Substituted pyrrolidines as G-protein coupled receptor 43 agonists
The present invention is directed to a process for the preparation of aryl-carbonyl-pyrrolidine carboxylic acid derivative compounds which are useful in treating metabolic diseases, said process consisting of coupling a pyrrolidine ester compound with an aryl carboxylic acid derivative, followed by alkaline or acidic treatment, hydrogenolysis or treatment with a fluoride of the obtained intermediate, to afford novel aryl-carbonyl-pyrrolidine carboxylic acid derivative compounds.
1. A process for the preparation of a compound of formula Ib-Ib′:
wherein:
D is —C(═O)—;
L 2 is a single bond;
R, R 1 and R 2 are independently —H;
R 3 is —H, cyano, alkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, acetyl or arylsulfonyl;
R 3′ is —H or C 1 -C 4 alkyl;
R 4 is —H, cyano or C 1 -C 4 alkyl;
Ar 1 is 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl or a linear or branched C 3 -C 6 alkyl, each of which being optionally substituted by one or more substituent group(s) selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, haloalkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino and haloalkylsulfonylamino, wherein each of the aryl or heteroaryl substituent group(s) may be optionally substituted by one or more further substituents selected from halo, cyano, alkyl, haloalkyl, hydroxy, alkoxy and haloalkoxy; or
two Ar 1 substituent groups form an alkylenedioxy group or a haloalkylenedioxy group; and
Ar 2 is 4′-(2-methoxy-4-methylsulfonamido-1,1′-biphenyl), 4′-(2-methyl-3-methylsulfonamido-1,1′-biphenyl), 4-(2-methoxypyridin-3-yl)phenyl, 4-(2,6-dimethoxypyrimidin-5-yl)phenyl, 3-methoxy-4-(2-methoxypyrimidin-5-yl)phenyl, 4-(3,6-dimethoxypyridazin-5-yl)phenyl, 4′-(5-cyano-2-methoxy-1,1′-biphenyl), 4′-(5-cyano-2-methyl-1,1′-biphenyl), 3-fluoro-4-(3,6-dimethoxypyridazin-5-yl)phenyl, (4-(4-methoxypyridin-3-yl)phenyl), (4′-(methylsulfonamido)-[1,1′-biphenyl]-4-yl), (3′-(methylsulfonamido)-[1,1′-biphenyl]-4-yl), (4-(2,4-dimethoxypyrimidin-5-yl)phenyl), (5-methoxy-6-phenylpyridin-3-yl), (4-(4-methoxypyrimidin-5-yl)phenyl), (2,2′-dimethoxy-[1,1′-biphenyl]-4-yl), (3-methoxy-4-(4-methoxypyridin-3-yl)phenyl), (4-(2,4-dimethoxypyrimidin-5-yl)-3-methoxyphenyl), (4′-acetamido-2′-methoxy-[1,1′-biphenyl]-4-yl), (2′-cyano-4′,5′-dimethoxy-[1,1′-biphenyl]-4-yl), (2′-methoxy-4′-(N-methylmethylsulfonamido)-[1,1′-biphenyl]-4-yl), (6-(2,4-dimethoxyphenyl)pyridin-3-yl), (4-(4,6-dimethoxypyrimidin-5-yl)phenyl) or (4-(3-methoxypyridin-4-yl)phenyl);
wherein the process consists of:
a) coupling a compound of formula C:
wherein:
R is methyl, ethyl, tert-butyl, benzyl, allyl, phenacyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, 2-trimethylsilylethyl or tert-butyldiphenylsilyl;
R 3 is —H, cyano, alkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, acetyl or arylsulfonyl;
R 3′ is —H or C 1 -C 4 alkyl;
R 4 is —H, cyano or C 1 -C 4 alkyl; and
Ar 1 is 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl or a linear or branched C 3 -C 6 alkyl, each of which being optionally substituted by one or more substituent group(s) selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, haloalkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino and haloalkylsulfonylamino, wherein each of the aryl or heteroaryl substituent group(s) may be optionally substituted by one or more further substituents selected from halo, cyano, alkyl, haloalkyl, hydroxy, alkoxy and haloalkoxy; or
two Ar 1 substituent groups form an alkylenedioxy group or a haloalkylenedioxy group;
with a compound of formula D:
wherein:
is selected from the group consisting of:
and
each R″ is independently —Cl or —OL, wherein L is benzotriazol-1-yl, 7-azabenzotriazol-1-yl or imidazol-1-yl;
in the presence of a base, to provide a compound of the formula:
wherein:
R is methyl, ethyl, tert-butyl, benzyl, allyl, phenacyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, 2-trimethylsilylethyl or tert-butyldiphenylsilyl;
R 3 is —H, cyano, alkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, acetyl or arylsulfonyl;
R 3′ is —H or C 1 -C 4 alkyl;
R 4 is —H, cyano or C 1 -C 4 alkyl; and
Ar 1 is 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl or a linear or branched C 3 -C 6 alkyl, each of which being optionally substituted by one or more substituent group(s) selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, haloalkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino and haloalkylsulfonylamino, wherein each of the aryl or heteroaryl substituent group(s) may be optionally substituted by one or more further substituents selected from halo, cyano, alkyl, haloalkyl, hydroxy, alkoxy and haloalkoxy; or
two Ar 1 substituent groups form an alkylenedioxy group or a haloalkylenedioxy group; and
is selected from the group consisting of:
b) either (i) treating the compound provided in step a) above with a base, an acid or a fluoride, or (ii) hydrogenating the compound provided in step a) above, to provide a compound of the formula:
