JP2023528624A - Intermediate of tolvaptan and its derivatives and method for preparing the same - Google Patents

Abstract

The present invention relates to novel intermediates for the synthesis of tolvaptan and its derivatives and processes for their preparation, including said intermediates.

Description

The present invention relates to novel intermediates for the synthesis of Tolvaptan and its pharmacologically acceptable derivatives, as well as processes for their preparation, including said intermediates.

Tolvaptan is N-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl)-3-methyl-phenyl]-2-methylbenzamide ( Also known as N-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-benzo[b]azepin-1-carbonyl)-3-methyl-phenyl]-2-methylbenzamide) , characterized by the following equation:

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

Tolvaptan is commercially available as a racemate.
Various synthetic approaches have been disclosed for the production of tolvaptan.
US Pat. Nos. 5,300,000 and 5,000,000 disclose benzoheterocyclic compounds, including tolvaptan and its derivatives, and methods for their preparation by reduction of the nitro group to give the corresponding amines, according to the following schemes.

Non-Patent Document 1 describes condensation of 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one with a suitable derivative of 4-nitrobenzoic acid to give the corresponding amide. It states that benzodiazepine compounds are synthesized by giving The nitro group is then reduced to give the aniline derivative.
In particular, the synthesis of tolvaptan involves reduction in the presence of _SnCl2 or _H2 in the presence of _PtO2 . This reaction formula is as follows.

Patent Document 3 discloses 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1- using 2-methyl-4-nitrobenzoyl chloride in the presence of N-methylmorpholine as a base. A process for the N-acylation of benzazepines is disclosed.

US Pat. No. 5,300,001 describes a method for the preparation of intermediate nitro derivatives for the synthesis of tolvaptan involving reaction of appropriate benzazepines with nitrobenzoyl chlorides in organic solvents in the absence of bases.

US Pat. No. 5,330,000 discloses the catalytic hydrogenation of nitro derivatives in the presence of a catalyst system consisting of a metal chloride and Pd—C, where the metal chloride is lithium chloride or indium trichloride, to give the corresponding amines. disclosed.

Patent Document 6 describes the amidation reaction of benzazepine with 1-bromo-2-methyl-4-nitrobenzene in the presence of PPh ₃ , PdCl ₂ or Pd(OAc) ₂ and a carbonylating agent, followed by Fe dust. Disclosed is a process for the preparation of tolvaptan comprising reduction in the presence of (dust) and NH ₄ Cl, followed by acylation and reduction reactions.

US Pat. No. 5,300,002 describes a process for preparing nitro derivatives by reacting appropriate benzazepines with nitrobenzoyl chlorides in acetonitrile in the presence of NaOH, KOH, _{K2CO3 , KHCO3 , Na2CO3} or _NaHCO3 . described.

US Pat. No. 6,200,000 describes a process for the preparation of tolvaptan by reaction between suitable benzazepines and suitable acid chlorides according to the scheme below.

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

Currently known synthetic methods for tolvaptan involve going through a nitro derivative followed by reduction to give the corresponding amine.

Several chemical structures have been associated with mutagenic and carcinogenic activity, including aromatic structures characterized by the presence of a nitro group (2).

Therefore, the presence of nitroaromatic compounds in the synthetic pathway of pharmaceuticals requires the burdensome analytical testing and purification steps recommended in the ICH M7 guidelines related to mutagenic impurities, and is not accompanied by positive carcinogenicity data. If so, the potential for mutagenicity and genotoxicity of intermediates and derived impurities, which is expected to be very difficult, poses a huge problem.

Applicants have found that the intermediate 1-(4-amino-2-methylbenzoyl)- A new efficient process has been developed for the purification of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.

With this purification system, the PMI content can be reduced by a factor of 10 or more, yielding values in accordance with regulatory requirements.

Although this purification method is effective, it requires additional steps with increased production costs.

Therefore, the use of aromatic nitro compounds and the use of intermediates containing nitro groups (especially when combined with aromatic structures) should be avoided in order to avoid the presence of potentially carcinogenic or mutagenic compounds. There remains a need to find new intermediates and alternative synthetic strategies that do not involve transit.

US5258510 US5559230 CN102060769 IN2012MUM634 CN108341780 CN106883175 CN102382053 CN104418803

Bioorganic & Medicinal Chemistry 7 (1999) 1743-1754 Reg. Tox. And Farm. 44 (2006) 198-211; Current Computer-Aided Drug Design, 2006, 2, 1-19, (2) 169-176

Invention description:
The present inventors have now discovered novel intermediates for the synthesis of tolvaptan or pharmacologically acceptable derivatives thereof and a method for the preparation of tolvaptan or its pharmacologically acceptable derivatives in high yield and high chemical purity without using aromatic nitro compounds.

A first object of the present invention is therefore novel intermediates of formula (I).

ここで、Ｘは、ハロゲン原子又はＯ－スルホン酸基であり、
Ｘ_１は、ハロゲン原子であり、
Ｗ及びＷ_１は一緒になって酸素原子（式（Ｉａ）の化合物）を形成するか、

where X is a halogen atom or an O-sulfonic acid group,
X ₁ is a halogen atom,
W and W ₁ together form an oxygen atom (a compound of formula (Ia)), or

又は、Ｗ及びＷ_１基の１つは水素であり、別の１つはＯＲｐ基（式（Ｉｂ）の化合物）であるか、

or one of W and W ₁ groups is hydrogen and another is an ORp group (compound of formula (Ib)), or

ここで、Ｒｐは、水素若しくはヒドロキシル保護基であり、

wherein Rp is hydrogen or a hydroxyl protecting group;

Alternatively, W and _W1 represent a carbonyl protecting group PG (compounds of formula (Ic)).

ここで、ＰＧは、好ましくは、環状若しくは非環状のケタール又はチオケタールを表す。

PG here preferably represents a cyclic or acyclic ketal or thioketal.

Examples of Ic compounds include those represented by formulas (I _c1 ), (I _c2 ), (I _c3 ), and (I _c4 ).

here,
R and R ¹ are the same or different from each other, linear or branched C ₁ -C ₆ alkyl; C ₅ -C ₆ cycloalkyl optionally substituted with a C ₁ -C ₄ alkyl group; CH ₂ -phenyl , CH ₂ -aryl, CH ₂ -heteroaryl, wherein phenyl, aryl, heteroaryl is one selected from linear or branched C ₁ -C ₆ alkyl, halogen, —NO ₂ , —OR ₂ groups. optionally substituted with one or more groups, provided that R ₂ is selected from H, linear or branched C ₁ -C ₆ alkyl, optionally substituted benzyl;
^{T is CRIIRIII-} ( ^CRIVRV ) _n ;
here,
n=0 to 3, and R ^II , R ^III , R ^IV , and R ^V are the same or different, hydrogen, linear or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ alkyl group; optionally substituted C ₅ -C ₆ cycloalkyl; CH ₂ -phenyl, CH ₂ -aryl, CH ₂ -heteroaryl, where phenyl, aryl, heteroaryl are linear or branched C ₁ -C ₆ optionally substituted with one or more groups selected from alkyl, halogen, —NO ₂ , —OR ₂ groups, where R ₂ is H, linear or branched C ₁ -C ₆ alkyl, optionally benzyl substituted with );

Preferably X ₁ 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 hydroxyl protecting group,
Benzyl (Bn); β-methoxyethoxymethyl ether (MEM); dimethoxytrityl; [bis-(4-methoxyphenyl)phenylmethyl] (DMT); ); methoxytrityl[(4-methoxyphenyl)diphenylmethyl] (MMT); p-methoxybenzyl ether (PMB); methylthiomethyl ether (MTM); pivaloyl (Piv); triphenylmethyl (Tr); Tetrahydrofuranyl ether; preferably trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triisopropylsilyloxymethyl (TOM), dimethylisopropylsilyl (IPDMS), Silyl derivatives selected from diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS); alkyl ethers and alkoxy ethers.

