"5-Substituted Indole Derivatives, their intermediates and processes for the
production thereof

Field of the invention

The present invention relates to a compound of formula II and formula III and a novel process for the preparation of (R)-3-((l-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)ethyl)-IH-indole and intermediates thereof

Background of the invention

Triptans are an important class of drugs for the treatment of migraine headaches. Currently sumatriptan, Eletriptan, naratriptan, rizatriptan, almotriptan, zolmitriptan and frovatriptan are used for the treatment of migraine headaches. Eletriptan is currently marketed in over 50 countries worldwide. The present invention relates to a novel process for the synthesis of Eletriptan.

Patents describing synthetic procedures for Eletriptan are listed below.

US5545644AI describes a synthetic process for Eletriptan. 5-Bromoindole was acylated at the 3-position by reacting the magnesium salt of 5-bromoindole. This process results in a dimer formation in the final Pd/C reduction stage which poses problems in purification which further leads to decrease in yields.

US2005059828A1 discloses methods to circumvent the problems associated with dimer formation described in US5545644A1. The indole-nitrogen was acetylated prior to hydrogenation and later deacetylated to give pure Eletriptan. However, this process introduced two additional steps into the synthesis which is time consuming and not cost effective.

WO2005103035A1 discloses Eletriptan synthesis by a Fischer Indole process. However, enantiomeric purity of the finished product depends on the purity of the acetal intermediate which might require asymmetric synthesis or optical resolution. Eletriptan obtained in the reported procedure had about 94%ee.

Summary of the invention

In light of the foregoing deficiencies in the art, one of the objects of the invention was to provide a process for preparing optically pure Eletriptan.

Another object of the invention was to develop a process devoid of any dimer impurity and provide an improved method for the synthesis of Eletriptan.

Yet another object of the invention was to develop shortest possible synthetic route to obtain Eletriptan which is commercially viable.
Another object of the invention is the synthesis of novel intermediates of Eletriptan viz, compounds of formula II and formula III.

This invention provides an alternative method for preparing Eletriptan. 5-bromoindole is acylated with Cbz-Proline acid chloride and later under Heck reaction conditions is coupled with phenyl vinyl sulfone. The product obtained is then reduced under catalytic hydrogenation conditions in presence of formaldehyde and then reduced in presence of a hydride reducing agent to give Eletriptan. The overall synthesis may be represented as shown in Scheme I.

Detailed description of the specific embodiments
The compound of formula I is prepared by reaction of the magnesium salt of 5-bromoindole with n-protected proline acid chloride.

Magnesium salt of 5-bromoindole is prepared in presence of alkyl or aryl magnesium halide preferably ethyl magnesium bromide. The reaction is carried out in THF, diethyl ether, dichloromethane, toluene preferably in dichloromethane and THF. The preparation of acid chloride of N-protected proline is carried out preferably in dichloromethane according to literature procedures in situ and added to the magnesium salt of formula II at temperatures of -40 to 50° C under inert atmosphere.

According to one aspect of the invention, compound of formula II can be prepared from compound of formula I under Heck reaction conditions in presence of a suitable coupling catalyst, phenyl vinyl sulfone and a base. The reaction can be carried out in acetonitrile, toluene, DMF, DME, DMAc preferably in DMF at temperatures of 50-120°0. The reaction can be achieved in presence of a suitable base selected from the group comprising K2CO3, NaiCO3, KOAc, NaOAc, CS2CO3, DABCO, DIPEA, and TEA. The base is preferably TEA and the coupling catalyst is preferably a palladium metal catalyst.

According to another aspect of the invention, the novel compound of formula II is characterized by the 1H NMR 5= 8.5 (d, IH), 8.05-7.92 (m, 2H), 7.88-7.73 (m, 2H), 7.70-7.30 (m, 8H), 7.11-7.29 (m, IH), 7.05-6.8 (m, 2H), 5.26-4.92 (m, 2H), 4.71-4.46 (m, 1H), 3.71-3.50 (m, 2H), 2.40-1.81 (m, 4H)

According to another aspect of the invention formula III used in the process may be obtained by catalytic reduction of formula II under hydrogen or hydrogen source in presence of a suitable catalyst such as Pd/C, Raney nickel, palladium hydroxide, platinum catalyst, rhodium, and ruthenium, and a suitable solvent. The reduction can also be achieved in presence of diborane, NaBH4, LiBH4, NaCNBH3, sodium triacetoxyborohydride or a suitable hydride reducing reagent. The reaction can be carried out at temperatures of 20-100° C and 15-80 psi hydrogen pressure. The reaction can be carried out, but not limited to, in alcohols, ethers or mixtures thereof. The most suitable solvents are methanol, ethanol, THF or mixtures thereof The reaction is preferably carried out in presence of 10% Pd/C in methanol at 20-30° C at 40-60 psi.

