Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-13
2002-04-02
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C564S303000
Reexamination Certificate
active
06365756
ABSTRACT:
BACKGROUD OF THE INVENTION
This invention relates to a process for the production of optically enriched (R)- or (S)-albuterol or (R)- or (S)-albuterol salts, by the resolution of a novel ketal derivative of the enantiomers of albuterol, with a chiral tartaric acid derivative.
Albuterol, 2-(N-t-butylamino)-1-(4-hydroxy-3-hydroxymethylphenyl) ethanol, (1), is a &bgr;-2 agonist with bronchodilatory action. It is widely used, as a racemic mixture, in the treatment of asthma.
1,2,3
Of the two possible optical isomers the (R)-enantiomer is reported to be significantly more potent with respect to &bgr;-2 agonist activity than the (S)-enantiomer.
4
A number of methods for producing optically enriched albuterol have been described. These include resolution of a mixture of enantiomers of 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate
5
or 5-[2-[(1.1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)benzoate
6
and enantioselective reduction of an &agr;-iminoketone to an &agr;-amino alcohol using a borane reducing agent and a chiral 1,3,2-oxazaborole catalyst.
7
SUMMARY OF THE INVENTION
According to a first aspect of the invention there is provided a process for the preparation of a compound of the formula (2)
viz. 2-(N-t-butylamino)-1-(2,2-dimethyl-1,2-benzodioxin-6-yl) ethanol, which is a novel ketal derivative of albuterol, which process includes the steps of:
(1) suspending a compound of the formula (1) (which is albuterol)
or a salt thereof, in acetone;
(2) adding to the mixture of step (1) a suitable acid with stirring to form the compound of the formula (2);
(3) adding to the mixture of step (2) a suitable aqueous or non-aqueous basic solution; and
(4) recovering the compound of the formula (2) from the mixture of step (3).
Thereafter, the compound of the formula (2) in crude form may be recrystallised from a suitable solvent, or purified using column chromatography, to yield pure crystalline compound of the formula (2).
When the compound of the formula (1) is a racemic mixture, then the, compound of the formula (2) is also produced as a racemic mixture.
According to a second aspect of the invention there is provided a process for the optical resolution of a mixture of enantiomers of a compound of the formula (2) above, into its (R)-isomer designated (R)-2 and its (S)-isomer designated (S)-2, which process includes the steps of:
(i) reacting the mixture of enantiomers of the compound of the formula (2), dissolved in a suitable solvent, with an enantiopure tartaric acid derivative such as (2S,3S)-(+)-di-O-benzoyl tartaric acid (3a), (2S,3S)-(+)-di-O-(p-toluoyl)-tartaric acid (4a), (2R,3R)-(−)-di-O-benzoyl tartaric acid (3b), or (2R,3R)-(-)-di-O-(p-toluoyl)-tartaric acid (4b), or the like;
(ii) precipitating selectively out of the solution of step (i) a compound of the formula:
(R)-2:tartaric acid derivative salt or
(S)-2:tartaric acid derivative salt;
(iii) suspending the (R)-2:tartaric acid derivative salt or the (S)-2: tartaric acid derivative salt in a suitable organic solvent and stirring to improve optical purity, and then recovering the (R)-2:tartaric acid derivative salt or the (S)-2:tartaric acid derivative salt by filtration;
(iv) adding the (R)-2:tartaric acid derivative salt or the (S)-2:tartaric acid derivative salt from step (iii) to a mixture of an aqueous solution of a base and a suitable organic solvent; and
(v) recovering the compound (R)-2 or the compound (S)-2 from the organic phase of step (iv).
According to a third aspect of the invention there is provided a process for the hydrolysis of a compound of the formula (2) to give a compound of the formula (1) either as the free base or as a salt, which includes the steps of:
(a) dissolving the compound of the formula (2), either enantiomerically enriched or as the racemic mixture, in an excess of an acid, and water or any suitable organic solvent, to hydrolyse the compound of the formula (2); and
(b) recovering the compound of the formula (1) either as a salt of the acid used in step (a), or as the free base.
Thereafter the compound of the formula (1) or a salt thereof, in crude form, may be purified, for example by recrystallisation from a suitable solvent system.
When the starting compound of the formula (2) is enantiomerically enriched, then the resulting compound of the formula (1) is also enantiomerically enriched. This provides a method for resolving the enantiomers of albuterol into the (R)-enantiomer and the (S)-enantiomer.
According to a fourth aspect of the invention there is provided a process for the racemisation of optically enriched compound of the formula (1) or a salt thereof or optically enriched compound of the formula (2) or a salt thereof, to give a mixture of enantiomers of the compound of the formula (1), which process includes the steps of:
(A) dissolving optically enriched compound of the formula (1) (i.e either the (R)-isomer designated (R)-1 or the (S)-isomer designated (S)-1) or a salt thereof, or optically enriched compound of the formula (2) (i.e either the (R)-isomer designated (R)-2 or the (S)-isomer designated (S)-2, in a solution of an excess of a suitable acid and a suitable solvent to produce racemised compound of the formula (1);
(B) adding to the solution of step (A) a suitable aqueous or non-aqueous base; and
(C) recovering a mixture of enantiomers of the compound of the formula (1) from the mixture of step (B).
This process provides a means for recycling the undesired enantiomer of compound of the formula (1) to produce more of the desired enantiomer. The mixture of enantiomers of the compound of the formula (1) which is produced may be derivatised, resolved and hydrolysed according to the processes described under aspects one to three of the invention, to obtain the compound of the formula (2) and hence the compound of the formula (1) enriched in the desired optical isomer.
REFERENCES:
patent: 5399765 (1995-03-01), Gao et al.
patent: 5545745 (1996-08-01), Gao et al.
patent: 5958456 (1999-09-01), Baichwal et al.
patent: 6083993 (2000-07-01), Barberich et al.
patent: 6235927 (2001-05-01), Vries et al.
patent: 23 10 142 (1974-09-01), None
patent: WO 95/32178 (1995-11-01), None
Caira Mino
Clauss Rainer
Gibson Joanne
Grimmbacher Tarron
Hunter Roger
Fine Chemical Corporation Limited
Lambkin Deborah C.
Pillsbury & Winthrop LLP
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