More preferably, Rp is hydrogen or tetrahydropyranyl, tetrahydrofuranyl, acetyl, benzoyl, pivaloyl, trimethylsilyl (TMS), triethylsilyl (TES) groups, tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triisopropylsilyloxymethyl (TOM), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS).
Rp is even more preferably hydrogen.

R and R ₁ are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, benzyl, p-methylbenzyl, p-methoxybenzyl, m-methoxybenzyl, p-nitrobenzyl, p- It can be selected from chlorobenzyl, 3,4-dimethoxybenzyl, cyclopentyl, cyclohexyl.

Preferably, T is selected from the group consisting of CH ₂ ; CHR ^III , where R ^III is selected from hydrogen, C ₁ -C ₆ alkyl groups, phenyl groups, optionally substituted aryl groups.
Preferably, R ^III is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, Ph, (CH ₂ -CHR ^IV ) (with the proviso that R ^IV is C ₁ - _C6 alkyl group, phenyl group, optionally substituted aryl group), preferably (CH ₂ -CH ^RIV ) is (CH ₂ -CHCH ₃ ), (CH ₂ -CHC ₂ H ₅ ), (CH ₃ CH—CHCH ₃ ), (CH ₂ —C(CH ₃ ) ₂ —CH ₂ ).

A preferred embodiment of the invention is a compound of formula (I _T ).

ここで、Ｘは臭素、ヨウ素又はトリフルオロメタンスルホネートであり、Ｗ及びＷ_１は上記のように定義される。

where X is bromine, iodine or trifluoromethanesulfonate and W and _W1 are defined as above.

When W and W ₁ together form a bond with an oxygen atom, the compound is represented by the formula (I _Ta ).

When one of W and W ₁ is hydrogen and the other is an ORp group, the compound is represented by the formula (I _Tb ).

ここで、Ｒｐは上記のように定義される。

where Rp is defined as above.

When W and W ₁ are carbonyl-protecting groups, the compound is represented by the formula (I _Tc ).

ここで、ＰＧは上記のように定義され、及びＩ_Ｔｃ化合物は、式（Ｉ_Ｔｃ１）、（Ｉ_Ｔｃ２）、（Ｉ_Ｔｃ３）、（Ｉ_Ｔｃ４）で表される。

Here, PG is defined as above, and the I _Tc compounds are represented by the formulas (I _Tc1 ), (I _Tc2 ), (I _Tc3 ), (I _Tc4 ).

ここで、Ｒ及びＲ^１及びＴは上記のように定義される。

wherein R and R ¹ and T are defined as above.

In compounds of formula (I _Tb ), Rp is preferably hydrogen and tetrahydropyranyl, tetrahydrofuranyl, acetyl, benzoyl, pivaloyl, trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS) , tri-iso-propylsilyl (TIPS), tri-iso-propylsilyloxymethyl (TOM), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBS), t-butyldiphenyl silyl (TBDPS); more preferably Rp is H;

In compounds of formulas (I _Tc1 ) and (I _Tc2 ), R and R ¹ are the same or different from each other, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, benzyl, is selected from p-methylbenzyl, p-methoxybenzyl, m-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, 3,4-dimethoxybenzyl, cyclopentyl, cyclohexyl, even more preferably R and R ¹ are , methyl, ethyl, propyl, isopropyl.

In compounds of formulas (I _Tc3 ) and (I _Tc4 ), T is preferably (CH ₂ —CHCH ₃ ), (CH ₂ —CHC ₂ H ₅ ), (CH ₃ CH—CHCH ₃ ), (CH ₂ selected from —C(CH ₃ ) ₂ —CH ₂ ) groups

A further object of the present invention is a process for preparing tolvaptan and pharmacologically acceptable derivatives thereof, comprising:
Reacting a compound of formula (I _T ) with a compound of formula (II) in the presence of a transition metal catalyst based, a base and a suitable solvent to provide a compound of formula (III _T ) The method includes the step of providing.

wherein X is selected from bromine, iodine, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate; more preferably bromine, iodine, trifluoromethanesulfonate, and W and W ₁ are defined as above.
The above reaction is carried out at a temperature between room temperature and the reflux temperature of the solvent.

When W and W ₁ together represent an oxygen atom, compounds (I _T ) and (III _T ) are represented by formulas (IT _a ) and (III _Ta )

When one of W and W ₁ is an ORp group and the other is hydrogen, compounds of formulas (I _T ) and (III _T ) are represented by formulas (I _Tb ) and (III _Tb ).

ここで、Ｘ及びＲｐは上記のように定義される。

where X and Rp are defined as above.

When W and W ₁ are carbonyl protecting groups, compounds of formulas (I _T ) and (III _T ) are represented by formulas (I _Tc ) and (III _Tc ).

ここで、Ｘ及びＰＧは上記のように定義される。

where X and PG are defined as above.

Preferably, the transition metal catalysts are Ru, Rh, Pt, Pd and Cu in metallic form or in oxides, halides, cyanides, alkoxides, carboxylates, salts and any suitable It is selected from a form complexed with a ligand or a form of a pre-formed complex with said ligand.

The catalyst is preferably Pd or Cu in metallic form or in oxides, halides, cyanides, alkoxides, carboxylates and salts, optionally complexed with suitable ligands. It is preferably based on the morphology or the morphology of a preformed complex with said ligand, preferably a phosphine or a carbene.

Bases are preferably hydroxides, carbonates, bicarbonates, phosphates, monohydrogen phosphates, dihydrogen phosphates, fluorides and alkoxides, alkylsilylamides of alkali metals and alkaline earth metals, and mixtures thereof.

