Process for preparing amidines from N-(alkyl lactams)

Abstract

A process for the preparation of an amidine or a derivative thereof comprising the step of dehydrating an N-(amino-alkyl) lactam in the presence of a heterogeneous catalyst selected from the group consisting of a Lewis acid, a Lewis acid having a Bronsted acid or a Bronsted acid component such as a cerium oxide catalyst; boron phosphate, cerium and zirconium; other zirconium salts; modified zirconium oxide; and phosphotungstic acid.

Description

Technical Field

[0001] The present invention relates to a method for preparing amidines. More specifically, the present invention relates to a method for producing amidines (e.g., 1,8-diazabicyclo-[5.4.0]-undec-7-ene (hereinafter referred to as DBU)) or derivatives thereof from lactams (e.g., ε-caprolactam and α,β-unsaturated nitrile (e.g., acrylonitrile)).

[0002] It is well known that DBU is a multifunctional molecule that lends itself to many applications; in fact, the chemical reactions in which this molecule can participate are diverse. A recent article by Jacques Muzart, "DBU: A Reaction Product Component' Chemistry Select 2020, Vol. 5, 11608-11620, provides a detailed summary of this, from salt formation to addition of carbon-carbon double bonds and more. In these aspects, DBU is used in polyurethane catalysis, the pharmaceutical industry, ionic liquids, and general organic synthesis. Further details on the application of DBU are also described in "1,8-Diazabicyclo[S.4.0]undec-7-ene (DBU): A Versatile reagent in Organic Synthesis" Bhaskara Nand et al. Current Organic Chemistry, 2015, Vol. 19, 790-812. In the prior art, the industrial production of DBU is mainly carried out 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, in the presence of anhydrous ammonia and Raney nickel (Nickel In the presence of a Raney catalyst, N-(2-cyanoethyl)-ε-caprolactam is hydrogenated to the corresponding amine. In a third step, N-(3-aminopropyl)-ε-caprolactam is dehydrated to DBU by acid catalysis. For industry, the most complex step in the synthesis is the hydrogenation step in the presence of ammonia. The catalyst commonly used is the Raney nickel catalyst, which is pyrophoric in its activated form. Anhydrous ammonia is also a toxic gas, and its storage, use and transportation require specific precautions and authorizations.

[0003] The following are some relevant documents of the prior art.

[0004] Patent DE1545855 describes a method for obtaining amidine (limited to the third step of the above industrial method), the structure of which is as follows:

[0005]

[0006] Wherein m is an integer from 3 to 7 and n is an integer from 2 to 4, starting from an N-(aminoalkyl)lactam of the formula:

[0007]

[0008] The method is carried out by catalyzing the dehydration of aminolactam by a mineral acid or sulfonic acid (e.g. p-toluenesulfonic acid) in the presence of a solvent (e.g. xylene). The reaction mixture is heated to boiling point, the dehydration water formed is condensed together with the solvent and then separated; the solvent is refluxed into the reaction flask. The patent does not describe the steps before dehydration, but reference is made to the prior art.

[0009] Patent application EP0347757 A2 describes a process for the synthesis of cyanoalkyl lactams by reaction of lactams and α,β-unsaturated nitriles using DBU itself as a basic catalyst (the first step of the above-mentioned industrial process); DBU can also be used as a solvent. The document does not mention the other reaction steps (second and third steps), but only the catalytic hydrogenation of the cyanoalkyl lactam as in the prior art; in fact, in Example 2, the hydrogenation in the presence of Raney nickel and ammonia is described. In this patent application, the use of DBU as a catalyst as an alternative to the KOH used in the first step of the industrial process is justified, because in order to be able to proceed from the first step to the second step, the base must first be neutralized, and this neutralization step is not necessary if DBU is used (Example 3).

[0010] Patent CN101279973 B describes a method for preparing 1,8-diazabicyclo[5.4.0]-undec-7-ene starting from ε-caprolactam and acrylonitrile in the presence of tert-butyl alcohol or tert-amyl alcohol as solvent and NaOH as catalyst. The reaction product of the first step is hydrogenated in the presence of anhydrous ammonia and Raney nickel as catalyst. As described in German patent DE1545855, after hydrogenation, the mixture is neutralized with sulfuric acid, and the recovered solvent and reaction product are dehydrated to remove water.

[0011] Patent publication CN109796458 A describes a method for preparing 1,8-diazabicyclo-[5.4.0]-undec-7-ene, also starting from ε-caprolactam and acrylonitrile. This time, the document no longer describes a hydrogenation step in the presence of ammonia, but instead introduces an alternative method using hydroquinone, anhydrous gaseous hydrochloric acid, dichloromethane, sodium perborate and ethylenediaminetetraacetic acid (EDTA). This method is much more complicated than the other methods described, and although ammonia and Raney nickel are eliminated, a highly corrosive reagent (anhydrous HCl) as well as a number of chemicals are introduced.

