Method for producing alkyl acrylate dimer

Abstract

The present invention relates to a process for preparing alkyl acrylate dimers.Furthermore, the present invention relates to a process for preparing hydrogenated alkyl acrylate dimers obtained by the dimerization process according to the present invention.In addition, the present invention relates to a process for preparing hydrolyzed alkyl acrylate dimers obtained by the dimerization process according to the present invention.

Description

[Technical field]

[0001] The present invention relates to a process for preparing alkyl acrylate dimers.Furthermore, the present invention relates to a process for preparing hydrogenated alkyl acrylate dimers obtained by the dimerization process according to the present invention.In addition, the present invention relates to a process for preparing hydrolyzed alkyl acrylate dimers obtained by the dimerization process according to the present invention. [Background technology]

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

[0003] US Patent No. 3,074,999A describes the alkyl acrylate dimerization reaction 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. Although not very good yields have been reported for the disclosed process, this is a major drawback for commercial production.

[0004] US Patent No. 3227745A describes the alkyl acrylate dimerization reaction 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 a low conversion rate of acrylic esters of less than 50%, which is not suitable for industrial production.

[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. When the reaction is carried out at 60-65°C, a methylene glutarate dimer yield of 70-80% is reported, but a significant amount of by-products is also generated. Furthermore, triaminophosphine is generally toxic and a CMR reagent (a carcinogenic, mutagenic, and reproductively toxic reagent), and when the catalyst is generated in situ, PCl3, a very dangerous chemical, is used as a precursor. These are major drawbacks for the commercialization and industrialization of this process.

[0006] US3342854A describes acrylic ester dimerization reactions catalyzed by either monoaminophosphines or bisaminophosphines. However, due to the low activity of diphenylaminophosphine for acrylic ester dimerization, high phosphine loadings must be used, which is a major drawback for commercial production. This is illustrated in two examples of this patent application using in situ generated dibutylaminodiphenylphosphine or diethylaminodiphenylphosphine catalysts, with dimer yields of 10% or less. Furthermore, the use of the process according to US3342854A results in significant amounts 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 using proazaphosphatrane as phosphine catalyst. Yields up to 82% are obtained with a catalyst loading of 1 mol%. However, the catalysts described in this paper are very complex and difficult to synthesize, which leads to high overall catalyst costs, which is a major drawback for industrialization. Furthermore, the use of low catalyst loadings (1 mol%) leads to slow reaction kinetics at room temperature and long reaction times (up to 24 hours), which are also drawbacks for industrial production. Summary of the Invention

[0008] It is an object of the present invention to provide an efficient process for producing alkyl acrylate dimers that uses a highly active, robust, reusable, inexpensive and readily available catalyst, which has relatively low toxicity, can be used at relatively low catalyst loadings and provides excellent selectivity.

[0009] Specifically, it is an object of the present invention to provide a process for the preparation of alkyl acrylate dimers, which can avoid the use of large amounts of tertiary alcohol as a solvent and the relatively large catalyst loadings. More specifically, it is an object of the present invention to provide an efficient process for the preparation of hydrogenated alkyl acrylate dimers and an efficient process for the preparation of hydrolyzed alkyl acrylate dimers.

[0010] It has now been found that these and other problems can be solved by the method according to the invention, which comprises the following reaction scheme: [ka] (In the formula, R is an alkyl group; R1 and R2 are the same or different and are an aliphatic group or together with the N atom form a heteroaliphatic ring; R a is a hydrocarbyl group, R b is an aliphatic group or NR3R4, where R3 and R4 are the same or different and are aliphatic groups or together with the N atom form a heteroaliphatic ring. i) dimerization of an alkyl acrylate of formula (I) using a catalyst of formula (III) to obtain a dimer of formula (II) according to wherein said dimerization step i) is carried out in the presence of a compound A which is a tertiary alcohol or a silanol.

[0011] Further, the present invention relates to a compound of formula (IV) [ka] (In the formula, X is chloride, bromide, or iodide, preferably chloride; R a is as defined above, R c is X(R b In the case of a catalyst of formula (III) where R is as defined above, or R b (R b is an aliphatic group) of, Formula (V): R1R2NH(V) (wherein R1 and R2 are R c R b or - an amine of formula (V) and a compound of formula (V'): R3R4NH(V') (wherein R3 and R4 are R c is as defined above for X, It relates to a process as defined above, further comprising an initial step 0) of preparing a catalyst of formula (III) by reacting

[0012] The present invention further relates to a process as defined above, followed by hydrogenation of the dimer of formula (II) obtained in the dimerization step using H and a hydrogenation catalyst to obtain a dimer of formula (VI) [ka] (wherein R is as defined above). and ii) step ii) to obtain a compound of formula (VI), wherein the hydrogenation catalyst is for example a Pd based catalyst, such as Pd / C, Pd / Al2O3, Pd / SiO2, a Ru based catalyst, such as Ru / C, a Pt based catalyst, such as Pt / C, a Ni based catalyst, such as supported nickel or Raney nickel catalyst, a Co based catalyst, such as supported cobalt or Raney cobalt, a Rh based catalyst, such as Rh / C, an Ir based catalyst, such as Ir / C, preferably Pd / C or Raney nickel, preferably Pd / C.

[0013] Finally, the present invention relates to a process as defined above, followed by a dimerization step, in which the dimer of formula (II) obtained is hydrolyzed using an acid catalyst such as a Lewis acid or a Brönsted acid, for example HCl, H2SO4, paratoluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, a solid acid catalyst such as Amberlyst resin or a zeolite, Nafion, to give a dimer of formula (VII) [ka] and step ii') of obtaining a compound of formula (VII).

[0014] The present invention is based on the recognition that an efficient method for producing alkyl acrylate dimers is provided, using a catalyst that is highly active, robust, reusable, inexpensive, and readily available. The catalyst for the dimerization of alkyl acrylates is a compound of formula (III), which is relatively low in toxicity, reusable, can be used at relatively low catalyst loading, and provides excellent selectivity. Furthermore, the present invention provides an efficient method for preparing alkyl acrylate dimers, using a compound of formula (III) as a catalyst, which can avoid using a large amount of tertiary alcohol relative to the alkyl acrylate and a relatively high catalyst loading. Specifically, the amount of tertiary alcohol relative to the alkyl acrylate can be reduced to a ratio of 0.01:1, and the catalyst loading can be reduced to 0.20 mol %. Finally, the present invention provides an efficient method for preparing hydrogenated alkyl acrylate dimers, and an efficient method for preparing hydrolyzed alkyl acrylate dimers. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] According to the present invention, the term "about" means ±10%, preferably ±5%, and most preferably ±2% of the specified numerical value.

[0016] The present invention relates to a method for producing a process according to the following reaction scheme: [ka] (In the formula, R is an alkyl group; R1 and R2 are the same or different and are an aliphatic group or together with the N atom form a heteroaliphatic ring; R a is a hydrocarbyl group, R b is an aliphatic group or NR3R4, where R3 and R4 are the same or different and are aliphatic groups or together with the N atom form a heteroaliphatic ring. i) dimerization of an alkyl acrylate of formula (I) using a catalyst of formula (III) to obtain a dimer of formula (II) according to wherein said dimerization step i) is carried out in the presence of a compound A which is a tertiary alcohol or a silanol.

[0017] Preferably, in the process for preparing a dimer of formula (II) as defined herein, compound A is a tertiary alcohol such as tert-butanol, tert-amyl alcohol or pinacol, more preferably tert-butanol.

[0018] Preferably, in the process for preparing the dimer of formula (II) defined herein, the molar ratio of [compound A] / [alkyl acrylate of formula (I)] is selected 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, in particular from about 0.5:1 to about 0.2:1.

