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CAS No. : | 16859-59-9 | MDL No. : | MFCD00956142 |
Formula : | C8H6O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JKNKNWJNCOJPLI-UHFFFAOYSA-N |
M.W : | 150.13 | Pubchem ID : | 3804259 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 36.93 |
TPSA : | 46.53 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) : | -6.81 cm/s |
Log Po/w (iLOGP) : | 1.2 |
Log Po/w (XLOGP3) : | 0.57 |
Log Po/w (WLOGP) : | 0.52 |
Log Po/w (MLOGP) : | 1.33 |
Log Po/w (SILICOS-IT) : | 1.28 |
Consensus Log Po/w : | 0.98 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.53 |
Solubility : | 4.39 mg/ml ; 0.0293 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.12 |
Solubility : | 11.4 mg/ml ; 0.0759 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.75 |
Solubility : | 2.65 mg/ml ; 0.0177 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.05 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium methylate In methanol at 0 - 20℃; for 1 h; | Dimethyl phosphite (11 g, 0.1 mol) at 0 ° CAdd dropwise to a solution of sodium methoxide in methanol (100 ml).Then 2-carboxy benzaldehyde (10.5g, 0.05mol)Add to the reaction system,The entire process temperature is controlled below 5 °C.Thereafter, the mixture was heated to room temperature for 1 hour.Methanesulfonic acid (10.6 g, 0.11 mol) was added.The reaction solution was concentrated and washed with water and chloroform.The organic layers were combined and dried over anhydrous NaSO4.Concentrated to:3-oxo-1,3-dihydroxy-isobenzofuran-1-phosphate dimethyl ester (16 g),The yield was 95percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: at 0 - 20℃; for 1 h; Stage #2: With methanesulfonic acid In methanol |
Dimethyl phosphite (22.0 g, 0.2 mol) was added drop-wise to a solution of sodium methoxide (43.0 g) in methanol (100 ml) at 0oC. 2- Carboxybenzaldehyde (21.0 g, 0.1 mol) was then added portion-wise to the reaction mixture as a slurry in methanol (40 ml), with the temperature kept below 5oC. The resulting pale yellow solution was warmed to 20oC over 1 hour. Methanesulphonic acid (21.2 g, 0.22 mol) was added to the reaction drop-wise and the resulting white suspension was evaporated in vacuo. The white residue was quenched with water and extracted into chloroform (3 x 100 ml). The combined organic extracts were washed with water (2 x 100 ml), dried over MGSO4, and evaporated in vacuo to yield (3-OXO-1, 3-dihydro-isobenzofuran-1-yl) phosphonic acid dimethyl ester as a white solid (32.0 g, 95 percent, 95 percent purity). This was then used without further purification in the next stage |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; toluene-4-sulfonic acid In dimethylsulfoxide-d6; chloroform-d1 at 30℃; half-time life; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Heating; | |
With toluene-4-sulfonic acid In dimethylsulfoxide-d6; chloroform-d1 at 30℃; half-time life; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.4% | General procedure: To a suspension of magnesium (6.0 equiv) and catalytic amounts of I2 in anhydrous THF (12 mL) was added the appropriate 1-bromoalkane (5.0 equiv) under argon atmosphere until the Grignard reaction had started. After addition was completed, the reaction mixture was refluxed for 2 h and allowed to cool to room temperature. Subsequently, the prepared Grignard solution was added dropwise to a solution of 4 (300 mg, 1.998 mmol) at -5C. The resulting reaction mixture was stirred at room temperature for 5 h. The mixture was quenched with 3N HCl to pH=2 at 0C and stirred for another 1 h at room temperature. The solution was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with 10% K2CO3 aqueous solution (10 mL×3) and brine (10 mL×2), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by column chromatography to give intermediates 5a-d as oils. 3-butylisobenzofuran-1(3H)-one (5a) It was synthesized from 1-bromobutane. Elution with petroleum ether/ethyl acetate (40:1) afforded 5a as brown oils. 87.4% Yield; 1H NMR (400 MHz, CDCl3) delta 7.90 (d, 1H, J = 7.6 Hz, Ar-H), 7.67 (t, 1H, J = 7.6 Hz, Ar-H), 7.53 (t, 1H, J = 7.6 Hz, Ar-H), 7.44 (d, 1H, J = 7.6 Hz, Ar-H), 5.48 (dd, 1H, J1 = 7.6 Hz, J2 = 4.0 Hz, CH), 2.08-2.01 (m, 1H, 1/2 × CH2), 1.80-1.72 (m, 1H, 1/2 × CH2), 1.52-1.33 (m, 4H, 2 × CH2), 0.91 (t, 3H, J = 7.2 Hz, CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium hydroxide In ethanol at 0℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In ethanol at 20℃; | |
55% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In chloroform at 20℃; for 5h; | |
With toluene-4-sulfonic acid at 85 - 95℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With iron(III) chloride; thionyl chloride for 1h; Reflux; | |
98% | With iron(III) chloride; thionyl chloride for 1h; Reflux; | 5 Carboxybenzaldehyde (16, 10.00 g, 66.61 mmol) and ferric chloride (0.030 g, 0.185 mmol) were diluted with thionyl chloride (25 mL) and the mixture was heated at reflux for 1 h. The reaction mixture was allowed to cool to room temperature and concentrated to provide a brown oil. The oil was diluted with hexanes (20 mL) and concentrated to provide a brown solid. The solid was extracted with boiling hexanes (5 x 50 mL), and concentration of the extract provided a white solid (10.96 g, 98%): mp 52-56 0C (Sloan, et al., 1983; mp 57-59 0C). 1H NMR (300 MHz, CDCl3) δ 7.95-7.93 (m, 1 H), 7.82 (t, J= 7.4 Hz, 1 H), 7.68-7.60 (m, 2 H), 7.10 (s, 1 H). |
90% | With thionyl chloride; iron(III) chloride at 110℃; for 1h; Further byproducts given; |
With iron(III) chloride; thionyl chloride Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In methanol; water for 72h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In methanol; water for 72h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In methanol; water for 72h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.1% | With n-butyllithium; diisopropylamine In tetrahydrofuran; diethyl ether; hexane at -78 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 3-hydroxy-1(3H)-isobenzofuranone; potassium cyanide With hydrogenchloride at 0℃; for 0.666667h; Stage #2: With dicyclohexyl-carbodiimide In ethyl acetate for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In ethanol at 20℃; | |
86% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In chloroform at 20℃; for 5h; | |
69% | Stage #1: 1H-indene-1,3(2H)-dione With 1,8-diazabicyclo[5.4.0]undec-7-ene In chloroform at 20℃; for 0.0833333h; Stage #2: 3-hydroxy-1(3H)-isobenzofuranone In chloroform for 5h; Reflux; |
69% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile for 7h; Reflux; | |
With 1,8-diazabicyclo[5.4.0]undec-7-ene In chloroform Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In ethanol at 20℃; | |
95% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In chloroform at 20℃; for 5h; | |
95% | Stage #1: dimedone With 1,8-diazabicyclo[5.4.0]undec-7-ene In chloroform for 0.0833333h; Stage #2: 3-hydroxy-1(3H)-isobenzofuranone at 20℃; for 5h; |
95% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In chloroform at 20℃; for 5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In ethanol at 20℃; | |
81% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In chloroform at 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With hydrogenchloride; potassium cyanide; dicyclohexyl-carbodiimide In water | 1 Cyanophthalide 5 Cyanophthalide 5 To a suspension of hydroxyphthalide 3 (1.391 g, 4.09 mmol) and potassium cyanide (399 mg, 6.14 mmol, 1.5 equiv.) in water (4 mL) was slowly added 33% aqueous HCl (1.2 mL) at 0° C. (ice bath). The ice bath was removed and stirring continued for 2 h. LCMS (m+1=368) showed the formation of compound 4. The reaction mixture was extracted with EtOAc, dried over MgSO4, and concentrated to 20 mL. After cooling to 0° C., the solution was treated with dicyclohexyl carbodiimide (DCC, 1.2 equiv.) and stirring was continued at RT for 8 h. The reaction mixture was filtered to remove the urea byproduct and the filtrate was concentrated by flash column chromatography with 30% EtOAc/hexane gradient to yield cyanophthalide 5 (1.116 g, 78% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J=2.0 Hz, 1H), 7.93 (dd, J=8.8, 2.0 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 6.06 (s, 1H), 4.87 (s, 1H). |
Multi-step reaction with 2 steps 1: 2.) concd. HCl / 1.) water, 0 deg C, 2.) -15 deg C, 12 h 2: 1.) Vilsmeier salt, 2.) pyridine / 1.) acetonitrile, -12 deg C, 5 min, 2.) -15 deg C, 30 min | ||
Multi-step reaction with 3 steps 1: triethylamine / 3 h / 80 °C / Inert atmosphere 2: triethylamine; trichlorophosphate / tetrahydrofuran / 2 h / -78 - 20 °C 3: 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride / dichloromethane / 6 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 3-hydroxy-1(3H)-isobenzofuranone; sodium methylate; Dimethyl phosphite In methanol at 0 - 20℃; for 1h; Stage #2: With methanesulfonic acid In methanol | b b. 2-Fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid (B) Dimethyl phosphite (22.0 g, 0.2 mol) was added drop-wise to a solution of sodium methoxide (43.0 g) in methanol (100 ml) at 0oC. 2- Carboxybenzaldehyde (21.0 g, 0.1 mol) was then added portion-wise to the reaction mixture as a slurry in methanol (40 ml), with the temperature kept below 5oC. The resulting pale yellow solution was warmed to 20oC over 1 hour. Methanesulphonic acid (21.2 g, 0.22 mol) was added to the reaction drop-wise and the resulting white suspension was evaporated in vacuo. The white residue was quenched with water and extracted into chloroform (3 x 100 ml). The combined organic extracts were washed with water (2 x 100 ml), dried over MGSO4, and evaporated in vacuo to yield (3-OXO-1, 3-dihydro-isobenzofuran-1-yl) phosphonic acid dimethyl ester as a white solid (32.0 g, 95 %, 95 % purity). This was then used without further purification in the next stage |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methanesulfonic acid; sodium 2,2-dimethylpropan-1-olate In 2-methyltetrahydrofuran at 2 - 20℃; | 4.a Example 4: Alternative synthesis of Compound DE ED D(a) 2-Fluoro-5-[(E/Z)-(3-oxo-2-benzofuran- 1 (3H)-ylidene)methyl]benzonitrile (E) Sodium t-amylate (99.00 g, 0.854 mol) and 2-methyltetrahydrofuran (960 ml) were cooled to 2°C under a nitrogen atmosphere. Diethyl phosphite (110 ml, 0.855 mol) was added dropwise maintaining the temperature at <5°C. 2-Methyltetrahydrofuran (40 ml) was added as line wash. The reaction was stirred at 2°C for 1 hour 40 minutes. A solution of 2-carboxybenzaldehyde (H)(80 g, 0.533 mol) in 2-methyltetrahydrofuran (200 ml) was added, maintaining the temperature at <7°C throughout the addition. A line wash of 2-methyltetrahydrofuran (40 ml) was added. The reaction mixture was warmed to 200C and held at 200C for 20 minutes. Methanesulphonic acid (66 ml, 1.01 mol) was added over 1 hour and 10 minutes, followed by 2- methyltetrahydrofuran (40 ml). The reaction mixture was stirred at 20°C over night. Methanesulphonic acid (7 ml, 0.101 mol) was added, followed by 2-methyltetrahydrofuran (7 ml) and the reaction stirred at 2O0C for a further 4 hours. Water (400 ml) was added at room temperature and the resulting biphasic mixture stirred at room temperature for 20 minutes. The lower aqueous layer was removed and a solution of potassium bicarbonate (53.50 g, 0.534 mol) in water (400 ml) was added to the organic layer. The biphasic mixture was stirred at room temperature for 20 minutes and then the lower aqueous solution was removed. The organic fraction was retained (solution of diethyl (3-oxo1 ,3-dihydro-2-benzofuran-1-yl)phosphonate). | |
Stage #1: diethyl phosphite With sodium tert-pentylate In 2-methyltetrahydrofuran at 20℃; for 0.5h; Stage #2: 1,3-dihydro-3-oxo-1-isobenzofuranol In 2-methyltetrahydrofuran | 3.1; 4.1 Step 1: Synthesis of (R/Z)-3-(3-bromo-4-fluorobenzylidene)isobenzofuran-1(3H)-one (compound formula Ib) Under mechanical stirring, add diethyl phosphite 20.6g (1.5eq, 150mmol), sodium tert-amylate 16.5g ((1.5eq, 150mmol)) and methyltetrahydrofuran 150ml to the three-necked flask, and react at 20°C for 30min; 15.0 g (1.0 eq, 100 mmol) of o-carboxybenzaldehyde was added, and after the reaction was completed, the mixture was washed with 75 ml of water and 75 ml of 20% potassium bicarbonate solution in turn. Separation, adding 20.3g (1.0eq, 100mmol) of 3-bromo-4-fluorobenzaldehyde to the organic phase, then adding 12.1g (1.2eq, 120mmol) of triethylamine dropwise, stirring at 40°C for 8h, filtration and drying at 50°C gave 30.2 g of white solid, compound formula Ib (there are two cis-trans isomers in a ratio of about 2:5), yield 94.01%, purity 99.88%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 3-hydroxy-1(3H)-isobenzofuranone With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile for 0.166667h; Stage #2: methyl iodide In acetonitrile at 20℃; for 4h; | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 3-hydroxy-1(3H)-isobenzofuranone With sulfuric acid Trituration; Stage #2: sodium S-(carbamoylmethyl)thiosulfate at 20℃; for 12h; | General procedure for synthesis of 6a,b. General procedure: 3.3 Mmol (0.5 g) o-formylbenzoic acid or opianic acid (0.62 g.) was triturated with 2 mL of conc. H2SO4 until dissolution and then was added 0.7 g (3.6 mmol) sodium carbamoylmethyl thiosulfate, triturated again and left for 12 hours at r.t. The reaction mixture was treated with 25 mL of cold water. The solid product was filtered off, washed with water and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: (2-phenylethyl)triphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 2.16h; Inert atmosphere; Stage #2: 3-hydroxy-1(3H)-isobenzofuranone In tetrahydrofuran at 20℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide In tetrachloromethane; water; ethyl acetate | 1 Hydroxyphthalide 3 Hydroxyphthalide 3 A suspension of carbamate 2 (17.0 g, 52.4 mmol), N-bromosuccinimide (NBS, 10.26 g, 57.6 mmol) in CCl4 (150 mL) was stirred and heated to reflux (85° C. oil bath). The reaction mixture was exposed to light from a sun lamp that was situated approximately 10 cm from the flask. After 2 h TLC showed the reaction was complete. HPLC showed multiple peaks due to the labile nature of the intermediate bromide. Concentration on a rotary evaporator yielded a brown solid. Water (200 mL) was added to the brown solid in situ and heated to reflux for 5 h to produce an almost clear solution with some insoluble material. TLC and HPLC showed reaction was complete. Concentration on a rotary evaporator followed by purification with a COMBIFLASH unit using a 0-50% EtOAc gradient in hexanes on a 120 g silica column afforded hydroxyphthalide 3 (13.55 g, 76%). LCMS: [M+1]=340. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine at 80℃; for 3h; Inert atmosphere; | 3-(Formylamino)isobenzofuran-1(3H)-ones 3a-l; General Procedure General procedure: A stirred solution of a phthalaldehydic acid 4 (6.00 mmol) dissolved in neat formamide (3 mL/mmol) was heated for 4 h (unless otherwisestated) at 80-100 °C with an argon balloon fitted with a condenser.The reaction was monitored by TLC. When the reaction was complete,the mixture was extracted with EtOAc (3 × 40 mL) and the combined organic extracts were washed with brine (6 × 20 mL) and dried(Na2SO4). Removal of the solvent gave a residue that was purified bycolumn chromatography (60-120 mesh size, CH2Cl2-MeOH, 95:5) or by recrystallization (MeOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With toluene-4-sulfonic acid In toluene Reflux; | 2-[2-Methyl-5,6-dihydropyrido[3",2":4',5']thieno[3',2':4,5]pyrimido[1,6-a]benzimidazol-6-yl]benzoic Acid (2a). General procedure: A mixture of 3-aminothienopyridine 1a (1.21 g, 4.3 mmol), ortho-formylbenzoic acid (0.77 g, 5.0 mmol), and p-TsOH (20 mg) was refluxed in toluene (30 ml) for 6-7 h. Cooling of the reaction mixture to room temperature gave a precipitate that was filtered off and recrystallized from EtOH. Yield 1.24 g (70%), yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With toluene-4-sulfonic acid In toluene Reflux; | 2-[2-Methyl-5,6-dihydropyrido[3",2":4',5']thieno[3',2':4,5]pyrimido[1,6-a]benzimidazol-6-yl]benzoic Acid (2a). General procedure: A mixture of 3-aminothienopyridine 1a (1.21 g, 4.3 mmol), ortho-formylbenzoic acid (0.77 g, 5.0 mmol), and p-TsOH (20 mg) was refluxed in toluene (30 ml) for 6-7 h. Cooling of the reaction mixture to room temperature gave a precipitate that was filtered off and recrystallized from EtOH. Yield 1.24 g (70%), yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With toluene-4-sulfonic acid In toluene Reflux; | 2-[2-Methyl-5,6-dihydropyrido[3",2":4',5']thieno[3',2':4,5]pyrimido[1,6-a]benzimidazol-6-yl]benzoic Acid (2a). General procedure: A mixture of 3-aminothienopyridine 1a (1.21 g, 4.3 mmol), ortho-formylbenzoic acid (0.77 g, 5.0 mmol), and p-TsOH (20 mg) was refluxed in toluene (30 ml) for 6-7 h. Cooling of the reaction mixture to room temperature gave a precipitate that was filtered off and recrystallized from EtOH. Yield 1.24 g (70%), yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With toluene-4-sulfonic acid In toluene Reflux; | 2-[2-Methyl-5,6-dihydropyrido[3",2":4',5']thieno[3',2':4,5]pyrimido[1,6-a]benzimidazol-6-yl]benzoic Acid (2a). A mixture of 3-aminothienopyridine 1a (1.21 g, 4.3 mmol), ortho-formylbenzoic acid (0.77 g, 5.0 mmol), and p-TsOH (20 mg) was refluxed in toluene (30 ml) for 6-7 h. Cooling of the reaction mixture to room temperature gave a precipitate that was filtered off and recrystallized from EtOH. Yield 1.24 g (70%), yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With copper(ll) bromide In acetic acid at 20℃; for 18h; regioselective reaction; | General procedure for the synthesis of 3-fur-2-yl-3H-isobenzofuran-1-ones. General procedure: To a stirred solution of phthalaldehydic acid 2 (3 mmol) and furan 3 (2.7 mmol;3.3 mmol for 4ab) in acetic acid (8 mL for 4aa, ab-ad; 13 mL for 4ba, ea, fa;20 mL for 4ca, da; 25 mL for 4ga) at room temperature CuBr2 (1.35 mmol;0.27 mmol for 4ea; 0.54 mmol for 4ab) was added. The resulting reactionmixture was stirred for 24 h (18 h for 4aa; 48 h for 4fa) and after reactioncompletion (TLC) was poured into water (150 mL), neutralized with NaHCO3and extracted using DCM (3 40 mL). The combined organic extracts weredried over anhydrous Na2SO4, and the solvent was removed under vacuum.The residue was purified by flash chromatography over silica gel using DCM/petroleum ether (1:1.5, v/v then 2:1, v/v (1:3, v/v for 4ad; 1:6, v/v for 4ac) aseluent and recrystallized from DCM/petroleum ether to afford 3-(fur-2-yl)-3Hisobenzofuran-1-ones 4aa-ad. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With copper(ll) bromide In acetic acid at 20℃; for 24h; regioselective reaction; | General procedure for the synthesis of 3-fur-2-yl-3H-isobenzofuran-1-ones. General procedure: To a stirred solution of phthalaldehydic acid 2 (3 mmol) and furan 3 (2.7 mmol;3.3 mmol for 4ab) in acetic acid (8 mL for 4aa, ab-ad; 13 mL for 4ba, ea, fa;20 mL for 4ca, da; 25 mL for 4ga) at room temperature CuBr2 (1.35 mmol;0.27 mmol for 4ea; 0.54 mmol for 4ab) was added. The resulting reactionmixture was stirred for 24 h (18 h for 4aa; 48 h for 4fa) and after reactioncompletion (TLC) was poured into water (150 mL), neutralized with NaHCO3and extracted using DCM (3 40 mL). The combined organic extracts weredried over anhydrous Na2SO4, and the solvent was removed under vacuum.The residue was purified by flash chromatography over silica gel using DCM/petroleum ether (1:1.5, v/v then 2:1, v/v (1:3, v/v for 4ad; 1:6, v/v for 4ac) aseluent and recrystallized from DCM/petroleum ether to afford 3-(fur-2-yl)-3Hisobenzofuran-1-ones 4aa-ad. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With copper(ll) bromide In acetic acid at 20℃; for 24h; regioselective reaction; | General procedure for the synthesis of 3-fur-2-yl-3H-isobenzofuran-1-ones. General procedure: To a stirred solution of phthalaldehydic acid 2 (3 mmol) and furan 3 (2.7 mmol;3.3 mmol for 4ab) in acetic acid (8 mL for 4aa, ab-ad; 13 mL for 4ba, ea, fa;20 mL for 4ca, da; 25 mL for 4ga) at room temperature CuBr2 (1.35 mmol;0.27 mmol for 4ea; 0.54 mmol for 4ab) was added. The resulting reactionmixture was stirred for 24 h (18 h for 4aa; 48 h for 4fa) and after reactioncompletion (TLC) was poured into water (150 mL), neutralized with NaHCO3and extracted using DCM (3 40 mL). The combined organic extracts weredried over anhydrous Na2SO4, and the solvent was removed under vacuum.The residue was purified by flash chromatography over silica gel using DCM/petroleum ether (1:1.5, v/v then 2:1, v/v (1:3, v/v for 4ad; 1:6, v/v for 4ac) aseluent and recrystallized from DCM/petroleum ether to afford 3-(fur-2-yl)-3Hisobenzofuran-1-ones 4aa-ad. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With copper(ll) bromide In acetic acid at 20℃; for 24h; regioselective reaction; | General procedure for the synthesis of 3-fur-2-yl-3H-isobenzofuran-1-ones. General procedure: To a stirred solution of phthalaldehydic acid 2 (3 mmol) and furan 3 (2.7 mmol;3.3 mmol for 4ab) in acetic acid (8 mL for 4aa, ab-ad; 13 mL for 4ba, ea, fa;20 mL for 4ca, da; 25 mL for 4ga) at room temperature CuBr2 (1.35 mmol;0.27 mmol for 4ea; 0.54 mmol for 4ab) was added. The resulting reactionmixture was stirred for 24 h (18 h for 4aa; 48 h for 4fa) and after reactioncompletion (TLC) was poured into water (150 mL), neutralized with NaHCO3and extracted using DCM (3 40 mL). The combined organic extracts weredried over anhydrous Na2SO4, and the solvent was removed under vacuum.The residue was purified by flash chromatography over silica gel using DCM/petroleum ether (1:1.5, v/v then 2:1, v/v (1:3, v/v for 4ad; 1:6, v/v for 4ac) aseluent and recrystallized from DCM/petroleum ether to afford 3-(fur-2-yl)-3Hisobenzofuran-1-ones 4aa-ad. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: dmap / dichloromethane / 5 h / -30 °C 2: dichloromethane / 24 h / -30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With dmap; triethylamine In dichloromethane at 20℃; | Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-solved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved(monitored by TLC). The solvent was removed under reduced pres-sure and the crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With dmap; triethylamine In dichloromethane at 20℃; | Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-solved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved(monitored by TLC). The solvent was removed under reduced pres-sure and the crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With dmap; triethylamine In dichloromethane at 20℃; | Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-solved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved(monitored by TLC). The solvent was removed under reduced pres-sure and the crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With dmap; triethylamine In dichloromethane at 20℃; | Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-solved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved(monitored by TLC). The solvent was removed under reduced pres-sure and the crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With dmap; triethylamine In dichloromethane at 20℃; | Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-solved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved(monitored by TLC). The solvent was removed under reduced pres-sure and the crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With dmap; triethylamine In dichloromethane at 20℃; | Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-solved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved(monitored by TLC). The solvent was removed under reduced pres-sure and the crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90 % ee | With 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-ol; Cinchonin In hexane at -10℃; for 48h; enantioselective reaction; | Synthesis of 2a-i through DKR of 1b; General Procedure C General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and (+)-cinchonine (4a; 0.1equiv) were dissolved either in n-hexane or chlorobenzene (0.15 M)and cooled to -10 °C. Carboxylic anhydride (2.0 equiv) was then added and the mixture was stirred at -10 °C until the starting material was consumed, which was monitored by TLC. The reaction wasquenched by addition of an excess of MeOH. The resulting mixture was stirred for 15-30 min at -10 °C, then the solvent was removedunder reduced pressure and the products were purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52 % ee | With 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-ol; Cinchonin In chlorobenzene at -10℃; for 48h; Overall yield = 28 %; enantioselective reaction; | Synthesis of 2a-i through DKR of 1b; General Procedure C General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and (+)-cinchonine (4a; 0.1equiv) were dissolved either in n-hexane or chlorobenzene (0.15 M)and cooled to -10 °C. Carboxylic anhydride (2.0 equiv) was then added and the mixture was stirred at -10 °C until the starting material was consumed, which was monitored by TLC. The reaction wasquenched by addition of an excess of MeOH. The resulting mixture was stirred for 15-30 min at -10 °C, then the solvent was removedunder reduced pressure and the products were purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 18h; | Synthesis of 2j,k through Acylation of (±)-3-Hydroxyphthalides; General Procedure B General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dissolved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride was formed in situ by adding carboxylic acid (4.0 equiv) and carbodiimide (2.0 equiv). The reaction mixturewas stirred at r.t. for 18 h, while the corresponding urea was formed as a pale-yellow precipitate. The reaction was monitored by TLC.Upon complete conversion of the starting material, the precipitatedurea was filtered off and the solvent was removed under reduced pressure. The crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With dmap; diisopropyl-carbodiimide; In dichloromethane; at 20℃; for 18h; | General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dissolved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride was formed in situ by adding carboxylic acid (4.0 equiv) and carbodiimide (2.0 equiv). The reaction mixturewas stirred at r.t. for 18 h, while the corresponding urea was formed as a pale-yellow precipitate. The reaction was monitored by TLC.Upon complete conversion of the starting material, the precipitatedurea was filtered off and the solvent was removed under reduced pressure. The crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Carboxylic acid (4.0 equiv) and DIC (2.0 equiv) were dissolved eitherin n-hexane or chlorobenzene (0.15 M) and cooled to -10 C. Afterstirring for 12 h at -10 C, 2-formylbenzoic acid (1a; 1.0 equiv) and(+)-cinchonine (4a; 0.1 equiv) were added and the mixture wasstirred at -10 C until the starting material was consumed, which wasmonitored by TLC (up to 48 h). The reaction was quenched by addi-tion of an excess of MeOH. The resulting mixture was stirred for 15-30 min at -10 C, then the solvent was removed under reduced pres-sure and the products were purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap In dichloromethane at -30℃; for 5h; | Synthesis of (±)-3-Alkoxyphthalides (3a-d); General Procedure E General procedure: 2-Formylbenzoic acid (1a; 0.045 g (0.30 mmol, 1.0 equiv) and DMAP(0.004 g, 0.03 mmol, 0.1 equiv) were dissolved in anhydrous CH2Cl2(2.0 mL; 0.15 M) and cooled to -30 °C. Triflic anhydride (0.172 g,0.102 mL, 0.60 mmol, 2.0 equiv) was carefully added in one portion and the mixture was stirred at -30 °C for 5 h. To the resulting clearyellow solution an excess of the desired alcohol (10 equiv) was added and the mixture was stirred for 24 h at -30 °C. The colorless clear solution was allowed to warm to r.t. and the solvent was removed under reduced pressure. The crude products were purified by column chromatography (n-hexane/EtOAc, 2:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With dmap; triethylamine In dichloromethane at 20℃; | Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dissolved in CH2Cl2 (0.15 M), producing a colorless clear solution. The desired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved (monitored by TLC). The solvent was removed under reduced pressure and the crude products were purified by column chromatography (n-hexane/EtOAc, 2:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: 3-hydroxy-1(3H)-isobenzofuranone With thionyl chloride at 100℃; for 4h; Stage #2: propylamine In dichloromethane at 0 - 20℃; for 24h; | Synthesis of (±)-Isoindolinones 12a-d; General Procedure G General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) was heated at reflux in SOCl2 (5-10 equiv) for 4 h at 100 °C. The remaining SOCl2 was removed in vacu-um and the obtained solid was dissolved in CH2Cl2 (10 mL). The mix-ture was cooled to 0 °C and the desired primary amine (2.0 equiv)was slowly added. The solution was stirred for 24 h at r.t. then thereaction mixture was diluted with EtOAc (70 mL), washed with citricacid (0.5 M), sat. aq Na2CO3 solution, and brine. The organic layer wasdried over MgSO4 and the solvent was removed under reduced pres-sure. The obtained products were used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | Stage #1: 3-hydroxy-1(3H)-isobenzofuranone With thionyl chloride at 100℃; for 4h; Stage #2: cyclohexylamine In dichloromethane at 0 - 20℃; for 24h; | Synthesis of (±)-Isoindolinones 12a-d; General Procedure G General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) was heated at reflux in SOCl2 (5-10 equiv) for 4 h at 100 °C. The remaining SOCl2 was removed in vacu-um and the obtained solid was dissolved in CH2Cl2 (10 mL). The mix-ture was cooled to 0 °C and the desired primary amine (2.0 equiv)was slowly added. The solution was stirred for 24 h at r.t. then thereaction mixture was diluted with EtOAc (70 mL), washed with citricacid (0.5 M), sat. aq Na2CO3 solution, and brine. The organic layer wasdried over MgSO4 and the solvent was removed under reduced pres-sure. The obtained products were used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Stage #1: 3-hydroxy-1(3H)-isobenzofuranone With thionyl chloride at 100℃; for 4h; Stage #2: 3,5-Bis-(trifluoromethyl)aniline In dichloromethane at 0 - 20℃; for 24h; | Synthesis of (±)-Isoindolinones 12a-d; General Procedure G General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) was heated at reflux in SOCl2 (5-10 equiv) for 4 h at 100 °C. The remaining SOCl2 was removed in vacu-um and the obtained solid was dissolved in CH2Cl2 (10 mL). The mix-ture was cooled to 0 °C and the desired primary amine (2.0 equiv)was slowly added. The solution was stirred for 24 h at r.t. then thereaction mixture was diluted with EtOAc (70 mL), washed with citricacid (0.5 M), sat. aq Na2CO3 solution, and brine. The organic layer wasdried over MgSO4 and the solvent was removed under reduced pres-sure. The obtained products were used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 3-hydroxy-1(3H)-isobenzofuranone With thionyl chloride at 100℃; for 4h; Stage #2: Propargylamine In dichloromethane at 0 - 20℃; for 24h; | Synthesis of (±)-Isoindolinones 12a-d; General Procedure G General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) was heated at reflux in SOCl2 (5-10 equiv) for 4 h at 100 °C. The remaining SOCl2 was removed in vacu-um and the obtained solid was dissolved in CH2Cl2 (10 mL). The mix-ture was cooled to 0 °C and the desired primary amine (2.0 equiv)was slowly added. The solution was stirred for 24 h at r.t. then thereaction mixture was diluted with EtOAc (70 mL), washed with citricacid (0.5 M), sat. aq Na2CO3 solution, and brine. The organic layer wasdried over MgSO4 and the solvent was removed under reduced pres-sure. The obtained products were used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap; triethylamine In dichloromethane at 20℃; | Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-solved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved(monitored by TLC). The solvent was removed under reduced pres-sure and the crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With dmap; triethylamine In dichloromethane at 20℃; | Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-solved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved(monitored by TLC). The solvent was removed under reduced pres-sure and the crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 % ee | With 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-ol; Cinchonin In hexane at -10℃; for 48h; enantioselective reaction; | Synthesis of 2a-i through DKR of 1b; General Procedure C General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and (+)-cinchonine (4a; 0.1equiv) were dissolved either in n-hexane or chlorobenzene (0.15 M)and cooled to -10 °C. Carboxylic anhydride (2.0 equiv) was then added and the mixture was stirred at -10 °C until the starting material was consumed, which was monitored by TLC. The reaction wasquenched by addition of an excess of MeOH. The resulting mixture was stirred for 15-30 min at -10 °C, then the solvent was removedunder reduced pressure and the products were purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56 % ee | Stage #1: acetic acid With diisopropyl-carbodiimide at -10℃; for 12h; Stage #2: 3-hydroxy-1(3H)-isobenzofuranone With Cinchonin In hexane at -10℃; Overall yield = 55 %; enantioselective reaction; | Synthesis of 2j-k through DKR of 1b; General Procedure D General procedure: Carboxylic acid (4.0 equiv) and DIC (2.0 equiv) were dissolved eitherin n-hexane or chlorobenzene (0.15 M) and cooled to -10 °C. Afterstirring for 12 h at -10 °C, 2-formylbenzoic acid (1a; 1.0 equiv) and(+)-cinchonine (4a; 0.1 equiv) were added and the mixture wasstirred at -10 °C until the starting material was consumed, which wasmonitored by TLC (up to 48 h). The reaction was quenched by addi-tion of an excess of MeOH. The resulting mixture was stirred for 15-30 min at -10 °C, then the solvent was removed under reduced pres-sure and the products were purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dmap; triethylamine In dichloromethane at 20℃; | Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-solved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved(monitored by TLC). The solvent was removed under reduced pres-sure and the crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.9% | Stage #1: 1-Bromopentane With iodine; magnesium In tetrahydrofuran for 2h; Reflux; Inert atmosphere; Stage #2: 3-hydroxy-1(3H)-isobenzofuranone In tetrahydrofuran at -5 - 20℃; for 5h; Inert atmosphere; | General procedure for the synthesis of intermediates 5a-d General procedure: To a suspension of magnesium (6.0 equiv) and catalytic amounts of I2 in anhydrous THF (12 mL) was added the appropriate 1-bromoalkane (5.0 equiv) under argon atmosphere until the Grignard reaction had started. After addition was completed, the reaction mixture was refluxed for 2 h and allowed to cool to room temperature. Subsequently, the prepared Grignard solution was added dropwise to a solution of 4 (300 mg, 1.998 mmol) at -5°C. The resulting reaction mixture was stirred at room temperature for 5 h. The mixture was quenched with 3N HCl to pH=2 at 0°C and stirred for another 1 h at room temperature. The solution was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with 10% K2CO3 aqueous solution (10 mL×3) and brine (10 mL×2), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by column chromatography to give intermediates 5a-d as oils. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.4% | Stage #1: 1-bromo-hexane With iodine; magnesium In tetrahydrofuran for 2h; Reflux; Inert atmosphere; Stage #2: 3-hydroxy-1(3H)-isobenzofuranone In tetrahydrofuran at -5 - 20℃; for 5h; Inert atmosphere; | General procedure for the synthesis of intermediates 5a-d General procedure: To a suspension of magnesium (6.0 equiv) and catalytic amounts of I2 in anhydrous THF (12 mL) was added the appropriate 1-bromoalkane (5.0 equiv) under argon atmosphere until the Grignard reaction had started. After addition was completed, the reaction mixture was refluxed for 2 h and allowed to cool to room temperature. Subsequently, the prepared Grignard solution was added dropwise to a solution of 4 (300 mg, 1.998 mmol) at -5°C. The resulting reaction mixture was stirred at room temperature for 5 h. The mixture was quenched with 3N HCl to pH=2 at 0°C and stirred for another 1 h at room temperature. The solution was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with 10% K2CO3 aqueous solution (10 mL×3) and brine (10 mL×2), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by column chromatography to give intermediates 5a-d as oils. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.1% | Stage #1: 1-Bromoheptane With iodine; magnesium In tetrahydrofuran for 2h; Reflux; Inert atmosphere; Stage #2: 3-hydroxy-1(3H)-isobenzofuranone In tetrahydrofuran at -5 - 20℃; for 5h; Inert atmosphere; | General procedure for the synthesis of intermediates 5a-d General procedure: To a suspension of magnesium (6.0 equiv) and catalytic amounts of I2 in anhydrous THF (12 mL) was added the appropriate 1-bromoalkane (5.0 equiv) under argon atmosphere until the Grignard reaction had started. After addition was completed, the reaction mixture was refluxed for 2 h and allowed to cool to room temperature. Subsequently, the prepared Grignard solution was added dropwise to a solution of 4 (300 mg, 1.998 mmol) at -5°C. The resulting reaction mixture was stirred at room temperature for 5 h. The mixture was quenched with 3N HCl to pH=2 at 0°C and stirred for another 1 h at room temperature. The solution was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with 10% K2CO3 aqueous solution (10 mL×3) and brine (10 mL×2), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by column chromatography to give intermediates 5a-d as oils. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.2% | With lithium hydroxide monohydrate at 100℃; for 3h; | 1 Example 1: Preparation of 3-hydroxyisobenzofuran-1(3H)-one (compound 2) Add 3-bromophthalide (30g, 0.14mol) into the round bottom flask,Using water (100 mL) as solvent, the reaction was refluxed at 100°C for 3 hours. TLC monitored the completion of the reaction. The reaction liquid was cooled in an ice bath to precipitate a solid, filtered with suction, washed with water, and dried to obtain 20.97 g of a white solid (compound 2) with a yield of 99.2%. |
86% | With lithium hydroxide monohydrate; potassium hydroxide for 2h; Reflux; | |
83.4% | With lithium hydroxide monohydrate Reflux; | 3-hydroxyisobenzofuran-1(3H)-one (4) 3-bromoisobenzofuran-1(3H)-one (3.7 g, 17.368 mmol) was heated to reflux in water (35 mL) for 2 h, then the mixture was cooled to room temperature for overnight. The white solid formed was collected by filtration, washed with water, and dried to afford intermediate 4, 83.4% yield; mp: 97-98°C. (lit.3 97-98°C). |
With lithium hydroxide monohydrate for 1h; Reflux; | ||
With lithium hydroxide monohydrate at 100℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium methoxide In methanol at 0 - 20℃; for 1h; | 1 Dimethyl phosphite (11 g, 0.1 mol) at 0 ° CAdd dropwise to a solution of sodium methoxide in methanol (100 ml).Then 2-carboxy benzaldehyde (10.5g, 0.05mol)Add to the reaction system,The entire process temperature is controlled below 5 °C.Thereafter, the mixture was heated to room temperature for 1 hour.Methanesulfonic acid (10.6 g, 0.11 mol) was added.The reaction solution was concentrated and washed with water and chloroform.The organic layers were combined and dried over anhydrous NaSO4.Concentrated to:3-oxo-1,3-dihydroxy-isobenzofuran-1-phosphate dimethyl ester (16 g),The yield was 95%. |
93% | With methanesulfonic acid; triethylamine In dichloromethane for 0.5h; | 1 Example 1 Combine 20 g (133 mmol) o-carboxybenzaldehyde, 17.5 g (173 mmol) of triethylamine and 200 mL of dichloromethane were added to a three-necked flask and mixed and stirred, then 19.1 g (173 mmol) of dimethyl phosphite were added, and the reaction was stirred at room temperature for 4 h. TLC monitored the reaction to complete. 17.9 g (186 mmol) of methanesulfonic acid was added dropwise, stirred for 30 min, TLC monitored that the reaction was complete, the reaction solution was concentrated to dryness, water was added to make a slurry for 2 hours, and then filtered to dryness. Then be beaten with petroleum ether to obtain 30 g of a white solid with a yield of 93%, which is (3-oxo-1,3-dihydroisobenzofuran-1-yl) dimethyl phosphate |
89.3% | Stage #1: Dimethyl phosphite With sodium methoxide In methanol at 0℃; for 0.166667h; Stage #2: 1,3-dihydro-3-oxo-1-isobenzofuranol In methanol at 0 - 25℃; for 1h; |
85% | In dichloromethane at 100℃; for 0.416667h; | 1.1 Example 1 (1) 3-hydroxyisobenzofuran-1(3H)-one (0.033 mol) in dichloromethane (50 mL) in a microchannel reaction apparatusAnd a solution of dimethyl phosphite (0.091 mol) in dichloromethane (50 mL) was pumped from the pump A1 pump B2 into the first mixing valve 3, the flow rate of the pump A1 was 0.18 mL/min, and the flow rate of the pump B2 was 0.026 mL/ Min. After thorough mixing, the first microreactor 4 was introduced. The volume of the first microreactor 4 was 40 mL, and the reaction residence time was 25 min. The reaction temperature is 100 ° C,The reaction liquid is collected in the first separation device 5,The first separating device 5 is a container for water and dichloromethane.Simple extraction and liquid separation(3-oxo-1,3-dihydroisobenzofuran-1-yl) dimethyl phosphateThe effluent of (Compound 1) had a yield of 85%. |
