Method for preparing cyclopropane compound using diazo compound

Abstract

A method for continuously producing a reaction product of a diazo compound and a substrate in a multi-stage flow reactor is disclosed.

Description

Field of the Invention

[0001] The present invention relates to improved processes and apparatus for the production and further conversion of diazo compounds. Background of the Invention

[0003] The diazo compound diazomethane is a highly reactive gas that has a wide range of uses in chemical synthesis. In particular, it has been used in cycloaddition reactions with olefins to form cyclopropanes. Unfortunately, diazomethane is also an explosive, a potent carcinogen, and is sensitizing and toxic, and difficulties with its safe handling have hampered its widespread adoption in the large-scale synthesis of industrially useful compounds.

[0004] Prior art solves the problem of safe handling of diazonium compounds, such as diazomethane, in synthetic organic chemistry. In particular, Poechlauer describes the continuous formation and continuous reaction of diazonium compounds in US9,249,088. More specifically, Poechlauer describes a flow method in which a precursor compound of diazomethane (e.g., N-methyl-N-nitrosourea) is continuously formed in the presence of a base and is continuously converted into diazomethane. The diazomethane in the solvent is continuously removed from the reactor, where it is formed by a hydrophobic membrane and fed into a second flow reaction chamber. The second flow reaction chamber contains a substrate reacted with the formed diazomethane, and the substrate reacts with the diazomethane to form a desired reaction product.

[0005] According to Poechlauer, this continuous process ensures that only relatively low levels of diazomethane (and its precursor compounds, which are also toxic) are formed in the flow reactor. This represents an improvement over existing batch processes involving the formation of high stable concentrations of diazomethane (and its precursor compounds). Nevertheless, the problem with the Poechlauer process is that it teaches the formation of diazomethane in a first reactor and its transfer across a membrane into a second reactor, where it reacts with a substrate provided therefor. In other words, the process necessarily involves the formation of a certain concentration of harmful diazomethane on one side of the membrane, as well as a large transfer of diazomethane across the membrane, which is not something that can be accomplished instantaneously, not even if the passage across the membrane is blocked or impeded for any reason.

[0006] Furthermore, the insertion of a membrane between the diazomethane (and its precursor compounds) formed in the first reactor and the substrate with which it is desired to react in the second reactor also creates process engineering complications, since a balance must be struck between the rate at which the diazomethane is formed and crosses the membrane and the rate at which it reacts with the substrate once it has crossed the membrane so that it is completely consumed rather than exiting the reactor in unreacted form.

[0007] Still need to provide a kind of improved method to continuously form diazo compound, and particularly diazomethane, and make it and suitable substrate such as olefin carry out continuous reaction, to ensure the good conversion of diazo compound, and the extremely high yield of the reaction product of following expectation.Ideally, the diazo compound precursor and the diazo compound itself should be quantitatively converted to avoid these reactants from polluting the reaction product of expectation.Also need a kind of improved method, to ensure the safe handling of diazo compound and its precursor compound in the following manner: ensure that the total inventory of diazo compound / precursor produced in a given reaction process must be within the danger level, at a specified time point or in any region or stage of the reactor, the concentration of diazo compound / precursor compound does not reach unsafe and / or explosive level. SUMMARY OF THE INVENTION

[0009] The applicants have addressed the deficiencies in the prior art and provide a process according to the present invention whereby a diazo compound, such as diazomethane, is continuously formed and then consumed by a substrate in a multi-stage continuous flow reactor to produce a reaction product of the diazo compound and the substrate, which product can be discharged from the multi-stage continuous flow reactor without any hazards associated with the presence of the diazo compound and during which reaction both the diazo compound is formed in the same reaction chamber and further reacts with the substrate to produce the reaction product.

[0010] Thus, the present invention provides, in a first aspect, a method for the continuous production of a reaction product of a diazo compound and a substrate (so-called "diazo reaction product") in a multistage continuous flow reactor comprising at least two connected reactors (also referred to as reaction chambers) in fluid communication with each other, wherein the reaction product formed at each stage of the multistage sequence is continuously discharged from the upstream reactor (or upstream reaction chamber) in which it is formed and fed as a continuous fluid stream to a downstream reactor (or downstream reaction chamber) where it can subsequently undergo further conversion, the method being characterized in that a precursor compound of the diazo compound continuously formed in the upstream reactor (upstream reaction chamber) is continuously discharged from the upstream reactor (upstream reaction chamber) to the downstream reactor (downstream reaction chamber) under conditions favouring its conversion into the diazo compound, and wherein the downstream reactor (downstream reaction chamber) comprises a substrate with which the diazo compound reacts to form the diazo reaction product.

[0011] Furthermore, in another aspect, the present invention provides a device suitable for carrying out the above-mentioned method, which is a multi-stage continuous flow reactor. DETAILED DESCRIPTION OF THE INVENTION

[0013] The advantage of the present invention is that the substrate used as the quenching medium is contained in the same reaction chamber in which the diazonium compound is formed. In this way, it is ensured that the substrate is consumed substantially immediately after the diazonium compound is formed to form the diazonium reaction product. This ensures that although a large amount of diazonium compound will be formed during the entire process of the continuous reaction, no harmful concentration of diazonium compound will be present at any given time point and at any location in the reaction chamber or multi-stage continuous flow reactor.

[0014] The diazo compound used in the present invention can be any compound having two connected nitrogen atoms as terminal functional groups. Simple forms of these compounds include diazomethane, diazoethane or diazoacetate, all of which can be used as reagents in the present invention, and diazomethane is particularly useful.

