ITMI20100770A1 - PROCEDURE FOR THE PREPARATION OF 3- (4-PYRIDINYL) -PROPANOL AND ITS INTERMEDIATES - Google Patents

PROCEDURE FOR THE PREPARATION OF 3- (4-PYRIDINYL) -PROPANOL AND ITS INTERMEDIATES Download PDF

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ITMI20100770A1
ITMI20100770A1 IT000770A ITMI20100770A ITMI20100770A1 IT MI20100770 A1 ITMI20100770 A1 IT MI20100770A1 IT 000770 A IT000770 A IT 000770A IT MI20100770 A ITMI20100770 A IT MI20100770A IT MI20100770 A1 ITMI20100770 A1 IT MI20100770A1
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formula
compound
salt
pyridinyl
reaction
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IT000770A
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Italian (it)
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Pietro Allegrini
Emanuele Attolino
Marco Alessandro De
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Dipharma Francis Srl
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Priority to PCT/EP2011/056885 priority patent/WO2011138250A1/en
Publication of ITMI20100770A1 publication Critical patent/ITMI20100770A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters

Description

Descrizione del brevetto per invenzione industriale avente per titolo: Description of the patent for industrial invention entitled:

“PROCEDIMENTO PER LA PREPARAZIONE DI 3-(4-PIRIDINIL)-PROPANOLO E SUOI INTERMEDI” "PROCEDURE FOR THE PREPARATION OF 3- (4-PYRIDINYL) -PROPANOL AND ITS INTERMEDIATES"

CAMPO DELL’INVENZIONE FIELD OF THE INVENTION

La presente invenzione riguarda un procedimento per la preparazione di 3-(4-piridinil)-propanolo o un suo sale, e intermedi utili nella sua sintesi. The present invention relates to a process for the preparation of 3- (4-pyridinyl) -propanol or a salt thereof, and intermediates useful in its synthesis.

STATO DELLA TECNICA STATE OF THE TECHNIQUE

Il composto 3-(4-piridinil)-propanolo di formula (I), The compound 3- (4-pyridinyl) -propanol of formula (I),

è l’intermedio chiave nella preparazione del 3-(4-piperidinil)-propanolo, di formula (A), is the key intermediate in the preparation of 3- (4-piperidinyl) -propanol, of formula (A),

composto impiegato nella sintesi di diversi principi attivi farmaceutici come descritto ad esempio in WO 2008081204, W02008081205 e WO 2009034388 impiegati nel trattamento di obesità e diabete. L’idrogenazione catalitica di (I), mediata da catalizzatori metallici a base di Pd, Pt o Rh, porta infatti alla formazione del composto idrogenato corrispondente alla struttura piperidinica di formula (A). compound used in the synthesis of various pharmaceutical active ingredients as described for example in WO 2008081204, WO2008081205 and WO 2009034388 used in the treatment of obesity and diabetes. The catalytic hydrogenation of (I), mediated by metal catalysts based on Pd, Pt or Rh, in fact leads to the formation of the hydrogenated compound corresponding to the piperidine structure of formula (A).

La sintesi del 3-(4-piridinil)-propanolo è già nota da tempo in letteratura ad esempio da J. Org. Chem. 1982, 47, 3008-3011 a partire da 4-picolina e ossido di etilene o suoi derivati o da 4-alopiridine come noto da Tetrahedron 2001, 57, 3125-3130. The synthesis of 3- (4-pyridinyl) -propanol has already been known for some time in the literature, for example by J. Org. Chem. 1982, 47, 3008-3011 starting from 4-picoline and ethylene oxide or its derivatives or from 4-halopyridines as known from Tetrahedron 2001, 57, 3125-3130.

Queste sintesi soffrono però deH’impiego di reattivi organometallici instabili o di materie prime costose, come le 4-alo piridine, o deH’impiego di reattivi pericolosi come l’ossido di etilene e complessi da gestire industrialmente. However, these syntheses suffer from the use of unstable organometallic reagents or expensive raw materials, such as 4-halo pyridines, or from the use of dangerous reagents such as ethylene oxide and complexes to be managed industrially.

Esiste pertanto la necessità di una via alternativa di sintesi che fornisca 3-(4-piridinil)-propanolo e quindi il 3-(4-piperidinil)-propanolo o un loro sale a partire da materie prime di basso costo con un processo facilmente scalabile industrialmente ed efficiente. There is therefore a need for an alternative synthesis route that provides 3- (4-pyridinyl) -propanol and therefore 3- (4-piperidinyl) -propanol or a salt thereof starting from low-cost raw materials with an easily scalable process. industrially and efficiently.

SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION

E stato qui trovato un procedimento alternativo, che permette di ottenere 3-(4-piridinil)-propanolo o un suo sale a partire da materie prime non tossiche e poco costose e con pochi passaggi sintetici. Ciò rende il nuovo procedimento dell’invenzione maggiormente vantaggioso rispetto ai procedimenti noti. An alternative process has been found here, which makes it possible to obtain 3- (4-pyridinyl) -propanol or a salt thereof starting from non-toxic and inexpensive raw materials and with few synthetic steps. This makes the new process of the invention more advantageous than the known processes.

DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION

Oggetto dell’invenzione è un procedimento per la preparazione di un composto di formula (I) o un suo sale, The subject of the invention is a process for the preparation of a compound of formula (I) or a salt thereof,

che comprende la riduzione di un composto di formula (II) o un suo sale, dove R è un gruppo Ci-C4alchile, con un idruro metallico, which includes the reduction of a compound of formula (II) or a salt thereof, where R is a C1-C4alkyl group, with a metal hydride,

caratterizzato dal fatto che un composto di formula (II) o un suo sale, è ottenuto mediante un procedimento comprendente: characterized in that a compound of formula (II) or a salt thereof, is obtained by a process comprising:

a) la eliminazione della funzione ossidrilica in un composto di formula (III) a) the elimination of the hydroxyl function in a compound of formula (III)

dove Y è OH, oppure di un gruppo uscente derivato da questo, preferibilmente un mesilato, tosilato, nosilato o triflato; oppure where Y is OH, or of a leaving group derived therefrom, preferably a mesylate, tosylate, nosylate or triflate; or

b) la reazione tra 4-piridincarbossaldeide di formula (IV) b) the reaction between 4-pyridincarboxaldehyde of formula (IV)

ed un composto di formula (V) and a compound of formula (V)

(V) (V)

dove R è come prima definito; e, se desiderato, la conversione di un composto di formula (I) in un suo sale, oppure la conversione di un suo sale nel composto basico libero. where R is as defined above; and, if desired, the conversion of a compound of formula (I) into a salt thereof, or the conversion of a salt thereof into the free basic compound.

Un gruppo Ci-C4alchile può essere lineare o ramificato, preferibilmente metile, etile o isopropile, in particolare isopropile. A C 1 -C4alkyl group can be linear or branched, preferably methyl, ethyl or isopropyl, in particular isopropyl.

Un idruro metallico è preferibilmente sodio boro idruro. A metal hydride is preferably sodium boron hydride.

La reazione di riduzione di un composto di formula (II) con un idruro metallico può essere condotta in un solvente scelto ad esempio tra un etere, tipicamente tetraidrofurano o diossano; un Ci-C6alcanolo lineare o ramificato, preferibilmente un Ci-C4alcanolo lineare o ramificato ad esempio metanolo, etanolo o isopropanolo; oppure una miscela di due o più, preferibilmente due o tre, di detti solventi; oppure in acqua o una soluzione acquosa con uno o più, preferibilmente due o tre, di detti solventi. The reduction reaction of a compound of formula (II) with a metal hydride can be carried out in a solvent selected for example from an ether, typically tetrahydrofuran or dioxane; a linear or branched C6-C6alkanol, preferably a linear or branched C6 -C6alkanol, for example methanol, ethanol or isopropanol; or a mixture of two or more, preferably two or three, of said solvents; or in water or an aqueous solution with one or more, preferably two or three, of said solvents.

L’eliminazione della funzione ossidrilica in un composto di formula (III), come prima definito, ad ottenere un composto di formula (II), come prima definito, può essere ad esempio condotta trasformando la funzione ossidrilica in un buon gruppo uscente, ad esempio un mesilato, tosilato, nosilato o triflato, e trattando con una base eventualmente in presenza di un solvente, ad esempio come prima riportato. Ad esempio un composto di formula (III) dove Y è un ossidrile può essere trasformato in un composto di formula (III) dove Y è mesilato, per trattamento con cloruro di mesile in presenza di una ammina terziaria. Il mesilato così ottenuto può essere trattato con un’ulteriore quantità di ammina terziaria, la stessa o un’altra, eventualmente scaldando la miscela di reazione fino alla temperatura di riflusso della miscela per ottenere il prodotto di eliminazione di formula (II). The elimination of the hydroxyl function in a compound of formula (III), as defined above, to obtain a compound of formula (II), as defined above, can be carried out for example by transforming the hydroxyl function into a good leaving group, for example a mesylate, tosylate, nosylate or triflate, and treating with a base optionally in the presence of a solvent, for example as reported above. For example, a compound of formula (III) where Y is a hydroxyl can be transformed into a compound of formula (III) where Y is mesylate, by treatment with mesyl chloride in the presence of a tertiary amine. The mesylate thus obtained can be treated with a further amount of tertiary amine, the same or another, possibly by heating the reaction mixture up to the reflux temperature of the mixture to obtain the elimination product of formula (II).

Un composto di formula (III), dove Y è idrossi, può essere ottenuto per reazione di un composto di formula (IV) con un composto di formula (V) ad esempio in presenza di una base, ed eventualmente di un solvente, ad esempio come prima riportato. La medesima miscela di reazione di formazione di un composto di formula (III), può portare ad un composto di formula (II) anche spontaneamente, per prolungato riscaldamento della miscela di reazione o alzando ancora il pH della miscela di reazione o lasciando semplicemente la miscela di reazione in agitazione per tempi lunghi. A compound of formula (III), where Y is hydroxy, can be obtained by reaction of a compound of formula (IV) with a compound of formula (V) for example in the presence of a base, and optionally of a solvent, for example as reported above. The same reaction mixture for the formation of a compound of formula (III), can lead to a compound of formula (II) also spontaneously, by prolonged heating of the reaction mixture or by raising the pH of the reaction mixture again or simply leaving the mixture of reaction under stirring for long times.

Un composto di formula (III) dove Y è idrossi, può anche essere ottenuto per riduzione di un composto di formula (VI) A compound of formula (III) where Y is hydroxy, can also be obtained by reduction of a compound of formula (VI)

secondo metodiche note, ad esempio mediante idrogenazione catalica o mediante l’impiego di un idruro metallico riducente, come prima esemplificato. according to known methods, for example by catalytic hydrogenation or by using a reducing metal hydride, as exemplified above.

