Synthesis of a CGRP Receptor Antagonist via an Asymmetric

Article Cite This: J. Org. Chem. 2019, 84, 8006−8018

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Synthesis of a CGRP Receptor Antagonist via an Asymmetric Synthesis of 3‑Fluoro-4-aminopiperidine Carmela Molinaro,†,⊥ Eric M. Phillips,*,† Bangping Xiang,*,† Erika Milczek,† Michael Shevlin,† Jaume Balsells,‡ Scott Ceglia,† Jiahui Chen,§ Lu Chen,§ Qinghao Chen,† Zhongbo Fei,† Scott Hoerrner,† Ji Qi,§ Manuel de Lera Ruiz,‡ Lushi Tan,† Baoqiang Wan,§ and Jingjun Yin† †

Process Research & Development, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States Process Research & Development, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States § STA Pharmaceutical R&D Co., Ltd., 90 Delin Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China

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‡

S Supporting Information *

ABSTRACT: A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.

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between compounds 2 and 3 and, finally, an amide coupling completes the synthesis of 1.

INTRODUCTION Migraine is a debilitating neurovascular disease that causes severe headaches often accompanied by nausea and vomiting in nearly 12% of adults worldwide.1 The main course of treatment for migraine has relied on the triptan class of 5HT1B/1D receptor agonists.2 Unfortunately, patients treated with these agents are frequently plagued by vasoconstrictive effects, and those with cardiovascular issues can be precluded from usage.3 Calcitonin gene-related peptide (CGRP) is also believed to have a role in migraines; its mechanism of action avoids the vasoconstrictor off-target effect of triptans and should, therefore, offer a significant advantage over triptans.4,5 As a part of our discovery CGRP program, compound 1 was identified as a potent CGRP receptor antagonist and was selected as a preclinical candidate (Scheme 1). We describe herein a robust, scalable, and enantioselective synthesis of 1. The molecule can be disconnected into three fragments of similar complexity: aryl bromide 2, tetrasubstituted arene 3, and chiral aminofluoropiperidine 4 (Scheme 1). The key structural component of the molecule, syn-1,2amino-fluoropiperidine 4, is prepared through two novel strategies: (1) asymmetric hydrogenation of fluoroenamide 8 and (2) a novel and sustainable enzymatic dynamic asymmetric transamination of ketone 9. Enantioenriched γlactam 6 was obtained through an enzyme-catalyzed desymmetrization of diester 7. An Ullmann coupling using a soluble Cu(I) catalyst forms the key bis-aryl ether functionality © 2019 American Chemical Society

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RESULTS AND DISCUSSION Synthesis of Piperidine 4 (Asymmetric Hydrogenation Route). Asymmetric hydrogenation has proven to be a highly robust and successful strategy for the construction of tertiary stereocenters bearing an amine functionality.6 The vicinal syn functionality of piperidine 4 rendered an asymmetric hydrogenation approach particularly attractive. Additionally, this method would allow us to employ a fluorinecontaining starting material, obviating the need for a potentially problematic stereoselective fluorination.7,8 Our success and rich experience in this field led us to believe that we could quickly identify and develop reliable hydrogenation conditions.9 Following the work of Stumpf et al.,10 we began by acylating pyridine 10 with benzoyl chloride (Scheme 2). Pyridinium formation with benzyl bromide was followed with regioselective NaBH4-mediated reduction to yield the key hydrogenation substrate, enamide 8.11 With substrate 8 in hand, we examined the desired asymmetric hydrogenation in the presence of rhodium, ruthenium, and iridium catalysts formed from a combination of 192 commercially available chiral phosphines and the Received: March 28, 2019 Published: May 24, 2019 8006

DOI: 10.1021/acs.joc.9b00569 J. Org. Chem. 2019, 84, 8006−8018

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The Journal of Organic Chemistry Scheme 1. Retrosynthetic Plan for CGRP Receptor Antagonist 1

alternative solvent, 2-MeTHF, did not undergo acid-catalyzed polymerization, mixtures of compound 12 and HBF4 in 2MeTHF formed gummy solids that proved difficult to stir. The addition of MeOH (10 vol %) was sufficient to solubilize the reaction mixture and provided similar results to THF (entry 6 vs 7). During the reaction optimization, it was observed that reactions would frequently stall with 1−10% remaining starting material 8, and an additional catalyst charge was required to achieve complete conversion. We hypothesized that free fluoride liberated during the formation of byproduct 14 was a potential catalyst poison. This was confirmed in an experiment where the addition of 10 mol % tetra-nbutylammonium fluoride resulted in a three-fold decrease of the reaction conversion.15 A number of additives were screened at 1 mol % Ru-catalyst loading in an attempt to sequester any free fluoride, with Ti(OiPr)4 providing significant enhancement in reactivity (entries 18−19).16 Under optimized conditions of 1.1 equiv HBF4·OEt2 and 2 equiv. Ti(OiPr)4, the complete conversion was obtained at 1 mol % catalyst loading (entry 10), giving 97% of compound 12 (86% ee) and only 3% of byproduct 14. With the optimal hydrogenation conditions in hand, we completed the synthesis of the amine side chain (Scheme 2). Following an optical purity upgrade (from 86% ee to 99.8% ee) via preparative supercritical fluid chromatography (SFC), we utilized Pd-catalyzed hydrogenolysis to remove the benzyl protecting group of compound 12. The secondary amine was successfully prepared using 5 mol % Pd/C under 45 psi H2 atmosphere. Subsequent reductive amination furnished piperidine 13 in 70% yield over two steps. Finally, hydrolysis of the benzamide moiety was accomplished with HCl in 87% yield to provide the bis-HCl salt of compound 4 in 28% yield over five steps. Even though the asymmetric hydrogenation protocol provided quick entry to the optically active piperidine side chain and allowed us to support preclinical studies, several challenges still remained. Synthesis of Piperidine 4 (Dynamic Asymmetric Transamination Route). With an eye toward increased sustainability of our processes, we wished to reduce the use of heavy transition metals in our long-term routes. To this end, we envisioned utilizing biocatalytic technology. Specifically, an enzyme-catalyzed dynamic asymmetric transamination (DA-

Scheme 2. Synthesis of Piperidine 4 via an Asymmetric Hydrogenation Routea

a

Conditions: (a) (1) BzCl, Et3N, tetrahydrofuran (THF), (2) BnBr, toluene, 70%. (b) NaBH4, MeOH, 0 °C, 93%. (c) (1) (COD)Ru(Meallyl)2/A108-1/HBF4·OEt2 (1:1.05:2), HBF4·OEt2, Ti(OiPr)4, 500 psi H2, 40 °C, 70%, 86% enantiomeric excess (ee). (2) Supercritical fluid chromatography (SFC) separation (IA 5 × 25 cm2, 5 μm, 15% EtOH/CO2, 400 g/min, 35 °C, 100 bar, 230 nm) 99.8% ee. (d) (1) H2, Pd/C, (5%), MeOH, (2) NaBH(OAc)3, CH2Cl2, tetrahydro-4Hpyran-4-one, 70%. (e) HCl, 87%.

corresponding metal precursors.12 Although iridium catalysts gave primarily reduction of both the olefin and the fluoride to form des-fluoro byproduct 14, rhodium and ruthenium complexes catalyzed significant conversions to the desired product 12 in up to 97% ee (see the Supporting Information). However, the reactions that were highly enantioselective also produced more of the des-fluoropiperidine 14. Since the formation of byproduct 14, which proved difficult to separate from the desired product, was minimized in the presence of ruthenium, we decided to focus our attention to the optimization of ruthenium-based systems (Table 1). The catalyst formed from (COD)Ru(Me-allyl)2 and MeOBIPHEP ligand13 (A108-1) initially provided the product in the best yield and ee in THF (entries 1−5). The reduction of the catalyst loading from 10 to 3% increased the ee from 79 to 86% while maintaining high conversion (entry 6); however, the presence of stoichiometric HBF4·OEt2 was required to avoid catalyst poisoning by the substrate14 but led to significant polymerization of the solvent and problematic isolation of the product. Although the reaction in the 8007

DOI: 10.1021/acs.joc.9b00569 J. Org. Chem. 2019, 84, 8006−8018

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The Journal of Organic Chemistry Table 1. Top Screening Results and Optimization of Asymmetric Hydrogenation of 8a

entry

Ru (mol %)

solvent

conc

1 2 3 4 5 6 7 8 9c 10d

10 10 10 10 10 3 3 1 1 1

MeOH TFE DCE EtOAc THF THF 2-MeTHFb 2-MeTHFb 2-MeTHFb 2-MeTHFb

0.02 0.02 0.02 0.02 0.02 0.2 0.2 0.2 0.2 0.2

ratio 8:12:14 61 7 0 1 1 1 1 26 15 0

12 (% ee)

36 87 95 82 94 96 97 72 82 97

3 6 5 17 5 3 2 2 3 3

60 12 43 83 79 86 88 85 86 86

Conditions: (COD)Ru(Me-allyl)2/A108-1/HBF4·OEt2 (1:1.05:2), 1 equiv HBF4·OEt2, 500 psi H2, 40 °C. b10% v/v MeOH added. c0.2 equiv Ti(OiPr)4 added. d2 equiv Ti(OiPr)4 added and 1.1 equiv HBF4·OEt2 used.

a

TA) process of α-fluoropiperidinone was identified (Scheme 3). Transaminations of ketones are well established,17,18 but no