The base is preferably sodium carbonate, potassium carbonate, cesium carbonate,
sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, cesium phosphate, tert-sodium butyrate, potassium tert-butyrate, cesium tert-butyrate, sodium fluoride, cesium fluoride, potassium fluoride, lithium bis(trimethylsilyl)amide, sodium methylate, more preferably potassium phosphate; cesium carbonate; potassium carbonate; potassium hydroxide; tert-sodium butyrate; tert-butyl sodium methylate; lithium bis(trimethylsilyl)amide;

Preferably, the solvent is selected from nonpolar 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,
Methyltetrahydrofuran, dimethylacetamide, dioxane, dimethoxyethane, toluene, xylene, cumene, cimanutene, cyclopentone-methyl methyl ethyl methyl methyl acetate, i methanol, n -propanol, n-butanol, t-butanol, sec-butanol, tert-amyl alcohol, and mixtures thereof, optionally in the presence of water,
More preferably toluene, dioxane, dimethoxyethane, t-butanol, n-butanol, tert-amyl alcohol, dimethylformamide, tetrahydrofuran, cyclopentyl methyl ether, N-methylpyrrolidone, methyltetrahydrofuran, dimethylacetamide and mixtures thereof , optionally in the presence of water.

Catalysts are metal Pd or its oxides; alkoxides; carboxylates, preferably acetates; halides; preferably Cl, Br and I; , triflates; complexes of said derivatives with ligands selected from tertiary phosphines, their π-allyl complexes, carbenes, salts and adducts thereof with solvents and said Preferred are those based on complexes of said preformed ligands; preferably phosphine or carbene complexes.

Preferably, said tertiary phosphine is 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-butylphosphine)pyrrole, 1-phenyl-2-(di-tert -butylphosphino)-1H-indene), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′ -biphenyl)], (2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)], [(2-di -tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)], [(2-dicyclohexylphos Phino-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′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)], (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)], chloro[(tri-tert-butyl phosphine)-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-1,1'-biphenyl), (2-dicyclohexyl phosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl), (2-di-tert-butylphosphino-2',4',6'-tri isopropyl-1,1′-biphenyl), (2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl), [(R)-2,2′ -bis(diphenylphosphine)-1,1′-binaphthalene], [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene], tricyclohexylphosphine, [5-(di-tert-butylphosphino )-1′,3′,5′-triphenyl-1′H-1,4′-bipyrazole], 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-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl), (1,4-naphthoquinone )-[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene], allylchloro-[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene], allylchloro-[1 ,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene], (3-phenylallylchloro)-[1,3-bis(2,6-diisopropylphenyl)- 4,5-dihydroimidazol-2-ylidene],
More preferably [(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′- biphenyl)],
(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] and chloro(2-dicyclohexylphosphine -2',4',6'-triisopropyl-1,1'-biphenyl).

The Pd-based catalyst is preferably chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl )] THF adduct of palladium(II), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl) ] 1.5THF adduct of palladium(II), [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′- MTBE adduct of amino-1,1′-biphenyl)]palladium(II) methanesulfonate, [(2-dicyclohexylphosphino-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'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-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-1,1′-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-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)-1,1′-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)-1′,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-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 -1,5-diene)palladium(II), palladium(II) trifluoroacetate,
Tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, tetrakis(triphenylphosphine)palladium(0), (1,4-naphthoquinone)-[1,3 -bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(0), allylchloro-[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II), allylchloro- [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]palladium(II), (3-phenylallylchloro)-[1,3-bis(2,6 -diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]palladium(II),
More preferably, [(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′ -biphenyl)]palladium(II) methanesulfonate, (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′ -biphenyl)]palladium(II) methanesulfonate and chloro(crotyl)(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium(II), .

In a further preferred embodiment metal Cu or oxides; alkoxides; carboxylates, preferably acetic acid; halides, preferably Cl, Br and I; cyanides; and complexes of said derivatives with ligands selected from diamines, dicarbonyl compounds, amino acids, salts and adducts thereof with solvents. , using catalysts based on their derivatives.

Ligands for Cu-based catalysts are preferably optionally substituted C ₁ -C ₆ beta ketoesters; optionally substituted C ₁ -C ₆ diketones; amino acids, C ₁ -C ₆ alkyl diamines, optionally substituted C ₄ -C ₈ cycloalkyldiamines, aryldiamines, heteroaryldiamines optionally substituted at a nitrogen atom and optionally substituted at a carbon atom, provided that the substituents at C and N are the same or different from each other. is selected from H, C ₁ -C ₄ alkyl groups, aryl groups, hydroxyl groups, OR _a groups, where R _a is selected from C ₁ -C ₄ alkyl groups and aryl groups;

The ligands are preferably ethylenediamine, NN'-dimethylethylenediamine, 1,2-cyclohexyldiamine, NN'-dimethyl-1,2-cyclohexylenediamine, proline, 4-hydroxyproline, glycine, N , N-dimethylglycine, bis(2-hydroxyethyl)glycine, 2-(dimethylamino)ethanol, picolinic acid, methyl N-methylprolinate.

More preferably, it is selected from metallic Cu, CuI-N-N'-dimethylethylenediamine, 1,2-cyclohexyldiamine, N,N'-dimethyl-1,2-cyclohexylenediamine, CuI-N,N-dimethylglycine. A Cu-based catalyst is used.

An object of the present invention is a process for preparing tolvaptan and its pharmacologically acceptable derivatives, further comprising the preparation of compounds of formula (I).

Compounds of formula (I) are prepared according to the present invention by a process comprising reacting a compound of formula (IV) with a compound of formula (V) in the presence of a suitable solvent at a temperature between room temperature and the reflux temperature of the solvent. be done.

wherein X, X ₁ , W and W ₁ have the meanings reported above,
X ₃ is a halogen atom, OH, O-sulfonate group; OR ₅ group with the proviso that R ₅ is linear or branched C ₁ -C ₆ alkyl; C ₅ optionally substituted with C ₁ -C ₄ alkyl —C ₆ cycloalkyl; C ₃ -C ₉ alkenyl; optionally substituted phenyl, naphthyl, heteroaryl),
Preferably X ₃ is selected from chlorine, bromine, iodine, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, more preferably X ₃ is selected from chlorine, bromine and iodine.

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

Examples of solvents include dichloromethane, acetonitrile, dimethylsulfoxide, sulfolane, N-methylpyrrolidone, N-butylpyrrolidone, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane. Dimethoxyethane, cyclopentyl methyl ether, toluene, xylene, cumene-propanol, methanol, n-propanol, n-butanol, t-butanol, sec-butanol, tert-amyl alcohol or mixtures thereof mentioned.

Preferably, the solvent is toluene, dioxane, dimethoxyethane, cyclopentyl methyl ether, t-butanol, n-butanol, tert-amyl alcohol, dimethylformamide, tetrahydrofuran, methyltetrahydrofuran, dimethyl It is selected from acetamide, N-methylpyrrolidone, N-butylpyrrolidone and mixtures thereof.

In a preferred embodiment of the invention X ₁ is a chlorine atom.

In a preferred embodiment of the present invention, the method of preparing tolvaptan comprises reducing a compound of formula (I _Ta ) in the presence of a reducing agent in a suitable solvent to give a compound of formula (I _Tb ) followed by an optional further comprising the step of protecting the hydroxyl group to

ここで、Ｒｐは水素又はヒドロキシル保護基であり、Ｘは上記で報告された意味を有する。

where Rp is hydrogen or a hydroxyl protecting group and X has the meaning reported above.

