The First Asymmetric Pilot-Scale Synthesis of TV-45070 - Organic

Article pubs.acs.org/OPRD

The First Asymmetric Pilot-Scale Synthesis of TV-45070 Joseph A. Sclafani,*,†,§ Jian Chen,†,∥ Daniel V. Levy,†,§ Harlan Reese,†,⊥ Mina Dimitri,† Partha Mudipalli,† Michael Christie,† Christopher J. Neville,‡ Mark Olsen,‡ and Roger P. Bakale†,# †

Chemical Process Research and Development, ‡Analytical Research and Development, Teva Branded Pharmaceutical Products R&D Inc., 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States S Supporting Information *

ABSTRACT: TV-45070 is a small-molecule lactam containing a chiral spiro-ether that has been reported as a potential topical therapy for pain associated with the Nav1.7 sodium ion channel encoded by the gene SCN9A. A pilot-scale synthesis is presented that is highlighted by an asymmetric aldol coupling at ambient temperature, used to create a quaternary chiral center. Although only a moderate ee is obtained, the removal of the undesired isomer is achieved through preferential precipitation of a near racemic mixture from the reaction, leaving the enantiopure isomer in solution. Cyclization to form the final API uses an uncommon diphenylphosphine-based leaving group which proved successful on the neopentyl system when other traditional leaving groups failed.

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INTRODUCTION Postherpetic neuralgia (PHN) is a rare disorder that is defined as significant pain or abnormal sensation 120 days or more after the presence of the initial rash caused by shingles. This pain persists after the healing of the associated rash. Generally, this affliction occurs in older individuals and individuals suffering from immunosuppression. There are about one million cases of shingles in the US per year, of which 10−20% will result in PHN.1 Topical analgesics such as lidocaine2 and capsaicin3 are traditionally used to treat this disorder. Both lidocaine and TV45070 have a mechanism of action that involves the inhibition of voltage-gated sodium ion channels. TV-45070 (formerly XEN-402) was in-licensed by Teva from Xenon Pharmaceuticals and is reported to be an antagonist of the Nav1.7 sodium ion channel protein. It is currently in Phase II clinical trials for PHN. Interestingly, the loss of function of the Nav1.7 sodium ion channel was reported to result in the inability to experience pain as a hereditary trait in certain individuals.4 Primary erythromelalgia5 is another rare disease where alterations in Nav1.7 or mutations in the corresponding encoding gene SCN9A have been reported to result in chronic burning pain that can last for hours or even days. Thus, compounds which regulate this protein have potential therapeutic value as analgesics for chronic pain. The first-generation process route6 (Scheme 1) used for Phase I clinical supplies began with the coupling of commercially available isatin and sesamol mediated by isopropylmagnesium chloride to give 2 in quantitative yield. The removal of the hydroxyl group in 2 was achieved in good yield using triethylsilane in neat trifluoroacetic acid. The addition of formaldehyde promoted by NaOH was not found to be chemoselective, giving racemic 4 that included hemiaminal formation from the addition of a second equivalent of formaldehyde. In situ removal of the hydroxymethyl group on the oxindole nitrogen, preceded by Mitsunobu cyclization, provided 5 in 49% yield and 89.4 area percent (A%) purity. Coupling of 5 with 6 was mediated by cesium carbonate and required large-scale chromatography to purify the crude © XXXX American Chemical Society

racemic drug substance prior to SMB chromatography. Coupling with 6 was found to be necessary to enhance solubility for the SMB resolution. Although the early synthesis proved vital to provide quantities of API for clinical trials, significant losses late in the synthesis highlighted the need for an asymmetric route. A first-generation asymmetric route7 performed on kilo lab scale focused on generating the desired S-isomer (1) directly, thus avoiding the need for SMB chromatography (Scheme 2). This synthesis again utilized the common raw materials isatin and sesamol to build the core of the final drug substance. However, this route featured an asymmetric alkylation promoted by the Lygo phase-transfer catalyst,8 which provided the desired center in 90% ee, when performed at −20 °C. No attempts with the allylated Corey variant8c of the catalyst were reported. To accommodate the asymmetric step, several protecting groups were added to the synthesis, resulting in an increase in the number of steps. This route also introduced the bromomethylfuran late in the synthesis, allowing for the possibility of genotoxic impurity 6 in the final API. Nonetheless, this route demonstrated that enrichment in ee was possible over several steps, ultimately leading to API of an enantiopurity which was comparable to the earlier SMB process. Thus, from this work it seemed possible that even moderate ee in the asymmetric step could be upgraded through crystallization. Additional improvements included the use of a phosphine which could be removed by treatment with aqueous acid thus facilitating chromatographic removal of impurities in the Mitsunobu step. Encouraged by this work, a shorter asymmetric route was planned that could similarly benefit from enantio-enrichment through successive crystallizations. Received: July 10, 2017

