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CAS No. : | 39585-32-5 | MDL No. : | MFCD07782180 |
Formula : | C9H7NO6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CKXXWBQEZGLFMV-UHFFFAOYSA-N |
M.W : | 225.16 | Pubchem ID : | 7172025 |
Synonyms : |
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.11 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 53.77 |
TPSA : | 120.42 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.15 cm/s |
Log Po/w (iLOGP) : | 0.25 |
Log Po/w (XLOGP3) : | 0.74 |
Log Po/w (WLOGP) : | 0.92 |
Log Po/w (MLOGP) : | 0.27 |
Log Po/w (SILICOS-IT) : | -1.12 |
Consensus Log Po/w : | 0.21 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.72 |
Solubility : | 4.33 mg/ml ; 0.0192 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.85 |
Solubility : | 0.32 mg/ml ; 0.00142 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -0.94 |
Solubility : | 26.0 mg/ml ; 0.115 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.13 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; In toluene; | 2-(2-Hydroxymethyl-5-nitrophenyl)ethanol (11) through alternative intermediate (10) A mixture of <strong>[39585-32-5]2-carboxymethyl-4-nitrobenzoic acid</strong> (13 g, 57.7 mmol), acetic anhydride (5.45 mL, 57.7 mmol) and toluene (130 mL) were heated to reflux for 5 hrs. The solvent was removed under vacuum to yield 6-nitro-isochroman-1,3-dione (compound (10) in Scheme 2) as a yellow solid (10.51 g, 88%). | |
With acetic anhydride; In toluene; | c'. 2-(2-hydroxymethyl-5-nitro-phenyl)-ethanol (4), alternative procedure A mixture of <strong>[39585-32-5]2-carboxymethyl-4-nitro-benzoic acid</strong> (13g, 57.7mmol), acetic anhydride (5.45mL, 57.7mmol) and toluene (130mL) were heated to reflux for 5 hrs. The solvent was removed under vacuum to yield 6-nitro-isochroman-1,3-dione (compound (3a) in Scheme 2) as a yellow solid (10.51 g, 88%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In tetrahydrofuran; | c. 2-(2-hydroxymethyl-5-nitro-phenyl)-ethanol (4) A THF (60 mL) solution of <strong>[39585-32-5]2-carboxymethyl-4-nitro-benzoic acid</strong> (3.0 g, 13.3 mmol) was treated with borane-THF complex (53.3 mL, 53.3 mmol) over 15 min at 0 C. The reaction was stirred for 18.5 hrs, quenched with THF/water (1:1, 30 mL), water (20 mL) added and the layers separated. The aqueous layer was reextracted with THF (30 mL); the combined organic phase washed with brine, dried with magnesium sulfate, and solvent removed under vacuum to give the product as a white solid (2.06 g, 78%) mp=79-81 C. IR(KBr) 3277, 3192, 2964, 2932, 1614, 1525, 1507, 1170, 1134, 1089, 1067 cm-1. 13 C NMR (CD3)2 SO delta 149.1, 146.6, 139.2, 127.8, 124.31 121.3, 61.2, 60.6, 34.9. Anal. Calcd for C9 H11 NO4: C, 54.82; H, 5.62; N, 7.10. Found: C, 54.54, H, 5.49; |
