Patent EA-002723-B1 (EA)
Title: Processes and intermediates useful to make antifolates
Inventor: BARNETT CHARLES JACKSON
IPC: C07D307/68
Filed: 1999-01-27
Abstract: 1. A. compound of formula III:   where: Y is CH=CH, O, or S; R is C1-C6 alkyl; R<1> and R<2> are independently C1-C6 alkyl or taken together with the nitrogen to which they are attached form a heterocycle; R<3> is hydrogen, chloro, or fluoro; R<4> is hydroxy, a carboxy protecting group, or NHC*H(C(O)R<5>)CH2CH2C(O)R<5> where the configuration about the carbon atom designated * is S; and R<5> is hydrogen or a carboxy protecting group; or a salt or solvate thereof. 2. A compound according to Claim 1 where Y is CH=CH or S, R is C1-C4 alkyl, R<1> and R<2> are independently C1-C4 alkyl, R<3> is hydrogen, and R<4> is C1-C4 alkoxy or benzyloxy; or a salt or solvate thereof. 3. A compound according to Claim 2 where R is methyl or ethyl, R<1> and R<2> are both methyl or ethyl, and R<4> is methoxy, ethoxy, or benzyloxy; or a salt or solvate thereof. 4. A compound of formula IV:   where: Y is CH=CH, O or S; R<3> is hydrogen, chloro or fluoro; R<4> is hydroxy, a carboxy protecting group. or NHC*H(C(O)R<5>)CH2CH2C(O)R<5> where the configuration about the carbon atom designated * is S; R<5> is hydrogen or a carboxy protecting group; R<6> is hydrogen or an amino protecting group; and R<7> is hydroxy; or a salt or solvate thereof. 5. A compound according to Claim 4 where Y is CH=CH or S and R<3> is hydrogen; or a salt or solvate thereof. 6. A compound according to Claim 5 where R<4> is methoxy, ethoxy, benzyloxy. or NHC*H(C(O)R<5>)CH2CH2C(O)R<5>;R<5> is C1-C6 alkyl; R<6> is an amino protecting group; and R<7> is hydroxy; or a salt or solvate thereof. 7. A compound according to Claim 6 where R<4> is NHC*H(C(O)R<5>)CH2CH2C(O)R<5 >; or a salt or solvate thereof. 8. A process for preparing a compound of formula IV:   where: Y is CH=CH, O, or S; R<3> is hydrogen, chloro, or fluoro; R<4> is hydroxy, a carboxy protecting group, or NHC*H(C(O)R<5>)CH2CH2C(O)R<5 >where the configuration about the carbon atom designated * is S; and R<5> is hydrogen or a carboxy protecting group; R<6> is hydrogen or an amino protecting group; and R<7> is hydroxy or amino; or a salt or solvate thereof; comprising: a) reacting a compound of formula III(a):   where: R is C1-C6 alkyl; R<1> and R<2> are independently C1-C6 alkyl or taken together with the nitrogen to which they are attached form a heterocycle; R<4>' is a carboxy protecting group or NHC*H(C(O)R<5>)CH2CH2C(O) 5', where the configuration about the carbon atom designated * is S; and R<5>' is a carboxy protecting group; with 2,4-diamino-6-hydroxypyrimidine in the presence of a suitable acid and solvent; b) optionally installing an amino protecting group at R<6>; and c) optionally removing any carboxy protecting groups at R4'. 9. A process according to Claim 8 where the compound of formula IV is a compound where R<7> is hydroxy, Y is CH=CH or S, and R<3> is hydrogen; or a salt or solvate thereof. 10. A process according to Claim 9 where the compound of formula III(a) is a compound where R<4>' is methoxy, ethoxy, or benzyloxy; or a salt or solvate thereof; and step b) of Claim 7 is performed. 11. A process according to Claim 10 where the compound of formula IV is a compound where R<6> is 2,2-dimethyl-1-oxopropyl; or a salt or solvate thereof. 12. A process according to Claim 8 where the acid is acetic acid and the solvent is acetonitrile. 13. A process for preparing a compound of formula IV:   where: Y is CH=CH, O, or S; R<3> is hydrogen, chloro, or fluoro; R<4> is hydroxy, a carboxy protecting group, or NHC*H(C(O)R<5>)CH2CH2C(O)R<5>, where the configuration about the carbon atom designated * is S; and R<5> is hydrogen or a carboxy protecting group; R<6> is hydrogen or an amino protecting group; and R7 is hydroxy or amino; or a salt or solvate thereof; comprising: a) reacting a compound of formula V(b):   where: R<4>' is a carboxy protecting group or NHCH(C(O)R<5>')CH2CH2C(O)R<5>'; and R<5>' is a carboxy protecting group; or a salt or solvate thereof; with an oxidizing reagent in the presence of a suitable solvent; and b) optionally removing any carboxy protecting groups at R<4>' and/or at R<6>; with the proviso that if R<6> is hydrogen in the compound of formula V(b) then the compound of formula V(b) must be an acid addition salt. 14. A process according to Claim 13 where the compound of formula IV is a compound where Y is CH=CH or S and R<3> is hydrogen; or a salt or solvate thereof. 15. A process according to Claim 14 where the compound of formula V(b) is a compound where R<4>' is NHCH(C(O)R<5>')CH2CH2C(O)R<5>', R<5>' is C1-C6 alkyl; R<6> is an amino protecting group; and R<7> is hydroxy; or a salt or solvate thereof. 16. A process according to Claim 15 where the compound of formula V(b) is a compound where R<5>' is methyl or ethyl and R<6> is 2,2-dimethyl-1-oxopropyl; or a salt or solvate thereof. 17. A process according to Claim 13 where the oxidizing agent is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the solvent is dichloromethane. 18. A process for preparing a compound of formula IV:   where: Y is CH=CH, O, or S; R<3> is hydrogen; R<4> is hydroxy, a carboxy protecting group, or NHC*H(C(O)R<5>)CH2CH2C(O)R<5>, where the configuration about the carbon atom designated * is S; and R<5> is hydrogen or a carboxy protecting group; R<6> is hydrogen or an amino protecting group; and R7 is hydroxy; or a salt or solvate thereof; comprising: a) reacting a compound of formula V(b):   where: R<4>' is a carboxy protecting group or NHCH(C(O)R<5>')CH2CH2C(O)R<5>'; and R<5>' is a carboxy protecting group; or a salt or solvate thereof; with an oxidizing reagent in the presence of a suitable solvent; and b) optionally removing any carboxy protecting groups at at R<6>; c) optionally hydrogenating a compound of formula IV(d): in a suitable solvent; to form a mixture comprising compounds of formula V(f) (R) and V(f) (S):   or a salt or solvate of each thereof.