Patent ID: 6340751
Filing Date: 2002-01-22
Classification: C07D,Y02P

Abstract:
A process for the preparation of a 4-substituted azetidinone derivative represented by the following formula (IV): wherein R represents a hydrogen atom or a protecting group for N, R1 represents a lower alkyl group which may be substituted by a protected or unprotected hydroxyl group, R2 represents a hydrogen atom or a lower C1-4 alkyl group, R3 represents (1) a C1-12 alkyl group, (2) a C2-5 alkenyl group, (3) a C1-6 organosilyl group selected from the group consisting of tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, triisopropylsilyl, dimethylthexylsilyl dimethylhexylsilyl and trimethylsilyl, (4) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom, (5) a C6-13 aralkyl group which may be substituted by a lower C1-4 alkyl group, (6) a 5- to 8-membered alicyclic group which may be substituted by a lower C1-4 alkyl group or (7) a naphthyl group, and R4 is an electron withdrawing group selected from a group consisting of â€”SO2R8, â€”C(&boxH;X)â€”Yâ€”R9, â€”C(&boxH;X)â€”R10, with the proviso that when R4 isâ€”SO2R8 R8 represents (1) a C1-12 alkyl group, (2) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom, (3) a benzyl group which may be substituted by a lower C1-4 alkyl group, (4) a 5- to 7-membered alicyclic group which may be substituted by a lower C1-4 alkyl group or (5) a naphthyl group; or R3 and R4 may form a heterocyclic ring together with the adjacent nitrogen atom, of the formula: wherein W represents an oxygen atom or a sulfur atom, and R12 to R23 are the same or different and each independently represents (1) a hydrogen atom, (2) a C1-2 alkyl group, (3) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom, (4) a benzyl group which may be substituted by a lower C1-4 alkyl group, (5) a 5- to 7-membered alicyclic group which may be substituted by a lower C1-4 alkyl group, or (6) a naphthyl group; or (7) any two of R12 to R23 on the same carbon atom may be coupled together to form a C4-6 alkylene group, (8) any two of R12 and R23 on the adjacent carbon atoms may form, together with the carbon atoms, an aromatic ring which may have a substituent wherein said substituent is a lower C1-4 alkyl group, a lower C1-4 alkoxy group, an aryl group, a hydroxy group or a halogen atom, (9) any two of R12 to R23 on the adjacent carbon atoms may be coupled together to form a C3-6 alkylene group, or (10) any two of R12 to R23 on the adjacent carbon atoms may form, together with the carbon atoms, a polycyclic group selected form the group consisting of: indan, norbornane, and 1,2,3,4-tetrahydronaphthalene;when R4 is â€ƒX represents an oxygen atom, a sulfur atom or an NR11 group, wherein R11 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted phenyl group, Y represents an oxygen atom or a sulfur atom, R9 represents (1) a C1-12 alkyl group, (2) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom, (3) a benzyl group which may be substituted by a lower C1-4 alkyl group, (4) a 5- to 7-membered alicyclic group which may be substituted by a lower C1-4 alkyl group or (5) a naphthyl group; or R4 may form a 4- to 6-membered ring together with R3 and the adjacent nitrogen of the formula: â€ƒwherein X and Y have the same meanings as defined above, Q represents an oxygen atom or a sulfur atom, and R24 to R32 are the same or different and each independently represents (1) a hydrogen atom, (2) a C1-12 alkyl group, (3) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom, (4) a benzyl group which may be substituted by a lower C1-4 alkyl group, (5) a 5- to 7-membered alicyclic group which may be substituted by a lower C1-4 alkyl group, or (6) a naphthyl group; or (7) any two of R24 to R31 on the same carbon atom may be coupled together to form a C4-6 alkylene group, (8) any two of R24 to R31 on the adjacent carbon atoms may form, together with the carbon atoms, an aromatic ring which may have a substituent wherein said substituent is a lower C1-4 alkyl group, a lower C1-4 alkoxy group, an aryl group, a hydroxy group or a halogen atom, (9) any two of R24 to R31 on the adjacent carbon atoms maybe coupled together to form a C3-6 alkylene, group, or (10) any two of R24 to R31 on the adjacent carbon atoms may form, together with the carbon atoms, a polycyclic group selected from the group consisting of: indan, norbornane, and 1,2,3,4-tetrahydronaphthalene; when R4 is â€ƒX represents an oxygen atom, a sulfur atom or an NR11 group, wherein R11 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted phenyl group, Y represents an oxygen atom or a sulfur atom, R10 represents (1) a C1-12 alkyl group, (2) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom, (3) a benzyl group which may be substituted by a lower C1-4 alkyl group, (4) a 5- to 7-membered alicyclic group which may be substituted by a lower C1-4 alkyl group or (5) a naphthyl group; or R4 may form a 4- to 6-membered ring together with R3 and the adjacent nitrogen of the formula: â€ƒwherein X has the same meaning as defined above, U represents an oxygen atom or a sulfur atom, and R32 to R47 are the same or different and each independently represents (1) a hydrogen atom, (2) a C1-12 alkyl group, (3) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom, (4) a benzyl group which may be substituted by a lower C1-4 alkyl group, (5) a 5- to 7-membered alicyclic group which may be substituted by a lower C1-4 alkyl group, or (6) a naphthyl group; or (7) any two of R32 to R47 on the same carbon atom may be coupled together to form a C4-6 alkylene group, (8) any two of R32 to R47 on the adjacent carbon atoms may form, together with the carbon atoms, an aromatic ring which may have a substituent wherein said substituent is a lower C1-4 alkyl group, a lower C1-4 alkoxy group, an aryl group, a hydroxy group or a halogen atom, (9) any two of R32 to R47 on the adjacent carbon atoms may be coupled together to form a C3-6 alkylene group, or (10) any two of R32 to R47 on the adjacent carbon atoms may form, together with the carbon atoms, a polycyclic group selected from the group consisting of: indan, norbornane, and 1,2,3,4-tetrahydronaphthalene; which comprises reacting an azetidinone derivative represented by the following formula (I): wherein R represents a hydrogen atom or a protecting group for N, Z represents an eliminative group and R1 has the same meaning as defined above, with an amide compound represented by the following formula (II): wherein R2, R3 and R4 have the same meaning as defined above, in the presence of a magnesium compound represented by the following formula (III):MgR5R6â€ƒâ€ƒ(III) wherein R5 represents (1) a C1-12 alkyl group, (2) a C2-5 alkenyl group, (3) a 5- to 8-member alicyclic group which may be substituted by a lower C1-4 alkyl group, (4) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group or a halogen atom, or (5) a benzyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group or a halogen atom, and R6 represents (1) a halogen atom, (2) a methanesulfonyloxy group, (3) a benzenesulfonyloxy group, (4) a p-toluenesulfonyloxy group, (5) a trifluoromethanesulfonyloxy group, (6) an acetoxy group which may be substituted by a halogen atom or a cyano group, or (7) an OR7 group wherein R7 represents a lower C1-4 alkyl group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted benzyl group.