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US 2003/0191121 A1Published application
Piperazine carboxamide intermediates of HIV protease inhibitors and processes for their preparation
OwnerRoss A. Miller, Sandor Karady +1inventors
InventorsRoss A. Miller, Sandor Karady, Paul J. Reider
Life of this patent
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Abstract
Piperazine carboxamide intermediates of HIV protease inhibitors and a process for their preparation are disclosed. The piperazine carboxamide compounds are of Formula (III): 1 wherein R1, R2, R3, R4, R5, and R6 are defined herein. The process for preparing the intermediates comprises coupling an iminium salt of Formula I: 2 with a metallated derivative of a compound of Formula (II): R1—H (II), wherein L− is a counterion. A process for preparing the iminium salt of Formula (I) is also disclosed, as is a process for preparing HIV protease inhibitors from Compound III.
Claims71
A compound of Formula (III):
- 123
- wherein:
- R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents each of which is independently:
- (1) cyano,
- (2) C1-C6 alkyl,
- (3) C2-C6 alkenyl,
- (4) C2-C6 alkynyl,
- (5) —O—C1-C6 alkyl,
- (6) —S—C1-C6 alkyl,
- (7) —N(Ra)(SO2Rb),
- (8) —NRcRd,
- (9) —C(═O)—NRcRd;
- (10) phenyl,
- (11) phenyl substituted with one or more substituents each of which is independently halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —O—C1-C6 alkyl, or S—C1-C6 alkyl,
- (12) heterocycle, or
- (13) heterocycle substituted with one or more substituents each of which is independently cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —O—C1-C6 alkyl, S—C1-C6 alkyl, NRcRd, or a 5- or 6-membered heteroaromatic ring consisting of from 1 to 3 heteroatoms selected from N, O and S and a balance of carbon atoms;
- 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-ORe;
- R4 and R5 are each independently
- (1) —H,
- (2) halogen,
- (3) —C1-C6 alkyl which is optionally substituted with one or more substituents each of which is independently:
- (a) halogen,
- (b) —O—C1-C6 alkyl,
- (c) —O—C1-C6 haloalkyl,
- (d) —C1-C6 alkyl-ORe, or
- (e) —N(Re)2,
- (4) aryl which is optionally substituted with one or more substituents each of which is independently:
- (a) halogen,
- (b) —O—C1-C6 alkyl,
- (c) —O—C1-C6 haloalkyl,
- (d) —C1-C6 alkyl-ORe, or
- (e) —N(Re)2,
- (5) heteroaryl which is optionally substituted with one or more substituents each of which is independently:
- (a) halogen,
- (b) —O—C1-C6 alkyl,
- (c) —O—C1-C6 haloalkyl,
- (d) —C1-C6 alkyl-ORe, or
- (e) —N(Re)2,
- or R4 and R5 together with the carbon atom to which they are attached form:
- (i) 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-ORe, or
- (ii) a group of formula:
- 124
- wherein each Q1 and Q2 is independently halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, —O—C1-C6 alkyl, or —O—C1-C6 haloalkyl;
- m1 and m2 are each independently integers equal to zero, 1, 2, 3 or 4;
- and
- n is an integer equal to zero, 1 or 2;
- 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-ORe,
- (5) —N(Re)2,
- (6) —CO2Re,
- (7) —N(Re)(SO2Re),
- (8) —C(═O)Re, or
- (9) —C(═O)—N(Re)2;
- each Ra is independently —H or —C1-C4 alkyl;
- each Rb is independently —H or —C1-C4 alkyl;
- Rc and Rd are each independently —H or —C1-C4 alkyl;
- or alternatively Rc and Rd together with the nitrogen to which they are attached form C3-C6 azacycloalkyl;
- and
- each Re is independently a —C1-C4 alkyl;
- or a salt thereof.
64 more elements
A compound of Formula (II-Al):
- 134
- wherein
- J is
- 135
- heterocycle, or substituted heterocycle;
- heterocycle is
- 136
- substituted heterocycle is heterocycle as defined above having one or more substituents independently selected from C1-C4 alkyl, —O—C1-C4 alkyl, —S—CH3, —N(CH3)2, thiazolyl, and oxazolyl;
- and
- each Q3 is independently hydrogen, halogen, cyano, C1-C4 alkyl, or —O—C1-C4 alkyl;
- t is an integer equal to zero, 1 or 2;
- R2 and R3 are each independently hydrogen or C1-C4 alkyl;
- and
- R4 and R5 are each independently —C1-C4 alkyl which is optionally substituted with one or more substituents each of which is independently:
- (a) halogen,
- (b) —O—C1-C4 alkyl,
- (c) —O—C1-C4 haloalkyl,
- (d) —C1-C4 alkyl-ORe, or
- (e) —N(Re)2;
- or a salt thereof.
