* 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.
A mixture of 4-methoxyphthalic anhydride (27.8 g, 0.16 mol) and formamide (175 ml) was stirred and held at 2100C for 5 hours and was then allowed to cool to room temperature overnight. The solid material was filtered off, washed sequentially with water (100 ml), 50percent aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford A- methoxyphthalimide (21.3 g, 77percent) as a pale yellow solid. 1H NMR (DMSOd6) 11.15 (1 H, br s), 7.74 (1H, d), 7.33-7.28 (2H, m), 3.92 (3H1 s).
77%
at 20 - 210℃;
A mixture of 4-methoxyphthalic anhydride (27.8 g, 0.16 mol) and formamide (175 ml) was stirred and held at 21O0C for 5 hours and was then allowed to cool to room temperature overnight. The solid material was filtered off, washed sequentially with water (100 ml), 50percent aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford A- methoxyphthalimide (21.3 g, 77percent) as a pale yellow solid. 1H NMR (DMSOd6) 11.15 (1 H, br s), 7.74 (1 H, d), 7.33-7.28 (2H, m), 3.92 (3H, s).
77%
at 210℃; for 5 h;
A mixture of 4-methoxyphthalic anhydride (27.8 g, 0.16 mol) and formamide (175 ml) was stirred and held at 2100C for 5 hours and was then allowed to cool to room temperature overnight. The solid material was filtered off, washed sequentially with water (100 ml), 50percent aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford 4- methoxyphthalimide (21.3 g, 77percent) as a pale yellow solid. 1H NMR (DMSO-d6) 11.15 (1 H, br s), 7.74 (1 H1 d), 7.33-7.28 (2H, m), 3.92 (3H1 s).
77%
at 20 - 210℃;
A mixture of 4-methoxyphthalic anhydride (27.8 g, 0.16 mol) and formamide (175 ml) was stirred and held at 2100C for 5 hours and was then allowed to cool to room temperature overnight. The solid material was filtered off, washed sequentially with water (100 ml), 50percent aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford A- methoxyphthalimide (21.3 g, 77percent) as a pale yellow solid. 1H NMR (DMSOd6) 11.15 (1 H, br s), 7.74 (1 H, d), 7.33-7.28 (2H, m), 3.92 (3H, s).
77%
at 210℃; for 5 h;
A mixture of 4-methoxyphthalic anhydride (27.8 g, 0.16 mol) and formamide (175 ml) was stirred and held at 210° C. for 5 hours and was then allowed to cool to room temperature overnight. The solid material was filtered off, washed sequentially with water (100 ml), 50percent aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford 4-methoxyphthalimide (21.3 g, 77percent) as a pale yellow solid. 1H NMR (DMSO-d6) 11.15 (1H, br s), 7.74 (1H, d), 7.33-7.28 (2H, m), 3.92 (3H, s).
Reference：
[1] Patent: WO2008/44029, 2008, A1, . Location in patent: Page/Page column 204
[2] Patent: WO2008/44041, 2008, A1, . Location in patent: Page/Page column 226
[3] Patent: WO2008/44045, 2008, A1, . Location in patent: Page/Page column 277-278
[4] Patent: WO2008/44054, 2008, A2, . Location in patent: Page/Page column 122
[5] Patent: US2010/152184, 2010, A1, . Location in patent: Page/Page column 73
[6] Journal of Medicinal Chemistry, 2010, vol. 53, # 16, p. 5956 - 5969
[7] Journal of the American Chemical Society, 2014, vol. 136, # 17, p. 6239 - 6242
[8] Chemistry - A European Journal, 2016, vol. 22, # 34, p. 11997 - 12001
[9] Chemische Berichte, 1988, vol. 121, p. 243 - 252
2
[ 1885-13-8 ]
[ 28281-76-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
With acetic anhydride In tetrahydrofuran for 4 h; Heating / reflux
Acetic anhydride (40 ml) was added to a mixture of 4-methoxyphthalic acid (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99percent) as an off white solid. 1H NMR (DMSO-d6) 8.02 (1 H, d), 7.59 (1 H, d), 7.49 (1 H, dd), 3.97 (3H, s). MS: [M+H]+ 179.