4 through a similar approach. In addition to minimizing heavymetal usage, this route potentially offered other benefits including higher enantioselectivity and minimization of byproduct 14, which was difficult to remove through recrystallization and column chromatography. The initial DA-TA screening was performed with commercially available Codexis Inc. transaminases using pyridoxal-5′-phosphate (PLP) as the cofactor and isopropylamine as the nitrogen source.19 The screening of the panel was carried out under previously established conditions for dynamic kinetic transaminations at pH 10.5 to promote epimerization of the starting material. We were pleased to find that the initial results confirmed the feasibility of a dynamic kinetic reaction for this substrate and delivered high selectivity. All of the enzymes tested enabled access to the syn-isomer with the (R)-configuration at the amine center (Table 2). We explored both immobilized and lyophilized enzymes, and the

Scheme 3. Proposed Dynamic Kinetic Transamination

example involving α-fluoroketones has been reported. The labile, fluorine-bearing α-position would potentially allow us to simultaneously set the two desired stereocenters in one step. Building upon our internal experience with Vernakalant,18 we envisioned that we could access enantio- and diastereoenriched

Table 2. Optimization of the Dynamic Kinetic Asymmetric Transamination of 9a

entry

[9] (g/L)

ATA-303 (wt %)

pH

ratio 15:16

15 (% ee)

conv 15 + 16

1 2 3d 4d 5g 6d 7d

5 5 50 100 100 100 100

2500b 100 10 2 2 10 2

7.5e 8.5e 10.5e 10.5e 10.5e 10.5f 10.5f

5:1 16:1 10:1 19:1 15:1 12:1 14:1

93 79 82 94 94 92 94

89c 100 90 63 75 92 96

a Conditions: ATA-303, 1 g/L PLP, 0.2 M borate buffer pH 8.5, 1 M iPrNH2, 20 vol % dimethyl sulfoxide (DMSO), 45 °C, 24 h. bImmobilized ATA-303, cyclopentyl methyl ether saturated with 0.1 M KPi at pH 7.5, 45 °C, 24 h. c2 days. dATA-303, 1 g/L PLP, 0.2 M borate at pH 10.5, 1 M i PrNH2, 20 vol % DMSO, 45 °C with N2 sweep, 24 h. eInitial pH of the reaction. fpH was controlled and maintained. gATA-303, 1 g/L PLP, 0.8 M borate at pH 10.5, 1 M iPrNH2, 20 vol % DMSO, 45 °C with N2 sweep, 24 h.

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The Journal of Organic Chemistry most promising enzyme was Codexis ATA-303 (entries 1 and 2).20 Since the immobilized version of the enzyme gave the product in a lower diastereomeric ratio (dr), we decided to pursue the optimization of this reaction with the lyophilized enzyme. In this first example, 79% ee was obtained with 16:1 dr. We maximized the efficiency of the reaction by increasing the substrate loading to 100 g/L and optimized the enzyme loading to 2 wt % while still maintaining high dr 19:1 and improving the enantiomeric excess from 74% ee to 94% ee (entries 2−4). The major byproducts of this reaction were the defluorination products 17 and 18, which form with the decrease in the pH of the reaction mixture over time. Minimization of 17 and 18 was achieved by controlling and maintaining high pH (>9.5) of the mixture during the course of the reaction (entries 6−7) with a borate buffer. Furthermore, any reversibility from 15 to 9 was addressed by continuously feeding isopropylamine into the reaction and removing acetone from the reaction mixture with a sweep of nitrogen or a slight vacuum, collectively leading to an increase in conversion to the desired product (Scheme 4).

break, compound 13 was isolated in 95% yield, 99.3% ee, and 98.4% purity with ∼1% of the undesired diastereomer remaining. Finally, HCl-mediated deprotection of 13 provided 4 as the HCl salt in 95% yield. Synthesis of Lactam 6. β-Substituted lactam 6 was prepared in five steps by desymmetrization of commercially available diester 7, as shown in Scheme 5. Following the

Scheme 4. Synthesis of Piperidine 4 through Dynamic Asymmetric-Transaminase Approacha

Conditions: (a) PLE, 2 M buffer (pH = 7.0), MeOH, 10 °C, 96, 89% ee. (b) DPPA, Et3N, BnOH, 85 °C, 73%. (c) 2 M LiOH, 30 °C, 85%. (d) Quinine, CH3CN, then, HCl, 82%, 99% ee. (e) (COCl)2, CH2Cl2, 30 °C, 94%. (f) H2, 5 wt % Pd/C, CH2Cl2, 45 psi, 30 °C, 82%.

Scheme 5. Synthesis of Lactam 6a

a

protocol of Silverman,21 the initial enantioselective hydrolysis of dimethyl 3-methylglutarate (7) to the corresponding acid 21 was possible using pig liver esterase (PLE) with strict control of the pH of the reaction mixture at pH 7. This allowed for a reproducible and scalable process providing 96% yield and 89% ee of the desired (S)-acid 21. A modified Curtius rearrangement with the use of diphenylphosphoryl azide (DPPA)22 in hot BnOH, followed by hydrolysis, provided the CBzprotected intermediate 23 in 62% yield, 89% ee, and 83% purity by HPLC analysis for the two steps. Enantiomeric purity upgrade of intermediate 23 was achieved by crystallization of its quinine salt in acetonitrile (CH3CN) yielding 99% ee in 82% yield.23 Finally, lactam formation via the corresponding acid chloride, followed by hydrogenolysis, provided chiral lactam 6 in 77% yield, 99% ee, and 96% purity.24 Synthesis of Phenol 3. The preparation of phenol 3 is presented in Scheme 6. The central arene core of 3 was synthesized by alkylation of methyl 2-fluoro-5-hydroxy-4methylbenzoate (25) with iodomethane followed by radical bromination with azobisisobutyronitrile (AIBN)/N-bromosuccinimide (NBS). Approximately 25% over-bromination product was observed in the reaction mixture; this impurity was

a

Conditions: (a) ATA-303, 1 g/L PLP, 0.2 M borate at pH 10.5, 1 M PrNH2, 20 vol % DMSO, 45 °C with N2 sweep, 24 h, 66%. (b) BzCl, Et3N, 2-MeTHF, 86%. (c) TFA, 100%. (d) (1) D-Benzoyl tartaric acid. (2) 7% NaHCO3, CH2Cl2, 86%. (e) Tetrahydro-4H-pyran-4one, NaBH(OAc)3, CH2Cl2, 87%. (f) (1) L-Dibenzoyl tartaric acid, (2) 10% Na2CO3, CH2Cl2, 95%. (g) HCl, 95%. i

Using this dynamic kinetic transamination, the piperidine 4 was prepared in four steps from the enzymatic product 15 (Scheme 4). Benzoylation, followed by trifluoroacetic acid (TFA)-mediated Boc deprotection, provided 20 in 86% yield over two steps. At this point, several chiral acids were screened to upgrade the enantioselectivity and diastereoselectivity of compound 20. D-Dibenzoyl tartaric acid was selected for further development since it allowed for an ee upgrade from 92 to 96% ee and removed ∼3.5% of the undesired diastereomer. At this stage, the overall recovery after two crystallizations was 86%, and the purity was >97% by high-performance liquid chromatography (HPLC). Reductive amination with tetrahydro-4H-pyran-4-one and NaBH(OAc)3 provided 13 in 87% yield, 99% ee, and 93% purity. A second chiral acid screen was explored at this stage to try to further improve the purity profile and diastereoselectivity of 13. It was found that Ldibenzoyl tartaric acid in a mixture of acetone and THF (1:1 ratio) removed 1.7% of the undesired diastereomer with minimal loss of the product to the mother liquors. After a salt

Scheme 6. Synthesis of Phenol 3a

Conditions: (a) MeI, K2CO3, dimethylformamide (DMF), 30 °C, 94%. (b) NBS, AIBN, iPrOAc, 75 °C; (EtO)2P(O)H, iPr2EtN, i PrOAc, 30 °C, 94%. (c) KHMDS, 6, THF, −5 °C, 84%. (d) AlCl3, CH2Cl2, 40 °C, 85%. a

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different solvents. Performing the reaction in toluene increased the yield to 92% while limiting the dehalogenated side product (entry 2). Switching to CH3CN yielded 2 in 95% yield while producing only 2% of impurity 32 (entry 3). We were able to limit the formation of 32 to 0.7% while maintaining a 97% assay yield (AY)27 by using boronic ester 3128 instead as the coupling partner (entry 4). Following recrystallization from water/CH3CN, compound 2 was isolated in 87% yield and 98.5% purity. Bis-aryl Ether Synthesis. The synthesis of diaryl ethers has received much attention in the last two decades.29 We envisioned that diaryl ether 33 could be obtained through a similar C−O coupling approach between arene 3 and aryl bromide 2 (Figure 1). We started our screen with palladiumbased catalyst systems.30 Although the reactions proceeded to ∼50% conversion at 5 mol % Pd (90% conversion at 10 mol % Pd), the high catalyst loadings required for this system would have made the process prohibitively expensive on scale (see the Supporting Information). Also, the isolation of diaryl ether 33 was challenging due to the presence of numerous impurities generated in these reactions. Given our lack of success with Pd systems, we turned our attention to copper-based systems.31 Among the copper sources tested,32 CuI was selected due to its efficiency, low cost, and availability. Arylations conducted in acetonitrile were cleaner and higher yielding than those conducted in other solvents,33 and cesium carbonate was found to be the most efficient base.34,35 A set of 24 amine and ketone ligands was examined for the arylation of phenol 3 with bromide 2. The reaction performance was reported as the ratio of the product against biphenyl as the internal standard (Pdt/IS ratio). Only the 1,3-diketone ligands 2-acetylcyclohexanone (AcHXn, L1) and 2,2,6,6-tetramethylheptane-3,5-dione (TMHD, L2)36 as well as trans-N,N′-dimethylcyclohexane-1,2-diamine gave more than 10% conversion to product. Arylation of the diamine ligand led us to focus on the diketone ligands for further optimization. To further improve the solubility of the copper catalyst and reaction rates, NaI and tetrabutylammonium iodide (Bu4NI)37 were added to the reaction mixtures. The best conversion and yield were obtained (89%) when using 10 mol % of CuI, 10 mol % Bu4NI, 25 mol % TMHD, and 3 equiv of Cs2CO3 at 60 °C in CH3CN. It is noteworthy that these conditions minimized the formation of byproducts 35 and 36, resulting from the diarylation of adventitious water by 2 equiv of bromide 2 and debromination of bromide 2, respectively. The superior reaction profiles of the optimized conditions enabled the downstream processing of biaryl ether ester 2 without further purity upgrade. Saponification of the crude reaction mixture with LiOH followed by crystallization of the dicyclohexylamine salt in THF/methyl tert-butyl ether (MTBE) (1:1) provided product 34 in 78% isolated yield for two steps and 95% purity (Scheme 8). Finally, after salt breaking with 1 M HCl, amide coupling between acid 34 and amine 4 afforded the final product 1 (Scheme 8). Although hexafluorophosphate azabenzotriazole tetramethyl uronium-mediated coupling yielded product in >85%, the side products generated under these reaction conditions rendered the isolation of 1 in >97% purity by crystallization challenging. Alternatively, the use of EDC/ HOAt, without an exogenous base, afforded compound 1 in 80% yield and 98.5% purity after recrystallization from a EtOAc/heptanes mixture.