According to another aspect of the invention, the novel compound of formula III is characterized by the , 1H NMR 5= 7.95-7.90 (m, 2H), 7.68-7.50 (m, 3H), 7.42-7.30 (m, 3H), 7.19-6.70 (m, 2H), 3.52-3.33 (m, 3H), 3.19-2.95 (m, 2H), 2.42-2.25 (m, 2H), 2.31 (s,3H), 2.22-1.71 (m,4H)

Surprisingly this method did not result in significant dimer formation and this process was found particularly advantageous. The process did not require acetylation and deacetylation of the indole Nl-position to avoid dimer formation. The process did not require column chromatography and was conveniently isolated as a solid.

Compound of formula IV is obtained by reduction of formula 111 in presence of a suitable hydride reducing agent in a suitable solvent. Inert solvent includes THF, diethyl ether, dichloromethane, 1,4-dioxane, methyl THF and 1,2-dimethoxyethane preferably in THF at 0-65° C. The suitable hydride reducing agent includes LiAlH4, NaBH4, LiBH4, NaCNBH3, sodium triacetoxyborohydride preferably LiAlH4.

EXAMPLES

Example 1

(R)-benzyI-2-(5-bromo-lH-indole-3-carbonyl)pyrroIidine-l-carboxylate

To a solution of CBZ-D-Proline in dichloromethane was charged oxalyl chloride and allowed to stir at rt for Ih. The solvent was distilled off and the reaction mass diluted with 10 ml dichloromethane.

In a separate setup ethyl magnesium bromide (2.63ml of a 3M solution in ether) was charged slowly to a solution of 5-bromoindole in dichloromethane. The reaction mixture was heated at reflux for 30 min. The reaction was cooled to -20 °C and the above prepared CBZ-prolinyl acid chloride in dichloromethane was charged slowly to the reaction at -20 °C. The resulting solution was stirred at -20 °C for 30-60 min. The completion of the reaction was monitored by TLC. The reaction mass was warmed to RT and diluted with 20 ml dichloromethane. The organic layer was sequentially washed with sat. ammonium chloride solution, sat. sodium bicarbonate solution and brine. The organic layer was dried-over sodium sulphate and concentrated under vacuum to give a pure product in about 85% yield.

Example 2

(R)-BenzyI-2-(5-(2-(phenylsulfonyl)vinyl)-lH-indole-3-carbonyl)-pyrrolidine-l-carboxylate
A solution of (R)-benzyl-2-(5-bromo-lH-indole-3-carbonyl)-pyrrolidine-l-carboxylate 5.0 g, 11.70 mmol), phenylvinylsulfone (3.45 g, 20.51 mmol), Pd(0Ac)2 (0.26 g, 1.17 mmol), tri-0-tolylphosphine (0.71 g, 2.34 mmol) and triethylamine (2.25 g, 20.51 mmol) was heated to 95-105 °C for 6-15h in DMF. The reaction mixture was cooled to RT, diluted with dichloromethane and filtered over a bed of filter aid. The filtrate was sequentially washed with water and brine, and dried over sodium sulphate. The organic layer was concentrated under vacuum and the product precipitated from dichloromethane and hexane as a solid in about 85-90% yield. Mass (M+Na) 537.2, 1H NMR (CDC13) 8= 8.5 (d, IH), 8.05-7.92 (m, 2H), 7.88-7.73 (m, 2H), 7.70-7.30 (m, 8H), 7.11-7.29 (m, IH), 7.05-6.8 (m, 2H), 5.26-4.92 (m, 2H), 4.71-4.46 (m, IH), 3.71-3.50 (m, 2H), 2.40-1.81 (m, 4H)

Example 3

(R)-(l-methylpyrrolidin-2-yl)(5-(2-(phenylsulfonyl)ethyl)-lH-indol-3-yl)methanone
A suspension of (R)-benzyl-2-(5-(2-(phenylsulfonyl)vinyl)-lH-indole-3-carbonyl)-pyrrolidine-1-carboxylate (5.0 g) in 50 ml acetone, methanesulfonic acid, formaldehyde and 10% Pd/C was subject to hydrogenation at 45 psi. Upon completion of the reaction the catalyst was filtered off and the solvent removed under vacuum to provide the title compound in about 75-85% yield. Mass (M+Na) 419.5, 1H NMR (CDCI3) 8= 7.95-7.90 (m, 2H), 7.68-7.50 (m, 3H), 7.42-7.30 (m, 3H), 7.19-6.70 (m, 2H), 3.52-3.33 (m, 3H), 3.19-2.95 (m, 2H), 2.42-2.25 (m, 2H), 2.31 (s, 3H), 2.22-1.71 (m, 4H)

Example 4

(R)-3-((l-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)ethyl)-lH-indole
To a suspension of LAH and THF was slowly charged (R)-(l-methylpyrrolidin-2-yl)(5-(2-(phenylsulfonyl)ethyl)-lH-indol-3-yl)methanone at 0 °C and then the reaction was slowly heated to reflux. Upon completion of the reaction in about 3-5 h, the reaction was cooled to 0-5 °C and IN NaOH soln and H20 were sequentially charged. The solids were filtered and the precipitate washed with additional THF. The filtrate was distilled to dryness under reduced pressure. The residue was dissolved in water and the aqueous layer extracted with dichloromethane and dried over sodium sulfate and distilled to give the title compound in 75-80% yield.

