Norephedrines

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

Nagai s ephedrine was obtained from Ma-Huang and the same alkaloid, together with its stereoisomeride pseudoephednne ( -ephedrine), was isolated by Merck from the European species, E. helvetica C. A. Meyer. From commercial Ma-Huang Smith prepared two additional bases, 1-W-methylephedrine and nnr-d- -ephedrine. Nagai and Kanao added two more, viz., d-W-methyl- -ephedrine and Z-norephedrine, and... 

Chen, Stuart and Chen isolated benzylmethylamine (B. HCl, m.p. 180-5° aurichloride, m.p. 139-140°), while Chou and Mei obtained a volatile base, ephedine, CgHig02N2 [m.p. 76° or 87° (dry) B. HCl, m.p. 90° pierate, m.p. 190°]. From the European speeies Wolfes has also isolated Z-iV-methylephedrine and Z-norephedrine, and fromE. mono tachya, Spehr obtained a base C gH gON, monoelinie prisms, m.p. 112°, whieh is said to be physiologieally inaetive, and is generally known as ephedrine, Spehr. ... 

A variety of 1,3-oxazolidines have been used as chiral formyl anion equivalents for addition to aldehydes. Thus, for example, reaction of N-protected norephedrine with Bu3Sn-CH(OEt)2 gives 48, and transmetallation with BuLi followed by addition of benzaldehyde affords the expected adduct 49. The selectivity at the newly formed alcohol center is poor, but the situation can be salvaged by oxidation and re-reduction, which affords the product 50 with >95% d.e. It is then a simple matter to hydrolyze off the oxazolidine, although the resulting hydroxyaldehydes... 

Acylation of norephedrine (56) with the acid chloride from benzoylglycolic acid leads to the amide (57), Reduction with lithium aluminum hydride serves both to reduce the amide to the amine and to remove the protecting group by reduction (58), Cyclization by means of sulfuric acid (probably via the benzylic carbonium ion) affords phenmetrazine (59), In a related process, alkylation of ephedrine itself (60) with ethylene oxide gives the diol, 61, (The secondary nature of the amine in 60 eliminates the complication of dialkylation and thus the need to go through the amide.) Cyclization as above affords phendimetra-zine (62), - Both these agents show activity related to the parent acyclic molecule that is, the agents are CNS stimulants... 

Common Name dl-norephedrine hydrochloride 2-amino-1-phenyl-1-propanol hydrochloride... 

The first partial chiral resolution reported in CCC dates from 1982 [120]. The separation of the two enantiomers of norephedrine was partially achieved, in almost 4 days, using (/ ,/ )-di-5-nonyltartrate as a chiral selector in the organic stationary phase. In 1984, the complete resolution of d,l-isoleucine was described, with N-dodecyl-L-proline as a selector in a two-phase buffered n-butanol/water system containing a copper (II) salt, in approximately 2 days [121]. A few partial resolutions of amino acids and dmg enantiomers with proteic selectors were also published [122, 123]. 

Most of the chiral membrane-assisted applications can be considered as a modality of liquid-liquid extraction, and will be discussed in the next section. However, it is worth mentioning here a device developed by Keurentjes et al., in which two miscible chiral liquids with opposing enantiomers of the chiral selector flow counter-currently through a column, separated by a nonmiscible liquid membrane [179]. In this case the selector molecules are located out of the liquid membrane and both enantiomers are needed. The system allows recovery of the two enantiomers of the racemic mixture to be separated. Thus, using dihexyltartrate and poly(lactic acid), the authors described the resolution of different drugs, such as norephedrine, salbu-tamol, terbutaline, ibuprofen or propranolol. 

Early examples of enantioselective extractions are the resolution of a-aminoalco-hol salts, such as norephedrine, with lipophilic anions (hexafluorophosphate ion) [184-186] by partition between aqueous and lipophilic phases containing esters of tartaric acid [184-188]. Alkyl derivatives of proline and hydroxyproline with cupric ions showed chiral discrimination abilities for the resolution of neutral amino acid enantiomers in n-butanol/water systems [121, 178, 189-192]. On the other hand, chiral crown ethers are classical selectors utilized for enantioseparations, due to their interesting recognition abilities [171, 178]. However, the large number of steps often required for their synthesis [182] and, consequently, their cost as well as their limited loadability makes them not very suitable for preparative purposes. Examples of ligand-exchange [193] or anion-exchange selectors [183] able to discriminate amino acid derivatives have also been described. 

