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CAS No. : | 4792-29-4 | MDL No. : | MFCD04117971 |
Formula : | C9H6O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QTWUWCFGWYYRRL-UHFFFAOYSA-N |
M.W : | 178.14 | Pubchem ID : | 78517 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
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91% | With thionyl chloride at 60℃; for 3 - 5h; Heating / reflux; | 1; 3 Example 1: synthesis of 5-chlorocarbonyl phthalide; There are introduced into a flask, in an inert nitrogen atmosphere: 5-carboxyphthalide (50 g, 0.2806 mole), thionyl chloride (125 ml, 1.71 mole), and dimethylformamide (0.5 ml). The system is heated under reflux (60°C) for 5 hours. The system is returned to ambient temperature and evaporated under vacuum to leave a residue. Toluene (3 x 100 ml) is introduced and a solid is obtained which is taken up with tetrahydrofuran (500 ml). A solution containing 5-chlorocarbonyl phthalide (purity HPLC (A%) 98%) 50 g (titrated in solution, molar yield 91%) is obtained.; Example 3: one-pot synthesis of cyanophthalide starting from 5-carboxyphthalide; There are introduced into a flask in an inert nitrogen atmosphere: 5-carboxyphthalide (50 g, 0.2806 mole), thionyl chloride (125 ml, 1.71 mole), and dimethylformamide (0.5 ml). The system is heated under reflux (60°C) for 3 hours. The system is returned to ambient temperature. The system is evaporated under vacuum to leave a residue, and toluene (3 x 100 ml) is introduced; a solid is obtained which is taken up with tetrahydrofuran (500 ml). A solution containing 5-chlorocarbonyl phthalide (purity HPLC (A%) 98%) 50 g (titrated in solution, molar yield 91 %) is obtained. An aqueous hydroxylamine solution (18 ml, 12.5 g, 0.378 mole) is introduced into a flask. The system is brought to 10°C. A chlorocarbonyl phthalide solution (100 ml corresponding to approximately 11 g of chlorocarbonyl phthalide 0.056 mole) is introduced (period of introduction 1 hour). The appearance of a solid is observed during the dropwise addition. The whole is left under agitation overnight and then filtered. The solid is washed with water (100 ml) and 5-hydroxamyl phthalide 10.5 g (molar yield 92% P%=99.%) is obtained. 1HNMR (DMSO-d6 400MHz) 5.45(2H,s), 7.87(1Hs), 7.91(1H,s), 7.98(1H,s),9.30 (1H,s), 11.52(1H,s) 2 g of 5-hydroxamyl phthalide (0.01 mole) are introduced into a flask to which thionyl chloride (15 ml) is added and the whole is heated under reflux (80°C) to give, after 6 hours, a light yellow solution. Toluene (20 ml) is introduced. The whole is evaporated under vacuum to leave a residue which is taken up with toluene (20 ml). The whole is heated under reflux and precipitation is awaited. Filtration is carried out and cyanophthalide 1.5 g (molar yield 91 %) (purity HPLC (A%) 99%) is obtained. 1HNMR (DMSO-d6 400MHz) 5.45(2H,s), 7.87(1Hs), 7.91(1H,s), 7.98(1H,s) |
With thionyl chloride | ||
With thionyl chloride In N,N-dimethyl-formamide; toluene | 1.a (a) (a) 5-Chlorocarbonylphthalide To a mixture of 1800 ml of thionyl chloride and 8.1 ml of N,N-dimethylformamide, 750 g (4.21 moles) of 5-carboxyphthalide are added under stirring. The mixture is heated slowly to reach an inner temperature of 60°C in one hour, then it is kept at this temperature for another hour and finally it is brought to the reflux. After refluxing for 6 hours, about 600 ml of thionyl chloride are distilled off at a temperature of 80÷85°C, by replacing them by addition of toluene. Distillation is continued for a total of 2800 ml with concurrent replacement of the solvent by addition of 3800 ml of toluene. The mixture is slowly cooled and, at 80°C, the crystallization of the product begins. Cool to 10÷15°C by continuing stirring for 15 hours. The hygroscopic product is filtered, washing with a total of 1500 ml of toluene, then it is dried under vacuum at 55°C to give 710 g (86%) of 5-chlorocarbonylphthalide with a purity of 99% (HPLC). |
With thionyl chloride In N,N-dimethyl-formamide for 6h; Heating / reflux; | ||
With thionyl chloride; N,N-dimethyl-formamide In toluene at 80℃; for 1h; Heating / reflux; | II II. Preparation of Hydroxy Amide (2) The phthalide acid (1) (900 g) was suspended in 5 volumes of toluene containing a catalytic amount of DMF. The mixture was heated to 70-80° C. and thionyl chloride (734 g) was added slowly to the mixture at less than 80° C. The mixture was heated for 1 hour at reflux. The resultant solution was concentrated by distillation at atmospheric pressure and cooled to about 75° C. Dimethylformamide was added slowly and the mixture was cooled to approximately 20° C. This solution was added at 15-20° C. to a solution of 2-amino-2-methyl propanol (993 g) in toluene (1.6 kg). After the addition was complete, the solution was stirred for 30 minutes and the pH adjusted to 2-3 by slow addition of hydrochloric acid. The mixture was stirred at 15-20° C. for one hour. The precipitated product was filtered off, washed with water, and dried at about 60° C. under reduced pressure. [0101] 1H NMR (CDCl3, 270 MHz): 1.6 (6H, s), 4.0 (2H, s), 5.4 (2H, s), 6.1 (1H, br), 7.8-8.1 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
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at 110℃; |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
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Multi-step reaction with 2 steps 1: thionyl chloride 2: ethanol | ||
With trichlorophosphate In ethanol | 1.A 5-tert.Butylcarbamylphthalid Method A): 5-Ethoxycarbonylphthalid 5-Carboxyphthalid (37 g, 0.2 mole) was suspended in ethanol (400 mL). POCl3 (10 g, 0.07 mole) was added drop-wise and the reaction mixture was heated to reflux temperature for 5 hours. Upon cooling to room temperature, the title compound crystallized. The crystals were filtered off and washed with ethanol (50 ml). Yield: 35 g, 87%. DSC onset: 151 ° C. 1H NMR (DMSO-d6, 250 MHz): 1.36 (3H, t, J=7 Hz), 4.38 (2H, q, J=7 Hz), 5.48 (2H, s), 7.95 (1H, d, J=7.5 Hz), 8.12 (1H, d, J=7.5 Hz),. 13C NMR (DMSO-d6, 62.5 MHz): 14.5, 61.5, 70.1, 124.0, 125.2, 128.8, 129.6, 134.8, 147.6, 164.9, 169.8. |
Yield | Reaction Conditions | Operation in experiment |
