WO2023152081A1 - Procédé de préparation de pyridinoylpipéridines agonistes de 5-ht1f et sels associés - Google Patents

Procédé de préparation de pyridinoylpipéridines agonistes de 5-ht1f et sels associés Download PDF

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Publication number
WO2023152081A1
WO2023152081A1 PCT/EP2023/052805 EP2023052805W WO2023152081A1 WO 2023152081 A1 WO2023152081 A1 WO 2023152081A1 EP 2023052805 W EP2023052805 W EP 2023052805W WO 2023152081 A1 WO2023152081 A1 WO 2023152081A1
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compound
acid addition
addition salt
formula
lasmiditan
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PCT/EP2023/052805
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English (en)
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Pere Dalmases Barjoan
Noelia Calcerrada Muñoz
Jesús RAMÍREZ ARTERO
Jordi Carles Cerón Bertran
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Inke, S.A.
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Publication of WO2023152081A1 publication Critical patent/WO2023152081A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention provides an efficient and environmentally friendly process suitable for industrial scale application for the preparation of pyridinoylpiperidines as 5-HTIF agonists and salts thereof, in particular 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4- carbonyl)pyridine-2-yl]benzamide or a pharmaceutically acceptable acid addition salt thereof, preferably the hemisuccinate salt, in good yield and high purity.
  • the present invention also provides crystalline acid addition salts of 2,4,6-trifluoro-N-[6- (1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamide suitable for purification at industrial scale.
  • 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamide also known as Lasmiditan
  • the recommended dose is 50 mg, 100 mg, or 200 mg film coated tablets taken orally as needed.
  • Pyridinoylpiperidines as 5-HTIF agonists, in particular Lasmiditan was first disclosed in WO03/084949 A1 to Eli-Lilly.
  • the process involves the reaction of a 2,6-dihalopyridine with n-butyllithium to form the 2-halo-6-lithiumpyridine which is then reacted with a substituted aminocarbonylpiperidine to provide the corresponding 2-halo-6-(piperidin-4- carbonyl)pyridine.
  • WO2011/123654 A1 discloses the preparation of Lasmiditan involving the reaction of a 2,6-dibromopyridine with a substituted aminocarbonylpiperidine in the presence of a Grignard reagent at room temperature followed by treatment with hydrobromic acid to form the corresponding 2-bromo-6-(piperidin-4-carbonyl)pyridine hydrobromide salt; which is then treated with ammonia with >0.02 wt % copper(l)oxide at less than 80° C to yield 2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine which is reacted with 2,4,6-trifluorobenzoylchloride in chlorobenzene at 100°C to provide Lasmiditan hydrochloride, which is neutralized and further converted into the hemisuccinate salt.
  • This process involves the use of unsuitable halogenated reagent 2,4,6-trifluorobenzoylchloride and unsuitable halogenated solvents
  • the present invention provides an efficient and environmentally friendly process for manufacturing pyridinoylpiperidines as 5-HTIF agonists and salts thereof, in particular Lasmiditan and salts thereof avoiding the use of halogenated reagents and halogenated solvents in high yield and high purity and applicable at industrial scale.
  • This process also allows obtaining Lasmiditan without requiring laborious and unfeasible purification steps, yielding a high purity which complies with pharmaceutical standards.
  • the first aspect of the present invention relates to a process for preparing a pyridinoylpiperidine compound of formula (I)
  • the second aspect of the present invention relates to a process for preparing key intermediate compound of formula II
  • R2 and R3 are the same or different and are each selected from C1-C3 alkyl, C1-C3 alkoxy, or wherein R2 and R3 form, together with the nitrogen to which they are attached, a 5 to 6-membered heterocycle optionally comprising one or more heteroatoms, preferably the heteroatom is an oxygen atom, preferably R1 is methyl and R2and R3, together with the nitrogen to which they are attached, combine to form azetidinyl, pyrrolidinyl, piperidinyl, or morpholine, more preferably R1 is methyl and R2 and R3 are the same and are methyl, ethyl or wherein R2 and R3, together with the nitrogen to which they are attached, combine to form pyrrolidinyl, with compound of formula VI
  • crystalline acid addition salts of compound I, wherein Ri is methyl suitable for purification, in particular, the hydrochloric acid addition salt, hydrobromic acid addition salt, the sulfuric acid addition salt, the fumaric acid addition salt, the oxalic acid addition salt, the L-tartaric acid addition salt, the formic acid addition salt, and the acetic acid addition salt of compound I, wherein Ri is methyl (Lasmiditan).
  • Further aspects of the present invention refer to the use of the crystalline acid addition salts of Lasmiditan selected from the hydrochloric acid addiction salt, hydrobromic acid addition salt, the sulfuric acid addition salt, the fumaric acid addition salt, the oxalic acid addition salt, the L-tartaric acid addition salt, the formic acid addition salt, and the acetic acid addition salt, suitable for purification of Lasmiditan.
  • organic solvent refers to an organic molecule capable of at least partially dissolving another substance (i.e., the solute).
  • Organic solvents may be liquids at room temperature.
  • the organic solvent may be formed by the combination of two or more organic solvents.
  • alcohol refers to a hydrocarbon derivative in which one or more hydrogen atoms have been replaced by an -OH group, known as hydroxyl group.
  • Suitable alcohols for the present invention include linear, cyclic or branched C1-C6 alkyl alcohols and any mixtures thereof. It also includes commercially available alcohols. Examples of alcohols are methanol, ethanol, isopropanol, 1-propanol and 1-butanol.
  • solvent extraction refers to the process of separating components of a mixture by using a solvent which possesses greater affinity for one component, and may therefore separate said one component from at least a second component which is less miscible than said one component with said solvent.
  • filtration refers to the act of removing solid particles greater than a predetermined size from a feed comprising a mixture of solid particles and liquid.
  • the expression “filtrate” refers to the mixture less the solid particles removed by the filtration process. It will be appreciated that this mixture may contain solid particles smaller than the predetermined particle size.
  • filter cake refers to residual solid material remaining on a feed side of a filtration element.
  • evaporation refers to the change in state of solvent from liquid to gas and removal of that gas from the reactor.
  • Various solvents may be evaporated during the synthetic route disclosed herein. As known to those of skilled in the art, each solvent may have a different evaporation time and/or temperature.
  • slurrying refers to any process which employs a solvent to wash, suspend or disperse a crude solid product.
  • phase separation refers to a solution or mixture having at least two physically distinct regions.
  • crystallization refers to any method known to a person skilled in the art such as crystallization from single solvent or combination of solvents by dissolving the compound optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as solvent/antisolvent or precipitation.
  • conventional isolation techniques or purification refers to the process of rendering a product clean of foreign elements whereby a purified product can be obtained.
