ACP196

Base Information

• Chemical Name: ACP196
• CAS No.: 1420477-60-6
• Molecular Formula: C26H23N7O2
• Molecular Weight: 465.514
• Mol file: 1420477-60-6.mol

Synonyms:ACP196;acalabrutinib;Benzamide, 4-[8-amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl]-N-2-pyridinyl-;(S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide;Acalabrutinib (ACP-196);ACP196,Acalabrutinib;4-[8-Amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl]-N-2-pyridinylbenzamide

Chemical Property of ACP196

Chemical Property:

• PKA: 11.47±0.70(Predicted)
• PSA: 118.51000
• Density: 1.37±0.1 g/cm3(Predicted)
• LogP: 3.90470
• Storage Temp.: Refrigerator
• Solubility.: Soluble in DMSO (up to at least 25 mg/ml)

Purity/Quality:

99% ,99.9%, ^*data from raw suppliers

Acalabrutinib ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Description: Acalabrutinib, also known as ACP-196, is a highly selective, potent, covalent inhibitor of Bruton tyrosine kinase (BTK). Its chemical structure includes a 2-pyridylbenzamide moiety and an electrophilic 2-butynamide moiety involved in covalent binding to the cysteine (C)481 of BTK.
• Uses and Mechanism of Action: Acalabrutinib belongs to the class of BTK inhibitors and is specifically designed for the treatment of B-cell malignancies. Acalabrutinib is indicated for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). It inhibits BTK, a validated target for B-cell malignancies, by selectively binding to its cysteine residue and interfering with downstream signaling pathways involved in cancer cell proliferation and survival.^[1][2][3]
• Pharmacokinetics: Acalabrutinib exhibits rapid absorption and fast elimination in healthy volunteers, with a median half-life ranging from 0.88 to 2.1 hours. It achieves a high BTK occupancy in plasma, particularly with twice-daily dosing. The recommended dosing regimen is 200 mg once daily or 100 mg twice daily orally.^[2]
• History and Development: Discovery: ; Acalabrutinib was developed as a second-generation BTK inhibitor with higher selectivity and improved tolerability compared to first-in-class BTK inhibitors like ibrutinib.; ; Regulatory Approval: ; It received FDA accelerated approval in 2017 for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and was subsequently approved for chronic lymphocytic leukemia (CLL) in 2019.^[2]
• References: [1] Acalabrutinib in treatment-naive chronic lymphocytic leukemia; DOI 10.1182/blood.2020009617; [2] Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for the Treatment of B-Cell Malignancies; DOI 10.3389/fonc.2021.668162; [3] Assessing the Burden of Adverse Events in a Head-to-Head Trial of Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia (CLL); DOI 10.1182/blood-2022-157060

Technology Process of ACP196

There total 68 articles about ACP196 which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 92.0%

(S)-2-{8-tert-butoxycarbonylamino-1-[4-(2-pyridylcarbamoyl)phenyl]imidazo[1,5-a]pyrazin-3-yl}-1-(2-butynoyl)pyrrolidine → 4-{8-amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (1420477-60-6,1952316-43-6)

Guidance literature:

With trifluoroacetic acid; In methanol; at 65 ℃; for 6h; Temperature; Concentration; Solvent;

Reference yield: 91.3%

(2S)-2-[(1-but-2-ynoyl)pyrrolidin-2-yl]-4-[4-[(N-pyridin-2-yl)carbamoyl]phenyl]-5-cyanoimidazole + Bromoacetaldehyde diethyl acetal (2032-35-1) → 4-{8-amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (1420477-60-6,1952316-43-6)

Guidance literature:

(2S)-2-[(1-but-2-ynoyl)pyrrolidin-2-yl]-4-[4-[(N-pyridin-2-yl)carbamoyl]phenyl]-5-cyanoimidazole; Bromoacetaldehyde diethyl acetal; With potassium carbonate; In N,N-dimethyl-formamide; at 40 - 45 ℃; for 7h;

With ammonium hydroxide; ammonium chloride; In N,N-dimethyl-formamide; at 50 - 55 ℃; for 6h;

Reference yield: 90.0%

2-Butynoic acid (590-93-2) + 4-{8-amino-3-[(2S)-pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (1420478-90-5) → 4-{8-amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (1420477-60-6,1952316-43-6)

Guidance literature:

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;

upstream raw materials:

benzyl (S)-2-(((3-chloropyrazin-2-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate

(S)-2-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylic acid benzyl ester

benzyl (2S)-2-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate

benzyl (2S)-2-(8-amino-1-bromo-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate

Refernces

• 1、 -. "PROCESSES FOR THE PREPARATION OF 4-{8-AMINO-3-[(2S)-1-(BUT-2-YNOYL)-PYRROLIDIN-2-YL]IMIDAZO[1,5-A]-PYRAZIN-1-YL}N-(PYRIDIN-2-YL)-BENZAMIDE". . . Retrieved 2020/03/23.
• 2、 -. "Preparation method capable of acalabrutinib being used for treating leukemia". . . Retrieved 2020/07/24.