Method for producing alkyl acrylate dimers

Abstract

This invention relates to a method for producing alkyl acrylate dimers. Furthermore, this invention relates to a method for producing hydrogenated alkyl acrylate dimers obtained by the dimerization process according to the present invention. In addition, this invention relates to a method for producing hydrolyzed alkyl acrylate dimers obtained by the dimerization process according to the present invention.

Description

[Technical Field]

[0001] This application claims priority under European Patent Application No. 23167673.5 filed on 13 April 2023, and the entire contents of this application are incorporated herein by reference for all purposes.

[0002] This invention relates to a method for producing alkyl acrylate dimers. Furthermore, this invention relates to a method for producing hydrogenated alkyl acrylate dimers obtained by the dimerization process according to the present invention. In addition, this invention relates to a method for producing hydrolyzed alkyl acrylate dimers obtained by the dimerization process according to the present invention. [Background technology]

[0003] The use of specific phosphines as catalysts to dimerize alkyl acrylates via the Rauhut-Currier reaction has already been described in the prior art.

[0004] U.S. Patent No. 3,074,999A describes the dimerization reaction of alkyl acrylates catalyzed by tertiary phosphines having three alkyl groups, three alicyclic groups, or three aryl groups, such as tributylphosphine or triphenylphosphine. However, these catalysts exhibit low activity in the dimerization reaction. Moderate yields have been reported for the disclosed process, which is a significant drawback for commercial production.

[0005] U.S. Patent No. 3,227,745A describes a dimerization reaction of alkyl acrylates catalyzed by a tertiary phosphine in the presence of a large amount of tert-butyl alcohol as a solvent. The disclosed tertiary phosphine is a trialkylphosphine. However, the described process achieves a low conversion rate of less than 50% of the acrylic ester, which is unsuitable for industrial production processes.

[0006] U.S. Patent No. 3,342,853A describes the dimerization of acrylic acid esters catalyzed by triaminophosphine, which can be generated from PCl3 prior to the dimerization reaction. While a 70-80% methylene glutarate dimer yield has been reported when the reaction is carried out at 60-65°C, a considerable amount of byproducts are also produced. Furthermore, triaminophosphine is generally toxic and a CMR reagent (a reagent with carcinogenic, mutagenic, and reproductive toxicity), and PCl3, a highly hazardous chemical, is used as a precursor when the catalyst is generated in situ. These are major drawbacks to the commercialization and industrialization of this process.

[0007] U.S. Patent No. 3,342,854A describes an acrylic acid ester dimerization reaction catalyzed by either monoaminophosphine or bisaminophosphine. However, the low activity of diphenylaminophosphine for acrylic acid ester dimerization necessitates the use of large amounts of phosphine, which is a significant drawback for commercial production. This is demonstrated in two examples of this patent application, which use in-situ generated dibutylaminodiphenylphosphine or diethylaminodiphenylphosphine catalysts, resulting in dimerization yields of less than 10%. Furthermore, the process described in U.S. Patent No. 3,342,854A produces a considerable amount of byproducts.

[0008] 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 using proazaphosphatran as a phosphine catalyst, with THF or dioxane as the solvent. A yield of up to 82% can be obtained with a catalyst addition of 1 mol%. However, the catalyst described in this paper is very complex and difficult to synthesize, resulting in a high overall catalyst cost, which is a major drawback to industrialization. Furthermore, using a low catalyst addition amount (1 mol%) results in a slow reaction rate at room temperature and a long reaction time (up to 24 hours), which is also a drawback for industrial production. [Overview of the Initiative]

[0009] The object of the present invention is to provide an efficient method for producing alkyl acrylate dimers using a highly active, robust, reusable, inexpensive, and readily available catalyst, which has relatively low toxicity, can be used in relatively low catalyst addition amounts, and provides excellent selectivity.

[0010] Specifically, the object of the present invention is to provide a method for preparing alkyl acrylate dimers that avoids the use of large amounts of tertiary alcohol as a solvent and relatively large amounts of catalyst addition. More specifically, the object of the present invention is to provide an efficient method for preparing hydride alkyl acrylate dimers and an efficient method for preparing hydrolyzed alkyl acrylate dimers.

[0011] This time, it was found that these and other problems can be solved by the method according to the present invention. The present invention has 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 an aliphatic group or together with the N atom form a heteroaliphatic ring) A process for producing a dimer of formula (II) comprising step i) of dimerizing an alkyl acrylate of formula (I) using a catalyst of formula (III) to obtain a dimer of formula (II), where step i) of the dimerization is carried out in the presence of a compound A which is a tertiary alcohol or a silanol, relates to a process in which an acid is added during step i).

[0012] Furthermore, the present invention relates to a compound of formula (IV)

Chemical formula

[0013] Furthermore, the present invention further comprises the method defined above and the subsequent dimerization step, in which the dimer of formula (II) obtained is hydrogenated using H2 and a hydrogenation catalyst to obtain formula (VI). [ka] The present invention provides a method for producing a compound of formula (VI), comprising step ii) obtaining a compound of formula (wherein R is as defined above), wherein the hydrogenation catalyst is, for example, a Pd-based catalyst, e.g., Pd / C, Pd / Al2O3, Pd / SiO2, a Ru-based catalyst, e.g., Ru / C, a Pt-based catalyst, e.g., Pt / C, a Ni-based catalyst, e.g., supported nickel or Raney nickel catalyst, a Co-based catalyst, e.g., supported cobalt or Raney cobalt, a Rh-based catalyst, e.g., Rh / C, an Ir-based catalyst, e.g., Ir / C, preferably Pd / C or Raney nickel, preferably Pd / C.

[0014] This invention relates to a compound of formula (VII') of formula HNR 5 R 5 The amine (wherein R in the formula) 5 and R 6 R is selected from saturated or unsaturated, linear or branched, optionally cyclic, optionally aromatic, and optionally substituted hydrocarbon groups, each having the same or different average number of carbon atoms in the range of 1 to 36, but R 5 and R 6 The process includes an additional step iii) in which the ring members of formula (VII') are reacted (which may optionally form ring members together, which may optionally be substituted and / or optionally contain heteroatoms). [ka] This also relates to the method of producing the compound.

[0015] R 5 Base and R 6The bases are the same or different, in particular C1~C 12 The group can be selected from alkyl groups, aryl groups, alkaryl groups, arylalkyl groups, or phenyl groups. 5 Base and R 6 The group may be optionally substituted, particularly with a hydroxyl group.

[0016] R 5 Base and R 6 The groups may be the same or different and can be selected from, in particular, methyl, ethyl, propyl (n-propyl), isopropyl, n-butyl, isobutyl, n-pentyl, amyl, isoamyl, hexyl, cyclohexyl, or hydroxyethyl groups. 5 Base and R 6 The groups may be such that they form a morpholine group, a piperazine group, a pyrrolidine group, or a piperidine group together with the nitrogen atom. According to a particular embodiment, R 5 =R 6 =methyl, or R 5 =R 6 =Ethyl, or R 5 =R 6 = 2-hydroxyethyl R 5 =R 6 Good results are obtained in the case of methylation.

[0017] Finally, the present invention hydrolyzes the dimer of formula (II) obtained in the method defined above and the subsequent dimerization step using an acid catalyst such as a Lewis acid or Brønsted acid, e.g., HCl, H2SO4, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or a solid acid catalyst such as Amberlyst resin or zeolite, or Nafion, to obtain formula (VII). [ka] The present invention relates to a method for producing a compound of formula (VII), comprising step ii') obtaining a compound of .