[0012] In patent publication JP2003286257, the first and third steps are carried out in the same manner as above (reaction of caprolactam with acrylonitrile by alkaline catalysis using KOH; acid catalyzed dehydration). The second step is carried out in the absence of ammonia and uses Cobalt Raney as a catalyst. The result is 86% by weight of the reduced product (primary amine of interest).

[0013] Patent EP0913388 B1 describes a method for obtaining amines by hydrogenating nitrile without using ammonia. Novelty lies in the treatment of the catalyst. The catalyst (Raney cobalt or sponge catalyst) is treated with lithium hydroxide aqueous solution, or the reaction is carried out in the presence of the solution. By this treatment, the catalyst must contain 0.1 to 100mmol lithium hydroxide / gram.

[0014] Patent EP0662476 B1 describes the synthesis of bicyclic amidines by acid-catalyzed reaction of lactones with diamines. The process is carried out in a single reaction step with subsequent purification. The patent also claims the use of these amidines as polyurethane catalysts. The synthesis of DBU is described in Example 6 and shows a very low product yield of 21%.

[0015] Patent publication CN1262274 A describes a method for preparing 1,8-diazabicyclo[5.4.0]-undec-7-ene from ε-caprolactam and acrylonitrile, characterized in that a mixture of an inorganic base and an organic base is used as a catalyst (KOH and DBU) in the first reaction step. The obtained cyano derivative is purified before reduction. The second hydrogenation step is carried out in the presence of active Ni as a catalyst (the catalytic form is undefined), but the presence or absence of ammonia is not mentioned. The dehydration is always carried out under acidic conditions using p-toluenesulfonic acid and in the absence of a solvent; the reaction is carried out for a relatively long time, i.e. 35 to 40 hours, and the yield of this step is 74.61%.

[0016] According to the prior art, the final cyclization step to obtain the bicyclic amidine is carried out with an acid catalyst (particularly p-toluenesulfonic acid, which is soluble in the reaction environment and requires the use of a high boiling point solvent to carry out the reaction). This leads to more complex production equipment and processes - also involving the need to separate the catalyst from the reaction mixture - thereby increasing costs.

[0017] Therefore, the object of the present invention is to provide an innovative process for the synthesis of amidines which can simplify and reduce the costs of equipment, process and maintenance.

[0018] This is achieved by using suitable heterogeneous catalysis in the dehydration / cyclization reaction, thereby eliminating solvent reflux and neutralization stages of the mixture (which would be necessary if homogeneous catalysis were used, such as using p-toluenesulfonic acid as a catalyst).

[0019] In particular, the present invention has as its object the preparation of 1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU) - useful for the above-mentioned applications - from the corresponding N-(amino-alkyl)lactams by using heterogeneous catalysis and subsequent elimination of solvent reflux and neutralization.

[0020] The applicant therefore set out to find a process for producing amidines from N-(amino-alkyl)lactams.

[0021] The applicant has now discovered a process for preparing amidines from N-(amino-alkyl)lactams, which comprises dehydrating / cyclizing an amine compound to obtain an amidine which can then be subjected to a final stage of isolation and purification to obtain the product in a form suitable for industrial use. The process can be carried out in a batch or continuous manner; the continuous manner is preferred.

[0022] N-(Amino-alkyl)lactams can be prepared using one of the methods described in the prior art, such as those described above, or, more preferably, according to the method described in Italian patent application No. 1020210005321, entitled “METHOD FORPREPARING AMIDINES”, filed on March 8, 2021 by the same applicant, which is incorporated herein by reference in its entirety.

[0023] The reduction of nitrile compounds, which is the most critical step in the synthesis of N-(aminoalkyl) lactams, is a reaction known and reported in the literature and is widely used in organic synthesis (see, e.g., Peter Vollhardt, Organic Chemistry, pp. 825-826, 1st edition). In the patents listed above, Raney catalysts (Ni or Co) or other sponge-form catalysts are used in the presence of anhydrous ammonia.

[0024] Suitable reduction catalysts described in the above-mentioned Italian patent application No. 1020210005321 are commercial or synthetic hydrogenation systems based on one or more metals of groups 8, 9 and 10 of the periodic table, such as iron, cobalt, nickel, or 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 dispersed, colloidal or supported / bound phases, preferably in supported / bound form on an inorganic phase with a high surface area, even more preferably in supported / bound phases on silica, alumina or silica-alumina.

