Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1996-06-13
1997-11-04
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
564220, C07C23120, C07C23343
Patent
active
056841990
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/EP94/04199, filed Dec. 16, 1994.
The present invention relates to a novel useful process for the preparation of the optically pure R,R-enantiomer of formoterol. Formoterol: )phenyl!formamide and the fumarate salt of this compound, q.v. Merck Index, Eleventh Edition No. 4159, belongs to the group of the selective .beta..sub.2 -sympathomimetic bronchodilutors which are useful antiasthmatic drugs. Preferred suitable dosage forms are aerosols for inhalation. A known commercial product in aerosol formulation for inhalation is .RTM.Foradil (Ciba), which is available in numerous countries.
The pair of (R,R),(S,S)-enantiomers of formoterol and their separation into two optically pure enantiomers and two diastereisomers are described in Chem. Pharm. Bull. 26, No.4, 1123-1129 (1978). Chirality 3:443-450 (1991) describes the enhanced activity of the R,R-enantiomer over the S,S-enantiomer. It is generally assumed of chiral beta-sympathomimetics that only one optically pure antipode of a pair of enantiomers is active. The other antipode of the pair of enantiomers is either inactive or may 13!, pp. 231-232. The preparation of the R,R-enantiomer in high optical purity is carried out, in poor yield, by a number of complicated, and therefore expensive, synthesis steps using chiral starting materials and intermediates.
It is the object of this invention to provide a simplified, improved, and therefore more cost-effective, process for the preparation of the R,R-enantiomer of the free base of formoterol in increased yield and, in particular, in high purity of optically pure product.
Surprisingly, this object is achieved by this invention, which relates to a process for the preparation of optically pure o)ethyl)phenyl!formamide and the fumarate salt thereof. The process comprises separating the racemic mixture or mixture of diastereoisomers of the free compound in a mobile phase containing a nonpolar solvent and optionally a further polar protic or aprotic solvent by chromatography on a chiral stationary phase consisting of a polysaccharide whose free hydroxyl groups are derivatised by the 4-methylbenzoyl group, and optionally an inert cartier material, and isolating the optically pure R,R compound from the eluate of the mobile phase and convening said compound into the fumarate salt.
An essential advantage of this process resides in its combination with known cost-effective methods of preparing racemic formoterol. Racemic formoterol is prepared in per se known manner and then subjected to the novel chromatographic separation method. In one process step, the racereit mixture of formoterol is separated into the optically pure enantiomers. No troublesome synthesis of optically pure intermediates is necessary.
The terms used in the description of this invention are preferably defined as follows.
The term "optically pure" denotes in respect of a defined compound having at least one centre of chirality that said compound contains more than 95% by weight, preferably more than 99% by weight, most preferably more than 99.9% by weight, of an antipode with defined configuration, e.g. according to the known rules of sequencing of Kahn, Ingold and Prelog.
The term "racemic mixture" denotes in respect of a defined compound having at least one centre of chirality a c. 1: mixture of two antipodes with defined configuration.
The term "mixture of diastereoisomers" denotes in respect of a defined compound having at least two centres of chirality a defined configuration with regard to one centre of chirality, whereas the configuration with regard to the further centre of chirality is racemic.
The term "mobile phase" defines a solvent or mixture of solvents in which the racemic mixture for separation into the optically pure antipodes, or a mixture of diastereoisomers of formoterol, is dissolved. However, an inert gas, conveniently argon, may also be used as mobile phase if the method of preparative gas chromatography is applied.
Suitable solvents for the mobile phase are mixtures of a nonpolar solvent with a polar protic or a
REFERENCES:
Murase et al., Chem. Pharm. Bull. 26(4) 1123-1129 (1978).
Ferraro Gregory D.
Novartis Corporation
Raymond Richard L.
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