[0019] Preferably, in the process for preparing the dimer of formula (II) defined herein, R is a C1-C 18 , more preferably C1 to C8 alkyl, further preferably C1 to C4 alkyl, and most preferably methyl.

[0020] Preferably, in the process for preparing a dimer of formula (II) as defined herein, R is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, 2-ethylhexyl, octyl, decyl, dodecyl, t-dodecyl, tetradecyl, hexadecyl or octadecyl, more preferably methyl, ethyl, isopropyl, butyl or 2-ethylhexyl, even more preferably methyl, ethyl, isopropyl or butyl, and most preferably methyl.

[0021] Preferably, in the process for preparing a dimer of formula (II) as defined herein, R1 and R2 are identical linear or branched alkyl groups containing 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, and most preferably ethyl.

[0022] Preferably, in the process for preparing a dimer of formula (II) as defined herein, R1 and R2 together with the N atom form a heteroaliphatic ring containing 3 to 5 carbon atoms, preferably 4 carbon atoms.

[0023] Preferably, in the process for the preparation of a dimer of formula (II) as defined herein, R a is either an aromatic group or an aliphatic group, more preferably an aromatic group, and even more preferably 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.

[0024] Preferably, R ais phenyl; ortho-, meta-, or para-tolyl; xylyl including all positional isomers, e.g., 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, 2-methoxy-3-methylphenyl, 2- Mesityl including all positional isomers, for example, 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; duryl including all positional isomers, for example, 2,3,4,5-tetramethylphenyl, 2,3,4,6-tetramethylphenyl, and 2,3,5,6-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 nyl, 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; 2-furyl, 3-furyl;It is selected from 1-pyrrolyl, 2-pyrrolyl, or 3-pyrrolyl; 2-thiophenyl, 3-thiophenyl; 2-indolyl, 3-indolyl, 2-benzofuryl, and 3-benzofuryl; preferably phenyl; ortho-, meta-, or para-tolyl; or xylyl and its positional isomers;

[0025] Preferably, in the process for the preparation of a dimer of formula (II) as defined herein, R b is NR3R4, where R3 and R4 are the same or different and are an aliphatic group or form a heteroaliphatic ring together with the N atom, more preferably R3 and R4 are the same linear or branched alkyl group containing 1 to 6 carbon atoms, even more preferably 1 to 3 carbon atoms, and most preferably ethyl.

[0026] Preferably, in the process for the preparation of a dimer of formula (II) as defined herein, R a is phenyl, R1 and R2 are ethyl, R b is NR3R4, where R3 and R4 are ethyl.

[0027] Preferably, in the process for the preparation of a dimer of formula (II) as defined herein, the catalyst of formula (III) is a compound of formulae (VIII) to (XIV): [ka] The compound is selected from the group consisting of:

[0028] More preferably, in the process for preparing a dimer of formula (II) as defined herein, the catalyst of formula (III) is a compound selected from the group consisting of compounds of formulae (IX) and (XI) to (XIV), more preferably selected from compounds of formulae (XI), (XII) and (XIV), more preferably selected from the group consisting of compounds of formulae (XI) and (XIV), and most preferably the catalyst of formula (III) is a compound of formula (XIV).

[0029] Preferably, in the process for the preparation of a dimer of formula (II) as defined herein, the dimerization step i) is carried out in an organic solvent, more preferably in an aprotic solvent, further preferably in a solvent selected from tetrahydrofuran (THF), methyl-tetrahydrofuran (MeTHF), toluene, xylene, anisole, diethyl ether, tert-butyl methyl ether (MTBE), dichloromethane (DCM), chloroform, dioxane, pentane, cyclopentane, hexane, cyclohexane, methylcyclohexane, benzene and acetonitrile, further preferably from MeTHF, anisole and toluene, most preferably from MeTHF and anisole.

[0030] Preferably, in the process for producing a dimer of formula (II) as defined herein, the dimerization step i) is carried out at a temperature in the range of about 20°C to about 120°C, more preferably about 20°C to about 80°C, even more preferably about 25°C to about 60°C, and most preferably about 30°C to about 60°C.

[0031] Preferably, in the process for producing a dimer of formula (II) defined herein, the catalyst of formula (III) in step i) is used in a catalyst addition amount of 0.20 mol % to 1.00 mol %, more preferably about 0.25 mol % to about 0.90 mol %, even more preferably about 0.30 mol % to about 0.90 mol %, even more preferably about 0.30 mol % to about 0.80 mol %, even more preferably about 0.30 mol % to about 0.70 mol %, even more preferably about 0.30 mol % to about 0.60 mol %, and most preferably about 0.30 mol % to 0.50 mol %, based on the alkyl acrylate of formula (I).

[0032] Preferably, in the process for the preparation of the dimer of formula (II) as defined herein, the dimerization step i) is carried out under anhydrous conditions and in the absence of oxygen.

[0033] Preferably, the process for the preparation of a dimer of formula (II) as defined herein comprises the step of reacting a compound of formula (IV) [ka] (In the formula, X is chloride, bromide, or iodide, preferably chloride; R a is a hydrocarbyl group, R c is X(R b In the case of a catalyst of formula (III) where R is NR3R4 as defined above, or R b (R b is an aliphatic group) of, Formula (V): R1R2NH(V) (wherein R1 and R2 are R c R b or - an amine of formula (V) and a compound of formula (V'): R3R4NH(V') (wherein R3 and R4 are R c is as defined above for X, The method further comprises an initial step 0) of preparing a catalyst of formula (III) by reacting

[0034] Preferably, in the process for preparing the dimer of formula (II) as defined herein, steps 0) and i) are consecutive steps carried out without isolating the catalyst after step 0).

[0035] Preferably, in the process for the preparation of a dimer of formula (II) as defined herein, R c is X.

[0036] Preferably, in the process for the preparation of the dimer of formula (II) as defined herein, step 0) is carried out in an organic solvent, more preferably in an aprotic solvent, further preferably selected from tetrahydrofuran (THF), methyltetrahydrofuran (MeTHF), toluene, xylene, anisole, diethyl ether, tert-butyl methyl ether (MTBE), dichloromethane (DCM), chloroform, dioxane, pentane, cyclopentane, hexane, cyclohexane, methylcyclohexane, benzene and acetonitrile, further preferably selected from MeTHF, anisole and toluene, most preferably selected from MeTHF and anisole.

[0037] Preferably, in the process for preparing the dimer of formula (II) defined herein, step 0) is carried out at a temperature in the range of about 20°C to about 100°C, preferably about 20°C to 80°C, more preferably about 25°C to 60°C, and most preferably about 40°C.

[0038] Preferably, in the process for preparing the dimer of formula (II) as defined herein, step 0) is carried out by slowly adding the reactant of (IV) to a solution of an amine R1R2NH in an aprotic solvent, where the amine is R c R b and R b When Rc in (IV) is an aliphatic group, it is used in an amount of 2 equivalents or more relative to the reactant of formula (IV). Step (0) can also be carried out by slowly adding the reactant of formula (IV) to a solution containing both amines R1R2NH and R3R4NH in an aprotic solvent, where the total amount of amines is 4 equivalents or more relative to the reactant of formula (IV) when Rc in (IV) is X.

[0039] Preferably, in the process for preparing the dimer of formula (II) as defined herein, step 0) is carried out under anhydrous conditions and in the absence of oxygen.

[0040] Preferably, in the process for preparing the dimer of formula (II) as defined herein, step 0) comprises a filtration step to remove the by-product ammonium chloride formed before carrying out step i).

