Process and intermediates for preparing GPR40 agonists

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 -cycloalkyl group wherein 1 CH 2 group is replaced by —NR N — or —O—, a second CH 2 group is replaced by —NR N —, —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 —NR N — or 1 CH 2 group by —NR N — 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;

and 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 —NR N —C(═O)—, and wherein in heteroaromatic rings with one or more NH groups each of them is replaced by NR N , and

each heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from F, Cl, —CH 3 , —CN, and —O—CH 3 ;

R 6 is selected from the group consisting of F, Cl, Br, I, CN, C 1-4 -alkyl, C 3-6 -cycloalkyl-, HO—C 1-4 -alkyl-, C 1-4 -alkyl-O—C 1-4 -alkyl-, R N HN—, C 1-4 -alkyl-O—, —S(═O)—C 1-4 -alkyl, and S(═O) 2 —C 1-4 -alkyl, wherein any alkyl and cycloalkyl group or sub-group within the groups mentioned is optionally substituted with one or more F atoms; and

R N is independently selected from the group consisting of H, C 1-4 -alkyl, C 1-4 -alkyl-C(═O)—, C 1-4 -alkyl-NH—C(═O)—, C 1-4 -alkyl-N(C 1-4 -alkyl)-C(═O)—, C 1-4 -alkyl-O—C(═O)—, and C 1-4 -alkyl-S(═O) 2 —;

wherein in formula IV.II

(Het)Ar is linked via a carbon atom and is selected from the group (Het)Ar-G1 consisting of phenyl, naphthyl and a mono- or bicyclic heteroaromatic group having 5 to 10 ring member atoms of which 2 to 9 ring members are carbon atoms and either one ring member is an unsubstituted or substituted heteroatom selected from N, NH, NR N-II , O, S, S(═O), and S(═O) 2 , or

one ring member is N and a second ring member is selected from N, NH, NR N-II , O, S, S(═O), and S(═O) 2 , or

two ring members are N and a third ring member is selected from N, NH, NR N-II , O, S, S(═O), and S(═O) 2 ,

wherein in naphthyl the ring not attached to the indanyl-O atom of formula IV.II is optionally partially saturated,

wherein in bicyclic heteroaromatic groups the ring not attached to the indanyl-O atom of formula IV.II is optionally partially saturated, while at least one aromatic ring includes a heteroatom, and optionally

one ring member in the partially or fully saturated bridge is replaced by N, NH, NR N-II , O, S, S(O), or S(═O) 2 , or

one ring member in the partially or fully saturated bridge is replaced by N, NH, or NR N-II and second ring member is replaced by NH, NR N-II , O, S, C(═O), S(═O), or S(═O) 2 , or

two not vicinal ring members in a fully saturated bridge are replaced by O atoms,

wherein any of these groups is optionally and independently substituted with 1 to 5 R 1-II groups;

R 1-II is selected from the group consisting of F, Cl, Br, I, CN, NO 2 , NH 2 , C 1-4 -alkyl-NH—, (C 1-4 -alkyl) 2 N—, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkinyl, OH, HO—C 1-4 -alkyl, C 1-4 -alkyl-O—, C 1-4 -alkyl-O—C 1-4 -alkyl, C 1-4 -alkyl S—, C 1-4 -alkyl-S(═O)—, C 1-4 -alkyl-S(═O) 2 —, C 3-6 -cycloalkyl, and C 3-6 -cycloalkyl-O—, wherein any alkyl and cycloalkyl group or submoiety is optionally substituted with 1 to 5 F atoms;

R N-II is selected from the group consisting of C 1-4 -alkyl, C 3-4 -alkenyl, HO—C 1-4 -alkyl, C 1-4 -alkyl-O C 1-4 -alkyl, C 1-4 -alkyl-C(═O)—, C 1-4 -alkyl-S(═O) 2 —, and C 3-6 -cycloalkyl-, wherein any alkyl and cycloalkyl group or submoiety is optionally substituted with 1 to 5 F atoms;

wherein in formula IV.III

R 1-III is selected from the group consisting of a monocyclic or bicyclic group having 5 to 12 ring member atoms of which 4 to 11 ring members are C atoms and 1 to 3 ring members are heteroatoms selected from N and NR N-III , or

1 or 2 ring members are heteroatoms selected from N and NR N-III and 1 ring member is selected from O and S, or

1 ring member is N and 2 ring members are independently selected from O and S, with the proviso that no O—O, S—S, or S—O bond is formed,

wherein the ring member atom attached to the —CH 2 — group in formula IV.III is an N atom,

wherein 1 CH 2 ring member attached to a ring member N atom is optionally replaced by a —C(═O)— group,

wherein the monocyclic or bicyclic group is saturated or partially unsaturated, with the proviso that in bicyclic groups the ring attached to the —CH 2 — group in formula IV.III is not aromatic, and

wherein the bicyclic group is optionally a fused, bridged, or spiro ring system;

wherein any of these groups is optionally and independently substituted with 1 to 3 R 2-III groups;