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DOI: 10.1021/acs.oprd.7b00237 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

Scheme 1. Early-Phase Synthesis of TV-45070

Scheme 2. First-Generation Asymmetric Route

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RESULTS AND DISCUSSION

protic sites in both starting materials, this amount of metalating reagent seemed to be insufficient and suggested that it was merely acting as a base. A quick base screen demonstrated that the chemistry could be performed in tetrahydrofuran (THF) or

While generating initial quantities of 2, it was noted that only a slight excess of one equivalent of Grignard reagent was necessary to complete the reaction. Given the number of B



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to be too labile, reverting to 3 upon prolonged exposure to air. As a result, it was not investigated further. The use of benzyl bromide with 3 resulted in exclusively C-benzylation adjacent to the carbonyl rather than substitution on the phenol. Unfortunately, in the case of Sharpless ligands, poorer ee was observed and longer reaction times, despite a cleaner impurity profile. Although no ee was observed when catalyst 2213 was employed with 3, the substitution of the phenol gave encouraging improvement (Table 2). In general, the TES protecting group gave inferior results when compared to the TBDMS protected substrate. Carbinolamine formation with formaldehyde continued to be observed in all reactions. Hoping to avoid hemiaminal formation, the functionalization of the oxindole with 6 was performed earlier in the synthesis. This also avoided the potential trace contamination by genotoxic raw material 6 in the final step. The incorporation of 6 also negated the need for a nitrogen protecting group, which would ultimately require a separate step for removal. As thiourea catalysts 21 and 22 (Figure 2) are proposed to bind to formaldehyde through hydrogen bonding14 in addition to functioning as chiral bases, hemiaminal formation could potentially impact the chiral event. When employing 18 as a substrate, a significant improvement in ee was observed at 25 °C (Table 3). When performed in acetonitrile, a modest improvement with both 21 and 22 was observed with trace amounts of impurities. However, when slurried in heptane, a significant increase in ee was observed. By lowering the concentration in heptane, the ee fell to levels comparable to those observed with solvents where the product was more soluble. This suggested that, by limiting the amount of product in solution, the competitive hydrogen bonding of the installed hydroxymethyl group with formaldehyde was reduced. This in turn could enhance the coordination of formaldehyde with the catalyst giving greater stereocontrol. Having obtained moderate ee under our best conditions, we sought to enrich the amount of preferred S-isomer, either by preferential crystallization15 of racemic material or through direct isolation of enantiopure product. Gratifyingly, when dissolved in methanol at elevated temperature, cooling selectively precipitated product measuring 5% ee. The remaining mother liquors contained the S-isomer in 98−99% ee, and the product could be isolated through further addition of water after the filtration of near racemic material. Obtaining sufficient quantities of enriched 19 allowed for the study of conditions to synthesize the spiro furan ring as the final step. Deprotection of 19 was found to be best performed in acetonitrile using catalytic 47% HBr in water at 37 °C. These conditions avoided retro aldol and gave peak-to-peak

dimethylformamide (DMF) using a slight excess of potassium carbonate (Scheme 3). Although it was necessary to use Scheme 3. Potassium Carbonate-Promoted Coupling of Sesamol and Isatin

carbonate with a small particle size for best results, this improvement removed a costly, moisture-sensitive base from the synthesis. This also provided a safer process which avoided the emission of propane. With 2 in hand, preliminary efforts to synthesize 3 focused on using a cosolvent in an attempt to reduce the amount of TFA called for in the former synthesis (Scheme 1). However, efforts to alter the conditions resulted in poor reactivity due either to the insolubility of triethylsilane9 or competitive formation of dimer impurity 15 (Figure 1). This impurity

Figure 1. Dimeric impurity.

proved difficult to remove by crystallization and initial quantities of 3 were produced using neat acid to focus on screening of conditions for an asymmetric aldol reaction. A number of catalysts10,11 in the literature have been reported to provide good to excellent ee under noncryogenic conditions using formaldehyde as an electrophile. Employing Sharpless ligands12 as catalysts gave encouraging results under mild conditions, using unprotected 3 (Table 1). However, significant levels of impurities were observed when long reaction times occurred, despite performing the reactions at lower temperatures. In addition, products associated with hemiaminal formation were again observed. Hoping to tune the enantioselectivity through substitution of the phenol, several derivatives were prepared with a focus mainly on silyl protecting groups. The TMS group was found Table 1. Asymmetric Aldol Reaction with Protected Phenol 3

entry

catalyst

temp. (°C)

time (h)

