Method for preparing amidine

Abstract

A method for preparing an amidine or a derivative thereof, comprising the steps of: synthesizing a nitrile lactam by reacting a lactam with an α-β unsaturated nitrile; synthesizing an N-(aminoalkyl) lactam by reducing the nitrile lactam; and synthesizing an amidine by dehydrating the N-(aminoalkyl) lactam.

Description

[Technical Field]

[0001] This invention relates to a process for preparing amidine.

[0002] More specifically, the present invention relates to a method for producing amidines such as 1,8-diazabicyclo[5,4,0]undeca-7-ene (hereinafter abbreviated as DBU) or derivatives thereof from lactams such as ε-caprolactam and α,β-unsaturated nitriles such as acrylonitrile. [Background technology]

[0003] DBU is a versatile molecule that is useful in many applications, and in fact, it is well known that DBU can be involved in a wide variety of chemical reactions.

[0004] A recent paper by Jacques Muzart, Non-Patent Document 1 ("DBU: A Reaction Product Component," Chemistry Select 2020, vol. 5, 11608-11620), provides a detailed overview of DBU, from salt formation to the addition of CC double bonds and many other aspects. In these embodiments, DBU is used in polyurethane catalysis, the pharmaceutical industry, ionic liquids, and organic synthesis in general. Further details on the applications of DBU can be found in Non-Patent Document 2 by Bhaskara Nand et al. ("1,8-Diazabicyclo[S.4.0]undec-7-ene (DBU): A Versatile reagent in Organic Synthesis," Current Organic Chemistry, 2015, 19, 790-812).

[0005] In the prior art, the industrial production of DBU is carried out primarily in three reaction steps. In the first step, ε-caprolactam is reacted with acrylonitrile to obtain N-(2-cyanoethyl)-ε-caprolactam. In the second step, N-(2-cyanoethyl)-ε-caprolactam is hydrogenated in the presence of anhydrous ammonia and a nickel Raney catalyst to the corresponding amine. In the third step, N-(3-aminopropyl)-ε-caprolactam is dehydrated with an acid catalyst to produce DBU. The most industrially complex step in this synthesis is the hydrogenation in the presence of ammonia. The catalyst commonly used is nickel Raney, which is spontaneously combustible in its activated form. Anhydrous ammonia is also a toxic gas, and its storage, use, and transport require specific precautions and approvals. The following are some prior art-related documents.

[0006] Patent Document 1 (DE1545855) describes the following structure in the German and English versions of the target country: [ka] A process for obtaining amidine having the following characteristics, where m is an integer from 3 to 7 and n is an integer from 2 to 4 (limited to the third step in the industrial process described above): formula: [ka] The process for obtaining amidine, starting from an N-(aminoalkyl)lactam, is described. This process is carried out by dehydration of an aminolactam catalyzed with a mineral acid or sulfonic acid (e.g., p-toluenesulfonic acid) in the presence of a solvent, such as xylene. The reaction mixture is heated to its boiling point, and the resulting dehydrated water is condensed and separated with the solvent, which is then backflowed into the reaction flask. This patent does not describe the steps prior to dehydration, but it does refer to the prior art.

[0007] Patent document 2 (EP0347757 A2) describes a method for synthesizing cyanoalkyl lactams by reaction of lactams with α,β unsaturated nitriles using DBU itself as a base catalyst (the first step in the industrial process described above), and DBU can also be used as a solvent. Patent document 2 does not mention other reaction steps (second and third steps), but it does briefly mention catalytic hydrogenation of cyanoalkyl lactams as described in the prior art, and in fact, Example 2 describes hydrogenation in the presence of Ni Raney and ammonia as catalysts. In this patent, it is necessary to neutralize the base first so that the process can proceed from the first step to the second step, but neutralization is not necessary when using DBU (Example 3), thus demonstrating that using DBU as a catalyst can replace KOH used in the first step of the industrial process.

[0008] Patent document 3 (CN101279973 B) describes a method for preparing 1,8-diazabicyclo[5,4,0]undeca-7-ene starting from ε-caprolactam and acrylonitrile in the presence of tert-butyl alcohol or tert-amyl alcohol as a solvent and NaOH as a catalyst. The reaction product from this first step is hydrogenated in the presence of anhydrous ammonia and Ni Raney as catalysts. After hydrogenation, the mixture is neutralized with sulfuric acid, and the solvent is recovered and the reaction product is dehydrated by removing water, as described in Patent document 4 (DE1545855).

[0009] Patent document 5 (CN109796458 A) also describes a method for preparing 1,8-diazabicyclo[5,4,0]undeca-7-ene starting with ε-caprolactam and acrylonitrile. Here, patent document 5 does not describe a hydrogenation step in the presence of ammonia, but incorporates an alternative method using hydroquinone, gaseous hydrochloric anhydride, dichloromethane, sodium perborate and ethylenediaminetetraacetic acid (EDTA). This process is considerably more complex than the other methods described above and eliminates ammonia and Ni Raney, but introduces a number of chemicals in addition to an extremely potent chemical (anhydrous HCl).

[0010] In Patent Document 6 (JP2003286257), the first and third steps are carried out in the same manner as described above (reaction of caprolactam and acrylonitrile by base catalyst using KOH, and dehydration by acid catalyst). The second step is carried out in the absence of ammonia, using cobaltranay as a catalyst. The result is 86% by weight of the reduced product (the target primary amine).

[0011] Patent document 7 (EP0913388 B1) describes a method for obtaining amines by hydrogenating nitriles without using ammonia. The novelty lies in the catalyst treatment. The catalyst (cobalt tranay or a sponge-like catalyst) is treated with an aqueous lithium hydroxide solution, or the reaction is carried out in the presence of this solution. Through this treatment, the catalyst absorbs 0.1 to 100 mmol of lithium hydroxide per gram.

[0012] Patent document 8 (EP0662476 B1) describes the synthesis of bicyclic amidines by an acid-catalyzed reaction of lactones and diamines. This process is carried out in a single reaction step followed by purification. The patent claims the use of these amidines as catalysts for polyurethanes. The synthesis of DBU is described in Example 6, showing a very low product yield of 21%.

[0013] Patent document 9 (CN1262274 A) describes a method for preparing 1,8-diazabicyclo[5,4,0]undeca-7-ene from ε-caprolactam and acrylonitrile, the special feature of which is the use of a mixture of inorganic and organic bases (KOH and DBU) as a catalyst in the first reaction step. The resulting cyano derivative is purified before reduction. The second hydrogenation step is carried out in the presence of activated Ni (the catalytic form is not specified) as a catalyst, but it is not mentioned whether ammonia is present or absent. Dehydration is always carried out under acidic conditions in the absence of a solvent using p-toluenesulfonic acid, and this reaction is carried out over a fairly long period of time, i.e., 35-40 hours, with a yield of 74.61% in this step.

[0014] In all of the processes described above, the majority primarily use a Raney catalyst (cobalt or nickel) and refer to the reduction of nitriles in the presence of ammonia. Of the cited literature, only two do not use ammonia, but they either use a Raney catalyst, i.e., a "sponge," or introduce a number of chemicals (including gaseous HCl), the latter of which considerably complicates the process.

