Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/16—Benzazepines; Hydrogenated benzazepines

Definitions

• Benzazepines and related molecules such as benzazepinones and benzodiazepines constitute families of compounds of interest for their pharmacological activities.
• the various modes of synthesis currently available for obtaining these benzazepine derivatives constitute a major obstacle on the one hand, to obtain these compounds under satisfactory conditions in terms of yield and cost and on the other hand, for the development of new derivatives .
• the process, represented in FIG. 1, which corresponds to the synthetic route currently used to obtain the OPC-41061 derivative comprises eleven consecutive steps, some of which involve drastic conditions which are not compatible with the presence of a certain number of functional groups. .
• the object of the present invention is precisely to propose a new access route to benzazepine type compounds, advantageously allowing, on the one hand, the preparation of known compounds under satisfactory conditions and, on the other hand, access to new derivatives. of these compounds.
• the present invention relates, according to a first of its aspects, to a process for the preparation of at least one benzazepine compound of general formula (TA): in which :
• R 1 represents a halogen atom chosen from chlorine, fluorine, bromine and iodine, an al yl, haloalkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl group, or else a hydrocarbon ring or a heterocycle, a polymer chain, a group - ⁇ CH 2 ) m -OR, -CHCOR ⁇ COR 1 ), - (CH 2 ) m -SR, - (CH 2 ) m -S (O) R k , - (CH 2 ) m -SO 2 R k , - (CH 2 ) m -SO 2 NR k R 1 , - (CH 2 ) m -SO 3 R k , - (CH 2 ) m -NO 2 , - (CH 2 ) m -CN, -
• - n represents an integer chosen from 0, 1, 2, 3 and 4, with when n is greater than or equal to 2, the corresponding groups R 1 can be identical or different, and if necessary can together form a hydrocarbon ring or a heterocycle, for example with 5 or 6 links.
• R 2 , R 3 , R 4 , R 5 , R 6 and R 7 independently represent one of the other a hydrogen atom, a halogen atom chosen from chlorine, fluorine and bromine, an alkyl, haloalkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl group, or a hydrocarbon ring or a heterocycle, a polymer chain, a group - (CH 2 ) m -OR k , -CH (OR k ) (OR 1 ), - (CH 2 ) m -SR k , - (CH 2 ) ffi -S (O) R k , - (CH 2 ) m -SO 2 R k , - (CH 2 ) m -SO 2 NR k R 1 , - (CH 2 ) m -SO 3 R k
• Z 1 represents a group chosen from: (i) alkyl, acyl, aryl, aralkyl, alkene or alkyne groups, hydrocarbon rings or heterocycles, (ii) a group -OR a or -SR a in which R a is a group chosen from: - an alkyl, haloalkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl group, or else a hydrocarbon ring or a heterocycle, or else a polymer chain; a group -CR b R ° PO (OR d ) (OR e ) in which: • R b and R c each represent, independently of one another, a hydrogen atom, a halogen atom, an alkyl or perfluoroalkyl group, a hydrocarbon ring or a heterocycle, or alternatively a group -NO 2 ,
• hydrocarbon chain comprising from 2 to 4 carbon atoms, optionally interrupted by a group -O-, -S-, or -NR h -, where R h corresponds to one of definitions given above for the group R f , (said hydrocarbon chain advantageously forming a 5-membered ring with the nitrogen atom to which R 1 and R j are attached),
• R 2a represents a group chosen from a hydrogen atom, a halogen atom, in particular fluorine, chlorine or bromine, an alkyl, haloalkyl, acyl, aryl, arylalkyl group, or else a hydrocarbon ring or a heterocycle, a polymer chain, a group - (CH 2 ) m -OR k , -CH OR k ) (OR 1 ), - (CH 2 ) m -SR k , - (CH 2 ) m -S (O) R k , - (CH 2 ) m - SO 2 R, - (CH 2 ) m -SO 2 NR k R 1 , - (CH 2 ) m -SO 3 R, - (CH 2 ) m -NO 2 , - (CH 2 ) m -CN, - (CH 2 ) m - - (CH 2 ) m -COOR,
• R 1 and n are as defined above, comprising at least the steps consisting in: a- reacting said compound of general formula (HA) with at least one olefin of general formula (A) in which :
• R 4 , R 5 , R 6 and R 7 are as defined above, with at least one of the groups R 4 , R 5 , R 6 or R 7 representing a hydrogen atom, to obtain at least one compound of general formula (IIIA) in which :
• R 1 , R 2a , R 4 , R 5 , R 6 , R 7 , Z 1 and n are as defined above, b- radicalizing said compound of general formula (IHA) to obtain at least one compound tetralone of general formula (INA)
• R 1 , R 2a , R 4 , R 5 , R 6 , R 7 and n are as defined above, c- transforming said compound of general formula (INA) into at least its oxime derivative of general formula (VA)
• R 1 , R 2a , R 4 , R 5 , R 6 , R 7 and n are as defined above, d- transforming said compound of general formula (VA) by a Beckmann rearrangement and consecutive reduction (s) ( s) in at least one compound of general formula (IA), and e- recovering said compound of general formula (IA).
