Organic Process Research & Development 2011, 15, 98–103 Second-Generation Process Research Towards Eletriptan: A Fischer Indole Approach Christopher P. Ashcroft,*,† Paul Hellier,‡ Alan Pettman,† and Simon Watkinson† Chemical Research and DeVelopment, Pfizer Global Research and DeVelopment, Sandwich, Kent CT13 9NJ, United Kingdom, and Process DeVelopment Centre, Pfizer Global Manufacturing, Loughbeg API Site, Loughbeg, Cork, Ireland Abstract: aldehyde 8 or a suitably protected form would be required, The development of a second-generation process for the synthesis together with the hydrazine 10. Formation of 8 or 9 and indeed of eletriptan via a Fischer indole cyclisation is described. The 10 however, proved to be quite challenging. The first successful finalised process offers several potential advantages over the synthesis (scheme 3) of 9 was via lithiation of N-methylpyrolle5 current route of manufacture including cost, throughput, and 11 and subsequent alkylation with 2-(2-bromoethyl)-1,3-diox- safety. olane, followed by hydrogenation of the pyrrole to yield the racemic pyrrolidine 9a. Eletriptan (R)-7 belongs to the class of drugs known as This synthesis was not amenable to further scale up, due to triptans and was approved in the United States in December the low yields, cryogenic reaction conditions and chromatog- 2002. It is a potent and selective 5-HT agonist and is marketed raphy. However sufficient material was isolated to validate the as Relpax for the treatment of migraine. It is currently a low use of 9a in the Fischer indole reaction by condensation with volume product; however, at the time the research was started, commercially available 4-bromophenyl hydrazine. This deliv- the development of novel formulations and drug delivery ered rac-5, a racemic form of an intermediate in the original systems could have significantly increased bulk demand for the synthesis, in good yield. drug. The current manufacturing route1 to eletriptan 7 is well The need for a more robust and scalable synthesis, led to developed and robust, but does suffer some limitations (scheme the development of two further routes. The first starts from 1). The key starting material 5 is extremely expensive and 4-methylaminobutyric acid 13 which is protected as the benzyl contributes approximately 50% of the total cost of manufacture. carbamate and transformed to the Weinreb amide 14. Addition It uses the costly, unnatural isomer of proline as well as the of the Grignard reagent formed from 2-(2-bromoethyl)-1,3- highly noxious and sensitizing reagent phenyl vinyl sulfone. dioxane 15, followed by deprotection with concomitant cycli- The synthesis also incorporates a lithium aluminium hydride sation and imine reduction gave a high yielding, robust four- reduction, generating large waste aqueous streams. Thus an step synthesis of compound 9b (Scheme 4). The acetal of choice alternative route of manufacture was sought that would be able was changed from the five-membered 1,3-dioxolane to the six- to deliver this increase in bulk demand. membered 1,3-dioxane due to the improved stability of the During the assessment of alternative routes to eletriptan, the respective Grignard reagent at the required reaction temperature. Fischer indole synthesis was highlighted as a particularly This route was reproducible, reliable, and very easily scaled, attractive way to build up the molecule. It had the potential to but suffers from the use of expensive reagents (all intermediates deliver a convergent, highly efficient synthesis (scheme 2), as being oils) and the need for a protecting group. However a 50-g well as being a well understood and reliable transformation. batch of the fumarate salt of 9b was easily made using this The Fischer indole reaction was discovered in 1883 by Hermann chemistry. Emil Fischer,2 and despite its age, is still one of the most The third successful synthesis of racemic pyrrolidine acetal commonly used methods to synthesise indole containing 9 starts from N-methylpyrrole-2-carboxaldehyde 20 (scheme molecules. Indeed several other members of the Triptan family 5). This undergoes a key Wittig olefination6 with a phosphorous of drugs are manufactured via this method.3 If this approach ylide derived from bromoacetaldeyde, followed by global were successful, then many of the issues associated with the hydrogenation and isolation as the fumarate salt. The acetal has current route of manufacture could be avoided. again been changed to the 5,5-dimethyl-1,3-dioxane as this gives The Fischer reaction proceeds via condensation of an aryl a crystalline intermediate 20 that was less prone to hydrolysis hydrazine with a carbonyl compound, followed by a 1,3- than either the unsubstituted dioxane or dioxolane acetals. Wittig sigmatropic rearrangement and subsequent elimination of am- reaction of Aldehyde 19 with the triphenylphosphonium ylide monia.4 In order to prove that the