Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/73—Unsubstituted amino or imino radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/52—Two oxygen atoms

Definitions

• the subject of the present invention is a new process for the preparation of enantiomerically pure compounds of N- (pyridinyl) -2-hydroxyalkylamide type corresponding to the following general formula (C)
• R'i represents a halogen atom
• R '2 represents an alkoxy-C 6
• R ' 3 and R' 4 which may be identical or different, represent a C 1 -C 4 alkyl
• R ' 2 C1-C6 alkoxy
• the method la disclosed in the application WO 2013/06468 1, also has the disadvantage of generating byproducts difficult to eliminate due to the use of an excess of certain reagents such as dicyclohexyl carbodiimide (DCC).
• DCC dicyclohexyl carbodiimide
• a first object of the invention is therefore a process for the preparation of an enantiomerically pure compound corresponding to the general formula (C),
• Ri represents a halogen atom, preferably Ri is bromine,
• R 2 represents a C 1 -C 4 alkyl, preferably R 2 is a methyl
• - R 3 represents a C 1 -C 2 alkyl, preferably R 3 is a methyl
• R 4 represents a C 3 -C 6 alkyl, preferably R 4 is an isobutyl, and said process comprising the following successive steps a) reacting in a halogenated solvent a chiral ⁇ -hydroxy acid intermediate of the formula
• step d) treatment of the reaction medium obtained in step d) comprising: i. a decantation step followed by filtration of the organic phase on activated carbon, and
• the process according to the invention makes it possible to lead to an enantiomerically pure compound corresponding to the general formula (C) whose asymmetric carbon asymmetric configuration is R or S, preferably S.
• This first embodiment has the advantage of achieving the synthesis of an enantiomerically pure compound corresponding to the general formula (I) at the scale of one kilogram and without resorting to a chiral chromatography step.
• This method of synthesis makes it possible to obtain a product in crystallized form, which facilitates its manipulation.
• the yields are better than those obtained with the method described in the application WO 2013/06468 1, which also makes the process more economically profitable.
• a second subject of the invention is a process, according to reaction scheme 5, for the preparation of the chiral ⁇ -hydroxy acid intermediate of general formula (A),
• R 3 represents a C 1 -C 2 alkyl, preferably R 3 is a methyl,
• R 4 represents a C 3 -C 6 alkyl, preferably R 4 is an isobutyl, and
• the absolute configuration of the asymmetric carbon is R or S, preferably S, said process comprising the following successive steps: a) stirring a solution comprising a cyanation agent and a ketone of general formula (Al) (A1)
• a chiral catalyst such as 2,2 '- ((1E, E) - (((1R, 2R) -cyclohexane-1,2-diyl) bis (azanylylidene) bis (methanylylidene) bis-4-bromophenolate of ethylaluminum (D) and ⁇ , ⁇ -dimethylaniline N-oxide as cocatalyst when the agent cyanation is a trialkylsilyl cyanide,
• R 5 represents a phenyl or a naphthyl, unsubstituted or substituted by a radical selected from the list comprising a methyl, a methoxy, a halogen and a nitro, and
• R 6 represents a C1-C3 alkyl
• This second embodiment has the advantage of preparing the chiral ⁇ -hydroxy acid intermediate of general formula (A) without resorting to a chiral phase chromatography step, a step that is generally difficult to implement on an industrial and expensive scale.
• a third subject of the invention is a process, according to reaction scheme 6, for the preparation of the aromatic intermediate of general formula (B),
• R 1 represents a halogen atom, preferably R 1 is bromine, and
• R 2 represents a C1-C4 alkyl, preferably R 2 is a methyl, said process comprising the following successive steps: a) stirring a solution comprising citrazinic acid and a phosphoryl halide in sulfolane,
• step b) heating the product obtained in step b) in the presence of an alcoholate
• R 2 0 " until the alkoxylated intermediate product of general formula (B2) is obtained, R 2 representing a C 1 -C 4 alkyl radical,
• step d) reacting the product obtained in step c) in ammonia until an intermediate amide of general formula (B3) is obtained,
• step d) reacting the product obtained in step d) with an aqueous solution of sodium hypochlorite in the presence of sodium hydroxide until the aromatic intermediate of general formula (B).
• This third embodiment has the advantage of being able to access the aminopyridine of formula (B) without using microwaves, which makes it possible to produce lots of several kilograms.
