WO2013114326A1 - Process for preparing taxol derivatives and certain intermediate compounds - Google Patents

Process for preparing taxol derivatives and certain intermediate compounds Download PDF

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WO2013114326A1
WO2013114326A1 PCT/IB2013/050861 IB2013050861W WO2013114326A1 WO 2013114326 A1 WO2013114326 A1 WO 2013114326A1 IB 2013050861 W IB2013050861 W IB 2013050861W WO 2013114326 A1 WO2013114326 A1 WO 2013114326A1
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compound
carbon atoms
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radical
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Grégoire BOURNAUD
Madeleine Delamare
Eric Didier
Pierrick Le-Dref
Jean-Perre MENDY
Jean-Christophe Thiery
Patrick Trouilleux
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Sanofi
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Definitions

  • the present invention relates to novel compounds used in the preparation of taxol derivatives and to processes which use these compounds for producing taxol derivatives by esterification of baccatin III derivatives with compounds comprising an oxazolidine ring.
  • the compounds and processes according to the invention are in particular used for preparing tesetaxel.
  • Taxanes are a widely used class of chemotherapy agents. This class comprises in particular taxol and taxotere.
  • the principal mechanism of action of the taxane class is the inhibition of the function of microtubules, which are essential for cell division, and taxanes block normal division of cells. They are also supposed to be radiosensitive.
  • Patent EP 1 221 445 describes taxol derivatives corresponding to the formula below which exhibit significant antitumor efficacy, in particular when administered orally.
  • R representing a dimethylamino group or a morpholino group
  • R' representing a halogen atom, or an alkoxy group having from 1 to 6 carbon atoms.
  • Patent EP 1 221 445 describes processes for preparing these same compounds from baccatin III derivatives, comprising the steps of condensation of said derivatives with a ⁇ -lactam derivative, and oxidation of the terminal olefin function present on the baccatin III derivative with an oxidizing agent, such as osmium tetroxide, in the presence of N-methylmorpholine-N-oxide, followed by oxidative cleavage using sodium periodate and reductive amination with an amine of formula RH, where R represents a dimethylamino group or a morpholino group, in the presence of a borohydride.
  • an oxidizing agent such as osmium tetroxide
  • patent EP 1 741 716 discloses a process for preparing these same compounds, in which the oxidation of the terminal olefin function present on the baccatin III derivative is carried out using an alkali metal, for example potassium, permanganate.
  • an alkali metal for example potassium, permanganate.
  • Patents EP0663907 and FR 2698363 describe intermediates comprising an oxazolidine ring in the synthesis of docetaxel. However, the use of these intermediates is not described for the synthesis of taxane derivatives corresponding to the formula above, which comprise an acetal in position 9-10, whereas docetaxel has a carbonyl group in position 9 and an alkoxy group in position 10.
  • a subject of the present invention is compounds of formula (IV) below: where F3 ⁇ 4 represents a halogen atom or an alkyl radical having from 1 to 4 carbon atoms, or an alkoxy radical having from 1 to 4 carbon atoms, or an aryl radical having from 6 to 10 carbon atoms, or an aryloxy radical containing from 6 to 10 carbon atoms, or an amino radical, or an alkylamino radical having from 1 to 4 carbon atoms, or dialkylamino radical of which each alkyl part contains from 1 to 4 carbon atoms, or acylamino radical of which the acyl part contains from 1 to 5 carbon atoms, an alkoxycarbonylamino radical containing from 1 to 5 carbon atoms, or an acyl radical containing from 1 to 5 carbon atoms, an arylcarbonyl radical of which the aryl part contains from 6 to10 carbon atoms, a cyano, nitro, hydroxyl, carboxy or carbamoyl radical, an alky
  • n is an integer between 0 and 4, and when n is greater than or equal to 2, two or more F3 ⁇ 4 may be identical or different,
  • R 3 represents an electron-donating group chosen from alkyl radicals containing from 1 to 4 carbon atoms, alkoxy radicals containing from 1 to 4 carbon atoms and dialkylamino radicals of which each alkyl part contains from 1 to 4 carbon atoms,
  • n is not zero and at least one F3 ⁇ 4 radical is a halogen atom, preferentially fluorine or chlorine, preferentially fluorine.
  • m is not zero and at least one R 3 radical is an alkoxy radical containing from 1 to 4 carbon atoms, preferentially a methoxy radical.
  • the compound (IV) according to the invention then corresponds to formula (IV) bis below:
  • Ri represents an amino group, or an alkylamino group where the alkyl group contains from 1 to 4 carbon atoms, or a dialkylamino group where the alkyl groups comprise from 1 to 4 carbon atoms, or a cycloalkylamino group where the cycloalkyl group comprises from 4 to10 carbon atoms, or a group of formula (V),
  • nitrogenous heterocyde is a saturated ring which comprises 5 or 6 atoms
  • X represents an oxygen atom, a sulfur atom, CH2, CH-Y, NH or N-Y, where Y is an alkyl group comprising from 1 to 4 carbon atoms, and where n and F3 ⁇ 4 have the same meaning as above.
  • the compound (IV) bis makes it possible to prepare tesetaxel, which is a compound of formula (l)a below derived from formula (I), where Ri is a dimethylamino group:
  • a subject of the present invention is also a process for preparing compounds of formula (IV) as described above, by esterification of the hydroxyl function in position 13 of a compound of formula (II) as described below, with a carboxylic acid comprising an oxazolidine unit of formula (III) where F3 ⁇ 4 and R3 have the same meaning as previously set out, it being possible for said acid to optionally be in anhydride or halide form, so as to form a compound of formula (IV).
  • a subject of the present invention is therefore a process for preparing a compound as claimed in one of claims 1 to 4, comprising a step (a) of esterification of a compound of formula (II) hereinafter,
  • n, m, R 2 and R 3 are as defined above.
  • n is not zero and at least one F3 ⁇ 4 radical is a halogen atom, preferentially fluorine or chlorine, preferentially fluorine.
  • m is not zero and at least one R 3 radical is an alkoxy radical containing from 1 to 4 carbon atoms, preferentially a methoxy radical.
  • the esterification can be carried out in the presence of a condensation agent, such as a carbodiimide, for instance dicyclohexylcarbodiimide, or a reactive carbonate, for instance di-2-pyridyl carbonate, and of an esterification catalyst, such as an aminopyridine, for instance dimethylamino-4-pyridine or pyrrolidino-4- pyridine, by operating in an organic solvent chosen from ethers such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, or dioxane, ketones such as methyl isobutyl ketone, esters such as ethyl acetate, isopropyl acetate or n-butyl acetate, nitriles such as acetonitrile, aliphatic hydrocarbons such as pentane, hexane or heptane, halogenated aliphatic hydrocarbons such as dichlorome
  • ethyl acetate it is advantageous to use ethyl acetate at a temperature of approximately 0°C.
  • a carbodiimide, in particular ⁇ , ⁇ '-dicyclohexylcarbodiimide, will be preferred as coupling agent.
