US2014107318A1PendingUtilityA1
Processes and intermediates
Est. expiryAug 19, 2025(expired)· nominal 20-yr term from priority
A61P 43/00A61P 31/18C07D 209/52C07K 7/06C07K 7/02C07K 5/0812C07D 451/14A61K 31/46A61P 31/14
57
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Claims
Abstract
The invention relates to compounds and processes useful for the preparation of protease inhibitors, particularly serine protease inhibitors. The protease inhibitors are useful for treatment of HCV infections.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A process for preparing a compound of Formula 3
wherein
R 1 is RW—, P 2 —, P 3 -L 2 -P 2 —, or P 4 -L 3 -P 3 -L 2 -P 2 —;
P 2 — is
P 3 -L 2 -P 2 is
P 4 -L 3 -P 3 -L 2 -P 2 is
W is a bond, —CO—, —O—CO—, —NR X —, —NR X —CO—, —O—, or —S—;
T is —C(O)—, —O—C(O)—, —NHC(O)—, —C(O)C(O)—, or —SO 2 —;
R is H, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
R 5 is H, an aliphatic, a cycloaliphatic, a heterocycloaliphatic, an aryl, or a heteroaryl; each of which, except for H, is optionally substituted with one or more substituents each independently selected from Group J, wherein Group J includes halo, cycloaliphatic, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl, nitro, cyano, amido, amino, sulfonyl, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, and hydroxy;
R 6 is an optionally substituted aliphatic, an optionally substituted heteroalkyl, an optionally substituted heteroaryl, an optionally substituted phenyl; or R 5 and R 6 , together with the atoms to which they are attached, may form a 5- to 7-membered, optionally substituted monocyclic heterocycle, or a 6- to 12-membered, optionally substituted bicyclic heterocycle, in which each heterocycle ring optionally contains an additional heteroatom selected from —O—, —S—, or —NR X —;
Each of R 7 and R 7 ′ is independently H, an optionally substituted aliphatic, an optionally substituted heteroalkyl, an optionally substituted heteroaryl, or an optionally substituted phenyl; or R 7 and R 7 ′, together with the atom to which they are attached, may form a 3- to 7-membered cycloaliphatic or heterocycloaliphatic ring; or
R 7 and R 6 , together with the atoms to which they are attached, may form a 5- to 7-membered optionally substituted monocyclic heterocycle, a 5- to 7-membered optionally substituted monocyclic aryl, a 6- to 12-membered optionally substituted bicyclic heterocycle, or a 6- to 12-membered optionally substituted bicyclic aryl, in which each heterocycle or aryl ring optionally contains an additional heteroatom selected from —O—, —S—, or —NR X —; or
When R 5 and R 6 together with the atoms to which they are attached form a ring, R 7 and the ring system formed by R 5 and R 6 may form an 8- to 14-membered optionally substituted bicyclic fused ring system, wherein the bicyclic fused ring system may further fuse with an optionally substituted phenyl to form an optionally substituted 10- to 16-membered tricyclic fused ring system;
R 8 is H or a protecting group; and
R X is H, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl;
R 2 is —(NH—CR 4 ′R 5 ′—C(O)—C(O))—NHR 4 or —(NH—CR 4 ′R 5 ′—CH(OH)—C(O))—NHR 4 ;
R 4 is H, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, an optionally substituted aralkyl or an optionally substituted heteroaralkyl; and
Each of R′ 4 and R′ 5 is independently H, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heteroaralkyl; or R 4 ′ and R 5 ′, together with the atom to which they are attached, may form a 3- to 7-membered optionally substituted cycloaliphatic ring;
comprising the step of carboxylation of an azabicyclooctane of formula 6,
wherein R′ is C 1-5 alkyl,
to give a racemic mixture of cis- and trans-octahydrocyclopenta[c]pyrrole-1-carboxylic acids of formula 7
2 . The process of claim 1 , wherein R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-12 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-6 alkyl, C 3-10 heterocyclyl, C 6-10 heterocyclyl-C 1-6 alkyl, C 5-10 heteroaryl, or C 5-10 heteroaryl-C 1-6 alkyl; each of which is optionally substituted with one to three substituents each independently selected from Group J; and up to three aliphatic carbon atoms in R 5 may be independently replaced by a heteroatom or group selected from O, NH, S, SO, or SO 2 in a chemically stable arrangement.
3 . The process of claim 2 , wherein R 5 is
4 . The process of claim 1 , wherein
R 7 ′ is H; R 7 is C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-12 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-6 alkyl, C 3-10 heterocyclyl, C 6-10 heterocyclyl-C 1-6 alkyl, C 5-10 heteroaryl, or C 5-10 heteroaryl-C 1-6 alkyl; and R 1 is optionally substituted with one to three substituents each independently selected from Group J; and up to three aliphatic carbon atoms in R 1 may be replaced by a heteroatom selected from O, NH, S, SO, or SO 2 in a chemically stable arrangement.
