Communication pubs.acs.org/OPRD
An Atom-Efficient Route to Ethyl 3‑(difluoromethyl)-1methyl‑1H‑pyrazole-4-carboxylate (DFMMP)A Key Building Block for a Novel Fungicide Family Janis Jaunzems* and Max Braun* Solvay Fluor GmbH, Hans-Boeckler Allee 20, 30173 Hannover, Germany In the present article we will show a new route to ethyl 3(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFMMP) developed and scaled-up in our laboratories, which is not only cost competitive to current industrial processes but also leaves a significantly smaller environmental footprint (kg waste/kg product).
ABSTRACT: A growing number of fluorine-containing active ingredients in the pharmaceutical and agrochemical industries inevitably raises the demand for new fluorinated building blocks. Their availability is mainly constricted by suitable chemistry and available bulk fluorine containing starting materials. Because of the high cost impact especially in the agrochemical industry, the choice of a synthetic route is heavily driven by economic aspects; thus, the environmental profile often is handled as a “secondary factor” or finally falls aside. DFMMP is a key building block for a fast growing new fungicide family, like Syngenta’s Sedaxane, and BASF’s Fluxapyroxad and Bayer’s Bixafen currently made by environmetally less friendly routes. Herein we present a cost-competitive and green route, developed at Solvay laboratories, displaying significantly lower environmental impact.
2. CURRENT INDUSTRIAL SYNTHESIS OF DFPA In spite of various synthesis routes reported so far, a key intermediate in the way to DFPA 6 remains ethyl-2,2difluoroacetate 3 (EDFA), which is produced in kiloton amounts mainly from tetrafluorethylene 1 (TFE) by several Asian companies,2 or from ethyl dichloroacetate by halogen exchange reaction.3 Later steps up to DFPA are in principal similar but carry crucial technological variations between different companies (Scheme 1). Tetrafluorethylene is a widely available multiton industrial intermediate, mainly used for PTFE production. The main drawback for its application to manufacture EDFA is that two out of four fluorines are lost as HF or KF. The Claisen condensation of EDFA with ethyl acetate is complicated to scale-up, because of the high load of salt generated by final neutralization process with acid. That affords high amounts of aqueous anorganic waste contaminated with haloorganic compounds.4 Furthermore, ethyl difluoracetoacetate 4 has a moderate stability and decomposes if stored at room temperature for a prolonged period of time.5 Condensation with triethylortoformiate (TEOF) to α,β-unsaturated ketone 5 is generally high yielding but requires excess of reagents, generating significant amounts of a halogen-contaminated organic waste. The control of regioselectivity in the cyclization step with methylhydrazine remains challenging, in spite of some methods published so far allowing control of it.
1. INTRODUCTION The world population is constantly growing and will reach 9 billion in 2050. On the other side, the amount of farmable land, availability of fresh water, and areas with a suitable climate for living are the main limiting factors. Therefore, to keep up the battle against new and more resistant plant diseases, more active and environmentally friendly agrochemicals are needed, thus increasing the output per hectare. It is well-known that fluorine substituents can alter the properties of APIs and agrochemicals like their activity, metabolic stability, and half-life in the desired direction. It is thus not surprising that up to 50% pharmaceutical and agrochemical compounds under development contain fluorine substituents. Recently a new SDHI fungicide family, based on the common structural element: 3-(difluoromethyl)-1-methyl-1Hpyrazole-4-carboxamide (DFPA), started to gain attention by main global agrochemical companies. Already five different compounds recently reached the market (Figure 1), and others are under development. The global demand for this key difluoromethyl pyrazole and smaller related building blocks is growing rapidly. That inevitably creates the request for them to be accessible for a reasonable price in a multiton scale. In a recent review, Leroux et al.1 presented different synthetic routes to this key intermediate, but only some of them could be applied on an industrial scale because of cost-intensive reagents or complexity of the process itself. None of them were optimized with regard to the use of green reagents, the minimization of waste, and atom efficiency. © XXXX American Chemical Society
3. SOLVAY ROUTE TO DFMMP To develop our own synthesis route, several criteria were highlighted to generate an advantage over the current industrial route: 1. All chemical steps should be scalable, to avoid potential issues like with Claisen condensation. 2. Green chemistry, green reagents and processes with low waste and a high atom economy, is desired. 3. In-house raw materials and technologies should be used. Special Issue: Fluorine Chemistry 14 Received: April 16, 2014
A
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Figure 1. Launched SDHI based on fluorinated pyrazoles.
