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CAS No. : | 1420477-60-6 | MDL No. : | MFCD29472294 |
Formula : | C26H23N7O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WDENQIQQYWYTPO-IBGZPJMESA-N |
M.W : | 465.51 | Pubchem ID : | 71226662 |
Synonyms : |
ACP-196
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P260-P314-P501 | UN#: | N/A |
Hazard Statements: | H373 | 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 |
---|---|---|
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 |
---|---|---|
18% | With triethylamine; HATU; In dichloromethane; at 20℃; for 0.5h; | General procedure: Example 2 (S,E)-4-(8-amino-3-(1-(4-(pyrrolidin-1-yl)but-2-enoyl)p 2-yl)benzamide To a solution of (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1 ,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (intermediate 2b, 19.7 mg, 0.049 mmol), triethylamine (20 mg, 0.197 mmol, 0.027 mL) and (E)-4- (pyrrolidin-1-yl)but-2-enoic acid hydrochloride (9.45 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 7.1 mg of (S,E)-4-(8-amino-3-(1-(4-(pyrrolidin-1-yl)but-2-enoyl)pyrrolidin-2-yl)imidazo[1 ,5^ 1-yl)-N-(pyridin-2-yl)benzamide (26.8 % yield). Data: UPLC (C) Rt : 1.25 min; m/z 537.4 (M+H)+. |
In dichloromethane; at 0 - 5℃; for 1h; | General procedure: 2 g of intermediate 10 was suspended in 40 ml of dichloromethane, and the temperature was lowered to 0-5 C.1 g of benzotriazole 2-propargyl ester intermediate was dissolved in 20 ml of dichloromethane and added dropwise to the suspension of intermediate 10.The reaction was performed at 0-5 C for 1 hour, and the reaction was detected by TLC.The solution was warmed to room temperature, quenched by adding water, separated, and washed with saturated brine.The organic layer was concentrated under reduced pressure to give a yellow solid. Purification by flash column chromatography on silica gel with ethyl acetate-methanol as eluent gave Example 1, 1.8 g of a yellow solid.Deuteration rate is 98.6%, LC-Ms ESI +: 467.1 [M + H] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20 - 30℃; for 3h; | A mixture of compound XI (4.14 g, 10 mmol) , compound IV (2.66 g, 11 mmol), dioxane (34 mL) and K2CO3 aqueous solution (4.14 g K2CO3 in 15 mL water) was added Pd(dppf)Cl2 (73 mg, 0.1 mmol) under nitrogen. The mixture was stirred for 3 h at 90~100 C. The organic phase was separated and concentrated. The residue was purified by silica gel column chromatography using heptane/EtOAc to afford compound XII (4.9 g, 92% yield). (0115) To a round-bottom flask was added compound XII (2.4 g), acetic acid (12 mL) and HBr (33% in acetic acid, 12 mL). The mixture was stirred for 2 h at 20~30 C. Water (300 mL) and DCM (100 mL) was added. The aqueous phase was separated and washed with DCM (100 mL). The aqueous phase was adjusted to pH > 10 with 30% NaOH aqueous solution and extracted with DCM (150 mL). The DCM phase was concentrated to give compound XII I (1.64 g, 91% yield). To a round-bottom flask was added compound XIII (0.50 g, 1.25 mmol), 2-butynoic acid (0.11 g, 1.31 mmol), HATU (0.48 g, 1.25 mmol), DCM (10 mL) and triethylamine (0.50 g, 5 mmol). The mixture was stirred for 3 h at 20~30 C. The reaction mixture was washed with water (5 mL) and concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH to afford compound XV (0.5 g, 90% yield). (0116) XH NMR (400 MHz, DMSO) delta 10.82 (s, 1H), 8.42 - 8.39 (m, 1H), 8.26 - 8.15 (m, 3H), 7.90 - 7.73 (m, 4H), 7.21 - 7.11 (m, 2H), 6.25 - 6.05 (m, 2H), 5.75 - 5.40 (m, 1H), 3.90 - 3.55 (m, 2H), 2.47 - 2.20 (m, 2H), 2.20 - 2.10 (m, 1H), 2.07 - 1.90 (m, 3H), 1.63 (s, 1H). |
74% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane;Large scale; | 4-{ 8-Amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-l-yl}-/V-(2-pyridinyl)- benzamide (Compound (VII), 131.7 kg, 1.0 mol. eq.) was slurried in dichloromethane (955 L, 7.25 rel. vol.) and triethylamine (90.1 kg, 2.7 mol. eq.). 2-butynoic acid (33.3 kg, 1.2 mol. eq.) in dichloromethane (263.4 L, 2.0 rel. vol.) was added, followed by l-propylphosphonic acid anhydride (T3P) (50%w/w solution in dichloromethane, 209.8 kg, 1.0 mol. eq.). The resulting organic solution of the product was washed twice with water (658.5 L, 5.0 rel. vol.) and then water (1317 L, 10.0 rel. vol.) was added. The mixture was then acidified using 6M aqueous hydrochloric acid to approximately pH 2.2 and then 2M aqueous hydrochloric acid added to reach a pH of 1.8 to 2.2 before separating the organic phase, which was discarded. Dichloromethane (1317 L, 10.0 rel. vol.) was added to the aqueous phase and the mixture is adjusted to a pH of 4.5 to 5.0 with triethylamine. The organic phase was separated off and the aqueous phase was re-extracted with dichloromethane (527 L, 4.0 rel. vol.). The combined dichloromethane extracts were screened and the organic phase was concentrated to approximately 5.0 rel. vol. Ethanol (1712 L, 13.0 rel. vol.) was added and the mixture distilled (at about 360 mbar) maintaining a constant volume (of 18.0 rel. vol.) by the addition of ethanol (1580 L, 12.0 rel. vol.). A portion of crystalline 4-{8-amino- 3-[(2S)-l-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[l,5-a]pyrazin-l-yl}-/V-(pyridin-2-yl)benzamide (Compound (VIII), 1.32 kg, 0.01 rel. wt.) was added as seed, and the solution held at 50C for 10 hours to crystallize the product. The mixture was then cooled over 7 hours and filtered. The product was washed twice with ethanol (527 L, 4.0 rel. vol.) and then dried at 50C under vacuum to yield a white crystalline solid acalabrutinib (Compound VIII, 113.6 kg, 74%). (0440) [00228] This compound exists as a mixture of conformers in solution and resonances are quoted for the major conformer only. 1H NMR (500 MHz, DMSO-d6) d 1.95-2.02 (m, 4H), 2.09- 2.15 (m, 1H), 2.23-2.38 (m, 2H), 3.81 (t, J = 6.7 Hz, 2H), 5.47 (dd, J = 7.6, 4.3 Hz, 1H), 6.13 (br s, 2H), 7.11 (d, J = 5.1 Hz, 1H), 7.17 (ddd, J = 7.4, 4.8, 0.8 Hz, 1H), 7.70-7.73 (m, 2H), 7.78 (d, J = 5.1 Hz, 1H), 7.82-7.87 (m, 1H), 8.13-8.16 (m, 2H), 8.20-8.23 (m, 1H), 8.39 (ddd, J = 4.8, 1.9, 0.8 Hz, 1H), 10.83 (s, 1H). 13C NMR (126 MHz, DMSO-d6) d 3.3, 23.9, 31.2, 48.2, 51.3, 74.3, 88.3, 107.0, 113.8, 114.7, 119.8, 127.9, 128.3, 129.0, 132.7, 133.2, 137.9, 138.1, 141.0, 148.0, 151.4, 151.8, 152.2, 165.7. |
72% | With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide; In dichloromethane; at -15 - 5℃; for 3h; | A clear, yellow solution of 2-butynoic acid (7) (42 mg, 0.50 mmol), /V-hydroxysuccinimide (58 mg, 0.50 mmol) and the compound of Formula (5- A) (200 mg, 0.50 mmol) in dichloromethane (6 mL) was cooled to -15 to -10 C. A solution of DCC (103 mg, 0.50 mmol) in dichloromethane (1 mL) was added dropwise to the reaction solution over a period of 15 minutes followed by warming the solution to 0-5 C. A slight suspension was formed