Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
  • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C311/09—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton the carbon skeleton being further substituted by at least two halogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B53/00—Asymmetric syntheses
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
  • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
  • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
  • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
  • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the main object of the present invention is new compounds 5 of diamine, mono- or polyfluorinated, sulfonylated or carbonylated type, their preparation process and their application in asymmetric catalysis.
• the claimed compounds are particularly advantageous in their optically active form as ligands of organometallic complexes.
• the corresponding metal complexes are in particular advantageous as catalysts for carrying out the asymmetric synthesis.
• optically active secondary alcohol derivatives are reagents which are particularly sought after in many fields, in particular pharmaceutical, agrochemical or perfumery. 0
• inactive enantiomer from which it is necessary to isolate the desired enantiomer.
• This catalyst is derived from the metal complex RuCI 2 (-7 6 mesitylene) 2 . This is used in a form chelated by a diphenylethylenediamine derivative of formula A
• Ra represents a radical chosen from C 6 H 5 CO-, pCH 3 OC 6 H 4 S0 2 -, C 6 H 5 SO 2 - and CF 3 S0 2 -.
• CF 3 S0 2 - which is considered to be the least interesting ligand in terms of enantioselective yield.
• the object of the present invention is precisely to propose new diamine derivatives or the like capable of constituting effective chiral ligands for asymmetric synthesis and in particular for asymmetric hydrogenation of ketone functions.
• - B represents (i) -CO-, or ( ⁇ ) -S0 2 -, - Rf represents
• - Y represents an OH, SH, NH 2 , NHR B or NR B R C group , with R B and R c different from a hydrogen atom and representing independently of one another a radical chosen from:
• an alkyl chain preferably from C to C 10 , optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more halogen atoms or carboxyl groups,
• an alkenyl chain preferably C 2 to C 10 , optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more atom (s) d halogen or carboxyl group (s);
• an aryl group preferably C 6 to C 12 , optionally substituted by one or more halogen atom (s) or alkyl or alkenyl group (s);
• an arylalkyl group preferably from C 7 to -I5, optionally substituted by one or more halogen atom (s);
• R - R 'and R independently of one another represent a hydrocarbon radical having from 1 to 20 carbon atoms which can be an acyclic saturated or unsaturated, linear or branched aliphatic radical; a saturated, unsaturated, aromatic cycloaliphatic radical, monocyclic or polycyclic incorporating or not incorporating one or more heteroatoms provided that when B represents a group S0 2 , na for zero, Rf represents a group CF 3 , Y represents a group NH 2 then R 'and R "do not simultaneously represent a unsubstituted phenyl ring; said cycloaliphatic radical optionally carrying a saturated or unsaturated, linear or branched aliphatic radical with the alkyl chain which can be interrupted by one or more oxygen atoms and / or carbonyl function and where appropriate preferably substituted at the end of chain by an aromatic or non-aromatic cyclic radical; said radicals possibly being substituted by one or more halogen atoms,
• - X represents a methylene group optionally substituted
• - n is an integer varying from zero to 3
• Ar, and Ar 2 symbolize, independently of one another, two substituted or unsubstituted aromatic rings, condensed or not and optionally carrying one or more heteroatoms, preferably C 6 to C 12 and which can form ortho systems or ortho and peri-condensed between them,
• derivatives is intended to cover in particular the organic or mineral salts of the compounds of formula I as well as their racemic mixtures and their optically active isomers.
• the electron-withdrawing group appearing on the nitrogen atom of the amine function of the general formula I is represented by a group BRf in which Rf represents (i) a halogen atom, preferably fluorine, (ii) a C 1 to C 10 preferably C 2 to C 6 alkyl or a C 3 to C 10 preferably C 6 to cycloalkyl radical, mono-, poly- or perhalogenated,
• Rf represents a radical CF 3 , C n F 2n + 1 with n representing an integer equal to or greater than 2 such as for example C 4 F 9 or a phenyl radical substituted by one or more halogen atoms, preferably fluorine , or by one or more mono-, poly- or perfluorinated CC 2 alkyl groups.