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Multi-step reaction with 2 steps 1: K2CO3 / dimethylformamide 2: SOCl2 |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; sodium hydroxide; sulfur trioxide In water | 1 EXAMPLE 1 EXAMPLE 1 To 800 ml of fuming sulfuric acid, containing about 27% of SO3, 260 g (1.56 m) of terephthalic acid are added, under stirring, in 15 minutes and without exceeding the temperature of 25° C. To the thick suspension thus obtained, 120 g (1.33 m) of 1,3,5-trioxane are added under stirring without exceeding the temperature of 35° C., then stirring is continued for 20-30 minutes without cooling, whereby the temperature of the mixture rises to 45-50° C. The mixture is heated to 120° C. and it is noted that, already at 90° C., the mass becomes clear whilst at 120° C. a light exothermia is observed which brings the temperature to 135-140° C. The mixture is kept 6 hour under stirring at this temperature, then it is cooled to 20° C. and poured in 3000 g of coushed ice without exceeding the temperature of 25° C. To the mixture thus obtained, a 15% w/w solution of sodium hydroxide is added to a pH≅6 (about 6500-7000 ml thereof are needed), by keeping the temperature at 35-40° C. by water-cooling, then a 5% w/w solution of sodium hydroxide is added thereto at the temperature of 35-40° C. up to pH≅8 (about 300 ml are needed). The solid is removed by filtration on Dicalite in a buchner and washed with water. To the filtered solution thus obtained, 35% hydrochloric acid is added up to pH≅1 (requiring about 1600-1800 ml of 35% HCl) and the suspension thus obtained is heated to 35° C. The solid is filtered, washed 3 times with 500 ml of deionized water at 40° C. and suspended in 1000 ml of deionized water. The suspension is heated under stirring at 50-55° C. and kept 1 hour under these conditions, then it is hot filtered. The solid is washed with deionized water and dried in vacuo at 50° C. to constant weight. Thus, 180 g of light-brown coloured 5-carboxyphthalide with a purity (HPLC) >95% are obtained. | |
With hydrogenchloride; sulfur trioxide; sodium hydrogencarbonate In water | 3 EXAMPLE 3 EXAMPLE 3 To 153 ml of fuming sulfuric acid, containing about 27% of SO3, 50 g (0.3 m) of terephthalic acid are added, under stirring, at room temperature, then 23 g (0.25 m) of 1,3,5-trioxane are added thereinto in two portions, by cooling to a temperature of 15-18° C. after any addition. At the end of the addition, the mixture is left 30 minutes under stirring at room temperature, then it is heated at 135-145° C. and let under stirring for 2-2.5 hours at this temperature until the end of the reaction. The reaction mixture is cooled to a temperature lower than 3° C., then 100 ml of glacial acetic are added thereto by keeping the temperature at about 25° C. At the end of the addition, the mixture is let to stand 60 minutes under stirring at 20-25° C. and filtered. The wet product is suspended in 1900 ml of water. The suspension is heated up to 25-30° C. under stirring, its pH is adjusted to about 8 by gradual addition of 175 g of sodium bicarbonate. The solid is filtered off on Celite by washing with hot water (40-45° C.). The pH of the mother liquors is brought to 1.5 by addition of about 125 ml of 37% hydrochloric acid and the obtained precipitate is filtered at 20-25° C. by washing with water until the filtrate reaches a neutral pH. Thus, 32 g of 5-carboxyphthalide with a titer (HPLC) >93% are obtained. | |
With hydrogenchloride; sulfur trioxide; sodium hydrogencarbonate In water; acetic acid | 4 EXAMPLE 4 EXAMPLE 4 To 892 g of fuming sulfuric acid, containing 25-27% of SO3, 100 g (0.6 m) of terephthalic acid are added at 20-23° C., under stirring, then 46 g (0.5 m) of 1,3,5-trioxane are added portionwise thereto at about 15° C. At the end of the addition, the mixture is heated 2 hours at 130-133° C. whereby a dark, clear solution is obtained. When the reaction is complete, as shown by a HPLC control, the mixture is cooled to 20-22° C. and 210 g of glacial acetic acid are slowly added thereto, without exceeding the temperature of 23-25° C. The mass is cooled to -5-0° C. and 1800 ml of cold deionized water are added thereto. During this operation the temperature rises to 43-45° C. At the end of the addition, the mixture is kept 1 hour under stirring at 23-25° C., then it is filtered, the solid is washed with deionized water abundantly and suspended, still wet, in 1200 ml of deionized water at room temperature. To the suspension thus obtained, about 1550 g of a 7% solution of NaHCO3 are added to a constant pH of 7,6-7,8. The mixture is filtered on Celite, washing with deionized water. The pH of the filtrate is brought to about 1 by slow addition of about 120 ml of 35% hydrochloric acid at 22-25° C. The suspension is kept 1 hour under stirring at 22-25° C., then it is filtered and washed with deionized water abundantly. The product is dried in vacuo at about 50° C. to give 81 g of 5-carboxyphthalide with a titer (HPLC)>94% and purity (HPLC)>95%. |
With hydrogenchloride; sodium hydroxide; sulfur trioxide In water | 1 EXAMPLE 1 EXAMPLE 1 To 800 ml of fuming sulfuric acid, containing about 27% of SO3, 260 g (1.56 m) of terephthalic acid are added, under stirring, in 15 minutes and without exceeding the temperature of 25°C. To the thick suspension thus obtained, 120 g (1.33 m) of 1,3,5-trioxane are added under stirring without exceeding the temperature of35°C, then stirring is continued for 20÷30 minutes without cooling, whereby the temperature of the mixture rises to 45÷50°C. The mixture is heated to 120°C and it is noted that, already at 90°C, the mass becomes clear whilst at 120°C a light exothermia is observed which brings the temperature to 135÷140°C. The mixture is kept 6 hour under stirring at this temperature, then it is cooled to 20°C and poured in 3000 g of coushed ice without exceeding the temperature of 25°C. To the mixture thus obtained, a 15% w/w solution of sodium hydroxide is added to a pH ≅ 6 (about 6500÷7000 ml thereof are needed), by keeping the temperature at 35÷40°C by water-cooling, then a 5% w/w solution of sodium hydroxide is added thereto at the temperature of 35÷40°C up to pH ≅ 8 (about 300 ml are needed). The solid is removed by filtration on Dicalite in a buchner and washed with water. To the filtered solution thus obtained, 35% hydrochloric acid is added up to pH ≅ 1 (requiring about 1600÷1800 ml of 35% HCl) and the suspension thus obtained is heated to 35°C. The solid is filtered, washed 3 times with 500 ml of deionized water at 40°C and suspended in 1000 ml of deionized water. The suspension is heated under stirring at 50÷55°C and kept 1 hour under these conditions, then it is hot filtered. The solid is washed with deionized water and dried in vacuo at 50°C to constant weight. Thus, 180 g of light-brown coloured 5-carboxyphthalide with a purity (HPLC) > 95% are obtained. | |
