Process for producing dihydrofuran-3( 2h)-one

Abstract

The present invention primarily relates to a process for producing a compound according to formula (I). Secondarily the present invention relates to the use of a process as described herein for producing a compound according to formula (I) and to the use of a compound according to formula (II) in a process as described herein for producing a compound according to formula (I).

Description

[0001] Process for producing dihydrofuran-3(2 / 7)-one

[0002] The present invention primarily relates to a process for producing a compound according to formula (I). Secondarily the present invention relates to the use of a process as described herein for producing a compound according to formula (I) and to the use of a compound according to formula (II) in a process as described herein for producing a compound according to formula (I).

[0003] Further aspects of the present invention will arise from the description below, in particular from the examples, as well as from the attached patent claims.

[0004] Oxygenation reactions that employ pure oxygen or ambient air provide an efficient route to synthesizing many oxygen-containing compounds and have been demonstrated in various industrial processes. However, oxidations using pure oxygen in batch reactors are often avoided at large-scale production sites due to associated productivity issues, such as insufficient heat and mass transfer rates, low interfacial areas, and back mixing of the liquid phase but mainly because of potential safety issues. Especially, aerobic oxidations present particular challenges to developing a safe and reliable process and therefore require strict handling protocols to ensure process safety. As a result, diluted oxygen concentrations are used to cope with the hazardous nature of the gas phase, drastically decreasing reaction productivity to achieve an acceptable conversion.

[0005] In the literature, a process for the preparation of aldehydes and ketones starting from primary and secondary alcohols by an oxidative reaction using either a catalyst system con- taining Cu / TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl) or Cu / ABNO (9-azabicy- clo[3.3.1]nonane-N’-oxyl) is described by Stahl and co-workers (Hoover, J. M. & Stahl, S. S. Highly practical copper(l) / TEMPO catalyst system for chemoselective aerobic oxidation of primary alcohols. J. Am. Chem. Soc. 133, 16901-16910 (2011), Lauber, M. B. & Stahl, S. S. Efficient aerobic oxidation of secondary alcohols at ambient temperature with an ABNO / NOx catalyst system. ACS Catal. 3, 2612-2616 (2013), Steves et Stahl._Cop- per(l) / ABNO-Catalyzed Aerobic Alcohol Oxidation: Alleviating Steric and Electronic Constraints of Cu / TEMPO Catalyst Systems, J. Am. Chem. Soc. 2013, 135, 42, 15742-15745).

[0006] When the system is used as described in the literature but for the preparation of tetrahy- drofuran-3-one, the problem occurs that the reaction parameters are so sensitive that the substrate is permanently overoxidized or there is no reaction due to, e.g., the degradation of the reactants.

[0007] In WO 2014 / 140017 A1 a method for the preparation of 3-oxotetrahydrofuran comprising oxidating 3-hydroxy-tetrahydrofuran in the presence of a catalytic amount of TEMPO with trichloroisocyanuric acid (TCCA) is described. The application of trichloroisocyanuric acid in such reactions has the drawback that toxic waste is produced during the process and the chemical itself is environmentally unfriendly and hazardous to health.

[0008] The primary object of the present invention was to provide an easy, cheap and scalable production of dihydrofuran-3(2 / 7)-one [CAS 22929-52-8], Furthermore, it was searched for a flexible reaction control, providing high selectivity and safety.

[0009] However, this was not an easy task, as a number of details and refinements had to be taken into account in this reaction. Apart from the disadvantages already described, it was particularly difficult to adjust the many individual parameters in such a way that favorable results were obtained on the one hand and the safety of the process was guaranteed on the other. Various parameters can be adjusted, such as the reaction pressure, the reaction temperature, the retention time, the oxygen flow and its corresponding equivalents and the reaction solvent. Furthermore, it was not trivial to establish this chemical process in such a way that it can be transferred to various industrially applicable processes. It is generally known from industry and research that reactions that work well at laboratory scale cause major problems when upscaled. This obstacle also had to be overcome.

