The present invention relates to a new process for the preparation of eletriptan, or its enantiomer, or a pharmaceutically acceptable salt of either.

Eletriptan, 3-{[1 -methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulfonylethyl)- 1 H-indole (also known as 5-(2-benzenesulfonylethyl)-3-(1-methylpyrrolidin-2-ylmethyl) -1 H- indole) and a process for its preparation, are disclosed in US-B-5,607,951. Further processes for the preparation of eletriptan are disclosed in EP-B-1088817 and WO- A-02/50063.

Eletriptan is currently marketed worldwide for the treatment of migraine as Relpax® and is therefore manufactured in bulk quantity. The large-scale synthesis of a drug molecule should be short, high-yielding and selective and avoid the use of toxic or dangerous materials. The prior art syntheses of eletriptan, exemplified in the prior art discussed above, suffer from the use of phenyl vinyl sulphone, which is a toxic chemical and hazardous to handle on a large scale and the use of palladium in a later-stage step which can necessitate extensive purification. Furthermore, the known routes are non-convergent and rather long which leads to a relatively high cost of goods.

There is therefore a need to find more efficient, convenient syntheses of eletriptan.

One possible way of preparing an indole-containing molecule is by application of the Fischer indole synthesis and such a reaction has been used to prepare other triptan drugs such as avitriptan (J. Org. Chem., 1997, 62, 9192-9202) and sumatriptan (WO- A-01/34561). The Fischer indole synthesis involves the condensation of a phenyl hydrazine with an enolisable aldehyde, or the functional equivalent thereof, as shown in Scheme 1. Scheme 1

(1) (2) (3)

Unexpectedly, attempts to apply the Fischer indole reaction to the preparation of eletriptan, or its enantiomer, have been fruitless, as shown in Scheme 2. It has not been possible to successfully carry out this reaction, primarily due to the instability of phenyl hydrazine (4).

Scheme 2

(4) (5) (I)

Surprisingly, however, it has been found that the condensation of aldehyde (5), or a functional equivalent thereof, with a protected form of phenyl hydrazine (4) proceeds in an efficient, high-yielding manner. This has made available a short, convergent, high-yielding synthesis of eletriptan in which the use of phenyl vinyl sulphone is avoided and purification problems associated with the late-stage use of palladium are obviated.

The present invention therefore provides a process for the preparation of a compound of formula (I)

(I)

comprising the reaction of a compound of formula (II)

(H)

wherein R1 is a suitable hydrazine protecting group, with a compound of formula (III)

(Ill)

wherein R2 is an aldehyde group (-CHO) or the functional equivalent thereof.

The reaction may optionally be carried out in the presence of an inert solvent. A preferred solvent is acetonitrile. The reaction is usually carried out in the presence of an acid catalyst, preferably sulphuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid or tetrafluoroboric acid, most preferably sulphuric acid.

The product may be isolated as the free base or, depending on which acid catalyst is used, as a salt.

A suitable hydrazine protecting group is one that is able to stabilise the hydrazine under the reaction conditions but does not prevent its participation in the reaction with compound (III). Such a protecting group will usually be acid-labile. Compounds of formula (II) embodying particularly preferred protecting groups include a compound of formula:

(HA)

or a salt thereof; and a compound of formula

(HB)

wherein R3 is a CrC6 tertiary alkyl group or a -CH2(aryl) group.

A tertiary alkyl group bears no hydrogen atoms on the carbon atom through which it is attached. Example of tertiary alkyl groups are -C(CH3)3 (1 ,1-dimethylethyl) and -C(CHa)2CH2CH3 (1 ,1-dimethylpropyl). Aryl means a radical formed by removing a hydrogen atom from an aromatic hydrocarbon and is preferably phenyl or naphthyl.

Preferred salts of a compound of formula (HA) are the ammonium salt and salts containing a Group I or Group Il metal cation. Most preferred is the calcium salt of formula:

(HAA) A functional equivalent of an aldehyde is one that will break down under the reaction conditions to release an aldehyde or one that will take part in the reaction as an electrophile as if it were an aldehyde. Particular functional equivalents worthy of mention are aldehyde hydrates, hemiacetals and acetals.

