Process for the synthesis of arformoterol

摘要

The present invention provides a process for preparing a compound of formula (VI) or a salt thereof, the process comprising: (i) reacting 4-methoxyphenyl acetone with an amine of formula (VIII) under conditions of reductive amination to produce a compound of formula (II) or a salt thereof, wherein there is no isolation of an imine intermediate formed during the reductive amination; (ii) condensing the compound (II) or the acid addition salt thereof with an α-haloketone of formula (III) to produce the compound of formula (IV); (iii) reducing the compound (IV) to a compound of formula (V); and (iv) reducing the compound (V) to the compound of formula (VI), wherein the reduction is carried out in the presence of either (1) a hydrogen donating compound in the presence of a hydrogen transfer catalyst; or (2) ammonium formate using a hydrogenation catalyst, wherein R1 and R2 are independently optionally substituted arylalkyl, and Hal is selected from chloro or bromo.;

主权项

1. A process for preparing a compound of formula (VI) or a salt thereof the process comprising: (i) reacting 4-methoxyphenyl acetone with an amine of formula (VIII) under conditions of reductive amination to produce a compound of formula (II) or a salt thereof, wherein there is no isolation of an imine intermediate formed during the reductive amination and wherein the reductive amination is carried out in the presence of an ionic compound and a reducing agent, wherein the ionic compound is sodium acetate trihydrate and the reducing agent is sodium borohydride, (ii) condensing the compound of formula (II) or an acid addition salt thereof with an α-haloketone of formula (III) to produce a compound of formula (IV) (iii) reducing the compound of formula (IV) to a compound of formula (V), wherein the compound of formula (IV) in step (iii) is subjected to chiral reduction using a chiral reducing agent selected from the group consisting of (−)-DIP-chloride, β-isopinocamphinyl-9BBN (R-Alpine-Borane); a chiral β-oxoaldiminatocobalt (II) complex, a dioxazaluminium complex derived from amino acid esters, LiAlH4 and borane methyl sulfide, and dihydrooxazaborins; in the presence of a catalytic amount of a single enantiomer of an oxazaborolidine reagent derived from a chiral oxazaborolidine catalyst, and (iv) reducing the compound of formula (V) to the compound of formula (VI), wherein the reduction of step (iv) is carried out by either (1) a hydrogen donating compound in the presence of a hydrogen transfer catalyst or (2) ammonium formate using a hydrogenation catalyst, wherein R1 and R2 are independently optionally substituted arylalkyl, and Hal is selected from chloro or bromo.