WO2021249877A1 - Intermediates and processes for the preparation of tolvaptan and its derivatives - Google Patents

Abstract

The present invention relates to new intermediates for the synthesis of Tolvaptan and of its derivatives and a process for its preparation involving said intermediates.

Description

INTERMEDIATES AND PROCESSES FOR THE PREPARATION OF TOLVAPTAN AND ITS DERIVATIVES

TECHNICAL FIELD

The present invention relates to new intermediates for the synthesis of Tolvaptan and its pharmacological acceptable derivatives and a process for its preparation comprising said intermediates. BACKGROUND ART

Tolvaptan, also known as N-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro- benzo[b]azepin-l-carbonyl)-3-methyl-phenyl]-2-methylbenzamide, is characterized by the following formula:

Tolvaptan is a non-peptide vasopressin antagonist that specifically blocks the binding of AVP (arginine vasopressin) to V2 receptors in the distal nephron and is used to treat hyponatremia associated with congestive heart failure, cirrhosis and inappropriate antidiuretic hormone syndrome (SIADH).

Tolvaptan is marketed as a racemate. Various synthetic approaches for the preparation of Tolvaptan have been described.

US 5 258 510 and US 5 559 230 disclose benzoheterocyclic compounds including Tolvaptan and its derivatives and processes for their preparation by reducing the nitro group to give the corresponding amine, according to the following scheme:

Bioorganic & Medicinal Chemistry 7 (1999) 1743-1754 , describes the synthesis of benzodiazepine compounds by condensation of 7-chloro-l,2,3,4-tetrahydro-5H- benzo[b]azepin-5-one with the suitable derivatives of 4-nitro-benzoic acid to give the corresponding amides. The nitro group is then reduced to yield the aniline derivatives.

Particularly, the synthesis of Tolvaptan includes the reduction in the presence of in the presence of

according to the following scheme:

CN 102060769 discloses a process for the N-acylation of 7-chloro-5-oxo-2, 3,4,5- tetrahydro-lH-l-benzazepine with 2-methyl-4-nitrobenzoic acid chloride in the presence of N-methyl morpholine as a base:

IN2012MUM0634 describes a process for the preparation of the intermediate nitro derivative for the synthesis of Tolvaptan, comprising the reaction of the suitable benzoazepine with nitro benzoyl chloride in an organic solvent, in the absence of a base:

CN 108 341 780 discloses the catalytic hydrogenation of the nitro derivative to yield the corresponding amine in the presence of a catalytic system consisting of a metal chloride with Pd-C wherein the metal chloride is lithium chloride or indium trichloride:

CN 106 883 175 discloses a process for the preparation of Tolvaptan comprising the amidation reaction between benzoazepine and 1-bromo-2-methyl-4-nitrobenzene in the presence of PPh₃ PdC1₂ or Pd(OAc)₂ and a carbonylating agent, followed by reduction in presence of Fe dust and NH₄C1, and subsequent acylation and reduction reaction:

CN 102 382 053 describes a process for the preparation of the nitro derivative by reacting the suitable benzazepine with nitrobenzoyl chloride in acetonitrile in the presence

CN 104 418 803 describes a process of preparation of Tolvaptan by reaction between the suitable benzoazepine and the suitable acid chloride according to the scheme:

The above mentioned acid chloride is prepared starting from the reduction of 2- methyl-4-nitrobenzoic acid to yield the corresponding amine which is condensed with 2- methylbenzoyl chloride to give 2-methyl-4-(2-methylbenzyl)benzoic acid subsequently activated as chloride.

Currently known Tolvaptan syntheses involve steps through nitro derivatives which are subsequently reduced to give the corresponding amines.

Several chemical structures have been associated with mutagenic and carcinogenic activity, including aromatic structures characterized by the presence of nitro groups {Reg. Tox. And Farm. 44 (2006) 198-211; Current Computer-Aided Drug Design, 2006, 2, 1-19, (2) 169-176 ).

The presence of aromatic nitro compounds in the routes of synthesis of pharmaceutical products, therefore represents a big problem due to the potential mutagenicity and genotoxicity of the intermediates and derived impurities that require a burdensome analytical study and purification steps recommended in the ICH M7 guidelines relating to mutagenic impurities, with positive carcinogenicity data, which can also be very challenging.

The Applicant has developed a new effective process for the purification of the intermediate l-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-l- benzazepine which, according to the traditional synthesis method, i.e. using nitro compounds, contains a potential mutagenic impurities (PMI) amount higher than 5000 ppm. Said purification system allows to obtain a reduction of more than 10 times of the PMI content, obtaining values according to the regulatory requirements.

Although said purification procedure is effective, it requires additional steps which involve an increase in production costs. The need therefore remains to find new intermediates and different synthesis strategies that do not involve the use of aromatic nitro compounds or the passage through intermediates containing nitro groups, especially if linked to aromatic structures, in order to avoid any possible presence of potentially carcinogenic or mutagenic compounds.

DESCRIPTION OF THE INVENTION

We have now found new intermediates for the synthesis of Tolvaptan or its pharmacologically acceptable derivatives and a process for their preparation with high yield and high chemical purity, which avoids the use of aromatic nitro compounds.

Therefore, a first object of the present invention is new intermediates of formula (I):

wherein

X is a halogen atom or an O-sulfonate group;

Xi a halogen atom;

W and Wi together form an oxygen atom (compounds of formula (la))

or one of W and Wi groups is hydrogen and the other is an OR_p group (compounds of formula (lb))

wherein Rp is hydrogen or a hydroxyl protective group; or W and Wi represent protective group PG of the carbonyl group (compounds of formula (Ic))

wherein PG preferably represents a cyclic or non-cyclic ketal or thioketal. Examples of Ic compounds are represented by formulas (I_c1), (I_c2), (I_c3), (I_c4):

R and Ri, the same or different from each other, are selected from linear or branched C₁-C₆ alkyl; C₅-C₆ cycloalkyl optionally substituted by C₁-C₄ alkyl groups; CH₂-phenyl,

CH₂-aryl, CH₂-heteroaryl, with phenyl, aryl and heteroaryl optionally substituted with one or more groups selected from linear or branched C₁-C₆ alkyl, halogens, -NO₂, -OR₂ groups where R₂ is selected from H, linear or branched C₁-C₆ alkyl, optionally substituted benzyl;

T is CR^IIR^III-(CR^IVR^V)n wherein n = 0-3, R^II,R^III,R^IV,R^V same or different from each other, are selected from hydrogen, linear or branched C₁-C₆ alkyl; C₅-C₆ cycloalkyl optionally substituted by C₁-C₄ alkyl groups; CH₂-phenyl, CH₂-aryl, CH₂-heteroaryl with phenyl, aryl and heteroaryl optionally substituted with one or more groups selected from linear or branched C₁-C₆ alkyl, halogen, NO₂, -OR₂ groups where R₂ is selected from H, linear C₁-C₆ alkyl or branched, optionally substituted benzyl. Preferably X₁ is chlorine, bromine and iodine; more preferably chlorine.

Preferably X is bromine, iodine, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, more preferably bromine, iodine or trifluoromethanesulfonate.

Preferably Rp is H or a protective group of hydroxyl, such as for example acetyl (Ac); benzoyl (Bz); benzyl (Bn); b-methoxyethoxymethyl ether (MEM); dimethoxytrityl; [bis- (4-methoxyphenyl)phenylmethyl] (DMT); methoxymethyl ether (MOM); methoxytrityl [(4-methoxyphenyl) diphenylmethyl] (MMT); p-methoxybenzyl ether (PMB); methylthiomethyl ether (MTM); pivaloyl (Piv); triphenylmethyl (Tr); tetrahydropyranyl ether; tetrahydrofuranyl ether; silyl derivatives, preferably selected from trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tri-iso- propylsilyl (TIPS), tri-iso-propylsilyloxymethyl (TOM), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBS), t-Butyldiphenylsilyl (TBDPS); alkyl ethers and alkoxy ethers. More preferably Rp is hydrogen or a tetrahydropyranil, tetrahydrofuranil, acetyl, benzoyl, pivaloyl, trimethylsilyl (TMS), triethylsilyl (TES) group, tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyl (TIPS), tri-iso- propylsilyloxymethyl (TOM), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS). Rp is still more preferably hydrogen. Preferably R and Ri are selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, benzyl, p-methylbenzyl, p-methoxybenzyl, m- methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, 3,4-dimethoxybenzyl, cyclopentyl, cyclohexyl.

Preferably, T is selected from the group consisting of CH₂; CHR^III where R^III is selected from hydrogen, a C1-C6 alkyl group, a phenyl group, an optionally substituted aryl group.

Preferably R^III is selected from H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, Ph; ( CH₂- CHR^IV) where R^IV is a C₁-C₆ alkyl group, a phenyl group, an optionally substituted aryl group, preferably (CH₂-CH^RIV) is selected from (CH₂-CHCH₃), (CH₂-CHC₂H₅), (CH₃CH- CHCH₃), (CH₂-C(CH₃)2-CH₂).