A preferred compound of formula (III) is an acetal of formula:

(MIA)

wherein R4 and R5 are each independently d-Cβ alkyl, or R4 and R5, taken together, form a 1 ,2-ethylene or 1 ,3-propylene group optionally substituted by one or more Cr Ce alkyl group(s). Such alkyl groups, containing the requisite number of carbon atoms, can be unbranched or branched chain. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Particularly preferred compounds of formula (IMA) are compounds of formula:

(MIB) (IMC)

A compound of formula (I) may exist in either of two enantiomeric forms (IA) and (IB):

the compound of formula (IB) being eletriptan. The process of the invention is equally suitable for preparing a compound of formula (IA) or (IB) or any mixture thereof. Individual enantiomers (IA) and (IB) may be prepared by using the corresponding enantiomerically pure starting material of formula (III) or by resolution of a racemic compound of formula (I), using, for example, chiral HPLC, or fractional crystallisation of diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base.

A compound of formula (IMA) may be prepared by the hydrogenation of a compound of formula:

(IV)

wherein R4 and R5 are as defined above. Typically, a solution of the compound of formula (IV) in an inert solvent such as ethanol is treated with a hydrogenation catalyst, preferably a rhodium catalyst, and hydrogen. The use of elevated temperature (preferably about 7O0C) and pressure (preferably about 690 kPa, 100 p.s.i.) is preferred.

A compound of formula (IV) may be prepared by the reaction of a compound of formula:

(V)

with a compound of formula:

(Vl)

wherein R4 and R5 are as defined above. Typically, a solution of the compound of formula (Vl) and the compound of formula (V), in an inert solvent such as dimethylformamide, is treated with a base such as sodium ethoxide. Preferably, the reaction is carried out at an elevated temperature, typically at about 8O0C.

A compound of formula (Vl) may be prepared by treating a compound of formula:

(VII)

wherein R4 and R5 are as defined above, with triphenylphosphine. Typically, a solution of the compound of formula (VII) in an inert solvent such as acetonitrile is treated with triphenylphosphine and heated to a temperature of about 8O0C.

Compounds of formula (VII) are either commercially available or are readily prepared by methods well known to the skilled person (see for instance 'Advanced Organic Chemistry1 by Jerry March (third edition, 1985, John Wiley and Sons) or 'Comprehensive Organic Transformations' by Richard C. Larock (1989, VCH Publishers)). In particular, R4/R5 groups can be interchanged by treating a compound of formula (VII) with an appropriate alcohol and an acid catalyst, such as sulphuric acid, optionally in an inert solvent such as toluene.

Other compounds of formula (III) can be prepared by functional group transformation performed on a compound of formula (IIIA) (see for instance 'Advanced Organic Chemistry' by Jerry March (third edition, 1985, John Wiley and Sons) or 'Comprehensive Organic Transformations' by Richard C. Larock (1989, VCH Publishers)). Alternatively, a compound of formula (IHA) may be prepared by the one-pot deprotection, cyclisation and reduction of a. compound of formula

wherein R4 and R5 are as defined above and P1 is a protecting group which is removable by hydrogenation, preferably benzyloxycarbonyl. Other suitable protecting groups are described in 'Protective Groups in Organic Synthesis' by Theorora Greene and Peter Wuts (third edition, 1999, John Wiley and Sons). Typically, a solution of a compound of formula (VIII) in an inert solvent such as methanol is treated with a hydrogenation catalyst, preferably a palladium catalyst such as palladium on carbon," and hydrogenated, preferably at elevated temperature (most preferably at about 5O0C) and elevated pressure (most preferably at about 414 Kpa, 60 psi).

A compound of formula (VIII) may be prepared by the reaction of a compound of formula:

(IX)

wherein L1 is a suitable leaving group and P1 is as defined above, with a compound of formula:

(X) wherein R4 and R5 are as defined above and M1 is a suitable metal (optionally bearing further ligands). Preferably, the compound of formula (IX) is a Weinreb amide, i.e. L1 is -N(OCH3)CH3. L1 may also be -0(CrC6 alkyl). Typically, M1 will be - Li, -MgX (wherein X is a halide) or an aluminium compound such as -AI(CH3)2. In a typical procedure, a solution of a compound of formula (IX) in a suitable inert solvent, such as tetrahydrofuran, is added to a solution of a compound of formula (X) in a suitable inert solvent, such as tetrahydrofuran. Compounds of formula (X) can be prepared by conventional methods well known to the skilled person. For instance, where M1 is -MgBr (i.e. the compound of formula (X) is a Grignard reagent), a solution of a compound of formula (X) wherein M1 is a bromo group in a suitable inert solvent, such as tetrahydrofuran, is treated with magnesium and a suitable catalyst such as iodine and heated, preferably to about 650C.