[0041] The present invention further relates to a process for the preparation of a dimer of formula (II) as defined herein, followed by hydrogenation of the dimer of formula (II) obtained in the dimerization step using H and a hydrogenation catalyst to obtain a dimer of formula (VI) [ka] (wherein R is as defined above). and ii) step ii) to obtain a compound of formula (VI), wherein the hydrogenation catalyst is for example a Pd based catalyst, such as Pd / C, Pd / Al2O3, Pd / SiO2, a Ru based catalyst, such as Ru / C, a Pt based catalyst, such as Pt / C, a Ni based catalyst, such as supported nickel or Raney nickel catalyst, a Co based catalyst, such as supported cobalt or Raney cobalt, a Rh based catalyst, such as Rh / C, an Ir based catalyst, such as Ir / C, preferably Pd / C or Raney nickel, preferably Pd / C.

[0042] In a preferred embodiment, the process for preparing the compound of formula (VI) comprises hydrolyzing the hydrogenated dimer of formula (VI) obtained in step ii) using an acid catalyst such as a Lewis acid or a Brønsted acid, e.g. HCl, H2SO4, paratoluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, a solid acid catalyst such as Amberlyst resin, zeolite, or Nafion, to give a compound of formula (XV): [ka] The method further comprises a step ii') of obtaining the compound of formula (1).

[0043] Finally, the present invention relates to a process as defined above, followed by hydrolysis of the dimer of formula (II) obtained in the dimerization step, using an acid catalyst such as a Lewis acid or a Brönsted acid, e.g. HCl, H2SO4, paratoluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, a solid acid catalyst, e.g. Amberlyst resin or a zeolite, Nafion, to obtain a dimer of formula (VII) [ka] and step ii') of obtaining a compound of formula (VII).

[0044] In a preferred embodiment, the method for preparing the compound of formula (VII) comprises hydrogenating the hydrolyzed dimer of formula (VII) obtained in step ii') using H and a hydrogenation catalyst to obtain a compound of formula (XV): [ka] wherein the hydrogenation catalyst is for example a Pd based catalyst, such as Pd / C, Pd / Al2O3, Pd / SiO2, a Ru based catalyst, such as Ru / C, a Pt based catalyst, such as Pt / C, a Ni based catalyst, such as supported nickel or Raney nickel catalyst, a Co based catalyst, such as supported cobalt or Raney cobalt, a Rh based catalyst, such as Rh / C, an Ir based catalyst, such as Ir / C, preferably Pd / C or Raney nickel, preferably Pd / C. EXAMPLES

[0045] 1. Dimerization of methyl acrylate catalyzed by aminophosphine catalysts Basic protocol for phosphine screening survey: a) Dimerization from dichlorophosphines catalyzed by symmetrical bisaminophosphines: All reactions were carried out under an inert argon atmosphere in carefully dried vessels. Prior to each reaction, methyl acrylate and tert-butanol were dried using 4A molecular sieves, and tert-butanol was distilled under argon. Dichlorophosphine and amines were used as received.

[0046] In a 25mL two-neck round-bottom flask, 3 mL of 2-methyltetrahydrofuran Dichlorophosphine precursor (1.8 mmol, 0.01 equivalent to methyl acrylate) Add the following.

[0047] In a 50 mL three-neck round bottom flask equipped with a magnetic stirrer, 1 mL of 2-methyltetrahydrofuran 4 equivalents (7.2 mmol) of the desired amine relative to the dichlorophosphine precursor was added.

[0048] The dichlorophosphine solution was added slowly to the amine solution over 1 hour with stirring (1400 rpm) while maintaining the temperature of the reaction medium below 40° C. (exothermic reaction). Upon addition of dichlorophosphine to the amine solution, a white precipitate was formed, which corresponds to the insoluble ammonium chloride salt by-product. After addition was complete, the mixture was stirred at ambient temperature and 31 The progress of the reaction was followed by P NMR ( 31 See Table 1 below for P chemical shift results).

[0049] After phosphine formation was complete (usually 1 hour of stirring at room temperature after addition of the chlorophosphine for unhindered amines and 2 hours for more hindered amines), the mixture was cannulated and placed 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 reactor over 1 hour (exothermic) to monitor the progress of the reaction. 1 The reaction was monitored by H NMR. The reaction was allowed to proceed until it stopped or until one day had passed from the start of the reaction. After that, the conversion rate of methyl acrylate was calculated by integrating the methylene protons of the product and the methylene protons of the starting material, methyl acrylate. 1 Estimated from 1 H NMR.

[0050] 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).

[0051] b) Dimerization from monochlorophosphines catalyzed by monoaminophosphines: All reactions were carried out under an inert argon atmosphere in carefully dried vessels. Prior to each reaction, methyl acrylate and tert-butanol were dried using 4A molecular sieves, and tert-butanol was distilled under argon. Monochlorophosphines and amines were used as received.

[0052] In a 25mL two-neck round-bottom flask, 3 mL of 2-methyltetrahydrofuran Monochlorophosphine precursor (1.8 mmol, 0.01 equivalent relative to methyl acrylate) was added.

[0053] In a 50 mL three-neck round bottom flask equipped with a magnetic stirrer, 1 mL of 2-methyltetrahydrofuran 2 equivalents (3.6 mmol) of the desired amine per monochlorophosphine precursor was added.

[0054] The monochlorophosphine solution was added slowly to the amine solution over 1 hour with stirring (1400 rpm) while maintaining the temperature of the reaction medium below 40° C. (exothermic reaction). The addition of monochlorophosphine to the amine solution resulted in the formation of a white precipitate corresponding to the insoluble ammonium chloride salt by-product. After the addition was complete, the mixture was stirred at ambient temperature and 31 The progress of the reaction was followed by P NMR.

[0055] After phosphine formation was complete (usually 1 hour of stirring at room temperature after addition of monochlorophosphine for unhindered amines and 2 hours for more hindered amines), the mixture was filtered through a cannula and placed 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 reactor over 1 hour (exothermic) to monitor the progress of the reaction. 1 The reaction was monitored by H NMR. The reaction was allowed to proceed until it stopped or until one day had passed from the start of the reaction. After that, the conversion rate of methyl acrylate was calculated by integrating the methylene protons of the product and the methylene protons of the starting material, methyl acrylate. 1 Estimated from 1 H NMR.

[0056] c) Dimerization of dichlorophosphine with diisopropylamine and an additional amine catalyzed by an unsymmetrical bisaminophosphine: All reactions were carried out under an inert argon atmosphere in carefully dried vessels. Prior to each reaction, methyl acrylate and tert-butanol were dried using 4A molecular sieves, and tert-butanol was distilled under argon. Dichlorophosphine and amines were used as received.

[0057] In a 25mL two-neck round-bottom flask, 3 mL of 2-methyltetrahydrofuran Dichlorophosphine precursor (1.8 mmol, 0.01 equivalent to methyl acrylate) was added.

[0058] In a 50 mL three-neck round bottom flask equipped with a magnetic stirrer, 1 mL of 2-methyltetrahydrofuran Three equivalents (5.4 mmol) of diisopropylamine were added to the dichlorophosphine precursor.

[0059] The dichlorophosphine solution was added slowly to the amine solution over 1 hour with stirring (1400 rpm) 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 corresponding to the insoluble ammonium chloride salt by-product (in this case diisopropylammonium chloride). The mixture was then stirred at ambient temperature and 31 The progress of the reaction was followed by P NMR. The formation of the intermediate chloro(diisopropylamino)phosphine was 31 This was confirmed by P NMR (e.g., a singlet was observed at +132.5 ppm for chlorophenyl(diisopropylamino)phosphine).

[0060] After the formation of chloroaminophosphine intermediate was complete (usually requires 1 hour of stirring at room temperature 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 at room temperature for another 1 hour.