78% | In tetrahydrofuran; | 2-(2-Hydroxymethyl-5-nitrophenyl)-ethanol (11) A THF (60 mL) solution of <strong>[39585-32-5]2-carboxymethyl-4-nitrobenzoic acid</strong> (3.0 g, 13.3 mmol) was treated with borane-THF complex (53.3 mL, 53.3 mmol) over 15 min at 0 C. The reaction was stirred for 18.5 hrs, quenched with THF/water (1:1, 30 mL), water (20 mL) added and the layers separated. The aqueous layer was backwashed with THF (30 mL), the combined organic phase was washed with brine, dried with magnesium sulfate, and the solvent removed under vacuum to give the product as a white solid (2.05 g, 78%) mp 79-81 C. IR(KBr) 3277, 3192, 2964, 2932, 1614, 1525, 1507, 1170, 1134, 1089, 1067 cm-1. 13 C NMR (DMSO) delta149.1, 146.6, 139.2, 127.8, 124.3, 121.3, 61.2, 60.6, 34.9. Anal. Calcd for C9 H11 NO4: C, 54.82; H, 5.62; N, 7.10. Found: C, 54.54; H, 5.49; N, 7.07. |
78% | In tetrahydrofuran; | c. 2-(2-hydroxymethyl-5-nitro-phenyl)-ethanol (4) A THF (60mL) solution of <strong>[39585-32-5]2-carboxymethyl-4-nitro-benzoic acid</strong> (3.0g, 13.3mmol) was treated with borane-THF complex (53.3mL, 53.3mmol) over 15 min at 0C. The reaction was stirred for 18.5 hrs, quenched with THF/water (1:1, 30mL), water (20mL) added and the layers separated. The aqueous layer was reextracted with THF (30mL), the combined organic phase washed with brine, dried with magnesium sulfate, and solvent removed under vacuum to give the product as a white solid (2.05g, 78%) mp=79-81C. IR(KBr) 3277, 3192, 2964, 2932, 1614, 1525, 1507, 1170, 1134, 1089, 1067 cm-1, 13C NMR (CD3)2SO delta 149,1, 146.6, 139.2, 127.8, 124.3, 121.3, 61.2, 60.6, 34.9, Anal. Calcd for C9H11NO4: C, 54.82; H, 5.62; N, 7.10. Found: C, 54.54; H, 5.49; N, 7.07. |
2-[2-(hydroxymethyl)-5-nitrophenyl1ethanol (7-4)A solution of boron trifluoride diethyl etherate (6.80 mL, 53.7 mmol, 3.02 equiv) in tetrahydrofuran (25 mL) was added portionwise via cannula over 1 h to a solution of 2-(carboxymethyl)- 4-nitrobenzoic acid (7-3, 4.00 g, 17.8 mmol, 1 equiv) and sodium borohydride (2.02 g, 53.3 mmol, 3.00 equiv) in tetrahydrofuran (90 mL) at 0 C. The resulting cloudy white suspension was allowed to warm to 23 C and stir for 20 h. An aqueous solution of sodium hydroxide (1 N) was carefully added to the precooled (0 C) reaction mixture. The mixture was partially concentrated to remove THF and the resulting precipitate was collected by filtration and dried to give 2-[2-(hydroxymethyl)-5- nitrophenyl]ethanol (7-4) as a pale yellow solid. 1H NMR (300 MHz, (CD3)2SO) delta 8.09 (br dd, 1H, J = 9.5, 2.4 Hz), 8.06 (br s, 1H), 7.68 (d, 1H, J = 9.5 Hz), 5.46 (br s, 1H), 4.77 (br s, 1H), 4.66 (s, 2H), 3.66 (t, 1H, J = 6.4 Hz), 2.82 (t, 2H, J = 6.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium hydroxide; In methanol; water; | Example 2 2-Carboxymethyl-4-nitro-benzoic acid Sodium hydroxide (10.10 g, 253 mmol) in water (120 mL) was added over 85 min to a solution of 2-(carboxy-5-nitro-phenyl)malonic acid dimethyl ester, (15.0 g, 51 mmol) in methanol (120 mL) at ambient temperature. After 3 hrs the reaction was complete, the methanol removed under vacuum, and the contents acidified with concentrated HCl (22.4 mL) at ambient temperature. The resulting white aqueous suspension was extracted twice with ethyl acetate (150 mL and 75 mL), the combined organic phases were dried with magnesium sulfate, and the volume of extracts reduced to 55 mL. The resulting ethyl acetate solution was heated to 65 C. for 6 hr effecting complete decarboxylation. The diacid