Preferred embodiments of the invention are the compounds of formula (IT):

wherein X is bromine, iodine or trifluoromethanesulfonate and W and Wi are defined as above.

When W and Wi taken together form a bond with an oxygen atom, the compounds are represented by the formula (I_Ta):

When one of W and Wi is hydrogen and the other is an OR_p group, the compounds are represented by the formula (I_Tb),

wherein Rp is defined as above.

When W and Wi are a protective group of the carbonyl group, the compounds are represented by the formula (I_Tc):

wherein PG is defined as above and the I_TC compounds are represented by the formulas (I_Tc1), (I_Tc2), (I_Tc3), (I_Tc4):

wherein R and Ri and T are defined as above.

In the compounds of formula (I_Tb) Rp is preferably selected from hydrogen and tetrahydropyranil, tetrahydrofuranil, acetyl, benzoyl, pivaloyl, trimethyl silyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyl (TIPS), tri-iso- propylsilyloxymethyl (TOM), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS); more preferably Rp is

H.

In the compounds of formula (I_Tc1) and (I_Tc2) R and R ', same or different from each other, are preferably selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, benzyl, p-methylbenzyl, p-methoxybenzyl, m-methoxybenzyl, p- nitrobenzyl, p-chlorobenzyl, 3,4-dimethoxybenzyl, cyclopentyl, cyclohexyl, even more preferably R and R' are selected from methyl, ethyl, propyl, isopropyl.

In the compounds of formula (I_Tc3) and (I_Tc4) T is preferably selected from the groups (CH₂-CHCH₃), (CH₂-CHC₂H₅), (CH₃CH-CHCH₃), (CH₂-C(CH₃)₂-CH₂).

A further object of the invention is a process for the preparation of Tolvaptan and its pharmacologically acceptable derivatives, comprising:

- the reaction of a compound of formula (IT) with a compound of formula (II) to give a compound of formula (IIIT)

wherein X is selected from bromine, iodine, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate; more preferably bromine, iodine, trifluoromethanesulfonate and W and W₁ are defined as above in the presence of a transition metal catalyst based, a base and in a suitable solvent.

The reaction is carried out at a temperature between room temperature and the reflux temperature of the solvent.

When W and Wi taken together represent an oxygen atom, the compounds (IT) and (IIIT) are represented by the formulas (I_Ta) and (III_Ta):

When one of W and Wi is an ORp group and the other is hydrogen, the compounds of formula (I_T) and (III_T) are represented by the formulas (I_Tb) and (Ill_Tb):

wherein X and Rp are defined as above.

When W and W₁ are a protective group of the carbonyl group, the compounds of formula (IT) and (IIIT) are represented by the formulas (IT_c) and (IIIT_C),

where X and PG are defined as above.

Preferably the transition metal catalyst is selected from Ru, Rh, Pt, Pd and Cu, in metallic form or in the form of oxides, halides, cyanides, alkoxides, carboxylates, salts optionally complexed with suitable ligands, or in the form of preformed complexes with said ligands.

The catalyst is preferably based on Pd or Cu in metallic form or in the form of oxides, halides, cyanides, alkoxides, carboxylates and salts, optionally complexed with suitable ligands, or in the form of preformed complexes of said ligands, preferably phosphines or carbenes.

The base is preferably selected from hydroxides, carbonates, bicarbonates, phosphates, monohydrogen phosphates, dihydrogen phosphates, fluorides and alkoxides, alkylsilyl amides of alkaline and alkaline earth metals, and mixtures thereof.

The bases are preferably selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, cesium phosphate, sodium tert-butylate, potassium tert-butylate, cesium tert-butylate, sodium fluoride, cesium fluoride, potassium fluoride, lithium bis (trimethyl silyl) amide, sodium methylate; even more preferably potassium phosphate; cesium carbonate; potassium carbonate; potassium hydroxide; sodium tert-butylate; potassium tert-butylate; sodium methylate, lithium bis (trimethyl silyl) amide.

Preferably the solvents are selected from apolar or polar aprotic, aromatic, aliphatic, ether, ester, ketone, alcoholic solvents, optionally in the presence of water and mixtures thereof.

Examples of solvents are dichloromethane, acetonitrile, dimethylsulfoxide, sulfolane, N-methylpyrrolidone, dimethylformamide, tetrahydrofuran, methyl- tetrahydrofuran, dimethylacetamide, dioxane, dimethoxyethane, toluene, xylenes, cumene, cimanutene, cyclopentone-methyl methyl ethyl methyl methyl acetate, i methanol, n- propanol, n-butanol, t-butanol, sec-butanol, teramyl alcohol, and mixtures thereof optionally in the presence of water, more preferably toluene, dioxane, dimethoxyethane, t- butanol, n-butanol, teramyl alcohol, dimethylformamide, tetrahydrofuran, cyclopentylmethyl ether N-methylpyrrolidone, methyl-tetrahydrofuran, dimethylacetamide, and mixtures thereof optionally in the presence of water.

The catalyst is preferably based on metallic Pd or its oxides; alkoxides; carboxylates, preferably acetate; halides, preferably Cl, Br and I; alkylsulfonates, aryl sulfonates, preferably methanesulfonate, ethanesulfonate, p-toluenesulfonate, triflate; and complexes of said derivatives with ligands selected from tertiary phosphines and their p-allyl complexes, carbenes, salts and their adducts with solvents and complexes of said preformed ligands, preferably phosphine or carbene complexes.

Preferably, said tertiary phosphines are selected from tri-tert-butylphosphine, 2-(di- tert-butylphosphino)-1,1 '-biphenyl, 2-(di-tert-butylphosphine) -2 '-methyl- 1,1 '-biphenyl, 2- (di-tert-butylphosphino)1, 1 '-binaphthyl, 2-dicyclohexylphosphino-2',6'-dimethoxy-1, 1 '- biphenyl, 2-dicyclohexylphosphino-2',6'-di-iso-propoxy-1, 1 '-biphenyl, N-phenyl-2-(di- tert-butyl phosphine)pyrrole, 1-phenyl-2-(di-tert-butylphosphino)-lH-indene), (2- dicyclohexylphosphino-2',4',6'-triisopropyl-l, 1 '-biphenyl) [2-(2'-amino-l, 1 '-biphenyl)], (2-dicyclohexylphosphino-2',6'-dimethoxy-l, 1 '-biphenyl) [2-(2'-amino-l, 1 '-biphenyl)], [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-l, 1 '-biphenyl)-2-(2 '-amino- 1, 1 '-biphenyl)], [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'- amino- 1 , 1 '-biphenyl)] , [(2-di-tert-butylphosphino-3 , 6-dimethoxy-2 ',4 ', 6 '-trii sopropyl- 1,1' -Biphenyl)-2-(2'-amino-1, 1 '-biphenyl)], (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1, 1'-biphenyl) [2-(2 '-amino- I,1'-biphenyl)], chlorine [(tri-tert-butylphosphine)-2-(2- aminobiphenyl)], chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'- amino-1, 1 '-biphenyl)], [2-(2'-amino-1, 1 '-biphenyl)] [4-(di-tert-butylphosphino)-N,N- dimethylaniline](chloro), chloro(tricyclohexylphosphine)[2-(2'-amino-1, 1 '-biphenyl)], chloro[(p-dimethylaminophenyl)(di-tert-butylphosphine)], tri-tert-butylphosphine

(chlorine), chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1, 1'-biphenyl), chloro(2- dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl), (2-dicyclohexylphosphino-2',4',6'- triisopropyl-3,6-dimethoxy-1, 1 '-biphenyl), (2-di-tert-butylphosphino-2',4',6'-triisopropyl- 1 , 1 ’-biphenyl), (2-di-tert-butylphosphino-2 ',4 ',6 '-trii sopropyl- 1 , 1 ’-biphenyl), [(R)-2,2 '-bi s (diphenylphosphine)-l, 1 '-binaftalene], [4,5-bis (diphenylphosphino)-9,9- dimethylxanthene], tricyclohexylphosphine, [5-(di-tert-butylphosphino)-1',3',5'-triphenyl- 1'H-1,4'-bipirazole]; tri-o-tolylphosphine, [2-(2'-amino-1,1'-biphenyl)] [4-(di-tert- butylphosphino)-N,N-dimethylaniline], [(2-di-tert-butylphosphine-3,6-dimethoxy-2',4',6'- triisopropyl- 1 , 1 '-biphenyl)-2-(2 '-amino- 1 , 1 '-biphenyl)], 4,5-Bis (diphenylphosphino)-9,9- dimethylxanthene, (tricyclohexylphosphine) [2-(2 '-amino- 1,1'-biphenyl)], chloro(2- dicy clohexylphosphino-2’,4',6’-triisopropyl- 1 , 1 ’-biphenyl); ( 1 ,4-naphthoquinone)-[ 1 ,3 - bis(2,6-diisopropylphenyl)imidazol-2-ylidene], allylchloro-[l,3-bis(2,6- diisopropylphenyl) imidazol-2-ylidene], allylchloro-[1,3-bis(2,6-diisopropylphenyl)-4,5- dihydroimidazol-2-ylidene], (3-phenylallylchloro)-[l,3-bis(2,6-diisopropylphenyl)-4,5- dihydroimidazol-2-ylidene]; more preferably [(2-di-cyclohexylphosphino-3,6-dimethoxy- 2 ',4', 6 '-trii sopropyl- 1 , 1 '-biphenyl)-2-(2 '-amino- 1 , 1 '-biphenyl)] , (2- dicyclohexylphosphino-2',4',6'-triisopropyl-l, 1 '-biphenyl) [2-(2'-amino-l, 1 '-biphenyl)] and chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-l, 1'-biphenyl).

