1092939-17-7
| Name | Ruxolitinib phosphate |
| CAS | 1092939-17-7 |
| Molecular Formula | C17H18N6.H3PO4 |
| MDL Number | MFCD18452860 |
| Molecular Weight | 404.36 |
| MOL File | 1092939-17-7.mol |
Chemical Properties
| Melting point | 186-190°C |
| storage temp. | Refrigerator |
| solubility | DMSO (Slightly), Methanol (Slightly) |
| form | Solid |
| color | White to Off-White |
Hazard Information
Uses
Definition
Clinical Use
Synthesis
The synthesis was initiated by SEM protection of commercially available chloropyrrolopyrimidine 201 to provide the protected chloropyrrolopyrimidine 202 in 89% yield. Suzuki coupling of 202 with the pyrazole pinacolatoboronate 203 gave pyrazole 204 in 64% yield. aza-Michael reaction of pyrazole 204 with 3-cyclopentylacrylonitrile 205 was accomplished in the presence of DBU to furnish SEM-protected ruxolitinib 206 in 98% yield as the racemate. The desired enantiomer 207 was isolated via chiral column separation in 93.5% yield and 99.4% ee, on 100 kg scale. Removal of the SEM group was accomplished through a two step process via treatment with lithium tetrafluoroborate and aqueous ammonium hydroxide, ultimately giving rise to ruxolitinib 208 in 84% yield. The phosphate salt was then prepared by treatment with phosphoric acid. Crystallization from MeOH/i-PrOH/n-heptane gave ruxolitinib phosphate (XX) in good overall yield in 99.8% ee. Pyrazole pinacolatoboronate 203 was prepared from pyrazole 209 via iodination with N-iodosuccinimide followed by reaction with trimethyl silyl chloride to give protected iodopyrazaole 210 in high yield. Reaction of 210 with i-PrMgCl to form the corresponding Grignard reagent followed by reaction with isopropylpinacolborane 211 provided Suzuki boronate synthon 203 in 55% yield.
storage
Questions And Answer
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Physical and Chemical Properties
Ruxolitinib, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3- cyclopentylpropanenitrile phosphate, has a molecular weight of 404.36 kDa. Ruxolitinib is soluble in aqueous solutions at pH 1-8. Ruxolitinib tablets are stable at 20-25°C and tolerate brief exposures to temperatures outside this range, if they stay within 15-30°C.
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Approval for Use
Ruxolitinib is an oral inhibitor of JAK1 and JAK2, which is approved for the treatment of myeloproliferative neoplasm-associated myelofibrosis, further myeloproliferative neoplasms, polycythemia vera and refractory cancer. In the USA, Canada and EU, ruxolitinib is approved for the treatment of patients with intermediate or high-risk PMF, post-PV MF or post-ET MF. In addition, ruxolitinib recently has been approved for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea, based on the results of Phase II and III clinical studies. To date, ruxolitinib has been approved for indications in MF in 83 countries.
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Side Effects
Common side effects of ruxolitinib treatment include anaemia and thrombocytopenia. The decline of circulating erythrocytes following ruxolitinib treatment could result in part from stimulation of eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the cell surface. Cellular mechanisms involved in the execution of eryptosis include oxidative stress, Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i), ceramide, decline of cytosolic ATP, caspases, stimulated activity of casein kinase 1α, Janus-activated kinase JAK3, protein kinase C, and p38 kinase, as well as impaired activity of AMP activated kinase AMPK, cGMP-dependent protein kinase, PAK2 kinase and sorafenib/sunitinib sensitive kinases.
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