  • Dimethylamino-4-pyridine will be preferred as esterification catalyst.
  • esterification can also be carried out under analogous conditions using the acid of formula (III) in anhydride form, mixed anhydride form or halide form of formula (lll)a,
  • Xi represents a halogen atom or an acyloxy (alkoxycarbonyl) or aroyloxy (aryloxycarbonyl) radical, optionally prepared in situ.
  • Ac represents an acetyl group
  • Bz represents a benzoyl group
  • Boc represents a t-butoxycarbonyl group
  • Me represents a methyl group
  • DCC represents dicyclohexylcarbodiimide
  • DMAP represents dimethylamino-4-pyridine
  • EtOAc represents ethyl acetate.
  • the compounds of formula (II) can be obtained from baccatin III or from 10- deacetylbaccatin III by known techniques, for example according to scheme 2 below by the steps of:
  • the carboxylic acid of formula (III) comprising an oxazolidine unit can be obtained, for example, by adapting the method described in application FR 2698363, page 8, line 17 to page 13, line 10, i.e. by replacing the compounds described in said application with analogous compounds, where the H e t radical is replaced with a substituted pyridinyl radical of formula (IX): where n and F3 ⁇ 4 are as defined previously.
  • This carboxylic acid of formula (III) can be obtained by adapting the method described in application WO 94/12482, i.e. by carrying out, under the same conditions as those described in said application, the cyclization of a compound of formula (X):
  • n, m, R 2 and R 3 are as defined previously and X represents a residue - * N of an optically active organic base, such as an L(+)-2,10-camphorsultam residue or an -OR" residue in which R" represents an alkyl radical comprising from 1 to 4 carbon atoms, optionally substituted with a phenyl radical, followed by hydrolysis and saponification of the resulting product.
  • an optically active organic base such as an L(+)-2,10-camphorsultam residue or an -OR" residue in which R" represents an alkyl radical comprising from 1 to 4 carbon atoms, optionally substituted with a phenyl radical, followed by hydrolysis and saponification of the resulting product.
  • the compounds of formula (III) can be prepared from substituted pyridines by means of a process as described in scheme 3 hereinafter, where n, m, R 2 and R 3 are as defined previously, and comprising a step of addition of an optionally substituted benzyl dimethyl acetal on a B-pyridinyl isoserine, in the presence of pyridinium para-toluenesulfonate, followed by hydrolysis and saponification of the resulting product.
  • a subject of the present invention is also a process for preparing the compounds of formula (III) by addition of a benzyl dialkyl acetal of formula (XI) hereinafter,
  • R 4 is an alkyl radical comprising from 1 to 4 carbon atoms, preferentially a methyl
  • n and R2 are as previously defined, and R5 is an alkyl radical comprising from 1 to 4 carbon atoms, preferentially a methyl,
  • n is not zero and at least one R2 radical is a halogen atom, preferentially fluorine or chlorine, preferentially fluorine.
  • m is not zero and at least one R 3 radical is an alkoxy radical containing from 1 to 4 carbon atoms, preferentially a methoxy radical.
  • the addition is carried out in the presence of pyridinium para-toluenesulfonate, in an organic solvent, preferentially toluene.
  • n, m, R 2 and R 3 are as defined above.
  • the compound of formula (III) corresponds to the formula (III) bis below, optionally in anhydride or mixed anhydride form:
  • a subject of the present invention is also processes using the compounds of formula (IV) that are described above, for preparing taxane derivatives of formula (I), comprising the steps of:
  • the opening of the oxazolidine ring can be carried out directly on the compound (IV), or else after conversion of the terminal olefin of the compound (IV) into a diol and then into an aldehyde, followed by the reaction with the amine.
  • the acetal present in position 9-10 of the compound (I) is preserved during the opening in acidic medium of the oxazolidine ring. It is possible to open the oxazolidine ring in acid medium without deacetylating in position 9-10.
  • the product of formula (IV) is directly subjected to oxidation with an alkali metal permanganate so as to form a compound of formula (VI).
  • the oxazolidine ring is preserved during the action of these strong oxidizing agents, which makes it possible to prevent, too far upstream in the process, the formation of toxic intermediates.
  • the product of formula (VI) is subsequently subjected to oxidative cleavage with periodate so as to form an aldehyde of formula (VII), followed by a reductive amination reaction with an amine of formula R-iH, where Ri is as defined above, or optionally one of its salts, preferentially its hydrochloride in the presence of sodium acetate, and with a reducing agent of borohydride type, for example chosen from sodium triacetoxyborohydride or sodium cyanoborohydride, so as to form the compound of formula (VIII).
  • a reducing agent of borohydride type for example chosen from sodium triacetoxyborohydride or sodium cyanoborohydride
  • the opening of the oxazolidine ring is carried out in the final step of the preparation of the compound of formula (I), by subjecting the product of formula (VIII) to a treatment in acidic medium.
  • the oxazolidine ring is maintained until the final step of the process, which minimizes the formation of toxic intermediates.
  • a subject of the present invention is therefore a process in which step (a) described above is followed by steps:
  • Ri represents an amino group, or an alkylamino group where the alkyl group contains from 1 to 4 carbon atoms, or a dialkylamino group where the alkyl groups comprise from 1 to 4 carbon atoms, or a cycloalkylamino group where the cycloalkyl group comprises from 4 to10 carbon atoms, or a group of formula (V),
  • nitrogenous heterocycle is a saturated ring which comprises 5 or 6 atoms
  • X represents an oxygen atom, a sulfur atom, CH 2 , CH-Y, NH or N-Y, where Y is an alkyl group comprising from 1 to 4 carbon atoms, and where n, m, R 2 and R 3 are as defined above.
  • n is not zero and at least one R 2 radical is a halogen atom, preferentially fluorine or chlorine, preferentially fluorine.
  • m is not zero and at least one R 3 radical is an alkoxy radical containing from 1 to 4 carbon atoms, preferentially a methoxy radical.
  • Ri is a dimethylamino group or a morpholino group, preferentially a dimethylamino group.
  • step (d) the opening, in acidic medium, of the oxazolidine ring of the compound (VIII) is carried out by means of an organic or inorganic acid, in an organic solvent, preferentially at a temperature between -10°C and 60°C.
  • the acid is chosen from hydrochloric acid, sulfuric acid, acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, used alone or as a mixture
  • the organic solvent is chosen from alcohols, ethers, esters, halogenated aliphatic hydrocarbons, aromatic hydrocarbons and nitriles.
  • step (d) in step (d), the opening, in acidic medium, of the oxazolidine ring of the compound (VIII) is carried out with aqueous hydrochloric acid in methanol.
  • a subject of the present invention is also the compounds of formulae (VI), (VII) and (VIII), used as intermediates in the processes according to the invention for preparing the compounds of formula (I), and in particular the compounds of formulae (VI) bis, (Vll)bis and (VIII) bis, used as intermediates in the processes according to the invention for preparing the tesetaxel of formula (l)a.