reduced to the desired product by adding diethyl phosphite following the consumption of the starting material,25 producing benzyl bromide 26 in 88% yield and 98% purity over two steps. The reaction of lactam 6 with electrophile 26 in the presence of potassium bis(trimethylsilyl)amide (KHMDS) produced the desired alkylated product in 84% yield. Finally, AlCl3-mediated deprotection of the methyl ether yielded compound 3 in 85% without any observable hydrolysis of the methyl ester. Synthesis of Aryl Bromide 2. The pyridazine side chain 2 was constructed via a pyrrolidine-promoted aldol reaction between isopropyl methyl ketone 27 and ethyl 2-oxoacetate to form the corresponding secondary alcohol. After aqueous (aq) work-up, the addition of hydrazine hydrate and heating the reaction mixture produced pyridazine 28 in 51% yield over two steps after recrystallization from a toluene/n-heptane mixture (Scheme 7). Subsequent aryl bromide formation was Scheme 7. Synthesis of Aryl Bromide 2a

a

Conditions: (a) ethyl 2-oxoacetate, pyrrolidine, AcOH, toluene, 48 °C. (b) NH2NH2·H2O, AcOH, 52 °C, 51%. (c) POBr3, CH3CN, 82 °C, 75%. (d) boronate ester 31, CH3CN/H2O, K3PO4, (dppf)PdCl2, 50 °C, 87%.

accomplished with POBr3 in CH3CN. Salt formation with HBr in iPrOAc/CH3CN (6:1) allowed for the isolation of bromopyridazine 29 in 75% yield with a significant purity upgrade from 90 to 98%. Our first attempt to affect a Suzuki coupling began by subjecting bromide 29 to boronic acid 3026 in the presence of (dppf)PdCl2 in THF. Although we successfully synthesized 2 in 81% yield, a significant amount of impurity 32 was produced (Table 3, entry 1). To obviate this challenge, we surveyed Table 3. Preparation of 2 through Suzuki Couplinga

entry

coupling partner

solvent

impurity 32d (%)

AYb (%)

IYc (%)

1 2 3 4

30 30 30 31

THF toluene CH3CN CH3CN

3.5 1.5 2.6 0.7

81 92 95 97

87

a

Conditions: 5 mol % PdCl2(dppf), K3PO4, solvent/H2O (1:3, v/v), 50 °C. bAY = assay yield, determined by reverse phase HPLC. cIY = isolated yield. d

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Figure 1. Ullmann coupling optimization.

Scheme 8. Endgame to CGRP Receptor Antagonist 1a

a Conditions: (a) 2, 10 mol % CuI·Bu4NI, 25 mol % TMHD, CH3CN, Cs2CO3; LiOH, water, 60 °C, then HCl; dicyclohexylamine, THF, MTBE, 78%, then HCl (b) 4, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), HOAt, THF/DMF (10:1), 80%.

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from commercial sources. 1H NMR spectra were recorded on a 300, 400, or 500 MHz spectrometer. Chemical shifts are reported in parts per million (ppm) from tetramethylsilane with the solvent resonance as the internal standard (DMSO-d6: δ 2.49, chloroform-d: δ 7.24). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), integration, and coupling constants (Hz). 13C NMR spectra were recorded on a 75, 100, or 125 MHz spectrometer with complete proton decoupling. Chemical shifts are reported in ppm from tetramethylsilane with the solvent as the internal reference (DMSOd6: δ 39.5, chloroform-d: δ 77.0). 19F NMR spectra were recorded on a 282 or 375 MHz spectrometer with complete proton decoupling. Chemical shifts are reported in ppm with α,α,α-trifluorotoluene added as an internal reference (δ −67). (R)-5-Methoxy-3-methyl-5-oxopentanoic Acid (21). To a reactor were charged K3PO4·3H2O (56.1 kg) and water (112 kg). The contents were mixed at room temperature (rt) for 30 min. HCl (35%, 9.1 kg) was added dropwise until the pH of the mixture was 7.0. The reaction mixture was cooled to 10−12 °C. PLE (1.39 kg) was charged, and the contents stirred for 30 min. 7 (14.1 kg) was charged to the mixture followed by MeOH (14 kg). The contents were mixed 24 h. Following consumption of 7, 35% HCl (20 kg) was added dropwise over 1 h until the pH of the mixture was pH = 2.0 and then heated to 15−20 °C. Water (42 kg) was added, followed by isopropyl acetate (IPAc) (140 kg) and isopropyl alcohol (IPA) (14 kg). The phases were cut. The aqueous layer was back-extracted with IPAc (2 × 70 kg). The combined organic layers were washed with 1 N HCl (29 kg) and concentrated to an approximate volume of 42 L. The solvent was switched to only IPAc via distillation with a final volume of ∼22 L. The desired product 21 was isolated as a 38.2 wt % IPAc solution (32.5 kg, 95.8%). Analytical data for 10:38 1H NMR (400 MHz, CDCl3) δ 3.67 (m, 3H), 2.36 (m, 5H), 1.03 (m, 3H). [α]25 D = −1.60 (c 10.02, DMSO).

CONCLUSIONS In summary, an efficient, asymmetric synthesis of 1 has been demonstrated. The overall route illustrates the positive impact chemo- and biocatalysis can have in enabling preclinical and early clinical synthesis of pharmaceutical drug candidates. The development of a robust C−O coupling using a diketone ligand enabled the formation of the penultimate intermediate 34. A first-generation asymmetric hydrogenation approach was undertaken for the preclinical delivery of piperidine 4. Fluoride liberated during the reaction was discovered to be a catalyst poison. As a result, Ti(OiPr)4 was employed as a fluoride sequestration reagent, which enabled full conversion during the hydrogenation. Moderate enantioselectivities and high catalyst loadings provided impetus to develop a more robust and sustainable synthesis of the amine side chain. In this vein, a novel dynamic kinetic resolution was developed using a transaminase. We were able to directly and simultaneously install the amine- and fluorine-bearing stereocenters. Additionally, a key biocatalytic approach was undertaken and realized to provide lactam 6. The lactam was prepared beginning with an enzymatic desymmetrization, subsequent Curtius rearrangement and ring closure provided 6. Finally, a straightforward amide coupling provided the final product 1. Eliminating the use of a heavy-metal-mediated asymmetric hydrogenation and SFC optical upgrades has made this route attractive for a more sustainable and long-term supply.

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EXPERIMENTAL SECTION

Reactions were carried out under an atmosphere of dry nitrogen unless otherwise stated. Reagents and solvents were used as received 8011

DOI: 10.1021/acs.joc.9b00569 J. Org. Chem. 2019, 84, 8006−8018

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The Journal of Organic Chemistry