Fischer reaction was viable derived from 18a failed to give any conversion to the olefin for the preparation of eletriptan (R)-7, the synthesis of either 20. However, switching to the trinbutylphosphonium ylide 18b n afforded complete conversion to olefin 20. Since the tri - * christopher.ashcroft@pfizer.com. † Pfizer Global Research and Development, U.K. butylphosphine oxide byproduct is partially water-soluble, it can ‡ Pfizer Global Manufacturing, Ireland. be removed with multiple water washes of the product solution. (1) Ogilvie, R. J. New Process for the Preparation of Anti-migraine Drug, Eletriptan; WO/2002/050063, 2002. Despite the increased stability of the dimethyldioxane acetal, (2) Fischer, E.; Jourdan, F. Chem. Ber. 1883, 16, 2241. olefin 20 still hydrolyses to the corresponding aldehyde upon (3) Li, J.-J.; Johnson, D. S.; Roth, B. D.; Sliskovic, D. R. Contemporary Drug Syntheses; John Wiley and Sons: Chichester, 2004. (5) Brittain, J. M.; Jones, R. A.; Arques, J. S.; Saliente, T. A. Synth. (4) Robinson, B. The Fischer Indole Synthesis; John Wiley and Sons: Commun. 1982, 12, 231. Chichester, 1982. (6) Spangler, C. W.; McCoy, R. K. Synth. Commun. 1988, 18,51. 98 • Vol. 15, No. 1, 2011 / Organic Process Research & Development 10.1021/op100251q 2011 American Chemical Society Published on Web 12/01/2010 Scheme 1. Current manufacturing route to eletriptan (R)-7a a Reagents and conditions: (a) EtMgBr, Et2O. (b) 3, DCM, 50% from 1. (c) LiAlH4, THF, 72%. (d) Ac2O, TEA, DMF. (e) Phenyl vinyl sulfone (PVS), Pd(OAc)2, P(°Tol)3, TEA, DMF, 80% from 5. (f) H2, Pd/C, MeSO3H, acetone, 95%. (g) K2CO3, MeOH, 92%. (h) HBr, acetone 73%. Scheme 2. Fischer indole approach to eletriptan (R)-7 Scheme 4. Improved synthesis of racemic pyrrolidine acetal 9ba Scheme 3. First synthesis of racemic pyrrolidine acetal 9aa a Reagents and conditions: (a) CbzCl, KOH, water, toluene. (b) CDI, TEA, DCM, HN(OMe)Me · HCl, 82% from 13. (c) THF, 60 °C, 85%. (d) H2, Pd/C, MeOH, 60 psi, 50 °C. (e) Fumaric acid, MeOH, EtOAc, 78% from 16. synthesized in two steps from commercially available 4-nitro- phenethyl bromide 21 (Scheme 6). However, conversion to the a Reagents and conditions: (a) nBuLi, TMEDA, hexane, 50 °C. (b) 2-(2- hydrazine 10 via the diazonium salt 23 was unsuccessful. It Bromoethyl)-1,3-dioxolane, THF, -60 °C 25% from 11. (c) H2, Rh/C, 100 psi, ° 100 C, 100%. (d) 4-Bromophenyl hydrazine hydrochloride, H2SO4 (4% w/v), was clear from LC/MS analysis that the diazotisation was 75%. working efficiently and that the problem lay with the stability of the free hydrazine 10. Even the hydrochloride salt of the prolonged exposure to water and as a result, the best isolated hydrazine 10 degraded rapidly at ambient temperature. The best yield of 20 from 18b was only 35%. A significantly improved results were obtained using tin(II) chloride as reductant and procedure was developed using the triethylphosphonium ylide isolating 10 as its hydrochloride salt, with storage of the material derived from 18c. Again the conversion to olefin 20 is high, at -20 °C. This yieded a meagre 13% of 10. but the triethylphosphine oxide byproduct is highly water- It was at this point that a recent patent7 was found, detailing soluble and so can be completely removed with a single water the reduction of diazonium salts with L-ascorbic acid (vitamin wash. This minimizes the contact of the product with water C). Of particular interest was the potential to form a stable, and a significantly improved yield is attained (77%). Trieth- isolable oxalyl hydrazide intermediate 24, which could be ylphosphine is extremely pyrophoric and difficult to handle, but cleaved to the free hydrazine on treatment with acid. It was can be conveniently purchased as a solution in THF which is hoped that we could utilize 24 as a hydrazine equivalent in the much easier and safer to handle. The different pyrrolidine acetals 9a,b and c were shown to react identically under Fischer (7) Lambert, J. F.; Norris, T. Preparation of N-(5-cyclopropyl-1-quinolin- reaction conditions. 5-yl-1H-pyrazole-4-carbonyl)guanidine and other sodium-hydrogen exchanger type-1 (NHE-1) inhibitors, with improved product color, via With racemic 9 in hand, attention switched to the synthesis an improved preparation of arylhydrazines using ascorbic acid reduction; of aryl hydrazine 10. The required aniline 22 was readily WO/2002/044133, 2002. Vol. 15, No. 1, 2011 / Organic Process Research & Development • 99 Scheme 5. Alternative synthesis of racemic pyrollidine Scheme 8. Resolution approach to give the desired (R)-7a acetal 9ca a Reagents and conditions: (a) Neopentyl glycol, H2SO4, toluene, 90%. (b) n PR3, MeCN, 100%. (c) NaOEt, DMF, EtOH R ) Ph ) 0%; R ) Bu ) 35%; R ) Et ) 77%. (d) H2, Rh/C, EtOH, 100 psi, 70 °C. (e) Fumaric acid, MeOH, a EtOAc, 95% from 20. Reagents and conditions: (a) NaOH(aq), DCM. (b) Dibenzoyl-L-tartaric acid, MEK, IPA, 35%, 94% ee from 9b.