Pseudoephedrine glycinamid

Asymmetric Synthesis of a-Amino Acids by the Alkylation of Pseudoephedrine Glycinamide. Preparation of L-Allylglycine and N-Boc L-Allylglycine. 

A modified procedure has since been developed that involves the direct alkylation of pseudoephedrine glycinamide hydrate. In... 

Alkylation of pseudoephedrine sarcosinamide can be used to prepare enantiomerically enriched A -methyl-a-amino acids. Anhydrous pseudoephedrine sarcosinamide has been prepared by the addition of sarcosine methyl ester to a mixture of pseudoephedrine, lithium chloride, and lithium methoxide. In contrast to the preparation of pseudoephedrine glycinamide, the amount of dipeptide by-product produced in the reaction is minimal, perhaps due to the increased steric hindrance of the N-methyl group of sarcosine. Thus, pure anhydrous pseudoephedrine sarcosinamide can be obtained from the crude acylation reaction mixture by precipitation from toluene and subsequent drying. Like anhydrous pseudoephedrine glycinamide, anhydrous pseudoephedrine sarcosinamide can be handled in the atmosphere for brief periods without consequence, but should be stored with scrupulous avoidance of moisture to prevent hydration. 

The alkylation of anhydrous pseudoephedrine sarcosinamide is similar to the alkylation of anhydrous pseudoephedrine glycinamide, with one important experimental modification, wherein the reaction is conducted in the presence of 1 equiv of N-methylethanolamine. The optimum conditions for alkylation of anhydrous pseudoephedrine sarcosinamide involve the addition of n-butyllithium or LDA (2.95 equiv) to a suspension of anhydrous pseudoephedrine sarcosinamide (1 equiv), anhydrous lithium chloride (6.00 equiv), and A-methylethanolamine (1.00 equiv) in THF at —78°C, followed by warming the resulting slurry to 0°C and the addition of an alkylating agent (1.1-1.5 equiv) (eq 17). The presence of A-methylethanolamine in the alkylation reaction is necessary to achieve reproducible diastere-oselectivity and may function by facilitating anionic equilibration. 

Many functional groups are stable under conditions for the alkylation of pseudoephedrine glycinamide enolates, including aryl benzenesulfonate esters (eq 18), rert-butyl carbamate and rerf-butyl carbonate groups (eq 19), tert-butyldimethylsilyl ethers, benzyl ethers, ferf-butyl ethers, methoxymethyl ethers, and alkyl chlorides. The stereochemistry of the alkylation reactions of pseudoephedrine glycinamide and pseudoephedrine sarcosinamide is the same as that observed in alkylations of simple A(-acyl derivatives of pseudoephedrine. 

Recently, the bis(methylthio)methylene imine of pseudoephedrine glycinamide was shown to undergo diastereoselective alkylation at 23 °C with lithium terf-butoxide or sodium ethoxide as base and various alkyl halides as electrophiles (eq 21 ). This procedure was used to prepare enantiomerically enriched a-amino acids. 

ASYMMETRIC SYNTHESIS OF a-AMINO ACIDS BY THE ALKYLATION OF PSEUDOEPHEDRINE GLYCINAMIDE L-ALLYLGLYCINE AND... 

Lithium methoxide was purchased from Aldrich Chemical Company, Inc., and used as received. Butyllithium (BuLi) (10 M in hexanes) may be substituted for lithium methoxide in this reaction and produces a more rapid reaction. For example, the use of 0.25 equiv of 10 M BuLi requires only 1-2 hr for complete reaction and affords 65-69% yield of anhydrous pseudoephedrine glycinamide on a 40-60-g scale.2 The submitters describe the use of lithium methoxide as a less hazardous alternative to the highly pyrophoric 10 M BuLi. 

Alternatively, azeotropic drying with acetonitrile may be employed in lieu of dichloromethane/potassium carbonate.2 A solution of 50.3 g of (R,R)-(-)-pseudoephedrine glycinamide monohydrate in ca. 200 mL of acetonitrile is concentrated under reduced pressure. The oily residue is dissolved in 250 mL of toluene and the resulting solution is concentrated under reduced pressure. The oily residue obtained may be carried on directly in the alkylation procedure with only a slight decrease in yield from the procedure described above. Alternatively, anhydrous (R,R)-(-)-pseudoephedrine glycinamide may be precipitated and the resulting solid dried and carried forward as outlined above. 

The second crop of product crystals (mp 69-71 °C) was contaminated with 2% of the starting material, (R,R)-(-)-pseudoephedrine glycinamide (as determined by GC analysis, Note 18), and was recrystallized to provide analytically pure product. 

R,R)-(-)-Pseudoephedrine glycinamide Acetamide, 2-amino-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl-, [R-(R, R )]- (13) (170115-98-7)... 

---