Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
  • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
  • B01J31/12—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing organo-metallic compounds or metal hydrides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
  • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
  • C07F15/0046—Ruthenium compounds
• • C—CHEMISTRY; METALLURGY
  • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
  • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
  • C09B57/00—Other synthetic dyes of known constitution
  • C09B57/10—Metal complexes of organic compounds not being dyes in uncomplexed form

Definitions

• Catalytic complexes based on ruthenium and use of such complexes for metathesis of olefins are known in the art.
• the present invention relates to novel catalytic complexes based ruthenium activated and recyclable and a method of synthesis thereof.
• the invention also relates to the use of such catalytic complexes for the metathesis of olefins.
• Grubbs IL catalyst The development of recyclable or activated ruthenium-based catalyst complexes is based on the work of R. Grubbs of the University of California (USA) on ruthenium complex 2a (pre-catalyst 2b) called Grubbs IL catalyst.
• a first advantage of this complex is to allow recycling of the precatalyst which is recovered at the end of the reaction and can be reused.
• the first activated complex 4 was described in 2002 based on the electron effect induced by the presence of a nitro group (NO 2 ) on the Hoveyda styrenylether ligand complex described above.
• This precatalyst is based on the strongly accelerated stall of the styrenyl ether ligand which leads to a rapid initiation of the catalytic cycle and therefore a significant increase in the reaction kinetics.
• the reactions can then take place under milder conditions, in practice at room temperature, and with lower catalyst charges.
• the object of the present invention is to describe activated and recyclable ruthenium complexes in which the compromise between these antinomic properties can be optimized, that is to say complexes capable of combining excellent activity while retaining good recycling.
• An object of the present invention is therefore to provide such complexes whose use can allow a reduction of the catalytic charge. Such an objective is important in view of the high cost of these catalysts.
• An object of the present invention is therefore also to provide such complexes whose degree of recyclability causes a significant reduction of toxic metal waste in the final products.
• the catalysts according to the present invention will make it possible to obtain products having a very low level of ruthenium, in practice less than 10 to 20 ppm.
• L is a neutral ligand
• R and R are independently hydrogen, C 1 -C 6, a perhaloalkyl C 1 -C 6, an aldehyde, a ketone, an ester, an amide, a nitrile, an optionally substituted aryl, an alkyl pyridinium, a perhalogénoalkyl- pyridinium or cyclohexyl, C 5 or C 6, optionally substituted radical C n H 2n Y, or C n F 2n Y with n between 1 and 6, and Y is an ionic marker, or a radical of formula:
• R can be a radical of formula (Ia) when the compound is of formula I,
• R is a C 1 -C 6 cycloalkyl or a C 5 or C 6 aryl or a C 5 or C 6;
• R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R are, independently, hydrogen, C 1 -C 6, a perhaloalkyl C 1 -C 6, or an aryl, C 5 or C 6 ;
• R, R, R being able to form a heterocycle X is an anion: halogen, tetrafluoroborate ([BF 4 ]), [tetrakis- (3,5-bis- (trifluoromethyl) -phenyl) borate] ([BARF]), hexafluorophosphate ([PF 6 ]), hexafluoroantimony ([ SbF 6 ]), Hexafluoroarsenate ([AsF 6 ]), trifluoromethylsulfonate ([(CF 3 ) 2 N] -).
• R and R being able to form with N and C to which they are attached a heterocycle of formula
• R is hydrogen, C 1 -C 6 cycloalkyl or a C 5 or C 6 aryl or a C 5 or C 6
• L is P (R) 3 , R being a C 1 to C 6 alkyl or a C 5 or C 6 aryl or cycloalkyl.
• L is a ligand of formula 7a, 7b, 7c, 7d or 7e
• n 1 0, 1, 2, 3;
• R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 are independently a C-alkyl 1 to C 6 , C 3 to C 20 cycloalkyl, C 2 to C 2 alkenyl ; a naphthyl, an anthracene or a phenyl, said phenyl being able to be substituted by up to 5 groups selected from alkyl C 1 -C 6 alkoxy groups the C 1 -C 6 and
• R and R on the one hand and R and R on the other hand can form a ring with 3, 4, 5, 6, 7 members; R can independently form an adjoined 6-membered aromatic ring.
• L is PCy 3 , Cy being cyclohexyl, or L is a ligand of formula 7a or 7b.
• X is a chlorine
• X ' is a chlorine
• the ionic marker Y is preferably chosen from the group consisting of:
• the compound according to the invention corresponds to formula (I) in which
• R is selected from the group consisting of CH 3 , CF 3 , C 6 F 5 , pNO 3 C 6 H 4.
• R is CF 3 .