[0010] According to a first aspect of the present invention, the stated object is achieved by a process for producing a compound according to formula (I)

[0011] O comprising or consisting of the following steps:

[0012] (a) providing a solution or suspension comprising or consisting of a compound according to formula (II) a copper source a nitroxyl source, wherein the nitroxyl source is present in an amount of from 0.01 to 5 mol-%, preferably in an amount of from 0.05 to 2.5 mol-%, more preferably in an amount of from 0.3 to 1 mol-%, based on the total amount of the compound of formula (II), a solvent, wherein the solvent provided in step (a) is selected from the group consisting of acetonitrile, ethyl acetate, 2-methyltetrahydrofuran, propylene carbonate, A / -methyl-2-pyrrolidone, sulfolane, and mixtures thereof, preferably wherein the solvent provided in step (a) is or comprises acetonitrile, and optionally a ligand,

[0013] (b) reacting the solution provided in step (a) with an oxygen source, preferably wherein the oxygen source is selected from the group consisting of oxygen, air or a mixture of oxygen and nitrogen, at a reaction temperature in a range of from 10 to 150 °C, preferably in a range of from 20 to 100 °C, more preferably in a range of from 40 to 70 °C, and optionally,

[0014] (c) purifying the compound of formula (I) obtained in step (b). Preferred is a process as defined above, wherein no trichloroisocyanuric acid is used in the process. Preferred is a process as defined above, wherein no trichloroisocyanuric acid is used in step (a) and / or step (b) and or step (c) in the process.

[0015] Preferred is a process as defined above, wherein no pyridinium chlorochromate is used in the process. Preferred is a process as defined above, wherein no pyridinium chlorochromate is used in step (a) and / or step (b) and or step (c) in the process.

[0016] Surprisingly it was found that the extensively optimized process as provided herein is particularly advantageous for an easy, cheap and scalable production of dihydrofuran-3(2 / 7)- one. The developed of the catalytic system based on 9-Azabicyclo[3,3,1 ]nonan-3-one-9- oxyl (keto-ABNO) and a copper salt for the oxidation of tetrahydrofuran-3-ol with oxygen in combination with the specifically adjusted reaction parameters surprisingly turned out to be safe and effective. Another advantage is that the use of trichloroisucyanuric acid is omitted thus preferably less / no toxic waste is generated during the process. Besides, the stirring and phase separation issues were overcome by the exact manipulation of the reaction parameters, in particular the solvent optimization as previously described. To develop the process according to the invention as defined herein, tedious parameter optimization of the reaction temperature, residence time, catalyst loading of the nitroxyl source, pressure and oxygen source equivalents needed to be performed. As it will be described herein, some of the optimizations were counterintuitive, thus surprisingly leading to this challenging puzzle of best mode conditions.

[0017] A preferred embodiment of the present invention is a process as defined above, wherein the concentration of the compound of formula (II) in the solution or suspension provided in step (a) is in a range of from 0.45 to 1 .05 M.

[0018] A preferred embodiment of the present invention is a process as defined above, wherein the copper source provided in step (a) is selected from the group consisting of copper (I) iodide, copper (I) bromide, tetrakisacetonitrile copper (I) triflate, copper (I) chloride, copper (II) triflate, copper (II) acetate, copper (II) acetylacetonate, and mixtures thereof, preferably wherein the copper source provided in step (a) is or comprises copper (I) iodide.

[0019] It is particularly advantageous in the process according to the invention as defined herein to use the copper source as described above as their application results in a high selectivity and reaction yield.

[0020] A preferred embodiment of the present invention is a process as defined above, wherein the copper source provided in step (a) is present in an amount of from 0.01 to 20 mol-%, preferably in an amount of from 0.1 to 15 mol-%, further preferably in an amount of from 1 to 10 mol-%, more preferably in an amount of from 3 to 8 mol-%, based on the total amount of the compound of formula (II).

[0021] A preferred embodiment of the present invention is a process as defined above, wherein the solution provided in step (a) does not comprise a nitroxyl source, wherein the nitroxyl source is dissolved and / or dispersed in a solvent as described above and added separately, for example by a continuous or semi-continuous flow or batch process.

[0022] According to another preferred embodiment of the present invention, a process as defined herein is preferred, wherein the nitroxyl source provided in step (a) is or comprises 9-azabi- cyclo[3.3.1]nonan-3-one-oxyl.

