WO2017060287A1 - Process for the preparation of encenicline from 7-chloro-benzo[b]thiophene-2-carboxylic acid chloride and (r)-quinuclidin-3-amine in the presence of imidazole - Google Patents

Process for the preparation of encenicline from 7-chloro-benzo[b]thiophene-2-carboxylic acid chloride and (r)-quinuclidin-3-amine in the presence of imidazole Download PDF

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Publication number
WO2017060287A1
WO2017060287A1 PCT/EP2016/073773 EP2016073773W WO2017060287A1 WO 2017060287 A1 WO2017060287 A1 WO 2017060287A1 EP 2016073773 W EP2016073773 W EP 2016073773W WO 2017060287 A1 WO2017060287 A1 WO 2017060287A1
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amine group
carboxylic acid
acid chloride
tertiary amine
quinuclidin
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PCT/EP2016/073773
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French (fr)
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Gerhard Laus
Sven Nerdinger
Erwin Schreiner
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Sandoz Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2

Definitions

  • the present invention relates to processes, process steps, and intermediates useful for selective amide bond formation for compounds having both a primary amine and a tertiary amine, in particular a conformationally locked tertiary amine, for example when the nitrogen atom of the tertiary amine group is the bridgehead atom of a bicyclic ring system.
  • the new processes, process steps and intermediates are useful for selective amidation at the site of 10 the primary amine. This is particularly useful in the preparation of amides from quinuclidin-3- amine, such as for the preparation of encenicline and related compounds.
  • Encenicline is an agonist exhibiting priming behavior at the a 7 receptor by potentiating the response to the natural agonist acetylcholine (ACh) (Prickaerts et al., Neuropharmacology (2012), (62), 1099-1 1 10)).
  • encenicline might function as a neuromodulator, impacting cognition mediated in part by modulating multiple neurotransmitter systems including dopamine, acetylcholine and glutamate in the prefrontal cortex and other brain regions (Huang et al, Psychopharmacology (2014), (231 ), 4541-4551 ).
  • al nicotinic acetylcholine receptors have been demonstrated to play an important role in cognition in both animals and humans and thereby having potential therapeutic applications in cognitive impairment in schizophrenia as well as Alzheimer's disease.
  • International patent application WO 2003/055878 discloses a two-step process for the preparation of encenicline involving preparation of 7-chlorobenzo[b]thiophene-2-carboxylic acid from 2,3-dichlorobenzaldehyde (Bogdal et al, 2000) followed by amide formation with (R)- quinuclidin-3-amine dichloride. The amide coupling was achieved by using HATU in the presence of hunig base (DIEA) in DMF.
  • DIEA hunig base
  • EP2036905A1 relates to the preparation of pyridylisoxazole derivatives and in particular the preparation of 3-(4-Fluorophenyl)-4-[4-[2-[1 -(2,5-dimethylpyrrolyl)]pyridyl]]-5-
  • the present inventors have found that the Schotten-Baumann reaction for the preparation of encenicline from (R)-quinuclidin-3-amine and benzo[b]thiophene-2-carboxylic acid chloride occurs with relatively low yield and suffers from the problem that side reactions of the carboxylic acid chloride with the tertiary amine generates by-products.
  • the present inventors have then found a general solution for selectively amidating a compound comprising both a primary and a tertiary amine at the primary amine, even if the reaction of the tertiary amine group with the acid chloride would proceed quickly due to a relatively high nucleophilicity of the tertiary amine group, for example when the nitrogen atom of the tertiary amine group is the bridgehead atom of a bicyclic ring system.
  • the present invention therefore relates to a process for the preparation of an amide from a carboxylic acid chloride and an organic molecule comprising both a primary amine group and a tertiary amine group, wherein the amide bond forms selectively with the primary amine group, and wherein the carboxylic acid chloride preferably does not comprise a non-aromatic nitrogen atom,
  • the process of the present invention has the advantages that the amidation reaction proceeds selectively with the primary amine group, even with organic molecules which comprise a tertiary amine group which is conformationally locked, such as with (R)-quinuclidin-3-amine.
  • the processes of the present invention use inexpensive reagents, such as imidazole and thionylchloride.
  • genotoxic impurities for example alkylchlorides such as compound II, do not form or form only at low levels. This can be advantageous compared to the processes of WO 2003/055878.
  • the process of the present invention is particularly useful for the preparation of encenicline or a salt thereof from (R)-quinuclidin-3-amine and benzo[b]thiophene-2-carboxylic acid chloride.
  • Crystalline encenicline hydrochloride monohydrate can be obtained if, after step a), at least one mole of water per mole of (R)-quinuclidin-3-amine is present in the reaction mixture.
  • the present invention also relates to the use of imidazole for the selective acylation of a primary amine group in an organic molecule comprising both the primary amine group and a tertiary amine group in the reaction of said organic molecule comprising both the primary amine group and a tertiary amine group, with a carboxylic acid chloride, wherein the carboxylic acid chloride does not comprise a non-aromatic nitrogen atom.
  • the present invention also relates to encenicline or a salt thereof, which comprises less than 50 ppm of an alkylchloride, such as compound II, preferably less than 20 ppm of an alkylchloride, such as compound II, more preferably less than 5 ppm of an alkylchloride, such as compound II.
  • Encenicline with such a low level of alkylchlorides becomes available because of the selectivity of the acylation reaction for the primary amine and because the imidazole in the reaction masks the bridgehead nitrogen atom and thereby protects it from attack by the electrophile, thus preventing ring-opening.
  • the present invention also relates to encenicline or a salt thereof, which comprises less than 50 ppm of compound II, preferably less than 20 ppm, more preferably less than 5 ppm.
  • Encenicline with such a low level of the genotoxic impurity compound II becomes available because of the selectivity of the acylation reaction for the primary amine and because the imidazole in the reaction masks the bridgehead nitrogen atom and thereby protects it from alkylation.
  • the invention specially relates to the processes described in each section.
  • the invention likewise relates, independently, to every single step described in a process sequence within the corresponding section. Therefore, each and every single step of any process, consisting of a sequence of steps, described herein is itself a preferred embodiment of the present invention.
  • the invention also relates to those embodiments of the process, according to which a compound obtainable as an intermediate in any step of the process is used as a starting material.
  • the invention likewise relates to novel starting materials which have been specifically developed for the preparation of the compounds according to the invention, to their use and to processes for their preparation.
  • the invention also relates to intermediates which have been specifically developed for the preparation of the compounds according to the invention, to their use and to processes for their preparation.
  • C1-Cn- defines a moiety with up to and including maximally n carbon atoms, said moiety being branched (one or more times) or straight-chained and bound via a terminal or a non-terminal carbon.
  • Alkyl being a radical or part of a radical is a straight or branched (one or, if desired and possible, more times) carbon chain, and is especially C1 -C7-alkyl, such as C1-C4-alkyl, in particular branched C1 -C4-alkyl, such as isopropyl.
  • lower or “C1-C7-” defines a moiety with up to and including maximally 7, especially up to and including maximally 4, carbon atoms, said moiety being branched (one or more times) or straight-chained and bound via a terminal or a non-terminal carbon.
  • Lower or C1-C7-alkyl for example, is n-pentyl, n-hexyl or n-heptyl or preferably C1 -C4-alkyl, especially as methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec- butyl, tert-butyl, in particular methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert- butyl.
  • Halo or halogen is preferably fluoro, chloro, bromo or iodo, preferably chloro; where halo is mentioned as a substituent, where possible, one or more (e.g. up to three or one) halogen atoms may be present, e.g. in halo-C1-C7-alkyl, such as trifluoromethyl, 2,2-difluoroethyl or 2,2,2- trifluoroethyl.
  • Alkenyl being a radical or part of a radical, is a straight or branched (one or, if desired and possible, more times) carbon chain containing at least one double bond, and includes, for example, C2-C20-alkenyl (such as C3-C8alkenyl).
  • Examples include ethenyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octacyl and eicosyl, each of which containing at least one double bond.
  • Alkylene is a bivalent radical derived from alkyl and includes C1-7alkylene and especially C2- C7-alkylene.
  • Alkenylene is a bivalent radical derived from alkenyl, including in particular C2-8 alkenylene.
  • Alkinyl being a radical or part of a radical, is a straight or branched (one or, if desired and possible, more times) carbon chain containing at least one triple bond, and includes, for example, C2-C20-alkinyl (such as C3-C7-alkinyl), for example, propargyl.
  • cycloalkyi being a radical or part of a radical, includes "C3-8-cycloalkyl" and defines a non-aromatic cycloalkyi moiety with up to and including maximally 14, such as up to and including 10, for example up to and including maximally 8, in particular up to and including maximally 6 carbon atoms.
  • Said cycloalkyi moiety is for example mono- or bicyclic, in particular monocyclic, which may include one or more double and/or triple bonds.
  • Embodiments include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • the heterocyclyl group may be aromatic or non-aromatic. When the heterocyclyl group is an aromatic group, it is also referred to as heteroaryl.
  • Aryl being a radical or part of a radical is an aromatic hydrocarbon group, for example, C6-10 aryl, and is preferably a mono- or polycyclic, especially monocyclic, bicyclic or tricyclic aryl moiety with 6 to 14 carbon atoms for example 6 to 10 carbon atoms, preferably phenyl, indenyl, indanyl or naphthyl.
  • arylalkyl includes aryl-C1-C7-alkyl, wherein aryl is as defined herein and is for example benzyl.
  • carboxyl or "free acid” refers to -C02H.
  • amine relates to compounds formally derived from ammonia by replacing one, two or three hydrogen atoms by hydrocarbyl groups, and having the general structures RNH2 (primary amines), R2NH (secondary amines), R3N (tertiary amines), with R being attached to N by a C-N single bond.
  • ester group comprises any ester of a carboxyl group generally known in the art; for example groups -COOR, wherein R is selected from the group consisting of: C1 -6alkyl, such as methyl, ethyl or t-butyl, C1-6alkoxyC1-6alkyl, heterocyclyl, such as tetrahydrofuranyl, C6- 10aryloxyC1-6alkyl, such as benzyloxymethyl (BOM), silyl, such as trimethylsilyl, t- butyldimethylsilyl and t-butyldiphenylsilyl, cinnamyl, allyl, C1-6alkyl which is mono-, di- or trisubstituted by halogen, silyl, cyano or C1-6aryl, wherein the aryl ring is unsubstituted or substituted by one, two or three, residues selected from the group consisting of C1 -7alkyl, C1-
  • amide group comprises any amide of a carboxyl group generally known in the art; for example groups -CONHR.
  • R can be selected from the group consisting of: substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkylamino, such as quinuclidinyl, substituted or unsubstituted aralkylamino, substituted or unsubstituted allylamino, wherein the amino group is a tertiary amino group.
  • any of the groups which are mentioned above as being optionally substituted can be substituted, for example, by one or more selected from the group consisting of halo, nitro, C1 -C7-alkyl, halo- C1-C7-alkyl, C1 -C7-alkoxy, halo-C1-C7-alkoxy, C1-C7-alkoxy-C1 -C7-alkyl, C1 -C7-alkyl-C1- C7-alkoxy and C1 -C7-alkoxy-C1-C7-alkoxy.
  • Protecting groups may be present and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter.
  • two or more protecting groups are present in one intermediate mentioned herein, they are chosen so that, if one of the groups needs to be removed, this can be done selectively, e.g. using two or more different protecting groups that are cleavable under different conditions, e.g. one class by mild hydrolysis, the other by hydrolysis under harder conditions, one class by hydrolysis in the presence of an acid, the other by hydrolysis in the presence of a base, or one class by reductive cleavage (e.g. by catalytic hydrogenation), the other by hydrolysis, or the like.
  • two or more protecting groups that are cleavable under different conditions, e.g. one class by mild hydrolysis, the other by hydrolysis under harder conditions, one class by hydrolysis in the presence of an acid, the other by hydrolysis in the presence of a base, or one class by reductive cleavage (e.g. by catalytic hydrogenation), the other by hydrolysis, or the like.
  • Nitrogen protecting groups can be introduced/removed according to standard methods of organic chemistry known in the art, in particular reference is made to conventional nitrogen protecting group methods described in J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, T. W. Greene and P. G. M. Wuts, "Greene's Protective Groups in Organic Synthesis", Fourth Edition, Wiley, New York 2007; and in Richard C. Larock, “Comprehensive Organic Transformations: A Guide to Functional Group Preparations", Second Edition, Wiley-VCH Verlag GmbH, 2000. It is, however, preferred that nitrogen protecting groups are absent from the starting material for the process of the present invention, i.e.
  • Hydroxyl protecting groups can be introduced/removed according to known methods; standard conditions for such methods are described, for example in reference books above-mentioned for nitrogen protecting groups.
  • spontaneousification reagent is to be understood as a base which is able to hydrolyze an ester to form an alcohol and the salt of a carboxylic acid, e.g. an alkali metal hydroxide such as KOH or NaOH.
