Details for Patent: 6,268,533

Title:	Formoterol process
Abstract:	A method is disclosed for the preparation of optically pure isomers of formoterol by the reaction of an optically pure 4-benzyloxy-3-formamidostyrene oxide with an optically pure 4-methoxy-.alpha.-methyl-N-(phenylmethyl)benzeneethanamine followed by debenzylation. Useful intermediates in the process are also disclosed, as are the novel L-tartrate salt of R,R-formoterol and pharmaceutical compositions thereof.
Inventor(s):	Gao; Yun (Southborough, MA), Hett; Robert (Aarau, CH), Fang; Kevin Q. (Wellesley, MA), Wald; Stephen A. (Sudbury, MA), Senanayake; Chris Hugh (Shrewsbury, MA)
Assignee:	Sepracor Inc. (Marlborough, MA)
Filing Date:	Jan 27, 2000
Application Number:	09/493,042
Claims:	1. A process for preparing a compound of formula ##STR19## or a salt thereof, comprising the sequential steps of: (a) reacting a compound of formula ##STR20## with a compound of formula ##STR21## wherein R is benzyl or substituted benzyl, and (b) reducing with a source of hydrogen in the presence of a noble metal catalyst. 2. A process according to claim 1 wherein said compound of formula ##STR22## is produced in situ from the corresponding bromohydrin ##STR23## by treatment with a base. 3. A process according to claim 1 wherein said compound of formula ##STR24## is produced in situ from a corresponding salt by treatment with a base. 4. A process according to claim 1 wherein said compound of formula ##STR25## is of the R,R configuration. 5. A process according to claim 1 wherein said compound of formula ##STR26## is of the R,S configuration. 6. A process for preparing a compound of formula ##STR27## or salt thereof, comprising the sequential steps of: (a) combining a compound of formula ##STR28## a compound of formula ##STR29## wherein R is benzyl or substituted benzyl and A.sup.- is an acid counter ion, and at least one equivalent of a base to produce a mixture comprising an epoxide and a free base; (b) heating said mixture of an epoxide and a free base at a temperature sufficient to cause a reaction to produce a benzyl-protected aminoalcohol; and (c) reducing said benzyl-protected aminoalcohol with hydrogen gas in the presence of a noble metal catalyst. 7. A process according to any of claims 1, 2, 3, 4 or 6 wherein said noble metal catalyst is palladium. 8. A process according to any of claims 2, 3, or 6 wherein said base is an alkali metal carbonate. 9. A process according to any of claims 1 to 6 wherein said salt is a tartrate salt. 10. A process according to any of claims 1 to 6 wherein said salt is a fumarate salt. 11. A process for synthesizing a compound of formula ##STR30## wherein R is benzyl or substituted benzyl, comprising the sequential steps of: (a) reducing 2-bromo-4'-RO-3'-nitroacetophenone with about one equivalent of a borane reagent in the presence of a catalytic amount of a single enantiomer of an oxazaborolidine reagent to produce substantially enantiomerically pure .alpha.-(bromomethyl)-4-RO-3-nitrobenzenemethanol (b) reducing said .alpha.-(bromomethyl)-4-RO-3-nitrobenzenemethanol with hydrogen in the presence of a noble metal catalyst to produce an aniline; and (c) formylating said aniline with formic acid and acetic anhydride. 12. A process according to claim 11 wherein said oxazaborolidine reagent is generated in situ from (1R,2S)-1-amino-2-indanol and two equivalents of borane reagent. 13. A process according to claim 11 wherein said noble metal catalyst is platinum and said oxazaborolidine is derived from cis 1-amino-2-indanol. 14. A process according to claim 11 wherein steps (b) and (c) are carried out without isolation of said aniline. 15. A process according to claim 11 wherein said single enantiomer of an oxazaborolidine is derived from (1R,2S)-1-amino-2-indanol, and said substantially enantiomerically pure .alpha.-(bromomethyl)-4-RO-3-nitrobenzenemethanol is R-.alpha.-(bromomethyl)-4-phenylmethoxy-3-nitrobenzenemethanol. 16. A process for preparing a substantially enantiomerically pure salt of 4-methoxy-.alpha.-methyl-N-(phenylmethyl)benzeneethanamine comprising: (a) reducing 4-methoxyphenyl acetone with hydrogen in the presence of a platinum catalyst and about 1 equivalent of benzylamine in methanol; (b) adding about one equivalent of a single enantiomer of mandelic acid; (c) heating to obtain a methanolic solution; (d) cooling to obtain a crystalline solid phase; and (e) recovering said crystalline solid from said methanolic solution. 17. A process according to claim 16 comprising the additional step of converting said crystalline solid from step (e) to a salt of an acid other than mandelic acid. 18. A process for preparing a compound of formula ##STR31## comprising the sequential steps of: (a) reducing 2-bromo-4'-benzyloxy-3'-nitroacetophenone with about one equivalent of a borane reagent in the presence of a catalytic amount of a single enantiomer of an oxazaborolidine derived from cis 1-amino-2-indanol to produce substantially enantiomerically pure .alpha.-(bromomethyl)-4-phenylmethoxy-3-nitrobenzenemethanol: ##STR32## (b) reducing said .alpha.-(bromomethyl)-4-phenylmethoxy-3-nitrobenzenemethanol with a source of hydrogen in the presence of a noble metal catalyst to produce an aniline; (c) formylating said aniline with formic acid and acetic anhydride to produce a compound of formula ##STR33## (d) combining said compound of formula ##STR34## a compound of formula ##STR35## wherein A.sup.- is an acid counter ion, and at least one equivalent of a base to produce a mixture comprising an epoxide and a free base; (e) heating said mixture of an epoxide and a free base at a temperature sufficient to cause a reaction to produce a benzyl-protected aminoalcohol; and (f) reducing said benzyl-protected aminoalcohol with hydrogen gas in the presence of a noble metal catalyst. 19. A compound of formula: ##STR36## wherein each of R.sup.1, R.sup.2 and R.sup.3 is independently chosen from the group consisting of hydrogen, C.sub.1 to C.sub.6 -alkyl, C.sub.1 to C.sub.6 -alkoxyl, and halogen and R.sup.4 is --NO.sub.2, --NH.sub.2 or --NHCHO. 20. A compound according to claim 19 wherein all of R.sup.1, R.sup.2 and R.sup.3 are hydrogen.