[0015] Raney catalysts are produced by treating a 50 / 50 Ni / Al alloy or Co / Al alloy with a NaOH solution. In this way, most of the present aluminum is removed, and the nickel is imparted with the characteristic porous "sponge" structure of the Raney catalyst. Once the catalyst is obtained, it must be stored in water or usually ethyl alcohol. Raney catalysts are spontaneously combustible in their dry, activated form. This complicates the handling of the catalyst and raises safety concerns during its introduction and removal. Furthermore, anhydrous ammonia is always used in reactions that reduce nitriles to amines.

[0016] The purpose of ammonia is to prevent the formation of secondary and tertiary amines when the product of interest is a primary amine. Secondary and tertiary amines arise from secondary reactions, and if their synthesis is not of interest, economically it represents not only a loss of material but also the problem of redistribution to the market or disposal. Anhydrous ammonia is a toxic gas, and therefore requires great care in its handling, resulting in complex plant solutions and inevitably increasing investment and operating costs. Furthermore, some countries, such as Italy, have specific laws regulating the use, storage, and transport of toxic gases (including anhydrous ammonia), and the use of toxic gases usually requires permits in the form of both technical and control requirements in accordance with these laws.

[0017] Patent document 10 (Chinese Patent Application Publication No. 112316949, Specification CN112316949A) describes the reduction of N-(2-cyanoethyl)caprolactam by hydrogen using a catalyst system such as a nickel alloy supported on coal and containing Cr and Fe, in order to reduce the formation of primary and secondary amines. Cr is used by using a salt of the highly unstable Cr(NO3)2. 2+ It is inserted into the catalyst in this form, and in fact, (as described in Non-Patent Literature 3: "Chemistry of the Elements" Vol. II, page 1238, Piccin Editore 1991 by NN Greenwood and A. Earnshaw) it is impossible to obtain Cr(NO3)2 in a stable form due to internal redox reactions that occur during synthesis.

[0018] For the reasons stated above, the method described in Patent Document 10 (CN112316949A) is not suitable for use with ion Cr. 2+ Because the Cr(NO3)2 salt used as a precursor to obtain it is unstable and therefore cannot be commercially available, it cannot be easily realized on an industrial scale.

[0019] In Patent Document 11 (CN 1546492), toluene is used as a solvent, starting from the reaction of caprolactam and acrylonitrile in the presence of a catalyst such as NaOH to obtain N-(2-cyanoethyl)caprolactam, and DBU (1,8-diazabicyclo[5,4,0]undec-7-ene) is prepared by a hydrogenation reaction in the presence of a catalyst derived from Al, Ni, Fe, and Cr in slurry form. N-(2-cyanoethyl)caprolactam is reduced by the hydrogenation reaction to become N-(3-aminopropyl)caprolactam, which is finally dehydrated to yield DBU. The reaction occurs by changing the type of solvent between one phase and another phase.

[0020] The hydrogenation catalyst is obtained by an alkaline solution and an alloy of Ni, Al, Cr, and Fe, and this operation is the same method used to produce a Raney catalyst or a sponge catalyst from a Ni or Co alloy. Therefore, the process described in Patent Document 11 (Chinese Patent Application Publication No. CN1546492) leads to the synthesis of a Raney catalyst or a sponge-type catalyst and has the same drawbacks as the process using these types of catalysts.

Prior Art Documents

Patent Documents

[0021]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

[0022] [Non-Patent Document 1] “DBU: A Reaction Product Component' Chemistry Select 2020, vol. 5, 11608- 11620 [Non-Patent Document 2] “1,8-Diazabicyclo[S.4.0]undec-7-ene (DBU): A Versatile reagent in Organic Synthesis” Bhaskara Nand et al. Current Organic Chemistry, 2015, 19, 790-812 [Non-Patent Document 3] NN Greenwood e A. Earnshaw in “Chemistry of the Elements” Vol. II page 1238 Piccin Editore 1991 [Overview of the project] [Problems that the invention aims to solve]

[0023] Therefore, the objective of the present invention is to realize an innovative amidine synthesis process that avoids the use of spontaneously combustible catalysts and the addition of further toxic reagents such as ammonia, while achieving an amidine yield suitable for industrial purposes.

[0024] In particular, an object of the present invention is to prepare 1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU) from ε-caprolactam and acrylonitrile for use in the above-mentioned applications, while limiting the number of intermediate purification steps and avoiding the use of anhydrous ammonia and Raney catalyst.

[0025] To that end, the applicant is attempting to discover a process for amidine production from lactams and α,β-unsaturated nitriles.

[0026] The applicant has found a method for preparing amidine from lactam and α,β unsaturated nitrile, comprising the following sequential reaction steps: adding an α,β unsaturated nitrile to a lactam; reducing the resulting cyano derivative in the absence of ammonia and a Raney-type catalyst; and dehydrating / cyclizing the resulting amine compound to obtain amidine, which can then undergo a final separation and purification step to obtain a product suitable for industrial use. The method can be carried out in batch or continuous mode, but continuous mode is preferred.

[0027] Remarkably, the applicant has found that the above series of reactions can be carried out without using ammonia and Raney-type catalysts, without using any processes with significant problems, or without requiring a step to separate intermediates of the desired product from other reaction products, and with a single final purification step, ensuring an acceptable final purity of the desired product and high yields and conversion rates to the desired product at each intermediate step. This reduces the number of devices used and significantly lowers the overall complexity of the process.

[0028] If high-purity semi-finished products and / or chemical intermediates are required, the use of an intermediate purification step can be considered at the discretion of the manufacturer.

[0029] The preparation process according to the present invention remarkably achieves these and other objectives. [Modes for carrying out the invention]

[0030] Therefore, the object of the present invention is to obtain a process for preparing amidine of formula (V) or its derivatives, [ka] A lactam having the following formula (I), and [ka] Starting with an α,β unsaturated nitrile having the following formula (II), [ka] During the ceremony, R1 is H, or an optionally substituted aliphatic hydrocarbon group having 1 to 5 carbon atoms, preferably 1 to 2 carbon atoms, and more preferably H. R2 is H, or an optionally substituted aliphatic hydrocarbon group having 1 to 5 carbon atoms, preferably 1 to 2 carbon atoms, and more preferably H. R3 is H, or an optionally substituted aliphatic hydrocarbon group having 1 to 5 carbon atoms, preferably 1 to 2 carbon atoms, and more preferably H. R4 is H, or an optionally substituted aliphatic hydrocarbon group having 1 to 5 carbon atoms, preferably 1 to 2 carbon atoms, and more preferably H. R5 is H, or an optionally substituted aliphatic hydrocarbon group having 1 to 5 carbon atoms, preferably 1 to 2 carbon atoms, and more preferably H. m is an integer between 3 and 7, more preferably between 3 and 6. Here, more preferably, (I) is ε-caprolactam, (II) is acrylonitrile, and (V) is 1,8-diazabicyclo[5,4,0]undeca-7-ene, The process described above proceeds sequentially through the following steps, namely: (A) Under additive conditions according to one of the methods known to those skilled in the art, the compound of formula (I) and the compound of formula (II) are reacted in the presence of a suitable base catalyst, preferably KOH, NaOH, LiOH, and tetrabutylammonium hydroxide, to obtain formula (III), i.e., [ka] Here, the base catalyst is preferably NaOH, LiOH, and tetrabutylammonium hydroxide, in the step of obtaining compound (III). Alternatively, the base catalyst is preferably DBU, a primary amine, a secondary amine, a tertiary amine, or another organic hydroxide, in the step of obtaining compound (III), (B) The step of reducing the compound of formula (III) obtained in step (A) by reaction with hydrogen in the presence of a catalyst derived from a metal of groups 8, 9 and 10 of the periodic table, such as iron, cobalt, nickel, or a noble metal such as ruthenium, rhodium, palladium, osmium, iridium, or platinum, preferably without an intermediate purification step of the compound from other reaction products, wherein the catalyst is not a Raney-type or sponge-type catalyst, but the corresponding formula (IV), i.e., [ka] The steps include obtaining the amine of formula (IV) (primary amine), and optionally separating the amine from the reaction solvent. (C) The present invention comprises the step of dehydrating the amine by one of the methods known to those skilled in the art to obtain the amidine of the corresponding formula (V). The amidine of formula (V) synthesized as described above in accordance with the present invention may be recovered in solvent and subsequently purified.