99%
With acetic anhydride In tetrahydrofuran for 4 h; Heating / reflux
Acetic anhydride (40 ml) was added to a mixture of 4-methoxyphthalic acid (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. <n="227"/>Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99percent) as an off white solid. 1H NMR (DMSOd6) 8.02 (1 H1 d), 7.59 (1 H, d), 7.49 (1H, dd), 3.97 (3H1 s). MS: [M+H]+ 179.
99%
With acetic anhydride In tetrahydrofuran for 4 h; Heating / reflux
Acetic anhydride (40 ml) was added to a mixture of 4-methoxyphthalic acid (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99percent) as an off white solid. 1H NMR (DMSO-d6) 8.02 (1 H, d), 7.59 (1 H, d), 7.49 (1 H, dd), 3.97 (3H, s). MS: [M+H]+ 179.
99%
With acetic anhydride In tetrahydrofuran for 4 h; Heating / reflux
Acetic anhydride (40 ml) was added to a mixture of 4-methoxyphthalic acid (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99percent) as an off white solid. 1H NMR (DMSO-d6) 8.02 (1 H, d), 7.59 (1 H, d), 7.49 (1 H1 dd), 3.97 (3H, s). MS: [M+H]+ 179.
99%
With acetic anhydride In tetrahydrofuran for 4 h; Reflux
Acetic anhydride (40 ml) was added to a mixture of 4-methoxyphthalic acid (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99percent) as an off white solid. 1H NMR (DMSO-d6) 8.02 (1H, d), 7.59 (1H, d), 7.49 (1H, dd), 3.97 (3H, s). MS: [M+H]+ 179.
78%
With 1,4-diaza-bicyclo[2.2.2]octane; thionyl chloride In dichloromethane at 0 - 20℃; for 0.833333 h;
1 ,4-Diazabicyclic[2,2,2]octane (336 mg, 3 mmol) was dissolved in anhydrous dichloromethane (3 ml_) and then stirred for five minutes while slowly adding distilled thionyl chloride (0.2 ml_, 3 mmol) at O0C. And then,4-methoxyphthalic acid (200 mg, 1 mmol) was slowly added dropwise at room temperature for 50 minutes. 10percent sodium bicarbonate was added to neutralize the reaction solution and the resultant was extracted with dichloromethane.Organic layers were dried with anhydrous sodium sulfate and filtered, and the filtrate was distilled under reduced pressure, separated and then purified by a column chromatography on silica gel (hexane/ethyl acetate=3:1), to obtain139 mg of the desired compound (yield 78percent).1H NMR (300 MHz, CDCI3) δ 7.92 (d, J=5.6 Hz, 1 H) 7.43 (d, J=2.9, 1 H),7.36 (dd, J=11.2, 3.0 Hz, 1 H), 3.99 (s, 1 H). 13C NMR (75 Hz, CDCI3) δ 166.17, 163.00, 162.43, 134.14, 127.28,123.22, 123.98, 108.89, 56.44.
58%
With 1,4-diaza-bicyclo[2.2.2]octane; thionyl chloride In dichloromethane at 20℃; for 2 h;
To a mixture of 4-methoxy-phthalic acid (1.8 g, 9.18 mmol), thionyl chloride (1.4 mL, 19.79 mmol) in CH2C12 (15 mL) is added DABCO (1.1 g, 9.81 mmol). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with CH2C12 (100 mL), washed with H20 (75 mL x2), dried with Na2S04 and filtered. The filtrate is concentrated under reduced pressure to afford 5-methoxy-isobenzofuran-l,3- dione (950 mg, 58percent).
