* 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.
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2 h; Inert atmosphere
To a solution of 3-methylisoxazole-5-carboxylic acid (3 g, 23.6 mmol) in tetrahydrofuran (20 mL) was added L1AIH4 (1.8 g, 47.37 mmol) in portions at 0 °C under nitrogen atmosphere. After additional 2 hours at room temperature, the reaction was then quenched by water (2 mL). The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 10 percent - 30 percent ethyl acetate in petroleum ether to afford (3-methylisoxazol-5-yl)methanol as colorless oil (1.5 g, 56 percent); (ES, m/z) [M+H] + 114.1 ; *H NMR (300 MHz, CDC13) δ 6.09 (s, 1H), 4.74 (s, 2H), 2.30 (s, 3H), 2.10 (brs, 1H).
Reference：
[1] Gazzetta Chimica Italiana, 1942, vol. 72, p. 411,422
[2] Journal of the American Pharmaceutical Association (1912-1977), 1953, vol. 42, p. 594,597
3
[ 7803-49-8 ]
[ 615-79-2 ]
[ 3405-77-4 ]
[ 4857-42-5 ]
Reference：
[1] Chemische Berichte, 1891, vol. 24, p. 3908[2] Chemische Berichte, 1909, vol. 42, p. 60
4
[ 67-56-1 ]
[ 4857-42-5 ]
[ 1004-96-2 ]
Yield
Reaction Conditions
Operation in experiment
76%
at 0 - 40℃; for 3.25 h;
To a solution of compound 9 (1 g, 7.9 mmoi, 1.0 eq) in dry MeOH (20 mi.) was added SOCI2 (1 g, 8,7 mmol, 1.1 eq) slowly at 0 °C. The reaction mixture was stirred at 25 °C for 15 min and heated to 40 °C for 3 h. The reaction mixture was concentrated under reduced pressure, dissolved in EtOAc (50 mL), washed with brine (2 x 50 mL), dried over anhydrous Na2SOa, filtered and concentrated in vacuum. The residue was purified by column chromatography (0-20percent EtOAc in PE) to afford 10 (850 mg, 6.0 mmol, 76percent yield) as a white solid: JH NM (400 M Hz, CDCI3) δ 2.40 (s, 3H), 3.98 (s, 3H), 6.82 (s, 1H).
Stage #1: With sodium hydroxide; water In tetrahydrofuran; methanol at 20℃; for 18 - 20 h; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water
A round bottom flask with magnetic stirrer was charged with 3-methyl-isoxazole-5- carboxylic acid ethyl ester (900 mg, 5.8 mmol) in tetrahydrofuran (2.0 mL). To the reaction was added a solution of sodium hydroxide (465 mg, 11.6 mmol) in water (2 mL), followed by methanol (4 mL). The reaction was stirred at room temperature for 18 - 20 hours under an argon atmosphere. The reaction was transferred to a separatory funnel and the pH adjusted to 2 via addition of IN hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 35 mL) and the combined extractions were washed with brine (1 x 50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to yield S-methyl-isoxazole-S-carboxylic acid as a white solid (660 mg, 90percent). The solid was used without purification in the next reaction.
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 29, p. 8353 - 8357[2] Angew. Chem., 2016, vol. 128, # 29, p. 8493 - 8497,5
[3] Patent: WO2006/91674, 2006, A1, . Location in patent: Page/Page column 79
[4] European Journal of Medicinal Chemistry, 1992, vol. 27, # 6, p. 581 - 593
6
[ 14716-89-3 ]
[ 4857-42-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9008 - 9018
Reference：
[1] Chemical and pharmaceutical bulletin, 1962, vol. 10, p. 607 - 611
15
[ 70753-36-5 ]
[ 4857-42-5 ]
Reference：
[1] Gazzetta Chimica Italiana, 1942, vol. 72, p. 99,106
16
[ 20577-61-1 ]
[ 3405-77-4 ]
[ 4857-42-5 ]
Reference：
[1] Gazzetta Chimica Italiana, 1942, vol. 72, p. 411,422
[2] Journal of the American Pharmaceutical Association (1912-1977), 1953, vol. 42, p. 594,597
A round bottom flask with magnetic stirrer was charged with 3-methyl-isoxazole-5- carboxylic acid ethyl ester (900 mg, 5.8 mmol) in tetrahydrofuran (2.0 mL). To the reaction was added a solution of sodium hydroxide (465 mg, 11.6 mmol) in water (2 mL), followed by methanol (4 mL). The reaction was stirred at room temperature for 18 - 20 hours under an argon atmosphere. The reaction was transferred to a separatory funnel and the pH adjusted to 2 via addition of IN hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 35 mL) and the combined extractions were washed with brine (1 x 50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to yield S-methyl-isoxazole-S-carboxylic acid as a white solid (660 mg, 90percent). The solid was used without purification in the next reaction.
