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US 2003/0225282 A1Published application
Enantioselective process for preparing arylated lactones and derivatives
OwnerTony Yantao Zhang, Hongbin Zhang +1inventors
InventorsTony Yantao Zhang, Hongbin Zhang, Christophor Scott Proctor
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Abstract
This invention provides a process for the arylation of lactones to form to chiral and achiral aryllactones having high enantioselectivity where applicable.
Claims20
A process for preparing a compound of the formula (I):
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- or a pharmaceutically acceptable salt thereof, wherein R is a H, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, heterocyclicaryl, carboxyalkyl, carboxyaryl, cyano, carbocyclic, or heterocyclic radical;
- Ar is an aryl group;
- Rm is a single or multiple substituent on the lactone ring other than at the α-position;
- and n is 1-20, comprising the steps of:
- (a) stirring a mixture of a palladium source and a ligand in a suitable solvent;
- (b) adding a compound of formula ArX, wherein Ar is aryl, X is the anion of a strong acid or a leaving group selected from the group comprising Br, Cl, I, OSO2 CnF2n+1, and OP(O)(OCH2n+1)2;
- (c) adding a lactone;
- (d) adding a suitable base
- (e) isolating the compound of formula I;
- (e) optionally preparing a pharmaceutically acceptable acid salt of the compound of formula I.
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A process for the preparation of a compound of formula (II)
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- wherein R and R1 are hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, carboxyalkyl, carboxyaryl, cyano, carbocyclic or heterocyclic radical or combine to form a substituted or unsubstituted carbocycle or heterocycle;
- R2 and R3 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, carboxyalkyl, carboxyaryl, cyano, carbocyclic or heterocyclic radical or combine to form a substituted or unsubstituted carbocycle or heterocycle, comprising the steps of:
- (a) arylating a compound of formula (a)
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- with an aryl halide (ArX) in the presence of a palladium source and a chiral ligand, in a suitable solvent to form a compound of formula (b)
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- wherein R and Ar are as described;
- (b) performing a 1,2-addition on the lactone to form the compound of formula (c),
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- wherein R1 is as described;
- (c) oxidizing the compound (c) to afford the compound of formula (d)
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- (d) performing a reductive amination using an amine (NHR2R3) and a reducing agent to form a compound of formula (II)
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- wherein R, R1, R2 and R3 are as described;
- and
- (e) optionally forming a salt of a compound of formula (II).
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Dependencies are inferred from the claim text.