Bis-aminophosphines as catalysts for the dimerization of alkyl acrylates

Abstract

The present invention relates to bis-aminophosphines useful as catalysts for the dimerization of alkyl acrylates. The present invention further relates to a process for preparing the bis-aminophophines, the use of these bis-aminophosphines as catalysts for the dimerization reaction of alkyl acrylates, and a process for obtaining dimers of alkyl acrylates using bis-aminophosphines as catalysts.

Description

[Technical field]

[0001] The present invention relates to bis-aminophosphines useful as catalysts for the dimerization of alkyl acrylates. The present invention further relates to a process for preparing the bis-aminophophines, the use of these bis-aminophosphines as catalysts for the dimerization reaction of alkyl acrylates, and a process for obtaining dimers of alkyl acrylates using bis-aminophosphines as catalysts. [Background technology]

[0002] The use of certain phosphines as catalysts for the dimerization of alkyl acrylates via the Rauhut-Currier reaction has already been described in the prior art.

[0003] US Patent No. 3,074,999A describes the dimerization reaction of alkyl acrylates catalyzed by tertiary phosphines having three alkyl groups, three cycloaliphatic groups, or three aryl groups, such as tributylphosphine or triphenylphosphine. However, these catalysts show low activity in the dimerization reaction. Moderate yields are reported for the disclosed process, which is a serious drawback for commercial production.

[0004] US Patent No. 3,227,745A describes the dimerization reaction of alkyl acrylates catalyzed by tertiary phosphines in the presence of a large amount of tert-butyl alcohol as a solvent. The tertiary phosphines disclosed are trialkylphosphines. However, the described process achieves only low conversion rates of less than 50%, which is not suitable for industrial production processes.

[0005] US Patent No. 3,342,853 A describes the dimerization of acrylic esters catalyzed by triaminophosphine, which can be generated from PCl3 prior to the dimerization reaction. A yield of 70-80% of methylene glutarate dimer is reported when the reaction is carried out at 60-65°C, but a large amount of by-products is also generated. Furthermore, triaminophosphine is generally toxic and a CMR agent (carcinogenic, mutagenic, and reproductively toxic agent), and when the catalyst is generated in situ, PCl3 is used as the precursor, which is a very hazardous chemical. These processes have significant drawbacks for commercialization and industrialization.

[0006] US 3,342,854 A describes the dimerization of acrylic esters catalyzed by either mono-aminophosphines or bis-aminophosphines. However, the low activity of diphenylaminophosphine for the dimerization of acrylic esters requires high phosphine loadings, which is a major drawback for commercial production. This is illustrated by two examples in this patent application, which use either in situ generated dibutylaminodiphenylphosphine or diethylaminodiphenylphosphine catalysts, resulting in a dimer yield of 10% or less. Furthermore, the use of the process of US 3,342,854 A results in a large amount of by-products.

[0007] Weiping Su et al. in “P(RNCH2CH2)3N: Catalysts for the Head-to-Tail Dimerization of Methyl Acrylate” J. Org. Chem. 2003, 68, 9499-9501 describe the dimerization of methyl acrylate at room temperature in THF or dioxane as solvent using proazaphosphatrane as phosphine catalyst. With a catalyst loading of 1 mol %, yields up to 82% are obtained. However, the catalyst described in this paper is very complex and difficult to synthesize, so the overall cost of the catalyst is high, which is a major drawback for industrialization potential. Furthermore, the use of low catalyst loading (1 mol %) leads to slow reaction kinetics at room temperature, which results in long reaction times (up to 24 hours), which is a drawback for industrial production.

[0008] Other specific phosphines are described by T. Aran Luiz et al. in "Synthesis and X-Ray Structural Characterization of (Diisopropylamino)(morpholino)(phenyl)phosphine and its dimeric copper(I)" Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal chemistry, 2007, 37:9, 669-675, or by Y. Chevallier et al. in "Les aminophosphines dans l'hydrogenation homogene par les catalyseurs au Rhodium" Tetrahedron Lett. 1969, 15, 1197-1200. However, neither of these two documents describes the use of such phosphines as catalysts for the dimerization reaction of alkyl acrylates. Summary of the Invention

[0009] It is an object of the present invention to provide a catalyst for the dimerization reaction of alkyl acrylates that is durable, robust, reusable, inexpensive and readily available. It is also an object of the present invention to provide a catalyst for the dimerization of alkyl acrylates that has relatively low toxicity, can be used at relatively low catalyst loadings, and provides excellent selectivity.

[0010] It is also an object of the present invention to provide an efficient process for preparing an inexpensive catalyst for the dimerization reaction of alkyl acrylates.

[0011] In addition, the object of the present invention is to provide an efficient process for preparing alkyl acrylate dimers. Specifically, the object of the present invention is to provide a process for preparing alkyl acrylate dimers, which can avoid using a large amount of tertiary alcohol as a solvent and a relatively high catalyst loading. More specifically, the object of the present invention is to provide an efficient process for preparing hydrogenated alkyl acrylate dimers and an efficient process for preparing hydrolyzed alkyl acrylate dimers.

[0012] It has now been found that these and other problems can be solved by the catalysts and processes of the present invention. The present invention relates to compounds of formula (I): [ka] During the ceremony, R1 and R2, which may be the same or different, are either linear alkyl groups containing 1 to 6 carbon atoms or together with the N atom form a heteroaliphatic ring containing 3 or 4 carbon atoms; R3 is an aryl or heteroaryl group.

[0013] Furthermore, the present invention provides a) a compound of formula (II): [ka] wherein both X's, the same or different, are chloride, bromide or iodide, and R3 is as defined above, with diisopropylamine to obtain a haloaminophosphine intermediate of formula (III): [ka] b) reacting the compound of formula (III) obtained in step a) with an amine of formula (IV): R1R2NH(IV), wherein R1 and R2 are as defined above, to obtain the compound of formula (I) as defined above.

[0014] Furthermore, the present invention provides the use of a compound of formula (I) as defined above as a catalyst for the dimerization reaction of alkyl acrylates.