[0031] According to the present invention, the term amidine refers to a compound that can be derived from an amide by the substitution of an oxygen atom of a carbonyl group (CO) with an imide group (N). Preferably, the present invention considers cyclic amidines such as those defined by formula (V).

[0032] According to the present invention, the term "amidine derivative" means any compound obtained from amidine by reaction with a carboxylic acid, epoxy ketone, chlorocarbonate, or diester carbonate.

[0033] According to the present invention, the singular indefinite article, one, is understood to also mean at least one, unless otherwise specified.

[0034] Another object of the present invention is the synthesis of an intermediate of formula (IV) starting from a compound of formula (III) as defined above, for use in the synthesis of amine derivatives containing an N-alkyl-lactam chain.

[0035] According to step (A) of the method according to the present invention, a controlled catalytic addition reaction is carried out in the presence of a suitable base catalyst, starting with a lactam of formula (I), preferably ε-caprolactam, and an α,β-unsaturated nitrile of formula (II), preferably acrylonitrile, to obtain a compound of formula (III) in high yield.

[0036] The molar ratio (II) / (I) is selected by those skilled in the art according to what is known in organic chemistry for the reaction of step A, and is preferably 1.4 to 0.7, more preferably 0.8 to 1.3, and for example, about 1.1.

[0037] In this document, unless otherwise specified, proportions should be understood as mass proportions.

[0038] In this document, unless otherwise specified, pressure should be considered absolute pressure.

[0039] Typically, the reaction is carried out at a temperature of 20 to 140°C and a pressure of 10 to 600 kPa (0.1 to 6 bar A) for a time that may range from 0.5 to 10 hours, preferably 0.8 to 4 hours, depending on the reactants (I) and (II), temperature, and pressure. In a preferred configuration, the pressure is atmospheric pressure. In another preferred configuration, the pressure is higher than atmospheric pressure, preferably 110 to 600 kPa (1.1 to 6 bar A).

[0040] The reaction of the compounds of formulas (I) and (II) may be carried out in the absence of a solvent, or in the presence of an appropriate amount of an organic solvent, preferably in the presence of an organic solvent in an amount of 5 to 70% by weight of the total amount of the reaction mixture.

[0041] The solvent may be, for example, a linear ether, a branched ether, or a cyclic ether, such as a polar solvent like methyl tert-butyl ether or tetrahydrofuran (THF), or an alcohol having 1 to 6 carbon atoms such as methanol or ethanol, isopropyl alcohol or tert-butyl alcohol, or an aromatic solvent such as benzene, toluene, xylene or ethylbenzene, or an aliphatic hydrocarbon such as heptane or cyclohexane.

[0042] Preferably, the solvent is selected from the types of compounds described above so as to be able to solubilize compound (II) in the reaction environment. Furthermore, it is preferable that the solvent has a boiling point lower than that of the compounds of formulas (I) and (III) so that it can be at least partially separated from these compounds by evaporation.

[0043] Preferred solvents are isopropyl alcohol, tert-butyl alcohol, MTBE, THF, toluene, ethylbenzene, and xylene.

[0044] According to this process, all bases known in the literature and suitable for the purpose can be used as catalysts.

[0045] In one form, the catalyst may be an inorganic base, preferably KOH, NaOH, and LiOH, or an organic hydroxide, preferably tetrabutylammonium hydroxide. In another form, the catalyst may be an organic base, preferably DBU, a primary amine, a secondary amine, a tertiary amine, or another organic hydroxide.

[0046] Compared to prior art, step (A) is distinguished by favorable operating conditions in terms of the reaction mixture composition and reaction time, and step (A), when combined with the innovative step (B), is a fundamental operation necessary to obtain the desired product in good yield.

[0047] The compound of formula (III) obtained in step (A) can be separated and purified from the reaction mixture containing it, including by-products, catalysts and / or their residues and any solvents that may be present.

[0048] However, the applicant has surprisingly found that in the case of reductions where the next step is performed in step (B), the separation and purification steps of the intermediate compound of formula (III) from such other reaction by-products are not required. However, partial evaporation of the solvent can be optionally performed to avoid excessive dilution. This avoids the costly separation and purification of by-products.

[0049] In a subsequent step (B) of the process according to the present invention, the intermediate of formula (III) produced in step (A) is reduced, preferably without separation from the reaction mixture except by partial evaporation of the solvent, to convert the intermediate of formula (III) into the corresponding amino derivative of formula (IV).

[0050] The reduction of nitriles is a reaction reported in known literature and widely used in organic synthesis (see, for example, Peter Vollhardt, *Organic Chemistry*, pp. 825-826, 1st edition). In the aforementioned patent, the above reaction is carried out with the compound of formula (III) in the presence of anhydrous ammonia using a Raney catalyst (Ni or Co) or other sponge-like catalysts.

[0051] In some patent applications for known technologies, such reactions are carried out using catalysts such as "alloys," for example, "nickel alloy catalysts," where "alloy" is a compound in which two or more metals are melted together and form close bonds between the metals. The catalyst of the present invention excludes this "alloy" type catalyst and is not considered to be identical to them.

[0052] For the definition of "alloy," one can refer to the definition in prominent scientific books and / or manuals, such as Alan Cottrel's book "Introduction to Metallurgy" (Chapter 14, page 189), 2nd edition, 1995 - London Institute for Materials Research.

[0053] Suitable reduction catalysts for the purposes of the present invention are commercially available or synthetic hydrogen reaction systems derived from one or more metals of groups 8, 9, and 10 of the periodic table, such as iron, cobalt, and nickel, or from noble metals such as ruthenium, rhodium, palladium, osmium, iridium, or platinum. Cobalt, nickel, palladium, and platinum are preferred. Cobalt and nickel are particularly preferred. Such catalysts can be used in a dispersed phase, colloidal phase, or solid-supported / bonded form, preferably solid-supported / bonded in an inorganic phase with a large surface area, and more preferably in a silica, alumina, or silica-alumina-supported / bonded phase, with the exception of spontaneously combustible catalysts in the form of metal sponges, such as nickel lanay or cobalt lanay, and metal catalysts defined as "alloys," which are not part of the present invention. Cobalt on an alumina support is particularly preferred.