5 . The process of claim 4 , wherein R 7 is
6 . The process of claim 1 , wherein R 7 and R 7 ′, together with the atom to which they are attached, form
7 . The process of claim 1 , wherein R is C 6-10 aryl, C 6-10 aryl-C 1-12 aliphatic, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 cycloalkyl-C 1-12 aliphatic, C 3-10 cycloalkenyl-C 1-12 aliphatic, C 3-10 heterocyclyl, C 3-10 heterocyclyl-C 1-12 aliphatic, C 5-10 heteroaryl, or C 5-10 heteroaryl-C 1-12 aliphatic; each of which is optionally substituted with one to three substituents each independently selected from Group J.
8 . The process of claim 7 , wherein R is
9 . The process of claim 7 , wherein R is
10 . The process of claim 7 , wherein R is
and
R 10 is H, C 1-12 aliphatic, C 6-10 aryl, C 6-10 aryl-C 1-12 aliphatic, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 cycloalkyl-C 1-12 aliphatic, C 3-10 cycloalkenyl-C 1-12 aliphatic, C 3-10 heterocyclyl, C 3-10 heterocyclyl-C 1-12 aliphatic, C 5-10 heteroaryl, or C 5-10 heteroaryl-C 1-12 aliphatic.
11 . The process according to claim 7 , wherein R is
12 . The process of claim 7 , wherein R is
13 . The process of claim 7 , wherein R is
14 . The process of any of claim 1 , wherein the carboxylation step includes forming a 2-anion of the compound of formula 6
in the presence of a complexing agent, and treating the 2-anion with carbon dioxide to produce a racemic mixture of trans-/cis-octahydrocyclopenta[c]pyrrole-1-carboxylic acids of formula 7.
15 . The process of claim 14 , wherein the 2-anion is prepared by treating the compound of formula 6 with a strong lithium base in the presence of a complexing agent and an aprotic solvent.
16 . The process of claim 15 , wherein the base is sec-butyl lithium.
17 . The process of claim 16 , wherein the complexing agent is tetramethylethylenediamine, tetraethylethylenediamine, tetramethyl-1,2-cyclohexyldiamine, sparteine, or 3,7-dipropyl-3,7-diazabicyclo[3.3.1]nonane.
18 . The process of claim 14 , wherein the complexing agent is tetramethylethylenediamine, tetraethylethylenediamine, tetramethyl-1,2-cyclohexyldiamine, or 3,7-dipropyl-3,7-diazabicyclo[3.3.1]nonane.
19 . The process of claim 14 , wherein the trans-/cis-ratio is 1 to 1.
20 . The process of claim 14 , wherein the trans-/cis-ratio is 60 to 40.
21 . The process of claim 14 , wherein the trans-/cis-ratio is 80 to 20.
22 . The process of claim 14 , wherein the trans-/cis-ratio is 90 to 10.
23 . The process of claim 14 , wherein the trans-/cis-ratio is greater than 98 to 2.
24 . The process of claim 14 , wherein the complexing agent is D-sparteine.
25 . The process of claim 1 , further comprising equilibrating a trans-/cis-mixture of the compounds of formula 7
in the presence of a suitable base to produce a predominantly trans-cis racemic acid of formula 8
wherein the trans-/cis-ratio is greater than 80 to 20.
26 . The process of claim 1 , further comprising equilibrating trans/cis-mixture of the compounds of formula 7 in the presence of a suitable base to produce a predominantly trans-cis racemic acid of formula 8 wherein the trans-/cis-ratio is greater than 90 to 10.
27 . The process of claim 1 , further comprising equilibrating trans-/cis-mixture of formula 7 in the presence of a suitable base to produce a predominantly trans-cis racemic acid of formula 8 wherein the trans-/cis-ratio is greater than 98 to 2.
28 . The process of claim 27 , wherein the base is lithium hexamethyldisilazide, lithium di-isopropylamide, or lithium 2,2,6,6-tetramethylpiperidide.
29 . The process of claim 28 , wherein the base is lithium hexamethyldisilazide.
30 . The process of claim 15 , wherein the lithium base is sec-butyl lithium and the complexing agent is 3,7-dipropyl-3,7-diazabicyclo[3.3.1]nonane to give a mixture of racemic trans-/cis-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acids of formula 7, in which the trans/cis-ratio is greater than 90 to 10.