[0015] Furthermore, the present invention relates to a process comprising a step i) of dimerizing an alkyl acrylate of formula (V) using a compound of formula (I) as defined above as catalyst to obtain a dimer of formula (VI) according to the following reaction scheme, in which R is an alkyl group: [ka]

[0016] Furthermore, the present invention relates to a process comprising step i) as defined above, [ka] wherein R is as defined above, and further comprising a step ii) of hydrogenating the dimer of formula (VI) obtained in the dimerizing step using H and a hydrogenation catalyst, such as a Pd-, Ru-, Pt-, Ni-, Co-, Rh-, or Ir-based catalyst, to obtain a compound of formula (VII), wherein R is as defined above.

[0017] Finally, the present invention relates to a process comprising step i) as defined above, further comprising a step ii') of hydrolysis, using an acid catalyst, such as a Lewis or Brönsted acid, of the dimer of formula (VI) obtained in the dimerization step, to obtain a compound of formula (VIII). [ka]

[0018] The present invention is based on the recognition that a durable, robust, reusable, inexpensive and readily available catalyst for the dimerization reaction of alkyl acrylate is provided in the form of a compound of formula (I). The catalyst for dimerization of alkyl acrylate of formula (I) is relatively low in toxicity, reusable, can be used at a relatively low catalyst dosage, and provides excellent selectivity. Furthermore, the present invention provides an efficient and simple process using relatively inexpensive starting materials for the preparation of the catalyst for the dimerization reaction of alkyl acrylate of the present invention in an inexpensive manner. In addition, the present invention provides an efficient process for preparing alkyl acrylate dimers using a compound of formula (I) as a catalyst, which can avoid using a large amount of tertiary alcohol relative to alkyl acrylate and a relatively high catalyst dosage. Specifically, the amount of tertiary alcohol relative to alkyl acrylate can be reduced to a molar ratio of 0.01:1, and the catalyst dosage can be reduced to 0.20 mol%. Finally, the present invention provides an efficient process for preparing hydrogenated alkyl acrylate dimers, and an efficient process for preparing hydrolyzed alkyl acrylate dimers. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] According to the present invention, the term "about" means ±10%, preferably ±5%, and most preferably ±2% of the specified numerical value.

[0020] The present invention relates to compounds of formula (I): [ka] During the ceremony, R1 and R2, which may be the same or different, are either linear alkyl groups containing 1 to 6 carbon atoms or together with the N atom form a heteroaliphatic ring containing 3 or 4 carbon atoms; R3 is an aryl or heteroaryl group.

[0021] Preferably, the compound of formula (I) is one in which R3 is phenyl; ortho-tolyl, meta-tolyl, or para-tolyl; xylyl, including all positional isomers, such as 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, and 3,5-dimethylphenyl; 3-methyl-4-methoxyphenyl, 2-methyl-4-methoxyphenyl, 2-methyl-3-methoxyphenyl, 4-methyl-3-methoxyphenyl, 5-methyl-3-methoxyphenyl, 6-methyl-3-methoxyphenyl, 7-methyl-3-methoxyphenyl, 8-methyl-3-methoxyphenyl, 9-methyl-3-methoxyphenyl, 10-methyl-3-methoxyphenyl, 11-methyl-3-methoxyphenyl, 12-methyl-3-methoxyphenyl, 13-methyl-3-methoxyphenyl, 14-methyl-3-methoxyphenyl, 15-methyl-3-methoxyphenyl, 16-methyl-3-methoxyphenyl, 17-methyl-3-methoxyphenyl, 18-methyl-3-methoxyphenyl, 19-methyl-3-methoxyphenyl, 20-methyl-3-methoxyphenyl, 21-methyl-3-methoxyphenyl, 22-methyl-3-methoxyphenyl, 23-methyl-3-methoxyphenyl, 24-methyl-3-methoxyphenyl, 25-methyl-3-methoxyphenyl, 26-methyl-3-methoxyphenyl, 27-methyl-3-methoxyphenyl, 28-methyl-3-methoxyphenyl, 29-methyl-3-methoxyphenyl, 30-methyl-3-methoxyphenyl, 31-methyl-3-methoxyphenyl, 32-methyl-3-methoxyphenyl, 33-methyl-3-methoxyphenyl, 34-methyl-3-methoxyphenyl, 35-methyl-3-methoxyphenyl, 36-methyl-3-methoxyphenyl, 37-methyl-3-methoxyphenyl, 38-methyl-3-methoxyphenyl mesityl, including all positional isomers, such as 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, and 3,4,5-trimethylphenyl; all positional isomers, such as 2,3,4,5-tetramethylphenyl, 2,3,4,6-tetramethylphenyl, pentamethylphenyl, 2,6-diisopropylphenyl; ortho-, meta-, or para-tert-butylphenyl; 2,3-di-tert-butylphenyl, 2,4-di-tert-butylphenyl, 2,5-di-tert-butylphenyl, 2,6-di-tert-butylphenyl, 3,4-di-tert-butylphenyl, and 3,5-di-tert-butylphenyl; ortho-, meta-, or para-methoxyphenyl; ortho-, meta-, or para-chlorophenyl; 2 ,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, and 3,5-dimethoxyphenyl; 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, ortho-, meta-, or para-nitrophenyl; ortho-, meta-, or para-biphenyl; ortho-, meta-, or para-trifluoromethylphenyl, ortho-, meta-, or para-fluorophenyl; 1- or 2-naphthyl; 2-pyridyl, 3-pyridyl, or 4-pyridyl;Compounds selected from 2-furyl, 3-furyl, 1-pyrrolyl, 2-pyrrolyl, or 3-pyrrolyl; 2-thiophenyl, 3-thiophenyl; 2-indolyl, 3-indolyl, and 2-benzofuryl, 3-benzofuryl, preferably phenyl; ortho-, meta-, or para-tolyl or xylyl, as well as their isomeric positions;

[0022] More preferably, the compound of formula (I) is one in which R3 is selected from phenyl, tolyl, xylyl, mesityl, duryl, pentamethylphenyl, 2,6-diisopropylphenyl, tert-butylphenyl, ditert-butylphenyl, methoxyphenyl, dimethoxyphenyl, methoxytolyl, methylenedioxyphenyl, biphenyl, nitrophenyl, halogen-substituted phenyl, trifluoromethylphenyl, naphthyl, pyridyl, furyl, pyrrolyl, thiophenyl, 2-indolyl, benzofuryl, and all positional isomers thereof.