  • industrial purification refers to purifications which can be carried out on an industrial scale such as solvent extraction, filtration, slurring, washing, phase separation, evaporation, centrifugation or crystallization.
  • purification and/or purifying refer to the process wherein a purified drug substance can be obtained, preferably having a purity greater than 80%, more preferably greater than 85%, more preferably greater than 90%, more preferably greater than 95%, more preferably greater than 99%, more preferably greater than 99.5%, even more preferably greater than 99.9%.
  • industrial purification refers to purifications, which can be carried out on an industrial scale such as solvent extraction, filtration, slurring, washing, phase separation, evaporation, centrifugation or crystallization.
  • FIG. 1 provides a representative X-ray Powder Diffraction (XRPD) pattern of Form B1 of hydrobromic acid addition salt of Lasmiditan.
  • FIG. 2 provides a representative Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA) plot of Form B1 of hydrobromic acid addition salt of Lasmiditan.
  • DSC Differential Scanning Calorimetry
  • TGA Thermal Gravimetric Analysis
  • FIG. 3 provides a representative XRPD pattern of Form SF1 of sulfuric acid addition salt of Lasmiditan.
  • FIG. 4 provides a representative DSC and TGA plot of Form SF1 of sulfuric acid addition salt of Lasmiditan.
  • FIG. 5 provides an overlay of representative XRPD patterns of Form SF1 , Form SF2 and Form SF3 of sulfuric acid addition salt of Lasmiditan.
  • FIG. 6 provides a representative XRPD pattern of Form FM1 of fumaric acid addition salt of Lasmiditan.
  • FIG. 7 provides a representative DSC and TGA plot of Form FM1 of fumaric acid addition salt of Lasmiditan.
  • FIG. 8 provides a representative XRPD pattern of Form 0X1 of oxalic acid addition salt of Lasmiditan.
  • FIG. 9 provides a representative DSC and TGA plot of Form 0X1 of oxalic acid addition salt of Lasmiditan.
  • FIG. 10 provides an overlay of representative XRPD patterns of Form 0X1 , Form 0X2, Form 0X3 and Form 0X4 of oxalic acid addition salt of Lasmiditan.
  • FIG. 11 provides a representative XRPD pattern of Form T1 of L-tartaric acid addition salt of Lasmiditan.
  • FIG. 12 provides a representative DSC and TGA plot of Form T1 of L-tartaric acid addition salt of Lasmiditan.
  • FIG. 13 provides a representative XRPD pattern of Form T3 of L-tartaric acid addition salt of Lasmiditan.
  • FIG. 14 provides a representative DSC and TGA plot of Form T3 of L-tartaric acid addition salt of Lasmiditan.
  • FIG. 15 provides a representative XRPD pattern of Form FR1 of formic acid addition salt of Lasmiditan.
  • FIG. 16 provides a representative DSC and TGA plot of Form FR1 of formic acid addition salt of Lasmiditan.
  • FIG. 17 provides a representative XRPD pattern of Form FR2 of formic acid addition salt of Lasmiditan.
  • FIG. 18 provides a representative DSC and TGA plot of Form FR2 of formic acid addition salt of Lasmiditan.
  • FIG. 19 provides a representative XRPD pattern of Form A1 of acetic acid addition salt of Lasmiditan.
  • FIG. 20 provides a representative DSC and TGA plot of Form A1 of acetic acid addition salt of Lasmiditan.
  • the present inventors found out that the process disclosed in the prior art that uses 2,4,6- trifluorobenzoylchloride provided Lasmiditan containing a major impurity difficult to be removed by means of conventional purification techniques such as crystallization.
  • the process of the present invention provides compound I, preferably wherein Ri is methyl, in high yield and high purity and applicable at industrial scale, avoiding the use of non-suitable halogenated reagents such as 2,4,6- trifluorobenzoylchloride and non-suitable halogenated solvents such as chlorobenzene which are environmentally unfriendly.
  • the coupling agent in step a) may be an activating carboxylic acid agent selected from a phosphonic acid derivative, preferably propanephosponic acid anhydride (T3P), benzotriazol-1yloxy)tris(dimethyl- amino)phosphonium hexafluorophosphate (BOP), chlorotri(pyrrolidino)phosphoniumhexafluorophosphate (PyCloP), bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBroP), benzotriazol- 1- yloxytri(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), 1-[(1-(cyano-2-ethoxy- 2-oxoethylideneaminooxy) dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate (COMII), N-[(1 H-benzo
  • T3P propanephosponic acid anhydr
  • the molar ratio of the coupling agent to compound of formula II, preferably wherein Ri of compound of formula II is methyl, may be of from 4:1 to 1 :1 , preferably of from 3:1 to 1 :1 , more preferably of from 2:1 to 1 :1 , even more preferably of from 1.75:1 to 1.25:1 as the cost of the process is reduced.
  • the base used in step a) may be an inorganic or an organic base.
  • Suitable inorganic bases include, but are not limited to metal carbonates, such as sodium carbonate, cesium carbonate and potassium bicarbonate; metal phosphates, such as sodium orthophosphate, cesium orthophosphate and potassium orthophosphate, metal acetates, such as sodium acetate and potassium acetate and mixtures thereof.
  • Suitable organic bases included ammonia derivatives, such as diethylamine, triethylamine, /V,/V- dicyclohexylmethylamine, /V,/V-dicyclohexylamine, and /V,/V-diisopropylethylamine (DI PEA), and heterocyclic bases such as pyridine, diazabicyclononene (DBN), and diazabicycloundecene (DBU), and mixtures thereof.
  • the base used in step a) is an organic base selected from triethylamine and diisopropylethylamine (DI PEA).
  • the molar ratio of the base to compound of formula II, preferably wherein Ri of compound of formula II is methyl, may be of from 4:1 to 1 :1 , preferably of from 3:1 to 1 :1 , more preferably of from 2:1 to 1 :1 as the number of impurities is reduced.
  • the solvent used in step a) may be an organic solvent selected from hydrocarbon solvents (e.g. n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.) which also includes aromatic hydrocarbon solvents (e.g., benzene, toluene, o-xylene, m-xylene, or p-xylene), ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, methyl isopropyl ketone, cyclohexanone, cyclopentanone, 2-pentanone etc
  • the organic solvent may be formed by the combination of two or more organic solvents.
  • the organic solvent is selected from 1 ,4-dioxane, N,N- dimethylformamide (DMF), tetra hydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, methyl ethyl ketone, and methyl isobutyl ketone, and mixtures thereof.
  • the organic solvent is 1 ,4- dioxane, methyltetrahydrofuran, toluene, acetonitrile or ethanol, or mixtures thereof.
  • the solvent used in step a) is ethyl acetate, butyl acetate, isopropyl acetate, tetra hydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, or mixtures thereof.