17 more elements
A process for preparing a compound of Formula (III):
- 139
- which comprises:
- (C) coupling an iminium salt of Formula I:
- 140
- with a metallated derivative of a compound of Formula (II):
- R1—H (II),
- in solvent to obtain Compound III;
- wherein
- L− is a counterion;
- R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, or heteroaryl;
- wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents each of which is independently:
- (1) cyano,
- (2) C1-C6 alkyl,
- (3) C2-C6 alkenyl,
- (4) C2-C6 alkynyl,
- (5) —O—C1-C6 alkyl,
- (6) —S—C1-C6 alkyl,
- (7) —N(Ra)(SO2Rb),
- (8) —NRcRd,
- (9) —C(═O)—NRcRd;
- (10) phenyl,
- (11) phenyl substituted with one or more substituents each of which is independently halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —O—C1-C6 alkyl, or S—C1-C6 alkyl,
- (12) heterocycle, or
- (13) heterocycle substituted with one or more substituents each of which is independently cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —O—C1-C6 alkyl, S—C1-C6 alkyl, NRcRd, or a 5- or 6-membered heteroaromatic ring consisting of from 1 to 3 heteroatoms selected from N, O and S and a balance of carbon atoms;
- 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-ORe;
- R4 and R5 are each independently
- (1) —H,
- (2) halogen,
- (3) —C1-C6 alkyl which is optionally substituted with one or more substituents each of which is independently:
- (a) halogen,
- (b) —O—C1-C6 alkyl,
- (c) —O—C1-C6 haloalkyl,
- (d) —C1-C6 alkyl-ORe, or
- (e) —N(Re)2,
- (4) aryl which is optionally substituted with one or more substituents each of which is independently:
- (a) halogen,
- (b) —O—C1-C6 alkyl,
- (c) —O—C1-C6 haloalkyl,
- (d) —C1-C6 alkyl-ORe, or
- (e) —N(Re)2,
- (5) heteroaryl which is optionally substituted with one or more substituents each of which is independently:
- (a) halogen,
- (b) —O—C1-C6 alkyl,
- (c) —O—C1-C6 haloalkyl,
- (d) —C1-C6 alkyl-ORe, or
- (e) —N(Re)2,
- or R4 and R5 together with the carbon atom to which they are attached form:
- (i) 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-ORe, or
- (ii) a group of formula:
- 141
- wherein each Q1 and Q2 is independently halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, —O—C1-C6 alkyl, or —O—C1-C6 haloalkyl;
- m1 and m2 are each independently integers equal to zero, 1, 2, 3 or 4;
- and
- n is an integer equal to zero, 1 or 2;
- 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-ORe,
- (5) —N(Re)2,
- (6) —CO2Re,
- (7) —N(Re)(SO2Re),
- (8) —C(═O)Re, or
- (9) —C(═O)—N(Re)2;
- each Ra is independently —H or —C1-C4 alkyl;
- each Rb is independently —H or —C1-C4 alkyl;
- Rc and Rd are each independently —H or —C1-C4 alkyl;
- or alternatively Rc and Rd together with the nitrogen to which they are attached form C3-C6 azacycloalkyl;
- and
- each Re is independently a —C1-C4 alkyl.
70 more elements
A process for preparing Compound 13:
- 161
- which comprises:
- (cc) coupling Compound 10:
- 162
- in the presence of a Lewis acid, or coupling compound I-A:
- 163
- with a metallated derivative of Compound 4:
- 164
- in solvent to obtain 13;
- wherein L− is a non-nucleophilic counterion.