Alternatively, the method of preparing tolvaptan of the present invention comprises the synthesis of a compound of formula (I _Ta ) under suitable reaction conditions in a known method described, for example, in Greene's Protective Groups in Organic Synthesis - IV ed. with a suitable alcohol, thiol, diol, dithiol to protect the carbonyl group of the compound of formula (I _Ta ) to give a compound of formula (I _Tc ).

ここで、ＰＧは上記のように定義され、Ｉ_Ｔｃ化合物は、上記報告された式（Ｉ_Ｔｃ１）、（Ｉ_Ｔｃ２）、（Ｉ_Ｔｃ３）、（Ｉ_Ｔｃ４）で表される。

Here, PG is defined as above and the I _Tc compounds are represented by the above reported formulas (I _Tc1 ), (I _Tc2 ), (I _Tc3 ), (I _Tc4 ).

In a further embodiment of the present invention, a method of preparing tolvaptan comprises reducing a compound of formula (IV _Ta ) with a suitable reducing agent to give a compound of formula (IV _Tb ), optionally followed by removal of the hydroxyl group. Protecting and then reacting with a compound of formula (V) to obtain the respective compound (I _Tb ).

ここで、Ｘ、Ｘ_３及びＲｐは上記の意味を有する。

wherein X, _X3 and Rp have the meanings given above.

Preferably Rp is hydrogen and tetrahydropyranyl, tetrahydrofuranyl, acetyl, benzoyl, pivaloyl, trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triisopropyl It is selected from silyloxymethyl (TOM), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS).

Preferably, the reducing agent is acetic acid, alcohols (e.g., methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g., hexane, cyclohexane, etc.), ethers (e.g., diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, etc.). , esters (e.g., ethyl acetate, methyl acetate _, etc.), polar aprotic solvents (e.g., dimethylformamide, etc.), and optionally _water and mixtures thereof. ₄ ) selected from ₂ , BH ₃ , Red-Al and LiBH ₄ or B ₂ H ₆ ;

An optional OH group protection reaction is carried out on the compound of formula (VI _Tb ) according to known methods, for example described in "Greene's Protective Groups in Organic Synthesis - IV ed.".

Alternatively, the method of preparing tolvaptan further comprises protecting the compound of formula (IV _Ta ) to give the compound of formula (IV _Tc ).

Compounds of formula (I _Tc ) are then obtained by reaction of compounds of formula (IV _Tc ) 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.

ここで、ＰＧは環状及び非環状ケタール及びチオケタールから選択され、化合物（ＩＶ_Ｔｃ）は、式（ＩＶ_Ｔｃ１）、（ＩＶ_Ｔｃ２）、（ＩＶ_Ｔｃ３）、（ＩＶ_Ｔｃ４）によって表される。

wherein PG is selected from cyclic and acyclic ketals and thioketals, and compounds (IV _Tc ) are represented by formulas (IV _Tc1 ), (IV _Tc2 ), (IV _Tc3 ), (IV _Tc4 ).

Preferably, compound (IV _Tc ) is combined with a compound of formula (IV _Ta ) under suitable conditions according to known methods, e.g., described in "Greene's Protective Groups in Organic Synthesis - IV ed." alcohols, thiols, diols and dithiols.

A further object of the present invention is therefore a method for preparing tolvaptan comprising the following steps:
a) reacting a compound of formula (IV _T ) with a compound of formula (V) in the presence of a suitable solvent at a temperature between room temperature and the reflux temperature of the solvent.

ここで、Ｘ、Ｘ_３、Ｗ及びＷ_１は上記報告された意味を有する。

wherein X, X ₃ , W and W ₁ have the meanings reported above.

b) reacting a compound of formula (I _T ) with a compound of formula (II) in the presence of a transition metal-based catalyst, a base, in a suitable solvent at a temperature between room temperature and the reflux temperature of the solvent to give formula (III _{T 1} ).

Preferably, in step a) the solvent is selected from non-polar or polar aprotic, aromatic, aliphatic, ether, ester, ketone, alcoholic solvents and mixtures thereof, optionally in the presence of water. be.

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

A further object of the present invention is the use of a compound of formula (I) in a process for preparing tolvaptan and its pharmacologically acceptable derivatives

ここで、Ｘ、Ｘ_１、Ｗ、Ｗ_１は、上記報告された意味を有する。

wherein X, X ₁ , W, W ₁ have the meanings reported above.

A further object of the present invention relates to a pharmaceutical composition comprising tolvaptan obtained according to the process of the present invention or a pharmacologically acceptable derivative thereof in admixture with one or more conventional pharmaceutical excipients. It is.

The process of the present invention is therefore a surprisingly advantageous option as it avoids the use of intermediates containing nitro groups and thus all the drawbacks associated with the production of potential carcinogens and mutagens. It has been shown that

In its preferred embodiment, the method of preparing tolvaptan of the present invention is represented by the following scheme.

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

BRIEF DESCRIPTION OF THE FIGURES FIG ^. (Example 3).
FIG. 2 shows ¹³ C-NMR of 7-chloro-1,2,3,4-tetrahydro-1-(2-methyl-4-bromobenzoyl)-5H-1-benzazepin-5-one (Example 3). is.
FIG. 3 shows the ¹ H-NMR of 4-bromo-2-methylphenyl-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methanone. (Example 4).
FIG. 4 shows the ¹³ C-NMR of 4-bromo-2-methylphenyl-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methanone. (Example 4).
FIG. 5 is ¹ H-NMR of tolvaptan (Example 9).
FIG. 6 is ¹³ C-NMR of tolvaptan (Example 9).

Analysis method
IR analysis (infrared spectroscopy)
IR spectra were recorded using a JASCO FT-IR 460 Plus spectrophotometer. Samples were prepared by grinding approximately 5 mg of sample with approximately 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 method)
NMR analysis was performed using a Bruker Avance 300MHz instrument.

Example 1
Purification of 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine to remove potentially mutagenic impurities
A reaction flask was charged with 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine hydrochloride (50.0 g, title ) 65%) and water (500 ml). The mixture is heated to about 60° C. and kept at the same temperature for 15 minutes. The suspension obtained is filtered on a dicalite (PALL filter press) by further washing the filter with hot water (50 ml).
The filtrate is cooled to about 20° C. and extracted with a 1:1 mixture of toluene:acetonitrile (3×150 ml). The phases are separated and dichloromethane (250 ml) is added to the aqueous phase. Sodium hydroxide 30% (50 ml) is added to the biphasic system and maintained at about 20±5°C. The suspension is kept under stirring for 30 minutes at about 20°C. Separate the phases and further extract the aqueous phase with dichloromethane (2×100 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 solids are collected by filtration on a Buchner and washed with acetonitrile (50 ml). After drying (45° C., 16 h) 23.7 g of 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine is obtained as a yellow solid (81% yield, 100% title, 99.8% HPLC purity).
The NITRO impurity content (1-(4-nitro-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine) is less than 50 ppm.