  • Suitable temperature used in step a) may be of from 20°C to 100°C, preferably of from 25°C to 85°C, more preferably the temperature of step a) is of from 35°C to 75°C, and even more preferably the temperature of step a) is of from 35°C to 65°C as the yield is increased.
  • the molar ratio of compound III to compound of formula II used in step a), preferably wherein Ri of compound of formula II is methyl, may be of from 3:1 to 1 :1 , preferably of from 2:1 to 1 :1 as the cost of the process is reduced.
  • the compound II used in step a) of the first aspect preferably wherein Ri is methyl (2- amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine) may be prepared according to the method described in WO03/084949 A1 (see Preparations 2).
  • the compound II used in step a) may be obtained by a method comprising the steps of: i. reacting the compound of formula V
  • R2 and R3 are the same or different and are each selected from C1-C3 alkyl, C1- C3 alkoxy, or wherein R2 and R3 form, together with the nitrogen to which they are attached, a 5 to 6-membered heterocycle optionally comprising one or more heteroatoms, preferably the heteroatom is an oxygen atom, preferably Ri is methyl and R2 and R3, together with the nitrogen to which they are attached, combine to form azetidinyl, pyrrolidinyl, piperidinyl, or morpholine, more preferably Ri is methyl and R2 and R3 are the same and are methyl, ethyl or wherein R2 and R3, together with the nitrogen to which they are attached, combine to form pyrrolidinyl, with compound of formula VI
  • Ra, Rb and Rc may be the same or different and may be each an optionally substituted straight or branched Ci-Cs alkyl and may be selected from the group of methyl (Me), ethyl (Et), propyl (Pr), i-propyl ('Pr), n-butyl (nBu), s-butyl (sBu), t-butyl (tBu), n-hexyl (nHex) and mixtures thereof.
  • the reagent of step i) is nBusMgLi, nBu2'PrMgLi, sBu2'PrMgLi and nHex2'PrMgLi, more preferably the reagent used in step i) is 'PrnHex2MgLi as the process is more suitable for industrial application.
  • the reagent RaRbRcMgLi of step i) as defined above may be prepared according to the methods described in Tetrahedron Letters, 1996, Vol 37, pages 2537-2540 and in W001/57046 A1 .
  • the solvent of step i) may be selected from hydrocarbon solvents (e.g. n-pentane, n- hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.), aromatic hydrocarbon solvents (e.g., benzene, toluene, o-xylene, m-xylene, and p-xylene), ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, methyl isopropyl ketone, cyclohexanone, cyclopentanone, 2-pentanone etc.), ether or
  • the solvent of step i) is hexane, tetra hydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, toluene or mixtures thereof as the reaction time is reduced.
  • Suitable temperature of step i) may be of from 20°C to -20°C, preferably of from 25°C to -20°C, more preferably of from 0°C to -10°C as the cost of the process is reduced.
  • step ii) may be carried out and the compound IV may be converted into a pharmaceutically acceptable acid addition salt, preferably into the hydrobromic acid addition salt, by treating compound of formula IV with an aqueous solution of HBr in a suitable solvent such as isopropanol, as the number of impurities is reduced.
  • the amine source used in step iii) may be ammonia or benzophenone imine in the presence of a Pd catalyst.
  • the compound IV wherein X2 is Cl, Br, I, OMs, OTs or ONs is reacted with benzophenoneimine in the presence of a Pd catalyst, such as Pd2(dba)s) or Pd(OAc)2, and a ligand, such as 2,2’-bis(diphenylphosphino)-1 ,1’binaphthyl (BINAP), and a base, such as sodium f-butoxide, in a suitable solvent, such as toluene, at reflux, to substitute the X2 group with the benzophenoneimino group.
  • a Pd catalyst such as Pd2(dba)s) or Pd(OAc)2
  • a ligand such as 2,2’-bis(diphenylphosphino)-1 ,1’binaphthyl (BINAP)
  • BINAP 2,2’-bis(diphenylphosphino)-1 ,1’binaph
  • the compound IV wherein X2 is Br is reacted with benzophenoneimine in the presence of Pd(OAc)2, Bl NAP and sodium f-butoxide in a suitable solvent, such as toluene, at reflux, to substitute the X2 group with the benzophenoneimino group.
  • a suitable solvent such as toluene
  • the obtained intermediate wherein X2 is the benzophenoneimino group is reacted with an acid such as hydrochloric acid in a suitable solvent to give the corresponding compound II intermediate.
  • the compound of formula II may be isolated and purified by standard purification techniques. In an embodiment, the compound of formula II may be isolated in the form of a pharmaceutically acceptable acid addition salt thereof.
  • the compound II preferably wherein R1 is methyl, which is a key intermediate for the preparation of compound I may be obtained according to the process of the second aspect of the invention in an efficient and reproducible manner.
  • the reagent RaRbRcMgLi of step i) wherein Ra, Rb and Rc are the same or different and are each an optionally substituted straight or branched Ci-Cs alkyl may be selected from the group of methyl (Me), ethyl (Et), propyl (Pr), i-propyl ('Pr), n-butyl (nBu), s-butyl (sBu), t-butyl (tBu), n- hexyl (nHex) and mixtures thereof.
  • the reagent of step i) is nBusMgLi, nBu2'PrMgLi, sBu2'PrMgLi and nHex2'PrMgLi, more preferably the reagent used in step i) is nHex2'PrMgLi as the process is more suitable for industrial application.
  • the reagent RaRbRcMgLi of step i) as defined above may be prepared according to methods described in Tetrahedron Letters, 1996, Vol 37, pages 2537-2540 and in W001/57046 A1 .
  • the solvent of step i) may be selected from hydrocarbon solvents (e.g. n-pentane, n- hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.), aromatic hydrocarbon solvents (e.g., benzene, toluene, o-xylene, m-xylene, and p-xylene), ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, methyl isopropyl ketone, cyclohexanone, cyclopentanone, 2-pentanone etc.), ether or
  • step i) is diethyl ether, dipropyl ether, diphenyl ether, tetra hydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, etc.), nitrile solvents, /V,/V-dimethylformamide, and mixtures thereof.
  • the solvent of step i) is hexane, tetra hydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, toluene or mixtures thereof as the reaction time is reduced.
  • Suitable temperature of step i) may be of from 20°C to -20°C, preferably of from 25°C to -20°C, more preferably of from 0°C to -10°C as the cost of the process is reduced.
  • the compound IV may be converted into a pharmaceutically acceptable acid addition salt, preferably into the hydrobromic acid addition salt, by treating compound of formula IV with an aqueous solution of HBr in a suitable solvent such as isopropanol, as the number of impurities is reduced.
  • the amine source used in step iii) may be ammonia or benzophenoneimine in the presence of a Pd catalyst.
