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Details for Patent: 5,631,365

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Details for Patent: 5,631,365

Title: Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
Abstract:A process for preparing compounds of the formula ##STR1## wherein R and R.sup.2 are independently --OH, --O(lower alkyl) or --0-benzyl and the remaining variables are as defined in the specification, comprising (a) treating with a strong base in an anhydrous organic solvent a lactone of the formula ##STR2## respectively, wherein Ar.sup.10 is Ar.sup.1 or a suitably protected hydroxy- or amino-substituted aryl, and R' and R.sup.2' are R and R.sup.2 as defined above or are suitably protected hydroxy groups; (b) reacting a product of step (a) with an imine of the formula ##STR3## wherein Ar.sup.20 and Ar.sup.30 are Ar.sup.2 or Ar.sup.3 or suitably protected hydroxy- or amino-substituted aryl; c) quenching the reaction with an acid; and d) removing protecting groups as necssary.
Inventor(s): Rosenblum; Stuart B. (West Orange, NJ), Dugar; Sundeep (Bridgewater, NJ), Burnett; Duane A. (Fanwood, NJ), Clader; John W. (Cranford, NJ), McKittrick; Brian A. (Bloomfield, NJ)
Assignee: Schering Corporation (Kenilworth, NJ)
Filing Date:Jun 09, 1994
Application Number:08/257,593
Claims:1. A process for preparing a compound of the formula ##STR69## wherein: Ar.sup.1 and Ar.sup.2 are independently selected from the group consisting of aryl and R.sup.4 -substituted aryl;

Ar.sup.3 is aryl or R.sup.5 -substituted aryl;

X, Y and Z are independently selected from the group consisting of --CH.sub.2 --, --CH(lower alkyl)- and --C(dilower alkyl)-;

R is --OH, --O(lower alkyl) or --O-- benzyl:

R.sup.1 and R.sup.3 are independently selected from the group consisitng of hydrogen, lower alkyl and aryl;

q is 0 or 1; m and n are independently 0, 1, 2, 3 or 4, and p is 0, 1, 2, 3 or 4; provided that the sum of m, n, p and q is 1, 2, 3, 4, 5 or 6;

R.sup.4 is 1-5 substituents independently selected from the group consisting of lower alkyl, --OH, --O(lower alkyl), --O-benzyl, --NR .sup.6 R.sup.7, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, -(lower alkylene)COOR.sup.6, --CH.dbd.CH--COOR.sup.6, --CF.sub.3, --CN, --NO.sub.2 and halogen;

R.sup.5 is is 1-5 substituents independently selected from the group consisting of --OH, --O(lower alkyl), --O-benzyl, --NR.sup.6 R.sup.7, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, -(lower alkylene)-COOR.sup.6 and --CH.dbd.CH--COOR.sup.6 ;

R.sup.5, R.sup.7 and R.sup.8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

R.sup.9 is lower alkyl, aryl or aryl-substituted lower alkyl, comprising:

(a) treating with a strong base in an anhydrous organic solvent a lactone of the formula ##STR70## wherein X, Y, Z, R', R.sup.3, m, n, p and q are as defined above, R' is R as defined above or a suitably protected hydroxy group, and Ar.sup.10 is Ar.sup.1 as defined above, a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl;

(b) reacting the product of step (a) with an Imine of the formula ##STR71## wherein Ar.sup.20 is Ar.sup.2, a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl, and Ar.sup.30 is Ar.sup.3, a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl;

c) quenching the reaction with an acid; and

d) removing as necessary a protecting group from any of substituents R', Ar.sup.10, Ar.sup.20 and Ar.sup.30 to obtain a compound wherein R, Ar.sup.1, Ar.sup.2 and Ar.sup.3 are as defined above.