after a period of 1 hour. The reaction was deemed complete after 2 hours by1H- NMR (consumption of the compound of Formula (5-A)). The reaction suspension was warmed to room temperature and filtered to remove the DCU by-product. The cake was washed with dichloromethane (2 x 2 mL) and the filtrate was washed with water (1 x 3 mL). The organic layer was then separated, dried over anhydrous sodium sulfate, and concentrated in vacuo at 30-35 C to afford a crude product as a yellow solid (0.31 g). The solid was then purified by column chromatography using ethyl acetate and methanol to afford Acalabrutinib (1 ) as a yellow solid (0.17 g, 0.36 mmol, 72% yield). |
18% | With triethylamine; HATU; In dichloromethane; at 20℃; for 0.5h; | (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, 18.0%). |
18% | With triethylamine; HATU; In dichloromethane; at 20℃; for 0.5h; | (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, 18.0%). |
18% | With triethylamine; HATU; In dichloromethane; at 20℃; for 0.5h; | (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, 18.0%). |
219 g | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | To a mixture of (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[l,5-alpyrazin-l-yl)-N- (pyridin-2-yl)benzamide (300 g), 2-butynoic acid (82.1 g), dichloromethane (6000 mL), 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (201.5 g) was added and reaction mixture was stirred at ambient temperature for 4 - 5 hours. Water (3000 mL) and isopropanol (1500 mL) was added to reaction mixture and stirred for 10-15 minutes at ambient temperature followed by layer separation. Lower organic layer was concentrated followed by addition of methanol (450 mL) and concentrated. Resulting residue was stirred in water (525 mL) and methanol (2250 mL) at 60-65 C for 30-40 minutes, treated with activated carbon and filtered. Water (625 mL) was added to combined filtrate and stirred at ambient temperature for 15-16 hours. The reaction mixture was cooled at 0-5 C and stirred for 1-2 hours. The resulting product was filtered, washed with methanol: water (1:1, 300 mL) and dried to give 219 g of Acalabrutinib with purity of 99.5% by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With ammonia; In isopropyl alcohol; at 0 - 120℃; for 25h;Autoclave; | Add in the autoclave4-[8-chloro-3-[(2S)-1-(1-oxo-2-butyn-1-yl)-2-pyrrolidinyl]imidazoleAnd [1,5-a]pyrazin-1-yl]-N-2-pyridylbenzamide(0.48g, 1mmol),Isopropanol (20mL),Cool down to 0 degrees Celsius,Access to ammonia(0.51g, 30mmol),Close the reaction kettle,Raise to room temperature for 1 h,The temperature was raised to 120 C for 24 h.Stop the reaction and drop to room temperature.80 mL of ethyl acetate was added, and washed with 80 mL of saturated brine and water, respectively.The aqueous phase was back extracted with 50 mL of ethyl acetate and the organic phases were combined.Dry over anhydrous sodium sulfate for 1 h,Evaporate under reduced pressure,Obtaining Acalabrutinib 0.409g with ethyl acetate/petroleum ether (2:1) column.The yield is 88%.The purity is 99%. |
