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CAS No. : | 87-41-2 | MDL No. : | MFCD00005906 |
Formula : | C8H6O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WNZQDUSMALZDQF-UHFFFAOYSA-N |
M.W : | 134.13 | Pubchem ID : | 6885 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 35.77 |
TPSA : | 26.3 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) : | -6.55 cm/s |
Log Po/w (iLOGP) : | 1.54 |
Log Po/w (XLOGP3) : | 0.8 |
Log Po/w (WLOGP) : | 1.21 |
Log Po/w (MLOGP) : | 1.54 |
Log Po/w (SILICOS-IT) : | 2.23 |
Consensus Log Po/w : | 1.46 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.62 |
Solubility : | 3.22 mg/ml ; 0.024 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.93 |
Solubility : | 15.6 mg/ml ; 0.117 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.54 |
Solubility : | 0.383 mg/ml ; 0.00286 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.34 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H319 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | at 20℃; for 69 h; | NBS (53.4 g, 300 mmol, 1.5 eq) was added portion wise to a solution of phthalide (Sl-I) (26.83 g, 200 mmol. 1 O eq) in a mixture of TFA (100 mL) and sulfuric acid (45 mL) at rt over 9 h. The reaction mixture (an orange solution) was stirred at rt for about 60 h. (Crude NMR showed the reaction is complete.) Then the reaction mixture was poured onto ice, extracted with methylene chloride (3 x 300 mL). The combined organic phase was dried over MgSO4, filtered and concentrated to afford a yellow solid. The residue was purified by flash-column chromatography (5-10percent ethyl acetate-hexanes) to afford the desired product Sl-2 (white solid, 28.17g, 66percent) and the other regioisomer S3-1 (white solid, 12.7g, 30percent). 1H NMR (400 MHz, CDCl3) 8 8.04 (d, J= 1.8 Hz, 1 H), 7.78 (dd, J= 1.8, 7.9 Hz, 1 H), 7.37 (d, J= 7.9 Hz, 1 H), 5.26 (s, 2 H). |
57% | With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid In ethyl acetate for 95 h; | 6-Bromoisobenzofuran-1(3H)-one (20a) In a 100 mL round bottom flask was dissolved isobenzofuran-1(3H)-one (4.01 g, 29.9 mmol) in trifluoroacetic acid (14 mL, 182 mmol) and sulfuric acid (6.5 mL, 122 mmol). N-Bromosuccinimide (7.95 g, 1.49 mmol) was added portionwise over 8 hours and the solution was stirred at room temperature for an additional 87 hours. The solution was diluted with water (40 mL) and ethyl acetate (40 mL). The pH of the aqueous layer was neutralized with 1M aq. NaOH and sat. aq. NaHCO3. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3*50 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, and concentrated on to silica. The crude product was then purified by flash column chromatography using 10-20percent ethyl acetate in hexanes to yield 20a as white solid in 57percent yield. 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J=1.5 Hz, 1H), 7.77 (dd, J=8.3, 1.5 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 5.27 (s, 2H). LCMS found 212.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With N-Bromosuccinimide In tetrachloromethane | Step (1) Preparation of 3-Bromophthalide A mixture of phthalide (7.5 g, 56 mmol) and N-bromosuccinimide (10 g, 55.5 mmol) in CCl4 (150 mL) was heated at reflux for 3 hours (reaction checked by TLC). The mixture was filtered hot and the filtrate was evaporated to dryness to yield the crude title compound (11.15 g, 97percent). It was used as such in the next step. |
81% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 2 h; Reflux | Bromination of phthalide (2.0 g, 14.71 mmol) was performed usingNBS (2.62 g, 14.71 mmol) containing a catalytic amount of AIBN (120 mg, 0.74 mmol) in dry CCl4 (50 mL)at reflux for 2 h to afford bromo compound 1a1a as a brown solid (2.56 g, 81percent). m.p. 79-81 C (Lit.1b 74-80oC). 1H NMR (300 MHz, CDCl3): = 7.84 (d, J = 7.5 Hz, 1 H, ArH), 7.72 (d, J = 7.5 Hz, 1 H, ArH), 7.57 (d, J= 7.8 Hz, 2 H, ArH), 7.34 (s, 1 H, CH) ppm. 13C NMR (75 MHz, CDCl3): = 167.4, 148.8, 135.3, 131.0,125.9, 124.0, 123.6, 74.7 ppm. |
79.8% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In benzene at 75℃; for 2.5 h; | Isobenzofuran-1(3H)-one (3.0 g, 22.366 mmol), NBS (4.38 g, 24.603 mmol) and AIBN (367 mg, 2.237 mmol) were diluted in dry benzene and heated to 75°C for 2.5 h. The mixture was cooled to room temperature for overnight, filtered, and the residue was washed with benzene. The filtrate was concentrated in vacuo to provide a crude product, which was recrystallized from cyclohexane to give 3 as an off-white solid. 79.8percent yield; mp: 79-82°C. (lit.2 78°C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | at 20℃; Cooling with ice | Step A: Synthesis of 6-nitrobenzofuran-l(3H)-one[0086] To an ice-cold stirred solution of phthalide (40.0 g, 298 mmol) in sulfuric acid (50.0 mL) was added potassium nitrate (30.4 g, 300 mmol) dissolved in sulfuric acid (80 mL) via dropwise addition. The reaction was stirred and allowed to warm to room temperature over 5 h. The resulting mixture was poured into ice-water, and the precipitate collected was recrystallized from ethanol (3 L) to afford 6-nirobenzofuran-l(3H)-one (50.4 g, 94percent) as an off-white solid (98percent of the desired regioisomer by NMR): 1H NMR (500 MHz, CDC13) δ 8.77 (d, J= 1.5 Hz, 1H), 8.58 (dd, J= 8.5, 2.0 Hz, 1H), 7.72 (d, J- 8.5 Hz, 1H), 5.45 (s, 2H). |
80% | With sulfuric acid; potassium nitrate In water at 0 - 20℃; for 1 h; | Step a: 6-Nitroisobenzofuran-1(3H)-one To a stirred solution of 3H-isobenzofuran-1-one (30.0 g, 0.220 mol) in H2SO4 (38 mL) was added KNO3 (28.0 g, 0.290 mol) in H2SO4 (60 mL) at 0° C. The mixture was stirred at 20° C. for 1 h. The reaction mixture was poured into ice and the resulting precipitate was filtered off. The solid was recrystallized from ethanol to give 6-nitroisobenzofuran-1(3H)-one (32.0 g, 80percent). 1H NMR (300 MHz, CDCl3) δ 8.76 (d, J=2.1, 1H), 8.57 (dd, J=8.4, 2.1, 1H), 7.72 (d, J=8.4, 1H), 5.45 (s, 2H). |
80% | at 0 - 20℃; for 1 h; | 6-Nitroisobenzofuran-1(3H)-one To a stirred solution of 3H-isobenzofuran-1-one (30.0 g, 0.220 mol) in H2SO4 (38 mL) was added KNO3 (28.0 g, 0.290 mol) in H2SO4 (60 mL) at 0° C. The mixture was stirred at 20° C. for 1 h. The reaction mixture was poured into ice and the resulting precipitate was filtered off. The solid was recrystallized from ethanol to give 6-nitroisobenzofuran-1(3H)-one (32.0 g, 80percent). 1H NMR (300 MHz, CDCl3) δ 8.76 (d, J=2.1, 1H), 8.57 (dd, J=8.4, 2.1, 1H), 7.72 (d, J=8.4, 1H), 5.45 (s, 2H). |
37% | at 0 - 20℃; for 5 h; | 3H-Isobenzofuran-1-one (4.00 g, 29.8 mmol) was dissolved in concentrated sulfuric acid (5.0 ml) at 0° C., and a solution of potassium nitrate (3.0 g, 30 mmol) in concentrated sulfuric acid (8.0 ml) was added dropwise thereto. After stirring at room temperature for 5 hours, the reaction solution was diluted with water. The precipitated solid was filtered and recrystallized from ethanol (20 ml) to obtain the title compound (2.0 g, 37percent). [1323] 1H NMR (400 MHz, DMSO-d6): δ 8.62-8.59 (m, 1H), 8.53 (d, J=2.8 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 5.57 (s, 2H) |
