Organic Process Research & Development 2006, 10, 109−117
Understanding the Origin of Unusual Stepwise Hydrogenation Kinetics in the Synthesis of the 3-(4-Fluorophenyl)morpholine Moiety of NK1 Receptor Antagonist Aprepitant Karel M. J. Brands,*,† Shane W. Krska,*,‡ Thorsten Rosner,*,‡ Karen M. Conrad,† Edward G. Corley,† Mahmoud Kaba,‡ Robert D. Larsen,† Robert A. Reamer,† Yongkui Sun,‡ and Fuh-Rong Tsay† Departments of Process Research and Chemical Engineering Research and DeVelopment, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, U.S.A.
Abstract: An efficient and highly stereoselective one-pot Grignard addition/hydrogenation procedure is a key step in the synthesis of the NK1 receptor antagonist aprepitant. The critical influence of pH on the nature and stability of the intermediate Grignard adducts, along with their reactivity in the hydrogenation reaction, is described. The observation of a defluorinated impurity under hydrogen-starved conditions led to mechanistic studies that revealed unusual kinetics in the hydrogenation reaction. Detailed analysis of the kinetic profiles under hydrogenstarved conditions indicated the two steps of the reaction, debenzylation of the Grignard adducts and reduction of the incipient imine, occurred in near perfect stepwise fashion wherein the debenzylation reaction was essentially complete before any imine reduction took place. Under hydrogensaturated conditions the inhibition of the imine reduction was less complete, but the partial buildup of reactive imine intermediate led to a dramatic spike in reaction rate toward the end of reaction. Possible mechanistic rationales to explain these observation are discussed.
Introduction The pharmacologic actions of the neuropeptide substance-P have been associated with conditions as diverse as inflammation,1 emesis,2 and CNS disorders.3 This has prompted a search for small-molecule antagonists for the human neurokinin-1 (NK1) receptor4 to which substance-P preferentially binds.5 Aprepitant (1),6 a potent and orally active NK1 antagonist, is the active ingredient in Emend * To whom correspondence should be addressed. E-mail: jos_brands@ merck.com;
[email protected]. † Department of Process Research. ‡ Department of Chemical Engineering Research and Development. (1) (a) Longmore, J.; Swain, C. J.; Hill, R. G. Drugs News Perspect. 1995, 8, 5-23. (b) Weisman, M. H.; Hagaman, C.; Yaksh, T. L.; Lotz, M. Semin. Arthritis Rheum. 1994, 23, 18-24. (c) Joos, G. F.; Germonpre, P. R.; Kips, J. C.; Peleman, R. A.; Pauwels, R. A. Eur. Respir. J. 1994, 7, 1161-1171. (d) Julia, V.; Morteau, O.; Bueno, L. Gastroenterology 1994, 107, 94102. (2) Andrews, P. L. R.; Rapeport, W. G.; Sanger, W. G. Trends Pharmacol. Sci. 1988, 9, 334-314. (3) (a) Barker, R. Neurosci. ReV. 1996, 7, 187-214. (b) Longmore, J.; Hill, R. G.; Hargreaves, R. J. Can. J. Phys. 1997, 75, 612-621. (c) Teixeira, R. M.; Santos, A. R. S.; Ribeiro, S. J.; Calixto, J. B.; Rae, G. A.; De Lima, T. C. M. Eur. J. Pharmacol. 1996, 311, 7-14. (4) Desai, M. C. Expert Opin. Ther. Pat. 1994, 4, 315-321 and references therein. (5) Regoli, D.; Boudon, A.; Fauchere, J.-L. Pharmacol. ReV. 1994, 46, 551599. 10.1021/op0501895 CCC: $33.50 © 2006 American Chemical Society Published on Web 12/07/2005
Scheme 1