Compounds of formula (IX) can be prepared by sequential protection and activation of an acid of formula:

(Xl)

or a salt thereof. Typical procedures are found in the Examples section below and in the text books referenced above.

A compound of formula (HA) may be prepared by diazotisation of a compound of formula:

(XII)

followed by reduction with ascorbic acid and optional conversion to a salt. In a typical procedure, a solution of a compound of formula (XII) in a suitable water-miscible solvent such as acetonitriie is treated with an acid, preferably sulphuric acid and an aqueous sojution of a nitrite, preferably sqdium nitrite. The diazonium salt so produced is then reduced by addition of an aqueous solution of ascorbic acid to give the compound of formula (UA). This compound is easily converted into a salt form by conventional techniques. For instance, treatment with potassium hydroxide and calcium chloride in a mixture of water and acetonitriie gives the calcium salt.

Other protected hydrazines of formula (II), including compounds of formula (HB) are prepared by methods analogous to the methods described above and by other standard methods in organic chemistry (see text books cited above).

The following examples illustrate various aspects of the invention.

1H Nuclear magnetic resonance (NMR) spectra were recorded using a Varian 400MHz machine and were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The mass spectra (m/z) were recorded using either electrospray ionisation (ESI) or atmospheric pressure chemical ionisation (APCI). The following abbreviations have been used for common solvents: CDCta deuterochloroform; D6DMSO, deuterodimethylsulphoxide; CD3OD, deuteromethanol; THF, tetrahydrofuran. 'Ammonia' refers to a concentrated solution of ammonia in water possessing a specific gravity of 0.88. Where thin layer chromatography (TLC) has been used it refers to silica gel TLC using silica gel 60 F254 plates, Rf is the distance travelled by a compound divided by the distance travelled by the solvent front on a TLC plate. Example 1 Preparation of 4-IT(benzyloxy)carbonvπ(methvDanπino1butanoic acid

A solution of 4-(methylamino)butanoic acid hydrochloride (30.Og, 195mmoles) in aqueous potassium hydroxide (3M, 260ml, 780mmoles) was treated with benzyl chloroformate (33.3g, 195mmoles) under an atmosphere of nitrogen and stirred for 2 hours. After this time the reaction mixture was diluted with aqueous hydrochloric acid (5M, 200ml) and extracted twice with terf-butylmethyl ether (2 x 100ml). The combined extracts were washed with water (100ml), dried over magnesium sulfate and filtered. Removal of solvent at reduced pressure gave the title compound as a clear oil (44.6g, 91%).

1H-NMR (400 MHz, CDCI3): δ = 1.86-1.92 (m, 2H), 2.33-2.40 (m, 2H), 3.34-3.38 (m, 2H), 5.13 (s, 2H), 7.30-7.36 (m, 5H).

Example 2 Preparation of benzyl {4-[methoxy(methvπamino1-4-oxobutyl}methylcarbamate

Carbonyldiimidazole (32g, 195mmoles) was added to a solution of the acid of Example 1 (44.6g, 177mmoles) in dichloromethane (200ml) under an atmosphere of nitrogen and the resulting mixture was stirred for 1 hour. Triethylamine (27ml, 195mmoles) and then N,O-dimethylhydroxylamine hydrochloride were added and the mixture was stirred for 16 hours. The reaction was poured into hydrochloric acid (2M1 200ml) and the organic layer was washed with water (200ml). Evaporation of the organic layer at reduced pressure gave the title compound (47.Og, 90%) as a clear oil.

1H-NMR (400 MHz, CDCI3): 5 = 1.86-1.89 (m, 2H), 2.37-2.44 (m, 2H), 2.93 (s, 3H), 3.13-3.15 (br.s, 3H), 3.33-3.37 (t, 2H), 3.59-3.63 (br.s, 3H), 5.11 (s, 2H), 7.26-7.34 (m, 5H).