[0023] Advantageously, the nitroxyl source as described herein preferably provides no impactsensitivity for normal handling in the process according to the invention as described herein.

[0024] A preferred embodiment of the present invention is a process as defined above, wherein the ligand provided in step (a) is a mono- or bidentate ligand, preferably a ligand selected from the group consisting of 2,2’-bipyridyl, / V-methylimidazole, 4-(dimethylamino)pyridine, (1 ,8-diazabicyclo(5.4.0)undec-7-ene and mixtures thereof, preferably wherein the ligand provided in step (a) is or comprises / V-methylimidazole.

[0025] In a process according to the invention as defined herein it is particularly advantageous to additionally use ligands as defined herein to obtain a higher selectivity and reaction yield.

[0026] A preferred embodiment of the present invention is a process as defined above, wherein the ligand provided in step (a) is present in an amount of from 0.01 to 20 mol-%, preferably in an amount of from 0.1 to 15 mol-%, further preferably in an amount of from 1 to 15 mol- %, more preferably in an amount of from 3 to 10 mol-%, based on the total amount of the compound of formula (II).

[0027] According to another preferred embodiment of the present invention, a process as defined herein is preferred, wherein step (b) is conducted at a reaction oxygen pressure in a range of from 0 to 100 bar, preferably in a range of from 0 to 60 bar, more preferably in a range of from 0 to 40 bar, preferably in a continuous or semi-continuous flow process.

[0028] According to another preferred embodiment of the present invention, a process as defined herein is preferred, wherein step (b) is conducted at a reaction oxygen pressure in a range of from 0 to 100 bar, preferably in a range of from 0 to 60 bar, more preferably in a range of from 0 to 40 bar, preferably in a batch process. In a process according to the invention as defined herein it is particularly advantageous to use a reaction oxygen pressure as defined herein to obtain a higher selectivity and reaction yield.

[0029] According to another preferred embodiment of the present invention, a process as defined herein is preferred, wherein the reaction time is in a range of from 0.08 to 48 hour(s), preferably in a range of from 1 to 24 hour(s), more preferably in a range of from 3 to 15 hour(s). Preferably, the process is a continuous or semi-continuous flow process. Preferably, the process is a batch process.

[0030] The process according to the invention as defined herein is particularly advantageous when performed with the above defined reaction times, as hereby the above defined disadvantages of processes known from the art are overcome.

[0031] A preferred embodiment of the present invention is a process as defined above, wherein the process is a batch process.

[0032] Advantageously, the process according to the invention as defined herein is designed to be applicable in a batch process yielding in high selectivity and reaction yields while simultaneously providing reaction safety.

[0033] A batch process is preferably a process that leads to the production of defined quantities of materials by subjecting quantities of input materials to an orderly sequence of process activities using one or more devices within a defined period of time.

[0034] Another preferred embodiment of the present invention is a process as defined above, wherein the total amount of oxygen in the oxygen source used in step (b) is in a range of from 15 to 30 wt.-%, preferably 18 to 25 wt.-%, further preferably of from 20 to 23 wt.-% based on the total weight of the oxygen source used in step (b).

[0035] Preferably, the total amount of oxygen as described herein is preferably to be understood as the amount, preferably average amount, which is permanently available during the entire reaction process, i.e. it does not decrease during the process but is constantly replenished after consumption.

[0036] A further preferred embodiment of the present invention is a process as defined above, wherein the process is operated above the upper explosion limit of the used solvent or solvent mixture. A further preferred embodiment of the present invention is a process as defined above, wherein the process is operated below the upper explosion limit of the used solvent or solvent mixture.

[0037] A further preferred embodiment of the present invention is a process as defined above, wherein the process is operated above the lower explosion limit of the used solvent or solvent mixture.

[0038] A further preferred embodiment of the present invention is a process as defined above, wherein the process is operated below the lower explosion limit of the used solvent or solvent mixture.

[0039] According to another preferred embodiment of the present invention, a process as defined herein is preferred, wherein the process is a continuous or semi-continuous flow process. With respect to this particular embodiment, the process is not a batch process.

