75percent. 1H NMR (400 MHz, CDCl3): δ 1.36-1.55 (m, 8H), 1.91-1.96 (m, 2H), 2.76 (br s, 2H, disappeared on treatment with D2O), 3.58 (dd, J = 11.0 and 4.1 Hz, 2H), 3.77 ppm (dd, J = 11.0 and 8.2 Hz, 2H). MS (ESI): m/z: 145 [M + H]+, 167 [M + Na]+. IR: ν 3389 cm-1. Anal. Calcd. for C8H16O2: C, 66.63percent; H, 11.18percent. Found: C, 66.57percent; H, 11.16percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | A solution of hexahydrophthalic anhydride (mixture of isomers, 5.00 g, 32.0 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise to a 0 C cooled suspension of lithium aluminium hydride (4.21 g, 110 mol) in anhydrous tetrahydrofuran (200 mL). The reaction mixture was heated to 60 C for 2 h. The reaction mixture was cooled to 0 C, and crushed ice was carefully added to neutralize the excess of lithium aluminium hydride. The precipitate was filtered, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and evaporated. The crude residue was triturated in diethyl ether to give 54. Yield 75%. 1H NMR (400 MHz, CDCl3): delta 1.36-1.55 (m, 8H), 1.91-1.96 (m, 2H), 2.76 (br s, 2H, disappeared on treatment with D2O), 3.58 (dd, J = 11.0 and 4.1 Hz, 2H), 3.77 ppm (dd, J = 11.0 and 8.2 Hz, 2H). MS (ESI): m/z: 145 [M + H]+, 167 [M + Na]+. IR: nu 3389 cm-1. Anal. Calcd. for C8H16O2: C, 66.63%; H, 11.18%. Found: C, 66.57%; H, 11.16%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; at 80℃; for 1h; | (1R,2R)-Cyclohexane-1,2-dicarboxylic acid (150 mg, 0.87 mmol) was suspended in acetic anhydride (2 mL) and stirred at 80° C. for 1 hour. The mixture was cooled, concentrated in vacuo, azeotroped once with toluene and dried under vacuum to give (3aR,7aR)-hexahydro-2-benzofuran-1,3-dione as a white solid. It was taken up in DMF (5 mL), 8-fluoro-2,3,4,5-tetrahydropyrido[4,3-B]indole (166 mg, 0.87 mmol) was added and the solution stirred at room temperature for 3 hours. 1-Aminocyclopropanecarbonitrile hydrochloride (114 mg, 0.96 mmol) was added followed by triethylamine (0.36 mL, 2.61 mmol) and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 499 mg, 0.96 mmol) and the mixture stirred overnight. DMF was removed in vacuo and the residue partitioned between DCM (2.x.30 mL) and 50percent brine (10 mL). The combined organics were treated with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried (magnesium sulphate), concentrated in vacuo and adsorbed onto silica for purification by flash chromatography (0-80percent ethyl acetate/isohexane). To purify further, the sample was triturated twice with anhydrous diethyl ether (2.x.5 mL), filtered and dried under vacuum. This gave (1R,2R)-N-(1-cyanocyclopropyl)-2-[(8-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide as a white solid (24.0 mg, 7percent).MS (+ve ESI): 408.9 (M+H)+ 1H NMR (400 MHz, DMSO) delta 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 2.4 (m, 1H), 2.7-3.0 (m, 3H), 3.8 (m, 2H), 4.5-4.7 (m, 2H), 9.9 (m, 1H), 7.2 (m, 1H), 7.3 (s, 1H), 8.65 (s, 1H), 11.0 (s, 1H) | |
With acetic acid; at 80℃; | (1 R,2R)-cyclohexane-1 ,2-dicarboxylic acid (300 mg, 1.74 mmol) was suspended in acetic anhydride and stirred at 80 °C overnight. The mixture was concentrated in vacuo and the residue was used directly in the next step. | |
With acetic anhydride; at 80℃; for 1h; | (li?,2R)-Cyclohexane-l,2-dicarboxylic acid (150 mg, 0.87 mmol) was suspended in acetic anhydride (2 mL) and stirred at 80 0C for 1 hour. The mixture was cooled, concentrated in vacuo, azeotroped once with toluene and dried under vacuum to give (3ai?,7ai?)-hexahydro-2-benzofuran-l,3-dione as a white solid. It was taken up in DMF (5 mL), 6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline hydrochloride (230 mg, 0.87 mmol) added followed by triethylamine (0.13 mL, 0.87 mmol) to free up the base and the mixture stirred at room temperature for 3 hours. 1-Aminocyclopropanecarbonitrile hydrochloride (114 mg, 0.95 mmol) was added followed by triethylamine (0.36 mL) and benzotriazol-1- yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 473mg, 0.91 mmol) and the solution stirred over the weekend. DMF was removed in vacuo and the residue partitioned between ethyl acetate (2 x 30 mL) and brine (10 mL). The separated organic portion was adsorbed onto silica for purification by flash chromatography (0-80percent ethyl acetate / isohexane) to give the product as a brittle white solid (119 mg, 33percent). MS (+ve ESI) : 411.9 (M+H)+1R NMR (400 MHz, DMSO) d 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H),2.4-3.0 (m, 4H), 3.75 (m, 8H), 4.5 (m, 2H), 6.75 (m, 2H), 8.7 (s, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Hydrogenation; | Example 5; Hydrogenation of Acid Anhydrides and Aromatic Acids to the Corresponding Cycloaliphatic Compounds |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 2h; | N, N-diethylamine (415 muL, 4 mmol) and 1,2- c/s-cyclohexanedicarboxylic anhydride (617 mg, 4 mmol) were dissolved in 10 mL dichloride methane. The reaction was kept at room temperature for 2 h with stirring. The solvent was then removed by rotary evaporation to obtain the raw product. The raw product was purified by recrystallizing from benzene to get 2- [(diethylamino)carbonyl]cyclohexanecarboxylic acid. iH NMR (400 MHz, CDC13): delta (ppm): 3.60-3.22 (m), 2.77 (m), 2.51-2.45 (m), 1.87-1.66 (m), 1.58-1.46 (m), 1.49-1.39 (m), 1.28 (q), 1.17 (t) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; at 20℃; for 18h; | (i) [(4) TRANS-2-({ [CYANO] (2-methoxyphenyl) methyls amino} carbonyl) cyclohexanecarboxylic acid A mixture of [(D :) TRANS-L,] 2-cyclohexanedicarboxylic anhydride (3. [0G),] N, N- diisopropylethylamine (5.03g) and [(=L)] [2- (2-METHOXYPHENYL) AMINOACETONITRILE] hydrochloride (3.87g) in tetrahydrofuran [(50ML)] was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue dissolved in water. The cooled [(0C)] aqueous solution was acidified by dropwise addition of dilute aqueous hydrochloric acid and the resultant mixture extracted with ethyl acetate. The organic layer was washed with aqueous brine, dried [(MGS04),] and evaporated under reduced pressure. The residue was purified by tritration with ethyl acetate (2 x [30ML).] Yield 0.53g MS: APCI (+ve) 317 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
titanium(IV) isopropylate; at 200℃; under 3.75038 - 570.057 Torr; for 7h;Product distribution / selectivity; | Example 2; In a 1000 ml four-neck reactor, 154 g of hexahydrophthalic anhydride (HHPA), 370 g of 2-ethylhexy alcohol (2-EH), 2.6 g of tetraisopropyl titanate (TIPT) catalyst were added. The esterification was carried out at 200 C. and pressure of 5760 mbar for 7 hours with inert gas, water formed during the reaction is removed from the reaction system.The complection of the esterification can be observed via acid number, when the acid number reduce 1.0 mgKOH/g or less, subsequently neutralization with sodium hydroxide until the acid number reduce 0.08 mgKOH/g or less. Subsequent to the neutralization the free 2-EH is separated from the reaction mixture by steam distillation until the residual of 2-EH reduce 300 ppm or less. The removal of the free 2-EH is followed by drying and filtration of the ester. The reaction resulting mixture of cyclohexane-1,2-dicarboxylic acid di(2-ethylhexyl)ester was obtain by the process.The analyst is shown in table 1 having the color of 10APHA, the acid number of 0.07 mgKOH/g and the purity of 99.6%. The resulting mixture can be used as plasticizer. | |
titanium(IV) isopropylate; at 200℃; under 3.75038 - 570.057 Torr; for 7h; | Example 2; In a 1000ml four-neck reactor, 154g of hexahydrophthalic anhydride (HHPA), 370g of 2-ethylhexy alcohol (2-EH), 2.6g of tetraisopropyl titanate (TIPT) catalyst were added. The esterification was carried out at 200C and pressure of 5~760mbar for 7 hours with inert gas, water formed during the reaction is removed from the reaction system. The complection of the esterification can be observed via acid number, when the acid number reduce 1.0mgKOH/g or less, subsequently neutralization with sodium hydroxide until the acid number reduce 0.08mgKOH/g or less. Subsequent to the neutralization the free 2-EH is separated from the reaction mixture by steam distillation until the residual of 2-EH reduce 300ppm or less. The removal of the free 2-EH is followed by drying and filtration of the ester. The reaction resulting mixture of cyclohexane-1,2-dicarboxylic acid di(2-ethylhexyl) ester was obtain by the process. The analyst is shown in table 1 having the color of 10APHA, the acid number of 0.07mgKOH/g and the purity of 99.6%. The resulting mixture can be used as plasticizer. | |