84% | Stage #1: 1,3-dihydro-3-oxo-1-isobenzofuranol; Dimethyl phosphite With sodium methoxide In methanol at 0 - 20℃; for 1h; Stage #2: With methanesulfonic acid In methanol for 0.5h; | 1 Example 1: Synthesis of Intermediate One Add 11.0 g of dimethyl phosphite, 6.5 g of sodium methoxide, and 100 mL of methanol into a 250 mL three-necked flask, and cool to 0-5 degrees Celsius in an ice bath. Add 7.5 g of SM1 in batches, and control the internal temperature to not exceed 10 degrees Celsius. After reacting for 1 hour at room temperature, 12.5 g of methanesulfonic acid was added dropwise. After dropping, stirring was continued for 0.5 hours. The methanol was distilled off under reduced pressure. 150 mL of water was added and extracted twice with 100 mL of dichloromethane. The organic layers were combined and used Drying with anhydrous magnesium sulfate for 0.5 hours and filtering, the filtrate was distilled under reduced pressure to obtain 10.2 g of white solid, with a yield of 84%. The liquid chromatogram is shown in Figure 1. The area normalization method is used to analyze the main peak purity of 99.03%. |
Stage #1: Dimethyl phosphite With sodium tert-pentylate In 2-methyltetrahydrofuran at 30℃; for 0.25h; Stage #2: 1,3-dihydro-3-oxo-1-isobenzofuranol In 2-methyltetrahydrofuran | 1.1; 2.1 Step 1: Synthesis of (R/Z)-3-(3-chloro-4-fluorobenzylidene)isobenzofuran-1(3H)-one (compound formula Ia) Under mechanical stirring, add dimethyl phosphite 16.5kg (1.5eq, 150mol), sodium tert-amylate 16.5kg (1.5eq, 150mol) and methyltetrahydrofuran 150L to the there-necked flask, and react at 30°C for 15min; 15.0 kg (1.0 eq, 100 mol) of o-carboxybenzaldehyde was added, and after the reaction was completed, the mixture was washed with 75 L of water and 75 L of 20% potassium bicarbonate solution in turn. Separation, adding 15.8kg (1.0eq, 100mol) of 3-chloro-4-fluorobenzaldehyde to the organic phase, then adding 12.1kg (1.2eq, 120mol) of triethylamine dropwise, stirring at 50°C for 6h, filtering, and drying at 50°C 25.6kg of white solid was obtained, That is, compound formula Ia (there are two cis-trans isomers in a ratio of about 2:5), the yield is 93.23%, and the purity is 99.85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-hydroxy-1(3H)-isobenzofuranone With pyridine; bis(trichloromethyl) carbonate In dichloromethane for 2h; Inert atmosphere; Heating; Stage #2: at 155℃; | Bis(1[3H]-isobenzofuranone-3-yl)ethers, (R,R/S,S)-5and meso-6 A solution of 255 mg (1.70 mmol) of 1 in 8 mL dichloromethanewas combined under N2(g) with 250 mg(0.085 mmol) triphosgene. Then, 69 μL (0.085 mmol) pyridinewas added slowly over 30 min. The reaction mixturewarmed. After 1.5 h, water was added, and the organic layerwas removed and evaporated in vacuo. The semi-solid materialobtained was recrystallized from benzene. A colorlesssolid was obtained, mp 78.5 °C (DSC peak), having IR(cm-1): 1786, 1763, 1741 (ν C=Os). On heating the solidto 155 °C (sand bath), gases were evolved and the orangesolid obtained was recrystallized from ethyl acetate producingtwo distinct phases: colorless needles, meso form6, IR (cm-1): 1771, (ν C=O), mp 218 °C (DSC peak), andcolorless plates, (R,R/S,S) form 5, IR (cm-1) 1778, (ν C=O);mp 234 °C (DSC peak). Both phases were also obtainedby thermal dehydration of 1 by heating to 250 °C, coolingand recrystallizing the solid residue from ethyl acetate [18]. Additionally, an anhydride was obtained from reactionof 1 with an equivalent of dicyclohexylcarbodiimide(DCCI) in CH2Cl2at 0 °C to which was added a smallamount of 4-dimethyl aminopyridine (DMAP, see preparationof 11-17). Anhydride has Rfabout 0.75 (TLC: silica, CHCl3:EtOAc 10:1) and after isolation by chromatography,the major product proves to be polymorphs of the (R,R/S,S)form 5 (5a, prisms; 5b rod-like needles). 1H-NMR (CDCl3,25 °C), δH: 7.85, d, 2H, aryl-H; 7.65, t, 2H, aryl-H; 7.60,d, 2H, aryl-H; 7.45, d, 2H, aryl-H; 6.90, s, 2H, Ps-H; 13CNMR(CDCl3, 25 °C), δC: 168.14, C=O; 144.10, 137.87,131.09, 126.65, 124.69, 123.92, Ar-C’s; 99.05, Ps-C. For5a and 5b, IR: (cm-1): 1769 cm-1, (ν C=O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: benzoic acid With dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 1h; Stage #2: 3-hydroxy-1(3H)-isobenzofuranone With dmap In dichloromethane at 4℃; | 3-Benzoyloxy-1[3H]-isobenzofuranone, 11 Benzoic acid (50 mg, 0.43 mmol) was dissolved in 8 mLCH2Cl2,and one equivalent of DCCI (87 mg, 0.43 mmol)was added at 0 °C, and stirred for an hour. Then, o-formylbenzoicacid (1) (65 mg, 0.43 mmol) was added and a catalyticamount of DMAP, and the mixture was allowed to standovernight at 4 °C. TLC (silica, CHCl3:EtOAc 10:1) showedfive components. The fastest running component (Rf 0.92)was the anhydride 11. After filtering the dicyclohexylureafrom the reaction mixture, and evaporating the solvent, athick layer chromatogram was run on the chloroform solubleresidue of the reaction, and the band at highest Rfwasremoved and extracted, producing a colorless solid fromethyl acetate. 1H-NMR (CDCl3, 26 °C), δH: 8.09, Ar-H5, d,1H; 7.78, Ar-H6, t, 1H; 7.61, Ar-H7, t, 1H; 7.99, Ar-H8, d,1H; 6.897, Ps-H, s, 1H; 7.695, Ph-ortho, d, 2H; 7.46, Phmeta,t, 2H; 7.27, Ph-para, d, 1H. IR: 1777 cm-1, ν(C=O)furanone; 1740 cm-1, ν (C=O) acyl. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-hydroxy-1(3H)-isobenzofuranone; dicyclohexyl-carbodiimide; 3-hydroxy-3,4-dihydro-4,4-dimethyl-1H-isobenzopyran-1-one In dichloromethane at 0℃; Stage #2: With dmap In dichloromethane at -10℃; for 48h; | (1[3H]-Isobenzofuranone-3-yl)(4,4,dimethyl-3,4-dihydro-[1H]-isobenzopyran-1-one-3-yl)ether, 19 To a solution of o-formylbenzoic acid (1, 75 mg, 0.50 mmol)and 3-hydreoxy-4,4-dimethyl-3,4-dihydroisobenzopyran-1-one (4, 96 mg, 0.50 mmol) in 5.0 mL CH2Cl2,103 mg (0.50 mmol) DCCI was added and stirred at 0 °C untilthe reactants were in solution. Then, a catalytic amountof DMAP was added. The mixture stood for 48 h at- 10 °C, then warmed to room temperature, and tlc [silica;CHCl3:ethyl acetate (10:1)] showed bands at Rf0.85 (major),0.75 (major), 0.60 (minor). Dicyclohexylurea was filteredand the dichloromethane solution was concentrated. Theoily mixture was separated by thick-layer chromatography [silica, CHCl3:ethyl acetate (10:1)]. The Rf0.85 band wasthe isophthalide of 4; the Rf0.6 band was the active ester of1, each determined by nmr. The Rf0.75 band by nmr showedabout 30% of the symmetric dipseudoanhydride 5 (RR/SS)or 6 (meso), and 70% of a second anhydride with pseudoacyl signals for both an arylfuran and an arylpyran group. Onfractional crystallization from ethyl acetate, the (R,R/S,S)form (5a) crystallized first, followed by the unsymmetric dipseudoanhydride 19. For 19: IR: 1778 cm-1 (νC=O furanone),1733 cm-1 (νC=O, pyranone); 1H-NMR (CDCl3,25 °C), δH: (6-ring) 8.1, d, 1H, ar-H nearest C=O; 7.7, t,1H; 7.6, t, 1H; 7.4, d, 1H; 5.65, s, 1H, Ps-H; 1.41, s, 3H,Me; 1.48, s, 3H, Me; (5-ring) 7.8, d, 1H, ar-H nearest C=O;7.6, t, 1H; 7.4, t, 1H; 7.6, d, 1H; 6.8, s, 1H, Ps-H; 13C-NMR(CDCl3, 25 °C), δC: 168.08; (5-ring)C=O; 163.26; (6-ring)C=O; benzopyran: 123.73, C-(C=O); 145.93, C(CMe2),124.69, C3; 131.38, C4; 127.40, C5; 130.23, C6; 104.85,Ps-C; 37.1, quat-C; 27.0, 22.0 Me’s; benzofuran: 144.29,134.86, 134.68, 126.57, 125.52, 123.07, ar-C’s; 98.4, benzofuranPs-C; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.6% | Stage #1: 3-Bromophthalide With water for 2h; Reflux; Stage #2: With water; pyrographite for 0.75h; Reflux; | 1-3; 5-11 The 100mL four-neck bottle is equipped with an electromagnetic stirrer, a Y-tube, a thermometer, and a condenser