86% | With ammonia; In isopropyl alcohol; at 0 - 120℃; | Add in pressure reactor4- [8-chloro-3- [(2S) -1- (1 -oxo- 2-butyn- 1 -yl) -2-pyrrolidinyl]Imidazo [1, 5-a] pyrazin-1 -yl] -N-2-pyridylbenzamide (VII)(0.48 g, 1 mmol) and isopropanol (15 mL), cooled to 0 C,Ammonia gas (0.51 g, 30 mmol) was dosed by dosing,The reactor was closed, warmed to room temperature, reacted for 1 hour,Then continue to increase the reaction temperature to 110 to 120 degrees,Maintain the temperature and pressure for 20 to 24 hours,TLC detection reaction is complete. Drop to room temperature, slowly vent,After concentration under reduced pressure, the resulting residue was dissolved with ethyl acetate,Saturated brine and water, dried over anhydrous sodium sulfate.After concentration, the resulting residue was purified by column chromatography with ethyl acetate and petroleum ether (2: 1 by volume)Obtained as white solid acatinib (I) 0.40g, the yield of 86.0% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With trifluoroacetic acid; In methanol; at 65℃; for 6h; | (S) -2- {8-tert-butoxycarbonylamino-1- [4- (2-pyridylcarbamoyl) phenyl] imidazo [1,5-a]Yl} -1- (2-butynoyl) pyrrolidine (7 g, 12.4 mmol) and in methanol (70 mL) were added trifluoroacetic acid(1.55 g, 13.6 mmol). The reaction was stirred for 6 h at 65 C until the reaction was complete. The reaction mixture was added dropwise to stirred water (150 mL) and cooled to 0 crystallization 3h, filtered to obtain the treatment of chronic lymphocytic leukemia BTK inhibitor Acalabrutinib, a white solid(5.3g), yield 92% |
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 10% 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, 78%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In dichloromethane; at 0 - 5℃; for 0.9h; | A thick suspension of the compound of Formula (5-A) (2.00 g, 4.99 mmol) in dichloromethane (40 mL) was cooled to 0-5 C. A solution of the compound of Formula (4-A) (0.90 g, 4.99 mmol) in dichloromethane (20 mL) was added to the suspension over 30 minutes. A clear, yellow solution resulted and stirring was continued at 0-5 C for 25 minutes when the reaction was deemed complete by TLC (aqueous work up of aliquot into dichloromethane, TLC solvent system: 3:7 methanol: ethyl acetate, Formula (5-A) rf = 0.05, Formula (1 ) rf = 0.45) and was allowed to warm to room temperature. The reaction solution was then washed with water (40 mL) and the organic layer was then separated, dried over anhydrous sodium sulfate, and concentrated in vacuo at 30-35 C to afford a yellow solid (2.49 g). The solid was then purified by column chromatography using ethyl acetate and methanol to afford Acalabrutinib (1 ) as a yellow solid (1 .99 g, 4.27 mmol, 86% yield).1H-NMR (DMSO-d6, 300 MHz; rotamers) delta: 1 .62 and 2.01 (3H, s (combined peaks)), 2.08-2.17 (1 H, m), 2.18-2.42 (2H, m), 3.31 (1 H, s), 3.51 - 3.69 (1 H, m), 3.82 (1 H, t, J = 6.5 Hz), 5.45-5.32 and 5.67-5.77 (1 H, each m), 6.14 and 6.20 (2H, each s), 7.14 (1 H, dd, J = 4.9 Hz, 1 1 .8 Hz), 7.18 (1 H, ddd, J = 0.9 Hz, 4.9 Hz, 7.32 Hz), 7.77-7.90 (4H, m), 8.16 (2H, dd, J = 1 .9 Hz, 8.37 Hz), 8.22 (1 H, d, J = 8.4 Hz), 8.41 (1 H, m), 10.85 (1 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In dichloromethane; at 0 - 5℃; for 1.5h; | A thick suspension of the compound of Formula (5-A) (0.20 g, 0.50 mmol) in dichloromethane (4 ml_) was cooled to 0-5 C. A solution of the compound of Formula (4-B) (0.10 g, 0.50 mmol) in dichloromethane (2 ml_) and was added to the reaction suspension over 30 minutes. The resulting thin suspension was stirred at 0-5 C. The reaction was deemed complete after 1 .5 hours by TLC (aqueous work up of aliquot into dichloromethane, TLC solvent system: 3:7 methanol: ethyl acetate, Formula (5-A) rf = 0.05, Formula (1 ) = 0.41 ) and was allowed to warm to room temperature. The reaction solution was then washed with water (4 mL) and the organic layer was then separated, dried over anhydrous sodium sulfate, and concentrated in vacuo at 30-35 C to afford a yellow solid (0.25 g). The solid was purified by column chromatography using ethyl acetate and methanol to afford Acalabrutinib (1 ) as a yellow solid (0.17 g, 0.36 mmol, 73% yield). Example 8: Preparation of Acalabrutinib (1 ) using DCC (Carbodiimide) and HOBt (Additive) a. Preparation of 1 -[(but-2-ynoyl)oxy]-1 H-benzotriazole (compound of Formula (4-C)) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In dichloromethane; at 0 - 5℃; for 0.75h; | A thick suspension of the compound of Formula (5-A) (0.20 g, 0.50 mmol) in dichloromethane (4 mL) was cooled to 0-5 C. A solution of the compound of Formula (4-C) (0.10 g, 0.50 mmol) in dichloromethane (2 mL) was added to the reaction suspension over 30 minutes and the resulting clear, light yellow solution was stirred at 0-5 C. The reaction was deemed complete after 45 minutes by TLC (aqueous work up of aliquot into dichloromethane, TLC solvent system: 3:7 methanol: ethyl acetate Formula (5-A) rf = 0.05, Formula (1 ) rf = 0.41 ) and was allowed to warm to room temperature. The reaction solution was then washed with water (4 mL) and the organic layer was then separated, dried over anhydrous sodium sulfate, and concentrated in vacuo at 30-35 C to afford a yellow solid (0.24 g). The solid was purified by column chromatography using ethyl acetate and methanol to afford Acalabrutinib (1 ) as a yellow solid (0.16 g, 0.34 mmol, 70% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 50℃; for 2h;Alkaline conditions; Inert atmosphere; | A clear solution of the compound of Formula (2-A) (0.20 g, 0.57 mmol), the compound of Formula (3-A) (0.21 g, 0.63 mmol), potassium carbonate (0.49 g, 2.29 mmol), water (3 mL), and 1 ,4-dioxane (6 mL) was degassed with nitrogen for 2 minutes prior to addition of [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (105 mg, 0.14 mmol). The reaction mixture was heated to 50 C. After 2 hours of heating the reaction was deemed complete by TLC (aqueous work up of aliquot into ethyl acetate, TLC solvent system: 1 .5:8.5 methanol: ethyl acetate, Formula (2-A) rf = 0.28, Formula (1 ) rf = 0.20), and was then cooled to room temperature. Water (8 mL) and dichloromethane (8 mL) were charged to the flask. The aqueous phase was then further extracted with dichloromethane (8 mL) and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo at 30-35 C to afford crude Acalabrutinib (1 ) as a dark residue (0.36 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.3% | To a 250 ml four-necked flask equipped with a stirring, thermometer, and reflux condenser was added 80 g of N, N-dimethylformamide.8.5 g (0.02 mol) of (S) -2- (1-but-2-ynylpyrrolidin-2-yl) -4- [4- (pyridin-2-yl) carbamoyl] prepared in Example 8 Phenyl-5-cyanoimidazole (VI),3.0 grams (0.022 moles) of potassium carbonate,4.9 g (0.025 moles) of 2-bromoacetaldehyde diethanol,Stir the reaction at 40 to 45 C for 7 hours, and then cool to 20 to 25 C.Add 2.7 g (0.05 mol) of ammonium chloride, 8.0 g (0.08 mol) of 17 wt% ammonia water, stir the reaction at 50 to 55 C for 6 hours, cool to 20 to 25 C, add the resulting reaction mixture to 200 g of ice water, and filter. The filter cake was washed twice with water, 20 g each time, and 20 g isopropanol once, and dried to obtain 8.5 g of acortinib with a yield of 91.3% and a liquid purity of 99.