• groups Y there may be mentioned more particularly the radicals NH 2 and NHR B , with R B as defined above.
• the halogen atom (s) mentioned as a substituent are preferably represented by a fluorine atom.
• the compounds of general formula I correspond to the general formula l'b
• R f. ( ⁇ ). (y) and Y are such ⁇ ue defined above and A and Ar 2 together represent an aromatic group.
• aromatic means the conventional notion of aromaticity as defined in the literature, including J. March “Advanced Organic Chemistry", 4 th ed., John Wiley & Sounds, 1992, pp 40 and following.
• the aromatic derivative can be monocyclic or polycyclic.
• a monocyclic derivative it can comprise, at the level of its cycle, one or more heteroatoms chosen from nitrogen, phosphorus, sulfur and oxygen atoms. According to a preferred mode, they are nitrogen atoms.
• the carbon atoms of the aromatic derivative can also be substituted.
• Two vicinal substituents present on the aromatic ring can also form together with the carbon atoms which carry them a hydrocarbon ring, preferably aromatic and comprising, where appropriate, at least one heteroatom.
• the aromatic derivative is then a polycyclic derivative.
• these compounds correspond to the general formula a
• R - R 'and R independently of one another represent a carbocyclic or heterocyclic radical, saturated, unsaturated, aromatic, monocyclic or polycyclic, provided that when n is zero, Rf represents a group CF 3 , Y a group NH 2 then R 'and R "do not simultaneously represent an unsubstituted phenyl ring or R' and R" can be linked so as to constitute, with the carbon atoms carrying them, a carbocyclic or heterocyclic radical having 4 to 20 atoms saturated , unsaturated, aromatic, monocyclic or polycyclic.
• Y represents an NH 2 or NHR B radical, with R B as defined above.
• R 'and R " identical or different, can take various meanings. Different examples are presented below, but they are in no way limiting.
• R 'and R " can represent, independently of each other, an acyclic, saturated or unsaturated, linear or branched aliphatic radical. More precisely, R' and R" represent an aliphatic, acyclic, linear or branched radical having preferably from 1 to 12 carbon atoms, saturated or comprising one to several, generally 1 to 3, double bonds.
• the hydrocarbon chain may optionally be interrupted by a group, preferably a heteroatom, and more particularly, an oxygen or nitrogen atom or alternatively carrying substituents, for example, a halogen atom, in particular, chlorine or a group -CF 3 .
• This acyclic, saturated or unsaturated, linear or branched aliphatic radical may optionally carry a cyclic substituent.
• cycle is meant a carbocyclic or heterocyclic, saturated, unsaturated or aromatic cycle.
• cyclic substituents it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic, substituents comprising 6 carbon atoms in the ring or benzenic, these cyclic substituents possibly being themselves carriers of one or more substituents.
• radicals mention may in particular be made of the benzyl radical.
• radicals R 'and R can also represent, independently of one another, a carbocyclic radical saturated or comprising 1 or 2 unsaturations in the ring, generally having 3 to 8 atoms carbon, preferably 6 carbon atoms in the ring, said ring possibly being substituted.
• radicals As preferred examples of this type of radicals, mention may be made of cyclohexyl radicals optionally substituted by linear or branched alkyl radicals having from 1 to 4 carbon atoms.
• R 'and R can also be linked to represent carbocyclic or heterocyclic, mono- or poly-cyclic, saturated, unsaturated or aromatic, preferably bicyclic, radicals which means that at least two rings have two carbon atoms in common.
• the number of carbon atoms in each cycle preferably varies between 3 and 6, the total number of carbon atoms being preferably equal to 5.