Un composto di formula (III), dove Y è un gruppo uscente derivato da un gruppo idrossi, preferibilmente un mesilato, tosilato, nosilato o triflato, può essere preparato a partire dal corrispondente composto di formula (III) dove Y è un gruppo idrossi in accordo a metodiche note, come precedentemente descritto. A compound of formula (III), where Y is a leaving group derived from a hydroxy group, preferably a mesylate, tosylate, nosylate or triflate, can be prepared starting from the corresponding compound of formula (III) where Y is a hydroxy group in according to known methods, as previously described.

Un composto di formula (VI) può essere preparato mediante condensazione di Claisen tra un composto di formula (VII) A compound of formula (VI) can be prepared by Claisen condensation between a compound of formula (VII)

dove R è come prima definito, con un composto di formula (V) where R is as defined above, with a compound of formula (V)

CH3COOR (V) CH3COOR (V)

dove R è come prima definito, secondo le metodiche note, ad esempio facendo reagire il composto di formula (VII) con un composto di formula (V) in presenza di una base forte, organica o inorganica, eventualmente in presenza di un solvente. where R is defined as above, according to known methods, for example by reacting the compound of formula (VII) with a compound of formula (V) in the presence of a strong, organic or inorganic base, optionally in the presence of a solvent.

L’estere di formula (VII), dove R è come prima definito, può essere preparato dall’acido isonicotinico commercialmente disponibile secondo metodiche note. The ester of formula (VII), where R is as defined above, can be prepared from commercially available isonicotinic acid according to known methods.

La 4-piridin carbossialdeide di formula (IV) è commercialmente disponibile e gli acetati CH3COOR di formula (V) sono commercialmente disponibili o ottenibili secondo metodiche note. The 4-pyridine carboxyaldehyde of formula (IV) is commercially available and the CH3COOR acetates of formula (V) are commercially available or obtainable according to known methods.

Un ulteriore oggetto della presente invenzione è un procedimento per la preparazione del composto di formula (A), o un suo sale, mediante un processo comprendente la conversione di un composto di formula (II), così ottenuto, ad esempio mediante riduzione, in particolare per idrogenazione catalitica come prima esemplificato. A further object of the present invention is a process for the preparation of the compound of formula (A), or a salt thereof, by means of a process comprising the conversion of a compound of formula (II), thus obtained, for example by reduction, in particular by catalytic hydrogenation as exemplified above.

Un sale di un composto di formula (A), (I), (II), (III), (IV), (VI) e (VII) può essere ad esempio un suo sale farmaceuticamente accettabile, preferibilmente è sale cloridrato. Questo può essere ottenuto mediante metodi noti nell’arte. Ad esempio un suo sale può essere ottenuto sciogliendo tale composto come base libera in etile acetato e quindi facendolo reagire con un acido protico organico, come ad esempio acido acetico, citrico, tartarico, fumario o succinico oppure con un acido protico minerale, come ad esempio acido cloridrico, bromidrico o solforico. Preferibilmente l’acido protico minerale è l’acido cloridrico acquoso o gassoso. Analogamente, la conversione di un sale di un composto di formula (I) nel composto basico libero può essere effettuata in accordo a metodi noti. A salt of a compound of formula (A), (I), (II), (III), (IV), (VI) and (VII) can be for example a pharmaceutically acceptable salt thereof, preferably it is hydrochloride salt. This can be achieved by methods known in the art. For example, one of its salt can be obtained by dissolving this compound as a free base in ethyl acetate and then making it react with an organic protic acid, such as for example acetic, citric, tartaric, fumary or succinic acid or with a mineral protic acid, such as for example hydrochloric, hydrobromic or sulfuric acid. Preferably the mineral protic acid is aqueous or gaseous hydrochloric acid. Similarly, the conversion of a salt of a compound of formula (I) into the free basic compound can be carried out according to known methods.

L’idrogenazione catalitica citate nei processi descritti può essere effettuata ad esempio con idrogeno ed un catalizzatore metallico, omogeneo o eterogeneo, ad esempio a base di palladio, platino, nichel, rodio o rutenio. The catalytic hydrogenation mentioned in the processes described can be carried out for example with hydrogen and a metallic catalyst, homogeneous or heterogeneous, for example based on palladium, platinum, nickel, rhodium or ruthenium.

L’idrogenazione catalitica può essere effettuata impiegando idrogeno a una pressione che può variare tra circa 1 atm e 20 atm. Catalytic hydrogenation can be carried out using hydrogen at a pressure that can vary between about 1 atm and 20 atm.

Quando il catalizzatore metallico è eterogeneo, esso è preferibilmente depositato su un supporto inerte quale, ad esempio, carbone, bario idrossido, allumina, calcio carbonato, preferibilmente carbone. La concentrazione del metallo sul supporto può variare tra circa l’l% ed il 30%, preferibilmente tra circa il 5% ed il 10%. When the metal catalyst is heterogeneous, it is preferably deposited on an inert support such as, for example, carbon, barium hydroxide, alumina, calcium carbonate, preferably carbon. The concentration of the metal on the support can vary between about 1% and 30%, preferably between about 5% and 10%.