was filtered off at ambient temperature and dried to afford 10 g of the diacid as a white solid (88%, mp 180-82 C.). IR 3080, 3055, 2983, 1707, 1611, 1585, 1516, 1491, 1424, 1358, 1298, 1237 cm-1.1 H NMR(CD3)2 SOdelta12.87 (bs,2H),8.25(d,J=2 Hz, 1H),8.18 (dd,J=2 Hz, J=8 Hz,1H), 8.07(d,J=8 Hz,1H),4.07 (s,2H).13 C NMR (CD3)2 SOdelta172.3, 167.5, 149.2, 138.8, 137.3, 132.1, 127,2, 122.4, 39.8. Anal. Calcd for C9 H17 NO6:C,48.01; H,3.13; N,6.22.Found:C, 47.67; H, 3.19; N, 6.31. |
88% | With sodium hydroxide; In methanol; water; | Example 2 2-Carboxymethyl-4-nitro-benzoic acid Sodium hydroxide (10.10g, 253mmol) in water (120mL) was added over 85min to a solution of 2-(carboxy-5-nitro-phenyl)malonic acid dimethyl ester, (15.0g, 51mmol) in methanol (120mL) at ambient temperature. After 3hrs the reaction was complete, the methanol removed under vacuum, and the contents acidified with concentrated HCI (22.4mL) at ambient temperature. The resulting white aqueous suspension was extracted twice with ethyl acetate (150mL and 75mL), the combined organic phases were dried with magnesium sulfate, and the volume of extracts reduced to 55mL. The resulting ethyl acetate solution was heated to 65C for 6hr effecting complete decarboxylation. The diacid was filtered off at ambient temperature and dried to afford 10g of the diacid as a white solid (88%, mp 180-82C). IR 3080, 3055, 2983,1707, 1611,1585, 1516,1491,1424, 1358, 1298, 1237 cm-1. 1H NMR (CD3)2SO delta12.87 (bs, 2H), 8.25 (d, J = 2Hz, 1H), 8.18 (dd, J = 2Hz, J = 8Hz, 1H), 8.07 (d, J = 8Hz, 1H), 4.07 (s, 2H). 13C NMR (CD3)2SO delta172.3, 167.5, 149.2, 138.8, 137.3, 132.1, 127,2, 122.4, 39.8. Anal. Calcd for C9H17NO6: C, 48.01; H, 3.13; N, 6.22. Found: C, 47.67; H, 3.19; N, 6.31. |
23% | Step 2: 2-Carboxymethyl-4-nitrobenzoic acid A solution of sodium hydroxide (5.0 g, 125 mmol) in water (60 mL) was added to a solution of dimethyl 2-(2-carboxy-5-nitrophenyl)malonate (7.0 g, 21.5 mmol) in methanol (60 mL) at room temperature. After the reaction solution was stirred at room temperature for 3 hours, methanol was distilled off. The resulting residue was acidified using 1N hydrochloric acid (11 mL). The suspension was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. After the crude product was stirred in ethyl acetate (20 mL) at 70 to 80C overnight, the temperature was allowed to return to room temperature. The precipitate was collected by filtration, and dried under reduced pressure to give the title compound (1.13 g, 23%). 1H-NMR (300 MHz, in CDCl3 + methanol d4) chemical shifts delta: 4.12 (2H, s), 8.15 (1H, s), 8.20 (2H, m). |
With sodium hydroxide; In methanol; dichloromethane; water; | b. 2-carboxymethyl-4-nitro-benzoic acid (3) To a solution of 2-(carboxy-5-nitro-phenyl)malonic acid dimethyl ester, (25.0 g, 84 mmol) in methanol (200 mL), sodium hydroxide (5 g, 125 mmol) in water (200 mL) was added. After 3 hrs the reaction was complete, the methanol removed under vacuum, contents cooled to 0 C. and acidified with concentrated HCl (37 mL). The aqueous layer was extracted twice with ethyl acetate (200 mL then 100 mL), the combined organic layers dried with magnesium sulfate, most of the solvent removed under vacuum, and methylene chloride (30 mL) was then added. The white solid was filtered off and dried to give 19.3 g of product as a white solid, mp=180-82 C. IR(KBr) 3080, 3055, 2983, 1707, 1611, 1585, 1516, 1491, 1424, 1358; 1298, 1237 cm-1. 13 C NMR (CD3)2 SO delta 172.3, 167.5, 149.2, 138.8, 137.3, 132.1, 127.2, 122.4, 39.8. Anal. Calcd for C9 H17 NO6: C, 48.01; H, 3.13; N, 6.22. Found: C, 47.67; H, 3.19; N, 6.31. | |
