ITMI20131836A1

ITMI20131836A1 - PROCESS AND INTERMEDIATE FOR LINAGLIPTINE PREPARATION

Info

Publication number: ITMI20131836A1
Application number: IT001836A
Authority: IT
Inventors: Graziano Castaldi; Marta Castaldi; Mauro Gaboardi
Original assignee: Chemelectiva S R L
Priority date: 2013-11-06
Filing date: 2013-11-06
Publication date: 2015-05-07
Also published as: WO2015067539A1

Description

”Processo ed intermedi per la preparazione di Linagliptina” "Process and intermediates for the preparation of Linagliptin"

DESCRIZIONE DESCRIPTION

La presente invenzione riguarda un processo per la sintesi di Linagliptina ed intermedi utili per la sua preparazione. The present invention relates to a process for the synthesis of Linagliptin and intermediates useful for its preparation.

Linagliptina è un inibitore reversibile e competitivo delle dipeptidil-peptidasi 4 (DPP-4), enzimi che degradano gli ormoni incretine, utilizzato in adulti affetti da diabete mellito di tipo 2 (diabete non insulina dipendente), per migliorare il controllo dei livelli di glucosio nel sangue. Linagliptin is a reversible and competitive inhibitor of dipeptidyl-peptidase 4 (DPP-4), enzymes that break down incretin hormones, used in adults with type 2 diabetes mellitus (non-insulin dependent diabetes), to improve the control of glucose levels in the blood.

Le incretine sono ormoni che vengono prodotti a livello gastrointestinale e sono principalmente il GLP-1 (Glucagon-Like Peptide 1) ed il GIP (Glucosedependent Insulinotropic Peptide). Vengono secrete dopo i pasti, in particolare il GLP-1, e hanno la funzione di controllare la glicemia in vari modi: aumento della secrezione di insulina da parte delle cellule beta del pancreas, diminuzione della secrezione di glucagone (antagonista dell’insulina) da parte delle cellule alfa del pancreas, rallentamento della motilità e dunque svuotamento gastrico, con conseguente diminuzione dell’appetito. Incretins are hormones that are produced at the gastrointestinal level and are mainly GLP-1 (Glucagon-Like Peptide 1) and GIP (Glucosedependent Insulinotropic Peptide). They are secreted after meals, in particular GLP-1, and have the function of controlling blood sugar in various ways: increase in insulin secretion by the beta cells of the pancreas, decrease in glucagon secretion (insulin antagonist) by part of the alpha cells of the pancreas, slowing of motility and therefore gastric emptying, with consequent decrease in appetite.

Il GLP-1 viene degradato rapidamente a peptide inattivo dalle DDP-4, inoltre la sua produzione diminuisce col diminuire della glicemia, quindi il suo controllo su quest’ultima risulta essere calibrato ed “al bisogno”, evitando così situazioni di ipersecrezione di insulina e conseguenti pericolose ipoglicemie. GLP-1 is rapidly degraded to an inactive peptide by DDP-4, moreover its production decreases with decreasing blood sugar, so its control over the latter is calibrated and "as needed", thus avoiding situations of hypersecretion of insulin and consequent dangerous hypoglycemia.

Nei diabetici, l’azione naturale del GLP-1 risulta essere deficitaria, quindi si è pensato di ripristinare tale attività in modo da sfruttarla, in particolare, per la terapia orale del diabete mellito di tipo 2, patologia in cui il pancreas non è in grado di produrre abbastanza insulina per controllare i livelli di glucosio nel sangue, o in cui l’organismo non è in grado di utilizzare in modo efficace l’insulina, col conseguente vantaggio della diminuzione degli svariati e problematici effetti avversi legati ad una terapia orale prolungata con i farmaci tradizionali. In diabetics, the natural action of GLP-1 appears to be deficient, so it was decided to restore this activity in order to exploit it, in particular, for the oral therapy of type 2 diabetes mellitus, a disease in which the pancreas is not in able to produce enough insulin to control blood glucose levels, or in which the body is unable to use insulin effectively, with the consequent advantage of decreasing the various and problematic adverse effects associated with prolonged oral therapy with traditional drugs.

Linagliptina, agendo da inibitore delle DDP-4, inibisce la degradazione degli ormoni incretine nell’organismo, in particolare del GLP-1, aumentando il loro livello nel sangue e stimolando il pancreas a produrre più insulina quando il tasso glicemico è alto, diminuendo così la quantità di glucosio prodotto dal fegato, inoltre diminuisce i livelli di glucagone, permettendo il controllo del diabete mellito di tipo 2. Linagliptin, acting as an inhibitor of DDP-4, inhibits the breakdown of incretin hormones in the body, particularly GLP-1, increasing their level in the blood and stimulating the pancreas to produce more insulin when the glycemic rate is high, thus decreasing the amount of glucose produced by the liver also decreases glucagon levels, allowing the control of type 2 diabetes mellitus.

Linagliptina è un composto di formula (I) Linagliptin is a compound of formula (I)

O OR

N No.

N N N N

N No.

N (I) N (I)

ON N ON N

NH2NH2

chimicamente noto come 8-[3(R)-aminopiperidin-1-yl]-7-(2-butinil)-3-metil-1-(4-metilquinazolin-2-ilmetil)xantina, descritto in US 7.407.955 e commercializzato col nome di Tradjenta<®>. chemically known as 8- [3 (R) -aminopiperidin-1-yl] -7- (2-butynyl) -3-methyl-1- (4-methylquinazolin-2-ylmethyl) xanthine, described in US 7,407,955 and marketed under the name of Tradjenta <®>.

Diversi sono i metodi di sintesi di Linagliptina noti in letteratura. There are several methods of synthesis of Linagliptin known in the literature.

US 7.407.955 descrive i seguenti processi per la sintesi di Linagliptina: US 7,407,955 describes the following processes for the synthesis of Linagliptin:

NH2NH2

O N O OR NOT

N H N H

N N N N N N

N N Z N N N Z N

N N N N

ONN ONN NH2ONN ONN NH2

(I) (THE)

O TFA o HCl o TBMS Either TFA or HCl or TBMS

o TMSI or TMSI

N O NO

N N Solvente N N Solvent

N N N N N O N N O N N N O N N O N N N N N N O N N O N N N O N N O N

(I) (THE)

dove Z rappresenta un gruppo uscente quale ad esempio un alogeno, un where Z represents a leaving group such as a halogen, a

gruppo ossidrilico, un gruppo mercapto o altri comunemente noti. hydroxyl group, a mercapto group or others commonly known.

US 7.820.815 descrive il seguente processo per la sintesi di Linagliptina US 7,820,815 describes the following process for the synthesis of Linagliptin

HN HN

O OR

N O NO

O OR

O N O N

N N N N

NN N NN N

Z ONN O N N ONN O Z ONN O N N ONN O

O NNN N N ONN NH2O NNN N N ONN NH2

(I) (THE)

dove Z rappresenta un gruppo uscente quale ad esempio un alogeno, un gruppo ossidrilico, un gruppo mercapto o altri comunemente noti. where Z represents a leaving group such as for example a halogen, a hydroxyl group, a mercapto group or others commonly known.

EP 2 468 749 descrive processi per la sintesi di Linagliptina che comprendono un riarrangiamento di Lossen o di Curtius dei seguenti composti in Linagliptina: EP 2 468 749 describes processes for the synthesis of Linagliptin which include a Lossen or Curtius rearrangement of the following compounds in Linagliptin:

O OR

N No.

N N N N

N No.

O N N O N N

COX COX

dove X rappresenta idrogeno o un gruppo ossidrilico, alchile C1-C8, alcossi C1-C4, arile, amminico, N3o un alogeno. where X represents hydrogen or a hydroxyl group, C1-C8 alkyl, C1-C4 alkoxy, aryl, amino, N3, or a halogen.

Abbiamo ora trovato un processo per la sintesi di Linagliptina che, attraverso l’introduzione del gruppo alchinico in forma mascherata, permette una riduzione delle reazioni secondarie e l’ottenimento di Linagliptina e dei suoi intermedi con rese e purezze elevate. We have now found a process for the synthesis of Linagliptin which, through the introduction of the alkynic group in masked form, allows a reduction of secondary reactions and the obtaining of Linagliptin and its intermediates with high yields and purities.

Costituisce quindi oggetto della presente invenzione un processo per la sintesi di Linagliptina che comprende: Therefore, the object of the present invention is a process for the synthesis of Linagliptin which includes:

d) la reazione dell’intermedio di formula (VI) d) the reaction of the intermediate of formula (VI)

Cl CH3Cl CH3

O OR

N (VI) N N N (VI) N N

Br Br

N No.

ON N ON N

CH3CH3CH3CH3

con un composto di formula (VII) with a compound of formula (VII)

R R.

(VII) (VII)

N No.