• the invention also relates to a process for the preparation of at least one compound of general formula (EB)
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n are as defined above, X represents O, R 9 , S, S (O), SO 2 , SO 2 NR 9 and
• R 8 and R 9 independently of one another represent a hydrogen atom, an alkyl, haloalkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, alkaryl, arylalkenyl, arylalkynyl group, or a hydrocarbon ring or a heterocycle , a polymer chain, optionally substituted, or else R 8 and R 9 form, together with the atom to which they are attached, a heterocycle, starting from at least one compound of general formula (TVB)
• R 1 , R 4 , R 5 , R 6 , R 8 , X and n are as defined above, and R 2a is as defined above, comprising at least the steps consisting in: a ' transforming said compound of general formula (IVB) into at least its oxime derivative of general formula (VB)
• R 1 , R, R 4 , R 5 , R 6 , R 8 , X and n are as defined above.
• alkyl group is intended to cover a saturated, linear or branched hydrocarbon radical, which may optionally include one or more saturated aliphatic ring (s).
• the alkyl groups can have up to 25 carbon atoms, in particular from 1 to 12 carbon atoms, and in particular from 1 to 6 carbon atoms. Mention may in particular be made, among the alkyl radicals, of the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, octyl, decyl or dodecyl radical.
• an alkyl group may also denote, within the meaning of the present description, a cycloalkyl group, that is to say a cyclic saturated hydrocarbon radical, having in particular from 3 to 10 carbon atoms.
• an "alkoxy” group denotes, within the meaning of the present description, a radical -OAlk, where Alk denotes an alkyl group as defined above.
• haloalkyl within the meaning of the present description, is meant an alkyl radical as defined above and substituted by at least one halogen atom, where the term “halogen atom” designates here, as in all of the description, a fluorine, chlorine, bromine or iodine atom, in particular a fluorine or chlorine atom.
• halogen atom designates here, as in all of the description, a fluorine, chlorine, bromine or iodine atom, in particular a fluorine or chlorine atom.
• the "haloalkyl” groups of the invention can thus be, for example, “perfluoroalkyl” groups, that is to say, within the meaning of the invention, groups corresponding to the formula -CH_C_T__ + ⁇ , where n represents an integer ranging from 1 to 20.
• the alkenyl groups of the invention can have from 2 to 25 carbon atoms, in particular from 2 to 12 carbon atoms, and in particular from 2 to 6 carbon atoms.
• alkynyl is intended to mean an unsaturated, linear or branched hydrocarbon-based radical having at least one C tripleC triple bond.
• the alkynyl groups of the invention generally have from 2 to 25 carbon atoms, in particular from 2 to 15 carbon atoms, and in particular from 2 to 6 carbon atoms.
• a radical of “hydrocarbon ring” type designates a saturated, unsaturated or aromatic cyclic group, in particular of cycloalkyl, cycloalkenyl or cycloalkynyl type, optionally substituted, and comprising from 3 to 20 carbon atoms.