With sodium hydroxide; In methanol; dichloromethane; water; | 2-Carboxymethyl-4-nitrobenzoic acid (9) To a solution of 2-(carboxy-5-nitrophenyl)malonic acid dimethyl ester, (25.0 g, 84 mmol) in methanol (200 mL), sodium hydroxide (5 g, 125 mmol) in water (200 mL) was added. After 3 hrs the reaction was complete, the methanol was removed under vacuum, the contents cooled to 0 C. and acidified with concentrated HCl (37 mL). The aqueous layer was extracted twice with ethyl acetate (200 mL then 100 mL), the combined organic layers were dried with magnesium sulfate, most of the solvent removed under vacuum, and methylene chloride (30 mL) was then added. The formed white solid was filtered off and dried to give 19.3 g of product as a white solid, mp 180-820 C. IR(KBr) 3080, 3055, 2983, 1707, 1611, 1585, 1516, 1491, 1424, 1358, 1298, 1237 cm-1. 13 C NMR (DMSO) delta172.3, 167.5, 149.2, 138.8, 137.3, 132.1, 127.2, 122.4, 39.8. Anal. Calcd for C9 H17 NO6: C, 48.01; H, 3.13; N, 6.22. Found: C, 47.67; H, 3.19; N, 6.31. | |
With sodium hydroxide; In methanol; dichloromethane; water; | b. 2-carboxymethyl-4-nitro-benzoic acid (3) To a solution of 2-(carboxy-5-nitro-phenyl)malonic acid dimethyl ester, (25.0g, 84mmol) in methanol (200mL), sodium hydroxide (5g, 125mmol) in water (200mL) was added. After 3 hrs the reaction was complete, the methanol removed under vacuum, contents cooled to 0C and acidified with concentrated HCI (37mL). The aqueous layer was extracted twice with ethyl acetate (200mL then 100mL), the combined organic layers dried with magnesium sulfate, most of the solvent removed under vacuum, and methylene chloride (30mL) was then added. The white solid was filtered off and dried to give 19.3g of product as a white solid, mp=180-82C. IR(KBr) 3080, 3055, 2983, 1707, 1611, 1585, 1516, 1491, 1424, 1358, 1298, 1237 cm-1. 13C NMR (CD3)2SO delta 172.3, 167.5, 149.2, 138.8, 137.3, 132.1, 127.2, 122.4, 39.8. Anal. Calcd for C9H17NO6: C, 48.01; H, 3.13; N, 6.22. Found: C, 47.67; H, 3.19; N, 6.31. | |
2-(carboxymethyl)-4-nitrobenzoic acid (7-3)Aquious sodium hydroxide solution (2 M, 60 mL) was added dropwise over 1 h to a solution of 2-[2-methoxy-1-(methoxycarbonyl)-2-oxoethyl]-4-nitrobenzoic acid (7-2, 7.00 g, 23.6 mmol, 1 equiv) in methanol (60 mL) at 23 C. The resulting deep-red reaction mixture was allowed to stir at 23 C for 20 h. The mixture was partially concentrated to remove MeOH, and the remaining aqueous solution was acidified with concentrated aqueous HCl solution to pH ~1. The resulting white solid slurry was extracted with ethyl acetate (2 x 75 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was dissolved in minimal ethyl acetate and heated at 65 C for 3 h. The mixture was then allowed to cool to 23 C and the resulting precipitate was collected by filtration and dried to afford 2-(carboxymethyl)-4-nitrobenzoic acid (7-3) as a white solid. 