[0025] Surprisingly, the applicant has found that the synthesis of amidines can be carried out by a series of reactions, removing the solvent before the cyclization / dehydration step, and carrying out a single final purification step, and the method does not have any critical problems, or does not require the step of separating the intermediate of the desired product from other reaction products, to ensure the acceptable final purity of the desired product and the high yield and high conversion rate of the desired product in each intermediate step. The method simplifies the number of equipment used and greatly reduces the complexity of the whole process. Optionally, if high-purity semi-finished products and / or chemical intermediates are required, it is contemplated to use intermediate purification steps.

[0026] These and other objects are surprisingly achieved by the preparation process according to the invention.

[0027] Therefore, the object of the present invention is to provide a process for preparing amidines of formula (V) or derivatives thereof from N-(amino-alkyl)lactams of formula (IV)

[0028]

[0029] in:

[0030] R1 is H or an optionally substituted aliphatic hydrocarbon group having 1 to 5, preferably 1 to 2 carbon atoms, more preferably H;

[0031] R2 is H or an optionally substituted aliphatic hydrocarbon group having 1 to 5, preferably 1 to 2 carbon atoms, more preferably H;

[0032] R3 is H or an optionally substituted aliphatic hydrocarbon group having 1 to 5, preferably 1 to 2 carbon atoms, more preferably H;

[0033] R4 is H or an optionally substituted aliphatic hydrocarbon group having 1 to 5, preferably 1 to 2 carbon atoms, more preferably H;

[0034] R5 is H or an optionally substituted aliphatic hydrocarbon group having 1 to 5, preferably 1 to 2 carbon atoms, more preferably H;

[0035] m is an integer from 3 to 7, more preferably from 3 to 6,

[0036] Among them, even more preferably, (V) is 1,8-diazabicyclo[5.4.0]undec-7-ene, (DBU),

[0037] The method comprises the following steps:

[0038] - dehydrating the amine of formula (IV) using a solid catalyst based on a compound containing a metal or semimetal selected from boron, cerium, tungsten, zirconium or a rare earth, possibly other than cerium, such as a catalyst based on or containing at least one compound selected from the following: oxides of boron, cerium, tungsten; phosphates or other salts of boron, cerium, tungsten, to obtain the corresponding amidine of formula (V);

[0039] Rare earth phosphates other than cerium; zirconium salts or modified zirconium oxides, phosphotungstic acid.

[0040] The amidine of formula (V) synthesized as described above according to the present invention can be subsequently purified by methods known to those skilled in the art.

[0041] According to the present invention, the term "amidine" refers to a compound derived from an amide by substitution of the oxygen of the carbonyl=CO by an imido=N-group. Preferably, the present invention also contemplates cyclic amidines as defined in formula (V).

[0042] According to the present invention, the term "amidine derivative" means any compound obtainable by reaction of an amidine with a carboxylic acid, an epoxyketone, a chloroformatic ester or a carbonic acid diester.

[0043] According to the present invention, the singular indefinite articles "a" and "an" are to be understood as also including the meaning of at least one, unless otherwise specified.

[0044] In this document, unless otherwise stated, percentages are to be understood as percentages by mass.

[0045] According to the invention, the term "based on" is intended to mean not only a catalyst "consisting of" the elements indicated as catalytically active, but also a catalyst "comprising" them.

[0046] The amino derivatives of the lactam of formula (IV) according to the invention are dehydrated by heterogeneous catalysis to give the corresponding amidines, preferably DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), as described below.

[0047] The amino derivative of the lactam of formula (IV) which is subjected to the dehydration process according to the invention may be pure or may be a mixture with a solvent and / or a hydrogenation product by which the amino-alkyllactam of formula (IV) is obtained from its corresponding cyano-alkyllactam.

[0048] The reaction mixture from the hydrogenation stage is preferably subjected to solvent recovery by evaporation and subsequent dehydration.

[0049] In another preferred form, the reaction mixture from the hydrogenation step is dehydrated and the solvent is then recovered by separating it from the water formed by the reaction. Alternatively, although in a less preferred embodiment, the amino derivative of the lactam of formula (IV) can be reacted in purified form.

[0050] The dehydration is carried out under warm / hot conditions, preferably 90 to 270°C, more preferably 130 to 230°C, even more preferably 150 to 200°C, continuously removing water generated during the dehydration process of the cyclization.

[0051] A catalyst is always necessary in the dehydration and can be selected from a heterogeneous acid catalyst selected from the group consisting of Lewis acids, Lewis acids with a Bronsted acid component or Bronsted acids, such as catalysts based on or comprising at least one compound selected from:

[0052] - cerium oxide (ceria) or its salts, preferably phosphates such as cerium phosphate, cerium pyrophosphate;

[0053] - Rare earth phosphates other than cerium (e.g. lanthanum);

[0054] - Boron phosphate;

[0055] - phosphotungstic acid;

[0056] - a zirconium salt, preferably a phosphate, or a modified zirconium oxide such as zirconium phosphate, sulfated zirconium oxide; and - combinations thereof.