Preferibilmente la reazione di riduzione è condotta in presenza di un solvente scelto ad esempio tra un solvente dipolare aprotico, tipicamente dimetilformammide, dimetilacetammide, acetonitrile, e dimetilsolfossido; un etere, tipicamente tetraidrofurano o diossano; un alcanolo lineare o ramificato CrCe, preferibilmente un alcanolo lineare o ramificato Ci-C4ad esempio metanolo, etanolo o isopropanolo; un acido carbossilico CÌ-CÈquale, ad esempio, acido acetico o acido propionico; o una miscela di due o più, preferibilmente due o tre, di detti solventi; oppure in acqua o una soluzione acquosa di un acido protico organico o minerale quale, ad esempio acido trifluoroacetico, metansolfonico e acido cloridrico, o una loro miscela con uno o più, preferibilmente due o tre, di detti solventi. Preferably, the reduction reaction is carried out in the presence of a solvent selected for example from an aprotic dipolar solvent, typically dimethylformamide, dimethylacetamide, acetonitrile, and dimethylsulfoxide; an ether, typically tetrahydrofuran or dioxane; a linear or branched CrCe alkanol, preferably a linear or branched C1-C4 alkanol, for example methanol, ethanol or isopropanol; a C1-CE carboxylic acid such as, for example, acetic acid or propionic acid; or a mixture of two or more, preferably two or three, of said solvents; or in water or an aqueous solution of an organic or mineral protic acid such as, for example trifluoroacetic acid, methanesulfonic acid and hydrochloric acid, or a mixture thereof with one or more, preferably two or three, of said solvents.

Il seguenti esempi illustrano l’invenzione. The following examples illustrate the invention.

Esempio 1: Sintesi di metil isonicotinato (VII) Example 1: Synthesis of methyl isonicotinate (VII)

In un pallone a 3 colli da 250 mi, dotato di agitazione magnetica, termometro, condensatore e sotto flusso di azoto viene caricato il cloruro di tionile (50 mi) e raffreddato con bagno di ghiaccio a 0°C. Viene quindi aggiunto l’acido isonicotinico (20 g, 162,5 mmol) a piccole porzioni, mantenendo la temperatura sotto i 20°C. Viene quindi rimosso il bagno di ghiaccio e si lascia rinvenire la miscela di reazione a temperatura ambiente. Dopo 10 minuti sotto agitazione viene rimosso il cloruro di tionile in eccesso sotto vuoto, fino ad ottenere un solido bianco. Posto a 0°C con bagno di ghiaccio viene lentamente gocciolato il metanolo (50 mi).. A fine aggiunta si lascia rinvenire a temperatura ambiente e si lascia sotto agitazione per 10 minuti. Rimosso il metanolo in eccesso sotto vuoto, il solido bianco ottenuto viene sciolto in H20 (70 mi) e neutralizzato con NaHC03fino ad un pH ~ 6. Si estrae quindi con AcOEt (3x80 mi) e le fasi organiche riunite vengono anidrificate e portate a secchezza a dare 22,3 g di prodotto (VII) (resa 100%). Thionyl chloride (50 ml) is charged into a 250 ml 3-neck flask, equipped with magnetic stirring, thermometer, condenser and under nitrogen flow and cooled with an ice bath to 0 ° C. Isonicotinic acid (20 g, 162.5 mmol) is then added in small portions, keeping the temperature below 20 ° C. The ice bath is then removed and the reaction mixture is allowed to rise to room temperature. After 10 minutes under stirring, the excess thionyl chloride is removed under vacuum, until a white solid is obtained. When placed at 0 ° C with an ice bath, the methanol is slowly dripped (50 ml). At the end of the addition it is allowed to rise to room temperature and left under stirring for 10 minutes. Removed the excess methanol under vacuum, the white solid obtained is dissolved in H20 (70 ml) and neutralized with NaHC03 up to a pH of ~ 6. It is then extracted with AcOEt (3x80 ml) and the combined organic phases are dried and dried. to give 22.3 g of product (VII) (yield 100%).

Esempio 2: Sintesi di 3-(4-piridinil)-3-cheto-propionato di isopropile (VI) Example 2: Synthesis of 3- (4-pyridinyl) -3-keto-propionate of isopropyl (VI)

In un pallone a 3 colli da 500 mi, dotato di agitazione magnetica, termometro, condensatore e sotto flusso di azoto viene sciolto il metil isonicotinato (22,3 g, 162,5 mmol) in AcOiPr (190 mi). Posto a 0°C con bagno di ghiaccio, viene aggiunto il tBuOK (36,5 g, 324,9 mmol) a piccole porzioni, mantenendo la temperatura sotto i 10°C. Finita l’aggiunta, la miscela di reazione viene scaldata a 50°C. e risulta completa dopo 1,5 h. Viene quindi aggiunta H20 (70 mi) e HC1 33% fino a pH ~ 6 e i prodotti vengono estratti con AcOEt (150 mi 2 x 80 mi). Le fasi organiche riunite vengono anidrificate e portate a secchezza a dare 33,6 g di liquido denso e scuro. L’analisi 1H-NMR del grezzo di reazione rivela la presenza dell’acetacetato di isopropile e degli esteri metilico ed isopropilico del 3-(4-piridinil)-3-cheto-propionato (VI). La miscela ottenuta viene utilizzata come tale nelle reazioni successive, senza essere sottoposta a processi di purificazione. Un campione di 0,8 g della miscela viene purificato per flash cromatografia, ottenendo un campione puro del 3-(4-piridinil)-3-chetopropionato di isopropile (VI). The methyl isonicotinate (22.3 g, 162.5 mmol) in AcOiPr (190 ml) is dissolved in a 500 ml 3-neck flask, equipped with magnetic stirrer, thermometer, condenser and under nitrogen flow. Placed at 0 ° C with an ice bath, tBuOK (36.5 g, 324.9 mmol) is added in small portions, keeping the temperature below 10 ° C. After the addition, the reaction mixture is heated to 50 ° C. and is complete after 1.5 h. H20 (70 ml) and 33% HC1 are then added up to pH ~ 6 and the products are extracted with AcOEt (150 ml 2 x 80 ml). The combined organic phases are dried and brought to dryness to give 33.6 g of dense and dark liquid. The 1H-NMR analysis of the reaction raw product reveals the presence of isopropyl acetacetate and the methyl and isopropyl esters of 3- (4-pyridinyl) -3-keto-propionate (VI). The mixture obtained is used as such in the subsequent reactions, without being subjected to purification processes. A 0.8 g sample of the mixture is purified by flash chromatography, obtaining a pure sample of isopropyl (VI) 3- (4-pyridinyl) -3-ketopropionate.