z: [M + Na]+ calcd for C13H15NNaO3 256.0944; found 256.0948. [α]25 D = +1.60 (c 10.01, DMSO). (S)-4-Methylpyrrolidin-2-one (6). To a reactor was charged 24 (17.4 kg, 49 wt % in CH2Cl2, 1 equiv) followed by wet 10 wt % Pd/C (0.5 kg) and CH2Cl2 (119 kg). Purge the system with N2 (3×) and H2 (3×). The reaction mixture was stirred at 25 °C at 0.30 MPa for 8−24 h. Following the consumption of 24, the mixture was filtered and rinsed with CH2Cl2 (35 kg). The solution was concentrated to ∼9 L and solvent switched to THF. The desired product 6 was isolated as a 26.3 wt % solution in THF (2.96 kg, 83%, 98.6% ee). Analytical data for 6:39 1H NMR (400 MHz, CDCl3) δ 6.14 (br s, 1H), 3.51 (t, J = 8.4 Hz, 1H), 2.97 (dd, J = 9.3, 6.3 Hz, 1H), 2.47 (m, 2H), 1.98 (m, 1H), 1.15 (d, J = 6.4 Hz, 3H). [α]25 D = −24.11 (c 0.16, CHCl3). Methyl 4-(Bromomethyl)-2-fluoro-5-methoxybenzoate (26). To a reactor were charged DMF (55.0 kg), methyl 2-fluoro-5hydroxy-4-methylbenzoate (25) (5.8 kg, 31.5 mol), and K2CO3 (9.9 kg, 2.3 equiv). The contents were mixed at room temperature for 30 min. Iodomethane (1.20 kg, 1.6 equiv) was added. The contents were mixed for 12 h. Following consumption of 14, AcOH (2.0 kg, 0.3 equiv) was added at 10 °C over 30 min and then mixed for 7 h. Water (90 kg) was added over 1 h while maintaining the temperature between 10 and 15 °C. IPAc (54 kg) was then added. The phases were cut. The organics were washed with water (3 × 30 kg). The organics were then concentrated to an approximate volume of 30 L. IPAc (35 kg) was then charged to the reactor followed by AIBN (0.9 kg, 19 mol %) and NBS (10.8 kg, 2.07 equiv) in portions at 70 °C of 12 h. The contents were mixed for 3 h at 70 °C. Upon consumption of the intermediate, the contents were cooled to room temperature, and IPAc (28 kg) was added to the reactor followed by 7% aqueous NaHCO3 (58 kg). The phases were separated, and the organics were washed with water (2 × 80 kg). The solution was then distilled to an approximate volume of 52 L. Diethyl phosphite (4.0 kg, 0.7 equiv) was added followed by N,N-diisopropylethylamine (2.1 kg, 0.3 equiv). The contents were mixed for 10 h. IPAc (40 kg) was added to the reactor followed by water (58 kg). The phases were separated, and the organics were washed with water (58 kg). The solvent was switched to THF via distillation with a final volume of approximately 25 L. The desired product 26 was isolated as a 28 wt % THF solution (7.6 kg, 94%). Analytical data for 26: 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 5.8 Hz, 1H), 6.93 (d, J = 11.0 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 2.25 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.6 (d, J = 4.2 Hz), 155.8 (d, J = 254.0 Hz), 152.9 (d, J = 2.4 Hz), 132.7 (d, J = 8.0 Hz), 119.0 (d, J = 25.3 Hz), 118.5 (d, J = 11.4 Hz), 113.1 (d, J = 1.0 Hz), 56.2, 52.4, 26.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C10H1179BrFO3 276.9870; found 276.9873; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C10H1181BrFO3 278.9850; found 276.9856. To a reactor was charged lactam 6 (2.25 kg, 26 wt % solution in THF, 1.1 equiv) followed by THF (7.8 kg). The internal temperature was adjusted to a temperature range of −15 to −5 °C. KHMDS (5.8 kg, 1.2 equiv) was added over 2 h while maintaining the temperature below −5 °C. The contents were mixed for 1 h. Alkyl bromide 15 (1.53 kg, 6.8 mol) was added as a solution in THF (5.4 kg) over 2 h so as to maintain the temperature of the reaction between −15 and −5 °C. The contents were mixed for 1 h. Upon consumption of 15, 20 wt % aqueous NH4Cl (5.63 kg) was charged to the reactor over 30 min followed by water (7.5 kg) and EtOAc (13.5 kg). The contents were mixed for 30 min at a temperature range of 20−30 °C. The phases were settled and separated. To the organic phase was charged water (5.0 kg), and the pH of the mixture was adjusted to ∼5 with 1 M HCl. The phases were separated. The organic layer was washed with water (10.5 kg). The aqueous layer was back-extracted with EtOAc (6.8 kg). The solvent was switched to heptanes via distillation to a total volume of ∼6 L causing crystallization of the desired product. n-Heptane (8.4 kg) was added, and the contents were mixed for 18 h. The solids were collected by vacuum filtration and washed with n-heptane (2 kg). The solids were dried in a vacuum oven at 40 °C for 20 h to yield 37 (1.34 kg, 84%). The material was used as is in the next step.

Methyl (S)-4-(((Benzyloxy)carbonyl)amino)-3-methylbutanoate (22). To a reactor was charged 21 (3.62 kg, 85.7 wt % in IPAc, 1.0 equiv) followed by Et3N (2.16 kg), BnOH (2.10 kg), and toluene (8.0 kg). The mixture was heated to 75−80 °C. DPPA (5.86 kg) was added over 4 h while maintaining the temperature. The contents were mixed for 1 h, and the mixture cooled to ∼20 °C. Aqueous NaHCO3 (7%,16 kg) was added, the layers mixed and separated. The aqueous layer back-extracted twice with toluene (26.8 kg total). The combined organic layers were washed with water (31 kg) and concentrated. The desired product 22 was isolated as a 46.9 wt % toluene solution (7.8 kg, 71.3%). Analytical data for 22: 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.10 (s, 2H), 3.67 (m, 3H), 3.16 (m, 3H), 2.19 (m, 2H), 0.98 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.2, 156.7, 136.6, 128.4, 128.3, 128.1, 128.0, 127.8, 66.5, 51.5, 46.4, 38.7, 31.1, 17.6; high-resolution mass spectrometry (HRMS) (electrospray ionization-time-of-flight (ESI-TOF)) m/z: [M + H]+ calcd for C14H20NO4 266.1314; found 266.1393. [α]25 D = +0.90 (c 12.27, DMSO). (S)-4-(((Benzyloxy)carbonyl)amino)-3-methylbutanoic Acid (23). To a reactor was charged 22 (3.66 kg, 46.9 wt % in toluene, 1 equiv) followed by 2 M LiOH (2.78 kg). The contents were mixed at room temperature for 16 h. Following the consumption of 22, the layers were separated. The aqueous layer was back-extracted 3 times with MTBE (25.5 kg total). Discard the organic layers. Acidify the aqueous layer with 5 M HCl (15 kg) to pH 1−2 and extract with EtOAc (14.8 kg). Cut the layers, and wash the organic layer twice with brine (21.5 kg total). Concentrate the organic layer to ∼8 L, and the solvent switched to ACN via distillation to a final volume of ∼35 mL. The desired product 23 was isolated as a 57.1 wt % CH3CN solution (5.1 kg, 85%). ee Upgrade (Quinine Salt Formation/Salt Break). To a reactor was charged quinine (17 kg, 1.4 equiv) followed by CH3CN (600 kg), and the contents were mixed for 1 h until the solution was clear. 23 was added (9.1 kg, 63.9 wt % in CH3CN, 0.49 equiv) at 55−65 °C. Seeds were added (42 g), and the mixture stirred for 1 h. Remaining 23 (9.59 kg, 63.9 wt % in CH3CN, 0.51 equiv) was added dropwise over 1.5 h. The contents were mixed at 55−65 °C for 1.5 h and then cooled to 15−30 °C and stirred for an additional 4 h. The solids were collected by filtration and washed 3 times with CH3CN (180 kg total). To a reactor at 25 °C were charged the cake (37.4 kg) and CH2Cl2 (150 kg). HCl (1 N, 98 kg) was added in portion over 1 h and adjusted to pH 1. The mixture was stirred for 2 h, and the layers separated. The aqueous layer was back-extracted with CH2Cl2 (72 kg). The combined organic layers were washed twice with water (141 kg total). The solution is distilled to a final volume of 40 L. The desired product was isolated as a 15.6 wt % solution (9.75 kg, 82, 98.7% ee). Analytical data for 23: 1H NMR (400 MHz, CDCl3) δ 7.36 (m, 5H), 5.11 (m, 2H), 3.17 (m, 2H), 2.25 (m, 3H), 1.02 (br d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.0, 156.9, 136.5, 128.6, 66.9, 46.3, 38.8, 31.0, 17.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H18NO4 252.1158; found 252.1235; HRMS (ESITOF) m/z: [M + Na]+ calcd for C13H17NNaO4 274.1158; found 274.1055. [α]25 D = −3.46 (c 10.10, CHCl3). Benzyl (S)-4-Methyl-2-oxopyrrolidine-1-carboxylate (24). To a reactor was charged 23 (62.6 kg, 15.6 wt %) followed by CH2Cl2 (15 kg). (COCl)2 (8.0 kg) was added dropwise at 30 °C over 5 h. The contents were mixed at that temperature for 1−2 h. Following consumption of 23, water (200 mL) was added dropwise over 3 h to quench the reaction. The phases were cut. The organic layer was washed 3 times with water (90 kg total). The pH of the organic layer was adjusted to 6−7 with 7% aqueous NaHCO3 (0.6 kg). The organic layer was washed twice with water (60 kg total). The organic layer was distilled to a final volume of ∼10 L. The desired product was isolated as a 49 wt % solution in CH2Cl2 (17.45 kg, 94%). Analytical data for 24: 1H NMR (400 MHz, CDCl3) δ 7.38 (m, 5H), 5.28 (s, 2H), 5.11 (s, 1H), 3.95 (dd, J = 10.8, 7.5 Hz, 1H), 3.36 (dd, J = 10.5, 7.0 Hz, 1H), 2.41 (m, 3H), 1.15 (d, J = 6.8 Hz, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ 176.8, 173.9, 151.4, 135.3, 128.4, 128.2, 68.0, 53.4, 40.9, 31.0, 25.9, 18.9; HRMS (ESI-TOF) m/ 8012