• a “heterocycle” type radical designates such a carbon ring interrupted by at least one heteroatom chosen for example from N, O, S, P and Si, said carbon ring being able to be saturated or i ⁇ sa-urea.
• An "aryl” group for its part, denotes, within the meaning of the present description, a mono- or poly-cyclic aromatic group generally having from 5 to 20 carbon atoms, and in particular from 6 to 10 carbon atoms. Thus, it may for example be a phenyl group, or alternatively 1- or 2-naphthyl. According to a particular variant, an "aryl" group within the meaning of the invention can integrate one or more heteroatoms such as sulfur, oxygen, or nitrogen.
• aryl denotes a heteroaromatic group mono- or polycyclic.
• arylalkyl alkenyl
• aralkynyl alkynyl groups substituted by an aryl group as defined above.
• __ + _ allyl, epoxy, alkoxy ( -OR), thioalkoxy or thioaryloxy (-SR), sulfones, phosphonates, a silyl group, a halogen atom, groups having a hydrophilic or ionic character such as the alkali salts of carboxylic acids, the alkali salts of acids sulfonic or phosphonic, polyalkylene oxide chains (POP, POE), cationic substituents (quaternary ammonium salts), R representing an alkyl or aryl group, or a polymer chain, said substituents possibly being interrupted by heteroatoms. It is the skill of a person skilled in the art to choose the nature of the different groups and substituents present in the compounds used to avoid any undesirable side reaction.
• the group R 1 may represent a halogen atom, in particular fluorine, chlorine, bromine or iodine, or an alkoxy group, in particular methoxy.
• the benzazepine compound can correspond to the formula (LA) or (EB) in which R 2 and R 3 each independently represent a hydrogen atom, or an alkyl group.
• the benzazepine compound can correspond to the general formula (IA) or (IB) in which R 2 and R 3 each represent a halogen atom, and in particular of chlorine, fluorine or bromine .
• disubstituted olefins may be cyclic olefins, for example cyclopentene or norbornene, with in this case either R 4 and R 7 or R 6 and R 5 each representing an atom d hydrogen, or terminal disubstituted olefins, that is to say with either R 4 and R 5 , or R 7 and R 6 each representing a hydrogen atom.
• the benzazepines according to the invention correspond to the general formula (LA) or (IB) in which at least two of the substituents R 4 , R 5 , R 6 and R 7 , and in particular either R 4 and R 5 , either R 7 and R 6 , or alternatively either R 4 and R 7 , or R 6 and R 5 each represent a hydrogen atom.
• the olefin is monosubstituted.
• the benzazepines according to the invention correspond to the general formula (LA) or (IB) in which R 4 , R 5 and R 6 simultaneously represent a hydrogen atom.
• the substituent (s) of this olefin can be chosen from -O acyl groups and groups of type - (CH 2) P CN, with p representing an integer varying from 1 to 10, and in particular equal to 1.
• Illustrative of the olefins of formula (A) capable of being used according to the invention there may be mentioned in particular: - vinyl pivalate, allyl cyanide, and N-vinyl phthalimide.
• This olefin is generally placed in the presence of the compound of formula (HA) in step a, in a molar ratio at least equal to 1, in particular greater than or equal to 1.5. Generally, the two compounds are brought into contact in a form soluble in an organic solvent. Steps a and b are generally carried out by radical route.
• the compounds of formula (HA) and / or (TUA) can undergo a photochemical activation, in particular by exposure to light and / or chemical, for example by decomposition of a peroxide, such as dilauryl peroxide or a diazo compound (thermal decomposition) or decomposition by autooxidation with oxygen of an organometallic compound such as triethylborane, diethylzinc, a trialkylaluminium.
• a peroxide such as dilauryl peroxide or a diazo compound (thermal decomposition)
• an organometallic compound such as triethylborane, diethylzinc, a trialkylaluminium.