31 . The process of claim 30 , wherein the trans-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid is trans-N-t-butoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid.
32 . The process of claim 1 , further comprising resolving racemic trans-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid to produce an (1S,2S,3R)trans-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid.
33 . The process of claim 32 , wherein the resolution comprises the steps of:
i) forming a salt with an optically active base; and ii) crystallizing the salt formed by step I) to provide an optically active salt of formula 9.
34 . The process of claim 33 , wherein the optically active base is (R)α-aminoethylbenzene.
35 . The process of claim 33 , wherein the optically active base is (S)1,2,3,4-tetrahydro-1-naphthylamine.
36 . The process of claim 33 , further comprising the steps of:
i) esterifying the caboxylic acid of formula 9 with a compound containing the R 3 group; and ii) removing the —COOR′ protecting group to produce a compound of Formula 1
wherein R 3 is an optionally substituted alkyl or aralkyl.
37 . The process of claim 36 , wherein R 3 is t-butyl.
38 . The process of claim 36 , further comprising reacting the amino-ester of Formula 1 with R 1 COOH in the presence of a coupling reagent to produce a compound of Formula 1a.
39 . The process of claim 38 , wherein the reaction between the amino ester of Formula 1 with R 1 COOH is carried out further in the presence of histamine, glycine, or lysine.
40 . The process of claim 38 , wherein R 1 is P 2 —.
41 . The process of claim 38 , wherein R, is P 3 -L 2 -P 2 —.
42 . The process of claim 38 , wherein R 1 is P 4 -L 3 -P 3 -L 2 -P 2 —.
43 . The process of claim 38 , wherein R 1 is RW—.
44 . The process of claim 38 , further comprising the steps of
iii) hydrolyzing the ester of a compound of Formula 1a; and iv) reacting the carboxylic acid of step iii) with a compound containing the R 2 group, wherein R 2 is —(NH—CR 4 ′R 5 ′—CH(OH)C(O))—NHR 4 , in the presence of a coupling reagent, to produce the compound of Formula 3.
45 . The process of claim 44 , wherein R 4 is H, an optionally substituted aliphatic, optionally substituted cycloaliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl;
R 4 ′ is H, an optionally substituted aliphatic, an optionally substituted aryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; and R 5 ′ is H, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted aryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or R 4 ′ and R 5 ′, together with the atom to which they are attached, form a 3- to 7-membered optionally substituted cycloaliphatic ring.
46 . The process of claim 44 , wherein R 2 is
47 . A process for preparing a compound of Formula 4
comprising the steps of:
i) providing an N-alkoxycarbonyl-3-azabicyclo[3.3.0]octane;
ii) forming a 2-anion of the N-alkoxycarbonyl-3-azabicyclo[3.3.0]octane in the presence of a chelating agent;
iii) treating the anion of step ii) with carbon dioxide to produce a cis-/trans-mixture of N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acids;
iv) treating the mixture of step iii) with a strong base to produce an essentially pure trans-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid;
v) forming a salt with an optically active amine;
vi) crystallizing the salt;
vii) esterifying the acid provided in step vi);
viii) removing the N-alkoxycarbonyl group to produce (1S,3aR,6aS)-t-butyl-octahydrocyclopenta[c]pyrrole-1-carboxylate, t-butyl ester;
ix) reacting the bicyclic aminoester of step viii) with a protected amino acid of formula 26,
wherein Z is an amine protecting group, in the presence of a coupling reagent, to produce an amide-ester of formula 27;
x) removing the protecting group Z from the amide-ester of step ix) to produce the amino compound of formula 28;
xi) reacting the amino compound of formula 28 with a protected amino acid of formula 29
in the presence of a coupling reagent to produce a tripeptide of formula 30;
xii) removing the protecting group Z in the tripeptide of Formula 30 to produce a free amino-tripeptide of formula 31;
xiii) reacting the amino-tripeptide of formula 31 with pyrazine-2-carboxylic acid in the presence of a coupling reagent to produce an amide-tripeptide ester of formula 33;
xiv) hydrolyzing the ester of the amide-tripeptide ester of formula 33 to produce an amide-tripeptide acid of formula 34;
xv) reacting the amide-tripeptide acid of formula 34 with an aminohydroxy-amide of formula 18
in the presence of a coupling reagent to produce a hydroxy-tetrapeptide of formula 35; and
xvi) oxidizing the hydroxy group of formula 35 to produce the compound of Formula 4.
48 . The process of claim 47 , wherein the oxidizing reagent used in step xvi) is sodium hyopochlorite and the oxidation is carried out in the presence of 2,2,6,6-tetramethylpiperidinyloxy free radical (TEMPO).