All’ anali NMR il 3-(4-piridinil)-3-cheto-propionato di isopropile è in equilibrio cheto-enolico spostato a favore del tautomero enolico per circa il 60%) : At NMR analysis, isopropyl 3- (4-pyridinyl) -3-keto-propionate is in keto-enol equilibrium shifted in favor of the enol tautomer for about 60%):

Tautomero enolico Enol tautomer

1H-NMR (CDC13) : δ= 12.50 (s, IH, Ar-C-O//); 8.69 (d, 2H, J=5.7 Hz, Ar -//); 7.59 (d, 2H, J=5.7 Hz, Ar-//); 5.73 (5, IH, CC//-COO); 5.16 (ep, IH, J=6.3 Hz, COOC//); 1.32 (d, 6H, J=6.3 Hz, CH(C//i)2). 1H-NMR (CDC13): δ = 12.50 (s, 1H, Ar-C-O //); 8.69 (d, 2H, J = 5.7 Hz, Ar - //); 7.59 (d, 2H, J = 5.7 Hz, Ar - //); 5.73 (5, 1H, CC // - COO); 5.16 (ep, 1H, J = 6.3 Hz, COOC //); 1.32 (d, 6H, J = 6.3 Hz, CH (C // i) 2).

<13>C-NMR (CDCI3): 5=171.7 (Ar-C-OH); 167.5 (COO); 149.9 (2C, Ar-CH); 140.2 (1C, Ar-C); 119.1 (2C, Ar-CH); 89.8(C=CHCOO); 67.8(COOCH); 21.1(2C, CH(CH3)2). <13> C-NMR (CDCI3): 5 = 171.7 (Ar-C-OH); 167.5 (COO); 149.9 (2C, Ar-CH); 140.2 (1C, Ar-C); 119.1 (2C, Ar-CH); 89.8 (C = CHCOO); 67.8 (COOCH); 21.1 (2C, CH (CH3) 2).

Tautomero chetonico Ketone tautomer

1H-NMR (CDCI3) : 5= 8.82 (d, 2H, J=5.7 Hz, Ar-//); 7.70 (d, 2H, J=5.7 Hz, Ar-//); 5.07 ( ep , IH, J=6.3 Hz, COOC//); 3.94 (s, 2H, COC//2COO); 1.22 (d, 6H, J=6.3 Hz, CH(C/3⁄42). 1H-NMR (CDCI3): 5 = 8.82 (d, 2H, J = 5.7 Hz, Ar - //); 7.70 (d, 2H, J = 5.7 Hz, Ar - //); 5.07 (ep, 1H, J = 6.3 Hz, COOC //); 3.94 (s, 2H, COC // 2COO); 1.22 (d, 6H, J = 6.3 Hz, CH (C / 3⁄42).

<13>C-NMR (CDCI3): 5=191.8 (Ar-COCH2); 165.8 (COO); 150.5 (2C, Ar-CH); 141.4 (1C, Ar-C); 120.7 (2C, Ar-CH); 68.6(COOCH); 45.7(COCH2COO); 21.0(2C, CH(CH3)2). <13> C-NMR (CDCI3): 5 = 191.8 (Ar-COCH2); 165.8 (COO); 150.5 (2C, Ar-CH); 141.4 (1C, Ar-C); 120.7 (2C, Ar-CH); 68.6 (COOCH); 45.7 (COCH2COO); 21.0 (2C, CH (CH3) 2).

3-(4-piridinil)-3-cheto-propionato di metile (in equilibrio cheto-enolico spostato a favore del tautomero enolico per circa il 65%) : Methyl 3- (4-pyridinyl) -3-keto-propionate (in keto-enol equilibrium shifted in favor of the enol tautomer for about 65%):

Tautomero enolico Enol tautomer

1H-NMR (CDC13) : δ= 12.35 (s, IH, Ar-C-O//); 8.70 (d, 2H, J=5.7 Hz, Ar -//); 7.60 (d, 2H, J=5.7 Hz, Ar -//); 5.77 (5, IH, C=C//-COO); 3.83 (5, 3H, COOC H3). 1H-NMR (CDC13): δ = 12.35 (s, 1H, Ar-C-O //); 8.70 (d, 2H, J = 5.7 Hz, Ar - //); 7.60 (d, 2H, J = 5.7 Hz, Ar - //); 5.77 (5, 1H, C = C // - COO); 3.83 (5, 3H, COOC H3).

