WO2006129190A1 - Procede de preparation de l'almotriptan - Google Patents

Procede de preparation de l'almotriptan Download PDF

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Publication number
WO2006129190A1
WO2006129190A1 PCT/IB2006/001471 IB2006001471W WO2006129190A1 WO 2006129190 A1 WO2006129190 A1 WO 2006129190A1 IB 2006001471 W IB2006001471 W IB 2006001471W WO 2006129190 A1 WO2006129190 A1 WO 2006129190A1
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group
almotriptan
derivative
pharmaceutically acceptable
ester
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PCT/IB2006/001471
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English (en)
Inventor
Nitin Sharad Chandra Pradhan
Vandanapu Loka Appala Purushotham
Samir Jaivant Naik
Ramasubramanian Sridharan
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Glenmark Pharmaceuticals Limited
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Publication of WO2006129190A1 publication Critical patent/WO2006129190A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention generally relates to an improved process for the preparation of almotriptan or a free base or a pharmaceutically acceptable salt, ester or derivative thereof.
  • Almotriptan also known as l-[[[3-[2-(dimethylamino)ethyl]indol-5- yl]methyl]sulfonyl]pyrrolidine, is represented by the following structure.
  • almotriptan binds with high affinity to 5-HT 1D , 5-HT 1 B and 5-HTJF receptors.
  • Almotriptan has weak affinity for 5-HTIA and 5-HT 7 receptors.
  • the malate salt of almotriptan is indicated for the acute treatment of migraine with or without aura in adults.
  • Almotriptan malate is sold under the trade names AXERT® and ALMOGRAN®. See, e.g., The Merck Index, Thirteenth Edition, 2001, pp. 56, monograph 301; and Physician's Desk Reference, "Axert," 60th Edition, pp. 2430-2434 (2005). [0004]
  • almotriptan base was purified by column chromatography (See Example 1) to obtain a white foam.
  • Bosch et al., Tetrahedron 57 pp. 1041-1048 discloses the synthesis of a tryptophol intermediate of almotriptan by the Heck approach in which aniline nitrogen is protected with a trifluoroacetyl group after iodination of the aniline using 1(CsHsN) 1 BF 4 .
  • the iodoaniline is, in turn, reacted with lithium diisopropylamide and methyl 4-bromo crotonate to provide an allylated derivative.
  • the allylated derivative undergoes palladium- catalyzed Heck cyclisation leading to the indole ester which is subsequently converted to tryptophol in three steps.
  • the tryptophol intermediate is then converted to almotriptan.
  • a process for preparing an intermediate of almotriptan or a free base or a pharmaceutically acceptable salt, ester or derivative thereof comprising the step of Heck coupling a 2-halo aniline derivative of Formula I:
  • X is a halogen with a protected butynol compound of the general formula:
  • Prot can be the same or different and is a suitable protecting group, to provide a protected indole derivative of Formula II.
  • a process for preparing an intermediate of almotriptan or a free base or a pharmaceutically acceptable salt, ester or derivative thereof comprising the steps of: (a) Heck coupling a 2-halo aniline derivative of Formula I:
  • X is a halogen with a protected butynol compound of the general formula:
  • X is a halogen with a protected butynol compound of the general formula:
  • Prot can be the same or different and is a suitable protecting group.
  • substantially pure almotriptan or a free base or a pharmaceutically acceptable salt, ester or derivative thereof is provided.
  • a pharmaceutical composition comprising a therapeutically effective amount of substantially pure almotriptan or a free base or a pharmaceutically acceptable salt, ester or derivative thereof is provided.
  • the advantages of the process of the present invention include at least:
  • the process is an industrially viable process utilizing a reduced number of steps.
  • treating means: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
  • terapéuticaally effective amount means the amount of a compound or crystalline form thereof that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound or crystalline form thereof, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated. Determining the therapeutically effective amount of a given compound or crystalline form thereof is within the ordinary skill of the art and requires no more than routine experimentation.