Pd-based catalysts are preferably selected from chlorine (2-dicyclohexylphosphino- 2', 4', 6 '-trii sopropyl- I,1'-biphenyl) [2-(2 '-amino- 1, 1 '-biphenyl)]palladium(II) adduct with THF; chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-l, 1 '-biphenyl) [2-(2'-amino-l, 1 '- biphenyl)]palladium(II) adduct with 1.5 THF; [(2-di-tert-butylphosphino-2',4',6'- trii sopropyl- 1, 1 '-biphenyl)-2-(2 '-amino- 1, 1 '-biphenyl)]palladium(II) methanesulfonate adduct with MTBE; [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- biphenyl)-2-(2 '-amino- 1, 1 '-biphenyl)]palladium(II) methanesulfonate; [(2-di-tert- butylphosphino-3,6-dimethoxy-2 ',4 ',6 '-trii sopropyl- 1, 1 '-biphenyl)-2-(2'-amino-l, 1 '- biphenyl)]palladium(II) methanesulfonate; (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1,1 '-biphenyl) [2-(2 '-amino- 1,1 '-biphenyl)] palladium(II)methanesulfonate; chloro[(tri- tert-butylphosphine)-2-(2-aminobiphenyl)] palladium (II); chloro[(4,5- bis(diphenylphosphine)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II); [2-(2'-amino-l,l '-biphenyl)] [4- (di-tert-butylphosphino) -N, N-dimethylaniline] (chloro)palladium(II); chloro(tricyclohexylphosphine) [2- (2 '-amino- 1,1'- biphenyl)]palladium(II); chloro (crotyl) (2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1,1'-biphenyl)palladium (II); chloro (crotyl) [(p-dimethylaminophenyl) (di-tert- butylphosphine)] palladium(II); tri-tert-butylphosphine (chloro) (crotyl)palladium(II); chloro (crotyl) (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) palladium(II); chloro (crotyl) (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1 '-biphenyl)palladium(II); crotyl (2-dicyclohexylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-l, 1 '- biphenyl)palladium(II) triflate; allyl (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)palladium(II) triflate; allyl [(R)-2,2'-bis(diphenylphosphino)-1,1'- binafthalene]palladium(II) chloride; allyl [4,5-bis(diphenylphosphino)-9,9- dimethylxanthene]palladium(II) chloride; chloro (crotyl)

(tricyclohexylphosphine)palladium(II); allyl [5-(di-tert-butylphosphino) - 1 ' , 3 5 '-tripheny 1- rH-l,4'-bipyrazole]palladium(II) triflate; chloro (crotyl) (tri-o- tolylphosphine)palladium(II), [(2-di-tert-butylphosphino-3 , 6-dimethoxy-2 ',4 ', 6 '- triisopropyl-1, 1 '-biphenyl)-2-(2 '-amino- 1, 1 '-biphenyl)]palladium(II) methanesulfonate, [2- (2'-amino- 1 , 1 '-biphenyl)] [4-(di-tert-butylphosphino)-N,N-dimethylaniline]

(chloro)palladium(II), chloro (tricyclohexylphosphine) [2-(2 '-amino- 1,1'- biphenyl)]palladium(II), sodium hexachloropalladate(IV) tetrahydrate, potassium hexachloropalladate(IV), palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) acetylacetonate, dichlorobis(benzonitrile)palladium(II), dichlorobis(acetonitrile)palladium(II), dichlorobis(triphenylphosphine)palladium(II), dichlorotetraaminopalladium (II), dichloro(cycloocta-l,5-diene)palladium(II), palladium(II) trifluoroacetate, tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0) adduct with chloroform, tetrakis (triphenylphosphine)palladium(O); (l,4-naphthoquinone)-[l,3-bis(2,6- diisopropylphenyl)imidazol-2-ylidene]palladium(0), allylchloro-[l,3-bis(2,6- diisopropylphenyl) imidazol-2-ylidene] palladium (II), allylchloro-[l,3-bis(2,6- diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]palladium(II), (3-phenylallylchloro)- [l,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]palladium(II); more preferably [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-l, 1 '-biphenyl)- 2-(2'-amino-l, 1 '-biphenyl)]palladium(II) methanesulfonate, (2-dicyclohexylphosphino- 2 ',4 ', 6 '-trii sopropyl- 1 , 1 '-biphenyl) [2-(2 '-amino- 1 , 1 '-biphenyl)]palladium

(Il)methanesulfonate and chloro (crotyl) (2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1 , 1 '-biphenyl)palladium(II).

In a further preferred embodiment, it is used a catalyst based on metallic Cu or its derivatives selected from oxides; alkoxides; carboxylates, preferably acetate; halides, preferably Cl, Br and I; cyanides; alkylsulfonates, arylsulfonates, preferably methanesulfonate, ethanesulfonate, p-toluenesulfonate, triflate; and complexes of said derivatives with ligands selected from diamines, di-carbonyl compounds, amino acids, salts and their adducts with solvents.

The ligands of said Cu-based catalysts are preferably selected from optionally substituted C₁-C₆ beta-ketoesters; optionally substituted C₁-C₆ diketones, amino acids, Ci- C₆ alkyldiamines, optionally substituted C₄-C₈ cycloalkyldiamines, aryldiamines, heteroaryldiamines; optionally substituted on the nitrogen atoms and optionally substituted on the carbon atoms, wherein substituents on C and on N are the same or different from each other and are selected from H, C₁-C₄ alkyl groups, aryl groups, hydroxyl groups, OR_a groups wherein R_a is selected from C₁-C₄ alkyl groups and aryl groups. The ligands are preferably selected from ethylenediamine, N-N'- dimethylethylenediamine, 1 ,2-cyclohexyldiamine, N-N'-dimethyl- 1 ,2- cyclohexylenediamine, proline, 4-hydroxy proline, glycine, N,N-dimethyl glycine, bis- (2- hydroxyethyl) glycine, 2- (dimethylamino) ethanol, picolinic acid, methyl N-methyl prolinate. More preferably Cu-based catalysts selected from metallic Cu, Cul-N-N'- dimethylethylendiamine, 1 ,2-cyclohexyldiamine, N,N'-dimethyl- 1 ,2- cyclohexylendiamine, CuI-N,N-dimethyl glycine are used.

An object of the invention is a process for the preparation of Tolvaptan and its pharmacologically acceptable derivatives which further comprises the preparation of the compounds of formula (I).

The compounds of formula (I) are prepared according to the invention by a process comprising the reaction of compounds of formula (IV) with compounds of formula (V):

In the presence of a suitable solvent: at a temperature between room temperature and the reflux temperature of the solvent: where X, Xi, W and Wi have the meanings above reported and

X₃ is selected from halogen atoms, OH, O-sulfonate groups; OR₅ groups wherein R₅ is selected from linear or branched C₁-C₆ alkyls; C₅-C₆ cycloalkyls; optionally substituted with C₁-C₄ alkyl groups; C₃-C₉ alkenyls; phenyls, naphthyls, hetero-aryls, optionally substituted; preferably X₃ is selected from chlorine, bromine, iodine, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate; more preferably X₃ is selected from chlorine, bromine and iodine.

The solvents are preferably selected from apolar or polar aprotic, aromatic, aliphatic, ethers, esters, ketone, alcoholic solvents, optionally in the presence of water and mixtures thereof. Examples of solvents are dichlorom ethane, acetonitrile, dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N-butylpyrrolidone, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dimethoxyethane, cyclopentylmethylether, toluene, xylene, cumene- propanol, methanol, n-propanol, n-butanol, t-butanol, sec-butanol, teramyl alcohol or mixtures thereof optionally in the presence of water. Preferably, said solvents are selected from toluene, dioxane, dimethoxyethane, cyclopentylmethylether, t-butanol, n- butanol, teramyl alcohol, dimethylformamide, tetrahydrofuran, methyl-tetrahydrofuran, dimethylacetamide, N-methylpyrrolidone, N-butylpyrrolidone and mixture thereof optionally in the presence of water. In a preferred embodiment of the invention Xi is a chlorine atom.

In a preferred embodiment of the present invention, the process for the preparation of Tolvaptan further comprises the reduction of the compounds of formula (I_Ta) to give the compounds of formula (I_Tb):

wherein Rp is hydrogen or a hydroxyl protective group and X has the meanings reported above, in the presence of a reducing agent in a suitable solvent, optionally followed by the protection of the hydroxyl group.

Alternatively, the process for the preparation of Tolvaptan of the present invention further comprises the protection of the carbonyl group of the compounds of formula (In) to give the compounds of formula (In):

wherein PG is defined as above and the In compounds are represented by the formulas (I_Tc1), (I_Tc2), (I_TC3), (I_Tc4) above reported, by reacting the compounds of formula (In) with suitable alcohols, thiols, diols, di- thiols, under suitable reaction conditions according to known methods described for example in "Greene's Protective Groups in Organic Synthesis - IV ed.

In a further embodiment of the present invention, the process for the preparation of Tolvaptan further comprises the reduction of the compound of formula(IV_Ta) with suitable reducing agents to give the compound of formula (IV-r_b),

optionally followed by the protection of the hydroxyl group, and subsequent reaction with the compound of formula (V) to give the respective compounds (I_Tb)

wherein X, X₃ and Rp have the meanings described above.

Preferably Rp is selected from hydrogen and tetrahydropyranil, tetrahydrofuranil, acetyl, benzoyl, pivaloyl, trimethyl silyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyl (TIPS), tri-iso-propylsilyloxymethyl (TOM), dimethylisopropyl silyl (IPDMS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS).

Preferably the reducing agents are selected from LiA1H4, NaBH₄, Zn(BH₄)₂, BH₃, Red-A1 and LiBH₄, or B₂H₆ in solvents selected from acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane, cyclohexane, etc.), ethers (e.g. diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, methyl-tetrahydrofuran, diethyl ether, etc.), esters (e.g. ethyl acetate, methyl acetate, etc.), polar aprotic solvents (eg dimethylformamide, etc.) and mixtures therof optionally with water.

The optional protecting reaction of the OH group is carried out on the compounds of formula (Vl_Tb) according to known methods, described for example in "Greene's Protective Groups in Organic Synthesis - IV

Alternatively, the process for the preparation of Tolvaptan further comprises protecting the compounds of formula (IV_Ta) to yield the compounds of formula (IV_Tc)

followed by the reaction of the compounds of formula (IVT_c) with compounds of formula (V) to give the compounds of formula (IT_c):

wherein PG is selected from cyclic and non-cyclic ketals and thioketals, and the compounds (IV_Tc) are represented by the formulas (IV_Tc1), (IV_Tc2), (IV_Tc3), (IV_Tc4)

and compounds I_Tc are represented by formulas (IV_Tc1), (IV_Tc2), (IV_Tc3), ; (IV_Tc4) in the presence of a suitable solvent, at a temperature between room temperature and the reflux temperature of the solvent. Preferably the compounds (IV_Tc) are obtained by reaction of the compounds of formula (IV_Ta) with suitable alcohols, thiols, diols, di-thiols, in the suitable reaction conditions according to known methods and described for example in " Greene’s Protective Groups in Organic Synthesis - IV ed. Therefore, a further object of the present invention is the process for the preparation of Tolvaptan comprising: a) reacting compounds of formula (IV_T) with compounds of formula (V):

wherein X, X₃, W and Wi have the above reported meanings; in the presence of a suitable solvent, at a temperature between room temperature and the reflux temperature of the solvent; b) reacting a compound of formula (I_T) with a compound of formula (II) to give a compound of formula (III_T)

in the presence of a a transition metal based catalyst, a base and in a suitable solvent at a temperature between room temperature and the reflux temperature of the solvent.

Preferably in step a) solvents are selected from apolar or polar aprotic, aromatic, aliphatic, ether, ester, ketone, alcoholic solvents, and mixtures thereof optionally in the presence of water.

In step b) the preferred bases, solvents and catalysts are the same as those reported above for the reaction between the compounds of formula I_TC and II.

A further object of the present invention is the use of compounds of formula (I)

Wherein X, X₁ e W e W₁ have the above reported meanings; in a process for the preparation of Tolvaptan and pharmacologically acceptable derivatives thereof.

A further object of the present invention relates to pharmaceutical compositions comprising Tolvaptan or its pharmacologically acceptable derivatives, obtained according to the process of the present invention, in admixture with one or more conventional pharmaceutical additives.

The process of the present invention has therefore shown to be a surprisingly advantageous alternative, since it avoids the use of intermediates containing nitro groups, and therefore avoinding all the drawbacks related to the formation of potentially carcinogenic and mutagenic substances.

In its preferred embodiments, the process for the preparation of Tolvaptan of the present invention is represented by the following scheme:

5

In order to better illustrate the invention the following examples are now reported.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: ¹H-NMR of 7-Chloro-1,2,3,4-tetrahydro-1-(2-methyl-4-bromobenzoyl)- 5H-l-benzazepin-5-one (Example 3)

Figure 2: ¹³C-NMR of 7-Chloro-l,2,3,4-tetrahydro-l-(2-methyl-4-bromobenzoyl)- 5H-l-benzazepin-5-one (Example 3)

Figure 3: ¹H-NMR of 4-bromo-2-methylphenyl-(7-chloro-5-hydroxy-2, 3,4,5- tetrahydro-lH-benzo[b]azepin-l-yl)methanone (Example 4)

Figure 4: ¹³C-NMR of 4-bromo-2-methylphenyl-(7-chloro-5-hydroxy-2, 3,4,5- tetrahydro-lH-benzo[b]azepin-l-yl)methanone (Example 4)

Figure 5: ¹H-NMR of Tolvaptan (Example 9)

Figure 6: ¹³C -NMR of Tolvaptan (Example 9)

ANALYTICAL METHODS

IR Analysis (Infrared Spectroscopy)

The IR spectra were recorded using a JASCO FT-IR 460 Plus spectrophotometer. The samples were prepared by grinding about 5 mg of sample with about 500 mg of KBr and analyzed in the range 4000-400 cm^"1 with a resolution of 4 cm^'1.

NMR Analysis (Nuclear Magnetic Resonance)

NMR analysis were performed using a Bruker Avance 300MHz instrument.

Example 1

Purification of l-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2, 3,4,5- tetrahydro-lH-l-benzazepine to remove potentially mutagenic impurities

In a reaction flask l-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2, 3,4,5- tetrahydro-lH-l-benzazepine hydrochloride (50.0 g, title 65%) and water (500ml) are loaded. The mixture is heated to about 60°C and kept at the same temperature for 15 minutes. The obtained suspension is filtered on Dicalite (PALL filter press) by washing the filter with more hot water (50 ml). The filtrate is cooled to about 20°C and extracting it with a mixture of toluene:acetonitrile 1:1 (3x150 ml). The phases are separated and dichloromethane (250 ml) is added onto the aqueous phase. Sodium hydroxide 30% (50 ml) is added onto the biphasic system, maintaining a temperature of about 20 ± 5°C. The suspension is maintained under stirring for 30 minutes at about 20°C. The phases are separated and the aqueous phase is extracted with more dichloromethane (2x100 ml). The organic phases are collected and concentrated to a residual volume of 200 ml. Acetonitrile (150 ml) is added and concentrated again to a residual volume of 200 ml. The suspension is cooled to 20°C in 1 hour and kept at that temperature for 30 minutes. The solid is recovered by filtration on Buchner and rinsed with acetonitrile (50 ml). After drying (45°C for 16 hours) 23.7g of l-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro- lH-l-benzazepine are obtained as a yellow solid (yield 81%, title 100%, HPLC purity 99.8%). The NITRO impurity content (l-(4-nitro-2-methylbenzoyl)-7-chloro-5-oxo- 2,3,4,5-tetrahydro-lH-l-benzazepine) is less than 50 ppm.

Example 2

2-methyl-4-bromo-benzoyl chloride

In a flask under nitrogen, 2-methyl-4-bromo-benzoic acid, (60.5 g, 1.0 eq); toluene (424 ml) and dimethylformamide (0.44 ml, 0.02 eq) are loaded in that order. The suspension is brought to 70°C under stirring. Thionyl chloride (36.8 g; 1.1 eq) is added dropwise, maintaining the temperature at about 70 ± 5 ° C and reacting at about 70°C for 2 hours. At the end of the reaction, the solution is brought to about 50°C and distilled under vacuum to a residual volume of 181 ml. The product in solution is directly subjected to the subsequent synthesis step. Theoretically obtained 65.7 g of 2-methyl-4-bromo-benzoyl chloride.