• R'i represents a halogen atom
• R '2 represents an alkoxy-C 6
• R ' 3 and R' 4 which may be identical or different, represent a C 1 -C 4 alkyl
• X represents CH.
• This method has the disadvantage of not being extrapolable on an industrial scale. On the other hand, it makes it possible to obtain only small quantities of each enantiomer, of the order of one gram. In addition, the enantiomers are obtained in the oily state and are therefore difficult to manipulate.
• the Applicant has developed a method of preparation for directly obtaining the enantiomers corresponding to the racemic compounds of general formula (I) without having recourse to chiral column separation.
• This method has the advantage of obtaining large quantities of enantiomer (of the order of several tens of kilograms) by carrying out several synthesis steps within the same reactor (so-called “one-pot” or “one-pot” reactions). a single pot), without isolating the reaction intermediates and isolating the final enantiomer in the crystalline state.
• a first object of the invention consists in preparing an enantiomerically pure compound corresponding to the general formula (C), in which:
• R 1 represents a halogen atom, preferably R 1 is bromine,
• R 2 represents a C 1 -C 4 alkyl, preferably R 2 is a methyl,
• R3 represents an alkyl-C 2, preferably R3 is methyl
• R 4 represents a C 3 -C 6 alkyl, preferably R 4 is an isobutyl, and according to a process comprising the following successive steps a) reacting in a halogenated solvent a chiral ⁇ -hydroxy acid intermediate of formula (A) )
• step d) treatment of the reaction medium obtained in step d) comprising: i. a decantation step followed by filtration of the organic phase on activated carbon, and
• enantiomerically pure compound a compound whose asymmetric carbon asymmetric configuration is R or S. In other words, the process according to the invention does not lead to a racemic mixture.
• Step a) of this process is carried out in a halogenated solvent.
• halogenated solvent is meant a halogenated hydrocarbon, for example a chlorinated hydrocarbon, a fluorinated hydrocarbon or a hydrochlorofluorocarbon (HCFC, a group of molecules containing chlorine, fluorine and carbon).
• chlorinated solvent mention may be made of chloroform, chlorobenzene, trichlorethylene (TCE), 1,2-dichloroethane, methylene chloride (dichloromethane), tetrachlorethylene (perchlorethylene) (PER), 1,1,1-trichloroethane (methylchloro form) .
• the chlorinated hydrocarbon is selected from dichloromethane, chloroform, 1,2-dichloroethane and chlorobenzene.
• the chiral ⁇ -hydroxy acid reaction intermediate (A), previously prepared, is dissolved in the halogenated solvent in the presence of an aminated organic base.
• the substituents R 3 and R 4 of the chiral ⁇ -hydroxy acid reaction intermediate (A) are chosen, respectively, from C 1 -C 2 alkyls and C 3 -C 6 alkyls.
• R 3 is methyl and R 4 is isobutyl.
• the configuration of the asymmetric center is (S).
• amino acid base means an amine corresponding to the general formula RaRbRcN, cyclic or acyclic, in which Ra, Rb and Rc represent hydrocarbon radicals which may or may not form a ring with the nitrogen atom.
• Ra, Rb and Rc represent hydrocarbon radicals which may or may not form a ring with the nitrogen atom.
• tributylamine triethylamine
• pyridine 4-dimethylaminopyridine and diisopropylethylamine.
• the organic amine base is preferably 4-dimethylaminopyridine or DMAP.
• a halotrialkylsilane is added to the reaction medium in order to temporarily protect the alcohol function.
• halotrialkylsilane is meant a C 1 -C 4 trialkyl halide silane.
• trimethylsilane chloride or TMSCl is used.
• the addition of the halotrialkylsilane is carried out at a temperature between 0 ° C and 5 ° C.
• Step b) of this process is carried out without isolating the intermediate product (C 1) obtained in step a).
• step b) ⁇ , ⁇ -dimethylformamide and a chlorinating agent of the carboxylic acids are added to the reaction medium which is then stirred for 1 to 2 hours at 5 ° to 20 ° C.
• the addition of the chlorinating agent of the carboxylic acids is carried out at a temperature between 0 ° C and 5 ° C.
• chlorinating agent of carboxylic acids is meant any reagent for obtaining an acyl chloride from a carboxylic acid.
• chlorinating agents may be thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride.
• the chlorinating agent is oxalyl chloride or thionyl chloride.
