Synthesis of {3-(2-dimethylamino-ethy1)-2-[3-(2-dimethylaminoethyl)-1 H -indol-5-ylmethyl]-1 H -indol-5-yl}- N - methyl-methanesulfonamide, the main Sumatriptan impurity

An improved multistep synthesis of {3-(2-dimethylamino-ethy1)-2-[3-(2-dimethylaminoethyl)-1 H -indol-5-ylmethyl]-1 H -indol-5-yl}- N -methyl-methanesulfonamide, the main Sumatriptan impurity, is described, as a model for other related triptan derivatives.


Introduction
Among the many serotonin-like compounds studied, the discovery of the anti-migraine drug sumatriptan 1 stimulated the development of other 5-HT 1D receptor agonists. 1 From the chemical point of view, several of them (sumatriptan 1, 2 avitriptan 2, 3 and almotriptan 3, 4 rizatriptan 4 5 ) have the common feature of a functionalized indole, with a XCH 2 -group in the 5 position, in which X can act as a leaving group (Figure 1).As a result, most of the synthesis of those compounds, based on the conventional Fischer indole synthesis, using acid catalysis, generates compounds 5 as impurities, with yields depending both of the product and the method used.The product corresponding to Sumatriptan, 5a, has long been identified as the main impurity. 6In the synthesis of Avitriptan 2, the corresponding 5b has been identified and Remuzon 7 has studied the process, proposing a protecting group for the methylaminosulphonyl moiety, while Brodfuehrer 8 studied the conditions of the Fischer indolization, in order to reduce the formation of the impurity.Moreover, Rizatriptan 4, bearing a triazole group, which can be converted in a good leaving group under acid catalysis, has similar problems in his preparation, and a recent patent has been published describing a synthesis adapted to reduce the presence of the corresponding impurity 5c to a minimum. 9No data have been found for Almotriptan 3, although by its structure should have the same problem.

Figure 1
As it is usual in the pharmaceutical compounds, impurities produced in the corresponding preparation method should be extensively controlled, and they should be regularly prepared to be used in the quality controls of the main product.As a general consideration, being the impurities mostly produced by side reactions in one step of the production process, its synthesis is a good training method to study side reactions, 10 and either minimize them to improve the quality of the final product, or develop selective preparation methods in order to get samples for use in quality control methods.

Results and Discussion
The compound 5a, is the main impurity detected in Sumatriptan, whose classical Fischer synthesis has been studied in detail by Toke et al. 11 The formation of 5a has been identified in the process as a consequence of the π-excedent character of indole and related with the temperature of the process.Thus, any indole with a sulfamoylmethyl group on the 5-position -or any other fragment bearing a different leaving group-would, in the presence of acid catalysis, or by thermal treatment, produce an intermediate like 7, which would act as an electrophile, attacking the only available indole position in 6. Intermediates related to 7 has been described as part of the chemistry of gramines, with the exocyclic vinyl fragment placed on the 3-position of the indole ring, which can be generated and substituted with the corresponding nucleophile. 12he present example, however, is a case in which the intermediate 7 is produced on the benzene fragment.Sumatriptan analogs would easily produce impurities similar to 5 in the synthesis of ARKAT USA, Inc.
the main product, and the process has been studied for compounds like 2, 7,8

Scheme 2
There has been a synthesis of 5a described by Skwierawska and Paluszkiewicz, 14 using Fischer indolization as a basis to build the indole fragment 10.In the present paper, the synthesis has been simplified, starting from commercial 8.As indicated in scheme 2, 8 was acylated in the 3-position with oxalyl chloride and dimethylamine.Then, 9 was treated with lithium aluminium hydride, to produce reduction of the amide, ketone and ester groups simultaneously.As a final step, sumatriptan 1 was suspended in HCl, and a solution of 10 was slowly added, which generates the reactive intermediate 7, to produce the impurity 5a.The method, simple and robust, can be easily adapted, using 10, to produce analog impurities from Rizatriptan 3, and Almotriptan 4.

Experimental Section
General Procedures.All melting points were measured in capillary tubes and are uncorrected.IR spectra were determined on KBr disks using a Nicolet Impact 410 spectrometer. 1H NMR spectra were obtained at 300 MHz ( 1 H) and 75 MHz ( 13 C).Chemical shifts (δ) were determined using TMS as internal standard, and multiplicity (s, singlet; d, doublet; dd, double-doublet; t, triplet; q, quartet; m, multiplet) and coupling constants are indicated for every signal.HPLC-MS analyses were performed on an Agilent 1100 apparatus.A chromatographic column Luna C18 (150 x 4.6 mm) 5 µm Phenomenex was used, with a mobile phase formed by a triple gradient of 4% aq.formic acid (A), water (B) and acetonitrile (C).The gradient started as A (2.5%), B (93%) and C (4.5%) and, in 30 min.reached A (2.5%), B (4.5%) and (93%).In the Mass detector, the fragmenter operated at 70eV.High Resolution Mass Spectra were performed on a Bruker Reflex IV (MALDI-TOF).All yields correspond to isolated pure compounds.1H-Indole-5-carboxylic acid methyl ester has been obtained from Aldrich.