[0023] Even more preferably, the compound of formula (I) is a compound where R3 is selected from phenyl, tolyl, xylyl, and mesityl. Even more preferably, the compound of formula (I) is a compound where R3 is selected from phenyl or tolyl. Most preferably, the compound of formula (I) is a compound where R3 is phenyl.

[0024] Preferably, the compound of formula (I) is a compound in which R1 and R2 are the same or different straight chain alkyl groups containing 1 to 6 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 carbon atoms.

[0025] Preferably, the compound of formula (I) is a compound in which R1 and R2 are identical straight chain alkyl groups containing 1 to 6 carbon atoms, preferably 2 to 6 carbon atoms, and even more preferably 2 carbon atoms.

[0026] Preferably, the compound of formula (I) is a compound in which R1 and R2 are different straight chain alkyl groups containing 1 to 6 carbon atoms, preferably 1 or 2 carbon atoms.

[0027] Preferably, the compounds of formula (I) are those in which R1 and R2 together with the N atom form a heteroaliphatic ring containing 3 or 4 carbon atoms, preferably 4 carbon atoms. Even more preferably, R1 and R2 together with the N atom form a heteroaliphatic ring containing 3 or 4 carbon atoms, preferably the heteroaliphatic ring does not contain any other type of heteroatom, preferably the formed heteroaliphatic ring contains only one heteroatom, which is a N atom.

[0028] Preferably, the compounds of formula (I) are those in which R3 is phenyl and R1 and R2 together with the N atom form a heteroaliphatic ring containing 4 carbon atoms.

[0029] Most preferably, the compound of formula (I) is compound (IX): [ka]

[0030] Furthermore, the present invention provides a) a compound of formula (II), [ka] wherein both X's, the same or different, are chloride, bromide or iodide, and R3 is as defined above, with diisopropylamine to obtain a haloaminophosphine intermediate of formula (III); [ka] b) reacting the compound of formula (III) obtained in step a) with an amine of formula (IV): R1R2NH(IV), wherein R1 and R2 are as defined above, to obtain the compound of formula (I) as defined above.

[0031] In a preferred embodiment, in the process for producing a compound of formula (I) as defined herein, steps a) and b) are carried out sequentially in the same reaction vessel.

[0032] Preferably, in the process for producing a compound of formula (I) as defined herein, steps a) and b) are carried out in an organic solvent which may be the same or different for each step, preferably an aprotic solvent, more preferably an aprotic solvent selected from tetrahydrofuran (THF), methyltetrahydrofuran (MeTHF), toluene, xylene, diethyl ether, tert-butyl methyl ether (TBME), dichloromethane (DCM), chloroform, dioxane, hexane, cyclohexane, benzene, anisole, and acetonitrile, even more preferably toluene, anisole, or MeTHF, most preferably MeTHF and anisole.

[0033] Preferably, in the process for producing a compound of formula (I) as defined herein, steps a) and b) are carried out at a temperature, which may be the same or different for each step, in the range of about 0° C. to about 100° C., preferably about 0° C. to about 80° C., more preferably about 25° C. to about 60° C., and most preferably about 40° C.

[0034] Preferably, in the process for producing a compound of formula (I) as defined herein, step a) is carried out by slowly adding the reactant of formula (II) to a solution of diisopropylamine in an aprotic solvent, diisopropylamine being used in an amount of 2 or more equivalents relative to reactant (II), since it has surprisingly been found that in (II) only one halogen X can be replaced by a diisopropylamino group.

[0035] Preferably, in the process for producing a compound of formula (I) as defined herein, both steps a) and b) are carried out under anhydrous conditions and in the absence of oxygen.

[0036] Preferably, in the process for producing a compound of formula (I) as defined herein, step b) is followed by a filtration step to remove the ammonium chloride salt by-product formed.

[0037] The present invention also relates to the use of the compounds of formula (I) as defined above as catalysts for the dimerization reaction of alkyl acrylates.

[0038] Furthermore, the present invention relates to a process comprising a step i) of dimerizing an alkyl acrylate of formula (V) to obtain a dimer of formula (VI) using a compound of formula (I) as defined herein as a catalyst according to the following reaction scheme, in which R is an alkyl group: [ka]

[0039] Preferably, in the process comprising step i) as defined herein, R is selected from the group consisting of C1 to C 18 Alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, pentyl, hexyl, 2-ethylhexyl, octyl, decyl, dodecyl, t-dodecyl, tetradecyl, hexadecyl, and octadecyl, preferably C1-C8 alkyl, more preferably C1-C4 alkyl, and most preferably methyl.

[0040] Preferably, in the process comprising step i) as defined herein, the dimerizing step i) is carried out in an organic solvent, preferably an aprotic solvent, more preferably an aprotic solvent selected from tetrahydrofuran (THF), methyltetrahydrofuran (MeTHF), toluene, xylene, anisole, diethyl ether, tert-butyl methyl ether (TBME), dichloromethane (DCM), chloroform, dioxane, hexane, cyclohexane, benzene, and acetonitrile, most preferably an aprotic solvent selected from MeTHF and anisole.

[0041] Preferably, in the process comprising step i) as defined herein, the dimerizing step i) is carried out in the presence of a co-solvent which is a tertiary alcohol or a silanol, preferably a tertiary alcohol, more preferably tert-butanol, pinacol, or tert-amyl alcohol, most preferably tert-butanol.

[0042] Preferably, in the process comprising step i) as defined herein, the molar ratio of the co-solvent of formula (V) to the alkyl acrylate is from about 4:1 to about 0.01:1, preferably from about 2:1 to about 0.1:1, more preferably from about 0.5:1 to about 0.1:1.