[0040] Flow chemistry is the ideal technology for the utilization of gases, particularly those that are toxic and / or associated with safety issues. Precise control can be easily achieved by mass flow controllers (MFC). Back pressure regulators (BPR) are valves meant to operate at a constant upstream system pressure. Working at elevated pressures not only allows processes to be performed above the boiling point of the reaction media but also enables superior control.

[0041] Continuous flow reactors are characterized by a decreasing concentration of reactants and increasing concentration of products in the direction of the flow. The reactants are preferably charged continuously at one end, and the products are preferably removed continuously at the other end.

[0042] The residence time is the period which the mixture of reactants spends inside the reactor, and it gives a measure of the reaction time. Residence time is dependent on the characteristics of the reactor (i.e., length, internal diameter, and wall), and the flow rate.

[0043] The process according to the invention as defined herein is particularly advantageous when applied in a continuous or semi-continuous flow process, since high product yields are obtained accompanied with a high reaction safety control.

[0044] In a continuous or semi-continuous process according to the invention, solutions or suspensions comprising compounds of formula (II) in a suitable solvent are continuously or semi-continuously fed to a reactor in order to obtain a solution or suspension of a variable amount of a compound of formula (I). According to another preferred embodiment of the present invention, in particular with respect to the previously described embodiment, a process as defined herein is preferred, wherein the reaction residence time is in a range of from 0.5 to 120 minute(s), preferably in a range of from 1 to 60 minute(s), more preferably in a range of from 5 to 30 minute(s).

[0045] The process according to the invention as defined herein is particularly advantageous when performed with the above defined reaction residence times, as hereby the above defined disadvantages of processes known from the art are overcome.

[0046] The residence time of a fluid parcel is the total time that the parcel has spent inside a control volume (e.g.: a chemical reactor, a lake, a human body). The residence time of a set of parcels is quantified in terms of the frequency distribution of the residence time in the set, which is known as residence time distribution (RTD), or in terms of its average, known as mean residence time (https: / / en.wikipedia.org / wiki / Residence_time).

[0047] A preferred embodiment of the present invention is a process as defined above, in particular as defined in the embodiment with a flow process, wherein the total amount of oxygen used in step (b) is in a range of from 0.2 to 5 equivalents, preferably from 0.3 to 3 equivalents, more preferably from 0.5 to 2 equivalents, based on the amount of the compound of formula (II).

[0048] The process according to the invention as defined herein is particularly advantageous when performed with the above defined total amount of oxygen, as hereby the above defined disadvantages of processes known from the art are overcome. Counterintuitively, a large excess of oxygen resulted in lower conversion. Thus, a high number of experiments needed to be performed in order to determine the optimal amount of oxygen equivalents.

[0049] According to a third aspect of the present invention, the stated object is achieved by the use of a process as defined herein for producing a compound according to formula (I)

[0050] O d

[0051] (I).

[0052] Surprisingly it has been found that the use of a process according to the invention as defined herein is particularly advantageous for producing a compound according to formula (I). According to a fourth aspect of the present invention the stated object is achieved by the use of a compound according to formula (II) in a process as defined herein for producing a compound according to formula (I)

[0053] O d

[0054] (I).

[0055] Surprisingly it has been found that the use of a compound of formula (II) in a process according to the invention as defined herein is particularly advantageous for producing a compound according to formula (I).

[0056] (Preferred) embodiments of the mixture according to the invention correspond to or can be derived from the (preferred) embodiments of the processes according to the invention which are explained above or vice versa. (Preferred) embodiments of the mixtures and the processes according to the invention correspond to or can be derived from the (preferred) embodiments of the uses according to the invention which are explained above or vice versa. Lastly, the (preferred) embodiments described herein can be arbitrarily combined with each other as long as technically sensible.

[0057] The invention will now be described in more detail hereinafter with references to the examples. Further aspects of the present invention are disclosed in the accompanying claims. Examples:

[0058] Experimental procedures:

[0059] Batch mode:

[0060] Preparation of Tetrahydrofuran-3-one via Cu / ABNO - catalyzed aerobic alcohol oxidation (continuous air flow)

[0061] In an Easymax system containing a 100 mL glass reactor, a solution was prepared containing copper iodide (0.550 g, 2.89 mmol), / V-methylimidazole (0.230 g, 2.80 mmol), ABNO (0.0350 g, 0.249 mmol), and 3-hydroxy tetrahydrofuran (5.00 g, 56.8 mmol) in acetonitrile (101 mL) at 200 rpm and 40 °C. All solids were added in solution / suspension in acetonitrile. The set-up was continuously fed with air (100 mL / min). The reaction showed 80.0 % yield after 5.00 hours and it was stirred for 24.0 hours.