1H NMR (300 MHz, (CD3)2SO) delta 13.5 (br s, 1H), 12.5 (br s, 1H), 8.28 (d, 1H, J = 2.1 Hz), 8.21 (dd, 1H, J = 8.6, 2.1 Hz), 8.10 (d, 1H, J = 8.5 Hz), 4.10 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | In toluene;Heating / reflux; | The diacid A (1 equivalent) was added to a flask equipped with a reflux condenser and dean stark trap and charged with dry TOLUENE. The mixture was heated to reflux and then 2- (2-FLUORO-4-METHOXY-PHENYL)- ethylamin B (1 equivalent) was added. The reaction was kept at reflux overnight, and then the toluene was removed by rotary evaporation. Purification by flash chromatography using ethyl acetate/hexanes provided the product C in 30% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.16 g (71%) | With sodium hydroxide; sodium tetrahydroborate; In tetrahydrofuran; BF3.Et2O; | Step 1 Preparation of 2-[2-(hydroxymethyl)-4-nitrophenyl]ethanol A solution of <strong>[39585-32-5]4-nitrohomophthalic acid</strong> (313.12 g, 58.27 mmol, J. Amer. Chem. Soc., 1969, 91, 2467) in dry THF (291 mL) under N2 is treated with NaBH4 (6.61 g, 174.8 mmol) portionwise over 15 mins. The resulting mixture is cooled in an ice bath and BF3.Et2O (22.15 mL, 174.8 mmol) is added dropwise over 35 mins. The cooling bath is removed, and the reaction mixture is stirred vigorously at ambient temperature for 18 hrs and is then cooled in an ice bath, quenched by the slow addition of 1N aqueous NaOH (233 mL, 4 equiv.) and stirred at ambient temperature for an additional 4 hrs. The THF is then removed under reduced pressure, the resulting precipitate is isolated by filtration, the filtrate is extracted with MeOH/CH2Cl2 (10/90, 3*150 mL), and the precipitate is combined with the organic extracts, diluted with additional MeOH/CH2Cl2 (10/90, 400 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure and recrystallized from EtOAc/hexane to give 8.16 g (71%) of the title compound as a beige solid, mp 80-81 C. (decomp.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; In toluene; | c. 2-(2-hydroxymethyl-5nitro-phenyl)-ethanol (4), alternative procedure A mixture of 2 carboxymethyl-4-nitro-benzoic acid (13 g, 57.7 mmol), acetic anhydride (5.45 mL, 57.7 mmol) and toluene (30 mL) were heated to reflux for 5 hrs. The solvent was removed under vacuum to yield 6-nitro-isochroman-1,3-dione (compound (3a) in Scheme 2) as a yellow solid (10.51 g, 88%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium borohydrid; | Example 3 2-(2-Hydroxymethyl-5-nitro-phenyl)-ethanol To a Tetrahydrofuran (THF) (220 mL) solution of <strong>[39585-32-5]2-carboxymethyl-4-nitro-benzoic acid</strong> (10.0 g, 44.4 mmol) was added sodium borohydride (5.06 g, 133 mmol) in portions. The contents were cooled to 0 C., and boron trifluoride diethyl etherate (21.3 mL, 133 mmol) was added dropwise over 1 hr. The contents were allowed to warm to 25 C. and stirred for 16 hrs. The reaction was cooled to 0 C. and cautiously quenched with