Example 3

7-Chloro-l,2,3,4-tetrahydro-l- (2-methyl-4-bromobenzoyl) -5H-l-benzazepin-

5-one

In a flask under nitrogen, 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine (50.0 g 1.0 eq) and toluene (200 ml) are loaded in that order. A suspension is obtained; 2- methyl-4-bromo-benzoyl chloride (65.7 g, 1.1 eq) in a solution of toluene obtained in example 2 is added dropwise in about 15 minutes at about 20°C. The suspension is brought to reflux (110 ° C) for about 3 hours under stirring. At the end of the reaction the solution is cooled to about 20°C. 5% sodium bicarbonate (250 ml) is dropped onto the mixture, maintaining the temperature at about 20 ± 5°C. The phases are separated and the aqueous phase is washed with 0.5 M hydrochloric acid (250 ml) and subsequently with water (250 ml). The organic phase is then concentrated in vacuum until a solid with constant weight is obtained. 95.4 g of the title compound were obtained as an off-white solid (yield 95%; HPLC purity 97%).

Solvent: DMSO-d6 at 80°C

¹H-NMR (ppm with respect to TMS): 2.00 (2H, t, J = 6 Hz); 2.30 (3H, s, -C¾); 2.79 (2H, t, J = 6 Hz); 3.88 (2H, m); 7.00 - 7.50 (4H, m, aromatics); 7.48 (1H, s); 7.61 (1H, s).

¹³C-NMR (ppm with respect to TMS): 18.6 (CH₃); 22.0 (CH₂); 39.7 (CH₂); 46.9 (CH₂); 122.3; 128.1 (CH); 128.3 (CH); 128.7 (CH); 130.8 (CH); 132.2; 132.3 (CH); 133.0 (CH); 135.2; 136.5; 137.6; 139.4; 167.1 (CONR); 200.4 (C=0).

Example 4

4-bromo-2-methylphenyl-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-lH- benzo[b]azepin-l-yl) methanone

In a flask under nitrogen, NaBH4 (8.2 g; 1.0 eq) with 2-methyl-tetrahydrofuran (682ml) are charged in that order. To the obtained suspension, under stirring, 7-Chloro-

1.2.3.4-tetrahydro-l-(2-methyl-4-bromobenzoyl)-5H-l-benzazepin-5-one (85,3 g; 1.0 eq) is added. The suspension is cooled to 5°C and a solution of methanol (25.5 ml; 2.9 eq) in 2-methyl-tetrahydrofuran (85ml) is slowly added dropwise, maintaining the temperature at 5°C. Reaction is carried on for 2h at 5°C. At the end of the reaction, acetone is slowly added onto the reaction mixture (56.3 ml; 3.5 eq) at 5°C, the reaction mixture is left to reach the temperature of 20°C and stirred for 30 min. 1.0M hydrochloric acid (512 ml) is added dropwise and stirred for a further 30 min at 20°C and the phases are separated. The organic phase is concentrated under vacuum to a residual volume of 256 ml. Acetonitrile (427 ml) is added to the concentrated solution. The mixture is fully concentrated to a residual volume of 341 ml, cooled to 20°C, stirred for 1 hour and the solid is filtered on buchner, washing again with acetonitrile (85 ml). 71.2 g of 4-bromo-2-methylphenyl-(7-chloro-5-hydroxy-

2.3.4.5-tetrahydro-lH-benzo[b]azepin-l-yl) methanone were obtained as an off-white solid (Yield 83%; HPLC purity 99.6%).

Solvent: DMSO-d6

¹H-NMR (ppm with respect to TMS): 1.52 and 2.12 (2H, m); 1.75 and 1.96 (2H, m); 2.33 (3H, s, -C¾); 2.70 and 4.62 (2H, m); 4.88 (1H, m); 5.70 (1H, d, J = 4 Hz, exch, OH); 6.73 (1H, d, J = 8 Hz); 6.78 (1H, d, J = 8 Hz); 7.00 - 7.15 (2H, m); 7.40 (1H, bs); 7.50 (1H, bs).

¹³C-NMR (ppm with respect to TMS): 18.9 (C¾); 25.6 (CH₂); 35.4 (CH₂); 45.9 (CH₂); 69.4 (CH); 121.7; 125.1 (CH); 126.7 (CH); 127.7 (CH); 127.8 (CH); 129.3 (CH); 132.8 (CH); 135.5; 137.8; 138.1; 144.9; 167.4 (CONR).

Example 5

2-methyl-benzoylamide

In a flask under nitrogen, 2-methyl-benzoic acid, (50.0 g, 1.0 eq); toluene (350 ml) and dimethylformamide (0.57 ml, 0.02 eq) are loaded in that order. The suspension is brought to 70°C under stirring. Thionyl chloride (29.5 g; 1.1 eq) is added dropwise, maintaining a temperature of about 70 ± 5°C. The mixture is left to react at about 70°C for 2 hours. At the end of the reaction, the solution is brought to about 50°C and distilled under vacuum to a residual volume of 150 ml. The product in solution is dropped onto a mixture of 2-methyl-tetrahydrofuran (150 ml) and ammonia 30% (150 ml) maintaining a temperature of 20 ± 5°C. The mixture is stirred for about 1 hour at about 20°C and the phases are separated. The organic phase is washed with 5% sodium bicarbonate (200 ml). The organic phase is concentrated under vacuum until a solid with constant weight is obtained. 46.6 g of 2-methyl-benzoylamide were obtained as a white solid (yield 94%; HPLC purity 98%).

Example 6

N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-oxo-1H-1-benzazepin-1-yl)carbonyl]-3- methylphenyl]-2-methyl-benzamide

In a nitrogen flask, 7-chloro-l,2,3,4-tetrahydro-l-(2-methyl-4-bromobenzoyl)-5H- 1-benzazepin-5-one (1.0 g, 1.0 eq), 2-methyl-benzoylamide (0.379 g, l.leq), chloro (crotyl) (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,1 '-biphenyl) palladium (II) (0.034 g, 2% mol) and potassium phosphate (0.757 g, 1.4 eq) are loaded in that order.

Three vacuum / nitrogen cycles are carried out and finally toluene (10ml) previously de-oxygenated with nitrogen is added. The suspension is brought to about 80°C and left to react for about 20°C yielding conversion greater than 90% with a product purity of 71%.

Example 7

TOLVAPTAN crude

In a flask under nitrogen, sodium borohydride (6.00 g, 1.05 eq), 2-methyl- tetrahydrofuran (270 ml) are loaded and the suspension is cooled to 5°C. To the obtained mixture, N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-oxo-lH-l-benzazepin-l-yl)carbonyl]-3- methylphenyl] -2-methyl-benzamide (67.3 g, 1.0 eq) in solution of toluene and 2-methyl- tetrahydrofuran obtained in Example 5, is added dropwise maintaining a temperature of about 5 ± 5°C. Separately a mixture of methanol (19.5 ml) in 2-methyl -tetrahydrofuran (67 ml) is prepared and in about 30 minutes maintaining a temperature of about 5 ± 5°C on the reaction mixture. The mixture is left to react at about 5°C for about 2 hours. When the reaction is complete, it is added dropwise onto the acetone mixture (39.1 ml, 3.5 eq) maintaining a temperature of about 5 ± 5°C. The temperature is left to raise at 20°C and the mixture is stirred at said temperature for 30 minutes. The organic phase is washed with 0.5 M hydrochloric acid (2x400ml). The organic phase is concentrated in vacuum to a residual volume of 270 ml and this solution is added dropwise to methyl-tert-butyl ether (MTBE, 670 ml). The suspension is stirred for 16 hours at about 20°C and the solid formed is recovered by filtration on Buchner, washing with MTBE (135 ml). After drying at about 45°C for 16 hours, 54.2 g of crude TOLVAPTAN are obtained as a white solid (Yield on two steps 80%, HPLC purity 99.8%).

Example 8

TOLVAPTAN crude

In a flask under nitrogen, 4-bromo-2-methyl- (7-chloro-5-hydroxy-2, 3,4,5- tetrahydro-lH-benzo[b]azepin-l-yl) methanone (20.0 g; 1.0 eq), 2-methyl-benzoylamide (6.85 g, 1.0 eq), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- biphenyl)-2-(2'-amino-1,1 '-biphenyl)] palladium (II) methanesulfonate (0.92g, 2% mol) and potassium phosphate (15.1 g, 1.4 eq) are added in that order. Two vacuum / nitrogen cycles are carried out and finally toluene (100 ml), previously degassed by bubbling nitrogen, is loaded. 2 vacuum / nitrogen cycles are carried out again and the suspension is brought to 50°C for 20 hours. When the reaction is completed, it is cooled to 20°C, water (120 ml) is added; the mixture is stirred for 15 minutes and the phases are separated by re extracting the aqueous phase with methyl-tetrahydrofuran (40 ml). The organic phases are collected and concentrated in vacuum to a residual volume of 80ml. The concentrated solution is added dropwise to methyl-terbutyl ether (200ml) and stirred at 20°C for 16 hours (slow precipitation). The solid is recovered on buchner by washing it again with methyl terbutyl ether (40 ml). After drying, 18.4 g of crude Tolvaptan are obtained as an off-white solid (yield 81%; purity 95.5%)

Example 9

TOLVAPTAN

In a flask under nitrogen crude TOLVAPTAN (50.0 g) and ethanol (600 ml) are loaded. The mixture is heated to reflux obtaining a clear solution. The mixture is stirred under reflux for about 30 minutes then concentrated up to a residual volume of 250 ml, then maintained under reflux for a further 30 minutes and cooled gradually over 1 hour to about 20°C. The mixture is maintained under stirring at 20 ° C for 1 hour and the solid obtained is recovered by filtration on a buchner and washed again with pre-cooled ethanol (100 ml). After drying at about 60°C for 16 hours, 42.0 g of TOLVAPTAN are obtained as a white solid (Yield 84%, Purity 99.9%).