[0061] After completion of the bisaminophosphine, the mixture was filtered through a cannula and placed 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 reactor over 1 hour (exothermic) to monitor the progress of the reaction. 1 The reaction was monitored by H NMR. The reaction was allowed to proceed until it stopped or until one day had passed from the start of the reaction. After that, the conversion rate of methyl acrylate was calculated by integrating the methylene protons of the product and the methylene protons of the starting material, methyl acrylate. 1 Estimated from 1 H NMR.

[0062] To confirm that the synthesis of the desired catalyst was successful, 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 using a Bruker Avance 400 MHz spectrometer.

[0063] Furthermore, - Recorded in Me-THF solution before transfer to dimerization reactor 31 NMR yield (%) of phosphine, corresponding to the molar selectivity of the aminophosphine synthesis reaction, estimated from the peak areas of the P NMR spectrum; - The maximum conversion during acrylate dimerization in some tests shown in Table 1 ( 1 corresponds to maximum conversion of methyl acrylate as determined by H NMR); was measured.

[0064] The v:v (and mol / mol) ratios of t-BuOH:acrylate are also shown.

[0065] For Inv4.4, 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 until an initial dichlorophenylphosphine loading of 0.33 mol % was reached) after 20 h reaction time.

[0066] All results are summarized in Table 1 below:

[0067] [Table 1]

[0068] All phosphines were synthesized.

[0069] The chlorodiphenylphosphine precursor reacted with diisopropylamine to give aminophosphines in moderate yields (Comp1), but did not give good catalytic activity. The chlorodiphenylphosphine precursor reacted with pyrrolidine (Comp2), but also did not give good catalytic activity. On the other hand, the aminophosphines according to the invention (Inv1-7) provided very good catalytic activity.

[0070] The best system, which showed the best performance, was diisopropylamino-pyrrolidino-phenylphosphine (Inv4.1-4.4). It was quite surprising that with diisopropylamino-pyrrolidino-phenylphosphine (Inv4.4), 91% acrylate conversion was reached with an initial dichlorophosphine loading of only 0.33 mol %. In addition, this phosphine was found to be very robust, easy to handle, and even recyclable over multiple batches.

[0071] The presence of tert-butyl alcohol during the dimerization reaction allowed the selectivity of the reaction towards the expected dimer to be improved. Surprisingly, suitable conditions were further found which allowed the use of t-BuOH and very small amounts of basic aminophosphines without compromising the catalytic activity of the phosphine and still gave good selectivity.

[0072] d) Optimization of the dimerization reaction: dimerization of methyl acrylate in t-butanol catalyzed by bis(diethylamino)phenylphosphine (initial amount of dichlorophenylphosphine precursor 0.7 mol % with respect to methyl acrylate) (1:4 v / v t-BuOH:methyl acrylate=0.24 mol (t-BuOH) / mol (methyl acrylate)) at 45° C. All reactions were carried out under an inert argon atmosphere in carefully dried vessels. Prior to each reaction, methyl acrylate and tert-butanol were dried using 4A molecular sieves, and tert-butanol was distilled under argon. Dichlorophenylphosphine and diethylamine were used as received.

[0073] In a 50mL two-neck round-bottom flask, 15mL of 2-methyltetrahydrofuran 4.2 mL of dichlorophenylphosphine (5.57 g, 0.031 mol, 0.007 equiv.) was added.

[0074] In a 100 mL three-neck round bottom flask equipped with a magnetic stirrer, 20mL of 2-methyltetrahydrofuran 12.9 mL of diethylamine (9.1 g, 0.124 mol, 0.028 equiv.) (4 equiv. relative to dichlorophenylphosphine) was added.

[0075] The solution of dichlorophenylphosphine in 2-methyltetrahydrofuran was added slowly to the amine solution over 1 h with stirring (1400 rpm) while maintaining the temperature of the reaction medium below 40° C. (exothermic reaction). Upon addition of dichlorophenylphosphine, a white precipitate was formed, which corresponds to the ammonium chloride salt by-product (in this case diethylammonium chloride). After the addition was complete, the mixture was stirred at ambient temperature and the progress of the reaction was followed by NMR.

[0076] After the formation of bis-(diethylamino)phenylphosphine is complete, which requires 1 hour of stirring at room temperature after the addition of dichlorophenylphosphine, the mixture is filtered through a cannula and placed in a flask equipped with a temperature probe, a condenser, a mechanical stirrer (propeller with four angled plows) and 100 mL of distilled tert-butanol (1:4 v / v tert-butanol:methyl acrylate) 400 mL of methyl acrylate (380.8 g, 4.42 mol, 1 equiv.) The mixture was placed in a 500 mL double jacketed reactor containing 100% ethanol and maintained at 45°C.

[0077] The mixture was then stirred at 45° C. for 19 hours. 1 The conversion of methyl acrylate was monitored by H NMR. The conversion of methyl acrylate was determined by integrating the methylene protons of the product and the methylene protons of the starting material, methyl acrylate. 1 The conversion rate of the starting material, methyl acrylate, was estimated from 1 H NMR. According to NMR, the conversion rate of the starting material, methyl acrylate, was about 92 mol %.

[0078] At the end of the reaction, the volatile materials (t-BuOH, Me-THF, and unconverted methyl acrylate) were distilled off, and 31 g of unreacted methyl acrylate was recovered. The target product (dimethyl 2-methyleneglutarate) was then vacuum distilled (160°C, 15 mbar) to give 283 g of analytically pure product (isolated yield = 75%). The high-boiling by-products (methyl acrylate oligomers) remaining in the distillation vessel accounted for about 57 g (15%).

[0079] 1 HNMR(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).

[0080] 13 C NMR (CDCl3, 101 MHz) δ (ppm): 172.73, 166.75, 138.76, 125.56, 51.59, 51.26, 32.66, and 27.17.

[0081] e) Dimerization of methyl acrylate in tert-butanol catalyzed by bis(diethylamino)phenylphosphine (0.7 mol % dichlorophenylphosphine precursor relative to methyl acrylate) (1:8 v / v t-BuOH:methyl acrylate=0.12 mol (t-BuOH) / mol (methyl acrylate)), 45° C. All reactions were carried out under an inert argon atmosphere in carefully dried vessels. Prior to each reaction, methyl acrylate and tert-butanol were dried using 4A molecular sieves, and tert-butanol was distilled under argon. Dichlorophenylphosphine and diethylamine were used as received.

[0082] In a 50mL two-neck round-bottom flask, 15mL of 2-methyltetrahydrofuran 4.2 mL of dichlorophenylphosphine (5.57 g, 0.031 mol, 0.007 equiv.) Add the following.

[0083] In a 100 mL three-neck round bottom flask equipped with a magnetic stirrer, 20mL of 2-methyltetrahydrofuran 12.9 mL of diethylamine (9.1 g, 0.124 mol, 0.028 equiv.) (4 equiv. relative to dichlorophenylphosphine) was added.

[0084] The solution of dichlorophenylphosphine in 2-methyltetrahydrofuran was added slowly to the diethylamine solution over 1 hour with stirring (1400 rpm) while maintaining the temperature of the reaction medium below 40° C. (exothermic reaction). The addition of dichlorophenylphosphine resulted in the formation of a white precipitate corresponding to the ammonium chloride salt by-product (in this case diethylammonium chloride). After the addition of dichlorophosphine was complete, the mixture was stirred at ambient temperature and the progress of the reaction was followed by NMR.

[0085] After the formation of bis-(diethylamino)phenylphosphine is complete, which requires 1 hour of stirring at room temperature after the addition of dichlorophenylphosphine, the mixture is filtered through a cannula and placed in a flask equipped with a temperature probe, a condenser, a mechanical stirrer (propeller with four angled plows) and 50mL distilled tert-butanol (1:8 v / v tert-butanol:methyl acrylate) 400 mL of methyl acrylate (380.8 g, 4.42 mol, 1 equiv.) The mixture was placed in a 500 mL double jacketed reactor containing 100% ethanol and maintained at 45°C.