  • group which can be saponified is to be understood as an ester group -C02R wherein R is alkyl, aryl or arylalkyl, which can be hydrolyzed, for example under basic conditions (e.g. alkalimetal base such as. NaOH, LiOH or KOH) or under acidic conditions (eg. by the use of mineral acids, such as HCI, H2S04, HBr, H3P04) to provide a carboxylic acid.
  • basic conditions e.g. alkalimetal base such as. NaOH, LiOH or KOH
  • acidic conditions eg. by the use of mineral acids, such as HCI, H2S04, HBr, H3P04
  • group which can be saponified can also include a group -C02R wherein R is aryl or arylalkyl, which can be reacted by use of a hydrogenation catalyst (eg Pd/C, Pt/C, Rh/C, Pd/AI203, Pt02), in the presence of an acid (eg. acetic acid) or a base (eg. triethylamine) or under neutral conditions, to provide a carboxylic acid.
  • a hydrogenation catalyst eg Pd/C, Pt/C, Rh/C, Pd/AI203, Pt02
  • an acid eg. acetic acid
  • a base eg. triethylamine
  • leaving group include halogen (e.g. chlorine, bromine or iodine) and a hydroxy group activated through esterification, for example with an alkanesulfonate group (e.g. methanesulfonyloxy, toluenesulfonyloxy, fluorosulfonyloxy, trifluoromethanesulfonyloxy or nonabutanesulfonyloxy).
  • halogen e.g. chlorine, bromine or iodine
  • alkanesulfonate group e.g. methanesulfonyloxy, toluenesulfonyloxy, fluorosulfonyloxy, trifluoromethanesulfonyloxy or nonabutanesulfonyloxy.
  • optically active base describes, for example, chiral amines, preferably chiral tertiary amines, more preferably cinchona alkaloids, such as quinidine and quinine, most preferably modified cinchona alkaloids.
  • modified cinchona alkaloids are detailed, for example, in Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDiad, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621 -631 and references cited therein.
  • chiral refers to molecules which have the property of non-superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • one-pot means that in a series (i.e. in a succession) of reactions, for example two or more successive reactions, each reaction product is provided for the next reaction without isolation and purification.
  • the one-pot processes defined herein encompass not only a series (i.e a succession) of reactions conducted in a single reaction vessel, but also a series (i.e. a succession) of reactions conducted in a plurality of reaction vessels (e.g., by transferring the reaction mixture from one vessel to other) without isolation and purification.
  • the one-pot process is conducted in a single reaction vessel.
  • step-wise process means that in a series (i.e a succession) of reactions, each reaction product is provided for the next reaction with isolation and optionally purification.
  • work-up means the work of isolation and/or purification which is carried out once the reaction is finished.
  • room temperature or “ambient temperature” means a temperature of from 15 to 30°C, such as from 20 to 30°C, such as from 20 to 25°C.
  • inert means unreactive with any of the reactants, solvents, or other components of the reaction mixture. Such inert conditions are generally accomplished by using inert gas such as carbon dioxide, helium, nitrogen, argon, among other gases.
  • Bonds with an asterisk ( * ) denote point of binding to the rest of the molecule.
  • the compounds of the present invention can possess one or more asymmetric centers.
  • the preferred absolute configurations are as indicated herein specifically. However, any possible pure enantiomer, pure diastereoisomer, or mixtures thereof, e.g., mixtures of enantiomers, such as racemates, are encompassed by the present invention.
  • the term "> ⁇ ", " “ “ or “ “ on a C-sp3 represents a covalent bond wherein the stereochemistry of the bond is not defined.
  • mixtures are also encompassed, e.g., mixtures of enantiomers, such as racemates, are encompassed by the present invention.
  • the term " > ⁇ ⁇ " or " " on a C-sp2 represents a covalent bond, wherein the stereochemistry or the geometry of the bond is not defined.
  • mixtures are also encompassed, e.g., mixtures of double bond isomers are encompassed by the present invention.
  • the compounds of the present invention can possess one or more asymmetric centers.
  • the preferred absolute configurations are as indicated herein specifically.
  • stereomeric purity at a given percentage means that the designated stereoisomer predominates at that given percentage in a mixture of stereosiomers.
  • stereoisomer relates to isomers that possess identical constitution, but which differ in the arrangement of their atoms in space. Included within the definition of a stereoisomer are enantiomers and diasteromers.
  • resolution refers to the separation or concentration or depletion of one of the stereoisomers of a molecule.
  • tautomer refers in particular to the aldehyde tautomer of compounds of the present invention, where such compounds can exists in either an enol or aldehyde form, or mixtures thereof.
  • conformationally locked refers in particular to amines, where the substituents at the nitrogen atom prevent inversion at the nitrogen atom.
  • An example of a conformationally locked amine is quinuclidine.
  • aromatic nitrogen refers to a nitrogen which is part of a heteroaromatic ring system.
  • the compound 4-amino-pyridine contains one aromatic nitrogen - the N at position 1 - and one non-aromatic nitrogen - the nitrogen of the amino group attached to carbon 4.
  • the term "essentially free" from a particular compound, such as e.g. the genotixic impurity compound II, means that said compound is present at at most 50 ppm, such as at most 20 ppm, and more preferably at most 5 ppm, in a sample of another compound or composition.
  • selective acylation of a primary amine group means that a compound comprising both, a primary amine group and a tertiary amine group, reacts with an amidating reagent, such as an acyl chloride, in such a way, that the molar ratio [amide formed by the amidating reagent reacting only with the primary amine group] : [(amide formed by the amidating reagent reacting only with the tertiary amine) + (amide formed by the amidating reagent reacting with both the primary amine group and the tertiary amine group)] is at least 20:1 , such as at least 50:1 , for example 99:1 .
  • nucleophilic refers to a tertiary amine group having a binding constant K for the adduct with the Lewis acidic Zn" Schiff- base complex of compound I on page 8880 of Olivieri et al., literature reference below, such that logK is greater or equal to 6.0 (Olivieri et al., Journal of Organic Chemistry (201 1 ), 76, 8879-8884), when determined according to Olivieri et al. Quinuclidine is a strong Lewis base in said assay, having a logK of about 6.73.
  • tertiary amines whichin the free electron pair of nitrogen is not exposed, are weak Lewis bases in said assay, with triethylamine having a logK of about 3.45.
  • the strength as a Lewis base in the Olivieri test system may be correlated with a tertiary amine's nucleophilicity.
  • the nucleophilicity of the tertiary amine group it is tested in the absence of the primary amine group.
  • the nucleophilicity of the tertiary amine group in quinuclidin-3-amine is determined by measuring the corresponding compound without the primary amine, i.e. by measuring quinuclidine in this example.
  • Salts are especially pharmaceutically acceptable salts or generally salts of any of the intermediates mentioned herein, where salts are not excluded for chemical reasons the skilled person will readily understand. They can be formed where salt forming groups, such as basic or acidic groups, are present that can exist in dissociated form at least partially, e.g. in a pH range from 4 to 10 in aqueous solutions, or can be isolated especially in solid, especially crystalline, form. Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds or any of the intermediates mentioned herein with a basic nitrogen atom (e.g. imino or amino), especially the pharmaceutically acceptable salts.
  • salt forming groups such as basic or acidic groups
  • Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds or any of the intermediates mentioned herein with a basic nitrogen atom (e.g. imino or amino), especially the pharmaceutically acceptable salts.
  • Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, lactic acid, fumaric acid, succinic acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, benzoic acid, methane- or ethane-sulfonic acid, ethane-1 ,2-disulfonic acid, benzene- sulfonic acid, 2-naphthalenesulfonic acid, 1 ,5-naphthalene-disulfonic acid, N-cyclohexylsulfamic acid, ⁇ -methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids
  • salts may also be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines for example triethylamine or tri(2-hydroxyethyl)amine, N- ethyl-piperidine, ⁇ , ⁇ '-dimethylpiperazine, t-butylamine, n-butylamine, phenylethylamine, dicyclohexylamine or cyclohexylamine.
  • bases e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines for example triethylamine or tri(2-hydroxyethyl)amine, N- ethyl-piperidine, ⁇ , ⁇ '-dimethylpipe
  • any of the intermediates mentioned herein may also form internal salts.
  • any reference to "com- pounds", “starting materials” and “intermediates” hereinbefore and hereinafter is to be understood as referring also to one or more salts thereof or a mixture of a corresponding free compound, intermediate or starting material and one or more salts thereof, each of which is intended to include also any solvate or salt of any one or more of these, as appropriate and expedient and if not explicitly mentioned otherwise.
  • Different crystal forms may be obtainable and then are also included.
  • FIG. 1 XRPD of (R)-7-Chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
  • the present invention relates to a process for the preparation of an amide starting from a carboxylic acid chloride and
  • an organic molecule which molecule comprises both a primary amine group and a tertiary amine group, in particular when the nitrogen atom of the tertiary amine group is the bridgehead atom of a bicyclic ring system.
  • the amide bond forms selectively between the acyl- radical of the carboxylic acid chloride and the primary amine group.
  • the carboxylic acid chloride does not comprise a non-aromatic nitrogen atom, such as a primary, secondary or tertiary amine group, an amide group or nitrogen in the context of a substituted urea group.
  • the tertiary amine group preferably does not comprise a bond between nitrogen and a nitrogen protecting group such as benzyl, trityl or benzylidene.
  • the process comprises the step of reacting the carboxylic acid chloride with the organic molecule comprising both a primary amine group and a tertiary amine group in the presence of imidazole.
  • the amidation reaction might proceed via the in situ formation of an imidazolide.
  • the organic molecule which comprises both a primary amine group and a tertiary amine group is not particularly limited as long as it contains at least a primary amine group and a tertiary amine group.
  • the nitrogen atom of the tertiary amine group is comprised in a non-aromatic heterocycle.
  • More preferred examples include bicyclic ring systems in which the two rings share at least two ring atoms and wherein one of the ring atoms is the nitrogen atom of the tertiary amine.
  • the process of the present invention is particularly useful for such compounds, where the tertiary amine group is conformationally locked. This is, for example, the case when the nitrogen atom of the tertiary amine group is the bridgehead atom of a bicyclic ring system.
  • the process of the present invention is also particularly useful for such compounds, where the tertiary amine group is nucleophilic, such as tertiary amine groups wherein the logK is greater or equal to 6.0 when tested according to Olivieri et al., Journal of Organic Chemistry (201 1 ), 76, 8879-8884, for example the logK being from 6.0 to 7.0.
  • the tertiary amine group of quinuclidine for example, has a logK of 6.73 according to said assay.
  • bicyclic ring systems are preferably of the type [2.2.2], [2.2.3], [2.2.4], [2.2.5], [2.3.3], [2.3.4], [2.3.5], [2.4.4], [2.4.5], [2.5.5], [3.3.3], [3.3.4], [3.3.5], [3.4.5] or [3.5.5], more preferably the bicyclic ring system is of type [2.2.2].
  • the nitrogen atom of the tertiary amine is the bridgehead atom of the bicyclic ring system and the primary amine group is present as a substituent of the bicyclic ring system, with the above-mentioned types being preferred.
  • An example of an organic molecule comprising both a primary amine group and a tertiary amine group is a quinuclidin-amine, such as quinuclidin-3-amine.
  • the carboxylic acid chloride should not comprise a non-aromatic nitrogen atom, such as a primary, secondary or tertiary amine group, an amide group or nitrogen in the context of a substituted urea group. This is because the carboxylic acid chloride could then have the potential for self-polymerization. It is preferred that the carboxylic acid residue is such that it allows amide bond formation in step a).
  • the carboxylic acid chloride can preferably be a heteroaryl acid chloride, an alkyl acid chloride, a cycloalkyl acid chloride, or an aryl acid chloride.
  • an alkyl acid clorides is acetylchloride, for a cycloalkyl acid chloride an example is cyclohexanecarbonylchloride.
  • the carboxylic acid chloride is an aryl-acid chloride (Ar- COCI).
  • Ar- can be a monocyclic, bicyclic or tricyclic aromatic ring system consisting of 6 to 14 atoms. The aromatic ring system can be substituted or unsubstituted.
  • Preferred aryl residues Ar- can be selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphtyl or substituted or unsubstituted indenyl.
  • the carboxylic acid chloride is a heteroaryl acid chloride.
  • the heteroaromatic ring system can be substituted or unsubstituted.
  • Preferred heteroaryl residues Ar- can be selected from substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted isochinolyl, substituted or unsubstituted chinolyl, substituted or unsubstituted benzothienyl substituted or unsubstituted benzofuryl, substituted or unsubstituted benzoxazol, substituted or unsubstituted benzothiazol.
  • the optional substituent can be, e.g., halogen, such as chloro.
  • halogen such as chloro.
  • a preferred example of a carboxylic acid chloride is a substituted or unsubstituted benzo[b]thiophene-2-carboxylic acid chloride.
  • the reactants, the carboxylic acid chloride and the organic molecule comprising both a primary amine group and a tertiary amine group, are preferably provided in approximately equimolar ratio.
  • Step a) the amide bond formation between the carboxylic acid chloride and the primary amine group, is carried out in the presence of imidazole.