[0015] Suitable substrates for reacting with the diazo compound and forming the desired diazo reaction product include olefins, aldehydes, ketones, cyclic ketones, carboxylic acids, and the like. Of particular interest as substrates in the present invention are olefins, and more particularly dienes or polyolefins, preferably having at least one terminal (monosubstituted) double bond. Particularly useful olefins are described in US 9,718,741, which is incorporated herein by reference, and more particularly include polyprene-type olefins, such as isoprene, myrcene, farnesene, and β-springene (β-springene) (a diterpene analog of farnesene), particularly farnesene.

[0016] Diazo compound precursors are well known in the art and typically include N-alkyl-N-nitroso compounds. The alkyl group is typically methyl, but may include ethyl analogs and even higher alkyl analogs, such as propyl, butyl, etc., which may be straight or branched and may be substituted or unsubstituted. Particularly useful precursor compounds include, but are not limited to, N-methyl-N-nitrosourea (MNU), N-methyl-N-nitroso-toluenesulfonamide (Diazald), methyl (nitroso) carbamate, methyl (nitroso) ethyl carbamate, and N-methyl-N-(2-methyl-4-oxopentan-2-yl) nitrosoamide (Liquizald), wherein Liquizald represents a particularly preferred precursor compound.

[0017] The N-alkyl-N-nitroso precursor compounds referred to above are typically formed when the corresponding N-alkyl compound, such as an alkylamine or an alkylamine derivative, such as methyl urea, is converted into a nitroso derivative by the action of an aqueous solution of nitrite ions, such as sodium nitrite, and an organic or inorganic acid.

[0018] Examples of N-alkyl compounds or their derivatives are commercially available or can be prepared from commercially available raw materials. Specific N-alkyl compounds include, but are not limited to, N-methylurea, N-methyl-toluenesulfonamide, ethyl methylcarbamate and 4-methyl-4-(methylamino)pentan-2-one, especially 4-methyl-4-(methylamino)pentan-2-one.

[0019] The process of the present invention is a continuous process, which means that the process involves feeding one or more continuous fluid streams containing reagents, reactants, solvents, etc. into a reactor (or reaction chamber) through a pipeline, so that the fluid streams can chemically react when they are in contact with each other, and the reaction products formed can be continuously discharged in the form of fluid streams, optionally entering further connected reactors (or reaction chambers). This is in contrast to batch reactions, in which a large amount of reaction mixture or reaction product remains in the reaction vessel until the reaction mixture or reaction product can be discharged at a selected time.

[0020] In addition, the process of the present invention can be carried out as a multi-stage reaction, which means that the diazo reaction product is formed through multiple consecutive reaction stages, wherein in each stage of the reaction, the reaction product formed in the previous stage is discharged from the reactor (or reaction chamber) in which it is produced and fed as a reactant to the continuous reactor (reaction chamber), thereby undergoing further chemical conversion, and the process is repeated until the diazo reaction product is produced.

[0021] The method of the present invention can be carried out in any form of reactor set for continuous flow conditions. According to the present invention, continuous flow reactors, such as microreactors are particularly useful. Microreactors are actually miniaturized flow reactors, usually in tubular form, and the most common is to arrange the pipeline on or in the chip, which has a characteristic pipeline diameter of at most about 1mm measured in microns. Such reactors are well known in the art and do not need to be described in detail herein, but it should be understood that, especially considering that when scaled up, the pipeline diameter can be increased to millimeters even if it is not centimeters, to allow for increased flux of reagents, reaction partners, solvents and reaction products. Within these dimensions, the general term "flow reactor" is simply used, which has all possibilities of fine structure or arrangement of corresponding pipelines. Alternatively, more than one and in principle an unlimited number of microreactors can be operated in parallel, which also increases the theoretical diameter (so-called "expansion") of the original single microreactor pipeline.

[0022] It is expected that the reagents, reactants, solvents, etc. introduced at a specific stage of the multi-stage reaction can be mixed with each other through a feed pipe and a T-connector to form a fluid stream, and then the mixture can be further transported as a single or multi-fluid feed stream to another pipeline or flow reactor (or reaction chamber) where a reaction may occur, and the corresponding reaction product is continuously discharged through the outlet of the reactor (or reaction chamber). The terms "reactor" and "reaction chamber" are interchangeable. Both describe the various parts of the overall multi-stage continuous flow reactor.

[0023] In a multistage process, a multistage continuous flow reactor comprises at least two reactors or reaction chambers, more specifically at least three reactors or reaction chambers, and more specifically at least four or more reactors or reaction chambers, which are connected to each other and in fluid communication, and into and through which a directed fluid can be applied. The reactors or reaction chambers are each equipped with an inlet and an outlet for feeding and discharging a fluid stream of reagents and reaction products, respectively, and the reactors or reaction chambers define an internal space in which reagents, reactants, solvents, etc. react to form a continuous reaction product.

[0024] Feed tubes and T-connectors can be assembled in such a way that the manner in which reagents, reactants, solvents, etc. are mixed, fed and discharged therein can be controlled in time and space so as to control or optimize reaction conditions, such as temperature, pressure and control the composition of the mixture to ensure the formation of continuous reaction products in an optimal manner. A particular object of the present invention is a method in which one or more reactants, reagents, solvents, etc. are fed into a reaction chamber in an optimized time and distribution manner to meet safety and performance requirements.

[0025] The process of the present invention is particularly suitable for adding diazomethane to an olefin substrate to provide a diazo reaction product comprising a cyclopropane functional group formed by the action of the diazomethane on the olefin double bond on the substrate.