tix oxide; In xylene; at 230℃; under 150.015 Torr; for 5h;Dean-Stark trap;Product distribution / selectivity; | [0470] Purified di(2-ethylhexyl) 1,2-cyclohexanedicarboxylate was produced by the same procedure as in Example I-2 with the exception of using 2-ethylhexanol having a peroxide value of 0.1 meq/kg and a carbonyl value of 0.2 and 1,2-cyclohexanedicarboxylic anhydride (prepared by hydrogenating 4-cyclohexene-1,2-dicarboxylic anhydride obtained by usual Diels-Alder reaction of maleic anhydride and 1,3-butadiene). Subsequently dehydration was carried out at 130 C. under a reduced pressure of 1330 Pa for 5 hours. [0471] The total acid number and kinematic viscosity of the obtained ester are shown in Table 1. The ester had a hue of 10 in terms of Hazen color number, a water content of 10 ppm, a sulfated ash content of 1 ppm, a sulfur content of less than 1 ppm, a phosphorus content of less than 1 ppm, a hydroxyl value of 0.3 mgKOH/g, a peroxide value of 0.3 meq/kg and a carbonyl value of 0.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tin hydroxide; In xylene; at 220℃; under 150.015 Torr; for 21h;Dean-Stark trap;Product distribution / selectivity; | Example I-6 Purified diisobutyl 1,2-cyclohexanedicarboxylate was produced following the procedure of Example I-1 with the exception of using isobutanol having a peroxide value of 0.2 meq/kg and a carbonyl value of 0.3 and 1,2-cyclohexanedicarboxylic anhydride (prepared by hydrogenating 4-cyclohexene-1,2-dicarboxylic anhydride obtained by usual Diels-Alder reaction of maleic anhydride and 1,3-butadiene). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tin oxide; In xylene; at 225 - 230℃; under 150.015 Torr; for 5 - 8h;Dean-Stark trap;Product distribution / selectivity; | [0472] Purified di(3,5,5-trimethylhexyl) 1,2-cyclohexanedicarboxylate was produced by the same procedure as in Example I-7 with the exception of using <strong>[3452-97-9]3,5,5-trimethylhexanol</strong> having a peroxide value of 0.4 meq/kg and a carbonyl value of 0.3 (the same as used in Example I-4). Subsequently dehydration was carried out at 130° C. under a reduced pressure of 1330 Pa for 5 hours. [0473] The total acid number and kinematic viscosity of the obtained ester are shown in Table 1. The ester had a hue of 10 in terms of Hazen color number, a water content of 28 ppm, a sulfated ash content of less than 1 ppm, a sulfur content of less than 1 ppm, a phosphorus content of less than 1 ppm, a hydroxyl value of 0.9 mgKOH/g, a peroxide value of 0.5 meq/kg and a carbonyl value of 0.2.; Example I-9 [0474] When <strong>[3452-97-9]3,5,5-trimethylhexanol</strong> was stored at room temperature for one year, it showed a peroxide value of 0.8 meq/kg and a carbonyl value of 17.2. The same procedure as in Example I-8 was performed with the exception of using said <strong>[3452-97-9]3,5,5-trimethylhexanol</strong>, thereby producing purified di(3,5,5-trimethylhexyl) 1,2-cyclohexanedicarboxylate. Then dehydration was carried out at 130° C. under reduced pressure of 1330 Pa for 5 hours. [0475] The total acid number and kinematic viscosity of the obtained ester are shown in Table 1. The ester had a hue of 30 in terms of Hazen color number, a water content of 23 ppm, a sulfated ash content of 4 ppm, a sulfur content of less than 1 ppm, a phosphorus content of less than 1 ppm, a hydroxyl value of 1.2 mgKOH/g, a peroxide value of 1.0 meq/kg and a carbonyl value of 9.8.; Example I-10 [0476] When <strong>[3452-97-9]3,5,5-trimethylhexanol</strong> was stored at room temperature for one year, it showed a peroxide value of 0.8 meq/kg and a carbonyl value of 17.2. Following the procedure of Example I-8 and using the <strong>[3452-97-9]3,5,5-trimethylhexanol</strong>, the starting materials were gradually heated to 225° C. in the presence of tin oxide catalyst (0.2 wt. percent based on the starting materials fed) in a nitrogen atmosphere. While water generated during the reaction was removed by means of water separator, the esterification reaction was conducted for 6 hours and at 225° C. under reduced pressure (20000 Pa) for 2 hours. [0477] After the reaction, excess <strong>[3452-97-9]3,5,5-trimethylhexanol</strong> was removed by distillation at 210° C. under a reduced pressure of 1330 Pa, and the obtained liquid residue was neutralized by adding thereto 33 g of a 4percent aqueous solution of sodium hydroxide and stirring the mixture at 80° C. for 2 hours, and then washed with water until the aqueous layer became neutral to thereby give a liquid crude ester. At this point, the crude ester had a total acid number of 0.01 mgKOH/g. Subsequently, to the ester was added activated alumina ("Tomita-AD 220P" manufactured by Tomita Pharmaceutical Co., Ltd.; 0.2 wt. percent based on the starting materials fed) and activated clay ("Galleon-earth V1" manufactured by Mizusawa Industrial Chemicals Ltd.; 0.2 wt. percent based on the starting materials fed), and the mixture was stirred at 90° C. and at 1330 Pa for 1 hour and filtered, whereby 390 g of purified di(3,5,5-trimethylhexyl) 4-cyclohexene-1,2-dicarboxylate was obtained. Dehydration was carried out at 130° C. under a reduced pressure of 1330 Pa for 5 hours. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.9% | A mixture of 1.54 grams of 1,2-cyclohexanedicarbolic acid anhydride, 8.6 grams of d-alpha-tocopherol, 1.34 grams of aluminum trichloride, and 100 ml of cyclohexane in a 250 ml flask was heated under reflux for about 30 minutes. After the mixture cooled to room temperature, it was filtered. The filtrate was washed with a dilute aqueous hydrochloric acid solution and then dried over anhydrous MgSO4. The mixture was concentrated, and crude product was purified by column chromatography on silica gel. (Yield: 3.325 grams, 56.9%). Preparation of tocopherol cyclohexane-1,2-dicarboxylate 7-ethyl-10-hydroxycamptothecin. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; hydroxylamine sulfate; | EXAMPLE III Synthesis of N-hydroxyhexahydrophthalimide 95 g of hexahydrophthalic anhydride (0.610 mol; 99% pure) was suspended in 130 ml of water in which 50 g (0.305 mol) of hydroxylamine sulphate was dissolved. To this 100 g of 25 wt % aqueous sodium hydroxide solution was metered in over 10 minutes. Afterwards the reaction mixture was heated to 85 C. and kept at this temperature for 1 hour. After that the mixture was cooled to room temperature and the oil formed extracted with 2*100 ml of chloroform. The combined chloroform phases were dried over sodium sulphate and afterwards concentrated by evaporation. The oil obtained slowly solidified. Yield 99 g, 95% pure product (90% with respect to hexahydrophthalic anhydride). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.5% | With acetic acid; at 120℃; for 2h; | Hexahydrophthalic anhydride (310 mg, 2.0 mmol) and 4-aminophenylacetic acid (300 mg, 2.0 mmol) were dissolved in 10 mL of glacial acetic acid and heated to 120 C for 2 h.The reaction was quenched with water (10 mL) and the NaOH solution (0.1 mol/L) was adjusted to pH 6-8.Dichloromethane extraction (10mL × 3), washed with saturated NaHCO3 solution, washed with water,The organic phase is combined, dried over anhydrous sodium sulfate, and purified by silica gel column.Made a yellow oil 525mg,LC-MS and 1 H-NMR confirmed the expected intermediate compound in a yield of 91.5%. |
(a) Equimolar amounts of cyclohexane-1,2-dicarboxylic acid anhydride and p-aminophenylacetic acid were reacted as described in step (a) of Example 1, yielding quantitatively 4-(1,3-dioxo-hexahydro-2-isoindolinyl)phenylacetic acid (melting point 219-221 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In acetic anhydride; toluene; | (A) Trans-cyclohexane-1,2-dicarboxylic acid anhydride trans-Cyclohexane-1,2-dicarboxylic acid (5.00 g, 29.0 mmol) was dissolved in acetic anhydride (10 mL), and the solution was heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure by azeotropy using toluene and ether. The residue was added with ether, and collected by filtration to obtain the title compound as colorless crystals (3.82 g, 85percent). 1H-NMR (DMSO-d6) delta: 1.22-1.34 (2H, m), 1.47-1.61 (2H, m), 1.90-2.00 (2H, m), 2.28-2.32 (2H, m), 2.54-2.63 (2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.5% | With acetic anhydride; at 180 - 230℃; under 760.051 Torr; for 3h; | Proportionally reactor was charged with hexahydrophthalic anhydride, Isononyl alcohol, Catalyst acetic anhydride, among them:Hexahydrophthalic anhydride and isononyl alcohol molar ratio of 1: 2.3, Acetic anhydride is added in an amount of 5% by mass of hexahydrophthalic anhydride, Under atmospheric pressure with heating and stirring, Heating to 180 deg C reflux start timing, Continue to heat up the reaction, The material 1 was obtained after being maintained at 230 C for 3 h, Material 1 is diisononyl cyclohexane-1,2-dicarboxylate crude; The material 1 after falling film evaporator, Excess alcohol was flashed off at a negative pressure of -0.06 MPa, Residence time is 0.002 h, Get material 2, Into the stripping tank; In the stripping tank access to water vapor and nitrogen bubbling, Steamed material 2 low molecular weight impurities, Get material 3, Into the decolorization kettle. Stripping tank pressure control at -0.05MPa, Stripper temperature control at 80 ~ 90 deg C, Material 2 in the stripping tank dwell time control in 0.5 h; 4 )In the decolorization kettle material 3 mass 3% activated carbon, Stir at a temperature of 90 C for 1.5 h, filter, The final product was diisononyl cyclohexane-1,2-dicarboxylate, Products for the colorless transparent oily liquid, Yield 98.5% Purity 99.8%. |
98.7% | at 180 - 200℃; for 2h; | Add hexahydrophthalic anhydride (51.4g), isononanol (115.4g) and 0.83g of catalyst B to a 500ml three-necked flask,The reaction was stirred and heated under normal pressure, and the temperature was maintained at 180-200 C for 2 hours.The esterified layer was separated from the reaction solution, and the obtained product was stripped of unreacted alcohol at 0.009 MPa and a temperature of 160 C, and cooled to room temperature.After decolorization, alkaline washing, water washing, pressure filtration, and steam stripping, the final product, cyclohexane 1,2-dicarboxylic acid diisononyl ester, is obtained.The product is a colorless transparent oily liquid. The yield was 98.7% and the purity was 99.6%. |