Example 3 Preparation of benzyl [6-(1 ,3-dioxan-2-yl)-4-oxohexyπmethylcarbamate

To a slurry of magnesium turnings (4.6g, 190mmoles) in tetrahydrofuran (THF) (100ml), under an atmosphere of nitrogen, was added a crystal of iodine followed by a solution of 2-(2-bromoethyl)-[1 ,3]-dioxane (7.4g, 38mmoles) in THF (10ml). The reaction was heated to 650C with stirring and further 2-(2-bromoethyl)-[1 ,3]-dioxane (29.6g, 152mmoles) was added as a solution in THF (40ml). After heating at 650C for a further 1 hour, the reaction was cooled to 2O0C. The freshly prepared Grignard solution was added to a solution of the Weinreb amide of Example 2 (4Og, 136mmoles) in THF (250ml) at 40C under an atmosphere of nitrogen. The mixture was refluxed for 2 hours, which gave a white precipitate. The reaction was poured into aqueous citric acid solution (10%w/v, 250ml) and the organic layer was separated, concentrated at reduced pressure and redissolved in (tert)-butylmethyl ether (200ml). The resulting solution was washed with the original citric acid solution and water (200ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (47.5g, 95%) as a clear oil. 1H-NMR (400 MHz, CDCI3): 6 = 1.31-1.35 (nπ, 1 H), 1.83-1.88 (m, 4H), 2.03-2.08 (m, 1 H), 2.38-2.54 (m, 4H), 2.92 (s, 3H), 3.27-3.31 (m, 2H), 3.71-3.77 (m, 2H), 4.05-4.09 (m, 2H), 4.54-4.56 (m, 1 H), 5.12 (s, 2H), 7.29-7.36 (m, 5H).

Example 4 Preparation of 2-f2-(1 ,3-dioxan-2-v0ethvπ-1-methylpyrrolidine fumarate

A solution of the ketone of Example 3 (35g, 95.5mmoles) in methanol (200ml) was treated with 5% palladium on carbon (50%, wet, 3.5g) and hydrogeήated at 5O0C and 414 kPa (60 p.s.i.) for 16 hours with stirring. The catalyst was removed by filtration through a filter aid (CelliteTM) and evaporation of the filtrate at reduced pressure gave the free base product as a clear oil. The free base was dissolved in a mixture of ethyl acetate (200ml) and methanol (20ml) and a solution of fumaric acid (10.5g, 95mmoles) in methanol (100ml) was added. The methanol was removed azeotropically by distilling off 180ml of solvent and further ethyl acetate (180ml) was added. The precipitated product was granulated for 16 hours, collected by filtration and dried under vacuum to constant mass to yield the title compound (20.2g, 71%) as a white crystalline solid.

1H-NMR (400 MHz, D6DMSO): 6 = 1.30-1.55 (m, 5H), 1.73-1.89 (m, 4H), 1.98-2.06 (m, 1 H), 2.48 (s, 3H), 2.50-2.67 (m, 2H), 3.26-3.31 (m, 1 H), 3.65-3.71 (m, 2H), 3.95- 3.99 (m, 2H), 4.50-4.52 (t, 1H), 6.49 (s, 2H). Example 5 Preparation of 2-(bromomethvO-5,5-dimethvl-1 ,3-dioxane

To a solution of 2-bromo-1 ,1-diethoxyethane (100g, 507mmoles) in toluene (250ml), under an atmosphere of nitrogen, was added the 2,2-dimethylpropane-1 ,3-diol (75g, 760mmoles) and then sulfuric acid (98%, 27ml, 507mmoles). The mixture was heated at 11O0C for 16 hours and then cooled to 40C and diluted with water (1000ml). The product was extracted with tø/t-butylmethyl ether (2 x 500ml) and the combined organic extracts were washed with water (500ml) and dried over magnesium sulfate. The organic solution was filtered and concentrated under reduced pressure to give the title compound (100g, 98%) as a brown oil.

1H-NMR (400 MHz, CDCI3): δ = 0.76 (s, 3H), 1.23 (s, 3H), 3.39-3.40 (d, 2H), 3.48-3.51 (d, 2H), 3.66-3.69 (d, 2H), 4.62-4.64 (t, 1 H).