  • the step of opening the oxazolidine ring on the compound of formula (IV) precedes the successive steps of oxidation with permanganate, followed by oxidative cleavage with periodate, followed by reaction with an amine of formula R-iH.
  • a subject of the present invention is therefore a process in which step (a) described above is followed by steps: (e) of opening, in an acidic medium, of the oxazolidine ring of the compound (VI) so as to form a compound of formula (IX),
  • Ri represents an amino group, or an alkylamino group where the alkyl group contains from 1 to 4 carbon atoms, or a dialkylamino group where the alkyl groups comprise from 1 to 4 carbon atoms, or a cycloalkylamino group where the cycloalkyl group comprises from 4 to10 carbon atoms, or a group of formula (V), where the nitrogenous heterocyde is a saturated ring which comprises 5 or 6 atoms, and where X represents an oxygen atom, a sulfur atom, CH 2 , CH-Y, NH or N-Y, where Y is an alkyl group comprising from 1 to 4 carbon atoms, where n, m, R 2 and R 3 are as defined above.
  • the diol, 20 volumes of dichloromethane, 5 equivalents of acrolein dimethyl acetal and 0.09 equivalent of HCI/Dioxane 4M are charged to a 100 ml Keller flask. The mixture is stirred at 25°C. After 45 min of contact, the medium is cooled to 0-5°C and then 0.09 equivalent of triethylamine is added. 10 volumes of a 2% NaHC03 solution are then added. The mixture is decanted and then the organic phase is washed with 10 volumes of water. The aqueous phases are counter-extracted with 10 volumes of dichloromethane. The 2 combined organic phases are concentrated to dryness at 30°C under reduced pressure.
  • the product is chromatographed on a silica gel column using a mixture: DCM/EtOAc (95/5 - 80/20 in 30min).
  • the core fractions are combined and concentrated to dryness in a rotary evaporator. 1 .82 g of product containing approximately 85% of product II are isolated.
  • III IV II 1.2 equivalents of III and 100 volumes of EtOAc are charged to a 50 ml Keller flask.
  • the medium is cooled to 0-5°C. 1.5 equivalents of DCC and 0.4 equivalent of DMAP are added in one step. The mixture is stirred for 6 h at 0-5°C. If the conversion is incomplete, it is possible to add DMAP and DCC.
  • the medium is filtered on silica gel, and elution is carried out with 5 times 100 volumes of EtOAc.
  • the filtrate is concentrated in a rotary evaporator at 30°C under reduced pressure and then stripping is carried out with 3 times 100 volumes of DCM.
  • the product is purified on silica gel, eluent MCH/EtOAc gradient 90/10 - 40/60. 400 mg of product are isolated.
  • the product is characterized by LC/MS.
  • the compound III is prepared according to the method described in scheme 3 above and characterized by 1 H NMR.
  • the solution of VII in EtOAc is charged to a 10 ml Keller flask.
  • the medium is cooled to 10°C.
  • 1.5 equivalents of NaOAc and 1 .5 equivalents of NHMe 2 -HCI are added.
  • the mixture is stirred at 10°C and then 1.5 equivalents of NaBH(OAc)3 are added.
  • the medium is heated to ambient temperature. It is maintained at ambient temperature for approximately 16 to 17 h and 50 volumes of EtOAc, 50 volumes of aqueous 15% KHCO 3 solution and 16 volumes of saturated NaCI solution are added. Decanting is followed by separation of the two phases.
  • the organic phase is washed with 50 volumes of water and 16 volumes of saturated aqueous NaCI solution.
  • aqueous phases are counter-extracted with 104 volumes of EtOAc.
  • the combined organic phases are concentrated to dryness in a rotary evaporator at 30°C. 310 mg of product are obtained.
  • 100 mg of crude product are chromatographed on a silica gel column with DCM / acetone / TEA (8:2:0.01 ) as eluent. 60 mg of product are obtained.
  • the product is analyzed by HPLC.
  • the product is purified by silica gel chromatography, with a DCM/acetone (6/4) mixture as eluent. 64 mg of tesetaxel are obtained.
  • the product is characterized by 1 H NMR and analyzed by HPLC.

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Abstract

The present invention relates to a novel process for preparing taxol derivatives, comprising a step of esterification of a baccatin III derivative with a carboxylic acid comprising an oxazolidine ring. A subject of the present invention is also certain novel intermediates involved in this process, and in particular the compound resulting from this esterification step. Said process can be carried out in order to prepare tesetaxel.

Description

PROCESS FOR PREPARING TAXOL DERIVATIVES AND CERTAIN
INTERMEDIATE COMPOUNDS
The present invention relates to novel compounds used in the preparation of taxol derivatives and to processes which use these compounds for producing taxol derivatives by esterification of baccatin III derivatives with compounds comprising an oxazolidine ring. The compounds and processes according to the invention are in particular used for preparing tesetaxel.
Taxanes are a widely used class of chemotherapy agents. This class comprises in particular taxol and taxotere. The principal mechanism of action of the taxane class is the inhibition of the function of microtubules, which are essential for cell division, and taxanes block normal division of cells. They are also supposed to be radiosensitive.
Patent EP 1 221 445 describes taxol derivatives corresponding to the formula below which exhibit significant antitumor efficacy, in particular when administered orally.
Figure imgf000002_0001
R representing a dimethylamino group or a morpholino group, R' representing a halogen atom, or an alkoxy group having from 1 to 6 carbon atoms.
Patent EP 1 221 445 describes processes for preparing these same compounds from baccatin III derivatives, comprising the steps of condensation of said derivatives with a β-lactam derivative, and oxidation of the terminal olefin function present on the baccatin III derivative with an oxidizing agent, such as osmium tetroxide, in the presence of N-methylmorpholine-N-oxide, followed by oxidative cleavage using sodium periodate and reductive amination with an amine of formula RH, where R represents a dimethylamino group or a morpholino group, in the presence of a borohydride.
It is, however, difficult to extend this method to the industrial scale owing to the use of highly toxic osmium tetroxide. Thus, patent EP 1 741 716 discloses a process for preparing these same compounds, in which the oxidation of the terminal olefin function present on the baccatin III derivative is carried out using an alkali metal, for example potassium, permanganate. However, the intermediates described have considerable toxicity.
Patents EP0663907 and FR 2698363 describe intermediates comprising an oxazolidine ring in the synthesis of docetaxel. However, the use of these intermediates is not described for the synthesis of taxane derivatives corresponding to the formula above, which comprise an acetal in position 9-10, whereas docetaxel has a carbonyl group in position 9 and an alkoxy group in position 10.
There is therefore a need for processes for preparing taxane derivatives as described above, and for example tesetaxel, using intermediates and reagents which are less toxic, so as to be able to be implemented on an industrial scale.