With hydrogenchloride; sulfur trioxide; sodium hydrogencarbonate In water | 3 EXAMPLE 3 EXAMPLE 3 To 153 ml of fuming sulfuric acid, containing about 27% of SO3, 50 g (0.3 m) of terephthalic acid are added, under stirring, at room temperature, then 23 g (0.25 m) of 1,3,5-trioxane are added thereinto in two portions, by cooling to a temperature of 15÷18°C after any addition. At the end of the addition, the mixture is left 30 minutes under stirring at room temperature, then it is heated at 135÷145°C and let under stirring for 2÷2.5 hours at this temperature until the end of the reaction. The reaction mixture is cooled to a temperature lower than 3°C, then 100 ml of glacial acetic are added thereto by keeping the temperature at about 25°C. At the end of the addition, the mixture is let to stand 60 minutes under stirring at 20÷25°C and filtered. The wet product is suspended in 1900 ml of water. The suspension is heated up to 25÷30°C under stirring, its pH is adjusted to about 8 by gradual addition of 175 g of sodium bicarbonate. The solid is filtered off on Celite by washing with hot water (40÷45°C). The pH of themother liquors is brought to 1.5 by addition of about 125 ml of 37% hydrochloric acid and the obtained precipitate is filtered at 20÷25°C by washing with water until the filtrate reaches a neutral pH. Thus, 32 g of 5-carboxyphthalide with a titer (HPLC) > 93% are obtained. | |
With sulfuric acid; sulfur trioxide at 140 - 150℃; for 4 - 8h; | I I. Preparation of Phthalide Acid (1) Terephthalic acid was suspended in 25-30% oleum. Trioxane was added and the mixture was heated to 140-150° C. for 4-8 hours. The reaction mixture was cooled and then quenched by cautious addition of water at less than 80° C. The resulting suspension was cooled to about 40° C. and the solid was filtered off. The filter cake was washed with water followed by propan-2-ol before slurrying the solid in propan-2-ol at reflux for 30 minutes. After cooling to 20-25° C. the product was filtered off, washed with propan-2-ol and dried at 60-70° C. under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
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88.3% | With sulfuric acid In toluene at 80 - 110℃; | 7 Example 7 Preparing ester of 5-CARBOXYPHTHALIDE large scale 143.7 kg crude wet 5-carboxyphthalide (correspond to APP. 39.5 kg dry material) is suspended in toluene (200 L), 1-butanol (42.5 L) and sulfuric acid (3.15 L, 96%). The suspension is heated to reflux (80-85 °C). Water (104,2 kg) removed by a Dean-Stark trap and the end temperature of the reaction mixture is 110 °C. The reaction mixture is concentrated by distillation and a total of 85 kg of solvent is removed from the mixture. After cooling to 80 °C heptanes (110 L) is added to the mixture and pH is adjusted to 8 by addition of triethylamine (about 5 L). Activated carbon (1 kg) and Dicalite (1.5 kg) is suspended in heptanes (16 L) and added to the reactor. The temperature is adjusted to 80 °C and pressure filtrated. The filtrate is washed two times with water (2* 40 L) and cooled to 25 °C in 5 hours and left at this temperature for 2 hours. The product is filtrated and washed with heptanes (60 L) and dried. Yield: 43. 0 KG Molar yield: 88.3% (purity based on HPLC area%) |
Yield | Reaction Conditions | Operation in experiment |
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76.4% | With sulfuric acid; sulfur trioxide at 100 - 150℃; for 5 - 6h; | 6 Example 6 5-Carboxyphthalide-"high temperature" A solution of terephthalic acid (30 g) in oleum (20-25% S03, 70 ml) is heated to 150 °C. To this solution is added a solution OF PARAFORMALDEHYDE (8. 8G) in oleum (20- 25% S03, 37 ml) over a period of 1-2H. THE REACTION mixture is stirred at 150 °C for additional 4 H and cooled to 90 °C. Water (190 ml) is added to the mixture at a rate so that the temperature stays below 100 °C. The precipitate is filtered of, washed with hot (90-95 °C) WATER and suspended in water (200 ml) and dicalite (1. 1 g) is added. The pH of the suspension is adjusted to about 7 WITH NAOH (APPROXIMATELY 60 ml) and activated carbon (1.1 G) is added. The mixture is filtered and the precipitate is rinsed with water. The temperature of the filtrate is adjusted to about 85 C, AND the pH is adjusted to about 2 with sulphuric acid (96%, approximated 8 ml). The 5-carboxyphthalide precipitated is separated by filtration and dried. Yield: 25.7g Molar yield: 76.4% (corrected for purity based on HPLC AREA%) |
Yield | Reaction Conditions | Operation in experiment |
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51% | With tetrachloromethane; triethylamine; 4-(N,N-Dimethylamino)triphenylphosphine In acetonitrile at 20℃; | 14.a Example 14 Preparation of 2-(2-piperidinoethyl)-5-{2-[((2-phenoxyethyl) thio) methyl] -1, 3,4- oxadiazol-5-yl} isoindolin-1-one a) 5-{2-[((2-Phenoxyethyl) thio) methyl]-1, 3, 4-oxadiazol-5-yl} phthalide To a mixture of 4-carboxyphthalide (178 mg, 1 mmol), 2-phenoxythioacetic hydrazide hydrochloride (316 mg, 1.2 mmol), 4- (N, N- dimethylamino) phenyldiphenylphosphine (917 mg, 3 mmol), and triethylamine (607 mg, 6 mmol) in acetonitrile (10 mmol) was added carbon tetrachloride (770 mg, 5 mmol). The resultant mixture was stirred at room temperature overnight and concentrated. The residue was partitioned between ether (50 mL) and 2 M HCl (30 mL). The organic layer was washed with 2 M HCl (5 x 20 mL), dried (MgS04), and concentrated. The residue was triturated from methylene chloride and hexanes to give a white solid (186 mg, 51%). The reaction was repeated on 3 mmol scale to give the same product (652 mg, 59%). |