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.2% | To a 250 ml four-necked flask equipped with a stirring, thermometer, and reflux condenser was added 80 g of N, N-dimethylformamide and 8.5 g (0.02 mol) of (S) -2- (1) prepared in Example 7 -But-2-ynylpyrrolidin-2-yl) -4- [4- (pyridin-2-yl) carbamoyl] phenyl-5-cyanoimidazole (VI),3.0 g (0.022 mol) of potassium carbonate, 4.4 g (0.026 mol) of 2-bromoacetaldehyde dimethyl acetal,Stir the reaction at 60 to 65 C for 5 hours, then cool to 20 to 25 C, add 2.7 g (0.05 mol) of ammonium chloride, 8.0 g (0.08 mol) of 17 wt% ammonia water, stir the reaction at 70 to 75 C for 5 hours, and cool to 20 At 25 C, the obtained reaction mixture was added to 200 g of ice water, filtered, and the filter cake was washed twice with water, 20 g each time, and 20 g isopropanol once, and dried to obtain 8.3 g of acortinib. Yield It was 89.2%, and the liquid purity was 99.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.1% | To a 250 ml four-necked flask equipped with a stirring, thermometer, and reflux condenser, add 80 g of acetonitrile.8.5 g (0.02 mol) prepared in Example 9 (S) -2- (1- but-2-yn-acyl-2-yl) -4- [4- (pyridin-2-yl) carbamoyl] phenyl-5-cyanoimidazole (),2.5 grams (0.025 moles) of triethylamine,3.5 g (0.028 mol) of 2-chloroacetaldehyde dimethyl acetal, stirred at 75 to 80 C for 4 hours, then cooled to 20 to 25 C, added 2.7 g (0.05 mol) of ammonium chloride, 8.0 g (0.08 mol) 17 wt% ammonia water, stirred at 80 to 82 C for 5 hours, cooled to 20 to 25 C, added the obtained reaction mixture to 200 g of ice water, filtered, and the filter cake was washed twice with water, 20 g each time, 20 g isopropyl The alcohol was washed once and dried to obtain 8.2 g of acortinib with a yield of 88.1% and a liquid phase purity of 99.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.3 g | With methanesulfonic acid In toluene at 50℃; for 72h; | 5 Example 5: Preparation of 4-{8-amino-3-[(2S)-l-(but-2-ynoyl)pyrroUdin-2- yl]imidazo[l,5-a]pyrazin-l-yl}-N-(pyridine-2-yl)benzamide (1; Acalabrutinib) as dihydrate 4- [8-[(4-Methoxyphenyl)methylamino] -3- [(2S)- 1 -( 1 -oxo-2-butyn- 1 -yl)-2- pyrrolidinyl] imidazo[l,5-a]pyrazin-l-yl]-N-2-pyridinylbenzamide (2) (150 gm), toluene (2250 ml) and Methanesulfonic acid (2250 ml) were added to the reaction flask and stirred for ~72h at ~50°C. After completion of the reaction, cooled and separated the layer. Further, the methansesulfonic acid layer was quenched into the mixture of DM water, methylene chloride and ammonia solution. The organic layer was separated, treated with activated carbon and concentrated under vacuum to afford the crude Acalabrutinib (1). The crude product was further purified from aqueous isopropyl alcohol to afford crystalline Acalabrutinib (1) as dihydrate. Weight: 84.3 g; HPLC Purity: 99.79%. 1 HNMR (d ppm; 400 MHz; DMSO-d6): 10.85 (1H, s); 8.40-8.41 (1H, m); 8.21- 8.24 (1H, m); 8.15-8.17 (2H, m); 7.84-7.88 (1H, m); 7.79-7.80 (7.84-7.88) (1H, d, 4.8 Hz); 7.72-7.75 (2H, m); 7.15-7.20 (1H, m); 7.11-7.13 (7.15-7.20) (1H, d, 4.8 Hz); 6.14 (6.20) (2H, br); 5.46-5.49 (5.70-5.73) (1H, dd, 7.2, 4.0 Hz); 3.81-3.84 (3.56-3.63) (2H, t, 6.8 Hz), 2.21-2.42 (1H, m); 2.21-2.42 (1H, m); 2.01 (1.62) (3H, s); 1.94-2.14 (1H, m); 1.94-2.14 (1H, m). 