Description of the invention
A subject of the present invention is compounds of formula (IV) below:
Figure imgf000004_0001
where F¾ represents a halogen atom or an alkyl radical having from 1 to 4 carbon atoms, or an alkoxy radical having from 1 to 4 carbon atoms, or an aryl radical having from 6 to 10 carbon atoms, or an aryloxy radical containing from 6 to 10 carbon atoms, or an amino radical, or an alkylamino radical having from 1 to 4 carbon atoms, or dialkylamino radical of which each alkyl part contains from 1 to 4 carbon atoms, or acylamino radical of which the acyl part contains from 1 to 5 carbon atoms, an alkoxycarbonylamino radical containing from 1 to 5 carbon atoms, or an acyl radical containing from 1 to 5 carbon atoms, an arylcarbonyl radical of which the aryl part contains from 6 to10 carbon atoms, a cyano, nitro, hydroxyl, carboxy or carbamoyl radical, an alkylcarbamoyi radical of which the alkyl part contains from 1 to 4 carbon atoms, a dialkylcarbamoyl radical of which each alkyl part contains from 1 to 4 carbon atoms, or an alkoxycarbonyl radical of which the alkoxy part contains from 1 to 5 carbon atoms,
where n is an integer between 0 and 4, and when n is greater than or equal to 2, two or more F¾ may be identical or different,
where R3 represents an electron-donating group chosen from alkyl radicals containing from 1 to 4 carbon atoms, alkoxy radicals containing from 1 to 4 carbon atoms and dialkylamino radicals of which each alkyl part contains from 1 to 4 carbon atoms,
where m is an integer between 0 and 4, and when m is greater than or equal to 2, two or more R3 may be identical or different. Preferentially, in the compounds of formula (IV) according to the invention, n is not zero and at least one F¾ radical is a halogen atom, preferentially fluorine or chlorine, preferentially fluorine.
According to one embodiment, in the compounds of formula (IV) according to the invention, m is not zero and at least one R3 radical is an alkoxy radical containing from 1 to 4 carbon atoms, preferentially a methoxy radical.
According to another particularly preferred embodiment, m=0, n=1 and F¾ is a fluorine atom located in position 3 of the pyridine ring. The compound (IV) according to the invention then corresponds to formula (IV) bis below:
Figure imgf000005_0001
The compounds of formula (IV) make it possible to prepare compounds of formula (I):
Figure imgf000005_0002
where Ri represents an amino group, or an alkylamino group where the alkyl group contains from 1 to 4 carbon atoms, or a dialkylamino group where the alkyl groups comprise from 1 to 4 carbon atoms, or a cycloalkylamino group where the cycloalkyl group comprises from 4 to10 carbon atoms, or a group of formula (V),
Figure imgf000006_0001
where the nitrogenous heterocyde is a saturated ring which comprises 5 or 6 atoms, and where X represents an oxygen atom, a sulfur atom, CH2, CH-Y, NH or N-Y, where Y is an alkyl group comprising from 1 to 4 carbon atoms, and where n and F¾ have the same meaning as above.
In particular, when m=0, n=1 and F¾ is a fluorine atom located in position 3 of the pyridine ring, the compound (IV) bis makes it possible to prepare tesetaxel, which is a compound of formula (l)a below derived from formula (I), where Ri is a dimethylamino group:
Figure imgf000006_0002
The compounds (IV) according to the invention, where the oxazolidine ring is not open, exhibit less toxicity than the intermediates already described for the preparation of the compounds of formula (I), in particular tesetaxel.
A subject of the present invention is also a process for preparing compounds of formula (IV) as described above, by esterification of the hydroxyl function in position 13 of a compound of formula (II) as described below, with a carboxylic acid comprising an oxazolidine unit of formula (III) where F¾ and R3 have the same meaning as previously set out, it being possible for said acid to optionally be in anhydride or halide form, so as to form a compound of formula (IV).
A subject of the present invention is therefore a process for preparing a compound as claimed in one of claims 1 to 4, comprising a step (a) of esterification of a compound of formula (II) hereinafter,
Figure imgf000007_0001
with an acid of formula (III), optionally in anhydride or mixed anhydride form:
Figure imgf000007_0002
so as to form the compound of formula (IV):
Figure imgf000007_0003
where n, m, R2 and R3 are as defined above.
Preferentially, in said process according to the invention, n is not zero and at least one F¾ radical is a halogen atom, preferentially fluorine or chlorine, preferentially fluorine. According to one embodiment, m is not zero and at least one R3 radical is an alkoxy radical containing from 1 to 4 carbon atoms, preferentially a methoxy radical.
According to a one preferred embodiment, m=0, n=1 and F¾ is a fluorine atom located in position 3 of the pyridine ring.
The esterification can be carried out in the presence of a condensation agent, such as a carbodiimide, for instance dicyclohexylcarbodiimide, or a reactive carbonate, for instance di-2-pyridyl carbonate, and of an esterification catalyst, such as an aminopyridine, for instance dimethylamino-4-pyridine or pyrrolidino-4- pyridine, by operating in an organic solvent chosen from ethers such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, or dioxane, ketones such as methyl isobutyl ketone, esters such as ethyl acetate, isopropyl acetate or n-butyl acetate, nitriles such as acetonitrile, aliphatic hydrocarbons such as pentane, hexane or heptane, halogenated aliphatic hydrocarbons such as dichloromethane or 1 ,2-dichloroethane, or aromatic hydrocarbons such as benzene, toluene, xylenes, ethylbenzene, isopropylbenzene or chlorobenzene, for example at a temperature of between -10 and 90°C.
It is advantageous to use ethyl acetate at a temperature of approximately 0°C. A carbodiimide, in particular Ν,Ν'-dicyclohexylcarbodiimide, will be preferred as coupling agent.
Dimethylamino-4-pyridine will be preferred as esterification catalyst.
The esterification can also be carried out under analogous conditions using the acid of formula (III) in anhydride form, mixed anhydride form or halide form of formula (lll)a,
(Ilia)
Figure imgf000008_0001
where Xi represents a halogen atom or an acyloxy (alkoxycarbonyl) or aroyloxy (aryloxycarbonyl) radical, optionally prepared in situ.
One preferred embodiment of this process according to the invention, where m=0, n=1 , and F¾ is a fluorine atom located in position 3 of the pyridine ring, is illustrated in scheme 1 hereinafter. This preferred embodiment constitutes a step in a process for preparing tesetaxel according to the invention.
Figure imgf000009_0001
Scheme 1
In the scheme above and the following schemes, Ac represents an acetyl group, Bz represents a benzoyl group, Boc represents a t-butoxycarbonyl group, Me represents a methyl group, DCC represents dicyclohexylcarbodiimide, DMAP represents dimethylamino-4-pyridine, and EtOAc represents ethyl acetate.
