Ibrutinib

Base Information

• Chemical Name: Ibrutinib
• CAS No.: 936563-96-1
• Molecular Formula: C₂₅H₂₄N₆O₂
• Molecular Weight: 440.505
• Mol file: 936563-96-1.mol

Synonyms:PCI-32765;1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)pyrazolo[3, 4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one;

Chemical Property of Ibrutinib

Chemical Property:

• Boiling Point: 715.0±60.0 °C at 760 mmHg
• PKA: 4.09±0.30(Predicted)
• Flash Point: 386.2±32.9 °C
• PSA: 99.16000
• Density: 1.3±0.1 g/cm³
• LogP: 4.73640
• Storage Temp.: -20°C
• Solubility.: Soluble in DMSO ( up to at least 25 mg/ml)

Purity/Quality:

99%, ^*data from raw suppliers

PCI-32765 95% ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Description: Ibrutinib (chemical name 1 [(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo [3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one) is a first-in-class,potent, orally administered covalently-binding inhibitor of BTK. Ibrutinib is a potent inhibitor of BTK that binds covalently to Cys-481 in the active site of BTK, resulting in inhibition of kinase activity. Ibrutinib does have significant activity against 19 other kinases, including seven with a cognate cysteine residue. These include BLK, BMX, ITK, TEC, EGFR, ERBB2, and JAK3. In November 2013, the US FDA approved ibrutinib (also referred to as PCI-32765), for the treatment of patients with mantle cell lymphoma (MCL) who had received at least one prior therapy. Ibrutinib is the second oral agent approved for the treatment of MCL. It works by irreversibly inhibiting Bruton’s tyrosine kinase (Btk) leading to the inhibition of B-cell receptor signaling and resulting in the reduction of malignant B-cell proliferation and induction of cell death. Btk plays an important role in the differentiation, development, proliferation, and survival of B cells via activation of cell-cycle regulators and regulating the expression of pro- and antiapoptotic proteins. Aberrant Btk activity results in a variety of B-cell malignancies including MCL. Ibrutinib inhibits Btk by irreversibly binding to cysteine-481 in the active site thereby inhibiting phosphorylation of tyrosine-223 and affecting downstream B-cell signaling pathways. Ibrutinib is a potent inhibitor of Btk (IC50=0.5 nM) and is efficacious in canine models of B-cell lymphoma. At dose ranges of 2.5–20 mg/kg, there was full occupancy of Btk in peripheral blood and tumor tissue for 24 h. A synthetic route to ibrutinib that employs Suzuki coupling of 3-iodo-1Hpyrazolo[3,4-d]pyrimidin-4-amine with (4-phenoxyphenyl)boronic acid followed by Mitsunobu reaction with N-Boc-3-hydroxypiperidine as key steps has been reported.
• Uses: Ibrutinib is a highly selective Bruton’s tyrosine kinase (Btk) irreversible inhibitor.
• Clinical Use: Tyrosine kinase inhibitor: Treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia (CLL) Treatment of Waldenstr?m’s macroglobulinaemia (WM)
• Drug interactions: Potentially hazardous interactions with other drugs Anti-arrhythmics: concentration possibly increased by amiodarone and dronedarone - avoid or reduce dose of ibrutinib. Antibacterials: concentration possibly increased by ciprofloxacin, clarithromycin, erythromycin and telithromycin - avoid or reduce dose of ibrutinib; concentration reduced by rifampicin - avoid. Antidepressants: concentration possibly reduced by St John’s wort - avoid. Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, phenobarbital and phenytoin - avoid. Antifungals: concentration possibly increased by fluconazole, itraconazole, ketoconazole and voriconazole - avoid or reduce dose of ibrutinib. Antipsychotics: avoid with clozapine, increased risk of agranulocytosis. Antivirals: concentration possibly increased by atazanavir, darunavir, fosamprenavir, indinavir, ritonavir and saquinavir - avoid or reduce dose of ibrutinib. Aprepitant: concentration possibly increased - avoid or reduce dose of ibrutinib. Calcium channel blockers: concentration possibly increased by diltiazem or verapamil - avoid or reduce dose of ibrutinib. Cobicistat: concentration possibly increased, avoid or reduce dose of ibrutinib. Cytotoxics: concentration possibly increased by crizotinib - avoid or reduce dose of ibrutinib; concentration possibly increased by imatinib - reduce dose of ibrutinib. Grapefruit juice and Seville oranges: avoid.

Technology Process of Ibrutinib

There total 116 articles about Ibrutinib 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: 95.0%

(R)-3-(4-phenoxyphenyl)-1-(piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine (1022150-12-4) + acryloyl chloride (814-68-6,25189-84-8) → ibrutinib (936563-87-0,936563-96-1,936563-97-2)

Guidance literature:

With sodium hydrogencarbonate; In 2-methyltetrahydrofuran; at -5 - 0 ℃; for 1h; Inert atmosphere;

Reference yield: 95.0%

3-(4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3.4-d]pyrimidin-4-amine hydrochloride salt (1553977-42-6,1642571-07-0) + acryloyl chloride (814-68-6,25189-84-8) → ibrutinib (936563-87-0,936563-96-1,936563-97-2)

Guidance literature:

With sodium hydrogencarbonate; In 2-methyltetrahydrofuran; at -5 - 0 ℃; for 1h; Inert atmosphere;

Reference yield: 93.4%

(3R)‐4‐amino‐3‐(4-phenoxyphenyl)‐1‐(1‐tert-butoxycarbonylpiperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (1022150-11-3) + acryloyl chloride (814-68-6,25189-84-8) → ibrutinib (936563-87-0,936563-96-1,936563-97-2)

Guidance literature:

(3R)‐4‐amino‐3‐(4-phenoxyphenyl)‐1‐(1‐tert-butoxycarbonylpiperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine; With triethylamine; In ethyl acetate; Industrial scale;

acryloyl chloride; In tetrahydrofuran; ethyl acetate; at 20 ℃; Solvent; Industrial scale;

upstream raw materials:

acryloyl chloride

tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

2-[(4-phenoxy-phenyl)-methoxy-methylene]-malononitrile

2-[hydroxy-(4-phenoxy-phenyl)-methylene]-malononitrile

Refernces

• 1、 Reddi, Rambabu N.,Resnick, Efrat,Rogel, Adi,Rao, Boddu Venkateswara,Gabizon, Ronen,Goldenberg, Kim,Gurwicz, Neta,Zaidman, Daniel,Plotnikov, Alexander,Barr, Haim,Shulman, Ziv,London, Nir. "Tunable Methacrylamides for Covalent Ligand Directed Release Chemistry". supporting information. p. 4979 - 4992. Retrieved 2021/05/04.
• 2、 -. "Preparation method of ibrutinib intermediate". Paragraph 0100-0104. . Retrieved 2021/08/06.