3 (A%)

4a (A%)

4 (A%)

impurities (A%)

ee of 4 (%)

1 2 3 4 5

(DHQ)2PHAL (DHQ)2PHAL (DHQ)2Pyr (DHQ)2Pyr 22

20 0 20 0 20

22 64 18 64 18

0.9 5.4 2.3 0.7 26

36 41 52 34 31

61 7 25 9 43

2.1 46.6 20.7 64.4

43 46 51 25 0

C



Article

Table 2. Asymmetric Aldol Reaction with Sharpless Ligands and Phenol-Protected Intermediates

a

entry

P

catalyst

solvent

time (h)

23 (A%)

23aa (A%)

ee of 23 (%)

1 2 3 4 5 6 7 8 9 10 11 12

TBDMS

(DHQ)2PHAL (DHQ)PHN (DHQ)PHN 21 21 21 21 22 22 22 (DHQ)2PHAL 21

CH2Cl2 CH2Cl2 THF CH2Cl2 THF toluene CH3CN toluene THF CH2Cl2 CH2Cl2 CH2Cl2

113 90 90 18 18 18 18 21 21 18 114 18

30 41 35 87 77 91 92 92.7 71.5 82 8 88

62 47 56 9 13 3.9 3.2 3.2 25.9 7.1 91 2.7

27 27 13 33 32 10 25 17 30 35 2 26

TES

The remainder is SM.

be the bromomethyl compound. This intermediate converted to the API upon addition of triethylamine, and product could be isolated through solvent exchange into methanol followed by addition of water. However, closer inspection of this intermediate by mass spectral analysis and NMR revealed an oxidized version of intermediate A as the phosphine oxide when isolated after chromatography. Use of other solvents with 24 did not reveal a bromomethyl intermediate when used with PBr3, and conversion was hindered. The examination of the ee of the isolated API revealed scrambling at the quaternary center. The mechanism for the scrambling was not elucidated and remains unclear. Due to the complexity of the intermediate and loss of stereochemical integrity, this initial approach was quickly abandoned. Recognizing that a phosphorus-containing leaving group could allow for ring closure to occur, several reagents used in ligand synthesis were examined. Diethyl chlorophosphate, dichlorophenyl phosphine, and diethylchlorophosphite did not provide sufficient conversion or a good impurity profile. However, chlorodiphenylphosphine16 completely consumed 24 when heated to 37 °C and provided the product 1 without an intermediate observed by HPLC. No scrambling of ee was observed with this leaving group, and no base was needed to complete the conversion. Byproducts observed from the reaction were a mixture of diphenylphosphine oxide, diphenylphosphinic acid, and diphenylphosphine. To remove the stench associated with trace amounts of diphenylphosphine, 30% hydrogen peroxide in water was added to the reaction mixture prior to workup which oxidized the malodorous byproduct to diphenylphosphinic acid. Plant-Scale Synthesis. With a route in hand, optimization resulted in a concise plant process (Scheme 5), which benefited from telescoping of several steps. For the synthesis of 16, it was found that the installation of 6 could be combined with the stepwise addition of sesamol in one vessel. This avoided the use of Cs2CO3 previously reported on scale to install the furan. Under the optimized conditions, 1.01 equiv of 6 was added to a slurry of K2CO3 and isatin in DMF at 48 ± 3 °C followed by heating for 1 h. Higher equivalents of isatin resulted in the competitive formation of 2 which complicated workup. Once the consumption of isatin was confirmed by in-process control

Figure 2. Thiourea catalysts for asymmetric aldol.

Table 3. Asymmetric Aldol Reaction with Thiourea Catalysts with Oxindole-Substituted and Phenol-Protected Intermediate Using Paraformaldehyde and 5% Catalyst

entry

catalyst

solvent

time (h)

18 (A%)

19b (A%)

ee (%)

1 2a 3 4a 5 6 7 8

22 22 22 22 21 21 21 21

CH3CN CH3CN heptane heptane heptane CH3CN THF toluene

18 18 18 18 18 18 40 18

30 28 5 29 2 2.7 18 32

70 72 95 71 98 97.3 82 68

45 50 73 54 58 36 41 54

a Performed using 30 mL/g vs 10 mL/g. bIntegration of product and starting material in all cases.

conversion in the HPLC to 24. The closure of 24 to provide 1 proved to be problematic. Eager to avoid the use of Mitsunobu reagents which complicated isolation through the generation of colored byproducts, an intramolecular Williamson ether approach was tried. All attempts to cleanly synthesize chloro or mesylate intermediates were unsuccessful due to the congested neopentyl center in 24. Traditional reagents such as thionyl chloride failed. Only in one case was the API synthesized in good yield using PBr3 in THF (Scheme 4) through an intermediate observed in HPLC, initially thought to D



