US 12,466,791 B2
Methods for synthesis of the tricyclic prostaglandin D2 metabolite methyl ester
Mingji Dai, Alpharetta, GA (US); and Hunter Sims, Decatur, GA (US)
Assigned to Purdue Research Foundation, West Lafayette, IN (US)
Filed by Purdue Research Foundation, West Lafayette, IN (US)
Filed on Dec. 5, 2022, as Appl. No. 18/061,969.
Claims priority of provisional application 63/285,590, filed on Dec. 3, 2021.
Prior Publication US 2023/0174477 A1, Jun. 8, 2023
Int. Cl. C07C 405/00 (2006.01); C07C 67/14 (2006.01); C07C 201/00 (2006.01); C07D 307/935 (2006.01); C07D 493/04 (2006.01)
CPC C07C 405/0075 (2013.01) 6 Claims
 
1. 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

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 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

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(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

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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

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(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

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(e) hydrolyzing the deprotected cyclopropanol compound by combining the deprotected cyclopropanol compound with THF and HCl and stirring to form a hemi-acetal compound

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(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

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(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

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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

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wherein Ra is alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, heteroaryl, or acyl.