[0086] The mixture was then stirred at 45° C. for 19 hours. 1 The conversion of methyl acrylate was monitored by H NMR. The conversion of methyl acrylate was determined by integrating the methylene protons of the product and the methylene protons of the starting material, methyl acrylate. 1 The reaction was estimated from H NMR. According to NMR, the conversion of the starting material methyl acrylate was about 88 mol%. At the end of the reaction, the volatile materials (t-BuOH, Me-THF, and unconverted methyl acrylate) were distilled off, and 44 g of unreacted methyl acrylate was recovered.

[0087] The target product (dimethyl 2-methyleneglutarate) was then vacuum distilled (160°C, 15 mbar) to give 271 g of analytically pure product (isolated yield = 71%). High-boiling by-products (methyl acrylate oligomers) remaining in the distillation vessel accounted for about 59 g (16%).

[0088] 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).

[0089] 13 C NMR (CDCl3, 101 MHz) δ (ppm): 172.73, 166.75, 138.76, 125.56, 51.59, 51.26, 32.66, and 27.17.

[0090] f) Dimerization of methyl acrylate in tert-butanol catalyzed by bis(diethylamino)phenylphosphine (0.7 mol % dichlorophenylphosphine precursor relative to methyl acrylate) (1:8 v / v t-BuOH:methyl acrylate=0.12 mol (t-BuOH) / mol (methyl acrylate)), 60° C., average of two batches. All reactions were carried out under an inert argon atmosphere in carefully dried vessels. Prior to each reaction, methyl acrylate and tert-butanol were dried using 4A molecular sieves, and tert-butanol was distilled under argon. Dichlorophenylphosphine and diethylamine were used as received.

[0091] In a 25mL two-neck round-bottom flask, 8 mL of 2-methyltetrahydrofuran 2.1 mL of dichlorophenylphosphine (2.79 g, 0.0155 mol, 0.007 equiv.) was added.

[0092] In a 50 mL three-neck round bottom flask equipped with a magnetic stirrer, 10 mL of 2-methyltetrahydrofuran 6.5 mL of diethylamine (4.6 g, 0.062 mol, 0.028 eq.) (4 eq. relative to dichlorophenylphosphine) was added.

[0093] The solution of dichlorophenylphosphine in 2-methyltetrahydrofuran was slowly added to the diethylamine solution over 1 hour with stirring (1400 rpm) while maintaining the temperature of the reaction medium below 40° C. (exothermic reaction). Upon addition of dichlorophenylphosphine, a white precipitate was formed, which corresponds to the by-product diethylammonium chloride salt. The mixture was then stirred at ambient temperature and the progress of the reaction was followed by NMR.

[0094] After the formation of bis-(diethylamino)phenylphosphine is complete, which requires 1 hour of stirring at room temperature after the addition of dichlorophenylphosphine, the mixture is filtered through a cannula and placed in a flask equipped with a temperature probe, a condenser, a mechanical stirrer (propeller with four angled plows) and 25 mL of distilled tert-butanol (1:8 v / v tert-butanol:methyl acrylate) 200 mL of methyl acrylate (190 g, 2.21 mol, 1 equiv.) The mixture was placed in a 500 mL double jacketed reactor containing 100 mL of ethyl acetate and maintained at 60°C.

[0095] The mixture was then stirred at 60° C. for 20 hours. 1 The conversion of methyl acrylate was monitored by H NMR. The conversion of methyl acrylate was determined by integrating the methylene protons of the product and the methylene protons of the starting material, methyl acrylate. 1 The conversion of the starting material methyl acrylate was estimated from H NMR. According to NMR, the conversion was about 95 mol% (average of two batches). At the end of the reaction, the volatiles (t-BuOH, Me-THF, and unconverted methyl acrylate) were distilled off.

[0096] The target product (dimethyl 2-methyleneglutarate) was then vacuum distilled (140°C, 5 mbar) to give 137 g of analytically pure product (average of two batches, isolated yield = 72%). High-boiling by-products (mainly methyl acrylate oligomers) remaining in the distillation vessel accounted for about 40 g (21%, average of two batches).

[0097] g) Dimerization of methyl acrylate in tert-butanol catalyzed by bis(diethylamino)phenylphosphine (0.9 mol % dichlorophenylphosphine precursor relative to methyl acrylate) (1:4 v / v t-BuOH:methyl acrylate = 0.24 mol (t-BuOH) / mol (methyl acrylate)), 30°C. All reactions were carried out under an inert argon atmosphere in carefully dried vessels. Prior to each reaction, methyl acrylate and tert-butanol were dried using 4A molecular sieves, and tert-butanol was distilled under argon. Dichlorophenylphosphine and diethylamine were used as received.

[0098] In a 50 mL two-neck round-bottom flask, 20mL of 2-methyltetrahydrofuran 5.43 mL of dichlorophenylphosphine (7.17 g, 0.04 mol, 0.009 equiv.) Add the following.

[0099] In a 100 mL three-neck round bottom flask equipped with a magnetic stirrer, 20mL of 2-methyltetrahydrofuran Add 16.6 mL of diethylamine (11.7 g, 0.16 mol, 0.036 equiv.) (4 equiv. relative to dichlorophenylphosphine).

[0100] The solution of dichlorophenylphosphine in 2-methyltetrahydrofuran was added slowly to the amine solution over 1 h with stirring (1400 rpm) while maintaining the temperature of the reaction medium below 40° C. (exothermic reaction). Upon addition of dichlorophenylphosphine, a white precipitate was formed, which corresponds to the by-product diethylammonium chloride salt. After the addition of dichlorophosphine was complete, the mixture was stirred at ambient temperature and the progress of the reaction was followed by NMR.

[0101] After the formation of bis-(diethylamino)phenylphosphine is complete, which requires 1 hour of stirring at room temperature after the addition of dichlorophenylphosphine, the mixture is filtered through a cannula and placed in a flask equipped with a temperature probe, a condenser, a mechanical stirrer (propeller with four angled plows) and 100 mL of distilled tert-butanol (1:4 v / v tert-butanol:methyl acrylate) 400 mL of methyl acrylate (380.8 g, 4.42 mol, 1 equiv.) The mixture was placed in a 500 mL double jacketed reactor containing 100 mL of ethyl acetate and maintained at 30°C.

[0102] The mixture was then stirred for 20 hours at 30° C. The progress of the reaction was 1 The reaction was monitored by H NMR. At this stage, the conversion level of methyl acrylate was 1 The purity was estimated to be 93% by H NMR. The volatiles (2-methyltetrahydrofuran, t-BuOH, and residual methyl acrylate) were then removed under vacuum to recover 27 g of methyl acrylate. The desired dimethyl 2-methyleneglutarate was then vacuum distilled (160 °C, 15 mbar) to recover 284 g of analytically pure product, corresponding to an isolated and purified yield of 75%. High-boiling by-products (mainly methyl acrylate oligomers) remaining in the distillation pot accounted for 49 g (13%).

[0103] h) Dimerization of methyl acrylate in tert-butanol catalyzed by bis(diethylamino)phenylphosphine (0.9 mol % dichlorophenylphosphine precursor relative to methyl acrylate) (1:4 v / v t-BuOH:methyl acrylate=0.24 mol (t-BuOH) / mol (methyl acrylate)), 30° C., gradual addition of methyl acrylate. All reactions were carried out under an inert argon atmosphere in carefully dried vessels. Prior to each reaction, methyl acrylate, tert-butanol, and diethylamine were dried using 4A molecular sieves, and tert-butanol was distilled under argon. Dichlorophenylphosphine was used as received.