titanium(IV) isopropylate; at 250℃; under 3.75038 - 570.057 Torr; for 5h;Product distribution / selectivity; | Example 1 In a 1000 ml four-neck reactor, 154 g of hexahydrophthalic anhydride (HHPA), 370 g of isononyl alcohol (INA), 2.6 g of tetraisopropyl titanate (TIPT)(TIPT) catalyst were added. The esterification was carried out at 250 C. and pressure of 5~760 mbar for 5 hours with inert gas, water formed during the reaction is removed from the reaction system. The completion of the esterification can be observed via acid number, when the acid number reduce 1.0 mgKOH/g or less, subsequently neutralization with sodium hydroxide until the acid number reduce 0.08 mgKOH/g or less. Subsequent to the neutralization the free INA is separated from the reaction mixture by steam distillation until the residual of INA reduce 300 ppm or less. The removal of the free INA is followed by drying and filtration of the ester. The reaction resulting mixture of cyclohexane-1,2-dicarboxylic acid diisononyl ester was obtain by the process. The analyst of the cyclohexane-1,2-dicarboxylic acid diisononyl ester is shown in table 1 having the color of 10APHA, the acid number of 0.05 mgKOH/g and the purity of 99.8%. The resulting mixture can be used as plasticizer. |
toluene-4-sulfonic acid; at 230℃; under 3.75038 - 570.057 Torr; for 8h;Product distribution / selectivity; | Comparison Example 1 In a 1000 ml four-neck reactor, 154 g of hexahydrophthalic anhydride (HHPA), 370 g of isononyl alcohol (INA), 2.6 g of Para-tolune sulfonic acid (PTSA) catalyst were added. The esterification was carried out at 230 C. and pressure of 5~760 mbar for 8 hours with inert gas, water formed during the reaction is removed from the reaction system. The complection of the esterification can be observed via acid number, when the acid number reduce 3.0 mgKOH/g or less, subsequently neutralization with sodium hydroxide until the acid number reduce 0.08 mgKOH/g or less. Subsequent to the neutralization the free INA is separated from the reaction mixture by steam distillation until the residual of INA reduce 300 ppm or less. The removal of the free INA is followed by drying and filtration of the ester. The reaction resulting mixture of cyclohexane-1,2-dicarboxylic acid diisononyl ester was obtain by the process. The analyst of the cyclohexane-1,2-dicarboxylic acid diisononyl ester is shown in table 1 having the color of 150 APHA, the acid number of 0.08 mgKOH/g and the purity of 99.5%. The resulting mixture can be used as plasticizer. | |
tin(II) octanoate; at 230℃; under 3.75038 - 570.057 Torr; for 7h;Product distribution / selectivity; | Comparison Example 2 In a 1000 ml four-neck reactor, 154 g of hexahydrophthalic anhydride (HHPA), 370 g of isononyl alcohol (INA), 2.6 g of stannous octoate catalyst were added. The esterification was carried out at 230 C. and pressure of 5~760 mbar for 7 hours with inert gas, water formed during the reaction is removed from the reaction system. The complection of the esterification can be observed via acid number, when the acid number reduce 1.0 mgKOH/g or less, subsequently neutralization with sodium hydroxide until the acid number reduce 0.08 mgKOH/g or less. Subsequent to the neutralization the free INA is separated from the reaction mixture by steam distillation until the residual of INA reduce 300 ppm or less. The removal of the free INA is followed by drying and filtration of the ester. The reaction resulting mixture of cyclohexane-1,2-dicarboxylic acid diisononyl ester was obtain by the process. The analyst of the cyclohexane-1,2-dicarboxylic acid diisononyl ester is shown in table 1 having the color of 40 APHA, the acid number of 0.07 mgKOH/g and the purity of 99.6%. | |
titanium(IV) isopropylate; at 250℃; under 3.75038 - 570.057 Torr; for 5h;Product distribution / selectivity; | Example 1; In a 1000ml four-neck reactor, 154g of hexahydrophthalic anhydride (HHPA), 370g of isononyl alcohol (INA), 2.6g of tetraisopropyl titanate (TIPT) catalyst were added. The esterification was carried out at 250C and pressure of 5~760mbar for 5 hours with inert gas, water formed during the reaction is removed from the reaction system. The completion of the esterification can be observed via acid number, when the acid number reduce 1.0mgKOH/g or less, subsequently neutralization with sodium hydroxide until the acid number reduce 0.08mgKOH/g or less. Subsequent to the neutralization the free INA is separated from the reaction mixture by steam distillation until the residual of INA reduce 300ppm or less. The removal of the free INA is followed by drying and filtration of the ester. The reaction resulting mixture of cyclohexane-1,2-dicarboxylic acid diisononyl ester was obtain by the process. The analyst of the cyclohexane-1,2-dicarboxylic acid diisononyl ester is shown in table 1 having the color of 10APHA, the acid number of 0.05mgKOH/g and the purity of 99.8%. The resulting mixture can be used as plasticizer. | |
toluene-4-sulfonic acid; at 230℃; under 3.75038 - 570.057 Torr; for 8h;Product distribution / selectivity; | Comparison example 1; In a 1000ml four-neck reactor, 154g of hexahydrophthalic anhydride (HHPA), 370g of isononyl alcohol (INA), 2.6g of Para-tolune sulfonic acid (PTSA) catalyst were added. The esterification was carried out at 230C and pressure of 5~760mbar for 8 hours with inert gas, water formed during the reaction is removed from the reaction system. The complection of the esterification can be observed via acid number, when the acid number reduce 3.0mgKOH/g or less, subsequently neutralization with sodium hydroxide until the acid number reduce 0.08mgKOH/g or less. Subsequent to the neutralization the free INA is separated from the reaction mixture by steam distillation until the residual of INA reduce 300ppm or less. The removal of the free INA is followed by drying and filtration of the ester. The reaction resulting mixture of cyclohexane-1,2-dicarboxylic acid diisononyl ester was obtain by the process. The analyst of the cyclohexane-1,2-dicarboxylic acid diisononyl ester is shown in table 1 having the color of 150 APHA, the acid number of 0.08mgKOH/g and the purity of 99.5%. The resulting mixture can be used as plasticizer. | |
stannous octoate; at 230℃; under 3.75038 - 570.057 Torr; for 7h;Product distribution / selectivity; | Comparison example 2; In a 1000ml four-neck reactor, 154g of hexahydrophthalic anhydride (HHPA), 370g of isononyl alcohol (INA), 2.6g of stannous octoate catalyst were added. The esterification was carried out at 230C and pressure of 5~760mbar for 7 hours with inert gas, water formed during the reaction is removed from the reaction system. The complection of the esterification can be observed via acid number, when the acid number reduce 1.0mgKOH/g or less, subsequently neutralization with sodium hydroxide until the acid number reduce 0.08mgKOH/g or less. Subsequent to the neutralization the free INA is separated from the reaction mixture by steam distillation until the residual of INA reduce 300ppm or less. The removal of the free INA is followed by drying and filtration of the ester. The reaction resulting mixture of cyclohexane-1,2-dicarboxylic acid diisononyl ester was obtain by the process. The analyst of the cyclohexane-1,2-dicarboxylic acid diisononyl ester is shown in table 1 having the color of 40 APHA, the acid number of 0.07mgKOH/g and the purity of 99.6%. The resulting mixture can be used as plasticizer. From the Table 1, it shows that the reaction product obtained by esterification in the presence of TIPT catalyst of the embodiment example 1 has the color, acid number and purity all better than that of comparison example 1 and comparison example 2; and the embodiment examples 2 and 3 has the color better than that of comparison example 1 and comparison example 2, too. | |
Comparison example 3; The esterification was carried out in two stages. In the first stage, without addition of any catalyst, the monoester of the dicarboxylic acid is formed. In a 1,000ml four-neck reactor, 154g of hexahydrophthalic anhydride, 370g of isononyl alcohol were added and carried out the reaction at temperature of 160C. The course and completion of the esterification in this case can be observed via the formation of water. In the second stage, the esterfication of the dicarboxylicis is then completed, it is carried out in the presence of 2.6g of TIPT catalyst at temperatures which are above those employed in the first stage and go up to about 250C, and pressure of 5~760mbar for 11 hours, the water formed is removed out the reaction system. The completion of the esterification can be observed via acid number, when the acid number reduce 1.0mgKOH/g or less, subsequently neutralization with sodium hydroxide until the acid number reduce 0.08mgKOH/g or less. Subsequent to the neutralization the free INA is separated from the reaction mixture by steam distillation until the residual of INA reduce 300ppm or less. The removal of the free INA is followed by drying and filtration of the ester. The reaction resulting mixture of cyclohexane-1,2-dicarboxylic acid diisononyl ester was obtain by the process. |
Yield | Reaction Conditions | Operation in experiment |