  • the molar ratio of imidazole : [organic molecule comprising both a primary amine group and a tertiary amine group] is at least 3:1 , such as from 3.0 : 1.0 to 5.0 : 1.0, with a molar ratio of approx. 4 : 1 being particularly preferred, for example if the organic molecule comprising both a primary amine group and a tertiary amine group is provided as a diacid salt, such as a dihydrochloride.
  • the amide bond formation between the carboxylic acid chloride and the primary amine group can be at a molar ratio of imidazole : [organic molecule comprising both a primary amine group and a tertiary amine group] of at least 1 :1 , such as from 1 .0 : 1 .0 to 3.0 : 1.0, with a molar ratio of approx. 2 : 1 being particularly preferred.
  • the optimal molar amount of imidazole for step a) could be explained by an amount sufficient to deprotonate the primary and tertiary amine group, when the organic molecule comprising both a primary amine group and a tertiary amine group is provided as a di-acid addition salt (explaining approximately two molar equivalents), sufficient to react with the carboxylic acid chloride, resulting in in-situ formation of an imidazolide (explaining a third equivalent) and sufficient to form a hydrogen- bonded complex with the tertiary amine group, thereby protecting the nitrogen of the tertiary amine group from attack by the electrophile (explaining a fourth equivalent).
  • Such a rationale also explains the lower optimal amount of imidazole if the free base of the organic molecule comprising both a primary amine group and a tertiary amine group is used as the starting material.
  • the solvent for the amidation step a) comprises only aprotic solvents, for example that it consists of an aprotic solvent.
  • aprotic solvent is acetonitrile, THF, dioxane or DMF, and the preferred aprotic solvent is acetonitrile.
  • the organic molecule comprising both a primary amine group and a tertiary amine group, e.g. (R)-quinuclidin-3-amine or an acid addition salt, and a sufficient amount of imidazole, in an aprotic solvent are added in sequential or simultaneous manner to the carboxylic acid chloride in an aprotic solvent, preferably in the same aprotic solvent.
  • Step a) is then carried out at a suitable temperature, such as from 0°C to 90°C, for example from 10°C to 50°C e.g. at room temperature, preferably for a time sufficient to complete the amidation reaction, for example 12h to 48h.
  • a suitable temperature such as from 0°C to 90°C, for example from 10°C to 50°C e.g. at room temperature, preferably for a time sufficient to complete the amidation reaction, for example 12h to 48h.
  • the pure product can be isolated by filtration, for example as a hydrochloride salt, from the reaction mixture.
  • a sufficient amount of a second solvent suitable for solvate formation e.g. water, can be added. This can help in product crystallization, thus facilitating the filtration step and improving the purity of the obtained product.
  • the process according to the present invention proceeds with good yields.
  • the amide formed by reacting the primary amine group with the acid chloride is typically obtained in from 60% to 100% yield, such as from 70% to 95%.
  • the process of the present invention can start from the carboxylic acid itself.
  • the carboxylic acid chloride Prior to step a) can be formed from the corresponding carboxylic acid.
  • Thionyl chloride, oxalyl chloride and phosphorus oxychloride are examples of compounds that can be used to prepare the carboxylic acid chloride from the carboxylic acid.
  • step a) can be carried out in a one-pot format.
  • carboxylic acid chloride formation can be done in the same reaction vessel as to be used for the amide formation step.
  • step a) of the process of the present invention imidazole and the organic molecule comprising both a primary amine group and a tertiary amine group are preferably the only bases present in the reaction mixture.
  • the processes of the present invention can advantageously provide the product as pure crystalline material, preferentially in the form of therapeutically acceptable salts, such as in the form of its hydrochloride salt, directly from the reaction mixture by filtration without the need for further workup and/or purification processes.
  • the advantageous direct preparation of the resulting monoamidation product as an HCI salt is believed to be facilitated by a) imidazole being a relatively weak base, allowing the protonation of the tertiary amine group of the resulting monoamidation product, and b) the absence of bases stronger than imidazole (other than the educts or products) which could prevent protonation, and thus HCI salt generation, at the tertiary amine group of the resulting monoamidation product.
  • the process of the present invention is for the preparation of encenicline or a salt thereof, wherein in step a) (R)-quinuclidin-3-amine is reacted with benzo[b]thiophene-2- carboxylic acid chloride. It is preferred that after step a), at least one mole of water per mole of (R)-quinuclidin-3-amine is added to the reaction mixture.
  • This process yields crystalline encenicline hydrochloride monohydrate, in particular as a single polymorph. We have found that the obtained crystalline encenicline hydrochloride monohydrate is pure encenicline hydrochloride Form 1.
  • the process of the present invention affords encenicline hydrochloride monohydrate as a pure single polymorph, termed Form 1 according to the nomenclature of WO 201 1/14651 1 , which discloses crystalline forms of encenicline dihydrochloride.
  • the product obtained is essentially free of potential genotoxic impurities, such as alkylchlorides, which could be generated, for example from acylation of the tertiary amine and following ring cleavage as described by Shiraishi and Takayama, 1985.
  • encenicline prepared by the process of the present invention is essentially free from 7-chloro- N-((3R)-1 -(7-chlorobenzo[b]thiophene-2-carbonyl)-4-(2-chloroethyl)piperidin-3- yl)benzo[b]thiophene-2-carboxamide (compound II) existing as their cis and trans isomers and mixtures thereof.
  • the present invention also relates to the use of imidazole for the selective acylation of a primary amine group in an organic molecule comprising both the primary amine group and the tertiary amine group,
  • protecting groups may be used where appropriate or desired, even if this is not mentioned specifically, to protect functional groups that are not intended to take part in a given reaction, and they can be introduced and/or removed at appropriate or desired stages. Reactions comprising the use of protecting groups are therefore included as possible wherever reactions without specific mentioning of protection and/or deprotection are described in this specification.
  • protecting group a readily removable group that is not a constituent of the particular desired end product.
  • the protection of functional groups by such protecting groups, the protecting groups themselves, and the reactions appropriate for their introduction and removal are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J.
  • protecting groups are those that they can be removed readily (i.e. without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (e.g., by enzymatic cleavage). Different protecting groups can be selected so that they can be removed selectively at different steps while other protecting groups remain intact.
  • reaction mixtures especially in order to isolate desired compounds or intermediates, follows customary procedures and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
  • the invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
  • those starting materials are preferably used which result in compounds of formula I which are described as being preferred. Special preference is given to reaction conditions that are identical or analogous to those mentioned in the Examples.
  • the invention relates also to novel starting compounds and intermediates described herein, especially those leading to compounds mentioned as preferred herein.
  • the invention especially relates to any of the methods described hereinbefore and hereinafter that leads to the product, or a pharmaceutically acceptable salt thereof.
  • Embodiments and Examples serve to illustrate the invention without limiting the scope thereof, while they on the other hand represent preferred embodiments of the reaction steps, intermediates and/or the process of manufacture of the product in free base form or as a pharmaceutically acceptable salt thereof.
  • imidazole for the selective acylation of a primary amine group in an organic molecule comprising both the primary amine group and a tertiary amine group, in the reaction of said organic molecule comprising both the primary amine group and the tertiary amine group with a carboxylic acid chloride, wherein the carboxylic acid chloride does not comprise a non-aromatic nitrogen atom and wherein the tertiary amine group is nucleophilic.
  • bicyclic ring system is of the type [2.2.2], [2.2.3], [2.2.4], [2.2.5], [2.3.3], [2.3.4], [2.3.5], [2.4.4], [2.4.5], [2.5.5], [3.3.3], [3.3.4], [3.3.5], [3.4.5] or [3.5.5].
  • heteroaryl or aryl is a monocyclic, bicyclic or tricyclic aromatic ring system consisting of 6 to 14 atoms, wherein 1 to 4 atoms of the aromatic ring system can be S, N or O, and wherein Ar- can be substituted or unsubstituted.
  • Ar- is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphtyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted isochinolyl, substituted or unsubstituted chinolyl, substituted or unsubstituted benzothienyl substituted or unsubstituted benzofuryl, substituted or unsubstituted benzoxazol, substituted or unsubstituted benzothiazol, and substituted or unsubstituted N-alkyl- or N- aryl-indolyl.
  • carboxylic acid chloride is a substituted or unsubstituted benzo[b]thiophene-2-carboxylic acid chloride.
  • organic molecule comprising both the primary amine group and a tertiary amine group is provided as a di-acid addition salt and wherein the molar ratio of imidazole : [organic molecule comprising both the primary amine group and the tertiary amine group] is at least 3:1 .
  • organic molecule comprising both the primary amine group and a tertiary amine group is provided as a free base and wherein the molar ratio of imidazole : [organic molecule comprising both a primary amine group and a tertiary amine group] is at least 1 :1.
  • Aryl- or Heteroaryl- is a monocyclic, bicyclic or tricyclic aromatic ring system consisting of 6 to 14 atoms, wherein 1 to 4 atoms of the aromatic ring system can be S, N or O, and wherein Ar- can be substituted or unsubstituted.
  • step a) (R)-quinuclidin-3-amine is reacted with benzo[b]thiophene-2- carboxylic acid chloride.
  • step a) The process according to item 41 , further comprising, after step a), the step of b) adding at least one mole of water per mole of (R)-quinuclidin-3-amine to the reaction mixture.
  • step a) is conducted in an aprotic solvent.
  • step a) The process according to any one of items 28 to 50, wherein the temperature for step a) is 0°C to 90°C, preferably 10°C to 50°C.
  • step a) The process according to any one of items 28 to 51 , wherein prior to step a) the carboxylic acid chloride is formed from the corresponding carboxylic acid.
  • reaction mixture does not comprise an additional base besides imidazole and the organic molecule comprising both a primary amine group and a tertiary amine group.
  • NMR spectra were recorded with a Bruker Avance DPX 300 spectrometer.
  • IR spectra were obtained with a Bruker Alpha FT instrument.
  • High resolution mass spectra were measured with a Finnigan MAT 95 mass spectrometer.
  • the solid was sequentially stirred with saturated aqueous sodium bicarbonate (10 ml.) and 1 M aqueous sodium hydroxide solution (12 ml_). After addition of dichloromethane (30 ml.) the pH value was adjusted to a value of 7 by addition of hydrochloric acid and sodium bicarbonate. A precipitate insoluble in both layers was separated by filtration. After washing with small amounts of water and drying in vacuo 0.21 g (12%) of a compound was obtained as a white solid. The compound was different from encenicline.

Abstract

The present invention relates to a process for the preparation of an amide from a carboxylic acid chloride and an organic molecule comprising both a primary amine group and a tertiary amine group, wherein the nitrogen atom of the tertiary amine group is comprised in a non-aromatic heterocycle and wherein the amide bond forms selectively with the primary amine group, comprising the step of reacting the carboxylic acid chloride with an organic molecule comprising both the primary amine group and the tertiary amine group, in the presence of imidazole. This is particularly useful in the preparation of amides from quinuclidin-3-amine, such as for the preparation of encenicline ((R) -7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide) from 7-chloro-benzo[b]thiophene-2-carboxylic acid chloride and (R)- quinuclidin-3-amine in the presence of imidazole. Encenicline is a nicotinic acetylcholine receptor agonist useful as a neuromodulator for the treatment of e.g. cognitive impairment, schizophrenia and Alzheimer's disease.

Description

PROCESS FOR THE PREPARATION OF ENCENICLINE FROM 7-CHLORO-BENZO[B]THIOPHENE-2-CARBOXYLIC ACID CHLORIDE AND (R)-QUINUCLIDIN-3-AMINE IN THE PRESENCE OF IMIDAZOLE
FIELD OF THE INVENTION
5 The present invention relates to processes, process steps, and intermediates useful for selective amide bond formation for compounds having both a primary amine and a tertiary amine, in particular a conformationally locked tertiary amine, for example when the nitrogen atom of the tertiary amine group is the bridgehead atom of a bicyclic ring system. For such compounds the new processes, process steps and intermediates are useful for selective amidation at the site of 10 the primary amine. This is particularly useful in the preparation of amides from quinuclidin-3- amine, such as for the preparation of encenicline and related compounds.
BACKGROUND OF THE INVENTION
15 Tertiary amines, although commonly used to balance hydrochloric acid generation in acylation reactions of carboxylic acid chlorides with alcohols and amines, are known to react with acyl chlorides too. This reaction is slow for simple unstrained trialkylamines compared to the reaction of a carboxylic acid chloride with a primary amino group. Nevertheless, an organic molecule comprising both, a primary amine group and a tertiary amine group, can react at two positions 0 with a carboxylic acid chloride, and impurities from this side reaction are observed, such as a diacylated reaction product or a product from the reaction of the carboxylic acid chloride with the tertiary amine. Thus, processes for the selective amidation of one amine group, but not the other, are desirable. The question of selective amidation of the primary amine group in the presence of a tertiary amine group becomes more formidable if the tertiary amine group is 5 unusually reactive due to an exposed free electron pair on the tertiary amine. Examples are quinuclidine and 1 ,4-diazabicyclo[2,2,2]octane (DABCO), which function as organocatalysts (Aggarwal et a, JOC (2003), (68), 692-700) and form stable adducts with electrophilic ketones (Schilling and Roth, JACS (1980), (102), 4271 -4272). 0 For conformationally locked amines, such as quinuclidine, the acylation reaction of the tertiary amine is fast and can proceed with ring opening, resulting in the formation of a potentially genotoxic alkyl chloride derivative (Shiraishi and Takayama, Nippon Kagaku Kaishi (1985), (1 ), 51-56).