<13>C-NMR (CDCI3): 5=173.0 (Ar-C-OH); 168.4 (COO); 150.5 (2C, Ar-CH); 140.7 (1C, Ar-C); 121.3 (2C, Ar-CH); 89.7 (C=CHCOO); 5 1.8(COOCH3). <13> C-NMR (CDCI3): 5 = 173.0 (Ar-C-OH); 168.4 (COO); 150.5 (2C, Ar-CH); 140.7 (1C, Ar-C); 121.3 (2C, Ar-CH); 89.7 (C = CHCOO); 5 1.8 (COOCH3).

Tautomero chetonico Ketone tautomer

1H-NMR (CDCI3) : 5= 8.84 (d, 2H, J=5.7 Hz, Ar-//); 7.71 (d, 2H, J=5.7 Hz, Ar-//); 4.00 (j, 2H, COC//2COO); 3.76 (5, 3H, COOC H3). 1H-NMR (CDCI3): 5 = 8.84 (d, 2H, J = 5.7 Hz, Ar - //); 7.71 (d, 2H, J = 5.7 Hz, Ar - //); 4.00 (j, 2H, COC // 2COO); 3.76 (5, 3H, COOC H3).

<13>C-NMR (CDCI3): 5=192.0 (Ar-COCH2); 167.1 (COO); 151.2 (2C, Ar-CH); 141.7 (1C, Ar-C); 119.8 (2C, Ar-CH); 52.7 (COOCH3); 45.6 (COCH2COO). <13> C-NMR (CDCI3): 5 = 192.0 (Ar-COCH2); 167.1 (COO); 151.2 (2C, Ar-CH); 141.7 (1C, Ar-C); 119.8 (2C, Ar-CH); 52.7 (COOCH3); 45.6 (COCH2COO).

Esempio 3: Sintesi di 3-(4-piridinil)-3-idrossi-propionato di isopropile (III, dove Y è idrossi) Example 3: Synthesis of 3- (4-pyridinyl) -3-hydroxy-propionate of isopropyl (III, where Y is hydroxy)

In un pallone a 3 colli da 250 mi, dotato di agitazione magnetica e sotto flusso di azoto vengono disciolti 9,0 g di una miscela grezza ottenuta come in Esempio 2 contenente l’isopropil 3-(4-piridinil)-3-cheto-propionato in 55 mi di AcOEt. Dopo aver addizionato il catalizzatore di idrogenazione (Pd/C 5%, H20 = 48%, 6,3 g, 1,4 mmol) e aver effettuato tre cicli di vuoto/H2, la miscela viene mescolata a temperatura ambiente in atmosfera di H2. La reazione viene monitorata tramite TLC e la reazione risulta completa in 6 ore, trascorse le quali viene filtrata su perlite, lavando con 2 x 5 mi di AcOEt. Il solvente viene rimosso a pressione ridotta a dare 8,0 g di grezzo (resa 88%). Tale residuo viene disciolto in 18 mi di H20, acidificato con HC1 36% fino a pH - l e lavato con 3 x 7 mi di toluene. Dopo aver basificato la fase acquosa con una soluzione satura di K2C03fino a pH - 8, il prodotto è estratto con AcOEt. Dopo aver anidrificato e portato a secchezza a pressione ridotta si ottengono 4,7 g di prodotto (III) come solido (resa 60%). 9.0 g of a crude mixture obtained as in Example 2 containing isopropyl 3- (4-pyridinyl) -3-keto- are dissolved in a 250 ml 3-necked flask, equipped with magnetic stirring and under nitrogen flow. propionate in 55 ml of AcOEt. After adding the hydrogenation catalyst (Pd / C 5%, H20 = 48%, 6.3 g, 1.4 mmol) and having carried out three vacuum / H2 cycles, the mixture is mixed at room temperature in an H2 atmosphere . The reaction is monitored by TLC and the reaction is complete in 6 hours, after which it is filtered on perlite, washing with 2 x 5 ml of AcOEt. The solvent is removed under reduced pressure to give 8.0 g of crude (yield 88%). This residue is dissolved in 18 ml of H20, acidified with 36% HC1 to pH - 1 and washed with 3 x 7 ml of toluene. After basifying the aqueous phase with a saturated solution of K2C03 up to pH - 8, the product is extracted with AcOEt. After drying and drying under reduced pressure, 4.7 g of product (III) are obtained as a solid (yield 60%).

1H-NMR (CDC13) : 5= 8.32 (d, 2H, J=5.7 Hz, Ar-ZZ); 7.22 (d, 2H, J=5.7 Hz, Ar-//); 5.54 (bs, IH, Ar-CHO//); 5.04 (dd, IH, J^.4, J2=7.2, Ar-CZ/OH); 4.91 (ep, IH, J=6.3 Hz, COOC//); 2.58 (m, 2H, C//2COO); 1.09 (d, 6H, J=6.3 Hz, CH(C/3⁄42). 1H-NMR (CDC13): 5 = 8.32 (d, 2H, J = 5.7 Hz, Ar-ZZ); 7.22 (d, 2H, J = 5.7 Hz, Ar - //); 5.54 (bs, 1H, Ar-CHO //); 5.04 (dd, 1H, J ^ .4, J2 = 7.2, Ar-CZ / OH); 4.91 (ep, 1H, J = 6.3 Hz, COOC //); 2.58 (m, 2H, C // 2COO); 1.09 (d, 6H, J = 6.3 Hz, CH (C / 3⁄42).