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Example 4 [(+) TRANS-N-(CYANOMETHYL)-2-{14-(4-FLUOROBENZYL) PIPERAZIN-1-] [YL]] carbonyl} cyclohexanecarboxamide A mixture of [()] [TRANS-1,] 2-cyclohexanedicarboxylic anhydride (0.4g), N, N- diisopropylethylamine (0.34g) and [1- (4-FLUOROBENZYL)] piperazine [(0.] [5G)] in tetrahydrofuran [(15ML)] was stirred at room temperature for 18 hours. At the end of this time the reaction mixture was treated with further N, N-diisopropylethylamine (0.84g) followed by aminoacetonitrile hydrochloride (0.36g), 1-hydroxybenzotriazole (0.53g) and finally [N- (3-] dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (0.75g). The mixture was stirred for 18 hours and subsequently partitioned between ethyl acetate and aqueous sodium bicarbonate, the organics dried [(MGS04)] and evaporated under reduced pressure. The residue was purified by chromatography on silica, eluting with a mixture of triethylamine (0.6%), methanol (2%) and dichloromethane (97.4%). Yield 0.045g MS: APCI (+ve) 387 (M+1) [1H] NMR: [(DMSO-D6) 8] 8.46 [(1H,] t), 7. [36-7.] 31 (2H, [M),] 7.17-7. 11 (2H, [M),] 4.03 (2H, d), 3.50-3. 35 (6H, [M),] 2.90-2. 80 [(1H,] [M),] 2.41-2. 24 (4H, [M),] 1.80-1. 77 [(1H,] [M),] 1.73-1. 65 (3H, [M),] 1.32-1. 15 (4H, [M).] |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In dichloromethane; | (35)-l,2,3,4-tetrahydroisoquinolin-3-ylmethanol (82.0 mg, 0.50 mmol) was added to a stirred solution of (3ai?,7ai?)-hexahydro-2-benzofuran-l,3-dione (77.0 mg, 0.50 mmol) and DIPEA (0.88 uL, 0.50 mmol) in DCM (2.5 mL). The reaction was stirred overnight and then concentrated in vacuo. To the residue was added fresh THF (2.5 mL) followed by l-aminocyclopropanecarbonitrile hydrochloride (65.0 mg 0.55 mmol), DMTMM (153 mg 0.55 mmol) and DIPEA (88 uL, 0.50 mmol) was added and the reaction stirred for 4 nights, poured into water (30 mL) and extracted with ethyl acetate (2 x 25 mL), the organics were washed with sat. sodium carbonate solution (25 mL), water (25 mL), IM HCl (25 mL), water (25 mL) and then brine (25 mL), dried over MgSO4, filtered and concentrated in vacuo. Purified on the basic preparative HPLC (NH4OH modifier).LCMS retention time 1.75 min. (+ve ESI) : 382 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
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In dichloromethane; at 20℃; for 18h; | A mixture of 5,6,7, 8-tetrahydro-l,6-naphthyridine (134 mg, 1 mmol) and (3ai?,7ai?)-hexahydro-2-benzofuran-l,3-dione (154 mg, 1.00 mmol) in DCM (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated, dissolved in T?F (5 mL) and used crude in the next step. To this solution was added DIPEA (175 ul, lmmol), l-aminocyclopropanecarbonitrile (65.0 mg, 0.55mmol) and the mixture stirred for 15 mins at RT. DMTMM (305 mg, 1.1 mmol) was added and the mixture stirred for 48 hours. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL) and the water extracted a further with ethyl acetate (2 x 30 mL). The combined organics were washed with sodium carbonate solution (25 mL), water (20 mL) and then IN HCl solution (20 mL). The organics were dried (magnesium sulphate) and concentrated. Purification by reverse phase ?PLC (?COO? 0.5%, CH3CN, H2O) furnished the desired compound as a pink gum (69.0 mg, 20 % yield). MS (+ve ESI) : 353 (M+H)+ 1H NMR (400.132 MHz, CDC13) d 0.99 - 1.94 (12H, m), 2.60 (IH, m), 2.91 - 3.22 (3H, m), 3.58 - 4.26 (2H, m), 4.54 - 4.96 (2H, m), 6.74 (IH, m), 7.16 (IH, m), 7.45 (IH, t), 8.44 (IH, m) |
Yield | Reaction Conditions | Operation in experiment |
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33% | In acetonitrile; at 80℃; for 3h; | A mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4'-piperidine]-5,6-dione (0.5 g, 1.66 mmol), hexahydro-2-benzofuran-1,3-dione (0.256 g, 1.66 mmol), and anhydrous acetonitrile (10 ml) was stirred for three hours at 80 C. The solvents were removed under vacuum and the crude product was purified by flash column chromatography (SiO2, 20% EtOAc in DCM to 20% EtOAC and 2% MeOH in DCM) to afford the product as a purple solid (0.246 g, 33%). M.p.=214-220 C.; 400 MHz 1H NMR (DMSO-d6) delta: 11.87 (s, 1H), 7.90-7.78 (m, 2H), 7.77-7.71 (m, 1H), 7.58-7.52 (m, 1H), 4.25-4.10 (m, 1H), 3.90-3.75 (m, 1H), 3.50-3.37 (m, 1H), 3.37-3.23 (m, 1H), 3.15-2.90 (m, 3H), 2.45-2.36 (m, 1H), 2.18-1.95 (m, 2H), 1.9-1.6 (m, 4H), 1.60-1.47 (m, 2H), 1.47-1.35 (m, 2H), 1.35-1.17 (m, 2H); LCMS: 456 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
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titanium(IV) isopropylate; In xylene; at 160 - 180℃; for 5h; | Embodiment 2 Hexahydrophthalic anhydride of 0.5 mole, triethylene glycol of 1.05 moles, catalyst TIPT (Tetraisopropyl titanate) of 1.0 g and xylene of 34.0 g are received in a four-neck flask equipped with magnetic stir bars and a condenser for reaction at 160 C.-180 C. for 5 hours while the reactant is dehydrated during esterification. Esterification lasts until the acidity of the reactant becomes less than 3 mgKOH/g. Afterward, 0.97 mole of 2-EHA is added and esterification continues at 160 C.-230 C. for 5 hours until the acidity of the reactant becomes less than 5 mgKOH/g to finalize esterification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
titanium(IV) isopropylate; In xylene; at 160 - 180℃; for 5h; | Embodiment 1 Hexahydrophthalic anhydride of 0.5 mole, diethylene glycol of 1.15 moles, catalyst TIPT (Tetraisopropyl titanate) of 1.0 g and xylene of 34.0 g are received in a four-neck flask equipped with magnetic stir bars and a condenser for reaction at 160 C.-180 C. for 5 hours while the reactant is dehydrated during esterification. Esterification lasts until the acidity of the reactant becomes less than 3 mgKOH/g. Afterward, 0.96 mole of 2-EHA is added and esterification continues at 160 C.-230 C. for 5 hours until the acidity of the reactant becomes less than 5 mgKOH/g to finalize esterification. |
Yield | Reaction Conditions | Operation in experiment |
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37% | At -30 C., 3.38 g (13.9 mmol) of methyl 2-cyclopropyl-6-ethyl-4-methylphenyl acetate are slowly added dropwise to a solution of lithium diethylamide, prepared from 3.5 g of diethylamine in 25 ml of THF, and 14 ml of a 2.5 molar solution of n-butyllithium in hexane, and the mixture is stirred at room temperature for another 30 min. 2.15 g (13.9 mmol) of cyclohexane-1,2-dicarboxylic anhydride, dissolved in 10 ml of THF, are then added at -20 C., and the mixture is stirred at room temperature for 12 h. Addition of 30 ml of sat. ammonium chloride solution, covering with a layer of ethyl acetate, washing with water, drying (magnesium sulphate) and concentration using a rotary evaporator gives about 5.4 g of a solid to which, without further purification, 2.2 g of potassium hydroxide in 50 ml of water are added, and which is heated under reflux for 24 h. The mixture is then acidified to pH 2 using 2N hydrochloric acid, and the resulting precipitated solid is filtered off with suction.This gives 1.68 g (37%) of the compound of the formula (XXXVII-1) in the form of yellowish crystals of m.p. 187-188 C. |
Yield | Reaction Conditions | Operation in experiment |
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[0676] In the same manner as in Example II-15, a reaction was carried out using 154.1 g (1 mole) of 1,2-cyclohexanedicarboxylic anhydride (prepared by hydrogenating 4-cyclohexene-1,2-dicarboxylic anhydride obtained by usual Diels-Alder reaction of maleic anhydride and 1,3-butadiene) and 74 g (1 mole) of isobutanol with a peroxide value of 0.1 meq/kg and a carbonyl value of 0.1 as alcohol component 1, whereby the total acid number of the reaction mixture became 246 mgKOH/g (theoretical value: 246 mgKOH/g). [0677] Then, to the reaction mixture was added tin oxide (0.2 wt. percent based on the starting materials fed) as a catalyst, and at 220° C., 7.4 g (0.1 mole) of said isobutanol and 158.4 g (1.1 moles) of <strong>[3452-97-9]3,5,5-trimethylhexanol</strong> with a peroxide value of 0.1 meq/kg and a carbonyl value of 0.2 as alcohol component 2 were further added dropwise. While water generated during the reaction was removed by water separator, the esterification reaction was carried out at 220° C. for about 9 hours until the total acid number of the reaction mixture became 3 mgKOH/g or less, and further continued at 220° C. and at 20000 Pa for 1 hour. [0678] After the reaction, the excess alcohols were removed by distillation at 180° C. under a reduced pressure of 1330 Pa, and the obtained liquid residue was neutralized by adding thereto 27 g of a 4percent aqueous solution of sodium hydroxide and stirring the mixture at 80° C. for 2 hours, and then washed with water until it became neutral, giving a crude ester mixture. At this point, the crude ester mixture had a total acid number of 0.01 mgKOH/g. Subsequently, to the crude ester mixture was added activated carbon ("Shirasagi M" manufactured by Sumitomo Chemical Co., Ltd.; 0.1 wt. percent based on the starting materials fed), and the mixture was stirred at 90° C. and at 1330 Pa for 1 hour and filtered, whereby 320 g of a purified ester mixture containing (isobutyl)(3,5,5-trimethylhexyl) 1,2-cyclohexanedicarboxylate was obtained. Dehydration was carried out at 100° C. under a reduced pressure of 1330 Pa for 6 hours. The total acid number and kinematic viscosity of the obtained ester are shown in Table 6. [0679] The ester mixture had a water content of 12 ppm, a sulfated ash content of less than 1 ppm, a sulfur content of less than 1 ppm, a phosphorus content of less than 1 ppm, a hydroxyl value of 0.2 mgKOH/g, a peroxide value of 0.1 meq/kg and a carbonyl value of 0.2. The obtained ester mixture had a cis:trans isomer ratio of 38:62 (area percent), as determined from the gas chromatogram thereof. Further, the obtained ester mixture was found to be a mixture of the following esters from the gas chromatogram thereof: [0680] (1) diisobutyl 1,2-cyclohexanedicarboxylate [0681] (2) (isobutyl)(3,5,5-trimethylhexyl) 1,2-cyclohexanedicarboxylate [0682] (3) di(3,5,5-trimethylhexyl) 1,2-cyclohexanedicarboxylate [0683] (1)/(2)/(3)=21.9/44.2/33.9 (area percent) |