tube. Add 33.4 g of the intermediate obtained in the previous step and 35 mL of water. The reaction was heated at reflux for 2 hours, cooled down to 0 ° C, and filtered after 8 hours. The mother liquor was left to stand. The filter cake was rinsed with ice water to obtain 22.4 g of a crude product.Add 75mL of water, 0.2g of activated carbon, reflux for 45min, hot filter, and cool and crystallize with stirring.Filtered, washed with cold water to obtain 18.8 g, and recrystallized twice with 45 mL of water to obtain 17.0 g (wet),After drying, 14.8 g of o-carboxybenzaldehyde was obtained with a purity of 99.7% and a yield of 66.6%.The 1H-NMR spectrum of the o-carboxybenzaldehyde is shown in FIG. 1, the liquid chromatography-mass spectrum in the positive ion mode is shown in FIG. 2, and the liquid chromatography-mass spectrum in the negative ion mode is shown in FIG. 3. The structural formula of o-carboxybenzaldehyde is shown below: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With (5aR,10bS)-5a,10b-dihydro-2-(2,4,6-trimethylphenyl)-4H,6H-indeno[2,1-b]-1,2,4-triazolo[4,3-d]-1,4-oxazinium chloride; 3,5,3',5'-tetra-tert-butyl-4,4'-diphenoquinone; N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 12h; Schlenk technique; Inert atmosphere; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With (5aR,10bS)-5a,10b-dihydro-2-(2,4,6-trimethylphenyl)-4H,6H-indeno[2,1-b]-1,2,4-triazolo[4,3-d]-1,4-oxazinium chloride; 3,5,3',5'-tetra-tert-butyl-4,4'-diphenoquinone; N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 12h; Schlenk technique; Inert atmosphere; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With (5aR,10bS)-5a,10b-dihydro-2-(2,4,6-trimethylphenyl)-4H,6H-indeno[2,1-b]-1,2,4-triazolo[4,3-d]-1,4-oxazinium chloride; 3,5,3',5'-tetra-tert-butyl-4,4'-diphenoquinone; N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 12h; Schlenk technique; Inert atmosphere; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With (5aR,10bS)-5a,10b-dihydro-2-(2,4,6-trimethylphenyl)-4H,6H-indeno[2,1-b]-1,2,4-triazolo[4,3-d]-1,4-oxazinium chloride; 3,5,3',5'-tetra-tert-butyl-4,4'-diphenoquinone; N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 12h; Schlenk technique; Inert atmosphere; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With (5aR,10bS)-5a,10b-dihydro-2-(2,4,6-trimethylphenyl)-4H,6H-indeno[2,1-b]-1,2,4-triazolo[4,3-d]-1,4-oxazinium chloride; 3,5,3',5'-tetra-tert-butyl-4,4'-diphenoquinone; N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 12h; Schlenk technique; Inert atmosphere; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With 3,5,3',5'-tetra-tert-butyl-4,4'-diphenoquinone; BF4(1-)*C18H13Cl3N3O(1+); N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 12h; Schlenk technique; Inert atmosphere; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With (5aR,10bS)-5a,10b-dihydro-2-(2,4,6-trimethylphenyl)-4H,6H-indeno[2,1-b]-1,2,4-triazolo[4,3-d]-1,4-oxazinium chloride; 3,5,3',5'-tetra-tert-butyl-4,4'-diphenoquinone; N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 12h; Schlenk technique; Inert atmosphere; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With (5aR,10bS)-5a,10b-dihydro-2-(2,4,6-trimethylphenyl)-4H,6H-indeno[2,1-b]-1,2,4-triazolo[4,3-d]-1,4-oxazinium chloride; 3,5,3',5'-tetra-tert-butyl-4,4'-diphenoquinone; N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 12h; Schlenk technique; Inert atmosphere; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With (5aR,10bS)-5a,10b-dihydro-2-(2,4,6-trimethylphenyl)-4H,6H-indeno[2,1-b]-1,2,4-triazolo[4,3-d]-1,4-oxazinium chloride; 3,5,3',5'-tetra-tert-butyl-4,4'-diphenoquinone; N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 12h; Schlenk technique; Inert atmosphere; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With (R)-2,6-di([1,1'-biphenyl]-4-yl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine 4-oxide; bismuth(III) acetate In acetonitrile at 20℃; for 12h; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With (11aS)-3,7-di-9-anthracenyl-10,11,12,13-tetrahydro-5-hydroxy-5-oxide diindeno[7,1de:10,70-fg][1,3,2] dioxaphosphocin; bismuth(III) acetate In dichloromethane at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.5% | Stage #1: 1,3-dihydro-3-oxo-1-isobenzofuranol; 2-(3,4-dimethoxyphenyl)-ethylamine In toluene at 90℃; for 2h; Sonication; Stage #2: With polyphosphoric acid In toluene at 100℃; for 0.166667h; | 2 Example 2: Preparation of 2,3-dihydro-5-methoxy-1-azabenzoanthrone (Compound 4) Add 3-hydroxyisobenzofuran-1(3H)-one (compound 2, 5g, 0.03mol), solvent toluene (20mL),3,4-Dimethoxyphenethylamine (compound 3, 7.24g, 0.04mol), ultrasonically dissolved to make the raw materials uniformly dispersed in the solvent, refluxed and stirred at 90°C for 2h to obtain a mixed reactant. Take a conical flask, add a catalytic cyclization amount of polyphosphoric acid PPA (25g, 0.07mol) into the conical flask, raise the temperature to 100°C, pour the aforementioned mixed reactants into the conical flask, and set a drying tube to reflux for 10 minutes. When the polyphosphoric acid turns from transparent and colorless to dark red to indicate the end of the reaction, add 100 mL of ice water to the reaction system to decompose the excess polyphosphoric acid, and ultrasonicate for 30 minutes to dissolve the dark red viscous product. The mixture of toluene and water was extracted with a separatory funnel, the aqueous layer was collected, the pH of ammonia was adjusted to 7-8, and the methylene chloride extracted three times. The organic layer was dried with anhydrous Na2SO4, dried under reduced pressure to remove the organic solvent, and silica gel column chromatography (200-300 mesh) Silica gel, the eluent is PE:EA=5:1V:V), 1.6 g of yellow solid (compound 4) is obtained, and the yield is 20.5%. |
Stage #1: 1,3-dihydro-3-oxo-1-isobenzofuranol; 2-(3,4-dimethoxyphenyl)-ethylamine In toluene for 2h; Reflux; Stage #2: With phosphoric acid In toluene at 100℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With toluene-4-sulfonic acid In toluene at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With C60H81N3O4Si In toluene at -20℃; for 15h; Overall yield = 97 percent; enantioselective reaction; |
Tags: 16859-59-9 synthesis path| 16859-59-9 SDS| 16859-59-9 COA| 16859-59-9 purity| 16859-59-9 application| 16859-59-9 NMR| 16859-59-9 COA| 16859-59-9 structure
[ 143726-85-6 ]
tert-Butyl 4-(hydroxymethyl)benzoate
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[ 27550-59-0 ]
5-Hydroxyisobenzofuran-1,3-dione
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[ 393522-78-6 ]
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6-Methylisobenzofuran-1(3H)-one
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[ 23405-32-5 ]
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[ 54120-64-8 ]
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[ 27550-59-0 ]
5-Hydroxyisobenzofuran-1,3-dione
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P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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