H H.

dove R rappresenta un gruppo COOR1oppure un gruppo NHCOOR1, dove R1rappresenta un gruppo C1-C6alchile lineare o ramificato, where R represents a COOR1 group or an NHCOOR1 group, where R1 represents a linear or branched C1-C6alkyl group,

in presenza di un catalizzatore e di una base, in un solvente polare aprotico, in the presence of a catalyst and a base, in an aprotic polar solvent,

a dare l’intermedio di formula (VIII) to give the intermediate of formula (VIII)

Cl CH3Cl CH3

O OR

N No.

N N N N

N (VIII) N (VIII)

N No.

ON N ON N

CH3CH3<R>CH3CH3 <R>

dove R ha i significati sopra riportati; where R has the above meanings;

e) l’eventuale trasformazione dell’intermedio (VIII) in cui R rappresenta un gruppo COOR1nell’intermedio (VIII) in cui R rappresenta un gruppo NHCOOR1; e) any transformation of the intermediate (VIII) in which R represents a COOR1 group into the intermediate (VIII) in which R represents an NHCOOR1 group;

f) la conversione a Linagliptina del composto (VIII) in cui R rappresenta un gruppo NHCOOR1, per trattamento con basi. f) conversion of compound (VIII) in which R represents an NHCOOR1 group to Linagliptin, by treatment with bases.

Nel passaggio d) del processo oggetto della presente invenzione il catalizzatore utilizzato è scelto preferibilmente tra potassio ioduro, tetrabutilammonio ioduro, sodio ioduro, rame ioduro, ancor più preferibilmente viene utilizzato potassio ioduro e la base utilizzata è preferibilmente scelta tra sodio idrossido, potassio idrossido, sodio carbonato, potassio carbonato, ancor più preferibilmente viene utilizzato potassio carbonato. In step d) of the process object of the present invention the catalyst used is preferably selected from potassium iodide, tetrabutylammonium iodide, sodium iodide, copper iodide, even more preferably potassium iodide is used and the base used is preferably selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, even more preferably potassium carbonate is used.

Nel passaggio d) il solvente polare aprotico utilizzato è preferibilmente scelto tra dimetilsolfossido, acetonitrile, dimetilformammide, dimetilacetammide o miscele di detti solventi tra loro. Preferibilmente viene utilizzato dimetilsolfossido. In step d) the aprotic polar solvent used is preferably selected from dimethyl sulfoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures of said solvents with each other. Dimethyl sulfoxide is preferably used.

Preferibilmente il passaggio e) del processo oggetto della presente invenzione viene effettuato in presenza didifenilfosforilazide e di una ammina terziaria scelta preferibilmente tra trietilammina, tributilammina, diisopropiletilammina, N,N-dimetilaminopiridina e di un alcol opportuno C1-C4lineare o ramificato preferibilmente scelto tra metanolo, etanolo, isopropanolo, ter-butanolo. Preferably step e) of the process object of the present invention is carried out in the presence of diphenylphosphorylazide and a tertiary amine preferably selected from triethylamine, tributylamine, diisopropylethylamine, N, N-dimethylaminopyridine and a suitable linear or branched C1-C4 alcohol preferably selected from methanol, ethanol, isopropanol, tert-butanol.

Nel passaggio f) del processo oggetto della presente invenzione, le basi utilizzate sono scelte preferibilmente tra sodio terbutossido, potassio terbutossido, sodio idruro, sodio ammide. Preferibilmente viene utilizzato potassio terbutossido. In step f) of the process object of the present invention, the bases used are preferably selected from sodium terbutoxide, potassium terbutoxide, sodium hydride, sodium amide. Preferably, potassium terbutoxide is used.

L’intermedio (VI) può essere ottenuto mediante un processo che comprende: The intermediate (VI) can be obtained through a process that includes:

a) la reazione del composto di formula (II) a) the reaction of the compound of formula (II)

HN N HN N

Br (II) Br (II)

ON N ON N

CH3CH3

con un composto di formula (III), in presenza di una base, in un with a compound of formula (III), in the presence of a base, in a

solvente polare aprotico polar aprotic solvent

Cl Cl (III) Cl Cl (III)

CH3CH3

a dare l’intermedio di formula (IV) to give the intermediate of formula (IV)

Cl CH3Cl CH3

O (IV) O (IV)

HN N HN N

Br Br

ON N ON N

CH3CH3

b) la reazione dell’intermedio di formula (IV) con un composto di b) the reaction of the intermediate of formula (IV) with a compound of

formula (V) formula (V)

N No.

X X

N (V) N (V)

CH3CH3

dove X rappresenta un alogeno, preferibilmente cloro, in presenza where X represents a halogen, preferably chlorine, in presence

di un catalizzatore e di una base, in solvente polare aprotico, a dare of a catalyst and a base, in aprotic polar solvent, to give

l’intermedio di formula (VI). the intermediate of formula (VI).

Rappresenta quindi un ulteriore oggetto della presente invenzione un A further object of the present invention therefore represents a

processo per la sintesi di Linagliptina che comprende: process for the synthesis of Linagliptin which includes:

O OR

H HN N (II) H HN N (II)

Br Br

ON N ON N

CH3CH3

solvente polare aprotico polar aprotic solvent

Cl Cl Cl Cl

CH3(III) CH3 (III)

a dare l’intermedio di formula (IV) to give the intermediate of formula (IV)

Cl CH3Cl CH3

O OR

HN N HN N

Br (IV) Br (IV)

ON N ON N

CH3CH3

formula (V) formula (V)

N No.

X X

N (V) N (V)

CH3CH3

l’intermedio di formula (VI) the intermediate of formula (VI)

Cl CH3Cl CH3

O OR

N No.

N N (VI) N N (VI)

Br Br

N No.

ON N ON N

CH3CH3CH3CH3

d) la reazione dell’intermedio di formula (VI) con un composto di formula (VII) d) the reaction of the intermediate of formula (VI) with a compound of formula (VII)

R R.

(VII) (VII)

N No.

H H.

Cl CH3Cl CH3

O (VIII) O (VIII)

N No.

N N N N

N No.

ON N ON N

CH3CH3<R>CH3CH3 <R>

dove R ha i significati sopra riportati; where R has the above meanings;

Nel passaggio a) del processo oggetto della presente invenzione viene utilizzata una base organica o inorganica preferibilmente scelta tra trietilammina, tributilammina, diisopropiletilammina, sodio idrossido, potassio idrossido, sodio carbonato, potassio carbonato. Preferibilmente viene utilizzata trietilammina. In step a) of the process object of the present invention an organic or inorganic base is used, preferably selected from triethylamine, tributylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate. Triethylamine is preferably used.

Il solvente polare aprotico utilizzato è scelto preferibilmente tra dimetilsolfossido, acetonitrile, dimetilformammide, dimetilacetammide o miscele di detti solventi tra loro. Preferibilmente viene utilizzato dimetilsolfossido. The used aprotic polar solvent is preferably selected from dimethyl sulfoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures of said solvents with each other. Dimethyl sulfoxide is preferably used.

Nel passaggio b) del processo oggetto della presente invenzione il catalizzatore utilizzato è scelto preferibilmente tra potassio ioduro, tetrabutilammonio ioduro, sodio ioduro, rame ioduro, ancor più preferibilmente viene utilizzato potassio ioduro e la base utilizzata è preferibilmente scelta tra sodio idrossido, potassio idrossido, sodio carbonato, potassio carbonato, ancor più preferibilmente viene utilizzato potassio carbonato e il solvente polare aprotico utilizzato è preferibilmente scelto tra dimetilsolfossido, acetonitrile, dimetilformammide, dimetilacetammide o miscele di detti solventi tra loro. Più preferibilmente viene utilizzato dimetilsolfossido. In step b) of the process object of the present invention the catalyst used is preferably selected from potassium iodide, tetrabutylammonium iodide, sodium iodide, copper iodide, even more preferably potassium iodide is used and the base used is preferably selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, even more preferably potassium carbonate is used and the aprotic polar solvent used is preferably selected from dimethylsulfoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures of said solvents with each other. More preferably, dimethyl sulfoxide is used.

Alternativamente l’intermedio di formula (VI) può essere ottenuto mediante un processo di sintesi che comprende: Alternatively, the intermediate of formula (VI) can be obtained through a synthesis process which includes:

O OR

H HN N (II) H HN N (II)

Br Br

ON N ON N

CH3CH3

solvente polare aprotico polar aprotic solvent

Cl Cl Cl Cl

CH3(III) CH3 (III)

a dare l’intermedio di formula (IV) to give the intermediate of formula (IV)

Cl CH3Cl CH3

O OR

HN N HN N

Br (IV) Br (IV)

ON N ON N

CH3CH3

b’) la reazione del composto di formula (IV) con cloroacetonitrile, in b ') the reaction of the compound of formula (IV) with chloroacetonitrile, in

presenza di un catalizzatore e di una base in un solvente polare presence of a catalyst and a base in a polar solvent

aprotico, a dare l’intermedio di formula (IX) aprotic, to give the intermediate of formula (IX)

Cl CH3Cl CH3

O OR

NC N N NC N N

Br (IX) Br (IX)

ON N ON N

CH3CH3

c) la reazione dell’intermedio di formula (IX) con 2-amminoacetofenone in presenza di acido cloridrico anidro in 1,4-diossano, a dare l’intermedio di formula (VI). c) the reaction of the intermediate of formula (IX) with 2-aminoacetophenone in the presence of anhydrous hydrochloric acid in 1,4-dioxane, to give the intermediate of formula (VI).

