A practical, safe, and high-yielding process for the cyclopropanation of a chiral epoxide has been developed using the inexpensive and nonhazardous reagents triethylphosphonoacetate and sodium tert-butoxide.
IntroductionCyclopropane ring systems are ubiquitous in nature and are contained in a large number of natural products, insecticides, and pharmaceutical drug candidates. 1 In conjunction with our work on the melatonergic agent 1 2 (Scheme 1), we needed to develop a cost-effective process for the large-scale preparation of the enantiomerically pure transcyclopropane carboxylic acid 2b.The reaction of epoxides with the anion of triethylphosphonoacetate (TEPA) in the synthesis of cyclopropane derivatives has been known for over four decades, 3 and there has been occasional additional application of the reaction between epoxides and phosphonates (either R-phosphono esters or phosphono ketones). 4 However, the utility of this reaction for the large-scale preparation of cyclopropane derivatives has not been explored. We were attracted toward developing the use of TEPA for the conversion of 3 to 2a due to its low cost, ease of availability and handling onscale. Most of the cited procedures use NaH as the base and afford the cyclopropane derivatives in fair yields (20-60%). Therefore, to make such a procedure scale-worthy, we needed to find a suitable substitute for NaH (dust hazard, hydrogen evolution, moisture sensitivity, etc.) and to identify reaction conditions to significantly improve the overall yield of the reaction.Herein, we wish to report the development of a safe, practical, and high-yielding process for the conversion of 3 to 2a by using the chemistry of TEPA anion and subsequent isolation of 2b.
The
development of a practical, commercial process for the preparation
of 4-fluoro-2-methyl-indol-5-ol and its subsequent coupling with a
pyrrolotriazine to form an advanced intermediate of the oncology therapy
brivanib alaninate is described. A key aspect is the multikilogram-scale
preparation of the fluoroindole intermediate from trifluoronitrobenzene
and the subsequent coupling while achieving impurity minimalization.
As brivanib alaninate is a high-dose drug, the synthesis of high-quality
API with low levels of impurities is critical.
Two well-known methodologies, the Jacobsen asymmetric
epoxidation (AE) and the Sharpless asymmetric dihydroxylation
(AD) followed by epoxidation, were evaluated for the large-scale preparation of a chiral dihydrobenzofuran epoxide. The
AE method was improved by substituting ethanol for dichloromethane for the dissolution of meta-chloroperbenzoic acid (m-CPBA). This change in solvent had a significant impact on
scaleability of the AE procedure by preventing crystallization
of the m-CPBA during addition to the cold reaction mixture.
Factors affecting the enantiomeric excess and yield of the chiral
epoxide resulting from AD followed by epoxidation were
studied. The Sharpless AD reaction provided the intermediate
chiral diol as a solid with high ee (>98.5%). The Sharpless−Kolb conversion of the chiral diol to a chiral epoxide was
modified to potassium tert-butoxide/tetrahydrofuran to obtain
the product in good yield (74−84%) and high ee (>98%). Both
the AE and AD processes were scaled up to prepare large
quantities of the chiral epoxide.
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