918639-08-4

Basic information

• Product Name: Bosutinib Monohydrate
• Synonyms: Bosutinib Monohydrate;bosutinib hydrate
• CAS NO: 918639-08-4
• Molecular Formula: C₂₆H₂₉Cl₂N₅O₃*H₂O
• Molecular Weight: 548.46144
• Mol File: 918639-08-4.mol

Chemical Properties

• Appearance: /
• CAS DataBase Reference: Bosutinib Monohydrate(CAS DataBase Reference)
• NIST Chemistry Reference: Bosutinib Monohydrate(918639-08-4)
• EPA Substance Registry System: Bosutinib Monohydrate(918639-08-4)

Safety Data

• Hazardous Substances Data: 918639-08-4(Hazardous Substances Data)

Usage

Definition

ChEBI: A hydrate that is the monohydrate form of anhydrous bosutinib.

Clinical Use

Bosulif ? (Bosutinib hydrate), also known as (SKI-606), is a novel 4-phenylamino-3-quinolinecarbonitrile kinase inhibitor approved for treatment of adults with chronic, accelerated, or blast phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML). Bosutinib is an orally-dosed, dual Src/Abl kinase inhibitor which provides an alternative treatment to patients exhibiting immunity to imatinib and other kinase inhibitors utilized for this treatment. In contrast to competitor tyrosine inhibitors, bosutinib inhibits autophosphorylation of both Srs and Abl kinases, leading to decreased cell growth and apoptosis. Bosutinib was originally developed by Wyeth and continues to be marketed by Pfizer after the merger of Wyeth and Pfizer in 2009.

Synthesis

Several synthetic routes to bosutinib have been reported, including synthetic work for scale up and processing to obtain pure salt forms of bosutinib for pharmaceutical applications.56-59 The current manufacturing route begins with reaction of 2-methoxy-5-nitrophenol (36) and 1-bromo-3- chloropropane (37) to provide aryl chloroether 38 in 82% yield. Reaction of 38 with Nmethylpiperazine (39) and NaI in refluxing DME provided the functionalized aryl-nitro-piperazine 40 (77% yield), which was converted directly to aniline 41 under hydrogenolysis conditions. Aniline 41 was then reacted with triethyl orthoformate and aryl cyanoamide 42, which was generated in one step from 2,4-dichloro-5-methoxy-aniline (44), 1,3-diisopropylcabodiimide (DIC), and cyanoacetic acid (45) under refluxing conditions, to yield advanced intermediate 43 (93% over 2 steps). Finally, conversion of 43 to bosutinib was facilitated by a POCl3-promoted cyclization in the presence of sulfolane. As shown in Scheme 8, employment of carefully optimized conditions for the isolation of bosutinib hydrate (VII) provided material in 75-82% yields and >99% purity.

Upstream product

• 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 
• 380843-75-4 bosutinib 

Relevant articles and documents

Rationalization of the formation and stability of bosutinib solvated forms

Crystallization of bosutinib from a wide variety of solvents resulted in many distinct structures, and displayed difficulties to crystallize without solvent incorporation. We have prepared 23 solvated/hydrated and one anhydrous solid form and for 11 of them solved the crystal structures. With the goal of rationalizing the high propensity to solvate formation and exploring the stability relationships between the phases, the solid forms were characterized by different experimental and computational methods. Their stability was compared theoretically by calculating the packing efficiency in the crystal structures and the binding energy of the solvent in the crystal lattice using differential scanning calorimetry. Experimental studies were completed by analysing the forms' physical stability in solid state and in suspension and their intrinsic dissolution rate. The survey conducted on the inclusion compounds has resulted in basic understanding of the underlying factors affecting discriminative solvate formation: the solvents are utilised to satisfy previously unused hydrogen bonding capabilities in the host molecule.

CRYSTALLINE FORMS OF 4-[(2,4-DICHLORO-5-METHOXYPHENYL)AMINO]-6-METHOXY-7-[3-(4-METHYL-1-PIPERAZINYL)PROPOXY]-3-QUINOLINECARB-ONITRILE AND METHODS OF PREPARING THE SAME

This invention is directed to a crystalline 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3- quinolinecarbonitrile monohydrate having an x-ray diffraction pattern wherein 20 angles (°) of significant peaks are at