Yield | Reaction Conditions | Operation in experiment |
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With thionyl chloride; SULFAMIDE; In sulfolane; water; | Example 1 5-Cyanophthalid 5-Carboxyphthalid (50 g, 0.28 mole) and sulfamide (31 g, 0.32 mole) were suspended in sulfolane (150 mL). Thionylchloride (41 g, 0.34 mole) was added and the temperature was raised to 130-140° C. for 2 hours. At about 90° C., gas evolution took place. The mixture was allowed to cool to 90° C. and water (150 mL) was added. The temperature was held at 85-90° C. for 15 min and then the solution was cooled to 35° C. The crystals were filtered off and washed with water (250 mL). The title compound was crystallized from acetic acid.Yield: 34.5 g, 77percent. DSC onset: 203° C. Purity: 98.5percent (hplc, peak area). 1H NMR (DMSO-d6, 500 MHz): 5.48 (2H, s), 8.03 (2H, s), 8.22 (1H, s). 13C NMR (DMSO-d6, 125 MHz): 70.0, 116.1, 188.0, 126.0, 127.5, 129.0, 132.8, 147.7, 169.3. | |
With thionyl chloride; SULFAMIDE; In sulfolane; water; | Example 2 5-Cyanophthalid Wet 5-carboxyphthalid (14 kg, approx. 6.3 kg dry, 35 mole) was suspended in sulfolane (23.5 kg). The water was removed by azeotropic distillation with toluene. Sulfamide (3.9 kg, 41 mole) and thionyl chloride (5.8 kg, 48 mole were added and the temperature was raised to 135-140° C. for 5 hours. At about 90° C. gas evolution took place. The mixture was allowed to cool to 90° C. and water (21.3 kg) was added. The temperature was held at 85-90° C. for 15 min and then the solution was cooled to 35° C. The crystals were filtered off and washed with water (14.2 kg). The title compound was crystallized from acetic acid. Yield: 3.8 kg, 68percent. Purity: 99.5percent (hplc, peak area). |
Yield | Reaction Conditions | Operation in experiment |
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285.3 g (76%) | With thionyl chloride In tetrahydrofuran; N,N-dimethyl-formamide; toluene | 1 Preparation of 2-[[(1-Oxo-1,3-dihydroisobenzofuran-5-yl)carbonyl]amino]-2-methyl-1-propanol Example 1 Preparation of 2-[[(1-Oxo-1,3-dihydroisobenzofuran-5-yl)carbonyl]amino]-2-methyl-1-propanol 5-carboxyphthalide (267 g, 1.5 mol) is added to thionyl chloride (950 mL) and then N,N-dimethylformamide (12 mL) is added dropwise. The mixture is heated at reflux for 1 hour and the thionyl chloride is destined off under reduced pressure followed by successive evaporations with toluene (2*50 mL) to give a solid residue. The crude acid chloride is then taken up with 1000 mL of tetrahydrofuran. To a solution of 2-amino-2-methyl-1-propanol (400.5 g, 4.5 mol) in tetrahydrofuran (500 mL), cooled to +5° C., the acid chloride solution is added dropwise whilst maintaining the temperature between +5→+10° C. After the addition is completed, the cooling is removed and the mixture is stirred overnight at ambient temperature. Then the mixture is poured into deionized water (2000 mL) and the organic solvent is removed under reduced pressure at 50° C. After cooling and stirring for 2 hours, the solid product is filtered off and washed with deionized water (2*100 mL). The obtained product is dried at 70° C. for 36 hours under reduced pressure. Yield: 285.3 g (76%) of an off-white product having a purity (HPLC, peak area)=90%. 1H NMR (DMSO d-6, 500 MHz): 1.18 (3H,s), 1.32 (3H,s), 3.55 (2H,s), 5.45 (2H,s), 7.88-7.98 (3H,m), 8.07 (1H,s). |
Yield | Reaction Conditions | Operation in experiment |
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60% | at 27 - 130℃; for 3h; Industry scale; Neat (no solvent); | 1; 2; 3; 4 EXAMPLE 1:In a 2500-1 glass lined reactor, 250 Kg of Chloromethyl chlorosulphate charged under vacuum and good ventilation, under constant stirring, 200 Kg of terephthalic acid was added at a temperature of 330C . The reactor is heated to a temperature of t 1290C .for a period of 3 hours, Thereafter the mixture was cooled to 340CAt the end of this operation, 1250 Kg of water are added portionwise, whereby the temperature is maintained at 350C . by circulation of water through the glass lined reactor jacket of the reactor . The mixture is stirred for about 1 hour at a temperature of 330C, then the product formed was centrifuged , was well squeezed, abundantly washed with deionized water and dried to give 144 Kg .of 5-carboxyphthalide (HPLC) purity>97%. Yield 67% .EXAMPLE 2:In a 2500-1 glass lined reactor, 250 Kg of Chloromethyl chlorosulphate charged under constant stirring, 200 Kg of terephthalic acid was added at a temperature of 280C . The reactor is heated to a temperature oft 1280C .for a period of 3 hours, Thereafter the mixture was cooled to 350CAt the end of this operation, 1250 Kg EPO of water are added portionwise, whereby the temperature is maintained at 340C . by circulation of water through the glass lined reactor jacket of the reactor . The mixture is stirred for about 1 hour at a temperature of 390C, then the product formed was centrifuged , was well squeezed, abundantly washed with deionized water and dried under vacuum to give 142 Kg .of 5-carboxyphthalide (HPLC) purity>97%. Yield 66% .EXAMPLE 3In a 2500-1 glass lined reactor, 350 Kg of Chloromethyl chlorosulphate charged under constant stirring, 200 Kg of terephthalic acid was added at a temperature of 270C . The reactor is heated to a temperature oft 13O0C .for a period of 3 hours, Thereafter the mixture was cooled to 350CAt the end of this operation, 1850 Kg of water are added portionwise, whereby the temperature is maintained at 360C . by circulation of water through the glass lined reactor jacket of the reactor . The mixture is stirred for about 1 hour at a temperature of 350C, then the product formed was centrifuged , was well squeezed, abundantly washed with deionized water and dried to give 136 Kg .of 5-carboxyphthalide (HPLC) purity>96%. Yield 64% .EXAMPLE 4In a 2500-1 glass lined reactor, 450 Kg of Chloromethyl chlorosulphate charged under pressure ,constant stirring, 200 Kg of terephthalic acid was added at a temperature of 270C . The reactor is heated to a temperature oft 13O0C .for a period of 3 hours, Thereafter the mixture was cooled to 340CAt the end of this operation, 2250 Kg of water are added portionwise, whereby the temperature is maintained at 4O0C . by circulation of water through the glass lined reactor jacket of the reactor . The mixture is stirred for about 1 hour at a temperature of 380C, then the product formed was centrifuged , was well squeezed, abundantly washed with deionized water and dried in Tray drier to give 128 Kg .of 5-carboxyphthalide (HPLC) purity>94%. Yield 60% . EPO Advantages of the invention |
