Ibrutinib

Iupac Name：1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one

Molecular Weight：440.507

Modify Date.: 2022-11-22 15:44

Introduction: 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. View more+

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1. Names and Identifiers

1.1 Name: Ibrutinib
1.2 Synonyms: (R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo-[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2- (R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one 2-Propen-1-one, 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]- According to Lu imatinib CRA 032765 IBRUTINIB IBRUTINIB (PCI-32765) Imbruvica JNJ 02 PCI 32765 PCI 32765-00 PCI32765 PCI-32765 PCI-32765 (Ibrutinib)

1.3 CAS No.: 936563-96-1

1.4 CID: 24821094

1.5 EINECS(EC#): 805-642-2

1.6 Molecular Formula: C25H24N6O2 (isomer)

1.7 Inchi: InChI=1S/C25H24N6O2/c1-2-21(32)30-14-6-7-18(15-30)31-25-22(24(26)27-16-28-25)23(29-31)17-10-12-20(13-11-17)33-19-8-4-3-5-9-19/h2-5,8-13,16,18H,1,6-7,14-15H2,(H2,26,27,28)/t18-/m1/s1

1.8 InChkey: XYFPWWZEPKGCCK-GOSISDBHSA-N

1.9 Canonical Smiles: C=CC(=O)N1CCCC(C1)N2C3=NC=NC(=C3C(=N2)C4=CC=C(C=C4)OC5=CC=CC=C5)N

1.10 Isomers Smiles: C=CC(=O)N1CCC[C@H](C1)N2C3=NC=NC(=C3C(=N2)C4=CC=C(C=C4)OC5=CC=CC=C5)N

2. Properties

2.1 Density: 1.34

2.1 Melting point: 149-158oC

2.1 Boiling point: 715.0±60.0 °C(Predicted)

2.1 Refractive index: 1.69

2.1 Flash Point: 386.2±32.9 °C

2.1 PSA: 99.16000

2.1 logP: 4.73640

2.1 Color/Form: White to off-white solid

2.2 pKa: 4.09±0.30(Predicted)

2.3 Water Solubility: Freely soluble in dimethyl sulfoxide; soluble in methanol

2.4 Toxicity Summary: IDENTIFICATION AND USE: Ibrutinib; is an oral tyrosine; kinase inhibitor that irreversibly binds and inhibits tyrosine;-protein kinase BTK (Bruton tyrosine; kinase). BTK is important in the function of B-cell receptor signaling and therefore in the maintenance and expansion of various B-cell malignancies. Targeting BTK with ibrutinib; is an effective strategy in treating these malignancies. Ibrutinib;, marketed as Imbruvica;, is indicated for the treatment of patients with mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. It is also indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion and patients with Waldenstrom's macroglobulinemia (WM). HUMAN EXPOSURE AND TOXICITY: Studies in humans have shown that ibrutinib; may enhance chemoimmunotherapy efficacy without additive toxicities. Ibrutinib; is cytotoxic to malignant plasma cells from patients with multiple myeloma (MM) and furthermore treatment with ibrutinib; significantly augments the cytotoxic activity of bortezomib; and lenalidomide; chemotherapies. Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and angioedema have been reported. The outcome of patients with MCL who experience disease progression following ibrutinib; therapy is poor, with both low response rates to salvage therapy and short duration of responses. ibrutinib; inhibited the proliferation and induced apoptosis of Germinal center B-cell like diffuse large B-cell lymphoma (GCB-DLBCL) cell lines through suppression of BCR signaling pathway and activation of caspase-3. Furthermore, the chemokines CCL3 and CCL4 production from tumor cells were also found to be attenuated by ibrutinib; treatment. Different cell lines exhibited distinct sensitivity after ibrutinib; treatment. Interestingly, the decreasing level of p-ERK after ibrutinib; treatment, but not the basal expression level of Btk, correlated with different drug sensitivity. Ibrutinib; could be a potentially useful therapy for GCB-DLBCL and the decreasing level of p-ERK could become a useful biomarker to predict related therapeutic response. Ibrutinib; is well tolerated when added to R-CHOP (chemotherapy named after the initials of the drugs used: rituximab, cyclophosphamide;, doxorubicin; (hydroxydaunomycin), vincristine; (Oncovin ), prednisolone;), and could improve responses in patients with B-cell non-Hodgkin lymphoma. ANIMAL STUDIES: Ibrutinib; caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL or WM, receiving the ibrutinib; dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures.

3. Use and Manufacturing

3.1 Definition: ChEBI: A member of the class of acrylamides that is (3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine in which the piperidine nitrogen is replaced by an acryloyl group. A selective and covalent inhibitor of he enzyme Bruton's tyrosine kinase, it is used for treatment of B-cell malignancies.