To a solution of 1 (5g) in EtOH(100mL) was added thionyl chloride(3.44mL), and the resulting solution was stirred at 50 °C. After termination of this reaction, the solution was cooled to room temp. and the volatile was removed under reduced pressure. The residue was dissolved in EtOAc and partitioned between Na2CO3 soln. and EtOAc, then extracted with EtOAc. The extraction was washed with water, brine and dried with MgSO4 and concentrated in vacuo to give ethylester(6.3g). To a solution of tetramethylammonium nitrate(6.81g) in CH2Cl2 (40mL)was added trifluoromethanesulfonic acid anhydride(8.41mL). Ethylester(5.17g) in CH2Cl2 (15ml)was added to the solution and the resulting mixture was refluxed overnight. The reaction mixture was cooled to room temp. and added sat. NaHCO3 soln., then partitioned between water and EtOAc and extracted with EtOAc. The extraction was washed with water and brine, dried with MgSO4 and concentrated in vacuo. The residue was purified by silicagel columnchromatography to give 16 (5.38g).
PREPARATION 15 3-Methyl-5-isoxazolecarboxamide <strong>[4857-42-5]3-Methyl-5-isoxazolecarboxylic acid</strong> (20 g.) was refluxed for 10 hours in 350 ml. of thionyl chloride, then stirred at room temperature for 16 hours, clarified by filtration and evaporated to an oil. The oil was multiply triturated with hot hexane, and the combined hexane triturates evaporated to yield acid chloride (16.2 to 21 g.) as a solid. With stirring, acid chloride prepared in the manner (35 g.) was added portionwise to 300 ml. of conc. ammonium hydroxide at room temperature. After granulating for 1 hour, title product was recovered by filtration (24.2 g., m.p 180°-182° C.).
4-methylamino-3-[(3-methylisoxazole-5-ylcarbonyl)amino]quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
361 mg (67%)
With thionyl chloride; In N,N,N,N,N,N-hexamethylphosphoric triamide; ice-water; acetonitrile;
Example 102 1-Methyl-2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline C102 To a solution of 245 mg of <strong>[4857-42-5]3-methylisoxazole-5-carboxylic acid</strong> in 20 ml of hexamethylphosphoramide and 0.4 ml of acetonitrile is added 226 mg of thionyl chloride at -5 - 0°C. After stirring at the same temperature for 30 minutes, 330 mg of 3-amino-4-methylaminoquinoline A15 is added and stirred at 0 - 5°C for 5 hours. The mixture is diluted with 50 ml of ice-water and neutralized with saturated aqueous sodium bicarbonate. The resulting solid is filtered and washed with water to give 361 mg (67percent) of 4-methylamino-3-[(3-methylisoxazole-5-ylcarbonyl)amino]quinoline.
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 5h;
To a 0° C. solution of (081) (160 mg, 0.43 mmol) and isoxazole-3-carboxylic acid (084) (65 mg, 0.5 mmol), HOBT (65 mg, 0.5 mmol) and HBTU (175 mg, 0.5 mmol) in tetrahydrofuran (50 mL) was added a solution of N,N-diisopropylethylamine (0.5 mL) in tetrahydrofuran (2 mL) and the mixture was stirred at room temperature for another 5 hours. The reaction was then diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (2.x.10 mL) and brine (10 mL). The organic layers were dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and the residue was purified by HPLC (aqueous ammonium acetate and acetonitrile) to provide (085) (71 mg) which was characterized by LC/MS (LCRS (MH) m/z: 483.24); >50percent proteasome CT-L inhibition at 20 mg/kg PO.
The carboxylic acid R'COOH (0.12 mmol) is treated with a solution of HATU (0.12 mmol) in DMF (0.25 ml) and DIPEA (0.052 ml, ca. 0.3 mmol) is added. The solution is shaken for 10 mins, and is treated with a solution of Intermediate 15 or 16 (0.1 mmol) in DMF (0.2 ml). The resulting solution is shaken for 10 mins and left to stand for 18 h (e.g. at room temperature), and then the DMF is removed in a Genevac vacuum centrifuge. The residue is dissolved in chloroform (0.3 ml), is applied to an SPE cartridge (1 g, aminopropyl) which has been pre-washed with chloroform (6 ml), and is eluted sequentially with chloroform (3 ml) and 10percent methanol in ethyl acetate (3 ml). Fractions containing the desired product are concentrated in vacuo in a Genevac vacuum centrifuge, and where necessary the residue is purified by mass directed autoprep HPLC (e.g. acetonitrile/water). Where necessary, the compound(s) is/are dissolved in chloroform, and is/are further purified by loading onto a SPE cartridge (0.5 g, aminopropyl) which has been prewashed with chloroform, eluting with 10percent methanol in ethyl acetate.