• peroxides which are particularly suitable as a source of free radicals in the process of the invention, mention may in particular be made of diisobutyryl peroxide, cumyl peroxynodeodecanoate, tert-amyl peroxynodecanoate, di (2-ethylhexyl) peroxydicarbonate, peroxynodecanoate tert-butyl, dibutyl peroxydicarbonate, diketyl peroxydicarbonate, dimyristyl peroxydicarbonate, tert-butyl peroxynoheptanoate, tert-amyl peroxypivalate, didecanoyl peroxide, tert-amyl peroxy-2-ethylhexanoate, tert-butyl peroxyisobutyrate , 4-di (tert-butylperoxycarbo) cyclohexane, tert-butyl peroxya
• step a can be carried out in the presence of an effective amount of at least one radical initiator, in particular dilauroyl peroxide.
• the source of free radicals used according to the method of the invention is used under conditions allowing the production of free radicals, which is generally achieved by thermal activation, that is to say by raising the temperature of the reaction medium, generally at a temperature of the order of ambient (about 20 ° C) at 200 ° C, in particular from 40 ° C to 180 ° C, in particular from 80 ° C to 160 ° C.
• the production of free radicals can also be carried out at low temperature, generally at a temperature below ambient, in particular from 10 ° C.
• the choice of the source of free radicals depends on the temperature at which it is desired to carry out the reaction.
• the quantity of the source of free radicals to be introduced into the medium depends on several parameters, in particular its efficiency, its mode of introduction, the purity of the reagents, the concentration of the reaction medium, the efficiency of the olefin as a radical trap. It is within the competence of those skilled in the art to adjust the amount of source of free radicals to be introduced into the medium as a function of these various parameters.
• the initiator is added in several stages to the reaction medium until total consumption of the compound of general formula (HA) or (HIA).
• the solvent used in step a- and fou b- is chosen from the solvents conventionally used in radical synthesis, such as 1,2-dichloroethane, dichloromethane, benzene, toluene, trifluoromethylbenzene (trifluorotoluene), chlorobenzene , hexane, cyclohexane, heptane, octane, ethyl acetate, tert-butyl alcohol, and mixtures thereof.
• the reaction is generally carried out at atmospheric pressure, at the boiling temperature of the chosen solvent.
• the radical cyclization is also generally carried out in an acid medium.
• reaction can be carried out in the presence of a catalytic amount of acid, in particular camphorsulfonic acid.
• a catalytic amount of acid in particular camphorsulfonic acid.
• the expected product of general formula (TVA) or (INB) can be isolated or directly transformed in the reaction medium into a compound of general formula (VA) or (VB).
• the step of forming Poxime (VA) or (VB) can be carried out in a conventional manner.
• the compound of formula (IVA) or (TVB) can be brought into contact with an effective amount of nitromethane or hydroxylamine, and in particular of hydroxylamine salt such as, for example, hydroxylamine hydrochloride.
• the hydroxylamine is introduced in molar excess relative to the compound of general formula (TVA) or (INB), in particular it is present in an amount of approximately 1.3 equivalent.
• the oxime formation reaction of formula (VA) or (VB) can be carried out in various solvents such as, for example, methanol, ethanol, pyridine, toluene, benzene and their mixtures, and in particular in ethanol.
• a weak base can be added, such as for example sodium acetate, triethylamine, ⁇ aHCO 3 , Na 2 CO 3 and their mixtures. This weak base can be present in a content greater than or equal to 1 equivalent with respect to the compound of formula (VAT) or (TVB) and or less than 1 equivalent with respect to hydroxylamine.
• the mixture comprising at least one compound of formula (TVA) or (TVB) and hydroxylamine can be heated, and in particular brought to reflux, for example for a duration varying from 30 minutes to 3 hours.
• the preparation methods according to the invention can comprise a step of recovering the product of formula (VA) or (VB), in particular by recrystallization.
• the compound obtained may not be purified and be used as such in the next step.
• the preparation methods according to the invention comprise a step of transforming the compounds (VA) or (VB) by Beckmann rearrangement, according to a conventional method, as described for example by Donaruma and Heldt in Org. React. (NY) 1960, 11, 1.