3.2 GHS Classification: Signal: Danger
GHS Hazard Statements
Aggregated GHS information provided by 5 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

H302 (20%): Harmful if swallowed [Warning Acute toxicity, oral]
H315 (20%): Causes skin irritation [Warning Skin corrosion/irritation]
H319 (20%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]
H335 (20%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]
H351 (20%): Suspected of causing cancer [Warning Carcinogenicity]
H360 (80%): May damage fertility or the unborn child [Danger Reproductive toxicity]
H373 (60%): Causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]
H410 (20%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

Precautionary Statement Codes
P201, P202, P260, P261, P264, P270, P271, P273, P280, P281, P301+P312, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P314, P321, P330, P332+P313, P337+P313, P362, P391, P403+P233, P405, and P501

4. Safety and Handling

4.1 Hazard Declaration: H302

4.1 Caution Statement: P201, P202, P260, P261, P264, P270, P271, P273, P280, P281, P301+P312, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P314, P321, P330, P332+P313, P337+P313, P362, P391, P403+P233, P405, P501

5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 4

Skin irritation, Category 2

Eye irritation, Category 2

Specific target organ toxicity – single exposure, Category 3

Reproductive toxicity, Category 1B

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word	Danger
Hazard statement(s)	H302 Harmful if swallowed H315 Causes skin irritation H319 Causes serious eye irritation H335 May cause respiratory irritation H360 May damage fertility or the unborn child
Precautionary statement(s)
Prevention	P264 Wash ... thoroughly after handling. P270 Do not eat, drink or smoke when using this product. P280 Wear protective gloves/protective clothing/eye protection/face protection. P261 Avoid breathing dust/fume/gas/mist/vapours/spray. P271 Use only outdoors or in a well-ventilated area. P201 Obtain special instructions before use. P202 Do not handle until all safety precautions have been read and understood.
Response	P301+P312 IF SWALLOWED: Call a POISON CENTER/doctor/…if you feel unwell. P330 Rinse mouth. P302+P352 IF ON SKIN: Wash with plenty of water/... P321 Specific treatment (see ... on this label). P332+P313 If skin irritation occurs: Get medical advice/attention. P362+P364 Take off contaminated clothing and wash it before reuse. P305+P351+P338 IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. P337+P313 If eye irritation persists: Get medical advice/attention. P304+P340 IF INHALED: Remove person to fresh air and keep comfortable for breathing. P312 Call a POISON CENTER/doctor/…if you feel unwell. P308+P313 IF exposed or concerned: Get medical advice/ attention.
Storage	P403+P233 Store in a well-ventilated place. Keep container tightly closed. P405 Store locked up.
Disposal	P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

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6. Other Information

6.0 Bruton tyrosine kinase (BTK) inhibitor: Ibrutinib is a kind of Bruton tyrosine kinase (BTK) inhibitor, it could be used for the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). MCL and CLL are belonged to the B-cell non-Hodgkin's lymphoma, which is difficult to cure and easy to recurrent. Common chemical immunotherapy does not have the targeting, often occurs 3 or 4 adverse reactions. Ibrutinib and B lymphocytes could target with BTK which is necessary for formation, differentiation, and transmission of information, inhibit BTK activity irreversibly, and inhibit tumor cell proliferation and survival effectively. Ibrutinib could be rapidly absorbed after oral administration, during 1~2h reach maximum blood concentration, adverse reactions belong to one or two, therefore, Ibrutinib will become a new choice of treatment of CLL and MCL.
Food and Drug Administration (FDA) of USA has speed up approval of Pharmacyclics Corporation and Johnson & Johnson's Imbruvica (generic name: Ibrutinib) came to market to the cure a kind of rarely aggressive leukemia-mantle cell lymphoma (MCL) in 13th November, 2013. Ibrutinib is a new kind of oral Bruton tyrosine kinase (BTK) inhibitor, it was awarded by FDA be a breakthrough drugs in February of 2013, and approved the MCL and CLL treatments in 13th November, 2013 and 12th February, 2014 respectively. It could covalently bound selectively with cysteine residues (Cys-481) in active site of Btk target protein, irreversible inhibit BTK, thereby effectively prevent tumor cells from migrating from B cell to lymphoid tissue where adapt for tumor growth. Information was collated by Xiaonan editor of .

6.1 Research and development process: Ibrutinib was developed by American Celera Genentech (Celera Genomics) that was well known because it was the first one drawn "human genome". Pan Zhengying (now Beijing University Shenzhen Graduate School Distinguished Fellow) as the first author of this research and published the process of Ibrutinib in 2007 (ChemMedChem 2 (1): 58-61). But Celera had transferred the development rights to Pharmacyclics Company of California due to funding and resources. Although Pharmacyclics Company was in a very difficult stage, only $ 0.64 for the stock, facing delisting and bankruptcy in that time, company's management has managed to raise funds, spent only $ 2 million to down payment, 100 million shares and future sales royalty and milestone payment of royalties more to get Ibrutinib. In 2011, Johnson & Johnson subsidiary Janssen pay $ 150 million upfront payment in order to get the right to cooperate with Pharmacyclics. Once the new drugs in clinical trials and approved to listing, Pharmacyclics company will get $ 975 million in total revenue, and they will share the sales.When the deal was announced, Pharmacyclics stock is only $ 12. Market value was only several hundred million dollars. However, the stock is already $ 123, $ 9.05 billion value now.