• radicals R ′ and R ′′ may represent, independently of one another according to a preferred mode, an aromatic hydrocarbon radical, and in particular benzene radical corresponding to the general formula l'c
• - n ' represents an integer from 0 to 5 and
• a linear or branched alkyl radical having from 1 to 4 carbon atoms “a linear or branched alkoxy radical having from 1 to 4 carbon atoms,
• R ′ and R ′′ can also represent, independently of one another, a polycyclic aromatic hydrocarbon radical with the rings which can form between them ortho-condensed, ortho and pericondensed systems. Mention may more particularly be made of a naphthyl radical; said ring can be substituted.
• R 'and R can also represent, independently of each other, a heterocyclic radical, saturated, unsaturated or aromatic, comprising in particular 5 or 6 atoms in the ring including one or two heteroatoms such as nitrogen, sulfur atoms and oxygen; the carbon atoms of this heterocycle can also be substituted.
• heterocyclic type R ′ and R ′′ groups include, among others, the furyl, pyrrolyl, thienyl, isoxazolyl, furazannyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, piridazinyl, pyrimidinyl, pyrannyl radicals and the quinolyl radicals. , naphthyridinyl, benzopyrannyl, benzofurannyl, indolyl.
• the number of substituents present on each cycle depends on the carbon condensation of the cycle and on the presence or not of unsaturation on the cycle. The maximum number of substituents capable of being carried by a cycle is easily determined by a person skilled in the art.
• n has the value 0.
• the compounds of general formula I are particularly advantageous when they are in an optically active form.
• Another subject of the invention lies in the process for the preparation of the compounds of general formula I.
• the second subject of the present invention is a process for the preparation of a compound of general formula I in which a compound of general formula II is reacted
• Rf and B being as defined above and X 'representing a halogen atom, preferably chlorine or fluorine or also in the case where B represents S0 2 an OS0 2 Rf group and in that one recovers said compound of general formula I.
• the reaction can be carried out in a usual organic solvent and preferably in dichloromethane or 1,2-dichloroethane.
• the temperature is generally between 0 ° C and the reflux of the solvent and is preferably close to or equal to room temperature.
• reaction is carried out at atmospheric pressure.
• reaction it is also preferred to carry out the reaction under an atmosphere composed of inert gases such as nitrogen or rare gases, for example argon. From a practical point of view, the process can be carried out batchwise or continuously.
• inert gases such as nitrogen or rare gases, for example argon.
• a practical embodiment consists in loading the derivative of formula II into the solvent and then slowly adding to it the sulfonylating agent of formula III. The reaction is carried out for a sufficient time to obtain the transformation of the product of formula 11 into formula I. The final compound is isolated by conventional techniques of reaction medium.
• the compounds of general formula I, a and l'b are very particularly advantageous in their optically active form.
• the present invention also relates to the use of a compound of general formulas I, a and b, in an optically active form for the preparation of ligands of catalytic metal complexes useful for carrying out asymmetric syntheses in organic chemistry.
• the compounds of formulas I, a and l'b, in an optically active form thus prove to be very particularly useful for the preparation of ligands of catalytic metal complexes useful for carrying out an asymmetric enantioselective hydrogenation of ketone derivatives. It has also been shown that these same compounds of general formulas I, a and b, in an optically active form, could be used to prepare ligands of catalytic metal complexes useful for carrying out an enantioselective oxidation of hydroxyl functions.
• the present invention also relates to a metal complex based on a transition metal and comprising as ligand of said metal at least one optically active form of a compound of general formulas I, a and l b, as defined above.
• transition metals capable of forming complexes in accordance with the present invention, mention may be made in particular of metals such as rhodium, ruthenium, rhenium, iridium, cobalt, nickel, platinum, palladium.
• rhodium, ruthenium and iridium are preferred.
• M is a transition metal chosen from rhodium, ruthenium, rhenium, iridium, cobalt, nickel, platinum and paladium,
• - L represents an unsaturated aliphatic ligand comprising at least one double bond or a carbocyclic or heterocyclic ligand preferably of 5 to 8 atoms and comprising at least one double bond, charged or not.