Solvent: DMSO-d6

¹H-NMR (ppm with respect to TMS): 1.52 and 2.12 (2H, m); 1.75 and 1.96 (2H, m ); 2.35 (6H, s, 2 C¾); 2.68 and 4.70 (2H, m ); 4.92 (1H, m ); 5.71 (1H, d, J = 4 Hz, OH); 6.77 (2H, m , aromatics); 7.07 (1H, d, J = 8 Hz); 7.25 - 7.50 (5H, m , aromatics); 7.52 (1H, bs ); 7.62 (1H, bs ); 10.27 (1H, bs , NH). ¹³C-NMR (ppm with respect to TMS): 19.3 (C¾); 19.6 (C¾); 25.7 (CH₂); 35.3 (CH₂); 45.8 (CH₂); 69.5 (CH); 115.9 (CH); 120.9 (CH); 125.0 (CH); 125.6 (CH); 126.5 (CH); 126.7 (CH); 127.2 (CH); 129.4 (CH); 129.6 (CH); 130.5 (CH); 131.5; 131.7; 135.2; 136.0; 137.0; 138.7; 139.4; 144.9; 167.9 (CON); 168.2 (CON). Examples 10-35

General procedure for the reaction for the preparation of the compounds of formula III:

In a flask under nitrogen, 1.0 eq of compound of formula I_TaBr wherein X = Br or compound of formula I_TbBr wherein X = Br, amide of formula (II), base (1.4eq) and the catalyst are loaded in that order. Two vacuum-nitrogen cycles are carried out. The previously degassed solvent is loaded onto the mixture of solids, bubbling nitrogen for 30 minutes. The mixture is stirred, two further vacuum-nitrogen cycles are carried out and the system is brought to operating temperature under nitrogen.

a) A: chloro (crotyl) (2-dicyclohexylphosphino-2',4',6'-triisopropy1-1,1 '-biphenyl) palladium (II)

B: chloro [(4,5-bis (diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1 '-biphenyl)] palladium (II)

C: (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2 '-amino- 1,1'-biphenyl)] palladium (II) methanesulfonate D: [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1 '-biphenyl)] palladium (II ) methanesulfonate MTBE adduct E: [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1 '-biphenyl) -2- (2'-amino-1,1 '-diphenyl) ] palladium (II) methanesulfonate b) The solvents in mixture are to be considered in a ratio of 1 : 1 by volume _w

TERTAM: teramyl alcohol

TOL: Toluene

Examples 36-39

General procedure for the reaction for the preparation of the compounds of formula III:

In a flask under nitrogen, 1.0 eq of compound of formula I_TaBr wherein X = Br or compound of formula I_TbBr wherein X = Br, amide of formula (II) 1.1 eq, K3PO4 (1.4 eq) , Cul (10 mol%) and the binder (20 mol%) are loaded in that order. Two vacuum- nitrogen cycles are carried out and DMF (5 Volumes) previously degassed by bubbling nitrogen for 30 minutes is loaded onto the mixture of solids.

The mixture is stirred, two more vacuum-nitrogen cycles are carried out and the system is broughtto operating temperature (100°C) under nitrogen, periodically monitoring the progress of the reaction by HPLC controls.

Claims

1. Compounds of formula (I):

wherein

X is a halogen atom or an O-sulfonate group;

X₁ a halogen atom;

W and W₁ together form an oxygen atom (compounds of formula (la))

or one of the W and Wi groups is hydrogen and the other is an ORp group (compounds of formula (lb))

wherein Rp is hydrogen or hydroxyl-protecting group; or W and Wi represent a carbonyl-protecting group PG (compounds of formula (Ic))

2. Compounds according to claim 1 wherein:

PG represents a cyclic or acyclic ketal or thioketal, in which case compounds I_c are represented by formulae (I_c1), (I_c2), (I_c3), (I_c4):

wherein R and R¹, which are the same or different from each other, are selected from linear or branched C₁-C₆ alkyl; C₅-C₆ cycloalkyl optionally substituted with C₁-C₄ alkyl groups; CH₂-phenyl, CH₂-aryl, CH₂-heteroaryl, with phenyl, aryl and heteroaryl optionally substituted with one or more groups selected from linear or branched C₁-C₆ alkyl, halogens, -NO2, -OR2 groups wherein R₂ is selected from H, linear or branched C₁-C₆ alkyl, optionally substituted benzyl;

T is CR^IIR^III-(CR^IVR^V)n wherein n = 0-3, R^II,R^III,R^IV,R^V, which are the same or different from each other, are selected from hydrogen, linear or branched C₁-C₆ alkyl; C₅- C₆ cycloalkyl optionally substituted with C₁-C₄ alkyl groups; CH₂-phenyl, CH₂-aryl, CH₂- heteroaryl with phenyl, aryl and heteroaryl being optionally substituted with one or more groups selected from linear or branched C₁-C₆ alkyl, halogen, NO₂, -OR₂ groups wherein R₂ is selected from H, linear or branched C₁-C₆ alkyl, optionally substituted benzyl.

3. Compounds according to claims 1-2 wherein:

X₁ is selected from chlorine, bromine and iodine; preferably chlorine;

X is selected from bromine, iodine, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, preferably bromine, iodine or trifluoromethanesulfonate;

Rp is selected from H and hydroxyl-protecting group selected from acetyl; benzoyl; benzyl; β-methoxyethoxy methyl ether; dimethoxytrityl; [bis-(4- methoxyphenyl)phenylmethyl]; methoxymethyl ether; methoxytrityl [(4- methoxyphenyl)diphenylmethyl]; p-methoxybenzyl ether; methylthiomethyl ether; pivaloyl; triphenylmethyl (Tr); tetrahydropyranyl ether; tetrahydrofuranyl ether; silyl derivatives selected from trimethylsilyl, triethyl silyl, tert-butyldimethylsilyl, tri-iso- propylsilyl, tri-iso-propylsilyloxymethyl, dimethylisopropylsilyl, diethylisopropylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl; alkyl ethers and alkoxy ethers; more preferably Rp is selected from hydrogen and tetrahydropyranyl, tetrahydrofuranyl, acetyl, benzoyl, pivaloyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tri-iso-propylsilyl, tri-iso- propylsilyloxymethyl, dimethylisopropylsilyl, diethylisopropylsilyl, t-butyldimethyl silyl, t-butyldiphenylsilyl; more preferably Rp is H; R and R¹ are selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, benzyl, p-methylbenzyl, p-methoxybenzyl, m-methoxybenzyl, p- nitrobenzyl, p-chlorobenzyl, 3,4-dimethoxybenzyl, cyclopentyl, cyclohexyl; more preferably R and R’ are methyl, ethyl, propyl, isopropyl; T is selected from CH₂; CHR^III groups wherein R^III is selected from hydrogen, a Ci-

C₆alkyl group, an optionally substituted phenyl or aryl group, preferably R^III is selected from H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, Ph; (CH₂-CHR^IV) wherein R^IV is a C₁-C₆alkyl group, an optionally substituted phenyl or aryl group, preferably (CH₂-CHR^IV) is selected from (CH₂-CHCH₃), (CH₂-CHC₂H₅), (CH₃CH-CHCH₃), (CH₂-C(CH₃)2-CH₂).

4. A process for the preparation of Tolvaptan and the pharmacologically acceptable derivatives thereof, which comprises: reacting a compound of formula (I_T) with a compound of formula (II) to afford a compound of formula (III_T)

wherein X is selected from bromine, iodine, metansulfonate, p-toluensulfonate, trifluorometansulfonate; more preferably bromine, iodine, trifluorometansulfonate and W and Wi are as defined above in the presence of a transition metal catalyst, a base and in a suitable solvent at a temperature comprised between room temperature and the solvent reflux temperature.