<13>C-NMR (CDCI3): 5=170.9 (COO); 152.9 (1C, Ar-C); 149.2 (2C, Ar-CH); 120.9 (2C, Ar-CH); 68.7(Ar-CHOH); 68.4(COOCH); 43.5(CH2COO); <13> C-NMR (CDCI3): 5 = 170.9 (COO); 152.9 (1C, Ar-C); 149.2 (2C, Ar-CH); 120.9 (2C, Ar-CH); 68.7 (Ar-CHOH); 68.4 (COOCH); 43.5 (CH2COO);

21.6(2C, CH(CH3)2). 21.6 (2C, CH (CH3) 2).

Esempio 4 : Sintesi di 3-(4-piridinil)-propenoato di isopropile (II) In un pallone a 3 colli da 100 mi, dotato di agitazione magnetica, termometro, imbuto gocciolatore e sotto flusso di azoto, vengono disciolti 5,2 g del grezzo ottenuto in Esempio 3 in toluene (35 mi). Dopo aver aggiunto la TEA (3,0 g, 29,6 mmol), la miscela di reazione viene raffreddata a 0°C con bagno di ghiaccio e viene lentamente gocciolata una soluzione di MsCl (3,1 g, 27 mmol) in toluene (7 mi), mantenendo la temperatura interna inferiore ai 15° C. La reazione viene fatta rinvenire a temperatura ambiente e dopo un’ora la TLC (eluente: AcOEt, Rfstarting: 0,34 e 0,49) risulta completa. Viene quindi addizionata TEA (6,0, 59,3 mmol) e la miscela viene mescolata a temperatura ambiente per 16 h. Trascorso questo periodo l’analisi TLC rivela la scomparsa del mesilato (III). Dopo aver filtrato i sali, lavando con 10 mi di toluene, la fase organica viene lavata con 60 mi di brine, anidrificata e portata a secchezza a pressione ridotta, ottenendo 4,3 g di solido (resa 90%), successivamente purificato per flash cromatografia, recuperando 3,2 g di estere isopropilico del 3-(4-piridinil)-propenoato (II). Example 4: Synthesis of isopropyl (II) 3- (4-pyridinyl) -propenoate In a 100 ml 3-neck flask, equipped with magnetic stirrer, thermometer, dropping funnel and under nitrogen flow, 5.2 g of the crude obtained in Example 3 in toluene (35 ml). After adding the TEA (3.0 g, 29.6 mmol), the reaction mixture is cooled to 0 ° C with an ice bath and a solution of MsCl (3.1 g, 27 mmol) in toluene is slowly dropped. (7 ml), keeping the internal temperature below 15 ° C. The reaction is brought to room temperature and after one hour the TLC (eluent: AcOEt, Rfstarting: 0.34 and 0.49) is complete. TEA (6.0, 59.3 mmol) is then added and the mixture is mixed at room temperature for 16 h. After this period, the TLC analysis reveals the disappearance of mesylate (III). After filtering the salts, washing with 10 ml of toluene, the organic phase is washed with 60 ml of brine, anhydrified and brought to dryness under reduced pressure, obtaining 4.3 g of solid (yield 90%), subsequently purified by flash chromatography, recovering 3.2 g of 3- (4-pyridinyl) -propenoate (II) isopropyl ester.

1H-NMR (CDC13) : 5= 8.23 (d, 2H, J=5.7 Hz, Ar-//); 7.15 (d, IH, J=16.2 Hz, Ar-C//=CH); 6.96 (d, 2H, J=5.7 Hz, Ar-//); 6.19 (d, IH, J=16.2 Hz, CH=C//COO); 4.72 (ep, IH, J=6.3 Hz, COOC//); 0.89 (d, 6H, J=6.3 Hz, CH(C/3⁄42). 1H-NMR (CDC13): 5 = 8.23 (d, 2H, J = 5.7 Hz, Ar - //); 7.15 (d, 1H, J = 16.2 Hz, Ar-C // = CH); 6.96 (d, 2H, J = 5.7 Hz, Ar - //); 6.19 (d, 1H, J = 16.2 Hz, CH = C // COO); 4.72 (ep, 1H, J = 6.3 Hz, COOC //); 0.89 (d, 6H, J = 6.3 Hz, CH (C / 3⁄42).

<13>C-NMR (CDCI3): 5=164.5 (COO); 149.8 (2C, Ar-CH); 140.9 (Ar-CH=CH); 140.6 (1C, Ar-C); 122.7 (2C, Ar-CH); 121.1 (CH=CHCOO); 67.4(COOCH); 21.1 (2C, CH(CH3)2). <13> C-NMR (CDCI3): 5 = 164.5 (COO); 149.8 (2C, Ar-CH); 140.9 (Ar-CH = CH); 140.6 (1C, Ar-C); 122.7 (2C, Ar-CH); 121.1 (CH = CHCOO); 67.4 (COOCH); 21.1 (2C, CH (CH3) 2).