• - M represents ruthenium, rhodium or iridium
• Z represents a halogen atom, preferably chlorine or bromine
• - L represents a C 6 to C 12 aromatic ligand or a cyclopentadienyl or cyclooctatriene ligand substituted where appropriate by one or more C 4 to C 4 alkyl groups.
• this complex corresponds to the general formula IVa
• R - R 'and R independently of one another represent a C, C 20 to saturated, unsaturated, aromatic, monocyclic or polycyclic carbocyclic or heterocyclic radical as defined above, provided that when Rf represents a group CF 3 , Y an NH 2 group then R 'and R "do not simultaneously represent an unsubstituted phenyl ring or R' and R" are linked together so as to constitute, with the carbon atoms carrying them, a carbocyclic or heterocyclic radical of 4 with 20 atoms saturated, unsaturated, aromatic, monocyclic or polycyclic, and
• halogen atom preferably fluorine
• alkyl C, -C 10 cycloalkyl or C 3 -C 10 poly- or per-halogenated
• Y represents an NH 2 or NHR B radical, with R B as defined above.
• - Z is a chlorine atom or a bromine atom
• the complexes according to the present invention having, as ligand, a compound chosen from (1 S, 2S) -N-trifluoromethanesulfonyl-1, 2-cyclohexanediamine, (1 S.2S) - N-trifluoromethanephenylsulfonyl- 1, 2-cyclohexanediamine, le (1S, 2S) -N- N- (Nonafluorobutanesulfonyl) -1, 2-diphenylethylenediamine, le (1 S, 2S) -N- (Nonafluorobutanesulfonyl) -1, 2 cyclohexanediamine, le (1S, 2S) -N- (pentafluorophenylsulfonyl) -1,2 cyclohexanediamine, le (1 S, 2S) -N- (pentafluorophenylsulfonyl) -1,2-diphenylethylened
• the present invention also provides a process for the preparation of said complexes comprising reacting an optically active form of a compound of general formula I as defined above with the transition metal compound retained in an appropriate organic solvent.
• the complexes comprising, as ligand, the above-mentioned compound of formula I and the transition metal can be prepared according to the known methods described in the literature.
• the reaction is generally carried out at a temperature between room temperature (15 to 25 ° C) and the reflux temperature of the reaction solvent.
• organic solvents there may be mentioned, inter alia, aliphatic hydrocarbons, halogenated or not and more particularly hexane, heptane, isooctane, decane, benzene, toluene, methylene chloride, chloroform ; solvents of ether or ketone type and in particular diethyl ether, tetrahydrofuran, acetone, methyl ethyl ketone; alcohol type solvents, preferably methanol, ethanol or isopropanol.
• the metal complexes according to the invention recovered according to conventional techniques (filtration or crystallization) are used in asymmetric hydrogenation reactions of substrates specified below.
• the present invention also relates to the use of a metal complex as defined above for carrying out asymmetric organic synthesis and more particularly the asymmetric reduction of ketone derivatives.
• ketone derivatives capable of being hydrogenated by a metal complex in accordance with the invention preferably correspond to the general formula V *
• an alkyl chain preferably from C to C 10 , optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more halogen atoms or carboxyl groups
• an alkenyl or alkynyl chain preferably C 2 to C 10 , optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more halogen atom (s) or carboxyl group (s);
• an arylalkyl group preferably from C 7 to C 15 , optionally substituted by one or more halogen atom (s);
• substituents R 2 having a center of asymmetry By way of representative of the substituents R 2 having a center of asymmetry, one can particularly mention the radicals R 2 in which the carbon atom carrying the center of asymmetry is substituted by a mono- or di-substituted amine function and by a function ester.
• a complex according to the invention to reduce a racemic mixture of ketone derivatives of this type, that is to say having in ⁇ of the ketone function a center of asymmetry, makes it possible to obtain the corresponding hydroxyl derivative by controlling the stereochemistry of two asymmetry centers. We are witnessing a kinetic dynamic resolution of the whole molecule.
