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  • C07F17/00—Metallocenes
  • C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic System
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  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B53/00—Asymmetric syntheses
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
  • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
  • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
  • C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
  • C07C215/32—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton containing hydroxy groups and carbon atoms of two six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
  • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
  • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
• • 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
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
  • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the present invention relates to N-substituted chiral derivatives of norephedrine and their use as ligands for the so-called reduction by hydrogen transfer of carbonyl derivatives.
• the invention therefore also relates to the methods of enantioselective reduction of optically active carbonyl derivatives by the hydrogen transfer method.
• N-substituted chiral derivatives of norephedrine constitute, according to the present invention, new ligands of the amino-alcohol type, simple to prepare and efficient in terms of activity and enantioselectivity for the synthesis of functional chiral alcohols by reduction of carbonyl derivatives by a method called hydrogen transfer.
• This method which is well known to those skilled in the art, is described for example in European patent application No. 916 637.
• R represents a C 1 _ 10 alkyl group, a saturated or unsaturated C 3 _ 9 cycloalkyl group, an aryl group, said groups optionally comprising one or more substituents selected from a halogen atom, such as chlorine, fluorine, bromine, -N0 2 group, a C 1 _ 5 alkoxy C 1 _ 5 _ cycloalkyl C ⁇ merged or not, aryl fused or unsaturated, optionally substituted with C ⁇ alkyl, alkoxy C x _, halogen, said alkyl C 1 _ 1 Q, saturated or unsaturated C 3 _ 9 cycloalkyl, aryl optionally comprising one or more heteroatoms such as O, N, or Si,
• R 1 represents a hydrogen atom, a C 1 _ 10 alkyl group such as methyl, ethyl, propyl, isopropyl, an aryl group such as phenyl, a saturated or unsaturated C 3 _ 9 cycloalkyl group, said groups comprising optionally one or more substituents chosen from a halogen atom, such as chlorine, fluorine, bromine, a group -NO 2 , a C 1 alkyl.
• a halogen atom such as chlorine, fluorine, bromine, a group -NO 2 , a C 1 alkyl.
• R2 represents a group chosen from saturated C 1 _ 10 alkyl or no, a C 3 _ 9 cycloalkyl, saturated or not, an aryl, a 2-furanyl, a 2-thiophenyl, a 3-thiophenyl, a ferrocenyl, said groups optionally comprising one or more substituents chosen from a halogen such as chlorine, fluorine, bromine, a group -N0 2 , a C 1-5 alkyl, a C 1 alkoxy, a C 1 _ 1 cycloalkyl saturated or not,
• RI represents and R2 have the same meaning as above and R3, R4, R5, R6 and R7, identical or different, are chosen from a hydrogen atom, a halogen atom, such as chlorine, fluorine, bromine, a group -N0 2 , a C x _ 5 alkyl group, a C 1 _ 5 alkoxy group , a C - ⁇ - cycloalkyl group, fused or not, a aryl group fused or not, optionally substituted by a C x _ 5 alkyl, a C 1 _ 5 alkoxy, a halogen, said groups optionally comprising one or more heteroatoms such as 0, N, or Si.
• a halogen atom such as chlorine, fluorine, bromine
• the invention more particularly contemplates the use as a ligand of derivatives of formulas (I) or (II) in which:
• Ri represents a hydrogen atom, a C- L alkyl. 4 such as methyl, ethyl, propyl, isopropyl, or phenyl,
• R2 represents a group chosen from a 2-furanyl, a 2 -thiophenyl, a 3 -thiophenyl, a ferrocenyl, an aryl of formula (III) below:
• R8, R9, RIO, R11 and R12 are chosen from a hydrogen atom, a halogen atom, such as chlorine, fluorine, bromine, a group -N0 2 , an alkyl group in C 1 _ 5 , a C ⁇ _ 5 alkoxy group, a C x _ 7 cycloalkyl group, fused or not, an aryl group fused or not, optionally substituted by C 1 _ 5 alkyl, C 1 alkoxy, halogen, said groups optionally comprising one or more heteroatoms such as 0, N, or Si.
• a halogen atom such as chlorine, fluorine, bromine
• a group -N0 2 an alkyl group in C 1 _ 5 , a C ⁇ _ 5 alkoxy group, a C x _ 7 cycloalkyl group, fused or not, an aryl group fused or not, optionally substituted by C 1 _ 5 alkyl, C 1
• RI, R3, R4, R5, R6 and R7 have the same meaning as in formula (I),
• R8, R9, R11 and R12 have the same meaning as in formula (III), and
• R13, R14, R15, R16 and R17 are chosen from a hydrogen atom, a halogen, such as chlorine, fluorine, bromine, a group -N0 2 , a C, alkyl, an alkoxy in C ⁇ , a cycloalkyl in C x _ 7 , a polystyryl group, an aryl group optionally substituted by a C 1 alkyl. 4, an alkoxy C 1 _ 4, or halogen, said alkyl, alkoxy, cycloalkyl, polystyryl, aryl optionally including one or more heteroatoms such as O, N, or Si.