[0104] In a 50mL two-neck round-bottom flask, 20mL of 2-methyltetrahydrofuran 5.43 mL of dichlorophenylphosphine (7.17 g, 0.04 mol, 0.009 equiv.) Add the following.

[0105] In a 100 mL three-neck round bottom flask equipped with a magnetic stirrer, 20mL of 2-methyltetrahydrofuran 16.6 mL of diethylamine (11.7 g, 0.16 mol, 0.036 eq.) (4 eq. relative to dichlorophenylphosphine) was added.

[0106] The solution of dichlorophenylphosphine in 2-methyltetrahydrofuran was slowly added to the diethylamine solution over 1 hour with stirring (1400 rpm) while maintaining the temperature of the reaction medium below 40° C. (exothermic reaction). Upon addition of dichlorophenylphosphine, a white precipitate was formed, which corresponds to the by-product diethylammonium chloride salt. After the addition of dichlorophosphine was complete, the mixture was stirred at ambient temperature and the progress of the reaction was followed by NMR.

[0107] After the formation of bis-(diethylamino)phenylphosphine is complete, which requires 1 hour of stirring at room temperature after the addition of dichlorophenylphosphine, the mixture is filtered through a cannula and placed in a flask equipped with a temperature probe, a condenser, a mechanical stirrer (propeller with four angled plows) and 100 mL of distilled tert-butanol (1:4 v / v tert-butanol:methyl acrylate) 100 mL of methyl acrylate (95.2 g, 1.105 mol, 0.25 equiv.) The mixture was placed in a 500 mL double jacketed reactor containing 100 mL of ethyl acetate and maintained at 30°C.

[0108] Then, 300 mL of methyl acrylate (285.6 g, 3.315 mol, 0.75 eq.) was slowly added to the reactor over a period of 4 hours. After the addition was complete, the mixture was stirred at 30° C. for 16 hours. The progress of the reaction was 1 The reaction was monitored by H NMR. At this stage, the conversion level of methyl acrylate was 1 Estimated to be 92% by 1 H NMR.

[0109] The volatile materials (2-methyltetrahydrofuran, t-BuOH, and residual methyl acrylate) were then removed under vacuum to recover 29 g of methyl acrylate. The desired dimethyl 2-methyleneglutarate was then vacuum distilled (160°C, 15 mbar) to recover 288 g of analytically pure product, corresponding to an isolated and purified yield of 76%. The high-boiling by-products (methyl acrylate oligomers) remaining in the distillation vessel accounted for 49 g (13%).

[0110] i) Dimerization of methyl acrylate in tert-butanol catalyzed by (diisopropylamino)pyrrolidinophenylphosphine (0.4 mol % dichlorophenylphosphine precursor relative to methyl acrylate) (1:8 v / v t-BuOH:methyl acrylate=0.12 mol (t-BuOH) / mol (methyl acrylate)), at 60° C., with catalyst recycle. All reactions were carried out under an inert argon atmosphere in carefully dried vessels. Prior to each reaction, methyl acrylate and tert-butanol were dried using 4A molecular sieves, and tert-butanol was distilled under argon. Dichlorophenylphosphine, diisopropylamine, and pyrrolidine were used as received.

[0111] In a 50mL two-neck round-bottom flask, 20mL of 2-methyltetrahydrofuran 3.6 mL of dichlorophenylphosphine (4.77 g, 0.027 mol, 0.012 eq.) was added.

[0112] In a 100 mL three-neck round bottom flask equipped with a magnetic stirrer, 20mL of 2-methyltetrahydrofuran 11.15 mL of diethylamine (8.05 g, 0.08 mol, 0.036 eq.) (3 eq. relative to dichlorophenylphosphine) was added.

[0113] The solution of dichlorophenylphosphine in 2-methyltetrahydrofuran was slowly added to the diisopropylamine solution over 1 hour with stirring (1400 rpm) 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 for a further hour at room temperature to complete the formation of the bis-(amino)phosphine.

[0114] The reaction mixture was filtered through a cannula and equipped with a temperature probe, a condenser, a mechanical stirrer (propeller with four angled plows) and 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.) The mixture was placed in a 500 mL double jacketed reactor containing

[0115] The mixture was then stirred at 60° C. for 19 hours. 1 The reaction was monitored by 1 H NMR. 1 NMR showed that the conversion of the starting methyl acrylate was about 86 mol %.

[0116] The volatiles (t-BuOH, Me-THF, and unconverted methyl acrylate) are distilled off and 20 g of methyl acrylate is recovered.

[0117] The desired product (dimethyl 2-methylene glutarate) is then vacuum distilled (125° C., 7 mbar) to give 103 g of analytically pure product.

[0118] Then 190 g of methyl acrylate (2.2 mol, 1 eq.) are added to the residue still containing the active phosphine catalyst, followed by 20 g of tert-butanol. The mixture is stirred for a further 16 h at 60° C. to effect conversion of the second batch of methyl acrylate. 37 g of methyl acrylate are recovered by distilling off the volatiles, and 126 g of analytically pure product is obtained by vacuum distillation of the product (125° C., 8 mbar).

[0119] Finally, an additional 190 g of methyl acrylate (2.2 mol, 1 eq.) is added to the residue still containing the active phosphine and the mixture is stirred again for 20 h at 70° C. After completion of the reaction, the volatiles are removed under vacuum to recover 44 g of methyl acrylate and the product is vacuum distilled to give 91 g of pure product.

[0120] A total of 320 g of dimethyl 2-methyleneglutarate product is recovered, corresponding to an overall isolated and purified yield of 56%.

[0121] This is the first example of an aminophosphine catalyst that can be recycled after an acrylate dimerization reaction.

[0122] j) Effect of the presence or absence of t-BuOH All reactions were carried out under an inert argon atmosphere in carefully dried vessels. Methyl acrylate was dried using 4A molecular sieves. Dichlorophosphine and amines were used as received.

[0123] In a 25mL two-neck round-bottom flask, 18 mL of 2-methyltetrahydrofuran Dichlorophosphine precursor (10.5 mmol, 0.005 equivalents relative to methyl acrylate) was added.

[0124] In a 50 mL three-neck round bottom flask equipped with a magnetic stirrer, 6 mL of 2-methyltetrahydrofuran 3 equivalents of diisopropylamine (31.4 mmol) relative to the dichlorophenylphosphine precursor was added.

[0125] The dichlorophosphine solution was added slowly to the amine solution over 1 hour with stirring (1400 rpm) while maintaining the temperature of the reaction medium below 40° C. (exothermic reaction). Upon addition of dichlorophosphine to the amine solution, a white precipitate was formed, corresponding to the insoluble diisopropylammonium chloride by-product. The mixture was then stirred at ambient temperature and 31 The progress of the reaction was followed by P NMR. The formation of the intermediate chloro(diisopropylamino)phosphine was 31 This was confirmed by P NMR (e.g., a singlet was observed at +132.5 ppm for chlorophenyl(diisopropylamino)phosphine).

[0126] After the formation of chloroaminophosphine intermediate was complete (usually requires 1 hour of stirring at room temperature 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 1 hour at room temperature.

[0127] After completion of the bisaminophosphine, the mixture was filtered through a cannula and placed in a 500 mL double jacketed reactor equipped with a mechanical stirrer (propeller with four angled plows), condenser, heater, temperature probe and 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 integration of the methylene protons in the product and the methylene protons in the starting methyl acrylate. 1 The methyl acrylate conversion rate was estimated from H NMR. 1 The selectivity towards dimer, as determined by 1 H NMR, was estimated to be 78 mol %.

[0128] In contrast, when t-BuOH was present in the reaction (1:1 v / v tert-BuOH:methyl acrylate), with an initial addition of 0.5 mol % dichlorophenylphosphine, at 60 °C (corresponding to Inv 4.3), and at a similar conversion level (66%), the selectivity towards dimer was 87%, clearly demonstrating the positive impact of t-BuOH on the reaction selectivity.

