380843-75-4

Basic information

• Product Name: Bosutinib
• Synonyms: 3-Quinolinecarbonitrile, 4-[(2,4-dichloro-5-Methoxyphenyl)aMino]-6-Methoxy-7-[3-(4-Methyl-1-piperazinyl)propoxy]-;Bosutinib(TINIBS );4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile Bosutinib (SKI-606);WAY-173606;Bosulif(bosutinib);SKI-606;BOSUTINIB;Bosutinib for research
• CAS NO: 380843-75-4
• Molecular Formula: C₂₆H₂₉Cl₂N₅O₃
• Molecular Weight: 530.45
• EINECS: 1308068-626-2
• Product Categories: Intermediates & Fine Chemicals;Pfizer compounds;Pharmaceuticals;API;Aromatics Compounds;Aromatics;Heterocycles;Inhibitors;Bosutinib ada@tuskwei.com whatsapp;8618031153937
• Mol File: 380843-75-4.mol

Chemical Properties

• Melting Point: 116-120 ºC
• Boiling Point: 649.7 °C at 760 mmHg
• Flash Point: 346.7 °C
• Appearance: off-white to light brown/
• Density: 1.36
• Vapor Pressure: 9.15E-17mmHg at 25°C
• Refractive Index: 1.651
• Storage Temp.: room temp
• Solubility: DMSO: ≥15mg/mL
• PKA: 7.63±0.10(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month.
• CAS DataBase Reference: Bosutinib(CAS DataBase Reference)
• NIST Chemistry Reference: Bosutinib(380843-75-4)
• EPA Substance Registry System: Bosutinib(380843-75-4)

Safety Data

• Hazard Codes: Xi
• Statements: 36
• Safety Statements: 26
• WGK Germany: 3
• Hazardous Substances Data: 380843-75-4(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
Bosutinib is used as an anticancer agent for the treatment of relapsed or refractory chronic myeloid leukemia (CML) in patients with resistance or intolerance to prior therapy. It inhibits 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines and has shown regression of CML tumors in preclinical in vivo studies.
Used in Cancer Cell Research:
Bosutinib is used as a novel Src kinase inhibitor to suppress the migration and invasion of human breast cancer cells, indicating its potential use in cancer cell research and development.
Used in Neurology:
Bosutinib is used as a peripheral vasolidator to increase cerebral blood flow, making it a potential therapeutic agent for Alzheimer's disease, cognitive impairment, and dementia.
Used in Pharmaceutical Research:
Bosutinib (SKI-606) is a novel, dual Src/Abl inhibitor with IC50 values of 1.2 nM and 1 nM, respectively, making it a valuable compound for pharmaceutical research and development.

Originator

Wyeth (United States)

Biochem/physiol Actions

Bosutinib (SKI-606) is an orally active; dual Src/Abl tyrosine kinase inhibitor with potent antiproliferative activity. It does not appear to inhibit c-Kit and PDGRF, which are thought to be the cause of numerous side effects in anticancer treatment with some other tyrosine kinase inhibitors.

Clinical Use

Protein kinase inhibitor: Treatment of Philadelphia chromosome-positive chronic myelogenous leukaemia resistant or intolerant to prior therapy

Drug interactions

Potentially hazardous interactions with other drugs Analgesics: possibly increased risk of ventricular arrhythmias with methadone. Anti-arrhythmics: possibly increased risk of ventricular arrhythmias with amiodarone and disopyramide; concentration possibly increased by dronedarone - avoid or consider reducing dose of bosutinib. Antibacterials: concentration possibly increased by ciprofloxacin, clarithromycin, erythromycin and telithromycin - avoid or consider reducing dose of bosutinib; possibly increased risk of ventricular arrhythmias with moxifloxacin; concentration reduced by rifampicin and possibly rifabutin - avoid. Antidepressants: concentration possibly reduced by St John’s wort - avoid. Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone - avoid. Antifungals: concentration increased by ketoconazole and possibly by fluconazole, itraconazole, posaconazole and voriconazole - avoid or consider reducing dose of bosutinib. Antimalarials: possibly increased risk of ventricular arrhythmias with chloroquine and hydroxychloroquine. Antipsychotics: possibly increased risk of ventricular arrhythmias with haloperidol; avoid with clozapine, increased risk of agranulocytosis. Antivirals: concentration possibly increased by atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, ritonavir, saquinavir and telaprevir - avoid or consider reducing dose of bosutinib; concentration possibly reduced by efavirenz and etravirine - avoid. Aprepitant: concentration possibly increased - avoid or consider reducing dose of bosutinib. Beta-blockers: possibly increased risk of ventricular arrhythmias with sotalol. Bosentan: concentration of bosutinib possibly reduced - avoid. Calcium channel blockers: concentration possibly increased by diltiazem or verapamil - avoid or consider reducing dose of bosutinib. Cytotoxics: concentration possibly increased by imatinib - avoid or consider reducing dose of bosutinib. Domperidone: avoid concomitant use, risk of ventricular arrhythmias. Fosaprepitant: concentration possibly increased by fosaprepitant - avoid or consider reducing dose of bosutinib Grapefruit juice: concentration possibly increased by grapefruit juice - avoid or consider reducing dose of bosutinib. Modafinil: concentration of bosutinib possibly reduced - avoid.