• the compound corresponds to the formula
• the compound corresponds to the formula Ib
• the compound corresponds to the formula in the formula Ic
• the compound corresponds to the formula in the formula Id
• the compound corresponds to the formula in the formula
• the compound corresponds to the formula of the formula If
• the compound corresponding to the formula corresponds to the Ig formula
• the compound corresponds to the formula of formula Ih
• the compound has the formula Ii
• the compound corresponds to the formula of formula Ij
• the compound has the formula Ik formula
• the compound corresponds to the formula corresponds to formula 11
• the compound corresponds to the formula in formula 12
• the compound corresponds to the formula in formula 13
• the compound corresponds to the formula in formula 14
• the invention also relates to any method for synthesizing a compound of formula (I), characterized in that it comprises a first step of reacting 4-isopropoxy-3-vinylaniline with a compound having an acyl function in order to obtaining an amide ligand and a second step of reacting this amide ligand with a compound of formula (III)
• said compound of formula (III) is the Grubbs precatalyst (2b) or the Nolan precatalyst (2c).
• this amide function can serve as a spacer for the introduction of an ionic tag ("tag”) for immobilization in aqueous and / or ionic phase as well as solid support.
• tag an ionic tag
• Such ionic labeling makes it possible to lead to a better recycling of the catalytic complexes in aqueous / ionic solvents or on a solid support (continuous flow reaction) and to obtain a clear reduction in the cost of the reaction while avoiding the contamination of the products in question. high added value, especially in the context of process for the synthesis of pharmaceutical molecules.
• FIG. 1 is a graph showing the rate of conversion of a metallyl-allyl diethylmalonate compound over time in the context of a cyclizing metathesis reaction at ambient temperature, in the presence of 1 mol% of the Hoveyda 3b complex. on the one hand and catalytic complexes according to the invention Ia, Ib, Ic, Id, on the other hand;
• FIG. 2 is a graph showing the rate of conversion of a metallyl-allyl diethylmalonate compound over time in the context of a metathesis reaction. cyclizing at room temperature, in the presence of 1 mol% of the Hoveyda 3b complex on the one hand and catalytic complexes according to the invention Ib, on the other hand;
• FIG. 3 is a graph showing the degree of conversion over time of a metallyl-allyl diethylmalonate compound in the context of a cyclizing metathesis reaction at 45 ° C., in the presence of 1 mol% of the catalytic complex according to FIG. invention;
• FIG. 4 is a graph showing the degree of conversion over time of a metallyl-allyl diethylmalonate compound in the context of a cyclizing metathesis reaction at 30 ° C. in the presence of 1 mol% of the catalytic complex according to FIG. invention Ib on the one hand and 0.3 mol% of the catalytic complex according to the invention Ib on the other hand;
• FIG. 5 is a graph showing the degree of conversion over time of a metallyl-allyl diethylmalonate compound in the context of a cyclizing metathesis reaction at 30 ° C. in the presence of 1 mol% of the catalytic complexes according to FIG. invention Ib, the and If:
• FIGS. 6 to 11 represent the NMR spectra of exemplary embodiments of various ruthenium complexes Ia, Ib, Ic, Id, Ie and If;
• 1st step synthesis of friendships 6a, 6b, 6c, 6d, 6f, 9a, 9b, IQa and IQb from 4-isopropoxy-3-vinylaniline 5.
• 4-isopropoxy-3-vinylaniline 0.2 mmol approx.
• anhydrous dichloromethane 2-3 mL
• Pyridine 1.5 eq
• Acyl chloride or anhydride 1.2 g
• the crude is then diluted with dichloromethane (10 mL), washed with an aqueous solution of 1N hydrochloric acid (2 mL) and then with a saturated solution of sodium hydrogencarbonate (2 x 2 mL) and finally with a saturated sodium chloride solution (3 x 2 mL). .
• the organic phases are combined, dried over magnesium sulphate and concentrated under vacuum. The residue is purified by chromatography on silica gel.
• the ⁇ -nitrobenzamide is obtained after chromatography on silica gel (eluent: CH 2 Cl 2 ) in the form of a yellow oil (67 mg, 96%).
• the 4-isopropoxy-3-vinylaniline (30m, 1eq, 0.2mmol) is introduced into a flask, placed under nitrogen, and dissolved in anhydrous dichloromethane (3mL).
• the pyridine (21 DL, 1.5 eq.) Is added to the solution which is then cooled to 0 ° C.
• the oxalyl chloride (8.8DL, 1.2 eq.) then added slowly and the reaction medium is stirred. at room temperature under nitrogen for 2h.
• the crude is then diluted with dichloromethane (10 mL), washed with an aqueous solution of 1N hydrochloric acid (2 mL) and then with a saturated solution of sodium hydrogencarbonate (2 x 2 mL) and finally with a saturated sodium chloride solution (3 x 2 mL). .