Figure imgf000002_0001
5 Without wishing to be bound to this theory, this reactivity might be one reason for the highly variable yields observed in the literature whenever the Schotten-Baumann reaction is used for the preparation of quinuclidin-3-amides, with the majority being in the lower or moderate range. A compound featuring quinuclidine as a structural motif is (R)-7-chloro-N-(quinuclidin-3- yl)benzo[b]thiophene-2-carboxamide (international non-proprietary name (INN): encenicline) represented by chemical structure
Figure imgf000003_0001
Compound I
The above mentioned compound will be referred to in the present application by its international non-proprietary name, i.e. encenicline. Encenicline is an agonist exhibiting priming behavior at the a 7 receptor by potentiating the response to the natural agonist acetylcholine (ACh) (Prickaerts et al., Neuropharmacology (2012), (62), 1099-1 1 10)). Furthermore, encenicline might function as a neuromodulator, impacting cognition mediated in part by modulating multiple neurotransmitter systems including dopamine, acetylcholine and glutamate in the prefrontal cortex and other brain regions (Huang et al, Psychopharmacology (2014), (231 ), 4541-4551 ). In the past, al nicotinic acetylcholine receptors (a7 receptors) have been demonstrated to play an important role in cognition in both animals and humans and thereby having potential therapeutic applications in cognitive impairment in schizophrenia as well as Alzheimer's disease. International patent application WO 2003/055878 discloses a two-step process for the preparation of encenicline involving preparation of 7-chlorobenzo[b]thiophene-2-carboxylic acid from 2,3-dichlorobenzaldehyde (Bogdal et al, 2000) followed by amide formation with (R)- quinuclidin-3-amine dichloride. The amide coupling was achieved by using HATU in the presence of hunig base (DIEA) in DMF. HPLC purification of the obtained residue and salt formation from dioxane/MeOH with hydrochloric acid provided encenicline hydrochloride in 65% yield. Other coupling agents used in the above mentioned patent application are the systems HBTU/HOBt and EDC/HOBt. All these agents are expensive and have to be separated from the product in the course of an aqueous workup and/or chromatographic purification. Stoner et. al, Organic Process Research & Development (1999), 3, 145-148, and Stoner et. al, Organic Process Research & Development (2000), 4, 264-269, describe an alternative protocol to carbodiimide-mediated peptide coupling for a carboxylic acid prone to polymerization and the use of this protocol for the synthesis of lopinavir, respectively. EP2036905A1 relates to the preparation of pyridylisoxazole derivatives and in particular the preparation of 3-(4-Fluorophenyl)-4-[4-[2-[1 -(2,5-dimethylpyrrolyl)]pyridyl]]-5-
(phenylacetylamino)isoxazole in example 189 on page 48. There is thus a need for an inexpensive process for the preparation of encenicline. There is also the need for an industrial scale process for the preparation of encenicline. There is also a need for a process for the preparation of encenicline where genotoxic impurities, such as
Figure imgf000004_0001
Compound II
do not form or form only at very low levels. And more generally, there is the need for a process that allows selective amidation at the primary amine group in molecules, where an unusually nucleophilic tertiary amine group is also present.
SUMMARY OF THE INVENTION
The present inventors have found that the Schotten-Baumann reaction for the preparation of encenicline from (R)-quinuclidin-3-amine and benzo[b]thiophene-2-carboxylic acid chloride occurs with relatively low yield and suffers from the problem that side reactions of the carboxylic acid chloride with the tertiary amine generates by-products.
The present inventors have then found a general solution for selectively amidating a compound comprising both a primary and a tertiary amine at the primary amine, even if the reaction of the tertiary amine group with the acid chloride would proceed quickly due to a relatively high nucleophilicity of the tertiary amine group, for example when the nitrogen atom of the tertiary amine group is the bridgehead atom of a bicyclic ring system.
The present invention therefore relates to a process for the preparation of an amide from a carboxylic acid chloride and an organic molecule comprising both a primary amine group and a tertiary amine group, wherein the amide bond forms selectively with the primary amine group, and wherein the carboxylic acid chloride preferably does not comprise a non-aromatic nitrogen atom,
comprising the step a) of reacting the carboxylic acid chloride with the organic molecule comprising both a primary amine group and a tertiary amine group in the presence of imidazole. The process of the present invention has the advantages that the amidation reaction proceeds selectively with the primary amine group, even with organic molecules which comprise a tertiary amine group which is conformationally locked, such as with (R)-quinuclidin-3-amine. The processes of the present invention use inexpensive reagents, such as imidazole and thionylchloride. In the processes of the present invention genotoxic impurities, for example alkylchlorides such as compound II, do not form or form only at low levels. This can be advantageous compared to the processes of WO 2003/055878.
The process of the present invention is particularly useful for the preparation of encenicline or a salt thereof from (R)-quinuclidin-3-amine and benzo[b]thiophene-2-carboxylic acid chloride. Crystalline encenicline hydrochloride monohydrate can be obtained if, after step a), at least one mole of water per mole of (R)-quinuclidin-3-amine is present in the reaction mixture.
The present invention also relates to the use of imidazole for the selective acylation of a primary amine group in an organic molecule comprising both the primary amine group and a tertiary amine group in the reaction of said organic molecule comprising both the primary amine group and a tertiary amine group, with a carboxylic acid chloride, wherein the carboxylic acid chloride does not comprise a non-aromatic nitrogen atom. The present invention also relates to encenicline or a salt thereof, which comprises less than 50 ppm of an alkylchloride, such as compound II, preferably less than 20 ppm of an alkylchloride, such as compound II, more preferably less than 5 ppm of an alkylchloride, such as compound II. Encenicline with such a low level of alkylchlorides becomes available because of the selectivity of the acylation reaction for the primary amine and because the imidazole in the reaction masks the bridgehead nitrogen atom and thereby protects it from attack by the electrophile, thus preventing ring-opening.
The present invention also relates to encenicline or a salt thereof, which comprises less than 50 ppm of compound II, preferably less than 20 ppm, more preferably less than 5 ppm. Encenicline with such a low level of the genotoxic impurity compound II becomes available because of the selectivity of the acylation reaction for the primary amine and because the imidazole in the reaction masks the bridgehead nitrogen atom and thereby protects it from alkylation.
The invention specially relates to the processes described in each section. The invention likewise relates, independently, to every single step described in a process sequence within the corresponding section. Therefore, each and every single step of any process, consisting of a sequence of steps, described herein is itself a preferred embodiment of the present invention. Thus, the invention also relates to those embodiments of the process, according to which a compound obtainable as an intermediate in any step of the process is used as a starting material. The invention likewise relates to novel starting materials which have been specifically developed for the preparation of the compounds according to the invention, to their use and to processes for their preparation. The invention also relates to intermediates which have been specifically developed for the preparation of the compounds according to the invention, to their use and to processes for their preparation.
It is noted that in the present application usually explanations made in one section are also applicable for other sections, unless otherwise stated. For example, the explanations for a residue QQ in formula (ZZ) given in one section also apply if formula (ZZ) occurs in other sections, unless otherwise stated.
General terms:
Listed below are definitions of various terms used to describe the present invention. These definitions, either by replacing one, more than one or all general expressions or symbols used in the present disclosure and thus yielding preferred embodiments of the invention, preferably apply to the terms as they are used throughout the specification unless they are otherwise limited in specific instances either individually or as part of a larger group.
The term "C1-Cn-" defines a moiety with up to and including maximally n carbon atoms, said moiety being branched (one or more times) or straight-chained and bound via a terminal or a non-terminal carbon. Alkyl being a radical or part of a radical is a straight or branched (one or, if desired and possible, more times) carbon chain, and is especially C1 -C7-alkyl, such as C1-C4-alkyl, in particular branched C1 -C4-alkyl, such as isopropyl. The term "lower" or "C1-C7-" defines a moiety with up to and including maximally 7, especially up to and including maximally 4, carbon atoms, said moiety being branched (one or more times) or straight-chained and bound via a terminal or a non-terminal carbon. Lower or C1-C7-alkyl, for example, is n-pentyl, n-hexyl or n-heptyl or preferably C1 -C4-alkyl, especially as methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec- butyl, tert-butyl, in particular methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert- butyl. Halo or halogen is preferably fluoro, chloro, bromo or iodo, preferably chloro; where halo is mentioned as a substituent, where possible, one or more (e.g. up to three or one) halogen atoms may be present, e.g. in halo-C1-C7-alkyl, such as trifluoromethyl, 2,2-difluoroethyl or 2,2,2- trifluoroethyl. Alkenyl, being a radical or part of a radical, is a straight or branched (one or, if desired and possible, more times) carbon chain containing at least one double bond, and includes, for example, C2-C20-alkenyl (such as C3-C8alkenyl). Examples include ethenyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octacyl and eicosyl, each of which containing at least one double bond.
Alkylene is a bivalent radical derived from alkyl and includes C1-7alkylene and especially C2- C7-alkylene.
Alkenylene is a bivalent radical derived from alkenyl, including in particular C2-8 alkenylene.
Alkinyl, being a radical or part of a radical, is a straight or branched (one or, if desired and possible, more times) carbon chain containing at least one triple bond, and includes, for example, C2-C20-alkinyl (such as C3-C7-alkinyl), for example, propargyl.
The term cycloalkyi, being a radical or part of a radical, includes "C3-8-cycloalkyl" and defines a non-aromatic cycloalkyi moiety with up to and including maximally 14, such as up to and including 10, for example up to and including maximally 8, in particular up to and including maximally 6 carbon atoms. Said cycloalkyi moiety is for example mono- or bicyclic, in particular monocyclic, which may include one or more double and/or triple bonds. Embodiments include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Heterocyclyl is a mono- or polycyclic, preferably a mono-, bi- or tricyclic-, most preferably a mono-, unsaturated, partially saturated, saturated or aromatic ring system with preferably 3 to 20 (more preferably 5 to 10) ring atoms and with one or more, preferably one to four, heteroatoms independently selected from nitrogen, oxygen, sulfur, -S(=0)- or -S-(=0)2. The heterocyclyl group may be aromatic or non-aromatic. When the heterocyclyl group is an aromatic group, it is also referred to as heteroaryl.
Aryl being a radical or part of a radical is an aromatic hydrocarbon group, for example, C6-10 aryl, and is preferably a mono- or polycyclic, especially monocyclic, bicyclic or tricyclic aryl moiety with 6 to 14 carbon atoms for example 6 to 10 carbon atoms, preferably phenyl, indenyl, indanyl or naphthyl.
Heteroaryl being a radical or part of a radical is formally derived from an aryl by replacement of one or more methine (-C=) and/or vinylene (-CH=CH-) groups by trivalent or divalent heteroatoms (examples are nitrogen, oxygen and sulfur) respectively, in such a way as to maintain the continuous π-electron system characteristic of aromatic systems and a number of out-of-plane π-electrons corresponding to the Huckel rule (4n+2).
The term arylalkyl includes aryl-C1-C7-alkyl, wherein aryl is as defined herein and is for example benzyl.
The term carboxyl or "free acid" refers to -C02H. The term "amine" relates to compounds formally derived from ammonia by replacing one, two or three hydrogen atoms by hydrocarbyl groups, and having the general structures RNH2 (primary amines), R2NH (secondary amines), R3N (tertiary amines), with R being attached to N by a C-N single bond.
The term "ester group" comprises any ester of a carboxyl group generally known in the art; for example groups -COOR, wherein R is selected from the group consisting of: C1 -6alkyl, such as methyl, ethyl or t-butyl, C1-6alkoxyC1-6alkyl, heterocyclyl, such as tetrahydrofuranyl, C6- 10aryloxyC1-6alkyl, such as benzyloxymethyl (BOM), silyl, such as trimethylsilyl, t- butyldimethylsilyl and t-butyldiphenylsilyl, cinnamyl, allyl, C1-6alkyl which is mono-, di- or trisubstituted by halogen, silyl, cyano or C1-6aryl, wherein the aryl ring is unsubstituted or substituted by one, two or three, residues selected from the group consisting of C1 -7alkyl, C1- 7alkoxy, halogen, nitro, cyano and CF3; or C1 -2alkyl substituted by 9-fluorenyl. The term "amide group" comprises any amide of a carboxyl group generally known in the art; for example groups -CONHR. For example, R can be selected from the group consisting of: substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkylamino, such as quinuclidinyl, substituted or unsubstituted aralkylamino, substituted or unsubstituted allylamino, wherein the amino group is a tertiary amino group.
Any of the groups which are mentioned above as being optionally substituted can be substituted, for example, by one or more selected from the group consisting of halo, nitro, C1 -C7-alkyl, halo- C1-C7-alkyl, C1 -C7-alkoxy, halo-C1-C7-alkoxy, C1-C7-alkoxy-C1 -C7-alkyl, C1 -C7-alkyl-C1- C7-alkoxy and C1 -C7-alkoxy-C1-C7-alkoxy.
