154323-57-6

Basic information

• Product Name: Almotriptan
• Synonyms: LAS-31416-d6;ALMOTRIPTAN(SUBJECTTOPATENETFREE);Almotriptan;N,N-Dimethyl-2-[5-(pyrrolidin-1-ylsulfonylmethyl)-1H-indol-3-yl]-ethanamine;dimethyl-[2-[5-(pyrrolidin-1-ylsulfonylmethyl)-1H-indol-3-yl]ethyl]amine;AlMotriptan API;N,N-dimethyl-5-[(1-pyrrolidinylsulfonyl)methyl]-1H-Indole-3-ethanamine;ALMOTRIPTAN-D6
• CAS NO: 154323-57-6
• Molecular Formula: C₁₇H₂₅N₃O₂S
• Molecular Weight: 335.47
• EINECS: 1312995-182-4
• Product Categories: Heterocyclic Compounds;Intermediates & Fine Chemicals;Isotope Labeled Compounds;Pharmaceuticals;APIs;Isotope Labelled Compounds
• Mol File: 154323-57-6.mol
• Article Data: 10

Chemical Properties

• Melting Point: 170-172°C
• Boiling Point: 538.7 °C at 760 mmHg
• Flash Point: 279.6 °C
• Appearance: light yellow or white power
• Density: 1.27 g/cm³
• Vapor Pressure: 1.13E-11mmHg at 25°C
• PKA: 16.92±0.30(Predicted)
• CAS DataBase Reference: Almotriptan(CAS DataBase Reference)
• NIST Chemistry Reference: Almotriptan(154323-57-6)
• EPA Substance Registry System: Almotriptan(154323-57-6)

Safety Data

• Hazardous Substances Data: 154323-57-6(Hazardous Substances Data)

Usage

Description

Almotriptan, also known by the brand name Almogran, is an indole compound with a 2-(dimethylamino)ethyl group at the 3-position and a (pyrrolidin-1-ylsulfonyl)methyl group at the 5-position. It is a serotonin 5HT1B/1D-receptor agonist and belongs to the "triptan" class of medications, specifically being the fifth agent launched after sumatriptan, naratriptan, zolmitriptan, and rizatriptan. Almotriptan is used to treat acute attacks of migraine and has a high oral bioavailability, rapid onset of action, and low recurrence rate.

Uses

Used in Pharmaceutical Industry:
Almotriptan is used as a medication for the treatment of acute migraine attacks. It acts as a dual 5-HT1D/1B agonist, selectively targeting these receptors with a high degree of selectivity over other serotonin receptors. This action helps to alleviate the symptoms of migraine by inhibiting the release of neuropeptides and constricting dilated blood vessels associated with migraine attacks.
Almotriptan is used as an oral medication for the rapid relief of migraine symptoms. Its high oral bioavailability (70%) and half-life of 3.5 hours contribute to its effectiveness in providing rapid onset of action and a well-tolerated therapeutic dose of 12.5 mg.

Originator

Almirall Prodesfarma (Spain)

Manufacturing Process

To a solution of previously dried 1-[[2-carboxy-3-(2-dimethylaminoethyl)-5- indolyl]methanesulphonyl]-pyrrolidine (1.6 g; 0.0442 moles) in anhydrous quinoline (75 ml) and under atmosphere of nitrogen, cuprous oxide (160 mg; 0.0011 moles) was added. The reaction mixture was heated to 190°C for 15 minutes, stirred to room temperature, poured into a mixture of 1 N hydrochloric acid (150 ml) and ethyl acetate (50 ml), shaken and decanted. The aqueous solution was washed several times with ethyl acetate, then solid sodium bicarbonate was added until pH = 7.8, and washed with n-hexane to eliminate the quinoline. The aqueous solution was made alkaline with solid potassium carbonate and extracted with ethyl acetate. The organic solution was dried (Na2SO4), the solvent removed under reduced pressure when a dark oil was obtained (1.3 g; yield 92%). This product was purified by column chromatography with silica gel and methylene chloride:ethanol:ammonium hydroxide (60:8:1) as eluent and a white foam (0.8 g) of 1-[[3-(2- dimethylaminoethyl)-5-indolyl]methanesulphonyl]-pyrrolidine was obtained. To a solution of the above product (0.8 g) in acetone (30 ml), a few drops of hydrogen chloride saturated dioxan solution, were added. The precipitated solid was collected by filtration, washed with acetone and dried to give 1-[(3- (2-(dimethylamino)ethyl)-5-indolyl)methanesulphonyl]-pyrrolidine hydrochloride (0.75 g). Melting point 218°-220°C. In practice it is usually used as malate salt.