Example 6 Preparation of 2-f(£)-2-(5.5-dimethvl-1.3-dioxan-2-vl)vinvn-1 -methvl-1 H-pvrrole

Tributylphosphine (100ml, 717mmoles) was added to a solution of the alky! bromide of Example 5 (96g, 458mmoles) in acetonitrile (400ml) under an atmosphere of nitrogen and the resulting mixture was heated at 8O0C for 16 hours. The solvent was removed at reduced pressure and the residue was dissolved in dimethylformamide (500ml) under an atmosphere of nitrogen. To this solution was added 1-methyl-1 H- pyrrole-2-carboxaldehyde (5Og, 458mmoles) and then a solution of sodium ethoxide in ethanol (21%w/w, 221 ml, 595mmoles). The resulting mixture was heated at 8O0C for 3 hours. The reaction mixture was diluted with water (500ml) and extracted twice with heptane (2 x 350ml). The combined organic extracts were repeatedly washed with water (7 x 250ml), dried over magnesium sulfate, filtered and concentrated to give a brown oil which crystallised on standing. Trituration with heptane (150ml) and filtration gave the title compound (35.5g, 35%) as a brown solid. 1H-NMR (400 MHz, D6DMSO): δ = 0.72 (s, 3H), 1.13 (s, 3H), 3.48-3.51 (d, 2H), 3.57- 3.59 (m, 5H), 4.97-4.98 (d, 1H), 5.82-5.87 (dd, 1H), 5.95-5.97 (m, 1H)1 6.32-6.33 (m, 1 H), 6.60-6.64 (d, 1 H), 6.71-6.72 (m, 1 H).

Example 7 Preparation of 2-r2-(5,5-dimethyl-1.3-dioxan-2-yl)ethvn-1-methylpyrrolidine fumarate

A solution of the pyrrole acetal of Example 6 (4.9g, 22.1 mmoles) in ethanol (100ml) was treated with 5% rhodium on carbon (50%, wet, 1g) and hydrogenated at 7O0C and 690 kPa (100 p.s.i.) for 16 hours with stirring. After this time the catalyst was removed by filtration through a filter aid (CelliteTM) and the filtrate was evaporated at reduced pressure. The residue was dissolved in ethyl acetate (25ml) and a solution of fumaric acid (2.57g, 22.1 mmoles) in methanol (25ml) was added. The methanol was removed by azeotropic distillation and replaced with ethyl acetate, maintaining a volume of 50ml. The precipitated product was granulated for 16 hours, collected by filtration and dried under vacuum to constant mass to yield the title compound (7.2g, 95%) as a white crystalline solid.

1H-NMR (400 MHz, (CDg)2SO): 5 = 0.68 (s, 3H), 1.08 (s, 3H)1 1.34-1.60 (m, 4H), 1.71- 1.82 (m, 3H), 1.96-2.05 (m, 1H), 2.45 (s, 3H), 2.51-2.61 (m, 2H), 3.21-3.26 (m, 1H), 3.36-3.39 (d, 2H), 3.50-3.52 (d, 2H), 4.42-4.44 (t, 1 H), 6.50 (s, 2H). Example 8 Preparation of 2-(4-nitrophenv0ethyl phenyl sulfone

4-Nitrophenylethyl bromide (1Og, 43.5 mmol), sodium benzenesulfinate (13.1g, 65.2 mmol), 2-propanol (120 ml) and water (30 ml) were charged to a flask. The resulting mixture was heated at 700C for 42 hours. The reaction mixture was cooled to ambient temperature and stirred for 1 hour. The resultant slurry was filtered and the filter cake washed with a mixture of 2-propanol and water (5:1 by volume, 2 x 30 ml). The product was dried in a vacuum oven at 400C giving a white crystalline solid (1Og), m.p. 156QC.

1H-NMR (300 MHz, CDCI3): δ = 3.17-3.22 (m, 2H), 3.37-3.42 (m, 2H), 7.31 (d, 2H), 7.59 (t, 2H), 7.69 (t, 1 H), 7.94 (d, 2H), 8.13 (d, 2H). 13C-NMR (75.5 MHz, CDCI3): δ = 28.6, 56.6, 124.0, 128.1 ,129.3, 129.5, 134.1 , 138.8, 145.1 , 147.1. Microanalysis: Found: C, 57.57; H, 4.51 ; N, 4.85%. Ci4Hi3NSO4. requires C, 57.71 ; H, 4.51 ; N, 4.81%.

