Formoterol process
AssigneeSepracor Inc.
InventorsYun Gao, Robert Hett, Kevin Q. Fang, Stephen A. Wald, Chris Hugh Senanayake
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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-α-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.
Claims20
A process for preparing a compound of formula
- or a salt thereof, comprising the sequential steps of:
- (a) reacting a compound of formula
- with a compound of formula
- wherein R is benzyl or substituted benzyl, and
- (b) reducing with a source of hydrogen in the presence of a noble metal catalyst.
A process for preparing a compound of formula
- or salt thereof, comprising the sequential steps of:
- (a) combining a compound of formula
- a compound of formula
- wherein R is benzyl or substituted benzyl and A− 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.
A process for synthesizing a compound of formula
- 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 α-(bromomethyl)-4-RO-3-nitrobenzenemethanol
- (b) reducing said α-(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.
A process for preparing a substantially enantiomerically pure salt of 4-methoxy-α-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.
A process for preparing a compound of formula
- 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 α-(bromomethyl)-4-phenylmethoxy-3-nitrobenzenemethanol:
- (b) reducing said α-(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
- (d) combining said compound of formula
- a compound of formula
- wherein A− 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.
A compound of formula:
- wherein each of R1, R2 and R3 is independently chosen from the group consisting of hydrogen, C1 to C6-alkyl, C1 to C6-alkoxyl, and halogen and R4 is —NO2, —NH2 or —NHCHO.
Dependencies are inferred from the claim text.