The compounds of formula (II) can be obtained from baccatin III or from 10- deacetylbaccatin III by known techniques, for example according to scheme 2 below by the steps of:
1 ) treatment of baccatin III with trifluoromethanesulfonic anhydride so as to form a triflate in position 7, then treatment with a base causing rupture of the C-O bond,
2) reduction of the double bond in position 6-7 in the presence of ammonium formate, on Pd/C catalyst, 3) hydrolysis of the ester function in position 10, for example in the presence of hydrogen peroxide and sodium bicarbonate, so as to form 10- deacetylbaccatin III,
4) asymmetric reduction of the ketone in position 9 with a tetrahydrofuran- borane complex,
5) treatment of the resulting compound with acrolein dimethyl acetal so as to form the compound of formula (II) in the presence of titanium bis cyclopentanedienyl)dichloride, in dichloromethane.
Figure imgf000010_0001
Scheme 2
The carboxylic acid of formula (III) comprising an oxazolidine unit can be obtained, for example, by adapting the method described in application FR 2698363, page 8, line 17 to page 13, line 10, i.e. by replacing the compounds described in said application with analogous compounds, where the Het radical is replaced with a substituted pyridinyl radical of formula (IX):
Figure imgf000010_0002
where n and F¾ are as defined previously.
This carboxylic acid of formula (III) can be obtained by adapting the method described in application WO 94/12482, i.e. by carrying out, under the same conditions as those described in said application, the cyclization of a compound of formula (X):
Figure imgf000011_0001
where n, m, R2 and R3 are as defined previously and X represents a residue -*N of an optically active organic base, such as an L(+)-2,10-camphorsultam residue or an -OR" residue in which R" represents an alkyl radical comprising from 1 to 4 carbon atoms, optionally substituted with a phenyl radical, followed by hydrolysis and saponification of the resulting product.
The compounds of formula (III) can be prepared from substituted pyridines by means of a process as described in scheme 3 hereinafter, where n, m, R2 and R3 are as defined previously, and comprising a step of addition of an optionally substituted benzyl dimethyl acetal on a B-pyridinyl isoserine, in the presence of pyridinium para-toluenesulfonate, followed by hydrolysis and saponification of the resulting product.
A subject of the present invention is also a process for preparing the compounds of formula (III) by addition of a benzyl dialkyl acetal of formula (XI) hereinafter,
Figure imgf000012_0001
where m and R3 are as previously defined, and R4 is an alkyl radical comprising from 1 to 4 carbon atoms, preferentially a methyl,
on a pyridinyl isoserine of formula (XII),
Figure imgf000012_0002
where n and R2 are as previously defined, and R5 is an alkyl radical comprising from 1 to 4 carbon atoms, preferentially a methyl,
followed by hydrolysis and saponification of the resulting compound.
Preferentially, in said process according to the invention, n is not zero and at least one R2 radical is a halogen atom, preferentially fluorine or chlorine, preferentially fluorine.
According to one embodiment, m is not zero and at least one R3 radical is an alkoxy radical containing from 1 to 4 carbon atoms, preferentially a methoxy radical.
According to a one preferred embodiment, m=0, n=1 and R2 is a fluorine atom located in position 3 of the pyridine ring. Preferentially, in this process according to the invention, the addition is carried out in the presence of pyridinium para-toluenesulfonate, in an organic solvent, preferentially toluene.
Figure imgf000014_0001
Figure imgf000014_0002
Pd(OH)2/C , Boc20, MeOH, H2,
Figure imgf000014_0003
reduction then protection with Boc20
Figure imgf000014_0004
Scheme 3 A subject of the present invention is also compounds of formula (III), optionally in anhydride or mixed anhydride form:
Figure imgf000015_0001
where n, m, R2 and R3 are as defined above.
According to one preferred embodiment, the compound of formula (III) corresponds to the formula (III) bis below, optionally in anhydride or mixed anhydride form:
Figure imgf000015_0002
A subject of the present invention is also processes using the compounds of formula (IV) that are described above, for preparing taxane derivatives of formula (I), comprising the steps of:
• opening of the oxazolidine ring present in the compound (IV) in acidic medium,
• oxidation of the terminal olefin present in the compound (IV) to give a diol using an alkali metal permanganate, followed by oxidative cleavage with sodium periodate so as to form the corresponding aldehyde, followed by a reductive amination reaction with an amine of formula R-iH, where Ri is as defined above, or optionally one of its salts, preferentially its hydrochloride in the presence of sodium acetate, and with a reducing agent of borohydride type, for example chosen from sodium triacetoxyborohydride or sodium cyanoborohydride.
These steps can be carried out in any order. In other words, the opening of the oxazolidine ring can be carried out directly on the compound (IV), or else after conversion of the terminal olefin of the compound (IV) into a diol and then into an aldehyde, followed by the reaction with the amine.
Surprisingly, the acetal present in position 9-10 of the compound (I) is preserved during the opening in acidic medium of the oxazolidine ring. It is possible to open the oxazolidine ring in acid medium without deacetylating in position 9-10.
According to one preferred embodiment, the product of formula (IV) is directly subjected to oxidation with an alkali metal permanganate so as to form a compound of formula (VI).
Surprisingly, the oxazolidine ring is preserved during the action of these strong oxidizing agents, which makes it possible to prevent, too far upstream in the process, the formation of toxic intermediates. The known taxane syntheses which use intermediates of this type with an oxazolidine ring, such as those described in patent EP 0663907, open the oxazolidine ring before action of the oxidizing agents.
According to this preferred embodiment, the product of formula (VI) is subsequently subjected to oxidative cleavage with periodate so as to form an aldehyde of formula (VII), followed by a reductive amination reaction with an amine of formula R-iH, where Ri is as defined above, or optionally one of its salts, preferentially its hydrochloride in the presence of sodium acetate, and with a reducing agent of borohydride type, for example chosen from sodium triacetoxyborohydride or sodium cyanoborohydride, so as to form the compound of formula (VIII). Here again, surprisingly, the oxazolidine unit is preserved during the treatment with periodate.
According to this preferred embodiment, the opening of the oxazolidine ring is carried out in the final step of the preparation of the compound of formula (I), by subjecting the product of formula (VIII) to a treatment in acidic medium. Thus, according to this preferred embodiment, the oxazolidine ring is maintained until the final step of the process, which minimizes the formation of toxic intermediates.
A subject of the present invention is therefore a process in which step (a) described above is followed by steps:
(b) of oxidation of the terminal olefin of the compound (IV) with an alkali metal permanganate, in the presence of a base, in at least one solvent chosen from aqueous pyridine, aqueous tetrahydrofuran and aqueous acetone, so as to give a compound of formula (VI),
Figure imgf000017_0001
(c) of oxidative cleavage of the compound (VI) with sodium periodate so as to form an aldehyde of formula (VII),
Figure imgf000017_0002
followed by a reaction for reductive amination of said compound (VII) with an amine of formula R-i H, or optionally one of its salts, preferentially its hydrochloride in the presence of sodium acetate, and with a reducing agent of borohydride type, for example chosen from sodium triacetoxyborohydride or sodium cyanoborohydride, so as to form the compound (VIII),
Figure imgf000018_0001
(d) of opening, in an acidic medium, of the oxazolidine ring of the compound (VIII) so as to form a compound of formula (I),
Figure imgf000018_0002
where Ri represents an amino group, or an alkylamino group where the alkyl group contains from 1 to 4 carbon atoms, or a dialkylamino group where the alkyl groups comprise from 1 to 4 carbon atoms, or a cycloalkylamino group where the cycloalkyl group comprises from 4 to10 carbon atoms, or a group of formula (V),
Figure imgf000018_0003
where the nitrogenous heterocycle is a saturated ring which comprises 5 or 6 atoms, and where X represents an oxygen atom, a sulfur atom, CH2, CH-Y, NH or N-Y, where Y is an alkyl group comprising from 1 to 4 carbon atoms, and where n, m, R2 and R3 are as defined above.