[0057] In embodiments, the catalyst is based on or comprises one or more compounds selected from:

[0058] - cerium oxide (ceria) and / or its salts, preferably phosphates;

[0059] - Boron phosphate;

[0060] - phosphotungstic acid;

[0061] - a zirconium salt, preferably a phosphate, and / or a modified zirconium oxide, preferably a sulfated zirconium oxide.

[0062] Preferred are boron phosphate, cerium oxide, sulfated zirconium oxide, zirconium salts or combinations thereof.

[0063] In embodiments, zirconium sulfate may be used as the modified zirconium oxide.

[0064] Catalysts based on or comprising at least one compound selected from boron phosphate, sulfated zirconium oxide and zirconium salts or combinations thereof are most preferred.

[0065] The catalyst based on or comprising one or more of the above-mentioned catalytically active compounds may also comprise other components, as they may optionally be supported on and / or combined with an inert "support" (for forming the catalyst), such as pumice, graphite or silica, although other supports known in the art may be used without departing from the scope of the present invention.

[0066] Catalysts based on or comprising boron phosphate can be prepared by reaction of boric acid with phosphoric acid according to techniques known to those skilled in the art, for example as described in the examples of the present application.

[0067] Catalysts based on or comprising sulfated zirconium oxide (“zirconium oxide, catalyst support, sulfated”; “zirconium oxide sulfated”; “sulfated zirconia”) may be commercial products or may be prepared according to known techniques (e.g. as reported on page 198 in the article F. Cavani et al., “The control of selectivity in gas-phase glycerol dehydration to acrolein catalysed by sulfated zirconia”, Applied Catalysis B: Environmental 100 (2010) 197-204).

[0068] The catalyst based on or comprising cerium oxide can be prepared by techniques known in the art, for example as described in the examples of the present application or as described in US Pat. No. 1,089,4750 B2.

[0069] At the end of the reaction, the major dehydration product is the amidine of interest of formula (V).

[0070] If desired by the end user, the amidine can be purified by one of the methods known in the art, for example by distillation to a purity of 95 to 98% by weight.

[0071] Preferably, in the process of the invention, no intermediate purification of the reaction mixture obtained from the hydrogenation is carried out, but only any solvent is evaporated for recovery and its use.

[0072] Therefore, the applicant has surprisingly found the possibility of carrying out solvent-free dehydration on solid acid catalyst without reflux solvent, so as to promote the removal of water, compared with using p-methyl benzenesulfonic acid, further simplified process and reduced cost.Yet, do not exclude using the solvent that is usually selected from the known hydrogenation reaction and is used to provide the employed solvent of formula (IV) intermediate, for example dimethylbenzene.

[0073] In the present process, the reaction step and the final purification step can be performed continuously.

[0074] In a particularly preferred embodiment of the present invention, the applicants have discovered a new and original process for producing amidines from lactams.

[0075] All conversion, selectivity and yield values ​​mentioned refer to the reaction mixture as described in the examples. 1 H and 13 Those values ​​determined by C NMR and GC-MS analyses.

[0076] The reagent stream from the hydrogenation step can be sent to a solvent recovery system. A preferred arrangement is based on an evaporator arrangement for solvent recovery. The reaction mixture containing trace amounts of solvent comes out of the bottom of the evaporator. The vapor from the evaporator is transported to a degasser, which contains a porous plate to facilitate the separation and contact of the liquid and vapor phases. The gas phase leaving the degasser is partially condensed in a reflux condenser, which operates at a temperature of 20-250° C., preferably 40-150° C., and even more preferably 60-130° C.; optionally; further condensation may be optionally performed to recover any by-products formed during the previous reaction.

[0077] The vapor leaving the reflux condenser is condensed in another condenser at a temperature of 2-50°C, preferably 10-30°C, more preferably 20°C.

[0078] The liquid collected at the outlet of the last condenser is a mixture of solvent and water. After separating the water, the solvent can be reused, while the mixture leaving the bottom of the evaporator can be sent to the dehydration step.

[0079] The dehydration is carried out continuously in a reactor called a dehydrator, which is preferably tubular, equipped with a heating system and a condensation system consisting of an aftercondenser, which condenses most of the water produced and sends the condensate to a phase separator. In the phase separator, any traces of organic matter are separated and reintroduced into the dehydrator, while the water can be partially recycled to the hydrogenation part that may be arranged upstream, and the excess water is sent for treatment. In a preferred form, the mixture is continuously conveyed to the reactor from the side, while steam comes out from the top of the reactor and the reaction products come out from the bottom. The reactor can optionally contain fillers (packings) at the top, such as rings, plates, spacers, so that only water vapor can escape.