Metabolism

Mainly hepatically metabolised. The major circulating metabolites identified in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as a minor circulating metabolite. All the metabolites are inactive. Excretion is mainly via the faeces.

References

Golas et al. (2003), SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice; Cancer Res., 63 375 Remsing Rix et al. (2009), Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells; Leukemia, 23 477 Redaelli et al. (2009), Activity of bosutinib, Dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants; J. Clin. Oncol., 27 469 MacDonald et al. (2018), Src family kinase inhibitor bosutinib enhances retinoic acid-induced differentiation of HL-60 leukemia cells; Leuk. Lymphoma, 59 2941 Vultur et al. (2008), SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells; Mol. Cancer Ther., 7 1185

InChI:InChI=1/C26H29Cl2N5O3/c1-32-6-8-33(9-7-32)5-4-10-36-25-13-21-18(11-24(25)35-3)26(17(15-29)16-30-21)31-22-14-23(34-2)20(28)12-19(22)27/h11-14,16H,4-10H2,1-3H3,(H,30,31)

Upstream product

• 846023-24-3 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide 
• 846023-55-0 4-methoxy-3-[3-(4-methylpiperazin-1-yl)propoxy]phenylamine 
• 492444-39-0 7-[3-(4-methylpiperazin-1-yl)propoxy]-6-methoxy-4-chloro-quinoline-3-carbonitrile 
• 98446-49-2 2,4-dichloro-5-methoxyaniline 
• 214470-57-2 methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate 
• 109-01-3 1-methyl-piperazine 
• 636-93-1 5-nitroguaiacol 
• 109-70-6 1.3-chlorobromopropane 
• 122-51-0 orthoformic acid triethyl ester 
• 263149-10-6 4-chloro-7-hydroxy-6-methoxyquinolin-3-carbonitrile 
• 65182-98-1 N-(2,4-dichloro-5-methoxybenzene)acetamide 
• 67669-19-6 N-(2,4-dichloro-5-hydroxyphenyl)acetamide 
• 621-42-1 meta-hydroxyacetanilide 

Downstream Products

• 1450912-84-1 C₃₃H₄₀Cl₂F₂N₈O₃ 
• 918639-10-8 4-((2,4-dichloro-5-methoxyphenyl)-amino)-6-methoxy-7-(3-(4-methyl-1-piperazinyl)-propoxy)-3-quinoline-carbonitrile methanol solvate 
• 918639-09-5 4-((2,4-dichloro-5-methoxyphenyl)-amino)-6-methoxy-7-(3-(4-methyl-1-piperazinyl)-propoxy)-3-quinoline-carbonitrile isopropanol solvate 
• 918639-08-4 bosutinib monohydrate 

Relevant articles and documents

A robust, streamlined approach to bosutinib monohydrate

This article describes a systematic approach used to streamline the process for the isolation of bosutinib monohydrate, a promiscuous solvate former. A thorough understanding of the complex solid form landscape was garnered, and this knowledge was used to

Preparation method of bosutinib

The invention provides a preparation method of bosutinib. The method comprises the following steps: under the protection of inert gas, adding SM-1 and alkaline salt into an organic solvent, dropwise adding phosphorus oxychloride at a controlled temperature, cooling a reaction solution to room temperature after a reflux reaction is finished, filtering, dissolving an obtained filter cake into a mixed solvent, filtering again, adding an organic alkali into a filtrate, stirring for crystallization, filtering, and carrying out vacuum drying on the filter cake to obtain the target product bosutinib.Compared with the prior art, the synthesis method for preparing bosutinib by adding the alkaline salt into the reaction system is mild in reaction condition, high in material solubility, short in reaction time, capable of effectively shortening the production period and suitable for industrial scale-up production.