Preferentially, in said process according to the invention, n is not zero and at least one R2 radical is a halogen atom, preferentially fluorine or chlorine, preferentially fluorine.
According to one embodiment, m is not zero and at least one R3 radical is an alkoxy radical containing from 1 to 4 carbon atoms, preferentially a methoxy radical.
According to a one preferred embodiment, m=0, n=1 and R2 is a fluorine atom located in position 3 of the pyridine ring.
According to one preferred embodiment, Ri is a dimethylamino group or a morpholino group, preferentially a dimethylamino group.
According to one particularly preferred embodiment of said process, n=1 and R2 is a fluorine atom in position 3 of the pyridine ring, m=0 and Ri is a dimethylamino group.
This preferred embodiment is illustrated by scheme 4 below for the preparation of tesetaxel.
According to one embodiment of said process according to the invention, in step (d), the opening, in acidic medium, of the oxazolidine ring of the compound (VIII) is carried out by means of an organic or inorganic acid, in an organic solvent, preferentially at a temperature between -10°C and 60°C.
According to one preferred embodiment of said process according to the invention, the acid is chosen from hydrochloric acid, sulfuric acid, acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, used alone or as a mixture, and the organic solvent is chosen from alcohols, ethers, esters, halogenated aliphatic hydrocarbons, aromatic hydrocarbons and nitriles.
According to one particularly preferred embodiment of said process according to the invention, in step (d), the opening, in acidic medium, of the oxazolidine ring of the compound (VIII) is carried out with aqueous hydrochloric acid in methanol.
A subject of the present invention is also the compounds of formulae (VI), (VII) and (VIII), used as intermediates in the processes according to the invention for preparing the compounds of formula (I), and in particular the compounds of formulae (VI) bis, (Vll)bis and (VIII) bis, used as intermediates in the processes according to the invention for preparing the tesetaxel of formula (l)a.
According to another embodiment of processes according to the invention, for preparing compounds of formula (I), the step of opening the oxazolidine ring on the compound of formula (IV) precedes the successive steps of oxidation with permanganate, followed by oxidative cleavage with periodate, followed by reaction with an amine of formula R-iH.
A subject of the present invention is therefore a process in which step (a) described above is followed by steps: (e) of opening, in an acidic medium, of the oxazolidine ring of the compound (VI) so as to form a compound of formula (IX),
Figure imgf000021_0001
(f) of oxidation of the terminal olefin of the compound (IX) with an alkali metal permanganate, in the presence of a base, in at least one solvent chosen from aqueous pyridine, aqueous tetrahydrofuran and aqueous acetone, so as to give a compound of formula (X),
Figure imgf000021_0002
(g) of oxidative cleavage of the compound (X) with sodium periodate so as to form an aldehyde of formula (XI),
Figure imgf000021_0003
followed by a reaction for reductive amination of said compound (XI) with an amine of formula R-i H, or optionally one of its salts, preferentially its hydrochloride in the presence of sodium acetate, and with a reducing agent of borohydride type, for example chosen from sodium triacetoxyborohydride or sodium cyanoborohydride, so as to form the compound (I),
Figure imgf000022_0001
where Ri represents an amino group, or an alkylamino group where the alkyl group contains from 1 to 4 carbon atoms, or a dialkylamino group where the alkyl groups comprise from 1 to 4 carbon atoms, or a cycloalkylamino group where the cycloalkyl group comprises from 4 to10 carbon atoms, or a group of formula (V),
Figure imgf000022_0002
where the nitrogenous heterocyde is a saturated ring which comprises 5 or 6 atoms, and where X represents an oxygen atom, a sulfur atom, CH2, CH-Y, NH or N-Y, where Y is an alkyl group comprising from 1 to 4 carbon atoms, where n, m, R2 and R3 are as defined above.
Figure imgf000023_0001
Tesetaxel (l)3
Scheme 4
Examples:
Example 1 : Preparation of II
Figure imgf000024_0001
The diol, 20 volumes of dichloromethane, 5 equivalents of acrolein dimethyl acetal and 0.09 equivalent of HCI/Dioxane 4M are charged to a 100 ml Keller flask. The mixture is stirred at 25°C. After 45 min of contact, the medium is cooled to 0-5°C and then 0.09 equivalent of triethylamine is added. 10 volumes of a 2% NaHC03 solution are then added. The mixture is decanted and then the organic phase is washed with 10 volumes of water. The aqueous phases are counter-extracted with 10 volumes of dichloromethane. The 2 combined organic phases are concentrated to dryness at 30°C under reduced pressure. The product is chromatographed on a silica gel column using a mixture: DCM/EtOAc (95/5 - 80/20 in 30min). The core fractions are combined and concentrated to dryness in a rotary evaporator. 1 .82 g of product containing approximately 85% of product II are isolated.
The product is characterized by 1 H NMR and analyzed by HPLC. Example 2: Preparation of IV
Figure imgf000024_0002
III IV II, 1.2 equivalents of III and 100 volumes of EtOAc are charged to a 50 ml Keller flask. The medium is cooled to 0-5°C. 1.5 equivalents of DCC and 0.4 equivalent of DMAP are added in one step. The mixture is stirred for 6 h at 0-5°C. If the conversion is incomplete, it is possible to add DMAP and DCC. The medium is filtered on silica gel, and elution is carried out with 5 times 100 volumes of EtOAc. The filtrate is concentrated in a rotary evaporator at 30°C under reduced pressure and then stripping is carried out with 3 times 100 volumes of DCM. The product is purified on silica gel, eluent MCH/EtOAc gradient 90/10 - 40/60. 400 mg of product are isolated.
The product is characterized by LC/MS.
The compound III is prepared according to the method described in scheme 3 above and characterized by 1 H NMR.
Example 3: Preparation of VI
Figure imgf000025_0001
IV, 15 volumes of pyridine and 2.5 volumes of water are charged to a 100 ml round-bottomed flask. 1 equivalent of KMn04 is added. The mixture is stirred for approximately 4 to 5 h at ambient temperature and filtered on an acrodisc filter, washing is carried out with 2x1 ml of pyridine and then 1 ml/0.5 ml pyhdine/H20, and then a further 0.35 equivalent of KMn04 is charged. The mixture is filtered on an acrodisc filter, washing is carried out with 3x1 ml of pyridine and a further 0.35 equivalent of KMn04 is charged. 50 volumes of EtOAc, 2.5 volumes of 10% citric acid solution (qs pH=7), 10 volumes of water and 10 volumes of saturated NaCI solution are added. The mixture is stirred for 30 min at ambient temperature. Decanting is performed followed by re-extraction with 10 volumes of EtOAc. The combined organic phases are washed with 25 volumes of saturated NaCI solution and 0.5 volume of 10% citric acid solution (qs pH=7). Finally, washing is carried out with 25 volumes of saturated NaCI solution and 25 volumes of aqueous 4% NaHCC>3 solution. The resulting product is concentrated under reduced pressure in a rotary evaporator at 30°C. 409.4 mg of product are obtained. The product is analyzed by HPLC.
