| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | April 2, 2002 |
| PATENT TITLE |
Process for the production of optically enriched (R)- or (S)-albuterol |
| PATENT ABSTRACT | 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 2-(N-t-butylamino)-1-(+2,2-dimethyl-1,2-benzodioxin-6-yl) ethanol, with a chiral tartaric acid derivative |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | November 13, 2000 |
| PATENT CT FILE DATE | February 19, 1999 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | August 26, 1999 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A process for the preparation of 2-(N-t-butylamino)-1-(2,2-dimethyl-1,3-benzodioxin-6-yl) ethanol (2), which process includes the steps of: (1) suspending albuterol (1) 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). 2. A process for the optical resolution of a mixture of enantiomers of 2-(N-t-butylamino)-1-(2,2-dimethyl-1,3-benzodioxin-6-yl) ethanol (2) 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; (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). 3. A process according to claim 2 wherein in step (i) the solvent is a lower alcohol. 4. A process according to claim 2 or claim 3 wherein in step (i) the tartaric acid derivative is selected from the group consisting of (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), and (2R,3R)-(-)-di-O-(p-toluoyl)-tartaric acid (4b). 5. A process for the hydrolysis of 2-(N-t-butylamino)-1-(2,2-dimethyl-1,3-benzodioxin-6-yl) ethanol (2) to give albuterol (1) either as the free base or as a salt, which process 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. 6. A process for resolving the enantiomers of albuterol (1) into the (R)-enantiomer designated (R)-1 and the (S)-enantiomer designated (S)-1, which process includes the steps of: (i) suspending albuterol (1) or a salt thereof, in acetone; (ii) adding to the mixture of step (i) a suitable acid with stirring to form 2-(N-t-butylamino)-1-(2,2-dimethyl-1,3-benzodioxin-6-yl) ethanol (2); (iii) adding to the mixture of step (ii) a suitable aqueous or non-aqueous basic solution; (iv) recovering the compound of the formula (2) as a mixture of enantiomers designated (R)-2 and (S)-2; (v) reacting the mixture of enantiomers of the compound of the formula (2) from step (iv), dissolved in a suitable solvent, with an enantiopure tartaric acid derivative; (vi) precipitating selectively out of the solution of step (v) a compound of the formula: (R)-2:tartaric acid derivative salt or (S)-2:tartaric acid derivative salt; (vii) suspending the (R)-2:tartaric acid derivative salt or the (S)-2: tartaric acid derivative salt from step (vi) 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; (viii) adding the (R)-2:tartaric acid derivative salt or the (S)-2:tartaric acid derivative salt from step (vii) to a mixture of an aqueous solution of a base and a suitable organic solvent; (ix) recovering the compound (R)-2 or the compound (S)-2 from the organic phase of step (viii); (x) dissolving the compound (R)-2 or the compound (S)-2 from step (ix) in an excess of an acid, and water or any other suitable organic solvent, to hydrolyse the compound (R)-2 or the compound (S)-2; and (xi) recovering the compound (R)-1 or the compound (S)-1 either as a salt or as the free base. 7. A process according to claim 6 for the recovery of the compound of the formula (R)-1. 8. A process according to claim 6 or claim 7 wherein in step (v) the enantiopure tartaric acid derivative is selected from the group consisting of (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), and (2R,3R)-(-)-di-O-(p-toluoyl)-tartaric acid (4b). 9. A process for the racemisation of optically enriched albuterol (1) or a salt thereof or optically enriched 2-(N-t-butylamino)-1-(2,2-dimethyl-1,3-benzodioxin-6-yl) ethanol (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) or a salt thereof, or optically enriched compound of the formula (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). 10. A process according to claim 9 wherein in step (A) the solvent is selected from the group consisting of water, a lower alcohol, acetonitrile and tetrahydrofuran, or a mixture of water and a lower alcohol, acetonitrile or tetrahydrofuran. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