[0129] k) Effect of the amount of addition on the dimerization of methyl acrylate The reaction is carried out under an inert argon atmosphere in a carefully dried vessel. The tert-butanol solvent was flash distilled under argon prior to reaction, and the anisole was dried overnight over activated molecular sieves 4A prior to reaction. The reactants diethylamine and methyl acrylate were also dried overnight over activated molecular sieves 4A prior to reaction.

[0130] K1) A 250 mL double-jacketed reactor equipped with a temperature probe, a mechanical stirrer (propeller with four inclined plows) and baffles was heated at room temperature. 40 g of anisole, 18.4 mL of diethylamine (12.98 g, 177 mmol), Add the following.

[0131] A solution of dichlorophenylphosphine (DCPP) in anisole (previously prepared by diluting 6.17 mL of 97% pure DCCP (8.14 g, 44 mmol) with 30 g of anisole) is slowly added (exothermic) over 1 h to the solution of diethylamine in anisole with stirring (500 rpm) at room temperature.

[0132] During the course of the addition a precipitate (NH2Et2Cl) forms, resulting in a gel-like solution. After the addition is complete, an additional amount of 30 g of anisole is added to the mixture in order to reduce the viscosity of the suspension and the reaction medium is stirred at room temperature for 1 hour and 30 minutes. 31 P NMR analysis confirms that DCPP is completely converted to the desired bis(diethylamino)phenylphosphine at this stage.

[0133] The suspension is then easily filtered in a filtration cell using a 6 μm filter cloth under argon. The solid is washed with an additional 60 g of anisole. A total of 138.4 g of a clear yellow solution is obtained as the filtrate. Quantitative analysis of the solution using triethyl phosphate as an internal probe 31 P NMR analysis allows the concentration of aminophosphine catalyst in solution to be determined: 4.6 wt % corresponds to 6.3 g of catalyst (25 mmol), which corresponds to a catalyst loading of only 0.28 mol % relative to the methyl acrylate.

[0134] In a 1.5 L double jacketed reactor equipped with a condenser, temperature probe, mechanical stirrer (propeller with four inclined plows) and baffles, 157.8 g of tert-butanol (200 mL) is added, followed by the previously prepared solution of catalyst in anisole (138.4 g). The solution is then stirred at 40° C. (500 rpm) and 760 g of methyl acrylate (8.828 moles) is added slowly to the solution over 4 hours (exothermic). After the addition of methyl acrylate is complete, the reaction mixture is stirred overnight at 40° C. and the progress of the reaction is followed by quantitative GC chromatography.

[0135] The conversion of methyl acrylate was followed over time (as was the dimer yield) and the reaction kinetics curves are shown in the graph below (left: methyl acrylate conversion over time, right: dimer yield over time). As can be seen in the graph below (black curve), with a catalyst loading of only 0.28 mol % a final conversion of 66% was obtained after 24 hours at 40°C, which corresponds to a dimer yield of 58%.

[0136] K2) A 250 mL double-jacketed reactor equipped with a temperature probe, a mechanical stirrer (propeller with four pitched plows), and baffles was heated at room temperature. 40 g of anisole, 25.7 mL of diethylamine (18.17 g, 247 mmol), Add the following.

[0137] A solution of dichlorophenylphosphine (DCPP) in anisole (previously prepared by diluting 8.44 mL of 99% pure DCCP (11.13 g, 62 mmol) with 30 g of anisole) is slowly added (exothermic) to the diethylamine solution over 1 h with stirring (500 rpm) at room temperature.

[0138] During the course of the addition a precipitate forms (NH2Et2Cl) which gives a gel-like solution. After the addition is complete, the reaction medium is stirred at 40° C. for 30 minutes. 31 P NMR analysis confirms that DCPP is completely converted to the desired bis(diethylamino)phenylphosphine at this stage.

[0139] The suspension is then filtered via cannula into the medium flask and the solid is washed with an additional 90 g of anisole. A total of 153.7 g of a clear yellow solution is obtained. Quantitative analysis of the solution using triethyl phosphate as an internal probe 31 P NMR analysis allows the concentration of aminophosphine catalyst in solution to be determined: 8.6 wt % corresponds to 13.2 g of catalyst (52 mmol), which corresponds to a catalyst loading of only 0.6 mol % relative to the methyl acrylate.

[0140] In a 1.5 L double jacketed reactor equipped with a condenser, temperature probe, mechanical stirrer (propeller with four inclined plows) and baffles, 157.8 g of tert-butanol (200 mL) is added, followed by the previously prepared solution of catalyst in anisole (153.7 g). The solution is then stirred at 40° C. (500 rpm) and 760 g of methyl acrylate (8.828 moles) is added slowly to the solution over 4 hours (exothermic). After completion of the addition of methyl acrylate, the reaction mixture is stirred overnight at 40° C. and the progress of the reaction is followed by quantitative GC chromatography.

[0141] Inspection of the methyl acrylate conversion (and dimer yield) over time and the reaction kinetics curves shows that after 25 hours at 40° C., a final conversion of over 99% is obtained with a catalyst loading of only 0.6 mol % (corresponding to a dimer yield of 82%).

[0142] K3) A 250 mL double-jacketed reactor equipped with a temperature probe, a mechanical stirrer (a propeller with four pitching plows) and a baffle was heated at room temperature. 40 g of anisole, 25.7 mL of diethylamine (18.17 g, 247 mmol), Add the following.

[0143] A solution of dichlorophenylphosphine (DCPP) in anisole (previously prepared by diluting 8.44 mL of 99% pure DCCP (11.13 g, 62 mmol) with 30 g of anisole) is slowly added (exothermic) to the diethylamine solution over 1 h with stirring (500 rpm) at room temperature.

[0144] During the course of the addition a precipitate forms (NH2Et2Cl) which gives a gel-like solution. After the addition is complete, the reaction medium is stirred at 40° C. for 30 minutes. 31 P NMR analysis confirms that DCPP is completely converted to the desired bis(diethylamino)phenylphosphine at this stage.

[0145] The suspension is then filtered via cannula into a medium flask and the solid is washed with an additional 90 g of anisole. A total of 142.0 g of a clear yellow solution is obtained. Quantitative analysis of the solution using triethyl phosphate as an internal probe 31 P NMR analysis allows the concentration of aminophosphine catalyst in solution to be determined: 7.2 wt % corresponds to 10.22 g of catalyst (41 mmol), which corresponds to a catalyst loading of only 0.46 mol % relative to the methyl acrylate.

[0146] In a 1.5 L double jacketed reactor equipped with a condenser, a temperature probe, a mechanical stirrer (propeller with four inclined plows) and a baffle, 157.8 g of tert-butanol (200 mL) is added, followed by 760 g of methyl acrylate (8.828 moles). The previously prepared solution of catalyst in anisole (142.0 g) is then added to the solution while stirring (500 rpm, exothermic). The solution is then stirred overnight at 40° C. and the progress of the reaction is followed by quantitative GC chromatography.

[0147] Methyl acrylate conversion (and dimer yield) and reaction kinetics curves followed over time show that after 48 h at 40° C., a final conversion of 87% is obtained (corresponding to a dimer yield of 76%) with a catalyst loading of only 0.46 mol %.