Example 2
2-methyl-4-bromo-benzoyl chloride
A flask under nitrogen is charged with 2-methyl-4-bromobenzoic acid (60.5 g, 1.0 eq), toluene (424 ml) and dimethylformamide (0.44 ml, 0.02 eq) in that order. The suspension is brought to 70° C. under stirring. Thionyl chloride (36.8 g, 1.1 eq) is added dropwise, keeping the temperature at about 70±5° C., and allowed 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 181 ml. The product in solution is directly used for the next synthetic step. Theoretically, 65.7 g of 2-methyl-4-bromo-benzoyl chloride are obtained.

Example 3
7-chloro-1,2,3,4-tetrahydro-1-(2-methyl-4-bromobenzoyl)-5H-1-benzazepin-5-one
A flask under nitrogen is charged with 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (50.0 g, 1.0 eq) and toluene (200 ml) in that order. obtain a suspension. 2-Methyl-4-bromo-benzoyl chloride (65.7 g, 1.1 eq) in the toluene solution obtained in Example 2 is added dropwise at about 20° C. over about 15 minutes. The suspension is brought to reflux (110° C.) under stirring for about 3 hours. At the end of the reaction, the solution is cooled to about 20°C. 5% sodium bicarbonate (250 ml) is added dropwise onto the mixture, maintaining the temperature at about 20±5°C. The phases are separated and the aqueous phase is washed with 0.5M hydrochloric acid (250ml) followed by water (250ml). The organic phase is then concentrated in vacuo until a constant weight of solid is obtained. 95.4 g of the title compound are obtained as an off-white solid (95% yield; HPLC purity 97%).
Solvent: DMSO-d ⁶ (80°C)
¹ H-NMR (ppm relative to TMS): 2.00 (2H, t, J = 6 Hz); 2.30 (3H, s, —CH ₃ ); 2.79 (2H, t, J = 6 Hz) ); 3.88 (2H, m); 7.00-7.50 (4H, m, aromatic); 7.48 (1 H, s); 7.61 (1 H, s).
¹³ C-NMR (ppm relative to TMS): 18.6 (CH ₃ ); 22.0 (CH ₂ ); 39.7 (CH ₂ ); 46.9 (CH ₂ ); 122.3; 128.3(CH); 128.7(CH); 130.8(CH); 132.2; 132.3(CH); 133.0(CH); 137.6; 139.4; 167.1 (CONR); 200.4 (C=O).

Example 4
4-bromo-2-methylphenyl-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methanone
A flask under nitrogen is charged with NaBH ₄ (8.2 g, 1.0 eq) and 2-methyl-tetrahydrofuran (682 ml) in that order. Under stirring, 7-chloro-1,2,3,4-tetrahydro-1-(2-methyl-4-bromobenzoyl)-5H-1-benzazepin-5-one (85. 3 g, 1.0 eq). The suspension is cooled to 5°C and a solution of methanol (25.5ml, 2.9eq) in 2-methyl-tetrahydrofuran (85ml) is slowly added dropwise keeping the temperature at 5°C. The reaction is carried out at 5°C for 2 hours. After completion of the reaction, acetone is slowly added to the reaction mixture (56.3 ml, 3.5 eq) at 5° C. and the reaction mixture is allowed to reach 20° C. and stirred for 30 minutes. Add 1.0 M hydrochloric acid (512 ml) dropwise, stir at 20° C. for a further 30 minutes and separate the phases. The organic phase is concentrated under vacuum to a residual volume of 256 ml. Acetonitrile (427 ml) is added to the concentrate. The mixture is concentrated completely to a residual volume of 341 ml, cooled to 20° C., stirred for 1 hour, the solid filtered on a Buchner and washed again with acetonitrile (85 ml). 71.2 g of 4-bromo-2-methylphenyl-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methanone are obtained as an off-white solid. (83% yield; 99.6% HPLC purity).
Solvent: DMSO- ^d6
1 H-NMR (ppm relative to TMS): 1.52 and 2.12 (2H, m); 1.75 and 1.96 (2H, m); 2.33 (3H, s, —CH ₃ ); 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 7.00-7.15 (2H, m); 7.40 (1H, bs); 7.50 (1H, bs).
¹³ C-NMR (ppm relative to TMS): 18.9 (CH ₃ ); 25.6 (CH ₂ ); 35.4 (CH ₂ ); 45.9 (CH ₂ ); 121.7; 125.1 (CH); 126.7 (CH); 127.7 (CH); 127.8 (CH); 129.3 (CH); 137.8; 138.1; 144.9; 167.4 (CONR).

Example 5
2-methyl-benzoylamide
A flask under nitrogen is charged with 2-methyl-benzoic acid (50.0 g, 1.0 eq), toluene (350 ml) and dimethylformamide (0.57 ml, 0.02 eq) in that order. The suspension is brought to 70° C. under stirring. Thionyl chloride (29.5 g, 1.1 eq) is added dropwise, maintaining the temperature at about 70±5° C., and the mixture is allowed 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 added dropwise onto a mixture of 2-methyl-tetrahydrofuran (150 ml) and ammonia 30% (150 ml), maintaining the temperature at 20±5°C. The mixture is stirred at about 20° C. for about 1 hour 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 constant weight of solid is obtained. 46.6 g of 2-methyl-benzoylamide are obtained as a white solid (94% yield, 98% HPLC purity).

Example 6
N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-oxo-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methyl-benzamide
Into a flask under nitrogen was added 7-chloro-1,2,3,4-tetrahydro-1-(2-methyl-4-bromobenzoyl)-5H-1-benzazepin-5-one (1.0 g, 1.0 eq. ), 2-methylbenzoylamide (0.379 g, 1.1 eq), chloro(crotyl)(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium (II ) (0.034 g, 2% mol) and potassium phosphate (0.757 g, 1.4 eq) are charged in that order. Three vacuum/nitrogen cycles are performed and finally toluene (10 ml) pre-deoxygenated with nitrogen is added. Bringing the suspension to about 80° C. and reacting at about 20° C. gives a conversion of over 90% with a product purity of 71%.

Example 7
crude tolvaptan
A flask under nitrogen is charged with sodium borohydride (6.00 g, 1.05 eq), 2-methyl-tetrahydrofuran (270 ml) and the suspension is cooled to 5°C. To the resulting mixture was added N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-oxo-1H-1 in toluene and 2-methyl-tetrahydrofuran solution obtained in Example 5. -benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methyl-benzamide (67.3 g, 1.0 eq) is added dropwise maintaining the temperature at about 5±5°C. Separately prepare a mixture of methanol (19.5 ml) in 2-methyl-tetrahydrofuran (67 ml) and place over the reaction mixture maintaining a temperature of about 5±5° C. for about 30 minutes. The mixture is allowed to react at about 5°C for about 2 hours. When the reaction is complete, it is added dropwise onto an acetone mixture (39.1 ml, 3.5 eq) maintaining a temperature of about 5±5°C. The temperature is allowed to rise to 20° C. and the mixture is stirred at said temperature for 30 minutes. The organic phase is washed with 0.5M hydrochloric acid (2x400ml). The organic phase is concentrated in vacuo 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 at about 20° C. for 16 hours and the solid formed is collected by filtration on a Buchner and washed 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 (2 step yield 80%, HPLC purity 99.8%).