Yield | Reaction Conditions | Operation in experiment |
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In a 100 niL round bottom flask, To a solution of S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) and hexa-hydro-phthalic anhydride (1 mmol) in CH2Cl2 (10 mL) was added N,N-diisopropyl- ethyl-amine (0.87 mL, 5 mmol). The solution was stirred at room temperature for 2 h. Then, the reaction was quenched by IN HCl (10 mL) and pH was adjusted to 2.0-3.0. The mixtures were extracted by ethyl acetate (15 mL x 3). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was further purified by preparative HPLC to yield a 7:3 mixture of Compound N-51a and Compound N-51b (352 mg, 73%). 1H-NMR (500 MHz, CDCl3): delta 1.18-1.48 (m, 4H), 1.53 (s, 6H), 1.59 (s, 3H), 1.61 (s, 3H), 1.71-1.88 (m, 4H), 1.88-2.00 (m, 8H), 2.79-2.89 (m, 3H), 3.01-3.18 (m, 3H), 4.51-4.77 (m, IH), 5.01- 5.03 (m, 2H), 5.13 (m, IH), 6.39 (m, 0.5H), 6.52 (d, J = 5.0 Hz, 0.5H). 13C-NMR (125 MHz, CDCl3): delta 15.00, 15.11, 15.18, 16.68, 20.77, 20.78, 21.32, 22.53, 22.94, 23.90, 24.71, 25.38, 25.52, 25.67, 25.69, 27.06, 27.72, 27.94, 28.20, 28.58, 28.65, 28.68, 28.72, 31.45, 31.64, 38.60, 38.65, 38.67, 38.70, 38.80, 40.83, 41.09, 41.27, 42.11, 43.21, 49.61, 50.42, 50.63, 52.79, 118.05, 118.24, 118.29, 122.67, 122.70, 122.77, 123.26, 123.30, 130.28, 130.33, 134.27, 134.34, 134.37, 139.11, 139.27,139.44, 171.39, 173.68, 173.85, 178.08, 178.12, 178.69; ES-MS: mass calcd for Chemical Formula: C26H4INO5S 479.67. Found (M+) m/z 480.4, (M+Na) m/z 502.3. |
Yield | Reaction Conditions | Operation in experiment |
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63% | In water; at 180℃;Heating; | General procedure: 0.1 mol of 2-benzofuran-1,3-dione, 3a,4,5,6,7,7a-hexahydroisobenzofuran-1,3-dione or 4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione were suspended in 20 ml of water and 2-aminoacetic acid (0.1 mol) was gradually added. The mixture was heated in term-regulated sand bath (ST 72 Roth, Karlsruhe, Germany), with simultaneous distillation of water. After the water was completely removed, the temperature of the reaction raised up to 180 C and was maintained 1 h. The crude products were recrystallized from toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.5 g | With triethylamine; In toluene; for 8h;Inert atmosphere; Reflux; | A solution of 3-aminopyridine (10 g, 0.106 mol) in toluene (100 ml) was added to the reaction vessel under nitrogen and stirred and stirred. To the reaction flask was added hexahydrophthalic anhydride (24.6 g, 0.159 mol) and triethylamine (21.4 g, 0.211 mol) and the temperature was refluxed for 8 hours to separate the water from the system. Stop the heating reaction, natural cooling to room temperature and then cooled to 0 C with ice water bath for 1 hour. The filter cake was washed three times with toluene (30 ml * 3). The filter cake was collected and dried to give 2- (3-pyridyl) -2H-hexahydroindoline-1,3-dione.Yield: 21.5 g (88% of theory) |
Yield | Reaction Conditions | Operation in experiment |
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With aluminum (III) chloride; In dichloromethane; for 24h;Reflux; | 1,2-Dimethoxybenzene (200 mol) was added slowly to an ice-cooled suspension of aluminum chloride (1.1 equiv) in CH2Cl2 (300 mL). After complete addition, the desired cyclic anhydride (1.0 equiv) was added to the reaction mixture. The resulting solution was refluxed until TLC showed completion of the reaction (24 h). The mixture was poured into ice water (0.10 1.0 L), the organic layer was dried over MgSO4, and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 and filtered over silica gel to remove the dicarboxylic acid formed during workup. The product was crystallized from diethyl ether. | |
With aluminum (III) chloride; In dichloromethane; for 24h;Cooling with ice; Reflux; | 1,2-Dimethoxybenzene (200 mol) was added slowly to an ice-cooled suspension of aluminum chloride (1.1 equiv) in CH2Cl2 (300 mL). The cyclic anhydride (1.0 equiv) was added and the resulting solution was refluxed until TLC showed completion of the reaction (24 h). The mixture was poured into ice water and the organic layer was separated and dried over MgSO4. The solvent was removed in vacuum and the residue was dissolved in CH2Cl2, filtered over silica gel. The solution was removed and the crude product was crystallized from diethyl ether |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine; dmap; In N,N-dimethyl-formamide; at 100℃; for 48h; | EXAMPLE 106; 2-([2,-Piperazin-1-yl-6-(pyrazin-2-ylamino)-2,4'-bipyridin-4- yl]amino}carbonyl)cyclohexanecarboxylic acid; a) 2-([2,-[4-(fert-Butoxycarbonyl)piperazin-1-yl]-6-(pyrazin-2-ylamino)-2,4'- bipyridin-4-yl]amino}carbonyl)cyclohexanecarboxylic acid; Hexahydro-2-benzofuran-1 ,3-dione (0.25 g, 1.6 mmol), A ,A/-dimethylpyridin-4-amine (15 mg, 0.12 mmol) and pyridine (0.17 mL, 2.1 mmol) were added to a solution of tert- butyl 4-[4-amino-6-(pyrazin-2-ylamino)-2,4'-bipyridin-2'-yl]piperazine-1-carboxylate (preparation 26, 0.15 g, 0.33 mmol) in dimethylformamide (5 mL) and mixture stirred at 100C for 48 hour. The crude was poured onto water, 2N sodium hydroxide was added and the product was extracted with ethyl acetate (99%).LR S (m/z): 603 (M+1)+. |
99% | With pyridine; dmap; In N,N-dimethyl-formamide; at 100℃; for 48h; | Hexahydro-2-benzofuran-1,3-dione (0.25 g, 1.6 mmol), N,N-dimethylpyridin-4-amine (15 mg, 0.12 mmol) and pyridine (0.17 mL, 2.1 mmol) were added to a solution of tert-butyl 4-[4-amino-6-(pyrazin-2-ylamino)-2,4'-bipyridin-2'-yl]piperazine-1-Carboxylate (preparation 26, 0.15 g, 0.33 mmol) in dimethylformamide (5 mL) and mixture stirred at 100 C for 48 hour. The crude was poured onto water, 2N sodium hydroxide was added and the product was extracted with ethyl acetate (99%).LRMS (m/z): 603 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With dmap; triethylamine; In dichloromethane; at 20℃; for 2h;Inert atmosphere; | Under nitrogen atmosphere and at room temperature 154.2 mg of hexahydroisobenzofuran-1,3-dione was mixed with 194 mg of 2-hydroxy-1-(3-(hydroxymethyl)phenyl)-2-methylpropan-1-one, 5 mg of N,N-dimethylpyridin-4-amine, and 0.12 mL of Et3N in 2 mL of dry dichloromethane. The mixture was stirred for 2 hrs and diluted by 15 mL of Et2O. The organic layer was washed by saturated NaHCO3 of equal volume. The separated aqueous layer was acidified to pH = 2 and extracted twice by ethyl acetate. The combined ethyl acetate layer was concentrated and thus obtained residue was loaded onto silica gel column and eluted by mixtures of hexane/ethyl acetate (V/V = 1/1) to give the target product A as colorless oil (94% yield). 1H NMR (CDCl3, ppm): 8.02 (s, 1H), 7.94 (d, 1H, J = 7.6 Hz), 7.52 (d, 1H, J = 7.2 Hz), 7.45 (dd, 1H, J = 7.6 Hz, J = 7.2 Hz), 5.18 (s, 2H), 2.90 (br, 2H), 1.63 (s, 6H), 2.08-1.95 (m, 2H), 1.84-1.44 (m, 8H); 13C NMR (CDCl3, ppm): 204.5, 179.2, 173.4, 136.4, 134.4, 132.2, 129.3, 129.1, 128.6, 76.8, 65.7, 42.5, 42.4, 28.2, 26.2, 26.0, 23.7, 23.6. |
94% | With dmap; triethylamine; In dichloromethane; at 20℃; for 2h;Inert atmosphere; | Under nitrogen atmosphere and at room temperature 154.2 mg of hexahydroisobenzofuran-1,3-dione was mixed with 194 mg of 2-hydroxy-1-(3-(hydroxymethyl)phenyl)-2-methylpropan-1-one, 5 mg of N,N-dimethylpyridin-4-amine, and 0.12 mL of Et3N in 2 mL of dry dichloromethane. The mixture was stirred for 2 hrs and diluted by 15 mL of Et2O. The organic layer was washed by saturated NaHCO3 of equal volume. The separated aqueous layer was acidified to pH=2 and extracted twice by ethyl acetate. The combined ethyl acetate layer was concentrated and thus obtained residue was loaded onto silica gel column and eluted by mixtures of hexane/ethyl acetate (V/V=1/1) to give the target product A as colorless oil (94% yield). 1H NMR (CDCl3, ppm): 8.02 (s, 1H), 7.94 (d, 1H, J=7.6 Hz), 7.52 (d, 1H, J=7.2 Hz), 7.45 (dd, 1H, J=7.6 Hz, J=7.2 Hz), 5.18 (s, 2H), 2.90 (br, 2H), 1.63 (s, 6H), 2.08-1.95 (m, 2H), 1.84-1.44 (m, 8H); 13C NMR (CDCl3, ppm): 204.5, 179.2, 173.4, 136.4, 134.4, 132.2, 129.3, 129.1, 128.6, 76.8, 65.7, 42.5, 42.4, 28.2, 26.2, 26.0, 23.7, 23.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
400 mg | With triethylamine; In dichloromethane; at 0℃; for 0.5h; | Triethylamine (352 mg, 3.48 mmol) was added at 0 C to a solution of the anhydride BB8-a and <strong>[74572-04-6]<strong>[74572-04-6](R)-3-methylmorpholin</strong>e</strong> (238 mg, 1.74 mmol) in DCM (40 ml). After stirring for 30 min at 0 C the mixture was washed with brine (2x5 ml) and the organic layer was concentrated which gave the title compound (400 mg). MS (ESI): 256 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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70% | With montmorillonite K10; at 170℃; for 0.35h;Microwave irradiation; Green chemistry; | General procedure: In a 25mL beaker, anhydride (1 mmol), semicarbazide (1mmol) were roughly mixed with montmorillonite K10 (1 g)and after 3 min of mechanical stirring, the mixture was irradiated into a single mode focused microwave reactor with continuous rotation.for18 min (optimized time) at 170 C. Upon completion of the reaction, monitored on TLC (nhexane:ethyl acetate, 3:1), the product was extracted in dichloromethane(2 Chi 25 mL), solvent removal of the solid residue was crystallized from EtOH to yield compounds a-l. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.0% | In dichloromethane; for 30h;Reflux; | General procedure: BE (1 mmol) and acid anhydride (1 mmol) were refluxed in methylene dichloride (50 mL) under stirring for 30 hours. After completion of the reaction, the reactant was washed with saturated sodium bicarbonate and brine solutions, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The product was purified by column chromatography with a mobile phase of ethyl acetate/petroleum ether (1/3). |