Rappresenta quindi un ulteriore oggetto della presente invenzione un processo per la sintesi di Linagliptina che comprende: Therefore, a further object of the present invention is a process for the synthesis of Linagliptin which includes:

O OR

H HN N (II) H HN N (II)

Br Br

ON N ON N

CH3CH3

con un composto di formula (III), in presenza di una base, in un solvente polare aprotico with a compound of formula (III), in the presence of a base, in an aprotic polar solvent

Cl Cl (III) Cl Cl (III)

CH3CH3

a dare l’intermedio di formula (IV) to give the intermediate of formula (IV)

Cl CH3Cl CH3

O OR

HN N HN N

Br (IV) Br (IV)

ON N ON N

CH3CH3

b’) la reazione del composto di formula (IV) con cloroacetonitrile, in presenza di un catalizzatore e di una base in un solvente polare aprotico, a dare l’intermedio di formula (IX) b ') the reaction of the compound of formula (IV) with chloroacetonitrile, in the presence of a catalyst and a base in an aprotic polar solvent, to give the intermediate of formula (IX)

Cl CH3Cl CH3

O OR

NC N N NC N N

Br (IX) Br (IX)

ON N ON N

CH3CH3

c) la reazione dell’intermedio di formula (IX) con 2-amminoacetofenone in presenza di acido cloridrico anidro, in 1,4-diossano a dare l’intermedio di formula (VI) c) the reaction of the intermediate of formula (IX) with 2-aminoacetophenone in the presence of anhydrous hydrochloric acid, in 1,4-dioxane to give the intermediate of formula (VI)

Cl CH3Cl CH3

O OR

N No.

N N (VI) N N (VI)

Br Br

N No.

ON N ON N

CH3CH3CH3CH3

R R.

(VII) (VII)

N No.

H H.

dove R ha i significati sopra riportati; where R has the above meanings;

Nel passaggio b’) il catalizzatore utilizzato è scelto preferibilmente tra potassio ioduro, tetrabutilammonio ioduro, sodio ioduro, rame ioduro, preferibilmente viene utilizzato potassio ioduro. In step b ') the catalyst used is preferably selected from potassium iodide, tetrabutylammonium iodide, sodium iodide, copper iodide, preferably potassium iodide is used.

La base utilizzata è scelta preferibilmente tra sodio idrossido, potassio idrossido, sodio carbonato, potassio carbonato, preferibilmente viene utilizzato potassio carbonato. The base used is preferably selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium carbonate is preferably used.

Il solvente polare aprotico utilizzato è scelto preferibilmente tra dimetilsolfossido, acetonitrile, dimetilformammide, dimetilacetammide, o miscele di detti solventi tra loro. Preferibilmente viene utilizzato dimetilsolfossido. The aprotic polar solvent used is preferably selected from dimethyl sulfoxide, acetonitrile, dimethylformamide, dimethylacetamide, or mixtures of said solvents with each other. Dimethyl sulfoxide is preferably used.

Una forma pratica preferita di attuazione del processo oggetto della presente invenzione è la seguente. A preferred practical embodiment of the process object of the present invention is the following.

Il composto (II) viene fatto reagire con il composto (III) in presenza di trietilammina in dimetilsolfossido a circa 50°C, a dare il composto (IV) che viene successivamente posto a reagire in dimetilsolfossido con 2-(clorometil)-4-metilchinazolina in presenza di potassio carbonato e potassio ioduro a circa 60°C fino ad ottenere il composto (VI). (R)-isopropil-piperidin-3-il carbammato in dimetilsolfossido viene fatto reagire con il composto (VI) in presenza di potassio carbonato e potassio ioduro a dare (R)-isopropil 1-(7-(3-clorobut-2-enil)-3-metil-1-((4-metilchinazolin-2-il)metil-2,6-diosso-2,3,6,7-tetraidro-1H-purin-8-il)piperidin-3-il carbammato che viene fatto successivamente reagire in presenza di dimetilacetammide e potassio terbutossido a dare (R)-isopropil 1-(7-(but-2-inil)-3-metil-1-((4-metilchinazolin-2-il)metil) - 2,6 - diosso - 2,3,6,7 - tetraidro-1H-purin - 8 - il) piperidin-3-il carbammato, che viene convertito in Linagliptina mediante reazione di idrolisi in presenza di acqua, dimetilacetammide e potassio idrossido. Compound (II) is reacted with compound (III) in the presence of triethylamine in dimethylsulfoxide at about 50 ° C, to give compound (IV) which is subsequently reacted in dimethylsulfoxide with 2- (chloromethyl) -4- methylquinazoline in the presence of potassium carbonate and potassium iodide at about 60 ° C until compound (VI) is obtained. (R) -isopropyl-piperidine-3-the carbamate in dimethyl sulfoxide is reacted with compound (VI) in the presence of potassium carbonate and potassium iodide to give (R) -isopropyl 1- (7- (3-chlorobut-2- enyl) -3-methyl-1 - ((4-methylquinazolin-2-yl) methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) piperidine-3-yl carbamate which is subsequently reacted in the presence of dimethylacetamide and potassium terbutoxide to give (R) -isopropyl 1- (7- (but-2-yl) -3-methyl-1 - ((4-methylquinazolin-2-yl) methyl ) - 2,6 - dioxus - 2,3,6,7 - tetrahydro-1H-purin - 8 - il) piperidin-3-carbamate, which is converted into Linagliptin by hydrolysis reaction in the presence of water, dimethylacetamide and potassium hydroxide.

I composti di formula (IV), (VI), (VIII) e (IX) sono nuovi intermedi utili nella sintesi di Linagliptina e rappresentano un ulteriore oggetto della presente invenzione. The compounds of formula (IV), (VI), (VIII) and (IX) are new intermediates useful in the synthesis of Linagliptin and represent a further object of the present invention.

Sebbene l’invenzione sia stata descritta nei suoi aspetti caratteristici, modifiche ed equivalenti che sono evidenti all’esperto del ramo sono incluse nella seguente invenzione. Although the invention has been described in its characteristic aspects, modifications and equivalents that are evident to those skilled in the art are included in the following invention.

La presente invenzione sarà ora illustrata per mezzo di alcuni esempi, che non devono essere visti come limitanti la portata dell’invenzione. The present invention will now be illustrated by means of some examples, which should not be seen as limiting the scope of the invention.

Tutti i termini utilizzati nella presente domanda, salvo indicazioni contrarie, devono essere compresi nel loro comune significato come conosciuti nell'arte. Altre definizioni più specifiche per alcuni termini, come utilizzati in questa domanda, sono messe in evidenza più avanti e si applicano costantemente per tutta la descrizione e le rivendicazioni, a meno che una diversa definizione fornisca esplicitamente una definizione più ampia. All the terms used in the present application, unless otherwise indicated, must be understood in their common meaning as known in the art. Other more specific definitions for some terms, as used in this question, are highlighted below and consistently apply throughout the description and claims, unless a different definition explicitly provides a broader definition.

Il termine “solvente polare” si riferisce ad un solvente che tende a fornire protoni, quale acqua; un alcool, per esempio, metanolo, etanolo, propanolo, iso-propanolo, butanolo, tert-butanolo; o un solvente polarizzato, quale, per esempio, esteri, per esempio, etil acetato, butil acetato; nitrili, per esempio, acetonitrile; eteri, per esempio, tetraidrofurano, diossano; chetoni, per esempio, acetone, metilbutilchetone; e simili. The term "polar solvent" refers to a solvent which tends to provide protons, such as water; an alcohol, for example, methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol; or a polarized solvent, such as, for example, esters, for example, ethyl acetate, butyl acetate; nitriles, for example, acetonitrile; ethers, for example, tetrahydrofuran, dioxane; ketones, for example, acetone, methylbutylketone; and similar.