  • the compound IV wherein X2 is Cl, Br, I, OMs, OTs or ONs is reacted with benzophenoneimine in the presence of a Pd catalyst, such as Pd2(dba)s) or Pd(OAc)2, and a ligand, such as 2,2’-bis(diphenylphosphino)-1 ,1’binaphthyl (BINAP), and a base, such as sodium f-butoxide, in a suitable solvent, such as toluene, at reflux, to substitute the X2 group with the benzophenoneimino group.
  • a Pd catalyst such as Pd2(dba)s) or Pd(OAc)2
  • a ligand such as 2,2’-bis(diphenylphosphino)-1 ,1’binaphthyl (BINAP)
  • BINAP 2,2’-bis(diphenylphosphino)-1 ,1’binaph
  • the compound IV wherein X2 is Br is reacted with benzophenoneimine in the presence of Pd(OAc)2, Bl NAP and sodium f-butoxide in a suitable solvent, such as toluene, at reflux, to substitute the X2 group with the benzophenoneimino group.
  • a suitable solvent such as toluene
  • the obtained intermediate wherein X2 is the benzophenoneimino group is reacted with an acid such as hydrochloric acid in a suitable solvent to give the corresponding compound II intermediate.
  • the compound of formula II may be isolated and purified by standard purification techniques. In an embodiment, the compound of formula II may be isolated in the form of a pharmaceutically acceptable acid addition salt thereof.
  • the compounds of formula II, wherein R1 is methyl, obtained by the process of the present invention may be in crystalline form either as free solvation compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention.
  • Methods of solvation are generally known within the art.
  • compound of formula I may be converted into a pharmaceutically acceptable acid addition salt, including any solvate or hydrate thereof, in step b) of the first aspect by reacting compound of formula (I) with an equimolar amount or excess of an acid, i.e. an inorganic acid or an organic acid.
  • an acid i.e. an inorganic acid or an organic acid.
  • hemi-salts can be formed by reacting compound of formula (I) with the acid in a 2:1.
  • Suitable inorganic acids may be hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid.
  • Suitable organic acids include, formic acid, acetic acid, fumaric acid, maleic acid, oxalic acid, succinic acid, citric acid, benzoic acid and L-tartaric acid.
  • compound I obtained according to step a), preferably wherein Ri is methyl, is not isolated before it is further converted into a pharmaceutically acceptable acid addition salt, as defined in step b) above.
  • the compounds of formula I, wherein Ri is methyl, obtained by the processes of the present invention may be in crystalline form either as free solvation compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention.
  • Methods of solvation are generally known within the art.
  • the process of the first aspect further comprises a purification process of compound of formula I, wherein Ri is methyl, the purification process comprising the steps of: a. reacting compound of formula I wherein Ri is methyl, with an acid selected from the group selected from hydrochloric, hydrobromic, sulfuric, fumaric, oxalic, L-tartaric, formic, and acetic acid, in a suitable solvent of mixtures of solvents, to provide the corresponding hydrochloric, hydrobromic, sulfuric, fumaric, oxalic, L-tartaric, formic, and acetic acid addition salt respectively, b.
  • step a) isolating the corresponding hydrochloric, hydrobromic, sulfuric, fumaric, oxalic, L-tartaric, formic, and acetic acid addition salt obtained in step a), c. optionally, purifying the acid addition salt obtained in step b) and d. optionally, converting the acid addition salt obtained either in step a), b) or c), into purified compound I, wherein Ri is methyl, or a pharmaceutically acceptable acid addition salt, preferably the hemisuccinate salt.
  • Suitable solvent used in step a. may be water or an organic solvent selected from alcohols solvents (e.g., methanol, ethanol, isopropanol, 1 -propanol, 2-methyl-1 - propanol, 1 -butanol, 2-butanol, 1 -pentanol, 3-methyl-1 -butanol, tert-butanol, 1 -octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m- cresol, etc.), ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, methyl isopropyl ketone, cyclohexanone, cycl
  • diethyl ether dipropyl ether, diphenyl ether, tetra hydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, etc.
  • nitrile solvents such as acetonitrile , nitrobenzene, /V,/V-dimethylformamide (DMF), /V,/V-dimethylacetamide, dimethyl sulfoxide (DMSO), /V-methyl-2-pyrrolidone and mixtures thereof.
  • the corresponding acid addition salt of compound of formula I, wherein Ri is methyl, of step b) may be isolated in crystalline solid form.
  • the process of the first aspect further comprises a purification process of compound of formula I, wherein Ri is methyl, the purification process comprising the steps of: a. reacting compound of formula I, wherein Ri is methyl, with an acid selected from the group selected from hydrochloric or hydrobromic acid, in a suitable solvent of mixtures of solvents, to provide the corresponding hydrochloric, or hydrobromic acid addition salt respectively, b. isolating the corresponding hydrochloric or hydrobromic acid addition salt obtained in step a), c. optionally, purifying the acid addition salt obtained in step b) and d. optionally, converting the acid addition salt obtained either in step a), b) or c), into purified compound I, wherein R1 is methyl, or a pharmaceutically acceptable acid addition salt, preferably the hemisuccinate salt.
  • Form B1 can be obtained from various solvents, including, but not limited to, solvent systems comprising acetone, isopropanol and ethyl acetate, and mixtures thereof.
  • Form B1 can be obtained using a fast-cooling crystallization process.
  • Form B1 is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 12.7, 17.5, 18.5,
  • Form B1 is characterized by an XRPD pattern which matches the pattern exhibited in Table 1 or FIG. 1. In certain embodiments, Form B1 is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 peaks matching peaks in the representative Form B1 pattern provided herein.
  • the hydrobromic acid addition salt Form B1 of Lasmiditan may be characterized by thermal analysis.
  • a representative DSC plot for Form B1 is shown in FIG. 2.
  • Form B1 is characterized by a DSC plot comprising an endothermic event with an onset temperature of about 278°C.
  • a representative TGA plot for Form B1 is also shown in FIG. 2.
  • Form B1 is characterized by a TGA plot comprising a mass loss of less than about 1 %, e.g., about 0.05%, of the total mass of the sample upon heating from about 25°C to about 200°C.
  • Form B1 does not contain substantial amounts of either water or other solvent in the crystal lattice.
  • Form B1 is unsolvated.
  • Form B1 is anhydrous.
  • the hydrobromic acid addition salt Form B1 of Lasmiditan Form B1 may be characterized by its stability profile.
  • Form B1 material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon compression.
  • Form SF1 can be obtained from various solvents, including, but not limited to, solvent systems comprising acetone, isopropanol and ethyl acetate, and mixtures thereof.
  • Form SF1 can be obtained using a fast-cooling crystallization process.
  • Form SF1 is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 10.9, 11.6, 13.5, 16.7, 20.9, 22.5, 22.7, 23.2, 23.5, 26.1 degrees 2Theta.