Example 9 Preparation of 2-(4-aminophenyl)ethyl phenyl sulfone

2-(4-Nitrophenyl)ethylphenyl sulfone (Example 8, 10g, 0.034 mol) was charged to a flask and tetrahydrofuran (340 ml) was added. The reaction mixture was placed under an inert atmosphere. Under a steady flow of inert gas, palladium on carbon (10%, 1g) was added and rinsed in with tetrahydrofuran (20 ml). A slurry of ammonium formate (10.9g, 0.17 moles) in methanol (70 ml) was charged to the flask and rinsed in with tetrahydrofuran (20 ml). After stirring at ambient temperature for 2 hours, no starting material remained, as shown by TLC (hexane/ethyl acetate, 2:1 by volume). The reaction mixture was filtered through a pad of filter aid to remove the catalyst and the filter pad was rinsed with further methanol (30 ml). The filtrate was evaporated and the residue was dissolved in a mixture of ethyl acetate (200 ml) and water (150 ml). The 2-phase mixture was separated and the aqueous phase was extracted with further ethyl acetate (2 x 50 ml).The combined organic phases were reduced in volume on a rotary evaporator to ca. 30 ml. Hexane (250 ml) was added, resulting in immediate precipitation. The product was collected by filtration and washed with further hexane (2 x 50 ml) to give an off-white solid (8.Og).

1H-NMR (300 MHz, CDCI3): 5 = 2.87-2.96 (m, 2H), 3.25-3.35 (m, 2H), 3.32-3.69 (b, 2H), 6.57 (d, 2H), 6.87 (d, 2H), 7.52-7.60 (m, 2H), 7.62-7.69 (m, 1 H), 7.92 (d, 2H). 13C-NMR (75.5 MHz1 CDCI3): 6 = 28.8, 57.4, 115.4, 125.7, 129.2, 130.3, 130.9, 135.2, 140.5, 148.7.

Example 10 Preparation of oxo(2-(4-r2-(phenylsulfonyl')ethyllphenyllhvdrazino1)acetic acid

Sulfuric acid (9.4M, 60ml, 563mmoles) and then an aqueous solution of sodium nitrite (5.9g, 85.0mmoles, 11.8ml) were added to a solution of 4-(2- benzenesulfonylethyl)phenylamine (Example 9, 20.2g, 77.3mmoles) in acetonitrile (60ml), under an atmosphere of nitrogen at 40C. After stirring for 1 hour at 40C, ascorbic acid (15.Og, 85.0mmoles) was added as an aqueous solution (30ml). After stirring for a further 1 hour at 40C, the reaction mixture was warmed to ambient temperature and stirred for 16 hours. The reaction mixture was diluted with water (40ml) and extracted twice with ethyl acetate (2 x 100ml). The combined organic extracts were washed with water (100ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (22.3g, 83%) as a red gum. 1H-NMR (400 MHz, D6DMSO): 5 = 2.75-2.78 (m, 2H), 3..50-3.53 (m, 2H), 6.59-6.61 (d, 2H), 6.95-6.97 (d, 2H), 7.62-7.66 (m, 2H), 7.71-7.75 (m, 1 H), 7.90-7.92 (m, 2H), 10.54 (s, 1 H).

Example 11 Preparation of calcium bisfoxo(2-(4-r2-(phθnylsulfonyl)ethyllphenyl)hvdrazino)ac Θtate1

An aqueous solution of potassium hydroxide (0.64M, 100ml, 64mmoles) was added to a solution of the hydrazinooxalate of Example 10 (22.3g, 64.0mmoles) in acetonitrile (100ml) and the mixture was stirred for 1 hour. Aqueous calcium chloride solution (1 M, 32ml, 0.32mmoles) was added and the resulting precipitate was granulated for 16 hours. The precipitated solid was collected by filtration and dried under vacuum to constant weight to give the title compound (20.2g 86%) as a white crystalline solid.

1H-NMR (400 MHz, D6DMSO): 6 = 2.71-2.75 (m, 2H), 3.49-3.53 (m, 2H), 6.56-6.58 (d, 2H), 6.92-6.94 (d, 2H), 7.60 (br.s, 1 H), 7.63-7.67 (m, 2H), 7.72,-7.75 (m, 1 H), 7.90- 7.92 (d, 2H), 10.13 (br.s, 1 H). Example 12 Preparation of 3-[(T-methylpyrroliclin-2-vπmethyll-5-f2-(phenylsulfonyl) ethyl1-1 H-inclole

Aqueous sulfuric acid (1.88M, 84ml, 158mmoles) was added to a slurry of the calcium salt of Example 11 (11.7g, 15.9mmoles) and the fumarate salt of Example 4 (10.0g, 31.8mmoles) in acetonitrile (84ml). The reaction mixture was heated at 8O0C with stirring for 16 hours, and then poured into aqueous potassium hydroxide solution (82ml, 2M, 164mmoles). The resulting mixture was extracted twice with ethyl acetate (2 x 200ml). The combined organic phases were washed with water (200ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (10.2g, 84%) as a brown oil.