• Step c) comprises adding the aromatic reaction intermediate (B) in a halogenated solvent and in the presence of an organic amine base as described above.
• halogenated solvent dichloromethane is preferred and as the organic amine base, pyridine is preferred.
• the substituents R 1 and R 2 of the aromatic reaction intermediate (B) are chosen, respectively, from a halogen atom and a C 1 -C 4 alkyl. Bromine is preferred as halogen and methyl as alkyl
• step d a solution of an organic or inorganic acid dissolved in an alkanol is added to the reaction medium while maintaining, preferably, the temperature below 25 ° C.
• organic acid is meant an aliphatic or aromatic carboxylic acid.
• acetic acid citric acid, trifluoroacetic acid, trichloroacetic acid, lactic acid and benzoic acid.
• the organic acid is acetic acid.
• mineral acid an acid derived from an inorganic mineral.
• hydrochloric acid sulfuric acid or nitric acid.
• the mineral acid is hydrochloric acid.
• Alcohol means a linear or branched alcohol having from 1 to 6 carbon atoms. As examples, mention may be made of ethanol, isopropanol and propanol.
• the alcohol is ethanol.
• the last step e) of this process consists in treating the reaction medium in order to isolate the enantiomerically pure compound corresponding to the general formula (C).
• This step optionally comprises a step of adding an aqueous solution of a mineral acid to the reaction medium obtained in step d).
• hydrochloric acid is used.
• a saturated hydrocarbon is then added to the clarified organic phase, the medium is heated, refluxed to distil a portion of the solvents, and then is cooled to between 20 ° and 30 ° C.
• the enantiomerically pure compound having the general formula (C) crystallizes. It is isolated by filtration.
• saturated hydrocarbon is meant an alkane, cyclic or acyclic, in the liquid state at room temperature.
• the saturated hydrocarbon is a C5-C12 cyclic or acyclic alkane.
• cyclohexane will be selected.
• one of the advantages of this process is to carry out several consecutive steps "in a single pot", without isolating any reaction intermediate, and to obtain directly the enantiomerically pure compound having the general formula (C) in crystallized form, without having use of a step of chiral chromatography, with yields greater than 65% and amounts of the order of several kilograms.
• a second subject of the invention is a process for preparing the chiral ⁇ -hydroxy acid intermediate of general formula (A),
• R3 represents a C1-C2 alkyl, preferably R3 is a methyl,
• R 4 represents a C 3 -C 6 alkyl, preferably R 4 is an isobutyl,
• the absolute configuration of the asymmetric carbon is R or S, preferably S, said process comprising the following successive steps: a) stirring a solution comprising a cyanation agent and a ketone of general formula (Al)
• a chiral catalyst such as 2,2 '- ((1 ⁇ , 1 ⁇ ) - (((1R, 2R) -cyclohexane-1,2-diyl) bis (N-Oxidyl) (N-oxide) bis (4-methylbenzene) bis-4-bromophenolate and N, N-oxide as a cocatalyst when the cyanation agent is a trialkylsilyl cyanide at a temperature between 15 and 25 ° C,
• a chiral catalyst such as 2,2 '- ((1 ⁇ , 1 ⁇ ) - (((1R, 2R) -cyclohexane-1,2-diyl) bis (N-Oxidyl) (N-oxide) bis (4-methylbenzene) bis-4-bromophenolate and N, N-oxide as a cocatalyst when the cyanation agent is a trialkylsilyl cyanide at a temperature between 15 and 25 °
• R 5 represents a phenyl or naphthyl aromatic ring unsubstituted or substituted by a radical selected from the list comprising a methyl, a methoxy, a halogen and a nitro, and
• R 6 represents a C1-C3 alkyl
• reaction scheme 5 The process corresponding to this second subject of the invention is represented by the reaction scheme 5.
• step a) consists of cyanation of the starting ketone (Al) and step b) consists of hydrolyzing the intermediate cyanohydrin in an acidic medium in order to obtain a ⁇ -hydroxy acid of general formula ( V).
• step a Two particular embodiments can be followed concerning step a).
• the ketone (Al) is reacted with a cyanation agent in water or in a halogenated solvent as defined above.
• cyanation agent a cyanide of formula XCN in which X represents a sodium, potassium or trialkylsilyl radical.
• the cyanation agent is sodium cyanide.
