Process for preparing piperazinepentaneamide HIV protease inhibitors
AssigneeMerck & Co., Inc.
InventorsNorihiro Ikemoto, Jinchu Liu
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Abstract
A process for preparing γ-hydroxy-4-[[2-oxazolyl]alkyl]-α-[(cyclo)alkyl- or aryl- or heteroaryl-substituted methyl]-2-[[(un)substituted alkyl]aminocarbonyl]-1-piperazinepentanamides is disclosed. The piperazinepentanamides are useful as HIV protease inhibitors. A process for making a 4-[[2-oxazolyl]alkyl]-2-[[(un)substituted alkyl]aminocarbonyl]piperazine by treating a ketoamide precursor with fuming sulfuric acid in the presence of polyphosphoric acid is also disclosed. In addition, a process for enhancing the optical purity of 4-[[2-oxazolyl]alkyl]-2-[[(un)substituted alkyl]aminocarbonyl]-piperazines via the formation 2-naphthalenesulfonic acid crystal salts thereof is disclosed, as well as a method for purifying 2-naphthalenesulfonic acid.
Claims15
A process for preparing a piperazine of Formula (II):
- which comprises:
- (A) treating a ketoamide of Formula (I):
- with fuming sulfuric acid in the presence of polyphosphoric acid to obtain the piperazine II;
- wherein
- stereocenter a is either in the R configuration or in the S configuration;
- G is a nitrogen-protecting group;
- R1 is:
- heterocycle, or substituted heterocycle;
- wherein each Q is independently hydrogen, cyano, C1-C4 alkyl, or —O—C1-C4 alkyl;
- heterocycle in R1 is:
- substituted heterocycle in R1 is a heterocycle as defined above with one or more substituents independently selected from cyano, C1-C4 alkyl, —O—C1-C4 alkyl, S—(C1-C4 alkyl), NRaRb, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl, isoxazolyl, and isothiazolyl;
- R2 and R3 are each independently hydrogen, C1-C6 alkyl, or aryl, wherein the alkyl group is optionally substituted with one or more substituents each of which is independently halogen, —O—C1-C6 alkyl, or —O—C1-C6 haloalkyl;
- and wherein the aryl group is optionally substituted with one or more substituents each of which is independently halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, —O—C1-C6 alkyl, or —O—C1-C6 haloalkyl;
- or
- R2 and R3 together with the carbon to which they are attached form C3-C8 cycloalkyl which is optionally substituted with one or more substituents each of which is independently halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, —O—C1-C6 alkyl, —O—C1-C6 haloalkyl, or —C1-C6 alkyl substituted with —O—C1-C6 alkyl;
- R6 is —H or C1-C6 alkyl optionally substituted with one or more substituents each of which is independently
- (1) halogen,
- (2) —O—C1-C6 alkyl,
- (3) —O—C1-C6 haloalkyl,
- (4) —C1-C6 alkyl substituted with —C1-C6 alkyl,
- (5) —N(Rc)2,
- (6) —CO2Rc,
- (7) —N(Rc)(SO2Rc),
- (8) —C(═O)Rc, or
- (9) —C(═O)—N(Rc)2;
- Ra and Rb are each independently —H or —C1-C4 alkyl;
- or alternatively Ra and Rb together with the nitrogen to which they are attached form C3-C6 azacycloalkyl;
- each Rc is independently —H or —C1-C4 alkyl;
- and
- t is an integer equal to zero, 1 or 2.
A process for preparing Compound 16:
- which comprises:
- (aa) treating ketoamide 15:
- with fuming sulfuric acid in the presence of polyphosphoric acid to obtain Compound 16.
Dependencies are inferred from the claim text.