1H-NMR (400 MHz, CDCI3): 6 = 1.51-1.85 (m, 4H), 2.22-2.28 (m, 1 H), 2.43-2.49 (m, 4H), 2.56-2.62 (m, 1 H), 3.11-3.18 (m, 4H), 3.42-3.46 (m, 2H), 6.91-6.93 (s, 1 H), 7.01 (s, 1 H), 7.23-7.27 (d, 1 H), 7.31 (s, 1 H), 7.56-7.60 (m, 2H), 7.65-7.68 (m, 1 H), 7.96- 7.98 (d, 2H), 8.14 (s, 1 H).

Example 13 Preparation of 3-IY1 -methylpyrrolidin-2-yl)methvn-5-r2-fphenylsulfonvπethvn-1 /-/-indole To a solution of the hydrazinooxalate of Example 10 (1.33g, 3.83mmoles) in acetonitrile (7ml) was added the pyrrolidine acetal fumarate salt of Example 4 (1.2g, 3.83mmoles) followed by aqueous sulfuric acid (1.88M, 7ml, 13.2mmoles). The resulting solution was heated at 8O0C, with stirring, for 16 hours and poured into aqueous potassium hydroxide solution (10ml, 2M, 19.7mmoles). The mixture was extracted twice with ethyl acetate (2 x 10ml). The combined organic phases were washed with water (10ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.05g, 72%) as a brown oil.

1H-NMR (400 MHz, CDCI3): δ = 1.51-1.85 (m, 4H), 2.22-2.28 (m, 1 H), 2.43-2.49 (m, 4H)1 2.56-2.62 (m, 1 H), 3.11-3.18 (m, 4H), 3.42-3.46 (m, 2H), 6.91-6.93 (s, 1 H), 7.01 (s, 1 H), 7.23-7.27 (d, 1 H), 7.31 (s, 1 H), 7.56-7.60 (m, 2H), 7.65-7.68 (m, 1 H), 7.96- 7.98 (d, 2H), 8.14 (S1 1 H).

Example 14 Preparation of 3-f(1-methylpyrrolidin-2-v0methvn-5-f2-(phenylsulfonvπeth vn-1 H-indole

To a solution of 4-(2-benzenesulfonylethyl)phenylamine (Example 9, 1.0g, 3.83mmoles) in acetonitrile (10ml), maintained under an atmosphere of nitrogen at 40C, was added sulfuric acid (9.4M, 7ml, 65.8mmoles) and an aqueous solution (1 ml) of sodium nitrite (0.29g, 4.20mmoles). After stirring for 1 hour at 40C, an aqueous solution (1.5ml) of ascorbic acid (0.74g, 4.20mmoles) was added. After stirring for a further 1 hour at 40C, the reaction was warmed to ambient temperature and stirred for 16 hours. The mixture was diluted with water and the pyrrolidine acetal fumarate salt of Example 4 (1.2g, 3.83mmoles) was added. The reaction mixture was heated at 8O0C for 16hours and subsequently neutralised with aqueous potassium hydroxide solution (15ml, 5M, 75.0mmoles) and diluted with water (50ml). The product was extracted twice with ethyl acetate (2 x 20ml) and the combined organic phases were washed with water (20ml), dried with magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.45g, 100%) as a brown oil.

1H-NMR (400 MHz1 CDCI3): δ = 1.51-1.85 (m, 4H), 2.22-2.28 (m, 1 H), 2.43-2.49 (m, 4H), 2.56-2.62 (m, 1 H), 3.11-3.18 (m, 4H), 3.42-3.46 (m, 2H), 6.91-6.93 (s, 1 H), 7.01 (s, 1 H), 7.23-7.27 (d, 1 H), 7.31 (s, 1 H), 7.56-7.60 (m, 2H), 7.65-7.68 (m, 1 H), 7.96- 7.98 (d, 2H), 8.14 (s, 1 H).