[0062] Preparation of Tetrahydrofuran-3-one via Cu / keto-ABNO - catalyzed aerobic alcohol oxidation (continuous air flow)

[0063] In an Easymax system containing a 100 mL glass reactor, a solution was prepared containing copper iodide (0.540 g, 2.81 mmol), / V-methylimidazole (0.230 g, 2.80 mmol), keto- ABNO (0.0340 g, 0.221 mmol), and 3-hydroxy tetrahydrofuran (5.00 g, 56.8 mmol) in acetonitrile or propylene carbonate (PC) (101 mL) at 200 rpm and 40.0 °C. All solids were added in solution / suspension in the solvent. The set-up was continuously fed with air (100 mL / min). The reaction showed 97.0 % yield after 5.00 hours, although it was stirred for 72.0 hours at 250 rpm. The obtained results are summarized in Table A:

[0064] Table A: Screening worksheet A

[0065] : of the substrate 3-hydroxy tetra hydrofuran Continuous flow mode:

[0066] Preparation of Tetrahydrofuran-3-one via Cu / keto-ABNO - catalyzed aerobic alcohol oxidation in continuous flow mode I

[0067] Feed 1 of a continuous flow reactor containing an acetonitrile solution of 3-hydroxy tetrahydrofuran (variable scale from 5.00 to 10.0 g, concentration kept constant at 0.50 M), copper iodide (5.00 mol%), / V-methyl imidazole (5.00 mol%), and the catalyst keto-ABNO (0.0500 to 0.300 mol%) was pumped using one high-pressure liquid pump (Knauer, 10.0 mL head) at variable flow rates. The liquid stream was combined in a T-mixer with the oxygen stream (1.7 equivalents of oxygen, 100 vol.-% O2) and mixed in a PFA tubing (OD: 1 / 8”, ID: 1 / 16”, length: 2.48 m, volume: 5.00 mL) at room temperature (22.0 °C) before entering a 3D metal zig-zag reactor (8.00 mL, T: from 5.00 to 10.0 min). The solution was then fed into a 3D metal zig-zag reactor to cool down to room temperature before collection. The HPLC pump flow rate and the oxygen flow rate were measured by Bronkhorst mass flow controllers. The pressure system was measured and monitored by digital and analogue gauges. Once the steady state was achieved, fractions were collected and diluted properly for GC analysis. Conversion and yield were determined by GC. The obtained results are summarized in Table 1 .

[0068] Table 1 : Screening worksheet I

[0069] Based on the obtained results and lack of full conversion, the following experiments were performed at 100 °C (Table 2):

[0070] Table 2: Screening worksheet II

[0071] Preparation of Tetrahydrofuran-3-one via Cu / keto-ABNO - catalyzed aerobic alcohol oxidation in continuous flow mode II

[0072] Feed 1 of a continuous flow reactor containing an acetonitrile solution of 3-hydroxy tetrahydrofuran (variable scale from 10.0 to 15.0 g but concentration kept to 0.50 M), copper iodide (5.00 mol%), / V-methyl imidazole (7.50 mol%), and keto-ABNO (0.300 to 0.600 mol%) was pumped using one high-pressure liquid pump (Knauer, 10 mL head) at variable flow rates. The liquid stream was combined in a T-mixer with the oxygen stream (100 vol.- % O2) and mixed in a PFA tubing (OD: 1 / 8”, ID: 1 / 16”, length: 2.48 m, volume: 5.00 mL) at room temperature (22.0 °C) before entering a 3D metal zig-zag reactor (32.0 mL, T: from 10.0 to 30.0 min) which was heated to the desired temperature. The solution was then fed into a 3D metal zig-zag reactor to cool down to room temperature before collection. The HPLC pump flow rate and the oxygen flow rate were measured by Bronkhorst mass flow controllers. The pressure system was measured and monitored by digital and analog gauges. Once the steady state was achieved, fractions were collected and diluted properly for GC analysis. Conversion and yield were determined by GC. The obtained results are summarized in Table 3.