DOI: 10.1021/acs.joc.9b00569 J. Org. Chem. 2019, 84, 8006−8018

Article

The Journal of Organic Chemistry

(2 × 12 kg). The solids were then dried under vacuum at 40 °C for 20 h to yield 28 (5.6 kg, 44%). Analytical data for 28: 1H NMR (400 MHz, CDCl3) δ 12.53 (br s, 1H), 7.22 (d, J = 9.6 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 2.90 (hept, J = 6.8 Hz, 1H), 1.22 (d, J = 7.2 Hz, 6H); 13 C{1H} NMR (100 MHz, CDCl3) δ 162.4, 153.4 132.6, 130.0, 33.3, 21.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C7H10N2O 139.0871; found 139.0865. 3-Bromo-6-isopropylpyridazine (29). To a reactor were charged CH3CN (170 kg), 28 (5.5 kg, 39.8 mol), and POBr3 (22.8 kg, 2.0 equiv). The temperature was adjusted to 25 °C, and the contents were mixed for 30 min. The contents were then heated at 80 °C for 13 h. Upon consumption of 28, the temperature was adjusted to 20 °C. The solution was then concentrated to an approximate volume of 100 L. The solvent was then switched via distillation to IPAc. Aqueous NaOH (10%, 116 kg) was added at 10 °C to bring the pH of the solution to 10. Aqueous Na2SO4 (20 wt %, 39 kg) was charged to the reactor followed by MTBE (81 kg) and celite (11 kg). The contents were mixed at 20 °C for 30 min and filtered. The cake was washed with MTBE (2 × 15 kg). The phases were settled and separated. The organic layer was washed with 20 wt % Na2SO4 (3 × 110 kg). The organics were then concentrated to ∼100 L, and the solvent was switched to IPAc via distillation. IPAc (44 kg) was then charged to the reactor followed by Ecosorb C-941 (1.7 kg), and the contents were mixed for 3 h. The solution was filtered, and the cake was washed with IPAc (3 × 13 kg). The filtrate was concentrated to approximately 150 L, and CH3CN (21.6 kg) was added. HBr (33% acetic acid solution, 10.4 kg) was added over 2 h while maintaining the temperature between 18 and 24 °C. The contents were mixed for 5 h. The solids were then collected by vacuum filtration and washed with IPAc (22 kg). The solids were charged to a reactor followed by IPAc (195 kg). The pH was adjusted to 9 with 7 wt % NaHCO3 (123 kg). The phases were then settled and separated. The organics were washed with 20 wt % Na2SO4 (3 × 85 kg). The organic layer was then concentrated to ∼100 L. IPAc (56 kg) and CH3CN (22 kg) were added to the reactor. HBr (33% acetic acid solution, 10.4 kg) was added over 2 h at 20 °C. The contents were mixed for 5 h, and the solution was filtered. The cake was washed with IPAc (22 kg). The solids were then charged to a reactor followed by IPAc (195 kg) and 7 wt % aqueous NaHCO3 (123 kg). The phases were settled and separated. The organics were washed with 20 wt % aqueous Na2SO4 (3 × 85 kg). The solvent was then switched to EtOAc via distillation, and the solution was filtered. The filtrate was concentrated to ∼30 L, and the solvent was switched to CH3CN via distillation to yield 29 (5.5 kg, 22 wt % CH3CN solution, 68%). Analytical data for 29: 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.28 (hept, J = 7.2 Hz, 1H), 1.34 (d, J = 7.2 Hz, 6H); 13 C{1H} NMR (100 MHz, CDCl3) δ 167.9, 146.2, 131.7, 127.0, 34.3, 22.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C7H1079BrN2 201.0027; found 201.0027; m/z [M + H]+ calcd for C7H1081BrN2 203.0007; found 203.0006. 3-(4-Bromophenyl)-6-isopropylpyridazine (2). To a reactor were charged 29 (5.3 kg, 22 wt % CH3CN solution, 26.4 mol), boronic ester 31 (5.7 kg, 0.77 equiv), CH3CN (11 kg), and a solution of K3PO4 (14.7 kg, 2.6 equiv) in water (26.5 kg). The mixture was sparged with argon for 1.5 h. PdCl2(dppf) (742 g, 3.8 mol %) was then added followed by sparging with argon for 30 min. The mixture was heated at 50 °C for 8 h. Upon consumption of boronic ester 20, the mixture was cooled to room temperature, and EtOAc (95 kg) and water (27 kg) were added. The phases were cut, and the organic layer was washed with 10 wt % aqueous Na2SO4 (2 × 60 kg). CH3CN was removed from the organic solution by continuous distillation with EtOAc with a final volume of approximately 20 L. EtOAc (53 kg) and Ecosorb C-941 (1.6 kg) were added. The contents were mixed for 3 h. The mixture was filtered, and the cake was washed with EtOAc (2 × 18 kg). The solution was concentrated to 30 L. The solvent was switched to CH3CN via distillation. Water (34 kg) was added dropwise over 3 h. The slurry was aged for 4 h at room temperature, and the solids were collected by filtration. The cake was washed with a 3:1 v/v H2O/CH3CN solution (43 kg). The solids were collected and dried in a vacuum oven at 45 °C for 6 h to yield 2 (4.6 kg, 82%).

Methyl (S)-2-Fluoro-5-hydroxy-4-((4-methyl-2-oxopyrrolidin-1-yl)methyl)benzoate (3). To a reactor were charged 37 (6.6 kg, 22.4 mol) and CH2Cl2 (204 kg). The contents were mixed at 25 °C for 30 min. AlCl3 (15.1 kg, 5.1 equiv) was charged in portions over 3 h while maintaining the internal temperature between 20 and 30 °C. Upon consumption of 37, the temperature was adjusted to ∼0 °C, and 2 N HCl (70 kg) was added. The phases were settled and separated. The aqueous layer was back-extracted with CH2Cl2 (56 kg). The combined organics were washed with 10 wt % aqueous NaCl (25.3 kg). The aqueous layer was back-extracted with CH2Cl2 (67 kg). The combined organics were then concentrated to ∼60 L. The solution was filtered. The solvent of the filtrate was switched to MTBE via distillation with a final volume of ∼60 L. The internal temperature was adjusted to a temperature range of 50−60 °C, and the contents were mixed for approximately 2 h. The temperature was adjusted to 20−30 °C, and n-heptane (69 kg) was added over 3 h. The contents were mixed for 2 h, and the solids were collected by vacuum filtration. The solids were washed with a 1:1 MTBE/nheptane solution (2.0 kg) followed by n-heptane (6.4 kg). The solids were then dried in a vacuum oven at 40 °C for 10 h to yield 3 (5.4 kg, 85%). Analytical data for 3: 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 7.49 (d, J = 6.3 Hz, 1H), 6.88 (d, J = 10.3 Hz, 1H), 4.31 (d, J = 2.5 Hz, 2H), 3.92 (s, 3H), 3.62 (t, J = 8.7 Hz, 1H), 3.08 (dd, J = 9.5, 6.0 Hz, 1H), 2.58 (m, 2H), 2.10 (dd, J = 16.8, 6.5 Hz, 1H), 1.12 (d, J = 6.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.6, 164.3, 154.8 (d, J = 252.1 Hz), 151.4 (d, J = 2.5 Hz), 128.2 (d, J = 7.1 Hz), 119.9, 118.9 (d, J = 11.1 Hz), 117.9 (d, J = 24.2 Hz), 55.2, 52.3, 43.0, 38.7, 26.6, 19.7; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C14H16FNNaO4 304.0956; found 304.0957. [α]25 D = +3.7 (c 12.3, DMSO, er = >99.5:0.5). 6-Isopropylpyridazin-3(2H)-one (28). To a reactor were charged toluene (32 kg) and 3-methyl-2-butanone (8.0 kg, 93 mol). The temperature was adjusted to 20 °C. To a separate reactor was charged pyrrolidine (6.6 kg, 1 equiv). The contents were adjusted to a temperature of 0 °C, and AcOH (3.3 kg, 0.6 equiv) was added while maintaining the temperature between 0 and 30 °C. The temperature was adjusted to 20 °C and mixed for 1 h. The pyrrolidine/AcOH mixture was then charged to the 3-methyl-2-butanone solution over 2 h while maintaining the temperature between 20 and 25 °C. The reactor that contained the pyrrolidine/AcOH solution was washed with toluene (8 kg), and the resulting solution was charged to the reaction solution. The contents of the reactor were then adjusted to a temperature range of 43−58 °C and mixed for 2 h. Glyoxylate ethyl ester (50 wt % toluene solution, 26.6 kg, 1.4 equiv) was added over 11 h. The contents were mixed at 43−48 °C for 14 h. Upon consumption of 3-methyl-2-butanone, the reaction was cooled to 20 °C. Aqueous NaCl (25 wt %, 54 kg) was added, and the contents were mixed for 30 min. The phases were settled and separated. The aq layer was back-extracted with toluene (3 × 63 kg). The combined organics were concentrated to an approximate volume of 50 L. Hydrazine hydrate (6.96 kg, 2.3 equiv) was added to a separate reactor and cooled to 0 °C under a N2 atmosphere. AcOH (16.7 kg, 3.0 equiv) was added to the hydrazine hydrate while maintaining the temperature below 30 °C. The contents were mixed for 1 h at 20 °C. The hydrazine/AcOH solution was then added to the reaction mixture over 1 h. The contents were then heated to ∼50 °C and mixed for 10 h. Upon consumption of the aldol intermediate, the reaction was cooled to 20 °C. The solution was then washed with 25 wt % aqueous NaCl (54 kg). The aqueous layer was back-extracted with a mixed solvent solution of 3.2 wt % CH3CN in EtOAc (2 × 70 kg). The combined organics were then concentrated to an approximate volume of 60 L. The solution was then switched to toluene until CH3CN and EtOAc were undetectable and AcOH was present at 3.4%. Toluene (233 kg) was added to the reactor followed by Ecosorb C-941 (4.0 kg). The contents were mixed for 2 h. The solution was then filtered, and the cake was washed with toluene (32 kg). The filtrate was concentrated to an approximate volume of 25 L. n-Heptane (12 kg) was added over 3 h. The contents were mixed for ∼3 h at 20 °C. The solids were then collected by vacuum filtration, and the cake was washed with a 1:1 v/v solution of n-heptane/toluene 8013