Protecting groups may be present and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter. Preferably, if two or more protecting groups are present in one intermediate mentioned herein, they are chosen so that, if one of the groups needs to be removed, this can be done selectively, e.g. using two or more different protecting groups that are cleavable under different conditions, e.g. one class by mild hydrolysis, the other by hydrolysis under harder conditions, one class by hydrolysis in the presence of an acid, the other by hydrolysis in the presence of a base, or one class by reductive cleavage (e.g. by catalytic hydrogenation), the other by hydrolysis, or the like.
Nitrogen protecting groups can be introduced/removed according to standard methods of organic chemistry known in the art, in particular reference is made to conventional nitrogen protecting group methods described in J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, T. W. Greene and P. G. M. Wuts, "Greene's Protective Groups in Organic Synthesis", Fourth Edition, Wiley, New York 2007; and in Richard C. Larock, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", Second Edition, Wiley-VCH Verlag GmbH, 2000. It is, however, preferred that nitrogen protecting groups are absent from the starting material for the process of the present invention, i.e. the compound comprising both a primary and a tertiary amine at the primary amine. Hydroxyl protecting groups can be introduced/removed according to known methods; standard conditions for such methods are described, for example in reference books above-mentioned for nitrogen protecting groups.
The term "saponification reagent" is to be understood as a base which is able to hydrolyze an ester to form an alcohol and the salt of a carboxylic acid, e.g. an alkali metal hydroxide such as KOH or NaOH.
The term "group which can be saponified" is to be understood as an ester group -C02R wherein R is alkyl, aryl or arylalkyl, which can be hydrolyzed, for example under basic conditions (e.g. alkalimetal base such as. NaOH, LiOH or KOH) or under acidic conditions (eg. by the use of mineral acids, such as HCI, H2S04, HBr, H3P04) to provide a carboxylic acid. As an extension, the term "group which can be saponified" can also include a group -C02R wherein R is aryl or arylalkyl, which can be reacted by use of a hydrogenation catalyst (eg Pd/C, Pt/C, Rh/C, Pd/AI203, Pt02), in the presence of an acid (eg. acetic acid) or a base (eg. triethylamine) or under neutral conditions, to provide a carboxylic acid.
The term "leaving group" include halogen (e.g. chlorine, bromine or iodine) and a hydroxy group activated through esterification, for example with an alkanesulfonate group (e.g. methanesulfonyloxy, toluenesulfonyloxy, fluorosulfonyloxy, trifluoromethanesulfonyloxy or nonabutanesulfonyloxy).
The term "optically active base" describes, for example, chiral amines, preferably chiral tertiary amines, more preferably cinchona alkaloids, such as quinidine and quinine, most preferably modified cinchona alkaloids. Examples of such modified cinchona alkaloids are detailed, for example, in Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDiad, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621 -631 and references cited therein.
The term "chiral" refers to molecules which have the property of non-superimposability on their mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.
The term "one-pot" "or "one-pot process" means that in a series (i.e. in a succession) of reactions, for example two or more successive reactions, each reaction product is provided for the next reaction without isolation and purification. The one-pot processes defined herein encompass not only a series (i.e a succession) of reactions conducted in a single reaction vessel, but also a series (i.e. a succession) of reactions conducted in a plurality of reaction vessels (e.g., by transferring the reaction mixture from one vessel to other) without isolation and purification. Preferably, the one-pot process is conducted in a single reaction vessel.
The term "step-wise process" means that in a series (i.e a succession) of reactions, each reaction product is provided for the next reaction with isolation and optionally purification. The term "work-up" means the work of isolation and/or purification which is carried out once the reaction is finished.
As used herein, unless specified otherwise, the term "room temperature" or "ambient temperature" means a temperature of from 15 to 30°C, such as from 20 to 30°C, such as from 20 to 25°C.
The term "inert" as used throughout this application, means unreactive with any of the reactants, solvents, or other components of the reaction mixture. Such inert conditions are generally accomplished by using inert gas such as carbon dioxide, helium, nitrogen, argon, among other gases.
Bonds with an asterisk (*) denote point of binding to the rest of the molecule.
The compounds of the present invention can possess one or more asymmetric centers. The preferred absolute configurations are as indicated herein specifically. However, any possible pure enantiomer, pure diastereoisomer, or mixtures thereof, e.g., mixtures of enantiomers, such as racemates, are encompassed by the present invention.
In the formulae of the present application the term ">ΛΛΛΓ", " " or " " on a C-sp3 represents a covalent bond wherein the stereochemistry of the bond is not defined. This means that the term " >ΛΛΛΓ" or " " on a C-sp3 comprises an (S) configuration as well as an (R) configuration of the respective chiral center. Furthermore, mixtures are also encompassed, e.g., mixtures of enantiomers, such as racemates, are encompassed by the present invention.
In the formulae of the present application the term " >Λ ΛΓ" or " " on a C-sp2 represents a covalent bond, wherein the stereochemistry or the geometry of the bond is not defined. This means that the term " >ΛΛΛΓ" on a C-sp2 comprises a cis (Z) configuration as well as a trans (E) configuration of the respective double bond. Furthermore, mixtures are also encompassed, e.g., mixtures of double bond isomers are encompassed by the present invention.
In the formulae of the present application, the term " " indicates a Csp3-Csp3 bond or a
Csp2-Csp2 bond. The compounds of the present invention can possess one or more asymmetric centers. The preferred absolute configurations are as indicated herein specifically.
In the formulae of the present application the term " ^ " on a C-sp3 indicates the absolute stereochemistry, either (R) or (S).
In the formulae of the present application the term "··■* " on a C-sp3 indicates the absolute stereochemistry, either (R) or (S).
Terms d,l and meso are used herein following stereodescriptor nomenclature according to: Gutsche, C. D.; Pasto, D. J. Fundamentals of Organic Chemistry, Prentice-Hall, Inc., Englewood Cliffs, New Jersey, 1975 and, Eliel, E. L; Wilen, S. H. Stereochemistry of Organic Compounds, John Wiley & Sons, Inc. 1994.
The term "stereomeric purity" at a given percentage means that the designated stereoisomer predominates at that given percentage in a mixture of stereosiomers.
The term "stereoisomer" relates to isomers that possess identical constitution, but which differ in the arrangement of their atoms in space. Included within the definition of a stereoisomer are enantiomers and diasteromers. The term "resolution" refers to the separation or concentration or depletion of one of the stereoisomers of a molecule.
The term "tautomer" refers in particular to the aldehyde tautomer of compounds of the present invention, where such compounds can exists in either an enol or aldehyde form, or mixtures thereof.
The term "conformationally locked" refers in particular to amines, where the substituents at the nitrogen atom prevent inversion at the nitrogen atom. An example of a conformationally locked amine is quinuclidine.
The term "aromatic nitrogen" refers to a nitrogen which is part of a heteroaromatic ring system. For example the compound 4-amino-pyridine contains one aromatic nitrogen - the N at position 1 - and one non-aromatic nitrogen - the nitrogen of the amino group attached to carbon 4.
Figure imgf000011_0001
The term "essentially free" from a particular compound, such as e.g. the genotixic impurity compound II, means that said compound is present at at most 50 ppm, such as at most 20 ppm, and more preferably at most 5 ppm, in a sample of another compound or composition. The term "selective acylation of a primary amine group" means that a compound comprising both, a primary amine group and a tertiary amine group, reacts with an amidating reagent, such as an acyl chloride, in such a way, that the molar ratio [amide formed by the amidating reagent reacting only with the primary amine group] : [(amide formed by the amidating reagent reacting only with the tertiary amine) + (amide formed by the amidating reagent reacting with both the primary amine group and the tertiary amine group)] is at least 20:1 , such as at least 50:1 , for example 99:1 .
The term "nucleophilic" as used herein to describe particular tertiary amine groups refers to a tertiary amine group having a binding constant K for the adduct with the Lewis acidic Zn" Schiff- base complex of compound I on page 8880 of Olivieri et al., literature reference below, such that logK is greater or equal to 6.0 (Olivieri et al., Journal of Organic Chemistry (201 1 ), 76, 8879-8884), when determined according to Olivieri et al. Quinuclidine is a strong Lewis base in said assay, having a logK of about 6.73. By contrast, simple tertiary amines, wherein the free electron pair of nitrogen is not exposed, are weak Lewis bases in said assay, with triethylamine having a logK of about 3.45. The strength as a Lewis base in the Olivieri test system may be correlated with a tertiary amine's nucleophilicity. In order to determine the nucleophilicity of the tertiary amine group, it is tested in the absence of the primary amine group. For example, the nucleophilicity of the tertiary amine group in quinuclidin-3-amine is determined by measuring the corresponding compound without the primary amine, i.e. by measuring quinuclidine in this example.
Salts are especially pharmaceutically acceptable salts or generally salts of any of the intermediates mentioned herein, where salts are not excluded for chemical reasons the skilled person will readily understand. They can be formed where salt forming groups, such as basic or acidic groups, are present that can exist in dissociated form at least partially, e.g. in a pH range from 4 to 10 in aqueous solutions, or can be isolated especially in solid, especially crystalline, form. Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds or any of the intermediates mentioned herein with a basic nitrogen atom (e.g. imino or amino), especially the pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, lactic acid, fumaric acid, succinic acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, benzoic acid, methane- or ethane-sulfonic acid, ethane-1 ,2-disulfonic acid, benzene- sulfonic acid, 2-naphthalenesulfonic acid, 1 ,5-naphthalene-disulfonic acid, N-cyclohexylsulfamic acid, Ν-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
In the presence of negatively charged radicals, such as carboxy or sulfo, salts may also be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines for example triethylamine or tri(2-hydroxyethyl)amine, N- ethyl-piperidine, Ν,Ν'-dimethylpiperazine, t-butylamine, n-butylamine, phenylethylamine, dicyclohexylamine or cyclohexylamine.
When a basic group and an acid group are present in the same molecule, any of the intermediates mentioned herein may also form internal salts.
For isolation or purification purposes of any of the intermediates mentioned herein it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates.
In view of the close relationship between the compounds and intermediates in free form and in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the compounds or salts thereof, any reference to "com- pounds", "starting materials" and "intermediates" hereinbefore and hereinafter is to be understood as referring also to one or more salts thereof or a mixture of a corresponding free compound, intermediate or starting material and one or more salts thereof, each of which is intended to include also any solvate or salt of any one or more of these, as appropriate and expedient and if not explicitly mentioned otherwise. Different crystal forms may be obtainable and then are also included.
Where the plural form is used for compounds, starting materials, intermediates, salts, pharmaceutical preparations, diseases, disorders and the like, this is intended to mean one (preferred) or more single compound(s), salt(s), pharmaceutical preparation(s), disease(s), disorder(s) or the like, where the singular or the indefinite article ("a", "an") is used, this is not intended to exclude the plural, but only preferably means "one".