[0026] Therefore, in a particular aspect of the present invention, there is provided a continuous process for producing a cyclopropanated compound, the process comprising the steps of:

[0027] - providing a multi-stage continuous flow reactor comprising at least two, more particularly at least three, and still more particularly at least four or more connected reaction chambers in fluid communication with each other;

[0028] - at each stage of the reaction, under conditions favorable to the formation of reaction products, a fluid stream of reactants, reagents, solvents, etc. is continuously fed into the reaction chamber in a directed flow;

[0029] - a fluid stream of reaction products is continuously withdrawn from the reaction chamber and fed into a continuous reaction chamber where it undergoes further conversion to form a continuous reaction product; characterized in that a diazomethane precursor compound formed as a reaction product in the reaction chamber is continuously withdrawn from the reaction chamber (upstream reactor) and continuously fed into a continuous reaction chamber (downstream reactor) under conditions that favor the conversion of the precursor compound into diazomethane, and wherein the continuous reaction chamber contains a substrate containing an olefin, and the diazomethane reacts with the substrate to form the desired cyclopropanated compound.

[0030] In one embodiment of the present invention, the process for forming a cyclopropanated compound comprises the steps of feeding a continuous fluid stream of a reaction mixture comprising an organic phase containing mesityl oxide and an aqueous phase comprising an alkylamine into a first reaction chamber under conditions favouring the formation of an N-alkyl compound derivative, such as 4-(alkylamino)-4-methylpentan-2-one or in particular 4-methyl-4-(methylamino)pentan-2-one as a reaction product.

[0031] In one embodiment of the present invention, an organic phase formed in a first reaction chamber comprising an N-alkyl compound derivative, such as 4-(alkylamino)-4-methylpentan-2-one and, for example, 4-methyl-4-(methylamino)pentan-2-one, is mixed with an acid and an aqueous phase comprising nitrite ions to form a reaction mixture, and a continuous stream of the reaction mixture is fed to a continuous reaction chamber downstream of the first reaction chamber under conditions that favor the formation of the diazomethane precursor N-methyl-N-(2-methyl-4-oxopentan-2-yl)nitrosamide (nitrous amide) (also known as Liquizald) as a reaction product.

[0032] In one embodiment of the present invention, an organic phase comprising N-methyl-N-(2-methyl-4-oxopentan-2-yl)nitrosamide (Liquizald) formed in a reaction chamber and separated from an aqueous phase by phase separation is mixed with an olefin substrate, a palladium catalyst and an aqueous phase comprising a suitable base in a continuous reaction chamber under conditions favouring the formation of diazomethane, and the diazomethane formed reacts with the olefin substrate to form a cyclopropanated compound which is discharged from the reaction chamber as a continuous fluid stream.

[0033] The following drawings are used to further illustrate the present invention or specific aspects of the present invention:

[0034] Figure 1 A diagrammatic representation showing a multi-stage continuous flow reactor suitable for a process for the continuous production of a "diazo reaction product";

[0035] Figure 2Shown is a schematic representation of the reaction chamber, where the diazo reaction product is formed, and a new pattern of reagent addition is employed during the flow process;

[0036] Figure 3 a schematic representation showing an alternative reaction chamber in which a diazo reaction product is formed and a batch-dependent reagent addition pattern is employed during a flow process; and

[0037] Figure 4 A schematic representation showing an alternative multi-stage continuous flow reactor suitable for the process of continuously producing a "diazo reaction product", also comprising a plurality of continuous stirred tank reactors (CSTRs) and a two-phase settler.

[0038] In the process of converting a precursor compound (such as Liquizald) into diazomethane and further converting it into a diazo reaction product, the order of adding reactants and reagents is particularly important. When this synthesis step is carried out as described in the batch method of the prior art (for example, as described in WO2015059290), Liquizald in a suitable organic solvent such as toluene is added to a two-phase mixture of vigorous stirring, and the two-phase mixture includes a substrate containing an olefin double bond, such as farnesene, a suitable catalyst, such as Pd (acac) 2, and a base, such as KOH. Representative examples of this type of batch method are given in the embodiments (see Example 1). However, there are problems with the use of this addition order in the method of the present invention using continuous flow. More specifically, this creates additional complexity in the device setting, because it is necessary to pre-mix and pump the two-phase mixture before adding Liquizald, so a large amount of pumps and microreactors are required. In addition, the reaction causes a much lower conversion rate of the substrate, which may be attributed to pumping an uneven mixture and poor phase mixing in the reactor. This is further demonstrated in the examples and more particularly in Examples 7 and 8, which represent Figure 3 settings, and Figure 2 and 3 comparison.

[0039] It was found that an addition sequence in which the aqueous phase (e.g. KOH in water) and the organic phase (Pd(acac)2, LiquidaZald and Farnesene in toluene) are mixed continuously is more efficient and simpler in terms of optimizing conversion and technical setup ( Figure 2 ). This example of the reaction is carried out in a single microreactor, which is equivalent to a reactor or a reaction chamber, and a residence unit is provided in Example 2. Figure 2 Example Figure 1 or Figure 4 The arrangement of the last reaction chamber in the reactor, in which the diazo reaction product is formed, can also be considered as a separate continuous flow reactor.

[0040] The steps in the multi-stage method for forming the cyclopropanated compound described above can be carried out in a two-phase medium comprising an organic phase and an aqueous phase. As an example, after forming 4-methyl-4-(methylamino)pentan-2-one, the continuous reaction products formed during each stage of the method can be soluble or dispersed in the organic phase. Therefore, if desired, water-soluble or dispersible effluents or by-products can be continuously separated from the organic phase by phase separation techniques.

