253128-17-5

Upstream product

• 98-59-9 p-toluenesulfonyl chloride 
• 253128-15-3 (1S,3S,6S,9S,12S,14R,16R,18S,20R,21R,22S,26R,29S,31R,32S,33R,35R,36S)-20-[(2S)-2,3-Dihydroxypropyl]-21-methoxy-14-methyl-8,15-bis(methylene)-2,19,30,34,37,39,40,41-octaoxanonacyclo[24.9.2.1^3,32.1^3,33.1^6,9.1^12,16.0^18,22.0^29,36.0^31,35]hentetracontan-24-one 
• 4124-41-8 p-toluenesulfonylanhydride 
• 929121-23-3 (1R,2S,3S,4S,5S,6RS,11S,14S,17S,19R,21R,23S,25R,26R,27S,31R,34S)-25-[(2S)-2,3-dihydroxypropyl]-2,5-dihydroxy-26-methoxy-19-methyl-13,20-bis(methylene)-24,35,36,37,38,39-hexaoxaheptacyclo[29.3.1.1^3,6.14,34.1^11,14.1^17,21.0^23,27] nonatriacontane-8,29-dione 

Downstream Products

• 253128-41-5 (1S,3S,6S,9S,12S,14R,16R,18S,20R,21R,22S,26R,29S,31R,32S,33R,35R,36S)-20-[(2S)-3-Amino-2-hydroxypropyl]-21-methoxy-14-methyl-8,15-bis(methylene)-2,19,30,34,37,39,40,41-octaoxanonacyclo [24.9.2.1^3,32.1^3,33.1^6,9.1^12,16.0^18,22.0^29,36.0^31,35]hentetracontan-24-one 
• 253128-34-6 C₄₆H₆₁ClO₁₁S 

Relevant academic research and scientific papers

Novel second generation analogs of eribulin. Part II: Orally available and active against resistant tumors in vivo

Eribulin mesylate is a newly approved treatment for locally advanced and metastatic breast cancer. We targeted oral bioavailability and efficacy against multidrug resistant (MDR) tumors for further work. The design, synthesis and evaluation of novel amine-containing analogs of eribulin mesylate are described in this part. Attenuation of basicity of the amino group(s) in the C32 side-chain region led to compounds with low susceptibility to PgP-mediated drug efflux. These compounds were active against MDR tumor cell lines in vitro and in xenograft models in vivo, in addition to being orally bioavailable.

PROCESS FOR THE PREPARATION OF ERIBULIN MESYLATE INTERMEDIATE

The present application provides improved processes for the synthesis of eribulin intermediate, which generally comprise the steps of: a) De-protecting the eribulin-enone (compound 1) in tetrahydrofuran by using TBAF solution, buffered with imidazole HCl in the presence of molecular sieve and sodium sulphate to get an insitu mixture of eribulin-dione diastereomer at C12 carbon (compound 2). Then ketalization may be performed of eribulin-dione insitu intermediate containing mixture of diastereomer at C12 carbon (compound 2) with PPTS in dichloromethane to yield eribulin-diol (compound 3).

METHODS USEFUL IN THE SYNTHESIS OF HALICHONDRIN B ANALOGS

In general, the present invention features improved methods useful for the synthesis of analogs of halichondrin B, such as eribulin and pharmaceutically acceptable salts thereof (e.g., eribulin mesylate).

Commercial manufacture of halaven: Chemoselective transformations en route to structurally complex macrocyclic ketones

The evolution of the synthesis of Halaven (E7389, INN eribulin mesylate) from a medicinal chemistry process to the execution of the final process on pilot scale is described. The completion of the synthesis of Halaven from C1-C13 ester and C14-C35 sulfone alcohol involves a series of chemo-, regio-, and stereoselective transformations. Furthermore, a high-dilution macrocyclization presented a number of challenges for industrial-scale manufacture (throughput, processing time, and side reactions). This paper describes studies at Eisai leading to an understanding, optimization, and control of the chemistry that realized the reproducible commercial production of Halaven.

Novel second generation analogs of eribulin. Part I: Compounds containing a lipophilic C32 side chain overcome P-glycoprotein susceptibility

Eribulin mesylate (Halaven), a totally synthetic analog of the marine polyether macrolide halichondrin B, has recently been approved in the United States as a treatment for breast cancer. It is also currently under regulatory review in Japan and the European Union. Our continuing medicinal chemistry efforts on this scaffold have focused on oral bioavailability, brain penetration and efficacy against multidrug resistant (MDR) tumors by lowering the susceptibility of these compounds to P-glycoprotein (P-gp)-mediated drug efflux. Replacement of the 1,2-amino alcohol C32 side chain of eribulin with fragments neutral at physiologic pH led to the identification of analogs with significantly lower P-gp susceptibility. The analogs maintained low- to sub-nM potency in vitro against both sensitive and MDR cell lines. Within this series, increasing lipophilicity generally led to decreased P-gp susceptibility. In addition to potency in cell culture, these compounds showed in vivo activity in mouse xenograft models.

Macrocyclic ketone analogues of halichondrin B

Synthesis and SAR studies of structurally simplified analogues of marine natural product halichondrin B resulted in the discovery of E7389, a new potential antitumor agent currently undergoing Phase I clinical trials. Structurally simplified macrocyclic ketone analogues of halichondrin B were prepared by total synthesis and found to retain the potent cell growth inhibitory activity in vitro, stability in mouse serum, and in vivo efficacy of the natural product.

Intermediate compounds for preparing macrocylcic analogs

Intermediate compounds of the formulas for use in the preparation of macrocyclic analogs.