Synthesis of a cis 2,5-Disubstituted Morpholine by De-epimerization: Application to the Multigram Scale Synthesis of a Mineralocorticoid Antagonist

Abstract

A convergent route to multigram quantities of a mineralocorticoid antagonist 3 is described. Starting from (R)phenylglycinol, the synthesis of cis 2,5-morpholine 2 is accomplished utilizing a de-epimerization to install the second stereogenic center. The multigram synthesis of 3 was completed through a sequence of an S N Ar reaction, Dakin oxidation, alkylation, and cyclization to provide a crystalline solid.

Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis

“…Alkyl substitution at position 2 of the morpholine ring, i.e., molecules 9 – 17 , turned out to be a suitable modification instantly abrogating activity toward dopamine transporter. This result represents the classic case of SAR-cliff or “magic methyl” discovery. − The cis-diasteroisomer 9 turned out to be a synthetically preferred isomer over the trans compound 10 , with coincident higher activity against chitinases. Increasing the size of the 2-substituent (e.g., compounds 11 – 17 ) led in general to equipotent inhibitors but with much inferior PK (e.g., compounds 11 , 15 , 16 , 17 ; see Supporting Information).…”

“…This result represents the classic case of SAR-cliff or "magic methyl" discovery. 43−45 The cis-diasteroisomer 9 turned out to be a synthetically preferred isomer over the trans compound 10, 46 with coincident higher activity against chitinases. Increasing the size of the 2-substituent (e.g., compounds Thus, compound 9 (OATD-01) was selected for further studies.…”

Identification of Morpholino-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-ones as Nonsteroidal Mineralocorticoid Antagonists

“…Base promoted intramolecular Williamson ether synthesis on amide 15 provided lactam intermediate 16 that could be separated ( cis / trans isomers) and further manipulated as required to provide morpholines with a range of C2 substituents. For example, the use of racemic 2-chloropropanoyl chloride for the acylation of ( R )-2-phenylglycinol and cyclization provided a mixture of morpholinone diastereomers 16 that could be controlled by judicious choice of conditions . Reduction of the morpholinone provided the required morpholines 17 .…”

“…Several routes to access morpholinones and morpholines have been reported and were used to synthesize analogs to explore the early SAR . Route improvements were made, as we have reported previously (Scheme ), which allowed for installation of the defined C5 stereocenter from commercially available ( R )-2-phenylglycinols 14 , which could be acylated to provide amide 15 . Base promoted intramolecular Williamson ether synthesis on amide 15 provided lactam intermediate 16 that could be separated ( cis / trans isomers) and further manipulated as required to provide morpholines with a range of C2 substituents.…”

“…Several routes to access morpholinones and morpholines have been reported and were used to synthesize analogs to explore the early SAR. 28 Route improvements were made, as we have reported previously (Scheme 3), 29 which allowed for installation of the defined C5 stereocenter from commercially available (R)-2-phenylglycinols 14, which could be acylated to a RRCK = modified Madin−Darby permeability assay. b The corresponding (S)-enantiomer had an order of magnitude lower affinity and functional activity and was not pursued further.…”