Example 15 Preparation of 5-(2-benzenesulfonylethyl)-3-(1 -methylpyrrolidin-2-ylmethyl)-1 H-indole

To a slurry of the hyazinooxalate calcium salt of Example 11 (0.10g, 0.136mmoles) and the pyrrolidine acetal fumarate salt of Example 7 (0.94g~ 0.272mmoles) in acetonitrile (3ml) was added aqueous sulfuric acid (1.88M, 7ml, 13.2mmoles). The solution was heated at 8O0C with stirring for 16 hours and then poured into aqueous potassium hydroxide solution (10ml, 2M, 20mmoles). The product was extracted twice with ethyl acetate (2 x 20ml) and the combined organic phases were washed with water (20ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (87mg, 83%) as a brown oil.

1H-NMR (400 MHz, CDCI3): δ = 1.51-1.85 (m, 4H), 2.22-2.28 (m, 1 H), 2.43-2.49 (m, 4H), 2.56-2.62 (m, 1 H), 3.11-3.18 (m, 4H), 3.42-3.46 (m, 2H), 6.91-6.93 (s, 1 H), 7.01 (s, 1 H), 7.23-7.27 (d, 1 H), 7.31 (s, 1 H), 7.56-7.60 (m, 2H), 7.65-7.68 (m, 1 H), 7.96- 7.98 (d, 2H), 8.14 (S1 1 H). Example 16 Preparation of (2RV2-r2-(1 ,3-dioxan-2yl)ethyl1-1-methylpyrrolidine (2R,3R)-2,3- bis(benzvloxv)succinic acid.

To a solution of the pyrrolidine (1.5g, 7.52mmoles) of Example 4 in butanone (7.5ml) at 750C, was added a solution of dibenzoyl-L-tartaric acid (2.7g, 7.53mmoles) in butanone (7.5ml). The reaction mixture was cooled to O0C and the precipitated product was granulated for 16 hours, collected by filtration and dried under vacuum to constant mass to yield the title compound (1.5g, 40% 72% enantiomeric excess (ee)) as a white crystalline solid. This solid was refluxed in 2-propanol for 60 minutes and the mixture was then cooled to O0C and granulated for 5 hours. The product was collected by filtration and dried under vacuum to constant mass to yield the title compound (1.3g, 35%, 94% ee) as a white crystalline solid.

1H-NMR (400 MHz, (CD3)2SO): 5 = 1.30-1.55 (m, 5H), 1.73-1.89 (m, 4H), 2.02-2.13 (m, 1 H), 2.48 (s, 3H), 2.80-2.93 (m, 1 H), 2.96-3.08 (m, 1 H), 3.37-3.46 (m, 1 H), 3.61- 3.71 (m, 2H), 3.95-3.99 (m, 2H), 4.51-4.54 (m, 1 H), 5.64 (s, 1 H), 7.42-7.54 (t, 2H), 7.60-7.64 (t, 1 H) 7.92-7.99 (d, 2H). Example 17 Preparation of (R)-3-r(1-methylpyrrolidin-2-vnmethyll-5-r2-(phenylsulfonyl) ethvn-1 H- indole

To a slurry of the hydrazinooxalate calcium salt of Example 11 (1.Og, 1.35mmoles) and the pyrollidine acetal dibenzoyl-L-tartrate salt of Example 16 (1.5g, 2.7mmoles in acetonitrile (8ml) was added aqueous sulfuric acid (10%v/v, 1.88M, 8ml, 15mmoles). The resulting solution was heated at 8O0C with stirring for 16hours, and then poured into aqueous potassium hydroxide solution (50ml, 2M, lOOmmoles). The product was extracted twice with ethyl acetate (2 x 50ml), and the combined organic layers were washed with water (50ml) and dried over magnesium sulfate. The mixture was filtered and concentrated under reduced pressure to give a brown oil which was purified via flash chromatography, eluting with dichloromethane/ethanol/ammonia (95:5:1) to yield the title compound as a pale brown oil (0.6g, 59%, 94% ee)

1H-NMR (400 MHz, CDCI3): 6 = 1.51-1.85 (m, 4H), 2.22-2.28 (m, 1 H), 2.43-2.49 (m, 4H), 2.56-2.62 (m, 1 H), 3.11-3.18 (m, 4H), 3.42-3.46 (m, 2H), 6.91-6.93 (s, 1 H), 7.01 (s, 1 H), 7.23-7.27 (d, 1 H), 7.31 (s, 1 H), 7.56-7.60 (m, 2H), 7.65-7.68 (m, 1 H), 7.96- 7.98 (d, 2H), 8.14 (s, 1 H).