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US 2023/0174477 A1Published application
Methods for synthesis of the tricyclic prostaglandin d2 metabolite methyl ester
AssigneePurdue Research Foundation
InventorsMingji DAI, Hunter SIMS
Life of this patent
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Abstract
Methods for the synthesis of a tricyclic-prostaglandin D2 metabolite methyl ester or a pharmaceutically acceptable salt thereof.
Claims19
A method for synthesis of a tricyclic-prostaglandin D2 metabolite (PGDM) methyl ester or a pharmaceutically acceptable salt thereof, the method comprising:
- subjecting an iodo-acetal compound to a cyclization reaction with a methyl ester to provide a cyclization product;
- reacting the cyclization product with a catalyst and a dialkyldialkoxytitanium reagent under conditions sufficient to produce a cyclopropanol compound;
- hydrolyzing the cyclopropanol compound to form a hemi-acetal compound;
- reacting the hemi-acetal compound under suitable Wittig reaction or olefination conditions to provide an olefin compound;
- subjecting the olefin compound to a carbonylative spirolactonization reaction to produce a compound having an oxaspirolactone moiety, the compound having the structure;
- and
- reacting a molecule having a terminal olefin with the compound having an oxaspirolactone moiety and a Z-selective catalyst under conditions suitable for a Z-selective cross metathesis reaction to produce tricyclic-PGDM methyl ester or a pharmaceutically acceptable salt thereof.
4 more elements
A method for synthesis of a tricyclic-prostaglandin D2 metabolite (PGDM) methyl ester or a pharmaceutically acceptable salt thereof, the method comprising:
- providing a first compound having a structure of the following formula:
- converting the first compound to the iodo-acetal compound and deprotecting a silyl ether moiety thereof, wherein the iodo-acetal compound has a structure of the following formula:
- reacting the iodo-acetal compound and the methyl ester with a nickel(II) chloride ethylene glycol dimethyl ether complex (NiCl2·glyme), neocupoine, methanol, and zinc oxide nanopowder to provide a cyclization product;
- reacting the cyclization product with ethyl magnesium bromide and a stoichiometric amount of CITi(OiPr)3 under conditions sufficient to produce a cyclopropanol compound, followed by deprotecting a silyl ether of the cyclopropanol compound;
- hydrolyzing the deprotected cyclopropanol compound to form a hemi-acetal compound having a structure of the following formula:
- reacting the hemi-acetal compound under suitable Wittig reaction or olefination conditions to provide an olefin compound, wherein the hemi-acetal compound is combined in a reaction solution with methyltriphenylphosphonium bromide (CH3PPh3Br), potassium hexamethyldisilazanide (KHMDS), and THF;
- subjecting the olefin compound to a carbonylative spirolactonization reaction to produce a compound having an oxaspirolactone moiety, the compound having a structure of the following formula:
- and
- reacting a molecule having a terminal olefin with the compound having an oxaspirolactone moiety and Ru—Z-Mes or Ru—Z-DIPP under conditions suitable for a Z-selective cross metathesis reaction to produce tricyclic-PGDM methyl ester or a pharmaceutically acceptable salt thereof.
6 more elements
Dependencies are inferred from the claim text.