[0054] Generally, these types of catalysts of the present invention are not metal alloys, as they are obtained using various techniques starting from an aqueous solution of a precursor salt.

[0055] In a preferred embodiment, the reduction catalyst is a Co- and Ni-based catalyst, preferably a Co- and Ni-based catalyst supported / bonded to a Lewis acid having a Lewis acid or Brønsted acid component, and more preferably a Co- and Ni-based catalyst supported / bonded to Al2O3 or SiO2, wherein the catalyst is not a Raney catalyst or a sponge-type catalyst.

[0056] In step (B) of the present invention process, the reduction of the compound of formula (III) is carried out using the reduction catalyst and H2, in the absence of ammonia, and in the presence of water with a molar ratio of H2O / (III) of 0.01 to 1 or a weight ratio of 0.1 to 11% relative to the reaction mixture.

[0057] The reaction temperature in step (B) is 30 to 250°C, preferably 50 to 200°C, and the pressure is 0.4 to 15 MPa (4 to 150 barA), preferably 1.1 to 10 MPa (11 to 100 barA), and more preferably 2 to 6 MPa (20 to 60 barA).

[0058] The reduction reaction may be carried out batchwise for a reaction time of 0.1 to 12.0 hours, preferably 0.8 to 7.0 hours, more preferably 1.5 to 5 hours (in a reactor equipped with a stirrer, a heating jacket, and inlets for gas and liquid flows), or continuously in a stirred reactor such as a single-tube reactor, a multi-stage tubular reactor, or a CSTR. The continuous form is preferred in terms of productivity, particularly in terms of productivity on an industrial scale.

[0059] The reduction reaction can be carried out in the presence of an organic solvent. In one embodiment, the organic solvent is preferably selected from methanol or ethanol, isopropyl alcohol or tert-butyl alcohol, MTBE, or THF, and more preferably THF. In other embodiments, the organic solvent is an aromatic solvent such as benzene, toluene, xylene, or ethylbenzene, with xylene (o, m, p or a mixture of isomers) and ethylbenzene being the most preferred.

[0060] When the compound of formula (III) is preferably a cyano derivative of ε-caprolactam, the main product of reduction is the corresponding amino derivative (IV), which is obtained mainly together with a certain amount of the cyclization product (V)(DBU).

[0061] The formation of corresponding secondary / tertiary amines may occur. However, when ammonia is used, these compounds are obtained in amounts consistent with those described in the literature, and in all cases, these amounts are negligible compared to the desired primary amine.

[0062] The amino derivative of the lactam of formula (IV) obtained in step (B) of the present invention process is dehydrated by step (C) of synthesizing the corresponding amidine, preferably DBU(1,8-diazabicyclo[5,4,0]undeca-7-ene).

[0063] With respect to step (C) used by the present applicant, step (C) has already been described in the prior art, in particular in Patent Document 1 (German Patent No. 1545855).

[0064] Dehydration is carried out at a high temperature, preferably 90-270°C, more preferably 130-230°C, and even more preferably 150-200°C, while continuously removing the water generated during dehydration that leads to cyclization. Boiling and partial condensation of vapor can be operated in reflux mode, and the water is separated and the condensate can be collected in a phase separator where the solvent is refluxed within the reaction system.

[0065] An acid catalyst is always necessary and can be selected by those skilled in the art from among the acid catalysts known in the literature; in the present invention, p-toluenesulfonic acid can be used. At the end of the reaction in step (C), the mixture needs to be neutralized with an appropriate amount of concentrated NaOH aqueous solution, and the solvent is finally recovered by evaporation. The main dehydration product is the target amidine.

[0066] End users can purify amidine using one of the methods known to the technical level as needed, for example, by distillation to a purity of 95-98% by weight.

[0067] Therefore, the process according to the present invention is advantageous because it can eliminate the problems of the Raney catalyst's spontaneous combustion and ammonia toxicity without disadvantageous to the generation of primary amines, and furthermore, the applicant was surprised to find that amidine was already formed in step (B).

[0068] None of the prior art methods described above mention the possibility of reducing nitriles in the absence of ammonia and Raney catalyst.

[0069] Preferably, in the process of the present invention, the intermediate of the reaction mixture obtained in step A) or B) is not purified, but the solvent is evaporated in order to recover and use the solvent.

[0070] Furthermore, the applicant has revealed the surprising possibility of using a single solvent in all reaction steps, which further simplifies the process.

[0071] This solvent can be selected from a variety of aprotic solvents, and it has been found that xylene (pure isomers or mixtures) is particularly suitable for this purpose.

[0072] In this process, all reaction steps and the final purification step can be carried out in sequence.

[0073] In particular, using a single solvent in all reactions further simplifies the process, making it even more efficient in terms of productivity and operating costs in a continuous configuration.

[0074] In a particularly preferred embodiment of the present invention, the applicant has discovered a novel and unique process for producing amidine from lactam.

[0075] Therefore, the process according to the present invention will be described in more detail below for the production of 1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU) starting from ε-caprolactam and acrylonitrile, but this is understood to limit the application of the same process of the present invention to compounds having different structures and different numbers of carbon atoms, within the limitations of formulas (I) and (II) above.

[0076] A mixture of compound (I) (e.g., ε-caprolactam) in a solvent (e.g., xylene) is continuously supplied to a CSTR or tubular recirculation reactor after the addition of a base catalyst (e.g., NaOH, LiOH, or tetrabutylammonium hydroxide), and compound (II) (e.g., acrylonitrile) is also continuously supplied to the reactor. A more preferred method is to use two reactors having these features arranged in series. Alternatively, a batch reactor can be used to deliver the reaction product to a tank, and the reaction product can be continuously supplied from the tank to step (B). The addition reaction is carried out at a temperature of 20-140°C, preferably 40-110°C, more preferably 60-80°C, with a residence time of 0.5-10 hours, preferably 0.8-4 hours.

[0077] Compound (I) (e.g., ε-caprolactam) can be supplied to the molten material in the absence of a solvent, but a solvent mixture is preferred. In the latter case, the solvent may be present up to 70% by weight of the total solution, preferably 5-50% by weight of the total solution, and more preferably 15-40% by weight of the total solution.

[0078] The pressure at which the reaction takes place is 10 to 600 kPa (0.1 to 6 bar A), preferably 10 to 400 kPa (0.1 to 4 bar A).

[0079] Since the reaction is exothermic, the reaction temperature can be controlled by partial evaporation of the reaction mixture through reflux condensation within the reactor, or alternatively, the reaction mixture can be recirculated by an external heat exchanger of the reactor itself.

[0080] The production and conversion rates in step (A) are usually high. For example, when compound (I) is ε-caprolactam and compound (II) is acrylonitrile, the main addition product, N-(2-cyanoethyl)-ε-caprolactam, is usually obtained in a yield of up to 90-95%, while the conversion rate of ε-caprolactam is usually 85-99.9%.

[0081] All conversion rate, selectivity, and yield values ​​mentioned are for the reaction mixture described in the examples. 1 1H NMR and 13 The values ​​are based on measurements taken using 1C NMR and GC-MS.

[0082] The flow exiting the reactor can be optionally cooled (with the possibility of partial heat recovery) or sent directly to the second step (B) of the reduction reaction.