[0041] It is particularly important to separate the precursor compound, Liquidzald, from the aqueous phase because Liquidzald is formed under acidic conditions, whereas the formation of diazomethane from Liquidzald occurs under basic conditions in a two-phase mixture. Therefore, before Liquidzald is continuously fed into the reaction chamber to form diazomethane, it is desirable to separate the organic phase containing Liquidzald from the aqueous phase by a suitable phase separation method, and it is also advantageous to remove trace amounts of acid from the Liquidzald-containing phase by washing with a portion of a suitable aqueous base before carrying out the subsequent synthesis step.

[0042] Phase separation and washing with aqueous alkali can be performed under continuous flow conditions by passing a biphasic reaction mixture containing a precursor compound (e.g., Liquid) through a continuous extraction device, such as a continuous stirred tank reactor (CSTR). For example, KP Col et al. described the use of countercurrent extraction in a multi-stage flow sequence in Science 356, 1144-1150 (2017). Ideally, the CSTR is miniaturized to reduce the volume of Liquid during extraction and washing, which can be performed, for example, by using a liquid-liquid separator (LLS) and an agitated cell extractor (ACX), which can reduce the fixed amount of Liquid and feed the Liquid-containing phase to a continuous reactor for the cyclopropanation step. For example, the principle of using a liquid-liquid separator (LLS) is described in a technical description from, for example, Zaiput Flow Technologies or in a multistage flow publication describing the application of such LLS, see, for example, J. Britton, CL Raston, Chem. Soc. Rev. 46, 1250-1271 (2017). The principle of countercurrent extraction using a stirred cell extractor is well known in the art and is described, for example, in a technical description from, for example, AM Technology or in a review describing such technical principles, see, for example, F. Visscher, J. van der Schaaf, TA Nijhuis, JC Schouten, Chemical Engineering Research and Design 91, 1923-1940 (2013).

[0043] Figure 1 A schematic representation of a method and apparatus for the continuous production of cyclopropanated compounds according to a particularly preferred embodiment of the present invention is described, and the figure and description serve to further describe the present invention. For simplicity, the description relates to the continuous synthesis of Liquizald and its use in the cyclopropanation of farnesene, but any other precursor compound may be prepared, such as any N-alkyl-N-(2-methyl-4-oxopentan-2-yl)nitrosamide precursor, and any other olefin substrate for cyclopropanation. Figure 1 The following elements are arranged: reservoirs 101-107, pumps 111-119, flow in the pipeline indicated by arrows, microreactor 121, retention coil 131 with static mixture, quenching vessel 141, piston flow reactor 151-152, liquid-liquid separator LLS 161, back pressure regulator 171, stirred cell extractor (ACX) 181, T-connectors 191-194.

[0044] Involved Figure 1 :

[0045] - In a first step, mesityl oxide (from reservoir 101 via feed A, pump 111) and methylamine (from reservoir 102 via feed B, pump 112) are mixed in a T-piece (191, T1) and a plug flow reactor (151, pfr1), wherein these components react to produce 4-methyl-4-(methylamino)pentan-2-one (MOMA=mesityl oxide / methylamine adduct);

[0046] - In the second and third steps, the acid in toluene (from reservoir 103, via feed C, pump 113) and the aqueous sodium nitrite solution (from reservoir 104, via feed D, pump 114) are added to two subsequent T-pieces (192, T2 and 193, T3), where these components react to obtain N-methyl-N-(2-methyl-4-oxopentan-2-yl)nitrosamide (Liquizald) in the third T-piece (193, T3) and the subsequent plug flow reactor (152, pfr2). Alternatively, the sodium nitrite can be added first and then the acid;

[0047] - In the fourth and fifth steps, the resulting two-phase mixture from step 3 is separated by a liquid-liquid separator (161, LLS, step 4), removing the acidic aqueous waste (via back pressure regulator 171). The organic phase moves forward (pump 115) and the residual acid is removed by continuous washing (step 5) in a stirred cell extractor (181, ACX), to which an aqueous base is added (from reservoir 105, via feed E, pump 116);

[0048] - In the sixth step, the organic layer containing Liquizald is pumped (pump 117) to a T-piece (194, T4) where it is mixed with the polyene substrate (farnesene) and catalyst (from reservoir 106, via feed F, pump 118) in toluene;

[0049] The obtained mixture containing Liquizald is pumped into a microreactor (121), where it is mixed with an aqueous base (from reservoir 107, via feed G, pump 119) in a seventh step, where the cyclopropanated product is formed in the microreactor 121 and the subsequent retention coil 131. The obtained cyclopropanated product mixture is conducted from the retention coil to a container 141 containing a quenching solution, where the two-phase mixture is allowed to settle. For safety reasons, a quenching solution is used. In the case of fully converted Liquizald and diazomethane, quenching is not necessary.

[0050] After step seven, the biphasic mixture contains the cyclopropanated compound (diazo reaction product) in the organic phase and the aqueous phase containing the waste mixture, which can be separated by conventional batch separation methods, because the reaction parameters can be adjusted to ensure that the mixture does not contain any unreacted Liquid and / or diazomethane. Optionally, of course, the work-up and purification of the product can be continued under flow conditions.

[0051] Below is a series of examples, which are used to further illustrate the present invention. The following examples are given to illustrate the preferred embodiments of the present invention. It will be understood that these examples are exemplary, and the present invention should not be considered to be limited thereto.

[0052] General Description:

[0053] Non-polar GC conditions: 100°C, 1 min, 20°C / min to 240°C, 5 min, 240°C. GC Agilent 7890B Series GC system. Non-polar column: HP-5 from Agilent Technologies, 0.32 mm x 0.25 mm x 30 m. Carrier gas: hydrogen. Injection temperature: 230°C. Split 1:50. GC calibration was performed with 80% Liquizald (as determined by NMR) and decane. rpa% = relative peak area.