Abbreviations:
μηη micrometre
ali aliphatic
aliph aliphatic
al-CH aliphatic-CH
ali-CH aliphatic-CH
aq aqueous
ar aromatic
arom aromatic
arom-H aromatic-H
ar-H aromatic-H
ar-NH aromatic-NH Ac acetyl
AcOH acetic acid
Bn benzyl
Boc tert-butoxycarbonyl
t-BuOK potassium tert-butoxide
CDI N,N-Carbonyldiimidazole
CH2CI2 dichloromethane
CH20 formaldehyde
C02 carbon dioxide
(COCI)2 oxalyl chloride
COD = cod cyclooctadiene
Cp cyclopentadienyl
Cy cyclohexyl
de diastereomeric excess
dr diastereomeric ratio
DABCO 1 ,4-diazobicyclo[2.2.2]octane
DBU 1 ,8-diazabicyclo[5,4,0]undec-7-ene
DCM dichloromethane
DEA diethyl amine
DIBAH diisobutylaluminium hydride
DMAP 4-(dimethylamino)pyridine
DME 1 ,2-dimethoxyethane
DMF = dmf dimethylformamide
DMPU 1 ,3-dimethyl-3,4,5,6-tetrahedrao-2(1 H)-pyrimidinone
DMSO dimethylsulfoxide
DMSO-d6 dimethylsulfoxide deuterated
ee enantiomeric excess
equiv equivalent
EDC-HCI N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride
ES electrospray
ES+ positive electrospray ionisation
ESI electrospray ionisation
Et ethyl
Et20 diethyl ether
EtOAc ethyl acetate
EtOH ethanol
g gram(s)
GC gass chromatography
h hour(s)
HCI hydrochloric acid
HCI(aq) hydrogen chloride aqueous solution
HNMR proton nuclear magnetic resonance
1 HNMR proton nuclear magnetic resonance
HMDS 1 , 1 ,1 ,3,3,3-hexamethyldisilazane
H202 hydrogen peroxide
HOBt 6-chloro-1-hydroxybenzotriazol
HPLC high performance liquid chromatography
H3P04 phosphoric acid
HRMS high resolution mass spectroscopy
H2S04 sulfuric acid
Hz hertz iPr isopropyl
iPr2NEt N-ethyldiisopropylamine
iPrOAc isopropyl acetate
iPrOH isopropanol
IR infrared
J coupling constant
K2C03 potassium carbonate
KHMDS potassium bis(trimethylsilyl)amide
L litre
LC-MS liquid chromatography-mass spectrometry LCMS liquid chromatography-mass spectrometry
LiCI lithium chloride
LDA lithium diisopropylamide
LHMDS lithium bis(trimethylsilyl)amide
LiOH lithium hydroxide
LRMS low resolution mass spectroscopy m/e mass-to-charge ratio
mg milligram
min minute(s)
ml milli litre
ml. millilitre
mmol(s) millimole(s)
mol(s) mole(s)
monosub. monosubstituted
mp melting point
m.p. melting point
m/z mass-to-charge ratio
M molarity/molar
Me methyl
2-MeTHF 2-methyltetrahydrofuran
Mel methyl iodide
MeOH methanol
MeONa sodium methoxide
MgS04 magnesium sulfate
Mn02 manganese dioxide
MS mass spectrometry
MTBE tertbutylmethylether
nm nanometre
N nitrogen atom
N2 nitrogen
NaCI sodium chloride
Na2C03 sodium carbonate
NaOCI sodium hypochlorite
NaH sodium hydride
NaHC03 sodium bicarbonate
NaHMDS sodium bis(trimethylsilyl)amide
NaOH sodium hydroxide
NaOMe sodium methoxide
NH4CI ammonium chloride NMR nuclear magnetic resonance
Np naphthyl
ppm parts per million
pyr pyridine
Pd/C palladium on carbon
Pd(PPh3)4 tetrakis(triphenylphosphine)palladiumi
Ph phenyl
Piv pivaloyl
Piv-CI pivaloyl chloride
PPTS pyridinium p-toluenesulfonate
RT = rt room temperature
temp. temperature
T temperature
tR retention time
tBu tertiary-butyl
TEA triethylamine
TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy
TES triethylsilyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
Tos- tosyl
TMEDA Ν,Ν,Ν,Ν-tetramethylethylenediamine
TMG 1 , 1 ,3,3-tetramethylguanidine
TMS trimethylsilyl
Tol toluene
Tos- tosyl
Ts tosylate/tosyl
UV ultraviolet light
vol. volume
wt. weight
Xyl xylene
Literature references for chemical processes/products
Standard conditions for group transformations are described, for example, in the relevant chapters in Richard C. Larock, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", Second Edition, Wiley-VCH Verlag GmbH, 2000.
General reactions and mechanisms in organic chemistry are described, for example, in Smith, M., B.; March, J.; March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 6th Edition, John Wiley & Sons, Inc., 2007; in particular as described in the relevant chapters thereof;
Stereochemistry is described, for example, in
Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds, John Wiley & Sons, Inc. 1994.
Protecting groups are described, for example, in J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; in T. W. Greene and P. G. M. Wuts, "Greene's Protective Groups in Organic Synthesis", Fourth Edition, Wiley, New York 2007; in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 , and in "Methoden der organischen Chemie" (Methods of Or-ganic Chemistry), Houben- Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974.
Famous chemical transformations ("name reactions"), such as the Schotten-Baumann reaction, are described, for example, at
http://www.organic-chemistry.org/namedreactions/
Pharmaceutically acceptable salts are described, for example, in
Handbook of Pharmaceutical Salts: Properties, Selection, and Use Edited by P. Heinrich Stahl and Camile G. Wermuth. VHCA, Verlag Helvetica Chimica Acta, Zurich, Switzerland, and Wiley- VCH, Weinheim, Germany. 2002.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 : XRPD of (R)-7-Chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
hydrochloride monohydrate obtained from example 1.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of an amide starting from a carboxylic acid chloride and
an organic molecule, which molecule comprises both a primary amine group and a tertiary amine group, in particular when the nitrogen atom of the tertiary amine group is the bridgehead atom of a bicyclic ring system.
In the process of the present invention the amide bond forms selectively between the acyl- radical of the carboxylic acid chloride and the primary amine group. In the process of the present invention the carboxylic acid chloride does not comprise a non-aromatic nitrogen atom, such as a primary, secondary or tertiary amine group, an amide group or nitrogen in the context of a substituted urea group. In the process of the present invention the tertiary amine group preferably does not comprise a bond between nitrogen and a nitrogen protecting group such as benzyl, trityl or benzylidene.
The process comprises the step of reacting the carboxylic acid chloride with the organic molecule comprising both a primary amine group and a tertiary amine group in the presence of imidazole. Without wishing to be bound to any theory, the amidation reaction might proceed via the in situ formation of an imidazolide. The organic molecule which comprises both a primary amine group and a tertiary amine group is not particularly limited as long as it contains at least a primary amine group and a tertiary amine group. In a preferred example the nitrogen atom of the tertiary amine group is comprised in a non-aromatic heterocycle. More preferred examples include bicyclic ring systems in which the two rings share at least two ring atoms and wherein one of the ring atoms is the nitrogen atom of the tertiary amine. The process of the present invention is particularly useful for such compounds, where the tertiary amine group is conformationally locked. This is, for example, the case when the nitrogen atom of the tertiary amine group is the bridgehead atom of a bicyclic ring system. The process of the present invention is also particularly useful for such compounds, where the tertiary amine group is nucleophilic, such as tertiary amine groups wherein the logK is greater or equal to 6.0 when tested according to Olivieri et al., Journal of Organic Chemistry (201 1 ), 76, 8879-8884, for example the logK being from 6.0 to 7.0. The tertiary amine group of quinuclidine, for example, has a logK of 6.73 according to said assay.
The nomenclature of bicyclic ring systems is described in detail in [http://www.chem.qmul.ac.uk/iupac/]. For the process of the present invention, the bicyclic ring systems are preferably of the type [2.2.2], [2.2.3], [2.2.4], [2.2.5], [2.3.3], [2.3.4], [2.3.5], [2.4.4], [2.4.5], [2.5.5], [3.3.3], [3.3.4], [3.3.5], [3.4.5] or [3.5.5], more preferably the bicyclic ring system is of type [2.2.2].
In preferred embodiments the nitrogen atom of the tertiary amine is the bridgehead atom of the bicyclic ring system and the primary amine group is present as a substituent of the bicyclic ring system, with the above-mentioned types being preferred.
An example of an organic molecule comprising both a primary amine group and a tertiary amine group is a quinuclidin-amine, such as quinuclidin-3-amine.
As far as the carboxylic acid chloride is concerned, it should not comprise a non-aromatic nitrogen atom, such as a primary, secondary or tertiary amine group, an amide group or nitrogen in the context of a substituted urea group. This is because the carboxylic acid chloride could then have the potential for self-polymerization. It is preferred that the carboxylic acid residue is such that it allows amide bond formation in step a). The carboxylic acid chloride can preferably be a heteroaryl acid chloride, an alkyl acid chloride, a cycloalkyl acid chloride, or an aryl acid chloride. An examples for an alkyl acid clorides is acetylchloride, for a cycloalkyl acid chloride an example is cyclohexanecarbonylchloride. In a preferred embodiment the carboxylic acid chloride is an aryl-acid chloride (Ar- COCI). For example Ar- can be a monocyclic, bicyclic or tricyclic aromatic ring system consisting of 6 to 14 atoms. The aromatic ring system can be substituted or unsubstituted. Preferred aryl residues Ar- can be selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphtyl or substituted or unsubstituted indenyl.
In a further preferred embodiment the carboxylic acid chloride is a heteroaryl acid chloride. The heteroaromatic ring system can be substituted or unsubstituted. Preferred heteroaryl residues Ar- can be selected from substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted isochinolyl, substituted or unsubstituted chinolyl, substituted or unsubstituted benzothienyl substituted or unsubstituted benzofuryl, substituted or unsubstituted benzoxazol, substituted or unsubstituted benzothiazol. The optional substituent can be, e.g., halogen, such as chloro. A preferred example of a carboxylic acid chloride is a substituted or unsubstituted benzo[b]thiophene-2-carboxylic acid chloride.
The reactants, the carboxylic acid chloride and the organic molecule comprising both a primary amine group and a tertiary amine group, are preferably provided in approximately equimolar ratio.
Step a), the amide bond formation between the carboxylic acid chloride and the primary amine group, is carried out in the presence of imidazole. It is preferred that the molar ratio of imidazole : [organic molecule comprising both a primary amine group and a tertiary amine group] is at least 3:1 , such as from 3.0 : 1.0 to 5.0 : 1.0, with a molar ratio of approx. 4 : 1 being particularly preferred, for example if the organic molecule comprising both a primary amine group and a tertiary amine group is provided as a diacid salt, such as a dihydrochloride.
If the organic molecule comprising both a primary amine group and a tertiary amine group is provided as a free base, the amide bond formation between the carboxylic acid chloride and the primary amine group, can be at a molar ratio of imidazole : [organic molecule comprising both a primary amine group and a tertiary amine group] of at least 1 :1 , such as from 1 .0 : 1 .0 to 3.0 : 1.0, with a molar ratio of approx. 2 : 1 being particularly preferred. Without wishing to be bound to any theory, the inventors believe that the optimal molar amount of imidazole for step a) could be explained by an amount sufficient to deprotonate the primary and tertiary amine group, when the organic molecule comprising both a primary amine group and a tertiary amine group is provided as a di-acid addition salt (explaining approximately two molar equivalents), sufficient to react with the carboxylic acid chloride, resulting in in-situ formation of an imidazolide (explaining a third equivalent) and sufficient to form a hydrogen- bonded complex with the tertiary amine group, thereby protecting the nitrogen of the tertiary amine group from attack by the electrophile (explaining a fourth equivalent). Such a rationale also explains the lower optimal amount of imidazole if the free base of the organic molecule comprising both a primary amine group and a tertiary amine group is used as the starting material.
It is preferred that the solvent for the amidation step a) comprises only aprotic solvents, for example that it consists of an aprotic solvent. Preferably the aprotic solvent is acetonitrile, THF, dioxane or DMF, and the preferred aprotic solvent is acetonitrile.
Typically the organic molecule comprising both a primary amine group and a tertiary amine group, e.g. (R)-quinuclidin-3-amine or an acid addition salt, and a sufficient amount of imidazole, in an aprotic solvent are added in sequential or simultaneous manner to the carboxylic acid chloride in an aprotic solvent, preferably in the same aprotic solvent.
Step a) is then carried out at a suitable temperature, such as from 0°C to 90°C, for example from 10°C to 50°C e.g. at room temperature, preferably for a time sufficient to complete the amidation reaction, for example 12h to 48h. After the reaction between the carboxylic acid chloride and the primary amine group is completed, the pure product can be isolated by filtration, for example as a hydrochloride salt, from the reaction mixture. Optionally, a sufficient amount of a second solvent suitable for solvate formation, e.g. water, can be added. This can help in product crystallization, thus facilitating the filtration step and improving the purity of the obtained product.
The process according to the present invention proceeds with good yields. The amide formed by reacting the primary amine group with the acid chloride is typically obtained in from 60% to 100% yield, such as from 70% to 95%.
It is also contemplated that the process of the present invention can start from the carboxylic acid itself. Prior to step a) the carboxylic acid chloride can be formed from the corresponding carboxylic acid. Thionyl chloride, oxalyl chloride and phosphorus oxychloride are examples of compounds that can be used to prepare the carboxylic acid chloride from the carboxylic acid.
It is further contemplated that the process including the formation of the carboxylic acid chloride and then step a) can be carried out in a one-pot format. For example carboxylic acid chloride formation can be done in the same reaction vessel as to be used for the amide formation step.
In step a) of the process of the present invention, imidazole and the organic molecule comprising both a primary amine group and a tertiary amine group are preferably the only bases present in the reaction mixture. The processes of the present invention can advantageously provide the product as pure crystalline material, preferentially in the form of therapeutically acceptable salts, such as in the form of its hydrochloride salt, directly from the reaction mixture by filtration without the need for further workup and/or purification processes. Without wishing to be bound by any theory, the advantageous direct preparation of the resulting monoamidation product as an HCI salt is believed to be facilitated by a) imidazole being a relatively weak base, allowing the protonation of the tertiary amine group of the resulting monoamidation product, and b) the absence of bases stronger than imidazole (other than the educts or products) which could prevent protonation, and thus HCI salt generation, at the tertiary amine group of the resulting monoamidation product.
In one embodiment the process of the present invention is for the preparation of encenicline or a salt thereof, wherein in step a) (R)-quinuclidin-3-amine is reacted with benzo[b]thiophene-2- carboxylic acid chloride. It is preferred that after step a), at least one mole of water per mole of (R)-quinuclidin-3-amine is added to the reaction mixture. This process yields crystalline encenicline hydrochloride monohydrate, in particular as a single polymorph. We have found that the obtained crystalline encenicline hydrochloride monohydrate is pure encenicline hydrochloride Form 1.
The process of the present invention affords encenicline hydrochloride monohydrate as a pure single polymorph, termed Form 1 according to the nomenclature of WO 201 1/14651 1 , which discloses crystalline forms of encenicline dihydrochloride.