Example 8
crude tolvaptan
4-bromo-2-methyl(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methanone (20.0 g, 1.0 eq), 2-methylbenzoylamide (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 (0.92 g, 2% mol) and potassium phosphate (15.1 g, 1.4 eq) are prepared in this order. Two vacuum/nitrogen cycles are performed and finally charged with toluene (100 ml) previously degassed by bubbling nitrogen. Two vacuum/nitrogen cycles are repeated and the suspension is held at 50° C. for 20 hours. When the reaction is complete, cool to 20° C., add water (120 ml), stir the mixture for 15 minutes and separate the phases by re-extracting the aqueous phase with methyl-tetrahydrofuran (40 ml). The organic phases are collected and concentrated in vacuo to a residual volume of 80 ml. The concentrated solution is added dropwise to methyl-tert-butyl ether (200 ml) and stirred at 20° C. for 16 hours (slow precipitation). The solids are recovered on the Buchner by rewashing with methyl tert-butyl ether (40 ml). After drying, 18.4 g of crude tolvaptan are obtained as an off-white solid (81% yield; 95.5% purity).

Example 9
Tolvaptan
A flask under nitrogen is charged with crude tolvaptan (50.0 g) and ethanol (600 ml). Heat the mixture to reflux to obtain a clear solution. The mixture is stirred under reflux for about 30 minutes, then concentrated to a residual volume of 250 ml, maintained under reflux for a further 30 minutes and gradually cooled to about 20° C. over 1 hour. The mixture is kept under stirring at 20° C. for 1 hour and the solid obtained is collected by filtration on a Buchner and washed again with pre-chilled ethanol (100 ml). After drying at about 60° C. for 16 hours, 42.0 g of tolvaptan are obtained as a white solid (84% yield, 99.9% purity).
Solvent: DMSO-d6
¹ H-NMR (ppm relative to TMS): 1.52 and 2.12 (2H, m); 1.75 and 1.96 (2H, m); 2.35 (6H, s, 2CH ₃ ) 2.68 and 4.70 (2H, m); 4.92 (1 H, m); 5.71 (1 H, d, J = 4 Hz, OH); 6.77 (2 H, m, aromatic); 7.07 (1H, d, J=8 Hz); 7.25-7.50 (5H, m, aromatic); 7.52 (1H, bs); 7.62 (1H, bs); 10.27 (1H, bs, NH).
¹³ C-NMR (ppm relative to TMS): 19.3 (CH ₃ ); 19.6 (CH ₃ ); 25.7 (CH ₂ ); 35.3 (CH ₂ ); ₂ ); 69.5 (CH); 115.9 (CH); 120.9 (CH); 125.0 (CH); 125.6 (CH); ); 127.2 (CH); 129.4 (CH); 129.6 (CH); 130.5 (CH); 138.7; 139.4; 144.9; 167.9 (CON); 168.2 (CON).

窒素下のフラスコに、１．０ｅｑの式Ｉ_ＴａＢｒの化合物（但し、Ｘ＝Ｂｒ）又は式Ｉ_ＴｂＢｒの化合物（但し、Ｘ＝Ｂｒ）、式（ＩＩ）のアミド、塩基（１．４ｅｑ）及び触媒を、この順序で仕込む。真空‐窒素サイクルを２回行う。あらかじめ脱気した溶媒を固体の混合物上に仕込み、窒素を３０分間バブリングする。
混合物を攪拌し、さらに２回の－窒素サイクルを行い、系（system）を窒素下で操作温度（operating temperature）にする。 Examples 10-35
General Procedure of Reaction for Preparation of Compounds of Formula III

In a flask under nitrogen, add 1.0 eq of the compound of formula I _TaBr (where X = Br) or the compound of formula I _TbBr (where X = Br), the amide of formula (II), the base (1.4 eq) and The catalysts are charged in this order. Two vacuum-nitrogen cycles are performed. Pre-degassed solvent is charged over the solid mixture and nitrogen is bubbled for 30 minutes.
The mixture is stirred and two more nitrogen cycles are performed to bring the system to operating temperature under nitrogen.

a) A: Chloro(crotyl)(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-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) methane Sulfonate 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 the mixture are considered in a 1:1 ratio by volume.
TERTAM: tert-amyl alcohol
TOL: toluene

Examples 36-39
General procedure of reactions for the preparation of compounds of formula (III).
In a flask under nitrogen, add 1.0 eq of compound of formula I _TaBr where X = Br or compound of formula I _TbBr where X = Br, 1.1 eq of amide of formula (II), _K3PO . ₄ (1.4 eq), CuI (10 mol %) and binder (20 mol %) are charged in this order. Two vacuum-nitrogen cycles are performed and DMF (5 volumes), previously degassed by bubbling nitrogen for 30 minutes, is charged onto the solid mixture.
The mixture is stirred and subjected to two additional vacuum-nitrogen cycles, the system brought to operating temperature (100° C.) under nitrogen, and the progress of the reaction monitored periodically by HPLC control.

Claims (18)

Compounds of formula (I):

where X is a halogen atom or an O-sulfonic acid group,
X ₁ is a halogen atom,
W and W ₁ together form an oxygen atom (a compound of formula (Ia)), or

or one of the W and _W1 groups is hydrogen and the other is an ORp group (compound of formula (Ib)), or

wherein Rp is hydrogen or a hydroxyl protecting group;
Alternatively, W and _W1 represent a carbonyl protecting group PG (compounds of formula (Ic)).