  • delivering means providing a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.
  • buffering agent as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali.
  • Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other such material known to those of ordinary skill in the art.
  • sweetening agent as used herein is intended to mean a compound used to impart sweetness to a preparation.
  • Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
  • binder as used herein is intended to mean substances used to cause adhesion of powder particles in tablet granulations.
  • Such compounds include, by way of example and without limitation, acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch, combinations thereof and other material known to those of ordinary skill in the art.
  • binders include starch, poly(ethylene glycol), guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONICTM F68, PLURONICTM F 127), collagen, albumin, celluloses in nonaqueous solvents, combinations thereof and the like.
  • Other binders include, for example, poly(propylene glycol), polyoxyethylene- polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, poly(ethylene oxide), microcrystalline cellulose, poly(vinylpyrrolidone), combinations thereof and other such materials known to those of ordinary skill in the art.
  • filler is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets and capsules.
  • Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
  • glidant as used herein is intended to mean agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect.
  • Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
  • lubricant as used herein is intended to mean substances used in tablet formulations to reduce friction during tablet compression. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
  • disintegrant as used herein is intended to mean a compound used in solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved.
  • exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pre- gelatinized and modified starched thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g. AvicelTM), carsium (e.g. AmberliteTM), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
  • starches such as corn starch, potato starch, pre- gelatinized and modified starched thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g. AvicelTM), carsium (e.g. AmberliteTM), alginates, sodium starch glycolate, gums such
  • wetting agent as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids.
  • exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g., TWEENTMs), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxye
  • Tyloxapol (a nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or triton) is another useful wetting agent, combinations thereof and other such materials known to those of ordinary skill in the art.
  • Tyloxapol a nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or triton
  • Most of these excipients are described in detail in, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein.
  • the present invention involves a process for preparing intermediates of almotriptan or a free base or a pharmaceutically acceptable salt, ester or derivative thereof.
  • a process for preparing almotriptan or a free base or a pharmaceutically acceptable salt, ester or derivative thereof includes the steps of (a) Heck coupling a 2-halo aniline derivative of Formula I:
  • X is a halogen, e.g., Cl, Br, I and the like, with a protected butynol compound of the general formula
  • a 2-halo aniline derivative of Formula I is disclosed in, e.g., Bosch et al., Tetrahedron 57 pp. 1041-1048 (2001), the contents of which are incorporated by reference therein.
  • a 2-halo aniline derivative of Formula I can be obtained by reacting 4-(pyrrolidinyl-sulfonylmethyl) aniline with a suitable halogenating agent in a solvent to halogenate the 2-position to form the corresponding 2- halo aniline derivative of Formula I.
  • Suitable halogenating agents include, but are not limited to, iodine monochloride, 1(CsH 5 N) 1 BF 4 , N-chlorosuccinimide/HI/KI (i.e., N- chlorosuccinimide/hydrogen iodide/potassium iodide), N-iodosuccinimide, iodine monobroraide and the like and mixtures thereof.
  • Useful solvents include, but are not limited to, alcohols, e.g., methanol, aqueous methanol, ethanol and the like, ethers, e.g., tetrahydrofuran (THF) and the like, halogenated hydrocarbons, e.g., methylene chloride and the like, and mixtures thereof, e.g., THF-water.
  • the solvent is an organic solvent such as 95% aqueous methanol.
  • the reaction of the 4-(pyrrolidinyl-sulfonylmethyl) aniline with a suitable halogenating agent can be carried out in the presence of a proton acceptor.
  • Suitable proton acceptors include, but not limited to, carbonates such as calcium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, magnesium carbonate, sodium bicarbonate and the like, hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like and mixtures thereof.
  • the reaction of the 4-(pyrrolidinyl-sulfonylmethyl) aniline with a suitable halogenating agent can be carried out under inert conditions at a temperature ordinarily ranging from about -10°C to about 10 0 C, and preferably at a temperature of about 0 0 C.
