ELETRIPTAN

Eletriptan, UK-116044-04(HBr salt), UK-116044, Relpax

143322-58-1  CAS OF FREE BASE

143577-61-1 (hemisuccinate), 179041-30-6 (monofumarate), 177834-92-3 (monoHBr salt), 180637-87-0 (monosuccinate)

Eletriptan hydrobromide is a selective serotonin (5-HT₁) agonist, used for the acute treatment of the headache phase of migraine attacks.

RELPAX (eletriptan hydrobromide) tablets contain eletriptan hydrobromide, which is a selective 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Eletriptan hydrobromide is chemically designated as (R)-3-[(1-Methyl-2-pyrrolidinyl)methyl]-5-[2-(phenylsulfonyl)ethyl]-1H-indole monohydrobromide, and it has the following chemical structure:

The empirical formula is C₂₂H₂₆N₂O₂S . HBr, representing a molecular weight of 462.43. Eletriptan hydrobromide is a white to light pale colored powder that is readily soluble in water.

Each RELPAX Tablet for oral administration contains 24.2 or 48.5 mg of eletriptan hydrobromide equivalent to 20 mg or 40 mg of eletriptan, respectively. Each tablet also contains the inactive ingredients microcrystalline cellulose NF, lactose monohydrate NF, croscarmellose sodium NF, magnesium stearate NF, titanium dioxide USP, hypromellose, triacetin USP and FD&C Yellow No. 6 aluminum lake.

EP 0592438; JP 1993507288; JP 1997003063; US 5545644; WO 9206973, EP 0776323; JP 1997512283; US 6110940; WO 9606842, EP 1088817

U.S. Pat. No. 5,545,644A1 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.

U.S. Pat. No. 7,288,662B2 discloses methods to circumvent the problems associated with dimer formation described in U.S. Pat. No. 5,545,644A1. 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 subsequently costly.

WO2005/103035A1 discloses Eletriptan synthesis by a Fischer Indole process. However, enantiomeric purity of the finished product depends on the purity of an acetal intermediate which might require asymmetric synthesis or optical resolution. Eletriptan obtained in the reported procedure had about 94% enantiomeric excess.

Eletriptan (trade name Relpax, used in the form of eletriptan hydrobromide) is a second generation triptandrug intended for treatment of migraineheadaches. It is used as an abortive medication, blocking a migraine attack which is already in progress. Eletriptan is marketed and manufactured by Pfizer Inc. It is sold in the US and Canada under the brand name Relpax, and in several other countries under the brand name Relert.

Eletriptan was approved by the U.S. Food and Drug Administration (FDA) on December 26, 2002, for the acute treatment of migraine with or without aura in adults.^[1] It is available only by prescription in the United States and Canada. It is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. It is available in 20 mg, 40 mg and 80 mg strengths.

Eletriptan is covered by U.S. Patent no. 5545644^[1][2] and U.S. Patent no. 6110940;^[1][3] the FDA lists the patents as scheduled for expiration on December 26, 2016, and August 29, 2017, respectively.^[1]

Eletriptan is believed to reduce swelling of the blood vessels surrounding the brain. This swelling is associated with the head pain of a migraine attack. Eletriptan blocks the release of substances from nerve endings that cause more pain and other symptoms like nausea, and sensitivity to light and sound. It is thought that these actions contribute to relief of symptoms by eletriptan.

Eletriptan is a serotonin agonist. Specifically, it is a selective 5-hydroxytryptamine 1_B/1_D (5-HT_1B) receptor agonist.

Eletriptan binds with high affinity to the 5-HT_{1B, 1D, 1F]} receptors.

It has a modest affinity to the 5-HT_{[1A, 1E, 2B, 7]} receptors.

And little to no affinity at the 5-HT_{[2A, 2C, 3, 4, 5A, 6]} receptors.

Eletriptan has no significant affinity or pharmacological activity at adrenergic alpha1, alpha2, or beta; dopaminergic D1 or D2; muscarinic; or opioid receptors. Eletriptan could be efficiently co-administrated with nitric oxide synthase (NOS’s) inhibitors for the treatment of NOS-dependent diseases (US patent US 2007/0254940)

Two theories have been proposed to explain the efficacy of 5-HT receptor agonists in migraine. One theory suggests that activation of 5-HT1 receptors located on intracranial blood vessels, including those on the arteriovenous anastomoses, leads to vasoconstriction, which is correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HT1 receptors on sensory nerve endings in the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.