[0083] Alternatively, the liquid stream may be supplied to an evaporator if possible to recover the solvent and reactants, i.e., unreacted compounds (I) and (II). Any type of evaporator known in the prior art may be advantageously used for the purposes of this invention. A kettle-type evaporator is preferred. Further details of the types of evaporators that can be used for this purpose can be found, for example, in Perry's Chemical Engineers' Handbook, McGraw-Hill (7 th This can be found in Ed.-1997, Chapter 11, pages 108-118. Alternative setups are based on the use of a tray distillation column or packing material. A distillation column allows for the recirculation of unreacted compound (I) and compound (II) or solvent with less reaction product than when using an evaporator.

[0084] The liquid stream exiting the distiller or the bottom of the distillation column, containing the addition product and solubilization catalyst, is then sent to an exchanger where it is heated to a temperature of 30-250°C, preferably 50-200°C, more preferably 100-160°C. The flow from the exchanger is then sent to a reactor for a reduction reaction, which is operated for 1-50 hours. -1Preferably 3 to 10 hours -1 The reactor operates at WHSV (weight space velocity per unit time relative to the total volume of incoming flow), and is preferably a fixed-bed reactor or a trickle-bed reactor. The reactor is equipped with a thermostat system and contains the hydrogenation catalyst described above.

[0085] The reduction reaction can be carried out in the presence of an organic solvent, which is preferably selected from MTBE, THF, methanol, ethanol, isopropanol, tert-butyl alcohol, or toluene, xylene (pure or mixed isomers), or ethylbenzene. THF, xylene, and ethylbenzene are preferred, and the solvent is preferably the same as the solvent used in step (A). The solvent may be 3 to 70% by weight of the reaction mixture, preferably 5 to 50% by weight, more preferably 15 to 40% by weight of the reaction mixture.

[0086] The reduction reaction is preferably carried out in the presence of 0.1 to 11% by weight of water in the reaction mixture, and the reactor is supplied with H2 to a pressure of 0.4 to 15 MPa (4 to 150 bar A), preferably 1.1 to 10 MPa (11 to 100 bar A), more preferably 2 to 6 MPa (20 to 60 bar A). The reactor is continuously flowed with gas by recirculating the gas exiting through a compressor / blower from the front to the bottom of the reactor. A portion of the recovered H2 is supplied to maintain the above pressure values. The flow consisting of a mixture of reaction products and optionally a solvent flows from the bottom of the reactor. A preferred configuration of this reactor is expected to be the recirculation of excess gas by a liquid jet extractor mounted on top of a trickle bed reactor. The motor fluid is the same reaction mixture recirculated by a pump.

[0087] When compound (I) is ε-caprolactam and compound (II) is acrylonitrile, the main reduction products are N-(3-aminopropyl)-ε-caprolactam and optionally 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), and the main by-products are secondary and tertiary amines of 3-aminopropyl-ε-caprolactam. These by-products do not exceed 7% by weight. The conversion rate of N-(2-cyanoethyl)-ε-caprolactam is 90 - 99%, and the total yield of N-(3-aminopropyl)-ε-caprolactam and DBU is over 92%. All the conversion rates, selectivities and yields mentioned refer to their values measured by 1 1H NMR and 13 13C NMR as well as GC-MS of the reaction mixture described in the examples.

[0088] This stream can be sent to a solvent recovery system. A preferred arrangement is based on an evaporator for recovering water and the solvent. The reaction mixture containing the remaining solvent exits from the bottom of the evaporator. The stream from the evaporator is fed to a degassing device containing a perforated plate that promotes both the separation and contact of the two-phase liquid stream. The vapor phase exiting the degassing device is partially condensed in a reflux condenser, which operates at a temperature of 20 - 250°C, preferably 40 - 150°C, more preferably 60 - 130°C, and optionally further condensation can be carried out to recover any by-products generated during the reactions of steps (A) and (B).

[0089] The vapor exiting the reflux condenser is condensed in another cooler at a temperature of 2 - 50°C, preferably 10 - 30°C, more preferably 20°C.

[0090] The liquid collected at the outlet of the cooler is the solvent with added water. While sending the mixture exiting from the bottom of the evaporator to the dehydration step (C), after separating the water, the solvent is reused.

[0091] However, in a preferred embodiment, the stream exiting the hydrogenation reactor is sent directly to the dehydration step.

[0092] Dehydration / cyclization of N-aminolactams is a known reaction in the literature that can be carried out in various ways by those skilled in the art. The following methods are not intended to be considered limiting to the methods of the present invention with respect to the conditions adopted by the applicant.

[0093] Dehydration is carried out continuously in a reactor, preferably of the CSTR type, which is called a dehydrator and is equipped with a heating system and a condensing system consisting of a partial reflux condenser and a post-condenser. The reactor condenses most of the water produced and sends the condensate to a phase separator into which the solvent is reintroduced. In the phase separator, the remaining organic matter is separated and reintroduced to the dehydrator, but the water is partially recycled back into the hydrogenation reaction, and the excess is sent for treatment. The reaction is carried out under reaction conditions in the presence of a soluble acid catalyst, preferably p-toluenesulfonic acid, for a residence time of 0.5 to 12 hours, preferably 2 to 8 hours. Optionally, the reaction can also be carried out in the absence of the solvent. Dehydration is carried out at a high temperature, preferably 90 to 270°C, more preferably 130 to 230°C, and even more preferably at the boiling point of the mixture. The reaction is carried out at a pressure of 8-500 kPa (0.08-5 BarA), preferably 50-300 kPa (0.5-3 BarA), and more preferably 100-200 kPa (1-2 BarA). At the end of the reaction, the mixture needs to be neutralized with an appropriate amount of a strong base aqueous solution such as high concentration NaOH, and the salt formed needs to be removed from the mixture. The stream of dehydrated product, solvent, any unreacted amine and by-products from the previous step is discharged from the bottom of the reactor, and the main product is DBU (1,8-diazabicyclo[5,4,0]undec-7-ene) when compound (I) is ε-caprolactam and compound (II) is acrylonitrile.

[0094] Subsequently, the flow is sent to a distillation section for solvent recovery and purification of compound (V), such as DBU. After distillation, the purity of this compound is typically 95-98%.

[0095] The purity of the aforementioned compound is measured by gas chromatography-mass analysis (GC-MS).

[0096] The compound after distillation can optionally be subjected to further purification, such as liquid-liquid extraction. Such operations can be carried out using techniques known to those skilled in the art.

[0097] According to different embodiments of the present invention, the dehydration / cyclization reaction of the amine of formula (IV) can be carried out using an alumina, silica-alumina, or zeolite catalyst to advantageously obtain the corresponding amidine of formula (V).

[0098] The amidine of formula (V) synthesized as described above according to the present invention may be subjected to further purification by methods known to those skilled in the art. In this embodiment, the reaction mixture from hydrogenation step (B) is preferably subjected to solvent recovery by evaporation and then dehydration. Alternatively, in a less preferred embodiment, the amino derivative of the lactam of formula (IV) can be reacted in a purified form. In yet another embodiment, dehydration may be carried out in the same solvent as in the previous step, for example, in xylene.