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Scheme 4. Phosphorous Tribromide-Promoted Cyclization

Scheme 5. Optimized Plant Synthesis

(IPC), a DMF solution of sesamol was added at 25−35 °C. The product 16 was then isolated directly from the reaction mixture through pH adjustment with aqueous acetic acid and addition of i-PrOH. Seeding was necessary to avoid gumming of the product as it precipitated. Product 16 from the two-step sequence was isolated in 94−97% yield with a typical assay of 97−98 wt % and purity of 99 area percent (A%) by HPLC. In the following step employing triethylsilane, most attempts at using cosolvents failed. Thus, optimization of the silane reduction conditions from the first asymmetric synthesis became a priority. Methylene chloride, although undesirable as a halogenated, class 2 solvent, had the advantage of poorly solubilizing both starting material and product, thus minimizing the formation of 15. Optimized conditions were 10 volumes of CH2Cl2, 1.3 equiv of triethylsilane, and 6 equiv of TFA. To avoid the formation of dimer 15, the slow addition of TFA at 0 °C, followed by warming to 25 °C and subsequent stirring at that temperature, gave clean, complete conversion. Isolation involved washing with water to remove TFA, followed by a partial solvent exchange into heptane (ca. 90:10 heptane− CH2Cl2) to give the product in 91% yield and 99.8 A% purity. The protection of 17 was straightforward in THF with TBDMSCl and triethylamine. To drive the reaction to completion, 1.2 equiv of silyl reagent was needed resulting in an indole silyl ether side product. This disilylated side product was cleanly converted to the desired product upon pH adjustment with HCl. The isolation of 18 was successfully completed in 90% yield and 99.7 A% purity by filtration after solvent exchange into i-PrOH.

The key asymmetric conversion of 18 to 19 was found to perform best with a mixture of solid paraformaldehyde and aqueous formaldehyde using only 1.1% of 2217 at 25 °C. High agitation in n-heptane was needed. However, on plant scale, additional time was called for (47 h) to reach 95% conversion after which the product was isolated by filtration. On a small scale, an increase in temperature allowed for shorter reaction time but resulted in lower enantioselectivity. After drying the crude mixture, which measured 70.5% ee, the solids were heated in methanol at 62 °C and cooled to 25 °C, where the near racemic product (ca. 5−6% ee) precipitated and was collected by filtration. Unlike the SMB process, racemic 19 could be recycled by conversion back to 18 through a separate retroaldol reaction. Recharging of the filtered solution to the cleaned reactor, followed by the addition of water, precipitated the product in 99% ee and 58% yield. The final step of the synthesis could be successfully telescoped when performed in acetonitrile. Although the amount of HBr was not found to be critical, the amount of water associated with the reagent was such that undercharging of water below 0.5 equiv stalled the deprotection due to incomplete formation of disiloxane. The removal of the byproduct disiloxane was achieved through extraction of the acetonitrile solution with cyclohexane. With the proper amount of water charged, the Karl Fischer (KF) titration measurement at the end of the reaction after extraction with cyclohexane measured ca. 0.1% water, allowing for the addition of chlorodiphenylphosphine without significant quenching of the reagent. Heating at 37 °C furnished the product after E



