* 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.
Reference：
[1] Patent: EP1346982, 2003, A1,
[2] Journal of the American Chemical Society, 1975, vol. 97, p. 7305 - 7312
[3] Journal of Medicinal Chemistry, 1994, vol. 37, # 15, p. 2308 - 2314
[4] Patent: WO2005/63767, 2005, A2, . Location in patent: Page/Page column 44-45
[5] Patent: WO2005/111038, 2005, A2, . Location in patent: Page/Page column 66-67
[6] Patent: US2005/250808, 2005, A1, . Location in patent: Page/Page column 40
[7] Patent: US4853027, 1989, A,
2
[ 651780-27-7 ]
[ 57764-49-5 ]
Yield
Reaction Conditions
Operation in experiment
96%
With hydrogen; triethylamine In ethanol at 0℃; for 1 h;
10percent Palladium on carbon (1.5g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, 0. 081mol) in ethanol (300ml) at 0 °C under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed by filtration through Celite. The filter cake was washed with ethanol (3 x 50 mL) and the filtrates were concentrated. The residue was dissolved in dichloromethane (200 mL) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96percent). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with the bicyclobase according to procedure A. Literature reference: Angell, R. M.; Baldwin, I. R.; Bamborough, P.; Deboeck, N. M.; Longstaff, T.; Swanson, S. W004010995A1 The following acid was prepared using this method: 1,2-Benzisoxazole-3-carboxylic acid.
96%
With hydrogen; triethylamine In ethanol at 0℃; for 1 h;
Diethyl malonate (12.6 g, 79 mmol) was added to a suspension of sodium hydride (3.16 g, 132 mmol) in dimethylsulfoxide (60 ml) over 30 min. The temperature of the reaction rose to 60 °C and the mixture clarified. 1,4-Dibromo-2-nitrobenzene (10 g, 36.0 mmol) was added and the solution was maintained for 2 h at 100 °C. The reaction mixture was allowed to cool to rt and was poured into ice (300g-400g). The precipitated solids were isolated by filtration and dried to provide 11.0 g of the product (89percent). The ester (11.0 g, 32.0 mmol) was diluted with a 2 N solution of sodium hydroxide (32 mL, 63 mmol) and the reaction mixture was maintained at room temperature for 16 h. The aqueous layer was extracted with dichloromethane (20 mL) and was acidified. The precipitated solids were isolated by filtration and dried to provide 7.00 g of the acid (89percent). Sulfuric acid (1 mL) was added to a solution of the acid (7.00 g, 27.0 mmol) in ethanol (60 ml). The reaction mixture was warmed to reflux, maintained for 2 h, and was concentrated under reduce pressure. The residue was partitioned between ethyl acetate (250 mL) and saturated sodium carbonate (50 mL) and the organic layer was washed with saturated sodium carbonate (50 mL) and brine (50 mL). The organic layer was dried (sodium sulfate) and concentrated to provide 8.00 g (98percent) of the ester as a liquid. Under N2 atmosphere, sodium ethylate was formed with sodium (33.5 g, 1.46 mol) in ethanol (1.0 L). Isoamylnitrite (225 mL) was added to a solution of the ester (420 g, 1.46 mol) in ethanol (3 L) in a 10 L three-necked round bottom flask and the mixture was warmed to 60 °C. A solution of sodium ethoxide, prepared from sodium metal (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to cool to rt and was neutralized with 2 N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4 x 2L) and the combined organic layers were washed with water (2 x 1 L) and brine (2 x 1 L) and dried (sodium sulfate). The residue was purified by chromatography (1/1 to 0/1 hexane/ethyl acetate) to provide 110 g of the product ( 28percent). 10percent Palladium on carbon (1.5g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, 0.081mol) in ethanol (300ml) at 0 °C under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed'by filtration through Celite. The filter cake was washed with ethanol (3 x 50 mL) and the filtrates were concentrated. The residue was- dissolved in dichloromethane (200 mL) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96percent). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according to procedure A.