[0043] Preferably, in the process comprising step i) as defined herein, in step i) the compound of formula (I) as defined herein is used in an amount of from about 0.20 mol % to about 0.90 mol %, more preferably from about 0.25 mol % to about 0.80 mol %, even more preferably from about 0.30 mol % to about 0.70 mol %, still more preferably from about 0.30 mol % to about 0.50 mol %, even more preferably from about 0.30 mol % to about 0.45 mol %, and most preferably about 0.33 mol %, based on the amount of alkyl acrylate.

[0044] Preferably, in the process comprising step i) as defined herein, the dimerization step i) is carried out at a temperature in the range of about 20° C. to about 100° C., preferably about 20° C. to about 80° C., more preferably about 25° C. to about 60° C., most preferably about 45° C.

[0045] Preferably, in the process comprising step i) as defined herein, the dimerization step i) is carried out under anhydrous conditions and in the absence of oxygen.

[0046] Preferably, the process comprising step i) as defined above further comprises step ii) of hydrogenating the dimer of formula (VI) obtained in the dimerization step using H and a hydrogenation catalyst, such as a Pd based catalyst, for example Pd / C, Pd / Al2O3, Pd / SiO2, a Ru based catalyst, for example Ru / C, a Pt based catalyst, for example Pt / C, a Ni based catalyst, for example supported nickel or Raney nickel, a Co based catalyst, for example supported cobalt or Raney cobalt, a Rh based catalyst, for example Rh / C, an Ir based catalyst, for example Ir / C, preferably Pd / C or Raney nickel, to obtain a compound of formula (VII), where R is as defined above. [ka]

[0047] In a preferred embodiment, in the process comprising steps i) and ii), steps i) and ii) are followed by a step ii') of hydrolyzing the hydrogenated dimer of formula (VII) obtained by the dimerization and hydrogenation steps using an acid catalyst such as a Lewis or Brönsted acid, e.g. HCl, H2SO4, para-toluenesulfonic acid, methanesulfonic acid, triflic acid, and a solid acid catalyst, e.g. Amberlyst resin, zeolite, or Nafion, to obtain a compound of formula (X). [ka]

[0048] Preferably, the process comprising step i) as defined above further comprises a step ii') of hydrolyzing the dimer of formula (VI) obtained in the dimerization step using an acid catalyst such as Lewis or Brønsted acid, e.g. HCl, H2SO4, para-toluenesulfonic acid, methanesulfonic acid, triflic acid, and solid acid catalysts, e.g. Amberlyst resin, zeolites, and Nafion, to obtain the compound of formula (VIII). [ka]

[0049] In a preferred embodiment, in the process comprising steps i) and ii), steps i) and ii') are followed by step ii) of hydrogenating the hydrolyzed dimer of formula (VIII) obtained in the dimerization and hydrolysis steps using H and a hydrogenation catalyst, such as a Pd-based catalyst, for example Pd / C, Pd / AlO, Pd / SiO, a Ru-based catalyst, for example Ru / C, a Pt-based catalyst, for example Pt / C, a Ni-based catalyst, for example supported nickel or Raney nickel, a Co-based catalyst, for example supported cobalt or Raney cobalt, a Rh-based catalyst, for example Rh / C, an Ir-based catalyst, for example Ir / C, preferably Pd / C or Raney nickel, to obtain a compound of formula (X). [ka]

[0050] Preferably, the process comprising steps i) and / or ii) and / or ii') further comprises an initial step 0) of preparing a catalyst of formula (I) as defined above.

[0051] In a preferred embodiment, in a process comprising steps i) and / or ii) and / or ii') and further comprising an initial step 0), steps 0) and i) are consecutive steps without isolating the catalyst after step 0). EXAMPLES

[0052] 1. Aminophosphine-catalyzed dimerization of methyl acrylate General protocol for screening studies of phosphines: The various phosphines were prepared by "in situ" reactions, i.e. the formed phosphine catalyst was not isolated from the reaction medium before initiating the dimerization reaction of methyl acrylate.

[0053] a) Dimerization from dichlorophosphines catalyzed by symmetrical bis-aminophosphines: All reactions were carried out in scrupulously dried vessels under an inert argon atmosphere. Methyl acrylate and tert-butanol were dried over 4A molecular sieves, and tert-butanol was distilled under argon before each reaction. Dichlorophosphine and amines were used as received.

[0054] To a 25 mL two-neck round bottom flask was added the following: 3 mL of 2-methyltetrahydrofuran Dichlorophosphine precursor (1.8 mmol, 0.01 equivalent to methyl acrylate)

[0055] To a 50 mL 3-neck round bottom flask equipped with a magnetic stirrer was added the following: 1 mL of 2-methyltetrahydrofuran · 4 equivalents of the desired amine relative to the dichlorophosphine precursor (7.2 mmol).

[0056] The dichlorophosphine solution was added gradually to the amine solution with stirring (1400 rpm) over a period of 1 hour, while maintaining the temperature of the reaction medium below 40° C. (exothermic reaction). The addition of the dichlorophosphine to the amine solution produced a white precipitate, corresponding to an insoluble ammonium chloride salt by-product. Upon completion of the addition, the mixture was continued to be stirred at ambient temperature, 31 The progress of the reaction was monitored by P NMR ( 31 P chemical shift results are shown in Table 1 below).

[0057] After phosphine formation was complete (this typically requires stirring at room temperature for 1 hour for unhindered amines and 2 hours for hindered amines after addition of the chlorophosphine), the mixture was then cannulated into a 100 mL three-neck round bottom flask equipped with a magnetic stirrer, condenser, heater, and temperature probe and containing 32 mL of molten tert-butanol (2:1 v / v with respect to methyl acrylate). The mixture was then stirred at 60° C. Immediately, 15.95 mL of methyl acrylate (15.15 g, 0.176 moles, 1 equiv.) was carefully added to the reaction vessel over 1 hour (exothermy), and the resulting mixture was cooled to 100° C. for 1 hour. 1 The progress of the reaction was monitored by H NMR. The reaction was followed until it stopped or for 1 day. The conversion of methyl acrylate was then determined by integrating the methylene protons of the product and the methylene protons of the starting methyl acrylate. 1 The structure was estimated by 1 H NMR.