[0054] Non-polar GCMS conditions: 50°C, 2 min, 20°C / min to 240°C, 35°C / min to 270°C. GCMS Agilent 5975C MSD with HP7890A series GC system. Non-polar column: BPX5 from SGE, 5% phenyl 95% dimethylpolysiloxane 0.2 mm x 0.25 mm x 12 m. Carrier gas: Helium. Injection temperature: 230°C. Split: 1:50. Flow rate: 1.0 ml / min. Transfer line: 230°C. MS-quad: 150°C. MS-source: 230°C. rpa% = relative peak area.

[0055] Example 1 (comparative)

[0056] The cyclopropanation reaction under batch conditions is as follows:

[0057]

[0058] A 46% solution of Liquizald in toluene (18.3 g, 53 mmol, 1.7 eq) was added to a stirred biphasic mixture of farnesene 98% (6.4 g, 31 mol) and Pd(acac)2 (6.3 mg, 20 μmol, 0.065%) in toluene (27 ml) and KOH (8 g, 0.12 mol) in water (34 ml) at 45°C over a period of 2 h. After 30 min at 45°C and complete conversion detected by GC, the reaction mixture was poured onto acetic acid (25 ml). After phase separation, the organic phase was washed with water, dried over MgSO4, filtered and the solvent was evaporated. According to GC, the brown-orange oil (7 g) contained 92% Δ-farnesene, 8% Δ2-farnesene, which corresponds to a GC-calibrated purity of Δ-farnesene (84%) to a calibrated yield of 86% Δ-farnesene based on farnesene.

[0059]

[0060] Example 2

[0061] like Figure 2 As shown in, the cyclopropanation reaction using 0.065% Pd(acac)2 under flow conditions and a new addition method.

[0062] Equipment: Sigma-Aldrich Microreaction Explorer Kit No.19979-1kt, 2007, Version 1.02, Sigma Aldrich Production GmbH, Buchs, Switzerland. Micro reaction plate: MR#437383, Little Things Factory, 0.7 ml volume, PTFE tubing, borosilicate glass, ceramic, maximum internal pressure 6.5 bar. Two 100 ml round bottom flasks. 200 ml sulfonated flask containing acetic acid as quencher. 1 gas scrubber containing acetic acid and 1 safety bottle. 2 Ismatec pumps. Dwelling coil: 1.25 m stainless steel tubing, 5 mm inner diameter, 18 ml volume, equipped with 19 static polypropylene mixers. The home-made residence unit is described in the bachelor's work of Fabian Ruethi ("TPO continuously for Silvanone", pages 72 and 124, Zürcher Hochschule für Angewandte Wissenschaften, 2012): 1.25 m stainless steel tube, 5 mm inner diameter, 18 ml volume, equipped with 19 static mixers. Static mixer: 6.5 mm long, 4.8 mm diameter. The pump, microreactor and residence coil are connected by Teflon tubing with an inner diameter of 1.5 mm.

[0063] Feed A: Farnesene (6.4 g, 31 mmol) with 98% purity, Pd(acac)2 (6.3 mg, 0.02 mmol. 0.065 mol%) [Note 1] in toluene (5 ml) premixed with 33% Liquizald (25.7 g, 53.6 mmol, 1.7 mol-eq) in toluene, pumped into the microreactor and residence unit at 3.4 ml / min. Feed B: 3.5 M aqueous KOH (34 ml, 117 mmol) pumped into the microreactor and residence unit at 2.2 ml / min.

[0064] Feed A (from reservoir 201) and feed B (from reservoir 202) are fed by Figure 2The set-up was pumped (pumps 211 and 212) into the microreactor 221 and the residence coil 231 in an oil bath heated to 75°C and with an internal temperature of 70-60°C [Note 2]. The product stream (5.6 ml / min, residence time in the microreactor and the residence unit 3.3 min) was subsurface quenched (in vessel 241) by acetic acid (15 g, 0.25 mol) under cooling (at an internal temperature of 10-20°C to avoid solidification of HOAc) [Note 3]. The biphasic quench mixture was transferred to a separatory funnel, the phases were separated, the organic phase was washed with water (100 ml), dried over MgSO4 (30 g), filtered and evaporated under reduced pressure. Crude Δ-farnesene (6.9 g) was obtained as a brown oil with a purity of 82.5% as determined by GC- and NMR-calibration [Note 4]. GCMS of this material showed quantitative conversion to Δ-farnesene (92% rpa) and Δ2-farnesene (8% rpa) and the absence of Liquizald. Δ-farnesene yield from farnesene (corrected by purity): 84% [Note 4]. The analytical data for Δ-farnesene and Δ2-farnesene were the same as described in WO2015059290.

[0065] Note:

[0066] [1] Catalyst Pd(acac)2 is soluble in toluene.

[0067] [2] The sensors in the microreactor are not connected to the reactant flow.

[0068] [3] Pure HOAc was used because complete cyclopropanation had to be demonstrated in the microreactor and possible after-reactions in the quench vessel had to be excluded. An excess of HOAc (2x molar excess over the KOH used) ensured non-basic quench conditions. Nitrogen was generated in the microreactor by controlled decomposition of diazomethane and passed from the quench vessel into a wash bottle containing pure HOAc. Only trace amounts of MeOAc (~0.02%) were detected in the wash bottle by NMR and only after several similar optimization experiments using the same wash bottle. For safety reasons, a quench solution can be used. In the case of fully converted Liquizald and diazomethane, quenching is not necessarily required.

[0069] [4] The content of Δ-farnesene was determined by NMR- and GC-calibration to be 82.5%.

[0070] Comparison of Example 1 (batch reaction) and Example 2 (flow reaction) shows that, under otherwise identical conditions, the yields and purities are similar (within 2% error) in batch and flow conditions.