  • Form SF1 is characterized by an XRPD pattern which matches the pattern exhibited in Table 2 or FIG. 3.
  • Form SF1 is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 peaks matching peaks in the representative Form SF1 pattern provided herein. Table 2. List of XRPD peaks of the Lasmiditan sulfuric acid addition salt form SF1.
  • the sulfuric acid addition salt Form SF1 of Lasmiditan may be characterized by thermal analysis.
  • a representative DSC plot for Form SF1 is shown in FIG. 4.
  • Form SF1 is characterized by a DSC plot comprising an endothermic event with an onset temperature of about 204°C.
  • a representative TGA plot for Form SF1 is also shown in FIG. 4.
  • Form SF1 is characterized by a TGA plot comprising a mass loss of less than about 1 %, e.g., about 0.05%, of the total mass of the sample upon heating from about 25°C to about 200°C.
  • Form SF1 does not contain substantial amounts of either water or other solvent in the crystal lattice.
  • Form SF1 is unsolvated.
  • Form SF1 is anhydrous.
  • the sulfuric acid addition salt Form SF1 of Lasmiditan may be characterized by its stability profile.
  • Form SF1 material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon compression.
  • Form SF2 can be obtained from various solvents, including, but not limited to, solvent systems comprising an alcohol solvent such as isopropanol.
  • Form SF2 can be obtained using a fast-cooling crystallization process.
  • Form SF2 is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 8.2, 10.8, 12.1 , 16.1 , 17.2, 18.0, 19.6, 21.6, 23.5, 25.2, degrees 2Theta.
  • Form SF3 can be obtained from various solvents, including, but not limited to, solvent systems comprising a ketone solvent such as ethyl acetate.
  • Form SF3 can be obtained using a fast-cooling crystallization process.
  • Form SF3 is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 12.1 , 14.2, 16.1 , 16.6, 22.6, 23.3, 24.4, 24.8, 25.4, 27.9 degrees 2Theta.
  • Form FM1 can be obtained from various solvents, including, but not limited to, solvent systems comprising acetone, isopropanol and ethyl acetate, and mixtures thereof.
  • Form FM1 can be obtained using a fast-cooling crystallization process.
  • Form FM1 may be characterized by X-ray powder diffraction analysis. A representative
  • Form FM1 is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 14.1 , 15.1 , 15.3, 16.1 , 16.4, 16.9, 19.4, 22.2, 23.3, 23.6 degrees 2Theta.
  • Form FM1 is characterized by an XRPD pattern which matches the pattern exhibited in Table 3 or FIG. 6.
  • Form FM1 is characterized by an XRPD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 peaks matching peaks in the representative Form FM1 pattern provided herein.
  • the fumaric acid addition salt Form FM1 of Lasmiditan may be characterized by thermal analysis.
  • a representative DSC plot for Form FM1 is shown in FIG. 7.
  • Form FM1 is characterized by a DSC plot comprising an endothermic event with an onset temperature of about 255°C.
  • a representative TGA plot for Form FM1 is also shown in FIG. 7.
  • Form FM1 is characterized by a TGA plot comprising a mass loss of less than about 1 %, e.g., about 0.05%, of the total mass of the sample upon heating from about 25°C to about 200°C.
  • Form FM1 does not contain substantial amounts of either water or other solvent in the crystal lattice.
  • Form FM1 is unsolvated.
  • Form FM1 is anhydrous.
  • the fumaric acid addition salt Form FM1 of Lasmiditan may be characterized by its stability profile.
  • Form FM1 material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon compression.
  • Form 0X1 can be obtained from various solvents, including, but not limited to, solvent systems comprising ketone solvents such as ethyl acetate, and mixtures thereof.
  • Form 0X1 can be obtained using a slurrying process.
  • Form 0X1 is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 12.8, 14.8, 15.3, 18.0, 18.5, 18.8, 20.6, 22.4, 22.8, 24.6 degrees 2Theta.
  • Form 0X1 is characterized by an XRPD pattern which matches the pattern exhibited in Table 4 or FIG. 8.
  • Form 0X1 is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 peaks matching peaks in the representative Form 0X1 pattern provided herein.
  • the oxalic acid addition salt Form 0X1 of Lasmiditan may be characterized by thermal analysis.
  • a representative DSC plot for Form 0X1 is shown in FIG. 9.
  • Form 0X1 is characterized by a DSC plot comprising an endothermic event with an onset temperature of about 178°C.
  • a representative TGA plot for Form 0X1 is also shown in FIG. 9.
  • Form 0X1 is characterized by a TGA plot comprising a mass loss of less than about 1 %, e.g., about 0.05%, of the total mass of the sample upon heating from about 25°C to about 150°C. In certain embodiments, Form 0X1 does not contain substantial amounts of either water or other solvent in the crystal lattice. In certain embodiments, Form 0X1 is unsolvated. In certain embodiments, Form 0X1 is anhydrous.
  • the oxalic acid addition salt Form 0X1 of Lasmiditan may be characterized by its stability profile.
  • Form 0X1 material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon compression.
  • Form 0X2 can be obtained from various solvents, including, but not limited to, solvent systems comprising acetone, isopropanol and ethyl acetate, and mixtures thereof.
  • Form 0X2 can be obtained using a fast-cooling crystallization process.
  • Form 0X2 is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 10.7, 12.9, 15.6, 18.9, 20.6, 21.3, 22.2, 27.8, 29.2, 29.8 degrees 2Theta.
  • Form 0X2 is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 peaks matching peaks in the representative Form 0X2 pattern provided herein.
  • the oxalic acid addition salt Form 0X2 of Lasmiditan may be characterized by thermal analysis.
  • Form 0X2 is characterized by a DSC plot comprising an endothermic event with an onset temperature of about 155°C.
  • Form 0X2 is characterized by a TGA plot comprising a mass loss of less than about 4%, e.g., about 3.6%, of the total mass of the sample upon heating from about 25°C to about 150°C.
  • Form 0X2 contains substantial amounts of either water or other solvent in the crystal lattice.
  • Form 0X2 is a hydrate.
  • Form 0X3 can be obtained from various solvents, including, but not limited to, solvent systems comprising an alcohol such as isopropanol.
  • Form 0X3 can be obtained using an evaporation process.
  • Form 0X3 is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 11.7, 12.5, 14.9, 15.4, 17.7, 18.7, 18.9, 20.7, 25.3, 29.0 degrees 2Theta.
  • Form 0X4 can be obtained from various solvents, including, but not limited to, solvent systems comprising a ketone solvent such as acetone.
  • Form 0X4 can be obtained using an evaporation process.
  • Form 0X4 is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 10.2, 13.0, 14.9, 15.3, 18.2, 18.9, 20.3, 21.0, 21.5, 22.6 degrees 2Theta.
  • Form T1 can be obtained from various solvents, including, but not limited to, solvent systems comprising an alcohol such as isopropanol.
  • Form T1 can be obtained using a fast-cooling crystallization process.
  • Form T1 is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 12.5, 13.1 , 16.4, 17.0, 17.8, 18.7, 20.7,
  • Form T1 is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 peaks matching peaks in the representative Form T1 pattern provided herein.
  • the L-tartaric acid addition salt Form T1 of Lasmiditan may be characterized by thermal analysis.
  • a representative DSC plot for Form T1 is shown in FIG. 12.
  • Form T1 is characterized by a DSC plot comprising an endothermic event with an onset temperature of about 158°C.
  • a representative TGA plot for Form T1 is also shown in FIG. 12.
  • Form T1 is characterized by a TGA plot comprising a mass loss of less than about 1 %, e.g., about 0.05%, of the total mass of the sample upon heating from about 25°C to about 170°C.
  • Form T 1 does not contain substantial amounts of either water or other solvent in the crystal lattice.
  • Form T1 is unsolvated.
  • Form T1 is anhydrous.
  • Form T2 can be obtained from various solvents, including, but not limited to, solvent systems comprising a ketone solvent such as acetone.
  • Form T2 can be obtained using a slurrying process.
  • the L-tartaric acid addition salt Form T2 of Lasmiditan may be characterized by thermal analysis.
  • Form T2 is characterized by a DSC plot comprising a broad endothermic event with an onset temperature of about 59°C.
  • Form T2 is characterized by a TGA plot comprising a mass loss of less than about 2%, e.g., about 1.5%, of the total mass of the sample upon heating from about 60°C to about 120°C.
  • Form T2 contains substantial amounts of either water or other solvent in the crystal lattice.
  • Form T2 is a hydrate.
  • Form T3 can be obtained from various solvents, including, but not limited to, solvent systems comprising ester solvents such as ethyl acetate, and mixtures thereof.
  • Form T3 can be obtained using a slurrying process.
  • Form T3 is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 10.0, 14.9, 15.3, 17.5, 18.9, 20.1 , 22.2, 24.3, 26.4, 27.0 degrees 2Theta.
  • Form T3 is characterized by an XRPD pattern which matches the pattern exhibited in Table 5 or FIG. 13.
  • Form T3 is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 peaks matching peaks in the representative Form T3 pattern provided herein.
  • the L-tartaric acid addition salt Form T3 of Lasmiditan may be characterized by thermal analysis.
  • a representative DSC plot for Form T3 is shown in FIG. 14.
  • Form T3 is characterized by a DSC plot comprising an endothermic event with an onset temperature of about 194°C.
  • a representative TGA plot for Form T3 is also shown in FIG. 14.
  • Form FM1 is characterized by a TGA plot comprising a mass loss of less than about 2%, e.g., about 1.2%, of the total mass of the sample upon heating from about 25°C to about 100°C.
  • Form T3 contains substantial amounts of either water or other solvent in the crystal lattice.
  • Form T3 is a hydrate.
  • the L-tartaric acid addition salt Form T3 of Lasmiditan may be characterized by its stability profile.
  • Form T3 material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon compression.
  • Form FR1 can be obtained from various solvents, including, but not limited to, solvent systems comprising ester solvents such as ethyl acetate, and mixtures thereof.
  • Form FR1 can be obtained using a slurrying process.
  • Form FR1 is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 14.8, 16.4, 16.7, 22.8, 23.3, 23.7, 25.2, 26.1 , 28.0, 28.5 degrees 2Theta.
  • Form FR1 is characterized by an XRPD pattern which matches the pattern exhibited in Table 6 or FIG. 15.
  • Form FR1 is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 peaks matching peaks in the representative Form FR1 pattern provided herein.
  • the formic acid addition salt Form FR1 of Lasmiditan may be characterized by thermal analysis.
  • a representative DSC plot for Form FR1 is shown in FIG. 16.
  • Form FR1 is characterized by a DSC plot comprising a first endothermic event with an onset temperature of about 96°C and a second first endothermic event with an onset temperature of about 168°C.
  • a representative TGA plot for Form FR1 is also shown in FIG. 16.
  • Form FR1 is characterized by a TGA plot comprising a mass loss of less than about 5%, e.g., about 4.6%, of the total mass of the sample upon heating from about 80°C to about 150°C.
  • Form FR1 contains substantial amounts of either water or other solvent in the crystal lattice.
  • Form FR1 is a hydrate.
  • the formic acid addition salt Form FR1 of Lasmiditan may be characterized by its stability profile.
  • Form FR1 material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon compression.
  • Form FR2 can be obtained from various solvents, including, but not limited to, solvent systems comprising ketone solvents such as ethyl acetate, an alcohol such as isopropanol, and mixtures thereof.
  • Form FR2 can be obtained using a fast-cooling crystallization process.
  • Form FR2 is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 15.8, 16.1 , 16.3, 16.9, 17.7, 19.8, 21.1 , 24.9, 28.3, 29.9 degrees 2Theta.
  • Form FR2 is characterized by an XRPD pattern which matches the pattern exhibited in Table 7 or FIG. 17.
  • Form FR2 is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 peaks matching peaks in the representative Form FR2 pattern provided herein. Table 7. List of XRPD peaks of the Lasmiditan formic acid addition salt form FR2.
  • the formic acid addition salt Form FR2 of Lasmiditan may be characterized by thermal analysis.
  • a representative DSC plot for Form FR2 is shown in FIG. 18.
  • Form FR2 is characterized by a DSC plot comprising an endothermic event with an onset temperature of about 172-173°C.
  • a representative TGA plot for Form FR2 is also shown in FIG. 18.
  • Form FR1 is characterized by a TGA plot comprising a mass loss of less than about 1%, e.g., about 0.05%, of the total mass of the sample upon heating from about 40°C to about 130°C.
  • Form FR2 does not contain substantial amounts of either water or other solvent in the crystal lattice.
  • Form FR2 is anhydrous.
  • Form A1 is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 10.4, 13.7, 16.2, 18.7, 20.9, 22.8, 23.2, 24.1 , 32.2, 34.4 degrees 2Theta.
  • Form A1 is characterized by an XRPD pattern which matches the pattern exhibited in Table 8 or FIG. 19.
  • Form A1 is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 peaks matching peaks in the representative Form A1 pattern provided herein.
  • the acetic acid addition salt Form A1 of Lasmiditan may be characterized by thermal analysis.
  • a representative DSC plot for Form A1 is shown in FIG. 20.
  • Form A1 is characterized by a DSC plot comprising an endothermic event with an onset temperature of about 101-102°C.
  • a representative TGA plot for Form A1 is also shown in FIG. 20.
