Patent EA-002204-B1 (EA)
Title: Processes and internediates for preparing substituted chromanol derivatives
Inventor: PISCOPIO ANTHONY D
IPC: C07F5/04
Filed: 1997-08-25
Abstract: 1. A process of preparing a compound of the formula   or the enantiomer of said compound, wherein in said compound of formula X the R<3>-substituted benzoic acid moiety is attached at carbon 6 or 7 of the chroman ring; R<1> is -(CH2)qCHR<5>R<6> wherein q is 0 to 4; each R<2> and R<3> is independently selected from the group consisting of H, fluoro, chloro, (C1-C6)alkyl, (C1-C6)alkoxy, phenylsulfinyl, phenylsulfonyl, and -S(O)n((C1-C6)alkyl) wherein n is 0 to 2, and wherein said alkyl group, the alkyl moiety of said alkoxy and -S(O)n((C1-C6)alkyl) groups, and the phenyl moiety of said phenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1 to 3 fluoro groups;  R<5> is H, (C1-C6) alkyl, or phenyl substituted by R<2>; R<6> is H, (C1-C6) alkyl, (C3-C8) cycloalkyl, phenyl, naphthyl, piridyl, furyl, thienyl, isoquinoline, pirimidinyl or pirazinyl, wherein last eight groups are optionally substituted by 1 or 2 substituents independently selected from phenyl, R<2>, and phenyl substituted by 1 or 2 R<2>; wherein a compound of the formula   or the enantiomer of said compound of formula IX in the preparation of the enantiomer of said compound of formula X, wherein R<1> , R<2>, and R<3> are as defined above, R<4> is (C1-C6) alkyl, and the benzoate moiety is attached to position 6 or 7 of the chroman ring is treated with a base. 2. The process of Claim 1 wherein the compound of formula IX, or the enantiomer of said compound, is prepared by treating a compound of the formula   or the enantiomer of said compound of formula VII in the preparation of the enantiomer of said compound of formula IX, wherein R<1> and R<2> are as defined in Claim 1 and the boronic acid moiety is attached at position 6 or 7 of the chroman ring, with a compound of the formula   wherein R<3> and R<4> are as defined in Claim 1 and Z is halo or (C1-C4)perfluoroalkylsulfonate, in the presence of a base or fluoride salt and a palladium catalyst. 3. The process of Claim 2 wherein the compound of formula VII, or the enantiomer of said compound, wherein R<1> and R<2> are as defined in Claim 2, is prepared by treating a compound of the formula   or the enantiomer of said compound of formula VI in the preparation of the enantiomer of said compound of formula VII, wherein R<1> and R<2> are as defined in Claim 2 and X is a halide and is attached at position 6 or 7 of the chroman ring, with (1) (C1-C4)alkyllithium, and (2) a borating agent. 4. The process of Claim 3 wherein the compound of formula VI, or the enantiomer of said compound, wherein R<1>, R<2> and X are as defined in Claim 3, is prepared by treating a compound of the formula   or the enantiomer of said compound of formula V in the preparation of the enantiomer of said compound of formula VI, wherein R<1>, R<2> and X are as defined in Claim 3 and X is attached at position 4 or 5 of the phenyl ring, and Y is halo or nitro, with a base, optionally in the presence of added copper salts. 5. The process of Claim 4 wherein the compound of formula V, or the enantiomer of said compound, wherein R<1>, R<2>, X and Y are as defined in Claim 4, is prepared by treating a compound of the formula   or the enantiomer of said compound of formula IV in the preparation of the enantiomer of said compound of formula V, wherein R<1>, R<2>, X and Y are as defined in Claim 4 and X is attached at position 4 or 5 of the phenyl ring, and Xc is a (R)-4-benzyl-2-oxasolidynon, (S)-4-benzyl-2-oxasolidynon, (4R,5S)-4-methyl-5-phenyloxazolidin-2-one or (4S,5R)-4-methyl-5-phenyloxazolidin-2-one attached to nitrogen atom of oxazolidin-2-one ring, with a hydride reducing agent. 6. The process of Claim 5 wherein the compound of formula IV, or the enantiomer of said compound, wherein R<1>, R<2>, X, Xc and Y are as defined in Claim 5, is prepared by treating a compound of the formula R<1>-CH2C(O)-Xc, wherein R<1> and Xc are as defined above, with (1) a Lewis acid, (2) a base, and (3) a compound of formula   wherein R<2>, X and Y are as defined in Claim 5 and X is attached at position 4 or 5 of the phenyl ring. 7. The process of Claim 5 wherein the compound of formula IV, or the enantiomer of said compound of formula IV, wherein R<1>, R<2>, X, Xc and Y are as defined in Claim 5. is prepared by treating a compound of the formula R<1>-CH2C(O)-Xc wherein R<1> and Xc are as defined in Claim 5, with (1) a titanium(IV) halide, (2) a base optionally followed by treatment with a donor ligand, and (3) a compound of formula   wherein R<2>, X and Y are as defined in Claim 5 and X is attached at position 4 or 5 of the phenyl ring. 8. The process of Claim 1 wherein the compound of formula IX, or the enantiomer of said compound, wherein R<1> , R<2>, R<3> and R<4> are as defined in Claim 1, is prepared by coupling a compound of the formula   or the enantiomer of said compound of formula VI in the preparation of the enantiomer of said compound of formula IX, wherein R<1> and R<2> are as defined in Claim 1 and X', which is attached at position 6 or 7 of the chroman ring, is halo or (C1-C4)perfluoroalkylsulfonate, with a compound of the formula   wherein R<3> and R<4> are as defined in Claim 1, in the presence of a base or fluoride salt and a palladium catalyst. 