[0071] Example 3

[0072] The flow reaction described in Example 2 was repeated under almost identical conditions and in the same apparatus but without the residence unit:

[0073] Feed A: Farnesene (6.76 g, 32 mmol) with 98% purity, Pd(acac)2 (6.5 mg, 21 μmol, 0.065 mol%) and 38% Liquizald (23.34 g, 55.3 mmol, 1.7 mol-eq) premixed in toluene (18 ml) were pumped at 1.7 ml / min into the microreactor without residence unit. Feed B: 3.5 M aqueous KOH (33 ml, 114 mmol) was pumped at 1 ml / min into the microreactor without residence unit.

[0074] Feed A and Feed B were pumped (described in Example 2 below, but without a residence coil) into a microreactor in an oil bath heated externally to 75° C. and with an internal temperature of 70-60° C. The product stream (2.7 ml / min, residence time in the microreactor was 15 seconds) was subsurface quenched by acetic acid (15 g, 0.25 mol) with cooling (at 10 to 20° C.). GC performed 30 min after complete quenching showed Liquidazone (26%), Farnesene (67%) and Δ-Farnesene (7%).

[0075] This experiment showed that the residence time was reduced 20 times due to the absence of a residence unit, which significantly reduced the conversion of farnesene and Liquizald to Δ-farnesene.

[0076] Example 4

[0077] The flow reaction described in Example 2 was performed using 1.2 mol-eq Liquizald (instead of 1.7 mol-eq for farnesene):

[0078] Feed A: Farnesene (8.96 g, 43 mmol), Pd(acac)2 (8.8 mg, 0.03 mmol) and 40% Liquizald (20.8 g, 52.6 mmol) premixed in toluene (22 ml) pumped into the microreactor and residence unit at 3.4 ml / min. Feed B: 1.75 M aqueous KOH (23 ml, 40 mmol) pumped into the microreactor and residence unit at 1.4 ml / min.

[0079] Feed A and feed B are passed through Figure 2The setup in was pumped into a microreactor and residence coil in an oil bath heated to an external temperature of 75°C and an internal temperature of 70-60°C. The product stream (4.8 ml / min, residence time 4 min) was quenched by acetic acid (15 g, 0.25 mol) subsurface and under cooling (10-20°C) [Note 3]. The biphasic quench mixture was transferred to a separatory funnel, the phases were separated, the organic phase was washed with water (100 ml), dried over MgSO4 (30 g), filtered and evaporated under reduced pressure. Crude Δ-farnesene (11.6 g) was obtained as a brown oil with a purity of 66% as determined by GC- and NMR-calibration. GCMS of this material showed 91% conversion to Δ-farnesene (85% rpa) and Δ2-farnesene (6% rpa) and the absence of Liquizald. Yield of Δ-farnesene from farnesene (corrected for purity): 82%.

[0080] Compared to Example 2, the results show that with less Liquizald (Liquizald / farnesene ratio of 1.2 instead of 1.7), the conversion of farnesene is still substantial and the calibrated yield of Δ-farnesene (82%) is still comparable to the calibrated yield obtained with more (1.7 eq) Liquizald (84% in Example 2). At this point it must be mentioned that incomplete conversion rather than excess cyclopropanation to Δ2-farnesene is acceptable, since the byproduct of the biscyclopropanation cannot be recycled, whereas the unconverted farnesene can be obtained after separation by distillation from Δ-farnesene and recycled as substrate.

[0081] Example 5

[0082] The flow reaction described in Example 2 was performed using 0.02% catalyst (instead of 0.065% catalyst).

[0083] Feed A: Farnesene 98% pure (6.48 g, 31 mmol), Pd(acac)2 (2 mg, 6.4 μmol) and 43% Liquizald (19.8 g, 54 mmol, 1.7 eq) in toluene premixed in toluene (24 ml) pumped into the microreactor and residence unit at 1.7 ml / min. Feed B: 3.55 M aqueous KOH (34 ml, 120 mmol) pumped into the microreactor and residence unit at 1.1 ml / min.

[0084] As in Example 2 and Figure 2Feed A and Feed B were pumped into the microreactor and residence coil as described in. Total flow rate: 2.8 ml / min. Residence time: 6.5 min. The product stream was quenched subsurface by acetic acid. GC performed 30 min after complete quench indicated 82% conversion to Δ-farnesene (77% rpa) and Δ2-farnesene (4% rpa) and the absence of Liquizald.

[0085] This example shows that acceptable conversion can be obtained in flow at much lower catalyst concentrations (0.02 instead of 0.065 mol %).

[0086] Example 6

[0087] The flow reaction described in Example 5 was performed in batch mode.

[0088] 37% Liquizald (23.1 g, 53 mmol, 1.7 eq) in toluene was added to a stirred biphasic mixture of farnesene 98% (6.4 g, 31 mol) and Pd(acac)2 (2 mg, 6.3 μmol, 0.02%) in toluene (27 ml) and KOH (8 g, 0.12 mol) in water (34 ml) at 45° C. over a period of 2 hours. GC performed 30 min after complete quenching indicated 78% conversion to Δ-farnesene (70%), Δ2-farnesene (4%) and another monocyclopropanated byproduct (2%).

[0089] Comparison of the results from batch (Example 6) and flow mode (Example 5) shows that the conversion and purity obtained under flow conditions (82% vs. 77% rpa Δ-farnesene) are as good, if not even better, than those obtained under batch conditions (77% vs. 70% rpa Δ-farnesene).