96%
With hydrogen; triethylamine In ethanol at 0℃; for 1 h;
10percent Palladium on carbon (1.5 g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20 g, 0.081 mol) in ethanol (300ml) at 0° C. under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed by filtration through Celite. The filter cake was washed with ethanol (3.x.50 mL) and the filtrates were concentrated. The residue was dissolved in dichloromethane (200 mL) and the solution was washed with water (4.x.50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96percent). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with the bicyclobase according to procedure A.
With sodium hydride In N,N-dimethyl-formamide at 130℃; for 8.41667 h;
A solution of the nitro oxime a (5.0 g, 21.0 mmol) prepared according to the procedures described by Kemp et al. (/. Am. Chem. Soc. 1975, 97, 7305-7312) in DMF (30 mL) was added drop wise over 25 min to a vigorously stirred suspension of hexane-washed NaH (60percent in mineral oil, 840 mg, 21.0 mmol) in DMF (40 mL) under N2. The resulting dark colored solution was heated slowly to 130 0C for 8 h. It was diluted with water (200 mL), extracted with EtOAc (2 x 200 mL), washed the EtOAc with brine, dried (MgSO4), and concentrated in vacuo. The crude product was adsorbed on to Celite and purified by ISCO CombiFlash 120 g EPO <DP n="90"/>column (1-10percent ethyl acetate-hexane) to afford 1.6 g (41percent) of benzisoxazole b as an off white solid.
Reference：
[1] Patent: WO2006/69063, 2006, A1, . Location in patent: Page/Page column 88-89
[2] Journal of the American Chemical Society, 1975, vol. 97, p. 7305 - 7312
[3] Journal of Medicinal Chemistry, 1994, vol. 37, # 15, p. 2308 - 2314
4
[ 57764-48-4 ]
[ 57764-49-5 ]
Reference：
[1] Patent: US4853027, 1989, A,
5
[ 3740-52-1 ]
[ 57764-49-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 15, p. 2308 - 2314
6
[ 31912-02-4 ]
[ 57764-49-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 15, p. 2308 - 2314
With sodium hydride; In diethylene glycol dimethyl ether; mineral oil; at 150℃; for 5h;Inert atmosphere;
Compound 41-c (8.00 g, 33.59 mmol, 1.00 eq) was dissolved in diglyme (80.00 mL), and the above solution was added dropwise to a mixed solution of sodium hydride (2.02 g, 50.39 mmol, purity of 60%, 1.50 eq) and diglyme (110.00 mL) with vigorously stirring under the protection of nitrogen gas. The reaction solution was slowly warmed up to 150C, and stirred for 5 hours. After the reaction was completed, the reaction solution was added with 200 mL of water, and extracted with ethyl acetate (400 mL). The organic phase was washed with water (150 mL 3 2), dried over anhydrous sodium sulfate, filtered, concentrated, and then dissolved in heated petroleum ether. The above solution was cooled down to 0C, the precipitated solid was filtered, and the product of compound 41-d (3.32 g, yield: 44%) as a pale yellow solid was obtained by concentration. 1H NMR (400 MHz, DMSO-d6) delta=8.04-8.11 (m, 1H), 7.91 (d, J=8.53 Hz, 1H), 7.76 (t, J=7.78 Hz, 1H), 7.55 (t, J=7.53 Hz, 1H), 4.48 (q, J=7.36 Hz, 2H), 1.40 (t, J=7.03 Hz, 3H).