Scheme 1. Main DFPA industrial synthesis
Scheme 2. New synthesis of DFMMP
(R123) production process by fluorination of tetrachlorethylene, which is used for trifluoracetyl chloride (TFAC) production in our facilities. In fact, it was possible for us to manufacture CDFAC in the existing equipment used for TFAC production by applying slight process modifications (Scheme 3).6 It is a continuous photooxidation process in a gas phase. CDFAC can be isolated by following distillation. Chlorine gas is used as photosensitizer to slightly elevate the overall yield and optimize the impurity pattern but in general process can be run also without use of it.
4. A cost competitive process is desired. Based on our in-house expertise with the photooxidation of 1,1-dichloro-2,2,2-trifluoroethane (R123) for the production of trifluoroacetyl chloride, we wondered if 1,1,2-trichloro-2,2difluoroethane (R122) could react similarly yielding chlordifluoroacetyl chloride (CDFAC). In such we could avoid the use of relatively expensive EDFA as a main building block that carries fluorine into the target molecule, by employing highly environmental friendly ketene condensation step instead of a Claisen condensation (Scheme 2). 3.1. Photooxidation of R122 to CDFAC. R122 is a coproduct of the industrial 1,1-dichloro-2,2,2-trifluoroethane B
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• It is much faster and generates almost no side products; • Liberated ethanol can be collected and reused for previous step; • Triethyl ortoformiate is consumed only in slight excess; • ECDFAA conversion is quantitative. This triethylamine catalysis shows general applicability to other 1,3-dicarbonyl compounds, like 4. 3.4. Cyclization with Methylhydrazine. The reaction of 1,3-ketoesters with methyl hydrazine is well-described.1 Its application in the conversion of EMECDFAA with anhydrous methyl hydrazine (instead of a 40% aqueous solution) in 1,1,1,3,3-pentafluorobutane (S365) as a solvent, the synthesis of CDFMMP, could be realized with a minimal amount of aqueous waste. Starting with equimolar amounts of the reagents, the final reaction mixture is simply evaporated, and the crude regioisomer mixture can be separated by distillation or crystallization (Scheme 6).11
Scheme 3. Step 1
3.2. CDFAC Condensation with Ketene. Having the acid chloride in place, an atom economical elongation to the ethyl 4chloro-4,4-difluoro-3-oxobutanoate (ECDFAA) may be accomplished by use of ketene as a 2-carbon unit. On an industrial scale ketene is produced by thermal cracking of acetic acid. Labscale synthesis of ketene is well-documented and can be generated in situ by various methods over thermal cracking of different carbonyl compounds.7 Due to its high reactivity and instability, the formation of ketene by thermal cracking must be performed in direct proximity, and it should be used in further chemical conversions within seconds. Not only the ketene production is a very green low-waste process, but also the following condensation surprisingly gives a very high yield with very low waste. Liberated hydrochloride gas is separated during workup and collected as a raw material for other purposes. In this continuous liquid/gas phase process the intermediate 7 is quenched with ethanol, and ECDFAA is purified by distillation (Scheme 4).8 Ketene condensation with CDFAC
Scheme 6. Step 4
Scheme 4. Step 2