[0080] In another embodiment, the reaction mixture can also be continuously fed from the bottom, the reaction product is withdrawn from the side of the reactor, and the water vapor escapes from the top of the reactor.

[0081] The reaction is carried out in the presence of a heterogeneous acidic catalyst as defined above, with a WHSV (weight hourly space velocity relative to the entire reagent mixture) of 1 to 50 h -1 , preferably 3 to 10 hours -1 .

[0082] The dehydration is carried out under warm / hot conditions, preferably 90 to 270°C, more preferably 130 to 230°C, even more preferably 150 to 200°C.

[0083] The reaction is carried out at a pressure of 0.08 to 5 BarA, preferably 0.5 to 3 BarA, more preferably 1 to 2 BarA.

[0084] A stream consisting of the dehydration product, any unreacted solvent and amine, and by-products of the previous step is discharged from the bottom of the reactor; in the case where the compound of formula (IV) is N-(3-aminopropyl)-ε-caprolactam, the main product is usually DBU (1,8-diazabicyclo[5.4.0]undec-7-ene).

[0085] The product stream is then sent to the distillation section to purify compound (V), such as DBU. After distillation, the purity of the compound is typically 95% to 98%.

[0086] The purity of the compounds was determined by gas chromatography analysis (GC-MS).

[0087] Optionally, the compound may be subjected to further purification such as liquid-liquid extraction after distillation. Such operations may be performed using techniques known to those skilled in the art.

[0088] As mentioned above, the above-mentioned N-(amino-alkyl)lactam compounds of formula (IV) subjected to the dehydration process according to the present invention can be prepared using one of the methods described in the prior art, such as those previously described in the background of the invention, or more preferably, according to the method described in Italian patent application No. 1020210005321 entitled "METHOD FORPREPARING AMIDINES" filed by the same applicant on March 8, 2021 (which is incorporated herein in its entirety), in particular with reference to the reduction step (B).

[0089] In the above-mentioned Italian patent application, the N-(amino-alkyl)lactam of formula (IV) is obtained by reducing the nitrile group to obtain the corresponding amine of formula (IV) by reacting a nitrile lactam compound of formula (III) with hydrogen in the presence of a catalyst based on a metal of Groups 8, 9 and 10 of the Periodic Table (for example iron, cobalt, nickel or a noble metal such as ruthenium, rhodium, palladium, osmium, iridium or platinum), wherein the catalyst is not a Raney or sponge-type catalyst,

[0090]

[0091] wherein R1, R2, R3, R4 and R5 have the meanings defined above for formula (IV) and (V).

[0092] Cobalt, nickel, palladium and platinum are preferred, and cobalt and nickel are particularly preferred.

[0093] Such reduction catalysts can be used in dispersed, colloidal or supported / bound phases, preferably in supported / bound form on an inorganic phase with a high surface area, even more preferably in a supported / bound phase on silica, alumina or silica-alumina, particularly preferably cobalt on an alumina support.

[0094] In a preferred embodiment, the reduction catalyst is a Co-based and Ni-based catalyst, preferably supported / bound on a Lewis acid or a Lewis acid with a Bronsted acid component, more preferably supported / bound on Al2O3 or SiO2, wherein the catalyst is not a Raney or sponge type catalyst.

[0095] The reduction step (hereinafter also referred to as step (B)) is carried out using the reduction catalyst under the following conditions: in the presence of H2, in the absence of ammonia, 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 reactant mixture.

[0096] The reaction temperature of step (B) is 30 to 250° C., preferably 50 to 200° C., and the pressure is 4 to 150 barA, preferably 11 to 100 barA, even more preferably 20 barA to 60 barA.

[0097] The reduction reaction can be carried out batchwise (in a reactor equipped with a stirrer, a heating jacket and an inlet for gas and liquid streams) for a reaction time of 0.1 to 12.0 h, preferably 0.8 to 7.0 h, more preferably 1.5 to 5 h; alternatively, the reduction reaction can be carried out continuously, for example in a single-stage or multi-stage tubular reactor or in a stirred reactor such as a CSTR. For productivity issues, a continuous mode is preferred, especially on an industrial scale.

[0098] The reduction reaction of step (B) can be carried out in the presence of an organic solvent. In one embodiment, the organic solvent is preferably selected from the following: methanol or ethanol, isopropanol or tert-butyl alcohol, MTBE, THF, more preferably THF. In another embodiment, the organic solvent is an aromatic solvent such as benzene, toluene, xylene, ethylbenzene, most preferably xylene (ortho, meta, para or mixture of isomers) and ethylbenzene.