[0099] Dehydration is carried out at a high temperature, preferably 90-270°C, more preferably 130-230°C, and even more preferably 150-200°C, while continuously removing the water generated during the dehydration process that causes cyclization.

[0100] A catalyst is always required and is selected from heterogeneous acid catalysts selected from Lewis acids having Lewis acid or Brønsted acid components such as aluminum oxide (γ-Al2O3), alumina silica (SiO2-Al2O3), acid clays such as lanthanum oxide and zirconium oxide, or heterogeneous catalysts derived from resins such as sulfonated resins or ion exchange resins. The catalyst may be supported on an inert support such as pumice, graphite, or silica. Aluminum oxide (γ-Al2O3) is preferred. At the end of the reaction, the main dehydration product is the target amidine of formula (V). If required by the end user, the amidine can be purified to a purity of 95-98% by weight by one of the methods already known in the art, for example, distillation.

[0101] The applicant has, remarkably, found the possibility of achieving solvent-free dehydration of a solid acid catalyst without refluxing the solvent, thereby facilitating water removal by further simplifying the process and reducing costs.

[0102] In the process of the present invention, the reaction step (C) and the final purification step can be carried out in succession.

[0103] Dehydration is carried out continuously in a preferably tubular reactor called a dehydrator, which includes a heating system and a condensation system consisting of a post-condenser that condenses most of the purified water and sends the condensate to a phase separator. In the phase separator, the remaining organic matter is separated and reintroduced to the dehydrator, while the water is partially recycled to a hydrogenation section, and the excess is sent for processing. In a preferred embodiment, the mixture is continuously fed laterally into the reactor, with the flow exiting from the top of the reactor and the reaction products exiting from the bottom. The reactor may optionally be equipped with packing material such as a ring, plate, or partition at the top to allow only water vapor to escape. In other embodiments, the reaction mixture can be continuously fed from the bottom while water vapor escapes from the top of the reactor, and the reaction products can be removed from the side of the reactor. The reaction is carried out in the presence of a heterogeneous acid catalyst, preferably γ-alumina, for 1 to 50 hours. -1 Preferably 3 to 10 hours -1 The reaction is carried out at WHSV (weight-space velocity per unit time for the total reaction mixture). Dehydration is carried out at high temperature, preferably 90-270°C, more preferably 130-230°C, and even more preferably 150-200°C. The pressure at which the reaction is carried out is 8-500 kPa (0.08-5 BarA), preferably 50-300 kPa (0.5-3 BarA), and more preferably 100-200 kPa (1-2 BarA). The stream consisting of the dehydrated product, unreacted amine, final solvent, and by-products from the previous step is discharged from the bottom of the reactor, and when the compound of formula (IV) is N-(3-aminopropyl)-ε-caprolactam, the main product is usually DBU (1,8-diazabicyclo[5,4,0]undeca-7-ene).

[0104] The product stream is then sent to a distillation section for solvent recovery and purification of compound (V), such as DBU. After distillation, the purity of the compound is typically 95-98%.

[0105] The purity of the aforementioned compound is measured by gas chromatography-mass analysis (GC-MS). [Examples]

[0106] In the following examples, unless otherwise indicated, the following abbreviations and materials will be used. - AN: Acrylonitrile (CAS 107-13-1, purity ≥99%, Sigma-Aldrich) - CPLT: ε-caprolactam (CAS 105-60-2, 99% purity, Sigma-Aldrich) - NaOH: Sodium hydroxide (CAS 1310-73-2, purity ≥ 98%, Sigma-Aldrich) - Minimum 45% NaOH aqueous solution (CAS 1310-73-2, Titer 45-50%, Sigma-Aldrich) - Xylene: Mixture of xylene isomers (CAS 1330-20-7, purity ≥ 98.5%, Sigma-Aldrich) - CTZ1: Commercial catalyst HTC CO2000 RP 1.2mm (alumina supported) JPEG0007894379000008.jpg1439) Johnson-Matthey (Data from Table 3 of Example J in columns 21-22 of U.S. Patent No. 8,293,676) - CTZ2: Commercial catalyst HTC Ni 500 Johnson-Matthey (data from Example 1 on page 6 of International Patent Application (PCT) WO2010 / 018405, in the form of a 1.2 mm trilobite extruded material containing 21% nickel as nickel oxide in a porous transition alumina support) - H2: Hydrogen (sapio titre5.5) - H2O: Ultrapure water (MilliQ Millipore system) - p-TSA: p-toluenesulfonic acid monohydrate (CAS 6192-52-5, purity 99%, Sigma-Aldrich)

[0107] (Gas mass spectrometry) Gas mass spectrometry to measure reactants and reaction products in the three reaction steps is performed using a GC HP6890 chromatograph connected to an MS HP 5973 mass spectrometer equipped with a split / splitless injector and functioning as a detector. The chromatography is characterized by an HP-1MS UI capillary column (100% polydimethylsiloxane, Agilent J&W), quartz glass WCOT, 30 m length, 0.25 mm ID, and 0.25 μm film thickness. The instrument parameters are as follows: ·Injection volume 20μl • Helium carrier gas 0.8 ml / min (constant flow mode) ·Split ratio 250:1 Injector temperature 300℃ • Programmable oven temperature 40-320°C, 10°C / minute (28 minutes), plus a 10-minute waiting period at 320°C (total execution time = 38 minutes)

[0108] Since no specific pure product (such as ε-caprolactam and its corresponding cyano derivative) is available on the market, quantification was performed by comparing the relative regions of various chromatographic peaks (and therefore, an approximation that they are identical chromatographic responses is accepted).

[0109] However, quantitative 1 H NMR analysis, 13 When 13C NMR analysis was performed on the same sample, the results obtained overlapped with those shown by gas chromatography.

[0110] (NMR analysis) The samples were analyzed using a Bruker Avance 400MHz spectrometer by dissolving approximately 50–70 mg of the sample in deuterated chloroform at a temperature of 300K. Spectra were recorded using the following instrument parameters.

[0111] [Table 1]

[0112] [Example 1: Reaction of ε-caprolactam and acrylonitrile in xylene] 123.3 g of ε-caprolactam and 62.5 g of xylene were placed in a 1-liter flask equipped with a nitrogen inlet, stirrer, reflux condenser, thermocouple, and dropping funnel. The suspension was heated with stirring at 45-50°C using an oil bath under a light flow of nitrogen until completely solubilized. Then, 0.1841 g of NaOH was added and the temperature was raised to 70°C. Once the sodium hydroxide was solubilized, acrylonitrile (67.4 g) was added dropwise, taking care to maintain the temperature at 70-80°C, as this is an exothermic reaction (the addition time is estimated to be approximately 1 hour). The temperature was maintained at 70°C at the end of the acrylonitrile addition, and the reaction was allowed to continue for 2.25 hours. As the addition reaction progressed, the solution was observed to gradually darken.

[0113] GC-MS analysis showed a conversion rate of 98.6% and a selectivity of 98.3% for caprolactam, and therefore the yield of the product was 96.9%. The basic raw material solution was hydrogenated in Example 2 as described below.

[0114] [Example 2: Hydrogenation of natural nitrile solution in xylene (catalyst Co)] In a 250 ml autoclave equipped with a mechanical turbine agitator, a heated mantle, a catalyst cage, and inlets for gas and liquid flow, 30 g of CTZ1 catalyst was introduced into a dedicated catalyst cage at room temperature and activated in a hydrogen atmosphere.

