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CAS No. : | 590-93-2 | MDL No. : | MFCD00004363 |
Formula : | C4H4O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LUEHNHVFDCZTGL-UHFFFAOYSA-N |
M.W : | 84.07 | Pubchem ID : | 68535 |
Synonyms : |
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 21.28 |
TPSA : | 37.3 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.26 cm/s |
Log Po/w (iLOGP) : | 0.98 |
Log Po/w (XLOGP3) : | 0.78 |
Log Po/w (WLOGP) : | 0.17 |
Log Po/w (MLOGP) : | 0.38 |
Log Po/w (SILICOS-IT) : | -0.19 |
Consensus Log Po/w : | 0.42 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -0.85 |
Solubility : | 11.8 mg/ml ; 0.14 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.14 |
Solubility : | 6.04 mg/ml ; 0.0718 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.39 |
Solubility : | 204.0 mg/ml ; 2.43 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.78 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P501-P260-P234-P264-P280-P390-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P406-P405 | UN#: | 3261 |
Hazard Statements: | H314-H290 | Packing Group: | Ⅲ |
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 |
---|---|---|
4.7% | Stage #1: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) at 25℃; for 0.333333 h; Stage #2: at 25℃; for 34 h; |
To a solution of 2-butynoic acid (196 mg, 2.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (385 mg, 2.0 mmol) in DMF (5 mL) stirring at 25° C. for 20 minutes was added 6-amino-4-[(3-bromophenyl)amino]quinazoline (316 mg, 1.0 mmol). The resulting solution was stirred under N2 at 25° C. for 14 hours further 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (206 mg, 1.0 mmol) and 2-butynic acid (82 mg, 1.0 mmol) were. After another 8 hours further, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (197 mg, 1.0 mmol) and the acid (93 mg, 1.0 mmol) were added to the reaction. After stirring at 25° C. a further 12 hours, the reaction was quenched with water. The yellow precipitate was collected, sonicated with acetone, treated with triethyl amine and purified by preparative tlc on silica, eluding with 1:1 EtOAc/acetone. The desired product was isolated as a yellow solid (20 mg, 4.7percent), mp 281-283° C. 1H NMR [(CD3)2SO]: δ 10.97 (brs, 1H, NH), 9.93 (s, 1H, NH), 8.76 (s, 1H, H5), 8.57 (s, 1H, H2), 8.14 (s, 1H, H2'), 7.84-7.76 (m, 3H, H7, H8, H4'), 7.34 (t, J=8.1 Hz, 1H, H5'), 7.29 (d, J=7.8 Hz, 1H, H6'), 2.09 (s, 3H, CH3). Mass Spectrum (APCI): 383 (100, 81BrMH+), 382 (23, 81BrM+), 381 (95, 79BrMH+). Calculated for C18H13N4BrO.0.3HCl.0.6C3H6O: C, 55.69; H, 3.99; N, 13.12percent. Found: C, 55.67; H, 3.96; N, 12.93percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 25 - 30℃; | 10 (50.88 g, 100 mmol) and N,N-dimethylformamide (254 mL) were added to a three-neck flask.Stir well and cool to 0~5 °C.Add butynoic acid (9.25 g, 110 mmol),Add EDCI (23.00g, 120mmol),N-methylmorpholine (40.46 g, 400 mmol) was added dropwise.After the addition, the reaction is carried out at 25 to 30 ° C for 6 to 8 hours.At the end of the reaction, water (254 mL) was added.Extracted 3 times with dichloromethane (127 mL),The combined organic phase 10percent sodium bicarbonate solution (127 mL) was washed once.Wash twice with saturated saline (127 mL),Dry over anhydrous sodium sulfate,After concentration, beat with isopropyl alcohol petroleum ether mixed solvent,filter,The product was dried (36.31 g, 78percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With triethylamine; HATU In dichloromethane at 20℃; for 0.5 h; | (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N- (pyridin-2-yl)benzamide was made from (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1 ,5- a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide and 2-butynoic acid as follows. To a solution of (S)- 4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (19.7 mg, 0.049 mmol), triethylamine (20 mg, 0.197 mmol, 0.027 mL) 2-butynoic acid (4.12 mg, 0.049 mmol) in dichloromethane (2 mL) was added HATU (18.75 mg, 0.049 mmol). The mixture was stirred for 30 min at room temperature. The mixture was washed with water dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing product were collected and reduced to dryness to afford the title compound (10.5 mg, 18.0percent). |
