Investigation of a Staudinger KeteneâImine Cycloaddition in Batch

Article pubs.acs.org/OPRD

Development of a Large-Scale Route to an MCH1 Receptor Antagonist: Investigation of a Staudinger Ketene−Imine Cycloaddition in Batch and Flow Mode Staffan Karlsson,*,† Rolf Bergman,† Christian Löfberg,† Peter R. Moore,‡ Fritiof Pontén,† Joakim Tholander,† and Henrik Sörensen*,† †

Medicinal Chemistry, Cardiovascular & Metabolic Diseases iMed, AstraZeneca R & D, Mölndal SE-431 83, Sweden Global Chemical Development, AstraZeneca R & D, Macclesfield SK10 4NX, United Kingdom

‡

S Supporting Information *

ABSTRACT: A practical large-scale route to an MCH1 receptor antagonist is described. A Staudinger β-lactam synthesis of an imine and an in situ generated ketene was utilized as a key step for the preparation of a spiro-azetidine building block. The reaction was demonstrated in both batch and flow mode and a comparison of these techniques is described.

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Staudinger lactam synthesis5 of an N-protected methyl imine 16 and the ketene generated from tetrahydrofuran-3-carbonyl chloride 14 followed by reduction of the resulting azetidinone 17 (Scheme 4).6 Thus, we planned to generate the acid chloride 14 from the easily accessible commercially available carboxylic acid 13 and use this as the crude solution in the next reaction with N-methylene-1-phenylmethanamine 16. A prerequisite was to find a clean and selective way to transform the carboxylic acid to the acid chloride as it was envisaged that use of excess reagent in the acid chloride formation may have a negative impact on the subsequent Staudinger synthesis. We found that. in the presence of a catalytic amount of pyridine, an almost stoichiometric amount of thionyl chloride as chlorinating agent was enough to give complete the conversion to desired acid chloride 14 within 90 min. The N-methylene-1-phenylmethanamine 16 required for the Staudinger synthesis was easily obtained from precursor 15 through treatment with BF3-OEt2.7 The imine was used as a freshly prepared solution in DCM, as slow decomposition was observed over time. Our initial efforts with the reaction of acid chloride 14 and imine 16 failed, and no trace of product 17 could be detected. Several attempts were made to run the reaction at different temperatures and with different orders of addition of reagents. In the event, successful reaction was achieved when all reagents were mixed at −78 to −37 °C followed by slow warming of the reaction mixture. At approximately −10 °C, a sudden and quite exothermic reaction was observed resulting in clean conversion to desired lactam 17 in good yield. Using this procedure, the reaction could be reliably performed on a 1.3 mol scale. Through three repeated syntheses on this scale, we were able to deliver >700 g of lactam 17 in 87% yield, which supported our initial needs. Despite the successful result, we were concerned about further scale-up of this reaction. In addition to the cryogenic conditions required, which are difficult to apply on a larger scale, we believed it

INTRODUCTION Melanin-concentrating hormone (MCH) receptor antagonists have been subject to extensive studies for the treatment of obesity1,2 and have resulted in many patents.3,4 During our screening program, compound 1 (Scheme 1) was identified for extended studies as an MCH1 receptor antagonist, and more than 300 g were required. First Generation Synthesis. The approach shown in Scheme 1 for the first generation synthesis of 1 was a logical choice in the sense that the attachment of amine A to fragment BCD was made as the last step through reductive amination, making the synthesis of an array of screening compounds with different terminal amines a seemingly simple task. The detailed first generation synthesis was performed as shown in Scheme 2. For scale-up purposes, the route was deemed impractical for several reasons: (a) toxic sodium cyanide was used as a catalyst for the formation of amide 3; (b) aldehyde 5 was practically insoluble in all solvents except for DCM, and its isolation by filtration took several hours, even on less than a 10 g scale; (c) HPLC purification of the poorly soluble API 1 required very large amounts of solvent; and (d) the sequence for preparation of building block 6, depicted in Scheme 3, encompassed an average yielding anion formation/alkylation of 8 at −78 °C, a hazardous OsO4-mediated oxidation of 9, an impractical DIAD (diisopropyl azodicarboxylate)-mediated Mitsunobu reaction of diol 11, and two time-consuming chromatographic purifications.

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RESULTS AND DISCUSSION Development of a Staudinger Ketene−Imine Cycloaddition for the Synthesis of Building Block 6. With a limited time frame for optimization of the first generation synthesis, we decided to focus on finding a scale-up friendly route to spiro-azetidine 6 while retaining most of our previously developed route but in a modified sequence to avoid problems associated with aldehyde 5. Our goal was to find a scalable, robust, safe, and chromatography-free synthesis. We envisioned that spiro-azetidine building block 6 could be obtained via a © XXXX American Chemical Society

Received: October 6, 2015

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DOI: 10.1021/acs.oprd.5b00319 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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Scheme 1. Retrosynthetic Strategies for the MCH1 Receptor Antagonist 1