Common side effects include hypertension, tachycardia, headache, dizzyness, and symptoms similar to angina pectoris. Severe allergic reactions are rare.^[4]

Eletriptan is contraindicated in patients with various diseases of the heart and circulatory system, such as angina pectoris, severe hypertension, and heart failure, as well as in patients that have had a stroke or heart attack. It is also contraindicated in severe renal or hepatic impairment.^[4]

The drug has a relatively low potential for interactions. Notably, it is unlikely to interact to a relevant extent with beta blockers, tricyclic antidepressants and SSRI type antidepressants. Strong inhibitors of the liver enzyme CYP3A4, such as erythromycin and ketoconazole, significantly increase blood plasma concentrations and half life of eletriptan. Ergot alkaloids add to the drug’s hypertensive effect.^[4]

• Merck Index: 3-[[(2R)-1-Methyl-2-pyrrolidinyl]methyl]-5-[2-(phenylsulfonyl)ethyl]-1H-indole
• 5-[2-(benzenesulfonyl)ethyl]-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1H-indole
• (R)-5-[2-(phenylsulfonyl)ethyl]-3-[(1-methyl-2-pyrrolidinyl)methyl]-1H-indole

• FDA label (December 2002)
• Physicians’ Desk Reference entry for Relpax
• Medline Plus Drug Information for Eletriptan
• Pfizer Relpax site

3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-5-[2-(phenylsulfonyl)ethyl]-1H-indole or Eletriptan, currently available in the market as a hydrobromide salt, is an agonist of the 5-hydroxytryptamine (5-HT_1B/1D) receptor and it is used for treating migraine.

Various processes of synthesis of such molecule are known, but the one generally used is the synthesis shown in the diagram of FIG. 1, which provides for a Heck reaction (step 4 or 4b) between 5-bromo-3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-1H-indole and phenyl vinyl sulfone to obtain the 1-(3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-5-[(E)-2-(phenylsulfonyl)ethenyl]-1H-indole-1-yl)ethanone intermediate.

This reaction uses a palladium-based catalyst which is very sensitive to the impurities present in the reaction environment. It is thus essential that the 5-bromo-3{[(2R)-1-methylpyrrolidin-2-yl]methyl}-1H-indole intermediate be thoroughly purified before being reacted with phenyl vinyl sulfone.

In prior art documents (EP 0 592 438, U.S. Pat. No. 5,545,644 and U.S. Pat. No. 6,100,291) purification of the 5-bromo-3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-1H-indole intermediate is performed by means of chromatographic column, a process almost exclusively implementable in a laboratory or at a high cost in any case with long processing times alongside being ecologically unadvisable due to the large amount of solvents used.

Furthermore, it is known that the crystallisation of 5-bromo-3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-1H-indole intermediate (WO 2008/150500 and U.S. Pat. No. 5,545,644) provides a purified intermediate with assay not exceeding 98% (established through the HPLC analysis).

US5545644A1 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.

US7288662B2 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 subsequently costly. WO2005/103035A1 discloses Eletriptan synthesis by a Fischer Indole process. However, enantiomeric purity of the finished product depends on the purity of an acetal intermediate which might require asymmetric synthesis or optical resolution. Eletriptan obtained in the reported procedure had about 94% enantiomeric excess.

Eletriptan and intermediates thereof, including 5-bromo-3-[(i?)-l-methyl- pyrrolidin-2-ylmethyl]-lH-indole (“BIP”) are described in US 5,545,644. Also disclosed is the synthesis of ELT, which is illustrated by the following scheme:

In the described process, intermediate I, BIP, is obtained by reacting intermediate II with lithium aluminium hydride (“LAH”). LAH spontaneously reacts with water, including atmospheric humidity, and the pure material is pyrophoric. The LAH is known as very unstable, and air-exposed samples are almost always contaminated with aluminium metal and or a mixture of lithium hydroxide and aluminium hydroxide, thus affecting the reactivity of the LAH powder. This leads to the use of a large excess of reagent in order to obtain moderate conversion. Furthermore, the described process requires heating to reflux for a long period of time (39 hours in total, according to example 29 in patent US 5,545,644) followed by a time consuming recovery process. The recovery process consists of diluting of the reaction mixture with ethyl acetate, filtering through cellulose filtration bar, as described in patent US 5,545,644 example 27, and purifying the obtained oily like residue by silica gel chromatography, wherein, dichloromethane, ethanol and concentrated aqueous ammonia are used as a mobile phase. This process provides BIP, which is then converted to ELT.

Anhydrous alpha-and beta-hydrobromide salt forms of eietriptan are disclosed in WO-A-96/06842.

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WO2010049952A2

5-Bromoindole under Heck reaction conditions is coupled with phenyl vinyl sulfone followed by acylation with Cbz-Proline acid chloride to obtain a compound of Formula IV which on reduction in presence of a hydride agent provide Eletriptan.

¹H NMR CDCI₃ δ= 8.10 (bs, NH), 7.92-7.99 5 (m, 2H), 7.62-7.69 (m, 1H), 7.53-7.61 (m, 2H), 7.30 (s, 1H), 7.22 (d, 1H), 7.03 (s, 1H), 6.93 (dd, 1 H), 3.38-3.45 (m, 2H), 3.09-3.21 (m, 4H), 2.45-2.55 (m, 2H), 2.45 (s, 3H), 2.20-2.30 (m, 1H), 1.50-1.90 (m, 4H).