[0018] The present invention is based on the recognition that an efficient method for producing alkyl acrylate dimers is provided using a highly active, robust, reusable, inexpensive, and readily available catalyst. The catalyst for the dimerization of alkyl acrylate is a compound of formula (III) that is relatively low in toxicity, reusable, can be used in relatively low catalyst addition amounts, 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 avoids the use of large amounts of tertiary alcohol relative to alkyl acrylate and relatively high catalyst addition amounts. Specifically, the molar ratio of tertiary alcohol to alkyl acrylate can be reduced to 0.01:1, and the catalyst addition amount can be reduced to 0.20 mol%. Finally, the present invention provides an efficient method for preparing hydride alkyl acrylate dimers and an efficient method for preparing hydrolyzed alkyl acrylate dimers. [Modes for carrying out the invention]

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

[0020] The present invention follows the following reaction scheme: [ka] (In the formula, R is an alkyl group, R1 and R2 are either the same or different, and are either aliphatic groups or, together with the N atom, form a heteroaliphatic ring. R a It is a hydrocarbyl group, R b (It is either an aliphatic group or NR3R4, where R3 and R4 are the same or different, and are either an aliphatic group or together with the N atom to form a heteroaliphatic ring.) A method for producing a dimer of formula (II), comprising step i) dimerizing an alkyl acrylate of formula (I) using a catalyst of formula (III) to obtain a dimer of formula (II), The dimerization step i) is carried out in the presence of compound A, which is a tertiary alcohol or silanol. The present invention relates to a method in which an acid is added during step i) above.

[0021] Preferably, in a method for producing the dimer of formula (II) as defined herein, compound A is a tertiary alcohol such as tert-butanol, tert-amyl alcohol, or pinacol, and more preferably tert-butanol.

[0022] Preferably, in a method for producing the dimer of formula (II) as 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 about 2:1 to about 0.1:1, more preferably about 0.5:1 to about 0.1:1, and particularly about 0.5:1 to about 0.2:1.

[0023] Preferably, in a method for producing the dimer of formula (II) as defined herein, R is C1 to C 18 More preferably C1-C8 alkyl, even more preferably C1-C4 alkyl, and most preferably methyl.

[0024] Preferably, in a method for producing the dimer of formula (II) as defined herein, R is a methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, 2-ethylhexyl group, octyl group, decyl group, dodecyl group, t-dodecyl group, tetradecyl group, hexadecyl group, or octadecyl group; more preferably a methyl group, ethyl group, isopropyl group, butyl group, or 2-ethylhexyl group; even more preferably a methyl group, ethyl group, isopropyl group, or butyl group; and most preferably a methyl group.

[0025] Preferably, in a method for producing the dimer of formula (II) as defined herein, R1 and R2 are the same linear or branched alkyl group having 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, and most preferably ethyl.

[0026] Preferably, in the method for producing the 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.

[0027] Preferably, in a method for producing the 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, ditert-butylphenyl, methoxyphenyl, dimethoxyphenyl, methoxytolyl, methylenedioxyphenyl, biphenyl, nitrophenyl, halogen-substituted phenyl, trifluoromethylphenyl, naphthyl, pyridyl, furyl, pyrrolyl, thiophenyl, 2-indolyl, benzofuryl, and all of these positional isomers.

[0028] Preferably, R aPhenyl; 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- Methoxy-4-methylphenyl, 2-methoxy-5-methylphenyl, 2-methoxy-6-methylphenyl; Mesityl containing all positional isomers, e.g., 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 containing all positional isomers, e.g., 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;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.

[0029] Preferably, in a method for producing the dimer of formula (II) as defined herein, R b The group is NR3R4, where R3 and R4 are the same or different, an aliphatic group or form a heteroaliphatic ring with an N atom, more preferably R3 and R4 are the same linear or branched alkyl group containing 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, and most preferably ethyl.

[0030] Preferably, in a method for producing the dimer of formula (II) as defined herein, R a R1 is phenyl, R1 and R2 are ethyl, and R b The compound is NR3R4, where R3 and R4 are ethyl acetate.

[0031] Preferably, in a method for producing the dimer of formula (II) as defined herein, the catalyst of formula (III) is a compound of formulas (VIII) to (XIV): [ka] It is a compound selected from the group consisting of the following:

[0032] More preferably, in a method for producing the dimer of formula (II) as defined herein, the catalyst of formula (III) is a compound selected from the group consisting of compounds of formulas (IX) and (XI) to (XIV), more preferably selected from compounds of formulas (XI), (XII), and (XIV), even more preferably selected from the group consisting of compounds of formulas (XI) and (XIV), and most preferably the catalyst of formula (III) is a compound of formula (XIV).

[0033] Preferably, in a method for producing the dimer of formula (II) as defined herein, step i) of dimerization is carried out in an organic solvent, more preferably in an aprotic solvent, and even more preferably in an organic solvent selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), toluene, xylene, anisole, diethyl ether, tert-butyl methyl ether (MTBE), dichloromethane (DCM), chloroform, 1,4-dioxane, pentane, cyclopentane, hexane, cyclohexane, methylcyclohexane, benzene, and acetonitrile, even more preferably from MeTHF, anisole, and toluene, and most preferably from MeTHF and anisole.

[0034] Preferably, in a method for producing the 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.

[0035] Preferably, in the method for producing the dimer of formula (II) as defined herein, the catalyst of formula (III) in step i) is used in an 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% relative to the alkyl acrylate of formula (I).

[0036] Preferably, in a method for producing the dimer of formula (II) as defined herein, the dimerization step i) is carried out under anhydrous conditions and in the absence of oxygen.

[0037] The applicant has found that good results are obtained when an acid is added during the dimerization step i). This acid is HCl, HNO3, H3PO4, H2SO4, H3BO3, HF, HBr, HClO4, HI, NaHSO4, KHSO4, NH4HSO4, NaHSO3, KHSO3, H3PO 3、 This can be selected from inorganic acids such as H3PO2. Alternatively, it can be selected from organic acids such as acetic acid, malic acid, tartaric acid, lactic acid, pyruvic acid, citric acid, formic acid, uric acid, ascorbic acid, gluconic acid, itaconic acid, propanoic acid, butanoic acid, (meth)acrylic acid, terephthalic acid, benzoic acid, toluic acid, levulinic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluic acid. This may also be a heterogeneous solid acid such as Amberlyst resin.

[0038] Preferably, the method for producing the dimer of formula (II) as defined herein is a compound of formula (IV). [ka] (In the formula, X is a chloride, bromide, or iodide, preferably a chloride. R a It is a hydrocarbyl group, R c X(R b (In the case of a catalyst of formula (III) as defined above, NR3R4) or R b (R b In the case of a catalyst of formula (III) where is an aliphatic group, -Equation (V): R1R2NH(V) (wherein R1 and R2 are R c R b The case is as defined above) an amine, or - The amine of formula (V) and formula (V'): R3R4NH(V') (wherein R3 and R4 are R c Both of the amines (as defined above for the case where X is) The process further includes a first step 0) of preparing the catalyst of formula (III) by reacting with .

[0039] Preferably, in a method for producing the dimer of formula (II) as defined herein, steps 0) and i) are consecutive steps carried out after step 0) without isolating the catalyst.

[0040] Preferably, in a method for producing the dimer of formula (II) as defined herein, R c X is X.

[0041] Preferably, in a method for producing the dimer of formula (II) as defined herein, step 0) is carried out in an organic solvent, more preferably in an aprotic solvent, and even more preferably in an organic solvent selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran (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 from MeTHF, anisole, and toluene, and most preferably from MeTHF and anisole.

[0042] Preferably, in a method for producing the dimer of formula (II) as 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.