Example 4: Preparation of VII
Figure imgf000026_0001
VI VII
VI, 50 volumes of ACN, 12.6 equivalents of pyridine and 188 equivalents of water are charged to a 50 ml round-bottomed flask. 2 equivalents of Nal04 are added and the medium is maintained at ambient temperature for 5 h 30 min. 0.5 equivalent of Nal04 is added. The medium is maintained at ambient temperature for 1 to 3 h, and then 50 volumes of EtOAc and 30 volumes of aqueous 20% solution of Na2S203.5H20 are added. The medium is stirred at ambient temperature. Decanting is performed and the organic phase is washed with 2 times 10 volumes of saturated aqueous NaCI solution and then 10 volumes of 5% NaHC03 solution. The aqueous phases are counter-extracted with 50 volumes of EtOAc. The combined organic phases are concentrated without bringing them to dryness. Stripping is carried out with 4 times 25 volumes of EtOAc, without bringing to dryness, and the product is used directly in the next step. Example 5: Preparation of VIII
Figure imgf000027_0001
The solution of VII in EtOAc is charged to a 10 ml Keller flask. The medium is cooled to 10°C. 1.5 equivalents of NaOAc and 1 .5 equivalents of NHMe2-HCI are added. The mixture is stirred at 10°C and then 1.5 equivalents of NaBH(OAc)3 are added. The medium is heated to ambient temperature. It is maintained at ambient temperature for approximately 16 to 17 h and 50 volumes of EtOAc, 50 volumes of aqueous 15% KHCO3 solution and 16 volumes of saturated NaCI solution are added. Decanting is followed by separation of the two phases. The organic phase is washed with 50 volumes of water and 16 volumes of saturated aqueous NaCI solution. The aqueous phases are counter-extracted with 104 volumes of EtOAc. The combined organic phases are concentrated to dryness in a rotary evaporator at 30°C. 310 mg of product are obtained. 100 mg of crude product are chromatographed on a silica gel column with DCM / acetone / TEA (8:2:0.01 ) as eluent. 60 mg of product are obtained.
The product is analyzed by HPLC.
Example 6: Preparation of tesetaxel
Figure imgf000027_0002
VIII and 100 volumes of MeOH are charged to a 50 ml Keller flask. 2.2 equivalents of aqueous 1 N HCI solution are added. The mixture is stirred at ambient temperature for approximately 1 to 2 h. 300 volumes of EtOAc and 100 volumes of aqueous 2% NaHCO3 solution are added. The mixture is stirred and left to decant. The organic phase is washed twice with 100 volumes of deionized water. The 2 aqueous phases are counter-extracted with 200 volumes of EtOAc. The combined organic phases are concentrated to dryness. 206 mg of product are obtained.
The product is purified by silica gel chromatography, with a DCM/acetone (6/4) mixture as eluent. 64 mg of tesetaxel are obtained. The product is characterized by 1 H NMR and analyzed by HPLC.

Claims

Claims
1. A compound of formula (IV):
Figure imgf000029_0001
where F¾ represents a halogen atom or an alkyl radical having from 1 to 4 carbon atoms, or an alkoxy radical having from 1 to 4 carbon atoms, or an aryl radical having from 6 to 10 carbon atoms, or an aryloxy radical containing from 6 to 10 carbon atoms, or an amino radical, or an alkylamino radical having from 1 to 4 carbon atoms, or dialkylamino radical of which each alkyl part contains from 1 to 4 carbon atoms, or acylamino radical of which the acyl part contains from 1 to 5 carbon atoms, or an alkoxycarbonylamino radical containing from 1 to 5 carbon atoms, or an acyl radical containing from 1 to 5 carbon atoms, or an arylcarbonyl radical of which the aryl part contains from 6 to10 carbon atoms, or a cyano, nitro, hydroxyl, carboxy or carbamoyl radical, an alkylcarbamoyl radical of which the alkyl part contains from 1 to 4 carbon atoms, a dialkylcarbamoyl radical of which each alkyl part contains from 1 to 4 carbon atoms, or an alkoxycarbonyl radical of which the alkoxy part contains from 1 to 5 carbon atoms, where n is an integer between 0 and 4, and when n is greater than or equal to 2, two or more F¾ may be identical or different, where R3 represents an electron-donating group chosen from alkyl radicals containing from 1 to 4 carbon atoms, alkoxy radicals containing from 1 to 4 carbon atoms, and dialkylamino radicals of which each alkyl part contains from 1 to 4 carbon atoms, where m is an integer between 0 and 4, and when m is greater than or equal to 2, two or more R3 may be identical or different.
2. The compound as claimed in claim 1 , in which n is not zero and at least one R2 radical is a halogen atom, preferentially fluorine or chlorine, preferentially fluorine.
3. The compound as claimed in either of claims 1 and 2, in which m is not zero and at least one R3 radical is an alkoxy radical containing from 1 to 4 carbon atoms, preferentially a methoxy radical.
4. The compound as claimed in either of claims 1 and 2, in which m=0, n=1 and R2 is a fluorine atom located in position 3 of the pyridine ring,
Figure imgf000030_0001
5. A process for preparing a compound as claimed in one of claims 1 to 4, comprising a step (a) of esterification of a compound of formula (II),
Figure imgf000030_0002
with an acid of formula (III), optionally in anhydride or mixed anhydride form:
Figure imgf000031_0001
so as to form the compound of formula (IV):
Figure imgf000031_0002
where n, m, R2 and R3 are either all defined as in claim 1 , or all defined as in claim 2, or all defined as in claim 3, or all defined as in claim 4.
6. The process as claimed in claim 5, in which the esterification step (a) is carried out in the presence of an esterification catalyst chosen from aminopyridines, and of a condensation agent chosen from carbodiimides or reactive carbonates, preferentially carbodiimides, in an organic solvent chosen from ethers, esters, ketones, nitriles, aliphatic hydrocarbons which are optionally halogenated, and aromatic hydrocarbons.
7. The process as claimed in claim 5 or 6, in which the esterification step (a) is carried out in the presence of 4-dimethylaminopyridine as esterification catalyst and of Ν,Ν'-dicyclohexylcarbodiimide as coupling agent, in ethyl acetate as organic solvent.