• the Beckmann rearrangement can be carried out in the presence of an effective amount of a reagent such as, for example PCI5, concentrated HSO, formic acid, liquid SO 2 , HMPA, SOCl 2 , silica gel, P 5 O 5 - methanesulfonic acid, HCl-acetic acid-acetic anhydride or polyphosphoric acid (PPA).
• a reagent such as, for example PCI5, concentrated HSO, formic acid, liquid SO 2 , HMPA, SOCl 2 , silica gel, P 5 O 5 - methanesulfonic acid, HCl-acetic acid-acetic anhydride or polyphosphoric acid (PPA).
• PCI 5 derivative proves to be particularly advantageous in particular by its effectiveness. It is generally brought into contact with the oxime of formula (VA) or (VB) in molar excess, in particular in a molar ratio greater than 2, in particular greater than or equal to 3, and very particularly ranging from 3 to 6.
• the Beckmann rearrangement can be carried out in many solvents such as for example pyridine, acetic acid, phenol toluene, benzene, ether, methylamine, cyclohexylamine, morpholine, dioxane, tetr-ydrofiirane (THF), chloroform, dichloromethane, aqueous hydrochloric acid solution , and in particular in dichloromethane.
• solvents such as for example pyridine, acetic acid, phenol toluene, benzene, ether, methylamine, cyclohexylamine, morpholine, dioxane, tetr-ydrofiirane (THF), chloroform, dichloromethane, aqueous hydrochloric acid solution , and in particular in dichloromethane.
• the oxime of formula (VA) and (VB) in solution is added dropwise to the solution of PCI 5 ,
• the reaction mixture is neutralized, for example with an aqueous solution of saturated NaHCO 3 , treated with an organic solvent, such as CH 2 C1 2 , dried, filtered and then concentrated.
• the product thus obtained can be used without further purification in the next reduction step.
• the product resulting from the Beckmann rearrangement, isolated or not, can be reduced by an effective amount of at least one metallic reducing agent, such as for example magnesium, zinc or iron, and in particular zinc.
• This metallic reducing agent is generally used in molar excess, and in particular approximately 6 equivalents.
• This reduction can take place in different solvents such as, for example, acetic acid, methanol, ethanol or their mixtures.
• the temperature at which this reduction takes place can in particular vary from 0 ° C.
• This reduction can be used without further purification in another reduction step, involving treatment with an effective amount of reducing agent, in particular BH 3 and in particular BH 3 .T ⁇ F, POC- 3 / NaBH- t , PCIs / NaBH-i, LiAlH-j or diisobutylalurninium hydride (DIBAH).
• This second reduction can be carried out at reflux of the solvent, in particular at reflux of THF.
• This reduction mode involving the two types of consecutive reduction leads to compounds of formula (LA) or (IB) in which R 2 and R 3 are hydrogen atoms.
• the reduction can be carried out in a single step with an effective amount of NaBH, the NaBH is generally present in molar excess relative to the Beckmann rearrangement product.
• Beckmann rearrangement and reduction by NaBEU can be carried out sequentially in the same container.
• the groups R 2 and R 3 are chlorine atoms.
• the present invention also relates to compounds of general formula (IA)
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n are as defined above, and in particular R 7 can represent -XR 8 , XR 8 being as defined here -above.
• the benzazepine compound can correspond to the formula (IA) in which R 2 and R 3 each represent md endently a hydrogen atom, or an alkyl group.
• the benzazepine compound can correspond to the general formula (LA) in which R 2 and R 3 each represent a chlorine atom.
• the compounds of formula (A) or (IB) there may be mentioned:
• the subject of the present invention is the compounds of general formula (VB) in which: R 1 , R 2a , R 4 , R 5 , R 6 , XR 8 and n are as defined above. More particularly, this compound can be chosen from - 4 - [(E) -hydroxyimino] -7-chloro-1,2,3,4-tetrahydro-naphthalen-1-2,2-dimethyl propionate, - 2,2 dimethyl propionate of 4 - [( ⁇ ) -hydroxyimino] -7-fluoro-1,2,3,4-tetrahydronaphtalen-1-yl, and - 2,2 dimethyl propionate of 4 - [(E) - hydroxyimino] -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl, and - their derivatives.