[0043] Preferably, in a method for producing the dimer of formula (II) as defined herein, step 0) is carried out by slowly adding the reactant of (IV) to a solution of amine R1R2NH in an aprotic solvent, wherein the amine is R in formula (IV). c R b And R bIf Rc 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 amine is 4 equivalents or more relative to the reactant of formula (IV) if Rc in (IV) is X.

[0044] Preferably, in a method for producing the dimer of formula (II) as defined herein, step 0) is carried out under anhydrous conditions and in the absence of oxygen.

[0045] Preferably, in a method for producing the dimer of formula (II) as defined herein, step 0) includes a filtration step to remove the ammonium salt, which is a by-product formed before carrying out step i).

[0046] Furthermore, the present invention provides a method for producing a dimer of formula (II) as defined herein, and a subsequent method for hydrogenating the dimer of formula (II) obtained in the dimerization step using H2 and a hydrogenation catalyst to produce formula (VI). [ka] The present invention provides a method for producing a compound of formula (VI), comprising step ii) obtaining a compound of formula (wherein R is as defined above), wherein the hydrogenation catalyst is, for example, a Pd-based catalyst, e.g., Pd / C, Pd / Al2O3, Pd / SiO2, a Ru-based catalyst, e.g., Ru / C, a Pt-based catalyst, e.g., Pt / C, a Ni-based catalyst, e.g., supported nickel or Raney nickel catalyst, a Co-based catalyst, e.g., supported cobalt or Raney cobalt, a Rh-based catalyst, e.g., Rh / C, an Ir-based catalyst, e.g., Ir / C, preferably Pd / C or Raney nickel, preferably Pd / C.

[0047] In a preferred embodiment, the method for producing the compound of formula (VI) involves hydrolyzing the hydrogenated dimer of formula (VI) obtained in step ii) using an acid catalyst such as a Lewis acid or Brønsted acid, for example HCl, H2SO4, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or a solid acid catalyst such as Amberlyst resin, zeolite, or Nafion to produce the compound of formula (XV). [ka] The process further includes step iii') to obtain the compound.

[0048] Finally, the present invention hydrolyzes the dimer of formula (II) obtained in the method defined above and the subsequent dimerization step using an acid catalyst such as a Lewis acid or Brønsted acid, e.g., HCl, H2SO4, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or a solid acid catalyst such as Amberlyst resin or zeolite, or Nafion, to obtain formula (VII). [ka] The present invention relates to a method for producing a compound of formula (VII), comprising step ii') obtaining a compound of .

[0049] In a preferred embodiment, the method for producing the compound of formula (VII) is to hydrogenate the hydrolyzed dimer of formula (VII) obtained in step ii') using H2 and a hydrogenation catalyst to produce the compound of formula (XV). [ka] The process further comprises step iii') to obtain the compound, wherein the hydrogenation catalyst is, for example, a Pd-based catalyst, e.g., Pd / C, Pd / Al2O3, Pd / SiO2, a Ru-based catalyst, e.g., Ru / C, a Pt-based catalyst, e.g., Pt / C, a Ni-based catalyst, e.g., supported nickel or Raney nickel catalyst, a Co-based catalyst, e.g., supported cobalt or Raney cobalt, a Rh-based catalyst, e.g., Rh / C, an Ir-based catalyst, e.g., Ir / C, preferably Pd / C or Raney nickel, preferably Pd / C. [Examples]

[0050] 1. Dimerization of methyl acrylate catalyzed by aminophosphine catalyst Basic protocol for phosphine screening surveys: a) Dimerization from dichlorophosphine catalyzed by symmetric 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 is.

[0051] In a 25 mL two-necked round-bottom flask, 3 mL of 2-methyltetrahydrofuran • Dichlorophosphine precursor (1.8 mmol, 0.01 equivalent relative to methyl acrylate) Add it.

[0052] A 50 mL three-necked round-bottom flask equipped with an electromagnetic stirring device, • 1 mL of 2-methyltetrahydrofuran • Add 4 equivalents (7.2 mmol) of the target amine to the dichlorophosphine precursor. Added.

[0053] The dichlorophosphine solution was gradually added to the amine solution while stirring (1400 rpm) for 1 hour, maintaining the reaction medium temperature below 40°C (exothermic reaction). Upon addition of dichlorophosphine to the amine solution, a white precipitate corresponding to an insoluble ammonium chloride byproduct was formed. After the addition was complete, the mixture was subsequently stirred at ambient temperature. 31 The reaction progress was monitored by 1P NMR (of the aminophosphine under investigation). 31 (See Table 1 below for the results of the P chemical shift.)

[0054] After phosphine formation was complete (usually this requires stirring at room temperature for 1 hour in the case of an unhindered amine and 2 hours in the case of a sterically hindered amine after the addition of chlorophosphine), the mixture was then filtered through a cannula and placed into a 100 mL three-necked round-bottom flask containing 32 mL of molten tert-butanol (2:1 v / v relative to methyl acrylate), equipped with an electromagnetic stirrer, condenser, heater, and temperature probe. The mixture was then stirred at 60°C. Immediately, 15.95 mL of methyl acrylate (15.15 g, 0.176 mol, 1 equivalent) was carefully added to the reaction vessel over 1 hour (exothermy). 1 The reaction was monitored by 1H NMR. The reaction was followed until it stopped or until it lasted for one day. Subsequently, the conversion of methyl acrylate was analyzed by integrating the methylene protons of the product and the starting methyl acrylate. 1 This was determined by 1H NMR.

[0055] 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).

[0056] b) Dimerization from monochlorophosphine catalyzed by monoaminophosphine: 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. Monochlorophosphine and amines were used as is.

[0057] In a 25 mL two-necked round-bottom flask, 3 mL of 2-methyltetrahydrofuran • Mono-chlorophosphine precursor (1.8 mmol, 0.01 equivalent relative to methyl acrylate) Added.

[0058] A 50 mL three-necked round-bottom flask equipped with an electromagnetic stirring device, • 1 mL of 2-methyltetrahydrofuran • Two equivalents (3.6 mmol) of the desired amine relative to the monochlorophosphine precursor. Added.

[0059] The mono-chlorophosphine solution was gradually added to the amine solution while stirring (1400 rpm) for 1 hour, maintaining the reaction medium temperature below 40°C (exothermic reaction). Upon addition of mono-chlorophosphine to the amine solution, a white precipitate corresponding to an insoluble ammonium chloride byproduct was formed. After the addition was complete, the mixture was subsequently stirred at ambient temperature. 31 The reaction progress was monitored using 1P NMR.

[0060] After phosphine formation was complete (usually this requires stirring at room temperature for 1 hour in the case of an unhindered amine and 2 hours in the case of a sterically hindered amine after the addition of mono-chlorophosphine), the mixture was then filtered through a cannula and placed into a 100 mL three-necked round-bottom flask containing 32 mL of molten tert-butanol (2:1 v / v relative to methyl acrylate), equipped with an electromagnetic stirrer, condenser, heater, and temperature probe. The mixture was then stirred at 60°C. Immediately, 15.95 mL of methyl acrylate (15.15 g, 0.176 mol, 1 equivalent) was carefully added to the reactor over 1 hour (exothermic) to allow the reaction to proceed. 1 The reaction was tracked by 1H NMR. The reaction was carried out until it stopped or until one day had elapsed since the start of the reaction. Subsequently, the conversion rate of methyl acrylate was determined by integrating the methylene protons of the product with those of the starting material methyl acrylate. 1 This was estimated from 1H NMR.

[0061] c) Dimerization of dichlorophosphine, diisopropylamine, and an additional amine catalyzed by asymmetric 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 is.