[0099] The compound of formula (III) used in the aforementioned step (B) is preferably obtained by reacting a lactam having the following formula (I) with an unsaturated α,β nitrile having the following formula (II),

[0100]

[0101] The reaction is carried out under addition reaction conditions by one of the methods known to those skilled in the art in the presence of a suitable alkaline catalyst (preferably KOH, NaOH and LiOH) to obtain a compound of formula (III) as defined above. The addition reaction step is also referred to hereinafter as step (A).

[0102] Preferably, in step (A), the lactam of formula (I) is ε-caprolactam and the α-β-unsaturated nitrile of formula (II) is acrylonitrile.

[0103] Therefore, another object of the present invention is to provide a method for preparing an amidine of formula (V) or a derivative thereof as defined above, which comprises the following steps:

[0104] - synthesizing the nitrile lactam of formula (III) as defined above by reaction between the lactam of formula (I) as defined above and the α-β-unsaturated nitrile of formula (II) according to the procedure of step (A) above;

[0105] - According to the method of step (B) above, the nitrile lactam of formula (III) as defined above is reduced with H2 to synthesize the N-(amino-alkyl) lactam of formula (IV) as defined above;

[0106] - According to the above dehydration method according to the present invention, the amidine of formula (V) as defined above is synthesized by dehydrating the N-(amino-alkyl)lactam of formula (IV) as defined above.

[0107] The following are some illustrative but non-limiting examples of the present invention. Example

[0108] In the following examples, unless otherwise specified, the following abbreviations and materials are used:

[0109] -AN: Acrylonitrile (CAS107-13-1, purity ≥99%, Sigma-Aldrich)

[0110] -CPLT: ε-caprolactam (CAS105-60-2, purity 99%, Sigma-Aldrich)

[0111] -NaOH: sodium hydroxide (CAS1310-73-2, purity ≥98%, Sigma-Aldrich)

[0112] -Xylene: mixture of xylene isomers (CAS 1330-20-7, purity ≥ 98.5%,

[0113] Sigma-Aldrich)

[0114] -CTZ1: Commercial catalyst HTC CO 2000RP 1.2mm (CO ≈ 15% supported on alumina)

[0115] Johnson-Matthey (data from U.S. Patent 8,293,676B2 Table 3 Column 21-22 Example J)

[0116] -H2: Hydrogen (Sapio, Title 5.5)

[0117] -H2O: ultrapure water (MilliQ microporous system)

[0118] -NH2 (in Table 1): N-(3-aminopropyl)-ε-caprolactam

[0119] Gas quality analysis

[0120] Gas mass analysis for determination of reagents and reaction products was performed using a GC HP6890 chromatograph equipped with a split / splitless injector and connected to a MS HP 5973 mass spectrometer used as a detector. The chromatograph was equipped with a HP-1MS UI capillary column (100% polydimethylsiloxane, Agilent J&W), fused silica WCOT, 30 m long, 0.25 mm ID, film thickness 0.25 μm. The instrument parameters were as follows:

[0121] Injection volume is 20 μL

[0122] Helium carrier gas flow rate is 0.8mL / min (constant flow mode)

[0123] Split ratio is 250:1

[0124] Injector temperature is 300°C

[0125] The oven temperature was programmed from 40°C to 320°C at a rate of 10°C / min (28 min) and held at 320°C for 10 min (total run time = 38 min). In the absence of commercial availability of some of the pure products (amines of ε-caprolactam), quantification was performed by comparing the relative areas of the various chromatographic peaks (thus accepting the approximation that they all had the same chromatographic response).

[0126] However, multiple identical samples were also quantified 1 H e 13C NMR analysis, the results obtained can be superimposed on those shown using chromatographic techniques.

[0127] NMR analysis

[0128] The provided samples were analyzed using a Bruker Avance 400 MHz spectrometer at 300 K by dissolving approximately 50-70 mg of sample in deuterated chloroform. The spectra were recorded using the following instrument parameters:

[0129]

[0130] Preparation 1: Reaction of ε-caprolactam and acrylonitrile in xylene

[0131] 123.3 g of ε-caprolactam and 62.5 g of xylene were placed in a 1 liter flask equipped with a nitrogen inlet, agitator, reflux condenser, thermocouple and dropping funnel. The suspension was heated at 45-50°C using an oil bath under a slight nitrogen flow while stirring; after complete dissolution, 0.1841 g of NaOH was added and the temperature was raised to 70°C. After the sodium hydroxide was dissolved, acrylonitrile (67.4 g) was added dropwise, taking care to maintain the temperature at 70 to 80°C; the reaction was exothermic. After the acrylonitrile addition was complete, it was allowed to react for 2.25 h; as the addition reaction proceeded, it was noted that the solution gradually darkened.

[0132] GC-MS analysis showed a caprolactam conversion of 98.6% and a selectivity of 98.3%, thus giving a product yield of 96.9%. The crude alkaline solution was hydrogenated as described below in Preparation 2. The synthesis was repeated so that there was sufficient product to be subsequently dehydrated.