• This first embodiment provides, after acid hydrolysis (step b)), for example using sulfuric acid or hydrochloric acid, a racemic mixture of ⁇ -hydroxy acid of general formula (V).
• cyanation agent is a trialkylsilyl cyanide
• a chiral metal catalyst whose ligand has the following structure (A4a) or (A4b) is used to induce an enantiomeric excess of ⁇ -hydroxy acid of general formula (V) after hydrolysis of cyanohydrin:
• the preferred trialkylsilyl cyanide is trimethylsilyl cyanide.
• Aluminum is the preferred metal for use with the structural ligand (A4a) or (A4b) to form the chiral metal catalyst.
• the preferred chiral metal catalyst is 2,2 '- ((1 ⁇ , 1 ⁇ ) - (((1 R, 2 R) -cyclohexane-1,2-diyl) bis (azanylylidene)) bis (methanylylidene) bis) 4-bromopheno late ethylaluminum (D)
• N-oxide co-catalyst is also used together with the chiral metal catalyst whose ligand has the structure (A4).
• N-oxide co-catalysts that can be used in this embodiment are described in Fu-Xue Chen et al., Chem.Eur.J., 2004, 74, 4790-4797.
• the Fu-Xue Chen et al. Document describes enantioselective cyano silylation reactions of ketones catalyzed by aluminum complexes and an N-oxide.
• the temperature used in steps a) and b) is between 15 and 25 ° C, even more preferably between 20 and 23 ° C.
• This second embodiment allows, after acid hydrolysis (step b)), to obtain a mixture of ⁇ -hydroxy acid of general formula (V) enantiomerically enriched in one of the two enantiomers, the formation of the majority enantiomer being related to the use of a chiral catalyst.
• the enantiomeric excess obtained is between 40% and 90%, preferably between 50% and 70%.
• Step c) consists of separating the enantiomers of ⁇ -hydroxy acid of general formula (V) obtained in racemic form or in enriched form and isolating one of the two enantiomers. We speak of resolution or resolution of enantiomers.
• This resolution is induced by an optically pure auxiliary of structure (A2), that is to say that a mixture of enantiomers of ⁇ -hydroxy acid of general formula (V) is reacted with this optically pure auxiliary of structure ( A2).
• the mixture of enantiomers (V) becomes a mixture of two diastereoisomers of structures (A3a) and (A3b) which can be more easily separated by conventional physicochemical techniques such as crystallization.
• the diastereoisomer (A3a) is insoluble and crystallizes preferentially with respect to the diastereoisomer (A3b) which remains in solution.
• the optically pure auxiliary is a chiral amine of structure (A2).
• This optically pure chiral amine is, for example, chosen from the list comprising ⁇ -methylbenzylamine ( ⁇ -MBA) or 1-phenylethylamine, ⁇ -ethylbenzylamine ( ⁇ -EBA), t-zreo-2-amino-1-p -Nitrophenyl) -1,3-propanediol (TANP), 1- (2-naphthyl) ethylamine (NEA), phenylglycine and further a sodium, potassium or lithium salt of phenylglycine.
• (S) -1-phenylethylamine (a-MBA, structure (A2) where R5 is phenyl and R6 is methyl) or (R) -1- (2-naphthyl) ethylamine (NEA, structure ( A2) for which R 5 represents a naphthyl and R6 represents a methyl).
• the chiral amine of preferred structure (A2) is (S) -1-phenylethylamine.
• the molar ratio between ⁇ -hydroxy acid of general formula (V) and the chiral amine of structure (A2) is preferably of the order of 1.
• ⁇ -hydroxy acid of general formula (V) obtained in stage b) is a racemic mixture
• the use of a molar equivalent of chiral amine of structure (A2) makes it possible to obtain a diastereoenriched mixture of compound ( A3a).
• a single recrystallization of the above mixture in a solvent such as ethyl acetate is sufficient to obtain the compound (A3a) enantiopur.
• Step d) consists in hydrolysing the diastereoisomer of formula (A3a) in the presence of a mineral acid so as to generate a chiral ⁇ -hydroxy acid of general formula (A) enantiomer pure.
• the ⁇ -hydroxy acid of general formula (V) obtained in step b) is a mixture enriched in one of the two enantiomers
• the addition of a molar equivalent of chiral amine of structure (A2) makes it possible to obtain directly after crystallization the diastereoisomer (A3a) enantiomer pure.
• this particular embodiment has the additional advantage of leading to a better mass yield.
