- A novel application of a Pd(0)-catalyzed nucleophilic substitution reaction to the regio- and stereoselective synthesis of lactam analogues of the epothilone natural products
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Several lactam analogues of the epothilones were prepared using a concise semisynthetic approach starting with the unprotected natural products. Highlighted in this strategy is a novel regio- and stereoselective Pd(0)-catalyzed azidation reaction of a macrocyclic lactone. Subsequent reduction and macrolactamization of the resulting azide acid intermediates provided the desired macrolactams in satisfactory overall yields. The entire three-step sequence was streamlined into a 'one-pot' process for the epothilone B-lactam, BMS-247550, which is currently undergoing phase I clinical trials. An initial total synthesis route to prepare the lactam analogue of epothilone C was completed and compared to the more direct semisynthesis approach. All of the lactam analogues were evaluated in vitro and the results are discussed.
- Borzilleri,Zheng,Schmidt,Johnson,Kim,DiMarco,Fairchild,Gougoutas,Lee,Long,Vite
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- PROCESS FOR THE PREPARATION OF (1S,3S,7S,10R,11S,12S,16R)-7,11-DIHYDROXY-8,8,10,12,16-PENTAMETHYL-3-[(1E)-1-METHYL-2-(2-METHYL-4-THIAZOLYL)ETHENYL]-17-OXA-4-AZABICYCLO[14.1.0]HEPTADECANE-5,9-DIONE AND INTERMEDIATES THEREOF
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The present invention relates to an improved process for the preparation of (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-2-(2- methyl-4-thiazolyl)ethenyl]- 17-oxa-4-azabicyclo[ 14.1.0]heptadecane-5,9-dione represented by the following structural formula I and intermediates thereof. The present invention also provides novel intermediate compounds useful for the preparation of compound of formula I and its intermediates.
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- PROCESS FOR IXABEPILONE, AND INTERMEDIATES THEREOF
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The present invention relates to a novel process of making ixabepilone, ixabepilone derivatives and analogues, and intermediates thereof.
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Paragraph 0288-0289; sheet 10; 20
(2014/09/29)
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- PROCESS FOR PREPARATION OF IXABEPILONE AND INTERMEDIATES USEFUL IN SAID PROCESS.
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The present invention describes a process for preparation of Ixabepilone and intermediates useful in said process.
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Page/Page column 11
(2013/11/19)
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- SOLID STATE FORMS OF IXABEPILONE
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Crystalline forms of Ixabepilone are described in the present application and processes for preparing the crystalline forms. The present invention also includes pharmaceutical compositions of such crystalline forms of Ixabepilone.
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Page/Page column 17
(2011/12/14)
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- On the interactivity of complex synthesis and tumor pharmacology in the drug discovery process: Total synthesis and comparative in vivo evaluations of the 15-Aza epothilones
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The total syntheses of 12,13,15-desoxy-15(S)-aza-epothilone B (aza-dEpoB; dEpoB-lactam) and 12,13,15-desoxy-15(R)-aza-epothilone B (15-epi-aza-dEpoB; 15-epi-dEpoB-lactam) have been accomplished via a highly convergent strategy. We have also successfully oxidized 12,13,15-desoxy-15(S)-aza-epothilone B to aza-epothilone B (aza-EpoB; EpoB-lactam). Aza-epothilone B has been advanced to phase I clinical trials by the Bristol-Myers Squibb group. Our synthesis is efficient and was amenable to the production of significant quantities of these lactams. Using our fully synthetically derived lactams, in vitro and in vivo studies were conducted in comparison with advanced clinical candidates, 12,13-desoxyepothilone B and 12,13-desoxyepothilone F, also derived by total synthesis.
- Stachel,Chul Bom Lee,Spassova,Chappell,Bornmann,Danishefsky,Chou,Guan
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p. 4369 - 4378
(2007/10/03)
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