  • a suitable halogenating agent can be carried out under inert conditions at a temperature ordinarily ranging from about -10°C to about 10 0 C, and preferably at a temperature of about 0 0 C.
  • ⁇ - OProt wherein Prot can be the same or different protecting group can be obtained, for example, by protecting 3-butyn-l-ol with a protecting group such as a silane-containing protecting agent in a suitable solvent using a lithiated base, e.g., n-butyl lithium.
  • suitable solvents include, but are not limited to, ethers, e.g., tetrahydrofuran, diethyl ether, dioxane, and the like, alkoxy groups, e.g., 2-dimethoxy ethane and the like, and mixtures thereof.
  • Suitable silane-containing protecting agents include, but are not limited to, halogenated hydrocarbyl silanes such as trimethyl chlorosilane, triethyl chlorosilane, and the like, and t-butyldimethylsilane (TBDMS) and the like and mixtures thereof.
  • halogenated hydrocarbyl silanes such as trimethyl chlorosilane, triethyl chlorosilane, and the like
  • TDMS t-butyldimethylsilane
  • the protected butynol compound thus obtained can be, for example, a trialkylsilyl butynol, e.g., a bis(trialkylsilyl) butynol such as bis (trimethylsilyl) butynol, bis (triethylsilyl) butynol and the like; t-butyldimethyl silylchloride butynol and the like and mixtures thereof.
  • the Heck coupling reaction can be carried out in a dry inert organic solvent which is capable of dissolving the reactants and in the presence of a palladium catalyst and base.
  • a suitable base includes an inorganic base, an organic base and the like and mixtures thereof.
  • Useful inorganic bases include, but are not limited to, common inorganic bases, such as the hydroxides, oxides or carbonates of Groups I or II of The Periodic Table Of The Elements, e.g., the alkali metal or alkaline earth metal bases such as lithium, sodium, potassium, barium, magnesium or calcium hydroxide; sodium, magnesium or calcium oxide; sodium or potassium carbonate; ammonia solutions and the like and mixtures thereof.
  • Useful organic bases include, but are not limited to, organic amines, such as trimethylamine, triethylamine, piperidine, 3-methylpyridine, piperazine, triethanolamine and the like and mixtures thereof.
  • Suitable solvents include, but are not limited to, amides, e.g., dimethylformamide, dimethylacetamide, and the like, ethers, e.g., diethyl ether, dipropyl ether, tetrahydrofuran (THF), dioxane and the like, alkoxy solvents, e.g., 1,2-dimethoxy ethane and the like, nitriles, e.g., acetonitrile and the like, hydrocarbons, e.g., toluene, xylene and the like and mixtures thereof.
  • the palladium catalyst may be in the form of a salt or a complex with organic ligands.
  • Particularly suitable palladium catalysts are, for example, the Group VIII metals, such as Pd(O) complexes or a Pd(II) salt.
  • the palladium catalyst used is not particularly limited provided that it is usually used for a Heck coupling reaction.
  • the ligands may be selected from, for example, phosphorus-containing ligands, such as triphenylphosphine (PPh 3 ), l,2-bis(diphenylphosphino)ethane and the like.
  • Non-limiting examples of suitable palladium catalysts include, but are not limited to, palladium (II) acetate, palladium (II) bromide, palladium (II) chloride, palladium (II) iodide, palladium tetrakis triphenyl phosphine and the like and mixtures thereof.
  • the temperature of the Heck coupling reaction can range from about 7O 0 C to about 120 0 C. If desired, the reaction can also be carried out in the presence of a suitable proton acceptor such as, for example, alkyl amines, aromatic amines, heterocyclic amines, Group I alkali metal carbonates and bicarbonates, Group II alkaline earth carbonates and bicarbonates and the like and mixtures thereof.