• a third subject of the invention is a process, according to scheme 3, for the preparation of the aromatic intermediate of general formula (B),
• R 1 represents a halogen atom, preferably bromine
• R 2 represents a C1-C4 alkyl, preferably a methyl, said process comprising the following successive steps: a) stirring a solution comprising citrazinic acid and a phosphoryl halide PO (Ri) 3 in sulfolane,
• step b) heating the product obtained in step b) in the presence of an alkoxide R 2 0 " until an alkoxylated intermediate product of general formula (B2) is obtained, R 2 representing a C 1 -C 4 alkyl radical,
• step d) reacting the product obtained in step c) in ammonia until an intermediate amide of general formula (B3) is obtained,
• step d) reacting the product obtained in step d) with an aqueous solution of sodium hypochlorite in the presence of sodium hydroxide until the aromatic intermediate of general formula (B) is obtained.
• step a) consists in carrying out a halogenation of citrazinic acid in the presence of a phosphoryl halide PO (Ri) 3 and of sulfolane.
• the phosphoryl halides used are phosphoryl bromide or chloride. It will be preferred to use phosphoryl bromide.
• the amount of phosphoryl used is preferably between 1 and 4 molar equivalents relative to citrazinic acid, preferably between 1.5 and 3, and even more preferably 1.5.
• the temperature is preferably between 90 ° C and 140 ° C, preferably between 120 ° C and 130 ° C, and even more preferably, it is 125 ° C.
• the amount of sulfolane used is between 2.5 and 8 volumes of sulfolane relative to citrazinic acid.
• One volume corresponds to one liter of solvent per kilogram of citrazinic acid.
• 5 volumes of sulfolane will be used
• sulfolane has the advantage of controlling the exothermicity of this reaction and of having a better impurity profile.
• step b) is carried out directly on the reaction medium obtained in step a).
• step b) a C1-C4 alcohol R 2 -OH is introduced into the reaction medium.
• Step b) makes it possible to obtain the intermediate (B1) or alkyl 2,6-dihalogenoisonicotinate.
• the preferred (B1) intermediate obtained is methyl 2,6-dibromoisonicotinate.
• Step c) consists in substituting only one of the two halogens of the intermediate (B1) with a C1-C4 alkoxy R20-. This reaction is carried out in the presence of 1 molar equivalent of R20- alcoholate in an ethereal organic solvent.
• ethereal solvents examples include tetrahydrofuran (THF) or methyl tetrahydrofuran (MeTHF). These solutions are or can be prepared according to methods well known to those skilled in the art.
• the temperature of this reaction is between 40 ° C and 70 ° C, preferably 60 ° C. This reaction makes it possible to isolate the intermediate (B2) or 2-halo-6-alkoxyisonicotinate alkyl.
• the preferred alcoholate is sodium methoxide.
• the preferred (B2) intermediate is methyl 2-bromo-6-methoxyisonicotinate.
• Step d) consists in converting the ester function of the intermediate (B2) to an amide function.
• This step d) is carried out in the presence of ammonia.
• the amide formed is generally insoluble in the medium, which allows it to be filtered.
• the 2-halo geno-6-alkoxyisonicotinamide intermediate of structure (B3) is thus isolated.
• the preferred (B3) intermediate is 2-bromo-6-methoxyisonicotinamide.
• Step e) which consists in converting the amide function of (B3) to an amine function.
• This step is carried out in water in the presence of sodium hydroxide.
• An aqueous solution of sodium hypochlorite is added to the reaction medium maintaining the temperature between 0 ° C and 10 ° C.
• the reaction medium is then heated between 50 ° C and 80 ° C until complete transformation of the amide (B3).
• the reaction medium is then cooled between 0 ° C. and 10 ° C. and then acidified by addition of a hydrochloric acid solution.
• the 2-halo-4-amino-6-alkoxy pyridine of structure (B) precipitates in the reaction medium. It is isolated by filtration.
• the preferred intermediate (B) is 2-bromo-4-amino-6-methoxy pyridine.
• the reaction medium is cooled to 30 ° C., then washed successively with a saturated solution of NaHCO 3 (8.0 L), then again with a saturated solution of NaHCO 3 (2.0 L), and finally with a saturated solution of NaCl (3.0 L). ).
• the solid is filtered, rinsed with isopropanol (1.2 L).