which is currently being marketed as a treatment for chemotherapy-induced nausea and vomiting.7 We recently reported an efficient and practical synthesis of 1 in only four operations (Scheme 1).8 In one of the key steps lactam 6 is stereoselectively converted to R-arylamine 7 via the addition (6) (a) Hale, J. J.; Mills, S. G.; MacCoss, M.; Shah, S. K.; Qi, H.; Mathre, D. J.; Cascieri, M. A.; Sadowski, S.; Strader, C. D.; MacIntyre, D. E.; Metzger, J. E. J. Med. Chem. 1996, 39, 1760-1762. (b) Hale, J. J.; Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicci, G. G.; Kurtz, M.; Metzger, J.; Eierman, G.; Tsou, N. N.; Tattersall, F. D.; Rupniak, N. M. J.; Williams, A. R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D. E. J. Med. Chem. 1998, 41, 4607-4614. (7) (a) Kris, M. G.; Radford, J. E.; Pizzo, B. A.; Inabinet, R.; Hesketh, A.; Hesketh, P. J. J. Natl. Cancer Inst. 1997, 89, 817-818. (b) Rupniak, N. M. J.; Tatersall, F. D.; Williams, A. R.; Rycroft, W.; Carlson, E. J.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Hale, J. J.; Mills, S. G.; MacCoss, M.; Seward, E.; Huscroft, I.; Owen, S.; Swain, C. J.; Hill, R. G.; Hargreaves, R. J. Eur. J. Pharmacol. 1997, 326, 201-209. (8) Brands, K. M. J.; Payack, J. F.; Rosen, J. D.; Nelson, T. D.; Candelario, A.; Huffman, M.; Zhao, M. M.; Li, J.; Craig, B.; Song, Z. J.; Tschaen, D. M.; Hansen, K.; Devine, P. N.; Pye, P. J.; Rossen, K.; Dormer, P. G.; Reamer, R. A.; Welch, C. J.; Mathre, D. J.; Tsou, N. N.; McNamara, J. M.; Reider, P. J. J. Am. Chem. Soc. 2003, 125, 2129-2135. Vol. 10, No. 1, 2006 / Organic Process Research & Development
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Scheme 2
Figure 1. Effect of acid/base stoichiometry on the composition of Grignard adducts 9-13 determined by 1H NMR spectroscopy. Samples were prepared by reacting 6 with 1.30 equiv of 4-fluorophenylmagnesium bromide in THF at 20 °C, followed by a quench into MeOH and addition of the indicated amount of 4-toluenesulfonic acid (see Experimental Section).
of a Grignard reagent followed by a quench and immediate hydrogenation. Under optimized conditions this operation provides 7 in 89-94% isolated yield as its hydrochloride salt. However, in initial scale-up of this chemistry unacceptable levels of defluorinated 8 were formed. This observation prompted a mechanistic study to understand the factors governing the selectivity of the hydrogenation. The results revealed significant insight into a rare example of stepwise kinetics in a heterogeneously catalyzed hydrogenation reaction. Results and Discussion Effect of Acid Charge. As illustrated in Scheme 2, the first step of the one-pot stereoselective conversion of N-benzyl lactam 6 into R-arylamine 7 involves the addition of 1.3 equiv of 4-fluorophenylmagnesium bromide in THF followed by a quench with methanol and acidification with 4-toluenesulfonic acid (p-TSA). This yields, according to NMR, an equilibrium mixture of five species whose relative proportions depend on the amount of added acid (Figure 1). Hemiaminal diastereomers 9 and 10 predominate at low equivalents of added acid, along with smaller amounts of aminals 11 and 12. Each pair of diastereomers is present in a 2:1 ratio. The relative stereochemistry of the major and minor diastereomers cannot be unambiguously deduced from NMR. Ring-opened ketone 13, which is presumably more 110
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Figure 2. Effect of acid/base stoichiometry on the hydrogenation yield of 7 (determined by HPLC). Reaction mixtures were prepared by reacting 6 with 1.30 equiv of 4-fluorophenylmagnesium bromide in THF at 20 °C, followed by a quench into MeOH and addition of indicated amount of 4-toluenesulfonic acid. Hydrogenations were carried out for 3 h at 22 °C and 5 psig of hydrogen in the presence of 5 wt % of a 5% Pd/C catalyst in a mixture of THF and MeOH.
