Patent EA-002452-B1 (EA)
Title: Processes and intermediates useful to make antifolates
Inventor: KJELL DOUGLAS PATTON
IPC: C07C231/12
Filed: 1998-09-18
Abstract: 1. A compound of formula IV:   wherein: M is a metal cation; n is 1 or 2; R<2> is NHCH(CO2R<3>)CH2CH2CO2R<3> or OR<3>; R<3> is independently at each occurrence a carboxy protecting group; and X is a bond or C1-C4 alk-diyl. 2. The compound according to Claim 1 wherein X is a bond, -CH2-, or -CH2CH2- and R<2> is NHC*H(CO2R<3>)CH2CH2CO2R<3> or OR<3> where the configuration about the carbon atom designated * is L. 3. The compound according to Claim 2 wherein X is -CH2-. 4. The compound according to Claim 1 wherein M is an alkali metal cation and n is 1 and R<2> is NHC*H(CO2R<3>)CH2CH2CO2R<3> or OR<3> where the configuration about the carbon atom designated * is L. 5. The compound according to Claim 4 wherein the alkali metal is sodium. 6. The compound according to Claim 1 wherein M is sodium, n is 1, X is -CH2-, and R<2> is NHC*H(CO2R<3>)CH2CH2CO2R<3> or OR<3> where the configuration about the carbon atom designated * is L. 7. A process for preparing a compound of formula III:   wherein: R<2> is NHCH(CO2R<3>)CH2CH2CO2R<3> or OR<3>; R<3> is independently at each occurrence a carboxy protecting group; and X is a bond or C1-C4 alk-diyl; comprising: reacting a compound of formula IV:   wherein: X and R<2> are defined above for formula III; M is a metal cation; and n is 1 or 2; with a trialkylsilyl halide in a solvent. 8. The process according to Claim 7 wherein the compound of formula IV is a compound wherein X is a bond, -CH2-, or -CH2CH2- and R<2> is NHC*H(CO2R<3>)CH2CH2CO2R<3> or OR<3> where the configuration about the carbon atom designated * is L. 9. The process according to Claim 8 wherein X is -CH2-. 10. The process according to Claim 7 wherein the compound of formula IV is a compound wherein M is an alkali metal cation, n is 1 and R<2> is NHC*H(CO2R<3>)CH2CH2CO2R<3> or OR<3> where the configuration about the carbon atom designated * is L. 11. The process according to Claim 10 wherein the alkali metal is sodium. 12. The process according to Claim 7 wherein the solvent is acetonitrile, the trialkylsilyl halide is trimethylsilyl chloride, and the reaction is performed at a temperature between 50 degree C and 70 degree C. 13. The process according to Claim 12 wherein the compound of formula IV is a compound wherein M is sodium, n is 1, X is -CH2-, and R<2> is NHC*H(CO2R<3>)CH2CH2CO2R<3> or OR<3> where the configuration about the carbon atom designated * is L. 14. A process for preparing a compound of formula IV:   wherein: M is a metal cation; n is 1 or 2; R<2> is NHCH(CO2R<3>)CH2CH2CO2R<3> or OR<3>; R<3> is independently at each occurrence a carboxy protecting group; X is a bond or C1-C4 alk-diyl; comprising: reacting a compound of formula III:   wherein: R<2> and X are as defined above for formula IV; with a compound of the formula M(HSO3<->)n, wherein: M is defined above for formula IV; and n is 1 or 2. 15. The process according to Claim 14 wherein the compound of formula III is a compound wherein X is a bond, -CH2-, or -CH2CH2- and R<2> is NHC*H(CO2R<3>)CH2CH2CO2R<3> or OR<3> where the configuration about the carbon atom designated * is L. 16. The process according to Claim 15 wherein X is -CH2-. 17. The process according to Claim 16 wherein the compound of the formula M(HSO3-)n is a compound wherein M is an alkali metal cation and n is 1 and the reaction is performed at a temperature between 35 degree C and 50 degree C. 18. The process according to Claim 17 wherein the alkali metal is sodium. 19. The process according to Claim 14 wherein the solvent is a mixture of ethyl acetate, 3A-ethanol, and water. 20. The process according to Claim 14 further comprising: reacting a compound of formula I:   wherein: R<4> is hydrogen or C1-C4 alkyl; and X' is a bond or C1-C4 alk-diyl; with the proviso that if X' is not a bond, then the carbon alpha to the alcohol must be a -CH2- moiety; with a compound of formula II:   wherein: R<2> is defined above for formula IV; and Lg is a leaving group; in a solvent, in the presence of a palladium catalyst and a phase transfer catalyst, and optionally in the presence of a metal cation chloride, to afford a compound of formula III. 21. A process according to Claim 7 further comprising: a) halogenating a compound of formula III to form a compound of formula V:   wherein: R<2> and X are as defined above for formula III; and halo is chloride, bromide, or iodide; in a solvent; and b) adding to the product of step a) a base and a compound of formula VI:   c) optionally removing carboxy protecting groups from the product of step b); and d) optionally salifying the product of step b) or step c) to afford a compound of formula VII:   wherein: R is NHCH(CO2R<1>)CH2CH2CO2R<1> or OR<1>; and R<1> is independently at each occurrence hydrogen or a carboxy protecting group; or a pharmaceutical salt or solvate thereof. 22. A process according to Claim 21 wherein the compound of formula V is a compound wherein X is a bond, -CH2-, or -CH2CH2- and R<2> is NHC*H(CO2R<3>)CH2CH2CO2R<3> or OR<3> where the configuration about the carbon atom designated * is L. 23. A process according to Claim 22 wherein step a) of Claim 21 is performed at a temperature between 35 degree C and 45 degree C. 24. A process according to Claim 22 wherein the compound of formula VII is a compound wherein R is NHCH (CO2R<1>) CH2CH2CO2R<1>. 25. A process according to Claim 24 wherein the compound of formula V is a compound wherein X is -CH2-. 26. A process according to Claim 25 wherein step c) of Claim 21 is performed and the compound of formula VII is the sodium hydroxide base addition salt. 27. A compound of formula IV according to Claim wherein the compound is selected from the group consisting of: 1-hydroxy-3-(4-carbomethoxyphenyl) propanesulfonic acid sodium salt; 1-hydroxy-3-(4-carboethoxyphenyl) propanesulfonic acid potassium salt; 1-hydrxy-2,3-dimethyl-4-(4carbomethoxyphenyl) butanesulfonic acid lithium salt; N-(4-[(3-hydroxy-3-sulfonic acid sodium salt)propyl]benzoyl)-L-glutamic acid dimethyl ester; N-(4-[(3-hydroxy-3-sulfonic acid potassium salt)propyl]benzoyl)-L-glutamic acid dimethyl ester; N-(4-[(1,2-dimethyl-4-hydroxy-4-sulfonic acid lithium salt)butyl]benzoyl)-L-glutamic acid dipropyl ester is substantially as hereinbefore described with reference to any of the Examples