DOI: 10.1021/acs.joc.9b00569 J. Org. Chem. 2019, 84, 8006−8018

Article

The Journal of Organic Chemistry Analytical data for 2: 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 3.35 (hept, J = 6.8 Hz, 1H), 1.42 (d, J = 7.2 Hz, 6H); 13 C{1H} NMR (100 MHz, CDCl3) δ 167.1, 156.4, 135.4, 132.1, 128.3, 125.1, 124.3, 123.8, 34.6, 22.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H1379BrN2 277.0340; found 277.0477; m/z calcd for C13H1381BrN2 279.0320; found 279.0457. N-(3-Fluoropyridin-4-yl)benzamide (38). To a three-neck round-bottom flask equipped with an overhead stirrer were charged 3-fluoropyridin-4-amine (130 g, 1.16 mol), THF (875 mL), and Et3N (245 g, 2.09 equiv). The internal temperature was adjusted to 3 °C. Benzoyl chloride (156 mL, 1.16 equiv) was dissolved in THF (225 mL) and added dropwise to the pyridine solution while maintaining the temperature of the solution to less than 15 °C. After 4 h, the material filtered, and the cake washed with THF (1 L) and EtOAc (2 L). The solution was then concentrated. The solids were transferred to a four-neck round-bottom flask equipped with an overhead stirrer, reflux condenser, and addition funnel. The solids were diluted with EtOAc (800 mL), and the internal temperature was adjusted to 65 °C. Hexanes (350 mL) were added, and the solution was removed from the heat. As the mixture cooled, hexanes (350 mL) were added over 1 h. After reaching room temperature, the slurry was cooled to 0 °C and aged for 2 h. The solids were collected by vacuum filtration, and the cake was washed with hexanes (500 mL). The solids were dried under N2 sweep to yield 38 as off white, slightly brown needles (186 g, 74%). The material was used as is in the next step. Analytical data matched the previously reported data. 4-Benzamido-1-benzyl-3-fluoropyridin-1-ium Bromide (11). To a four-neck round-bottom flask equipped wih an overhead stirrer and reflux condenser were charged N-(3-fluoropyridin-4-yl)benzamide (38, 180 g, 833 mmol) and toluene (1.4 L). Benzyl bromide (139 mL, 1.4 equiv) was added, and the internal temperature was adjusted to 90 °C with a heating mantle. As the reaction progresses, a thick slurry is produced. After aging for 20 h, the solution was cooled to rt, and MTBE (1 L) was added. The solids were collected by vacuum filtration, and the cake was washed with MTBE (1.5 L). The solids were dried under N2 sweep to yield pyridinium 11 as a white solid (305 g, 95%). Analytical data for 11: 1 H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H), 9.73 (dd, J = 6.0, 1.2 Hz, 1H), 9.08 (dd, J = 7.0, 1.0 Hz, 1H), 8.77 (t, J = 7.3 Hz, 1H), 8.01−7.98 (m, 2H), 7.74−7.41 (m, 8H), 5.87 (s, 2H); 13C{1H} NMR (75 MHz, DMSO-d6) 167.2, 150.1 (d, J = 253.7 Hz), 142.3, 142.3, 142.1, 142.0, 134.3, 133.8, 133.3, 132.5, 19.3, 129.1, 128.8, 128.8, 128.5, 118.16, 118.14, 61.9; 19F NMR (376 MHz, CDCl3) δ −133.43; HRMS (ESI-TOF) m/z: [M] calcd for C19H16FN2O 307.1241; found 307.1251. N-(1-Benzyl-5-fluoro-1,2,3,6-tetrahydropyridin-4-yl)benzamide (8). To a 5 L reactor with an overhead stirrer were charged pyridium 11 (295 g, 763 mmol) and MeOH (2.28 L). The internal temperature was adjusted to 0 °C, and NaBH4 was added in portions over 30 min to maintain the temperature below 9 °C. The reaction was aged for 30 min. Saturated aqueous NH4Cl (1 L) was added, and the mixture was aged for 1 h at 0 °C. Saturated aqueous NaHCO3 was then added, and the mixture was aged for an additional hour. The mixture was warmed to room temperature, and the methanol was removed under vacuum. The aqueous layer was then extracted with EtOAc (2 L). The phases were cut, and the aqueous layer was back-extracted with EtOAc (500 mL). The combined organics were washed with water (400 mL) and brine (500 mL). The organics were dried over Na2SO4 and filtered through 750 g of SiO2. The SiO2 was washed with EtOAc (1.5 L). The solution was concentrated and then purified by column chromatography in three portions using 1.5 kg of SiO2 prepacked columns with a gradient of 10−100% EtOAc in heptanes. The fractions containing product were combined and concentrated to yield 8 as a light yellow solid in >95% purity (220 g, 93%). Analytical data for 8: 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 5.4 Hz, 2H), 7.54−7.26 (m, 9H), 3.68 (s, 2H), 3.18 (s, 2H), 2.92−2.90 (m, 2H), 2.72 (t, J = 4.2 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.4, 145.0 (d, J = 251.0 Hz), 137.6, 134.5, 131.9, 129.0, 128.7, 128.4, 127.4, 127.1, 114.0 (d, J = 5.0 Hz),

61.9, 51.1, 50.7, 49.6, 25.7; 19F NMR (376 MHz, CDCl3) δ −128.61; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19FN2O 311.1559, found 311.1570. N-((3S,4R)-1-Benzyl-3-fluoropiperidin-4-yl)benzamide (12). Catalyst Solution. In a glovebox, SL-A108-1 (5.26 g, 3.15 mol %), (COD)Ru(Me-allyl)2 (2.95 g, 3 mol %), and CH2Cl2 (37 mL) were charged in a visually clean 250 mL round-bottom flask. After mixing for 15 min, HBF4·OEt2 (3.25 mL) and CH2Cl2 (30 mL) were added. To a 2 L, visually clean bottle were charged enamide 8 (95.5 g, 308 mmol), 2-MeTHF (700 mL), and MeOH (117 mL). The contents were mixed until solids dissolved. HBF4·OEt2 (57.8 g, 1.16 equiv) and Ti(OiPr)4 (175 g, 2 equiv) were added. The solution was combined with 23 mL of the catalyst solution in an autoclave and purged with N2 3 times. The reaction mixture was then purged with H2 gas 3 times and pressurized with H2 (500 psi). The contents were adjusted to 40 °C and mixed for 72 h. The mixture was then concentrated to approximately 500 mL and diluted with EtOAc (1.5 L) in a 5 L reactor equipped with an overhead stirrer. Potassium glycolate (322 mL, 5 M, 5 equiv) and K2CO3 (579 mL, 10 wt %) were added, and the contents were mixed for 2 h. The phases were settled and separated. The aqueous layer was back-extracted with EtOAc (2 × 1 L). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on a 1.5 kg of SiO2 prepacked column with an eluent gradient of 5− 30% EtOAc in CH2Cl2. The fractions containing product were combined and concentrated. The residue was further purified by Prep-SFC (column: IA 5 × 25 cm2, 5 μm, mobile phase: 25% EtOH/ CO2, flow rate: 250 mL/min, oven temp: 35 °C). The desired compound 12 (67 g, 70%) was obtained as a white solid in >97% purity. Analytical data for 12: 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 9.0 Hz, 2H), 7.53−7.25 (m, 8H), 6.42 (d, J = 8.7 Hz, 1H), 4.75 (d, J = 49.5 Hz, 1H), 4.26−4.15 (m, 1H), 3.61 (dd, J = 18.0, 13.2 Hz, 2H), 3.28−3.21 (m, 1H), 2.95 (dd, J = 11.5, 1.9 Hz, 1H), 2.38−2.17 (m, 2H), 1.99−1.83 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 166.9, 137.6, 134.2, 131.7, 129.0, 128.6, 128.3, 127.2, 127.0, 88.7 (d, J = 176.2 Hz), 87.5, 62.7, 55.6 (d, J = 18.6 Hz), 51.5, 48.7 (d, J = 18.1 Hz), 27.1; 19F NMR (282 MHz, CDCl3) δ −201.19; HRMS (ESITOF) m/z: [M + H]+ calcd for C19H21FN2O 313.1716; found 313.1722; [α]25 D = −56.2 (c 0.5, MeOH). N-((3S,4R)-3-Fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin4-yl)benzamide (13). To a 2 L vessel were charged 12 (47 g, 151 mmol) in MeOH (940 mL) and 5% Pd/C (39 g). The vessel was purged with H2 3 times. H2 was then charged to a pressure of 45 psi, and the temperature was adjusted to 35 °C. After 6 h, the starting material was consumed, and the reaction mixture was filtered through a small pad of celite. The cake was washed with CH2Cl2 (200 mL), and the filtrate was concentrated to dryness and used without further purification. To a 1 L round-bottom flask equipped with an overhead stirrer and internal temperature probe were charged crude piperidine (26.7 g, 120 mmol) and CH2Cl2 (400 mL). Tetrahydro-4H-pyran-4-one (13.2 g, 1.1 equiv) was then added. NaHB(OAc)3 (31.0 g, 1.22 equiv) was added portion wise over 30 min to ensure that the reaction did not exceed 27 °C. The reaction mixture was aged overnight at a temperature range of 21−26 °C. Upon consumption of the piperidine starting material, 5 wt % aqueous K2CO3 was added. An additional 8.8 g of K2CO3 was added to bring the pH of the aqueous layer to 10. The layers were separated. The organic phase was dried over MgSO4, filtered, and concentrated. The solids were dissolved in CH2Cl2 and purified by column chromatography on a 750 g SiO2 column with 0− 17% MeOH in CH2Cl2 as an eluent. The fractions containing product were combined and concentrated to yield 13 as a white solid in 98% purity (32.4 g, 70%). Characterization of 13 is described below. tert-Butyl (3S,4R)-4-Amino-3-fluoropiperidine-1-carboxylate (15). The two following solutions were prepared in advance of running the reaction: Solution 1 (0.8 M sodium borate containing 1 M isopropylamine at a final pH of 10.5): Sodium tetraborate decahydrate (7.6 g) was dissolved in deionized water (100 mL) at room temperature. The pH of the solution was ∼9.5. To this solution was added neat 8014