wherein:
R is H;
R 3 is —H, cyano, alkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, acetyl or arylsulfonyl;
R 3′ is —H or C 1 -C 4 alkyl;
R 4 is —H, cyano or C 1 -C 4 alkyl; and
Ar 1 is 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl or a linear or branched C 3 -C 6 alkyl, each of which being optionally substituted by one or more substituent group(s) selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, haloalkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino and haloalkylsulfonylamino, wherein each of the aryl or heteroaryl substituent group(s) may be optionally substituted by one or more further substituents selected from halo, cyano, alkyl, haloalkyl, hydroxy, alkoxy and haloalkoxy; or
two Ar 1 substituent groups form an alkylenedioxy group or a haloalkylenedioxy group;
is selected from the group consisting of:
and
c) performing chiral resolution on the compound provided in step b) above, to provide a compound of the formula Ib-Ib′ above represented by:
or
b) performing chiral resolution on the compound provided in step a) above, to provide a compound of the formula:
wherein:
R is methyl, ethyl, tert-butyl, benzyl, allyl, phenacyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, 2-trimethylsilylethyl or tert-butyldiphenylsilyl;
R 3 is —H, cyano, alkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, acetyl or arylsulfonyl;
R 3′ is —H or C 1 -C 4 alkyl;
R 4 is —H, cyano or C 1 -C 4 alkyl; and
Ar 1 is 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl or a linear or branched C 3 -C 6 alkyl, each of which being optionally substituted by one or more substituent group(s) selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, haloalkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino and haloalkylsulfonylamino, wherein each of the aryl or heteroaryl substituent group(s) may be optionally substituted by one or more further substituents selected from halo, cyano, alkyl, haloalkyl, hydroxy, alkoxy and haloalkoxy; or
two Ar 1 substituent groups form an alkylenedioxy group or a haloalkylenedioxy group;
is selected from the group consisting of:
and
c) either (i) treating the compound provided in step b) above with a base, an acid or a fluoride, or (ii) hydrogenating the compound provided in step b) above, to provide a compound of the formula Ib-Ib′ above represented by:
2. A process for the preparation of a compound of formula Ib-1h″:
wherein:
R is —H;
(i) R 8 is —Cl; and
R 9 is —H; or
(ii) R 8 is —F; and
R 9 is —H; or
(iii) R 8 is —F; and
R 9 is —F; and
is selected from the group consisting of: D-4 c1,
wherein the process consists of:
a) coupling a compound of formula C:
wherein:
R is methyl, ethyl, tert-butyl, benzyl, allyl, phenacyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, 2-trimethylsilylethyl or tert-butyldiphenylsilyl;
R 3 is —H;
R 3′ is —H;
R 4 is —H; and
(i) R 8 is —Cl; and
R 9 is —H; or
(ii) R 8 is —F; and
R 9 is —H; or
(iii) R 8 is —F; and
R 9 is —F;
with a compound of formula D:
wherein:
is selected from the group consisting of:
each R″ is independently —Cl or —OL, wherein L is benzotriazol-1-yl, 7-azabenzotriazol-1-yl or imidazol-1-yl;
in the presence of a base, to provide a compound of the formula:
wherein:
R is methyl, ethyl, tert-butyl, benzyl, allyl, phenacyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, 2-trimethylsilylethyl or tert-butyldiphenylsilyl;
R 3 is —H;
R 3′ is —H;
R 4 is —H; and
(i) R 8 is —Cl; and
R 9 is —H; or
(ii) R 8 is —F; and
R 9 is —H; or
(iii) R 8 is —F; and
R 9 is —F; and
is selected from the group consisting of:
b) either (i) treating the compound provided in step a) above with a base, an acid or a fluoride, or (ii) hydrogenating the compound provided in step a) above, to provide a compound of the formula:
wherein:
R is —H;
R 3 is —H;
R 3′ is —H;
R 4 is —H; and
(i) R 8 is —Cl; and
R 9 is —H; or
(ii) R 8 is —F; and
R 9 is —H; or
(iii) R 8 is —F; and
R 9 is —F; and
is selected from the group consisting of:
and
c) performing chiral resolution on the compound provided in step b) above, to provide the compound of formula Ib-1h″ above; or
b) performing chiral resolution on the compound provided in step a) above, to provide a compound of the formula:
wherein:
R is methyl, ethyl, tert-butyl, benzyl, allyl, phenacyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, 2-trimethylsilylethyl or tert-butyldiphenylsilyl;
R 3 is —H;
R 3′ is —H;
R 4 is —H; and
(i) R 8 is —Cl; and
R 9 is —H; or
(ii) R 8 is —F; and
R 9 is —H; or
(iii) R 8 is —F; and
R 9 is —F; and
is selected from the group consisting of:
and
c) either (i) treating the compound provided in step b) above with a base, an acid or a fluoride, or (ii) hydrogenating the compound provided in step b) above, to provide a compound of the formula:
wherein:
R is —H;
R 3 is —H;
R 3′ is —H;
R 4 is —H; and
(i) R 8 is —Cl; and
R 9 is —H; or
(ii) R 8 is —F; and
R 9 is —H; or
(iii) R 8 is —F; and
R 9 is —F; and
is selected from the group consisting of: