Patent EA-002056-B1 (EA)
Title: Endothelin intermediates by asymmetric conjugate addution reaction using a chiral additive
Inventor: TILLYER RICHARD D
IPC: C07D213/55
Filed: 1998-01-09
Abstract: 1. A process for the preparation of a compound of formula I:   wherein   represents: a) 5- or 6-membered heterocyclyl containing one, two or three double bonds, but at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R<4>, Br, Cl, F, I, CF3, N(R<5>)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R<5>)2, b) 5- or 6-membered carbocyclyl containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R<4>, Br, C1, F, I, CF3, N(R<5>)2, Cl-C8 alkoxy, Cl-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R<5>)2, c) aryl, wherein aryl is as defined below, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R<4>, Br, Cl, F, I, CF3, N(R<5>)2, C1-C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and  CO(CH2)nCH2N(R<5>)2, aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R<4>, Br, Cl, F, I, CF3, N(R<5>)2, C1-C8 alkoxy, Cl-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R<5>)2, and when two substituents are located on adjacent carbons they can join to form a 5- or 6 membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: H, OH, CO2R<6>, Br, Cl, F, I, CF3, N(R<7>)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R<5>)2, R<1> is: a) C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, b) aryl, or c) heteroaryl; heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R<4>, Br, Cl, F, I, CF3, N(R<5>)2 Cl-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R<5>)2, R<2> is OR<4> or N(R<5>)2; R<3> is a) H, b) C1-C8 alkyl, c) C1-C8 alkenyl, d) Cl-C8 alkynyl, e) Cl-C8 alkoxyl, f) C3-C7 cycloalkyl, g) S(O)tR<5>, h) Br, Cl, F, I, i) aryl, j) heteroaryl, k) N(R<5>)2, l) NH2, m) CHO, n) -CO-C1-C8 alkyl, o) -CO-aryl, p) -CO-heteroaryl, q) -CO2R<4>, or r) protected aldehyde; X and Y are independently: O, S, or NR<5>; n is: 0 to 5; t is: 0, 1 or 2; R<4> is Cl-C8 alkyl; R<5> is: C1-C8 alkyl, or aryl; and R<6> is: H, C1-C8 alkyl, and aryl; and R<7> are independently: H, C1-C8 alkyl, and aryl, when there are two R<7> substituents on a nitrogen they can join to form a 3 through 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R<4>, Br, Cl, F, I, CF3, N(R<5>)2, Cl-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R<5>)2; comprising reacting a α, β-unsaturated ester or amide    with an organolithium compound, R<1>Li, in the presence of a chiral additive,  wherein the chiral additive is selected from the group consisting of: a) (-)-sparteine, b) N,N,N' ,N' -tetra(C1 -C6)-alkyltrans- 1 ,2-diamino-cyclohexane, or c)    wherein R<8> and R<9> are independently: H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R<8> and R<9> cannot simultaneously be H; and R<10> is H, C1-C6 alkyl or aryl, and  an aprotic solvent, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl t-butyl ether, benzene, toluene, hexane, pentane, and dioxane, or a mixture of said solvents at a temperature range of about -78 degree C to about 0 degree C. 2. The process as recited in Claim 1, wherein the number of equivalents of the organolithium compound, R<1> Li, is 1 to about 4. 3. The process as recited in Claim 2, wherein the temperature range is about -78 degree C to about -20 degree C. 4. A process for the preparation of a compound of formula I:   wherein   represents: a) 5- or 6-membered heterocyclyl containing one, two or three double bonds, but at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R<4>, Br, Cl, F, I, CF3, N(R<5>)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R<5>)2, b) 5- or 6-membered carbocyclyl containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R<4>, Br, Cl, F, I, CF3, N(R<5>)2, Cl-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R<5>)2, c) aryl, wherein aryl is as defined below, C1-C8 alkoxy, C1-C8 alkyl, C2-Cg alkenyl, C2-Cg alkynyl, or C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R<4>, Br, Cl, F, I, CF3, N(R<5>)2, C1-C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R<5>)2, aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R<4>, Br, Cl, F, I, CF3, N(R<5>)2, C1-C8 alkoxy, Cl-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R<5>)2, and when two substituents are located on adjacent carbons they can join to form a 5- or 6 membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: H, OH, CO2R<6>, Br, Cl, F, I, CF3, N(R<7>)2, C1-C8 alkoxy, Cl-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R<5>)2, R<1> is: a) Cl-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, b) aryl, or c) heteroaryl; heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R<4>, Br, Cl, F, I, CF3, N(R<5>)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R<5>)2, R<2> is OR<4> or N(R<5>)2; R<3> is a) CHO, b) CH(oR<4>)2; n is: 0 to 5, t is: 0, 1 or 2; X and Y are independently: O, S, or NR<5>; R<4> is C1-C8 alkyl; R<5> is: C1-C8 alkyl, or aryl; R<6> is: H, C1-C8 alkyl, and aryl; R<7> are independently: H, Cl-C8 alkyl, and aryl, when there are two R<7> substituents on a nitrogen they can join to form a 3 through 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R<4>, Br, Cl, F, I, CF3, N(R<5>)2, C1-C8 alkoxy, Cl-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R<5>)2; comprising the steps of: 1) reacting α, β-unsaturated ester or amide   where R<3> is CH(OR<4>)2; with an organolithium compound, R<1>Li, in the presence of a chiral additive, wherein the chiral additive is selected from the group consisting of: a) (-)-sparteine, b) N,N,N' ,N' -tetra(C1-C6)-alkyltrans- 1 ,2-diamino-cyclohexane, or c)    wherein R<8> and R<9> are independently: H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R<8> and R<9> cannot simultaneously be H; and R<10> is H, C1-C6 alkyl or aryl, and an aprotic solvent at a temperature, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl t-butyl ether, benzene, toluene, hexane, pentane, and dioxane, or a mixture of said solvents range of about -78 degree C to about 0 degree C to give the conjugate adduct; and 2) removing the protecting group with an acid to give the compound of Formula I, where R<3> is CHO. 5. The process as recited in Claim 4, wherein the number of equivalents of the organolithium compound, R<1>Li, is 1 to about 4. 6. The process as recited in Claim 9, wherein the temperature range is about -78 degree C to about -20 degree C. 7. A process for the preparation of   comprising reacting α, β-unsaturated ester or amide   with an organolithium compound   in the presence of a chiral additive, wherein the chiral additive is selected from the group consisting of: a) (-)-sparteine, b) N,N,N' ,N' -tetra(C 1 -C6)-alkyltrans- 1 ,2-diamino-cyclohexane, or c)   wherein R<8> and R<9> are independently: H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R<8> and R<9> cannot simultaneously be H; and R<10> is C1-C6 alkyl or aryl. and an aprotic solvent, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl t-butyl ether, benzene, toluene, pentane, hexane, and dioxane, or a mixture of said solvents at a temperature range of about -78 degree C to about -20 degree C. 8. The process as recited in Claim 7, wherein the number of equivalents of the organolithium compound, R<1>Li, is 1 to about 4. 9. The process as recited in Claim 8, wherein the temperature range is about -78 degree  C to about -50 degree C. 10. The process as recited in Claim 9, wherein the number of equivalents of the organolithium compound, R<1> Li, is 1.5 to about 2.5. 11. The process as recited in Claim 10, wherein the number of equivalents of the organolithium compound, R<1> Li, is 1.5 to ab