Process for the Synthesis of Arformoterol

Abstract

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 R 1 and R 2 are independently optionally substituted arylalkyl, and Hal is selected from chloro or bromo.

What is claimed is: 
     
         1 . A process for preparing the (R,R)-diastereromer of 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 (R)-enantiomer of compound (II) or the acid addition salt thereof with an α-haloketone of formula (III) to produce the (R)-enantiomer of a compound of formula (IV) 
       
         
           
           
               
               
           
         
       
       (iii) reducing the (R)-enantiomer of compound (IV) to the (R,R)-diastereomer of a compound of formula (V) 
       
         
           
           
               
               
           
         
       
       and (iv) reducing the (R,R)-diastereomer of compound (V) to the (R,R)-diastereomer of the compound of formula (VI), wherein the reduction 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 R 1  and R 2  are independently optionally substituted arylalkyl, and Hal is selected from chloro or bromo. 
     
     
         2 . The process according to  claim 1 , wherein R 2  is benzyl. 
     
     
         3 . The process according to  claim 1 , wherein R 1  is benzyl or 1-phenylethyl. 
     
     
         4 . The process according to  claim 1 , wherein R 1  is benzyl and reductive amination produces compound (II) in racemic form, and the process further comprises resolving the racemic compound (II) with a chiral acid, to form the corresponding acid addition salt of compound (II), wherein the chiral acid is preferably (S)-mandelic acid. 
     
     
         5 . The process according to  claim 1 , wherein R 1  is 1-phenylethyl, and compound (VIII) is (R)-phenylethylamine, and reductive amination produces the R-enantiomer of compound (II). 
     
     
         6 . The process according to  claim 1 , wherein reductive amination is carried out in the presence of a reducing agent, wherein the reducing agent is preferably selected from the group consisting of sodium borohydride, sodium cyano borohydride, sodium triacetoxyborohydride, potassium borohydride and potassium cyanoborohydride, preferably sodium borohydride; an ionic compound, wherein the ionic compound is preferably selected from the group consisting of ammonium acetate, ammonium chloride-ammonium hydroxide, ammonium citrate, ammonium tartrate, calcium phosphate, citrate, phosphate, potassium phosphate, potassium acetate, potassium chloride, potassium citrate, sodium acetate, sodium chloride, triethylammonium formate, pyridinium formate, sodium perchlorate, triethylammonium formate or a mixture thereof; and a solvent selected from an organic solvent, an aqueous solvent or a mixture thereof, and wherein the solvent is preferably selected from the group consisting of methanol, ethanol, IPA, n-propanol, t-butanol, n-butanol, acetonitrile, THF, DMSO, acetone, DMF, acetic acid, formic acid or mixtures thereof, preferably methanol and acetic acid. 
     
     
         7 . The process according to  claim 1 , wherein reductive amination is carried out with hydrogen in the presence of a hydrogenation catalyst, wherein the hydrogenation catalyst is preferably selected from the group consisting of Raney Nickel, palladium, palladium hydroxide, palladium on activated carbon palladium on alumina, platinum, platinum on activated carbon, Rh(I) and Ru(II) triphenylphosphine complexes, more preferably Raney Nickel. 
     
     
         8 . The process according to  claim 1 , wherein the molar ratio of compound (II) to compound (III) in step (ii) ranges from about 1.5:1, preferably about 1.1:1. 
     
     
         9 . The process according to  claim 1 , wherein the condensation in step (ii) is carried out in the presence of a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol (IPA), t-butanol, methyl isobutylketone, acetone, methyl ethyl ketone, n-butanone, toluene, t-amylalcohol, acetonitrile, diglyme, THF, DMSO, xylene and HMPA; preferably acetone, and is further preferably carried out in the presence of a base selected from triethylamine, potassium carbonate, sodium carbonate and disiopropylamine and is preferably carried out in the presence of a catalyst selected from the group consisting of potassium iodide, sodium iodide, tetrabutyl ammonium bromide, 18-crown 6 ether, tetrabutyl ammonium sulphate and tetrabutyl ammonium iodide. 
     