Ulteriori informazioni sui solventi non polari o polari, protici o aprotici possono essere trovate nei manuali di chimica organica o in monografie specializzate, per esempio: Organic Solvents Physical Properties and Methods of Purification, 4th ed., John A. Riddick, et al., Vol. II, in “Techniques of Chemistry Series”, John Wiley & Sons, NY, 1986. Tali solventi sono noti alla persona esperta del ramo, ed è evidente alla persona esperta del ramo, che i diversi solventi o loro miscele possono essere preferiti a secondo dei composti specifici e delle condizioni di reazione, essendo la loro scelta influenzata, per esempio, dalla solubilità e reattività dei reagenti, dai range di temperature preferite. Further information on non-polar or polar, protic or aprotic solvents can be found in organic chemistry textbooks or specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., John A. Riddick, et al., Vol. II, in "Techniques of Chemistry Series", John Wiley & Sons, NY, 1986. Such solvents are known to the person skilled in the art, and it is evident to the person skilled in the art that the different solvents or mixtures thereof may be preferred depending on the specific compounds and reaction conditions, their choice being influenced, for example, by the solubility and reactivity of the reagents, by the preferred temperature ranges.

ESEMPI EXAMPLES

ESEMPIO 1. Sintesi di 8-bromo-7-(3-clorobut-2-enil)-3-metil-1H-purin-2,6(3H,7H)-dione. EXAMPLE 1. Synthesis of 8-bromo-7- (3-chlorobut-2-enyl) -3-methyl-1H-purin-2,6 (3H, 7H) -dione.

In un pallone di reazione sono stati caricati 8-bromo-3-metil-1H-purina-2,6-(3H,7H)-dione (10,00 g, 41,00 mmol), dimetilsolfossido (30 ml), trietilammina (6,25 mL, 45,10 mmol), la temperatura è stata portata a circa 50°C ed è stato caricato 1,3-diclorobutene (4,40 ml, 41,00 mmol). La miscela di reazione è stata mantenuta in queste condizioni per circa un’ora. A reazione terminata, il solido formatosi è stato filtrato ed essiccato in stufa sottovuoto a 50°C a dare 12,10 g di 8-bromo-7-(3-clorobut-2-enil)-3-metil-1H-purin-2,6(3H,7H)-dione. 8-bromo-3-methyl-1H-purine-2,6- (3H, 7H) -dione (10.00 g, 41.00 mmol), dimethyl sulfoxide (30 ml), triethylamine were loaded into a reaction flask. (6.25 mL, 45.10 mmol), the temperature was raised to about 50 ° C and 1,3-dichlorobutene (4.40 mL, 41.00 mmol) was loaded. The reaction mixture was kept under these conditions for about an hour. At the end of the reaction, the solid formed was filtered and dried in a vacuum oven at 50 ° C to give 12.10 g of 8-bromo-7- (3-chlorobut-2-enyl) -3-methyl-1H-purin- 2.6 (3H, 7H) -dione.

<1>H-NMR (DMSO, 300MHz): δ 11,32 (s, 1H), δ 5,84 ( t, 1 H), δ 4,98 (d, 2H), δ 3,33 (m, 3H), δ 2,50 (s, 1H), δ 2,13 (s, 2H). <1> H-NMR (DMSO, 300MHz): δ 11.32 (s, 1H), δ 5.84 (t, 1 H), δ 4.98 (d, 2H), δ 3.33 (m, 3H), δ 2.50 (s, 1H), δ 2.13 (s, 2H).

<13>C-NMR (DMSO, 300MHz): δ 154,54 (C), δ 151,11 (C), δ 149,87 (C), δ 133,77 (C), δ 128,16 (C), δ 121,09 (CH), δ 109,18 (C), δ 46,00 (CH2), δ 29,10 (CH3), δ 26,16 (CH3). <13> C-NMR (DMSO, 300MHz): δ 154.54 (C), δ 151.11 (C), δ 149.87 (C), δ 133.77 (C), δ 128.16 (C ), δ 121.09 (CH), δ 109.18 (C), δ 46.00 (CH2), δ 29.10 (CH3), δ 26.16 (CH3).

ESEMPIO 2. Sintesi di 8-bromo-7-(3-clorobut-2-enil)-3-metil-1-((4-metilchinazolin-2-il)metil)-1H-purin-2,6(3H,7H)-dione. EXAMPLE 2. Synthesis of 8-bromo-7- (3-chlorobut-2-enyl) -3-methyl-1 - ((4-methylquinazolin-2-yl) methyl) -1H-purin-2,6 (3H, 7H) -dione.

In un pallone di reazione sono stati caricati 8-bromo-7-(3-clorobut-2-enil)-3-metil-1H-purin-2,6(3H,7H)-dione (5,00 g, 14,98 mmol), dimetilsolfossido (50 ml), potassio carbonato (2,07 g, 14,98 mmol), potassio ioduro (0,25 g, 1,50 mmol) e 2-(clorometil)-4-metilchinazolina (2,89 g, 14,98 mmol). La temperatura è stata portata a circa 60°C e la reazione è stata mantenuta in queste condizioni per circa tre ore. A reazione terminata, è stata aggiunta acqua demineralizzata (40 ml) e il solido formatosi è stato filtrato sottovuoto e lavato con acqua demineralizzata (1 x 20 ml) ed essiccato in stufa sottovuoto a 50°C a dare 6,43 g di 8-bromo-7-(3-clorobut-2-enil)-3-metil-1-((4-metilchinazolin-2-il)metil)-1H-purin-2,6(3H,7H)-dione. 8-bromo-7- (3-chlorobut-2-enyl) -3-methyl-1H-purin-2,6 (3H, 7H) -dione (5.00 g, 14, 98 mmol), dimethyl sulfoxide (50 ml), potassium carbonate (2.07 g, 14.98 mmol), potassium iodide (0.25 g, 1.50 mmol) and 2- (chloromethyl) -4-methylquinazoline (2, 89 g, 14.98 mmol). The temperature was brought to about 60 ° C and the reaction was maintained under these conditions for about three hours. At the end of the reaction, demineralized water (40 ml) was added and the solid formed was filtered under vacuum and washed with demineralized water (1 x 20 ml) and dried in a vacuum oven at 50 ° C to give 6.43 g of 8- bromo-7- (3-chlorobut-2-enyl) -3-methyl-1 - ((4-methylquinazolin-2-yl) methyl) -1H-purin-2,6 (3H, 7H) -dione.

<1>H-NMR (DMSO, 300MHz): δ 8,04 (d, 1H), δ 7,84 (d, 1H),δ 7,78 (t, 1H), δ 7,54 (t, 1H) δ 5,70 (t, 1 H), δ 5,55 (s, 2 H), δ 5,12 (d, 2H), δ 3,59 (s, 3H), δ 2,89 (s,3H) δ 2,12 (s, 3H). <1> H-NMR (DMSO, 300MHz): δ 8.04 (d, 1H), δ 7.84 (d, 1H), δ 7.78 (t, 1H), δ 7.54 (t, 1H ) δ 5.70 (t, 1 H), δ 5.55 (s, 2 H), δ 5.12 (d, 2H), δ 3.59 (s, 3H), δ 2.89 (s, 3H) δ 2.12 (s, 3H).

<13>C-NMR (DMSO, 300MHz): δ 168,74 (C), δ 160,54 (C), δ 154,26 (C), δ 151,44 (C), δ 149,95 (C), δ 148,85 (C), δ 134,88 (C), δ 133,44 (CH), δ 128,89 (CH), δ 127,64 (C), δ 126,92 (CH), δ 124,96 (CH), δ 123,22 (C), δ 119,63 (CH), δ 109,06 (C), δ 77,19 (CH2), δ 45,92 (CH2), δ 29,99 (CH3), δ 26,20 (CH3), δ 21,87 (CH3). <13> C-NMR (DMSO, 300MHz): δ 168.74 (C), δ 160.54 (C), δ 154.26 (C), δ 151.44 (C), δ 149.95 (C ), δ 148.85 (C), δ 134.88 (C), δ 133.44 (CH), δ 128.89 (CH), δ 127.64 (C), δ 126.92 (CH), δ 124.96 (CH), δ 123.22 (C), δ 119.63 (CH), δ 109.06 (C), δ 77.19 (CH2), δ 45.92 (CH2), δ 29 , 99 (CH3), δ 26.20 (CH3), δ 21.87 (CH3).

ESEMPIO 3. Sintesi di (R)-isopropil 1-(7-(3-clorobut-2-enil)-3-metil-1-((4-metilchinazolin-2-il)metil-2,6-diosso-2,3,6,7-tetraidro-1H-purin-8-il)piperidin-3-il carbammato. EXAMPLE 3. Synthesis of (R) -isopropyl 1- (7- (3-chlorobut-2-enyl) -3-methyl-1 - ((4-methylquinazolin-2-yl) methyl-2,6-dioxo-2 , 3,6,7-tetrahydro-1H-purin-8-yl) piperidine-3-carbamate.