[0148] 2. Catalytic hydrogenation of dimethyl 2-methyleneglutarate to dimethyl 2-methylglutarate The substrate dimethyl 2-methyleneglutarate (50 g, 0.29 mol) obtained according to the dimerization reaction (Inv4.4) described above was first placed in a 100 mL autoclave reactor equipped with a mechanical stirrer (Rushton turbine), followed by the addition of the Pd / C (3%) catalyst (powder, water content 51%, corresponding to 1 g wet and 0.49 g dry, 1% by weight with respect to the substrate). The reactor was then sealed and purged three times with 20 bar nitrogen and then three times with 5 bar hydrogen. The reaction mixture was stirred at 1400 rpm and then the temperature of the reaction mixture was set to 40 ° C. The reaction medium was then stirred at 40 ° C and 5 bar hydrogen pressure (1400 rpm) for 6 hours, and the hydrogen consumption was followed over time.

[0149] 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 reactor was purged with nitrogen, the crude product was removed from the reactor 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 yield of 99%) and was used as is.

[0150] 3. Synthesis of 2-methylenepentanedioic acid from dimethyl 2-methylenepentanedioate [ka] A 2 L double jacketed reactor equipped with a mechanical stirrer (propeller with four inclined plows), baffles, a temperature probe, and a distillation column connected to a receiver was 700 g (4.07 mol, 1 eq.) of dimethyl 2-methylenepentanedioate, 879 mL of water (48.8 mol, 12 eq.), 95% sulfuric acid (9 mL, 16.6 g, 0.163 mol, 4 mol % relative to dimethyl 2-methylenepentanedioate, added dropwise from the addition funnel to the reaction mixture at room temperature) Add the following.

[0151] The mixture was then stirred at 120°C to monitor the progress of the reaction. 1The reaction is followed by H NMR analysis. During the course of the reaction, the methanol produced is distilled off from the reaction medium in order to drive the reaction equilibrium towards the desired methylene glutaric acid.

[0152] After stirring at 120°C for 2 hours and 30 minutes, 1 H NMR analysis indicates slow conversion of the diester to the diacid, so an additional amount of sulfuric acid (2.26 mL (0.04 mol, 1 mol %)) is added to the reaction mixture to increase the reaction rate. The temperature of the mixture increases to 130 °C.

[0153] However, even 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 H 2 SO 4 is added again to the reaction mass.

[0154] After stirring at 130° C. for 11 h 30 min, 1060 mL of the water / MeOH mixture is distilled off and 50 mL of fresh water is added to the reaction vessel.

[0155] After stirring at 130°C for 16 hours and 30 minutes, 1 1 H NMR analysis indicates that approximately 10 mol % of unhydrolyzed ester functionality remains and significant formation of polymeric by-products.

[0156] At this stage the mass of distillate recovered is 1195 g including 6 g of insoluble starting diester.

[0157] 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 per H2SO4) are slowly added to the vessel to neutralize the catalyst (exothermic).

[0158] The contents of the reactor, maintained at 80° C., are discharged into a beaker with constant stirring. The mixture solidifies upon cooling and gradually turns into a stiff white paste.

[0159] 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 precipitation of the diacid product.

[0160] The product is then filtered through a sintered filter, giving a very viscous filtrate.

[0161] Wash the cake four times with 80 mL of water, then six times with 70 mL of water, shaking the mixture well before each filtration.

[0162] The resulting aqueous filtrate, allowed to precipitate overnight at room temperature, is filtered and rewashed ten times with 20 mL portions of water to recover additional product.

[0163] The solid fraction is collected and the product is dried under vacuum at 50° C. (10 mbar) for 2 h to give 286 g of a white powder with an organic purity of more than 98% by weight and containing 3% by weight of water (corresponding to an isolated yield of 48%).

[0164] 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. The reaction scheme below: 【Chemical 1】 (In the formula, R is an alkyl group; R １ and R ２ are the same or different and each is an aliphatic group or forms a heteroaliphatic ring together with the N atom, R ａ is a hydrocarbyl group, R ｂ is an aliphatic group or NR ３ R ４ and R ３ and R ４ are the same or different and each is an aliphatic group or forms a heteroaliphatic ring together with the N atom. a process for producing a dimer of formula (II), comprising a step i) of dimerizing an alkyl acrylate of formula (I) using a catalyst of formula (III) to obtain a dimer of formula (II), according to A process wherein the dimerization step i) is carried out in the presence of a compound A which is a tertiary alcohol or a silanol.

2. The method of claim 1, wherein compound A is a tertiary alcohol such as tert-butanol, tert-amyl alcohol, or pinacol, more preferably tert-butanol.

3. 2. The method of claim 1, wherein the molar ratio of [compound A] to [alkyl acrylate of formula (I)] is selected 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.

4. R is C １ ~C １８ , preferably C １ ~C ８ Alkyl, more preferably C １ ~C ４ 2. The method of claim 1, wherein the alkyl is alkyl, most preferably methyl.

5. R １ and R ２ 2. The method of claim 1, wherein are identical straight or branched alkyl groups containing 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, most preferably ethyl.

6. R １ and R ２ The method of claim 1, wherein together with the N atom, forms a heteroaliphatic ring containing 3 to 5 carbon atoms, preferably 4 carbon atoms.

7. R ａ is either an aromatic group or an aliphatic group, preferably an aromatic group, and more preferably 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.

8. R ｂ But NR ３ R ４ and R ３ and R ４ are the same or different, and each is an aliphatic group or forms a heteroaliphatic ring together with the N atom, and preferably ３ and R ４ 2. The method of claim 1, wherein each of the alkyl groups is an identical straight or branched alkyl group containing 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, and most preferably ethyl.

9. R ａ is phenyl, and R １ and R ２ is ethyl, and R ｂ NR ３ R ４ and R ３ and R ４ The method of claim 1 , wherein is ethyl.

10. 2. The process according to claim 1, wherein the dimerization step i) is carried out in an organic solvent, preferably in an aprotic solvent, more preferably in a solvent selected from tetrahydrofuran (THF), methyl-tetrahydrofuran (MeTHF), toluene, xylene, anisole, diethyl ether, tert-butyl methyl ether (MTBE), dichloromethane (DCM), chloroform, dioxane, pentane, cyclopentane, hexane, cyclohexane, methylcyclohexane, benzene, and acetonitrile, even more preferably MeTHF and toluene.

11. 2. The process of claim 1, wherein the dimerization step i) is carried out at a temperature ranging from about 20°C to about 120°C, preferably from about 20°C to about 80°C, more preferably from about 25°C to about 60°C.

12. Compound of formula (IV) 【Chemistry 2】 (In the formula, X is chloride, bromide, or iodide, preferably chloride; R ａ is as defined in claim 1, R ｃ is X or R ｂ and R ｂ is as defined in claim 1) of, - Formula V:R １ R ２ NH(V) (wherein, R １ and R ２ is R ｃ is R ｂ as defined in claim 1 when an amine of formula (V) and a compound of formula (V'): R ３ R ４ NH(V') (wherein, R ３ and R ４ is R ｃ is as defined in claim 1 when X is X, 10. The method of claim 1, further comprising an initial step 0) of preparing a catalyst of formula (III) by reacting

13. 13. The process of claim 12, wherein steps 0) and i) are consecutive steps carried out without isolating the catalyst after step 0).

14. 2. The method according to claim 1, followed by treating the dimer of formula (II) obtained in the dimerization step with H ２ and hydrogenating the compound represented by formula (VI) using a hydrogenation catalyst such as a Pd-based catalyst, a Ru-based catalyst, a Pt-based catalyst, a Co-based catalyst, a Rh-based catalyst, an Ir-based catalyst, and a Ni-based catalyst. 【Chemistry 3】 (wherein R is as defined in claim 1) and ii) obtaining a compound of formula (VI).

15. 10. The method of claim 1, followed by hydrolysis of the dimer of formula (II) obtained in the dimerization step using an acid catalyst such as a Lewis acid or a Bronsted acid to give a dimer of formula (VII): 【Chemistry 4】 and ii′) obtaining a compound of formula (VII).

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