[0058] NMR spectrum of the product: 1 H NMR(CDCl3,400MHz)δ(ppm):6.03(s,1H),5.46(s,1H),3.60(s,3H),3.51(s,3H),2.48(t,J=7.6Hz,2H),2.37(t,J=7.6Hz,2H).

[0059] b) Dimerization of mono-chlorophosphines catalyzed by mono-aminophosphines: All reactions were carried out in scrupulously dried vessels under an inert argon atmosphere. Methyl acrylate and tert-butanol were dried over 4A molecular sieves, and tert-butanol was distilled under argon before each reaction. Mono-chlorophosphines and amines were used as received.

[0060] To a 25 mL two-neck round bottom flask, add the following: 3 mL of 2-methyltetrahydrofuran Mono-chlorophosphine precursor (1.8 mmol, 0.01 equivalent relative to methyl acrylate)

[0061] To a 50 mL 3-neck round bottom flask equipped with a magnetic stirrer was added the following: 1 mL of 2-methyltetrahydrofuran 2 equivalents of the desired amine relative to the mono-chlorophosphine precursor (3.6 mmol).

[0062] The mono-chlorophosphine solution was added gradually to the amine solution with stirring (1400 rpm) over a period of 1 hour, while maintaining the temperature of the reaction medium below 40° C. (exothermic reaction). The addition of the mono-chlorophosphine to the amine solution produced a white precipitate, corresponding to an insoluble ammonium chloride salt by-product. Upon completion of the addition, the mixture was continued to be stirred at ambient temperature, 31 The progress of the reaction was monitored by P NMR.

[0063] After phosphine formation was complete (this typically requires stirring at room temperature for 1 hour for unhindered amines and 2 hours for hindered amines after addition of the mono-chlorophosphine), the mixture was then cannulated into a 100 mL three-neck round bottom flask equipped with a magnetic stirrer, condenser, heater, and temperature probe and containing 32 mL of molten tert-butanol (2:1 v / v with respect to methyl acrylate). The mixture was then stirred at 60° C. Immediately, 15.95 mL of methyl acrylate (15.15 g, 0.176 moles, 1 equiv.) was carefully added to the reaction vessel over 1 hour (exothermy), and the resulting mixture was cooled to 100° C. for 1 hour. 1 The progress of the reaction was monitored by H NMR. The reaction was followed until it stopped or for 1 day. The conversion of methyl acrylate was then determined by integrating the methylene protons of the product and the methylene protons of the starting methyl acrylate. 1 The structure was estimated by 1 H NMR.

[0064] c) Dimerization catalyzed by an unsymmetrical bis-aminophosphine from dichlorophosphine, diisopropylamine, and an additional amine: All reactions were carried out in scrupulously dried vessels under an inert argon atmosphere. Methyl acrylate and tert-butanol were dried over 4A molecular sieves, and tert-butanol was distilled under argon before each reaction. Dichlorophosphine and amines were used as received.

[0065] To a 25 mL two-neck round bottom flask was added the following: 3 mL of 2-methyltetrahydrofuran Dichlorophosphine precursor (1.8 mmol, 0.01 equivalent to methyl acrylate)

[0066] To a 50 mL 3-neck round bottom flask equipped with a magnetic stirrer was added the following: 1 mL of 2-methyltetrahydrofuran · 3 equivalents of diisopropylamine (5.4 mmol) relative to the dichlorophosphine precursor.

[0067] The dichlorophosphine solution was gradually added to the amine solution with stirring (1400 rpm) over a period of 1 hour, while maintaining the temperature of the reaction medium below 40° C. (exothermic reaction). The addition of dichlorophosphine to the amine solution resulted in the formation of a white precipitate, which corresponds to the insoluble ammonium chloride salt by-product (in the case of diisopropylammonium chloride of the present invention). The mixture was then stirred at ambient temperature and cooled to room temperature. 31 The progress of the reaction was monitored by P NMR. The formation of the intermediate chloro(diisopropylamino)phosphine was confirmed by 31 This was confirmed by P NMR (e.g., in the case of chlorophenyl(diisopropylamino)phosphine, a singlet was observed at +132.5 ppm).

[0068] After the formation of chloroaminophosphine intermediate was complete (usually this requires stirring at room temperature for 1 hour after addition of dichlorophosphine), 1 equivalent of second amine (1.8 mmol) was added to the mixture with stirring at room temperature and the reaction mass was stirred for another hour at room temperature.

[0069] After completion of the bis-aminophosphine, the mixture was then cannulated into a 100 mL three-neck round bottom flask equipped with a magnetic stirrer, condenser, heater, and temperature probe and containing 32 mL of molten tert-butanol (2:1 v / v to methyl acrylate). The mixture was then stirred at 60° C. Immediately, 15.95 mL of methyl acrylate (15.15 g, 0.176 moles, 1 equiv.) was carefully added to the reaction vessel over 1 hour (exothermy), 1 The progress of the reaction was monitored by H NMR. The reaction was followed until it stopped or for 1 day. The conversion of methyl acrylate was then determined by integrating the methylene protons of the product and the methylene protons of the starting methyl acrylate. 1 The structure was estimated by 1 H NMR.

[0070] To confirm that the target catalyst was successfully synthesized, 31 The crude reaction medium was analyzed using P NMR. In fact, this parameter ( 31 The P NMR chemical shifts were characteristic of the synthesized aminophosphines and the areas under the peaks were proportional to the molar concentration of the aminophosphine in solution. 31 P NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer. 31 The NMR yield (%) of phosphine, which corresponds to the molar selectivity of the aminophosphine synthesis reaction estimated from the peak area of ​​the 1H NMR spectrum, was also measured.

[0071] All the results regarding the phosphine catalysts and their preparation processes are summarized in Table 1 below.

[0072] [Table 1]

[0073] Conclusion: All phosphines were synthesized except for di-tert-butylpyrrolidinophosphine (Cp4), the chlorophosphine precursors being too bulky to accommodate the amine ligand in the substitution reaction under our conditions.