R 2-III is selected from the group consisting of F, Cl, Br, I, C 1-4 -alkyl, NC—, HO—C 1-4 -alkyl, HO—, C 1-4 -alkyl-O—, C 1-4 -alkyl-O—C 1-4 -alkyl, C 1-4 -alkyl-S—, C 1-4 -alkyl-S(═O)—, C 1-4 -alkyl-S(═O) 2 —, C 3-6 -cycloalkyl-, and C 3-6 -cycloalkyl-O—, wherein any alkyl and cycloalkyl group or submoiety is optionally substituted with 1 to 3 F atoms; and

R N-III is selected from the group consisting of H, C 1-4 -alkyl-C(O)—, and C 1-4 -alkyl-O—C(O)—;

wherein any alkyl group or sub-group is straight-chained or branched, unless specified otherwise,

the process comprising:

a) performing asymmetric catalytic hydrogenation in the presence of a transition metal catalyst and a chiral auxiliary, optionally in the presence of a base, on the compound of formula I or a salt thereof:

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

b) reacting the compound of formula V based on the identity of Z, as follows:

b-1) if Z is Cl, Br, I, reacting the compound of formula V with a compound of formula R 1 —X, wherein X is B(OH) 2 , B(OCMe 2 CMe 2 O), B(O 2 CCH 2 ) 2 NCH 3 , BF 3 K, ZnHal, or MgHal (where Hal is Cl, Br, or I), to obtain a compound of formula IV′, which is subsequently saponified if R a of the compound of formula IV′ is C 1-4 -alkyl, to obtain a compound of formula IV

b-2) if Z is B(OH) 2 , B(OC 1-4 -alkyl) 2 , B[OC(CH 3 ) 2 C(CH 3 ) 2 O], B(O 2 CCH 2 ) 2 NCH 3 , or BF 3 M [where M is Li + , Na + , K + , NH 4 + , + N(CH 3 ) 4 , or other cationic metal or ammonium group], reacting the compound of formula V with a compound of formula R 1 —X1, wherein X1 is Cl, Br, I, methylsulfonyloxy, phenylsulfonyloxy, p-tolylsulfonyloxy, or trifluoromethylsulfonyloxy, to obtain a compound of formula IV′, which is subsequently saponified if R a of the compound of formula IV′ is C 1-4 -alkyl, to form a compound of formula IV

b-3) if Z is OH, reacting the compound of formula V with a compound of formula (Het)Ar—X2, wherein X2 is F, Cl, Br, I, methylsulfonyloxy, phenylsulfonyloxy, p-tolylsulfonyloxy, trifluoromethylsulfonyloxy, B(OH) 2 , B(OC 1-4 -alkyl) 2 , B[OC(CH 3 ) 2 C(CH 3 ) 2 O], B(O 2 CCH 2 ) 2 NCH 3 , or BF 3 M [where M is Li + , Na + , K + , NH 4 + , + N(CH 3 ) 4 , or other cationic metal or ammonium group], to obtain a compound of formula IV′″, which is subsequently saponified if R a of the compound of formula IV′″ is C 1-4 -alkyl, to form a compound of formula IV″

b-4) if Z is Cl, Br, I, methylsulfonyloxy, phenylsulfonyloxy, p-tolylsulfonyloxy, trifluoromethylsulfonyloxy, B(OH) 2 , B(OC 1-4 -alkyl) 2 , B[OC(CH 3 ) 2 C(CH 3 ) 2 O], B(O 2 CCH 2 ) 2 NCH 3 , or BF 3 M [where M is Li + , Na + , K + , NH 4 + , + N(CH 3 ) 4 , or other cationic metal or ammonium group], reacting the compound of formula V with a compound of formula (Het)Ar—OH, to obtain a compound of formula IV′, which is subsequently saponified if R a of the compound of formula IV′ is C 1-4 -alkyl, to form a compound of formula IV

or

b-5) if Z is Cl, Br, I, methylsulfonyloxy, phenylsulfonyloxy, p-tolylsulfonyloxy, trifluoromethylsulfonyloxy, reacting the compound of formula V with a compound of formula R 1-III —CH 2 —X3, wherein X3 is B(OH) 2 , B(OC 1-4 -alkyl) 2 , B[OC(CH 3 ) 2 C(CH 3 ) 2 O], B(O 2 CCH 2 ) 2 NCH 3 , or BF 3 M [where M is Li + , Na + , K + , NH 4 + , + N(CH 3 ) 4 , or other cationic metal or ammonium group], and subsequent saponification of a compound of formula IV V , wherein R a is C 1-4 -alkyl, to obtain a compound of formula IV V , which is subsequently saponified if R a of the compound of formula IV V is C 1-4 -alkyl, to form a compound of formula IV IV