Yield | Reaction Conditions | Operation in experiment |
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In tetrahydrofuran; thionyl chloride; N,N-dimethyl-formamide; toluene | 1.A 5-Chlorocarbonylphthalid Method A): 5-tert.Butylcarbamylphthalid 5-Carboxyphthalid (36 g, 0.2 mole) was suspended in thionylchloride (100 mL). DMF (1.5 mL) was added and the mixture was refluxed for 1 hour. Toluene (200 mL) was added and the solvents were evaporated in vacuo. The residue was dissolved in tetrahydofuran (THF) (200 mL) and added to a solution of tert.butylamine (31 g, 0.42 mole) in THF (200 mL) at 5 ° C. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was then poured into ice water (400 niL) and the precipitated crystals were filtered off. The crystals were washed with water (100 mL)Yield: 41 g, 87%. DSC onset: 189.5 ° C. | |
In tetrahydrofuran; thionyl chloride; N,N-dimethyl-formamide; toluene | 3 5-tert.Butylcarbamylphthalid Example 3 5-tert.Butylcarbamylphthalid 5-Carboxyphthalid (36 g, 0.2 mole) is suspended in thionylchloride (100 mL). DMF (1.5 mL) is added and the mixture is refluxed for 1 hour. Toluene (200 mL) is added and the solvents are evaporated in vacuo. The residue is dissolved in THF (200 mL) and added to a solution of tert.butylamine (31 g, 0.42 mole) in THF (200 mL) at 5° C. The mixture is allowed to warm to room temperature and stirred overnight. The reaction is then poured into ice water (400 mL) and the precipitated crystals are filtered off. The crystals are washed with water (100 mL). Yield: 41 g, 87%. DSC onset: 189.5° C. |
Yield | Reaction Conditions | Operation in experiment |
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With thionyl chloride In n-heptane; toluene | 1 5-Chlorocarbonylphthalid 5-Chlorocarbonylphthalid 5-Carboxyphthalid (53 g, 0.3 mole) was suspended toluene (200 mL) and thionylchloride (44 g, 0.6 mole). N,N-dimethylformamide (DMF) (1 mL) was added and the mixture was heated at reflux temperature for 3 hours. The mixture was cooled to room temperature and n-heptane was added (200 ml). The crystals formed were collected and washed with heptane (100 mL). Yield 52 g, 88%. DSC onset: 131° C. 1H NMR (CDCl3, 500 MHz): 5.47 (2H, s), 8.06 (1H, d, J=7.5 Hz), 8.28 (1H, d, J=7.5 Hz), 8.3 (1H, s). 13C NMR (CDCl3, 125 MHz): 69.4, 125.1, 126.1, 131.1, 131.6, 137.8, 146.6, 167.4, 169.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sulfuric acid; paraformaldehyde In water | 2 5-Carboxyphthalid Example 2 5-Carboxyphthalid Oleum (20-25% SO3 43 kg) is charged into a reactor. Terephthalic acid (13 Kg) and then paraformaldehyde (3.8 Kg) is added. The mixture is agitated at 138-148° C. for 41/2 hours. Water (87 L) is added and the temperature is adjusted to about 100° C. The precipitate is filtered of, washed with water and suspended in water. The pH of the suspension is adjusted to about 7 with NaOH (about 10%), activated carbon, 0.5 Kg is added, and then the mixture is filtered, the precipitate is rinsed with water. The temperature of the filtrate is adjusted to about 85° C. and the pH is adjusted to about 2 with 96% sulfuric acid. The 5-carboxyphthalide precipitated is separated by filtration washed and dried. Yield 82%. |
With hydrogenchloride; sodium hydroxide; sulfur trioxide In 1,3,5-Trioxan; water | 2 EXAMPLE 2 EXAMPLE 2 To 800 ml of fuming sulfuric acid, containing about 27% of SO3, 260 g (1.56 m) of terephthalic acid are added, under stirring, in 15 minutes without exceeding the temperature of 25° C. By maintaining the stirring, 60 g (0.665 m) of 1,3,5-trioxane are added portionwise to the thick suspension thus obtained, whereby the temperature rises to bout 25° C. The mixture is cooled to 10-15° C. in 30 minutes, then a further 60 g (0.665 m) of 1,3,5-trioxane is added thereinto. The mixture is heated and it is observed that at 90° C. the mass becomes clear. The temperature is brought to 120° C. and the mixture is kept 10-15 minutes under these conditions, whereby the temperature may rise to 135-140° C. If no exothermia is observed, the mixture is nevertheless heated to 130-135° C. and kept 4 hours under these conditions. The cooled mixture is poured, in about 1 hour and without exceeding the temperature of 25-35° C., into 3000 g of crushed ice. To the mixture thus obtained, 8000-8500 ml of a 15% w/w solution of sodium hydroxide are added to a pH=5-6, by letting the temperature to rise to 35-40° C. and by keeping it at these values by a water-cooling. Then, at 35-40° C., 300 ml of 5% w/w solution of sodium hydroxide are added to the mixture to a pH≅8. The solid is removed by filtration on a Dicalite bed in a buchner and washed with water. To the solution thus obtained, 2000 ml of 35% hydrochloric acid are added to a pH≅1 and the suspension thus obtained is heated to 35° C. The solid is filtered, washed 3 times with 500 ml of deionized water at 40° C. The wet product is treated with 4000 ml of warm deionized water (about 45° C.) and the suspension is heated 30 minutes under stirring at 45° C. Without cooling, the product is filtered, washed with deionized water and dried in vacuo at 50° C. to constant weight. Thus, 215-225 g of light-brown coloured 5-carboxyphthalide with a purity (HPLC) >95% are obtained. | |
