Methods for synthesis of the tricyclic prostaglandin D2 metabolite methyl ester

A method for synthesis of a tricyclic-prostaglandin D2 metabolite (PGDM) methyl ester or a pharmaceutically acceptable salt thereof, the method comprising:

• (a) converting a first compound having the structure
• to an iodo-acetal compound by:
• (1) combining the first compound with anhydrous dichloromethane (DCM) and N-iodosuccinimide to form a solution;
• and
• (2) adding ethyl vinyl ether to the solution and mixing at about −20° C. for at least 30 minutes and mixing at about 0° C. for at least 4 hours to produce the iodo-acetal compound having the structure
• (b) subjecting the iodo-acetal compound to either a first cyclization reaction with a methyl ester or a second cyclization reaction with a methyl ester to provide a cyclization product having the structure
• wherein the first cyclization reaction comprises:
• combining the iodo-acetal compound with 2,2′-azobis (2-methylpropionitrile) (AIBN), sodium cyanoborohydride (NaCNBH3), tert-Butyl alcohol (BuOH), methyl acrylate, and nBu3SnCl to form an iodo-acetal solution;
• and
• heating the iodo-acetal solution to about 85° C. and mixing for at least 72 hours to produce the cyclization product;
• and
• wherein the second cyclization reaction comprises:
• combining the iodo-acetal compound with nickel (II) chloride ethylene glycol dimethyl ether complex and neocuproine to form a mixture;
• stirring the mixture at room temperature for at least 10 minutes, and then to 40° C. for at least 10 minutes;
• and
• adding Zn nanopowder and methyl acrylate and stirring at 40° C. for at least 1 hour to produce the cyclization product;
• (c) reacting the cyclization product to form a cyclopropanol compound by:
• combining the cyclization product with ClTi(OiPr)3 or titanium tetrachloride/tetra n-butyl titanate (TiCl4) to form a second solution;
• and
• adding a Grignard reagent and mixing at about 0° C. for at least one hour and then to room temperature for at least 30 minutes to produce the cyclopropanol compound having the structure
• (d) deprotecting the cyclopropanol compound to form a deprotected cyclopropanol compound by:
• combining the cyclopropanol compound with anhydrous tetrahydrofuran (THF) to form a third solution and cooling to about 0° C.;
• adding tetra-n-butylammonium fluoride (TBAF) and allowing the third solution to warm to room temperature;
• and
• mixing the third solution for at least 43 hours to give the deprotected cyclopropanol compound having the structure
• (e) hydrolyzing the deprotected cyclopropanol compound by combining the deprotected cyclopropanol compound with THF and HCl and stirring to form a hemi-acetal compound
• (f) reacting the hemi-acetal compound by:
• combining methyltriphenylphosphonium bromide (CH3PPh3Br) with anhydrous THF, and potassium hexamethyldisilazanide (KHMDS) and mixing at room temperature for at least 1 hour and, subsequently, mixing at about 0° C. for at least another 1 hour to form a cooled ylide solution;
• combining the cooled ylide solution and a hemi-acetal solution comprising the hemi-acetal and THF;
• and
• stirring the combined hemi-acetal and cooled ylide solution at about 0° C. for at least 37 minutes to form an olefin compound having the structure
• (g) subjecting the olefin compound to a carbonylative spirolactonization reaction by:
• to form a solution, combining and mixing (1) the olefin compound with anhydrous benzene or anhydrous THE, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), and (2) palladium(II) acetate (Pd(OAc)2) or palladium(II) trifluoroacetate (Pd(TFA)2;
• and
• quenching the solution with triethyl amine (TEA) and mixing for at least 30 minutes to produce a compound having an oxaspirolactone moiety having the structure
• and
• (h) combining the compound having an oxaspirolactone moiety with a solvent, dichloroethane (DCE) or THF, a molecule having a terminal olefin, and a Z-selective catalyst comprising Ru-Mes or DIPP, and allowing the resulting combination to mix for at least 2 hours at between 30-53° C. to produce tricyclic-PGDM methyl ester or a pharmaceutically acceptable salt thereof;
• wherein the molecule having a terminal olefin has the structure
• wherein Ra is alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, heteroaryl, or acyl.