[0115] Catalyst activation was performed by first washing the catalyst with nitrogen at atmospheric pressure, then heating the reactor to 150°C with a temperature gradient of 25-50°C / h, and once that temperature was reached, supplying hydrogen at a flow rate of 30 ml / min to raise the temperature to 180°C.

[0116] At this point, the hydrogen flow rate was gradually increased by decreasing the nitrogen flow rate until the gas flushing became entirely hydrogen-based (flow rate 200 ml / min). Under these temperature and flow rate conditions, the activation was continued for 18 hours, after which the nitrogen flow was restored (and the hydrogen flow was simultaneously reduced), the catalyst was maintained in an inert atmosphere, and the system was gradually cooled to room temperature.

[0117] 143.9 g of the solution obtained in Example 1 was mixed with 2.5 g of water (approximately 3% of the total volume), then introduced into the reactor, and the line was flushed by introducing 20.1 g of xylene. The reactor pressure was increased to 2.1 MPa (21 bar A) by driving a stirring motor (750 rpm), and the internal temperature was set to 130°C by turning on the heater. Meanwhile, the reactor was pressurized with hydrogen to a pressure of 4.1 MPa (41 bar A). Hydrogenation was carried out at this pressure as long as the hydrogen flow from the line to the reactor was approximately 0.2-0.3 L / h. The amount of hydrogen introduced into the reactor was indicated by a counter and compared with the stoichiometric amount calculated based on the amount of nitrile introduced. Finally, the product was cooled and released.

[0118] GC-MS analysis showed a conversion rate of 96.1% and a selectivity of 99.3% for the nitrile product, and therefore, a yield of 95.4% for the products N-(3-aminopropyl)-ε-caprolactam and DBU(1,8-diazabicyclo[5,4,0]undeca-7-ene). To obtain a sufficient amount of dehydrated product, this synthesis was reproduced twice under identical conditions (the results obtained overlapped with those shown in this example).

[0119] [Example 3: Dehydration of crude amine solution in xylene] To 159.4 g of the solution obtained as described in Example 2, 1.3 g of p-toluenesulfonic acid monohydrate was added. This mixture was heated to 150-160°C by reflux using a dry hemispherical heater connected to a temperature controller. The reaction flask was connected to a Dean-Stark trap and condenser to remove water generated in the reaction environment, and the generated vapor was condensed at the top of the trap, removing the resulting water by gravity (the solvent returned to the flask in a nearly constant amount). After 4 hours from the start of reflux, no further accumulation of water was observed in the trap, so the reaction was considered complete, and the mixture was then cooled to room temperature. The resulting solution was neutralized with 800 mg of aqueous NaOH solution (minimum concentration 45%).

[0120] GC-MS analysis revealed a conversion rate of 92.3% and a selectivity of 99.4% for N-(3-aminopropyl)-ε-caprolactam, resulting in a DBU yield of 91.7%.

[0121] [Example 4: Hydrogenation of crude nitrile solution in xylene (catalyst Ni)] The same reaction as in Example 2 described above was carried out, but with catalyst CTZ2 replaced by catalyst CTZ1 (the activation mode was the same as already described).

[0122] GC-MS analysis showed a conversion rate of 96.9% and a selectivity of 78.5% for the nitrile product, and therefore a yield of 76.1% for the product N-(3-aminopropyl)-ε-caprolactam and DBU (1,8-diazabicyclo[5,4,0]undeca-7-ene).

[0123] [Example 5: Reaction of caprolactam and acrylonitrile in the absence of solvent] The same reaction described in Example 1 was carried out in the absence of a solvent.

[0124] 123.4 g of ε-caprolactam was placed in a 500 ml flask equipped with a nitrogen inlet, stirrer, refluxer, condenser, thermocouple, and dropping funnel. Under a gentle stream of nitrogen, the solid was heated to 70-75°C using an oil bath (external temperature control). Once completely melted, 0.1230 g of NaOH was added, and the temperature was raised to 70°C (internal temperature control). Once the sodium hydroxide was solubilized, acrylonitrile (67.4 g) was added dropwise, taking care to maintain the temperature at 70-80°C. The reaction was exothermic. At the end of the acrylonitrile addition, the temperature was maintained at 70°C and the reaction was allowed to continue for 2 hours. As the addition reaction progressed, it was observed that the solution gradually darkened.

[0125] GC-MS analysis showed a conversion rate of 95.4% for caprolactam, a selectivity of 98.9%, and therefore a product yield of 94.4%.

[0126] [Example 6: Dehydration of crude amine solution in xylene using a heterogeneous acid catalyst] The solution from Example 2 (138.3 g) was introduced into a flask (containing a small amount of glass ball) connected to a Dean-Stark apparatus equipped with a bubble condenser. Then, 1 gram of SASOL SPHERES 1.0 / 160 alumina, which had been pre-activated in an oven at 150°C for 8 hours, was added. The flask was heated to 170°C, and the water produced by the reaction was separated while the solvent was recovered. After about 4 hours, once it was confirmed that no water had been produced, the flask was cooled and the contents were subjected to GC-MS analysis. The results of the analysis showed a conversion rate of 94.7% and a selectivity of 99.5% for N-(3-aminopropyl)-ε-caprolactam, and therefore the yield of DBU was 94.2%.

[0127] [Example 7: Dehydration of amines using a solvent-free heterogeneous acid catalyst] The solvent of the mixture obtained from Example 2 was removed using a rotary evaporator (T=60°C, P=30 mbar), resulting in 113.9 g of a mixture of N-(3-aminopropyl)-ε-caprolactam and DBU. This solution was introduced into a flask (containing a small amount of glass ball) connected to a Liebig condenser for the removal of reaction water. Then, 1 gram of SASOL SPHERES 1.0 / 160 alumina, which had been pre-activated in an oven at 150°C for 8 hours, was added. Dehydration was carried out under a gentle flow of nitrogen to facilitate the removal of water. The flask was then heated at 170-180°C for approximately 5 hours (no aggregation was observed), and the flask was cooled and the contents were subjected to GC-MS analysis. The results of the analysis showed a conversion rate of 93.6% and a selectivity of 83.1% for N-(3-aminopropyl)-ε-caprolactam, and therefore a yield of 77.8% for DBU.

[0128] Tables 1, 2, and 3 show summary data from the previous examples.

[0129] Finally, although not specifically mentioned in the text, further modifications and variations of the methods described and illustrated herein are also acceptable and should be considered obvious variations of the present invention within the scope of the attached claims.

[0130] (Calculation of conversion rate, selectivity, and yield (GC-MS))

number

[0131] Table 1: Addition reactions [Table 2] (1) Reaction time at the end of AN addition (addition time for all examples is 1 hour)

[0132] Table 2: Reduction reactions [Table 3] (2) Yield and selectivity for all desired products (primary amines and DBU)

[0133] Table 3: Dehydration reaction [Table 4] Considering the results of consecutive Examples 1, 2, and 3, the overall yield of the synthesis (using p-TSA acid) could be calculated.