[0062] In a 25 mL two-necked round-bottom flask, 3 mL of 2-methyltetrahydrofuran • Dichlorophosphine precursor (1.8 mmol, 0.01 equivalent relative to methyl acrylate) Added.

[0063] A 50 mL three-necked round-bottom flask equipped with an electromagnetic stirring device, • 1 mL of 2-methyltetrahydrofuran • 3 equivalents (5.4 mmol) of diisopropylamine relative to the dichlorophosphine precursor Added.

[0064] The dichlorophosphine solution was gradually added to the amine solution while stirring (1400 rpm) for 1 hour, maintaining the reaction medium temperature below 40°C (exothermic reaction). When dichlorophosphine was added to the amine solution, a white precipitate corresponding to an insoluble ammonium chloride byproduct was formed (in the case of diisopropylammonium chloride in this invention). Subsequently, the mixture was stirred at ambient temperature, 31 The reaction progress was monitored by 1P NMR. The formation of the intermediate chloro(diisopropylamino)phosphine was observed. 31 This was confirmed by 1P NMR (for example, in the case of chlorophenyl(diisopropylamino)phosphine, a singlet NMR spectrum was observed at +132.5 ppm).

[0065] After the formation of the chloroaminophosphine intermediate was complete (typically requiring stirring at room temperature for 1 hour after the addition of dichlorophosphine), 1 equivalent of the second amine (1.8 mmol) was added to the mixture while stirring at room temperature, and the reaction mixture was stirred at room temperature. The mixture was then stirred for another 1 hour at room temperature.

[0066] After the bis-aminophosphine reaction was complete, the mixture was filtered through a cannula and placed in a 100 mL three-necked round-bottom flask equipped with an electromagnetic stirrer, condenser, heater, and temperature probe, containing 32 mL of molten tert-butanol (2:1 v / v relative to methyl acrylate). The mixture was then stirred at 60°C. Immediately, 15.95 mL of methyl acrylate (15.15 g, 0.176 mol, 1 equivalent) was carefully added to the reactor over 1 hour (exothermic reaction) to allow the reaction to proceed. 1 The reaction was tracked by 1H NMR. The reaction was carried out until it stopped or until one day had elapsed since the start of the reaction. Subsequently, the conversion rate of methyl acrylate was determined by integrating the methylene protons of the product with those of the starting material methyl acrylate. 1 This was estimated from 1H NMR.

[0067] To confirm that the synthesis of the target catalyst was successful, 31 The crude reaction medium was analyzed using 1P NMR. In fact, this parameter ( 31 The chemical shift of the P NMR spectrum was characteristic of the synthesized aminophosphine, and the area under the peak was proportional to the molar concentration of aminophosphine in solution. 31 The P NMR spectrum was recorded using a Bruker Avance 400 MHz spectrometer.

[0068] Furthermore, - Recorded in Me-THF solution before being transferred to the dimerization reactor. 31 The NMR yield (%) of phosphine, corresponding to the molar selectivity of the aminophosphine synthesis reaction, is estimated from the peak area of ​​the P NMR spectrum; - Maximum conversion rate during acrylic acid ester dimerization in several tests shown in Table 1 above ( 1This corresponds to the maximum conversion rate of methyl acrylate measured from 1H NMR. We measured it.

[0069] The ratio of t-BuOH:acrylic acid ester v:v (and mol / mol) is also shown.

[0070] In Inv4.4, the reaction was started with an initial dichlorophenylphosphine content of 0.5 mol%, followed by the addition of methyl acrylate (0.5 equivalents until the initial dichlorophenylphosphine content reached 0.33 mol%) after 20 hours of reaction time.

[0071] All results are summarized in Table 1 below:

[0072] [Table 1]

[0073] All phosphines were synthesized.

[0074] The chlorodiphenylphosphine precursor reacted with diisopropylamine to yield aminophosphine in a relatively low yield (Comp1), and did not exhibit good catalytic activity. The chlorodiphenylphosphine precursor also reacted with pyrrolidine (Comp2), but this also did not yield good catalytic activity. On the other hand, the aminophosphines according to the present invention (Inv1~7) provided very good catalytic activity.

[0075] The system that demonstrated the best performance was diisopropylamino-pyrrolidino-phenylphosphine (Inv4.1~4.4). It was remarkable that using diisopropylamino-pyrrolidino-phenylphosphine (Inv4.4), a 91% acrylic acid ester conversion rate was achieved with an initial dichlorophosphine addition of only 0.33 mol%. Furthermore, this phosphine was found to be very robust, making it easy to handle and recyclable across multiple batches.

[0076] The presence of tert-butyl alcohol during the dimerization reaction improved the selectivity of the reaction for the expected dimer. Surprisingly, we were able to find suitable conditions that allowed the use of t-BuOH and a very small amount of basic aminophosphine without impairing the catalytic activity of the phosphine, while still achieving good selectivity.

[0077] d) Optimization of the dimerization reaction: Dimerization of methyl acrylate in tert-butanol catalyzed by bis(diethylamino)phenylphosphine (initial amount of dichlorophenylphosphine precursor: 0.7 mol% relative to methyl acrylate) (1:4 v / v t-BuOH:methyl acrylate = 0.24 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 is.

[0078] In a 50 mL two-necked round-bottom flask, 15 mL of 2-methyltetrahydrofuran • 4.2 mL of dichlorophenylphosphine (5.57 g, 0.031 mol, 0.007 equivalents) Added.

[0079] In a 100 mL three-necked round-bottom flask equipped with a magnetic stirring device, 20 mL of 2-methyltetrahydrofuran • 12.9 mL of diethylamine (9.1 g, 0.124 mol, 0.028 equivalents) (4 equivalents relative to dichlorophenylphosphine) Add it.

[0080] While maintaining the reaction medium temperature below 40°C (exothermic reaction), a solution of dichlorophenylphosphine in 2-methyltetrahydrofuran was gradually added to the amine solution over 1 hour with stirring (1400 rpm). Upon addition of dichlorophenylphosphine, a white precipitate corresponding to the by-product (in this case, diethylammonium chloride), an ammonium chloride salt, was formed. After the addition was complete, the mixture was stirred at ambient temperature, and the progress of the reaction was tracked by NMR.

[0081] After the addition of dichlorophenylphosphine, stirring at room temperature for 1 hour is required to complete the formation of bis-(diethylamino)phenylphosphine, and the mixture is filtered through a cannula, and equipped with a temperature probe, a condenser, and a mechanical stirrer (a propeller with four inclined 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 equivalent) It was placed in a 500 mL double-jacketed reactor maintained at 45°C.

[0082] Next, the mixture was stirred at 45°C for 19 hours to allow the reaction to proceed. 1 The conversion rate of methyl acrylate was determined by the integration of the methylene protons in the product and the methylene protons in the starting material, methyl acrylate. 1 This was estimated from 1H NMR. According to the NMR, the conversion rate of the starting material, methyl acrylate, was approximately 92 mol%.

[0083] At the end of the reaction, volatile substances (t-BuOH, Me-THF, and unconverted methyl acrylate) were removed by distillation, and 31 g of unreacted methyl acrylate was recovered. Subsequently, the target product (dimethyl 2-methyleneglutarate) was subjected to vacuum distillation (160°C, 15 mbar) to obtain 283 g of analytically pure product (isolation yield = 75%). The high-boiling by-product (methyl acrylate oligomer) remaining in the distillation vessel accounted for approximately 57 g (15%). 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). 13 C NMR(CDCl3,101MHz)δ(ppm):172.73,166.75,138.76,125.56,51.59,51.26,32.66,and 27.17.

[0084] 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 is.