9. The process of Claim 8 wherein the compound of formula XIV wherein R<3> and R<4> are as defined in Claim 8, is prepared by hydrolyzing a compound of the formula   wherein R<3> and R<4> are as defined in Claim 8, the dashed line indicates a bond or no bond between the B and N atoms, n and m are independently 2 to 5, and R<8> is H or (C1-C6)alkyl. 10. The process of Claim 9 wherein the compound of formula XVI, wherein R<3>, R<4> and R<8> are as defined in Claim 9, is prepared by reacting a compound of formula   wherein R<3> and R<4> are as defined in Claim 9, with a compound of formula HO(CH2)m-N(R<8>)-(CH2)nOH, wherein n, m, and R<8> are as defined in Claim 9. 11. The process of Claim 8 wherein the compound of formula XIV, wherein R<4> and R<3> are as defined in Claim 8, is prepared by hydrolyzing a compound of the formula   wherein R<3> and R<4> are as defined in Claim 8 and R<7> is (C1-C6) alkyl. 12. The process of Claim 11 wherein the compound of formula XIII, wherein R<3>, R<4> and R<7> are as defined in Claim 11, is prepared by treating a compound of the formula   wherein R<3> and R<4> are as defined in Claim 11, with a metalamide base in the presence of tri-((C1-C6)alkyl)borate. 13. The process of Claim 1 and further comprising reacting the compound of formula X, or the enantiomer of said compound, wherein R<1>, R<2>, and R<3> are as defined in Claim 1, with a secondary amine of the formula NHR<5>R<6>, wherein R<5> and R<6> are as defined in Claim 1, to form an ammonium carboxylate of the formula   or the enantiomer of said compound of formula XVII when prepared from the enantiomer of said compound of the formula X, wherein R<1>, R<2>, R<3>, R<5> and R<6> are as defined in Claim 1. 14. A process of preparing a compound of the formula   or the enantiomer of said compound, wherein R<1> is -(CH2)qCHR<5>R<6> wherein q is 0 to 4; each R<2> is independently selected from the group consisting of H, fluoro, chloro, (C1-C6)alkyl, (C1-C6)alkoxy, phenylsulfinyl, phenylsulfonyl, and -S(O)n((C1-C6)alkyl) wherein n is 0 to 2, and wherein said alkyl group, the alkyl moiety of said alkoxy and -S(O)n((C1-C6)alkyl) groups, and the phenyl moiety of said phenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1 to 3 fluoro groups; R<5> is H, (C1-C6) alkyl, or phenyl substituted by R<2>; R<6> is H, (C1-C6) alkyl, (C3-C8) cycloalkyl, phenyl, naphthyl, piridyl, furyl, thienyl, isoquinoline, pirimidinyl or pirazinyl, wherein last eight groups are optionally substituted by 1 or 2 substituents independently selected from phenyl, R<2>, and phenyl substituted by 1 or 2 R<2>; Xc is a (R)-4-benzyl-2-oxasolidynon, (S)-4-benzyl-2-oxasolidynon, (4R,5S)-4-methyl-5-phenyloxazolidin-2-one or (4S,5R)-4-methyl-5-phenyloxazolidin-2-one attached to nitrogen atom of oxazolidin-2-one ring, and, R<11> is (C1-C9)alkyl, (C2-C9)alkenyl or phenyl substituted by Y in the 2 position, X in the 4 or 5 position, and R<2> in one of the remaining positions of the phenyl moiety, wherein Y is halo, nitro or (C1-C4)alkoxy, and X is a halide, which comprises treating a compound of the formula R<1>-CH2C(O)-Xc, wherein R<1> and Xc are as defined above, with (1) a titanium(lV) halide, (2) a base optionally followed by treatment with a donor ligand, and (3) less than 2 equivalents of a compound of the formula R<11>C(O)H, wherein R<11> is as defined above, relative to the amount of said compound of formula R<1>-CH2C(O)-Xc. 15. A compound of the formula   or the enantiomer of said compound, wherein R<1> is (CH2)qCHR<5>R<6> wherein q is 0 to 4; each R is independently selected from the group consisting of H, fluoro, chloro, (C1-C6)alkyl, (C1-C6)alkoxy, phenylsulfinyl, phenylsulfonyl, and -S(O)n((C1-C6) alkyl) wherein n is 0 to 2, and wherein said alkyl group, the alkyl moiety of said alkoxy and -S(O)n((C1-C6) alkyl) groups, and the phenyl moiety of said phenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1 to 3 fluoro groups; R<5> is H, (C1-C6) alkyl, or phenyl substituted by R<2>; R<6> is H, (C1-C6) alkyl, (C3-C8) cycloalkyl, phenyl, naphthyl, piridyl, furyl, thienyl, isoquinoline, pirimidinyl or pirazinyl, wherein last eight groups are optionally substituted by 1 or 2 substituents independently selected from phenyl, R<2>, and phenyl substituted by 1 or 2 R<2>; X is a halo group and is attached at position 4 or 5 of the phenyl ring; and, Y is halo or nitro. 16. A compound of the formula   or the enantiomer of said compound, wherein R<1> is -(CH2)qCHR<5>R<6> wherein q is 0 to 4; each R<2> is independently selected from the group consisting of H, fluoro, chloro, (C1-C6) alkyl, (C1-C6) alkoxy, phenylsulfinyl, phenylsulfonyl, and -S(O)n((C1-C6) alkyl) wherein n is 0 to 2, and wherein said alkyl group, the alk