  • Form A1 is characterized by a TGA plot comprising a mass loss of less than about 1%, e.g., about 0.05%, of the total mass of the sample upon heating from about 40°C to about 80°C.
  • Form A1 does not contain substantial amounts of either water or other solvent in the crystal lattice.
  • Form A1 is anhydrous.
  • the compounds of the present invention were characterized by common analytical techniques such as 1 H-NMR, X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Thermogravimety (TGA) and High Performance Liquid Chromatography (HPLC) using the following methods: Proton Nuclear Magnetic Resonance ( 1 H-NMR) analyses were recorded in a deuterated solvent in a Bruker 300 Fourier-Transform (FT) NMR spectrometer and chemical shifts are given in part per million (ppm) downfield from the solvent residual peak as internal standard. The coupling constants are given in Hz. Spectra were acquired dissolving 5- 10 mg of sample in 0.7 mL of deuterated solvent.
  • FT Fourier-Transform
  • the system is equipped with a VANTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions auto changer sample stage, fixed divergence slits and radial soller.
  • the sample was measured in a 30-minute scans with a step size of 0.05° 20 in a range from 4° to 40° in 20.
  • Thermogravimetric analyses were recorded in a Mettler Toledo SDTA851e thermobalance. Experimental conditions: 40 pL aluminum crucibles; atmosphere of dry nitrogen at 80 mL/min flow rate; heating rate of 10°C/min between 30 and 300°C. Data collection and evaluation was done with software STARe.
  • HPLC High Performance Liquid Chromatography
  • 1-methylpiperidine-4-carboxylic acid hydrochloride was charged in a reactor vessel, and isopropyl alcohol (4 L) and H2O (0.1 L) were charged. The suspension was heated to a temperature of 60-62°C and kept at said temperature for 1 hour. The suspension was cooled down to 20-25°C and kept for 1 hour. The solid was isolated by filtration and washed with isopropyl alcohol. The product, 1-methylpiperidine-4-carboxylic acid hydrochloride was dried under vacuum (1.2 kg; Yield: 92%).
  • reaction mixture was allowed to reach 20- 25°C.
  • a solution of NaCI in water was charged and the resulting mixture maintained at 20-25°C for 30 min.
  • the mixture was taken to a pH 12-13 by addition of an aqueous solution of NaOH 20% w/w (1 .8 L). Phases were separated and product was reextracted from aqueous phase with Toluene.
  • the solvent was distilled under vacuum to obtain compound Vb as an oil (1.0 kg; 91 % yield).
  • Aqueous phase was basified with aqueous NaOH 20% reaching pH 9-9.5 and extracted with isopropyl acetate (2x30 ml). The organic layers were combined, and solvent was evaporated under reduced pressure to give an oily residue (compound IVa). To this residue, isopropyl alcohol (50 ml) was charged followed by an aqueous solution of HBr 48% (6.5ml) allowing product to precipitate. The obtained suspension was cooled down to 0°C, kept at 0°C for 2 hours, filtered and washed with precooled isopropyl alcohol. 6- bromopyridin-2-yl)(1 -methylpiperidin-4-yl)methanone hydrobromide (compound IVa- HBr) was obtained after drying (Yield: 73%; HPLC purity: 97.4%).
  • BINAP 470 mg; 755 pmol
  • Pd(OAc)2 67.8 mg
  • toluene 30 ml
  • BINAP 470 mg; 755 pmol
  • Pd(OAc)2 67.8 mg
  • toluene 30 ml
  • the mixture was degassed (vacuum/nitrogen cycle, repeated 3 times).
  • the mixture was heated to a temperature of 45°C and kept at said temperature for 30 min.
  • Benzophenoneimine (6.57 g; 36.3 mmol) was charged at 45°C, and the mixture was degassed (vacuum/nitrogen cycle, repeated 3 times).
  • the resulting suspension was kept at 45°C for 30 min.
  • 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide obtained above was purified by preparing a solution in isopropyl alcohol (15 ml) and adding aqueous HCI 35% (1.3 ml). The suspension was cooled down to 0°C and kept for 2 hours, filtered off and washed with precooled isopropyl alcohol. 2,4,6-trifluoro-N-(6-(1- methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hydrochloride (Lasmiditan- HCI) was obtained.
  • Example 7 General method for the preparation of acid addition salts of Lasmiditan (base/acid 1 :1)
  • Lasmiditan (20 mg, 0.053 mmol) was dissolved in methanol (0.5 mL), and the corresponding acid was added (see table 9). The obtained mixture was stirred for 30 minutes. Afterwards, solvent was evaporated to dryness in vacuum, and the obtained residue was tried to be dissolved in the corresponding solvent at reflux or a maximum of 75°C, by addition of small portions (0.2 to 0.5 mL). If solution was not produced, the suspensions were stirred for 30 minutes at high temperature, followed by separation of mother liquors. Obtained solutions were slowly cooled to room temperature, and, if crystallization was not produced, cooled to lower temperatures, or evaporated (see table 10). Table 9.
  • Example 8 General method for the preparation of acid addition salts of Lasmiditan (base/acid 2:1)
  • Lasmiditan (30 mg, 0.0795 mmol) was dissolved in methanol (0.5 mL), and the corresponding acid was added (see table 11). The obtained mixture was stirred for 30 minutes. Afterwards, solvent was evaporated to dryness in vacuum, and the obtained residue was tried to be dissolved in the corresponding solvent (see table 4) at reflux or a maximum of 75°C, by addition of small portions (0.2 to 0.5 mL). If solution was not produced, the suspensions were stirred for 30 minutes at high temperature, followed by separation of mother liquors. Obtained solutions were slowly cooled to room temperature, and, if crystallization was not produced, cooled to lower temperatures, or evaporated (see table 12).
  • Lasmiditan 500 mg, 1.33 mmol was suspended in isopropanol (5mL) and hydrobromic acid (3M in water, 1 equiv., 440 pL) was added dropwise. The obtained mixture was stirred for 15 minutes and evaporated. Ethyl acetate (10 mL) was added to the residue, and the suspension was stirred at room temperature overnight. The obtained solid was filtered off and dried in vacuum, yielding 576 mg of hydrobromic acid addition salt form B1 unpurified (unknown peaks in the PXRD).
  • Lasmiditan hydrobromic acid addition salt obtained above (550 mg) was suspended in isopropanol (40 mL) at 80 °C and stirred for 30 minutes. Afterwards, solvent volume was reduced to 20 mL by rotavaporation, and the obtained solid was filtered off and dried in vacuum, yielding 490 mg of hydrobromic acid addition salt form B1.
  • Example 10 Lasmiditan sulfuric acid addition salt Form SF1
  • Lasmiditan 500 mg, 1.33 mmol
  • isopropanol 5 mL
  • sulfuric acid 3 M in water, 1 equiv., 440 pL
  • the obtained suspension was stirred for an hour at room temperature and for another hour in an ice bath, and the obtained solid was filtered off and dried in vacuum, yielding 520 mg of sulfuric acid addition salt solid form SF1.