• R. and R 2 represent independently of each other:
• an alkyl chain preferably from C to C 10 , optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more halogen atoms or groups carboxyl,
• an alkenyl or alkynyl chain preferably C 2 to C 10 , optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more atom (s) ) halogen or carboxyl group (s);
• an aryl group preferably C 6 to C 12 , optionally substituted by one or more halogen atom (s) or alkyl or alkenyl group (s);
• an arylalkyl group preferably from C 7 to C 15 , optionally substituted by one or more halogen atom (s);
• an arylalkenyl group preferably from C 8 to C 15 , optionally substituted by one or more halogen atom (s)
• the complex corresponds to one of the formulas IV specified above.
• the complex is generated in situ in the reaction medium of the catalytic reduction according to the process mentioned above. It is only after the complex has been prepared that the ketone derivative of formula V to be treated is added to said medium.
• the reduction of the ketone derivative is generally carried out at a temperature between 5 ° C and 100 ° C in the presence of a hydrogen donor.
• the hydrogen donor is conventionally represented by a lower secondary alcohol or a formic acid / tertiary amine mixture. Generally, this hydrogen donor is used as a solvent.
• this hydrogen donor is used as a solvent.
• the lower secondary alcohols mention may be made of 2- or 3- butanol and isopropanol.
• the complex based on the compound of general formula I and the transition metal is used at a rate of 1/10000 to 1/1 moles relative to the carbonyl compound of general formula V. It appears that the increase in the catalyst / substrate ratio has no significant effect on the enantioselectivity of the reduction.
• the reaction is preferably carried out in an organic co-solvent. Any solvent is used insofar as it is stable under the operating conditions. Use is preferably made of a polar organic solvent such as dichloromethane.
• the concentration of the substrate in the solvent advantageously varies between 0.01 and 3 moles per liter.
• a basic compound can be added.
• This basic compound can be an alkaline base such as sodium or potassium hydroxide or else a primary, secondary or tertiary amine, and more particularly pyridine, pyperidine, triethylamine, and preferably triethylamine. It activates the catalyst by generating the corresponding metal hydride.
• the use of the compounds of general formula I as ligands makes it possible to significantly improve the enantiomeric excess and the kinetics in certain asymmetric reactions, in particular in the reactions for the hydrogenation of ketone functions into secondary alcohols.
• the reaction mixture is left at room temperature (22 ° C) with stirring.
• the reaction time is listed in the table below.
• Example 5 The same reducing medium is used as in Example 5, the procedure of which is reproduced by modifying the temperature.
• Example 5 The same reducing medium is used as in Example 5, the procedure of which is reproduced by modifying the substrate / catalyst ratio.
• Example 5 The same reducing medium is used as in Example 5, the procedure of which is reproduced, but by modifying the nature of the complex. metallic.
• the selected complex is ligated with (1 S, 2S) N-trifluoromethanesulfonyl-1, 2-cyclohexanediamine.
• Example 5 The same reducing medium is used as in Example 5, the procedure of which is reproduced using either the ligand prepared in Example 1 or the ligand prepared in Example 3.
• ⁇ -ketone- ⁇ -amino acid derivatives used are the following
• RMN- 1 H 300 MHz, CDCI 3 ): ⁇ 2.84-2.86 (m, 3H, Nme), 3.62-3.91 (m, 9H, C0 2 Me, 2xOMe), 5.13-5.14 (m, 2H, ⁇ _H 2 Ph ), 6.12 and 6.40 (2s, 0.8H, CH keto), 6.58-7.62 (m, 8H, CH 2 Ph).
• ketonic amino acid 1 b is prepared from the chloride of 3,4-dimethoxybenzoic acid according to the protocol described for the derivative 1 a.