In un pallone di reazione sono stati caricati (R)-isopropil-piperidin-3-il carbammato (0,92 g, 4,90 mmol), dimetilsolfossido (10 ml) e, mantenendo la miscela di reazione sotto agitazione, sono stati caricati 8-bromo-7-(3-clorobut-2-enil) -3-metil - 1 - ((4-metilchinazolin-2-il)metil) -1H-purin-2,6(3H,7H)-dione (2,42 g, 4,90 mmol) e potassio carbonato (0,74 g, 5,39 mmol). La temperatura è stata portata a circa 80°C ed è stato caricato potassio ioduro in quantità catalitiche e la miscela di reazione è stata mantenuta in queste condizioni x 40 ore. A reazione terminata, la temperatura è stata portata a quella ambiente ed è stata aggiunta acqua demineralizzata (15 ml) e il solido ottenuto è stato filtrato e lavato con acqua demineralizzata (1 x 15 ml) ed essiccato in stufa sottovuoto a 50°C a dare 2,30 g di (R)-isopropil-1-(7-(3-clorobut-2-enil)-3-metil-1-((4-metilchinazolin-2-il)metil-2,6-diosso-2,3,6,7-tetraidro-1H-purin-8-il)piperidin-3-il carbammato. (R) -isopropyl-piperidine-3-carbamate (0.92 g, 4.90 mmol), dimethylsulfoxide (10 ml) were charged into a reaction flask and, keeping the reaction mixture under stirring, they were charged 8-bromo-7- (3-chlorobut-2-enyl) -3-methyl - 1 - ((4-methylquinazolin-2-yl) methyl) -1H-purin-2,6 (3H, 7H) -dione ( 2.42 g, 4.90 mmol) and potassium carbonate (0.74 g, 5.39 mmol). The temperature was brought to about 80 ° C and potassium iodide was added in catalytic quantities and the reaction mixture was maintained under these conditions for 40 hours. At the end of the reaction, the temperature was brought to room temperature and demineralized water (15 ml) was added and the solid obtained was filtered and washed with demineralized water (1 x 15 ml) and dried in a vacuum oven at 50 ° C to give 2.30 g of (R) -isopropyl-1- (7- (3-chlorobut-2-enyl) -3-methyl-1 - ((4-methylquinazolin-2-yl) methyl-2,6-dioxo -2,3,6,7-tetrahydro-1H-purin-8-yl) piperidin-3-carbamate.

<1>H-NMR (DMSO, 300MHz): δ 7,99 (d, 1H), δ 7,85 (d, 1H), δ 7,75 (t, 1H), δ 7,51 (t, 1H), δ 5,84 (t, 1H), δ 5,54 (s, 2H), δ 5,28 (s, 1H), δ 4,88 (t, 1H), δ 4,83 (d, 1H), δ 3,89 (m, 1H), δ 3,58 (m, 3H), δ 3,19 (m, 3 H), δ 2,88 (m, 3H), δ 2,14 (s, 2H), δ 2,10 (s, 3H), δ 1,83 (m, 2H), δ 1,73 (m, 2H), δ 1,21 (d, 6H). <1> H-NMR (DMSO, 300MHz): δ 7.99 (d, 1H), δ 7.85 (d, 1H), δ 7.75 (t, 1H), δ 7.51 (t, 1H ), δ 5.84 (t, 1H), δ 5.54 (s, 2H), δ 5.28 (s, 1H), δ 4.88 (t, 1H), δ 4.83 (d, 1H ), δ 3.89 (m, 1H), δ 3.58 (m, 3H), δ 3.19 (m, 3H), δ 2.88 (m, 3H), δ 2.14 (s, 2H), δ 2.10 (s, 3H), δ 1.83 (m, 2H), δ 1.73 (m, 2H), δ 1.21 (d, 6H).

<13>C-NMR (DMSO, 300MHz): δ 168,63 (C), δ 161,13 (C), δ 156,47 (C), δ 155,63 (C), δ 153,00 (C), δ 151,92 (C), δ 150,03 (C), δ 149,00 (C), δ 133, 33 (CH), δ 128,97 (CH), δ 126,81 (CH), δ 124,93 (CH), δ 123,25 (C), δ 121,45 (CH), δ 105,00 (C), δ 68,04 (CH), δ 54,69 (CH2), δ 51,84 (CH2), δ 46,45 (CH), δ 46,34 (CH2), δ 44,58 (CH2), δ 44,46 (CH2), δ 29,85 (CH3), δ 29,80 (CH2), δ 26,17 (CH3), δ 22,17 (2 CH3), δ 21,85 (CH3). <13> C-NMR (DMSO, 300MHz): δ 168.63 (C), δ 161.13 (C), δ 156.47 (C), δ 155.63 (C), δ 153.00 (C ), δ 151.92 (C), δ 150.03 (C), δ 149.00 (C), δ 133, 33 (CH), δ 128.97 (CH), δ 126.81 (CH), δ 124.93 (CH), δ 123.25 (C), δ 121.45 (CH), δ 105.00 (C), δ 68.04 (CH), δ 54.69 (CH2), δ 51 , 84 (CH2), δ 46.45 (CH), δ 46.34 (CH2), δ 44.58 (CH2), δ 44.46 (CH2), δ 29.85 (CH3), δ 29.80 (CH2), δ 26.17 (CH3), δ 22.17 (2 CH3), δ 21.85 (CH3).

ESEMPIO 4. Sintesi di (R)-etil 1-(7-(3-clorobut-.2-enil)-3-metil-1-((4-metilchinazolin-2-il)metil)-2,6-diosso-2,3,6,7-tetraidro-1H-purin-8-il)piperidin-3-carbossilato. EXAMPLE 4. Synthesis of (R) -ethyl 1- (7- (3-chlorobut-.2-enyl) -3-methyl-1 - ((4-methylquinazolin-2-yl) methyl) -2,6-dioxo -2,3,6,7-tetrahydro-1H-purin-8-yl) piperidine-3-carboxylate.

In un pallone di reazione sono stati caricati (R)-etil-piperidin-3-carbossilato (0,29 g, 1,02 mmol), dimetilsolfossido (5 ml) e, mantenendo la miscela di reazione sotto agitazione, sono stati caricati potassio ioduro in quantità catalitiche, potassio carbonato (0,14 g, 1,02 mmol) e 8-bromo-7-(3-clorobut-2-enil) - 3 - metil - 1 - ((4-metilchinazolin-2-il)metil)-1H-purin-2,6(3H,7H)-dione (0,50 g, 1,02 mmol). La temperatura è stata portata a circa 60°C e mantenuta in queste condizioni per circa 15 ore. A reazione terminata, la temperatura è stata portata a quella ambiente ed è stata aggiunta acqua demineralizzata (5 ml). Il solido ottenuto è stato filtrato e lavato con acqua demineralizzata (1 x 5 ml) ed essiccato in stufa sottovuoto a 50°C a dare 0,48 g di (R)-etil 1-(7-(3-clorobut-.2-enil)-3-metil-1-((4-metilchinazolin-2-il)metil)-2,6-diosso-2,3,6,7-tetraidro-1H-purin-8-il)piperidin-3-carbossilato. (R) -ethyl-piperidine-3-carboxylate (0.29 g, 1.02 mmol), dimethyl sulfoxide (5 ml) were charged into a reaction flask and, while maintaining the reaction mixture under stirring, potassium was charged iodide in catalytic quantities, potassium carbonate (0.14 g, 1.02 mmol) and 8-bromo-7- (3-chlorobut-2-enyl) - 3 - methyl - 1 - ((4-methylquinazolin-2-yl) ) methyl) -1H-purin-2,6 (3H, 7H) -dione (0.50 g, 1.02 mmol). The temperature was raised to about 60 ° C and maintained under these conditions for about 15 hours. At the end of the reaction, the temperature was brought to room temperature and demineralized water (5 ml) was added. The solid obtained was filtered and washed with demineralized water (1 x 5 ml) and dried in a vacuum oven at 50 ° C to give 0.48 g of (R) -ethyl 1- (7- (3-chlorobut-.2 -enyl) -3-methyl-1 - ((4-methylquinazolin-2-yl) methyl) -2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) piperidin-3 -carboxylate.

<1>H-NMR (DMSO, 300MHz): δ 7,98 (d, 1H), δ 7,84 (d, 1H), δ 7,74 (t, 1H), δ 7,50 (t, 1H), δ 5,87 (m, 1H), δ 5,54 (s, 2H), δ 4,81 (d, 2H), δ 4,17 (m, 2H), δ 3,69 (m, 1H), δ 3,55 (s, 3H), δ 3,43 (m, 1H), δ 3,17 (m, 1H), δ 3,00 (m, 1H), δ 2,87 (s, 3H), δ 2,76 (m, 1H), δ 2,09 (m, 4H), δ 1,84 (m, 3H), δ 1,26 (t, 3H). <1> H-NMR (DMSO, 300MHz): δ 7.98 (d, 1H), δ 7.84 (d, 1H), δ 7.74 (t, 1H), δ 7.50 (t, 1H ), δ 5.87 (m, 1H), δ 5.54 (s, 2H), δ 4.81 (d, 2H), δ 4.17 (m, 2H), δ 3.69 (m, 1H ), δ 3.55 (s, 3H), δ 3.43 (m, 1H), δ 3.17 (m, 1H), δ 3.00 (m, 1H), δ 2.87 (s, 3H ), δ 2.76 (m, 1H), δ 2.09 (m, 4H), δ 1.84 (m, 3H), δ 1.26 (t, 3H).