[0074] The chlorodiphenylphosphine precursor (Cp1) gave only moderate yields of aminophosphines upon reaction with diisopropylamine. Bis-pyrrolidino-tert-butylphosphine (Cp5.1 and 5.2) was very sensitive to air and moisture and the phosphine synthesis afforded only moderate yields of aminophosphines.

[0075] In some of the tests shown in Table 1 above, the maximum conversion during the dimerization of the acrylic ester was also measured, which was 1 This corresponds to the maximum conversion of methyl acrylate as determined from H NMR. The ratio of tBuOH:acrylate in units v:v (and mol / mol) is also given.

[0076] In invention 1.3, the reaction was started with an initial dichlorophenylphosphine loading of 0.5 mol % followed by the addition of an additional amount of methyl acrylate (0.5 equivalents to reach an initial dichlorophenylphosphine loading of 0.33 mol %) after 20 hours reaction time. All results regarding the dimerization process are summarized in Table 2 below.

[0077] [Table 2]

[0078] Conclusion: As can be seen from Table 2, diphenylaminophosphines (Comp1 and 2) did not provide good catalytic activity (maximum conversion equal to zero or 10). Bis-pyrrolidino-phenylphosphine (Comp3) provided only moderate conversion of methyl acrylate (maximum conversion of 55). As mentioned above, di-tert-butylchlorophosphine (Comp4) is too bulky to accommodate the amine ligand in the substitution reaction and therefore does not provide conversion of the chlorophosphine precursor to aminophosphine.

[0079] On the other hand, the aminophosphines of the present invention (Inv 1.1-1.4) gave moderate to good catalytic activity. The best system, which showed the best performance, was diisopropylamino-pyrrolidino-phenylphosphine (Inv 1.1-1.3).

[0080] Quite surprisingly, it was observed that 91% acrylate conversion was achieved with diisopropylamino-pyrrolidino-phenylphosphine (Inv 1.3) at an initial dichlorophosphine loading of only 0.33 mol %. Furthermore, it was observed that this phosphine is very robust, allowing for easier handling and even re-use in several batches (see below).

[0081] The presence of tert-butyl alcohol during the dimerization reaction made it possible to improve the selectivity of the reaction towards the expected dimer. Surprisingly, it was still possible to find suitable conditions using t-BuOH together with very small amounts of basic aminophosphines, which did not impair the catalytic activity of the phosphine and still provided good selectivity.

[0082] d) (Diisopropylamino)pyrrolidinophenylphosphine catalyzed dimerization of methyl acrylate (0.4 mol % chlorophosphine precursor relative to methyl acrylate) in tert-butanol (1:8 v / v t-BuOH:methyl acrylate=0.12 mol / mol) at 60 °C with catalyst recycling. All reactions were carried out under an inert argon atmosphere in carefully dried vessels. Methyl acrylate and tert-butanol were dried over 4A molecular sieves, and tert-butanol was distilled under argon before each reaction. Dichlorophenylphosphine, diisopropylamine, and pyrrolidine were used as received.

[0083] To a 50 mL two-neck round bottom flask was added the following: 20mL of 2-methyltetrahydrofuran 3.6 mL of dichlorophenylphosphine (4.77 g, 0.027 mol, 0.012 eq.)

[0084] To a 100 mL three-neck round bottom flask equipped with a magnetic stirrer was added the following: 20mL of 2-methyltetrahydrofuran 11.15 mL of diisopropylamine (8.05 g, 0.08 mol, 0.036 eq.) (3 eq. relative to dichlorophenylphosphine)

[0085] The solution of dichlorophenylphosphine in 2-methyltetrahydrofuran was gradually added to the amine solution with stirring (1400 rpm) over a period of 1 hour, while maintaining the temperature of the reaction medium below 40° C. (exothermic reaction). The mixture was stirred at room temperature and 1 equivalent (0.027 moles, 1.92 g) of pyrrolidine was added to the reaction mixture, which was stirred at room temperature for an additional hour to complete the formation of the bis-(amino)phosphine.

[0086] The reaction mixture was cannulated into a 500 mL double-jacketed reaction vessel equipped with a temperature probe, condenser, and mechanical stirrer (propeller with four inclined plows). 25 mL of distilled tert-butanol (1:8 v / v tert-butanol:methyl acrylate) 200 mL of methyl acrylate (190.1 g, 2.2 mol, 1 equiv.)

[0087] The mixture was then stirred at 60° C. for 19 hours. The progress of the reaction was monitored by 1 Monitored by 1 H NMR. 1 Conversion of the starting methyl acrylate was about 86 mol% according to H NMR. Volatiles (t-BuOH, Me-THF, and unconverted methyl acrylate) were distilled off to recover 20 g of methyl acrylate. The desired product (dimethyl 2-methyleneglutarate) was then distilled under vacuum (125° C., 7 mbar) to give 103 g of analytically pure product.

[0088] Then, 190 g of methyl acrylate (2.2 moles, 1 equivalent) was added to the residue still containing the active phosphine catalyst, followed by 20 g of tert-butanol. The mixture was stirred at 60° C. for a further 16 hours to convert the second batch of methyl acrylate. Volatiles were distilled off to recover 37 g of methyl acrylate, which was distilled under vacuum (125° C., 8 mbar) to give 126 g of analytically pure product.

[0089] Finally, an additional 190 g of methyl acrylate (2.2 moles, 1 equivalent) was added to the residue still containing the active phosphine and the mixture was stirred again for 20 hours at 70° C. Upon reaction completion, the volatiles were removed under vacuum to recover 44 g of methyl acrylate and the product was distilled under vacuum to give 91 g of pure product.

[0090] A total of 320 g of dimethyl 2-methyleneglutarate product was recovered, representing a global isolated purified yield of 56%.

[0091] This is the first example of an aminophosphine catalyst that can be reused after an acrylate dimerization reaction.

[0092] e) Effect of the presence or absence of t-BuOH All reactions were carried out in scrupulously dried vessels under an inert argon atmosphere. Methyl acrylate was dried over 4A molecular sieves. Dichlorophosphine and amines were used as received.