41%
With sodium hydride; In N,N-dimethyl-formamide; at 130℃; for 8.41667h;
A solution of the nitro oxime a (5.0 g, 21.0 mmol) prepared according to the procedures described by Kemp et al. (/. Am. Chem. Soc. 1975, 97, 7305-7312) in DMF (30 mL) was added drop wise over 25 min to a vigorously stirred suspension of hexane-washed NaH (60% in mineral oil, 840 mg, 21.0 mmol) in DMF (40 mL) under N2. The resulting dark colored solution was heated slowly to 130 0C for 8 h. It was diluted with water (200 mL), extracted with EtOAc (2 x 200 mL), washed the EtOAc with brine, dried (MgSO4), and concentrated in vacuo. The crude product was adsorbed on to Celite and purified by ISCO CombiFlash 120 g EPO <DP n="90"/>column (1-10% ethyl acetate-hexane) to afford 1.6 g (41%) of benzisoxazole b as an off white solid.
(Step 3) Synthesis of benzo(d)isoxazole-3-carboxylic acid To ethyl benzo (d)isoxazole-3-carboxylate (2.0 g, 10.5 mmol) was added 50 ml of 70% H2SO4. The mixture was heated at 80ØC for 4 hours. The reaction mixture was poured in ice, followed by extraction with ether. The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, whereby benzo(d)isoxazole-3-carboxylic acid (980 mg, 57%) was obtained as a colorless solid. 1H-NMR (DMSO-d6) delta: 7.53 (dt, J=1.0,7.1Hz, 1H), 7.74 (dt, J=1.2,7.1Hz, 1H), 7.89 (dd, J=1.0,8.5Hz, 1H), 8.10 (dt, J=1.0,8.1Hz, 1H).
With sodium hydroxide; water;
10% Palladium on carbon (1.5g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, 0. 081mol) in ethanol (300ml) at 0 C under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed by filtration through Celite. The filter cake was washed with ethanol (3 x 50 mL) and the filtrates were concentrated. The residue was dissolved in dichloromethane (200 mL) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96%). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with the bicyclobase according to procedure A. Literature reference: Angell, R. M.; Baldwin, I. R.; Bamborough, P.; Deboeck, N. M.; Longstaff, T.; Swanson, S. W004010995A1 The following acid was prepared using this method: 1,2-Benzisoxazole-3-carboxylic acid.
With sodium hydroxide;
Diethyl malonate (12.6 g, 79 mmol) was added to a suspension of sodium hydride (3.16 g, 132 mmol) in dimethylsulfoxide (60 ml) over 30 min. The temperature of the reaction rose to 60 C and the mixture clarified. 1,4-Dibromo-2-nitrobenzene (10 g, 36.0 mmol) was added and the solution was maintained for 2 h at 100 C. The reaction mixture was allowed to cool to rt and was poured into ice (300g-400g). The precipitated solids were isolated by filtration and dried to provide 11.0 g of the product (89%). The ester (11.0 g, 32.0 mmol) was diluted with a 2 N solution of sodium hydroxide (32 mL, 63 mmol) and the reaction mixture was maintained at room temperature for 16 h. The aqueous layer was extracted with dichloromethane (20 mL) and was acidified. The precipitated solids were isolated by filtration and dried to provide 7.00 g of the acid (89%). Sulfuric acid (1 mL) was added to a solution of the acid (7.00 g, 27.0 mmol) in ethanol (60 ml). The reaction mixture was warmed to reflux, maintained for 2 h, and was concentrated under reduce pressure. The residue was partitioned between ethyl acetate (250 mL) and saturated sodium carbonate (50 mL) and the organic layer was washed with saturated sodium carbonate (50 mL) and brine (50 mL). The organic layer was dried (sodium sulfate) and concentrated to provide 8.00 g (98%) of the ester as a liquid. Under N2 atmosphere, sodium ethylate was formed with sodium (33.5 g, 1.46 mol) in ethanol (1.0 L). Isoamylnitrite (225 mL) was added to a solution of the ester (420 g, 1.46 mol) in ethanol (3 L) in a 10 L three-necked round bottom flask and the mixture was warmed to 60 C. A solution of sodium ethoxide, prepared from sodium metal (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to cool to rt and was neutralized with 2 N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4 x 2L) and the combined organic layers were washed with water (2 x 1 L) and brine (2 x 1 L) and dried (sodium sulfate). The residue was purified by chromatography (1/1 to 0/1 hexane/ethyl acetate) to provide 110 g of the product ( 28%). 10% Palladium on carbon (1.5g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, 0.081mol) in ethanol (300ml) at 0 C under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed'by filtration through Celite. The filter cake was washed with ethanol (3 x 50 mL) and the filtrates were concentrated. The residue was- dissolved in dichloromethane (200 mL) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96%). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according to procedure A.