ESEMPIO 5. Sintesi di (R)-isopropil 1-(7-(but-2-inil)-3-metil-1-((4-metilchinazolin-2-il)metil)-2,6-diosso-2,3,6,7-tetraidro-1H-purin-8-il) piperidin-3-il carbammato. EXAMPLE 5. Synthesis of (R) -isopropyl 1- (7- (but-2-yl) -3-methyl-1 - ((4-methylquinazolin-2-yl) methyl) -2,6-dioxo-2, 3,6,7-tetrahydro-1H-purin-8-yl) piperidin-3-carbamate.

In un pallone di reazione sono stati caricati sotto atmosfera inerte (R)-isopropil 1-(7-(3-clorobut-2-enil)-3-metil-1-((4-metilchinazolin-2-il)metil-2,6-diosso-2,3,6,7-tetraidro-1H-purin-8-il)piperidin-3-il carbammato (0,50 g, 0,84 mmol), dimetilacetammide (5 ml), la temperatura è stata portata ad una temperatura compresa tra circa 0°C e 5°C e, mantenendo la miscela di reazione sotto agitazione, è stato caricato potassio tert-butossido (0,16 g, 1,70 mmol) e la miscela di reazione è stata mantenuta in queste condizioni per circa 13 ore. A reazione terminata, sono stati aggiunti acqua demineralizzata (5 ml) e toluene (5 ml); la fase organica è stata ridotta a residuo mediante distillazione sottovuoto a dare 0,32 g di (R)-isopropil 1-(7(but-2-inil)-3-metil-1-((4-metilchinazolin-2-il)metil)-2,6-diosso-2,3,6,7-tetraidro-1H-purin-8-il)piperidin-3-il carbammato. (R) -isopropyl 1- (7- (3-chlorobut-2-enyl) -3-methyl-1 - ((4-methylquinazolin-2-yl) methyl-2 , 6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) piperidine-3-carbamate (0.50 g, 0.84 mmol), dimethylacetamide (5 ml), the temperature is was brought to a temperature between about 0 ° C and 5 ° C and, keeping the reaction mixture under stirring, potassium tert-butoxide (0.16 g, 1.70 mmol) was added and the reaction mixture was maintained under these conditions for about 13 hours. At the end of the reaction, demineralized water (5 ml) and toluene (5 ml) were added; the organic phase was reduced to residue by vacuum distillation to give 0.32 g of (R) -isopropyl 1- (7 (but-2-yl) -3-methyl-1 - ((4-methylquinazolin-2-yl) methyl) -2,6-dioxo-2,3,6,7-tetrahydro-1H -purin-8-yl) piperidin-3-carbamate.

<1>H-NMR (DMSO, 300MHz): δ 8,20 (d, 1H), δ 7,86 (t, 1H), δ 7,75 (d, 1H), δ 7,65 (t, 1H), δ 7,19 (d, 1H), δ 5,30 (s, 2H), δ 4,86 (s, 2H), δ 4,75 (m, 2H), δ 3,65 (m, 3H), δ 3,38 (d, 2H), δ 3,00 (t, 1H), δ 2,95 (s, 4H), δ 1,84 (m, 2H), δ 1,80 (m, 3H), δ 1,77 (m, 1H), δ 1,45 (m, 1H), δ 1,15 (d, 6H). <1> H-NMR (DMSO, 300MHz): δ 8.20 (d, 1H), δ 7.86 (t, 1H), δ 7.75 (d, 1H), δ 7.65 (t, 1H ), δ 7.19 (d, 1H), δ 5.30 (s, 2H), δ 4.86 (s, 2H), δ 4.75 (m, 2H), δ 3.65 (m, 3H ), δ 3.38 (d, 2H), δ 3.00 (t, 1H), δ 2.95 (s, 4H), δ 1.84 (m, 2H), δ 1.80 (m, 3H ), δ 1.77 (m, 1H), δ 1.45 (m, 1H), δ 1.15 (d, 6H).

<13>C-NMR (DMSO, 300MHz): δ 170,00 (C), δ 163,89 (C), δ 157 (C), δ 156,30 (C), δ 155,75 (C), δ 153,49 (C), δ 150 (C), δ 147,90 (C), δ 133,89 (CH), δ 129 (CH), δ 127,71 (CH), δ 126,29 (CH), δ 123,06 (C), δ 103,93 (C), δ 81,65 (C), δ 75,00 (C), δ 68,30 (CH), δ 53,00 (CH2), δ 50,00 (CH2), δ 47,25 (CH3), δ 45,00 (CH2), δ 33,70 (CH2), δ 32,17 (CH2), δ 30,00 (CH3), δ 23,69 (CH2), δ 22,61 (CH3), δ 22,61 (CH3), δ 3,63 (CH3) <13> C-NMR (DMSO, 300MHz): δ 170.00 (C), δ 163.89 (C), δ 157 (C), δ 156.30 (C), δ 155.75 (C), δ 153.49 (C), δ 150 (C), δ 147.90 (C), δ 133.89 (CH), δ 129 (CH), δ 127.71 (CH), δ 126.29 (CH ), δ 123.06 (C), δ 103.93 (C), δ 81.65 (C), δ 75.00 (C), δ 68.30 (CH), δ 53.00 (CH2), δ 50.00 (CH2), δ 47.25 (CH3), δ 45.00 (CH2), δ 33.70 (CH2), δ 32.17 (CH2), δ 30.00 (CH3), δ 23 , 69 (CH2), δ 22.61 (CH3), δ 22.61 (CH3), δ 3.63 (CH3)

ESEMPIO 6. Sintesi di Linagliptina. EXAMPLE 6. Linagliptin synthesis.

In un pallone di reazione sono stati caricati sotto atmosfera inerte (R)-isopropil 1-(7-(but-2-inil)-3-metil-1-((4-metilchinazolin-2-il)metil)-2,6-diosso-2,3,6,7-tetraidro-1H-purin-8-il)piperidin-3-il carbammato (0,30 g, 0,55 mmol), dimetilacetammide (5 ml), la temperatura miscela di reazione è stata portata ad una temperatura compresa tra circa 0°C e 5°C e, sotto agitazione, sono stati caricati potassio idrossido (0,032 g, 0,57 mmol) e acqua (3 ml). La temperatura è stata portata a circa 50°C e la miscela di reazione è stata mantenuta in queste condizioni per circa cinque ore. A reazione terminata, è stata aggiunta acqua demineralizzata (5 ml), il solido formatosi è stato filtrato e lavato con acqua demineralizzata (1 x 5 ml) e seccato in stufa sottovuoto a circa 50°C a dare 0,23 g. di Linagliptina. (R) -isopropyl 1- (7- (but-2-yl) -3-methyl-1 - ((4-methylquinazolin-2-yl) methyl) -2, 6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) piperidine-3-carbamate (0.30 g, 0.55 mmol), dimethylacetamide (5 ml), the mixture temperature of reaction was brought to a temperature between about 0 ° C and 5 ° C and, under stirring, potassium hydroxide (0.032 g, 0.57 mmol) and water (3 ml) were charged. The temperature was brought to about 50 ° C and the reaction mixture was kept under these conditions for about five hours. At the end of the reaction, demineralized water (5 ml) was added, the solid formed was filtered and washed with demineralized water (1 x 5 ml) and dried in a vacuum oven at about 50 ° C to give 0.23 g. of Linagliptina.