Yield | Reaction Conditions | Operation in experiment |
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This example demonstrates the production of 4-(1 ,3-Dioxo-octahydro- isoindol-2-yl)-2-hydroxy-benzoic acid having the following structure. In a 500 mL four-neck round bottom flask equipped with temperature probe, heating mantle, agitator, and condenser, 21 .20 g of hexahydrophthalic anhydride and 50 mL of acetic acid were charged. At 70 00, the mixture was stirred until uniform and then 21 .7 g of 4-aminosalicylic acid and 100 mL of acetic acid were charged. After heating to reflux for 6 hours, the contents were poured into ice cold Dl H20 and vacuum filtered to collect the solid. After washing with Dl H20 and drying, 33.07 g of product were obtained. This example demonstrates the production of the zinc salt of 4-(1 ,3- dioxo-octahydro-isoindol-2-yl)-2-hydroxy-benzoic acid having the following structure. In a beaker, 4-(1 ,3-dioxo-octahydro-isoindol-2-yl)-2-hydroxy-benzoic acid is suspended in about 100-150 mL of water with a magnetic stirrer. Then, a 25% solution of sodium hydroxide was slowly added until the pH stabilized at 12.5 and the solution became clear. Then, one equivalent of zinc chloride was added (used 1 eq instead of 0.5 because metal ions can coordinate with the meta hydroxy group as well). The products precipitated out, and the mixture was filtered to collect the product. | ||
This example demonstrates the production of 4-(1 ,3-Dioxo-octahydro- isoindol-2-yl)-2-hydroxy-benzoic acid having the following structure. In a 500 mL four-neck round bottom flask equipped with temperature probe, heating mantle, agitator, and condenser, 21 .20 g of hexahydrophthalic anhydride and 50 mL of acetic acid were charged. At 70 00, the mixture was stirred until uniform and then 21 .7 g of 4-aminosalicylic acid and 100 mL of acetic acid were charged. After heating to reflux for 6 hours, the contents were poured into ice cold Dl H20 and vacuum filtered to collect the solid. After washing with Dl H20 and drying, 33.07 g of product were obtained. This example demonstrates the production of the zinc salt of 4-(1 ,3- dioxo-octahydro-isoindol-2-yl)-2-hydroxy-benzoic acid having the following structure. In a beaker, 4-(1 ,3-dioxo-octahydro-isoindol-2-yl)-2-hydroxy-benzoic acid is suspended in about 100-150 mL of water with a magnetic stirrer. Then, a 25% solution of sodium hydroxide was slowly added until the pH stabilized at 12.5 and the solution became clear. Then, one equivalent of zinc chloride was added (used 1 eq instead of 0.5 because metal ions can coordinate with the meta hydroxy group as well). The products precipitated out, and the mixture was filtered to collect the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | In toluene; for 12h;Dean-Stark; Reflux; | General procedure: Suspension of anhydride (18.725 mmol) in toluene in an oven dried round-bottom flask fitted with Dean-Starkset up was heated at reflux until complete dissolution of the anhydride and no additional water was removed. To this solution was added tryptamine (3.000 g, 18.725mm ol) and refluxing was continued until the water evolution was completed (12 h). Reaction mixture was concentrated under reduced pressure to give a residue which was purified through neutral alumina column chromatography using ethyl acetate:hexane as eluent (1:4). |
Yield | Reaction Conditions | Operation in experiment |
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90% | With acetic acid; at 140℃; for 3h; | A 50 mL round-bottom flask equipped with a magnetic stirrer was charged with 0.5584 g (1.00 mmol) of diamine 3, 0.3237 g (2.10 mmol) of 1,2-cyclohexanedicarboxylic anhydride, and 5 mL acetic acid. The reaction mixture was heated with stirring at 140 C for 3 h. The resulting reaction solution was poured into 200 mL of stirring methanol giving rise to white precipitate. The product was collected by filtration, washed thoroughly with hot water and methanol, and dried in vacuo at 80 C to give 0.75 g (90% in yield) of white powder with a melting point of 241-248 C (by DSC at a heating rate of 10 C/min). IR (KBr; cm-1): 2941, 2862 cm-1 (aliphatic C-H stretch), 1714 cm-1 (sym. imide C=O stretch) and 1783 cm-1 (asym. imide C=O stretch) (Fig. S2). 1H NMR (600 MHz, CDCl3, delta, ppm): 1.54 (m, 8H, Hi), 1.89?2.08 (m, 8H, Hh), 3.09 (m, 4H, Hg), 7.20 (d, J = 8.4 Hz, 2H, Hd), 7.39 (dd, J = 8.4, 2.4 Hz, 2H, Hb), 7.59 (dd, J = 8.4, 2.4 Hz, 2H, He), 7.78 (d, J = 2.4 Hz, 2H, Ha), 7.85 (d, J = 2.4 Hz, 2H, Hf), 8.32 (d, J = 8.4 Hz, 2H, Hc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | at 120℃; for 0.1h;Microwave irradiation; | General procedure: p-Toluene sulfonohydrazide(1a; 186 mg; 1mmol) and furan-2,5-dione (98 mg; 1mmol)were mixed thoroughly and subjected to a focused microwaveirradiation at 120 C for 3 min. TLC of reactionmixture over silica gel G using CHCl3: MeOH (9.5:0.5) asmobile phase showed absence of starting materials andhence completion of the reaction. This crude product waspurified by crystallization from chloroform : methanol(4:1) to give pure product 2a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | at 120℃; for 0.1h;Microwave irradiation; | General procedure: p-Toluene sulfonohydrazide(1a; 186 mg; 1mmol) and furan-2,5-dione (98 mg; 1mmol)were mixed thoroughly and subjected to a focused microwaveirradiation at 120 C for 3 min. TLC of reactionmixture over silica gel G using CHCl3: MeOH (9.5:0.5) asmobile phase showed absence of starting materials andhence completion of the reaction. This crude product waspurified by crystallization from chloroform : methanol(4:1) to give pure product 2a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | at 150℃; for 0.0333333h;Microwave irradiation; | General procedure: Sulfathiazole (6a; 255mg;1mmol) and furan-2,5-dione (98mg; 1mmol) were mixedthoroughly and subjected to focused microwave irradiationat 150 C for 5 min. TLC of reaction mixture over silicagel G using CHCl3: MeOH (9:1) as mobile phase showedabsence of starting materials and hence completion of thereaction. This crude product was purified by crystallizationfrom methanol to give pure product 7a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | at 150℃; for 0.0333333h;Microwave irradiation; | General procedure: Sulfathiazole (6a; 255mg;1mmol) and furan-2,5-dione (98mg; 1mmol) were mixedthoroughly and subjected to focused microwave irradiationat 150 C for 5 min. TLC of reaction mixture over silicagel G using CHCl3: MeOH (9:1) as mobile phase showedabsence of starting materials and hence completion of thereaction. This crude product was purified by crystallizationfrom methanol to give pure product 7a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | at 150℃; for 0.0333333h;Microwave irradiation; | General procedure: Sulfathiazole (6a; 255mg;1mmol) and furan-2,5-dione (98mg; 1mmol) were mixedthoroughly and subjected to focused microwave irradiationat 150 C for 5 min. TLC of reaction mixture over silicagel G using CHCl3: MeOH (9:1) as mobile phase showedabsence of starting materials and hence completion of thereaction. This crude product was purified by crystallizationfrom methanol to give pure product 7a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.4% | In toluene; at 110 - 120℃; for 8h;Inert atmosphere; | 30.0 g (0.19 mol) of 1,2-cyclohexanedicarboxylic anhydride, 62.7 g (0.16 mol) of cholesterol and 200 g of toluene as a solvent was charged, heated to 110 to 120 C. in a nitrogen stream, and reacted for 8 hours. After the reaction, 14.8 g of methyl ethyl ketone and 59.1 g of purified water were added, and the organic layer was washed with water at 50 to 60 C. After repeated washing with water until the aqueous layer became neutral, the organic layer was concentrated. Next, heptane was added to the concentrate for dissolution, and the solution was cooled to 5 C., and crystallization and filtration were carried out. The obtained crystal was rinsed with cold heptane and dried overnight at 25 C. under reduced pressure to obtain 63.5 g of monocholesteryl 1,2-cyclohexanoic acid dicarboxylate as a target compound as white crystals (yield 72. 4%). |