In spite of these optimizations, the regioselectivity still remains the main challenge for this step. 3.5. Catalytic Hydrodechlorination of CDFMMP. The final hydrodechlorination to obtain the difluormethyl pattern remained to be the most challenging part in the development, as the chloro substituent shows high resistance towards any kind of reduction procedures.12 The finally found rather harsh conditions (Scheme 7) therefore give rise to small amounts of byproducts 8 and 9 due to hydrodefluorination as well. Surprisingly only a certain combination of solvent, base, metal catalyst, and catalyst modifierquaternary ammonium
itself is very rapid and exothermic and proceeds within a few seconds. Thus, adequate temperature management plays an important role to keep the side reactions under control. 3.3. Condensation to EMECDFAA. The condensation with triethyl ortoformiate in the presence of acetic anhydride is well-described in literature,9 and is used “as is” in the current industrial process. The main drawback here is the use of reagents in high excess to drive the reaction to completion. This inevitably generates high amounts of haloorganic waste. During optimization of this reaction we surprisingly found that a catalytic amount of triethylamine can be used instead of acetic anhydride together with the continuous separation of liberated ethanol by destillation (Scheme 5).10 These changes generated the following advantages over the process known so far: • The reaction can be conducted at a lower temperature;
Scheme 7. Step 5
Scheme 5. Step 3
C
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Table 1. Selected screening examples of catalytic hydrodechlorination to DFMMP Pd/C modifier (eq) 1 2 3 4 5 6 7 8 a
TMAF 0.075 TMAF 0.075; CsF 0.2 CsF 0.2 N+Me4 Cl− 0.11 CsF 1 eq CsF 1 eq
solvent
base
temp. (°C)
H2 (bar)
time (h)
yield (%)
Qa
THF THF THF THF THF THF EtOH EtOH
K2CO3 K2CO3 K2CO3 K2CO3 K2CO3
110 110 110 110 110 110 110 110
11 11 11 11 11 11 11 15
1 1 1 1 1 2 4 4
97 85 94 88 63 36 65 20
32 13.6 16.5 8.2 12 7 2.2
Q = DFMMP (%)/8 (%) + 9 (%). It gives a quick comparison about reduction selectivity to DFMMP against over reduction side products 8 and 9.
fluoride (TMAF)resulted in a high yield with a high selectivity for the hydrodechlorination (Table 1).13
forerun of COCl2, pure CDFAC (bp. 27 °C). Recovered R122 was again metered into the prevaporizer using a pump. Ethyl-4-chloro-4,4-difluoro-3-oxobutanoate (ECDFAA). In a double-jacketed glass reactor, chlorodifluoroacetyl chloride (161 g, 1.08 mol) was dissolved in S365 (200 mL), and the solution was cooled to −25 °C. During 1 h and 40 min, ketene (at a rate of ca. 15 L/h) was passed through the solution of chlorodifluoroacetyl chloride. To the resulting mixture ethanol (53 g, 1.15 mol) was added, maintaining the temperature below −20 °C. The solution was warmed up to the room temperature, while extensive HCl gas evolution was observed. The reaction mixture was concentrated on a rotary evaporator under reduced pressure (30 °C, 300 mbar). The residue was further distilled over a 60 cm Vigreux column under a pressure of 10 mbar. Ethyl- 4,4-difluoro-4-chloro 3-oxobutanoate was recovered at a temperature of 50 °C as a colorless liquid. The yield was 95% of the theoretical yield, and a purity of 99% was obtained. 1 H NMR (500 MHz, CDCl3) δ: ppm (spectrum shows 1.2:1 keto/enol mixture) 1.30, 1.33 (2t, 6H), 3.78 (s, 2H), 4.25, 4.29 (2q, 4H), 5.59 (s, 1H), 12.04 (bs, 1H). Ethyl-4-chloro-2-(ethoxymethylene)-4,4-difluoro-3oxobutanoate (EMECDFAA). TEOF (606 g, 4.1 mol), ECDFAA (164 g, 0.82 mol), and triethylamine (250 mg, 2.5 mmol) were placed in a flask with a Liebig condenser suitable for vacuum destillation. The pressure was decreased to 300 mbar, and the mixture was heated to 110 °C (oil bath), resulting in a continuous removal of ethanol by distillation (vapour t ∼ 60 °C). After material consumption completed (∼3−4 h, GC: Optima delta-6, 30 m × 0.25 mm, 0.25 μm DF), the ethanolic fraction was removed. The mixture was further heated at 100 °C, slowly lowering vacuum from 300 mbar to 10 mbar whereupon excess of triethylorthoformiate was recovered in high purity for reuse. The product remains in the flask as amber-yellow oil with a purity of 99% (GC/NMR) 205 g and a yield of 97%. 