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Chemical Structure| 1420478-90-5 Chemical Structure| 1420478-90-5
Chemical Structure| 1420478-90-5

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Synonyms: (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide

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Product Details of Acalabrutinib Impurity 25

CAS No. :1420478-90-5
Formula : C22H21N7O
M.W : 399.45
SMILES Code : O=C(NC1=NC=CC=C1)C2=CC=C(C3=C4C(N)=NC=CN4C([C@H]5NCCC5)=N3)C=C2
Synonyms :
(S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide
MDL No. :MFCD32205328

Safety of Acalabrutinib Impurity 25

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H373
Precautionary Statements:P260-P314-P501

Application In Synthesis of Acalabrutinib Impurity 25

* 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.

  • Downstream synthetic route of [ 1420478-90-5 ]

[ 1420478-90-5 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 590-93-2 ]
  • [ 1420478-90-5 ]
  • [ 1420477-60-6 ]
YieldReaction ConditionsOperation 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.

  • 2
  • [ 1420478-90-5 ]
  • [ 74549-10-3 ]
  • [ 1420477-60-6 ]
YieldReaction ConditionsOperation 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).
  • 3
  • [ 1420478-90-5 ]
  • 4-nitrophenyl butan-2-ynoate [ No CAS ]
  • [ 1420477-60-6 ]
YieldReaction ConditionsOperation 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))
  • 4
  • [ 1420478-90-5 ]
  • 1-[(but-2-ynoyl)oxy]-1H-benzotriazole [ No CAS ]
  • [ 1420477-60-6 ]
YieldReaction ConditionsOperation 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).
 

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