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an Agilent Technologies 6520 QTOF accurate mass system coupled with an Agilent 1260 Infinity HPLC. 3-Hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-[[5(trifluoromethyl)-2-furyl]methyl]indoline-2-one (16). A 200 L Hastelloy reactor was inerted, then charged with isatin (9.0 kg, 61.2 mol, LR), powdered anhydrous potassium carbonate (13.5 kg, 97.7 mol, 1.6 equiv), and N,Ndimethylformamide (DMF) (33.6 kg, 4 vol). The resulting slurry was kept under nitrogen and heated to 45 °C over 25 min. Neat 6 (14.45 kg, 63.1 mol, 1.03 equiv) was added over about an hour such that the internal temperature was kept between 45 and 54 °C. Once the addition was complete, the reaction mixture was stirred at 48 °C for an hour and then analyzed by HPLC for completeness. The reaction mixture was then cooled to 30 °C, and a solution of sesamol (9.3 kg, 67.3 mol, 1.1 equiv) in DMF (8.5 kg, 1 vol) was added over 76 min such that the temperature was maintained between below 30 °C. The reaction mixture was stirred at 30 °C for 3 h. An inprocess control (IPC) sample was removed to determine reaction completeness by HPLC. The contents of the 200 L reactor were transferred to a 400 L glass-lined jacketed reactor with retreat-curve agitator. The 200 L reactor was rinsed with isopropanol (45.4 kg, 6.4 vol), and the rinse solution was added to the 400 L reactor. The contents of the 400 L reactor were then heated to 53 °C over about 0.5 h. Water (212 kg, 23.6 vol) was added over 54 min while keeping the reaction temperature between 53 and 55 °C. Next a slurry of 16 seeds (0.53 kg, 2 wt %) in water (1.35 kg) was charged and the mixture agitated for an additional 30 min. The contents of the reactor was cooled to 40 °C prior to charging acetic acid (3.6 kg, 59.3 mol, 1 equiv) in water (124 kg, 13.8 vol) over 89 min while maintaining the temperature between 41 and 44 °C. The reaction solution was cooled to 20 °C over an hour to crystallize a tan solid. The slurry was aged at 20 °C overnight. The solid was collected on an Aurora filter/ dryer, washed with water (81.3 kg, 9 vol), and then dried at 60 ± 5 °C under a reduced pressure of 80 Torr for 3 days to afford 16 (25.5 kg, 94.1% yield) as a brown solid with purity 98.9 A% (HPLC-UV at 230 nm) and 97.0% assay. 1H NMR (DMSO, 400 MHz) δ 9.13 (s, 1H), 7.25 (s, 1H), 7.24−7.18 (m, 2H), 7.00 (d, J = 7.8 Hz, 1H), 6.90 (m, 2H), 6.58 (m, 2H),6.23 (s, 1H), 5.90 (d, J = 6.4 Hz, 1H), 5.90 (d, J = 6.4 Hz, 1H), 4.99 (s, 2H). 13C NMR (100 MHz, DMSO-d6,): 176.37, 153.69, 148.11, 146.72, 142.82, 139.48 139.30 (q, JCF = 42.4 Hz), 132.34, 128.61. 123.53, 122.18, 119.66, 119.03 (q, JCF = 266.4 Hz), 114.03 (q, JCF = 3.2 Hz), 109.08, 108.28, 106.68, 100.70, 97.35, 74.50, 36.28. 3-(6-Hydroxy-1,3-benzodioxol-5-yl)-1-[[5-(trifluoromethyl)-2-furyl]methyl]indolin-2-one (17). Solid 16 (18.7 kg, 43.1 mol, LR) was charged to a 400 L glass-lined reactor. Dichloromethane (253 kg, 10.0 vol) was added, and the resultant slurry was cooled to 0 ± 3 °C over 16 min. Triethylsilane (6.64 kg, 1.30 equiv) was added over 2 min, keeping the internal temperature at 0 ± 3 °C. Trifluoroacetic acid (30.0 kg, 259 mol, 6.0 equiv) was charged in one continuous stream to the slurry over 1 h, maintaining the reaction temperature at ≤10 °C. A mild exotherm was noted. The internal temperature was raised to 25 ± 3 °C for 1 h to complete the reaction as determined by an in-process test (0.75 A% 16 remaining, HPLC-UV). DI water (190 kg, 10 vol) was charged to the reactor. The mixture was stirred at 25 °C for 5 min. The stirring was stopped, and the contents of the reactor held at 25 °C for 16

subsequent addition of chlorodiphenylphosphine. Isolation involved the addition of hydrogen peroxide, which was confirmed to be completely consumed by IPC with peroxide paper before continuing with the workup. Solvent exchange into methanol followed by seeding gave the product in 81% yield and 99.6 A% purity with an ee greater than 99.9%.

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CONCLUSION In summary, despite the use of a protecting group, the optimized asymmetric plant synthesis represents the shortest synthesis of TV-45070 (XEN-402) to date. No chromatography was used for any of the steps, and all intermediates were isolated through direct isolation. This route uses mild, processfriendly reagents in the first step, avoids the need for high molecular weight bases, and quickly builds molecular complexity. The modified reduction step addresses issues with dimer formation and optimizes the amount of TFA. The use of the TBDMS group on the phenol was shown to greatly improve the enantiomeric excess in the subsequent aldol chemistry. The key asymmetric step was successfully performed using a low loading of 1.1% of thiourea catalyst. This asymmetric step did not require cryogenic conditions and produced product in high purity and moderate ee, which could be then upgraded to >98% ee through recrystallization in methanol. The final stage of the synthesis combined deprotection of the TBDMS group and cyclization in one vessel. The use of the diphenylphosphino group offered a cleaner alternative to the Mitsunobu reaction, avoiding the use of azodicarboxylate reagents in the final step. The overall yield for the five-step sequence was 35.3% from isatin, compared with 9% in the first generation and 11.4% for the racemic synthesis. This overall yield could be increased further through the recycling of the racemic intermediate.