• Step 1 Synthesis of (S) - 1-phenylethylammonium (S) -2-hydroxy-2,4-dimethylpentanoate (2.1)
• the organic phase is heated to 70-75 ° C and then a solution of 33% hydrochloric acid (1712 Kg) is added, and the reaction mixture is refluxed for 3 hours.
• the medium is concentrated (distillate 250L) then the mixture is cooled to 50 ° C and water (248 Kg) is added.
• the aqueous phase is extracted with MTBE (3X579 Kg).
• the organic phases are combined and washed with water (257 kg).
• the organic phase is concentrated (distilled 821 kg) and then cooled to 25 ° C.
• (S) -1-Phenylethylamine (283 Kg) is added maintaining the temperature below 25 ° C.
• the reaction mixture is cooled to 10 ° C.
• Ethylaluminum (((1R, 2R) -cyclohexane-1,2-diyl) bis (azanylylidene) bis (methanylylidene) bis-4-bromophenolate (Catalyst (D)) (55.92 g, 104.67 mmol, 0.004 eq) ) in methyl isobutyl ketone (3276.25 ml, 26.17 mol, 1.00 eq.) and dichloromethane (7.86 L) is stirred for 1 hour. This solution is added to the trimethylsilyl cyanide solution at 20-23 ° C. and then stirred for one hour at this temperature.
• the reaction medium is concentrated to the minimum stirrable, then a mixture of heptane / ethyl acetate (80/20) and 1% diisopropylethylamine (3L) is added.
• This solution is filtered on a filter packed with a thin layer of silica, then rinsed with a mixture of heptane / ethyl acetate (80/20) and 1% diisopropylethylamine (IL), the filtrate is loaded into the reactor then concentrated under reduced pressure to afford 2,4-dimethyl-2 - ((trimethylsilyl) oxy) pentanenitrile as a pale yellow liquid; (4772 g, 91.5%).
• reaction mixture is stirred for one hour at this temperature and then N, N-dimethylformamide (27.50 ml, 0.36 mol, 0.02 eq.) Is added.
• the reaction mixture is heated to 20 ° C and stirred for one hour at this temperature.
• an aqueous solution of hydrochloric acid (2.4 L, 12.00 M, 28.77 mol, 0.78 V) in water (27 L) is prepared and then poured on the reaction medium, and then stirred for 10 minutes.
• the aqueous phase is discarded, then the organic phase is washed with water (30 L).
• the aqueous phase is discarded and the organic phase is washed again with a solution prepared from NaOH (1177.29 g, 29.43 mol, 1.40 eq.) In water (30L).
• the aqueous phase is discarded and the organic phase is washed again with water (30 L).
• the aqueous phase is discarded.
• the organic phase is clarified on a filter packed with activated carbon (921 g) and the cake is washed with dichloromethane (10L).
• the filtrate is then charged into the reactor and then concentrated to reflux, distillate (37L).
• Cyclohexane (43 L) is added to the reactor and heated under reflux until the overhead temperature reaches 75 ° C (distilled volume 22.5 L). Cyclohexane (10 L) is added and the reactor is allowed to cool to 27 ° C.
• a primer of (S) -N- (2-bromo-6-methoxypyridin-4-yl) -2-hydroxy-2,4-dimethylpentanamide (138 g, 0.42 mol, 0.02 eq.) Is added to promote crystallization.
• the reaction mixture is cooled to 20 ° C and then filtered through a 25 micron cloth filter.
• the medium is then stirred at room temperature for 2 hours.
• the solution is then added to the reaction medium.
• the addition funnel is rinsed with acetonitrile.
• the reaction medium is stirred at room temperature.
• a first test is carried out by means of liquid chromatography (HPLC) combined with a mass analysis after one hour.
• HPLC liquid chromatography
• the reaction medium is stirred overnight at room temperature at the end of which a second control is performed.
• the desired end product is not detected. Only the starting products are detected. The test is stopped.

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Family Applications (1)

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• 2015
  • 2015-11-30 FR FR1561602A patent/FR3044311B1/fr not_active Expired - Fee Related
• 2016
  • 2016-11-08 WO PCT/EP2016/076962 patent/WO2017092977A1/fr active Application Filing
  • 2016-11-08 EP EP16794298.6A patent/EP3383850A1/de not_active Withdrawn
  • 2016-11-08 US US15/780,164 patent/US10343999B2/en active Active

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