2. The process of claim 1 further comprising converting a compound as defined in claim 1 having a hydroxy substituent at R, or a hydroxy or amino substituent at any of Ar.sup.1, Ar.sup.2 and Ar.sup.3, to another compound of claim 1 wherein a hydroxy at R and at the carbon to which the R.sup.3 substituent is attached is converted to a --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 or --O(CO)NR.sup.6 R.sup.7 group: or a hydroxy group at Ar.sup.1, Ar.sup.2 or Ar.sup.3 is converted to a --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9, --O(CH.sub.2).sub.1-5 OR.sup.6, --O(CO)NR.sup.6 R.sup.7, --O(CH.sub.2).sub.1-10 --COOR.sup.6 or --O(CH.sub.2).sub.1-10 CONR.sup.6 R.sup.7 group: or an amino group at Ar.sup.1, Ar.sup.2 or Ar.sup.3 is converted to a --NR.sup.6 R.sup.7, --NR.sup.6 (CO)R.sup.7, --NR.sup.6 (CO)OR.sup.9, --NR.sup.6 (CO)NR.sup.7 R.sup.8 or --NR.sup.6 SO.sub.2 R.sup.9 group.

3. A process for preparing a compound of the formula ##STR72## wherein: Ar.sup.1 and Ar.sup.2 are independently selected from the group consisting of aryl and R.sup.4 -substituted aryl:

Ar.sup.3 is aryl or R.sup.5 -substituted aryl;

X, Y and Z are independently selected from the group consisting of --CH.sub.2 --, --CH(lower alkyl)- and --C(dilower alkyl)-;

R.sup.2 is --OH, --O(lower alkyl) or --O-benzyl:

R.sup.1 and R.sup.3 are independently selected from the group consisitng of hydrogen, lower alkyl and aryl; Pl r is 0 or 1; m, n and p are independently 0, 1, 2, 3 or 4; provided that the sum of m, n. p and r is 1, 2, 3, 4, 5 or 6, and further provided that when r and n are each zero, p is 1, 2, 3 or 4;

R.sup.4 is 1-5 substituents independently selected from the group consisting of lower alkyl, --OH. --O(lower alkyl), --O-benzyl, --NR.sup.6 R.sup.7, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, -(lower alkylene)COOR.sup.6, --CH.dbd.CH--COOR.sup.6, --CF.sub.3, --CN, --NO.sub.2 and halogen;

R.sup.5 is is 1-5 substituents independently selected from the group consisting of --OH, --O(Iower alkyl), --O-benzyl --NR.sup.6 R.sup.7, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, -(lower alkylene)-COOR.sup.6 and --CH.dbd.CH--COOR.sup.6 ;

R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

R.sup.9 is lower alkyl, aryl or aryl-substituted lower alkyl, comprising:

(a) treating with a strong base in an anhydrous organic solvent a lactone of the formula ##STR73## wherein X, Y, Z, R.sup.1, R.sup.3, m, n, r and p are as defined above, with the further proviso that if n and r are each zero, p is 1, 2, 3 or 4; Ar.sup.10 is Ar.sup.1 as defined above, a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl; and R.sup.2' is R.sup.2 as defined above or a suitably protected hydroxy group;

(b) reacting the product of step (a) with an imine of the formula ##STR74## wherein Ar.sup.20 is Ar.sup.2, a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl, and Ar.sup.30 is Ar.sup.3, a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl;

c) quenching the reaction with an acid; and

d) removing as necessary a protecting group from any of substituents R.sup.2', Ar.sup.10, Ar.sup.20 and Ar.sup.30 to obtain a compound wherein R, Ar.sup.1, Ar.sup.2 and Ar.sup.3 are as defined above.

4. The process of claim 3 further comprising converting a compound as defined in claim 3 having a hydroxy substituent at R.sup.2, or a hydroxy or amino substituent at any of Ar.sup.1, Ar.sup.2 and Ar.sup.3, to another compound of claim 1 wherein a hydroxy at R.sup.2 and at the carbon to which the R.sup.1 substituent is attached is converted to a --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 or --O(CO)NR.sup.6 R.sup.7 group; or a hydroxy group at Ar.sup.1, Ar.sup.2 or Ar.sup.3 is converted to a --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9, --O(CH.sub.2).sub.1-5 OR.sup.6, --O(CO)NR.sup.6 R.sup.7, --O(CH.sub.2).sub.1-10 --COOR.sup.6 or --O(CH.sub.2).sub.1-10CONR.sup.6 R.sup.7 group; or an amino group at Ar.sup.1, Ar.sup.2 Ar.sup.3 is converted to a --NR.sup.6 R.sup.7, --NR.sup.6 (CO)R.sup.7, --NR.sup.6 (CO)OR.sup.9, --NR.sup.6 (CO)NR.sup.7 R.sup.8 or --NR.sup.6 SO.sub.2 R.sup.9 group.
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