Reference：
[1] Patent: WO2008/44029, 2008, A1, . Location in patent: Page/Page column 204
[2] Patent: WO2008/44041, 2008, A1, . Location in patent: Page/Page column 225-226
[3] Patent: WO2008/44045, 2008, A1, . Location in patent: Page/Page column 277-278
[4] Patent: WO2008/44054, 2008, A2, . Location in patent: Page/Page column 122
[5] Patent: US2010/152184, 2010, A1, . Location in patent: Page/Page column 72; 73
[6] Journal of Medicinal Chemistry, 2010, vol. 53, # 16, p. 5956 - 5969
[7] RSC Advances, 2016, vol. 6, # 52, p. 46170 - 46185
[8] Journal of Natural Products, 2018, vol. 81, # 6, p. 1460 - 1467
[9] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5701 - 5704
[10] Patent: WO2009/54653, 2009, A2, . Location in patent: Page/Page column 25
[11] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 5, p. 1628 - 1631
[12] Patent: WO2011/68821, 2011, A1, . Location in patent: Page/Page column 108
[13] Chemische Berichte, 1883, vol. 16, p. 1964
[14] Journal of the Chemical Society, 1909, vol. 95, p. 1883
[15] Helvetica Chimica Acta, 1931, vol. 14, p. 513
[16] Chemische Berichte, 1938, vol. 71, p. 907,910
[17] Chemische Berichte, 1988, vol. 121, p. 243 - 252
[18] Journal of the American Chemical Society, 2014, vol. 136, # 17, p. 6239 - 6242
[19] Chemistry - A European Journal, 2016, vol. 22, # 34, p. 11997 - 12001
[20] Molecules, 2017, vol. 22, # 2,
3
[ 794-94-5 ]
[ 28281-76-7 ]
Reference：
[1] Journal of the American Chemical Society, 1956, vol. 78, p. 6137
4
[ 4741-63-3 ]
[ 28281-76-7 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1987, vol. 22, p. 229 - 238
5
[ 610-35-5 ]
[ 28281-76-7 ]
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 2, 1998, # 5, p. 1249 - 1256
[2] Chemische Berichte, 1988, vol. 121, p. 243 - 252
[3] Journal of the American Chemical Society, 2014, vol. 136, # 17, p. 6239 - 6242
[4] Chemistry - A European Journal, 2016, vol. 22, # 34, p. 11997 - 12001
6
[ 22895-19-8 ]
[ 28281-76-7 ]
Reference：
[1] Journal of the American Chemical Society, 2014, vol. 136, # 17, p. 6239 - 6242
[2] RSC Advances, 2016, vol. 6, # 52, p. 46170 - 46185
7
[ 186581-53-3 ]
[ 27550-59-0 ]
[ 28281-76-7 ]
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 2, 1998, # 5, p. 1249 - 1256
[2] Journal of the Chemical Society, 1935, p. 1367,1368, 1369
8
[ 22479-95-4 ]
[ 28281-76-7 ]
Reference：
[1] Journal of the American Chemical Society, 2014, vol. 136, # 17, p. 6239 - 6242
[2] Chemistry - A European Journal, 2016, vol. 22, # 34, p. 11997 - 12001
9
[ 86-90-8 ]
[ 28281-76-7 ]
Reference：
[1] Journal of Natural Products, 2018, vol. 81, # 6, p. 1460 - 1467
10
[ 5368-81-0 ]
[ 28281-76-7 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1987, vol. 22, p. 229 - 238
11
[ 3168-59-0 ]
[ 28281-76-7 ]
Reference：
[1] Chemische Berichte, 1883, vol. 16, p. 1964
[2] Journal of the Chemical Society, 1909, vol. 95, p. 1883
A mixture of <strong>[28281-76-7]4-methoxyphthalic anhydride</strong> (27.8 g, 0.16 mol) and formamide (175 ml) was stirred and held at 2100C for 5 hours and was then allowed to cool to room temperature overnight. The solid material was filtered off, washed sequentially with water (100 ml), 50% aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford A- methoxyphthalimide (21.3 g, 77%) as a pale yellow solid. 1H NMR (DMSOd6) 11.15 (1 H, br s), 7.74 (1H, d), 7.33-7.28 (2H, m), 3.92 (3H1 s).