  • a suitable proton acceptor such as, for example, alkyl amines, aromatic amines, heterocyclic amines, Group I alkali metal carbonates and bicarbonates, Group II alkaline earth carbonates and bicarbonates and the like and mixtures thereof.
  • step (b) of a process of the present invention the protected indole is then deprotected to provide a tryptophol-containing compound.
  • Deprotection of the protected indole e.g., desilylation of the indole, may be achieved using suitable deprotecting agent, for example, MeOH-HCl, tetrabutylammonium fluoride, and the like, to obtain a tryptophol-containing compound.
  • suitable deprotecting agent for example, MeOH-HCl, tetrabutylammonium fluoride, and the like.
  • the temperature for deprotection can range of about O 0 C to about 35°C.
  • Suitable basifying agents include the inorganic and organic bases discussed above such as sodium carbonate and ammonia.
  • the tryptophol-containing compound thus obtained is thereafter converted to almotriptan or a free base or pharmaceutically acceptable salt, ester or derivative thereof by techniques well known in the art.
  • pharmaceutically acceptable salt, ester or derivative thereof is meant those salts, esters and derivatives which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • Representative acid additions salts include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, malate, maleate, fumarare, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, lauryl sulphate salts and the like.
  • Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts, and the like.
  • almotriptan can be obtained by first forming a mesylate compound from tryptophol followed by displacement with dimethylamine. The salt formation can be carried out in a solvent, for example diethyl ether, THF and the like.
  • conversion of the tryptophol-containing compound to almotriptan or a free base or pharmaceutically acceptable salt, ester or derivative thereof can be carried out by reacting tryptophol with mesyl chloride in a dry inert organic solvent, e.g., THF, dioxane, diethyl ether, 1,2-dimethoxy ethane, and methylene dichloride.
  • a dry inert organic solvent e.g., THF, dioxane, diethyl ether, 1,2-dimethoxy ethane, and methylene dichloride.
  • the reaction can be carried out at a temperature of about -30 0 C to about -10 0 C under nitrogen atmosphere and in the presence of a suitable proton acceptor such as triethylamine (TEA), pyridine, diisopropyl ethylamine, dimethylaminopyridine (DMAP) and the like and mixtures thereof.
  • a suitable proton acceptor such as triethylamine (TEA), pyridine, diisopropyl ethylamine, dimethylaminopyridine (DMAP) and the like and mixtures thereof.
  • TAA triethylamine
  • pyridine pyridine
  • DMAP dimethylaminopyridine
  • the tryptophol-containing compound can be tosylated and the tosyl group can be displaced with a N, N- dimethylamino group, e.g., N(CH 3 ) 2 .
  • the N, N-dimethylamino group can be added as is or part of a solution, e.g., as a 40% aqueous solution or dimethylamine in an alcohol such as methanol, ethanol and isopropanol, or as gaseous dimethylamine which can be spurged directly or as a salt of dimethylamine hydrochloride or any other salt of dimethylamine.
  • a solution e.g., as a 40% aqueous solution or dimethylamine in an alcohol such as methanol, ethanol and isopropanol, or as gaseous dimethylamine which can be spurged directly or as a salt of dimethylamine hydrochloride or any other salt of dimethylamine.
  • a process for preparing almotriptan or a free base or pharmaceutically acceptable salt, ester or derivative thereof includes the steps of at least (a) iodination of 4-(pyrrolidinyl-sulfonylmethyl) aniline to provide the corresponding 2-iodo aniline derivative; (b) triethyl silyl protection of 3- butyn-1-ol to provide bis-triethyl silyl butynol; (c) Heck coupling of the 2-iodo aniline derivative with the bis-triethyl silyl butynol followed by its deprotection to provide a tryptophol-containing compound; and (d) converting the tryptophol-containing compound to almotriptan by mesylation followed by displacement with N,N-dimethylamine.
  • This reaction is generally set forth below in Scheme I.
  • the almotriptan or free base or pharmaceutically acceptable salt, ester or derivative thereof thus obtained can then be purified to provide a substantially pure compound.