2. The claim 1, wherein PG represents a cyclic or acyclic ketal or thioketal, wherein compound Ic is represented by formula ( _Ic1 ), ( _Ic2 ), ( _Ic3 ), ( _Ic4 ). A compound of:

here,
R and R ¹ are the same or different from each other, linear or branched C ₁ -C ₆ alkyl; C ₅ -C ₆ cycloalkyl optionally substituted with a C ₁ -C ₄ alkyl group; CH ₂ -phenyl , CH ₂ -aryl, CH ₂ -heteroaryl, wherein phenyl, aryl, heteroaryl is one selected from linear or branched C ₁ -C ₆ alkyl, halogen, —NO ₂ , —OR ₂ groups. optionally substituted with one or more groups, provided that R ₂ is selected from H, linear or branched C ₁ -C ₆ alkyl, optionally substituted benzyl;
^{T is CRIIRIII-} ( ^CRIVRV ) _n ;
here,
n=0 to 3, and R ^II , R ^III , R ^IV , and R ^V are the same or different, hydrogen, linear or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ alkyl group; optionally substituted C ₅ -C ₆ cycloalkyl; CH ₂ -phenyl, CH ₂ -aryl, CH ₂ -heteroaryl, where phenyl, aryl, heteroaryl are linear or branched C ₁ -C ₆ optionally substituted with one or more groups selected from alkyl, halogen, —NO ₂ , —OR ₂ groups, where R ₂ is H, linear or branched C ₁ -C ₆ alkyl, optionally 3. The compound of claim 1, wherein the compound is selected from benzyl substituted with . X ₁ is selected from chlorine, bromine and iodine, preferably chlorine,
X is selected from bromine, iodine, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, preferably bromine, iodine or trifluoromethanesulfonate,
Benzyl; β-methoxyethoxymethyl ether; dimethoxytrityl; [bis-(4-methoxyphenyl)phenylmethyl]; methoxymethyl ether; methoxytrityl[(4-methoxyphenyl)diphenylmethyl] triphenylmethyl (Tr); tetrahydropyranyl ether; tetrahydrofuranyl ether; trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tri-iso-propylsilyl, tri-iso- silyl derivatives selected from propylsilyloxymethyl, dimethylisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl; alkyl ethers; and hydroxyl protecting groups selected from alkoxy ethers;
More preferably Rp is hydrogen and tetrahydropyranyl, tetrahydrofuranyl, acetyl, benzoyl, pivaloyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tri-iso-propylsilyl, tri-iso-propylsilyloxymethyl, dimethyl is selected from isopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, Rp is more preferably H,
R and R ¹ are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
is selected from benzyl, p-methylbenzyl, p-methoxybenzyl, m-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, 3,4-dimethoxybenzyl, cyclopentyl, cyclohexyl, more preferably R and R ¹ are , methyl, ethyl, propyl, isopropyl,
T is selected from CH ₂ ; CHR ^III groups, wherein R ^III is selected from hydrogen, C ₁ -C ₆ alkyl groups, optionally substituted phenyl groups or aryl groups, preferably R ^III is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, Ph, (CH ₂ -CHR ^IV ), wherein R ^IV is C ₁ -C ₆ an alkyl group, an optionally substituted phenyl group, or an aryl group, preferably (CH ₂ —CHR ^IV ) is (CH ₂ —CHCH ₃ ), (CH ₂ —CHC ₂ H ₅ ), (CH ₃ CH—CHCH ₃ ), (CH ₂ —C(CH ₃ ) ₂ —CH ₂ ). A method for preparing tolvaptan and pharmacologically acceptable derivatives thereof, comprising:
- reacting a compound of formula (I _T ) with a compound of formula (II) in the presence of a transition metal catalyst, a base and a suitable solvent at a temperature comprised between room temperature and the reflux temperature of the solvent to form formula (III) A method comprising obtaining a compound of _T ):

wherein X is selected from bromine, iodine, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate; more preferably bromine, iodine, trifluoromethanesulfonate and W and W ₁ are as above Defined. said transition metal catalyst is selected from the metals Ru, Rh, Pt, Pd and Cu, and oxides, halides, cyanides, alkoxides, carboxylates and salts, optionally complexed with suitable ligands; and preformed complexes of said ligands and said transition metals, preferably metal Pd catalysts or metal Cu catalysts, or oxides, halides, cyanides, alkoxides , carboxylates and salts, optionally complexed with a suitable ligand, or preformed with said ligand, preferably a phosphine or carbene complex,
Prebases include hydroxides, carbonates, bicarbonates, phosphates, monohydrogen phosphates, dihydrogen phosphates, fluorides and alkoxides, alkylsilylamides of alkali metals and alkaline earth metals, and preferably said base is selected from a mixture of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, Cesium phosphate, tert-butyl sodium, tert-butyl potassium, tert-butyl cesium, sodium fluoride, cesium fluoride, potassium fluoride, sodium phosphate, cesium phosphate, potassium phosphate, cesium phosphate, tert-butyl sodium tert-butyrate, cesium tert-butyrate, sodium fluoride, cesium fluoride, potassium fluoride, lithium bis(trimethylsilyl)amide, sodium methoxide, more preferably potassium phosphate, cesium carbonate, carbonate selected from potassium, potassium hydroxide, sodium tert-butyrate, potassium tert-butyrate, sodium methoxide, lithium bis(trimethylsilyl)amide;
Said solvent is preferably selected from aprotic non-polar or polar solvents, aromatic, aliphatic, ether, ester, keto, alcoholic solvents and mixtures thereof, optionally in the presence of water. in the presence of dichloromethane, acetonitrile, dimethylsulfoxide, sulfolane, N-methylpyrrolidone, dimethylformamide, tetrahydrofuran, methyltetrahydrofuran, dimethylacetamide, dioxane, dimethoxyethane, toluene, xylene, cumene, cymene, valerolactone, cyclopentylmethyl ether, methylisobutyl ketone, ethanol, i-propanol, methanol, n-propanol, n-butanol, t-butanol, sec-butanol, t-amyl alcohol or mixtures thereof, preferably said solvent is toluene, dioxane, 5. Process according to claim 4, selected from dimethoxyethane, t-butanol, n-butanol, tert-amyl alcohol, dimethylformamide, tetrahydrofuran, cyclopentyl methyl ether, N-methylpyrrolidone, 2-methyl-tetrahydrofuran, dimethylacetamide. . carboxylate, preferably acetate; chloride, preferably Cl, Br and I; alkylsulfonate, arylsulfonate, preferably methanesulfonate, ethanesulfonate, p - derivatives thereof selected from toluenesulfonates, triflates; and from said derivatives and tertiary phosphines, their π-allyl complexes, carbenes, salts and adducts thereof with solvents. Complexes with selected ligands and pre-formed complexes with said ligands; preferably pre-formed complexes of phosphines or carbenes, preferably tertiary phosphines, are tri-tert-butylphosphine, 2-(di-tert-butylphosphino)-1,1'-biphenyl, 2-(di-tert-butylphosphino)-2'-methyl-1,1'-biphenyl, 2-(di-tert-butylphosphino)-1,1'-binaphthyl, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, 2-dicyclohexylphosphino-2',6 ′-diisopropoxy-1,1′-biphenyl, N-phenyl-2-(di-tert-butylphosphine)pyrrole, 1-phenyl-2-(di-tert-butylphosphino)-1H-indene), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)], (2-dicyclohexylphosphino -2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)], [(2-di-tert-butylphosphino-2′,4 ',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)], [(2-dicyclohexylphosphino-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′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)], (2-dicyclohexylphosphino-2′,6 ′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-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)], (p-dimethylaminophenyl)(di-tert-butylphosphine), tri-tert-butylphosphine (chloro ), 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'-triisopropyl-1,1'-biphenyl) [(R) -2,2′-bis(diphenylphosphino)-1,1′-binaphthalene], [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene], tricyclohexylphosphine, [5-(di -tert-butylphosphino)-1′,3′,5′-triphenyl-1′H-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-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) , (1,4-naphthoquinone)-[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene], allylchloro-[1,3-bis(2,6-diisopropylphenyl)imidazole-2- ylidene], allylchloro-[1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene], (3-phenylallylchloro)-[1,3-bis(2, 6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene],
Preferably, [(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′- biphenyl)], (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)], and chloro (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)],
More preferably, the Pd metal catalyst is chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′- THF adduct of palladium(II), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl )] 1.5THF adduct of palladium(II), [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′ -amino-1,1′-biphenyl)]palladium(II) methanesulfonate MTBE adduct, [(2-dicyclohexylphosphino-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′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-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-1,1′-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-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)-1,1′-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)-1′,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- 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-1,5-diene)palladium(II), palladium(II) trifluoroacetate, tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, tetrakis( triphenylphosphine)palladium(0), (1,4-naphthoquinone)-[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(0), allylchloro-[1,3-bis (2,6-diisopropylphenyl)imidazol-2-ylidene]palladium (II), allylchloro-[1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]palladium ( II), (3-phenylallylchloro)-[1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]palladium (II),
More preferably, [(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′ -biphenyl)]palladium(II) methanesulfonate,
(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate and A process according to claim 4 or 5, selected from chloro(crotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II). carboxylate, preferably acetate; chloride, preferably Cl, Br and I; cyanide; alkylsulfonate, arylsulfonate, preferably methanesulfonate, ethanesulfonate , p-toluenesulfonate, triflates and derivatives thereof, and complexes of said derivatives with ligands selected from diamines, dicarbonyl compounds, amino acids, salts and adducts thereof with solvents,
Preferably, the ligands are optionally substituted C ₁ -C ₆ beta ketoesters; optionally substituted C ₁ -C ₆ diketones; amino acids, C ₁ -C ₆ alkyldiamines, optionally substituted C _{4 —C8} cycloalkyldiamine, aryldiamine, and heteroaryldiamine optionally substituted at a nitrogen atom and optionally substituted at a carbon atom, provided that the substituents at C and N are the same or different from each other, and H , C ₁ -C ₄ alkyl groups, aryl groups, hydroxy groups, OR _a groups, wherein R _a is selected from C ₁ -C ₄ alkyl groups and aryl groups;
More preferably, the ligand is ethylenediamine, NN'-dimethylethylenediamine, 1,2-cyclohexyldiamine, N,N'-dimethyl-1,2-cyclohexyldiamine, proline, 4-hydroxyproline, glycine, N , N-dimethylglycine,
bis-(2-hydroxyethyl)glycine, 2-(dimethylamino)ethanol, picolinic acid, methyl N-methylprolinate,
Most preferably, metal Cu, CuI-N-N'-dimethylethylenediamine, CuI-1,2-cyclohexyldiamine, CuI-N-N'-dimethyl-1,2-cyclohexyldiamine, CuI-N,N-dimethylglycine 6. The method of claim 4 or 5, wherein the Cu catalyst is selected from 8. Any of claims 4-7, comprising reacting a compound of formula (IV) with a compound of formula (V) in the presence of a suitable solvent at a temperature comprised between room temperature and solvent reflux temperature. or the method according to item 1:

wherein X, X ₁ , W and W ₁ have the meanings reported in the preceding claims, X ₃ is a halogen atom, OH, O-sulfonic acid group; OR ₅ group with the proviso that R ₅ is linear or branched C ₁ -C ₆ alkyl; C ₅ -C ₆ alkyl optionally substituted with optionally substituted C ₁ -C ₄ alkyl; C ₃ -C ₉ cycloalkyl; phenyl, naphthyl, heteroaryl groups), preferably X ₃ is selected from chlorine, bromine, iodine, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, more preferably X ₃ is chlorine, bromine and iodine. Said solvents are aprotic nonpolar or polar solvents, aromatic, aliphatic, ether, ester, keto, alcoholic solvents, optionally in the presence of water, and mixtures thereof, preferably dichloromethane, acetonitrile, dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N-butylpyrrolidone, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, toluene, xylene, 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 solvent mixtures thereof, optionally water 9. The method of claim 8, in the presence of and selected from: A compound of formula IV where W and W ₁ form an oxygen atom (formula IV _Ta ) is reacted with a compound of formula (V) where X ₁ is a chlorine atom to form a compound of formula (I _Ta 10. A method according to claim 8 or 9 to obtain a compound of

reacting a compound of formula IV where W is an ORp group and W ₁ is hydrogen (formula (IV _T )) with a compound of formula (V) where X ₁ is a chlorine atom 10. A process according to claim 8 or 9, wherein a compound of formula (I _Tb ) is obtained.

A compound of formula IV where W is an OPG group and W ₁ is hydrogen (formula (IV _Tc )) is reacted with a compound of formula (V) where X ₁ is a chlorine atom. to obtain a compound of formula (I _Tc ):

wherein X, _X3 and PG have the meanings reported in the preceding claims. Further reduction of the compound of formula (I _Ta ) in the presence of a reducing agent in a suitable solvent yields a compound of formula (I _Tb ), where Rp has the meaning reported in the preceding claim. A process according to any one of claims 8 to 11, comprising the step of obtaining and optionally followed by protection of the hydroxy group.

Further reducing the compound of formula (IV _Ta ) with a suitable reducing agent to obtain a compound of formula (IV _Tb ),

A process according to any one of claims 8 to 11, comprising optionally protecting the hydroxy group and then reacting with a compound of formula (V) to obtain the respective compound (I _Tb ). :

wherein X, _X3 and Rp have the meanings reported in the preceding claims. 13. The method of claim 12, further comprising protecting the compound of formula (IV _Ta ) to give the compound of formula (IV _Tc ):

wherein X, _X3 and PG have the meanings reported in the preceding claims. acetic acid; alcohols, preferably methanol, ethanol, isopropanol; hydrocarbons, preferably hexane, cyclohexane; ethers, preferably diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether; esters, preferably ethyl acetate, methyl acetate; aprotic polar _{solvents , preferably} dimethylformamide; or mixtures of said solvents _{; 3} , Red-Al and LiBH ₄ , or B ₂ H ₆ . a) reacting a compound of formula (IV _T ) with a compound of formula (V) in the presence of a suitable solvent at a temperature comprised between room temperature and solvent reflux temperature:

wherein X, X ₃ , W and W ₁ have the meanings reported in the preceding claims;
b) reacting a compound of formula (I _T ) with a compound of formula (II) in the presence of a transition metal catalyst, a base, in a suitable solvent at a temperature comprised between room temperature and the reflux temperature of the solvent, to give formula ( Steps to obtain compounds of III _T ):

A method according to any one of claims 4 to 16, comprising Use of a compound of formula (I) in a process for preparing tolvaptan and its pharmacologically acceptable derivatives:

wherein X, X ₁ and W and W ₁ have the meanings reported in the preceding claims.

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