6.2 Mechanism: Signaling pathway of B cell antigen receptor (BCR) is a key driver of tumor growth and spread. BTK as an indispensable participant for BCR signal peptide, it is very important for formation, differentiation, messaging and survival of B lymphocyte. BTK is an identifiable signal peptide molecules of BCR channel. When the signal peptide molecules across the B lymphocyte surface receptors, required channel is activated for transportation, chemotaxis and adhesion, which provide a convenience to be B-cell malignancies.
Ibrutinib is a small molecule can selectively and covalently bound to a cysteine residue (Cys-481) BTK active site, and irreversibly inhibit BTK activity, thereby inhibiting BCR activated signaling pathway, which could effectively prevent the tumor from B cells to lymphoid tissues where suitable for tumor growth, to reduce B cell proliferation and induce apoptosis of malignant cells, which play a role in the treatment of CLL and MCL. Non-clinical studies have shown that Ibrutinib can inhibit malignant B lymphocyte proliferation and survival.

6.3 Metabolism and Elimination: Ibrutinib primarily metabolized by the cytochrome P450 (CYP3A and a small part of the CYP2D6) and produce a variety of metabolites after metabolism. The metabolite (PCI-45227) is a kind of dihydrodiol substance which is an activity of inhibiting BTK.Compared with Ibrutinib, PCI-45227 has much stronger inhibition on BTK, which is about 15 times stronger. At steady state, the average rate of metabolism of PCI-45227 is around 1~2.8.
Apparent clearance (CL/F) of Ibrutinibis is approximately 1 000 L/h, the half-life (t1/2) is 4~6 h. Ibrutinib mainly be metabolites in the body, excrete with the feces. To healthy subjects by oral radioactive 14C-labeled Ibrutinib, found that nearly 90% of the radiation were eliminated in 168 h, most (about 80%) of them were excreted with the feces, and nearly 10% were excreted in the urine, about 1 % be prototypes were excreted with the feces.
Elimination of Ibrutinib will not make a difference in age (37 to 84 years) and gender, but systemic exposure of patients with moderate hepatic injury will be 6 times higher than in healthy subjects.

6.4 Synthetic method: 4-phenoxy-benzoic acid (1) as raw materials, through chlorination, condensation with malononitrile, methylation and cyclization with hydrazine hydrate to obtain intermediate 5,5. With formamide cyclization to give the compound 6, 6 by Mitsunobu reaction and de-Boc protecting group was intermediate 8; intermediate 8 is reacted with acrylic acid chloride obtained Ibrutinib.

Fig. 1 Chemical react ion synthesis route of Ibrutinib

6.5 Patents: Foreign patents: WO 2008039218 (compound); WO 2013003629 (purposes)
US Patent Number: 7,514,444, 7,718,662, patents is valid: December 2026
Domestic patent: CN101610676A, CN101610676B, CN101805341A, CN101805341B, CN102746305A, CN102887900A

6.6 Definition: ChEBI: A member of the class of acrylamides that is (3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine in which the piperidine nitrogen is replaced by an acryloyl group. A selective and covalent inhibitor of he enzyme Bruton's tyrosine kinase, it is used for treatment of B-cell malignancies.

7. Computational chemical data

Molecular Weight: 440.507g/mol
Molecular Formula: C₂₅H₂₄N₆O₂
Compound Is Canonicalized: True
XLogP3-AA: 3.6
Exact Mass: 440.19607403
Monoisotopic Mass: 440.19607403
Complexity: 678
Rotatable Bond Count: 5
Hydrogen Bond Donor Count: 1
Hydrogen Bond Acceptor Count: 6
Topological Polar Surface Area: 99.2
Heavy Atom Count: 33
Defined Atom Stereocenter Count: 1
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 1
CACTVS Substructure Key Fingerprint: AAADceB7sAAAAAAAAAAAAAAAAAAAAWAAAAA8eIEAAAAAAFgB/AAAHgAYAAAADCzBnwQ1tt9IFACqAydzdACSjCsxoKAd2CAuTNiMbqLE+duWvCjszhPI6KeQ0OEOIAAAAAAAAABAAAAAAAAAAAAAAAAAAA==

8. Question & Answer

What is Ibrutinib? Jun 30 2020
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.[1] Ibrutinib is a potent inhibitor of BTK that binds covalently to Cys-481 in the act...

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