[0090] Example 7

[0091] like Figure 3 As shown in , the cyclopropanation reaction was carried out under flow conditions with a catalyst / substrate ratio of 0.065% and in an addition pattern related to batch-(Example 1):

[0092] Equipment: As described in Example 2, but using two microreactors (instead of one) and three pumps (instead of two).

[0093] Feed A: Farnesene (6.3 g, 31 mmol) at 98% purity, Pd(acac)2 (6.2 mg, 0.02 mmol. 0.065 mol%) in toluene (13 ml) pumped at 1.5 ml / min. Feed B: 3.5 M aqueous KOH (34 ml, 118 mmol) pumped at 2.2 ml / min. Feed C: 33.5% solution in toluene (24.9 g) and toluene (1 ml) pumped at 1.9 ml / min.

[0094] Feed A (from reservoir 301) and feed B (from reservoir 302) are fed by Figure 3 The setup is pumped (micro pumps 311 and 312) into the first microreactor (321, mrx 1), where a two-phase mixture is formed. From the first microreactor, the fluid (3.7 ml / min) is introduced into the second microreactor (322, mrx 2), where it is mixed with feed C (from reservoir 303) and pumped (pump 313) into the second microreactor 322 at 1.9 ml / min. The flow from mrx 2 was directed to retention coil 331 from which the product stream (5.6 ml / min) was quenched subsurface by acetic acid (15 g, 0.25 mol) under cooling (at an internal temperature of 10-20° C.) (in vessel 341). Work-up as described in Example 2 gave a mixture of unconverted farnesene and crude Δ-farnesene (7 g) as a brown oil with a purity of 47% by GC- and NMR-calibration. GC of this material showed farnesene (44% rpa), Δ-farnesene (56% rpa) and traces of Liquid and Δ2-farnesene. Yield of Δ-farnesene from farnesene (corrected for purity): 48%.

[0095] This experiment shows that the addition of Liquizald to a preformed two-phase mixture of farnesene, Pd(acac)2 in toluene and aqueous KOH under flow conditions in the addition mode described in Batch Example 1 has two major drawbacks:

[0096] - Higher complexity (more pumps and microreactors)

[0097] - Significantly lower farnesene conversion (56% instead of 100%), which may be attributed to the inhomogeneous mixture (Feed A + Feed B) pumped into the second microreactor.

[0098] Embodiment 8:

[0099] like Figure 3 As shown, the cyclopropanation reaction under flow conditions, with a catalyst / substrate ratio of 0.02% and using a batch- (Example 1)-related addition method:

[0100] Feed A: Farnesene (6.4 g, 31 mmol) with 98% purity and Pd(acac)2 (1.9 mg, 0.02 mmol, 0.02 mol%) in toluene (13 ml) pumped at 0.74 ml / min. Feed B: 3.5 M aqueous KOH (34 ml, 118 mmol) pumped at 1.1 ml / min. Feed C: Toluene (21.3 g) and 39% Liquizald in toluene (5 ml) pumped at 0.96 ml / min.

[0101] The flow reaction described in Example 7 was carried out with the same equipment setup, but the feed was slightly changed and 2 mg (6.4 μmol, 0.02 mol%) Pd(acac)2 was used instead of 6.2 mg (0.02 mmol, 0.065 mol%). Work-up as described in Example 2 gave a mixture of unconverted farnesene and crude Δ-farnesene (7 g) as a brown oil with a purity of 43% as determined by GC- and NMR-calibration. GC of this material showed farnesene (47% rpa), Δ-farnesene (50% rpa), Δ3-farnesene (3% rpa) and traces of Δ2-farnesene and Liquid. Yield of Δ-farnesene from farnesene (corrected for purity): 44%.

[0102]

[0103] At lower catalyst concentrations, this experiment showed similar effects to Example 7.

[0104] Example 9

[0105] like Figure 4 Multistage flow experiment shown.

[0106] Equipment: As in Example 2 ( Figure 1 The flow reaction described in (and represented by Figure 1 ), but with some additional devices:

[0107] -5 additional feed pumps (7 in total)

[0108] - 6 peristaltic pumps

[0109] - 3 additional T-connectors (4 total)

[0110] -2 plug flow reactors (pfr)

[0111] -5 additional reservoirs for additional reagents, reactants and solvents (7 total)

[0112] - 4 CSTRs (Continuous Stirred Tank Reactors) with Dual Phase Settlers

[0113] - 2 back pressure regulators

[0114] The pump, T-connector, microreactor, plug flow reactor and CSTR are connected by Teflon tubing. The T-connector is also made of polytetrafluoroethylene and can be purchased from Sigma-Aldrich (Merck), for example. The plug flow reactor is a 1.25 m stainless steel tube. A retention coil equipped with a static mixer is described in Example 2.

[0115] Feed A: mesityl oxide (700 g, 7 mol). Feed B: 40% methylamine in water (580 ml, 7.5 mol). Feed C: acid (11.4 mol) in 700 ml toluene. Feed D: NaNO2 (543 g, 7.6 mol) in water (820 ml). Feed E: 25% base in water (1400 ml). Feed F: farnesene (640 g, 3 mol) and Pd(acac)2 (0.2 mg, 0.65 mmol. 0.02 mol%) in toluene (550 ml). Feed G: 3.5 M aqueous KOH (3400 ml, 11.7 mol). Flow rates, residence times and tube diameters are omitted for clarity.