5. The process according to claim 4 wherein the transition metal catalyst is selected from metal Ru, Rh, Pt, Pd and Cu, and derivatives thereof selected from oxides, halides, cyanides, alkoxides, carboxylates and salts, optionally complexed with suitable ligands, and pre-formed complexes of said ligands with said transition metals; preferably metal Pd catalysts or metal Cu catalysts, or derivatives thereof selected from oxides, halides, cyanides, alkoxides, carboxylates and salts, optionally complexed with suitable ligands, or pre-formed, preferably phosphine or carbene complexes, of said ligands; the base is selected from hydroxides, carbonates, bicarbonates, phosphate, monohydrogen phosphate, dihydrogen phosphate, fluorides and alkoxides, alkylsilylamides of alkali and alkaline-earth metals, and mixtures thereof, preferably bases are selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, cesium phosphate, sodium tert- butylate, potassium tert-butylate, cesium tert-butylate, sodium fluoride, cesium fluoride, potassium fluoride, lithium bis(trimethylsilyl)amide, sodium methoxide; more preferably potassium phosphate; cesium carbonate; potassium carbonate; potassium hydroxide; sodium tert-butylate; potassium tert-butylate; sodium methoxide, lithium bis(trimethylsilyl)amide; solvents are selected from aprotic apolar or polar solvents , aromatic, aliphatic, ether, ester, keto, alcohol solvents, optionally in the presence of water, and mixtures thereof, preferably selected from dichloromethane, acetonitrile, dimethylsulfoxide, sulfolane, N-methylpyrrolidone, dimethylformamide, tetrahydrofuran, methyl- tetrahydrofuran, dimethylacetamide, dioxane, dimethoxyethane, toluene, xylenes, cumene, cymene, valerolactone, cyclopentyl methyl ether, methyl isobutyl ketone, ethanol, i- propanol, methanol, n-propanol, n-butanol, t-butanol, sec-butanol, tert-amyl alcohol, or mixtures thereof, optionally in the presence of water, preferably said solvents are selected from toluene, dioxane, dimethoxyethane, t-butanol, n-butanol, tert-amyl alcohol, dimethylformamide, tetrahydrofuran, cyclopentyl methyl ether, N-methylpyrrolidone, 2- methyl-tetrahydrofuran, dimethylacetamide.

6. The process according to claims 4-5 wherein the catalyst is a metal Pd catalyst or derivatives thereof selected from oxides; alkoxides; carboxylates, preferably acetate; halides, preferably Cl, Br and I; alkylsulfonates, arylsulfonates, preferably methanesulfonate, ethanesulfonate, p-toluenesulfonate, triflate; and complexes of said derivatives with ligands selected from tertiary phosphines and the p-allyl complexes, carbenes, salts and adducts thereof with solvents and pre-formed complexes said ligands, preferably phosphine or carbene pre-formed complexes; preferably said tertiary phosphines are selected from tri-tert-butylphosphine, 2-(di-tert-butylphosphino)-l,1 '-biphenyl, 2-(di- tert-butylphosphino)-2 '-methyl- 1 , 1 '-biphenyl, 2-(di-tert-butylphosphino) 1 , 1 '-binaphthyl, 2-dicyclohexylphosphino-2',6'-dimethoxy-l, 1 '-biphenyl, 2-dicyclohexylphosphino-2',6'- di-iso-propoxy- 1 , 1 '-biphenyl, N-phenyl-2-(di-tert-butylphosphine)pyrrole, 1 -phenyl-2-(di- tert-butylphosphino)-lH-indene), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l, 1 '- biphenyl) [2-(2'-amino-1, 1 '-biphenyl)], (2-dicyclohexylphosphino-2',6'-dimethoxy-l, 1 '- biphenyl) [2-(2 '-amino- I,1'-biphenyl)], [(2-di-tert t-butylphosphino-2',4',6'-triisopropyl-

1,1 '-biphenyl)-2-(2 '-amino- 1, 1 '-biphenyl)], [(2-dicyclohexylphosphino-3,6-dimethoxy- 2 ',4 ', 6 '-trii sopropyl- 1 , 1 '-biphenyl)-2-(2 '-amino- 1 , 1 '-biphenyl)] , [(2-di-terz- butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-l, 1 '-biphenyl)-2-(2'-amino-l, 1 '- biphenyl)], (2-dicyclohexylphosphino-2',6'-diisopropoxy-1, 1 '-biphenyl)[2-(2'-amino-l, 1 '- biphenyl)], chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)], chloro[(4,5- bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2 '-amino- 1, 1 '-biphenyl)], [2-(2’-amino-

1,1 '-biphenyl)], [4-(di-tert-butylphosphino)-N,N-dimethylaniline](chloro), chloro(tricyclohexylphosphine)[2-(2'-amino-1, 1 '-biphenyl)], chloro[(p- dimethylaminophenyl)(di-tert-butylphosphine)], tri-tert-butylphosphine (chloro), chloro (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1 '-biphenyl), chloro(2- dicyclohexylphosphino-2',6'-dimethoxy-l,1 '-biphenyl), (2-dicyclohexylphosphino-2',4',6'- triisopropyl-3,6-dimethoxy-1, 1 '-biphenyl), (2-di-tert-butylphosphino-2',4',6'-triisopropyl-

1 , 1 ’-biphenyl), (2-di-tert-butylphosphino-2 ',4 ', 6 '-trii sopropyl- 1 , 1 ’-biphenyl), [(R)-2,2 '- bis(diphenylphosphino)-l, 1 '-binaphthalene], [4,5-bis(diphenylphosphino)-9,9- dimethylxanthene], tricyclohexylphosphine, [5-(di-tert-butylphosphino)-1,3',5’-triphenyl- 1 Ή- 1 ,4 ’ -bipyrazole] ; tri-o-tolylphosphine, [2-(2'-amino- 1 , 1 '-biphenyl)] [4-(di-tert- butylphosphino)-N,N-dimethylaniline] , [(2-di-tert-butylphosphino-3 , 6-dimethoxy-2 ',4 ', 6 '- triisopropyl- 1 , 1 '-biphenyl)-2-(2 '-amino- 1 , 1 '-biphenyl)], 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene, (tricyclohexylphosphine)[2-(2 '-amino- 1, 1 '-biphenyl)], chloro(2- dicy clohexylphosphino-2',4',6'-triisopropyl- 1 , 1' -biphenyl);

(l,4-naphthoquinone)-[l,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene], allylchloro-[l,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene], allylchloro-[l,3-bis(2,6- diisopropylphenyl)-4,5-diidroimidazol-2-ylidene], (3-phenylallylchloro)-[l,3-bis(2,6- diisopropylphenyl)-4,5-diidroimidazol-2-ylidene]; preferably [(2-di-cyclohexylphosphino- 3 , 6-dimethoxy-2 ',4 ',6 '-trii sopropyl- 1 , 1 '-biphenyl)-2-(2 '-amino- 1 , 1 '-biphenyl)] , (2- dicyclohexylphosphino-2',4',6'-triisopropyl-l, 1 '-biphenyl)[2-(2'-amino-l, 1 '-biphenyl)] and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,1 '-biphenyl); more preferably Pd metal catalysts are selected from: chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1,1'-biphenyl)[2-(2 '-amino- 1,1'-biphenyl)]palladium(II) adduct with THF; chloro(2- dicyclohexylphosphino-2',6'-dimethoxy-l, 1 '-biphenyl)[2-(2'-amino-l, 1 '- biphenyl)]palladium(II) adduct with 1.5 THF; [(2-di-tert-butylphosphino-2',4',6'- trii sopropyl- 1, 1 '-biphenyl)-2-(2 '-amino- 1, 1 '-biphenyl)]palladium(II) methanesulfonate adduct with MTBE; [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- biphenyl)-2-(2'-amino-l,l' -biphenyl)]palladium(II) methanesulfonate; [(2-di-tert- butylphosphino-3,6-dimethoxy-2 ',4 ',6 '-trii sopropyl- 1, 1 '-biphenyl)-2-(2'-amino-l, 1 '- biphenyl)]palladium(II) methanesulfonate; (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1,1 '-biphenyl)[2-(2'-amino-l, 1 '-biphenyl)]palladium(II) methanesulfonate; chloro[(tri-tert- butylphosphine)-2-(2-aminobiphenyl)]palladium(II); chloro[(4,5-bis(diphenylphosphine)- 9,9-dimethylxanthene)-2-(2'-amino-l, 1 '-biphenyl)] palladium(II); [2-(2'-amino-l, 1 '- biphenyl)][4-(di-tert-butylphosphino)-N,N-dimethylaniline](chloro)palladium(II); chloro(tricyclohexylphosphine)[2-(2'-amino-l, 1 '-biphenyl)]palladium(II); chloro

(crotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l, 1 '-biphenyl)palladium(II); chloro (crotyl) [(p-dimethylaminophenyl) (di-tert-butylphosphine)]palladium(II); tri-tert- butylphosphine (chloro) (crotyl) palladium(II); chloro (crotyl) (2-dicyclohexylphosphino- 2',6'-diisopropoxy-l, 1 '-biphenyl)palladium(II); chloro (crotyl)(2-dicyclohexylphosphino- 2',6'-dimethoxy-1,1 '-biphenyl)palladium(II); crotyl (2-dicyclohexylphosphino-2',4',6'- triisopropyl-3,6-dimethoxy-1,1'-biphenyl) palladium(II) triflate; allyl (2-di-tert- butylphosphino-2',4',6'-triisopropyl-1,1 '-biphenyl) palladium(II) triflate; allyl [(R)-2,2'- bis(diphenylphosphino)-l,1 '-binaphthalene] palladium(II) chloride; allyl [4,5- bis(diphenylphosphino)-9,9-dimethylxanthene] palladium(II) chloride; chloro (crotyl)(tricyclohexylphosphine) palladium(II); allyl [5-(di-tert-butylphosphino)-l',3',5'- triphenyl-1'H-1,4’-bipyrazole] palladium(II) triflate; chloro (crotyl) (tri-o-tolylphosphine) palladium(II), [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1, 1 '- biphenyl)-2-(2 '-amino- 1, 1 '-biphenyl)]palladium(II) methanesulfonate, [2-(2'-amino-l, 1 '- biphenyl)] [4-(di-tert-butylphosphino)-N,N-dimethylaniline] (chloro) palladium(II), chloro (tricyclohexylphosphine)[2-(2'-amino-1, 1 '-biphenyl)]palladium(II), sodium hexachloro- palladate(IV) tetrahydrate, potassium hexachloro-palladate(IV), palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) acetylacetonate, dichlorobis(benzonitrile)palladium(II), dichlorobis(acetonitrile)palladium(II), dichlorobis(triphenylphosphine)palladium(II), dichlorotetraaminopalladium(II), dichloro(cycloocta-l,5-diene)palladium(II), palladium(II)trifluoroacetate, tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, tetrakis(triphenylphosphine)palladium(0); (1,4-naphthoquinone)-[l,3- bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(0), allylchloro-[l,3-bis(2,6- diisopropylphenyl)imidazol-2-ylidene]palladium(II), allylchloro-[l,3-bis(2,6- diisopropylphenyl)-4,5-diidroimidazol-2-ylidene]palladium(II), (3-phenylallylchloro)- [l,3-bis(2,6-diisopropylphenyl)-4,5-diidroimidazol-2-ylidene]palladium(II); more preferably [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-l, 1 '-biphenyl)- 2-(2'-amino-l, 1 '-biphenyl)]palladium(II)metansulfonate, (2-dicyclohexylphosphino- 2 ',4 ', 6 '-trii sopropyl- 1 , 1 '-biphenyl)[2-(2 '-amino- 1 , 1 '-biphenyl)] palladium (II) methanesulfonate and chloro(crotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l, 1'- biphenyl)palladium(II).

7. The process according to claims 4-5 wherein the catalyst is a Cu catalyst selected from metal Cu and derivatives thereof, selected from oxides; alkoxides; carboxylates, preferably acetate; halides, preferably Cl, Br and I; cyanides; alkylsulfonates, aryl sulfonates, preferably methanesulfonate, ethanesulfonate, p-toluenesulfonate, triflate; and complexes of said derivatives with ligands selected from diamines, dicarbonyl compounds, amino acids, salts and adducts thereof with solvents; preferably ligands are selected from optionally substituted C₁-C₆ beta-ketoesters; optionally substituted C₁-C₆ diketones, amino acids, C₁-C₆ alkyldiamines, optionally substituted C₄-C₈ cicloalkyldiamines, aryldiamines and heteroaryldiamines optionally substituted at the nitrogen atoms and optionally substituted at the carbon atoms, wherein substituents at C and N are the same or different from each other and are selected from H, C₁-C₄ alkyl groups, aryl groups, hydroxy groups, OR_a groups wherein R_a is selected from C₁-C₄ alkyl groups and aryl groups; more preferably ligands are selected from ethylenediamine, N-N'- dimethylethylenediamine, 1 ,2-cyclohexyldiamine, N,N'-dimethyl- 1 ,2-cy clohexyldiamine, proline, 4-hydroxyproline, glycine, N,N-dimethylglycine, bis-(2-hydroxyethyl)glycine, 2- (dimethylamino)ethanol, picolinic acid, methyl N-methyl prolinate; most preferably metal Cu, CuI-N-N'-dimethylethylenediamine, Cul-1,2-cyclohexyldiamine, CuI-N-N'-dimethyl- 1,2-cy clohexyldiamine, CuI-N,N-dimethyl glycine.

8. The process according to claims 4-7 which comprises reacting compounds of formula (IV) with compounds of formula (V):

in the presence of a suitable solvent at a temperature comprised between room temperature and the solvent reflux temperature; wherein X, X₁, W and W₁ have meanings reported in the previous claims and X₃ is selected from halogen atoms, OH, O-sulfonate groups; OR₅ groups wherein R₅ is selected from linear or branched C₁-C₆ alkyl; C₅-C₆ alkyl; optionally substituted with optionally substituted C₁-C₄ alkyl; C₃-C₉ cycloalkyl; phenyl, naphthyl, heteroaryl groups; preferably X₃ is selected from chlorine, bromine, iodine, methanesulfonate, p- toluenesulfonate, trifluoromethanesulfonate; more preferably X₃ is selected from chlorine, bromine and iodine.

9. The process according to claim 8 wherein solvents are selected from aprotic apolar or polar solvents , aromatic, aliphatic, ether, ester, keto, alcohol solvents, optionally in the presence of water, and mixtures thereof, preferably dichloromethane, acetonitrile, dimethylsulfoxide, sulfolane, N-methylpyrrolidone, N-butylpyrrolidone, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dimethoxy ethane, cyclopentyl methyl ether, toluene, xylenes, cumene, cymene, valerolactone, , methyl isobutyl ketone, ethanol, i-propanol, methanol, n-propanol, n-butanol, t-butanol, sec- butanol, tert-amyl alcohol, or mixtures thereof, optionally in the presence of water, preferably toluene, dioxane, dimethoxyethane, cyclopentyl methyl ether, t-butanol, n- butanol, tert-amyl alcohol, dimethylformamide, tetrahydrofuran, 2-methyl-tetrahydrofuran, dimethylacetamide, N-methylpyrrolidone, N-butylpyrrolidone and mixtures of said solvents, optionally in the presence of water.

10. The process according to claims 8-9 in which compound of formula IV wherein W and Wi form an oxygen atom

is reacted with a compound of formula (V) wherein XI is chlorine atom, to afford a compound of formula (I_Ta):

11. The process according to claims 8-9 wherein compound of formula IV wherein W is an ORp group and Wi is hydrogen (Formula (IVT)) is reacted with a compound of formula (V) wherein Xi is chlorine atom to afford compounds of formula (IT_IT

12. The process according to claims 8-9 wherein compound of formula IV wherein W is an OPG group and Wi is hydrogen (Formula (IVT_C)) is reacted with a compound of formula (V) wherein XI is a chlorine atom to afford compounds of formula (IT_c)

wherein X, X₃ and PG have the meanings reported in the previous claims.

13. The process according to claims 8-11 further comprising reducing compounds of formula (I_Ta); to afford compounds of formula (I_Tb) wherein Rp has the meanings reported in the previous claims

in the presence of a reducing agent in a suitable solvent, optionally followed by protection of the hydroxy group.

14. Process according to claims 8-11 further comprising reducing compound of formula (IVxa) with suitable reducing agents to afford a compound of formula (IVxb),

optionally followed by protection of the hydroxy group, and subsequent reaction with compound of formula (V) to afford the respective compounds (I_Tb)

wherein X, X₃ and Rp have the meanings reported in the previous claims.

15. Process according to claim 12 further comprising the protection of compounds of formula (IVxa) to afford compounds of formula (IV_Tc)

wherein X, X₃ and PG have the meanings reported in the previous claims.

16. The process according to claims 13-14 wherein the reducing agents are selected from LiA1H₄, NaBH₄, Zn(BH₄)₂, BH₃, Red-A1 and LiBH₄, or B₂H₆ in solvents selected from acetic acid, alcohols, preferably methanol, ethanol, isopropanol, hydrocarbons, preferably hexane, cyclohexane, ethers, preferably diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, 2-methyl-tetrahydrofuran, diethyl ether, esters preferably ethyl acetate, methyl acetate, aprotic polar solvents, preferably dimethylformamide or mixtures of said solvents or mixtures thereof with water.

17. The process according to claims 4-16 which comprises: a) reacting compounds of formula (IVT) with compounds of formula (V):

wherein X, X₃, W and Wi have the meanings reported in the previous claims, in the presence of a suitable solvent; at a temperature comprised between room temperature and the solvent reflux temperature; b) reacting a compound of formula (IT) with a compound of formula (II) to afford a compound of formula (HIT)

in the presence of a transition metal catalyst, a base and in a suitable solvent at a temperature comprised between room temperature and the solvent reflux temperature.

18. The use of compounds of formula (I):

wherein X, Xi,and W and Wi have the meanings reported in the previous claims, in a process for the preparation of Tolvaptan and the pharmacologically acceptable derivatives thereof.