Omeprazole Resolution (I)

From WikidChem

SLIDE 2 There are a few ways to end up with only one enantiomer of something that could be chiral:

• Resolution (in which a racemic mixture is "resolved" to just R or just S), which can be done by separating Pasteur conglomerates (crystals in which there are "chunks" of R and "chunks" of S that can be physically picked apart) or by creating temporary diastereomers by reacting the mixture with one hand of another chiral molecule and creating diastereomers with different properties that can then be separated.

• Alternately, you can go through a process that destroys one of the enantiomers so that you are left with only the other one.

• Or, you can prepare only one enantiomer by a) using a resolved starting material, or b) using a resolved reagent or catalyst, both of which will preferentially create only one of the possible enantiomers.

SLIDE 3: Resolution of Omeprazole

Is there any reason that AstraZeneca would want to prepare only 1 of the enantiomers of omeprazole? By the time it gets to its reaction with the acid in the stomach, it is achiral, so the handedness of the starting material might not matter at all! Still, one of the enantiomers might be able to get through the bloodstream to the stomach more efficiently, so in order to test both enantiomers, the chemists had to resolve omeprazole.

To do this, they performed column chromatography on omeprazole using a column that contained a chiral molecule, cellulose. The cellulose itself had had its OH groups replaced with N=C=O groups, since those are "more organic" and thus it would work better in a chromatography column. (This replacement is similar to the reaction we saw that created urea from adding H-N=C=O to NH3+.)

When the chemists used 6 injections of omeprazole, they were able to resolve 3 mg of the enantiomer that rotated light positively (+) and 4 mg of the other enantiomer (-). This is not enough for biological tests (the human dose is ~20 mg) but it was enough to determine how fast the enantiomers racemize if they change back to a 50:50 mixture very quickly, there would be no point in making solely R or solely S in the first place. They found, however, that the half-life of racemization is about 1 hour at 75 degrees Celsius and from this predicted a rate of about 100 hours at 37 degrees Celsius, so that's slow enough to warrant making only one enantiomer, if the s enantiomer, the active ingredient in Nexium, proves to be more efficient than the racemate.

SLIDE 4: Resolution of Omeprazole, cont.

The next thing chemists tried in order to make more of the single enantiomers was using a reversible formation of crystalline mandelate ester; essentially, they reacted just the S enantiomer of the mandelic acid with the racemic mixture of omeprazole, which created both S-R and S-S molecules. They then crystallized and separated these diastereomers, removed the acid, and were left with S-omeprazole and R-omeprazole separately, so they could move on to biological tests.

They found that R-omeprazole was 4x as active as S in rats, but oddly enough, the result was reversed in humans.