Article Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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Development of a Scalable Process for the Insecticidal Candidate Tyclopyrazoflor. Part 1. Evaluation of [3 + 2] Cyclization Strategies to 3‑(3-Chloro‑1H‑pyrazol-1-yl)pyridine Qiang Yang,*,† Xiaoyong Li,† Beth A. Lorsbach,‡ Gary Roth,† David E. Podhorez,† Ronald Ross, Jr.,‡ Noormohamed Niyaz,‡ Ann Buysse,‡ Daniel Knueppel,† and Jeffrey Nissen† †
Product Design & Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States Discovery Chemistry, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
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ABSTRACT: The evaluation of [3 + 2] cyclization strategies to prepare a key intermediate, 3-(3-chloro-1H-pyrazol-1yl)pyridine, for the insecticidal candidate tyclopyrazoflor (1) is described. Among the validated strategies, the route involving [3 + 2] cyclization of 3-hydrazinopyridine·2HCl with methyl acrylate was selected for further optimization. This route provided ready access to 3-(3-chloro-1H-pyrazol-1-yl)pyridine in three steps via cyclization, chlorination, and oxidation. Further functionalization of 3-(3-chloro-1H-pyrazol-1-yl)pyridine via nitration, reduction, and amide formation with 3-((3,3,3trifluoropropyl)thio)propanoic acid followed by ethylation rendered 1 in a total of seven steps. KEYWORDS: pyrazole, 3-(3-chloro-1H-pyrazol-1-yl)pyridine, [3 + 2] cyclization, 3-hydrazinopyridine·2HCl, methyl acrylate, agrochemicals
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INTRODUCTION To address the food security needs of the growing world population, modern agriculture must continually develop technologies that increase production.1 Especially with the continuing decrease of arable land, it is crucial to minimize crop losses due to damage from pests.2 Over the past decades, pyrazole derivatives have been actively researched for the development of agrochemicals such as fungicides, herbicides, and insecticides.3 Pyrazoles are also a common structural motif in a variety of pharmaceutical targets.4 Tyclopyrazoflor (1), a pyridinylpyrazole derivative (Figure 1), was discovered to have
indicated that 3-(3-chloro-1H-pyrazol-1-yl)pyridine (2) could serve as a key intermediate for the synthesis of tyclopyrazoflor (1). This intermediate could potentially be obtained via the [3 + 2] cyclization of 3-hydrazinopyridine·2HCl (3) or its derivatives with a variety of commercially available α,βunsaturated electrophiles such as acrylates, acrylonitriles, and maleates (Scheme 1). It was envisioned that this intermediate could be readily converted to 1 via selective nitration, reduction, and amide formation with 3-((3,3,3trifluoropropyl)thio)propanoic acid followed by ethylation. Routes 1 and 2: [3 + 2] Cyclization of 3Hydrazinopyridine·2HCl with Acrylonitriles. Acrylonitriles have been frequently used for the synthesis of pyrazoles via [3 + 2] cyclization with hydrazines.6 In our preliminary investigations, 3-amino-4,5-dihydropyrazole 5 was obtained in 74% yield when 3 was treated with acrylonitrile (4) in the presence of 3.0 equiv of sodium ethoxide (NaOEt) in ethanol (EtOH). Compound 5 was then oxidized with manganese dioxide (MnO2) in acetonitrile (MeCN) at 60 °C for 18 h to give 7 in 69% yield after column chromatographic purification (Scheme 2).7 Alternatively, compound 7 was obtained in 84% yield in one step when readily available 3-ethoxyacrylonitrile (6) was treated with 3 in the presence of 3.0 equiv of NaOEt in EtOH. The desired product was easily isolated by filtration as a white solid with high purity (>95 wt % by 1H NMR analysis) because of its low solubility in ethyl acetate (EtOAc).8 Compound 7 was subsequently converted to diazonium salt 8 by treatment with sodium nitrite (NaNO2) in hydrochloric
Figure 1. Structure of tyclopyrazoflor (1)
excellent activities against sap-feeding pests.5 To support further evaluation of this compound, the identification and optimization of scalable and cost-effective routes were keys to success of this exciting new opportunity. This report details the evaluation of several [3 + 2] cyclization strategies to prepare the key intermediate, 3-(3-chloro-1H-pyrazol-1-yl)pyridine (2).