18% | With triethylamine; HATU In dichloromethane at 20℃; for 0.5 h; | (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N- (pyridin-2-yl)benzamide was made from (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1 ,5- a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide and 2-butynoic acid as follows. To a solution of (S)- 4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (19.7 mg, 0.049 mmol), triethylamine (20 mg, 0.197 mmol, 0.027 mL) 2-butynoic acid (4.12 mg, 0.049 mmol) in dichloromethane (2 mL) was added HATU (18.75 mg, 0.049 mmol). The mixture was stirred for 30 min at room temperature. The mixture was washed with water dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing product were collected and reduced to dryness to afford the title compound (10.5 mg, 18.0percent). |
18% | With triethylamine; HATU In dichloromethane at 20℃; for 0.5 h; | (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N- (pyridin-2-yl)benzamide was made from (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1 ,5- a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide and 2-butynoic acid as follows. To a solution of (S)- 4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (19.7 mg, 0.049 mmol), triethylamine (20 mg, 0.197 mmol, 0.027 mL) 2-butynoic acid (4.12 mg, 0.049 mmol) in dichloromethane (2 mL) was added HATU (18.75 mg, 0.049 mmol). The mixture was stirred for 30 min at room temperature. The mixture was washed with water dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing product were collected and reduced to dryness to afford the title compound (10.5 mg, 18.0percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h; | After 2-butylnoic acid (34 mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (78 mg), 1-hydroxybenzotriazole (HOBt) (62 mg), and triethylamine (114 μL) were added to a solution of the compound prepared in Example 7 (100 mg) in dimethyl formamide (3 mL), the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and extraction with ethyl acetate was performed. The organic layer was washed with saturated sodium carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by thin layer chromatography (dichloromethane: methanol: 28percent ammonia water = 90: 10: 1) to obtain the title compound (75 mg) with the physical property values shown below. TLC: Rf 0.68 (ethyl acetate: methanol = 9: 1); 1H-NMR(CDCl3):δ 1.94-2.03, 2.23-2.39, 2.80-3.01, 3.50-3.63, 3.67-3.80, 3.86-4.02, 4.03-4.18, 4.23-4.33, 4.42-4.51, 5.11-5.25, 7.04-7.23, 7.34-7.45, 8.20-8.23 |
75 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h; | Step 8: After 2-butylnoic acid (34 mg), 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (78 mg), 1-hydroxybenzotriazole (HOBt) (62 mg), and triethylamine (114 mL) are added to a solution of the compound prepared in Step 7 (100 mg)dimethyl formamide (3 mL), the mixture is stirred at room temperature for 3 hours. Water is added to the reaction mixture and extraction with ethyl acetate is performed. The organic layer is washed with saturated sodium carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is purified by thin layer chromatography (dichloromethane:methanol:28percent ammonia water=90: 10:1) to obtain 6-amino-9-[(3R)- 1 -(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)- 7,9-dihydro-8H-purin-8-one (Formula (XVI)) (75 mg). |
75 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h; | After 2-butylnoic acid (34 mg), 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (78 mg), 1-hydroxybenzotriazole (HOBt) (62 mg), and triethylamine (114 mL) are added to a solution of the compound prepared in Step 7 (100 mg) in dimethyl formamide (3 mL), the mixture is stirred at room temperature for 3 hours. Water is added to the reaction mixture and extraction with ethyl acetate is performed. The organic layer is washed with saturated sodium carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is purified by thin layer chromatography (dichloromethane:methanol:28percent ammonia water=90: 10:1) to obtain 6-amino-9-[(3R)- 1 -(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)- 7,9-dihydro-8H-purin-8-one (Formula (XVI)) (75 mg). |
75 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h; | Step 8: After 2-butylnoic acid (34 mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (78 mg), 1-hydroxybenzotriazole (HOBt) (62 mg), and triethylamine (114 mL) are added to a solution of the compound prepared in Step 7 (100 mg) in dimethyl formamide (3 mL), the mixture is stirred at room temperature for 3 hours. Water is added to the reaction mixture and extraction with ethyl acetate is performed. The organic layer is washed with saturated sodium carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is purified by thin layer chromatography (dichloromethane:methanol:28percent ammonia water=90:10:1) to obtain 6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)- 7,9-dihydro-8H-purin-8-one (Formula (XXI)) (75 mg). |
