Process and intermediates for preparing GPR40 agonists

Patent metadata

Field	Value
Publication number	US-9051289-B2
Application number	US-201414494631-A
Country	US
Kind code	B2
Filing date	Sep 24, 2014
Priority date	Sep 26, 2013
Publication date	Jun 9, 2015
Grant date	Jun 9, 2015

Abstract

The present invention relates to compounds of formula I

wherein R S denotes F or CF 3 , R a denotes H or C 1-4 -alkyl and Z denotes a leaving group or an optionally substituted or protected hydroxyl group, suitable as intermediates in the synthesis of indanyloxydihydrobenzofuranylacetic acids, which are GPR40 agonists, to a process for preparing these intermediates and to the process for preparing the GPR40 agonists making use of an asymmetric catalytic hydrogenation reaction in the presence of a transition metal catalyst and a chiral auxiliary.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
R S is F or CF 3 ;
R a is H or C 1-4 -alkyl; and
Z is a leaving group or an optionally protected hydroxyl group,
or a salt of the compound of formula (I) wherein R a is H.

2. The compound of formula (I) according to claim 1 , wherein R a is —CH 3 , or a salt thereof.

3. The compound of formula (I) according to claim 1 , wherein:
Z is Cl, Br, I, or an optionally protected hydroxyl group.

4. (6-(R)-(4-Bromo-7-fluoroindan-1-yloxy)benzofuran-3-yl)acetic acid, or a salt thereof.

5. (6-(R)-(4-Bromo-7-fluoroindan-1-yloxy)benzofuran-3-yl)acetic acid methyl ester.

6. A process for preparing a compound of formula (I′) according to claim 1 , comprising reacting a compound of formula (II) with a compound of formula (III):

wherein R S is F or CF 3 , R a is C 1-4 -alkyl and, Z′ is a leaving group or a protected hydroxyl group.

7. The process of claim 6 , further comprising ester cleavage to convert R a to H.

8. The process of claim 6 , wherein R a is —CH 3 .

9. The process of claim 6 , wherein Z is Cl, Br, I, or a protected hydroxyl group.

10. A process for preparing indanyloxydihydrobenzofuranylacetic acids of formulae IV.I, IV.II, and IV.III

wherein in formula IV.I
R 1 is selected from the group consisting of a phenyl ring, a tetrazolyl ring, and a 5- or 6-membered heteroaromatic ring which contains 1, 2, or 3 heteroatoms independently selected from ═N—, —NH—, —O—, and —S—, wherein optionally a second ring is annulated to the phenyl or heteroaromatic ring, and the second ring is 5- or 6-membered, partially unsaturated or aromatic and optionally contains 1, 2, or 3 heteroatoms independently selected from ═N—, —NH—, —O—, and —S— with the proviso that only up to two of the heteroatoms are O and S and no O—O, S—S, and S—O bond is formed, and wherein in the second ring independently of the presence of heteroatoms 1 or 2 CH 2 groups are optionally replaced by —C(═O)—, —S(═O)—, or —S(═O) 2 —, and the phenyl ring, tetrazolyl ring, heteroaromatic ring, annulated phenyl ring, and annulated heteroaromatic ring are substituted with one group R 3 , and each of the phenyl ring, tetrazolyl ring, heteroaromatic ring, annulated phenyl ring, and annulated heteroaromatic ring is optionally additionally substituted with 1 to 4 groups independently selected from R 4 , and wherein in the heteroaromatic ring and/or the second ring the H-atom in one or more NH groups is replaced by R N or R 3 ;
R 3 is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkinyl, C 3-6 -cycloalkyl, C 1-4 -alkyl-NH—, (C 1-4 -alkyl) 2 N—, C 1-6 -alkyl-O—, C 3-6 -cycloalkyl-O—, C 1-4 -alkyl-S—, C 1-4 -alkyl-S(═O)—, or C 1-4 -alkyl-S(═O) 2 , wherein each alkyl and cycloalkyl group and each alkyl and cycloalkyl sub-group within the groups mentioned is substituted with 1 to 3 groups independently selected from R 5 and optionally substituted with 1 or more F atoms, or
C 1-4 -alkyl-C(═O)—, heterocyclyl-C(═O)—, HNR N —C(═O)—, C 1-4 -alkyl-NR N —C(═O)—, C 3-6 -cycloalkyl-NR N —C(═O)—, heterocyclyl-NR N —C(═O)—, phenyl-NR N —C(═O)—, heteroaryl-NR N —C(═O)—, HO 2 C—, C 1-4 -alkyl-O—C(═O)—, C 3-6 -cycloalkyl-O—C(═O)—, heterocyclyl-O—C(═O)—, —NHR N , C 1-4 -alkyl-C(═O)NR N —, C 3-6 -cycloalkyl-C(═O)NR N —, heterocyclyl-C(═O)NR N —, phenyl-C(═O)NR N —, heteroaryl-C(═O)NR N —, C is -alkyl-S(═O) 2 NR N —, C 3-6 cycloalkyl-S(═O) 2 NR N —, heterocyclyl-S(═O) 2 NR N —, phenyl-S(═O) 2 NR N —, heteroaryl-S(═O) 2 NR N —, heterocyclyl-O—, phenyl-O—, heteroaryl-O—, C 3-6 -cycloalkyl-S—, heterocyclyl-S—, phenyl-S—, heteroaryl-S—, C 3-6 -cycloalkyl-S(═O)—, heterocyclyl-S(═O)—, phenyl-S(═O)—, heteroaryl-S(═O)—, C 3-6 -cycloalkyl-S(═O) 2 —, heterocyclyl-S(═O) 2 —, phenyl-S(═O) 2 —, heteroaryl-S(═O) 2 —, HNR N —S(═O) 2 —, C 1-4 -alkyl-NR N —S(═O) 2 —, heterocyclyl, phenyl, and heteroaryl, wherein each alkyl, cycloalkyl, and heterocyclyl group or sub-group within the groups mentioned is optionally substituted with 1 to 3 groups independently selected from R 5 and optionally substituted with 1 or more F atoms, and wherein each phenyl and heteroaryl group is optionally substituted with 1 to 5 substituents independently selected from R 6 ;
wherein heterocyclyl is selected from
a cyclobutyl group wherein 1 CH 2 group is replaced by —NH— or —O—,
a saturated or partially unsaturated C 5-7 -cycloalkyl group wherein 1 CH 2 group is replaced by —C(═O)—, —NH—, —O—, —S(═O)— or —S(═O) 2 — and/or 1 CH group by N;
a saturated or partially unsaturated C 5-7 -cycloalkyl group wherein 1 CH 2 group is replaced by —NH— or —O—, a second CH 2 group is replaced by —NH—, —C(═O)—, —S(═O)— or —S(═O) 2 — and/or 1 CH group is replaced by N; and
a saturated or partially unsaturated C 5-7 -cycloalkyl group wherein 2 CH 2 groups are replaced by —NH— or 1 CH 2 group by —NH— and the other by —O— and a third CH 2 group is replaced by —C(═O)—, —S(═O)— or —S(═O) 2 — and/or 1 CH group by N;