33% | With pyridine;Reflux; | General procedure: A solution of cholesterol (38.6 g, 100 mmol) and dicarboxylic acid anhydride (10 mmol) was refluxed in dry pyridine (100 mL) for 8-10 h., The reaction mixture was concentrated under reduced pressure using rotary evaporator to produce a wet residue, which was dissolved in 50 mL of boiling acetone, and on cooling it gave colorless product. The crude compound was purified by two recrystallizations from acetone and one from absolute ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | In acetonitrile;Reflux; | A. General Procedure for the Synthesis of Cyclic and Bicyclic Anhydride/Phenylhydrazine Compounds HHPH [0073] To a 1000 mL four-neck round bottom flask, equipped with a condenser, thermocouple, mechanical stirrer, an addition funnel, and a nitrogen inlet, was added HHPA (77.8 g, 0.505 mol), and CH3CN (500 mL) with stirring. The solution was heated to reflux. Phenylhydrazine (54.0 g, 0.50 mol) was added dropwise over a period of time of about 15 - 20 minutes, and the reaction was stirred at reflux for a period of time of 30 minutes. The product precipitated from solution on cooling to ambient temperature. Crude Yield = 107.0g (81 %); Melting point = 152C. The product was recrystallized from CHsCN. Crystallized Yield = 77.1 g (59%): 1H NMR (d6-DMSO) deltadelta 12.0 (s, 1 , OH), 9.5 (s, 1 , NH), 7.6 (s, 1 , NH), 7.1 (t, 2, Ar-H), 6.7 (m, 3, Ar-H), 2.8 (m, 1 , CO-CH), 2.6 (m, 1 , CO-CH), 1.1-2.1 (m, 8, CH2); 13C NMR (de-DMSO) 175, 173, 148, 128, 118, 1 12, 42, 28, 25, 24, 22; IR (neat) 2928, 1698, 1665, 1602, 1495, 1265, 1239, 750, 690 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; at 50℃; for 7h;Ionic liquid; | General procedure: A mixture ofcompound 2 (0.188 g, 0.001 mol) and the correspondinganhydrides (0.001 mol) in DES (Choline chloride:urea) (1 gm) and catalytic amount of glacial acetic acid(2 drops) was stirred at 50C for 5-8 h. After completionof the reaction (TLC check with dichloromethane/methanol 9:1) the viscous mass was cooled and extractedwith a mixture of hexane/ethyl acetate (1:4) fourtimes (4 × 10 mL). The organic layer was then washedwith brine solution, water and dried over anhydroussodium sulfate. Then, solvent was removed underreduced pressure to obtain solid which was purified bycolumn chromatography (eluting with 5% methanol indichloromethane) to furnish 14a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | at 120℃; for 0.0666667h;Microwave irradiation; | Hexahydroisobenzofuran-1,3-dione (1a; 308 mg; 2mmol) and 2-(2-(2-aminoethoxy)ethoxy)ethanamine (2a; 148 mg; 1mmol) were mixed thoroughly and subjected to a focused microwave irradiation at 120 C for 4 minutes. TLC of reaction mixture over silica gel G using CHCl3: MeOH (9.5:0.5) as mobile phase showed absence of starting materials and presence of a new spot of the product. Hence, the reaction is complete. Crude product, so obtained was purified by column chromatography over silica gel using solvent of elution: CHCl3:MeOH (9.7:0.3) to give pure product 3a. Yield: 85%. Semi solid. IR (KBr) numax: 1704 (-CO-N-CO-) cm-1. 1H NMR (400 MHz, CDCl3) delta: 1.363-1.413 (t, 8H, 4×CH2), 1.725-1.821 (dd, 8H, 4×CH2), 2.823-2.833 (d, 4H, 4×-CO-CH-), 3.460-3.691 (m, 12H, 6×CH2). 13C NMR (100 MHz, CDCl3) delta: 21.43, 23.57, 37.40, 39.60, 66.93, 69.72, 179.63. GC-MS: m/z 420 (M+, 4.75%), 267 ( , 12.41%), 250 ( , 5.91%), 225 ( , 4.92%), 208 ( , 26.33%), 207 ( , 71.32%), 206 ( , 100%), 195 ( , 2.74%), 152 ( , 7.84%), 73 ( , 97.20%). Elemental Anal. Calcd. for C22H32N2O6: C 62.86, H 7.62, N 6.67. Found: C 62.91, H 7.58, N 6.59%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | at 120℃; for 0.0666667h;Microwave irradiation; | General procedure: Hexahydroisobenzofuran-1,3-dione (1a; 308 mg; 2mmol) and 2-(2-(2-aminoethoxy)ethoxy)ethanamine (2a; 148 mg; 1mmol) were mixed thoroughly and subjected to a focused microwave irradiation at 120 C for 4 minutes. TLC of reaction mixture over silica gel G using CHCl3: MeOH (9.5:0.5) as mobile phase showed absence of starting materials and presence of a new spot of the product. Hence, the reaction is complete. Crude product, so obtained was purified by column chromatography over silica gel using solvent of elution: CHCl3:MeOH (9.7:0.3) to give pure product 3a. Yield: 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | at 150℃; for 0.0833333h;Microwave irradiation; | General procedure: Hexahydroisobenzofuran-1,3-dione (1a; 308 mg; 2mmol) and 2-(2-(2-aminoethoxy)ethoxy)ethanamine (2a; 148 mg; 1mmol) were mixed thoroughly and subjected to a focused microwave irradiation at 120 C for 4 minutes. TLC of reaction mixture over silica gel G using CHCl3: MeOH (9.5:0.5) as mobile phase showed absence of starting materials and presence of a new spot of the product. Hence, the reaction is complete. Crude product, so obtained was purified by column chromatography over silica gel using solvent of elution: CHCl3:MeOH (9.7:0.3) to give pure product 3a. Yield: 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | at 150℃; for 0.0333333h;Microwave irradiation; | General procedure: Hexahydroisobenzofuran-1,3-dione (1a; 308 mg; 2mmol) and 2-(2-(2-aminoethoxy)ethoxy)ethanamine (2a; 148 mg; 1mmol) were mixed thoroughly and subjected to a focused microwave irradiation at 120 C for 4 minutes. TLC of reaction mixture over silica gel G using CHCl3: MeOH (9.5:0.5) as mobile phase showed absence of starting materials and presence of a new spot of the product. Hence, the reaction is complete. Crude product, so obtained was purified by column chromatography over silica gel using solvent of elution: CHCl3:MeOH (9.7:0.3) to give pure product 3a. Yield: 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With isoquinoline; In N,N-dimethyl acetamide; at 210℃; for 5h; | 5.0 g of MeOTPPA-diNH2 was mixed with 3.06 g of HHPA in a reaction flask. Take 7.5mL of DMAc as a solvent to the reaction flask, and take a small amount of isoquinoline as a catalyst to join the reaction bottle. The mixture in the reaction flask was heated to 210 C for 5 hours and then cooled to room temperature. The reaction was diluted with methanol and poured into water to precipitate a solid. Collect the solid and rinse and dry to obtain the white product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With isoquinoline; In N,N-dimethyl acetamide; at 210℃; for 5h; | Take 1.50 g of MeOTPA-diNH2 and 1.70 g of hexahydrophthalic anhydride (HHPA) in a reaction flask and mix. Take 2.5mL of DMAc as a solvent into the reaction flask, and take a small amount of isoquinoline as a catalyst to join the reaction bottle. The mixture in the reaction flask was heated to 210 C for 5 hours and then cooled to room temperature. The reaction was diluted with methanol and poured into water to precipitate a solid. Collect the solid and rinse and dry to obtain the white product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | General procedure: Triphenylphosphine (1.60g, 6.00mmol) was dissolved in 6mL of THF and the solution was cooled to 0C under N2. A solution of CBr4 (1.00g, 3.00mmol) in THF (1.00mL per mmol PPh3) was added to the THF (6mL) solution of PPh3 and the reaction was stirred until the color changed to yellow. Triethylamine (TEA) (1.1mL, 6.0mmol) was added dropwise to the mixture over 5min, after which a solution of an anhydride compound (1-9d, 1.00mmol) in THF (1.0mL per mmol phthalic anhydride) was incrementally added. The reaction was stirred for 1hat 0C, after which it was allowed to warm to room temperature and stirred overnight. The reaction was quenched by addition of sat aq NH4Cl solution (30mL). The phases were then separated, and the crude product was extracted with hexane from the aqueous layer (30×3mL). The combined organic layers were concentrated under reduced pressure. The residue was dissolved in Et2O (25mL) and filtered over a Celite pad (7.0×3.0cm). The resulting filtrate was concentrated by rotary evaporation and the crude products were purified through the use of silica gel column chromatography (5-15% EtOAc in hexane). The desired products were obtained. | |
40% | Triphenylphosphine (0.79 g, 3.0 mmol) was dissolved in 3 ml of THF, which was cooled down to 0 C. under nitrogen gas. THF (3.0 ml) solution containing CBr4 (0.50 g, 1.5 mmol) dissolved therein was added thereto, followed by stirring until the color of the solution turned yellow. After the color change, TEA (0.27 ml, 1.5 mmol) was added drop by drop for 5 minutes, to which THF (1 ml) solution containing cyclohexanedicarboxylic acid anhydride (0.15 g, 1.0 mmol) dissolved therein was added gradually. The reaction solution was stirred at 0 C. for 30 minutes. Then, the temperature of the reaction solution was adjusted to room temperature, followed by stirring for 3 hours. The reaction was quenched with a saturated NH4Cl aqueous solution. When the phases were separated, the water layer was extracted by using hexane. The combined organic layer was concentrated under reduced pressure. The obtained residue was dissolved in ethoxyethane and filtered through a celite pad. The obtained solution was concentrated by rotary evaporation and purified by flash column chromatography. As a result, a target compound was obtained (0.12 g, 40%). NMR graphs of the obtained target compound are shown in . The upper graph of is a graph showing the results of 1H NMR of Example 1, and the lower graph of is a graph showing the results of 13C NMR of Example 1. 1H NMR (CDCl3, 500 MHz) delta 3.31-3.19 (m, 1H), 2.98 (t, J=6.8 Hz, 1H), 2.22 (t, J=14.3 Hz, 2H), 1.72 (d, J=15.0 Hz, 2H), 1.35-1.05 (m, 4H). 13C NMR (CDCl3, 125 MHz) delta 174.1, 158.2, 68.9, 40.7, 40.0, 26.5, 23.0, 22.