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EXPERIMENTAL SECTION General Experiment. All reactions were carried out under an atmosphere of dry nitrogen unless otherwise specified. All reagents and solvents were used as received without further purification unless otherwise specified. For all steps, reactions were monitored, and the purity was assessed by HPLC, using an Agilent 1100 or 1200 series instrument (Table 4). Diluent: Table 4. HPLC Gradient Program time (min)

%A

%B

initial 7 14 17 17.1 22

90 50 50 20 90 90

10 50 50 80 10 10

acetonitrile. Mobile phase A: 0.1% TFA/water. Mobile phase B: 0.1% TFA/acetonitrile. Column: Zorbax Bonus-RP 150 × 4.6 mm; 3.5 μm packing. Column temperature: 40 °C. Detector wavelengths: 230 and 250 nm. Injection volume: 5 μL. Flow rate: 1.0 mL/min. 1 H NMR (400 MHz) were recorded on a Bruker Avance II spectrometer. Chemical shifts are reported in ppm (δ units) downfield of internal tetramethylsilane [(CH3)4Si]; coupling constants are reported in hertz (Hz). Multiplicities are as follows: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet. LC/MS was performed on F



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3-[6-[tert-Butyl(dimethyl)silyl]oxy-1,3-benzodioxol-5yl]-3-(hydroxymethyl)-1-[[5-(trifluoromethyl)-2-furyl]methyl]indolin-2-one (19). A 400 L glass-lined vessel was charged with 18 (19.2 kg, 36.1 mol, LR), 22 (238 g, 0.399 mol, 0.011 equiv), and paraformaldehyde (1.08 kg, 36.1 mol, 1.0 equiv). n-Heptane (144 kg, 11 vol) was added by vacuum, and the suspension was agitated (123 rpm) at 25 °C for 20 min. Aqueous formaldehyde (37% in H2O, 3.23 kg, 39.7 mol, 1.1 equiv) was added in one portion. The reaction was stirred at 25 °C for 47 h, at which point 3.0 A% of 18 remained. The crude product was isolated at 25 °C using an Aurora filter. The initial filtration took 16 min. The crude product was then washed with n-heptane (19.8 kg, 1.5 vol) over 12 min. The solids were dried on the Aurora filter under vacuum at 45 °C for 27 h to give 19.5 kg (96% yield) of crude 19. The remaining water content was measured to be 0.6% by Karl Fischer (KF) titration, and the chiral purity of the solids was 70.5% ee. The crude product was then charged back into the reactor and suspended in a premixed solution of methanol (91.2 kg, 6.0 vol) and acetic acid (5.03 kg, 0.25 vol). The slurry was stirred at 20 °C for 30 min followed by heating to 50 °C and stirring for 1 h. The slurry was cooled back to 20 °C and stirred for approximately 20 h at 75 rpm. The racemic solids were filtered using an Aurora filter, and the vessel and solids were washed with methanol (30.3 kg) over 25 min. The filtrate was then transferred into a clean 400 L glass-lined vessel through a 1 μm cartridge filter to remove any trace racemic solids. DI water (15.4 kg, 0.8 vol) was then added over at least 20 min, giving crystal growth. After a 1 h hold, the remaining DI water (49.9 kg, 2.6 vol) was added over 20 min. The batch was stirred for 2 h and the solids isolated by filtration at 22 °C. The reactor and solids were washed with a premixed solution of methanol (17.0 kg, 1.12 vol) and DI water (9.22 kg, 0.48 vol). The overall time for the filtration was 21 min. The solids were dried on an Aurora filter under vacuum at 45 °C for 91 h to give 0.18% remaining H2O by KF titration. Overall, 11.8 kg (58.0%) of 19 was isolated as a light tan solid with an HPLC chemical purity of 100.0 A% and chiral purity of 99.2% ee. An HPLC assay showed 99.9 wt % purity. 1H NMR (CDCl3, 400 MHz) δ 7.23 (d, J = 7.6 Hz, 1H), 7.19 (s, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 3.5 Hz, 1H), 6.37 (s, 1H), 6.36 (d, J = 3.5 Hz, 1H), 5.94 (d, J = 11.1 Hz, 1H), 5.94 (d, J = 11.1 Hz, 1H), 5.45 (d, J = 16.3 Hz, 1H), 4.54 (d, J = 16.3 Hz, 1H), 4.24 (t, J = 11.3 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 2.59 (d, J = 10.1 Hz, 1H), 0.69 (s, 9H), −0.05 (s, 6H). 13C NMR (100 MHz, DMSO-d6): 176.83, 153.63, 147.94, 146.33, 142.50, 140.59, 139.32 (q, JCF = 41.8 Hz), 132.13, 127.09, 123.36, 121.90, 120.24, 119.00 (q, JCF = 266.8 Hz), 113.88 (q, JCF = 3.0 Hz), 109.37, 108.84, 108.14, 101.17, 99.52, 66.09, 55.57, 36.37, 25.93, 18.64, −3.79, −3.92. (S)-1′-[(5-Methyl-2-furyl)methyl]spiro[6H-furo[3,2-f ][1,3]benzodioxole-7,3′-indoline]-2′-one (1). To a 200 L glass-lined reactor was charged 19 (10.7 kg, 19.0 mol, LR), acetonitrile (33.1 kg, 4 vol), and 47−49% HBr in water (258 mL, 0.13 equiv). The batch was then heated to 37 ± 3 °C over 20 min. Upon reaching temperature, the batch was stirred for 6 h. After this period an IPC was performed indicating no starting material remaining by HPLC. The batch was then cooled to 20 ± 3 °C and extracted with cyclohexane (8.35 kg, 1 vol) to remove disiloxane. Next an IPC was performed for KF, and the batch was found to contain 0.1% water. Next chlorodiphenylphosphine (4.6 kg, 20.9 mol, 1.1 equiv) was added and the temperature raised to 37 ± 3 °C. The batch

