Process for the preparation of enantiomerically enriched cyclic beta-aryl or heteroaryl carbocyclic acids
AssigneeHoffmann-La Roche Inc.
InventorsStephan Bachmann, Michelangelo Scalone, Patrick Schnider
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Abstract
The present invention relates to a process for the preparation of cis substituted cyclic β-aryl or heteroaryl carboxylic acid derivatives in high diastereo- and enantioselectivity by enantioselective hydrogenation in accordance with the following scheme wherein X, Ar, n, and m are defined herein and corresponding salts thereof.
Claims41
A process for the preparation of enantiomerically enriched cyclic β-arylcarboxylic acid derivatives of formula
- wherein
- X is —C(R)(R′)—, —N(R″)—, —O—, —S(O)O—, C(O)N(R″), —N(R″)C(O)— or —C(O)—;
- R and R′ are each independently hydrogen, C1-7-alkyl, C1-7-alkyl substituted by halogen, C1-7-alkoxy, hydroxy or —(CH2)p—Ar;
- R″ is hydrogen, C1-7-alkyl, C1-7-alkyl substituted by halogen, —S(O)o—C1-7-alkyl, —S(O)o—Ar, —S(O)o—NRR′, —(CH2)p—Ar, —C(O)—Ar, —C(O)—NRR′ or —C(O)O—C1-7-alkyl;
- Ar is aryl1 or heteroaryl1;
- n is 0, 1, 2 or 3;
- m is 0, 1, 2 or 3;
- o is 0, 1 or 2;
- and
- p is 0, 1, or 2;
- or a pharmaceutically acceptable salt thereof
- comprising catalytic homogeneous enantioselective hydrogenation of a compound of formula (II)
- in the presence of a catalyst comprising
- Ru(Z)2D XVII
- or
- [Ru(Z)2-p(D)(L1)m](B)p XVIII
- wherein Z represents halogen or the group A-COO,
- A represents lower alkyl, aryl2, halogenated lower alkyl or halogenated aryl2,
- D represents a chiral diphosphine ligand,
- B represents a non-coordinating anion,
- L1 represents a neutral ligand,
- p represents the numbers 1 and 2,
- the ligands can be the same or different, and
- m represents the numbers 1, 2 or 3.
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A process for the preparation of enantiomerically enriched cyclic β-arylcarboxylic acid derivatives of formula
- wherein
- X is —C(R)(R′)—, —N(R″)—, —O—, C(O)N(R″), —N(R″)C(O)— or —C(O)—;
- R and R′ are each independently hydrogen, C1-7-alkyl, C1-7-alkyl substituted by halogen, C1-7-alkoxy, hydroxy or —(CH2)p—Ar;
- R″ is hydrogen, C1-7-alkyl, C1-7alkyl substituted by halogen, —S(O)o—C1-7-alkyl, —S(O)o—Ar, —S(O)o—NRR′, —(CH2)p—Ar, —C(O)—Ar, —C(O)—NRR′ or
- Ar is aryl1 or heteroaryl1;
- n is 0, 1, 2 or 3;
- m is 0, 1, 2 or 3;
- o is 0, 1 or 2;
- p is 0, 1, or 2;
- or a pharmaceutically acceptable salt thereof
- comprising catalytic homogeneous enantioselective hydrogenation of a compound of formula (II)
- in the presence of a catalyst comprising
- [Rh(chiral diphosphine)LX] or [Rh(chiral diphosphine)L]+A−
- wherein X is Cl−, Br− or I−,
- L is a neutral ligand, selected from the group consisting of ethylene, propylene, cyclooctene, 1,3-hexadiene, norbornadiene, 1,5-cyclooctadiene, benzene, hexamethylbenzene, 1,3,5-trimethylbenzene, p-cymene, tetrahydrofuran, dimethylformamide, acetonitrile, benzonitrile, acetone and methanol, A is an anion of an oxyacid or a complex acid selected from the group consisting of ClO4, PF6, BR4, wherein R is halogen or aryl, SbF6 and AsF6.
Dependencies are inferred from the claim text.