Formoterol process

Details Formoterol process Formoterol process

2000-01-27

2001-07-31

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C549S520000, C549S553000, C564S220000, C564S221000, C564S389000, C564S417000, C564S447000, C568S586000

Reexamination Certificate

active

06268533

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a method of preparation of optically pure isomers of formoterol, to specific salts of formoterol and polymorphs thereof and to their use in pharmaceutical compositions.
BACKGROUND OF THE INVENTION
Formoterol, whose chemical name is (+/−) N-[2-hydroxy-5-[1-hydroxy-2[[2-(p-methoxyphenyl)-2-propyl]amino]ethyl]phenyl]-formamide, is a highly potent and &bgr;
2
-selective adrenoceptor agonist having a long lasting bronchodilating effect when inhaled. The structure of formoterol is as shown:
Formoterol has two chiral centers in the molecule, each of which can exist in two possible configurations. This gives rise to four combinations: (R,R), (S,S), (R,S) and (S,R). (R,R) and (S,S) are mirror images of each other and are therefore enantiomers; (R,S) and (S,R) are similarly an enantiomeric pair. The mirror images of (R,R) and (S,S) are not, however, superimposable on (R,S) and (S,R), which are diastereomers. Formoterol is available commercially only as a racemic diastereomer, (R,R) plus (S,S) in a 1:1 ratio, and the generic name formoterol refers to this enantiomeric mixture. The racemic mixture that is commercially available for administration is a dihydrate of the fumarate salt.
The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr
J. Chem. Ed.
62, 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. Thus, the formula for formoterol above reflects the racemic nature of the commercial material, while among the structures below, those having open wedges are intended to encompass a pure, single configuration which is one of the two possible at that carbon, and those having solid wedges are intended to encompass the single, pure isomer having the absolute stereochemistry shown.
All four isomers of formoterol have been synthesized and briefly examined for relaxing activity on the guinea pig trachea [Murase et al.,
Chem. Pharm. Bull.
26, 1123-1129 (1978). It was found that the (R,R)-isomer is the most potent, while the others are 3-14 times less potent. More recently, the four isomers have been examined with respect to their ability to interact in vitro with &bgr;-adrenoceptors in tissues isolated from guinea pig [Trofast et al.,
Chirality
3, 443-450 (1991)]. The order of potency was (R,R)>>(R,S)=(S,R)>(S,S). It was found that the (R,R)-isomer is 1000-fold more potent than the (S,S)-isomer. Preliminary research indicates that administration of the pure (R,R)-isomer may offer an improved therapeutic ratio.
Two reports have been published describing the synthesis of all four isomers of formoterol. In the first report [Murase et al op. cit.], the (R,R)- and (S,S)-isomers were obtained by diastereomeric crystallization of racemic formoterol with tartaric acid. In the second report [Trofast et al. op. cit.], racemic 4-benzyloxy-3-nitrostyrene oxide was coupled with an optically pure (R,R)- or (S,S)-N-(1-phenylethyl)-N-(1-(p-methoxyphenyl)-2-propyl)amine to give a diastereomeric mixture of formoterol precursors, which were then separated by semipreparative HPLC and transformed to the pure formoterol isomers. Both syntheses suffer long synthetic procedure and low overall yield and are impractical for large scale production of optically pure (R,R)- or (S,S)-formoterol. For example, the Trofast reference describes reacting 4.5 grams of the styrene oxide with 4.8 grams of the phenethylamine to produce 94 milligrams of the pure S,S enantiomer. Therefore, there exists a need for a more economical and efficient method of making optically pure formoterol.
SUMMARY OF THE INVENTION
The processes of the invention provide a practical synthesis of optically pure formoterol, for example, (R,R)- and (S,S)-formoterol:
In its broadest aspect, the invention relates to a process for preparing a compound of formula F
or a salt thereof, comprising the sequential steps of: (a) reacting a compound of formula
wherein R is benzyl or substituted benzyl, with a compound of formula FBA:
and (b) reducing with hydrogen gas in the presence of a noble metal catalyst.
The term “substituted benzyl” refers to any protecting group for a phenol that contains the benzyl (or phenylmethyl) nucleus substituted with one or more substituents that do not interfere with its function as a protecting group. Suitable substituents include: C
1
to C
6
-alkyl, C
1
to C
6
-alkoxyl, halogen and combinations thereof. In a particular embodiment, R is benzyl (Bn), and the compound is referred to herein as FAE:
The epoxide may be produced in situ from the corresponding bromohydrin:
by treatment with a base, and the benzylamine may be produced in situ from a corresponding salt by treatment with a base. In one embodiment, the steps may be combined to provide a process wherein a compound of formula FBH3:
a compound of formula FBA-HA:
and at least one equivalent of a base are combined to produce a mixture comprising an epoxide and a free base. The mixture of epoxide and free base is heated at a temperature sufficient to cause a reaction to produce a benzyl-protected aminoalcohol, and the benzyl-protected aminoalcohol is reduced with a source of hydrogen in the presence of a noble metal catalyst. In the above structure A
−
is the anion of a conjugate acid HA having a pKa sufficient to protonate the amine.
In the foregoing processes a preferred noble metal catalyst is palladium and a preferred base is an alkali metal carbonate, particularly potassium carbonate. The source of hydrogen may be hydrogen gas or a hydrogen-donating compound such as ammonium formate.
Suitable acid addition salts for the compounds of the present invention include for example, acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. The mandelic acid salt is especially preferred for compounds of formula FBA; the tartrate and fumarate are preferred for formoterol enantiomers F.
In another aspect, the invention relates to a process for synthesizing a compound of formula
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 derived from a chiral aminoalcohol, preferably from cis 1-amino-2-indanol, to produce substantially enantiomerically pure &agr;-(bromomethyl)-4-RO-3-nitrobenzenemethanol:
(b) reducing the &agr;-(bromomethyl)-4-RO-3-nitrobenzenemethanol with hydrogen in the presence of a noble metal catalyst to produce an aniline; and (c) formylating the aniline with formic acid and acetic anhydride. A preferred noble metal catalyst for this process is platinum. Steps (b) and (c) may be carried out without isolation of the aniline. In a preferred embodiment, R is benzyl and 2-bromo-4′-benzyloxy-3′-nitroacetophenone is reduced to produce substantially enantiomerically pure &agr;-(bromomethyl)-4-phenylmethoxy-3-nitrobenzenemethanol (FBH):
In a more preferred embodiment the single enantiomer of an oxazaborolidine is derived from (1R,2S)-1-amino-2-indanol, which produces &agr;-(bromomethyl)-4-phenylmethoxy-3-nitrobenzenemethanol of the R configuration. The oxazaborolidine may be generated in situ from (1R,2S)-1-amino-2-indanol and two equivalents of borane-THF or borane-me

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