With hydrogenchloride; sodium hydroxide; sulfur trioxide In 1,3,5-Trioxan; water | 2 EXAMPLE 2 EXAMPLE 2 To 800 ml of fuming sulfuric acid, containing about 27% of SO3, 260 g (1.56 m) of terephthalic acid are added, under stirring, in 15 minutes without exceeding the temperature of 25°C. By maintaining the stirring, 60 g (0.665 m) of 1,3,5-trioxane are added portionwise to the thick suspension thus obtained, whereby the temperature rises to about 25°C. The mixture is cooled to 10÷15°C in 30 minutes, then a further 60 g (0.665 m) of 1,3,5-trioxane is added thereinto. The mixture is heated and it is observed that at 90°C the mass becomes clear. The temperature is brought to 120°C and the mixture is kept 10÷15 minutes under these conditions, whereby the temperature may rise to 135÷140°C. If no exothermia is observed, the mixture is nevertheless heatedto 130÷135°C and kept 4 hours under these conditions. The cooled mixture is poured, in about 1 hour and without exceeding the temperature of 25÷35°C, into 3000 g of crushed ice. To the mixture thus obtained, 8000÷8500 ml of a 15% w/w solution of sodium hydroxide are added to a pH = 5÷6, by letting the temperature to rise to 35÷40°C and by keeping it at these values by a water-cooling. Then, at 35÷40°C, 300 ml of 5% w/w solution of sodium hydroxide are added to the mixture to a pH ≅ 8. The solid is removed by filtration on a Dicalite bed in a buchner and washed with water. To the solution thus obtained, 2000 ml of 35% hydrochloric acid are added to a pH ≅ 1 and the suspension thus obtained is heated to 35°C. The solid is filtered, washed 3 times with 500 ml of deionized water at 40°C. The wet product is treated with 4000 ml of warm deionized water (about 45°C) and the suspension is heated 30 minutes under stirring at 45°C. Without cooling, the product is filtered, washed with deionized water and dried in vacuo at 50°C to constant weight. Thus, 215÷225 g of light-brown coloured 5-carboxyphthalide with a purity (HPLC) > 95% are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sulfur trioxide In water; acetic acid | 4 EXAMPLE 4 EXAMPLE 4 To 892 g of fuming sulfuric acid, containing 25÷27% of SO3, 100 g (0.6 m) of terephthalic acid are added at 20÷23°C, under stirring, then 46 g (0.5 m) of 1,3,5-trioxane are added portionwise thereto at about 15°C. At the end of the addition, the mixture is heated 2 hours at 130÷133°C whereby a dark, clear solution is obtained. When the reaction is complete, as shown by a HPLC control, the mixture is cooled to 20÷22°C and 210 g of glacial acetic acid are slowly added thereto, without exceeding the temperature of 23÷25°C. The mass is cooled to -5÷0°C and 1800 ml of cold deionized water are added thereto. During this operation the temperature rises to 43÷45°C. At the end of the addition, the mixture is kept 1 hour under stirring at 23÷25°C, then it is filtered, the solid is washed with deionized water abundantly and suspended, still wet, in 1200 ml of deionized water at room temperature. To the suspension thus obtained, about 1550 g of a 7% solution of NaHCO3are added to a constant pH of 7,6÷7,8. The mixture is filtered on Celite, washing with deionized water. The pH of the filtrate is brought to about 1 by slow addition of about 120 ml of 35% hydrochloric acid at 22÷25°C. The suspension is kept 1 hour under stirring at 22÷25°C, then it is filtered and washed with deionized water abundantly. The product is dried in vacuo at about 50°C to give 81 g of 5-carboxyphthalide with a titer (HPLC) > 94% and purity (HPLC) > 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In pyridine | 1 5-tert. Butoxycarbonylphthalid Example 1 5-tert. Butoxycarbonylphthalid 5-Carboxyphthalid (100 g, 0.56 mole) is suspended in pyridine (1200 mL). p-toluenesulfonyl chloride (211 g, 1.12 mole) is added and the mixture is stirred for 30 minutes at room temperature. Tert.Butanol (54 g, 0.73 mole) is added and the reaction mixture is left at room temperature with efficient stirring for 3 days. The clear solution is poured into ice water and the precipitated crystals are filtered off. The product is recrystallized from 2-propanol (500 mL). Yield: 123 g, 94%. DSC onset: 151.5° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.8% | Stage #1: 5-carboxyphtalide With chloroformic acid ethyl ester; triethylamine In acetone at -10 - 13℃; for 0.5h; Stage #2: 2-Amino-2-methyl-1-propanol In acetone at -10 - 20℃; Stage #3: With thionyl chloride; ammonia more than 3 stages; | |
59.8% | Stage #1: 5-carboxyphtalide With thionyl chloride In ISOPROPYLAMIDE at 60 - 80℃; for 6.5h; Stage #2: 2-Amino-2-methyl-1-propanol With potassium carbonate In tetrahydrofuran at 0 - 10℃; for 0.5h; Stage #3: With thionyl chloride; ammonia more than 3 stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: tetrahydrofuran / 2 h / 20 °C 2: sodium tetrahydroborate / tetrahydrofuran; water / 0.08 h / 20 °C 3: pyridinium chlorochromate on silica gel / dichloromethane / 3 h / 20 °C | ||
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 2 h / 20 °C 1.3: pH 2 2.1: pyridinium chlorochromate / dichloromethane / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 5-carboxyphtalide With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water Stage #3: With hydrogenchloride In tetrahydrofuran; water | 121 1 -Oxo-1 j3-dihydroisoberizofuran-5-carboxylic acid (3.00 g, 16.8 mmol) was dissolved in THF (300 mL), to which was added carbonyldiimidazole (CDI; 5.46 g, 33.7 mmol). After stirring for 2 h. at room temperature, this reaction mixture was slowly added to a solution of NaBFL, (3.18 g, 84.0 mmol) in water (80 mL), stirred for a further 5 minutes, then quenched with c. HC1 to pH=2. This aqueous mixture was extracted with EtOAc (2x50 mL), the fractions combined, dried (Na2S04) and filtered, then the solvent removed under reduced pressure to afford a crude solid which was purified by flash column chromatography on silica gel (EtOAc as eluant). The title compound was isolated as a white solid (2.59 g, 94%). *H NMR in agreement with literature values.10 |
Multi-step reaction with 2 steps 1: tetrahydrofuran / 2 h / 20 °C 2: sodium tetrahydroborate / tetrahydrofuran; water / 0.08 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: tetrahydrofuran / 2 h / 20 °C 2: sodium tetrahydroborate / tetrahydrofuran; water / 0.08 h / 20 °C 3: pyridinium chlorochromate on silica gel / dichloromethane / 3 h / 20 °C 4: pyridine; hydroxylamine hydrochloride / methanol / 1.5 h / 60 °C | ||