DOI: 10.1021/acs.joc.9b00569 J. Org. Chem. 2019, 84, 8006−8018

Article

The Journal of Organic Chemistry

sulfate and concentrated under reduced pressure to afford 20 as a white solid (0.8 g, 80% yield). Analytical data for 20: 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.2 Hz, 2H), 7.53−7.42 (m, 3H), 6.45 (d, J = 8.0 Hz, 1H), 4.71 (d, J = 50.4 Hz, 1H), 4.38−4.17 (m, 1H), 3.39−3.22 (m, 1H), 3.17−3.12 (m, 1H), 2.92−2.70 (m, 2H), 1.88− 1.84 (m, 1H), 1.72−1.67 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.7, 134.2, 131.7, 128.6, 126.9, 88.8 (d, J = 171.4 Hz), 49.3 (d, J = 20.5 Hz), 48.8 (d, J = 18.4 Hz), 44.8, 28.6; 19F NMR (376 MHz, CDCl3) δ −204.99; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H15FN2O 223.1246; found 223.1250. [α]25 D = +71.8 (c 0.5, MeOH). N-((3S,4R)-3-Fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin4-yl)benzamide (13). To a three-neck round-bottom flask were charged 20 (0.62 g, 2.79 mmol), tetrahydro-4H-pyran-4-one (559 mg, 2 equiv), and NaBH(OAc)3 (1.06 g, 1.8 equiv) in CH2Cl2 (6.2 mL). The reaction mixture was stirred at room temperature for 18 h. Aqueous Na2CO3 (5%) was then added dropwise until pH 8. The aqueous layer was extracted with CH2Cl2 (8 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The solid obtained was slurried with nheptane, filtered, and dried in an oven under vacuum. 13 was isolated as a white solid (0.76 g, 86, 99% ee). ee and Purity Upgrade (L-Benzoyl Tartaric Acid Salt Formation/ Salt Break). To a round-bottom flask were charged THF (7 mL), acetone (7 mL), and a solution of 13 (750 mg) in THF (4 mL) and acetone (4 mL). The reaction mixture was heated at 60 °C with heating mantle, and a solution of L-dibenzoyl tartaric acid in solvent (THF/acetone = 1:1) was added dropwise. The reaction mixture was stirred for 5 h at ∼60 °C, then cooled to 0 °C, and stirred for 10 h. The slurry was filtered to obtain the salt. To a round-bottom flask were charged 10% aqueous Na2CO3, CH2Cl2 (45 mL), and the wet cake. The mixture was stirred at ∼30 °C for 2 h. The phases were separated, and the aqueous layer was extracted 3 times with CH2Cl2. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to afford 13 as a white solid in >97% purity (0.58 g, 80, 99.4% ee). Analytical data for 13: 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.53−7.42 (m, 3H), 6.40 (d, J = 8.4 Hz, 1H), 4.80 (d, J = 49.6 Hz, 1H), 4.29−4.12 (m, 1H), 4.03 (dd, J = 11.0, 3.8 Hz, 2H), 3.41−3.28 (m, 3H), 3.03−2.99 (m, 1H), 2.60−2.37 (m, 3H), 1.95−1.89 (m, 2H), 1.76−1.73 (m, 2H), 1.66−1.58 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.9, 134.2. 131.7, 128.3, 126.9, 88.7 (d, J = 176.2 Hz), 67.5, 67.5, 60.5, 51.8 (d, J = 18.6 Hz), 49.0 (d, J = 18.0 Hz), 47.6, 29.1 (d, J = 18.0 Hz), 27.4; 19F NMR (376 MHz, CDCl3) δ −200.38; HRMS (ESITOF) m/z: [M + H]+ calcd for C17H23FN2O2 307.1822; found 307.1819. [α]25 D = +55.2 (c 0.4, MeOH). (3S,4R)-3-Fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin-4amine Bis-HCl Salt (4). To a round-bottom flask were charged 13 (0.4 g, 1.306 mmol), 12 N HCl (3 mL). The reaction mixture was heated at 100 °C in an oil bath and stirred for 24 h. The reaction mixture is cooled to ∼25 °C and filtered. The cake was washed with water, and the aqueous layer was extracted with EtOAc. The organic layer was concentrated under reduced pressure, and IPA was added. The slurry is stirred for 1 h and filtered. The cake was washed with IPA and dried to provide 4 in >97% purity (0.3 g, 90, >99.5% ee). Analytical data for 4: 1H NMR (300 MHz, DMSO-d6) δ 5.32 (d, J = 49.6 Hz, 1H), 4.08−3.90 (m, 3H), 3.88−3.27 (m, 7H), 2.36−2.25 (m, 2H), 2.10−2.02 (m, 2H), 1.89−1.70 (m, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 85.4 (d, J = 178.7 Hz), 65.9, 62.71, 49.3 (d, J = 18.6 Hz), 47.1, 46.9, 27.4, 26.9, 25.9, 22.2; 19F NMR (282 MHz, CD3OD) δ: −203.78; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C10H19FN2O 203.1559; found 203.1566. [α]25 D = +19.4 (c 0.5, MeOH). (S)-2-Fluoro-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4methyl-2-oxopyrrolidin-1-yl)methyl)benzoic Acid (34). A 300 mL three-neck flask equipped with an overhead stirrer and reflux condenser was charged with 2,2,6,6-tetramethylheptane-3,5-dione (0.819 g, 0.25 equiv) and 20 mL of CH3CN. CuI·Bu4NI (0.995 g, 10 mol %) was charged followed by 2 (5.91 g, 1.2 equiv) and 3 (5.0 g, 17.8 mmol). Cs2CO3 (17.4 g, 3 equiv) was added in one portion.

isopropylamine (4.25 mL) bringing buffer to 0.5 M isopropylamine. The pH was >11.0. The pH of the solution was adjusted to pH 10.5 using concentrated HCl. The solution was cooled to room temperature, and the pH was readjusted to 10.5. Let the buffer cool to rt and checked the pH before dissolving PLP and enzyme. Solution 2 (8.0 M aqueous isopropylamine was prepared for pH control): Isopropylamine (68 mL) was dissolved in deionized water (32 mL). To a reactor were added pyridoxal-5-phosphate (30 mg, 13.81 mmol) and ATA-303 (60 mg, 2.000 μmol) in 0.8 M sodium borate and 1 M isopropylamine at a final pH of 10.5 (24 ml) at room temperature. The solids slowly went into the solution with gentle overhead stirring, and the solution turned bright yellow. The solution was not heated while the enzyme dissolved. After the enzyme went into the solution, the stirring was increased. In a small vial, 9 (3 g, 13.81 mmol) was dissolved in DMSO (6 mL). This solution was then added dropwise to the yellow enzyme solution at room temperature over 7 min while heating and maintaining the solution at 45 °C. The pH was adjusted to pH 10.5 using 8 M isopropylamine. The reaction stirred overnight, and a pH control was used to maintain pH 10.5 by adding 8.0 M isopropylamine. The reaction vessel was placed under vacuum to remove the iPrNH2. MeTHF (30 mL) was added to the reaction followed by 10% brine (20 mL) and methanol (10 mL). The phases were separated, and the aqueous layer was back-extracted with MeTHF (15 mL). The combined organic layers were concentrated. The desired product was isolated as an orange oil (7.52 g, 66%, 15:1 dr, 96% ee). Analytical data for 15: 1H NMR (300 MHz, CDCl3) δ 4.57 (d, J = 47.7 Hz, 1H), 4.31−4.06 (m, 2H), 3.09−2.83 (m, 3H), 1.83 (s, 2H), 1.69−1.67 (m, 2H), 1.50 (s, 9H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 154.7, 90.6 (d, J = 174.8 Hz), 79.2, 50.4 (d, J = 19.5 Hz), 29.9, 28.5; 19F NMR (376 MHz, CDCl3) δ −205.73, −206.00; HRMS (ESI-TOF) m/z: [M + H − Boc + H] calcd for C10H19FN2O2 119.0987; found 119.0996; [α]25 D = +26.4 (c 0.5, MeOH). tert-Butyl (3S,4R)-4-Benzamido-3-fluoropiperidine-1-carboxylate (19). In a three-neck round-bottom flask were charged 15 (1.15 g, 5.27 mmol), 2-MeTHF (11 mL), and Et3N (0.90 g, 8.9 mmol). The reaction mixture was cooled to ∼5 °C and stirred at that temperature for ∼30 min. BzCl was added dropwise and then the mixture was stirred at ∼25 °C for 15 h. The resulting solution was washed twice with 10% aqueous critic acid, aqueous NaHCO3, and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under vacuum. The desired product was isolated as a 60 wt % solution in 2-MeTHF (1.6 g, 83%). Analytical data for 19: 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.2 Hz, 2H), 7.54−7.42 (m, 3H), 6.42 (s, 1H), 4.76 (d, J = 48.8 Hz, 1H), 4.68−4.11 (m, 3H), 3.04−2.84 (m, 2H), 1.86−1.81 (m, 2H), 1.47 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.9, 155.1, 133.9, 131.8, 130.0, 128.6, 127.0, 87.7 (d, J = 177.2 Hz), 80.2, 48.9 (d, J = 18.6 Hz), 28.3, 28.3, 26.3; 19 F NMR (282 MHz, CDCl3) δ −204.41; HRMS (ESI-TOF) m/z: [M + H − Boc + H] calcd for C17H23FN2O3 223.1249; found 223.1250; [α]25 D = +60.4 (c 0.46, MeOH). N-((3S,4R)-3-Fluoropiperidin-4-yl)benzamide (20). To a three-neck round-bottom flask was charged TFA (10 mL). 19 (1.45 g, 4.5 mmol) was added in portions at ∼25 °C. The mixture was stirred at room temperature for 3 h. The reaction mixture was poured into H2O (10 mL), and aqueous NaHCO3 was then added dropwise until pH = 8−9. Then, CH2Cl2 was added, and the mixture backextracted 10 times. The combined organics were dried over Na2SO4, concentrated under vacuum to afford 20 (1.0 g, 100%). ee Upgrade (D-Benzoyl Tartaric Acid Salt Formation/Salt Break). To a three-neck round-bottom flask were charged 20 and EtOH (10 mL) at room temperature. A solution of D-dibenzoyl tartaric acid (1.6 g) in EtOH (10 ml) was added dropwise via cannula over 10 min. The reaction mixture was stirred at 25 °C for 5 h and filtered to obtain the salt. In a round-bottom flask, were charged 7% aqueous NaHCO3 (23 mL) and CH2Cl2 (45 mL), followed by the wet cake. The mixture was stirred at ∼25 °C for 2 h. The phases were cut, and the aqueous layer was back-extracted 3 times with CH2Cl2. The combined organic layers were dried over anhydrous magnesium 8015