[0073] Table 3: Screening worksheet III

[0074] Furthermore, the effect of pressure and residence time at 100 °C on the reaction conversion was elucidated (Table 4):

[0075] Table 4: Screening worksheet IV

[0076] As a next step, milder conditions have been considered (Table 5):

[0077] Table 5: Screening worksheet V

[0078] Furthermore, degradation of the catalyst (nitroxyl source) was considered; thus, experiments have been performed with higher amounts (Table 6):

[0079] Table 6: Screening worksheet 6

[0080] Additionally, other copper sources were elucidated (Table 7):

[0081] Table 7: Screening worksheet 7 (0.5M 3-hydroxyl tetrahydrofuran; Cui and NMI in 5 mol-%): As it becomes apparent, a large number of experiments in variating directions needed to be performed in order to find out the optimum reaction conditions for the process according to the invention as defined herein.

Claims

Claims:1 . Process for producing a compound according to formula (I)comprising or consisting of the following steps:(a) providing a solution or suspension comprising or consisting of a compound according to formula (II)(II), a copper source a nitroxyl source, wherein the nitroxyl source is present in an amount of from 0.01 to 5 mol-%, preferably in an amount of from 0.05 to 2.5 mol-%, more preferably in an amount of from 0.3 to 1 mol-%, based on the total amount of the compound of formula (II), a solvent, wherein the solvent provided in step (a) is selected from the group consisting of acetonitrile, ethyl acetate, 2-methyltetrahydrofuran, propylene carbonate, A / -methyl-2-pyrrolidone, sulfolane, and mixtures thereof, and optionally a ligand,(b) reacting the solution provided in step (a) with an oxygen source, preferably wherein the oxygen source is selected from the group consisting of oxygen, air or a mixture of oxygen and nitrogen, at a reaction temperature in a range of from 10 to150 °C, preferably in a range of from 20 to 100 °C, more preferably in a range of from 40 to 70 °C, and optionally,(c) purifying the compound of formula (I) obtained in step (b).

2. Process according to claim 1 , wherein the copper source provided in step (a) is selected from the group consisting of copper (I) iodide, copper (I) bromide, tetrakisac- etonitrile copper (I) triflate, copper (I) chloride, copper (II) triflate, copper (II) acetate, copper (II) acetylacetonate, and mixtures thereof.

3. Process according to claim 1 or 2, wherein the nitroxyl source provided in step (a) is or comprises 9-azabicyclo[3.3.1]nonan-3-one-oxyl.

4. Process according to any of the preceding claims, wherein the ligand provided in step (a) is a mono- or bidentate ligand preferably a ligand selected from the group consisting of 2,2’-bipyridyl, / V-methylimidazole, 4-(dimethylamino)pyridine, (1 ,8-di- azabicyclo(5.4.0)undec-7-ene and mixtures thereof.

5. Process according to any of the preceding claims, wherein step (b) is conducted at a reaction oxygen pressure in a range of from 0 to 100 bar, preferably in a range of from 0 to 60 bar, more preferably in a range of from 0 to 40 bar.

6. Process according to any of the preceding claims, wherein the reaction time is in a range of from 0.08 to 48 hour(s), preferably in a range of from 1 to 24 hour(s), more preferably in a range of from 3 to 15 hour(s).

7. Process according to any of the preceding claims, wherein the process is a batch process.

8. Process according to any of the claims 1 - 6, wherein the process is a continuous or semi-continuous flow process.

9. Process according to claim 8, wherein the total amount of oxygen used in step (b) is sufficient to provide from 0.2 to 5 equivalents, preferably from 0.3 to 3 equivalents, more preferably from 0.5 to 2 equivalents, based on the amount of the compound of formula (II).

10. Use of a process according to any of claims 1 to 10 for producing a compound according to formula (I)11 . Use of a compound according to formula (II)in a process according to any of claims 1 to 10 for producing a compound according to formula (I)

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