75 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h; | Step 8: After 2-butylnoic acid (34 mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (78 mg), 1-hydroxybenzotriazole (HOBt) (62 mg), and triethylamine (114 mL) are added to a solution of the compound prepared in Step 7 (100 mg) in dimethyl formamide (3 mL), the mixture is stirred at room temperature for 3 hours. Water is added to the reaction mixture and extraction with ethyl acetate is performed. The organic layer is washed with saturated sodium carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is purified by thin layer chromatography (dichloromethane:methanol:28percent ammonia water=90:10:1) to obtain 6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)- 7,9-dihydro-8H-purin-8-one (Formula (XXVIII-R)) (75 mg). |
75 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h; | Step 8: After 2-butylnoic acid (34 mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (78 mg), 1-hydroxybenzotriazole (HOBt) (62 mg), and triethylamine (114 mL) are added to a solution of the compound prepared in Step 7 (100 mg) in dimethyl formamide (3 mL), the mixture is stirred at room temperature for 3 hours. Water is added to the reaction mixture and extraction with ethyl acetate is performed. The organic layer is washed with saturated sodium carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is purified by thin layer chromatography (dichloromethane:methanol:28percent ammonia water=90:10:1) to obtain 6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)- 7,9-dihydro-8H-purin-8-one (Formula (XXVIII-R)) (75 mg). |
75 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h; | Step 8: After 2-butylnoic acid (34 mg), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (78 mg), 1 -hydroxybenzotriazole (HOBt) (62 mg), and triethylamine (114 mL) are added to a solution of the compound prepared in Step 7 (100 mg) in dimethyl formamide (3 mL), the mixture is stirred at room temperature for 3 hours. Water is added to the reaction mixture and extraction with ethyl acetate is performed. The organic layer is washed with saturated sodium carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is purified by thin layer chromatography (dichloromethane:methanol:28percent ammonia water=90: 10: l) to obtain 6-amino-9-[(3i?)-l-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)- 7,9-dihydro-8H-punn-8-one (Formula (XXI)) (75 mg). |
167.7 kg | With 4-methyl-morpholine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In methanol; water; ethyl acetate; acetonitrile at 10 - 65℃; for 5 h; Large scale | A mixture of the compound produced in Example 7(1) (185.0 kg), 2-butynoic acid (CAS registration number: 590-93-2) (40.5 kg) and acetonitrile (463 L) was cooled to 10° C., a mixture of N-methylmorpholine (243.4 kg) and a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide (PPACA) in 50percent ethyl acetate solution (306.2 kg) was added, heated to 40° C. and stirred for 3 hours. To the reaction mixture was added water (740 L) and extracted twice with ethyl acetate (370 L). The combined organic layer was washed sequentially with water (740 L) and a 15percent sodium chloride solution (740 L), 85percent phosphoric acid (4.62 kg) was added and the solvent was distilled off. To the residue were added acetone (222 L) and water (26 L) and heated to 50° C. After addition of water (463 L) and methanol (555 L) and then addition of seed crystals, the reaction was matured at 50° C. for 60 minutes. Water (648 L) was then added and the reaction was matured at 50° C. for 1 hour and 5° C. for 1 hour. The obtained crystals were filtered, washed with methanol and dried under reduced pressure at 65° C. to obtain the titled compound (167.7 kg) having the following physical properties as white crystals. TLC: Rf 0.68 (ethyl acetate:methanol=9:1); 1H-NMR (CDCl3): δ 1.94-2.03, 2.23-2.39, 2.80-3.01, 3.50-3.63, 3.67-3.80, 3.86-4.02, 4.03-4.18, 4.23-4.33, 4.42-4.51, 5.11-5.25, 7.04-7.23, 7.34-7.45, 8.20-8.23. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h; | After 2-butylnoic acid (34 mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (78 mg), 1-hydroxybenzotriazole (HOBt) (62 mg), and triethylamine (114 mL) are added to a solution of the compound prepared in Step 7 (100 mg) in dimethyl formamide (3 mL), the mixture is stirred at room temperature for 3 hours. Water is added to the reaction mixture and extraction with ethyl acetate is performed. The organic layer is washed with saturated sodium carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is purified by thin layer chromatography (dichloromethane:methanol:28percent ammonia water=90:10:1) to obtain 6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one (Formula (21)) (75 mg). |
[ 762-21-0 ]
Diethyl acetylenedicarboxylate
Similarity: 0.71
[ 762-21-0 ]
Diethyl acetylenedicarboxylate
Similarity: 0.71