• the organic phases are combined, dried over magnesium sulphate and concentrated under vacuum.
• the chlorinated amide 9a (20 mg, 0.07 mmol) is dissolved in anhydrous toluene (2.5 ml). N-methylimidazole (ImL, 20eq) is added to the solution which is then refluxed overnight. The volatile phases are then removed under reduced pressure and the tagged compound is recovered in the form of a dark orange oil.
• the amide ligand (léq.), The copper (I) chloride (leq) and the indenylidene precatalyst (léq.) are introduced into a flask under argon. Anhydrous dichloromethane (2-3mL) is added thereto. The reaction medium is then degassed three times, placed at 30-33 ° C. under an argon atmosphere and stirred for about 5 hours. The crude reaction product is then concentrated under vacuum. The residue is taken up in acetone (1-2 mL) and filtered through Celite. The filtrate is concentrated in vacuo and the residue is purified by chromatography on silica gel.
• Ligand N- (4-isopropoxy-3-vinylphenyl) trifluoroacetamide 6b 22mg, 0,08mmol, leq.
• Copper (I) chloride 8mg, leq
• Nolan's pre-catalyst 2 nd generation 68mg, léq.
• formula 2c is introduced into a flask under argon.
• Anhydrous dichloromethane (3mL) is added thereto.
• the reaction medium is then degassed three times, placed at 30-33 ° C. under an argon atmosphere and stirred for about 5 hours.
• the crude reaction product is then concentrated under vacuum.
• the residue is taken up in acetone (1-2 mL) and filtered through Celite.
• the filtrate is concentrated in vacuo and the residue is purified by chromatography on silica gel.
• the N, N'-bis (4-isopropoxy-3-vinylphenyl) oxamide ligand 6f (8mg, 0.02mmol, leq), the copper (I) chloride (4mg, 2, leq) and the indenylidene precatalyst (37mg , 2, lq.) are introduced into a flask under argon. Anhydrous dichloromethane (5mL) is added thereto. The reaction medium is then degassed three times, placed at 30-33 ° C. under an argon atmosphere and stirred for about 5 hours. The crude reaction product is then concentrated under vacuum. The residue is taken up in acetone (2 ml) and filtered on a frit. The IJ complex is thus isolated in the form of a green solid (15 mg, 59%).
• the present invention proposes to substitute the chlorine atom of the compound 10a with a tertiary amine (imidazole, pyridine, etc.).
• the inventors have carried out the substitution with pyridine on 4-chloro-N- (4-isopropoxy-3-vinylphenyl) butanamide IQa to easily lead to the desired ionic ligand IQb. Its complexation with the Grubbs II catalyst leads to the complex 11.
• the invention thus offers the possibility of performing metathesis reactions of olefins under more drastic conditions (higher heating) with the complex activated when the substrates are heavily congested (for example: tetrasubstituted olefins).
• FIG. 4 is a graph showing the degree of conversion over time of a metallyl-allyl diethylmalonate compound in the context of a cyclizing metathesis reaction at 30 ° C. in the presence of 1 mol% of the catalytic complex according to the invention Ib on the one hand and 0.3 mol% of the catalytic complex according to the invention Ib on the other hand.
• the graph shows a slight decrease in reactivity however it remains remarkable since 75% conversion is observed after only 40 minutes of reaction.
• FIG. 5 is a graph showing the degree of conversion over time of a metallyl-allyl diethylmalonate compound in the context of a cyclizing metathesis reaction at 30 ° C., in the presence of 1 mol% of the catalytic complexes according to the invention Ib, the and If.

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• Chemical & Material Sciences (AREA)
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• Chemical Kinetics & Catalysis (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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• 2007
  • 2007-01-30 FR FR0700634A patent/FR2909382B1/fr not_active Expired - Fee Related
  • 2007-11-30 CN CN201310436838.0A patent/CN103601758B/zh not_active Expired - Fee Related
  • 2007-11-30 EP EP07847578.7A patent/EP2097431B1/fr active Active
  • 2007-11-30 WO PCT/EP2007/063062 patent/WO2008065187A1/fr not_active Ceased
  • 2007-11-30 US US12/517,322 patent/US8394965B2/en active Active
  • 2007-11-30 BR BRPI0721051A patent/BRPI0721051B1/pt not_active IP Right Cessation
  • 2007-11-30 EP EP11192598.8A patent/EP2476688B1/fr active Active
  • 2007-11-30 CA CA002671082A patent/CA2671082A1/fr not_active Abandoned
  • 2007-11-30 JP JP2009538722A patent/JP5284269B2/ja not_active Expired - Fee Related
  • 2007-11-30 IN IN2409KON2009 patent/IN2009KN02409A/en unknown
• 2013
  • 2013-02-13 US US13/736,236 patent/US8586757B2/en active Active

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