[0093] To a 25 mL two-neck round bottom flask was added the following: 18 mL of 2-methyltetrahydrofuran Dichlorophosphine precursor (10.5 mmol, 0.005 equivalents relative to methyl acrylate)

[0094] To a 50 mL 3-neck round bottom flask equipped with a magnetic stirrer was added the following: 6 mL of 2-methyltetrahydrofuran · 3 equivalents of diisopropylamine (31.4 mmol) relative to the dichlorophosphine precursor.

[0095] The dichlorophosphine solution was added gradually to the amine solution with stirring (1400 rpm) over a period of 1 hour, while maintaining the temperature of the reaction medium below 40° C. (exothermic reaction). The addition of dichlorophosphine to the amine solution produced a white precipitate, corresponding to an insoluble ammonium chloride salt by-product. The mixture was then stirred at ambient temperature and cooled to room temperature. 31 The progress of the reaction was monitored by P NMR. The formation of the intermediate chloro(diisopropylamino)phosphine was confirmed by 31 This was confirmed by P NMR (e.g., in the case of chlorophenyl(diisopropylamino)phosphine, a singlet was observed at +132.5 ppm).

[0096] After the formation of chloroaminophosphine intermediate was complete (usually this requires stirring at room temperature for 1 hour after addition of dichlorophosphine), 1 equivalent of pyrrolidine (10.5 mmol) was added to the mixture with stirring at room temperature and the reaction mass was stirred for another hour at room temperature.

[0097] After completion of the bis-aminophosphine, the mixture was then cannulated into a 500 mL double-layered jacketed reaction vessel equipped with a mechanical stirrer (propeller with four pitched plows), condenser, heater, and temperature probe, containing 190 mL of methyl acrylate (180 g, 2.1 moles). The mixture was then stirred at 60° C. for 20 hours. The conversion of methyl acrylate was then determined by integrating the methylene protons of the product and the methylene protons of the starting methyl acrylate. 1 The structure was estimated by 1 H NMR.

[0098] At a conversion rate of 66% of methyl acrylate, 1 The selectivity towards dimer was estimated to be 78 mol % as determined by 1 H NMR.

[0099] At a similar conversion (66%), with 0.5 mol % dichlorophenylphosphine initial loading, at 60 °C (corresponding to Inv 1.2bis), the selectivity towards dimer was 87% compared to when t-BuOH was present in the reaction (1:1 v / v tert-BuOH:methyl acrylate), indicating a positive impact of t-BuOH on the reaction selectivity.

[0100] 2. Catalytic hydrogenation of dimethyl 2-methyleneglutarate to dimethyl 2-methylglutarate The substrate dimethyl 2-methyleneglutarate (50 g, 0.29 mol) (Inv 1.3), obtained in the dimerization reaction described above, was first added to a 100 mL autoclave reaction vessel equipped with a mechanical stirrer (Rushton turbine), followed by the addition of the Pd / C (3%) catalyst (powder, water content 51%, 1 g of water corresponds to 0.49 g of dry matter, 1% by weight with respect to the substrate). The reaction vessel was then tightly sealed and purged three times with 20 bar of nitrogen, followed by three times with 5 bar of hydrogen. The reaction mixture was stirred at 1400 rpm, and the temperature of the reaction mixture was then set to 40° C. The reaction medium was then stirred at 5 bar of hydrogen pressure (1400 rpm) at 40° C. for 6 hours, and the hydrogen consumption was followed over time.

[0101] Upon completion of the reaction, as determined by the absence of hydrogen consumption, the reaction mixture was cooled to room temperature, stirring was stopped, and the autoclave was depressurized. The reaction vessel was purged with nitrogen, the crude product was removed from the reaction vessel, and the catalyst was removed by filtration. After filtering off the catalyst, the product dimethyl 2-methylglutarate was obtained as a clear liquid (50 g corresponding to a 99% yield) and was used as is.

[0102] 3. Synthesis of 2-methylenepentanedioic acid from dimethyl 2-methylenepentanedioate [ka] Into a 2 L double-jacketed reactor equipped with a mechanical stirrer (propeller with 4 pitched plows), baffle, temperature probe, and a distillation column connected to a receiver, the following was added: - 700 g (4.07 mol, 1 eq) of dimethyl 2-methylenepentanedioate. -879 mL of water (48.8 moles, 12 equivalents). -Sulfuric acid 95% (9 mL, 16.6 g, 0.163 mol, 4 mol % relative to dimethyl 2-methylenepentanedioate) which is added dropwise to the reaction mixture via an addition funnel at room temperature.

[0103] The mixture is then stirred at 120° C. 1 The progress of the reaction is followed by H NMR analysis. Throughout the course of the reaction, the methanol produced is distilled off from the reaction medium in order to shift the reaction equilibrium towards the desired methylene glutaric acid.

[0104] After stirring at 120℃ for 2h30, 1 H NMR analysis indicates slow conversion of the diester to the diacid, so an additional 2.26 mL (0.04 mol, 1 mol %) of sulfuric acid is added to the reaction mixture to increase the reaction rate, and the temperature of the mixture is increased to 130 °C.

[0105] However, after stirring for another 2 h at 130° C., the conversion of the diester is still too slow, so 2.26 mL (0.04 mol, 1 mol %) of H2SO4 is added again to the reaction mass.

[0106] After stirring at 130° C. for 11 h30, 1060 mL of the water / MeOH mixture is distilled off and 50 mL of fresh water is added to the reaction vessel.

[0107] After stirring at 130℃ for 16h30, 1 1 H NMR analysis indicates around 10 mol % residual unhydrolyzed ester functionality and significant polymer by-product formation.

[0108] At this stage the mass of distillate recovered was 1195 g, which contained 6 g of insoluble starting diester.

[0109] The temperature of the reaction medium is reduced to 80° C. and 36 mL of a 35% by weight aqueous solution of NaOH (2 equivalents relative to H2SO4) is slowly added to the vessel to neutralize the catalyst (exothermy).

[0110] The contents of the reaction vessel, held at 80°C, are poured into a beaker with constant stirring and when cooled the mixture solidifies into a white paste that continues to thicken.