Scheme 2. First Generation Synthesis of the MCH1 Receptor Antagonist 1

Scheme 3. First Generation Synthesis of Spiro-Azetidine 6

Scheme 4. Large Scale Synthesis of Spiro-Azetidine 6

would be difficult to control the exotherm resulting from an “all in” procedure. Also, the addition of Et3N to the acidic mixture of acid chloride 14 was highly exothermic and would be very time-consuming on a larger scale. We realized that for long-

term supply of lactam 17 an alternative strategy was required. A Staudinger synthesis in flow was considered as a safe alternative.5f,8 Reaction in flow would benefit from efficient heat transfer of the highly exothermic reaction, and the sudden B



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In batch mode, although N-methylpiperidine gave a lower yield (68%) of product 17 compared with Et3N (87%), the quality after extractions was comparable, and therefore, further time-consuming purification procedures of the crude mixture were unnecessary. Using N-methylpiperidine as the base, optimization of the Staudinger synthesis under continuous processing conditions using an in-line IR detector was then undertaken (Scheme 5). We found that lactam 17 had a specific CO IR-band (1750 cm−1) different from that of starting acid chloride 14 (1795 cm−1). Consequently, these wave numbers were used for monitoring the relative amounts of each of these components in the eluent (Figure 1). As shown in Figure 1, the Staudinger synthesis of acid chloride 14 and imine 16 was best performed at temperatures of 20 °C (at points c, g, and h). Significantly lower yield was indicated when the reaction was performed at 0 °C (at b). During the evaluated conditions, the residence time was of minor importance, although marginally higher yield of the product was indicated at lower flow rates. Furthermore, it was found that the best way to perform the reaction was to mix all of the reagents at the same time to minimize the risk of undesired side reactions. For example, premixing of acid chloride 14 with the amine base followed by reaction with imine 16 gave no product, presumably due to ketene formation followed by oligomerization. Premixing of 16 with 14 followed by mixing with the amine base was also found to be inferior for the outcome of the reaction, and premixing of the amine base with 16 resulted in regeneration of triazinane imine-precursor 15. Using the optimized conditions10 in Figure 1 at 20 °C and using a flow rate of 1 mL/min of acid chloride (1.05 M) 14, 1.31 mL/min of imine 16 (0.8 M, 1 equiv), and 0.38 mL/min of N-methylpiperidine (3 equiv), we were able to run the reaction continuously for 5 h with no interruptions. By using in-line FT-IR monitoring of the reaction, we could conclude that the yield of 17 was stable over time. However, we observed that the starting pregenerated imine 16 was not stable over time at room temperature, and therefore, this was used as an icecooled solution during the course of the reaction.11 After workup of the continuous 5 h reaction, we isolated the desired lactam in 56% effective yield. The yield is comparable to what was obtained in batch mode with N-methylpiperidine but inferior to the batch mode using Et3N (87% effective yield) as the amine base. We then searched for a method to reduce lactam 17 to the corresponding azetidine 18.12 The reducing agents BH3-DMS and LiAlH4 both resulted in a significant amount of the amino alcohol byproduct resulting from ringopening and reduction of the lactam. Instead, we turned our attention to a milder reduction of the lactam using a combination of LiAlH4 and AlCl3.13 To our delight, it was found that this method selectively gave desired azetidine 18 in good yield. Much time was then spent on finding optimal conditions for the workup and removal of Al salts. It was found that quenching with EtOAc followed by the addition of 2aminoethanol furnished a suspension of Al salts that could be removed through filtration. The reaction was run on a 500 g scale, and desired azetidine 18 could be obtained in 81% effective yield. As the crude product was obtained in high quality (90% w/w), no further purification was necessary. In the subsequent step, our plan was to remove the benzyl protecting group through conventional hydrogenation using Pd/C as catalyst. Because azetidine 6 is very hydrophilic, extractions should be avoided. Thus, after a filtration of the Pd

exotherm associated with this reaction would also be easier to control in a flow mode. Therefore, an experiment was set up in which preformed acid chloride 14 was mixed in a 0.6 mL glass chip cooled at 0 °C with preformed imine 16 (1 equiv) followed by reaction with Et3N (neat, 3 equiv) in a second 0.6 mL glass chip cooled at 0 °C. Although the lactam was obtained in good quality, the flow conditions resulted in heavy precipitation of salts that quickly blocked the glass chip and made the operation impossible. Running the reaction using more dilute conditions solved the problem with precipitation but delivered product 17 in low yield and with poor quality. In the search for a more suitable base for this reaction, six different amines that did not give rise to precipitation were identified. NMethylpiperidine was selected on the basis that it provided the required product at the highest quality as determined by 1H NMR (Table 1). Table 1. Screen of Amine Bases for the Staudinger Synthesis in Flowa

a

Conditions: acid chloride 14 and preformed imine 16 were each pumped at a rate of 1 mL/min as 0.86 M solutions in DCM. These were allowed to mix in a 0.6 mL glass reactor chip at 0 °C and then reacted in a second ice-cooled chip (0.6 mL) with the amine bases (neat, 3 equiv) followed by collection into small vials. 1H NMR (CDCl3) was recorded on the crude mixtures. C



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Scheme 5. Photo and Schematic View of the Experimental Setup