ESI Mass (M+H) 383.69

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http://beilstein-journals.org/bjoc/single/printArticle.htm?publicId=1860-5397-7-57

Eletriptan (87, Relpax) is yet another indole-containing antimigraine drug. A process route for the synthesis of eletriptan published by Pfizer starts from a preformed bromo-indole 88 [28] (Scheme 20). In order to perform the acylation of the indole ring on larger scale, ethylmagnesium bromide and the corresponding acid chloride 89 are added concurrently from two different sides of the reactor to stop these reagents reacting with each other. This method of adding the reagents circumvents the necessity to isolate the magnesium salt of the indole and increases the yield from 50 to 82%. The carbonyl group of the proline side chain is then reduced simultaneously with the complete reduction of the Cbz-group to a methyl group with lithium aluminium hydride. Finally, the sulfonate side chain is introduced via a Heck-type coupling similar to that of naratriptan (Scheme 15), followed by hydrogenation of the double bond to afford eletriptan (Scheme 20).

A rather ingenious Mitsunobu coupling reaction has been used to create a highly functionalised substrate 96 for an intramolecular Heck reaction resulting in a very short and succinct synthesis of eletriptan and related analogues 97 [29] (Scheme 21).

Interestingly, it was found that the most obvious approach, the direct Fischer indole synthesis, to prepare the core of eletriptan as shown in Scheme 22 is not successful [30]. This is believed to be due to the instability of the phenyl hydrazine species 98 under the relatively harsh reaction conditions required to promote the cyclisation.

However, this problem could be avoided by using an acid-labile oxalate protected hydrazine 104 as depicted in Scheme 23. The yield of this step can be further improved up to 84% if the corresponding calcium oxalate is used.

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Synthetic route of eletriptan hydrobromide. Reagents and conditions: (i) Acetic anhydride, TEA, DMF, 90–100 °C; (ii) palladium acetate, tri-(o-tolyl)phosphine, TEA, DMF, 90–100 °C; (iii) methanol, K₂CO₃, acetonitrile, H₂O, 5–10 °C; (iv) palladium on carbon, acetone, H₂O, aqueous hydrobromic acid, IPA, 25–30 °C.

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http://pubs.acs.org/doi/full/10.1021/op100251q

^aReagents 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%.

¹H NMR (CDCl₃): δ = 1.51−1.85 (m, 4H), 2.22−2.28 (m, 1H), 2.43−2.49 (m, 4H), 2.56−2.62 (m, 1H), 3.11−3.18 (m, 4H), 3.42−3.46 (m, 2H), 6.91−6.93 (s, 1H), 7.01 (s, 1H), 7.23−7.27 (d, 1H), 7.31 (s, 1H), 7.56−7.60 (m, 2H), 7.65−7.68 (m, 1H), 7.96−7.98 (d, 2H), 8.14 (s, 1H); LC/MS: R_t = 2.30 min; m/z 383 [MH]⁺

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ELETRIPTAN HYDROBROMIDE MONOHYDRATE

http://www.sumobrain.com/patents/wipo/Eletriptan-hydrobromide-monohydrate/WO2000032589.html

‘H-NMR (400MHz, ds-DMSO): delta = 10.90 (1H, d, J=2.2Hz), 9.35 (1 H, br s), 7.95 (2H, d, J=7.5Hz), 7.76 (1 H, t, J=7.5Hz), 7.66 (2H, t, J=7.5Hz), 7.38 (1 H, s), 7.24 (1 H, d, J=8.3Hz), 7.23 (1 H, d, J=2.2Hz), 6.92 (1 H, dd, J=8.3,1.4Hz), 3.63 (2H, m), 3.58 (2H, br m), 3.24 (1 H, m), 3.06 (1 H, m), 2.95 (2H, m), 2.86 (1 H, m), 2.83 (3H, s), 2.00 (1 H, m), 1.90 (2H, m), 1.70 (1 H, m).

Found: C, 54.85; H, 6.03; N, 5.76. C22H29N203SBr requires C, 54.87; H, 6.08; N, 5.82%.

UPDATED 29 MAR 2015

http://pubs.acs.org/doi/full/10.1021/op100251q

Found: C, 54.85; H, 6.03; N, 5.76. C22H29N203SBr requires C, 54.87; H, 6.08; N, 5.82%.
1H NMR

13C PREDICT

COSYPREDICT

SYNTHESIS

Reference:

KANSAL, Vinod Kumar; MISTRY, Dhirenkumar N.; PATEL, Rakesh Ravjibhai; PANDEY, Saurabh Patent: US2009/299077 A1, 2009 ; Location in patent: Page/Page column 8 ;

USV Limited B.S.D. Mar Patent: US2012/71669 A1, 2012 ; Location in patent: Page/Page column 11 ;

US2012/71669 A1, ;

US2011/166364 A1, ;
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US2008/287519 A1, ; Page/Page column 10 ;

WO2011/4391 A2, ; Page/Page column 19 ;
US2008/287519 A1, ; Page/Page column 8 ;