49 . The process of claim 47 , wherein the oxidizing reagent used in step xvi) is 1,1-dihydro-1,1,1-triacetoxy-1,2-benzoiodooxol-3(1H)-one.
50 . The process of claim 47 , further comprising dissolving the compound of Formula 4 in an organic solvent to obtain a solution of the compound of Formula 4, and then adding an acid to the solution.
51 . The process of claim 50 , wherein the organic solvent is methylene chloride, and the acid is acetic acid.
52 . The process of claim 50 , further comprising concentrating the solution of the compound of Formula 4 to obtain the compound in a solid form.
53 . A process of purifying the compound of Formula 4, comprising:
xvii) dissolving the compound of Formula 4 in an organic solvent to obtain a solution of the compound of Formula 4,
xviii) adding an acid to the solution of the compound of Formula 4, and
xix) concentrating the solution of the compound of Formula 4 to obtain the compound in a solid form.
54 . The process of claim 53 , wherein the organic solvent is methylene chloride, and the acid is acetic acid.
55 . A compound of Formula 1a
wherein
R 1 is P 2 —;
P 2 — is
R 5 is H, an aliphatic, a cycloaliphatic, a heterocycloaliphatic, an aryl, or a heteroaryl; each of which, except for H, is optionally substituted with one or more substituents each independently selected from Group J consisting of halo, cycloaliphatic, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl, nitro, cyano, amido, amino, sulfonyl, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, and hydroxy;
R 6 is an optionally substituted aliphatic, an optionally substituted heteroalkyl, an optionally substituted heteroaryl, an optionally substituted phenyl; or R 5 and R 6 , together with the atoms to which they are attached, may form a 5- to 7-membered, optionally substituted monocyclic heterocycle, or a 6- to 12-membered, optionally substituted bicyclic heterocycle, in which each heterocycle ring optionally contains an additional heteroatom selected from —O—, —S—, or —NR X —;
R X is H, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl;
R 8 is H or a protecting group; and
R 3 is an optionally substituted alkyl.
56 . The compound of claim 55 , wherein R 3 is t-butyl.
57 . The compound of claim 56 , wherein P 2 — is
58 . The compound of claim 56 , wherein P 2 — is
59 . A compound of Formula 1a
wherein
R 1 is P 3 -L 2 -P 2 —;
P 3 -L 2 -P 2 — is
R 5 is H, an aliphatic, a cycloaliphatic, a heterocycloaliphatic, an aryl, or a heteroaryl; each of which, except for H, is optionally substituted with one or more substituents each independently selected from Group J consisting of halo, cycloaliphatic, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl, nitro, cyano, amido, amino, sulfonyl, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, and hydroxy;
R 6 is an optionally substituted aliphatic, an optionally substituted heteroalkyl, an optionally substituted heteroaryl, an optionally substituted phenyl; or R 5 and R 6 , together with the atoms to which they are attached, may form a 5- to 7-membered, optionally substituted monocyclic heterocycle, or a 6- to 12-membered, optionally substituted bicyclic heterocycle, in which each heterocycle ring optionally contains an additional heteroatom selected from —O—, —S—, or —NR X —;
R 7 is H, an optionally substituted aliphatic, an optionally substituted heteroalkyl, an optionally substituted heteroaryl, or an optionally substituted phenyl; or
R 7 and R 6 , together with the atoms to which they are attached, may form a 5- to 7-membered optionally substituted monocyclic heterocycle, a 5- to 7-membered optionally substituted monocyclic aryl, a 6- to 12-membered optionally substituted bicyclic heterocycle, or a 6- to 12-membered optionally substituted bicyclic aryl, in which each heterocycle or aryl ring optionally contains an additional heteroatom selected from —O—, —S—, or —NR X —; or
When R 5 and R 6 together with the atoms to which they are attached form a ring, R 7 and the ring system formed by R 5 and R 6 may form an 8- to 14-membered optionally substituted bicyclic fused ring system, wherein the bicyclic fused ring system may further fuse with an optionally substituted phenyl to form an optionally substituted 10- to 16-membered tricyclic fused ring system;
R X is H, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl;
R 8 is H or a protecting group; and
R 3 is an optionally substituted alkyl.
60 . The compound of claim 59 , wherein R 3 is t-butyl.
61 . The compound of claim 59 , wherein P 3 -L 2 -P 2 — is
62 . The compound of claim 59 , wherein P 3 -L 2 -P 2 — is
63 . A compound which is 3,7-dipropyl-3,7-diazabicyclo[3.3.1]nonane.
64 . A compound which is 3,7-dipropyl-3,7-diazabicyclo[3.3.1]nonan-9-one.Join the waitlist — get patent alerts
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