[0085] In a 50 mL two-necked round-bottom flask, 15 mL of 2-methyltetrahydrofuran • 4.2 mL of dichlorophenylphosphine (5.57 g, 0.031 mol, 0.007 equivalents) Add it.

[0086] A 100 mL three-necked round-bottom flask equipped with an electromagnetic stirring device, 20 mL of 2-methyltetrahydrofuran • 12.9 mL of diethylamine (9.1 g, 0.124 mol, 0.028 equivalents) (4 equivalents relative to dichlorophenylphosphine) Added.

[0087] While maintaining the reaction medium temperature below 40°C (exothermic reaction), a solution of dichlorophenylphosphine in 2-methyltetrahydrofuran was gradually added to the amine solution over 1 hour with stirring (1400 rpm). Upon addition of dichlorophenylphosphine, a white precipitate corresponding to the by-product (in this case, diethylammonium chloride), an ammonium chloride salt, was formed. After the addition of dichlorophosphine was complete, the mixture was stirred at ambient temperature, and the progress of the reaction was tracked by NMR.

[0088] After the addition of dichlorophenylphosphine, stirring at room temperature for 1 hour is required to complete the formation of bis-(diethylamino)phenylphosphine, and the mixture is filtered through a cannula, and equipped with a temperature probe, a condenser, and a mechanical stirrer (a propeller with four inclined plows) and 50 mL of distilled tert-butanol (1:8 v / v tert-butanol:methyl acrylate) • 400 mL of methyl acrylate (380.8 g, 4.42 mol, 1 equivalent) It was placed in a 500 mL double-jacketed reactor maintained at 45°C.

[0089] Next, the mixture was stirred at 45°C for 19 hours to allow the reaction to proceed. 1 The conversion rate of methyl acrylate was determined by the integration of the methylene protons in the product and the methylene protons in the starting material, methyl acrylate. 1 The conversion rate was estimated from 1H NMR. According to the NMR, the conversion rate of the starting material, methyl acrylate, was approximately 88 mol%. At the end of the reaction, volatile substances (t-BuOH, Me-THF, and unconverted methyl acrylate) were removed by distillation, and 44 g of unreacted methyl acrylate was recovered.

[0090] Subsequently, the target product (dimethyl 2-methyleneglutarate) was subjected to vacuum distillation (160°C, 15 mbar) to obtain 271 g of analytically pure product (isolation yield = 71%). The high-boiling by-product (methyl acrylate oligomer) remaining in the distillation vessel accounted for approximately 59 g (16%). 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). 13 C NMR(CDCl3,101MHz)δ(ppm):172.73,166.75,138.76,125.56,51.59,51.26,32.66,and 27.17.

[0091] (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 2 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 is.

[0092] In a 25 mL two-necked round-bottom flask, 8 mL of 2-methyltetrahydrofuran • 2.1 mL of dichlorophenylphosphine (2.79 g, 0.0155 mol, 0.007 equivalents) Added.

[0093] A 50 mL three-necked round-bottom flask equipped with an electromagnetic stirring device, 10 mL of 2-methyltetrahydrofuran • 6.5 mL of diethylamine (4.6 g, 0.062 mol, 0.028 equivalents) (4 equivalents relative to dichlorophenylphosphine) Added.

[0094] While maintaining the reaction medium temperature below 40°C (exothermic reaction), a solution of dichlorophenylphosphine in 2-methyltetrahydrofuran was gradually added to the amine solution over 1 hour with stirring (1400 rpm). Upon addition of dichlorophenylphosphine, a white precipitate corresponding to the by-product, diethylammonium chloride, was formed. The mixture was then stirred at ambient temperature, and the progress of the reaction was monitored by NMR.

[0095] After the addition of dichlorophenylphosphine, stirring at room temperature for 1 hour is required to complete the formation of bis-(diethylamino)phenylphosphine, and the mixture is filtered through a cannula, and equipped with a temperature probe, a condenser, and a mechanical stirrer (a propeller with four inclined 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 equivalent) It was placed in a 500 mL double-jacketed reactor maintained at 60°C.

[0096] Next, the mixture was stirred at 60°C for 20 hours to allow the reaction to proceed. 1 The conversion rate of methyl acrylate was determined by the integration of the methylene protons in the product and the methylene protons in the starting material, methyl acrylate. 1 The conversion rate was estimated from 1H NMR. According to the NMR, the conversion rate of the starting material, methyl acrylate, was approximately 95 mol% (average of 2 batches). At the end of the reaction, volatile substances (t-BuOH, Me-THF, and unconverted methyl acrylate) were removed by distillation.

[0097] Subsequently, the target product (dimethyl 2-methyleneglutarate) was subjected to vacuum distillation (140°C, 5 mbar) to obtain 137 g of analytically pure product (average of 2 batches, isolation yield = 72%). High-boiling by-products (mainly methyl acrylate oligomers) remained in the distillation vessel, accounting for approximately 40 g (21%, average of 2 batches).

[0098] 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 is.

[0099] In a 50 mL two-necked round-bottom flask, 20 mL of 2-methyltetrahydrofuran • 5.43 mL of dichlorophenylphosphine (7.17 g, 0.04 mol, 0.009 equivalents) Add it.

[0100] In a 100 mL three-necked round-bottom flask equipped with a magnetic stirring device, 20 mL of 2-methyltetrahydrofuran • 16.6 mL of diethylamine (11.7 g, 0.16 mol, 0.036 equivalents) (4 equivalents relative to dichlorophenylphosphine) Add it.

[0101] While maintaining the reaction medium temperature below 40°C (exothermic reaction), a solution of dichlorophenylphosphine in 2-methyltetrahydrofuran was gradually added to the amine solution over 1 hour with stirring (1400 rpm). Upon addition of dichlorophenylphosphine, a white precipitate corresponding to the by-product, diethylammonium chloride, was formed. After the addition of dichlorophosphine was complete, the mixture was stirred at ambient temperature, and the progress of the reaction was monitored by NMR.

[0102] After the addition of dichlorophenylphosphine, stirring at room temperature for 1 hour is required to complete the formation of bis-(diethylamino)phenylphosphine, and the mixture is filtered through a cannula, and equipped with a temperature probe, a condenser, and a mechanical stirrer (a propeller with four inclined 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 equivalent) It was placed in a 500 mL double-jacketed reactor maintained at 30°C.

[0103] Next, the mixture was stirred at 30°C for 20 hours to allow the reaction to proceed. 1 This was monitored by 1H NMR. At this stage, the conversion level of methyl acrylate was 1 The purity was estimated to be 93% by 1H NMR. Subsequently, volatile substances (2-methyltetrahydrofuran, t-BuOH, and residual methyl acrylate) were removed under vacuum, and 27 g of methyl acrylate was recovered. Then, the target dimethyl 2-methyleneglutarate was subjected to vacuum distillation (160°C, 15 mbar), recovering 284 g of analytically pure product, corresponding to a 75% isolation and purification yield. High-boiling by-products (mainly methyl acrylate oligomers) remained in the distillation vessel, accounting for 49 g (13%).

[0104] 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, methyl acrylate was added gradually. 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 is.

[0105] In a 50 mL two-necked round-bottom flask, 20 mL of 2-methyltetrahydrofuran • 5.43 mL of dichlorophenylphosphine (7.17 g, 0.04 mol, 0.009 equivalents) Add it.

[0106] A 100 mL three-necked round-bottom flask equipped with an electromagnetic stirring device, 20 mL of 2-methyltetrahydrofuran • 16.6 mL of diethylamine (11.7 g, 0.16 mol, 0.036 equivalents) (4 equivalents relative to dichlorophenylphosphine) Added.