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 .beta.-2 agonist with bronchodilatory action. It is widely used, as a racemic mixture, in the treatment of asthma..sup.1,2,3 Of the two possible optical isomers the (R)-enantiomer is reported to be significantly more potent with respect to .beta.-2 agonist activity than the (S)-enantiomer..sup.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.sup.5 or 5-[2-[(1.1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)benzoate. sup.6 and enantioselective reduction of an .alpha.-iminoketone to an .alpha.-amino alcohol using a borane reducing agent and a chiral 1,3,2-oxazaborole catalyst..sup.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) ##STR1## 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) ##STR2## 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. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a .sup.1 H-NMR spectrum of (rac)-2 with (R)-O-acetyl mandelic acid in CDCl.sub.3 ; FIG. 2 is a .sup.1 H-NMR spectrum of (R)-2 with (R)-O-acetyl mandelic acid in CDCl.sub.3 ; FIG. 3 is a .sup.1 H-NMR spectrum of 2(R)-2:3a in CDCl.sub.3 ; and FIG. 4 is a .sup.1 H-NMR spectrum of 2(R)-2:4a in CDCl.sub.3. DESCRIPTION OF EMBODIMENTS The present invention encompasses four processes: (1) A process for the preparation of compound (2), i.e a ketal derivative of compound (1), which is albuterol. (2) A process for the optical resolution of a mixture of enantiomers of compound (2) into its (R)-isomer and its (S)-isomer. (3) A process for the hydrolysis of compound (2) and enantiomerically enriched compound (2) to give compound (1) or enantiomerically enriched compound (1). (4) A process for the racemisation of optically enriched compound (1) or compound (2) to give a mixture of enantiomers of compound (1). When these four processes are combined, there is provided a process for producing optically enriched albuterol or albuterol salts with enantiomeric excesses greater than 99% achievable, as well as a process whereby the undesired isomer of albuterol may be racemised and recycled to achieve a higher yield of the desired isomer of albuterol. The designations (R)-1, (S)-1, (R)-2 and (S)-2 and their respective salts used herein refer to enantiomerically enriched compounds usually of 90% ee or greater, unless otherwise stated. The four processes of the invention are described in more detail below. A Ketalisation In the first process of the invention, a mixture of enantiomers of compound (1) or a salt thereof is condensed with acetone in the presence of an acid and, if required, a dehydrating agent, which may be added simultaneously with or after the acid, to form compound (2), See Scheme 1. Preferable acid/dehydrating agent systems include sulfuric acid; sulfuric acid and anhydrous copper sulphate; and boron trifluoride diethyl etherate. The acid is preferably present in an amount of between 1 to 5 molar equivalents and the reaction is preferably cooled to a temperature of between -15.degree. C. to 10.degree. C. ##STR3## Acetone, which has the formula: ##STR4## is utilised both as a solvent and a reagent. Compound (2) is isolated from the reaction mixture after neutralisation of the excess acid with a suitable base, such as sodium hydroxide (NaOH), potassium hydroxide (KOH), or sodium carbonate (Na.sub.2 CO.sub.3) dissolved in either water or a mixture of water and a lower alcohol, giving an aqueous basic solution, or a lower alcohol, giving a non-aqueous basic solution. The lower alcohol may be methanol. When an aqueous basic solution is used, the acetone is removed under reduced pressure and compound (2) is extracted into a suitable organic solvent such as ethyl acetate, chloroform, toluene or any other water non-miscible solvent in which compound (2) is soluble. The organic phase is then dried over anhydrous Na.sub.2 SO.sub.4, filtered and the solvent removed under reduced pressure. When a non-aqueous basic solution is used, compound (2) is recovered after filtration of solids and removal of solvent under reduced pressure. The crude compound (2) may then be purified by dissolving it in a suitable organic solvent, such as ethyl acetate, chloroform or toluene and washing the organic phase with water. Further purification of compound (2) may be performed, for example by recrystallisation from suitable solvents such as acetonitrile, methyl ethyl ketone or acetone or a mixture of the organic solvent and water, or by column chromatography. B Resolution and liberation of ketal The second process of the invention is a process for the optical resolution of a mixture of enantiomers of compound (2) into its (R)-isomer designated (R)-2 and its (S)-isomer designated (S)-2 which have the formulae: ##STR5## In terms of this process, compound (2) as a mixture of enantiomers, is dissolved in a suitable solvent, preferably a lower alcohol such as methanol or ethanol, and a solution of the resolving agent, a chiral tartaric acid derivative such as that of the formulae (3a), (3b), (4a) or (4b), in the chosen solvent, is added. One isomer of compound (2) selectively crystallises from solution as a salt of the tartaric acid derivative used. When the chiral acid used is a compound of the formulae (3a) or (4a): ##STR6## i.e. either (2S,3S)-(+)-di-O-benzoyl tartaric acid (3a), or (2S,3S)-(+)-di-O-(p-toluoyl)-tartaric acid (4a), then there is precipitated out a salt of the formula 2(R)-2:3a i.e a salt of (R)-2 and (3a) in a ratio of 2:1, or of the