13 CNMR (d ppm; 100 MHz; DMSO-d6): 165.72; 152.23; 151.84 (151.88); 151.51 (151.66); 147.98; 141.05 (141.94); 138.16; 137.96 (137.85); 133.27 (133.82); 132.79 (132.83); 129.12; 128.35; 127.88; 119.85; 114.78; 113.87 (113.76); 107.02 (106.40); 88.35 (87.51); 74.32 (74.14); 51.34 (53.71); 48.29 (45.95); 31.19 (32.31); 23.93 (22.86); 3.28 (3.19) Mass: m/z 466.22, [M+H]+ (as anhydrous) IR (l, cm-1; neat): 3446; 3287 (N-H str.); 3117, 3069 (Aromatic C-H str.); 2970 (Aliphatic C-H str.); 2245 (-CC str.); 1671(C=0 str.); 1606 (N-H Bending). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In tetrahydrofuran; water at 50℃; for 1h; Large scale; | 12.A A. Conversion of Acalabrutinib Free Base to Acalabrutinib Maleate Acalabrutinib (18 kg, 1.0 molar equivalents) in tetrahydrofuran (162 L, 9.0 relative volumes) and water (9 L, 0.5 relative volumes) was heated to 50°C, and filtered. Tetrahydrofuran (9 L, 0.5 relative volumes) was used as a line-wash. Maleic acid (5 kg, 1.1 molar equivalents) in tetrahydrofuran (68 L, 3.75 relative volumes) was added at 50°C, followed by a tetrahydrofuran (5 L, 0.25 relative volumes) line-wash. The mixture was seeded with acalabrutinib maleate (18 mg, 0.001 relative weight), held for 1 hour at 50°C and then cooled to 20°C over 1 hour and held for 1 hour, before being circulated through a wet mill to achieve the desired particle size distribution. The product was then filtered and washed with tetrahydrofuran (36 L, 2.0 relative volumes), and then dried by a flow of nitrogen (at >20% relative humidity) at 40°C to yield acalabrutinib maleate (20.4 kg, 88%) as the monohydrate. |
88% | In tetrahydrofuran; water at 50℃; for 1h; Large scale; | 12.A A. Conversion of Acalabrutinib Free Base to Acalabrutinib Maleate Acalabrutinib (18 kg, 1.0 molar equivalents) in tetrahydrofuran (162 L, 9.0 relative volumes) and water (9 L, 0.5 relative volumes) was heated to 50°C, and filtered. Tetrahydrofuran (9 L, 0.5 relative volumes) was used as a line-wash. Maleic acid (5 kg, 1.1 molar equivalents) in tetrahydrofuran (68 L, 3.75 relative volumes) was added at 50°C, followed by a tetrahydrofuran (5 L, 0.25 relative volumes) line-wash. The mixture was seeded with acalabrutinib maleate (18 mg, 0.001 relative weight), held for 1 hour at 50°C and then cooled to 20°C over 1 hour and held for 1 hour, before being circulated through a wet mill to achieve the desired particle size distribution. The product was then filtered and washed with tetrahydrofuran (36 L, 2.0 relative volumes), and then dried by a flow of nitrogen (at >20% relative humidity) at 40°C to yield acalabrutinib maleate (20.4 kg, 88%) as the monohydrate. |
4.8 g | at 25 - 30℃; | 6 Example-6: Preparation of crystalline Form-M of Acalabrutinib maleate. Amorphous Acalabrutinib (5.0 gm) was dissolved in ethyl formate (100.0 ml) at 25-30°C and stirred for 10 minutes. A solution of maleic acid (1.249 gm) and ethyl formate (5.0 ml) was added to the mixture at 25-30°C and stirred for 2 hours. Filtered the solid, washed with ethyl formate and dried to get the title compound. Yield: 4.8 gm.The PXRD pattern of the obtained compound is shown in figure-5. |
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Code | Phrase |
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H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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