US 2003/0144512 A1Published application

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.

Claims20

Dependent claims

A process for preparing a piperazine of Formula (II):

67
which comprises:
(A) treating a ketoamide of Formula (I):
68
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:
69
heterocycle, or substituted heterocycle;
wherein each Q is independently hydrogen, cyano, C1-C4 alkyl, or —O—C1-C4 alkyl;
heterocycle in R1 is:
70
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.

31 more elements

A process for enhancing the optical purity of a piperazine of Formula (II):

75
which comprises:
(X) forming a solution comprising piperazine II containing a minor portion of undesired optical isomer, 2-naphthalenesulfonic acid, and solvent;
and
(Y) crystallizing from the solution a crystalline 2-naphthalenesulfonic acid salt of II having enhanced optical purity;
wherein
stereocenter a is either in the R configuration or in the S configuration;
R1 is:
76
heterocycle, or substituted heterocycle;
wherein each Q is independently hydrogen, cyano, C1-C4 alkyl, or —O—C1-C4 alkyl;
heterocycle in R1 is:
77
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;
t is an integer equal to zero, 1 or 2.

29 more elements

Dependencies are inferred from the claim text.