Patent GB-1421951-A (GB)
Title: Complexed copper-lithium reagents and their use in the preparation of prostaglandins
IPC: C07C405/00
Filed: 1973-05-08
Abstract: 1421951 Complexed copper-lithium reagents SYNTEX CORP 8 May 1973 [12 May 1972] 21975/73 Headings C2C and C2J A composition useful in the preparation of prostaglandins consists essentially of a (dl) or optically active (S) isomer mixture of compounds of the formulae where OR is an acid labile ether group, X is a halide and the " t " indicates the trans configuration, complexed by an electron rich neutral complexing agent, in an inert organic solvent mixture. The complexing agent may be a tri(C 1-4 ) alkyl phosphme or phosphite, bis- (trimethyl phosphite) copper (I) iodide, an alkyl alkylene diamine of formula where n is 2 or 3 and R<SP>1</SP> 2 -R<SP>1</SP> 4  are C 1-4  alkyl, a naphthalene bridge diamine of formula an alkylpiperazine of formula or a polycyclic diazoheterocyclic such as sparteine. The group OR may particularly be methoxymethoxy, 2<SP>1</SP>-methoxyprop-2<SP>1</SP>-oxy or tetrahydropyranyl-2<SP>1</SP>-oxy and the solvent mixture may especially comprise hexane and diethyl ether. Certain of the compositions are prepared by (a) admixing a C 1-4  n-alkyl lithium or mixture thereof and (dl)- or (S)-1-iodo-trans-1 octen-3-ol or mixture thereof at about from -100 to -50 C. for about from 1 to 60 minutes in an alkane solvent having in melting point below the treatment temperature; (b) admixing a copper (I) halide and a tri-(C 1-4 ) alkyl phosphite or phosphine in an ether solvent having a melting point below the treatment temperature subsequently used in step (c), or dissolving bis-(trimethylphosphite) copper (I) iodide in such solvent; and (c) admixing the product mixtures of steps (a) and (b) at about from -80 to -20 C. for about from five minutes to 6 hours. When the complexing agent is a tetraalkylalkylene diamine of the above general formula, the composition is prepared by; step (a) as above; (b) admixing the diamine and the product solution of step (a) at about from -100 to -50 C. for about from 1-60 minutes; (c) dissolving a copper (I) halide in an ether solvent having a melting point below the treatment temperature subsequently used in step (e); (d) cooling the solution of step (c) to about from -100 to -50 C.; and (e) admixing the product solutions of steps (b) and (d) at about from -100 to -50C., raising the temperature of the admixture to about from -50 to 0 C. and maintaining it within this range for about from five minutes to six hours. Prostaglandins and prostaglandin derivatives are prepared by treating a compound of general Formula V where R<SP>2</SP> is H or a C 3-10  acid labile ether group and R<SP>3</SP> is C 1-10  alkyl, chloroethyl, dichloroethyl or trichloroethyl, with a reagent composition as described above at about from -100 to -30 C. for about from five minutes to 24 hours to yield products of the formulae where #OR is an acid labile ether group corresponding to and having the same (dl) or (S) configuration as that present in thd complexed copper-lithium reagent. The following starting materials and intermediates are also prepared:- The compounds of Formula V above; methyl, ethyl and hexyl 3 - hydroxy - 5 - oxo - 1 - cyclopentene - 1- heptanoate, methyl, ethyl and hexyl 3- bromo - 5 - oxo - 1 - cyclopentene - 1 - heptanoate, methyl, ethyl and hexyl 5 - oxo - 1- cyclopentene - 1 - heptanoate, methyl, ethyl and hexy 1 - bromo - 2 - oxocyclopentaneheptanoate, methyl, ethyl and hexyl 2- acetoxy - 1 - cyclopentene - 1 - heptanoate, dl - 1 - iodo - trans - 1 - octen - 3 - ol, (3s) - 1- iodo - trans - 1 - octen - 3 - ol, (3s) - 3 - (2 - tetrahydropyranyloxy) - 1 - octyne, 1 -iodo -trans-1- octen-3-one, and compounds of the formula