ESEMPIO 7. Sintesi di 2-(8-bromo-7-(3-clorobut-2-enil)-3-metil-2,6diosso-2,3,6,7-tetraidro-1H-purin-1-il)acetonitrile EXAMPLE 7. Synthesis of 2- (8-bromo-7- (3-chlorobut-2-enyl) -3-methyl-2,6dioxy-2,3,6,7-tetrahydro-1H-purin-1-yl) acetonitrile

In un pallone di reazione sono stati caricati 8-bromo-7-(3-clorobut-2-enil)-3-metil-1H-purin-2,6(3H,7H)-dione (1,00 g, 3,00 mmol), dimetilsolfossido (10 ml), potassio carbonato (0,46 g, 3,30 mmol), potassio ioduro in quantità catalitiche e 2-cloroacetonitrile (0,19 mL, 3,00 mmol). La temperatura viene portata a circa 70°C e la miscela di reazione viene mantenuta in queste condizioni per circa tre ore. A reazione terminata sono stati aggiunti acqua demineralizzata (10 ml) e toluene (10 ml); la fase acquosa è stata estratta con toluene (4 x 10 ml) e le fasi organiche riunite sono state ridotte a residuo mediante distillazione sottovuoto a dare 1,05 g di 2 - (8-bromo-7-(3-clorobut-2-enil) - 3 - metil - 2,6-diosso - 2,3,6,7 - tetraidro - 1H-purin-1-il)acetonitrile. 8-bromo-7- (3-chlorobut-2-enyl) -3-methyl-1H-purin-2,6 (3H, 7H) -dione (1.00 g, 3, 00 mmol), dimethyl sulfoxide (10 ml), potassium carbonate (0.46 g, 3.30 mmol), potassium iodide in catalytic quantities and 2-chloroacetonitrile (0.19 ml, 3.00 mmol). The temperature is brought to about 70 ° C and the reaction mixture is kept under these conditions for about three hours. At the end of the reaction, demineralized water (10 ml) and toluene (10 ml) were added; the aqueous phase was extracted with toluene (4 x 10 ml) and the combined organic phases were reduced to residue by vacuum distillation to give 1.05 g of 2 - (8-bromo-7- (3-chlorobut-2- enyl) - 3 - methyl - 2,6-dioxus - 2,3,6,7 - tetrahydro - 1H-purin-1-yl) acetonitrile.

<1>H-NMR (DMSO, 300MHz): δ 5,66 (t, 1H), δ 5,07 (d, 2H), δ 4,88 (s, 2H), δ 3,58 (s, 3H), δ 2,18 (s, 3H). <1> H-NMR (DMSO, 300MHz): δ 5.66 (t, 1H), δ 5.07 (d, 2H), δ 4.88 (s, 2H), δ 3.58 (s, 3H ), δ 2.18 (s, 3H).

ESEMPIO 8. Sintesi di (R)-isopropil 1-(7-(3-clorobut-2-enil)-1-(cianometil)-3-(metil-2,6-diosso-2,4,6,7-tetraidro-1H-purin-8-il)peridin-3-il carbammato. EXAMPLE 8. Synthesis of (R) -isopropyl 1- (7- (3-chlorobut-2-enyl) -1- (cyanomethyl) -3- (methyl-2,6-dioxo-2,4,6,7- tetrahydro-1H-purin-8-yl) peridine-3-carbamate.

In un pallone di reazione sono stati caricati 2-(8-bromo-7-(3-clorobut-2-enil)-3-metil-2,6-diosso-2,3,6,7-tetraidro-1H-purin-1-il)acetonitrile (1 g, 2,70 mmol), dimetilsolfossido (10 ml), potassio carbonato (0,41 g, 3,00 mmol), (R)-isopropil-piperidin-3-il carbammato (0,50 g, 2,70 mmol). La temperatura è stata portata a circa 70°C e la miscela di reazione viene mantenuta in queste condizioni per circa 5 ore. A reazione terminata sono stati aggiunti acqua demineralizzata (5 ml) e toluene (5 ml); la fase acquosa è stata estratta con toluene (3 x 5 ml) e le fasi organiche riunite sono state ridotte a residuo mediante distillazione sottovuoto a dare 1,37 g di (R)-isopropil 1-(7-(3-clorobut-2-enil)-1-(cianometil)-3-(metil-2,6-diosso-2,4,6,7-tetraidro-1H-purin-8-il)piperidin-3-il carbammato. 2- (8-bromo-7- (3-chlorobut-2-enyl) -3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin were loaded into a reaction flask -1-yl) acetonitrile (1 g, 2.70 mmol), dimethyl sulfoxide (10 ml), potassium carbonate (0.41 g, 3.00 mmol), (R) -isopropyl-piperidine-3-il carbamate (0 , 50 g, 2.70 mmol). The temperature was brought to about 70 ° C and the reaction mixture was kept under these conditions for about 5 hours. At the end of the reaction, demineralized water (5 ml) and toluene (5 ml) were added; the aqueous phase was extracted with toluene (3 x 5 ml) and the combined organic phases were reduced to residue by vacuum distillation to give 1.37 g of (R) -isopropyl 1- (7- (3-chlorobut-2 -enyl) -1- (cyanomethyl) -3- (methyl-2,6-dioxo-2,4,6,7-tetrahydro-1H-purin-8-yl) piperidine-3-carbamate.

<1>H-NMR (DMSO, 300MHz): δ 5,78 (t, 1H), δ5,56 (m, 1H), δ 4,90 (s, 2H), δ 4,80 (d, 2H), δ 3,87 (s, 1H), δ 3,48 (m, 4H), δ 3,18 (m, 3H), δ 2,20 (m, 3H), δ 1,87 (m, 2H), δ 1,73 (m, 3H), δ 1,23 (m, 6H). <1> H-NMR (DMSO, 300MHz): δ 5.78 (t, 1H), δ5.56 (m, 1H), δ 4.90 (s, 2H), δ 4.80 (d, 2H) , δ 3.87 (s, 1H), δ 3.48 (m, 4H), δ 3.18 (m, 3H), δ 2.20 (m, 3H), δ 1.87 (m, 2H) , δ 1.73 (m, 3H), δ 1.23 (m, 6H).

13C-NMR (DMSO, 300MHz): δ 157,14 (C), δ 155,55 (C), δ 152,67 (C), δ 150,55 (C), δ 148,55 (C), δ 134,22 (C), δ 121,84 (CH), δ 115,18 (C), δ 104,32 (C), δ 68,14 (CH), δ 54,59 (CH2), δ 51,20 (CH2), δ 46,36 (CH), δ 44,68 (CH2), δ 43,81 (CH2), δ 41,08 (CH), δ 30,00 (CH3), δ 29,61 (CH2), δ 28,44 (CH2), δ 26,24 (CH3), δ 22,27 (2 CH3). 13C-NMR (DMSO, 300MHz): δ 157.14 (C), δ 155.55 (C), δ 152.67 (C), δ 150.55 (C), δ 148.55 (C), δ 134.22 (C), δ 121.84 (CH), δ 115.18 (C), δ 104.32 (C), δ 68.14 (CH), δ 54.59 (CH2), δ 51, 20 (CH2), δ 46.36 (CH), δ 44.68 (CH2), δ 43.81 (CH2), δ 41.08 (CH), δ 30.00 (CH3), δ 29.61 ( CH2), δ 28.44 (CH2), δ 26.24 (CH3), δ 22.27 (2 CH3).

ESEMPIO 9 . Sintesi di (R)-isopropil 1-(7-(3-clorobut-2-enil)-3-metil-1-((4-metilchinazolin-2-il)metil-2,6-diosso-2,3,6,7-tetraidro-1H-purin-8-il)piperidin-3-il carbammato. EXAMPLE 9. Synthesis of (R) -isopropyl 1- (7- (3-chlorobut-2-enyl) -3-methyl-1 - ((4-methylquinazolin-2-yl) methyl-2,6-dioxo-2,3, 6,7-tetrahydro-1H-purin-8-yl) piperidin-3-carbamate.

In un pallone di reazione sono stati caricati 2-amminoacetofenone (0,17 g, 1,26 mmol), 1,4-diossano (1 ml), la temperatura è stata portata a circa 10°C ed sono stati caricati acido cloridrico gassoso (0,29 g, 7,56 mmol), (R)-isopropil 1-(7-(3-clorobut-2-enil)-1-(cianometil)-3-(metil-2,6-diosso-2,4,6,7-tetraidro-1H-purin-8-il)peridin-3-il carbammato (0,5 g, 1,05 mmol) e la miscela di reazione è stata mantenuta in queste condizioni per circa tre ore. A reazione terminata, la temperatura è stata portata a circa 5°C e sono stati aggiunti sodio idrossido soluzione 50% (0,60 g, 7,56 mmol) e il solido formatosi è stato filtrato e lavato con acqua demineralizzata (1 x 0,5 ml) e 1,4-diossano (1 x 0,5 ml) ed essiccato in stufa sottovuoto a 50°C a dare 0,47 g di (R)-isopropil 1-(7-(3-clorobut-2-enil)-3-metil-1-((4metilchinazolin-2-il)metil-2,6-diosso-2,3,6,7-tetraidro-1H-purin-8-il)piperidin-3-il carbammato. In a reaction flask 2-aminoacetophenone (0.17 g, 1.26 mmol), 1,4-dioxane (1 ml) were charged, the temperature was brought to about 10 ° C and gaseous hydrochloric acid was charged. (0.29 g, 7.56 mmol), (R) -isopropyl 1- (7- (3-chlorobut-2-enyl) -1- (cyanomethyl) -3- (methyl-2,6-dioxo-2 , 4,6,7-tetrahydro-1H-purin-8-yl) peridine-3-carbamate (0.5 g, 1.05 mmol) and the reaction mixture was kept under these conditions for about three hours. At the end of the reaction, the temperature was brought to about 5 ° C and 50% sodium hydroxide solution (0.60 g, 7.56 mmol) was added and the solid formed was filtered and washed with demineralized water (1 x 0 , 5 ml) and 1,4-dioxane (1 x 0.5 ml) and dried in a vacuum oven at 50 ° C to give 0.47 g of (R) -isopropyl 1- (7- (3-chlorobut-2 -enyl) -3-methyl-1 - ((4methylquinazolin-2-yl) methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) piperidine-3-carbamate .