[0107] While maintaining the reaction medium temperature below 40°C (exothermic reaction), a solution of dichlorophenylphosphine in 2-methyltetrahydrofuran was gradually added to the amine solution over 1 hour with stirring (1400 rpm). Upon addition of dichlorophenylphosphine, a white precipitate corresponding to the by-product, diethylammonium chloride, was formed. After the addition of dichlorophosphine was complete, the mixture was stirred at ambient temperature, and the progress of the reaction was monitored by NMR.

[0108] After the addition of dichlorophenylphosphine, stirring at room temperature for 1 hour is required to complete the formation of bis-(diethylamino)phenylphosphine, and the mixture is filtered through a cannula, and equipped with a temperature probe, a condenser, and a mechanical stirrer (a propeller with four inclined 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 equivalents) It was placed in a 500 mL double-jacketed reactor maintained at 30°C.

[0109] Next, 300 mL of methyl acrylate (285.6 g, 3.315 mol, 0.75 equivalents) was gradually added to the reactor over 4 hours. After the addition was complete, the mixture was stirred at 30°C for 16 hours. The reaction proceeded as follows: 1 This was tracked by 1H NMR. At this stage, the conversion level of methyl acrylate was 1 It was estimated to be 92% by 1H NMR.

[0110] Subsequently, 29 g of methyl acrylate was recovered by removing volatile substances (2-methyltetrahydrofuran, t-BuOH, and residual methyl acrylate) under vacuum. Then, 288 g of analytically pure product, corresponding to a 76% isolation and purification yield, was recovered by vacuum distillation (160°C, 15 mbar) of the target dimethyl 2-methyleneglutarate. High-boiling by-products (methyl acrylate oligomers) remained in the distillation vessel, accounting for 49 g (13%).

[0111] 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)), 60°C, with catalyst recycling. 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 is.

[0112] In a 50 mL two-necked round-bottom flask, 20 mL of 2-methyltetrahydrofuran • 3.6 mL of dichlorophenylphosphine (4.77 g, 0.027 mol, 0.012 equivalents) Added.

[0113] A 100 mL three-necked round-bottom flask equipped with an electromagnetic stirring device, 20 mL of 2-methyltetrahydrofuran • 11.15 mL of diethylamine (8.05 g, 0.08 mol, 0.036 equivalents) (3 equivalents relative to dichlorophenylphosphine) Added.

[0114] While maintaining the reaction medium temperature below 40°C (exothermic reaction), a solution of dichlorophenylphosphine in 2-methyltetrahydrofuran was gradually added to the diisopropylamine solution over 1 hour with stirring (1400 rpm). The mixture was stirred at room temperature, and 1 equivalent (0.027 mol, 1.92 g) of pyrrolidine was added to the reaction mixture. This mixture was then stirred at room temperature for another 1 hour to complete the formation of bis-(amino)phosphine.

[0115] The reaction mixture is filtered through a cannula and is equipped with a temperature probe, a condenser, and a mechanical stirrer (a 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 moles, 1 equivalent) It was placed in a 500 mL double-jacketed reactor containing [the substance].

[0116] Next, the mixture was stirred at 60°C for 19 hours to allow the reaction to proceed. 1 It was monitored by 1H NMR. 1 According to 1H NMR, the conversion rate of the starting methyl acrylate was approximately 86 mol%.

[0117] The volatile substances (t-BuOH, Me-THF, and unconverted methyl acrylate) are removed by distillation, and 20 g of methyl acrylate is recovered.

[0118] Next, the target product (dimethyl 2-methyleneglutarate) is subjected to vacuum distillation (125°C, 7 mbar) to obtain 103 g of analytically pure product.

[0119] Subsequently, 190 g of methyl acrylate (2.2 mol, 1 equivalent) was added to the residue still containing the active phosphine catalyst, followed by the addition of 20 g of tert-butanol. The mixture was stirred at 60°C for a further 16 hours to perform the conversion of the second batch of methyl acrylate. After removing volatile substances by distillation, 37 g of methyl acrylate was recovered, and the product was subjected to vacuum distillation (125°C, 8 mbar) to obtain 126 g of analytically pure product.

[0120] Finally, an additional 190 g of methyl acrylate (2.2 mol, 1 equivalent) is added to the residue, which still contains active phosphine, and the mixture is stirred again at 70°C for 20 hours. After the reaction is complete, volatile substances are removed under vacuum to recover 44 g of methyl acrylate, and the product is vacuum distilled to obtain 91 g of pure product.

[0121] In total, 320 g of dimethyl 2-methyleneglutarate product was recovered, corresponding to an overall isolation and purification yield of 56%.

[0122] This is the first example of an aminophosphine catalyst that can be recycled after the acrylic acid ester dimerization reaction.

[0123] j) Influence of the presence or absence of t-BuOH All reactions were carried out in carefully dried containers under an inert argon atmosphere. Methyl acrylate was dried using 4A molecular sieves. Dichlorophosphine and amines were used as is.

[0124] In a 25 mL two-necked round-bottom flask, • 18 mL of 2-methyltetrahydrofuran • Dichlorophosphine precursor (10.5 mmol, 0.005 equivalents relative to methyl acrylate) was added.

[0125] To a 50 mL three-neck round-bottom flask equipped with a magnetic stirring device, ·6 mL of 2-methyltetrahydrofuran ·3 equivalents of diisopropylamine (31.4 mmol) relative to the dichlorophenylphosphine precursor was added.

[0126] The dichlorophosphine solution was gradually added to the amine solution with stirring (1400 rpm) over 1 hour while maintaining the temperature of the reaction medium below 40 °C. (Exothermic reaction). When dichlorophosphine was added to the amine solution, a white precipitate corresponding to the by-product, insoluble diisopropylammonium chloride, was formed. Subsequently, the mixture was stirred at ambient temperature, 31 and the progress of the reaction was monitored by ³¹P NMR. The formation of the intermediate chloro(diisopropylamino)phosphine was 31 confirmed by ³¹P NMR (for example, a singlet was observed at +132.5 ppm for chlorophenyl(diisopropylamino)phosphine).

[0127] After the formation of the chloroaminophosphine intermediate was complete (usually requiring 1 hour of stirring at room temperature after the 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 at room temperature for an additional 1 hour.

[0128] After the completion of bisaminophosphine, the mixture was filtered by cannula and placed into a 500 mL double-jacketed reactor equipped with a mechanical stirrer (a propeller with four inclined blades), a condenser, a heater, and a temperature probe and containing 190 mL of methyl acrylate (180 g, 2.1 mol). Subsequently, the mixture was stirred at 60 °C for 20 hours. Subsequently, the conversion of methyl acrylate was estimated by 1 ¹H NMR by integrating the methylene protons of the product and the methylene protons of the starting methyl acrylate. With a conversion of 66% of methyl acrylate, 1Based on 1H NMR, the selectivity for the dimer was estimated to be 78 mol%.

[0129] In contrast, when t-BuOH was present during the reaction (1:1 v / v tert-BuOH:methyl acrylate), with an initial addition of 0.5 mol% dichlorophenylphosphine, at 60°C (corresponding to Inv4.3), and at a similar conversion level (66%), the selectivity for the dimer was 87%, clearly demonstrating the positive effect of t-BuOH on reaction selectivity.

[0130] k) Effect of the amount of methyl acrylate added on the dimerization of methyl acrylate The reaction is carried out in a carefully dried container under an inert argon atmosphere.

[0131] The tert-butanol solvent was flash-distilled under argon before the reaction, and the anisole was dried overnight on activated molecular sieves 4A before the reaction. The reactants, diethylamine and methyl acrylate, were also dried overnight on activated molecular sieves 4A before the reaction.