<strong>[4857-42-5]3-Methyl-5-isoxazolecarboxylic acid</strong> (6.59 g, 0.052 mol, 1.0 equivalent), O-(benzotriazol-1-yl)-N,N,N,N'-tetramethyluronium hexafluorophosphate (HBTU) (20.88 g, 1.08 equivalents) and diisopropylethylamine (18 ml, 2 equivalents) in dimethyl formamide (DMF, 314 ml, 20 volumes) were stirred under nitrogen for 10 minutes. 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (15.7 g, 0.052 mol, 1.0 equivalent) (e.g. which can be as prepared in Intermediate 16) was added to the mixture with extra DMF (20 ml) to wash it into the flask. The reaction mixture was left to stir for three (3) hours, and then left under nitrogen overnight. The reaction mixture was partitioned between saturated sodium hydrogen carbonate solution (3 L) and dichloromethane (800 mL). The aqueous layer was extracted again with dichloromethane (800 mL). The combined organic layers were backwashed with water (2.x.500 mL), dried over MgSO4 (50 g), filtered, reduced in vacuo, and cooled to give a crude brown oil (about 30 g) which appeared to include DMF.This crude brown oil was slurried in 1:0.98:0.2 DCM: EtOAc: MeOH, whereupon the crude product precipitated, was filtered and the filtered solid was washed with diethyl ether (100 ml) to give a damp mass (12 g). The reduced liquors (the reduced slurry liquids remaining after filtration and the diethyl ether washings) were purified by column chromatography (silica, 800 ml), using 1:0.98:0.2 DCM:EtOAc:MeOH (4 L) as eluent, to give a further batch of product (4 g).Both batches of product were combined (appeared impure by 1H NMR), and were purified by column chromatography (silica, 800 ml), using 3 to 4percent MeOH in DCM (3 L) as eluent, to give 13 g of material which still appeared impure (by TLC).This resulting impure solid (13 g) was slurried in 1:0.96:0.4 of DCM:EtOAc:MeOH and the solid remaining was separated by filtration and dried, to give the title compound N-[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-3-methyl-5-isoxazolecarboxamide as an off-white solid (9 g).The reduced liquors (the reduced slurry liquids) were purified by column chromatography (silica, 400 ml) using 1:0.96:0.4 DCM: EtOAc: MeOH (2 L) as eluent, giving, after reduction in vacuo, a further batch of product.The two batches of product were combined to give 10.714 g in total of the title compound N-[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-3-methyl-5-isoxazolecarboxamide as an off-white solid (more than about 95percent purity as measured by NMR in CDCl3 solvent (not the NMR given below)).1H NMR (500 MHz in d6-DMSO, delta (delta) ppm): 9.38 (br t, 1H), 8.04 (s, 1H), 7.00 (s, 1H), 6.64 (d, 1H), 4.52 (d, 2H), 4.33 (q, 2H), 4.12 (br s, 1H), 3.88 (d, 2H), 3.57 (t, 2H), 2.95 (q, 2H), 2.29 (s, 3H), 1.93 (d, 2H), 1.54 (q, 2H), 1.35 (t, 3H), 1.24 (t, 3H). Plus trace other peaks: possibly solvent.
With triethylamine; In tetrahydrofuran; hexane; N,N-dimethyl-formamide;
Example 109 Production of N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-methylisoxazole-5-carboxamide To a solution of <strong>[4857-42-5]3-methylisoxazole-5-carboxylic acid</strong> (87 mg, 0.679 mmol) in tetrahydrofuran (2.0 mL) were added N,N-dimethylformamide (1 drop) and oxalyl chloride (75.8 muL, 0.88 mmol), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL), and added to a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (140 mg, 0.453 mmol) in tetrahydrofuran (12 mL). Then, triethylamine (138 mg, 1.36 mmol) was added to the mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and extracted three times with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80-->80/20) and precipitated from ethyl acetate/hexane to give the title compound (42 mg, 22percent) as a white powder. 1H-NMR (DMSO-d6, 300 MHz) delta 0.73-0.87 (4H, m), 1.86-1.98 (1H, m), 2.32 (3H, s), 7.01-7.14 (3H, m), 7.45 (1H, t, J=8.2 Hz), 7.62-7.74 (2H, m), 7.98 (1H, s), 8.06 (1H, d, J=9.8 Hz), 10.82 (1H, s), 11.10 (1H, s).