For scaling up, it was reasoned that this facile transformation may be utilized in aminolysis of oxadiazole ester 2 as a final step, thus avoiding the virtually insoluble14 and difficult to isolate aldehyde 5. Thus, intermediate aldehyde 21 containing fragments B and C (Scheme 1 and 6) was targeted as our first intermediate for large-scale synthesis. Two routes to aldehyde 21 were explored. The first route, shown in Scheme 6, gave 21 in excellent yield by alkylation of 4-hydroxybenzaldehyde with mesylate 20. Mesylate 20 was readily prepared from BOCprotected azetidin-3-ol 19 under standard conditions. However, we found an alternative route to aldehyde 21 by the aromatic nucleophilic substitution of 4-fluorobenzaldehyde with 19 in the presence of potassium hydroxide (Scheme 7). Despite a lower yield (67%) for the latter route, it was chosen for our large-scale synthesis based on facile isolation of aldehyde 21 and avoidance of the additional step of mesylation of 19. Spiroazetidine 6 was subsequently reductively alkylated with aldehyde 21 to give BOC-protected amine 22. This fragment was deprotected using TFA, and after neutralization, free amine 23 was isolated as an oil after extractive workup. The final step was accomplished by facile reaction of amine 23 with known ester 215 in MeOH. Crystalline API 1 was isolated by simple filtration of the reaction mixture. Ester 2 was easily prepared using a chromatography-free one pot procedure as shown in Scheme 8 starting from 4-methoxybenzohydrazide via in situ generated 24. Compound 24 was ring closed with thionyl chloride to give ester 2.

catalyst, we hoped to be able to use resulting product 6 in the next step without further purification. However, after screening several catalysts, such as PtO2, Pd/C, and Pd(OH)2, for this transformation under different hydrogen pressures, we found that either incomplete reactions or mixtures of products were obtained in combination with inconsistent results. Fortunately, transfer hydrogenation conditions using formic acid or salts thereof in the presence of large amounts of Pd/C catalyst selectively furnished desired product 6. The most consistent results were obtained using highly diluted ammonium formate in EtOH as a hydrogen source. Because of time constraints, this method was selected for further scale-up despite the obvious drawbacks in terms of high Pd/C loading and large reaction volume. After the reaction was complete, azetidine 6 was protected as the BOC derivative 12 to allow for aqueous washing and removal of salts. During this operation, some reaction of ammonia with BOC2O was also observed. However, this byproduct did not interfere in subsequent steps. Desired BOC-protected azetidine building block 12 was obtained in 87% effective yield (2 steps) on a 400 g scale. We found that no further purification of building block 12 was necessary (80% w/ w), and the material obtained was used as such in the following step. By treatment of 12 with 6.5 equiv of TFA, we could, after concentration, isolate compound 6 as a trifluoroacetate salt. Large-Scale Synthesis of 1. During the initial large-scale development work, it was observed that aminolysis of carboxylic ester 2 could take place without cyanide catalysis. D



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reaction by FT-IR spectroscopy in real time facilitated the optimization process.

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EXPERIMENTAL SECTION All materials were purchased from commercial suppliers and used as such without further purification. All reactions were performed under an atmosphere of nitrogen. Continuous flow reactions were performed in PFA coiled tube reactors using a Vaportec instrument (E-series) coupled to a Mettler Toledo React IR 15 instrument integrated with a DiComp (diamond) in-line flow cell. IPCs (In Process Control) were recorded either by HPLC or 1H NMR analysis of the crude reaction mixtures. Assays were determined by 1H NMR integration using benzyl benzoate or maleic acid as internal standards. High resolution mass spectrometry was performed on a QTOF 6530 instrument (Agilent), mass precision ±5 ppm. NMR measurements were performed using a Bruker Avance III spectrometer. LC/MS analyses were recorded on a Waters ZMD, LC column x Terra MS C8 (Waters) detection with an HP 1100 MSdetector diode array. 2-Benzyl-6-oxa-2-azaspiro[3.4]octan-1-one (17), Batch Mode. A 2 L 3-necked round bottomed flask was charged with carboxylic acid 13 (152 g, 1.31 mol), DCM (1.1 L), and pyridine (2.2 mL, 26 mmol). The mixture was heated to 30 °C in a water bath. Sulfurous dichloride (100 mL, 1.37 mol) was added over 10 min. The reaction temperature was maintained in the interval of 25 to 30 °C. After 90 min, 1H NMR analysis of the crude mixture indicated full conversion to the corresponding acid chloride 14. The mixture was cooled in a dry ice bath. At a reaction temperature of −72 °C, Et3N (397 g, 3.93 mol) was slowly added while keeping the reaction temperature below −50 °C. In a separate flask at 20 °C, to a solution of 1,3,5-tribenzyl-1,3,5-triazinane 15 (159 g, 0.44 mol) in DCM (250 mL) was added BF3-OEt2 (186 g, 1.31 mol) within 5 min. After 20 min of stirring, 1H NMR analysis of the crude mixture indicated full conversion to desired intermediate N-methylene-1-phenylmethanamine 16. This mixture was now slowly (15 min) added to the crude dark brown solution of acid chloride 14 above. The reaction temperature was kept below −37 °C during this addition. The mixture was slowly allowed to attain room temperature in the ice bath. When the reaction temperature reached approximately −10 °C, a rapid increase in reaction temperature to 12 °C was detected. 1H NMR analysis of the crude mixture indicated full conversion of imine 16 to desired product 17. Water (500 mL) was added, and the biphasic mixture was stirred vigorously overnight. 1H NMR analysis of the crude mixture indicated complete decomposition of an unwanted Et3N-BF3 complex. The organic layer was washed with 2 M KHSO4 solution (aq, 500 mL). Some

Figure 1. IR recording of eluent from the flow reaction as pictured in Scheme 5. Compounds 14 (1.05 M) and 16 (0.8 M) were prepared as solutions in DCM, and N-methylpiperidine was used as the neat liquid. The three solutions were mixed in a 4-way junction and then allowed to react in a 2 mL standard coil tube reactor followed by the IR detector, 75 cm tubing, a BPR (back pressure regulator), and another 32 cm tubing.9 Arrows indicate (a) 14, 1.05 M, 1 mL/min, 0 °C; (b) 14, 1 mL/min, 16, 1.31 mL/min, and N-methylpiperidine, 0.38 mL/ min, 0 °C; (c) 14, 1 mL/min, 16, 1.31 mL/min, and Nmethylpiperidine, 0.38 mL/min, 20 °C; (d) 14, 1 mL/min, 16, 1.31 mL/min, and N-methylpiperidine, 0.38 mL/min, 40 °C; (e) 14, 4 mL/ min, 16, 5.24 mL/min, and N-methylpiperidine, 1.52 mL/min, 40 °C; (f) 14, 2 mL/min, 16, 2.62 mL/min, and N-methylpiperidine, 0.76 mL/min, 40 °C; (g) 14, 1 mL/min, 16, 1.31 mL/min, and Nmethylpiperidine, 0.38 mL/min, 20 °C; and (h) 14, 0.5 mL/min, 16, 0.66 mL/min, and N-methylpiperidine, 0.19 mL/min, 20 °C.

Scheme 6. Alternative Route to Aldehyde 21

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CONCLUSIONS A convergent large-scale route to MCH1 receptor antagonist 1 was developed in 37% overall yield. Compared with the first generation synthesis, key achievements were the exclusion of chromatography in the sequence and the development of a new route to spiroazetidine 6 in which the handling of toxic and hazardous reagents were avoided. The sensitive Staudinger synthesis used for the formation of spiroazetidinone 17 was optimized in both batch and flow mode, and monitoring of the Scheme 7. Large-Scale Synthesis of 1

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Scheme 8. Synthesis of Oxadiazole Ethyl Ester 2

precipitate formed was removed by filtration. The organic layer was washed with NaHCO3 solution (aq, sat., 500 mL) and water (500 mL) followed by concentration to give the title compound as a pale brown nonviscous oil (257.6 g, 96% w/w, 87% effective yield). 1H NMR (400 MHz, CDCl3): δ 7.20− 7.38 (m, 5H), 4.42 (d, J = 15.0 Hz, 1H), 4.36 (d, J = 15.0 Hz, 1H), 4.01 (d, J = 9.3 Hz, 1H), 3.97 (d, J = 9.3 Hz, 1H), 3.83− 3.93 (m, 2H), 3.24 (d, J = 5.5 Hz, 1H), 3.20 (d, J = 5.5 Hz, 1H), 2.42 (dt, J = 7.3, 12.8 Hz, 1H), 2.11 (dt, J = 6.6, 12.8 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 170.1, 135.3, 128.8 (2 Cs), 127.9 (2 Cs), 127.7, 72.0, 68.2, 59.9, 53.6, 45.8, 32.8. HRMS (ESI): [M + H]+ m/z calcd for C13H16NO2, 218.1181; found, 218.1171. 2-Benzyl-6-oxa-2-azaspiro[3.4]octan-1-one (17), Flow Mode. Reaction performed in a continuous flow tube reactor (2 mL) coupled to an FT-IR flow cell. Under ice-cooling, Nmethylene-1-phenylmethanamine 16 was generated from 1,3,5tribenzyl-1,3,5-triazinane 15 and BF3-OEt2 (3 equiv) using the same procedure as above. The resulting imine was diluted with DCM to give a final concentration of the imine of 0.8 M. This was used freshly as an ice-cooled solution. Acid chloride 14 was prepared using the same procedure as described above and was used as a 1.05 M solution in DCM. N-Methylpiperidine was used as the amine base for the Staudinger synthesis and pumped as a neat solution. The imine (0.8 M, 1.31 mL/min), acid chloride (1.05 M, 1.0 mL/min), and N-methylpiperidine (neat, 0.38 mL/min) were mixed in a 4-way junction and then directly reacted in a 2 mL tube reactor followed by in-line recording with an FT-IR flow cell. This was followed by collection of the stream into a 2 L receiver flask equipped with a magnetic stir bar containing 600 mL of water. The back pressure regulator was set at 1.5 bar, and the temperature of the reactor was set at 20 °C. The continuous reaction was run for 295 min corresponding to 41.7 g (310 mmol) of starting acid chloride 14 consumed. The biphasic product mixture was stirred at 20 °C over the weekend followed by separation of the layers. The organic layer was extracted with KHSO4 solution (2M, 500 mL) followed by NaHCO3 (aq, sat., 300 mL) and water (200 mL). The organic layer was concentrated to give the title compound as a pale yellow nonviscous oil (44 g, 85% w/w, 56% effective yield). NMR data were in agreement with those given above. 2-Benzyl-6-oxa-2-azaspiro[3.4]octane (18). In a 10 L reactor, to a −20 °C solution of THF (2.8 L) was added in small portions AlCl3 (368.8 g, 2.76 mol). With a mantle temperature set at −5 °C, to the white suspension was slowly added a solution of LiAlH4 (1.0 M in THF, 2.72 L, 2.72 mol) over 1.5 h. The reaction temperature was kept below 3 °C during this addition. The resulting homogeneous solution was stirred at 20 °C for 1 h followed by recooling to −2 °C. With the mantle temperature set at −10 °C, a solution of 2-benzyl-6oxa-2-azaspiro[3.4]octan-1-one 17 (507.8 g, 97% w/w, 2.27

mol) dissolved in THF (0.5 L) was slowly added over 1.5 h. The reaction temperature was kept below 10 °C during this addition. After an additional 1 h of stirring at 5 °C, 1H NMR analysis indicated full conversion. With the mantle temperature set at −5 °C, the reaction was quenched by careful addition of EtOAc (311 mL) over 1.5 h. The reaction temperature was kept below 10 °C during this addition. The mixture was stirred at 5 °C for 24 h followed by cooling to 0 °C. 2-Aminoethanol (1039 g) was added over 1 h. At 10 °C, the resulting white thick suspension was stirred for 22 h followed by filtration and rinsing with THF (2 L). The filtrate was concentrated. The residue was dissolved in DCM (3 L) followed by washing with water (1.7 L). The organic layer was filtered through a Celite filter (6 μm) followed by concentration. Water present was azeotropically removed using DCM (0.5 L). This furnished the title compound as a yellow oil (414 g, 90% w/w, 81% effective yield). 1H NMR (400 MHz, MeOD): δ 7.24−7.34 (m, 5H), 3.79 (s, 2H), 3.74 (t, J = 7.0 Hz, 2H), 3.63 (s, 2H), 3.26−3.30 (m, 4H), 2.09 (t, J = 7.0 Hz, 2H). 13C NMR (MeOD, 101 MHz): δ 138.4, 129.9 (2 Cs), 129.5 (2 Cs), 128.4, 77.9, 68.3, 64.7 (2 Cs), 64.2, 42.4, 38.6. HRMS (ESI): [M + H]+ m/z calcd for C13H18NO, 204.1388; found, 204.1387. tert-Butyl 6-Oxa-2-azaspiro[3.4]octane-2-carboxylate (12). A 25 L reactor was charged with Pd/C (10% on charcoal, 390 g) followed by the addition of 2-benzyl-6-oxa-2azaspiro[3.4]octane 18 (414 g, 90% w/w, 1.83 mol) dissolved in EtOH (16.5 L). Ammonium formate (462 g, 7.33 mol) dissolved in water (4.1 L) was added, and the mixture was heated at 50 °C for 20 h. 1H NMR analysis of the crude mixture indicated >98% conversion to amine 12. To the crude mixture at 10 °C were added Et3N (555 g, 5.5 mol) and di-tert-butyl dicarbonate (583 g, 2.67 mol) in small portions over 2 h. 1H NMR analysis of the crude mixture indicated >98% conversion. The reaction mixture was filtered through a Celite filter (Seitz, K200) and rinsed with EtOH (2 × 2.5 L). The filtrate was concentrated to dryness. To the residue were added MTBE (4 L) and water (2 L). The pH of the aqueous layer was adjusted to ∼7 using 3.8 M NaOH solution. The organic layer was filtered through a Celite filter followed by concentration to give the title compound as a pale yellow oil (423 g, 80% w/w, 87% effective yield). 1H NMR (600 MHz, MeOD): δ 4.85 (s, 2H), 3.86−3.92 (m, 3H), 3.82 (s, 2H), 3.81 (t, J = 7.0 Hz, 1H), 2.15 (t, J = 7.0 Hz, 2H), 1.44 (s, 9H). 13C NMR (MeOD, 101 MHz): δ 158.0, 81.0, 79.7, 77.7, 68.4, 41.5, 38.6, 28.6. HRMS (ESI): [M + H]+ m/z calcd for C11H20NO3, 214.1443; found, 214.1448. tert-Butyl 3-Hydroxyazetidine-1-carboxylate (19). In a 5 L reactor, azetidine-3-ol hydrochloride (301 g, 2.75 mol) was dissolved in MeOH (2.25 L) and Et3N (508 mL, 3.67 mol) at 20 °C. The mixture was cooled to −17 °C, and di-tert-butyl dicarbonate (500 g, 2.29 mol) was added portion wise at a rate such that the reaction temperature was kept below −5 °C. The F



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mixture was stirred at 0 °C for 17 h and then concentrated at 40 °C to give a residue that was dissolved in EtOAc (1.6 L). The solution was washed with water (0.6 L), 10% aqueous citric acid (2 × 0.6 L), 4% aqueous NaHCO3 solution (1 L), and 8% aqueous NaHCO3. The EtOAc was removed under reduced pressure with the aid of heptane (3 × 320 mL) to give the title compound as a white solid (325.9 g, 100% w/w, 82% effective yield). 1H NMR (400 MHz, CDCl3): δ 1.46 (s, 9H), 3.83 (dd, J = 10.0, 4.4 Hz, 2H), 4.15 (dd, J = 10.0, 6.7 Hz, 2H), 4.58 (m, 1H). 13C NMR (101 MHz, CDCl3): δ 156.62, 79.89, 61.23, 59.02, 28.45. tert-Butyl 3-(4-Formylphenoxy)azetidine-1-carboxylate (21). In a 10 L reactor at a temperature of 20−25 °C, solid potassium hydroxide (86%, 313 g, 4.8 mol) was added over a 20 min period (slightly exothermic reaction) to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate 19 (343 g, 1.98 mol) and 4-fluorobenzaldehyde (248 g, 2.00 mol) in DMF (1.8 L). The mixture was stirred for 1.5 h at 20 °C whereupon MTBE (7 L) and water (1 L) were added. The organic phase was washed successively with water (3 × 1 L), 5% aqueous citric acid (200 mL), 8% aqueous NaHCO3 (200 mL), and brine (500 mL). The mixture was dried (magnesium sulfate) and concentrated to approximately 3 L followed by the addition of heptane (1 L). The mixture was stirred for 1 h at 20 °C, cooled to 0 °C, and diluted with more heptane (2 L). The suspension formed was filtered, and the crystals isolated were dried to give the title compound (369 g, 67%). 1H NMR (400 MHz, CDCl3): δ 1.45 (s, 9H), 4.03 (dd, J = 10.5, 4.1 Hz, 2H), 4.34 (m, 2H), 4.96 (tt, J = 6.4, 6.4, 4.1, 4.1 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 9.90 (s, 1H). 13C NMR (101 MHz, CDCl3): δ 190.65, 161.52, 156.04, 132.14, 130.69, 114.97, 80.05, 66.18, 56.22, 28.37. 6-Oxa-2-azaspiro[3.4]octane (6) x 2 TFA. In a 3 L reactor, tert-butyl 6-oxa-2-azaspiro[3.4]octane-2-carboxylate 12 (260 g, 80% w/w, 975 mmol) was added at a temperature of 18−20 °C to trifluoroacetic acid (600 mL) over a 30 min period. The reaction was slightly exothermic and effervescent. The temperature was increased to 25 °C, and the mixture was allowed to stir for an additional 135 min. The trifluoroacetic acid was removed by coevaporation with 3 × 1000 mL MeOH at a temperature of 35 °C to give the title compound as a bis(trifluoroacetate) pale oil (351 g, 95% w/w, 100% effective yield). 1H NMR (400 MHz, MeOD): δ 2.25 (t, J = 7.1, 7.1 Hz, 2H), 3.80 (t, J = 7.1, 7.1 Hz, 2H), 3.89 (s, 2H), 4.09 (s, 4H). 13 C NMR (101 MHz, MeOD): δ 162.41, 117.66, 77.02, 68.39, 56.39, 44.80, 38.31. tert-Butyl 3-(4-(6-Oxa-2-azaspiro[3.4]octan-2ylmethyl)phenoxy)azetidine-1-carboxylate (22). A 10 L reactor was charged with 6-oxa-2-azaspiro[3.4]octane bis(trifluoroacetate) 6 x 2 TFA (351 g, 975 mmol), EtOAc (2.5 L), and DIPEA (455 g, 3.52 mol). tert-Butyl 3-(4formylphenoxy)azetidine-1-carboxylate 21 (275 g, 991 mmol) was added portion wise over a 15 min period to give a clear solution. The mixture was cooled to 17 °C, and sodium triacetoxyborohydride (255 g, 1.2 mol) was added over a 10 min period. The reaction was slightly exothermic, and the temperature reached 27 °C during the addition. The mixture was stirred at 20 °C for 20 h. Another portion of sodium triacetoxyborohydride (54 g, 255 mmol) was added, which completed the reaction as determined by 1H NMR after another 24 h reaction time. Water (1.350 L) was added, and most of the organic solvent was removed under reduced pressure at 35 °C. Dilute acetic acid (3.66 L of a 5% aqueous

solution, 3.05 mol) was added followed by a mixture of toluene (750 mL) and heptane (750 mL). After thorough mixing, the aqueous phase had a pH of 4.81. The organic phase was removed, and the aqueous one was washed with another portion of 150 mL of toluene and 150 mL of heptane. After separation, MTBE (1000 mL) was added to the aqueous phase followed by 50% sodium hydroxide (403 g, 5 equiv) solution to give a pH of 9.5. To the aqueous phase were added another portion of MTBE (1000 mL) and sodium hydroxide (120 g 50% solution, 1.5 equiv) to give a pH of 9.74. The organic phases were pooled, dried (potassium carbonate), and then filtered through Celite. The solution was concentrated to 1.5 L and diluted to 4.5 L with heptane. The mixture was heated to 45 °C, then cooled to 5 °C over 3 h and stirred at 5 °C for 16 h. The crystals formed were isolated by filtration, washed with heptane (400 mL), and dried under reduced pressure at 25 °C to give the title compound as colorless crystals (211 g, 97% w/ w, 56% effective yield). By reworking the mother liquor and the lining of the reactor, another crop (60 g, 97% w/w, 16% effective yield) was isolated. 1H NMR (500 MHz, MeOD): δ 1.45 (s, 9H), 2.10 (t, J = 7.0, 7.0 Hz, 2H), 3.27 (dd, 4H), 3.57 (s, 2H), 3.75 (t, J = 7.0, 7.0 Hz, 2H), 3.79 (s, 2H), 3.84−3.92 (m, 2H), 4.28−4.37 (m, 2H), 4.91−4.99 (m, 1H), 6.77 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 155.91, 155.50, 130.95, 129.66, 114.22, 79.52, 77.10, 67.23, 65.45, 64.03, 62.73, 56.18, 41.29, 37.66, 28.19. HRMS (ESI): [M + H]+ m/z calcd for C21H31N2O4, 375.2284; found, 375.2296. 2-(4-(Azetidin-3-yloxy)benzyl)-6-oxa-2-azaspiro[3.4]octane (23). In a 5 L reactor, trifluoroacetic acid (860 g, 7.54 mol) was added at 30 °C over a 50 min period to a solution of tert-butyl 3-(4-(6-oxa-2-azaspiro[3.4]octan-2-ylmethyl)phenoxy)azetidine-1-carboxylate 22 (321 g, 0.84 mol) in DCM (400 mL). After 3 h of reaction time from the final addition of trifluoroacetic acid, the reaction mixture was cooled to 5 °C, and sodium hydroxide solution (1.48 L of a 6.25 M solution in water, 9.25 mol) was added portion wise (exothermic). The mixture was stirred for 15 min at 20 °C followed by extractions with DCM (250 mL + 2 × 500 mL), eventually adding MeOH (250 mL) to facilitate separation of the phases. The combined organic extracts were dried (potassium carbonate), and the solvent was removed under reduced pressure, eventually with the aid of MeOH to give the title compound as a pale oil (251.6 g, 80% w/w, 87% effective yield). 1H NMR (400 MHz, MeOD): δ 2.09 (t, J = 7.0, 7.0 Hz, 2H), 3.2−3.29 (m, 4H), 3.55 (s, 2H), 3.62−3.68 (m, 2H), 3.74 (t, J = 7.0, 7.0 Hz, 2H), 3.78 (s, 2H), 3.86−3.95 (m, 2H), 5.00 (p, J = 6.2, 6.2, 6.1, 6.1 Hz, 1H), 6.74 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H). 13C NMR (151 MHz, MeOD): δ 157.66, 131.32, 131.10, 115.60, 77.88, 71.57, 68.26, 64.54, 63.48, 54.75, 42.33, 38.58. (3-(4-(6-Oxa-2-azaspiro[3.4]octan-2-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone (1). In a 10 L reactor, ethyl 5-(4methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate 2 (182 g, 732 mmol) was added at 20 °C over 1 min to a solution of 2-(4(azetidin-3-yloxy)benzyl)-6-oxa-2-azaspiro[3.4]octane 23 (251 g 80% w/w, 732 mmol) in MeOH (2.5 L). Precipitation was evident after 5 min. After 13 h, the crystals formed were isolated by filtration and washed with MeOH (0.5 L). Drying under reduced pressure at 35 °C gave the title compound as off-tan crystals (334.6 g, 99.6% w/w, 96% effective yield). 1H NMR (400 MHz, CDCl3): δ 2.10 (t, J = 6.9, 6.9 Hz, 2H), G



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3.16−3.29 (m, 4H), 3.56 (s, 2H), 3.77 (t, J = 6.9, 6.9 Hz, 2H), 3.84 (s, 2H), 3.90 (s, 3H), 4.26−4.37 (m, 1H), 4.64 (ddd, J = 11.3, 6.2, 1.6 Hz, 1H), 4.74 (ddd, J = 10.9, 3.5, 1.5 Hz, 1H), 5.01−5.16 (m, 2H), 6.68−6.78 (m, 2H), 6.98−7.07 (m, 2H), 7.23 (d, J = 8.6 Hz, 2H), 8.06−8.14 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 165.54, 163.03, 157.28, 155.33, 153.26, 131.76, 129.90, 129.44, 115.19, 114.63, 67.48, 66.17, 64.34, 62.94, 60.92, 56.09, 55.53, 41.51, 37.89. HRMS (ESI): [M + H]+ m/z calcd for C26H29N4O5, 477.2138; found, 477.2148. Ethyl 2-(2-(4-Methoxybenzoyl)hydrazinyl)-2-oxoacetate (24). In a 5 L reactor, Et3N (304 g, 3.00 mol) was added to 4-methoxybenzohydrazide (200 g, 1.2 mol) in anisole (1.8 L). Ethyl 2-chloro-2-oxoacetate (197 g, 1.44 mol) was added over a period of 1 h. The addition was slightly exothermic. After addition, the mixture was heated and kept at 50 °C for 1 h. The mixture was used in the subsequent step without further processing or characterization. Ethyl 5-(4-Methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (2).14 At a temperature of 20 °C, thionyl chloride (174 g, 1.44 mol) was added to the reaction mixture from the preparation of intermediate ethyl 2-(2-(4-methoxybenzoyl)hydrazinyl)-2-oxoacetate 24. The temperature was increased to 95 °C. After a period of 3 h, minor amounts of intermediate 24 were still present as indicated by HPLC-MS (pH 3). Addition of more thionyl chloride (29 g, 0.24 mol) followed by continued heating at 95 °C for another 2 h completed the reaction. The mixture was cooled to 10 °C, and water (1.6 L) and magnesium sulfate (160 g) were added followed by an adjustment of the temperature to 40 °C. The phases were separated and the organic phase was washed twice with aqueous sodium carbonate (190 g dissolved in 1.6 L of water in each wash). The mixture was concentrated to 1 L, and heptane (1.6 L) was added followed by heating to 55 °C for 1 h. The mixture was cooled to 10 °C over a period of 4 h and then stirred at 10 °C for 16 h. Filtration and washing with heptane (2 × 640 mL) followed by drying under reduced pressure at 40 °C for 16 h gave the title compound as an off white solid (202 g, 99% w/w, 67% effective yield over two steps). 1H NMR (400 MHz, CDCl3): δ 1.48 (t, J = 7.1, 7.1 Hz, 3H), 3.89 (s, 3H), 4.54 (q, J = 7.1, 7.1, 7.1 Hz, 2H), 6.97−7.1 (m, 2H), 8.04−8.16 (m, 2H). 13C NMR (126 MHz, CDCl3, 30 °C): δ 166.56, 163.31, 156.22, 154.64, 129.61, 115.26, 114.79, 63.48, 55.64, 14.21.