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RESULTS AND DISCUSSION The [3 + 2] cyclization of hydrazines with α,β-unsaturated electrophiles is undeniably one of the most powerful strategies for the construction of pyrazole rings.6 Retrosynthetic analysis © XXXX American Chemical Society
Special Issue: Corteva Agriscience Received: March 22, 2019
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DOI: 10.1021/acs.oprd.9b00127 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
Scheme 1. Retrosynthetic Analysis
Scheme 2. Synthesis of 2 via [3 + 2] Cyclization of Hydrazinopyridine with Acrylonitriles
acid (HCl) between −5 and 0 °C. Diazonium salt 8 was directly added into a suspension of 1.2 equiv of copper(I) chloride (CuCl) in toluene at room temperature, which after standard aqueous workup and purification by column chromatography afforded 2 as a yellow solid in 68% yield (Scheme 2).7,8 It is worthwhile to note that no significant foaming or exotherm was observed. The major impurity was determined to be 3-(1H-pyrazol-1-yl)pyridine at 10.8% (area
under the curve, AUC) by HPLC analysis. Although these strategies afforded the desired product 2 in two or three steps in good overall yields, they were less appealing for large-scale practice because of the involvement of hazardous diazonium chemistry. Route 3: [3 + 2] Cyclization of (E)-2-(2-(Pyridin-3yl)hydrazono)acetic Acid·HCl (10) with Acrylonitrile and Methyl Acrylate. (E)-2-(2-Phenylhydrazono)acetic acid, B
DOI: 10.1021/acs.oprd.9b00127 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
Scheme 3. Synthesis of 2 via [3 + 2] Cyclization of 10 with Acrylonitrile or Methyl Acrylate
Scheme 4. Synthesis of 2 from Diethyl Maleate
aqueous lithium hydroxide (LiOH) to give acid 15, followed by decarboxylation with 0.2 equiv of copper(II) oxide (CuO) in DMF, afforded the desired product 2 in 64% yield over two steps.10 However, these routes were not further pursued because of the uncontrollable exotherms observed in the reactions of 10 with acrylonitrile and methyl acrylate in the presence of NCS. Route 4: [3 + 2] Cyclization of 3-Hydrazinopyridine· 2HCl with Diethyl Maleate. Because of their low cost and ready availability, maleates are also very attractive starting materials for the synthesis of pyrazole analogues via cyclization with hydrazines.11 Condensation of 3 with diethyl maleate (16) in the presence of 3.5 equiv of NaOEt afforded pyrazolidinone 17 in 51% yield; 17 was then treated with 1.2 equiv of phosphoryl chloride (POCl3) in MeCN at 60 °C to give 18 in 79% yield. Oxidation of 18 using 5.0 equiv of MnO2 in MeCN at 60 °C afforded 19 in 93% yield. Similar to the modifications of 14 in Scheme 3, hydrolysis of 19 followed by decarboxylation of the resulting acid 15 with CuO in DMF afforded the desired product 2 in 70% yield over two steps (Scheme 4).12 While this route successfully delivered the desired intermediate 2, we continued our investigation to identify a more concise, economical, and process-friendly route. Route 5: [3 + 2] Cyclization of 3-Hydrazinopyridine· 2HCl with 2-Methylenemalonate. Initially we planned to prepare diethyl 2-methylenemalonate (21) from diethyl
prepared from the reaction of phenylhydrazine with glyoxylic acid (9) in 20 wt % HCl, has been reported for the preparation of 2-bromopyrazole derivatives via [3 + 2] cyclization with α,βunsaturated electrophiles such as acrylonitrile and acrylates.9 It was envisioned that the corresponding 3-chloropyrazole derivatives could also be obtained following this methodology and then converted to the desired product 2 after additional modification. To this end, 3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carbonitrile (11) was obtained in 58% yield after column chromatographic purification when 10 was treated with 3.0 equiv of 4 in the presence of 2.0 equiv of N-chlorosuccinimide (NCS), 3.0 equiv of potassium bicarbonate (KHCO3), and a catalytic amount of water in EtOAc. Treatment of 11 with 1.5 equiv of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) in N,N-dimethylformamide (DMF) successfully afforded compound 2 in 93% yield (Scheme 3).10 It is worth noting that an uncontrollable exotherm was observed upon the addition of NCS to the mixture of compound 10, acrylonitrile, KHCO3, and a catalytic amount of water in EtOAc, probably caused by the polymerization of acrylonitrile. Through a similar mechanism, compound 13 was obtained in 63% yield by treating 10 with methyl acrylate in the presence of NCS, KHCO3, and a catalytic amount of water in EtOAc. Oxidation of 13 with 2.5 equiv of ceric ammonium nitrate (CAN) in a mixture of tetrahydrofuran (THF) and water afforded 14 in 52% yield. Saponification of 14 with C
DOI: 10.1021/acs.oprd.9b00127 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
Scheme 5. Attempted Synthesis of 2 via [3 + 2] Cyclization with 2-Methylenemalonate 21
Scheme 6. Synthesis of 2 via [3 + 2] Cyclization with Methyl Methacrylate (26)
malonate (20)13 and then treat it with 3 to construct the pyrazolidinone moiety 22. Subsequent chlorination, oxidation, hydrolysis, and decarboxylation would then lead to the key intermediate 2 (Scheme 5). However, initial attempts to synthesize compound 21 resulted in low yields and difficult separation caused by the unstable nature of 21. In addition, literature precedent indicated that the purification of 21 required a nonscalable fractional distillation of this highly reactive compound from a mixture of oligomeric side products under high vacuum (95% conversion after 21 h of stirring at 40 °C. Typically the desired product 29 was obtained as a light-yellow solid in >95% yield with ∼98% (AUC) purity after filtration over a pad of Celite followed by removal of solvents.14 Initial attempts to oxidize the 4-methyl group of 29 to the corresponding carboxylic acid using 2.5 equiv of sodium permanganate (NaMnO4) in 20:1 water/tert-butyl alcohol (tBuOH) at 70 °C did not afford the desired product after 24 h. We propose that this was caused by the low solubility of starting material 29 in the solvent system. When the reaction was performed using 4.0 equiv of NaMnO4 in 5:1 water/tBuOH at 80 °C, the desired product 25 was observed, but the oxidation stalled at