[0132] K1) A 250 mL double-jacketed reactor equipped with a temperature probe, a mechanical stirrer (propeller with four inclined plows), and baffles is heated at room temperature. 40g of anisole, • 18.4 mL of diethylamine (12.98 g, 177 mmol) Add it.

[0133] A solution of dichlorophenylphosphine (DCPP) in anisole (prepared by diluting 6.17 mL of 97% pure DCPP (8.14 g, 44 mmol) with 30 g of anisole) is gradually added to a solution of diethylamine in anisole over 1 hour while stirring (500 rpm) at room temperature (exothermic).

[0134] During the addition process, a precipitate (NH2Et2Cl) is formed, resulting in a gel-like solution. After the addition is complete, an additional 30g of anisole is added to the mixture to reduce the viscosity of the suspension, and the reaction medium is stirred at room temperature for 1 hour and 30 minutes. 31 3P NMR analysis confirms that DCPP has been completely converted to the target bis(diethylamino)phenylphosphine at this stage.

[0135] 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 clear yellow solution is obtained as the filtrate. Quantitative analysis of the solution is performed using triethyl phosphate as an internal probe. 31 3P NMR analysis can determine the concentration of the aminophosphine catalyst in the solution: 4.6% by weight corresponds to 6.3 g of catalyst (25 mmol), which is equivalent to only 0.28 mol% of the catalyst added relative to methyl acrylate.

[0136] 157.8 g of tert-butanol (200 mL) was added to a 1.5 L double-jacketed reactor equipped with a condenser, a temperature probe, a mechanical stirrer (propeller with four inclined plows), and baffles, followed by the addition of a previously prepared solution of the catalyst in anisole (138.4 g). The solution was then stirred at 40°C (500 rpm), and 760 g of methyl acrylate (8.828 mol) was gradually added to the solution over 4 hours (exothermic reaction). After the addition of methyl acrylate was complete, the reaction mixture was stirred overnight at 40°C, and the progress of the reaction was monitored by quantitative GC chromatography.

[0137] The conversion rate of methyl acrylate was tracked over time (as well as the dimer yield), and the reaction rate curve is shown in the graph below (left: conversion rate of methyl acrylate over time, right: dimer yield over time). As can be seen from the graph below (black curve), with only 0.28 mol% of catalyst added, a final conversion rate of 66% was obtained after 24 hours at 40°C, which corresponds to a dimer yield of 58%.

[0138] A 250 mL double-jacketed reactor equipped with a K2) temperature probe, a mechanical stirrer (propeller with four inclined plows), and baffles was heated at room temperature. 40g of anisole, • 25.7 mL of diethylamine (18.17 g, 247 mmol) Add it.

[0139] A solution of dichlorophenylphosphine (DCPP) in anisole (prepared by diluting 8.44 mL of 99% pure DCPP (11.13 g, 62 mmol) with 30 g of anisole) is gradually added to the diethylamine solution over 1 hour while stirring at room temperature (500 rpm) (exothermic).

[0140] During the addition process, a precipitate (NH2Et2Cl) is formed, resulting in a gel-like solution. After the addition is complete, the reaction medium is stirred at 40°C for 30 minutes. 31 3P NMR analysis confirms that DCPP has been completely converted to the target bis(diethylamino)phenylphosphine at this stage.

[0141] Next, the suspension is filtered through a cannula into an intermediate flask, and the solid is washed with an additional 90 g of anisole. A total of 153.7 g of clear yellow solution is obtained. Quantitative analysis of the solution is performed using triethyl phosphate as an internal probe. 31 3P NMR analysis can determine the concentration of the aminophosphine catalyst in the solution: 8.6% by weight corresponds to 13.2 g of catalyst (52 mmol), which is equivalent to only 0.6 mol% of the catalyst added relative to methyl acrylate.

[0142] 157.8 g of tert-butanol (200 mL) was added to a 1.5 L double-jacketed reactor equipped with a condenser, a temperature probe, a mechanical stirrer (propeller with four inclined plows), and baffles, followed by the addition of a previously prepared solution of the catalyst in anisole (153.7 g). The solution was then stirred at 40°C (500 rpm), and 760 g of methyl acrylate (8.828 mol) was gradually added to the solution over 4 hours (exothermic). After the addition of methyl acrylate was complete, the reaction mixture was stirred overnight at 40°C, and the progress of the reaction was monitored by quantitative GC chromatography.

[0143] Observing the conversion rate (and dimer yield) of methyl acrylate over time and the reaction rate curve, it can be seen that a final conversion rate of over 99% (corresponding to a dimer yield of 82%) can be obtained after 25 hours at 40°C with only 0.6 mol% of catalyst added.

[0144] A 250 mL double-jacketed reactor equipped with a K3) temperature probe, a mechanical stirrer (propeller with four inclined plows), and baffles was heated at room temperature. 40g of anisole, • 25.7 mL of diethylamine (18.17 g, 247 mmol) Add it.

[0145] A solution of dichlorophenylphosphine (DCPP) in anisole (prepared by diluting 8.44 mL of 99% pure DCPP (11.13 g, 62 mmol) with 30 g of anisole) is gradually added to the diethylamine solution over 1 hour while stirring at room temperature (500 rpm) (exothermic).

[0146] During the addition process, a precipitate (NH2Et2Cl) is formed, resulting in a gel-like solution. After the addition is complete, the reaction medium is stirred at 40°C for 30 minutes. 31 3P NMR analysis confirms that DCPP has been completely converted to the target bis(diethylamino)phenylphosphine at this stage.

[0147] Next, the suspension is filtered into an intermediate flask via a cannula, 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. The quantitative 31 31

[0148] To a 1.5 L double-jacketed reactor equipped with a condenser, a temperature probe, a mechanical stirrer (a propeller with four inclined blades), and a baffle, 157.8 g of tert-butanol (200 mL) is added, followed by 760 g of methyl acrylate (8.828 mol). Then, with stirring, the previously prepared solution of the catalyst in anisole (142.0 g) is added to the solution (500 rpm, exothermic). The solution is then stirred at 40 °C overnight, and the progress of the reaction is followed by quantitative GC chromatography.

[0149] Tracking the conversion of methyl acrylate (and dimer yield) and the reaction rate curve over time shows that after 48 hours at 40 °C, a final conversion of 87% is obtained with a catalyst loading of only 0.46 mol% (corresponding to a dimer yield of 76%).

[0150] Catalytic hydrogenation of dimethyl 2.2-methylenebutanedioate to dimethyl 2-methylbutanedioate 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 Pd / C (3%) catalyst (powder, 51% water content, equivalent to 1 g wet and 0.49 g dry, 1 wt% relative to the substrate). The reactor was then sealed and purged three times with 20 bar nitrogen, followed by three times with 5 bar hydrogen. The reaction mixture was stirred at 1400 rpm, and the temperature of the reaction mixture was then set to 40°C. Subsequently, the reaction medium was stirred at 40°C and a hydrogen pressure of 5 bar (1400 rpm) for 6 hours, and hydrogen consumption was tracked over time.

[0151] Upon confirmation of the end of the reaction by the absence of hydrogen consumption, the reaction mixture was cooled to room temperature, stirring was stopped, and the autoclave was reduced in pressure. The reactor was purged with nitrogen, the crude product was removed from the reactor, and the catalyst was removed by filtration. After filtering out the catalyst, the product, dimethyl 2-methylglutarate, was obtained as a clear liquid (50 g, corresponding to 99% yield). This was used as is.

[0152] 3. Synthesis of 2-methylenepentanedioic acid from dimethyl methylenepentanedioic acid [ka] A 2L 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, 700g (4.07 mol, 1 equivalent) of dimethyl 2-methylenepentanedioate • 879 mL of water (48.8 moles, 12 equivalents) • 95% sulfuric acid (9 mL, 16.6 g, 0.163 mol, 4 mol% relative to dimethyl 2-methylenepentanedioate) (This is added dropwise to the reaction mixture using an addition funnel at room temperature) Add it.