• R 1 , R 2a , R 4 , R 5 , R 6 , XR 8 and n are as defined above. More
• the present invention also relates to a process for the preparation of benzazepine of general formula (NIA):
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n are as defined above, and
• R 10 represents a hydrogen atom, an alkyl or acyl group, and in particular a methyl group, comprising at least the transformation of a compound of general formula (IIA) into a compound of formula (LA) according to a process in accordance with l 'invention.
• the present invention also relates to a process for the preparation of benzazepine of general formula (VLB):
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , X and n are as defined above, and
• R 10 represents a hydrogen atom, an alkyl or acyl group, and in particular a methyl group, comprising at least the transformation of a compound of general formula (TVB) into a compound of formula (LB), according to a process in accordance with the invention.
• Example 3 Dithiocarbonate 5-r2-f4-methoxy-phenyl -2-oxo-emyl1-O-ethyl Prepared according to the protocol described in the translation Letters, 1997, 38, 1759-1762.
• Example 4 2.2-Dimethyl- ⁇ ropionate of l-ethoxythiocarbonylsul-ànyl-4-r4-chlorophenyr.-4-oxo-butyl
• a solution of 5 g. (18 mmol) of xanthate of Example 1 and 5.38 mL (3.1 g, 36.3 mmol) of vinyl pivalate in 18 L of 1,2-dichloroethane is brought to reflux and treated with DLP .
• the title product is obtained after chromatography on silica gel (eluent petroleum ether / ethyl acetate (95: 5)) with 97% yield (yellow oil).
• Example 5 2.2-Dimethyl- ⁇ ropionate of l-ethoxythiocarbonylsulfanyl-4- (4-fluorophenyl-oxo-butyl) Following general method 2, a solution of 5 g (19.3 mmol) of xanthate from the example 2 and 5.72 mL (4.9 g, 38.7 mmol) of vinyl pivalate in 19 mL of 1,2-dichloroethane is brought to reflux and treated with DLP. The title product is obtained after gel chromatography silica (eluent petroleum ether / ethyl acetate (95: 5)) with 90% yield (yellow oil).
• silica eluent petroleum ether / ethyl acetate (95: 5)
• EXAMPLE 6 2.2-Dimethylpropionate of 1-ethoxymiocarbonylsulfanyl-4-f4-methoxyphenyl) -4-oxo-butyl According to general method 2, 0.5 g (1.85 mmol) of xanthate from Example 3 and 0.55 mL (2.7 mmol) of vinyl pivalate are dissolved in 2 mL of 1,2-dichloroethane. The product is purified by chromatography on silica gel (eluent petroleum ether / ethyl acetate (95: 5)) to give the title product with 86% yield (yellow oil).
• Example 7 Dithiocarbonate 5-ri-cvanomethyl-4- ( ' 4-fluoro-phenyl -4-oxo-butvn-O-ethyl
• a solution of 2 g. (7.74 mmol) of xanthate of Example 2 and 1.25 mL (1.03 g, 15.48 mmol) of allyl cyanide in 8 mL of 1,2-dichloroethane is brought to reflux and treated with DLP.
• the title product is obtained after chromatography on silica gel (eluent petroleum ether / ethyl acetate (9: 1)) with 81
• Example 8 2.2-Dimethyl-propionate of 7-chloro-4-oxo-1.2.3.4-tet - hvdro-naphthalén-l-yle
• a solution of 3.5 g (8.67 mmol ) of compound of Example 4 and 0.2 g (0.86 mmol) of ACS in 87 ml of 1,2-dichloroethane is brought to reflux and treated with DLP.
• NMR NMR
• Example 10 2.2-Dimethyl-propionate of 7-methoxy-4-oxo-1.2.3.4-tetrahydro-naphthalen- 1-yle
• 3 g (7.5 mmol) of compound of Example 6 are dissolved in 75 mL of 1,2-dichloroethane and treated with DLP.