To demonstrate the potential of the process in obtaining both enantiomers at a high purity, experiments were performed using racemic norephedrine as the compound to be separated. Two columns of seven small membrane modules were used. The enantiomer ratios in the outflows during start-up are shown in Fig. 5-15. It can be concluded that the system reaches equilibrium within approximately 24 h, and that both enantiomers are recovered at 99.3-99.8 % purity. 

Fig. 5-15. Enantiomer ratio in the outflow versus time for the separation of raeemie norephedrine.

With the chiral methyltitanium reagents 39, modified by the bidentate ligands A-sulfonyl-norephedrine 38, a pronounced enantioselectivity is observed in reactions with aromatic aldehydes. Considerably lower enantiosclcction is obtained with aliphatic aldehydes36. 

Chiral amide and imide enolates are amongst the most effective reagents providing. yv -3-hy-droxycarboxylic acids in both high simple diastereoselectivity and induced stereoselectivity, e.g., the amides 1 and 2, and especially, the imides 3 and 4 (derived from (S(-valine and (l/ ,2S)-norephedrine, respectively)93 and the C2-symmetric amide 594 are highly effective systems ... 

Similar methodology has been applied in the syntheses of 2-amino-3-hydroxycarboxylic acids in high diastereomeric and enantiomeric purity. Two separate pathways give either the antt- or. WM-products. The first strategy relies on haloacetate precursors derived either from (S )-valine 17"- oi or from norephedrine 18102, which are converted into the boron enolates103 and subsequently reacted with aldehydes to deliver. ym-adducts99 102. The diastereomeric ratio, defined as the ratio of the desired diastereomer/the sum of all others, is 50 1 for the former and about 95 5 for the latter adducts. 

An entry to. yyrt-2-methoxy-3-hydroxycarboxylic acids is also opened using similar methodology. Thus the norephedrine derived (4/ ,5S)-3-(2-methoxy-l-oxoethyl)-4-methyl-5-phenyl-1,3-oxazolidine-2-one 23105a, as well as the phenylalanine derived (4S)-4-benzyl-3-(2-methoxy-l-oxoethyl)-l,3-oxazolidin-2-one 25105b, can be added to aldehydes via the boron enolates to give, after oxidative workup, the adducts in a stereoselective manner (d.r. 96 4, main product/sum of all others). Subsequent methanolysis affords the methyl esters. 

Chiral oxazolidines 6, or mixtures with their corresponding imines 7, are obtained in quantitative yield from acid-catalyzed condensation of methyl ketones and ( + )- or ( )-2-amino-l-phcnylpropanol (norephedrine, 5) with azeotropic removal of water. Metalation of these chiral oxazolidines (or their imine mixtures) using lithium diisopropylamide generates lithioazaeno-lates which, upon treatment with tin(II) chloride, are converted to cyclic tin(II) azaenolates. After enantioselective reaction with a variety of aldehydes at 0°C and hydrolysis, ft-hydroxy ketones 8 are obtained in 58-86% op4. 

Reaction of the enantiomerically pure alkoxyamines 3, prepared from L-ephedrine or norephedrine derivatives 1 with acetaldehyde, isobutyraldehyde or benzaldehyde using ethanol as the solvent, afford the corresponding oxime ethers 4 as mixtures of E/Z-stereoisomers11. 

Chiral (-E)-vinyl-substituted sulfoximines, in which the iV-substituent was derived from (+)-norephedrine or ( —)-(S)-l-phenylethylamine2, underwent addition reactions with organolithi-um and organocopper reagents1,2. The diastereoselection ranged from moderate to good. 

Ephedrine is the principal active ingredient in the herb ephedra, or ma huang. It is similar in form to the appetite-control drug phenylpropanolamine (banned in the United States), which is also known as norephedrine, meaning ephedrine whose methyl group has been replaced by a hydrogen. 

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