  • substantially pure is meant almotriptan or a free base or pharmaceutically acceptable salt, ester or derivative thereof having a purity greater than or equal to about 98%, and preferably greater than or equal to about 99%.
  • the almotriptan or free base or pharmaceutically acceptable salt, ester or derivative thereof can be purified by column chromatography, e.g., silica gel column chromatography using isopropyl acetate.
  • the almotriptan or free base or pharmaceutically acceptable salt, ester or derivative thereof of the present invention may then be formulated into a pharmaceutical composition or dosage form.
  • Such pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc.
  • Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes.
  • Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like.
  • the almotriptan or free base or pharmaceutically acceptable salt, ester or derivative thereof of the present invention also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes.
  • the dosage forms may contain the almotriptan or free base or pharmaceutically acceptable salt, ester or derivative thereof of the present invention as is or, alternatively, as part of a composition.
  • the pharmaceutical compositions may further contain one or more pharmaceutically acceptable excipients as described herein.
  • Capsule dosages will contain the almotriptan or free base or pharmaceutically acceptable salt, ester or derivative thereof of the present invention within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating.
  • the enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents.
  • a coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.
  • compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors.
  • the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, macrocrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art.
  • Suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
  • excipients contemplated herein may include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
  • binders such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes
  • disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others
  • lubricants like magnesium and calcium stearate and sodium stearyl fumarate
  • flavorings sweeteners
  • compositions of the invention may be varied to obtain an amount of almotriptan or free base or pharmaceutically acceptable salt, ester or derivative thereof that is effective to obtain a desired therapeutic response for a particular composition and method of administration.
  • the selected dosage level therefore depends upon such factors as, for example, the desired therapeutic effect, the route of administration, the desired duration of treatment, and other factors.
  • the total daily dose of the compounds of this invention administered to a host in single or divided dose can vary widely depending upon a variety of factors including, for example, the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs, the severity of the particular condition being treated, etc.
  • Step I Preparation of 2-iodo-4-(l-pyrrolidinyl methane sulfonyl) aniline
  • step I The crude material obtained in step I was suspended in 6N hydrochloric acid (65ml) and stirred for a period of 30 minutes. The product was filtered and washed with water. The solid was suspended in a 6N ammonia solution (75 ml) and stirred for a period of 30 minutes. The solid was filtered and washed with water. The product was dried to a constant weight. Weight: 29 g.
  • N-butyl lithium (1.6 M, 267 ml) was added to a mixture of 3-butynol (15 g) and tetrahydrofuran (250 ml) at a temperature below -20 0 C.
  • the reaction mixture was stirred for a period of 1 hour at -2O 0 C.
  • Triethylchlorosilane (66.12 g) was added at a temperature below -15°C. After completion of the addition, the reaction mass was allowed to warm to room temperature. The reaction mass was stirred at room temperature for a period of 2 hours. After completion of the reaction as determined by TLC, the reaction mass was cooled to a temperature of -10 0 C.
  • Methanesulfonyl chloride was added to a solution of 5-(l-pyrrolidinyl methane sulfonyl)-lH-indole-3-ethanol (7 g) of Example 3 in tetrahydrofuran (140 ml) and triethylamine (6 g) at a temperature below -20°C.
  • the reaction mass was stirred at a temperature of about -20 0 C for a period of 30 minutes.
  • a dimethyl amine solution (40%, 55 ml) was added at a temperature of about -20 0 C. After the addition, the reaction mass was allowed to rise to room temperature. The reaction mass was stirred at room temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • Public Health (AREA)
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  • Indole Compounds (AREA)

Abstract

L'invention porte sur un procédé de préparation d'un intermédiaire de l'almotriptan, ce procédé consistant à: réaliser le couplage de Heck avec un dérivé de 2-halo aniline de formule (I) dans laquelle X représente un halogène avec un composé butynol protégé de formule générale (III) dans laquelle Prot peut être identique ou différent et est un groupe de protection approprié pour obtenir un dérivé d'indole protégé de formule (II).
