| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | August 13, 1996 |
| PATENT TITLE |
Enantioselective preparation of optically pure albuterol |
| PATENT ABSTRACT |
The invention relates to a method for producing albuterol by the resolution of a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)benzoate or .alpha.-[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedi methanol using a chiral acid such as (+/-) di-toluoyltartaric acid or (+/-) di-benzoyltartaric acid. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | January 20, 1995 |
| PATENT REFERENCES CITED |
Hartley et al. "Absolute Configuration of the Optical Isomers of Salbutamol" J. Med. Chem. 14, 895-896 (1971). Hopkins, "Salbutamol" Drugs of the Future IV 629-633 (1979). Floyd et al. "The Oxidation of Aetophenones to Arylglyoxals with Aqueous Hydrobromic Acid in Dimethyl Sulfoxide" J. Org. Chem. 50 5022-5027 (1985). Collin et al. "Saligenin Analogs of Sympathomimetic Catecholamines" Chemistry Dept., Allen and Hansburys Ltd. (1970). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method for obtaining a single enantiomer of albuterol, comprising: dissolving a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)benzoate and a chiral acid in methanol, ethanol or a mixture of the two by heating to form a solution, said chiral acid being selected from the group consisting of (-)-di-toluoyl-L-tartaric acid, (+)-di-toluoyl-D-tartaric acid, (-)-di-benzoyl-L-tartaric acid and (+)-di-benzoyl-D-tartaric acid; allowing said solution to cool, whereby a salt of primarily one enantiomer crystallizes; separating said salt from said solution; liberating the enantiomer from said salt by treatment with a base; reducing said enantiomer; debenzylating said enantiomer and recovering a single enantiomer of albuterol. 2. A method according to claim 1 wherein said chiral acid is (+)-di-toluoyl-D-tartaric acid and said enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)benzoate is the R enantiomer. 3. A method according to claim 1 wherein said chiral acid is (+)-di-benzoyl-D-tartaric acid and said enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)benzoate is the R enantiomer. 4. A method according to claim 1 wherein said enantiomer is debenzylated by catalytic hydrogenation. 5. The method of claim 1 wherein said enantiomer is reduced with a borane complex. 6. The method of claim 1 further comprising forming a slurry of said salt in methanol, ethanol or a mixture of the two and refluxing said slurry and allowing said slurry to cool, whereby a salt of primarily one enantiomer crystallizes. 7. A method for obtaining a single enantiomer of albuterol, comprising: dissolving a mixture of enantiomers of .alpha.-[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedi methanol and a chiral acid in methanol, ethanol or a mixture of the two by heating to form a solution, said chiral acid being selected from the group consisting of (-)-di-toluoyl-L-tartaric acid, (+)-di-toluoyl-D-tartaric acid, (-)-di-benzoyl-L-tartaric acid and (+)-dibenzoyl-D-tartaric acid; allowing said solution to cool, whereby a salt of primarily one enantiomer crystallizes; separating said salt from said solution; liberating said single enantiomer from said salt by treatment with a base; debenzylating said enantiomer and recovering optically pure albuterol. 8. A method according to claim 7 wherein said chiral acid is (+)-di-toluoyl-D-tartaric acid and said enantiomer of .alpha.-[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedi methanol is the R enantiomer. 9. A method according to claim 7 wherein said chiral acid is (+)-di-benzoyl-D-tartaric acid and said enantiomer of .alpha.-[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedi methanol is the R enantiomer. 10. A method according to claim 7 wherein said enantiomer is debenzylated by catalytic hydrogenation. 11. The method of claim 7 further comprising forming a slurry of said salt in methanol, ethanol or a mixture of the two and refluxing said slurry and allowing said slurry to cool, whereby a salt of primarily one enantiomer crystallizes. 12. A method for obtaining a single enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)benzoate comprising: (a) dissolving a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)benzoate and a chiral acid in methanol, ethanol or a mixture of the two by heating to form a solution, said chiral acid being selected from the group consisting of (-)-di-toluoyl-L-tartaric acid, (+)-di-toluoyl-D-tartaric acid, (-)-di-benzoyl-L-tartaric acid and (+)-di-benzoyl-D-tartaric acid by heating to form a solution; (b) allowing said solution to cool, whereby a salt of primarily one stereoisomer crystallizes; (c) separating said salt from said solution; (d) recrystallizing said salt from the alcohol solvent, whereby a diastereomeric salt having greater than 90% ee of an enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)benzoate is obtained; (e) separating said diastereomeric salt from the alcohol solvent; and (f) liberating said enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)benzoate from said diastereomeric salt by treatment with base. 13. A method according to claim 12 wherein said chiral acid is (+)-di-toluoyl-D-tartaric acid and said enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)benzoate is the R enantiomer. 