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With acetic acid;Reflux; | A solution of N-benzyl-5 - ((1,3-dioxoisoindolin-2-yl) methyl) -2-methoxy-N-methylbenzenesulfonamide of Example 19 (35 mg, 0.077 mmol, 1 eq,) was dissolved in ethanol (2 ml)Hydrazine hydrate (50ul, 0.62mmol, 8eq) was added and the mixture was stirred at reflux for 2 hours. The mixture was allowed to cool, filtered and the filtrate was concentrated. The residue was subjected to column chromatography to give deprotected amine.The deprotected amine (16 mg, 0.05 mmol, 1 eq) was dissolved in acetic acid (5 ml), cyclohexyl dicarboxylic anhydride (8 mg, 0.05 mmol, 1 eq) was added and the mixture was stirred at reflux overnight. The solvent was evaporated and the residue was subjected to column chromatography to give the title compound as a white oil (yield 77%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With acetic acid; for 18h;Reflux; | To a solution of hexahydroisobenzofuran-1,3-dione (3.08 g, 20 mmol) in acetic acid (30 ml) was added (4-methoxyphenyl) methylamine (2.62 ml, 20 mmol)The mixture was stirred at reflux for 18 hours.The residue was washed with methylene chloride, washed sequentially with 1 M hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated by filtration. The residue was used directly in the next reaction (pale yellow solid, 5.46 g, yield 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dmap; ammonium chloride; at 150℃; for 0.166667h;Microwave irradiation; Sealed tube; Green chemistry; | General procedure: 2-(2,6-Dioxopiperidin-3-yl)isoindole-1,3-dione. (1): phthalicanhydride (0.10 g, 0.68mmol), glutamic acid (0.10 g,0.68mmol), DMAP (0.02 g, 0.16mmol), and NH4Cl (0.04 g,0.75mmol) were mixed thoroughly in a CEM-sealed vialwith a magnetic stirrer.The sample was heated for 10min at150?C in a CEM Discover microwave powered at 150W. Itwas then cooled rapidly to 50?C.When at room temperatureit was dissolved in 15mL of (1 : 1) ethyl acetate : acetone. Theorganic layer was washed with 2x (10 mL) distilled water andthen dried over sodium sulfate (anhydrous). The organiclayer was concentrated under vacuum. The residue wastreated with hexanes (30mL) affording a white solid (0.14 g,80%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With N-((1R,2R)-2-(dimethylamino)-1-(4-nitrophenyl)-3-(trityloxy)propyl)-3,5-bis-(trifluoromethyl)benzamide; In tert-butyl methyl ether; at 20℃; for 60h;Inert atmosphere; | General procedure: An alcohol (5 mmol) was added dropwise at room temperature under nitrogen to astirred solution of an anhydride 8 (0.5 mmol) and 7i (36.1 mg, 0.05 mmol) in MTBE(20 mL). The reaction was monitored by using thin-layer chromatography. Onceanhydride consumption was complete, the solvent was evaporated under reducedpressure and the residue was dissolved in CH2Cl2 (10 mL). The solution was washedwith saturated Na2CO3 (2 × 5 mL) and the combined aqueous phase were acidifiedwith excess 2 N HCl, followed by extraction with EtOAc (3 × 10 mL). The combinedorganic phases were dried over Na2SO4 and concentrated to afford the correspondingmonoester, without further purification by flash chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With CBV780; In 1,2-dichloro-benzene; at 90℃; for 0.75h;Sealed tube; Microwave irradiation; | 10243] A mixture of 3.2 mmol of (ethoxy)trimethylsilane (Ia), 2.6 mmol of cyclohexane-1,2-dicarboxylic anhydride (IIBc), 60 mg of CBV78O (manufactured by Zeolyst International) and 2 mE of 1 ,2-dichiorobenzene was introduced into a reaction tube. The reaction tube was then sealed, followed by stirring at 90 C. for 45 minutes using a microwave irradiation apparatus (Initiator; manufactured by Biotage AB). The post-treatment and the distillation were carried out in the same manner as in Example 86, to obtain 1.56 mmol (yield: 60%) of (2-ethoxycarbonyl)cyclohexa- nylcarbonyloxy]trimethylsilane (IIIBc).10244] The physical property values and the spectral data of the resulting compound (IIIBc) were as follows.10245] Boiling point: from 125 to 130 C/S mmHg (distillation temperature in short path distillation)10246] ?H-NMR (CDC13): oe 0.25 (s, 9H, SiCH3), 1.22 (t, J=7.2 Hz, 3H, CCH3), 1.32-1.55, 1.67-1.80, and 1.90-2.03 (each m, each 2H, (CH2)4), 2.70-2.85 (m, 2H, CHCH), 4.07-4.17 (m, 2H, OCH2)10247] ?3C-NMR (CDC13): oe -0.4, 14.2, 23.7, 23.9, 26.2,26.5, 42.7, 43.7, 60.2, 173.7, 174.210248] 29Si-NMR (CDC13): oe 23.610249] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.00 parts of a salt represented by the formula (I-1-a)28 parts of dimethylformamide and 1.74 parts of dimethylaminopyridine were mixed and stirred at 23 C. for 30 minutes. To the obtained mixed solution,2.20 parts of the compound represented by the formula (I-23-b) was added,Further, the mixture was stirred at 23 C. for 18 hours. To the obtained reaction mass,150 parts of chloroform and 18 parts of a 5% oxalic acid aqueous solution were added and the mixture was stirred at 23 C. for 30 minutes, then separated, and the organic layer was taken out.45 parts of ion-exchanged water was added to the recovered organic layer, and the mixture was stirred at 23 C. for 30 minutes, then separated, and the organic layer was taken out. This washing operation was repeated 5 times.After concentrating the recovered organic layer, to the concentrated mass,After 25 parts of ethyl acetate was added, the mixture was stirred at 23 C. for 30 minutes,The supernatant was removed and concentrated,5.19 parts of a salt represented by the formula (I-23-c) was obtained. | ||
Mix 7.00 parts of the salt represented by (I-1-a), 28 parts of dimethylformamide and 1.74 parts of dimethylaminopyridine,Stirred at 23 C. for 30 minutes.In the mixture obtained,2.20 parts of a compound represented by formula (I-1-b) are added,Furthermore, it stirred at 23 degreeC for 18 hours.In the reaction mixture obtained,After adding 150 parts of chloroform and 18 parts of 5% aqueous solution of oxalic acid and stirring at 23 C. for 30 minutes,The layers were separated and the organic layer was taken out.After 45 parts of ion-exchanged water is added to the obtained organic layer and stirred at 23 C. for 30 minutes,The layers were separated and the organic layer was taken out.This water washing operation was repeated 5 times.After concentrating the obtained organic layer, a concentrated mixture is obtained byAfter adding 25 parts of ethyl acetate and stirring at 23 C. for 30 minutes,By removing the supernatant and concentrating,5.19 parts of a salt represented by the formula (I-1-c) were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dmap; In dichloromethane; at 20℃; | General procedure: The key intermediate H6 was obtained from the raw H according to the previous experimental method [16]. To a solution of H6 and 4-dimethylaminopyridine (DMAP) in dry pyridine, different anhydride was added. The key intermediates X1a-X1c were obtained through action at room temperature (r.t.), then obtained 1-3 through catalytic reduction of hydrogen (see Scheme 1). The compound 4 was obtained through catalytic reduction of hydrogen H6 (see Scheme 1). To a solution of H6 in dry 51 pyridine, 54 acetic anhydride was slowly added. The reaction mixture was stirred at r.t. for 5h, then obtained the key intermediate X3 through catalytic reduction of 49 hydrogen, and 55 oxalyl chloride was added to a solution of 56 X3 in dry 57 dichloromethane (8.0mL) in 0C. After, Acyl Chloride, the appropriate branched chain and dry 58 DCM were obtained X4a-X4e and X4h-X4n. To a solution of X4a-X4e and X4h-X4n in 60 tetrahydrofuran with 61 methanol (MA) or 62 water, 10% 63 sodium hydroxide was slowly added. Compounds 5-9 were obtained at room temperature for 10h by hydrolysis reaction (see Scheme 2. The intermediate 64 X7 was prepared from the reaction of a solution of the intermediate X6 in DMF with formic acid and 30% hydrogen peroxide (H2O2), then compound X7 in absolute acetone was stirred with 10% hydrogen chloride (10% HCl) to removal of C-23 protective groups at r.t. A mixture of X8 and 10% Pd/C in methanol was stirred at r.t. under H2 (see Scheme 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With acetic acid; for 1.5h;Reflux; | General procedure: A mixture of tyramine 8 (274 mg, 2.0 mmol) and the correspondinganhydride (1.9 mmol) in glacial acetic acid (3 mL) were refluxed for 1.5 h. After cooling of the reactionmixture to ambient temperature, cold H2O (10 mL) was added and the resultant precipitate wasfiltered, washed several times with cold water, and dried under reduced pressure (7a, 7e). When theproduct did not precipitate from the solution (7b-d, 7h-j), H2O (15 mL) was added, and the aqueousphase was extracted several times with EtOAc. The combined organic layers were washed with 1 MNaHCO3, dried over Na2SO4, and concentrated in vacuo to yield the crude products, which were usedwithout further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With choline chloride; urea; at 140℃; for 1.0h;Green chemistry; | General procedure: DES ChCl/urea was synthesized as described in literature(Abbott et al. 2004). Briefly, choline chloride and urea with the molar ratio of 1:2 were stirred at 80 C for 1 h until a clear and transparent solution was formed (Fig. 1). The obtained DES was used without additional purification. Into a 25-mL round-bottom flask were added ChCl/urea (5.19 g, 20 mmol), phthalic anhydride (1.48 g, 10 mmol) and urea (0.60 g, 10 mmol) in successive, then the mixture was heated at 140 C for 1 h under vigorous stirring. The reaction progress was monitored by GC analysis. After reaction, the reaction mixture was cooled to room temperature, followed by addition of 2 mL of water. The DES was dissolved and the product was precipitated. The solid was collected by filtration and washed thoroughly with water. The white solid was dried thoroughly to afford the product in a yield of 84%. The DES was recovered by evaporation of water under vacuum, and subjected to next run. The product was received in a yield of yield of 95% in the second run. |
Tags: 85-42-7 synthesis path| 85-42-7 SDS| 85-42-7 COA| 85-42-7 purity| 85-42-7 application| 85-42-7 NMR| 85-42-7 COA| 85-42-7 structure
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