77%
With formamide; at 20 - 210℃;
A mixture of <strong>[28281-76-7]4-methoxyphthalic anhydride</strong> (27.8 g, 0.16 mol) and formamide (175 ml) was stirred and held at 21O0C for 5 hours and was then allowed to cool to room temperature overnight. The solid material was filtered off, washed sequentially with water (100 ml), 50% aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford A- methoxyphthalimide (21.3 g, 77%) as a pale yellow solid. 1H NMR (DMSOd6) 11.15 (1 H, br s), 7.74 (1 H, d), 7.33-7.28 (2H, m), 3.92 (3H, s).
77%
With formamide; at 210℃; for 5h;
A mixture of <strong>[28281-76-7]4-methoxyphthalic anhydride</strong> (27.8 g, 0.16 mol) and formamide (175 ml) was stirred and held at 2100C for 5 hours and was then allowed to cool to room temperature overnight. The solid material was filtered off, washed sequentially with water (100 ml), 50% aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford 4- methoxyphthalimide (21.3 g, 77%) as a pale yellow solid. 1H NMR (DMSO-d6) 11.15 (1 H, br s), 7.74 (1 H1 d), 7.33-7.28 (2H, m), 3.92 (3H1 s).
77%
With formamide; at 20 - 210℃;
A mixture of <strong>[28281-76-7]4-methoxyphthalic anhydride</strong> (27.8 g, 0.16 mol) and formamide (175 ml) was stirred and held at 2100C for 5 hours and was then allowed to cool to room temperature overnight. The solid material was filtered off, washed sequentially with water (100 ml), 50% aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford A- methoxyphthalimide (21.3 g, 77%) as a pale yellow solid. 1H NMR (DMSOd6) 11.15 (1 H, br s), 7.74 (1 H, d), 7.33-7.28 (2H, m), 3.92 (3H, s).
77%
With formamide; at 210℃; for 5h;
A mixture of <strong>[28281-76-7]4-methoxyphthalic anhydride</strong> (27.8 g, 0.16 mol) and formamide (175 ml) was stirred and held at 210 C. for 5 hours and was then allowed to cool to room temperature overnight. The solid material was filtered off, washed sequentially with water (100 ml), 50% aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford 4-methoxyphthalimide (21.3 g, 77%) as a pale yellow solid. 1H NMR (DMSO-d6) 11.15 (1H, br s), 7.74 (1H, d), 7.33-7.28 (2H, m), 3.92 (3H, s).
EXAMPLE 158 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-methoxyphthalimide A stirred mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.63 g, 0.01 mole) and <strong>[28281-76-7]4-methoxyphthalic anhydride</strong> (1.78 g, 0.01 mole) in dichloromethane (100 ml) is stirred at room temperature for 3 hours. The solvent is then removed under reduced pressure and the residual material is purified by flash chromatography. The product is purified further by recrystallization to give N-[2-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]ethyl]-4-methoxyphthalimide.
The starting material is prepared as follows: The mixture of 2.0 g of <strong>[28281-76-7]4-methoxyphthalic anhydride</strong> 1.7 g of 4-nitro-o-toluidine and 20 ml of acetic acid is refluxed for 4 hours, cooled in an ice-bath and filtered, to yield the N-(4-nitro-o-tolyl)-4-methoxyphthalimide melting at 170-171.
5-methoxy-2-(4-pyridinylamino)isoindol-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; acetic acid;
EXAMPLE 43 2,3-Dihydro-5-methoxy-N-(4-pyridinyl)-1H-isoindol-2-amine A mixture of <strong>[28281-76-7]5-methoxyisobenzofuran-1,3-dione</strong> (33.0 g), 4-pyridinylhydrazine hydrochloride (25.7 g) and glacial acetic acid (100 ml) was heated overnight, under reflux, under nitrogen, with stirring. Water (100 ml) was added, and the mixture was evaporated and dried in vacuo. The residue was triturated with acetone, the acetone decanted, and the residue was triturated with methanol to give 16.1 g of 5-methoxy-2-(4-pyridinylamino)isoindol-1,3-dione.