• Example 11 (7-Fluoro-4-oxo-l-2 1 3.4-tetrahvdro-naphthalen-l-yl1-acetonitrile
• a solution of 2 g (6.14 mmol) of compound of Example 7 and 0.143 g (0.61 mmol) of ACS in 61 mL of 1,2-dichloroethane is brought to reflux and treated with DLP.
• Example 12 2.2-Dimethyl-pro ⁇ ionate of 4-r (E) -hvdroxyiminol-7-chloro-1.2.3,4- tétrahvdro-naphthalen- 1 -vie
• Example 13 4-rffiVhv 2.2-Dimethyl-propionate (lroxyi Sprintino1-7-fluoro-l.2.3.4- tétrahvdro-naphthalen- 1 -vie
• Example 14 2.2-Dimethyl- ⁇ ropionate of 4-r ( ⁇ ) -hvdroxyimino1-7-methoxy-l .2.3,4- tetrahydro-naphthalen- 1 -vie
• 0.065 g (1.011 mmol) of hydrochloride hydroxylamine and 0.127 g (0.933 mmol) of sodium acetate are dissolved in 0.2 mL of water. This solution is added to a solution containing 0.215 g (0.778 mmol) of tetralone from Example 10 in 0.6 ml of ethanol and brought to reflux.
• Example 15 ⁇ 7-Fluoro-4-r (EVhvdroxyimino1 - 1.2.3.4-tetrahydro-naphthalen- 1 -vil - acetonitrile
• a solution of 0.4 g (1.96 mmol) of tetralone of example 11 in 0.9 ml of ethanol is added a solution of 0.165 g (2.55 mmol) of NH 2 OH ⁇ CI and 0.321 g (2.36 mmol) of sodium acetate in 0.4 ml of
• the reaction is brought to reflux and treated as described
• the resulting mixture is then diluted with ethyl acetate, filtered through celite, washed with saturated N-1HCO 3 solution and concentrated in vacuo.
• the product obtained in this way is then dissolved in 1.5 ml of THF and added dropwise to a solution of 2 mmol of BH 3 ⁇ F complex in 1.5 ml of THF at 0 ° C.
• the solution is brought to reflux for 30 minutes and allowed to cool, then it is treated with a few drops of a saturated solution of citric acid, the THF is evaporated, the aqueous phase is basified with an aqueous solution of Na2 ⁇ O 3 and extracted with CH2Cl2.
• the residue obtained is purified by chromatography.
• Example 16 2.2-Dimethyl- ⁇ ro ⁇ ionate de 7-cMoro-2.3.4,5-tétrahvdro-1H-benzorZ, 1azépin- 5-yl ester
• a solution of 1.1 g (3.71 mmol ) of oxime of Example 12 in 37 ml of C ⁇ 2 C1 2 is treated with a solution of 3.1 g (14.8 mmol) of PCI 5 in 37 ml of CH 2 C1 2 .
• the residue thus isolated is dissolved in 35 ml of acetic acid and then 1.4 g (21.45 mmol) of Zn are added.
• a solution of 1.1 (3.71 mmol) of the product thus obtained in 5.5 ml of THF is reduced with a 1 M solution of BH 3 -THF in 5.5 ml of THF according to the general method.
• Example 18 2.2-Dimethylpropionate of 7-methoxy-2.3A5-tetrahvdro-1H-benzorfrlazepin-5-yle
• a solution of 0.1 g (0.343 mmol) of oxime from Example 14 in 3.4 mL of C ⁇ 2CI2 is first treated with 0.286 g (1.37 mmol) of PCI 5 in dichloromethane (3.4 mL).
• Second, the crude reaction thus obtained is dissolved in acetic acid (3.4 mL) and 0.135 g (2.05 mmol) of powdered Zn is added.
• Example 19 (7-Fluoro-2.3.4.5-téfaahv ⁇ o-1H-ber ⁇ zortlazépin-5-ylVacétomtrile Following general method 5, a solution of 0.25 g (1.14 mmol) of oxime from Example 15 in 12 mL of C ⁇ 2 C1 2 is treated with a solution of 0.954 g (4.58 mmol) of PCI 5 in 12 mL of CH 2 C1 2.