[0133] Preparation 2: Hydrogenation of crude solution in xylene

[0134] In a 250 ml autoclave equipped with a mechanical turbine stirrer, a heating jacket, a catalyst basket, inlets for gas and liquid streams, 30 g of CTZ1 catalyst were introduced into a special catalyst basket at room temperature and activated in a hydrogen atmosphere.

[0135] The catalyst was first activated by flushing with nitrogen at atmospheric pressure, and then the reactor was heated to 150°C at a heating rate of 25-50°C / h. After reaching this temperature, hydrogen was supplied at a flow rate of 30 ml / min to increase the temperature to 180°C.

[0136] At this point, the hydrogen flow was increased by gradually reducing the nitrogen flow until the gas flush was completely based on hydrogen (flow rate of 200 ml / min). Under these temperature and flow conditions, the activation lasted for 18 hours, after which the nitrogen flow was resumed (while reducing the hydrogen flow) in order to keep the catalyst in an inert atmosphere and the system was gradually cooled to room temperature.

[0137] 4.5 g (about 3% of the total amount) of H2O were added to 143.9 g of the solution obtained from Preparation 1 and then charged to the reactor; the line was then washed by introducing another 20.1 g of xylene.

[0138] The pressure of the reactor was increased to 21 barA by driving the stirrer motor (750 rpm) and turning on the heater and setting the internal temperature to 130°C.

[0139] Simultaneously, continue to pressurize with hydrogen, thereby reach the pressure of 41barA at desired temperature.As long as there is about 0.2-0.3L / h of hydrogen gas stream to flow to reactor, it is hydrogenated under this pressure.The hydrogen volume that is incorporated in the reactor also shows by counter, and compares with the stoichiometric amount calculated based on the amount of the nitrile introducing.At last, product is cooled and discharged.

[0140] GC-MS analysis showed a conversion of 96.1% to the nitrile product with a selectivity of 99.3%, and thus a yield of 95.4% for the product N-(3-aminopropyl)-ε-caprolactam and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). The synthesis was repeated two more times in order to obtain sufficient product for subsequent dehydration.

[0141] Example 1: Dehydration of a crude solution in xylene over boron phosphate

[0142] The solution from preparation 2 (138 g) is introduced into a flask (containing several glass balls) connected to a Dean-Stark apparatus equipped with a bubble cooler. One gram of boron phosphate is then added, obtained by evaporating a solution of boric acid and phosphoric acid (molar ratio 1:1) and calcining at 450° C. for 10 hours according to a technique known to those skilled in the art. The flask is heated to 170° C.; the water formed by the reaction is separated and the solvent is recovered. After about 4 hours, the flask is then cooled and the contents are analyzed by GC-MS.

[0143] Based on the analysis, the conversion rate, selectivity and DBU yield of N-(3-aminopropyl)-ε-caprolactam were calculated as shown in Table 1.

[0144] Example 2: Dehydration of crude solution in xylene over sulfated zirconium oxide

[0145] This example was carried out as in Example 1, but using one gram of sulfated zirconium oxide ("Zirconium Oxide, Catalyst Support, Sulfated", Alfa Aesar, No. 45600, 3 mm pellets) instead of boron phosphate.

[0146] Based on the analysis, the conversion rate, selectivity and DBU yield of N-(3-aminopropyl)-ε-caprolactam were calculated as shown in Table 1.

[0147] Example 3: Dehydration of crude solution in xylene over cerium oxide

[0148] Example 3 was carried out as in Example 1, but one gram of cerium oxide was used instead of boron phosphate.

[0149] Cerium oxide was prepared in the laboratory according to the following procedure: 500 g of a commercial aqueous solution of approximately 30% ammonium hydroxide (NH4OH) (28%-30% NH3 Basis ACS Reagent Aldrich) was added to 500 g of water in a first 3 liter beaker equipped with a Teflon crescent blade stirrer and incorporating an electrode for pH measurement.

[0150] The pH meter used is a Metrohom model 780, which is equipped with a Metrohm glass pH electrode model 6.0248.030. In a second 2-liter beaker equipped with a magnetic anchor stirrer, a solution is prepared by introducing 100 g of cerium nitrate hexahydrate (Aldrich, code 238538, purity 99%) into 1000 g of water: the cerium nitrate hexahydrate is then dissolved by vigorous stirring at room temperature (25°C). The obtained solution is added to a dropping funnel and conveyed dropwise to the above-mentioned ammonium hydroxide solution contained in a 3-liter beaker over 2 hours while continuing vigorous stirring. The pH of the obtained suspension is equal to 10.2. The solid in the suspension is filtered, washed with 2 liters of water and then dried in an oven at 120°C for 2 hours. The synthesis is repeated until 2000 g of solid is obtained.