In the case of the process of the present invention starting from an organic molecule comprising both a primary amine group and a tertiary amine group which is a quinuclidin-amine, such as quinuclidin-3-amine, the product obtained is essentially free of potential genotoxic impurities, such as alkylchlorides, which could be generated, for example from acylation of the tertiary amine and following ring cleavage as described by Shiraishi and Takayama, 1985. Thus, encenicline prepared by the process of the present invention is essentially free from 7-chloro- N-((3R)-1 -(7-chlorobenzo[b]thiophene-2-carbonyl)-4-(2-chloroethyl)piperidin-3- yl)benzo[b]thiophene-2-carboxamide (compound II) existing as their cis and trans isomers and mixtures thereof.
The present invention also relates to the use of imidazole for the selective acylation of a primary amine group in an organic molecule comprising both the primary amine group and the tertiary amine group,
in the reaction of said organic molecule comprising both the primary amine group and the tertiary amine group with a carboxylic acid chloride, wherein the carboxylic acid chloride does not comprise a non-aromatic nitrogen atom, such as the uses of imidazole described in the process of the present invention above or the uses of imidazole described in the embodiment section below. General Process Conditions
The following, in accordance with the knowledge of a person skilled in the art about possible limitations in the case of single reactions, applies in general to all processes mentioned hereinbefore and hereinafter, while reaction conditions specifically mentioned above or below are preferred.
In any of the reactions mentioned hereinbefore and hereinafter, protecting groups may be used where appropriate or desired, even if this is not mentioned specifically, to protect functional groups that are not intended to take part in a given reaction, and they can be introduced and/or removed at appropriate or desired stages. Reactions comprising the use of protecting groups are therefore included as possible wherever reactions without specific mentioning of protection and/or deprotection are described in this specification.
However, in the context of the present invention, the absence of nitrogen protecting groups and in particular of amine groups which are protected by nitrogen protecting groups, such as benzyl, is preferred. The skilled person will appreciate that the present invention enables the amidation of a primary amine in the context of a compound, where also an unprotected, but reactive, tertiary amine group is present.
Within the scope of this disclosure only a readily removable group that is not a constituent of the particular desired end product is designated a "protecting group", unless the context indicates otherwise. The protection of functional groups by such protecting groups, the protecting groups themselves, and the reactions appropriate for their introduction and removal are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 , in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jesch- keit, "Aminosauren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, in "Protecting Groups", Philip J. Kocienski, 3rd Edition, GeorgThieme Verlag, Stuttgart, ISBN 3-13-137003-3 and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974, in particular in the relevant chapters thereof. A characteristic of protecting groups is that they can be removed readily (i.e. without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (e.g., by enzymatic cleavage). Different protecting groups can be selected so that they can be removed selectively at different steps while other protecting groups remain intact. The corresponding alternatives can be selected readily by the person skilled in the art from those given in the standard reference works mentioned above or the description or the Examples given herein. Where required, the working-up of reaction mixtures, especially in order to isolate desired compounds or intermediates, follows customary procedures and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like. The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ. In the process of the present invention those starting materials are preferably used which result in compounds of formula I which are described as being preferred. Special preference is given to reaction conditions that are identical or analogous to those mentioned in the Examples. The invention relates also to novel starting compounds and intermediates described herein, especially those leading to compounds mentioned as preferred herein.
The invention especially relates to any of the methods described hereinbefore and hereinafter that leads to the product, or a pharmaceutically acceptable salt thereof.
The following Embodiments and Examples serve to illustrate the invention without limiting the scope thereof, while they on the other hand represent preferred embodiments of the reaction steps, intermediates and/or the process of manufacture of the product in free base form or as a pharmaceutically acceptable salt thereof.
Embodiment Section
1. Use of imidazole for the selective acylation of a primary amine group in an organic molecule comprising both the primary amine group and a tertiary amine group, in the reaction of said organic molecule comprising both the primary amine group and the tertiary amine group with a carboxylic acid chloride, wherein the carboxylic acid chloride does not comprise a non-aromatic nitrogen atom.
2. Use according to item 1 , wherein the nitrogen atom of the tertiary amine group of said organic molecule comprising both the primary amine group and the tertiary amine group is comprised in a non-aromatic heterocycle.
3. Use of imidazole for the selective acylation of a primary amine group in an organic molecule comprising both the primary amine group and a tertiary amine group, in the reaction of said organic molecule comprising both the primary amine group and the tertiary amine group with a carboxylic acid chloride, wherein the carboxylic acid chloride does not comprise a non-aromatic nitrogen atom, wherein the tertiary amine group is conformationally locked.
4. Use according to item 3 or items 1 or 2, wherein the nitrogen atom of the conformationally locked tertiary amine group is the bridgehead atom of a bicyclic ring system. Use according to item 4, wherein the bicyclic ring system is of the type [2.2.2], [2.2.3], [2.2.4], [2.2.5], [2.3.3], [2.3.4], [2.3.5], [2.4.4], [2.4.5], [2.5.5], [3.3.3], [3.3.4], [3.3.5], [3.4.5] or [3.5.5].
Use according to item 5, wherein the bicyclic ring system is of the type [2.2.2].
Use according to any one of items 1 to 6, wherein the organic molecule comprising both a primary amine group and a tertiary amine group is a quinuclidin-amine.
Use according to any one of items 1 to 7, wherein the organic molecule comprising both a primary amine group and a tertiary amine group is quinuclidin-3-amine.
Use according to any one of items 1 to 8, wherein the organic molecule comprising both a primary amine group and a tertiary amine group is (R)-quinuclidin-3-amine.
Use of imidazole for the selective acylation of a primary amine group in an organic molecule comprising both the primary amine group and a tertiary amine group, in the reaction of said organic molecule comprising both the primary amine group and the tertiary amine group with a carboxylic acid chloride, wherein the carboxylic acid chloride does not comprise a non-aromatic nitrogen atom and wherein the tertiary amine group is nucleophilic.
Use according to item 10, wherein the nitrogen atom of the nucleophilic tertiary amine group is the bridgehead atom of a bicyclic ring system.
Use according to item 1 1 , wherein the bicyclic ring system is of the type [2.2.2], [2.2.3], [2.2.4], [2.2.5], [2.3.3], [2.3.4], [2.3.5], [2.4.4], [2.4.5], [2.5.5], [3.3.3], [3.3.4], [3.3.5], [3.4.5] or [3.5.5].
Use according to item 12, wherein the bicyclic ring system is of the type [2.2.2].
Use according to any one of items 10 to 13, wherein the organic molecule comprising both a primary amine group and a tertiary amine group is a quinuclidin-amine.
Use according to any one of items 10 to 14, wherein the organic molecule comprising both a primary amine group and a tertiary amine group is quinuclidin-3-amine.
Use according to any one of items 10 to 15, wherein the organic molecule comprising both a primary amine group and a tertiary amine group is (R)-quinuclidin-3-amine. Use according to any one of items 1 to 16, wherein the carboxylic acid chloride is a heteroaryl acid chloride or an aryl acid chloride.
Use according to item 17, wherein the heteroaryl or aryl is a monocyclic, bicyclic or tricyclic aromatic ring system consisting of 6 to 14 atoms, wherein 1 to 4 atoms of the aromatic ring system can be S, N or O, and wherein Ar- can be substituted or unsubstituted.
Use according to item 18, wherein Ar- is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphtyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted isochinolyl, substituted or unsubstituted chinolyl, substituted or unsubstituted benzothienyl substituted or unsubstituted benzofuryl, substituted or unsubstituted benzoxazol, substituted or unsubstituted benzothiazol, and substituted or unsubstituted N-alkyl- or N- aryl-indolyl.
Use according to any one of items 1 to 19, wherein the carboxylic acid chloride is a substituted or unsubstituted benzo[b]thiophene-2-carboxylic acid chloride.
Use according to any one of items 1 to 20, wherein the carboxylic acid chloride is 7- chlorobenzo[b]thiophene-2-carboxylic acid chloride.
Use according to any one of items 1 to 21 , wherein the organic molecule comprising both the primary amine group and a tertiary amine group is provided as a di-acid addition salt and wherein the molar ratio of imidazole : [organic molecule comprising both the primary amine group and the tertiary amine group] is at least 3:1 .
Use according to item 22, wherein said molar ratio is from 3.0 : 1.0 to 5.0 : 1 .0..
Use according to item 22, wherein said molar ratio is about 4 : 1.
Use according to any one of items 1 to 21 , wherein the organic molecule comprising both the primary amine group and a tertiary amine group is provided as a free base and wherein the molar ratio of imidazole : [organic molecule comprising both a primary amine group and a tertiary amine group] is at least 1 :1.
Use according to item 25, wherein said molar ratio is from 1 .0 : 1.0 to 3.0 : 1 .0..
Use according to item 25, wherein said molar ratio is about 2 : 1.
Process for the preparation of an amide from a carboxylic acid chloride and an organic molecule comprising both a primary amine group and a tertiary amine group, wherein the amide bond forms selectively with the primary amine group, wherein the carboxylic acid chloride does not comprise a non-aromatic nitrogen atom, comprising the step of
a) reacting the carboxylic acid chloride with an organic molecule comprising both the primary amine group and the tertiary amine group in the presence of imidazole. The process according to item 28, wherein the nitrogen atom of the tertiary amine group is comprised in a non-aromatic heterocycle.
The process according to any one of items 28 or 29, wherein the tertiary amine group is nucleophilic.
The process according to any one of items 28 or 29, wherein the tertiary amine group is conformationally locked.
The process according to any one of items 28 to 31 , wherein the nitrogen atom of the tertiary amine group is the bridgehead atom of a bicyclic ring system. 33. The process according to item 32, wherein the bicyclic ring system is of the type [2.2.2], [2.2.3], [2.2.4], [2.2.5], [2.3.3], [2.3.4], [2.3.5], [2.4.4], [2.4.5], [2.5.5], [3.3.3], [3.3.4], [3.3.5], [3.4.5] or [3.5.5].
34. The process according to item 33, wherein the bicyclic ring system is of type [2.2.2]. 35. The process according to item 34, wherein the organic molecule comprising both a primary amine group and a tertiary amine group is a quinuclidin-amine.
36. The process according to item 35, wherein the organic molecule comprising both a primary amine group and a tertiary amine group is quinuclidin-3-amine.
37. The process according to any one of items 28 to 36, wherein the carboxylic acid chloride is Aryl- COCI or Heteroaryl - COCI.
38. The process according to item 37, wherein Aryl- or Heteroaryl- is a monocyclic, bicyclic or tricyclic aromatic ring system consisting of 6 to 14 atoms, wherein 1 to 4 atoms of the aromatic ring system can be S, N or O, and wherein Ar- can be substituted or unsubstituted.
39. The process according to any one of items 37 to 38, wherein Aryl- or Heteroaryl- is selected from
substituted or unsubstituted phenyl, substituted or unsubstituted naphtyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted isochinolyl, substituted or unsubstituted chinolyl, substituted or unsubstituted benzothienyl substituted or unsubstituted benzofuryl, substituted or unsubstituted benzoxazol, substituted or unsubstituted benzothiazol, and substituted or unsubstituted N-alkyl- or N- aryl-indolyl.
40. The process according to any one of items 28 to 39, wherein the carboxylic acid chloride is a substituted or unsubstituted benzo[b]thiophene-2-carboxylic acid chloride.
41. The process according to item 28 for the preparation of encenicline or a salt thereof, wherein in step a) (R)-quinuclidin-3-amine is reacted with benzo[b]thiophene-2- carboxylic acid chloride.
42. The process according to item 41 , further comprising, after step a), the step of b) adding at least one mole of water per mole of (R)-quinuclidin-3-amine to the reaction mixture.
43. The process according to item 42, wherein crystalline encenicline hydrochloride monohydrate is obtained.
44. The process according to item 43, wherein crystalline encenicline hydrochloride monohydrate is obtained as a single polymorph.
45. The process according to item 44, wherein crystalline encenicline hydrochloride monohydrate is obtained as pure encenicline hydrochloride Form 1. 46. The process according to any one of items 28 to 45, wherein the amide formed by reacting the primary amine group with the acid chloride is obtained in from 70% to 100% yield.
47. The process according to item 46, wherein the yield is from 70% to 90%.
48. The process according to any one of items 28 to 47, wherein step a) is conducted in an aprotic solvent.
49. The process according to item 48, wherein the aprotic solvent is acetonitrile, THF, dioxane or DMF.
50. The process according to any one of items 48 to 49, wherein the aprotic solvent is acetonitrile.
51. The process according to any one of items 28 to 50, wherein the temperature for step a) is 0°C to 90°C, preferably 10°C to 50°C.
52. The process according to any one of items 28 to 51 , wherein prior to step a) the carboxylic acid chloride is formed from the corresponding carboxylic acid.
53. The process according to item 52, wherein carboxylic acid chloride formation and step a) are conducted in the same reaction vessel as to be used for step a).
54. The process according to any one of items 28 to 52, wherein the reaction mixture does not comprise an additional base besides imidazole and the organic molecule comprising both a primary amine group and a tertiary amine group.
