| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | March 21, 1995 |
| 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 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate using ditoluoyltartaric acid. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | May 23, 1994 |
| PATENT REFERENCES CITED |
Hartley et al. "Absolute Configuration of the Optical Isomers of Salbutamol" J. Med. Chem. 14, 895-896 (Apr. 17, 1971). Hopkins "Salbutamol" Drugs of the Future IV 629-633 (May 2, 1979). Floyd et al. "The Oxidation of Acetophenones to Arylglyoxals with Aqueous Hydrobromic Acid in Dimethyl Sulfoxide" J. Org. Chem. 50, 5022-5027 (Jun. 1, 1985). Collin et al. "Saligenin Analogs of Sympathomimetic Catecholamines" Chemistry Dept., Allen and Hanburys Ltd. (Apr. 13, 1970). |
| PATENT CLAIMS |
What is claimed is: 1. A method for obtaining a single enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate comprising the steps of: (a) dissolving a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate and a chiral acid selected from the group consisting of (-)-di-toluoyl-L-tartaric acid and (+)-di-toluoyl-D-tartaric acid in methanol 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 methanol, whereby a diastereomeric salt having greater than 90% ee of an enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is obtained (e) separating said diastereomeric salt from the methanol solvent; and (f) liberating said enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate from said diastereomeric salt by treatment with base. 2. A method according to claim 1 wherein said chiral acid is (-)-di-toluoyl-L-tartaric acid and said enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is the S enantiomer. 3. 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-hydroxybenzoate is the R enantiomer. 4. A method for making optically pure albuterol comprising the steps of: (a) dissolving a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate and a chiral acid selected from the group consisting of (-)-di-toluoyl-L-tartaric acid and (+)-di-toluoyl-D-tartaric acid in methanol 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 methanol, whereby a diastereomeric salt having greater than 90% ee of an enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is obtained; (e) separating said diastereomeric salt from the methanol solvent; (f) liberating the enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate from said diastereomeric salt by treatment with base; and (g) reducing said enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate thereby forming optically active albuterol. 5. The method of claim 4 wherein said enantiomer of 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is reduced with borane-methyl sulfide. 6. The method of claim 4 wherein said enantiomer of 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is reduced with lithium aluminum hydride. 7. The method of claim 4 wherein said mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is obtained by the steps of: (a) reacting methyl 5-acetylsalicylate with hydrogen bromide in dimethyl sulfoxide, thereby forming a keto aldehyde; (b) reacting said keto aldehyde with tert butylamine, thereby forming an .alpha.-iminoketone; and (c) reducing said .alpha.-iminoketone to provide methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate. 8. A method according to claim 7 wherein said .alpha.-iminoketone is reduced with a hydride reducing agent. 9. The method of claim 7 wherein said hydride reducing agent is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. 10. A method according to claim 7 wherein said .alpha.-iminoketone is reduced by catalytic hydrogenation. 11. A method according to claim 10 wherein said catalytic hydrogenation is carried out over a heterogeneous noble-metal catalyst. 12. The method of claim 11 wherein said heterogeneous noble-metal catalyst is Pd/C. 13. The method of claim 11 wherein said heterogeneous noble-metal catalyst is Pt/C. 14. The method of claim 11 wherein said heterogeneous noble-metal catalyst is PtO.sub.2. -------------------------------------------------------------------------------- |
| 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-hydroxybenzoate 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 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 albuterol precursors are described only for precursors having the phenolic group protected as a benzyl ether. Hartley et al. op. cit. disclosed that optical resolutions of albuterol or any phenolic precursor were unsuccessful; resolution was possible only when the phenolic precursor was protected as a benzyl ether. 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 phenolic 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 to a process for obtaining a single enantiomer of 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate, a precursor to albuterol, comprising the steps of: (a) dissolving a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate and a chiral acid selected from the group consisting of (-)-di-toluoyl-L-tartaric acid and (+)-di-toluoyl-D-tartaric acid in methanol 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 methanol, whereby a diastereomeric salt having greater than 90% ee of an enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is obtained; (e) separating said diastereomeric salt from the methanol solvent; and (f) liberating said enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate from said diastereomeric salt by treatment with base. In the process described above, a chiral acid such as (-)-di-toluoyl-L-tartaric acid will give the S enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate; (+)-di-toluoyl-D-tartaric acid will give the R enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate. In addition, the invention encompasses a process for making optically pure