DOI: 10.1021/acs.joc.9b00569 J. Org. Chem. 2019, 84, 8006−8018

Article

The Journal of Organic Chemistry CH3CN (55 mL) was added to rinse down the sides of the flask. The mixture was degassed for 30 min by subsurface sparging with N2. Agitation was started, and the mixture was heated at an internal temperature of 75 °C with a heating mantle for 16 h. Upon consumption of 3, the reaction mixture was adjusted to 20 °C. A solution of 2 N aqueous LiOH (17.8 mL, 2 equiv) was added followed by water (32 mL). The mixture was aged for 1 h at 20 °C and then heated at 60 °C for 3.5 h. The reaction was then cooled to room temperature, and the solvent was switched to toluene via distillation. A total of 30 mL of toluene and 10 mL was added followed by concentrated HCl (2.5 equiv). The phases were then separated, and the aqueous layer was back-extracted with 30 mL of toluene. The pH of the aqueous layer was adjusted to 3.7 with conc HCl and extracted with EtOAc (30 mL). The organic layer was washed with 10 wt % aqueous NaCl (15 mL). The solvent was switched to THF (32 mL). The internal temperature was adjusted to 40 °C, and dicyclohexylamine (3.87 g, 1.2 equiv) was added over 10 min. MTBE (24 mL) was added over 30 min via syringe pump, which resulted in a slurry. After 1 h, the temperature was gradually cooled to 20 °C and aged overnight. The solids were collected by vacuum filtration and washed with 1:1 THF/MTBE (2 × mL) and MTBE (2 × 3 mL). The solids were then dried under vacuum to yield 34 as the dicyclohexylamine salt in 95% purity (8.93 g, 78%). Analytical data for 34: 1H NMR (500 MHz, CD3OD) δ 8.11 (overlapped d, 1H), 8.10 (d, J = 8.6 Hz, 2H), 7.75 (br d, J = 8.9 Hz, 1H), 7.54 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 10.5 Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H), 4.56 (d, J = 15.5 Hz, 1H), 4.48 (d, J = 15.5 Hz, 1H), 3.52 (dd, J = 9.7, 7.7 Hz, 1H), 3.38−3.31 (m, 1H), 2.98 (dd, J = 9.7, 6.0 Hz, 1H), 2.48 (dd, J = 16.3, 8.6 Hz, 1H), 2.45−2.37 (m, 1H), 1.97 (dd, J = 16.3, 6.7 Hz, 1H), 1.40 (d, J = 6.6 Hz, 6H), 1.07 (d, J = 6.6 Hz, 3H); 13C NMR{1H} (126 MHz, CD3OD) δ 177.5, 168.7 (br), 165.9 (br), 160.6, 160.0 (d, J = 256.8 Hz), 159.0 (br), 151.0, 136.9 (d, J = 7.9 Hz), 132.7, 130.2, 128.0, 127.1, 124.5, 119.6 (d, J = 25.2 Hz), 119.1, 56.0, 42.6, 40.0, 35.8, 27.9, 22.7, 19.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H26FN3O4 464.1985; found 464.1981. [α]25 D = +6 (c 0.5, CDCl3, er = >99.5:0.5). 2-Fluoro-N-((3S,4R)-3-fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4(((S)-4-methyl-2-oxopyrrolidin-1-yl)methyl)benzamide (1). To a 500 mL round-bottom flask were charged 34 (18.8 g, 29.2 mmol), EtOAc (180 mL), and 1 M HCl (180 mL). The contents were mixed for 1 h at room temperature. The mixture was transferred to a separatory funnel, and the phases were cut. The organics were washed with water (2 × 20 mL) and aqueous saturated sodium chloride (50 mL). The organics were dried over Na 2 SO 4 , filtered, and concentrated. To a three-neck round-bottom flask equipped with an overhead stirrer was charged the free acid of 34 (8.6 g, 18.6 mmol), 4 (4.13 g, 1.1 equiv), and HOAt (0.505 g, 0.2 equiv). The solids were dissolved in 10:1 THF/DMF (44 mL). EDC·HCl (4.62 g, 1.3 equiv) was then added. The contents were mixed overnight. Upon consumption of carboxylic acid, EtOAc (86 mL) and water (40 mL) were added. The phases were cut, and the aqueous layer was back-extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with water (40 mL) and brine (40 mL). The organics were dried over Na2SO4, filtered, and concentrated. The solids were charged to a three-neck round-bottom flask equipped with an overhead stirrer. EtOAc (80 mL) was added, and the contents were mixed at 50 °C. Heptanes (40 mL) were added dropwise over 2 h producing a cloudy solution. The mixture was then cooled to room temperature and mixed for 8 h. The solids were collected by vacuum filtration and washed with heptanes to produce 1 as a white solid in 98.5% purity (9.6 g, 80%). Analytical data for 1: 1H NMR (500 MHz, CDCl3) δ 8.10−8.03 (m, 2H), 7.75 (d, J = 8.9 Hz, 1H), 7.71 (d, J = 6.5 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.15 (d, J = 11.6 Hz, 1H), 7.07−7.02 (m, 2H), 7.00 (dd, J = 13.3, 8.6 Hz, 1H), 4.80 (br d, J = 49.5 Hz, 1H), 4.54 (d, J = 15.6 Hz, 1H), 4.48 (d, J = 15.6 Hz, 1H), 4.20 (br d, J = 29.4 Hz, 1H), 4.04 (dd, J = 11.4, 4.3 Hz, 2H), 3.45 (dd, J = 9.5, 7.7 Hz, 1H), 3.41−3.27 (overlapped m, 4H), 3.03 (br m, 1H), 2.91 (dd, J = 9.5, 6.1 Hz, 1H), 2.67−2.35 (overlapped m, 3H), 2.56 (dd, J = 16.7, 8.6 Hz, 1H), 2.47−2.37 (m, 1H), 2.03 (dd, J =

16.7, 7.0 Hz, 1H), 2.00−1.88 (br m, 2H), 1.83−1.71 (br m, 2H), 1.68−1.55 (br m, 2H), 1.42 (d, J = 7.0 Hz, 6H), 1.09 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 174.9, 166.6, 161.7, 158.6, 157.9 (d, J = 245.7 Hz) 156.6, 150.3, 134.8 (d, J = 7.9 Hz), 131.8, 128.7, 125.0, 123.7, 122.8, 121.2 (d, J = 12.2 Hz), 117.76, 117.45 (d, J = 27.4 Hz), 88.0, (br d, J = 179 Hz), 67.46, 67.39, 60.7, 54.6, 51.5, 48.9, 47.5, 40.8, 39.0, 34.6, 29.1, 28.9, 27.2, 26.5, 22.4, 19.8. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C36H43F2N5O4 648.3361; found 648.3353. [α]25 D = +107 (c 0.5, CDCl3, er = >99.5:0.5).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00569. General experimental methods for reaction screening and copies of 1H and 13C NMR spectra for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (E.M.P.). *E-mail: [email protected] (B.X.). ORCID

Eric M. Phillips: 0000-0003-3530-8876 Erika Milczek: 0000-0003-3123-2923 Michael Shevlin: 0000-0003-2566-5095 Ji Qi: 0000-0003-4585-6534 Present Address ⊥

C.M.: Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, United States. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Lisa Frey, Jimmy DaSilva, Amanda Marie Makarewicz, Jonathan Wilson (Merck & Co., Inc., Kenilworth, NJ) as well as Xianghui Wen, Fei Jiang, Mingzhong Cao, and Chao Liu (Wuxi AppTec) for overall execution and their extensive experiments. Authors also acknowledge Nobuyoshi Yasuda, Jeffrey Kuethe, Rebecca Ruck, and Louis-Charles Campeau for helpful discussions.

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REFERENCES

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