[0153] Next, stir the mixture at 120°C. 1The reaction is tracked by 1H NMR analysis. Throughout the reaction, methanol is removed from the reaction medium by distillation to shift the reaction equilibrium toward the desired methylene glutarate.

[0154] After stirring at 120°C for 2 hours and 30 minutes, 1 Since 1H NMR analysis showed a slow conversion from the diester to the dibasic acid, an additional 2.26 mL (0.04 mol, 1 mol%) of sulfuric acid was added to the reaction mixture to increase the reaction rate, and the temperature of the mixture was raised to 130°C.

[0155] However, after stirring at 130°C for another 2 hours, the conversion rate of the diester was still too slow, so 2.26 mL (0.04 mol, 1 mol%) of H2SO4 was added to the reaction mixture again.

[0156] After stirring at 130°C for 11 hours and 30 minutes, 1060 mL of the water / MeOH mixture is removed by distillation, and 50 mL of fresh water is added to the reaction vessel.

[0157] After stirring at 130°C for 16 hours and 30 minutes, 1 1H NMR analysis revealed approximately 10 mol% of residual, unhydrolyzed ester functional groups and significant polymer byproduct formation.

[0158] At this stage, the mass of the recovered distillate is 1195g, which contains 6g of insoluble starting diester.

[0159] The temperature of the reaction medium is lowered to 80°C, and 36 mL of 35 wt% NaOH aqueous solution (2 equivalents relative to H2SO4) is slowly added to the container to neutralize the catalyst (exothermy).

[0160] The contents of the reaction vessel, kept at 80°C, are poured into a beaker while being continuously stirred. When cooled, the mixture solidifies into a white paste that continues to harden.

[0161] To obtain a filterable liquid paste, 147 mL of water is added to the paste, and the mixture is allowed to cool to room temperature to complete the precipitation of the dibasic acid product.

[0162] Next, the product is filtered through a sintered filter to obtain a highly viscous filtrate.

[0163] 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.

[0164] The aqueous filtrate obtained by precipitation overnight at room temperature is filtered, and the mixture is washed 10 times with 20 mL of water to recover additional product.

[0165] The solid fraction was collected, and the product was dried under vacuum (10 mmbar) at 50°C for 2 hours to obtain 286 g of a white powder, which had an organic purity of over 98% by weight and contained 3% by weight of water, corresponding to an isolation yield of 48%.

[0166] 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 following reaction scheme: 【Chemistry 1】 (In the formula, R is an alkyl group, R １ and R ２ They are either the same or different, an aliphatic group, or together with an N atom to form a heteroaliphatic ring. R ａ It is a hydrocarbyl group, R ｂ is an aliphatic group, or NR ３ R ４ And R ３ and R ４ (These are either the same or different, and are either aliphatic groups or, together with the N atom, form a heteroaliphatic ring.) A method for producing a dimer of formula (II), comprising step i) using a catalyst of formula (III) to dimerize an alkyl acrylate of formula (I) to obtain a dimer of formula (II), The dimerization step i) is carried out in the presence of compound A, which is a tertiary alcohol or silanol. A method wherein an acid is added during step i) above.

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

3. The method according to claim 1 or 2, wherein the molar ratio of [compound A] / [alkyl acrylate of formula (I)] is selected from about 4:1 to about 0.01:1, preferably about 2:1 to about 0.1:1, and more preferably about 0.5:1 to about 0.1:

1.

4. R is C １ to C １８ , preferably C １ to C ８ alkyl, more preferably C １ to C ４ alkyl, most preferably methyl, a method according to any one of claims 1 to 3.

5. R １ and R ２ The method according to any one of claims 1 to 4, wherein the alkyl group is the same linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, and most preferably ethyl.

6. R １ and R ２ The method according to any one of claims 1 to 4, wherein the N atom forms a heteroaliphatic ring containing 3 to 5 carbon atoms, preferably 4 carbon atoms.

7. R ａ The method according to any one of claims 1 to 6, wherein the group 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, 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.

8. R ｂ However, NR ３ R ４ And R ３ and R ４ However, they are the same or different, and are either an aliphatic group or form a heteroaliphatic ring together with the N atom, preferably R ３ and R ４ The method according to any one of claims 1 to 7, wherein the alkyl group is the same linear or branched alkyl group having 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 according to any one of claims 1 to 8, wherein is ethyl.

10. The method according to any one of claims 1 to 9, wherein step i) of dimerization is carried out in an organic solvent, preferably an aprotic solvent, more preferably in an organic solvent selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), toluene, xylene, anisole, diethyl ether, tert-butyl methyl ether (MTBE), dichloromethane (DCM), chloroform, dioxane, pentane, cyclopentane, hexane, cyclohexane, methylcyclohexane, benzene, and acetonitrile, and even more preferably from MeTHF and toluene.

11. The method according to any one of claims 1 to 10, wherein the dimerization step i) is carried out at a temperature in the range of about 20°C to about 120°C, preferably about 20°C to about 80°C, more preferably about 25°C to about 60°C.

12. Compound of formula (IV) 【Chemistry 2】 (In the formula, X is a chloride, bromide, or iodide, preferably a chloride. R ａ This is as defined in any one of claims 1, 7, or 9, R ｃ is X or R ｂ And R ｂ (as defined in any one of claims 1, 8, or 9), -Formula V:R １ R ２ NH(V) (wherein R １ and R ２ R ｃ R ｂ If so, an amine as defined in any one of claims 1, 5, 6, or 9, or - Amine of formula (V) and formula (V'): R ３ R ４ NH(V') (wherein, R ３ and R ４ R ｃ Both of the amines (as defined in any one of claims 1, 8, or 9 if X is X) The method according to any one of claims 1 to 11, further comprising a first step 0) of preparing a catalyst of formula (III) by reacting with .

13. The method according to claim 12, wherein steps 0) and i) are consecutive steps performed after step 0) without isolating the catalyst.

14. A method according to any one of claims 1 to 13, and a subsequent step of dimerizing the dimer of formula (II) obtained therefrom, H ２ Hydrogenation is performed using hydrogenation catalysts such as Pd-based catalysts, Ru-based catalysts, Pt-based catalysts, Co-based catalysts, Rh-based catalysts, Ir-based catalysts, and Ni-based catalysts to obtain formula (VI). 【Transformation 3】 A method for producing a compound of formula (VI), comprising the step of obtaining a compound of formula (wherein R is as described in claim 1 or 4).

15. The method according to any one of claims 1 to 13, and the subsequent dimerization step, wherein the dimer of formula (II) obtained therefrom is hydrolyzed using an acid catalyst such as a Lewis acid or a Brønsted acid to obtain formula (VII). 【Chemistry 4】 A method for producing a compound of formula (VII), comprising the step ii') of obtaining a compound of .

16. Formula (VII') 【Transformation 5】 A method for producing a compound of formula (VI), the method according to claim 14, and thereafter, the compound of formula (VI) of formula HNR ５ R ６ The amine (wherein R in the formula) ５ and R ６ R is selected from saturated or unsaturated, linear or branched, hydrocarbon groups that are the same or different, each having an average number of carbon atoms in the range of 1 to 36, and which may be optionally cyclic, optionally aromatic, or optionally substituted. ５ and R ６ These may optionally form ring members together, which may optionally be substituted and / or optionally contain heteroatoms, preferably R ５ = R ６ A method comprising step iii) reacting with (=methyl).

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