alpha-D-lactose → (S)-1-[2,3-dihydroxy-5-hydroxymethyl-4-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-furan-2-ylmethyl]-4-isobutyl-pyrrolidin-2-one

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Pregabalin undergoes a Maillard reaction to form conjugates with lactose in formulated product. Seven of these conjugates, which exist in the lactam form of the pregabalin moiety, were generated in milligram to gram quantities by heating pregabalin in the presence of lactose. The compounds were then isolated by preparative liquid chromatography. The assigned structures of the isolated lactose-lactam conjugates were consistent with the NMR and mass spectrometry data. Of the seven compounds identified, one compound ((S)-1-[3,4-dihydroxy-6-hydroxymethyl-5-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-pyran-2-yl]-4-isobutyl-pyrrolidin-2-one) is the Maillard reaction product of pregabalin and lactose. The lactose used in the reaction was originally the α-lactose. However, upon dissolution in the above reaction conditions, the lactose rapidly equilibrates between the α and β forms. The conjugate (S)-1-[3,4-dihydroxy-6-hydroxymethyl-5-(3,4,5 -trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-pyran-2-yl]-4-isobutyl-pyrrolidin-2-one is the β-anomer. Two of the compounds ((S)-4-isobutyl-1-[2,3,5-trihydroxy-4-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-pyran-2-ylmethyl]-pyrrolidin-2-one and (S)-1-[2,3-dihydroxy-5-hydroxymethyl-4-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-furan-2-ylmethyl]-4-isobutyl-pyrrolidin-2-one) result from the Amadori rearrangement of (S)-1-[3,4-dihydroxy-6-hydroxymethyl-5-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-pyran-2-yl]-4-isobutyl-pyrrolidin-2-one. One product is the β-furanose form ((S)-1-[2,3-dihydroxy-5-hydroxymethyl-4-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-furan-2-ylmethyl]-4-isobutyl-pyrrolidin-2-one), and the other is the β-pyranose form ((S)-4-isobutyl-1-[2,3,5 -trihydroxy-4-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-pyran-2-ylmethyl]-pyrrolidin-2-one). The remaining four conjugates are monosaccharides, resulting from the Maillard reaction/Amadori rearrangement of pregabalin with either the galactose ((S)-4-isobutyl-1-(2,3,4,5-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-pyrrolidin-2-one and (S)-4-isobutyl-1-(2,3,4,5-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-pyrrolidin-2-one) or glucose ((S)-4-isobutyl-1-(2,3,4,5-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-pyrrolidin-2-one and (S)-4-isobutyl-1-(2,3,4-trihydroxy-5-hydroxymethyl-tetrahydro-furan-2-ylmethyl)-pyrrolidin-2-one) moiety of lactose. In separate experiments, pregabalin (300 mg) was reacted in 5 mL H2O (adjusted to pH 11 with KOH) at 80° C. with glucose (600 mg) and galactose (600 mg). In the glucose reaction, a 3:1 mixture of (S)-4-isobutyl-1-(2,3,4,5-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-pyrrolidin-2-one and (S)-4-isobutyl-1-(2,3,4-trihydroxy-5-hydroxymethyl-tetrahydro-furan-2-ylmethyl)-pyrrolidin-2-one resulted. In the galactose reaction, a 5:1 mixture of (S)-4-isobutyl-1-(2,3,4,5-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-pyrrolidin-2-one and (S)-4-isobutyl-1-(2,3,4,5-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-pyrrolidin-2-one resulted. These experimental results support the structural assignments of the monosaccharide conjugates.

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