To a mixture of 5-methoxy-isobenzofuran-l,3-dione (950 mg, 5.33 mmol) is added 0.5 M NaOMe in MeOH (16 mL, 18 mmol). The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated under reduced pressure and the resulting residue subsequently quenched with 1M HC1 aq (100 mL). The quenched reaction mixture is extracted with EtOAc (100 mL x2) and the combined organic layers are dried with Na2S04 and filtered. The filtrate is concentrated under reduced to afford crude 4-methoxy-phthalic acid 2-methyl ester (850 mg).
The solution of 4-methoxyphthalic acid (16 mmol) and Ac2O (0.4 mL) in 2 mL THF was refluxedfor 4 h. Once completed, the solvent was evaporated and the intermediate 4-methyl phthalic anhydridewas afforded. Then it was mixed with aniline (0.16 mL) in 5 mL acetic acid under reflux to afford thefinal product quantitively [27].
4-chloro-6-methoxy-2-methylphthalazin-1-(2H)-one[ No CAS ]
4-chloro-7-methoxy-2-methylphthalazin-1-(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step 1: 6-methoxy-2-methyl-2,3-dihydrophthalazine-1,4-dione and 7-methoxy-2-methyl-2,3-dihydrophthalazine-1,4-dione: A mixture of <strong>[28281-76-7]5-methoxyisobenzofuran-1,3-dione</strong> (4.0 g, 22.45 mmol) and methylhydrazine (40% aq., 7.76 g, 67.36 mmol) in ethanol (80 mL) was heated at reflux for 15 h, at which time LCMS indicated that the reaction had gone to completion. The mixture was concentrated under reduced pressure to give the title compound (3.60 g, 78% yield) (2 : 1 ratio of regioisomers) as a yellow solid. This crude material was used in the next step without further purification. LCMS M/Z (M+H) 207. Step 2: 4-chloro-6-methoxy-2-methylphthalazin-l(2H)-one and 4-chloro-7-methoxy-2-methylphthalazin-l(2H)-one A mixture of 6- and 7-methoxy-2-methyl-2,3-dihydrophthalazine-1,4-dione (2.7 g, 13.09 mmol) in POCl3 (50 mL) was heated at reflux for 15 h, at which time LCMS indicated that the reaction had gone to completion. The mixture was concentrated under reduced pressure, the residue was quenched by addition of a saturated aqueous solution of NaHCO3 (100 mL), and then extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether : Ethyl acetate = 5: 1) to give the title compounds (1.1 g, 37% yield) (2 : 1 ratio of regioisomers) as a white solid. LCMS M/Z (M+H) 225.
6-methoxy-2-methyl-2,3-dihydrophthalazine-1,4-dione[ No CAS ]
7-methoxy-2-methyl-2,3-dihydrophthalazine-1,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; water; at 80℃; for 15h;
A mixture of <strong>[28281-76-7]5-methoxyisobenzofuran-1,3-dione</strong> (4.0 g, 22.45 mmol) and methylhydrazine (40% aq., 7.76 g, 67.36 mmol) in ethanol (80 mL) was heated at reflux for 15 h, at which time LCMS indicated that the reaction had gone to completion. The mixture was concentrated under reduced pressure to give the title compound (3.60 g, 78% yield) (2 : 1 ratio of regioisomers) as a yellow solid. This crude material was used in the next step without further purification. LCMS M/Z (M+H) 207.
With acetic acid; for 3h;Reflux; Inert atmosphere; Schlenk technique;
General procedure: To a solution of the anhydride (67.5 mmol) in acetic acid (50 mL), was added slowly benzylamine (6.89 g, 64.3mmol, 0.95 eq), and then the reaction mixture was refluxed for 3 h. After removing acetic acid, the residue was added into water (25 mL). The product was precipitate in cold water and filtered with Buechner funnel. Then crude product was recrystallized in ethanol to give the product.
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