formula 2(R)-2:4a i.e a salt of (R)-2 and (4a) in a ratio of 2:1; and the optically enriched compound (R)-2 may be liberated by treatment with a base. When the chiral acid used is a compound of the formulae (3b) or (4b): ##STR7## i.e (2R,3R)-(-)-di-O-benzoyl tartaric acid (3b) or (2R,3R)-(-)-di-O-(p-toluoyl)-tartaric acid (4b), then there is precipitated out a salt of the formula 2(S)-2:3b i.e a salt of (S)-2 and (3b) in a ratio of 2:1, or of the formula 2(S)-2:4b i.e a salt of (S)-2 and (4b) in a ratio of 2:1; and the optically enriched compound (S)-2 may be liberated by treatment with a base. The ratios of the resolving agent to the ketal, i.e compound (2), may be in the range of from 0.5 to 1 mole equivalents inclusive, and the solutions may be combined hot or may be mixed at ambient temperature. The solution (if hot) is allowed to cool, with or without stirring, to ambient temperature, and may be chilled to facilitate crystallisation. Solvent volumes may be reduced by distillation, either under reduced pressure or at ambient pressure, to increase the yield of salt. The salt is recovered by filtration, dried and the degree of enrichment of the desired enantiomer of compound (2) determined by measurement of optical rotation or HPLC using a suitable chiral column. The salts 2(R)-2:3a, 2(R)-2:4a, 2(S)-2:3b, or 2(S)-2:4b, may be further purified by slurry of the crude salt in a suitable solvent such as a lower alcohol, e.g methanol or ethanol. The mixture is stirred to improve optical purity, and the relevant salt is then recovered by filtration. This step may be repeated, if necessary, further to improve optical purity. Recovery of the resolved compound (2) is achieved by dissociation of the salt in a vigorously stirred mixture of an aqueous solution of a suitable base such as sodium carbonate, or sodium hydroxide, and a suitable organic solvent such as ethyl acetate, toluene or chloroform, into which compound (2) is extracted. The phases are separated, the organic phase dried over a suitable dehydrating agent such as anhydrous Na.sub.2 SO.sub.4 or MgSO.sub.4, and the organic solvent is removed under reduced pressure to yield optically enriched compound (2). Optical purity of compound (2) may be determined by NMR assay, using a suitable chiral shift reagent such as O-acetylmandelic acid, by measurement of optical rotation or, preferably, by HPLC analysis using a suitable chiral column. Optical purity may be enhanced by recrystallisation of the optically enriched compound (2) from a suitable solvent such as acetonitrile, acetone or methyl ethyl ketone or a mixture of the chosen organic solvent and water. C Hydrolysis of ketal The third process of the invention is a process for the hydrolysis of compound (2). In terms of this process, preferably optically enriched compound (2) is hydrolysed to yield optically enriched compound (1), i.e albuterol or a salt thereof. This may be achieved by dissolution of compound (2) in a solution of a suitable acid such as acetic acid, sulfuric acid, hydrochloric acid, trifluoroacetic acid, toluenesulfonic acid or camphorsulfonic acid, in water or other suitable solvents, including lower alcohols, acetonitrile and tetrahydrofuran, or a mixture of water and an organic solvent. The reaction is carried out at a temperature of between 0.degree. C. and reflux temperature, preferably between 20.degree. C. and reflux temperature and with greater than 1 up to 5 molar equivalents of a strong acid such as a mineral acid, or up to 30 molar equivalents of a weaker acid such as acetic acid. Depending on the temperature, acid and solvent used, the hydrolysis is carried out for between 10 minutes and 6 hours. Under these conditions the enantiomeric excess did not change significantly. In the case of an aqueous process, when an inorganic acid is used, once hydrolysis is complete, the excess acid is neutralised with a suitable base, such as NaOH or Na.sub.2 CO.sub.3 to pH of ca 3.5 and the solvent removed under reduced pressure. The residue may then be neutralised further using the preferred base to a pH of ca 10 in a suitable organic solvent, preferably a lower alcohol, the solids filtered off and the solvent removed under reduced pressure to give compound (1) in crude form as its free base. In the case of a non-aqueous hydrolysis, once hydrolysis is complete, the excess acid is neutralised with a suitable base, such as NaOH or Na.sub.2 CO.sub.3 to a pH of ca 10, the solids filtered off and the solvent removed under reduced pressure to give compound (1) in crude form as its free base. Alternatively, in order to isolate compound (1) as a salt, for example as an acetate salt, solvent and excess acid may be removed under reduced pressure and the resulting salt of optically enriched compound (1) isolated by crystallisation from a suitable solvent system such as methanol/ethyl acetate. In