• a halogen such as chlorine, fluorine, bromine
• a group -N0 2 a C, alkyl, an alkoxy in C ⁇ , a cycloalkyl in C x _ 7
• a polystyryl group an aryl group optionally substituted by a C 1 alky
• the invention also covers the corresponding ligands derived from the (1R, 2S) enantiomer of norephedrine.
• the derivatives of the invention comprise at least two asymmetric carbons, and can therefore exist in several optically active forms all covered by the present invention.
• the ligands according to the invention can be obtained by a reaction between norephedrine and a substituted benzaldehyde derivative.
• norephedrine is understood to mean the (1S, 2R) enantiomer of 1-phenyl-2-amino-propan-1-ol.
• the invention obviously includes also the ligands derived from the other enantiomer of norephedrine, namely the (1R, 2S) of 1-phenyl-2-amino-propan-1-ol.
• the enantiomeric purity of norephedrine is greater than 98%. So the derivatives E, F, G, H, I, J, K, L, M,
• N, 0, P and Q of the invention were synthesized by a known method, analogous to that used to synthesize molecules C and D (J. Saavedra, J " . Org. Chem. 1985, 50, 2273).
• compounds C and D are respectively:
• the derivatives of formula (I), preferably the derivatives of formula (II) and (IV), most preferably the derivatives of formula (V), and more particularly the derivatives E, F, G, H, I , J, K, L, M, N, 0, P and Q constitute, according to the invention, effective ligands for the so-called reduction by hydrogen transfer of carbonyl compounds and allow, according to preferred embodiments, obtain alcohols with high catalytic activities, and in some cases, with high enantiomeric purities.
• the invention therefore also relates to the use of derivatives of formulas (I), (II), (IV) and (V) and very particularly of derivatives E, F, G, H, I, J, K, L , M, N, 0, P and Q, as a ligand in a process of enantioselective reduction of unsaturated compounds carrying functional groups by the so-called hydrogen transfer method.
• Said unsaturated compounds carrying functional groups are more particularly carbonyls, imines, iminiums, oximes or compounds comprising a carbon-carbon double bond.
• the invention relates more particularly to the use of said derivatives as ligand in a reduction process enantioselective by the hydrogen transfer method of compounds of formula (VI) below:
• R18 is chosen from C 1 _ 5 alkyl, an aryl group, a heteroaryl group comprising one or more heteroatoms such as oxygen or nitrogen optionally substituted by a C 1 alkyl, by a C 1-4 alkoxy or by halogen,
• R19 other than R18 is selected from oxyalkyl, alkoxycarbonyl, optionally substituted by alkyl aryl, C ⁇ , by an alkoxy C x _ 4 or halogen, heteroaryl, heteroaryl comprising one or more heteroatoms such as oxygen or nitrogen optionally substituted by a C 1 _ 4 alkyl, by a C 1 _ i alkoxy or by a halogen, and z represents an oxygen atom, a group of formula -NR20; -NOR20, -N (R20) 2 Y or -C (R20) 2 , where the R20 groups, identical or different, represent chosen from C 1 _ 5 alkyl, an aryl group, a heteroaryl group comprising one or more heteroatoms such as oxygen or nitrogen optionally substituted by a C x _ 4 alkyl, and Y is a counter anion, such as an anionic organic or inorganic molecule such as for example a halogen, an a
• the invention therefore also relates to a method of enantioselective reduction of compounds of formula (VI) by a hydrogen transfer method characterized in that a derivative of formulas (I), (II), ( IV) or (V), preferably a derivative E, F or G, with a compound of formula (VI), in basic or neutral medium, in the presence of a catalytic amount of a complex of a transition metal and a secondary alcohol as a reducing agent.
• the transition metal is preferably iridium, rhodium or ruthenium, and is advantageously of the type [MCI (arene)], where M ' represents a
• R24 transition metal such as rhodium, iridium or ruthenium, and arene means a compound of the following formula (VII): in which R21, R22, R23, R24, R25, R26, identical or different, are chosen from one hydrogen atom, halogen, C 1-5 alkyl group, isoalkyl, tertioalkyl, alkoxy, said alkyl and alkoxy groups comprising one or more heteroatoms such as 0, N and Si.
• the amount of substrate of formula (VI) relative to the catalytic amount of the complex of a transition metal is from 1 to 50,000, preferably from 10 to 10,000 and most preferably from 100 to 1,000.
• the medium basic in which the reaction of the process of the invention is carried out is advantageously carried out by potassium isopropylate.
• the source of hydrogen, in the process of the invention is advantageously a secondary alcohol and preferably isopropanol.
• the Applicant has studied in detail the enantioselective reduction process above in order to determine which are the various intermediate products which form and which could be isolated for the implementation of a variant of said process.