[0151] 1270 g of the solid thus obtained, sieved through 0.125 mm, are added to the extruder, to which 175.9 g of a 25% ammonium hydroxide (NH4OH) solution (obtained by diluting a solution 28%-30% NH3 BasisACS reagent Aldrich) are also added using a Watson Marlow peristaltic pump type 323DU / D set at 5 rpm. Thereafter, 158 g of demineralized water are also added to provide a suitable consistency for extrusion. The "pellets" obtained at the outlet of the extruder are dried in air and subsequently heated to 800°C at a heating rate of 1°C / min, and a 100 g portion of the pellets is calcined at 800°C and then kept constant for 6 hours. The calcined solid is granulated and sieved, and the particle portion with a size of 0.5 mm to 1 mm is used as a catalyst.

[0152] Based on the analysis, the conversion rate, selectivity and DBU yield of N-(3-aminopropyl)-ε-caprolactam were calculated as shown in Table 1.

[0153] Table 1 shows the summary data of the previous examples. Finally, it should be understood that further modifications and variations may be made to the process as described and illustrated herein which are not specifically mentioned herein but which are to be considered obvious variations of the invention within the scope of the appended claims. Calculation of conversion (conv), selectivity (sel) and yield (GC-MS)

[0154]

[0155] in:

[0156] mol = number of moles

[0157] Table 1: Dehydration reactions

[0158]

[0159]

[0160] The catalysts according to the invention have shown advantages over known homogeneous toluenesulfonic acid catalysts, because they are solid, they remain on the fixed bed, while known homogeneous catalysts disappear at the end of the synthesis. In addition, the catalysts according to the invention show very good selectivity for DBU.

Claims

1. A process for preparing an amidine of formula (V) or a derivative thereof starting from a compound of formula (IV), in R1 is H or an optionally substituted aliphatic hydrocarbon group having 1 to 5, preferably 1 to 2 carbon atoms, more preferably H; R2 is H or an optionally substituted aliphatic hydrocarbon group having 1 to 5, preferably 1 to 2 carbon atoms, more preferably H; R3 is H or an optionally substituted aliphatic hydrocarbon group having 1 to 5, preferably 1 to 2 carbon atoms, more preferably H; R4 is H or an optionally substituted aliphatic hydrocarbon group having 1 to 5, preferably 1 to 2 carbon atoms, more preferably H; R5 is H or an optionally substituted aliphatic hydrocarbon group having 1 to 5, preferably 1 to 2 carbon atoms, more preferably H; m is an integer from 3 to 7, more preferably from 3 to 6, The method comprises the step of dehydrating the compound of formula (IV) in the presence of an acid catalyst, wherein the acid catalyst is selected from a heterogeneous acid catalyst based on or comprising one or more compounds selected from - cerium oxide (ceria) and / or its salts, preferably phosphates; - Boron phosphate; - phosphotungstic acid; - a zirconium salt, preferably a phosphate, and / or a modified zirconium oxide, preferably a sulfated zirconium oxide.

2. The process according to claim 1, wherein the catalyst is selected from catalysts based on or comprising boron phosphate, cerium oxide, sulfated zirconium oxide, zirconium salts or combinations thereof.

3. The process according to any one of claims 1 or 2, wherein the catalyst is supported and / or bound on an inert carrier, preferably selected from pumice, graphite and silica.

4. The method according to any one of claims 1 to 3, wherein the dehydration reaction is carried out at a temperature of 90 to 270°C, or 130 to 230°C, or 150 to 200°C in the absence of a solvent, while continuously removing water produced during the dehydration process.

5. The method according to any one of claims 1 to 3, wherein the dehydration reaction is carried out in the presence of a solvent selected from xylene and ethylbenzene at a temperature of 90 to 270° C., or 130 to 230° C., or 150 to 200° C., while continuously removing water produced during the dehydration process.

6. A process according to any one of claims 1 to 5, wherein the dehydration reaction is carried out continuously in a tubular reactor equipped with a heating system and a condensation system, the condensation system comprising a condenser which condenses most of the produced water and sends the condensate to a phase separator, and the process comprises separating any trace amounts of organic products in the phase separator and reintroducing them into the dehydration reactor.

7. The method according to any one of claims 1 to 6, wherein the dehydration reaction is carried out in a tubular reactor for 1 to 50 hours. -1 , or 3 to 10 hours -1 The WHSV (weight hourly space velocity, relative to the total reagent mixture) was performed continuously.

8. The method according to any one of claims 1 to 7, wherein the dehydration reaction is carried out at a pressure of 0.08 to 5 BarA, or 0.5 to 3 BarA, or 1 to 2 BarA.

9. The method according to any one of claims 1 to 8, wherein the compound of formula (V) is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

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