14. A method according to claim 12 wherein said chiral acid is (+)-di-benzoyl-D-tartaric acid and said enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)benzoate is the R enantiomer. 15. A method for obtaining a single enantiomer of .alpha.-[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedi methanol comprising: (a) dissolving a mixture of enantiomers of .alpha.-[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedi methanol and a chiral acid in methanol, ethanol or a mixture of the two by heating to form a solution, said chiral acid being selected from the group consisting of (-)-di-toluoyl-L-tartaric acid, (+)-di-toluoyl-D-tartaric acid, (-)-di-benzoyl-L-tartaric acid and (+)-di-benzoyl-D-tartaric acid in methanol by heating to form a solution; (b) allowing said solution to cool, whereby a salt of primarily one stereoisomer crystallized; (c) separating said salt from said solution; (d) recrystallizing said salt from the alcohol solvent, whereby a diastereomeric salt having greater than 90% ee of an enantiomer of .alpha.-[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedi methanol is obtained; (e) separating said diastereomeric salt from the alcohol solvent; and (f) liberating said enantiomer of .alpha.-[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedi methanol from said diastereomeric salt by treatment with base. 16. A method according to claim 15 wherein said chiral acid is (+)-di-toluoyl-D-tartaric acid and said enantiomer of .alpha.-[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedi methanol is the R enantiomer. 17. A method according to claim 15 wherein said chiral acid is (+)-di-benzoyl-D-tartaric acid, said solvent ethanol and said enantiomer of .alpha.-[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzen edimethanol is the R enantiomer. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
TECHNICAL FIELD The present invention relates to a method of preparing optically pure (R) and (S) albuterol. More particularly, the present invention relates to the preparation and resolution of the albuterol precursor methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy) benzoate or .alpha.-[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedi methanol with a chiral acid. BACKGROUND OF THE INVENTION Albuterol, also referred to as .alpha.-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol or as salbutamol, is a .beta.-2 agonist useful as a bronchodilator. It possesses a high degree of selectivity between .beta.-1 receptors (which are present in the heart) and .beta.-2 receptors (which are present in bronchial tissue and elsewhere), for which reason it is widely used in the treatment of asthma, since in therapeutic doses it exhibits fewer cardiac side effects than many other .beta.-agonists. It is known that among many drugs having chiral centers one enantiomer of a racemic pair is often more active than the other in treating a medical condition. Recent data suggest that the levorotatory R-isomer of albuterol is approximately 80 times more potent than the dextrorotatory S-isomer (Hartley and Middlemis, J. Med. Chem. 14 895-896 (1971)), and preliminary research indicates that administration of the pure R-enantiomer may offer an improved therapeutic ratio. Methods of producing optically pure albuterol by resolving methyl benzoate albuterol precursors are described only for precursors having the amine protected by a benzyl group. Hartley et al. op. cit. teaches optical resolutions only when both the phenolic group and the amine of the precursor were protected with a benzyl group. The process described by Hartley required the use of expensive starting materials, involved at least 6 independent steps and produced low overall yields. Therefore, there exists a need for a more economical and efficient method of making optically pure albuterol. SUMMARY OF THE INVENTION It is an object of the invention to provide a method for obtaining an optically pure isomer of albuterol from a mono-protected albuterol precursor. It is a further object to provide a manipulatively simple synthesis of optically pure albuterol from a commercially available prochiral starting material in only four steps involving one highly efficient resolution. This and other objects, features and advantages are provided by the present invention which relates in one aspect to a process for obtaining a single enantiomer of albuterol, comprising: dissolving a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)benzoate and a chiral acid in methanol, ethanol or a mixture of the two by heating to form a solution, said chiral acid being selected from the group consisting of (-)-di-toluoyl-L-tartaric acid, (+)-di-toluoyl-D-tartaric acid, (-)-di-benzoyl-L-tartaric acid and (+)-di-benzoyl-D-tartaric acid; allowing said solution to cool, whereby a salt of primarily one enantiomer crystallizes; separating said salt from said solution; liberating the enantiomer from said salt by treatment with a base; reducing said enantiomer; debenzylating said enantiomer and recovering a single enantiomer of albuterol. In a further aspect, the invention may be characterized as a process for making optically pure albuterol, comprising: dissolving a mixture of enantiomers of .alpha.