  • Lasmiditan 500 mg, 1.33 mmol was suspended in isopropanol (4 mL) and fumaric acid (78.4 mg, 0.66 mmol, 0.5 equiv.) was added. The obtained suspension was stirred for 30 minutes at 75°C, and afterwards, at room temperature for 30 minutes. The obtained solid was filtered off and dried in vacuum, yielding 534 mg of hemifumaric acid addition salt solid form FM1.
  • Lasmiditan 250 mg, 0.66 mmol was suspended in ethyl acetate (2 mL), the obtained suspension was heated to 75°C and oxalic acid (60 mg, 0.66 mmol, 1 equiv.) was added. An oil was formed. The system was cooled to room temperature, seeded with form OX1 and stirred overnight. The obtained solid was filtered off and dried in vacuum, yielding 260 mg of a mixture of oxalate salts.
  • Lasmiditan 500 mg, 1.33 mmol was suspended in ethyl acetate (4 mL) and tartaric acid (100 mg dissolved in 0.4 mL of ethanol, 0.66 mmol, 0.5 equiv.) was added. The obtained suspension was stirred at room temperature overnight. The obtained solid was filtered off, washed with ethyl acetate, and dried in vacuum, yielding 285 mg of L-tartaric acid addition salt form T3.
  • Lasmiditan obtained in above example A was purified by preparing a solution in isopropyl alcohol (15ml) and adding aqueous HCI 35% (2.0 ml). The obtained suspension was kept at 20-25°C for 30 min. Said suspension was cooled down to 0°C and kept for 1-2 hours. The product was filtered and washed with precooled isopropyl alcohol. Lasmiditan hydrochloride was obtained (6.9 g; Yield: 60.7%; Purity HPLC: 96.5%).
  • Lasmiditan obtained in above example A was purified by preparing a solution in isopropyl alcohol (15 ml) and adding aqueous HBr 48% (3.0 ml). The obtained suspension was kept at 20-25°C for 30min. Said suspension was cooled down to 0°C and kept for 1-2 hours. The product was filtered and washed with precooled isopropyl alcohol. Lasmiditan hydrobromide was obtained (6.2 g; Yield: 49.8%; Purity HPLC: 96.9%).
  • Lasmiditan obtained in above example A was purified by preparing a solution in isopropyl alcohol (15ml) and adding aqueous H2SO4 98% (1 ,5ml). The obtained solution was kept at 20-25°C for 30min and water was charged (1 ,5ml). When precipitation occurred, the suspension was cooled down to 0°C and kept for 1-2h. The product was filtered and washed with precooled isopropyl alcohol. Lasmiditan sulphate was obtained (7.7 g; Yield: 59.6%; Purity HPLC: 91.8%).
  • Lasmiditan obtained in above example A was purified by preparing a solution in isopropyl alcohol (15ml) and adding succinic acid (1 ,6g). The obtained suspension was kept at 20- 25°C for 30min. Said suspension was cooled down to 0°C and kept for 1-2h. The product was filtered and washed with precooled isopropyl alcohol. Lasmiditan succinate was obtained (5.2 g; Yield: 43.7%; Purity HPLC: 96.1%).

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Abstract

La présente invention concerne un procédé efficace et respectueux de l'environnement approprié pour une application à l'échelle industrielle pour la préparation de pyridinoylpipéridines en tant qu'agonistes de 5-HT1F et des sels associés, en particulier le 2,4,6-trifluoro-N-[6-(l-méthylpipéridine-4-carbonyl)pyridine-2-yl]benzamide ou un sel d'addition d'acide pharmaceutiquement acceptable de celui-ci, de préférence le sel d'hémisuccinate, avec un bon rendement et une pureté élevée. La présente invention concerne également des sels d'addition d'acide cristallin de 2,4,6-trifluoro-N-[6-(l-méthylpipéridine-4-carbonyl)pyridine-2-yl]benzamide appropriés pour une purification à l'échelle industrielle.
PCT/EP2023/052805 2022-02-09 2023-02-06 Procédé de préparation de pyridinoylpipéridines agonistes de 5-ht1f et sels associés WO2023152081A1 (fr)

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Citations (5)

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WO2001057046A1 (fr) 2000-02-02 2001-08-09 Banyu Pharmaceutical Co., Ltd. Procede de conversion d'un groupe fonctionnel par reaction d'echange halogene-metal
WO2003084949A1 (fr) 2002-03-29 2003-10-16 Eli Lilly And Company Pyridinoylpiperidines utilisees comme agonistes de 5-ht1f
WO2011123654A1 (fr) 2010-04-02 2011-10-06 Colucid Pharmaceuticals, Inc. Compositions et méthodes de synthèse d'agonistes des récepteurs 5-ht1f dérivés de la pyridinoylpipéridine
CN111943930A (zh) * 2020-08-25 2020-11-17 南京三元阳普医药科技有限公司 Lasmiditan的合成工艺
WO2021007155A1 (fr) * 2019-07-09 2021-01-14 Eli Lilly And Company Procédés et intermédiaire de préparation à grande échelle d'hémisuccinate de 2,4,6-trifluoro-n-[6-(1-méthyl-pipéridine-4-carbonyl)-pyridine-2-yl]-benzamide, et préparation d'acétate de 2,4,6-trifluoro-n-[6-(1-méthyl-pipéridine-4-carbonyl)-pyridine-2-yl]-benzamide

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WO2001057046A1 (fr) 2000-02-02 2001-08-09 Banyu Pharmaceutical Co., Ltd. Procede de conversion d'un groupe fonctionnel par reaction d'echange halogene-metal
WO2003084949A1 (fr) 2002-03-29 2003-10-16 Eli Lilly And Company Pyridinoylpiperidines utilisees comme agonistes de 5-ht1f
WO2011123654A1 (fr) 2010-04-02 2011-10-06 Colucid Pharmaceuticals, Inc. Compositions et méthodes de synthèse d'agonistes des récepteurs 5-ht1f dérivés de la pyridinoylpipéridine
WO2021007155A1 (fr) * 2019-07-09 2021-01-14 Eli Lilly And Company Procédés et intermédiaire de préparation à grande échelle d'hémisuccinate de 2,4,6-trifluoro-n-[6-(1-méthyl-pipéridine-4-carbonyl)-pyridine-2-yl]-benzamide, et préparation d'acétate de 2,4,6-trifluoro-n-[6-(1-méthyl-pipéridine-4-carbonyl)-pyridine-2-yl]-benzamide
CN111943930A (zh) * 2020-08-25 2020-11-17 南京三元阳普医药科技有限公司 Lasmiditan的合成工艺

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