Method for preparing bosutinib intermediate

The invention provides a method for preparing a bosutinib intermediate. The method comprises the following steps: A, adding SM-1, 1-bromo-3-chloropropane and an acid-binding agent into a reaction solvent, controlling the temperature until the reaction is

Bosutinib compound and preparation method thereof

The invention provides a novel bosutinib impurity (I) and a preparation method thereof. The impurity serves as a reference standard or reference and can be used for quality control in raw materials and/or preparations of bosutinib. The invention further p

Bosutinib purification method

The invention provides a bosutinib purification method. The method includes the steps of firstly, dissolving crude bosutinib in an acetonitrile-water mixed solvent; secondly, optionally performing activated carbon decoloring, and filtering to obtain filtrate; thirdly, cooling, crystallizing, filtering, and drying to obtain purified bosutinib. The bosutinib purification method has the advantages that the method can replace a column chromatography purification method or a preparative chromatography purification method to remove impurities, which is hard to purify by a conventional crystallizingmethod, in the crude bosutinib, and the method is low in solvent use amount, simple in process, high in purification yield and product purity and beneficial to industrial production.

Preparation method of disubstituted 4-chloroquinoline-3-carbonitrile derivative and preparation method of bosutinib

The invention provides a preparation method of a disubstituted 4-chloroquinoline-3-carbonitrile derivative and a preparation method of bosutinib. The preparation method of the disubstituted 4-chloroquinoline-3-carbonitrile derivative comprises the following steps: disubstituted o-nitrobenzoate (II) used as a raw material and acetonitrile are condensed under the action of an alkali to obtain a compound of formula III; the compound of formula III and a chloroformylating reagent undergo a chloroformylating reaction to obtain a compound of formula IV1 or formula IV2; and the compound of formula IV1 undergoes catalytic hydrogenation cyclization in the presence of a hydrogenation catalyst to prepare 7-[3-(4-methyl-1-piperazinyl)propoxy]-6-methoxy-4-chloroquinoline-3-carbonitrile (Ia), or the compound of formula IV2 is subjected to catalytic hydrogenation cyclization and anhydride amidation to prepare 6-acetamido-7-ethoxy-4-chloroquinolin-3-carbonitrile (Ib). The compound of formula Ia or Ibis used to prepare bosutinib, neratinib or pelitinib. The method of the invention has the advantages of short process flow, simplicity in operation, easiness in realization, low cost, few three wastes, high yield, high purity, and easiness in industrial production.

Purification method of bosutinib

The invention provides a purification method of bosutinib. The purification method comprises the following steps: (1) dissolving a crude product of a compound of a formula I into a solvent A, and reacting with a benzoic acid solution containing benzoic acid and a solvent B, so as to obtain a compound of a formula II; (2) optionally, dissolving the compound of the formula II obtained in the step (1) into a solvent C, and reacting with a benzoic acid solution containing benzoic acid and a solvent D, so as to obtain the compound of the formula II; and (3) hydrolyzing the compound by the formula II obtained in the step (1) or the step (2) in the presence of alkali, water and other optional solvents, so as to obtain a pure product of the compound of the formula I. The purification method has the beneficial effects that a column chromatography manner or a preparative chromatography purification manner is not adopted, and impurities with potential genotoxicity which are unlikely to be removedin a manner that the column chromatography or the preparative chromatography purification manner is not adopted and a conventional crystallization method is directly adopted can be substantially reduced; and the amount of the adopted solvent is small, the after-treatment is convenient, the purification yield and the product purity are relatively high, and the method is applicable to industrial production.

AMORPHOUS FORM OF BOSUTINIB

The present invention provides an amorphous form of bosutinib, a process for its preparation, its pharmaceutical composition, and a method of use thereof.

NOVEL CRYSTALLINE POLYMORPHS OF 4-[(2.4-DICHIORO-5-METHOXVPHENVL)ANIINOL- 6-METHOXV-7-13-(4-METHYL-L-PIPERAZINVL)PROPOXVL-3-QUINOLINECARBONITRILE AND PROCESS FOR PREPARATION THEREOF

The present invention relates to novel crystalline polymorphs of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinoline carbonitrile represented by the following structural formula- 1 and process for preparation thereof.

New Synthetic Process for Bosutinib

A new and improved synthetic route to bosutinib is described on a hectogram scale. The key step is the intramolecular cyclization of a 3-(2-aminophenyl)-3-oxopropanenitrile with N,N-dimethylformamide dimethyl acetal to form the 3-cyano-4-hydroxyquinoline ring of 7-(3-chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile. A practical synthetic method to 2,4-dichloro-5-methoxyaniline is also established. Bosutinib is obtained in 18.0% yield over nine steps from acetovanillone with 98.9% purity (HPLC).