aqueous sodium hydroxide (1 N, 178 mL). The contents were stirred for 3 hrs, THF was removed under vacuum, the resulting aqueous suspension was cooled to 0 C. and the product was filtered off. After drying, the product was obtained as a white solid 7.78 g (89%, mp 79-81 C.). IR 3277, 3192, 2964, 2932, 1614, 1525, 1507, 1170, 1134, 1089, 1067 cm-1.1 H NMR (CD3)2 SO delta8.05 (d,J=9 Hz, 1H), 8.04 (s, 1H), 7.66 (d, J=9 Hz, 1H), 5.42 (t,J=5 Hz, 1H), 4.74 (t, J=5 Hz, 1H), 4.64 (d, J=5 Hz, 2H), 3.63 (m, 2H), 2.80 (t, J=6 Hz, 2H). 13 C NMR (CD3)2 SO delta149.1, 146.6, 139.2, 127.8, 124.3, 121.3, 61.2, 60.6, 34.9. Anal. Calcd for C9 H11 NO4:C, 54.82; H, 5.62; N, 7.10. Found: C, 54.54; H, 5.49; N, 7.07. | |
With sodium borohydrid; | Example 3 2-(2-Hydroxymethyl-5-nitro-phenyl)-ethanol To a Tetrahydrofuran (THF) (220mL) solution of <strong>[39585-32-5]2-carboxymethyl-4-nitro-benzoic acid</strong> (10.0g, 44.4mmol) was added sodium borohydride (5.06g, 133mmol) in portions. The contents were cooled to 0C, and boron trifluoride diethyl etherate (21.3mL, 133mmol) was added dropwise over 1 hr. The contents were allowed to warm to 25C and stirred for 16hrs. The reaction was cooled to 0C and cautiously quenched with aqueous sodium hydroxide (1 N , 178mL). The contents were stirred for 3hrs, THF was removed under vacuum, the resulting aqueous suspension was cooled to 0C and the product was filtered off. After drying, the product was obtained as a white solid 7.78g (89%, mp 79-81C). IR 3277, 3192, 2964, 2932, 1614, 1525, 1507, 1170,1134, 1089, 1067 cm-1. 1H NMR (CD3)2SO delta8.05 (d, J = 9Hz, 1H), 8.04 (s, 1H), 7.66 (d, J = 9Hz, 1H), 5.42 (t, J = 5Hz, 1H), 4.74 (t, J = 5Hz, 1H), 4.64 (d, J = 5Hz, 2H), 3.63 (m, 2H), 2.80 (t, J = 6Hz, 2H). 13C NMR (CD3)2SO delta149.1, 146.6, 139.2, 127.8, 124.3, 121.3, 61.2, 60.6, 34.9. Anal. Calcd for C9H11NO4: C, 54.82; H, 5.62; N, 7.10. Found: C, 54.54; H, 5.49; N, 7.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.51 g (82%) | In water; acetic acid; | 2-Benzyl-6-nitro-4H-isoquinoline-1,3-dione (16) To a suspension of the diacid (9) (55 g, 0.244 mole) in acetic acid (550 mL) was added benzylamine (28.91 g, 0.27 mole). The reaction was heated to 115 C. for 18 hrs., cooled to 25 C., water was added (450 mL), the contents stirred for 2 hrs., and the product filtered off as a white solid. The product was washed with water (400 mL) and vacuum dried to give 59.51 g (82%). 1 H NMR (DMSO) delta8.29-8.20 (m, 3H); 7.3-7.19 (m, 5H); 5.03 (s, 2H); 4.35 (s, 2H). IR 3076, 2976, 1712, 1669, 1618, 1528, 1338, 1308 cm-1. Anal. Calc'd for C16 H12 N2 O4: C, 64.83; H, 4.08; N, 9.46. Found C, 64.72; H, 3.97; N, 9.49. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydrogencarbonate; In ethyl acetate; benzyl alcohol; | EXAMPLE 4 Preparation of 7-Nitro-3-Benzyloxy-4-Chloroisocoumarin <strong>[39585-32-5]4-Nitro-homophthalic acid</strong> (5.0 g) was suspended in benzyl alcohol (50 mL) and H2 SO4 (3 drops) added. The reaction mixture was heated at 70-80 degrees centigrade for 45 min, diluted into 100 mL of ethyl acetate, and washed with 1 L of 4% NaHCO3. The aqueous layers were combined, acidified to pH 3 using concentrated HCl, and extracted with 500 mL of ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and concentrated to give ca. 4 g of crude product, which was titurated with isopropyl ether to give 3.8 grams of benzyl 2-carboxy-4-nitrophenyl acetate: mp. 171-172. Anal. Calcd. for C16 H13 NO6: C, 60.96; H, 4.18. Found: C, 60.86; H, 4.18. | |