wherein heteroaryl is selected from
a tetrazolyl ring, and a 5- or 6-membered heteroaromatic ring which contains 1, 2, or 3 heteroatoms independently selected from ═N—, —NH—, —O—, and —S—, wherein in heteroaromatic groups containing a —HC═N— unit this group is optionally replaced by —NH—C(═O)—;

wherein in heteroaryl and heterocyclyl rings with one or more NH groups each of them is replaced by NR N or NR 5 ,

R 4 is selected from the group consisting of F, Cl, Br, I, CN, —OH, C 1-4 -alkyl, C 3-6 -cycloalkyl, HO—C 1-4 -alkyl, —NR N H, C 1-4 -alkyl-NR N —, C 1-4 -alkyl-O—, C 3-6 -cycloalkyl-O—, C 1-4 -alkyl-S(═O)—, and C 1-4 -alkyl-S(═O) 2 —, wherein any alkyl and cycloalkyl group or sub-group within the groups mentioned is optionally substituted with 1 or more F atoms;
R 5 is selected from the group consisting of Cl, Br, I, C 1-4 -alkyl-, CN, C 3-6 -cycloalkyl, heterocyclyl-C(═O)—, H 2 N—C(═O)—, C 1-4 -alkyl-NR N —C(═O)—, C 3-6 -cycloalkyl-NR N —C(═O)—, heterocyclyl-NR N —C(═O)—, phenyl-NR N —C(═O)—, heteroaryl-NR N —C(═O)—, HO—C(═O)—, C 1-4 -alkyl-O—C(═O)—, —NHR N , C 1-4 -alkyl-NR N —, C 1-4 -alkyl-C(═O)NR N —, C 3-6 -cycloalkyl-C(═O)NR N —, heterocyclyl-C(═O)NR N —, phenyl-C(═O)NR N —, heteroaryl-C(═O)NR N —, C 1-4 -alkyl-S(═O) 2 NR N —, C 3-6 -cycloalkyl-S(═O) 2 NR N —, heterocyclyl-S(═O) 2 NR N —, phenyl-S(═O) 2 NR N —, heteroaryl-S(═O) 2 NR N —, —OH, C 1-4 -alkyl-O—, C 1-4 alkyl-O—C 1-4 -alkyl-O—, C 3-6 -cycloalkyl-O—, heterocyclyl-O—, phenyl-O—, heteroaryl-O—, C 1-4 -alkyl-S—, C 3-6 -cycloalkyl-S—, heterocyclyl-S—, phenyl-S—, heteroaryl-S—, C 1-4 -alkyl-S(═O)—, C 3-6 -cycloalkyl-S(═O)—, heterocyclyl-S(═O)—, phenyl-S(═O)—, heteroaryl-S(═O)—, C 1-4 -alkyl-S(═O) 2 —, C 3-6 -cycloalkyl-S(═O) 2 —, heterocyclyl-S(═O) 2 —, phenyl-S(═O) 2 —, heteroaryl-S(═O) 2 —, H 2 N—S(═O) 2 —, C 1-4 -alkyl-NR N —S(═O) 2 —, heterocyclyl, phenyl, and heteroaryl, wherein any alkyl, cycloalkyl and heterocyclyl group or sub-group within the groups mentioned is optionally substituted with 1 or more F atoms and optionally substituted with 1 or 2 groups independently selected from H 3 C—, HO—, H 3 C—O—, and —CN;
wherein heterocyclyl is selected from
a cyclobutyl group wherein 1 CH 2 group is replaced by —NR N — or —O—,
a saturated or partially unsaturated C 5-7 -cycloalkyl group wherein 1 CH 2 group is replaced by —C(═O)—, —NR N —, —O—, —S(═O)— or —S(═O) 2 — and/or 1 CH group by N;
a saturated or partially unsaturated C 5-7 -cycloalky

Assignees

• Dahmann Georg
• Wagner Holger
• Eckhardt Matthias
• Frank Markus
• Santagostino Marco
• Schnaubelt Juergen
• Stertz Uwe
• Pachur Thorsten
• Boehringer Ingelheim Int

Inventors

• Dahmann Georg
• Wagner Holger
• Eckhardt Matthias
• Frank Markus
• Santagostino Marco
• Schnaubelt Juergen
• Stertz Uwe
• Pachur Thorsten

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D307/80 Primary

  Radicals substituted by oxygen atoms · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title