With sodium hydroxide; In water;
10% Palladium on carbon (1.5 g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20 g, 0.081 mol) in ethanol (300ml) at 0 C. under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed by filtration through Celite. The filter cake was washed with ethanol (3×50 mL) and the filtrates were concentrated. The residue was dissolved in dichloromethane (200 mL) and the solution was washed with water (4×50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96%). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with the bicyclobase according to procedure A.
With sulfuric acid; In water;
8.6 g of 3B was mixed with 175 ml of 70% sulfuric acid and the mixture was heated at 80 C. for 4 hours. The mixture was cooled, 200 ml of cold water was added, the mixture was extracted with ether, and the extract was dried (Na2 SO4) and stripped of solvent. The residue was triturated with pentane, and the solid was collected and dried to give 3-benzisoxazolecarboxylic acid (3C), as a white solid, m.p.: 132-134 C. (with decomposition).
With sulfuric acid; at 80℃; for 3.5h;
Compound 41-d (3.32 g, 17.37 mmol, 1.00 eq) was dissolved in 70% sulfuric acid solution (80.00 mL), and the resulting reaction solution was stirred at 80C for 3.5 hours. After the reaction was completed, the reaction solution was added with 150 mL of ice water, and extracted with ethyl acetate (300 mL). The organic phase was washed with water (100 mL 3 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the product of compound 41-e (1.50 g, crude) as a gray solid, which was used directly in the next step without purification. 1H NMR (400 MHz, DMSOd6) delta = 8.09 (d, J=8.03 Hz, 1H), 7.89 (d, J=8.53 Hz, 1H), 7.74 (t, J=7.53 Hz, 1H), 7.52 (t, J=7.53 Hz, 1H).
With hydrogen; triethylamine;palladium 10% on activated carbon; In ethanol; at 0℃; for 1h;
10% Palladium on carbon (1.5g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, 0. 081mol) in ethanol (300ml) at 0 C under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed by filtration through Celite. The filter cake was washed with ethanol (3 x 50 mL) and the filtrates were concentrated. The residue was dissolved in dichloromethane (200 mL) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96%). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with the bicyclobase according to procedure A. Literature reference: Angell, R. M.; Baldwin, I. R.; Bamborough, P.; Deboeck, N. M.; Longstaff, T.; Swanson, S. W004010995A1 The following acid was prepared using this method: 1,2-Benzisoxazole-3-carboxylic acid.