min, allowing the phases to separate. The lower organic layer was dropped to drums, and the upper aqueous layer was removed and discarded. The organic layer was returned to the reactor, and then the DI water washing was repeated two more times. The final wash was with a 10% brine solution (209 kg, 11 vol) . The organic layer was concentrated over 4.3 h at reduced pressure (267 mbar) and an internal temperature of 10−13 °C. Approximately 150 L of distillate was collected, resulting in a reaction volume of 35 L. During this period the reactor internal temperature was in the range of 10−13 °C. Heptane (104 kg, 8 vol) was next added, and the suspension was stirred for 10 min. Analysis by 1H NMR indicated that a target level of 9.7 wt % DCM in heptane was obtained. After cooling to 0 °C the solid was collected by filtration. The off-white crystalline product was washed with heptane (44 kg) and dried at 50−55 °C for 24 h to an LOD of 0.28%. The yield was 16.4 kg, 91.1%, and chemical purity measured 100 A% (HPLC-UV, 230 nm). 1H NMR (CDCl3, 400 MHz) δ 8.49 (s, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.2 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.72, (d, J = 3.5 Hz, 1H), 6.59 (s, 1H), 6.35, (d, J = 3.5 Hz, 1H), 6.34 (s, 1H), 5.86 (d, J = 16.5 Hz, 1H), 5.86 (d, J = 16.5 Hz, 1H), 5.09 (s, 1H), 4.94 (s, 2H). 13C NMR (100 MHz, DMSO-d6): 175.80, 153.59, 149.98, 146.77, 142.39, 139.69, 139.37 (q, JCF = 42.1 Hz), 129.92, 127.44, 123.64, 122.25, 120.29, 118.96 (q, JCF = 266.8 Hz), 115.38, 113.99 (q, JCF = 2.9 Hz), 109.38, 108.41, 100.75, 97.77, 47.05, 36.16. 3-[6-[tert-Butyl(dimethyl)silyl]oxy-1,3-benzodioxol-5yl]-1-[[5-(trifluoromethyl)-2-furyl]methyl]indolin-2-one (18). A 200 L Hastelloy reactor was charged with 17 (16.2 kg, 38.8 mol, LR) and tert-butyldimethylsilyl chloride (7.60 kg, 50.4 mol, 1.3 equiv). Tetrahydrofuran (57.7 kg, 4 vol) was next added to the vessel by vacuum. The contents were agitated at 120 rpm, while a solution formed. Next, triethylamine (8.63 kg, 85.3 mol, 2.2 equiv) was added over 14 min, giving a slight exotherm from 20 to 30 °C. The reaction was stirred for 20 h after which no 17 was detected by IPC through HPLC. A solution of conc. HCl (36.5−38%, 4.01 kg, 1.05 equiv) and sodium chloride (8.02 kg) in DI water (43.3 kg, 2.7 vol) was added over 50 min to adjust the pH to below 1. The temperature of the batch was maintained between 11 and 16 °C during the addition. The batch was then stirred at 22 °C for 30 min. The top layer was sampled, and no bis-silylated side product was detected by HPLC. The bottom layer was then removed and discarded to waste. Next, solvent exchange was performed into isopropanol and the temperature lowered to 10 °C. Seeds (40 g) were added, and crystallization was observed after 37 min at 10 °C. The mixture was then stirred for 2 h. DI water (13.0 kg, 0.8 vol) was next added over 25 min. After a 15 min hold, additional DI water (27.5 kg, 1.7 vol) was added over 28 min allowing the temperature to rise to 25 °C. The slurry was stirred for 21 h and then isolated using an Aurora filter. The solids were washed with isopropanol−DI water (1:1, 48.6 L, 3.0 vol) and dried on the Aurora filter below 30 °C for 22 h. The in-process control showed a weight loss of 4.5% by TGA. The solids were transferred into the tray dryer and dried for 26 h at 28−30 °C. TGA analysis showed 0.07% weight loss at this point. This gave 18.2 kg (88%) of 18 as a white solid with 100 A% purity. 1H NMR (DMSO, 400 MHz) δ 7.32 (d, J = 7.5 Hz, 1H)7.18 (m, 1H), 7.14 (d, J = 7.9 Hz, 1H), 7.00 (m, 2H), 6.77 (d, J = 3.5 Hz, 1H), 6.58 (s, 1H), 6.02 (s, 1H), 5.95 (d, J = 10.1 Hz, 2H), 5.07 (m, 3H), 0.96 (s, 9H), 0.69 (s, 6H). G