• - ligand consisting of a derivative of formulas (I), (II), (IV) or (V), preferably a derivative E, F or G, with: - a complex of a transition metal of the type
• M, R, Ri and R2 have the same meaning as above, Arene means a compound of formula (VII) above, and R27 represents a halogen such as chlorine or bromine.
• the first metal complex of formula (VIII) leads, in basic medium, to the formation of a second metal complex of formula (IX) below: in which: M, R, Ri and R2 have the same meaning as above, Arene means a compound of formula (VII) above, R29 and R28 each represent a pair of electrons .
• the second metal complex of formula (IX) leads, in the presence of a secondary alcohol as reducing agent, to a third metal complex of formula
• M, R, Ri and R2 have the same meaning as above, Arene means a compound of formula (VII) above, R30 represents a hydrogen atom or a pair of electrons, R31 represents a hydrogen, a halogen like chlorine or bromine, an electron doublet.
• a subject of the invention is also the compounds of formulas - (VIII), (IX), (X) and of general formula (XI), their preparation and their use in a process of enantioselective reduction of compounds of formula (VI) carrying of functional groups, by a hydrogen transfer method, in the presence or absence of base.
• the subject of the invention is therefore a method of enantioselective reduction of unsaturated compounds carrying functional groups, advantageously of formula (VI), by a hydrogen transfer method, characterized in that it comprises the implementation of a catalytic amount of a compound of formula (VIII), in basic medium and in the presence of a secondary alcohol as reducing agent.
• a further subject of the invention is therefore a method of enantioselective reduction of unsaturated compounds carrying functional groups, advantageously from formula (VI), by a hydrogen transfer method, characterized in that it comprises the use of a catalytic amount of a compound of formulas (IX) or (X), in a neutral medium and in the presence a secondary alcohol as a reducing agent.
• the invention relates to the implementation of the complex of formula (IX) in a process of enantioselective reduction of unsaturated compounds carrying functional group, advantageously of formula (VI,) by a hydrogen transfer method consisting in reacting , in the absence of a base, said complex of formula (IX) with a compound of formula (VI) in the presence of a secondary alcohol as reducing agent.
• This process has the advantage of not being carried out in a basic medium.
• Example 1 The preparation and characterization of N-substituted derivatives of norephedrine.
• HMRS m / z calculated for C 18 H 24 N0 2 [M + 1] + : 286.1807; found 286.1802.
• Example 3 Preparation and characterization of the
• Example 3 (IS.2R) -N- (Cyclohexylmethyl) -norephedrine.
• Examples 28 to 36 Use of the ligands of the invention in the reduction by transfer of hydrogen of 2-acetylpyridine.
• Examples 39 to 42 Use of the ligands of the invention in the reduction by transfer of hydrogen of methoxyacetone.
• Examples 47 to 51 below describe the preparation and characterization of the VlIIa-c precursor complexes and of the catalytically active complexes IXa and Xa from the complex [RuCl2 (776-p-cymene)] 2 and ligands ⁇ -amino alcohols .
• Example 47 [RuCl ⁇ 6 - p- cymene ⁇ ⁇ 2 - (1 S, 2 R) - N- (4 - biphenylmethyl) -norephedrine ⁇ ] (Villa).
• Example 48 [RuCl ⁇ 6 -p-cymene ⁇ ⁇ 2 - (IS, 2 R) -ephedrine ⁇ ] (VlIIb).
• Example 49 [RuCl ⁇ 6 -p- cymene ⁇ ⁇ 2 - (1 S, 2 R) -N-ben zy1 - norephedrine ⁇ ] (City).
• Example 51 [RuH ⁇ T) 6 -p-cymene ⁇ ⁇ ? 2 - (lS, 2R) -iV- (4- bipheny lmethyl) -norephedrine ⁇ ] (Xa).
• Example 53 The procedure was the same as in Example 42 but without adding potassium isopropylate. After 4 h of stirring at temperature, the conversion of 2-acetylpyridine to alcohol was less than 2%.
• Example 56 The procedure was as in Example 44 but without adding potassium isopropylate. After 4 h of stirring at temperature, the conversion of acetophenone to phenyl-2-ethanol was less than 2%.
• Example 56 The procedure was as in Example 44 but without adding potassium isopropylate. After 4 h of stirring at temperature, the conversion of acetophenone to phenyl-2-ethanol was less than 2%.
• Example 58 The procedure was as in Example 11 using 316 mg (2.0 mmol) of tert-butyl acetoacetate in place of the acetophenone. After 4 h, the conversion to tert-butyl 3-hydroxybutyrate was 51% and was complete after 14 h; alcohol was obtained with an enantiomeric excess of 30% (S).
• Example 59 below below illustrates the application of the catalytic complement IXa in enantioselective hydrogen transfer of acetophenone in the absence of base.
• Example 58 The procedure was as in Example 58 using the Xa complex in place of the IXa complex. The same results have been observed.
• Example 60 RX structures of the ligand E.HC1 of example 1 and of the Villa. MeOH complex of example 47.

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