[0111] 147 mL of water is added to the paste to give a filterable liquid paste, and the mixture is allowed to cool at room temperature to complete the precipitation of the diacid product.

[0112] The product is then filtered through a sintered filter to give a very viscous filtrate.

[0113] The cake is washed four times with 80 mL of water, followed by six times with 70 mL of water, shaking the mixture well before each filtration.

[0114] The aqueous filtrate obtained after overnight precipitation at room temperature is filtered and rewashed ten times with 20 mL portions of water to recover additional product.

[0115] The solid fraction was collected and the product was dried under vacuum (10 mbar) at 50° C. for 2 h to give 286 g of a white powder with an organic purity of >98 wt % and containing 3 wt % water, corresponding to an isolated yield of 48%.

[0116] NMR spectrum: 1 H NMR(MeOD-d4,400MHz)δ(ppm):6.16(s,1H),5.63(s,1H),2.6-2.56(t,J=7.6Hz,2H),2.51-2.47(t,J=7.6Hz,2H). 13 C NMR(MeOD-d4,101MHz)δ(ppm):176.7,170.12,141.16,126.38,34.07,28.52.

Claims

1. Formula (I): 【Chemical 1】 [In the formula, R １ and R ２ are the same or different and each is a linear alkyl group containing 1 to 6 carbon atoms or together with the N atom forms a heteroaliphatic ring containing 3 or 4 carbon atoms; R ３ is an aryl group or a heteroaryl group. Compound.

2. In the formula, R ３ is selected from phenyl, tolyl, xylyl, mesityl, duryl, pentamethylphenyl, 2,6-diisopropylphenyl, tert-butylphenyl, di-tert-butylphenyl, methoxyphenyl, dimethoxyphenyl, methoxytolyl, methylenedioxyphenyl, biphenyl, nitrophenyl, halogen-substituted phenyl, trifluoromethylphenyl, naphthyl, pyridyl, furyl, pyrrolyl, thiophenyl, 2-indolyl, benzofuryl, and all positional isomers thereof.

3. R １ and R ２ Compounds of formula (I) according to claim 1 or 2, wherein are identical straight chain alkyl groups containing 1 to 6 carbon atoms, preferably 2 to 6 carbon atoms.

4. R １ and R ２ together with the N atom form a heteroaliphatic ring containing 3 or 4 carbon atoms, preferably 4 carbon atoms, and the heteroaliphatic ring does not contain any other kind of heteroatom, preferably the heteroaliphatic ring formed contains only one heteroatom, which is the N atom.

5. a) Formula (II): 【Chemistry 2】 wherein both X are the same or different and are chloride, bromide, or iodide; ３ is as defined in claim 1 or 2] The compound diisopropylamine to give a compound of formula (III): 【Chemistry 3】 obtaining a haloaminophosphine intermediate of formula b) converting the compound of formula (III) obtained in step a) into a compound of formula (IV): R １ R ２ NH(IV) amines, where R １ and R ２ is as defined in claim 1 with an amine of formula (IV) to obtain a compound of formula (I) as defined in claim 1 or 2.

6. 6. The process of claim 5, wherein steps a) and b) are carried out in an organic solvent, which may be the same or different for each step, preferably an aprotic solvent, more preferably selected from tetrahydrofuran (THF), methyltetrahydrofuran (MeTHF), toluene, xylene, anisole, diethyl ether, tert-butyl methyl ether (TBME), dichloromethane (DCM), chloroform, dioxane, hexane, cyclohexane, benzene, and acetonitrile, more preferably toluene or MeTHF.

7. 6. The process of claim 5, wherein step b) is followed by a filtration step to remove any formed ammonium chloride salt by-product.

8. 3. Use of a compound of formula (I) as defined in claim 1 or 2 as a catalyst for the dimerization reaction of alkyl acrylates.

9. The reaction scheme below: 【Chemistry 4】 wherein R is an alkyl group. i) dimerizing an alkyl acrylate of formula (V) using a compound of formula (I) as defined in claim 1 or 2 as a catalyst according to the formula (I) to obtain a dimer of formula (VI).

10. R is C １ ~C １８ Alkyl, preferably C １ ~C ８ Alkyl, more preferably C １ ~C ４ 10. The process of claim 9, wherein the alkyl is alkyl, most preferably methyl.

11. 11. The process according to claim 10, wherein the dimerization step i) is carried out in an organic solvent, preferably an aprotic solvent, more preferably an aprotic solvent selected from tetrahydrofuran (THF), methyltetrahydrofuran (MeTHF), toluene, xylene, anisole, diethyl ether, tert-butyl methyl ether (TBME), dichloromethane (DCM), chloroform, dioxane, hexane, cyclohexane, benzene, and acetonitrile, most preferably MeTHF.

12. 12. The process of claim 11, wherein the dimerization step i) is carried out in the presence of a co-solvent which is a tertiary alcohol or a silanol, preferably a tertiary alcohol, more preferably tert-butanol, pinacol, or tert-amyl alcohol.

13. 13. The process of claim 12, wherein the molar ratio of the co-solvent of formula (V) to the alkyl acrylate is from about 4:1 to about 0.01:1, preferably from about 2:1 to about 0.1:1, and more preferably from about 0.5:1 to about 0.1:

1.

14. The dimer of formula (VI) obtained in the dimerization step is reacted with H ２ and hydrogenating the compound using a hydrogenation catalyst such as a Pd-based catalyst, a Ru-based catalyst, a Pt-based catalyst, a Ni-based catalyst, a Co-based catalyst, a Rh-based catalyst, or an Ir-based catalyst, preferably a Pd-based catalyst or a Ni-based catalyst, to obtain a compound of formula (VII): 【Chemistry 5】 wherein R is as defined in claim 9.

10. The process of claim 9, further comprising step ii) of obtaining a compound of formula:

15. The dimer of formula (VI) obtained in the dimerization step is hydrolyzed using an acid catalyst such as a Lewis acid or a Bronsted acid to give a compound of formula (VIII): 【Chemistry 6】 10. The process of claim 9, further comprising step ii') of obtaining a compound of formula:

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