11. The process of claim 10 , wherein the transition metal catalyst is Ir, Rh, Ru, Pd, or Fe catalyst.

12. The process of claim 10 , wherein Z is Cl, Br, I, or an optionally protected hydroxyl group.

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

wherein R 1 , (Het)Ar, and R 1-III are defined as in claim 10 , comprising:

c) reacting the compound of formula I, wherein R S is F or CF 3 and R a is H or C 1-4 -alkyl, based on the identity of Z, as follows:

c-1) if Z is Cl, Br, I, reacting the compound of formula I with a compound of formula R 1 —X, wherein X is B(OH) 2 , B(OCMe 2 CMe 2 O), B(O 2 CCH 2 ) 2 NCH 3 , BF 3 K, ZnHal, or MgHal (where Hal is Cl, Br, or I), to obtain a compound of formula VI,

c-2) if Z is B(OH) 2 , B(OC 1-4 -alkyl) 2 , B[OC(CH 3 ) 2 C(CH 3 ) 2 O], B(O 2 CCH 2 ) 2 NCH 3 , or BF 3 M [where M is Li + , Na + , K + , NH 4 + , + N(CH 3 ) 4 , or other cationic metal or ammonium group], reacting the compound of formula I with a compound of formula R 1 —X1, wherein X1 is Cl, Br, I, methylsulfonyloxy, phenylsulfonyloxy, p-tolylsulfonyloxy, or trifluoromethylsulfonyloxy, to obtain a compound of formula VI

c-3) if Z is OH, reacting the compound of formula I with a compound of formula (Het)Ar—X2, wherein X2 is F, Cl, Br, I, methylsulfonyloxy, phenylsulfonyloxy, p-tolylsulfonyloxy, trifluoromethylsulfonyloxy, B(OH) 2 , B(OC 1-4 -alkyl) 2 , B[OC(CH 3 ) 2 C(CH 3 ) 2 O], B(O 2 CCH 2 ) 2 NCH 3 , or BF 3 M [where M is Li + , Na + , K + , NH 4 + , + N(CH 3 ) 4 , or other cationic metal or ammonium group], to obtain a compound of formula VI′

c-4) if Z is Cl, Br, I, methylsulfonyloxy, phenylsulfonyloxy, p-tolylsulfonyloxy, trifluoromethylsulfonyloxy, B(OH) 2 , B(OC 1-4 -alkyl) 2 , B[OC(CH 3 ) 2 C(CH 3 ) 2 O], B(O 2 CCH 2 ) 2 NCH 3 , or BF 3 M [where M is Li + , Na + , K + , NH 4 + , + N(CH 3 ) 4 , or other cationic metal or ammonium group], reacting the compound of formula I with a compound of formula (Het)Ar—OH, to form a compound of formula VI′

or

c-5) if Z is Cl, Br, I, methylsulfonyloxy, phenylsulfonyloxy, p-tolylsulfonyloxy, or trifluoromethylsulfonyloxy, reacting the compound of formula I with a compound of formula R 1-III —CH 2 —X3, wherein X3 is B(OH) 2 , B(OC 1-4 -alkyl) 2 , B[OC(CH 3 ) 2 C(CH 3 ) 2 O], B(O 2 CCH 2 ) 2 NCH 3 , or BF 3 M [where M is Li + , Na + , K + , NH 4 + , + N(CH 3 ) 4 , or other cationic metal or ammonium group], to obtain a compound of formula VI″

and

d) performing asymmetric catalytic hydrogenation in the presence of a transition metal catalyst and a chiral auxiliary, optionally in the presence of a base, on the compound of formula VI″ or a salt thereof, wherein Z″ is R 1 , O-(Het)Ar, or CH 2 —R 1-III

14. The process of claim 13 , wherein the transition metal catalyst is Ir, Rh, Ru, Pd, or Fe catalyst.

15. The process of claim 13 , wherein Z is Cl, Br, I, or an optionally protected hydroxyl group.

16. A process for preparing indanyloxydihydrobenzofuranylacetic acids of formula V

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, and salts thereof, the process comprising performing an asymmetric catalytic hydrogenation reaction in the presence of a transition metal catalyst and a chiral auxiliary, optionally in the presence of a base, applied to a (in case R a is H), on a compound of formula I or a salt thereof: