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Tetramethylammonium Fluoride Tetrahydrate for Snar Fluorination of 4‑Chlorothiazoles at a Production Scale Mai Khanh Hawk,* Sarah J

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Tetramethylammonium Fluoride Tetrahydrate for Snar Fluorination of 4‑Chlorothiazoles at a Production Scale Mai Khanh Hawk,* Sarah J pubs.acs.org/OPRD Article Tetramethylammonium Fluoride Tetrahydrate for SNAr Fluorination of 4‑Chlorothiazoles at a Production Scale Mai Khanh Hawk,* Sarah J. Ryan,* Xin Zhang, Ping Huang, Jing Chen, Chuanren Liu, Jianping Chen, Peter J. Lindsay-Scott, John Burnett, Craig White, Yu Lu, and John R. Rizzo Cite This: https://doi.org/10.1021/acs.oprd.1c00042 Read Online ACCESS Metrics & More Article Recommendations *sı Supporting Information fl · ABSTRACT: This article describes the use of tetramethylammonium uoride tetrahydrate (TMAF 4H2O) for the large-scale fl · preparation of a challenging 4- uorothiazole. Commercially available TMAF 4H2O was procured on a large scale and rigorously dried by distillation with isopropyl alcohol and then dimethylformamide at elevated temperature. This method of drying provided anhydrous TMAF [TMAF (anh)] containing <0.2 wt % water and <60 ppm isopropanol. The use of TMAF (anh) was essential for production of the 4-fluorothiazole. When the chlorothiazole starting material was treated with other anhydrous fluoride sources, fl · poor conversion of the starting material or potential safety issues were observed. SNAr uorination using dried TMAF 4H2O was carried out at a 45.1 kg scale at 95−100 °C to produce 36.8 kg of 4-fluorothiazole 1b. fl fl fl fl KEYWORDS: uorination, SNAr, tetramethylammonium uoride, uorothiazole, heteroarene, anhydrous uoride ■ INTRODUCTION demonstrated that anhydrous tetrabutylammonium fluoride fl [TBAF (anh)] could be prepared in situ from tetrabutylam- The substitution of hydrogen for uorine can result in fl monium cyanide (TBACN) and hexa uorobenzene (C6F6) improved bioavailability or metabolic stability of bioactive 11 1 (Scheme 2A). This reagent was used for the room- molecules. For this reason, the number of fluorinated temperature fluorination of a variety of electron-deficient aryl heteroaromatics found in active pharmaceutic ingredients 2 chlorides and nitroarenes. A 4-fluoroimidazole was even (APIs) and agrochemicals is increasing. Despite the frequency reported in the reaction scope, suggesting that this method that fluorine is incorporated into bioactive heteroarenes, large- could be applied to synthetically challenging 4-fluoroazoles.11c scale production of these molecules remains challenging, However, this method requires expensive (C F ) and toxic particularly under mild, process-friendly conditions.3 6 6 (TBACN) as stoichiometric reagents, limiting its feasibility on One of the most common methods for the industrial-scale an industrial scale. More recently, Sanford reported the room- preparation of heteroaryl fluorides is nucleophilic aromatic temperature fluorination of electron-deficient aryl halides and substitution (S Ar).3,4 This reaction involves the substitution N nitroarenes using anhydrous tetramethylammonium fluoride of an electron-deficient aryl halide with a nucleophilic fluoride 12 Downloaded via WUXI APPTEC on April 27, 2021 at 02:19:56 (UTC). [TMAF (anh)] (Scheme 2B). This reagent is more stable source via the Meisenheimer intermediate (Scheme 1).3b The than other anhydrous tetraalkylammonium salts.13 Unlike most commonly used fluoride source for S Ar fluorination is N TBAF (anh), it cannot undergo problematic Hofmann an anhydrous alkali metal fluoride. However, the low solubility elimination as it lacks the β-protons required for E2 of alkali fluorides under anhydrous conditions often results in 14 See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. elimination. For this reason, TMAF (anh) is commercially the requirement for high temperature and long reaction time. available and can be stored in its anhydrous form under S Ar fluorination is particularly challenging when used to N ambient conditions. prepare five-membered azoles with fluorine at the 4 or 5 5 π We realized that TMAF (anh) would be an attractive position. The high -electron density at these positions reagent to use for the large-scale production of a 4- further exacerbates the requirement for forcing reaction fluorothiazole. However, even though TMAF (anh) is readily conditions,6 which can limit functional group tolerance and 7 available in gram quantities, it does not have good bulk lead to the formation of undesired impurities. In fact, there commercial availability, limiting its feasibility for use at a large are relatively few procedures of any kind that have been 15 fl 8,9 scale. To address this challenge, we have pursued an reported for the preparation of 4- uoroazoles. Moreover, approach that involves drying TMAF tetrahydrate (TMAF· many of these conditions involve the use of expensive electrophilic fluorinating reagents.9 Thus, there is a need for the development of scalable, process-friendly methods for the Received: February 4, 2021 production of five-membered fluoroarenes. Many recent reports have demonstrated that electron- fi fl de cient aromatics can undergo SNAr uorination under mild conditions if a soluble anhydrous fluoride source is − employed.10 12 For example, the pioneering work of DiMagno © XXXX American Chemical Society https://doi.org/10.1021/acs.oprd.1c00042 A Org. Process Res. Dev. XXXX, XXX, XXX−XXX Organic Process Research & Development pubs.acs.org/OPRD Article Scheme 1. SNAr Fluorination Mechanism Scheme 2. Methods for SNAr Fluorination Using Soluble, Anhydrous Nucleophilic Fluorination Table 1. SNAr Fluorination of Chlorothiazole 2a and 2b entrya anhydrous fluoride solvent temperature (scale) 2 area % 1 area % (yield) 1 CsF DMSO 130−135 °C (38 g) 2a 36.8 1a 58.5 (36%)b 2 CsF DMSO 130−135 °C (300 g) 2a 40.2 1a 48.2 (23%)b 3 TMAF (anh) (4 equiv) DMF RT 2a 100 1a ND 4 TMAF (anh) (4 equiv) DMF 100 °C 2a 100 1a 94.4 2b 12 1b 80.5 (69%)c 5 TMAF (anh) (4 equiv) DMSO 100 °C 2a 100 1a ND 6 TBAF (anh)d DMF RT 2a 100 1a ND 100 °C 2a 100 1a ND 100 °C 2b 100 1a ND 7 TMAOPh + BzF DMF 100 °C 2a 100 1a ND 8 TMACl + CsF DMSO 110 °C 2a 14.0 1a 75.8 130 °C 2b 5.0 1b 61.1 (32%)c 9 TMACl + CsF DMF 130 °C 2b 79.8 1b 20.1 aUnless otherwise stated, reactions were completed on 50 mg of chlorothiazole 2a or 2b. bYield adjusted based on the amount of fluorothiazole 1a in the crude mixture of 1a and 2a. cIsolated yield after flash column chromatography. dTBAF (anh) was prepared in situ by the reaction of TBACN and C6F6. fi 4H2O) for the production of a challenging ve-membered procedure developed by the discovery chemistry group heteroaryl fluoride (Scheme 2C). The readily available TMAF· involved the reaction of the Boc-protected chlorothiazole 2a 4H2O is rigorously dried by distillation with isopropyl alcohol with CsF in dimethyl sulfoxide (DMSO) at elevated (IPA) and then dimethylformamide (DMF) at elevated temperature (Table 1, entries 1 and 2). Unfortunately, these fl temperature to provide TMAF (anh). The SNAr uorination reaction conditions were not amenable to large-scale · using dried TMAF 4H2O was carried out at a 45.1 kg scale at production. When the reaction was completed with 38 g of 95−100 °C to produce 36.8 kg of aryl fluoride 1b. chlorothiazole 2a, the reaction mixture needed to be heated to 130−135 °C for 48 h to achieve greater than 50% conversion ■ RESULTS AND DISCUSSION (Table 1, entry 1). When the scale was increased to 300 g, the We required 35 kg of the five-membered fluoroarene 1 reaction mixture required 60 h of heating to achieve a similar (Scheme 2) as an intermediate for an API. The initial level of conversion (Table 1, entry 2). The resulting mixture of B https://doi.org/10.1021/acs.oprd.1c00042 Org. Process Res. Dev. XXXX, XXX, XXX−XXX Organic Process Research & Development pubs.acs.org/OPRD Article Figure 1. Scanning reaction calorimetry of the reaction of chlorothiazole 1b with TMACl and CsF in DMSO. The safety data were collected on a 2.0 g scale reaction using 4 equiv of TMACl and 10 equiv of CsF in 20 vol of DMSO. chlorothiazole 2a and fluorothiazole 1a could only be obtain large quantities of TMAF (anh), we began to investigate separated by supercritical fluid chromatography (SFC).16 methods to prepare it in situ. Unfortunately, when TMAF Moreover, a significant amount of decomposition was observed (anh) was prepared in situ according to the procedure of under the forcing reaction conditions, resulting in poor mass Sanford, using tetramethylammonium phenoxide (TMAOPh) balance and low yield (Table 1, entries 1 and 2). These and benzoyl fluoride (BzF), we did not see any conversion of conditions provided access to hundreds of grams of the target the starting material (Table 1, entry 7).12b We were initially fluorothiazole for preclinical development. However, the low excited to find moderate to good conversion of the starting conversion of the starting material, poor mass balance, and the material when tetramethylammonium chloride (TMACl) was need for SFC purification prompted us to investigate alternate used as a superstoichiometric phase-transfer reagent in the fl fl SNAr uorination conditions. presence of CsF as the stoichiometric uoride source in We hypothesized that a soluble, anhydrous fluoride source DMSO (Table 1, entry 8).7b,14b However, reaction calorimetry would facilitate higher conversion under milder reaction of these conditions indicated that the safety profile of this conditions. To test this hypothesis, the chlorothiazoles 2a reaction was not desirable for scaleup (Figure 1). The reaction and 2b were reacted in the presence of commercially available mixture was heated in a high-pressure Hastelloy cell from room TMAF (anh). The reaction did not proceed at room temperature to 250 °C with a temperature increase of 0.5 °C/ temperature (Table 1, entry 3). However, when the reaction min. Two exothermic peaks were observed: the first peak (with mixture was heated to 100 °C, we were delighted to see good an onset temperature of 100 °C) is likely to be the heat of the conversion of the starting material and high product area % in reaction of the desired reaction, and the second peak (onset the high-performance liquid chromatography (HPLC) chro- temperature of 193 °C) indicates the thermal decomposition matogram (Table 1, entry 4).
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