the case of an inorganic acid such as HCl or H.sub.2 SO.sub.4 being used for the hydrolysis, the n the salt of compound (1) may be isolated by partial neutralisation with an organic base, such as triethylamine, and allowed to crystallise in a reduced volume of solvent. (R)-1 or (S)-1 in crude form as its free base, may be purified by recrystallisation from solvent systems such as methanol, ethanol, methanol/ethyl acetate, ethanol/ethyl acetate, ethyl acetate, isopropanol/ethyl acetate, acetone or tetrahydrofuran. Recrystallisation of optically enriched compound (1) may be used to improve the enantiomeric excess. D Racemisation of optically enriched ketal The fourth process of this invention is the racemisation of optically enriched compound (1), preferably as its derivative, compound (2), to give a mixture of enantiomers of compound (1). In terms of this process optically enriched compound (2) is dissolved in a solution of an excess of an acid such as sulfuric acid, hydrochloric acid, acetic acid or trifluoroacetic acid, and water, or any suitable organic solvent, such as a lower alcohol, acetonitrile or tetrahydrofuran, or a mixture of water and an organic solvent. Water is by far the preferred solvent since it reduces byproduct formation. The amount of acid used may be from 5 to 50 molar equivalents inclusive. The reaction is preferably heated to between ca 0.degree. C. and reflux temperature. Deprotection of compound (2) to compound (1) is rapid with excess acid and thereafter racemisation proceeds according to the mechanism of D. P. Venter..sup.8 The decrease in enantiomeric excess may be measured by optical rotation or by HPLC analysis using a suitable chiral column. Once sufficient racemisation has been achieved, the solution is cooled and the excess acid neutralised with, preferably, an aqueous base such as NaOH or Na.sub.2 CO.sub.3 to a pH of ca 3.5. The solvent is then removed under reduced pressure and the salt of compound (1) freed by addition of further base in a lower alcohol until a pH of ca 10 is obtained. The solids may then be filtered off and the filtrate concentrated under reduced pressure to give crude, racemised compound (1) as its free base. Alternatively, in order to isolate racemised compound (1) as a salt, the excess acid may be neutralised, as above, to a pH of ca 3.5. The solvent may then be removed under reduced pressure to give crude compound (1) and salts of neutralisation. The mixture of the salt of compound (1) and the inorganic salts may then be slurried in acetone and ketalised directly, according to the first process of this invention. EXAMPLES General Melting points were measured using a Reichert-Jung Thermovar hot-stage microscope and are uncorrected. Optical rotations were measured on a Perkin-Elmer 141 polarimeter. Microanalyses. were determined using a Fisons EA 1108 CHNS-O instrument. .sup.1 H-NMR spectra were recorded on a Varian VXR-200 (200 MHz) or a Varian Unity Spectrometer (400 MHz). .sup.13 C-NMR spectra were recorded on the same instruments at 50 or 100 MHz. The relevant solvent peak (CHCl.sub.3 or DMSO) was used as an internal standard in each case. High performance liquid chromatography was performed on a Hewlett Packard 1090 system with a diode array detector and a Hewlett Packard 3393A integrator. Thin layer chromatography was performed on aluminium backed silica gel 60 F.sub.254 plates. The plates were visualised under ultraviolet light and by spraying with ceric ammonium sulphate in 8 mol.dm.sup.-3 sulfuric acid and baking at 200.degree. C. Column chromatography was conducted with Merck Kieselgel 60, 70-230 mesh. Determination of Optical Purity (a) High Performance Liquid Chromatography Chiral HPLC column Chirex (S)-ICA and (R)-NEA (phase 3022) with a suitable mobile phase system. or Chirobiotic Teicoplanin with a suitable mobile phase. The enantiomeric excesses were calculated using ##EQU1## (b) .sup.1 H-NMR Typically compound (2) (5mg) and (R)- or (S)-O-acetylmandelic acid (6 mg) were dissolved in CDCl.sub.3 (1 cm.sup.3) and the .sup.1 H-NMR spectra recorded (400 MHz). Several of the protons in compound (2) gave well distinguished peaks for each diastereomer formed in solution and integration of these pairs (usually the t-Bu peaks) allowed determination of the optical purity. Spectra obtained with (rac)-2 (racemic compound (2)) and (R)-2 respectively have been reproduced in FIGS. 1 and 2. Hereinafter the compound of the formula (2) is referred to simply as 2. Likewise the compounds of the formulae (1), (3a), (4a), (3b) and (4b) are simply referred to by number. Confirmation of Absolute Configuration in 2 The (R)-phenylethyl urea of (+)-2 was prepared and the structure elucidated using X-ray crystallography. The absolute configuration at the chiral centre in (+)-2 was shown to be (S). |
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