-[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedi methanol and a chiral acid in methanol, ethanol or a mixture of the two by heating to form a solution, said chiral acid being selected from the group consisting of (-)-di-toluoyl-L-tartaric acid, (+)-di-toluoyl-D-tartaric acid, (-)-di-benzoyl-L-tartaric acid and (+)-dibenzoyl-D-tartaric acid; allowing said solution to cool, whereby a salt of primarily one enantiomer crystallizes; separating said salt from said solution; liberating said single enantiomer from said salt by treatment with a base; debenzylating said enantiomer and recovering optically pure albuterol. In either process described above, a chiral acid such as (-)-di-toluoyl-L-tartaric acid or (-)-di-benzoyl-L-tartaric acid will give the S enantiomer of albuterol; (+)-di-toluoyl-D-tartaric acid or (+)-di-benzoyl-D-tartaric acid will give the R enantiomer of albuterol. DETAILED DESCRIPTION The present invention relates to a more economical and efficient process for making optically pure albuterol. The method is particularly economical and efficient because it proceeds via readily available and inexpensive starting materials, as set forth in Scheme A below: ##STR1## The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Mayer J. Chem. Ed. 62, 114-120 (1985). Thus, solid and broken wedges are used to denote the absolute configuration of a chiral element; wedge outlines and dotted or broken lines denote enantiomerically pure compounds of unspecified absolute configuration (e.g. structures Ib and IIIb). As usual, a wavy line indicates a mixture of enantiomers of indeterminate proportion, commonly a racemic mixture. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. There is no correlation between nomenclature for the absolute stereochemistry and for the rotation of an enantiomer. Thus, D-lactic acid is the same as (-) lactic acid, and L-lactic acid is (+). Compounds having a single chiral center exist as a pair of enantiomers which are identical except that they are non-superimposable mirror images of one another. A one-to-one mixture of enantiomers is often referred to as a racemic mixture. The term "enantiomeric excess" is well known in the art and is defined for a resolution of ab.fwdarw.a+b as ##EQU1## The term "enantiomeric excess" is related to the older term "optical purity" in that both are measures of the same phenomenon. The value of ee will be a number from 0 to 100, 0 being racemic and 100 being pure, single enantiomer. A compound which in the past might have been called 98% optically pure is now more precisely described as 96% ee. Processes that yield products of ee less than about 80% are not generally regarded as commercially attractive. Processes that yield albuterol of ee greater than about 96% are particularly attractive because the eutectic of albuterol is about 96-97% and thus substantially pure single enantiomers can be obtained by simple recrystallization of the product. "Optically pure" and "substantially optically pure" as used herein refer to albuterol of 96% ee or greater. 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate (structure Ia and hereinafter "compound Ia") may be prepared by procedures well known to persons skilled in the art. The starting material shown in Scheme A above, compound Ia, is commercially available from Cipla (Bombay, India). Without further purification compound Ia is resolved with a chiral acid such as (-) or (+) di-p-toluoyltartaric acid or (-) or (+) di-benzoyltartaric acid. This may be accomplished by dissolving compound Ia and the chiral acid in refluxing methanol. The solvent may alternatively comprise ethanol or a methanol/ethanol mixture. Resolution of compound Ia may be accomplished with either about 1 mole equivalent of the tartaric acid derivative or with about 0.5 mole equivalent of the chiral acid (structure Ib and hereinafter "compound Ib salt") in the form of a solid. Compound Ib salt is filtered off, washed with ethyl acetate to remove impurities and then dried. TABLE 1 __________________________________________________________________________ Resolution of racemic compound Ia Scale Yield Chem. of compound Ia Conditions of compound Ib purity ee __________________________________________________________________________ 3 mmol 1.0 eq of D-TA 31.6% N.D. 10.0% 10 mmol 0.5 eq of (D)-TA 23.0% N.D. 10.6% 200 mmol 0.5 eq. of D-DBTA 28.7% 99.9% area 99.3% 100 mmol 0.5 eq of D-DBTA 37.2% 99.9% area 99.0% 3 mmol 1.0 eq. of D-DTTA 37.2% N.D. 84.3% __________________________________________________________________________ The solid, compound Ib salt, is preferably dissolved again in refluxing methanol and the resulting solution cooled to room temperature and stored at 0.degree. to 5.degree. C. for 10 to 20 hours. The solid is again collected by means known in the art, such as by filtration, and dried to produce a diastereomeric salt of approximately 99.0% ee, from which optically active (S) or (R) methyl 5-[2-[(1,1-dimethyl ethyl)amino]-1-hydroxyethyl-2-(phenylmethoxy)benzoate (structure Ic and hereinafter "compound Ic") may be obtained by treatment with base and, if desired, recrystallization from ethyl acetate. Compound Ic is reduced to substantially optically pure .alpha.