We claim:

1. A compound of formula II

2. A process for the preparation of compound of formula II comprising reacting
compound of formula (I)with phenyl vinyl sulfone in the presence of a coupling catalyst, and a base.

3. The process of claim 2, wherein the base is chosen from the group comprising
K2CO3, Na2C03, KOAc, NaOAc, CS2CO3, DABCO, DIPEA, and TEA.

4. The process of claim 2, wherein the coupling catalyst is a palladium metal
coupling catalyst.

5. The process of claim 3, wherein the base is TEA.

6. The process of claim 2, wherein the reaction is carried out additionally in a
solvent.

7. The process of claim 6, where in the solvent is chosen from the group comprising
acetonitrile, toluene, DMF, DME, DMAc.

8. A compound of formula III

9. A process for the preparation of compound of formula III comprising reduction of
compound of formula II in a suitable solvent.

10. The process of claim 9, wherein the reduction is a catalytic reduction carried out in the presence of a catalyst chosen from the group comprising Pd/C, Raney nickel, palladium hydroxide, platinum catalyst, rhodium, and ruthenium.

11. The process of claim 10, wherein the reaction is carried out in the presence of Pd/C.

12. A process of claim 9, wherein the reduction is carried out in presence of diborane, NaBH4, LiBH4, NaCNBH3, sodium triacetoxyborohydride or a suitable hydride reducing reagent.

13. The process of claim 9, wherein the solvent is selected from the group comprising alcohols, ethers or mixtures thereof.

14. The process of claim 13, wherein the reaction is carried out in methanol.

15. A process for the preparation of compound of formula III by the reduction of compound of formula II in presence of Pd/C in methanol.

16. A process for the preparation of Eletriptan by the reduction of compound of formula III in the presence of a hydride reducing agent and an inert solvent.

17. The process of claim 16, wherein the hydride reducing agent is chosen from the group comprising LiAlH4, NaBH4, LiBH4, NaCNBH3, sodium triacetoxyborohydride.

18. The process of claim 17, wherein the reducing agent is LiAlH4.

19. The process of claim 16, wherein the inert solvent is selected from the group comprising THF, diethyl ether, dichloromethane, 1,4-dioxane, methyl THF and 1,2-dimethoxyethane.

20. The process of claim 19, wherein the solvent is THF.

21. A process for the preparation of Eletriptan comprising the following steps

i) reaction of the magnesium salt of 5-bromoindole with N-protected proline
acid chloride to obtain a compound of formula I

ii) reacting compound of formula I with phenyl vinyl sulfone in the presence
of a base and a coupling catalyst to give the compound of formula II

iii) reduction of compoimd of formula II to obtain compound of formula III

iv) reduction of compound of formula III obtain Eletriptan

22. The process of claim 21, wherein the base used to prepare compound of formula II in step ii is chosen from the group comprising K2CO3, Na2C03, KOAc, NaOAc, CS2CO3, DABCO, DIPEA, and TEA .

23. The process of claim 21, wherein the coupling catalyst in step ii is a palladium metal coupling catalyst and the base is TEA.

24. The process of claim 21, wherein the reduction in step iii is a catalytic reduction carried out in the presence of a catalyst chosen from the group comprising Pd/C, Raney nickel, palladium hydroxide, platinum catalyst, rhodium, and ruthenium.

25. The process of claim 24, wherein the reaction is carried out in the presence of Pd/C.

26. The process of claim 21, wherein step iii is carried out in a solvent chosen from the group comprising alcohols, ethers or mixtures thereof

27. The process of claim 26, wherein the solvent employed is methanol.

28. The process of claim 21, wherein the reduction in step iii is carried out in presence of diborane, LiAlH4, NaBH4, LiBH4, NaCNBH3, sodium triacetoxyborohydride or a suitable hydride reducing reagent.

29. The process of claim 28 wherein the hydride reducing agent is LiAlH4

30. The process of claim 28 wherein the reduction of compound of formula III is carried out in the presence of LiAlH4 and additionally a solvent THF.

31. A compound of formula II substantially as herein described with reference to the foregoing description and the accompanying examples.

32. A process for the preparation of compound of formula II substantially as herein described with reference to the foregoing description and the accompanying examples.

33. A compound of formula III substantially as herein described with reference to the foregoing description and the accompanying examples.

34. A process for the preparation of compound of formula III substantially as herein described with reference to the foregoing description and the accompanying examples.