Hydro-de-halogenation and consecutive deprotection of chlorinated N-amido-pyrrolidin-2-ones with Raney-Ni: an effective approach to gabapentin
The benzoylamino group was identified as a useful radical cyclization auxiliary that can be smoothly removed on hydro-de-halogenation of chlorinated N-substituted-pyrrolidin-2-ones with Raney-Ni. This methodology was successfully implemented in a new and appealing route to the anti-epileptic drug gabapentin.
Introduction
Gabapentin (1), which is sold under the name neurontin®, is an anti-epileptic drug marketed by Pfizer that displays an extremely low toxicity (Fig. 1). Although originally designed as a lipophilic GABA analogue, it is now known that gabapentin 1 does not interact with any of the enzymes on the GABA metabolic pathway. It also does not directly interact with either the GABAA or GABAB receptors.1 Instead, gabapentin 1 has been shown to bind with high affinity to a binding site of a calcium channel and it is thought that it exerts the biological activity through interaction at this site.2
Until relatively recently, all the reported syntheses of 13 followed the route outlined by Sircar in 1928,4 which involved formation of the intermediate glutaric-anhydride derivative 3 (in several steps) from cyclohexanone (2) (Scheme 1, path i). Unfortunately, this route, which entails a Hofmann, Curtius or Lossen rearrangement to form 1, requires expensive safety precautions for the handling of thermally unstable azides and isocyanates. In 1990, Mettler devised a more economical and technically more attractive pathway to gabapentin 1, which exploited the addition of hydrocyanic acid to cyano(cyclohexylidene)acetate (4) (Scheme 1, path ii).5 However, the problem of using toxic HCN6 spurred the development of a safer procedure by Geibel.7 In this approach, nitromethane was reacted with cyclohexylideneacetate (5) in order to introduce the aminomethyl moiety in 1 (Scheme 1, path iii).8 Although all of these approaches utilise cyclohexanone as a starting material, more recently, alternative routes to 1 have appeared that start from benzonitrile9a or cyclohexane carboxaldehyde.9b
The main problem with these approaches is the difficulty in preparing a wide range of analogues. Hence, although a variety of different groups have been placed at different sites within the cyclohexane ring, it is not easy to locate substituents at the C-2 and C-4 positions of 1.10
A short time ago we were involved in a project to develop potentially more flexible routes to gabapentin 1.11 Among the pathways we proposed, the 5-exo halogen atom transfer radical cyclisation of the cyclohexene derivative 7 to form 8, using copper(I) chloride and TMEDA, emerged as the most efficient and promising approach (Scheme 2). The cyclohexyl precursor 7 was prepared by condensation of 1,1-dimethylhydrazine with cyclohex-1-ene carboxaldehyde 6, followed by reduction of the hydrazone and N-acylation of the resulting hydrazine.12 Heating trichloride 8 with Raney nickel resulted in the formation of spirocycle 9 in high yield, thereafter the nitrogen protecting group was efficiently removed on treatment of 9 with magnesium monoperoxyphthalate in methanol. This afforded the 2-azaspiro[4.5]decan-3-one (GBP-L) 10 and since the spirocycle 10 can be easily hydrolyzed to 1, this completed our formal synthesis of gabapentin 1.6., 7., 8., 13.
Importantly, this new approach to 1 involves the formation of trichloride 8, which has chlorine atoms adjacent to the lactam carbonyl and within the cyclohexane ring. These chlorine atoms can potentially be used to further functionalise the cyclohexane ring and the C-2 position of 1. Another useful feature of our route to gabapentin 1 is the preparation of GBP-L 10, which also exhibits significant pharmacological activity.14
The choice of the dimethylamino group as a ‘cyclization auxiliary’15 offers the opportunity to combine N-deprotection with C–Cl bond reduction by for example, hydrogenation using Raney-Ni, as has been observed for more simple 2-pyrrolidinones.15 Unfortunately, this expectation was not realized and the synthesis of GBP-L 10 needed to be lengthened so as to include a final N-deprotection step (under oxidizing conditions).
This approach would certainly gain in appeal if a quicker route to GBP-L 10 from chlorinated pyrrolidin-2-one 8 could be realized. Hence we have been prompted to look for a more easily removable cyclization auxiliary such as the benzoylamino group, which we now report to be smoothly removed by Raney-Ni during the hydro-de-chlorination step.
Section snippets
Results and discussion
While Raney-Ni16 has regularly been employed in the reductive cleavage of the N–N bond of hydrazines, the situation is much more different for hydrazides, which are preferably cleaved with alkali metals in liquid ammonia.17., 18. In fact, the few reported cases for preparing N-unsubstituted γ-lactams from N-(NRR′)-pyrrolidin-2-ones generally use Li0/NH3.19 Although this method is efficient it is short of practicality. In contrast the use of Raney-Ni, which is inexpensive, easily prepared in the
Conclusion
Our endeavour to increase the appeal of a new route to gabapentin 1 from cyclohexane carboxaldehyde 6 was fulfilled by the discovery that the benzoylamino group is an effective radical cyclization auxiliary, which can be smoothly removed during the hydro-de-halogenation of the chlorinated spirocycle intermediate 18 with Raney-Ni. Importantly, the formation of the polychlorinated adduct 18, which has chlorine atoms adjacent to the lactam carbonyl and within the cyclohexane ring, has the
General
1H NMR spectra were recorded in CDCl3 solutions with a Bruker 400AMX WB and a Jeol EX 270 spectrometer, and the chemical shifts are reported in ppm relative to tetramethylsilane as external standard. Conditions for HMQC30a spectra were: evolution delay=3.57 ms, spectral width=10 ppm with 2048 complex points in f2; 256 t1 values and 32 scans for t1 value. A squared sine function (SSB=2) in f2 and f1 was applied before Fourier transformation. Similar conditions were used for HMBC30b experiments
Acknowledgements
We thank the Ministero della Università e della Ricerca Scientifica e Tecnologica (MURST) for financial assistance.
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