-[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedi methanol (structure IIc and hereinafter "4-benzyl albuterol"), by treatment with 2 to 3 equivalents of borane-THF solution (BH.sub.3 -THF) in a suitable solvent, such as tetrahydrofuran (THF). The solution may be refluxed and then cooled and quenched with methanol. In addition, these steps are preferably performed under anhydrous conditions, such as a dry nitrogen or argon atmosphere, and the reactants and products protected from light. The reaction is quenched with methanol and then worked up as usual in the art. TABLE 2 ______________________________________ Reduction of resolved compound Ic Scale of Isolated yield Chem. compound Ic Reagent of compound IIc purity ee ______________________________________ 33.3 mmol BH.sub.3 -THF 73.8% 99.8% 99.4% 33.3 mmol BH.sub.3 -THF 54.7% 97.7% 99.8% ______________________________________ The optically pure 4-benzyl albuterol (structure IIc), may then be debenzylated to provide optically pure albuterol (structure IIIa). For example, 4-benzyl albuterol may undergo debenzylation with hydrogen in the presence of a catalytic amount of Pd/C in methanol or ethanol at ambient temperature under 50 psi of hydrogen for several hours. After debenzylation the catalyst may be removed by filtration. Optically pure albuterol (structure IIIa) may then be further purified and readily obtained from the filtrate as an acid salt (structure IIIb) by treating the albuterol with an appropriate acid, such as anhydrous HCl, in an ethanol and ether solution. TABLE 3 ______________________________________ Debenzylation and hydrochloride salt formation Scale of Yield of (R)- Chem. (ee %) albuterol HCl (%).sup.a (g) purity (%) ee (%) ______________________________________ 20.0 mmol 83.5 (4.60) 99.3 99.6 (99.4) 15.0 mmol 80.4 (3.33) 99.4 99.8 (99.8) ______________________________________ .sup.a Yield after recrystallization. The highly efficient synthesis shown in Scheme A is made possible by the surprising discovery that the mono-protected ether of compound Ia can be resolved in good yield in a single recrystallization employing a relatively inexpensive chiral acid. Previous syntheses required either more expensive starting materials or additional protection and deprotection steps. In an alternative embodiment, optically pure albuterol may be economically and efficiently made by similarly starting with inexpensive starting materials and proceeding via a process that further minimizes the requisite steps. This alternative embodiment may be seen in reference to Scheme B as set forth below: ##STR2## The alternative embodiment begins with a mixture of enantiomers of .alpha.-1[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzened imethanol (structure IIa and hereinafter "4-benzyl albuterol"). As with the compound Ia above, racemic 4-benzyl albuterol (IIa) is commercially available from Cipla (Bombay, India). Alternatively, compound IIa (racemic 4-benzyl albuterol) can be prepared by reduction of racemic Ia with borane or LiAlH.sub.4. Racemic 4-benzyl albuterol, as well as non one-to-one mixtures of enantiomers, may be resolved using about 1 equivalent of a chiral acid such as (-) or (+) di-p-toluoyltartaric acid (DTTA) or (-) or (+) dibenzoyltartaric acid (DBTA). The solvent may comprise ethanol or ethyl acetate, although ethanol is a preferred solvent when using dibenzoyltartaric acid as the resolving agent. The resolved chiral acid salt (structure IIb) is isolated as a solid and is treated with a base, such as 5 wt % aqueous Na.sub.2 CO.sub.3 in the presence of ethyl acetate in order to obtain the resolved free base of 4-benzyl albuterol (structure IIc). The resolved free base of 4-benzyl albuterol may be further purified by crystallization from ethyl acetate and heptanes in order to achieve 99.8% chemical purity and a .gtoreq.98% ee. TABLE 4 __________________________________________________________________________ Resolution of racemic benzyl albuterol: Scale Yield.sup.a Entry of compound IIa Conditions of compound IIb ee __________________________________________________________________________ 1 30.0 mmol 1 eq of D-DBTA 32.5% 98.4% ethanol.sup.b 2 90.0 mmol 1 eq of D-DBTA 34.0% 99.6% 3 2 mmol 1 eq of D-DBTA.sup.c 21.7% 94.4% 4 2 mmol 1 eg of D-DBTA 50.0% 83.5% 5 2 mmol 1 eq of D-DTTA 46.0% 75.9% ethyl acetate __________________________________________________________________________ .sup.a Yield is based upon racemic 4benzyl albuterol compound. .sup.b Denatured ethanol. .sup.c 95% ethanol. The free base of optically pure 4-benzyl albuterol (IIc) may then be debenzylated to form optically pure albuterol (IIIa) and recrystallized in the form of an acid salt (structure IIIb) as described above in reference to scheme A. TABLE 5 ______________________________________ Debenzylation of compound IIc and hydrochloride salt formation Yield of (R)- albuterol Chem. Entry Scale (ee %) HCl (%) (g) purity (%) ee (%) ______________________________________ 1 9.7 mmol (98.4) 80.9 (2.17) 99.6 99.6 2 10.0 mmol (99.6) 78.3 (2.16) 99.6 99.4 3 10.0 mmol (99.6) 80.5 (2.22) 99.4 99.8 ______________________________________ |
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