With hydrogenchloride; sodium hydrogencarbonate; In ethyl acetate; benzyl alcohol; | EXAMPLE 4 Preparation of 7-Nitro-3-Benzyloxy-4-Chloroisocoumarin <strong>[39585-32-5]4-Nitro-homophthalic acid</strong> (5.0 g) was suspended in benzyl alcohol (50 mL) and H2 SO4 (3 drops) added. The reaction mixture was heated at 70-80 degrees centigrade for 45 min, diluted into 100 mL of ethyl acetate, and washed with 1 L of 4% NaHCO3. The aqueous layers were combined, acidified to pH 3 using concentrated HCl, and extracted with 500 mL of ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and concentrated to give ca. 4 g of crude product, which was titurated with isopropyl ether to give 3.8 grams of benzyl 2-carboxy-4-nitrophenyl acetate: mp. 171-172. Anal. Calcd. for C16 H13 NO6: C, 60.96; H, 4.18. Found: C, 60.86; H, 4.18. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.8% | With acetic acid; urea; at 110℃; for 4.5h;Cooling with ice; Large scale; | A suspension of 15 <strong>[39585-32-5]2-(carboxymethyl)-4-nitrobenzoic acid</strong> (1.5 kg, 6.67 mol, 1 eq) in 18 acetic acid (6 L) was heated at 110 C. The suspension became a clear solution when the temperature reached 90 C. Solid 16 urea (2.85 kg, 47.5 mol, 7.1 eq) was then added slowly into the reaction mixture. The reaction was stirred at 110 C. for about 4 h. The reaction mixture was combined with another parallel batch (from 1.5 kg of <strong>[39585-32-5]2-(carboxymethyl)-4-nitrobenzoic acid</strong>) and poured into a mixture of 44 ice water (20 kg) and stirred for 0.5 h. The resulting solid was filtered and washed with water (10 L×3) and air dried to produce the title compound as a tan solid (2 kg, yield 72.8%). 1H-NMR (300 MHz, DMSO-d6) delta 11.61 (s, 2H), 8.30 (s, 1H), 8.24 (s, 1H), 4.17 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With sulfuric acid;Heating / reflux; | Step 3: Methyl 2-methoxycarbonylmethyl-4-nitrobenzoate Sulfuric acid was added in excess to a solution of <strong>[39585-32-5]2-carboxymethyl-4-nitrobenzoic acid</strong> (3.00 g, 13.68 mmol) in methanol (30 mL). The reaction solution was stirred overnight while heating under reflux. After the solution was cooled to room temperature, water was added thereto and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, and then with brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The title compound was obtained as colorless oily material (1.74 g, 50%). 1H-NMR (300 MHz, in CDCl3) chemical shifts delta: 3.72 (3H, s), 3.93 (3H, s), 4.12 (2H, s), 8.14-8.23 (3H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; under 2250.23 Torr; for 3.0h; | Fifteen grams (66.7 mmol) of starting material 22 and 1.5 g of 10% Pd/C (purchased from Aldrich) were suspended 100 mL of EtOH and subjected to hydrogenation at 6 bar pressure for 3 h at rt. The resulting suspension was mixed with 100 mL of water, refluxed for 10 min, and filtered through Celite 545 (Aldrich) while hot. The filtrate was then evaporated to a minimum amount of solvent and the resulting solid was collected by filtration. The solid was washed with water, dried at rt overnight and weights at 11.1 g (56.9 mmol, 85%). 