basic9 than 9-12, predominates at higher acid charges and is the exclusive species above 1.6 equiv. In the second part of the one-pot conversion of 6 to 7 the above mixture of intermediates is hydrogenated over 5% Pd/C in a 1:1 mixture of MeOH and THF. Here the equivalency of added p-TSA exerts a profound influence on the rate and selectivity. As illustrated in Figure 2, when less than one equivalent of p-TSA is added relative to Grignard reagent, very little of 7 is produced after 3 h of reaction. While unreacted 9-13 constitute the majority of the endof-reaction mixture in this case, small amounts (12 area % by HPLC) of N-benzyl sec-amine 14 are observed along with ring-opened amino-alcohols 15 and 16 which are presumably derived from reduction of 13 (Scheme 3). As the amount of acid increases, the yield of 7 also increases to a maximum of ∼95% at 1.3-1.4 equiv of p-TSA relative to the Grignard adduct, before it dramatically drops to zero when the amount of p-TSA exceeds 1.7 equiv. Under the latter conditions, the reaction mixture after 3 h only contains unconverted ringopened ketone 13. Interestingly, a reaction using 1.66 equiv of p-TSA gave only a 50% yield of 7, with the balance (9) Bell, R. P. In AdVances in Physical Organic Chemistry; Gold, V., Ed.; Academic Press: New York, 1966; Vol 4, pp 1-29.
Scheme 3
according to HPLC being imine 17 (Scheme 3). Imine 17 and N-benzyl sec-amine 14 are potential intermediates leading to the desired product 7. As shown in Scheme 3, debenzylation of 9-13 followed by elimination of water or MeOH would give imine 17; a second reduction, which can be expected to be highly stereoselective, would then lead to 7. The observation of N-benzyl sec-amine 14 is likely the result of an initial stereoselective reduction of 18. Debenzylation of 14 in a consecutive step would then also give 7. Indeed, in a control experiment 14 provided 7 smoothly under the reaction conditions. Iminium 18 is also a likely intermediate in the previously described rearrangement8 of 9-13 to a pair of lactone diastereomers 19 and 20. Interestingly, the rate of this rearrangement reaches a maximum when 1.31.7 equiv of p-TSA are present relative to the Grignard reagent, mirroring the conditions where the maximum rate and selectivity occur in the hydrogenation reaction. The performance of the hydrogenation reaction as a function of the p-TSA charge may be qualitatively rationalized as follows. Under overall basic conditions (i.e., 1.6 equiv relative to the Grignard reagent) the starting material is largely present as ring-opened ketone 13 (in its protonated form). Debenzylation and ketone reduction of 13 under these conditions are apparently slow. The rearrangement to 19/20 does not occur either under these conditions because the equilibrium between 18 and 13 lies completely on the side of the latter. After workup of a hydrogenation reaction performed under optimum conditions, 7 can be crystallized as its hydrochloride salt in 89-94% overall isolated yield with >350:1 diastereoselectivity at the newly formed stereogenic center and >99.7 area % purity according to HPLC analysis. This overall yield indicates that each step (one nucleophilic addition step and two reduction steps) occurs with >95% efficiency. However, when this procedure was first performed on multikilogram scale, the reaction required several more hours to reach completion and produced up to 0.5 area % of desfluoro 8 in the isolated solid. This impurity was not rejected in a recrystallization of 7. It was established that the formation of 8 did not occur before the start of the Vol. 10, No. 1, 2006 / Organic Process Research & Development
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Figure 3. Comparison of the rate of hydrogen uptake for hydrogenations using agitation rates of 500 and 1000 rpm (kLa ) 0.03 and 0.3 s-1, respectively). The substrate solution was prepared as outlined in the Experimental Section and then hydrogenated with 10 wt % of 5% Pd/C at 20.0 °C and 5 psig of H2.
Figure 4. Reaction profile of the hydrogenation performed at relatively low agitation (kLa ) 0.03 s-1). The hydrogenation was performed at 500 rpm agitation as described under Figure 3. Samples were taken, immediately filtered, diluted, and analyzed by LC-MS.
hydrogenation as the 4-fluorophenylmagnesium bromide from the sources we used did not contain any phenylmagnesium bromide. In addition, the amount of 8 also did not increase significantly upon aging of the hydrogenation reaction mixture for an extended time. It was determined that, after the hydrogen uptake ceases, 8 grows at