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Process Development, Forskargatan 20J, SE-151 36 Södertälje, Sweden) and co-workers for supply and optimized synthesis protocols of ester 2.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.5b00319. 1 H NMR, 13C NMR, HRMS, and HPLC analyses (PDF)

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REFERENCES

(1) Johansson, A.; Löfberg, C.; von Unge, S.; Antonsson, M.; Hogner, A.; Hayes, M.; Judkins, R.; Ploj, K.; Benthem, B.; Lindén, D.; Fredenwall, M.; Li, L.; Persson, J.; Bergman, R. Manuscript in preparation. (2) (a) MacNeil, D. J. Front. Endocrinol. 2013, 4, 1−14. (b) Högberg, T.; Frimurer, T. M.; Sasmal, P. K. Bioorg. Med. Chem. Lett. 2012, 22, 6039−6047. (c) Luthin, D. R. Life Sci. 2007, 81, 423−440. (3) Johansson, A. Expert Opin. Ther. Pat. 2011, 21, 905−925. (4) Johansson, A.; Löfberg, C. Expert Opin. Ther. Pat. 2015, 25, 193− 207. (5) (a) Kamath, A.; Ojima, I. Tetrahedron 2012, 68, 10640−10664. and references cited therein. (b) Singh, G. S.; Sudheesh, S. ARKIVOC (Gainesville, FL, U. S.) 2014, 337−385. (c) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988−4035. (d) Fu, N.; Tidwell, T. T. Tetrahedron 2008, 64, 10465−10496. (e) Pitts, C. R.; Lectka, T. Chem. Rev. 2014, 114, 7930−7953. (f) Hafner, A.; Ley, S. V. Synlett 2015, 26, 1470−1474. (g) Allen, A. D.; Tidwell, T. T. Chem. Rev. 2013, 113, 7287−7342. (6) (a) Macías, A.; Ramallal, A. M.; Alonso, E.; del Pozo, C.; González, J. J. Org. Chem. 2006, 71, 7721−7730. (b) Alonso, E.; del Pozo, C.; González, J. Synlett 2002, 2002, 0069−0072. (c) Alonso, E.; Pozo, C. d.; Gonzalez, J. J. Chem. Soc., Perkin Trans. 1 2002, 571−576. (7) Cainelli, G.; Galletti, P.; Giacomini, D. Synlett 1998, 1998, 611− 612. (8) Generation of ketenes in flow: Henry, C.; Bolien, D.; Ibanescu, B.; Bloodworth, S.; Harrowven, D. C.; Zhang, X.; Craven, A.; Sneddon, H. F.; Whitby, R. J. Eur. J. Org. Chem. 2015, 2015, 1491− 1499. (9) Diameter pf 1 mm. (10) The reaction volume in the setup was calculated to 3.2 mL (including the IR flow cell and subsequent tubing), resulting in a residence time of 71 s. (11) Later, we have shown that in-line premixing of triazinane 15 dissolved in CH2Cl2 with BF3-OEt2 (3 equiv) at 20 °C requires only seconds of residence time to transform to the corresponding imine. Consequently, the preferred setup would include the generation of the imine in flow. (12) AstraZeneca AB; AstraZeneca UK Ltd; Preparation of azetidine derivatives for treatment of melanin related disorders. WO2013011285A1, Jan 24, 2013; p 57−59. (13) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K.; Yamashita, M.; Abe, R. J. Org. Chem. 1991, 56, 5263−5277. (14) Aldehyde 5 has medium solubility in DCM. (15) (a) Dost, J.; Heschel, M.; Stein, J. J. Prakt. Chem. (Leipzig) 1985, 327, 109−116. (b) Dost, J.; Stein, J.; Heschel, M. Z. Chem. (Stuttgart, Ger.) 1986, 26, 203−204. (c) Kumar, N. N. B.; Kuznetsov, D. M.; Kutateladze, A. G. Org. Lett. 2015, 17, 438−441.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: staff[email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank our lead optimization group for valuable discussions, our NMR specialist group for help with structure elucidation, and our Structure Analysis group for HRMS and HPLC purity analyses. Thanks are also due to Esmail Yousefi (currently at SP H


Investigation of a Staudinger KeteneâImine Cycloaddition in Batch

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