Multi-step reaction with 3 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 2 h / 20 °C 1.3: pH 2 2.1: pyridinium chlorochromate / dichloromethane / 3 h / 20 °C 3.1: pyridine; hydroxylamine hydrochloride / methanol / 1.5 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: tetrahydrofuran / 2 h / 20 °C 2: sodium tetrahydroborate / tetrahydrofuran; water / 0.08 h / 20 °C 3: pyridinium chlorochromate on silica gel / dichloromethane / 3 h / 20 °C 4: pyridine; hydroxylamine hydrochloride / methanol / 1.5 h / 60 °C 5: pyridine; N-chloro-succinimide / tetrahydrofuran / 0.5 h / 60 °C 6: triethylamine / tetrahydrofuran / 2 h / 50 °C | ||
Multi-step reaction with 4 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 2 h / 20 °C 1.3: pH 2 2.1: pyridinium chlorochromate / dichloromethane / 3 h / 20 °C 3.1: pyridine; hydroxylamine hydrochloride / methanol / 1.5 h / 60 °C 4.1: pyridine; N-chloro-succinimide / tetrahydrofuran / 0.5 h / 60 °C 4.2: 2 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: tetrahydrofuran / 2 h / 20 °C 2: sodium tetrahydroborate / tetrahydrofuran; water / 0.08 h / 20 °C 3: pyridinium chlorochromate on silica gel / dichloromethane / 3 h / 20 °C 4: pyridine; hydroxylamine hydrochloride / methanol / 1.5 h / 60 °C 5: pyridine; N-chloro-succinimide / tetrahydrofuran / 0.5 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: pyridine / tetrahydrofuran / 2 h / 20 °C 2: tetrahydrofuran / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: pyridine / tetrahydrofuran / 2 h / 20 °C 2: tetrahydrofuran / 0.5 h / 20 °C 3: copper(II) choride dihydrate; bis(benzonitrile)palladium(II) dichloride; oxygen / N,N-dimethyl-formamide / 2 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: pyridine / tetrahydrofuran / 2 h / 20 °C 2: tetrahydrofuran / 0.5 h / 20 °C 3: copper(II) choride dihydrate; bis(benzonitrile)palladium(II) dichloride; oxygen / N,N-dimethyl-formamide / 2 h / 100 °C 4: acetic acid; 3-amino propanoic acid / 15 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: tetrahydrofuran / 2 h / 20 °C 2: sodium tetrahydroborate / tetrahydrofuran; water / 0.08 h / 20 °C 3: pyridinium chlorochromate on silica gel / dichloromethane / 3 h / 20 °C 4: pyridine; hydroxylamine hydrochloride / methanol / 1.5 h / 60 °C 5: pyridine; N-chloro-succinimide / tetrahydrofuran / 0.5 h / 60 °C 6: triethylamine / tetrahydrofuran / 2 h / 50 °C 7: pyridinium chlorochromate on silica gel / dichloromethane / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: tetrahydrofuran / 2 h / 20 °C 2: sodium tetrahydroborate / tetrahydrofuran; water / 0.08 h / 20 °C 3: pyridinium chlorochromate on silica gel / dichloromethane / 3 h / 20 °C 4: pyridine; hydroxylamine hydrochloride / methanol / 1.5 h / 60 °C 5: pyridine; N-chloro-succinimide / tetrahydrofuran / 0.5 h / 60 °C 6: triethylamine / tetrahydrofuran / 2 h / 50 °C 7: pyridinium chlorochromate on silica gel / dichloromethane / 3 h / 20 °C 8: acetic acid; 3-amino propanoic acid / 15 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: Dess-Martin periodane / tetrahydrofuran; N,N-dimethyl-formamide / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 16 h / 20 °C 2: Dess-Martin periodane / tetrahydrofuran; N,N-dimethyl-formamide / 3 h / 20 °C 3: acetic acid; 3-amino propanoic acid / 15 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine; In tetrahydrofuran; at 20℃; for 2h; | 1-Oxo-1,3-dihydroisobenzofuran-5-carboxylic acid 65 (370 mg, 2.08 mmol) was dissolved in THF (15 mL). To this solution was added pyridine (1.64 g, 20.8 mmol), followed by pentafluorophenyltrifluoroacetate (2.91 g, 10.4 mmol) and the resulting mixture stirred at rt for 2 h. All solvent was removed under reduced pressure to give an oil which was dissolved in EtOAc (100 mL) and washed with 1 M HCl (2 × 50 mL), water (50 mL), satd NaHCO3 (2 × 50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered, and the solvent removed under reduced pressure to give a crude product which was purified by flash column chromatography on silica gel (20% EtOAc/hexanes as eluant) to give the intermediate pentafluorophenyl ester (666 mg, 93%) which was used immediately in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran at 20℃; for 2h; | 4.1.39. General procedure F: 5-(hydroxymethyl)isobenzofuran-1(3H)-one (66) Compound 65 (3.00 g, 16.8 mmol) was dissolved in THF (300 mL), to which was added carbonyldiimidazole (CDI; 5.46 g, 33.7 mmol). After stirring at rt for 2 h., this reaction mixture was slowly added to a solution of NaBH4 (3.18 g, 84.0 mmol) in water (80 mL), stirred for a further 5 minutes, then quenched with concd HCl to pH 2. This aqueous mixture was extracted with EtOAc (2 × 50 mL), the fractions combined, dried (Na2SO4) and filtered, then the solvent removed under reduced pressure to afford a crude solid which was purified by flash column chromatography on silica gel (EtOAc as eluant). The title compound 66 was isolated as a white solid (2.59 g, 94%). 1H NMR in agreement with literature values.45 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 16h; | 4.1.86. N-(3-Hydroxypropyl)-1-oxo-1,3-dihydroisobenzofuran-5-carboxamide (73) To a stirred solution of 65 (500 mg, 2.81 mmol) in dry DMF (30 mL) was added triethylamine (398 mg, 3.93 mmol), EDCI·HCl (700 mg, 3.65 mmol) and HOBt (493 mg, 3.65 mmol). 3-Amino-1-propanol (338 mg, 4.49 mmol) was then added in one portion and the whole mixture stirred at rt for 16 h. The reaction mixture was concentrated, diluted with NaHCO3 (100 mL), and extracted with EtOAc (3 × 100 mL). The combined organic fractions were dried (Na2SO4), filtered, and the solvent removed under reduced pressure to give a crude oil, which was dry-loaded onto silica gel. Flash column chromatography (EtOAc followed by 0.5-1% MeOH/EtOAc as eluant) yielded 73 as a white crystalline solid (343 mg, 52%); mp 130-132 °C. 1H NMR [(CD3)2SO] δ 8.68 (br t, J = 5.1 Hz, 1H), 8.07 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 5.46 (s, 2H), 4.45 (t, J = 5.2 Hz, 1H), 3.44-3.52 (m, 2H), 3.29-3.40 (m, 2H), 1.65-1.74 (m, 2H). LRMS (APCI+) calcd for C12H13NO4 236 (MH+), found 236. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-methyl-morpholine / dichloromethane / 20 °C 2: hydrogenchloride / 1,4-dioxane / 1.5 h / 20 °C 3: sodium cyanoborohydride; acetic acid / methanol / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-methyl-morpholine / dichloromethane / 20 °C 2: hydrogenchloride / 1,4-dioxane / 1.5 h / 20 °C 3: ethanol / 1 h / 150 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-methyl-morpholine / dichloromethane / 20 °C 2: hydrogenchloride / 1,4-dioxane / 1.