7 more elements
A process for preparing an iminium salt of Formula (I):
- 169
- which comprises:
- (A) reacting a piperazine of Formula (VIII):
- 170
- with a carbonyl-containing compound of Formula (IX):
- 171
- optionally in the presence of at least a catalytic amount of an acid to form an acetonide of Formula (X):
- 172
- (B) reacting the acetonide of Formula (X) with (i) HL and a carbonyl-containing compound of Formula (XI):
- 173
- or a ketal of Formula (XI-A):
- 174
- or (ii) with an alcohol of Formula (XII):
- 175
- to form Compound I;
- wherein
- L− is a counterion;
- R2 and R3 are each independently hydrogen, C1-C6 alkyl, or aryl, wherein the alkyl or aryl group is optionally substituted with one or more substituents each of which is independently halogen, —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, —O—C1-C6 alkyl, —O—C1-C6 haloalkyl, or —C1-C6 alkyl-ORa;
- R4 and R5 are each independently
- (1) —H,
- (2) halogen,
- (3) —C1-C6 alkyl which is optionally substituted with one or more substituents each of which is independently:
- (a) halogen,
- (b) —O—C1-C6 alkyl,
- (c) —O—C1-C6 haloalkyl,
- (d) —C1-C6 alkyl-ORe, or
- (e) —N(Re)2,
- (4) aryl which is optionally substituted with one or more substituents each of which is independently:
- (a) halogen,
- (b) —O—C1-C6 alkyl,
- (c) —O—C1-C6 haloalkyl,
- (d) —C1-C6 alkyl-ORe, or
- (e) —N(Re)2,
- (5) heteroaryl which is optionally substituted with one or more substituents each of which is independently:
- (a) halogen,
- (b) —O—C1-C6 alkyl,
- (c) —O—C1-C6 haloalkyl,
- (d) —C1-C6 alkyl-ORe, or
- (e) —N(Re)2,
- or R4 and R5 together with the carbon atom to which they are attached form (i) C3-C8 cycloalkyl which is optionally substituted with one or more substituents each of which is independently halogen, —O—C1-C6 alkyl, —O—C1-C6 haloalkyl, or —C1-C6 alkyl-ORe or (ii) a group of formula:
- 176
- wherein each Q1 and Q2 is independently halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, —O—C1-C6 alkyl, or —O—C1-C6 haloalkyl;
- m1 and m2 are each independently integers equal to zero, 1, 2, 3 or 4;
- and n is an integer equal to zero, 1 or 2;
- 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-ORe,
- (5) —N(Re)2,
- (6) —CO2Re,
- (7) —N(Re)(SO2Re),
- (8) —C(═O)Re, or
- (9) —C(═O)—N(Re)2;
- R10 and R12 are each independently C1-C4 alkyl;
- and
- Re is —C1-C4 alkyl.
55 more elements
A process for preparing an iminium salt of Formula (I-A):
- 178
- which comprises:
- (aa) reacting a piperazine carboxamide 7:
- 179
- with acetone to form an acetonide 9:
- 180
- (bb) reacting acetonide 9 with HL and acetone or a ketal of acetone to form I-A;
- wherein L− is a non-nucelophilic counterion.
5 more elements
A process for preparing Compound 10:
- 182
- which comprises:
- (A) reacting a piperazine carboxamide 8:
- 183
- with acetone to form an acetonide 9:
- 184
- and
- (B) reacting acetonide 9 with acetone cyanohydrin to form 10.
5 more elements
A compound of Formula (I-A):
- 185
- wherein L− is a counterion.
A compound of Formula (X):
- 190
- wherein R4 and R5 are each independently
- (1) —H,
- (2) halogen,
- (3) —C1-C6 alkyl which is optionally substituted with one or more substituents each of which is independently:
- (a) halogen,
- (b) —O—C1-C6 alkyl,
- (c) —O—C1-C6 haloalkyl,
- (d) —C1-C6 alkyl-ORe, or
- (e) —N(Re)2,
- (4) aryl which is optionally substituted with one or more substituents each of which is independently:
- (a) halogen,
- (b) —O—C1-C6 alkyl,
- (c) —O—C1-C6 haloalkyl,
- (d) —C1-C6 alkyl-ORe, or
- (e) —N(Re)2,
- (5) heteroaryl which is optionally substituted with one or more substituents each of which is independently:
- (a) halogen,
- (b) —O—C1-C6 alkyl,
- (c) —O—C1-C6 haloalkyl,
- (d) —C1-C6 alkyl-ORe, or
- (e) —N(Re)2,
- or R4 and R5 together with the carbon atom to which they are attached form:
- (i) 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-ORe, or
- (ii) a group of formula:
- 191
- wherein each Q1 and Q2 is independently halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, —O—C1-C6 alkyl, or —O—C1-C6 haloalkyl;
- m1 and m2 are each independently integers equal to zero, 1, 2, 3 or 4;
- and n is an integer equal to zero, 1 or 2;
- 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-ORe,
- (5) —N(Re)2,
- (6) —CO2Re,
- (7) —N(Re)(SO2Re),
- (8) —C(═O)Re, or
- (9) —C(═O)—N(Re)2;
- and
- each Re is independently a —C1-C4 alkyl;
- or a salt thereof.
39 more elements
An oxazole of formula (II-A), or a salt thereof:
- 195
- wherein J is pyridyl or pyrimidinyl, either of which is optionally substituted with from 1 to 3 substituents each of which is independently C1-C4 alkyl, —O—C1-C4 alkyl, —S—CH3, —N(CH3)2, thiazolyl, or oxazolyl.
Dependencies are inferred from the claim text.