PCT/IB2006/001471 2005-06-03 2006-06-02 Procede de preparation de l'almotriptan WO2006129190A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN666/MUM/2005 2005-06-03
IN666MU2005 2005-06-03
US69149805P 2005-06-17 2005-06-17
US60/691,498 2005-06-17

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008151584A1 (fr) * 2007-06-13 2008-12-18 Zentiva, A.S. Procédé de préparation d'almotriptan de haute pureté
WO2012085723A1 (fr) * 2010-12-20 2012-06-28 Orchid Chemicals And Pharmaceuticals Limited Procédé pour la purification d'un sel d'addition acide d'almotriptan
CN102827062A (zh) * 2012-09-17 2012-12-19 扬子江药业集团四川海蓉药业有限公司 苹果酸阿莫曲坦的制备方法
CN109928910A (zh) * 2017-12-19 2019-06-25 上海医药工业研究院 抗偏头痛药物阿莫曲坦的制备方法
CN113527173A (zh) * 2021-08-30 2021-10-22 河南师范大学 Heck串联反应合成吲哚萜类似物的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0548813A1 (fr) * 1991-12-19 1993-06-30 Bristol-Myers Squibb Company Dérivés antimigraines de 4-pyrimidine- et pyridine-indol-3-ylalkylpiperazines
US5565447A (en) * 1992-07-28 1996-10-15 Laboratorios Almirall S.A. Indole derivatives

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
EP0548813A1 (fr) * 1991-12-19 1993-06-30 Bristol-Myers Squibb Company Dérivés antimigraines de 4-pyrimidine- et pyridine-indol-3-ylalkylpiperazines
US5565447A (en) * 1992-07-28 1996-10-15 Laboratorios Almirall S.A. Indole derivatives

Non-Patent Citations (2)

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Title
BOSCH J ET AL: "Synthesis of 5-(sulfamoylmethyl)indoles", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 57, no. 6, 4 February 2001 (2001-02-04), pages 1041 - 1048, XP004316535, ISSN: 0040-4020 *
CHEN C-Y ET AL: "SYNTHESIS OF THE 5-HT1D RECEPTOR AGONIST MK-0462 VIA A PD-CATALYZED COUPLING REACTION", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 35, no. 38, 19 September 1994 (1994-09-19), pages 6981 - 6984, XP000608320, ISSN: 0040-4039 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008151584A1 (fr) * 2007-06-13 2008-12-18 Zentiva, A.S. Procédé de préparation d'almotriptan de haute pureté
CZ302424B6 (cs) * 2007-06-13 2011-05-11 Zentiva, A. S. Zpusob prípravy almotriptanu o vysoké cistote
EA016759B1 (ru) * 2007-06-13 2012-07-30 Зентива, К.С. Способ получения алмотриптана высокой чистоты
WO2012085723A1 (fr) * 2010-12-20 2012-06-28 Orchid Chemicals And Pharmaceuticals Limited Procédé pour la purification d'un sel d'addition acide d'almotriptan
CN102827062A (zh) * 2012-09-17 2012-12-19 扬子江药业集团四川海蓉药业有限公司 苹果酸阿莫曲坦的制备方法
CN109928910A (zh) * 2017-12-19 2019-06-25 上海医药工业研究院 抗偏头痛药物阿莫曲坦的制备方法
CN109928910B (zh) * 2017-12-19 2022-07-22 上海医药工业研究院 抗偏头痛药物阿莫曲坦的制备方法
CN113527173A (zh) * 2021-08-30 2021-10-22 河南师范大学 Heck串联反应合成吲哚萜类似物的方法
CN113527173B (zh) * 2021-08-30 2022-12-16 河南师范大学 Heck串联反应合成吲哚萜类似物的方法

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