[0134] [Table 5]

Claims

1. A preparation process for amidine of formula (V), 【Chemistry 1】 A lactam having the following formula (I), and 【Chemistry 2】 Starting with an α,β unsaturated nitrile having the following formula (II), 【Transformation 3】 During the ceremony, R1 is H, or an aliphatic hydrocarbon group having 1 to 5 carbon atoms. R2 is H, or an aliphatic hydrocarbon group having 1 to 5 carbon atoms. R3 is H, or an aliphatic hydrocarbon group having 1 to 5 carbon atoms. R4 is H, or an aliphatic hydrocarbon group having 1 to 5 carbon atoms. R5 is H, or an aliphatic hydrocarbon group having 1 to 5 carbon atoms. m is an integer between 3 and 7. The process described above proceeds sequentially through the following steps, namely: (A) Reacting the compound of formula (I) with the compound of formula (II) under additive conditions, in the presence of an organic or inorganic base catalyst, or in the presence of a solvent, or in the absence of a solvent, to obtain the compound of formula (III), that is, 【Chemistry 4】 The steps include obtaining a compound of formula (III), (B) The compound of formula (III) obtained in step (A) is reduced by reaction with hydrogen in the presence of a non-Raney or non-sponge cobalt catalyst, without a step of purifying compound intermediates from other reaction products, to obtain the corresponding compound of formula (IV), i.e., 【Transformation 5】 The steps include obtaining the amine of formula (IV), and optionally separating the amine from the reaction solvent, (C) The step of dehydrating the amine in the presence of an acid catalyst to obtain the amidine of the corresponding formula (V), A process for preparing amidine, comprising the following:

2. A process according to claim 1, wherein (I) is ε-caprolactam, (II) is acrylonitrile, and (V) is 1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU).

3. The process according to claim 1 or 2, wherein in step (A), the molar ratio (II) / (I) is 1.4 to 0.

7.

4. A process according to any one of claims 1 to 3, wherein step (A) is carried out at a temperature of 20 to 140°C and a pressure of 10 to 600 kPa for a period of 0.5 to 10 hours, depending on the type of reactants (I) and (II), temperature, and pressure.

5. In the process according to any one of claims 1 to 4, when step (A) is carried out in the presence of a solvent, the solvent is selected from polar solvents such as linear ethers, branched ethers and cyclic ethers selected from methyl tert-butyl ether (MTBE) and tetrahydrofuran (THF), C1-C6 alcohols selected from methanol, ethanol, isopropyl alcohol and tert-butyl alcohol, aromatic solvents selected from benzene, toluene, xylene and ethylbenzene, and aliphatic hydrocarbons selected from heptane and cyclohexane. The process wherein the amount of the solvent is 5 to 70% by weight relative to the total amount of the reaction mixture.

6. A process according to any one of claims 1 to 5, wherein in step (A), the catalyst is selected from KOH, NaOH, LiOH, tetrabutylammonium hydroxide, DBU, primary amines, secondary amines, tertiary amines, and other organic hydroxides.

7. In the process according to any one of claims 1 to 6, in step (B), the intermediate of formula (III) from step (A) is prepared in the absence of ammonia and in molar ratio H ２ A process in which a reduction reaction is carried out in the presence of water in an O / (III) ratio of 0.01 to 1 or 0.1 to 11% by weight relative to the reaction mixture, without separation from the reaction mixture except for possible partial evaporation of the solvent.

8. In the process according to any one of claims 1 to 7, the catalyst is Al ２ O and SiO ２ A process in which a cobalt-based catalyst is supported / bonded to a Lewis acid having a Lewis acid or Brønsted acid component selected from the above.

9. A process according to any one of claims 1 to 8, wherein the reaction temperature in step (B) is 30 to 250°C and the pressure is 0.4 to 15 MPa, which is in the absence of a solvent or in the presence of an organic solvent selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, MTBE, THF, benzene, toluene, xylene and ethylbenzene.

10. A process according to any one of claims 1 to 9, wherein steps (B) and (C) are carried out continuously in a stirred reactor CSTR.

11. A process according to any one of claims 1 to 10, wherein step (C) is carried out in the presence of p-toluenesulfonic acid, in the presence of a solvent, at a temperature of 90 to 270°C and a pressure of 8 to 500 kPa, while continuously removing the water generated during dewatering.

12. In the process according to any one of claims 1 to 10, step (C) is, for example, aluminum oxide (γ-Al ２ O ３ ), silica alumina (SiO ２ - Al ２ O ３ A process in which, in the presence of a catalyst selected from a Lewis acid, a Lewis acid having a Brønsted acid component, an acidic clay selected from lanthanum oxide and zirconium oxide, or a heterogeneous catalyst derived from a resin such as a sulfonated resin and an ion exchange resin, the catalyst is optionally supported on an inert support, and the process is carried out in the absence of a solvent, at a temperature of 90 to 270°C and a pressure of 8 to 500 kPa, while continuously removing the water generated during dewatering.

13. A process according to any one of claims 1 to 12, wherein steps (A), (B), and (C) are carried out sequentially in the presence of a solvent selected from xylene and ethylbenzene.

14. In the process according to any one of claims 1 to 13, the reaction mixture from step (A) is fed to an evaporator or a tray-type distillation column, or to an evaporator or a tray-type distillation column having packing material, and the solvent and as many reactants as possible are recovered. The liquid stream coming out of the bottom of the distiller or distillation column containing the addition product and solubilization catalyst is fed to a heat exchanger and heated to a temperature of 30 to 250°C. The flow from the exchanger is supplied to the reactor for the reduction reaction of step (B) at a pressure of 0.4 to 15 MPa. The reactor is selected from a fixed bed reactor and a trickle bed arrangement and operates at a WHSV (weight hourly space velocity per unit time relative to the total incoming flow) of 1 to 50 h －１ , or 3 to 10 h －１ process.

15. The compound of formula (IV), that is, 【Transformation 6】 This is the synthesis process of the compound, We begin with the compound of formula (III), that is, 【Transformation 7】 During the ceremony, R1 is H, or an aliphatic hydrocarbon group having 1 to 5 carbon atoms. R2 is H, or an aliphatic hydrocarbon group having 1 to 5 carbon atoms. R3 is H, or an aliphatic hydrocarbon group having 1 to 5 carbon atoms. R4 is H, or an aliphatic hydrocarbon group having 1 to 5 carbon atoms. R 5 is H, or an aliphatic hydrocarbon group having 1 to 5 carbon atoms. m is an integer between 3 and 7. A synthesis process for a compound of formula (IV), starting with a compound of formula (III), Al ２ O ３ and SiO ２ The process comprises a hydrogenation step of a compound of formula (III) by reaction with hydrogen in the presence of a non-Raney or non-sponge cobalt-based catalyst supported / bonded to a support selected from the following: Hydrogenation occurs in the absence of ammonia, with a molar ratio of H ２ The reaction is carried out in the presence of water in a ratio of 0 / (III) 0.01 to 1 or 0.1 to 11% by weight relative to the reaction mixture. The reaction temperature is 30 to 250°C, and the pressure is 0.4 to 15 MPa. The hydrogenation is a synthesis process for the compound of formula (IV), carried out in the absence of a solvent or in the presence of an organic solvent selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, MTBE, THF, benzene, toluene, and xylene and ethylbenzene.

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