8. A compound of formula (III), optionally in anhydride or mixed anhydride
Figure imgf000032_0001
where n, m, R2 and R3 are either all defined as in claim 1 , or all defined as in claim 2, or all defined as in claim 3, or all defined as in claim 4.
9. The process as claimed in one of claims 5 to 7, in which step (a) is followed, in any order, by the steps of:
• opening, in acidic medium, of the oxazolidine ring present in the compound (IV),
• oxidation of the terminal olefin present in the compound (IV) to give a diol using an alkali metal permanganate, followed by oxidative cleavage with sodium periodate so as to form the corresponding aldehyde, followed by a reductive amination reaction with an amine of formula R-iH, or optionally one of its salts, preferentially its hydrochloride in the presence of sodium acetate, and with a reducing agent of borohydride type, for example chosen from sodium triacetoxyborohydride or sodium cyanoborohydride, where Ri represents an amino group, or an alkylamino group where the alkyl group contains from 1 to 4 carbon atoms, or a dialkylamino group where the alkyl groups comprise from 1 to 4 carbon atoms, or a cydoalkylamino group where the cycloalkyl group comprises from 4 to10 carbon atoms, or a group of formula (V), where the nitrogenous heterocycle is a saturated ring which comprises 5 or 6 atoms, and where X represents an oxygen atom, a sulfur atom, CH2, CH-Y, NH or N-Y, where Y is an alkyl group comprising from 1 to 4 carbon atoms,
10. The process as claimed in claim 9, in which step (a) is followed by steps: (b) of oxidation of the terminal olefin of the compound (IV) with an alkali metal permanganate, in the presence of a base, in at least one solvent chosen from aqueous pyridine, aqueous tetrahydrofuran and aqueous acetone, so as to give a compound of formula (VI),
Figure imgf000033_0001
(c) of oxidative cleavage of the compound (VI) with sodium periodate so as to form an aldehyde of formul
Figure imgf000033_0002
followed by a reaction for reductive amination of said compound (VII) with an amine of formula R-i H, or optionally one of its salts, preferentially its hydrochloride in the presence of sodium acetate, and with a reducing agent of borohydride type, for example chosen from sodium triacetoxyborohydride or sodium cyanoborohydride, so as to form the compound (VIII),
Figure imgf000034_0001
(d) of opening, in an acidic medium, of the oxazolidine ring of the compound (VIII) so as to form a compound of formula (I),
Figure imgf000034_0002
where Ri represents an amino group, or an alkylamino group where the alkyl group contains from 1 to 4 carbon atoms, or a dialkylamino group where the alkyl groups comprise from 1 to 4 carbon atoms, or a cydoalkylamino group where the cycloalkyl group comprises from 4 to10 carbon atoms, or a group of formula (V),
Figure imgf000034_0003
where the nitrogenous heterocycle is a saturated ring which comprises 5 or 6 atoms, and where X represents an oxygen atom, a sulfur atom, CH2, CH-Y, NH or N-Y, where Y is an alkyl group comprising from 1 to 4 carbon atoms, and where n, m, R2 and R3 are either all defined as in claim 1 , or all defined as in claim 2, or all defined as in claim 3, or all defined as in claim 4.
11. The process as claimed in claim 10, in which Ri represents a dimethylamino group or a morpholino group, preferentially a dimethylamino group.
12. The process as claimed in claim 1 1 , in which m=0, Ri is a dimethylamino group, n=1 and R2 IS a fluorine atom in position 3 of the pyridine ring.
13. The process as claimed in one of claims 10 to 12, in which step (b) is carried out in the presence of potassium permanganate in aqueous pyridine.
14. The process as claimed in one of claims 10 to 13, in which, in step (c), the compound (VI) is treated with sodium periodate, in aqueous pyridine, in the presence of acetonitrile.
15. The process as claimed in one of claims 10 to 14, in which, in step (c), the reducing agent is sodium triacetoxyborohydride.
16. The process as claimed in one of claims 10 to 15, in which, in step (d), the opening, in acidic medium, of the oxazolidine ring of the compound (VIII) is carried out by means of an organic or inorganic acid, in an organic solvent, preferentially at a temperature between -10°C and 60°C.
17. The process as claimed in one of claims 10 to 16, in which the acid is chosen from hydrochloric acid, sulfuric acid, acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, used alone or as a mixture, and in which the organic solvent is chosen from alcohols, ethers, esters, halogenated aliphatic hydrocarbons, aromatic hydrocarbons and nitriles.
18. The process as claimed in one of claims 10 to 17, in which, in step (d), the opening, in acidic medium, of the oxazolidine ring of the compound (VIII) is carried out with aqueous hydrochloric acid in methanol.
19. A compound of formula (VI)
Figure imgf000036_0001
where n, m, R2 and R3 are either all defined as in claim 1 , or all defined as in claim 2, or all defined as in claim 3.
A compound of formula (VI) bis
Figure imgf000036_0002
A compound of formula (VII)
Figure imgf000036_0003
where n, m, R2 and R3 are either all defined as in claim 1 , or all defined as in claim 2, or all defined as in claim 3.
22. A compound of formula (VII) bis
Figure imgf000037_0001
23. A compound of formula (VIII)
Figure imgf000037_0002
where n, m, R2 and R3 are either all defined as in claim 1 , or all defined claim 2, or all defined as in claim 3.
A compound of formula VIII) bis
Figure imgf000037_0003
25. The process as claimed in claim 9, in which step (a) is followed by steps: (e) of opening, in an acidic medium, of the oxazolidine ring of the compound (VI) so as to form a compound of formula (IX),
Figure imgf000038_0001
(f) of oxidation of the terminal olefin of the compound (IX) with an alkali metal permanganate, in the presence of a base, in at least one solvent chosen from aqueous pyridine, aqueous tetrahydrofuran and aqueous acetone, so as to give a compound of formula (X),
Figure imgf000038_0002
(g) of oxidative cleavage of the compound (X) with sodium periodate so as to form an aldehyde of formula (XI),
Figure imgf000038_0003
followed by a reaction for reductive amination of said compound (XI) with an amine of formula R-iH, or optionally one of its salts, preferentially its hydrochloride in the presence of sodium acetate, and with a reducing agent of borohydride type, for example chosen from sodium triacetoxyborohydride or sodium cyanoborohydride, so as to form the compound (I),
Figure imgf000039_0001
where Ri represents an amino group, or an alkylamino group where the alkyl group contains from 1 to 4 carbon atoms, or a dialkylamino group where the alkyl groups comprise from 1 to 4 carbon atoms, or a cycloalkylamino group where the cycloalkyl group comprises from 4 to10 carbon atoms, or a group of formula (V),
Figure imgf000039_0002
where the nitrogenous heterocycle is a saturated ring which comprises 5 or 6 atoms, and where X represents an oxygen atom, a sulfur atom, CH2, CH-Y, NH or N-Y, where Y is an alkyl group comprising from 1 to 4 carbon atoms, where n, m, R2 and R3 are either all defined as in claim 1 , or all defined as in claim 2, or all defined as in claim 3, or all defined as in claim 4.
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