• the concentrated residue is then purified by chromatography (eluent: hexane / EtOAc 3: 1, then 2: 1) and crystallized (hexane / EtOAc) to yield a yield of 60% of derivative 1b.
• reaction medium is then extracted with ethyl acetate (15 ml) in the presence of a saturated solution of sodium bicarbonate (15 ml).
• organic phase is then washed with a sodium chloride solution (15 ml), dried over MgSO 4 and concentrated so as to yield the hydroxy derivative of the expected amino acid.
• threo-2a and erythro-2a derivatives obtained at the end of the catalytic hydrogenation are characterized by NMR:
• RMN- 1 H 300 MHz, CDCI 3 ): ⁇ 2.92 and 3.08 (2 br s, 3H, Nme), 3.69- 3.91 (m, 9H, C0 2 Me, 2xOMe), 4.71-5.39 (m, 4H, CHN , ⁇ H 2 Ph, ⁇ HOH), 6.83-6.93 (m, 3H, C 6 H 3 ), 7.15-7.35 (m, 5H, CH 2 Ph).
• RMN- 1 H 300 MHz, CDCI 3 ): ⁇ 2.58 and 2.60 (2 br s, 3H, NMe), 3.65 and 3.74 (2s, 3H, C0 2 Me), 3.80 and 3.87 (2s, 6H, 2xOMe), 4.08-4.17 (m, 1 H, CHN), 4.71 (br s, 1 H, OH), 5.04-5.26 (m. 3H, ⁇ H 2 Ph, ⁇ HOH), 6.72-6.92 (m, 3H, C 6 H 3 ), 7.24-7.39 (m, 5H, CH 2 Ph).
• the compounds 2a, b (0.5 mmol) are then deprotected according to the following protocol: They are stirred with 10% Pd-C (15 mg) and HCO 2 NH 4 (0.13 g, 4 eq.) In the methanol overnight. The mixture is then filtered through Celite, concentrated, and extracted with dichloromethane (10 ml) in the presence of a saturated solution of sodium chloride (5 ml) and a saturated aqueous solution of NaHCO 3 (2 ml). The organic phase is dried (Na 2 S0 4 ) and concentrated to yield approximately 95% of 2a, b. Before determining the enantiomeric excess by HPLC on a Chiralpack AD column, the sample is purified on a PLC plate (CH 2 CI 2 / EtOH 40: 1). The products thus obtained are characterized by NMR.
• Table 5 reports the operating conditions in terms of time and substrate / catalyst ratio used for each chiral ligand tested and the yields of hydroxyl derivatives obtained as well as enantiomers.
• the medium is stirred under an argon atmosphere at 30 ° C.
• the first ligand has the following formula
• the second ligand has the following formula:
• a first test carried out in acetone leads to a pink reaction medium. After 5 hours at 30 ° C., 53% of 4 and an enantiomeric excess of 85% in favor of alcohol 3b are obtained in area percentage.
• the aqueous phase is adjusted to a pH between 7 and 8 by adding a 2M aqueous sodium hydroxide solution and then is extracted with 2 x 25 ml of dichloromethane.
• the organic phase is dried over Na 2 S0 4 and then evaporated under vacuum. 330 mg of a white solid corresponding to (1 S, 2S) - ⁇ / - [3,5-bis (trifluoromethyl) benzenesulfonyl] -1, 2-cyclohexanediamine are recovered.
• the reducing medium used - an azeotropic mixture of formic acid and triethylamine
• the reaction mixture is left at room temperature (22 ° C) with stirring.
• the reaction time is listed in the table below.
• Example 24 The same reducing medium is used as in Example 24, the procedure of which is reproduced using either ligand 1 or ligand 2.
• Example 24 The same reducing medium is used as in Example 24, the procedure of which is reproduced using the ligand prepared in Example 1, namely (1S, 2S) -N- (trifluoromethanesulfonyl) -1, 2 cyclohexanediamine, or the ligand 2 of example 24.

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