96%
With hydrogen; triethylamine;palladium 10% on activated carbon; In ethanol; at 0℃; for 1h;
Diethyl malonate (12.6 g, 79 mmol) was added to a suspension of sodium hydride (3.16 g, 132 mmol) in dimethylsulfoxide (60 ml) over 30 min. The temperature of the reaction rose to 60 C and the mixture clarified. 1,4-Dibromo-2-nitrobenzene (10 g, 36.0 mmol) was added and the solution was maintained for 2 h at 100 C. The reaction mixture was allowed to cool to rt and was poured into ice (300g-400g). The precipitated solids were isolated by filtration and dried to provide 11.0 g of the product (89%). The ester (11.0 g, 32.0 mmol) was diluted with a 2 N solution of sodium hydroxide (32 mL, 63 mmol) and the reaction mixture was maintained at room temperature for 16 h. The aqueous layer was extracted with dichloromethane (20 mL) and was acidified. The precipitated solids were isolated by filtration and dried to provide 7.00 g of the acid (89%). Sulfuric acid (1 mL) was added to a solution of the acid (7.00 g, 27.0 mmol) in ethanol (60 ml). The reaction mixture was warmed to reflux, maintained for 2 h, and was concentrated under reduce pressure. The residue was partitioned between ethyl acetate (250 mL) and saturated sodium carbonate (50 mL) and the organic layer was washed with saturated sodium carbonate (50 mL) and brine (50 mL). The organic layer was dried (sodium sulfate) and concentrated to provide 8.00 g (98%) of the ester as a liquid. Under N2 atmosphere, sodium ethylate was formed with sodium (33.5 g, 1.46 mol) in ethanol (1.0 L). Isoamylnitrite (225 mL) was added to a solution of the ester (420 g, 1.46 mol) in ethanol (3 L) in a 10 L three-necked round bottom flask and the mixture was warmed to 60 C. A solution of sodium ethoxide, prepared from sodium metal (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to cool to rt and was neutralized with 2 N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4 x 2L) and the combined organic layers were washed with water (2 x 1 L) and brine (2 x 1 L) and dried (sodium sulfate). The residue was purified by chromatography (1/1 to 0/1 hexane/ethyl acetate) to provide 110 g of the product ( 28%). 10% Palladium on carbon (1.5g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, 0.081mol) in ethanol (300ml) at 0 C under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed'by filtration through Celite. The filter cake was washed with ethanol (3 x 50 mL) and the filtrates were concentrated. The residue was- dissolved in dichloromethane (200 mL) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96%). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according to procedure A.
96%
With hydrogen; triethylamine;palladium 10% on activated carbon; In ethanol; at 0℃; for 1h;
10% Palladium on carbon (1.5 g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20 g, 0.081 mol) in ethanol (300ml) at 0 C. under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed by filtration through Celite. The filter cake was washed with ethanol (3×50 mL) and the filtrates were concentrated. The residue was dissolved in dichloromethane (200 mL) and the solution was washed with water (4×50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96%). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with the bicyclobase according to procedure A.
20 g of 3A was dissolved in 100 ml of diglyme and the solution was added dropwise to a vigorously stirred mixture of 2.5 g of sodium hydride and 100 ml of diglyme, under nitrogen at room temperature. The mixture was heated slowly to and held at 150 C. for 6 hours, then cooled, mixed with 200 ml of water and extracted with ether. The extract was dried and stripped of solvent. The residue was distilled in a Kugelrohr apparatus (60 C./0.05 Torr); the resulting residue was dissolved in warm petroleum ether, the solution was chilled to 0 C., and the solid phase was collected and dried, to give ethyl 3-benzisoxazolylcarboxylate (3B), as a white solid, m.p.: 53-55 C.
(Step 2) Synthesis of ethyl benzo(d)isoxazole-3-carboxylate Ethyl 2-nitrophenyl)acetate (12.3 g, 58.6 mmol) and isoamyl nitrate (8.92 g, 76.1 mmol) were dissolved in ethanol (100 ml). Sodium methoxide (19.9 ml, 58.6 mmol, a 20% solution in ethanol) was added, followed by stirring at 50ØC for 1.5 hours. The reaction mixture was cooled to room temperature and neutralized with 1M HCl (30 ml), followed by extraction with ether. The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was crystallized by the addition of chloroform/n-hexane and the crystals were dried under reduced pressure for 18 hours. The crystals thus obtained were dissolved in 1,2-dimethoxyethane (100 ml) and to the resulting solution, a solution of sodium hydride (2.81 g, 70.3 mmol) in 1,2-dimethoxyethane (100 ml) was added in portions. The reaction mixture was stirred at 150ØC for 8 hours. Under cooling, the reaction mixture was poured to a saturated aqueous solution of sodium bicarbonate, followed by extraction with ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (middle pressure chromatography system Yamazen, n-hexane/ethyl acetate 9:1, 20 ml/min, phi 80 x 300) to give ethyl benzo(d)isoxazole-3-carboxylate (5.75 g, 51%) as a brown solid. 1H-NMR (DMSO-d6) delta: 1.50 (m, 3H), 4.56 (m, 2H), 7.45 (dt, J=1.2, 6.8Hz, 1H), 7.62 (dt, J=1.2,8.5Hz, 1H), 7.66 (dt, J=1.0,8.5Hz, 1H), 8.14 (dd, J=1.0,8.0Hz, 1H). MS (ESI) m/z 192 (M+1)+.
18
[ 52727-57-8 ]
[ 57764-49-5 ]
[ 668969-99-1 ]
Yield
Reaction Conditions
Operation in experiment
[ETHYL-1,] 2-benzisoxazole-3-carboxylate (10 g, 52 mmol) was dissolved in 100 mL of [CHLOROSULFONIC] acid and heated to 80 C. After 16 h the reaction was cooled to room temperature, poured onto ice and then extracted with EtOAc. The organic solution was dried over [NA2S04] and then concentrated to a brown oil. This oil was dissolved in 60 [ML] of thionyl chloride and heated to 50 C. After 6 h excess reagent was removed in vacuo and the remaining residue dissolved in 300 mL [CHCLS.] [METHYL-2-AMINO-5-] bromobenzoate was added as a solution in 100 mL CHCl3 and 10 [ML] pyridine. After stirring overnight at room temperature the resulting precipitate was filtered providing 3.96 g of the title compound. H NMR (400 MHz, CDCl3) 3.80 (s, [3H),] 7.77 (dd, [1H),] 7.92 (d, [1H),] 8.27 (d, [1H),] 8.32 (dd, [1H),] 8.82 (d, [1H),] 9.12 (d, [1H),] 12.63 (s, [1H)]
To a stirred solution of <strong>[57764-49-5]ethyl benzo[d]isoxazole-3-carboxylate</strong>2 (0.50 g, 2.62 mmol) in MeOH (80 mL) wasadded H2SO4 (0.5 mL) and the resulting solution was stirred at 65 C for further 48 h. The reactionmixture was cooled to rt. Sat. NH4Cl aq. was added to the reaction mixture and the resultingsolution was extracted with AcOEt. The combined organic layer was dried over Na2SO4 andconcentrated in vacuo. The crude product was purified by flash column chromatography on silica gel(hexane/AcOEt = 5/1). The product was obtained as pale yellow solid (0.41 g, 88%);
22.1: Benzoisoxazol-3-ylmethanol; 589 mg (3.0 mmol) of ethyl 1.2-benzoisoxazole-3-carboxylate in solution in 10 ml of tetrahydrofuran are added to a suspension of 129 mg (3.5 mmol) of lithium aluminum hydride in 5 ml of tetrahydrofuran. The reaction mixture is stirred for one hour at 60 C. and then treated by adding 2 ml of methanol dropwise, filtered through celite and rinsed with ethyl acetate. The organic phases are combined, dried over sodium sulfate and evaporated. The residue obtained is purified by chromatography on silica gel, elution being carried out with a 60/40 heptane/ethyl acetate mixture. 180 mg (39%) of benzoisoxazol-3-ylmethanol are obtained in the form of a white solid.
