The structure of Omeprazole in the solid state: a 13 C and 15 N NMR/CPMAS study

The 13 C and 15 N CPMAS spectra of a solid sample of Omeprazole have been recorded and all the signals assigned. The sample consists uniquely of the 6-methoxy tautomer. For analytical purposes, the signals of the other tautomer, the 5-methoxy one, were estimated from the data in solution ( Magn. Reson. Chem . 2004 , 42 , 712).


Introduction
Omeprazole, 5(6)-methoxy-2-{(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazole [1(2)], is an important ulcer drug, 1 that has been classified amongst the blockbuster drugs. 2 This compound presents two sources of structural differentiation.First, Omeprazole is chiral (a vs. b) 3 since it has a stereogenic center on the sulfur atom but the commercial form has been sold, until recently, as a racemate.In 2001, Esomeprazole magnesium, the S enantiomer was approved. 4The second source of diversity is that these compounds present tautomerism (1 vs. 2).We have already devoted a paper to the tautomerism of Omeprazole in solution using 1 H and 13 C NMR spectroscopy. 5In this paper a complete assignment of the signals was carried out and the tautomeric equilibrium constant, K T = [2]/ [1], was determined in THF at 195 K, to be 0.59 in favor of the 6-methoxy tautomer 2.

Results and Discussion
We have devoted some publications to determine the relationships between tautomerism in solution and tautomerism in the solid state: the most frequent situation is that the tautomer predominant in solution is the only one present in the solid state. 6In the case of Omeprazole (37% of 1 -63% of 2) the prediction should be that in the solid state only 2 will be present.We recorded the 13 C and 15 N CPMAS/NMR spectra of the sample without further purification.We have represented in Figure 1 the general 13 C CPMAS NMR spectrum and in Figure 2, the corresponding NQS spectrum where only quaternary carbons are apparent.The first important observation is that there is only one series of signals, that is, only one tautomer is present in the solid.
The chemical shifts of Figure 1 are in good agreement with the data in solution for tautomer 2 and are rather different of those of tautomer 1 (see Table 1).The 4 th and 5 th columns of Table 1 correspond to the same spectra, those of Figure 1  b numbered as tautomer 2; c for 15 N data see also Table 2.
A regression for each pair of values lead to two equations: The second hypothesis is better.Note that both tautomers only differ in the effects of the 5(6)-methoxy group that are only important for carbons C 3a(7a) and C 4 (7) .Considering only these Concerning 15 N NMR results in solution, only N 14 and N 1 were observed, the N 3 signals could not be detected even using different delays for evolution of long-range couplings.
In our previous paper we reported the absolute shieldings, σ ppm, calculated at the GIAO/DFT/6-311++G** level (Table 2).Here again, the correlation is better with tautomer 2 (eq.6) than with tautomer 1 (eq.5), but, as expected from the small effect of the 5( 6)-methoxy group on the benzimidazole nitrogens, both are rather similar: In conclusion, the sample of Omeprazole we have studied in this work is pure (or, at least, more than 95% pure) 6-methoxy tautomer 2. When Omeprazole has been crystallized to obtain single crystals good enough for X-ray crystallography, the structure shows that they are 6methoxy tautomers (unfortunately, in both cases the authors named them 5-methoxybenzimidazoles!): they are reported in the Cambridge Structural Database 7 with the refcodes VAYXOI and VAYXOI01(02).It is possible that other samples of Omeprazole correspond to mixtures of 1 and 2. The most useful signals to determine the tautomerism of Omeprazole in the solid state are C 4 /C 7 and C 3a /C 7a .We have represented in Figure 3 the 13 C CPMAS spectra of 2 (Eq.[2] fitted) and 1 (Eq.[2] predicted from the solution data).A 13 C CPMAS NMR study of Omeprazole and its inclusion in β-cyclodextrin has been published in 2003. 8The spectrum, unassigned, is identical to that reported here, so it belongs to tautomer 2 although it is named as a 5-methoxy derivative 1.
The same tautomer was used by the Chemical Abstract to describe it under the Registry Number methoxy-(R)-(+)-Omeprazole 2b H 1

Table 1 .
in the case of 13 C. Due to benzimidazole numbering, save C 2 , the remaining six carbon and the two nitrogen atoms are different for each one of them.For instance, in tautomer 1 C 5 bears the methoxy group while in tautomer 2 it is ortho to the methoxy group and so on.Consequently, the signal of C 7 appears at 113.1 and 94.0 ppm for tautomers 1 and 2 in solution (2 nd and 3 rd columns) and has to be compared with signals at 120.6 and 91.6 ppm of the CPMAS spectrum.Figure 1. 13 C CPMAS NMR spectrum of Omeprazole Figure 2. Expanded region of the NQS spectrum of Omeprazole a Numbered as tautomer 1;