To a solution of 1 (2g) in THF(40mL) was added n-Butyllithium(12.8mL, 2.71M hexane solution) at -78 °C under N2 atmosphere, then the reaction solution was allowed warm up to -30 °C. After cooling again to -78 °C, benzaldehyde(1.76mL) in THF(10mL) was added to the reaction solution. After termination of this reaction, dilute hydrochloric acid was added to the solution. The solution was partitioned between water and Et2O, extracted with Et2O and washed with brine. The extraction was back extracted with sat.NaHCO3 soln. and the back extraction was washed with Et2O. It was neutralized with conc.HCl, extracted with Et2O, washed with brine, dried with MgSO4 and concentrated in vacuo to give 9 (2.81g).
To a solution of 1 (3g) in THF(60mL) was added n-Butyllithium(32.9mL, 1.58M hexane solution) at -78 °C under N2 atmosphere, then the reaction solution was allowed warm up to -30 °C. After cooling again to -78 °C, dimethylformamide(3.66mL) in THF(10mL) was added to the reaction solution and allowed warm up to 0 °C. After termination of this reaction, dilute hydrochloric acid was added to the solution. The solution was partitioned between water and Et2O, extracted with Et2O and washed with brine. The extraction was back extracted with sat.NaHCO3 soln. and the back extraction was washed with Et2O. It was neutralized with conc.HCl, extracted with Et2O, washed with brine, dried with MgSO4 and concentrated in vacuo to give 11 (2.32g).
To a solution of 1(5g) in THF(100mL) was added n-Butyllithium(3.19mL, 2.71M hexane solution) at -78 °C under N2 atmosphere, then the reaction solution was allowed warm up to -30 °C. After cooling again to -78 °C, diphenylsulfide(10.31g) in THF(40mL) was added to the reaction solution. After termination of this reaction, dilute hydrochloric acid was added to the solution. The solution was partitioned between water and Et2O, extracted with Et2O and washed with brine. The extraction was back extracted with sat.NaHCO3 soln. and the back extraction was washed with Et2O. It was neutralized with conc.HCl and the resulting precipitates were collected by filtration and washed with water to give 2 (6.41g).
To a solution of 1 (lg) in THF(30mL) was added n-Butyllithium(6.39mL, 2.71M hexane solution) at -78 °C under N2 atmosphere, then the reaction solution was allowed warm up to -30 °C. After cooling again to -78 °C, iodine(2.4g) in THF(20mL) was added to the reaction solution. After termination of this reaction, dilute hydrochloric acid was added to the solution. The solution was partitioned between water and EtOAc, extracted with EtOAc and washed with sodium thiosulfate soln., water and brine. The extraction was dried with MgSO4 and concentrated in vacuo. To a solution of the residue in DMF(25mL) were added 1-adamantanamine(1.43g), 1-hydroxybenzotriazole(1.28g) and 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride(1.81g), the resulting solution was stirred at room temp. After termination of this reaction, the mixture was partitioned between 2N HCl soln. and EtOAc, and extracted with EtOAc. The extraction was washed with 2N HCl soln., sat.NaHCO3 soln., brine successively then dried with MgSO4 and concentrated in vacuo. The residue was purified by silicagel columnchromatography to give 14 (2.47g).
3-Methyl-isoxazole-5-carboxylic acid (0.900 g, 7.08 mmol) was dissolved in N,N-Dimethylformamide (10.0 mL). N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (2.80 g, 7.36 mmol) and triethylamine (2.50 mL, 17.9 mmol) was added.The mixture was stirred at room temperature for 20 minutes.The resulting mixture was added dropwise to a mixture of [5-((R)-1-Amino-ethyl)-1H-indol-2-yl]-methanol (1.66 g, 7.44 mmol) and triethyl amine (2.0 mL) in N,N-dimethylformamide (10 mL) and then left stirring at room temperature overnight.The mixture was poured into brine and extracted with EtOAc.The combined organic layers were washed with brine and dried over MgSO4.Flash chromatography (silica, EtOAc) gave the crude amide as a red oil (1.8 g).This residue was dissolved in a mixture of dimethylsulfoxide (50 mL) and THF (50).
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;
To a solution of <strong>[4857-42-5]3-methylisoxazole-5-carboxylic acid</strong> (3 g, 23.6 mmol) in tetrahydrofuran (20 mL) was added L1AIH4 (1.8 g, 47.37 mmol) in portions at 0 °C under nitrogen atmosphere. After additional 2 hours at room temperature, the reaction was then quenched by water (2 mL). The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 10 percent - 30 percent ethyl acetate in petroleum ether to afford (3-methylisoxazol-5-yl)methanol as colorless oil (1.5 g, 56 percent); (ES, m/z) [M+H] + 114.1 ; *H NMR (300 MHz, CDC13) delta 6.09 (s, 1H), 4.74 (s, 2H), 2.30 (s, 3H), 2.10 (brs, 1H).
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