1 H NMR (500 MHz, CDCl3) δ: ppm (spectrum shows 1:2 E/Z mixture) 1.25−1.35 (4 t, 6H), 4.20−4.38 (4q, 4H), 7.76 (s, 1H). Ethyl 3-(chlorodifluoromethyl)-1-methyl-1H-pyrazole4-carboxylate (CDFMMP). Into 600 mL of S365 (under N2 as inert gas) cooled to −10 °C, anhydrous methyl hydrazine (36.7 g, 0.8 mol) was dissolved. To the resulting mixture, a solution of EMECDFAA (205 g, 0.8 mol) in 100 mL of S365 was added under vigorous stirring while the reaction temperature was maintained below 0 °C. After the addition, the reaction mixture was allowed to come to room temperature. The solvent was evaporated, yielding 193 g of a yellow oil consisting of CDFMMP (88%) and ethyl 1-methyl-5clorodifluoromethyl-pyrazole-4-carboxylate (i-CDFMMP,
4. PROCESS WASTE AND CONCLUSIONS The best chemical process sooner or later will run into trouble, if proper waste management is not realized or the waste/ product ratio is strongly shifted to the left. In particular for large-scale processes, where hundreds or thousands tons of products are made, a low waste/product ratio is crucial. The Environmental Protection Agency (EPA) defined 12 principles of green chemistry,14 which should be followed by the process design, manufacturing, and safety. Following these guidelines we were able to elaborate and scale-up a synthesis route described above with a significant lower waste than the current industrial process, use of green reagents like ketene, green chemical transformations like photo oxidation, and catalytic reduction with elemental hydrogen (Table 2). Table 2. Waste comparison estimated15a waste (kg/kg product)
Solvay route from R122 to DFMMP
TFE 1 to EDFA 3
∼4.0 kg
EDFA 3 to EDFAA 4 EDFAA 4 to EMEDFAA 5 EMEDFAA 5 to DFPA 6
∼1.3 kg
R122 to CDFAC CDFAC to ECDFAA ECDFAA to EMECDFAA EMECDFAA to CDFMMP CDFMMP to DFMMP total waste
current industrial route from TFE to DFPA (Scheme 1)
estimated total waste
∼2.5 kg ∼2.3 kg
∼10 kg
waste15b (kg/kg product) 0.17 kg 0.065 kg 0.3 kg 0.71 kg 0.76 kg 2.4 kg
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EXPERIMENTAL SECTION Chlordifluoroacetyl Chloride (CDFAC). In a 400 mL exchange-shaft photolysis reactor, a mixture of R122 (from prevaporizer, T = 150 °C) and pure oxygen in a molar ratio of 1:2.2 was introduced in gaseous form at an internal reactor temperature of 100 °C. Under exclusion of moisture the mixture was simultaneously irradiated through quartz glass with a high-pressure Hg-vapor lamp TQ 718 from Heareus (700W). The condensation of the products leaving the reactor in gaseous form was carried out in a downstream condenser cooled to −60 °C (HCl and COF2 removal). Over a period of 30 min 155.9 g (920 mmol) of R122 were reacted. The conversion was 89%. The yield of CDFAC was 92.9% of theory (GC: CP-SIL-8 CB 50 m × 0.32 mm 5 μm DF) besides COCl2, CO2, and COF2 as secondary components. A subsequent fine distillation via 40 cm packed column gave, after taking off a D