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | A Step A: ferf-Butyl 4-(l-oxo-1 -dihvdroisobenzofuran-5-carboxarnido)piperidine-l-carboxylate To a solution of l-oxo-l,3-dihydroisobenzofuran-5-carboxylic acid (100 mg, 0.56 mmol), 4- amino-l-BOC-piperidine (110 mg, 0.56 mmol), HOBt (100 mg, 0.67 mmol), and EDC (160 mg, 0.84 mmol) in dichloromethane (2.8 mL) was added N-methylmorpholine (120 μ, 1.1 mmol) at room temperature. The reaction mixture was stirred at rt overnight. The mixture was concentrated and purified by prep TLC (silica gel, 10% methanol/dichloromethane) to provide tert-butyl 4-( 1 -oxo- 1 ,3 -dihydroisobenzofuran-5-carboxamido)piperidine- 1 -carboxylate. -NMR (CDC13, 500 MHz), δ 8.02 (m, 2H), 7.88 (d, J= 7.5 Hz, 1H), 6.18 (m, 1H), 5.39 (s, 2H), 4.20 (m, 4H), 2.95 (m, 2H), 2.09 (m, 2H), 1.43 (s, 9H); LC/MS: [(M+l)]+ = 361. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | A Step A: tert-Butyl 4-(N-methyl-l-oxo-L3-dihvdroisobenzofuran-5-carboxamido)piperidine-l- carboxylate To a solution of l-oxo-l ,3-dihydroisobenzofuran-5-carboxylic acid (100 mg, 0.56 mmol), l-BOC-4-methylaminopiperdine (120 mg, 0.56 mmol), HOBt (100 mg, 0.67 mmol), and EDC (160 mg, 0.84 mmol) in dichloromethane (2.8 mL) was added N-methylmorpholine (120 μ, 1.1 mmol) at room temperature. The reaction mixture was stirred at rt overnight. The mixture was concentrated and purified by prep TLC (silica gel, 10% methanol/dichloromethane) to provide tert-butyl 4-(N-methyl- 1 -oxo- 1 ,3 -dihydroisobenzofuran-5-carboxamido)piperidine- 1 - carboxylate. 1H-NMR (CDCI3, 500 MHz), δ 8.01 (d, J= 7.5 Hz, 1H), 7.56 (m, 2H), 5.39 (s, 2H), 4.72 (m, 1H), 4.30 (m, 4H), 2.95 (m, 2H), 2.82 (s, 3H), 2.09 (m, 2H), 1.43 (s, 9H); LC/MS: [(M+l)]+ - 375. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 5-carboxyphtalide With 1,1'-carbonyldiimidazole In tetrahydrofuran for 1h; Reflux; Stage #2: tert-butyl 3-amino-5,6-dihydropyrazine-1(2H)-carboxylate In tetrahydrofuran for 16h; Reflux; | 26.A Step A: tert-butyl 3-(1-oxo-1 ,3-dihydroisobenzofuran-5-carboxamido)-5,6-dihydropyrazine-5 1 (2H)-carboxylate To a mixture of 1-oxo-J ,3-dihydroisobenzofuran-5-carboxylic acid (894mg,5.02 mmol) and CD (895mg, 5.52 mmol) was added THF (10 ml) at rt. The mixture wasrefluxed for 1 h. To the above mixture was added tert-butyl3-amino-5,6-dihydropyrazine-1(2H)carboxylate(l.Og, 5.02 mmol) in THF (10 ml), then refluxing was continued for additional16 h.The mixture was partitioned between EtOAc and aq. NaHC03 (sat'd) and aqueous layer wasI 0 extracted with EtOAc (3X). Combined organic layer was washed with brine, dtied over MgS04,filtered. Concentration of filtrate followed by purification via silica gel column chromatographyusing (0-10)% MeOHDCM gave the title compound as solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; | 15.A Step A: tert-butyl 3-hydroxy-4-( 1-oxo-1 ,3-dihydroisobenzofuran-5-carboxamido)piperidine-lcarboxy1ate To a solution of 5-carboxyphthalide (60 mg, 0.337 mmol), tert-butyl 4-amino-3-hydroxypiperidine-1-carboxy1ate (72.8 mg, 0.337 mmol), HOBT (61 .9 mg, 0.404 mmol), and30 EDC (97 mg, 0.505 mmol) in DCM (1684 11l) was added N-methylmorpholine (74.1 111, 0.674 mmol) at rt and the reaction mixture was stirred at rt 16 h. The mixture was concentrated and theresidue was purified by preparative TLC using I 0% MeOHIDCM as mobile phase to give thetitle compound as white solid. LC/MS:[M+Ht = 377.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.5 h 2.1: N-Bromosuccinimide / chlorobenzene / 0.08 h 2.2: 2 h / 80 °C 3.1: sodium hydroxide / water; 2-methyltetrahydrofuran / 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.5 h 2.1: N-Bromosuccinimide / chlorobenzene / 0.08 h 2.2: 2 h / 80 °C 3.1: sodium hydroxide / water; 2-methyltetrahydrofuran / 2 h 4.1: oxygen / 2,2,2-trifluoroethanol / 48 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.5 h 2.1: N-Bromosuccinimide / chlorobenzene / 0.08 h 2.2: 2 h / 80 °C 3.1: sodium hydroxide / water; 2-methyltetrahydrofuran / 2 h 4.1: oxygen / water; 2,2,2-trifluoroethanol / 48 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.5 h 2.1: N-Bromosuccinimide / chlorobenzene / 0.08 h 2.2: 2 h / 80 °C 3.1: sodium hydroxide / water; 2-methyltetrahydrofuran / 2 h 4.1: oxygen / water; 2,2,2-trifluoroethanol / 20 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.5 h 2.1: N-Bromosuccinimide / chlorobenzene / 0.08 h 2.2: 2 h / 80 °C 3.1: sodium hydroxide / water; 2-methyltetrahydrofuran / 2 h 4.1: oxygen / 2,2,2-trifluoroethanol / 16 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.5 h 2.1: N-Bromosuccinimide / chlorobenzene / 0.08 h 2.2: 2 h / 80 °C 3.1: sodium hydroxide / water; 2-methyltetrahydrofuran / 2 h 4.1: 26 h / 60 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.5 h 2.1: N-Bromosuccinimide / chlorobenzene / 0.08 h 2.2: 2 h / 80 °C 3.1: sodium hydroxide / water; 2-methyltetrahydrofuran / 2 h 4.1: 60 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.5 h 2.1: N-Bromosuccinimide / chlorobenzene / 0.08 h 2.2: 2 h / 80 °C 3.1: sodium hydroxide / water; 2-methyltetrahydrofuran / 2 h 4.1: propionic acid / 20 h / 80 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.5 h 2.1: N-Bromosuccinimide / chlorobenzene / 0.08 h 2.2: 2 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With thionyl chloride; at 5.0℃; for 2h;Reflux; | 1,3-Dihydro-1-oxoisobenzofuran-5-carboxylic acid (1) was converted into methyl-1,3-dihydro-1-oxoisobenzofuran-5-carboxylate by esterification. The mixture of 1,3-dihydro-1-oxoisobenzofuran-5-carboxylic acid (5.6 mmol) was taken in methanol (10 mL), thionyl chloride (1.33 g) was added slowly at 5-10 C. The reaction mass was refluxed for 2 h and then cooled to room temperature and poured into crushed ice. The solid mass was filtered,dried and the white colour solid was obtained (Yield: 90 %). |
Tags: 4792-29-4 synthesis path| 4792-29-4 SDS| 4792-29-4 COA| 4792-29-4 purity| 4792-29-4 application| 4792-29-4 NMR| 4792-29-4 COA| 4792-29-4 structure
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