     
         10 . The process according to  claim 1 , wherein the compound (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 dioxazaluminium complex (derived from amino acid esters, LiAlH 4  and borane methyl sulfide), dihydrooxazaborins and a borane reducing agent, wherein the borane reducing agent is preferably BH 3 .THF or borane-methyl sulfide; in the presence of a catalytic amount of a single enantiomer of an oxazaborolidine reagent derived from a chiral oxazaborolidine catalyst, wherein the chiral oxazaborolidine catalyst is preferably selected from the group consisting of cis-(1R, 2S)-aminoindanol, R-diphenyl prolinol, R-methyl oxazaborolidine (derived from R-diphenyl prolinol, trimethylboroxine and methyl boronic acid) and non-α-substituted (R)-indoline-2-carboxylic acid, more preferably R-methyl oxazaborolidine. 
     
     
         11 . The process according to  claim 1 , wherein the reduction in step (iv) is carried out by a hydrogen donating compound in the presence of a hydrogen transfer catalyst preferably FeCl 3 .6H 2 O-activated carbon, and the hydrogen donating compound is hydrazine hydrate. 
     
     
         12 . The process according to  claim 1 , wherein the reduction in step (iv) is carried out by a hydrogen donating compound in the presence of a hydrogen transfer catalyst, and the reduction is carried out in a solvent selected from an alcohol or dioxane. 
     
     
         13 . The process according to  claim 1 , wherein the reduction in step (iv) is carried out by a hydrogen donating compound in the presence of a hydrogen transfer catalyst, and the hydrogen transfer catalyst is on a support of solid materials selected from alumina, silica gel or clay. 
     
     
         14 . The process according to  claim 1 , wherein the reduction in step (iv) is carried out by ammonium formate using a hydrogenation catalyst, and the hydrogenation catalyst is selected from palladium, platinum, ruthenium or rhodium supported on carbon, clay, silica or alumina and is preferably carried out in the presence of an inert solvent selected from methanol, ethanol, isopropyl alcohol or butanol, acetonitrile, DMF (Dimethylformamide), DMSO or THF. 
     
     
         15 . A process for preparing the (R,R) diastereomer of fomoterol or a pharmaceutically acceptable salt thereof, the process comprising preparing the (R,R) diastereomer of compound (VI) according to  claim 1 , convering the (R,R) diastereomer of the compound of formula (VI) to the (R,R) diastereomer of fomoterol, and optionally converting the (R,R) diastereomer of fomoterol to a pharmaceutically acceptable salt thereof. 
     
     
         16 . The process according to  claim 15 , wherein the conversion comprises formylating the (R,R)-diastereomer of compound (VI), preferably carried out with formic acid and acetic anhydride to produce the (R,R)-diastereomer of compound (VII) 
       
         
           
           
               
               
           
         
       
       wherein compound (VII) is preferably isolated in the form of an acid addition salt thereof as a compound of formula (VIIa) 
       
         
           
           
               
               
           
         
       
       and wherein R 1  and R 2  are independently optionally substituted arylalkyl and A −  is an anion. 
     
     
         17 . The process according to  claim 16 , wherein the process further comprises converting the (R,R)-diastereomer of compound (VII) to the corresponding (R,R) diastereomer of formoterol (I), wherein the conversion to (R,R)-formoterol preferably comprises deprotecting the NR 1  and OR 2  groups preferably by hydrogenolysis of the compound of formula (VII) with hydrogen gas in the presence of a noble metal catalyst preferably selected from the group consisting of palladium, palladium hydroxide, palladium on activated carbon, palladium on alumina, platinum, platinum on activated carbon and Raney nickel, and wherein the deprotection of compound (VII) is carried out in the presence of a solvent, preferably selected from the group consisting of an alkyl acetate, a C 1  to C 6  alkylamine, an alcohol, an aliphatic hydrocarbon, an aromatic hydrocarbon, a heterocycle, a dialkylether, an acid, a mixture of water and a water miscible solvent, an ionic liquid, a halogenated solvent and mixtures thereof, more preferably denatured spirit. 
     
     
         18 . The process according to  claim 15 , wherein the formoterol is converted to a pharmaceutically acceptable salt thereof, preferably the tartarate salt. 
     
     
         19 . (R,R)-formoterol or a salt thereof prepared according to a process according to  claim 15 . 
     
     
         20 . The pharmaceutical composition comprising formoterol according to  claim 19 , together with one or more pharmaceutically acceptable excipients. 
     
     
         21 . A method of treating asthma or chronic obstructive pulmonary disease (COPD) comprising administering to a patient in need thereof (R,R)-formoterol or a salt thereof according to  claim 19 .