[0116] Feed A (from reservoir 401) and feed B (from reservoir 402) are pumped (pumps 411 and 412) into T-connector T1 (491) and the first piston flow reactor (451, pfr1) through the above-mentioned arrangement, where these reactants are subjected to Michael addition to obtain isopropylmethyl acetone methylamine adduct (MOMA) and then introduced into T-connector T2 (492), where acid in toluene (from reservoir 403, through feed C) and NaNO2 in water (rom reservoir 404, through feed D) are subsequently added through two pumps (413, 414). After acidic nitrosation in T-connector T3 (493) and the second plug flow reactor (452, pfr2), the Liquid obtained in the biphasic mixture of toluene and water is fed to the first CSTR (461a, continuous stirred tank reactor) and the biphasic settler (461b), where the phases are separated into the acidic wastewater stream (via back pressure regulator 471) and the Liquid stream in toluene, which are fed to the next three CSTRs (462a, 463a, 464a) and the corresponding biphasic settlers (462b, 463b, 464b) through several peristaltic pumps. Washing is effected by an aqueous base (from reservoir 405, feed E) which is pumped (pump 415) countercurrently from the fourth CSTR (464a) and its two-phase settler (464b) via the third CSTR (463a) and its two-phase settler (463b) to the second CSTR (462a) from which an alkaline wastewater stream is discarded, passing through the two-phase settler (462b) and backpressure regulator 472. From the two-phase settler 464b of CSTR 4 (464a), a stream of essentially acid-free Liquid in toluene is directed (pump 416) to T-connector T4 (494). At the same time, farnesene and catalyst Pd(acac)2 (from reservoir 406, feed F) are pumped (pump 417) into T-connector T4 (494) to obtain a uniform organic stream, which is introduced into a microreactor (421) and a retention unit (431) rc3 equipped with a static mixer. At the same time, a uniform aqueous base (from reservoir 407, feed G) is pumped (pump 418) into a microreactor (421) and a retention unit (431, rc3). After the cyclopropanation reaction is carried out at 60°C in the microreactor, the product is subsurface quenched (container 441) in a retention unit equipped with a static mixer, and acetic acid (1.5 kg, 22.5 mol) is passed under cooling. The two-phase quenched mixture is separated, the organic phase is washed with water (10 l), azeotropically dried, and evaporated under reduced pressure. Crude Δ-farnesene (600 g) was obtained as a brown oil with a purity of 80% (GCrpa), which contained Δ2-farnesene (3% rpa) and unconverted farnesene (16% rpa). Yield of Δ-farnesene from farnesene (corrected for purity): 78%.The crude product was further purified by distillation.

Claims

1. A process for the continuous production of a reaction product of a diazo compound with a substrate in a multistage continuous flow reactor comprising at least two reactors connected in fluid communication with each other, wherein the reaction product formed at each stage of the multistage sequence is continuously discharged from the upstream reactor in which it is formed and fed as a continuous fluid stream to a downstream reactor where it can subsequently undergo further conversion, the process being characterized in that a precursor compound of the diazo compound formed continuously in the upstream reactor is continuously discharged to the downstream reactor under conditions favouring its conversion into the diazo compound, and wherein the downstream reactor contains a substrate with which the diazo compound reacts to form a reaction product of the diazo compound with the substrate, wherein the diazo compound is diazomethane, the substrate is an olefin, and their reaction product is a cyclopropanated compound, and wherein the diazomethane precursor compound formed in an upstream reactor is mixed with the olefin substrate, a catalyst and an organic solvent to form an organic phase, and the organic phase is mixed with an aqueous phase containing a base to form a two-phase reaction mixture, which reacts in a downstream reactor to form a cyclopropanated compound.

2. The process according to claim 1, wherein the substrate is an olefin selected from di- or polyolefins.

3. The process according to claim 1, wherein the olefin has at least one terminal double bond.

4. The process according to claim 1, wherein the olefin is selected from the group consisting of isoprene, myrcene, farnesene and β-presne.

5. The method according to any one of claims 1 to 4, wherein the diazo compound precursor is an N-alkyl-N-nitroso compound selected from N-methyl-N-nitrosourea, N-methyl-N-nitroso-p-toluenesulfonamide, N-methyl-N-nitrosocarbamic acid methyl ester, N-methyl-N-nitrosocarbamic acid ethyl ester and N-methyl-N-(2-methyl-4-oxopentan-2-yl)nitrosoamide.

6. The process according to claim 1, wherein the diazomethane precursor compound formed in the upstream reactor is contained in the organic phase of the two-phase mixture, and wherein the organic phase containing the diazomethane precursor compound is separated from the aqueous phase of the two-phase mixture before mixing with the olefin substrate, the catalyst and the organic solvent.

7. The method according to claim 1, comprising the steps of: - providing a multi-stage continuous flow reactor comprising at least three reactors connected in fluid communication with each other; - continuously feeding a fluid stream of reactants into the reactor in a directed flow manner under conditions that favor the formation of reaction products at each stage of the reaction; - continuously withdrawing a fluid stream of the reaction product from said reactor and feeding it to a continuous reactor where it undergoes further conversion to form a continuous reaction product; characterized in that The diazomethane precursor compound formed as a reaction product in the reactor is continuously fed to a continuous reactor under conditions that favor conversion of the precursor compound to diazomethane, and wherein the continuous reactor contains a substrate with which the diazomethane reacts to form a cyclopropanated compound.

8. The method according to claim 7, wherein the multi-stage continuous flow reactor comprises at least four or more connected reactors in fluid communication with each other.

9. The method according to claim 1, wherein the diazomethane precursor compound discharged from the reactor is continuously mixed with a catalyst, a substrate and a solvent to form an organic phase, and the organic phase is continuously mixed and reacted with an aqueous phase containing a base in a continuous reactor, thereby forming a cyclopropanated compound.

10. The process of claim 9, wherein the base is KOH.

11. The process according to claim 1, which is carried out under flowing conditions.

12. The method according to claim 11, wherein the reaction is carried out in a microreactor.

Images