Therapeutic Function

Migraine therapy

Drug interactions

Potentially hazardous interactions with other drugs Antidepressants: increased risk of CNS toxicity with citalopram - avoid; possibly increased serotonergic effects with duloxetine or venlafaxine; increased serotonergic effects with St John’s wort - avoid. Antifungals: concentration increased by ketoconazole (increased risk of toxicity). Dapoxetine: possible increased risk of serotonergic effects - avoid for 2 weeks after stopping 5HT1 agonists. Ergot alkaloids: increased risk of vasospasm - avoid.

Metabolism

The major biotransformation route is via monoamine oxidase (MAO-A) mediated oxidative deamination to the indole acetic metabolite. Cytochrome P450 (3A4 and 2D6 isozymes) and flavin mono-oxygenase are other enzymes involved in the metabolism of almotriptan. None of the metabolites are significantly active pharmacologically. More than 75% of a dose is eliminated in urine, and the remainder in faeces. Approximately, 50% of the urinary and faecal excretion is unchanged almotriptan.

InChI:InChI=1/C17H25N3O2S.C4H6O5/c1-19(2)10-7-15-12-18-17-6-5-14(11-16(15)17)13-23(21,22)20-8-3-4-9-20;5-2(4(8)9)1-3(6)7/h5-6,11-12,18H,3-4,7-10,13H2,1-2H3;2,5H,1H2,(H,6,7)(H,8,9)

Upstream product

• 51599-68-9 1-(methylsulfonyl)-pyrrolidine 
• 17274-65-6 5-bromo-3-[2-(N,N-dimethylamino)ethyl]-1H-indole 
• 22120-32-7 2-(5-chloro-1H-indol-3-yl)-N, N-dimethylethanamine 
• 22120-38-3 2-(5-iodo-1H-indol-3-yl)-N,N-dimethylethanamine 
• 334981-10-1 4-((pyrrolidin-1-ylsulfonyl)methyl)aniline 
• 124-40-3 dimethyl amine 
• 334981-30-5 2-(5-((pyrrolidin-1-ylsulfonyl)methyl)-1H-indol-3-yl)ethan-1-ol 
• 1112206-16-2 C₁₇H₂₈N₄O₂S 
• 1018676-02-2 C₁₈H₂₇N₃O₃S 
• 50-00-0 formaldehyd 
• 181178-24-5 1-[[3-(2-aminoethyl)-1H-indol-5-yl]methylsulfonyl]pyrrolidine 

Downstream Products

• 181183-52-8 almotriptan malate 
• 922735-96-4 almotriptan 2-hydroxy benzoate 

Relevant articles and documents

Preparation method of anti-migraine drug almotriptan

The invention discloses a preparation method of an anti-migraine drug almotriptan. The method comprises the following steps: (1) N-protected o-haloaniline represented by formula (I) and 4-acetoxycrotonate represented by formula (II), which are used as raw materials, undergo a cascade reaction under the action of the basic skeleton of a palladium catalyst and a phosphine ligand, and an almotriptanbasic skeleton represented by formula (III) is collected from the obtained reaction product; and (2) the almotriptan basic skeleton represented by formula (III) undergoes reduction, deprotection, hydroxyl group activation and amino group substitution to obtain the product almotriptan. The preparation method has the advantages of simple and easily available raw materials and reagents, simplicity inoperation of the preparation, no harsh conditions, convenience in purification of the intermediate and the product, and high overall yield. The reaction formula is shown in the description.

Method for synthesizing almotriptan

The invention relates to the technical field of medicines, and particularly relates to a method for synthesizing almotriptan. The method comprises the following steps: drying nickel salt in vacuum under protection of argon, adding an anhydrous organic solvent and phosphine ligand, and stirring at room temperature; then, adding an alkaline substance in the mixed solution, stirring at room temperature, adding tetrahydropyrrole methyl sulfonamide and 3,5-disubstituted indole derivative; and keeping on reaction, extracting and drying after the reaction is quenched, and concentrating at reduced pressure, and purifying to obtain almotriptan. The reaction general formula is shown in the specification. The method is simple and short in synthesis route, only needs one-step reaction. The almotriptan has the characteristics of high yield, high purity and the like, has a yield of 80-92 percent and purity of 90-95 percent, and has wide industrial application.

NOVEL PROCESS

The present invention relates to a novel process for the preparation of almotriptan and pharmaceutically acceptable salts thereof, which affords product conveniently and efficiently with commercially acceptable yields and purity. The present invention also relates to a novel synthetic intermediate used in the process.