| 摘要 |
The present invention relates to a process for the preparation of carbapenem compound of Formula (I), wherein P1 is hydrogen or a carboxyl protecting group, P3 is hydrogen or a hydroxyl protecting group, R1 is C1-3 alkyl, and A is selected from a group consisting of a) Formula (II), b) Formula (III), c) Formula (IV), d) Formula (V), e) Formula (VI), f) Formula (VII), wherein P2 is hydrogen or an amino protecting group, R2 and R3 may be same or different and are hydrogen, C1-5 alkyl, optionally substituted aryl, or optionally substituted heteroaryl, and X1 is O or S, or its stereoisomers, or salts thereof.; |
| 主权项 |
1. A process for the preparation of a compound of Formula I wherein
P1 is hydrogen or a carboxyl protecting group,P3 is hydrogen or a hydroxyl protecting group,R1 is a C1-3 alkyl, and A is selected from the group consisting of wherein
P2 is hydrogen or an amino protecting group,R2 and R3 may be the same or different and are hydrogen, C1-5 alkyl, optionally substituted aryl, or optionally substituted heteroaryl, andX1 is O or S,or its stereoisomers, or salts thereof, the process comprising the steps of, a) reacting a compound of Formula II wherein
X1 is O or S,X2 is O, S, NR7 or C(R4)R5, provided that both X1 and X2 are not simultaneously S,R1 is C1-3 alkyl,R4 and R5 may be the same or different, and are(i) hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, optionally substituted C6-C12 aryl, optionally substituted C7-C19 aralkyl, C3-18 cycloalkyl, or saturated or partially unsaturated heterocyclyl or heterocyclylalkyl having optionally substituted 1 to 4 ring systems, wherein each ring has 3 to 12 ring members and at least one ring member of at least one ring system is N, O, or S, or(ii) R4 and R5 may be joined together to form a C3-18 cycloalkyl group, or saturated or partially unsaturated heterocycle having optionally substituted 1 to 4 ring systems, wherein each ring has 3 to 12 ring members and at least one ring member of at least one ring system is N, O, or S, R6 is
(i) hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, optionally substituted C6-C12 aryl, optionally substituted C7-C19 aralkyl, C3-18 cycloalkyl, or saturated or partially unsaturated heterocyclyl or heterocyclylalkyl having optionally substituted 1 to 4 ring systems, wherein each ring has 3 to 12 ring members and at least one ring member of at least one ring system is N, O, or S, or(ii) R6 may be joined together with R4 or R5 of X2 to form a C3-18 cycloalkyl group, optionally substituted C6-C12 aromatic ring or saturated or partially unsaturated heterocycle having optionally substituted 1 to 4 ring systems, wherein each ring has 3 to 12 ring members and at least one ring member of at least one ring system is N, O, or S,R7 is hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, optionally substituted C6-C12 aryl, optionally substituted C7-C19 aralkyl, C3-18 cycloalkyl, or saturated or partially unsaturated heterocyclyl or heterocyclylalkyl having optionally substituted 1 to 4 ring systems, wherein each ring has 3 to 12 ring members and at least one ring member of at least one ring system is N, O, or S,P3 is hydrogen or a hydroxyl protecting group, andn is 0 to 3, and imidazole or carbonyldiimidazole in the presence of an organic solvent to obtain a compound of Formula III wherein
R1 is C1-3 alkyl andP3 is hydrogen or a hydroxyl protecting group, b) reacting the compound of Formula III and a compound of Formula IV or its magnesium salt,
P1O2C—CH2—CO2H FORMULA IV wherein P1 is hydrogen or a carboxyl protecting group, to obtain a compound of Formula V wherein
R1 is C1-3 alkylP1 is hydrogen or a carboxyl protecting group andP3 is hydrogen or a hydroxyl protecting group, c) reacting the compound of Formula V and an azide to obtain a compound of Formula VI, wherein P1, P3, and R1 are as defined in Formula V, d) cyclizing the compound of Formula VI to obtain a compound of Formula VII, wherein P1, P3, and R1 are as defined in Formula V, e) reacting the compound of Formula VII and a compound X—B, wherein B is —P(O)(OR)2 or —SO2R, wherein R is substituted or unsubstituted C1-6 alkyl, aralkyl, or aryl, and X is halogen, to obtain a compound of Formula VIII, wherein
R1 is C1-3 alkylB is —P(O)(OR)2 or —SO2R, wherein R is substituted or unsubstituted C1-6 alkyl, aralkyl, or aryl,P1 is hydrogen or a carboxyl protecting group andP3 is hydrogen or a hydroxyl protecting group, f) reacting the compound of Formula VIII with a compound of Formula IX
HS-A FORMULA IX wherein A is as defined in Formula I, to obtain a compound of Formula I, and g) isolating the compound of Formula I or its stereoisomers, or salts thereof from the reaction mixture, wherein the compounds of Formula III, VI, and VII are not isolated from the reaction mixture in solid form during the process. |