• Example 20 2.2-Dimethyl-propionate of 3.3.7-trichloro-2.3.4.5-tetrahvdro-1H-benzorfrlazepin-5-yl
• a solution of 0.1 g (0.338 mmol) of oxime of Example 12 in the same solvent is then stirred at room temperature until the starting material disappears.
• Example 21 2.2-Dime yl-propionic acid 7-chloro-l- (2-methyl-4-nitro-benzoylV2.3.4.5- tetrahvdro-1H-benzor> lazepin-5-yl ester
• a solution of 0.212 g (1.06 mmol) of 2-methyl-4-nitrobenzoyl chloride in 2 ml of dichloromethane in a solution of 0.1 g (0.35 mmol) of the compound of Example 16 is added and 2 mL (0.143 g, 1.41 mmol) of sorted ylamine in 0.1 mL of dichloromethane
• Example 22 2-2-Dimethylpropionate of 7-fluoro-1- (2-methyl-4-metro-benzoyl> 2.3A5-tetrahvdro-1H-benzor & 1azepin-5-yle)
• the residue thus obtained is purified by chromatography on silica gel, eluting petroleum ether / ethyl acetate (9: 1) to give a yellow oil with a yield of 97%.
• Example 23 1- (4-Amino-2-methyl-benzoyl) -7-chloro-2.3.4.5-tetrahvdro-1H-benzo rfrlazepin-5-yl-2.2-dimethylpropionate
• a solution of 0.15 g ( 0.337 mmol) of the compound of Example 21 in 0.6 ml of ethanol and 0.2 ml of concentrated ⁇ Cl at reflux are added 0.32 g (1.68 mmol) of SnCl 2 .
• the reaction is heated at this temperature until the total consumption of the starting product (1 h 30). Then, the reaction is allowed to return to ambient temperature, the solution is basified by the addition of a saturated solution of Na 2 C ⁇ 3 , extracted with acetate
• Example 24 2.2- Dimethylpropionate 1- (4-amino-2-methyl-benzoyl) -7-fluoro-2.3.4.5- tetrahvdro-1H-benzortilazepin-5-yl
• a solution of 0.054 g (0.130 mmol) of the compound of Example 22 in 0.3 ml of ethanol and 0.1 ml of concentrated ⁇ Cl at reflux are added 0.124 g (0.654 mmol) of SnCl 2 . The reaction is heated at this temperature until the total consumption of the starting product (1 h 30).
• Example 25 Tolvaptan Following general method 6, treating a solution of 0.05 g (0.12 mmol) of the compound of Example 23 and 0.07 mL (0.048 g, 0.48 mmol) of triemylamine in 1 mL of dichloromethane with 0.046 g (0.301 mmol) of 2-methylbenzoyl chloride. Then, the crude product of the acylation reaction is dissolved in 1.5 ml of ethanol and 2 ml of a 2N NaOH solution are added to the reaction medium. The resulting solution is heated at 50 ° C for 2 hours. After allowing the reaction to cool, a few milliliters of water are added and the product precipitates. The crystals are drained, washed with cold water and recrystallized from methanol / ether to yield Tolvaptan with a yield of 85% over the 2 stages. The spectroscopic characteristics of this product correspond to those reported in the literature.
• Example 26 Fluoro-Tolvaptan Following general method 6, a solution of 0.04 g (0.10 mmol) of the compound of Example 24 and 0.05 mL (0.04 g, 0.40) is treated. mmol) of txiethylamine in 1 mL of dichloromethane with 0.046 g (0.301 mmol) of 2-methylbenzoyl chloride. Then, the crude product of the acylation reaction is dissolved in 1 ml of ethanol and 1.5 ml of a 2N NaOH solution are added to the reaction medium. The resulting solution is heated at 50 ° C for 2 hours. After allowing the reaction to cool, a few milliliters of water are added and the product precipitates. The crystals are drained, washed with cold water and recrystallized from methanol / ethyl ether to give the title product (white solid) with a quantitative yield over the 2 stages.

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