1H NMR (400 MHz, DMSO-d6) delta 7.65 (d, J = 8.5 Hz, 1H, HAr), 6.49-6.30 (m, 2H, HAr), 5.79 (br s, 2H), 3.76 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-d6) delta 173.1 (CO), 168.4 (CO), 152.7 (Cq,Ar), 139.3 (Cq,Ar), 133.4 (CHAr), 117.2 (CHAr), 116.5 (Cq,Ar), 111.7 (CHAr), 41.0 (CH2); HRMS (ESI-) calcd for [M-H]- 194.0459, found 194.0459; Mp: 208-209 C (water-ethanol); HPLC tR 2.2 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.5 g | The crude product 21 (9.9 g, 41 mmol) from last step was stirred with a solution of 12 g (0.3 mol) of NaOH in 100 mL of MeOH at rt overnight. The mixture was then acidified (to pH 1) with conc. aq HCl, evaporated to dryness and co-evaporated with toluene several times. The residue was extracted with 20% MeOH in DCM several times. Combined organic phases were evaporated to dryness and the residue was recrystallized with minimum amount of EtOAc to give the product 4.5 g (20 mmol, 49%) of off-white solid. 1H NMR (400 MHz, DMSO-d6) delta 8.26 (d, J = 2.4 Hz, 1H, HAr), 8.19 (dd, J = 8.6, 2.4 Hz, 1H, HAr), 8.08 (d, J = 8.6 Hz, 1H, HAr), 4.08 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-d6) delta 172.2 (CO), 167.4 (CO), 149.2 (Cq,Ar), 138.8 (Cq,Ar), 137.2 (Cq,Ar), 132.0 (CHAr), 127.1 (CHAr), 122.4 (CHAr), 39.8 (CH2, overlapped with CH3-DMSO); HRMS (ESI-) calcd for [M-H]- 224.0201, found 224.0201; Mp: 171-172 C (EtOAc); HPLC tR 2.2 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.7% | With potassium hydroxide; at 20℃;Large scale; | The aqueous layer of the crude 29 2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-4-nitrobenzoic acid was charged into a 100 L reactor, followed by the addition of solid 24 KOH (7.58 kg, 135.3 mol). The basic reaction mixture was stirred at RT overnight. After 2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-4-nitrobenzoic acid was consumed as indicated by HPLC analysis, the reaction mixture was carefully acidified with concentrated HCl to pH 67. 42 EtOAc (50 L) was then added and the mixture was further acidified with concentrated HCl to pH 23. The organic layer was separated. The aqueous layer was extracted with EtOAc (40 L×2). The combined organic layers were washed with water (10 L×2) and brine (10 L), dried over anhydrous Na2SO4, filtered and concentrated to remove about half the solvent. The resulting solid was filtered and washed with EtOAc to provide the 15 title compound as a yellow solid (5 kg, yield 49.7%). HPLC purity: 98.2%; 1H-NMR (300 MHz, DMSO-d6) delta 13.0 (s, 2H), 8.28 (d, J=2.2 Hz, 1H), 8.21 (dd, J=8.6 Hz, 2.3, 1H), 8.09 (d, J=8.6 Hz, 1H), 4.10 (s, 2H). |
Tags: 39585-32-5 synthesis path| 39585-32-5 SDS| 39585-32-5 COA| 39585-32-5 purity| 39585-32-5 application| 39585-32-5 NMR| 39585-32-5 COA| 39585-32-5 structure
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