ESEMPIO 10. Sintesi di 8-bromo-7-(3-clorobut-2-enil)-3-metil-1-((4-metilchinazolin-2-il)metil)-1H-purin-2,6(3H,7H)-dione. EXAMPLE 10. Synthesis of 8-bromo-7- (3-chlorobut-2-enyl) -3-methyl-1 - ((4-methylquinazolin-2-yl) methyl) -1H-purin-2,6 (3H, 7H) -dione.

In un pallone di reazione sono stati caricati 2-amminoacetofenone (0,43 g, 3,20 mmol), 1,4-diossano (2,5 ml), la temperatura è stata portata a circa 10°C ed sono stati caricati acido cloridrico gassoso (0,70 g, 19,2 mmol), 2-(8-bromo-7-(3-clorobut-2-enil)-3-metil-2,6-diosso-2,3,6,7-tetraidro-1H-purin-1-il)acetonitrile (1,0 g, 2,70 mmol) e la miscela di reazione è stata mantenuta in queste condizioni per circa tre ore. A reazione terminata, la temperatura è stata portata a circa 5°C e sono stati aggiunti sodio idrossido soluzione 50% (1,54 g, 19,2 mmol) e il solido formatosi è stato filtrato e lavato con acqua demineralizzata (1 x 1 ml) e 1,4-diossano (1 x 1 ml) ed essiccato in stufa sottovuoto a 50°C a dare 1,1 g di 8-bromo-7-(3-clorobut-2-enil)-3-metil-1-((4-metilchinazolin-2-il)metil)-1H-purin-2,6(3H,7H)-dione. 2-aminoacetophenone (0.43 g, 3.20 mmol), 1,4-dioxane (2.5 ml) were charged into a reaction flask, the temperature was brought to about 10 ° C and acid was charged. hydrochloric gas (0.70 g, 19.2 mmol), 2- (8-bromo-7- (3-chlorobut-2-enyl) -3-methyl-2,6-dioxo-2,3,6,7 -tetrahydro-1H-purin-1-yl) acetonitrile (1.0 g, 2.70 mmol) and the reaction mixture was kept under these conditions for about three hours. At the end of the reaction, the temperature was brought to about 5 ° C and 50% sodium hydroxide solution (1.54 g, 19.2 mmol) was added and the solid formed was filtered and washed with demineralized water (1 x 1 ml) and 1,4-dioxane (1 x 1 ml) and dried in a vacuum oven at 50 ° C to give 1.1 g of 8-bromo-7- (3-chlorobut-2-enyl) -3-methyl- 1 - ((4-methylquinazolin-2-yl) methyl) -1H-purin-2,6 (3H, 7H) -dione.

Claims

CLAIMS 1. A process for the synthesis of Linagliptin which includes: d) the reaction of the intermediate of formula (VI) Cl CH3 OR N (VI) N N Br No. ON N CH3CH3 with a compound of formula (VII) R. (VII) No. H. where R represents a COOR1 group or an NHCOOR1 group, where R1 represents a linear or branched C1-C6alkyl group, in the presence of a catalyst and a base, in an aprotic polar solvent, to give the intermediate of formula (VIII) Cl CH3 OR No. N N N (VIII) No. ON N CH3CH3 <R> where R has the above meanings; e) any transformation of the intermediate (VIII) in which R represents a COOR1 group into the intermediate (VIII) in which R represents an NHCOOR1 group; f) conversion of compound (VIII) in which R represents an NHCOOR1 group to Linagliptin, by treatment with bases.

2. A process for the synthesis of Linagliptin which includes: a) the reaction of the compound of formula (II) OR H HN N (II) Br ON N CH3 with a compound of formula (III), in the presence of a base, in an aprotic polar solvent Cl Cl CH3 (III) to give the intermediate of formula (IV) Cl CH3 OR HN N Br (IV) ON N CH3 b) the reaction of the intermediate of formula (IV) with a compound of formula (V) No. X N (V) CH3 where X represents a halogen, preferably chlorine, in the presence of a catalyst and a base, in an aprotic polar solvent, to give the intermediate of formula (VI) Cl CH3 OR No. N N Br (VI) No. ON N CH3CH3 d) the reaction of the intermediate of formula (VI) with a compound of formula (VII) R. (VII) No. H. where R represents a COOR1 group or an NHCOOR1 group, where R1 represents a linear or branched C1-C6alkyl group, in the presence of a catalyst and a base, in an aprotic polar solvent, to give the intermediate of formula (VIII) Cl CH3 OR No. N N N (VIII) No. ON N CH3CH3 <R> where R has the above meanings; e) any transformation of the intermediate (VIII) in which R represents a COOR1 group into the intermediate (VIII) in which R represents an NHCOOR1 group; f) conversion of compound (VIII) in which R represents an NHCOOR1 group to Linagliptin, by treatment with bases.

3. A process for the synthesis of Linagliptin which includes a) the reaction of the compound of formula (II) OR H HN N (II) Br ON N CH3 with a compound of formula (III), in the presence of a base, in an aprotic polar solvent Cl Cl CH3 (III) to give the intermediate of formula (IV) Cl CH3 OR HN N Br (IV) ON N CH3 b ') the reaction of the compound of formula (IV) with chloroacetonitrile, in the presence of a catalyst and a base in an aprotic polar solvent, to give the intermediate of formula (IX) Cl CH3 OR NC N N Br (IX) ON N CH3 c) the reaction of the intermediate of formula (IX) with 2-aminoacetophenone in the presence of anhydrous hydrochloric acid, in 1,4-dioxane to give the intermediate of formula (VI) Cl CH3 OR No. N N (VI) Br No. ON N CH3CH3 d) the reaction of the intermediate of formula (VI) with a compound of formula (VII) R. (VII) No. H. where R represents a COOR1 group or an NHCOOR1 group, where R1 represents a linear or branched C1-C6alkyl group, in the presence of a catalyst and a base, in an aprotic polar solvent, to give the intermediate of formula (VIII) Cl CH3 OR No. N N N (VIII) No. ON N CH3CH3 <R> where R has the above meanings; e) any transformation of the intermediate (VIII) in which R represents a COOR1 group into the intermediate (VIII) in which R represents an NHCOOR1 group; f) conversion of compound (VIII) in which R represents an NHCOOR1 group to Linagliptin, by treatment with bases.

4. Process according to any one of the preceding claims, in which in step d) the catalyst is preferably selected from potassium iodide tetrabutylammonium iodide, sodium iodide, copper iodide, more preferably potassium iodide and the base is preferably selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, more preferably potassium carbonate; the aprotic polar solvent is preferably selected from dimethylsulfoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures of said solvents with each other, more preferably dimethylsulfoxide; step e) is carried out in the presence of diphenylphosphorylazide, and of a tertiary amine preferably selected from triethylamine, tributylamine, diisopropylethylamine, N, N-dimethylaminopyridine and a suitable linear or branched C1-C4 alcohol preferably selected from methanol, ethanol, isopropanol -butanol; in step f) the bases used are selected from sodium terbutoxide, potassium terbutoxide, sodium hydride, metallic sodium, sodium amide, more preferably potassium terbutoxide.

5. Process according to claim 2, wherein in step a) an organic or inorganic base is used, preferably selected from triethylamine, tributylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, more preferably triethylamine and the aprotic polar solvent used is preferably selected from dimethylsulfoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures of said solvents with each other, more preferably dimethylsulfoxide; in step b) the catalyst used is preferably selected from potassium iodide, tetrabutylammonium iodide, sodium iodide, copper iodide even more preferably potassium iodide, the base used is preferably selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, more preferably potassium carbonate and the aprotic polar solvent is preferably selected from dimethylsulfoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures of said solvents with each other, more preferably dimethylsulfoxide.

6. Process according to claim 3, in which in step b ') the catalyst used is selected from potassium iodide, tetrabutylammonium iodide, sodium iodide, copper iodide, preferably potassium iodide; the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, preferably potassium carbonate; the aprotic polar solvent is selected from dimethylsulfoxide, acetonitrile, dimethylformamide, dimethylacetamide, or mixtures of said solvents with each other, preferably dimethylsulfoxide.

7. The compounds of formula (IV), (VI), (VIII) and (IX) Cl CH3 OR HN N Br (IV) ON N CH3 Cl CH3 O (VI) No. N N Br No. ON N CH3CH3 Cl CH3 OR N (VIII) N N No. No. ON N CH3CH3 <R>

8. Use of the compounds according to claim 8 for the synthesis of Linagliptin.