55. The process according to any one of items 28 to 52, wherein the nitrogen atom of the tertiary amine group of the organic molecule comprising both a primary amine group and a tertiary amine group is not bonded to a nitrogen protecting group, such as benzyl-, trityl- or benzylidene.
56. The use according to any one of items 1 to 27 wherein the nitrogen atom of the tertiary amine group of the organic molecule comprising both a primary amine group and a tertiary amine group is not bonded to a nitrogen protecting group, such as benzyl-, trityl- or benzylidene.
57. The use according to any one of items 1 to 21 , wherein the amide formed by reacting the primary amine group with the acid chloride is further isolated from the reaction mixture as an acid addition salt, preferably as the hydrochloride salt.
58. The use according to item 57, wherein the acid addition salt, preferably the hydrochloride salt, is crystalline.
59. The process according to any one of items 28 to 45, wherein the amide formed by reacting the primary amine group with the acid chloride is further isolated from the reaction mixture as an acid addition salt, preferably as the hydrochloride salt.
60. The process according to item 59, wherein the acid addition salt, preferably the hydrochloride salt, is crystalline. 61. Use according to item 22, wherein the reaction mixture does not comprise an additional base besides imidazole and the organic molecule comprising both a primary amine group and a tertiary amine group.
62. The use according to item 61 , wherein the amide formed by reacting the primary amine group with the acid chloride is further isolated from the reaction mixture as a hydrochloride salt.
63. The use according to any one of items 61 or 62, wherein the nitrogen atom of the tertiary amine group of the organic molecule comprising both the primary amine group and the tertiary amine group is comprised in a non-aromatic heterocycle.
Examples
NMR spectra were recorded with a Bruker Avance DPX 300 spectrometer. IR spectra were obtained with a Bruker Alpha FT instrument. High resolution mass spectra were measured with a Finnigan MAT 95 mass spectrometer.
Example 1
(R)-7-Chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate from 7-chlorobenzo[b]thiophene-2-carboxylic acid chloride
To a stirred solution of 7-chlorobenzo[b]thiophene-2-carboxylic acid chloride (5.40 g, 23.4 mmol) in acetonitrile (100 mL) imidazole (3.18 g, 46.7 mmol) was added. Formation of a sticky precipitate was observed. Then, (R)-quinuclidin-3-amine dihydrochloride (4.75 g, 23.8 mmol) and imidazole (3.25 g, 47.7 mmol) in acetonitrile (50 mL) were added. The reaction mixture was then stirred at room temperature for 24 hours. Next, water (0.42 g, 23.3 mmol) was added dropwise. Stirring was continued for 1 hour. A crystalline product formed, was separated by filtration and then washed with acetonitrile (10 mL). Drying of the residue obtained in vacuo provided 6.84 g (78%) of crystalline encenicline hydrochloride monohydrate Form I. The identity of the product with (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate was confirmed by 1 H NMR in d6-DMSO. An X-ray powder diffraction pattern of the obtained crystalline material is shown in figure 1 ,
Example 2
(R)-7-Chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate from 7-chlorobenzo[b]thiophene-2-carboxylic acid - one-pot
To 7-chlorobenzo[b]thiophene-2-carboxylic acid (5.00 g, 23.5 mmol) in toluene (3 mL) thionyl chloride (15 mL, 207 mmol) was added and the mixture stirred at 85 °C for 4 hours. The clear solution was cooled down to room temperature and toluene together with volatile remains of the reagent was removed in vacuo. To the residue were added 5 ml of toluene and the solvent was again removed in vacuo. Then acetonitrile (100 mL) and imidazole (3.18 g, 46.7 mmol) were added to the crude 7-chlorobenzo[b]thiophene-2-carboxylic acid chloride (5.40 g, 23.4 mmol). Formation of a sticky precipitate was observed. Then, (R)-quinuclidin-3-amine dihydrochloride (4.75 g, 23.8 mmol), imidazole (3.25 g, 47.7 mmol) in acetonitrile (50 mL) were added. The reaction mixture was then stirred at room temperature for 24 hours. Next, water (0.42 g, 23.3 mmol) was dropwisely added. Stirring was continued for 1 hour. The crystalline product was separated by filtration and washed with acetonitrile (10 mL). Drying of the residue obtained in vacuo did provide crystalline encenicline hydrochloride monohydrate Form I.
Example 3
(R)-N-(quinuclidin-3-yl)benzamide hydrochloride
To a solution of imidazole 0.68 g, 10 mmol) in acetonitrile (10 mL) benzoylchloride (0.67 g, 4.8 mmol) in acetonitrile (1 mL) was slowly added at room temperature. Formation of a sticky precipitate was observed. Then, solid (R)-quinuclidin-3-amine dihydrochloride (1.0 g, 5.0 mmol) and solid imidazole (0.68 g, 10.0 mmol) were added. The reaction mixture was then stirred at room temperature until completion. Then, water (0.09 g, 5 mmol) was added dropwise. Stirring was continued for 3 hours. The crystalline product was separated by filtration and washed with diethylether (5 mL). Drying of the residue obtained in vacuo provided pure (R)-N-(quinuclidin-3- yl)benzamide hydrochloride as a crystalline solid. M.p: 248 °C (upon a phase transition at 217- 220 °C).
1 H NMR (300 MHz, DMSO-d6): δ 1.69 (m, 1 H), 1.89 (m, 2H), 2.10 (m, 1 H), 2.17 (m, 1 H), 3.17 (m, 3H), 3.38 (m, 2H), 3.58 (m, 1 H), 4.33 (m, 1 H), 7.46 (t, J=7.3 Hz, 2H), 7.54 (t, J=7.2 Hz, 1 H), 7.96 (d, J=7.0 Hz, 2H), 8.84 (d, J=6.1 Hz, 1 H), 10.8 (br, 1 H) ppm
13C NMR (75 MHz, DMSO-d6): δ 17.2, 21.5, 24.5, 44.7, 44.9, 45.3, 50.2, 127.6 (2C), 128.2 (2C), 131.4, 133.9, 166.7 ppm.
IR (neat): v 3230 (w), 2916 (w), 2632 (w), 2538 (m), 2479 (m), 1651 (s), 1521 (s), 1486 (m), 131 1 (m), 707 (s), 619 (s) cm-1 .
Example 4
N-(1 -Methyl-4-piperidinyl)benzamide hydrochloride
To a solution of imidazole (0.36 g, 5.3 mmol) in acetonitrile (5 mL) benzoylchloride (0.36 g, 2.5 mmol) in acetonitrile (1 mL) was slowly added at room temperature. Formation of a sticky precipitate was observed. Then, solid 4-amino-1 -methylpiperidine dihydrochloride (0.5 g, 2.7 mmol) and solid imidazole (0.36 g, 5.3 mmol) were added. The reaction mixture was then stirred at room temperature until completion. Then, water (0.05 g, 5 mmol) was added dropwise. Stirring was continued for 3 hours. The crystalline product was separated by filtration and washed with diethylether (5 mL). Drying of the residue obtained in vacuo provided N-(1-Methyl-4- piperidinyl)benzamide hydrochloride as a crystalline solid. M.p: 213-214 °C (upon a phase transition at 205 °C). 1 H NMR (300 MHz, DMSO-d6): δ 1.97 (m, 4H), 2.69 (s, 3H), 3.37 (m, 4H), 4.02 (m, 1 H), 7.44 (t, J=7.2 Hz, 2H), 7.52 (t, J=7.2 Hz, 1 H), 7.89 (d, J=7.2 Hz, 1 H), 8.60 (d, J=6.4 Hz, 1 H), 1 1.0 (br, 1 H) ppm.
13C NMR (75 MHz, DMSO-d6): δ 28.6, 42.4, 44.4, 52.4, 127.4, 128.1 , 131.2, 134.2, 165.8 ppm. IR (neat): v 3243 (w), 3055 (w), 2945 (w), 2455 (m), 1628 (s), 1537 (s), 1467 (m), 131 1 (m), 960 (m), 696 (s) cm-1.
Reference example 1 :
(R)-7-Chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
To a stirred solution of (R)-quinuclidin-3-amine dihydrochloride (0.86 g, 4.3 mmol) in pyridine (1.1 ml.) a solution of 7-chlorobenzo[b]thiophene-2-carboxylic acid chloride (1.0 g, 4.3 mmol) in dichloromethane (10 ml.) were slowly added at room temperature. The reaction mixture was then stirred at room temperature for 48 hours. Formation of a brownish precipitate was observed. Upon filtration the residue was suspended in a mixture of water (10 ml.) and acetone (5 ml.) and the pH was adjusted from an original value of 5 to 8 by addition of 1 M aqueous sodium hydroxide solution and stirred at room temperature for 30 minutes. Filtration and drying of the residue obtained in vacuo did provide 0.44 g (32%) of encenicline free base as an off-white solid.
Reference example 2:
To a stirred solution of (R)-quinuclidin-3-amine dihydrochloride (0.86 g, 4.3 mmol) in triethylamine (1 .8 ml.) a solution of 7-chlorobenzo[b]thiophene-2-carboxylic acid chloride (1 .0 g, 4.3 mmol) in dichloromethane (10 ml.) were slowly added at room temperature. The reaction mixture was then stirred at room temperature for 48 hours. The crude material was separated by filtration, extracted twice with dichloromethane (2 ml.) and dried in vacuo. The solid was sequentially stirred with saturated aqueous sodium bicarbonate (10 ml.) and 1 M aqueous sodium hydroxide solution (12 ml_). After addition of dichloromethane (30 ml.) the pH value was adjusted to a value of 7 by addition of hydrochloric acid and sodium bicarbonate. A precipitate insoluble in both layers was separated by filtration. After washing with small amounts of water and drying in vacuo 0.21 g (12%) of a compound was obtained as a white solid. The compound was different from encenicline.

Claims

Claims
Process for the preparation of an amide from a carboxylic acid chloride and an organic molecule comprising both a primary amine group and a tertiary amine group, wherein the nitrogen atom of the tertiary amine group is comprised in a non-aromatic heterocycle and wherein the amide bond forms selectively with the primary amine group, comprising the step of a) reacting the carboxylic acid chloride with an organic molecule comprising both the primary amine group and the tertiary amine group,
in the presence of imidazole.
The process according to claim 1 , wherein the carboxylic acid chloride does not comprise a non-aromatic nitrogen atom.
The process according to any one of claims 1 to 2, wherein the nitrogen atom of the tertiary amine group is the bridgehead atom of a bicyclic ring system
The process according to claim 3, wherein the bicyclic ring system is of type [2.2.2].
The process according to any one of claims 1 to 4, wherein the organic molecule comprising both a primary amine group and a tertiary amine group is quinuclidin-3- amine.
The process according to any one of claims 1 to 5, wherein the carboxylic acid chloride is Heteroaryl- COCI or Aryl- COCI.
The process according to claim 6, wherein Heteroaryl- or Aryl- is a monocyclic, bicyclic or tricyclic aromatic ring system consisting of 6 to 14 atoms, wherein 1 to 4 atoms of the aromatic ring system can be S, N or O, and wherein Heteroaryl- or Aryl- can be substituted or unsubstituted.
8. The process according to claims 6 or 7, wherein Heteroaryl- COCI is a substituted or unsubstituted benzo[b]thiophene-2-carboxylic acid chloride.
9. The process according to any one of claims 1 to 8 for the preparation of encenicline or a salt thereof, wherein in step a) (R)-quinuclidin-3-amine is reacted with benzo[b]thiophene-2-carboxylic acid chloride.
10. The process according to claim 9, further comprising, after step a), the step of b) adding at least one mole of water per mole of (R)-quinuclidin-3-amine to the reaction mixture to obtain crystalline encenicline hydrochloride.
1 1. The process according to any one of claims 9 to 10, wherein (R)-quinuclidin-3-amine is provided as a free base and wherein the molar ratio of imidazole : (R)-quinuclidin-3- amine is about 2:1 .
12. The process according to any one of claims 9 and 10, wherein (R)-quinuclidin-3-amine is provided as its dihydrochloride salt and wherein the molar ratio of imidazole : (R)- quinuclidin-3-amine is about 4:1 .
13. Use of imidazole for the selective acylation of a primary amine group in an organic molecule comprising both a primary amine group and a tertiary amine group, wherein the nitrogen atom of the tertiary amine group is comprised in a non-aromatic heterocycle, in the reaction of said organic molecule comprising both the primary amine group and the tertiary amine group with a carboxylic acid chloride.
14. Use according to claim 13 wherein the carboxylic acid chloride does not comprise a non- aromatic nitrogen atom.
15. Use according to any one of claims 13 to 14 for the preparation of encenicline or a salt thereof, wherein (R)-quinuclidin-3-amine is reacted with benzo[b]thiophene-2-carboxylic acid chloride in the presence of imidazole.
PCT/EP2016/073773 2015-10-05 2016-10-05 Process for the preparation of encenicline from 7-chloro-benzo[b]thiophene-2-carboxylic acid chloride and (r)-quinuclidin-3-amine in the presence of imidazole WO2017060287A1 (en)

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