Esempio 5 : Sintesi di 3-(4-piridinil)-propanolo (I) Example 5: Synthesis of 3- (4-pyridinyl) -propanol (I)

In un pallone a 3 colli dotato di termometro, agitatore magnetico, refrigerante, imbuto gocciolatore, sotto flusso di azoto e raffreddato a 0°C con bagno di ghiaccio, viene addizionato NaBH4(2,1 g, 55 mmol) al MeOH (6 mi). Viene quindi gocciolata una soluzione di 0,9 g del isopropil 3-(4-piridinil)-propenoato (II) disciolta in 4 mi di MeOH. A effervescenza terminata viene rimosso il bagno di ghiaccio e la reazione viene portata a riflusso con bagno di olio a 80°C. La reazione viene monitorata tramite TLC e risulta completa dopo 4 ore, trascorse le quali si registra la scomparsa dei reagenti e la formazione prevalente di un prodotto. Dopo aver raffreddato la miscela di reazione a temperatura ambiente, la reazione viene spenta con 10 mi di H20 e il MeOH viene rimosso a pressione ridotta. Il prodotto viene estratto con CH2C12e le fasi organiche riunite vengono anidrificate e portate a secchezza a dare 0,5 g di solido (resa sul grezzo 74%). La successiva purificazione per flash cromatografia ha portato al recupero di 0,3 g di prodotto (I) come solido bianco. NaBH4 (2.1 g, 55 mmol) is added to MeOH (6 ml ). A 0.9 g solution of isopropyl 3- (4-pyridinyl) -propenoate (II) dissolved in 4 ml of MeOH is then dropped. At the end of the effervescence the ice bath is removed and the reaction is brought to reflux with an oil bath at 80 ° C. The reaction is monitored by TLC and is complete after 4 hours, after which the disappearance of the reagents and the prevailing formation of a product are recorded. After cooling the reaction mixture to room temperature, the reaction is quenched with 10 ml of H2 O and the MeOH is removed under reduced pressure. The product is extracted with CH2C12 and the combined organic phases are anhydrified and dried to give 0.5 g of solid (yield on the crude 74%). The subsequent purification by flash chromatography led to the recovery of 0.3 g of product (I) as a white solid.

1H-NMR (CDC13) : 5= 8.46 (d, 2H, J=5.7 Hz, Ar-//); 7.13 (d, 2H, J=5.7 Hz, Ar-//); 3.67 (t, 2H, J=6.3 Hz, C//2OH); 2.72 (t, 2H, J=7.8 Hz, Ar-C//2); 2.37 (bs, IH, CH20//); 1.90 (m, 2H, CH2C//2CH2). 1H-NMR (CDC13): 5 = 8.46 (d, 2H, J = 5.7 Hz, Ar - //); 7.13 (d, 2H, J = 5.7 Hz, Ar - //); 3.67 (t, 2H, J = 6.3 Hz, C // 2OH); 2.72 (t, 2H, J = 7.8 Hz, Ar-C // 2); 2.37 (bs, 1H, CH20 //); 1.90 (m, 2H, CH2C // 2CH2).

<13>C-NMR (CDCI3): 5=151.5 (Ar-C); 148.5 (2C, Ar-CH); 123.7 (2C, <13> C-NMR (CDCI3): 5 = 151.5 (Ar-C); 148.5 (2C, Ar-CH); 123.7 (2C,

Claims (4)

RIVENDICAZIONI 1. Procedimento per la preparazione di un composto di formula (I) o un suo sale, CLAIMS 1. Process for the preparation of a compound of formula (I) or a salt thereof, che comprende la riduzione di un composto di formula (II), o un suo sale, dove R è un gruppo CrC4alchile, con un idruro metallico, which includes the reduction of a compound of formula (II), or a salt thereof, where R is a CrC4alkyl group, with a metal hydride, caratterizzato dal fatto che un composto di formula (II), o un suo sale, è ottenuto mediante un procedimento comprendente: a) la eliminazione della funzione ossidrilica in un composto di formula (III) characterized in that a compound of formula (II), or a salt thereof, is obtained by a process comprising: a) the elimination of the hydroxyl function in a compound of formula (III) dove Y è OH, oppure di un gruppo uscente derivato da questo, preferibilmente un mesilato, tosilato, nosilato o trillato; oppure b) la reazione tra 4-piridincarbossaldeide di formula (IV) where Y is OH, or of a leaving group derived therefrom, preferably a mesylate, tosylate, nosylate or trillate; or b) the reaction between 4-pyridincarboxaldehyde of formula (IV) ed un composto di formula (V) (V) dove R è come prima definito; e, se desiderato la conversione di un composto di formula (I) in un suo sale, oppure la conversione di un suo sale nel composto basico libero. and a compound of formula (V) (V) where R is as defined above; and, if desired, the conversion of a compound of formula (I) into a salt thereof, or the conversion of a salt thereof into the free basic compound. 2. Un procedimento in accordo alla rivendicazione 1, dove l’eliminazione della funzione ossidrilica in un composto di formula (III) è condotta trasformando la funzione ossidrilica in un buon gruppo uscente, ad esempio un mesilato, tosilato, nosilato o trillato, e trattando con una base, eventualmente in presenza di un solvente. 2. A process according to claim 1, where the elimination of the hydroxyl function in a compound of formula (III) is carried out by transforming the hydroxyl function into a good leaving group, for example a mesylate, tosylate, nosylate or trillate, and treating with a base, possibly in the presence of a solvent. 3. Un procedimento in accordo alla rivendicazione 1, dove la reazione tra 4-piridincarbossaldeide di formula (IV) ed un composto di formula (V), come definiti in rivendicazione 1, è condotta in presenza di una base, ed eventualmente di un solvente. 3. A process according to claim 1, where the reaction between 4-pyridincarboxaldehyde of formula (IV) and a compound of formula (V), as defined in claim 1, is carried out in the presence of a base, and optionally of a solvent . 4. Un procedimento in accordo alla rivendicazione 1, comprendente inoltre la conversione di un composto di formula (II), o un suo sale, così ottenuto, in un composto di formula (A), o un suo sale. 4. A process according to claim 1, further comprising the conversion of a compound of formula (II), or a salt thereof, thus obtained, into a compound of formula (A), or a salt thereof.
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