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10%). The ratio was determined using GC (Optima δ-6, 30 m × 0.25 mm, 0.25 μm DF). CDFMMP can be further separated from its regioisomer by vacuum distillation or crystallization. 1 H NMR (500 MHz, CDCl3) δ: ppm 1.35 (t, 3H) 3.96 (s, 3H) 4.32 (q, 2H) 7.95 (s, 1H). Ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFMMP). Twenty grams of CDFMMP (83.8 mmol, 1 equiv), 7 g of K2CO3 (50.7 mmol, 1.2 equiv), 0.2 g of tetramethylammonium fluoride tetrahydrate (1.2 mmol, 0.014 equiv), and 1.2 g of Pd/C−5% on activated carbon were suspended in 200 mL of anhydrous THF in a hastelloy reactor stirred by a magnetic stirring bar. The reactor was purged with nitrogen, then with hydrogen, and pressurized to 8 bar. The mixture was heated up to 120 °C (takes about 15 min) while stirring (700 rpm) whereupon consumed hydrogen was added maintaining about 11 bar pressure. The mixture was stirred for 6 h at 120 °C, then cooled down to room temperature. The mixture was filtered from solids; the solids were shortly washed with THF, and the filtrate was evaporated yielding a white crystalline mass (17 g, contains 1.16% 9, 96.2% DFMMP, 2.09% 8). The crude product is further purified by crystallization, yielding 15.4 g of product with a purity of 99% (GC/NMR). 1 H NMR (500 MHz, CDCl3) δ: ppm 1.35 (t, 3H), 3.96 (s, 3H), 4.33 (q, 2H), 7.10 (t, 1H) 7.90 (s, 1 H).
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(11) Braun, M.; Jaunzems, J.; Kasubke, M. World Patent WO2012025469. (12) Braun, M.; Jaunzems, J. World Patent WO2012010692. (13) Jaunzems, J. European Patent EP2687514. (14) The 12 Principles of Green Chemistry; United States Environmental Protection Agency: Washington, DC, 2014; http://www2.epa. gov/green-chemistry/basics-green-chemistry. (15) (a) Estimated waste based on public literature, patents, and inhouse trials in pilot scale.. (b) Waste is based on DFMMP process material balance; re-isolated solvents and reagents are not considered.
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Giornal, F.; Pazenok, S.; Rodefeld, L.; Lui, N.; Vors, J.-P.; Leroux, F. R. J. Fluorine Chem. 2013, 152, 2−11. (2) Wang, T. et al. China Patent CN102115428. Yamauchi, A. et al. Japan Patent JP2008280305. Hashimoto, T. et al. World Patent WO08156104. Ohtsuka, T. et al. Japan Patents JP2012025697 and JP2013147474. (3) Buisine, O. U.S. Patent US20130131375. (4) Hughes, N. E.; Hurst, B.; Woods, T. A. U.S. Patent US20120302608. Volker, M. et al. World Patent WO2009106619. Johannes, H. U. et al. World Patent WO2007115766. Zumpe, F. L. et al. World Patent WO2011113789. Gharat, L. A. et al. U.S. Patent US20130210844. Pazenok, S. et al. U.S. Patent US20110207940. (5) During our comparative trials on Claisen condensation of EDFA and EtOAc to EDFAA, we observed a substantial decomposition of isolated and purified EDFAA by prolonged storage at room temperature. Probably, this instability could originate from a proton in the CF2 group, which allows an additional enol form. On the other hand EDFAA has a pretty high solubility in water (vice versa) and builds an azeotrope with it. Traces of water in EDFAA could catalyze decomposition even more. (6) Braun, M.; Rudolph, W.; Eichholz, K. U.S. Patents US5545298 and US5569782. (7) (a) Ullmann’s Encyclopedia of Industrial Chemistry; Ketenes; Wiley: New York, 1999; DOI: 10.1002/14356007.a15_063. (b) Georgieff, K. K. Can. J. Chem. 1952, 30, 332−347. (c) Stage, H. Chem. Zeitung 1973, 97 (2), 67−73. (8) Braun, M. World Patents WO2010094746 and WO09021987. (9) Jones, R. G. J. Am. Chem. Soc. 1951, 73 (8), 3684−3686. Jones, R. G. J. Am. Chem. Soc. 1952, 74 (19), 4889−4891. (10) Jaunzems, J. World Patent WO2013171102. E
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