39%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 60℃; for 1h;
589 mg (3.0 mmol) of ethyl 1.2-benzoisoxazole-3-carboxylate in solution in 10 ml of tetrahydrofuran are added to a suspension of 129 mg (3.5 mmol) of lithium aluminum hydride in 5 ml of tetrahydrofuran. The reaction mixture is stirred for one hour at 60 C. and then treated by adding 2 ml of methanol dropwise, filtered through celite and rinsed with ethyl acetate. The organic phases are combined, dried over sodium sulfate and evaporated. The residue obtained is purified by chromatography on silica gel, elution being carried out with a 60/40 heptane/ethyl acetate mixture. 180 mg (39%) of benzoisoxazol-3-ylmethanol are obtained in the form of a white solid
To a solution of CH3CN (0.46mL, 8.80mmol) in anhydrous THF (8mL) was added 1.6M methyl lithium in diethyl ether (2.75mL, 4.40mmol) at-78C under nitrogen. The mixture was stirred at-78C for 0.5h, and <strong>[57764-49-5]ethyl benzo[d]isoxazole-3-carboxylate</strong> 28 (420mgg, 2.20mmol) in THF (10mL) was then added dropwise. The solution was stirred at-78C for 1h and then quenched with acetic acid (0.26mL, 4.40mmol). The mixture was warmed to 0C and poured onto ice/ water (10mL) and extracted with ethyl acetate (20mL). The organic lay was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue 29 (400mg, 98%) was obtained as a yellow solid and directly used for next step without further purification. 1H NMR (300MHz, CDCl3) delta 8.24 (d, J=8.0Hz, 1H), 7.77-7.66 (m, 2H), 7.57-7.49 (m, 1H), 4.40 (s, 2H). 13C NMR (75MHz, CDCl3) delta 182.38, 164.73, 131.23, 126.16, 123.23, 118.36, 112.60, 110.18, 30.34.
With methyllithium; In tetrahydrofuran; diethyl ether; at -78℃; for 1.5h;Inert atmosphere;
2-(Benzo[d]isoxazol-3-yl)-N-(3-chlorophenyl)-2-oxoacetohydrazonoyl cyanide (30).To a solution of CH3CN (0.46 mL, 8.80 mmol) in anhydrous THF (8 mL) was added 1.6 Mmethyl lithium in diethyl ether (2.75 mL, 4.40 mmol) at -78 C under nitrogen. The mixture wasstirred at -78 C for 0.5 h, and <strong>[57764-49-5]ethyl benzo[d]isoxazole-3-carboxylate</strong> 28 (0.42 g, 2.20 mmol) inTHF (10 mL) was then added dropwise. The solution was stirred at -78 C for 1 h and thenquenched with acetic acid (0.26 mL, 4.40 mmol). The mixture was warmed to 0 C and pouredonto ice/water (10 mL) and extracted with ethyl acetate (20 mL). The organic lay was dried overNa2SO4, filtered and concentrated under reduced pressure. The crude residue 29 (400 mg, 98%)was obtained as a yellow solid and directly used for next step without further purification. ?HNMR (300 MHz, CDC13) 8.24 (d, J= 8.0 Hz, 1H), 7.77-7.66 (m, 2H), 7.57-7.49 (m, 1H),4.40 (s, 2H). ?3C NIVIR (75 IVIHz, CDC13) 182.38, 164.73, 131.23, 126.16, 123.23, 118.36,112.60, 110.18, 30.34.
With hydrazine hydrate; In ethanol; for 96h;Reflux;
To a solution of <strong>[57764-49-5]1,2-benzisoxazole-3-carboxylic acid ethyl ester</strong> (commercially available fromAstaTech, Inc., 1.0 g, 5.23 mmol) in EtOH (7.93 mL) was added hydrazine, monohydrate (0.78 mL, 10.46 mmol), and the reaction was heated to reflux. After 3 d, the reaction showed 80% conversion to product by LCMS. A furthur 2 equiv. of hydrazine was added and the reaction sirred at 60oC. After a further day, the reaction was judged complete by LCMS. The reaction was then cooled to RT, EtOAc was added, and the mixture was stirred for 30 min. The mixture was then concentrated in vacuo to yieldbenzo[d]isoxazole-3-carbohydrazide (1.1 g,), the material was carried forward without purification. LCMS-ESI (pos.) m/z: 178.1 (M+H)+.
(Z)-2-(benzo[d]isoxazole-3-carbonyl)-N'-(2,6-dimethoxyphenyl)-N-(((2S,3R)-3-(5-methylpyrimidin-2-yl)butan-2-yl)sulfonyl)hydrazinecarboximidamide[ No CAS ]
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