albuterol from a mixture of enantiomers of 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate. The process comprises steps (a) through (f) as described above, followed by reducing the enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate thereby forming optically active albuterol. The reduction may be accomplished with either borane-methyl sulfide or lithium aluminum hydride. In a specific aspect the invention relates to a method for producing optically pure albuterol from methyl 5-acetylsalicylate comprising the resolution and reduction described above in combination with a method for producing 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate. According to this aspect the methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is obtained by: (a) reacting methyl 5-acetylsalicylate with hydrogen bromide in dimethyl sulfoxide, thereby forming a keto aidehyde; (b) reacting said keto aldehyde with tertbutylamine, thereby forming an .alpha.-iminoketone; and (c) reducing said .alpha.-iminoketone to provide methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate. The .alpha.-iminoketone may be reduced with either a hydride reducing agent, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride or by catalytic hydrogenation with a heterogeneous noble-metal catalyst, such as Pd/C, Pt/C or PtO.sub.2. DETAILED DESCRIPTION The present invention relates to a more economical and efficient process for making an 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 (e.g. IV) denote enantiomerically pure compounds of indeterminate absolute configuration. 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 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 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. Arylglyoxals (II) are most conveniently prepared from acetophenone derivatives by the procedure of U.S. Pat. No. 5,283,359, although other syntheses, well known to persons skilled in the art, are also suitable. The starting material shown in Scheme A above, methyl 5-acetylsalicylate, is commercially available. Oxidation in DMSO (1.0 M) in the presence of 2 equivalents of aqueous HBr proceeds smoothly at 60.degree. C. over 20 hours to give the arylglyoxal II in greater than 80% yield. However, prolonged reaction times and temperatures exceeding 70.degree. C. may result in lower yields. Without further purification, this compound is treated with 1.0-1.2 eq of t-butylamine in warm toluene or ethyl acetate to give the .alpha.-iminoketone V in greater than 70% yield. The .alpha.-iminoketone can be further purified by recrystallization from toluene/heptane and is used in the reduction after drying. The overall yield from the salicylate is greater than 60%. The .alpha.-iminoketone V is dissolved in a suitable solvent such as methanol and cooled with ice water. Approximately 2.5 equivalents of a hydride reducing agent are added in portions and the mixture is stirred at room temperature overnight. Thereafter the mixture is concentrated, quenched with water, and extracted into a suitable solvent, washed and recrystallized from ethyl acetate-heptane in overall yield of about 78%. The product may be analyzed for purity by any one of many methods well known in the art, an example being HPLC analysis. If the solid amino-alcohol of formula III is not greater than 95 area % pure by HPLC analysis, recrystallization is preferably repeated until this level of purity is met prior to use of the same in the resolution step. Alternatively, the compound of formula III may also be prepared directly from the corresponding .alpha.-iminoketone V by the catalytic reductive amination with t-butylamine in the presence of heterogeneous noble-metal catalysts such as Pd/C, Pt/C or PtO.sub.2. The precursor III is resolved with a chiral acid such as (-) or (+) di-p-toluoyltartaric acid. This may be accomplished by dissolving the phenolic precursor III and the chiral acid in refluxing methanol. Although this solvent may alternatively comprise ethanol or a methanol/ethanol mixture, methanol is the preferred solvent. The methanol solution is then cooled and stirred at 20.degree.-25.degree. C. for 3 to 20 hours, preferably 2 to 3 hours, thereby forming a tartrate salt in the form of a white solid. The salt is filtered off, washed with ethyl acetate to remove impurities and then dried. At this point the diastereomeric salt may represent approximately a 50% yield, of 93% ee. The solid 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 white solid is again collected by means known in the art, such as by filtration, and dried to produce a diastereomeric salt of approximately 98.5% ee, from which the product 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate may be obtained by treatment with base, extraction, and, if desired, recrystallization from ethyl acetate. The salicylic ester III is reduced to substantially optically pure albuterol by treatment with 2 to 3 equivalents of borane-methyl sulfide complex (BH.sub.3.Me.sub.2 S) in a suitable solvent, such as dichloromethane or toluene at temperatures from 50.degree. to 60.degree. C. It is preferred that the reaction is not heated over 60.degree. C. since higher temperatures may result in overreduction of the product. In addition, these steps are preferably performed under a dry nitrogen or argon atmosphere and the reactants and products protected from light. The reaction is quenched with methanol and worked up as usual in the art. The highly efficient synthesis shown in Scheme A is made possible by the surprising discovery that the free phenol of formula III 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, because arriving at unresolved III was considered a synthetic dead end. |
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| PATENT PHOTOCOPY | available on request |
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