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was agitated at this temperature for 21 h. An IPC was performed, and the remaining amount of 24 was measured to be 0.15 A% by HPLC. After cooling to 20 ± 5 °C, a solution of 30% hydrogen peroxide in water (0.65 kg, 0.3 equiv) in acetonitrile (8.3 kg, 0.5 vol) was charged such that the temperature did not rise above 35 °C. The batch was then cooled to 20 ± 5 °C and an IPC to measure peroxide showed none detected. Next, using an Aurora filter, the precipitated diphenylphosphinic acid was separated from the reaction mixture. The resulting solution containing the product was recharged to the reactor, and solvent was exchanged for methanol. An IPC showed no acetonitrile detected by GC. Once the solvent exchange was completed, the temperature of the batch was raised to 65 ± 5 °C and cooled to 50 ± 5 °C where IPC was performed and showed the concentration was 227 mg/mL. Estimating the volume of the batch at 38 L, an additional amount of methanol (12 kg) was added to adjust the concentration to the nominal range of 135−163 mg/mL. To begin the crystallization of the product, the batch was cooled to 35 ± 3 °C, and TV-45070 seeds (110 g) were added. After agitating for 1 h, DI water (12.7 kg, 1.19 vol) was added while maintaining the temperature at 35 °C. The batch was then cooled to 22 ± 3 °C over 30 min and agitated at that temperature for 12.5 h. The product was then filtered using an Aurora filter, and the cake was washed with a preprepared 23% aqueous methanol solution (4 vol) followed by water (18 kg). The solids were agitated in the wash solvent while on the filter prior to application of vacuum. The solids were then dried under vacuum (50−80 mmHg) for 3.5 days. After that period, the product was found to have LOD of 0.087%. The final weight was 6.59 kg (80.7% yield). The purity was 99.6 A% with 100% ee. 1H NMR (DMSO, 400 MHz) δ 7.32 (t, J = 7.7 Hz, 1H), 7.20 (m, 3H), 7.07 (t, J = 7.3 Hz, 1H), 6.77 (d, J = 3.3 Hz, 1H), 6.72 (s, 1H), 6.10 (s, 1H), 5.94 (d, J = 9.1 Hz, 1H), 5.94 (d, J = 9.1 Hz, 1H), 5.13 (d, J = 16.5 Hz, 1H), 5.02 (d, J = 16.5 Hz, 1H), 4.82 (d, J = 9.5 Hz, 1H), 4.73 (d, J = 9.5 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): 176.48, 155.28, 153.02, 148.40, 141.80, 141.51, 139.54 (q, JCF = 41.9 Hz), 131.63, 128.79, 123.64, 123.29, 119.69, 118.92 (q, JCF = 266.4 Hz), 114.01 (q, JCF = 2.9 Hz) 109.86, 109.21, 102.55, 101.44, 93.31, 79.52, 57.41, 36.44.

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H.R.: Dermira Inc., Menlo Park, California 94025, United States. # R.P.B.: Receptos Inc., 3033 Science Park Rd., San Diego, California 92121, United States. Notes

The authors declare no competing financial interest.

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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.oprd.7b00237. Spectral data of selected intermediates and of the final compound (PDF)

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Joseph A. Sclafani: 0000-0003-4126-9463 Present Addresses §

J.A.S., D.V.L.: Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States. ∥ J.C.: Celgene Corporation, 86 Morris Ave., Summit, New Jersey 07901, United States. H



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Olsen, M. A.; Neville, C. J.; Muthukumaran, K. Org. Process Res. Dev. 2017, 21, 408−413.

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The First Asymmetric Pilot-Scale Synthesis of TV-45070 - Organic

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