1 g | at 0℃; for 0.5 h; | To a solution of phthalide (2.5 g, 18.65 mmol) in conc.H2S04 was added a solution of potassium nitrate (2.22 g, 18.65 mmol) in cone. H2S04. The reaction mixture was stirred at 0°C for 30 minutes and quenched with water and filtered. The filtrate was concentrated and purified by column chromatography to afford 1.00 g of the title product. 1H NMR (300 MHz, DMSO-Je): δ 5.45 (s, 2H), 7.72 (d, / = 8.4 Hz, 1H), 8.58 (d, / = 8.1 Hz, 1H), 8.78 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.8% | Stage #1: With sodium hydroxide In methanol; ethyl acetate at 80℃; Stage #2: at 80℃; |
Isobenzofuran-l(3H)-one (0.50 g, 1.0 eq.) was dissolved in methanol (2.0 mL) and ethyl acetate (10.0 mL) and then 4-chlorobenzaldehyde (0.52 g, 1.0 eq.) was added thereto. NaOH (0.60 g, 4.0 eq.) was dissolved in methanol (8.0 mL) and added to the reaction solution. The mixture was then stirred overnight at 80°C. After confirming the disappearance of the starting material by TLC, the reaction solution was concentrated under reduced pressure. Water and ethyl acetate were added to the obtained residue, and the extracted organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hydrazine hydrate (20.0 mL) was added to the obtained residue, followed by stirring overnight at 80°C. The reaction solution was cooled at room temperature and concentrated under reduced pressure. Ethanol (10.0 mL) was added to the obtained residue and cooled to 0°C using ice. After confirming that a transparent red solid was crystallized, it was filtered to obtain the desired intermediate 4- (4-chlorobenzyl)phthalazin-l(2H)-one (0.25 g, yield 24.8percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.3% | Stage #1: With sodium methylate In methanol; N,N-dimethyl-formamide at 100 - 130℃; Stage #2: With water In methanol; N,N-dimethyl-formamide at 100℃; Stage #3: With hydrogenchloride In methanol; water; N,N-dimethyl-formamide at 10℃; |
Example 1 Synthesis of the Intermediate 4-(2-Carboxybenzyloxy)Phenylacetic Acid (Olo-IM1) A solution of 4-hydroxyphenylacetic acid (90.0 g, 0.58 mol; assay >98percent) and phthalide (85.07 g, 0.63 mol) in DMF (323 g) was heated to an internal temperature of 130° C. The pressure was reduced to 800 mbar and sodium methoxide (224.6 g, 1.25 mol, assay: 30percent methanolic solution) was added slowly to the mixture maintaining the internal temperature above 100° C. During the addition methanol was distilled off, and after the addition the distillation was continued under normal pressure until the internal temperature increased to 130° C. again (260 g distillate). After stirring at this temperature for 6.5 h, phthalide (8.5 g, 0.06 mol) was added and the mixture was stirred overnight (16 h). Afterwards the mixture was cooled to 100° C. and hydrolyzed with water (1040 g). After cooling to <10° C., the pH of the mixture was adjusted to pH 1 with hydrochloric acid (163.5 g, 1.43 mol; assay: 32percent). The product was filtered off, washed with water (700 g) and dried under vacuum for 15 hours at 60° C. to give crude 4-(2-carboxybenzyloxy)phenylacetic acid (Olo-IM1) (yield: 174.6 g, 0.48 mol, 82.1percent; HPLC assay: 78.0percent). The crude Olo-IM1 (50.0 g, assay: 78.0percent, 0.14 mol) was recrystallized from acetonitrile/water (40 ml, 1/1). After filtration, the wet product washed successively with acetonitrile/water (98 ml, 1/1) and water (20 ml) to give slightly orange colored 4-(2-carboxybenzyloxy)phenylacetic acid (Olo-IM1) (yield: 35.27 g, 0.12 mol, 88.1percent; HPLC assay: 97.4percent; overall yield: 72.3percent). |
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