Practical and Scalable Synthetic Method for Preparation of

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Practical and Scalable Synthetic Method for Preparation of Dolutegravir Sodium: Improvement of a Synthetic Route for LargeScale Synthesis Yasunori Aoyama,*,† Toshikazu Hakogi,‡ Yuki Fukui,† Daisuke Yamada,† Takao Ooyama,§ Yutaka Nishino,‡ Shoji Shinomoto,† Masahiko Nagai,§ Naoki Miyake,‡ Yoshiyuki Taoda,§ Hiroshi Yoshida,§ and Tatsuro Yasukata†

Org. Process Res. Dev. Downloaded from pubs.acs.org by WEBSTER UNIV on 03/01/19. For personal use only.

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API R&D Laboratory, CMC R&D Division, Shionogi and Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan ‡ Production Technology Department, Manufacturing Division, Shionogi and Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan § Shionogi Pharmaceutical Research Center, Shionogi and Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan ABSTRACT: A practical and scalable synthetic method to obtain dolutegravir sodium (1) was established starting from the readily accessible material maltol (2). This synthetic method includes a scalable oxidation process of maltol and palladiumcatalyzed amidation for introduction of an amide moiety, leading to a practical manufacturing method in short synthetic steps. The synthetic method demonstrated herein enables multikilogram scale manufacturing of 1 of high purity. KEYWORDS: dolutegravir sodium, oxidation of maltol methyl group, intramolecular aminolysis, palladium-catalyzed amidation

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INTRODUCTION Human Immunodeficiency Virus type-1 (HIV-1) integrase inhibitor is one of the important categories for the treatment of HIV/AIDS (acquired immunodeficiency syndrome). Among them, dolutegravir sodium (1) has significant properties in terms of its potent antiviral activity and high genetic barrier to resistance and has been widely used worldwide since its launch into the market in 2013. Dolutegravir sodium (1) has a highly functionalized tricyclic core structure (Figure 1), and thus

yield (∼2%) and difficult application to practical scale production (Scheme 1).2 The issue of many synthetic steps could be attributed to the functionalization of the starting material maltol (2) and the subsequent functional group transformation.3 In particular, many synthetic steps were needed for oxidation of the methyl group of the protected maltol 3 via pyridine N-oxide 8 and the introduction of the difluorobenzyl amide moiety into the cyclic core structure. Considering these issues of the medicinal chemistry route shown in Scheme 1, we attempted to retrosynthetically find a more efficient and practical synthetic route (Scheme 2). At first, direct oxidation of the methyl group of 3 was investigated in pursuit of a practical and scalable method to prepare pyrone carboxylic acid 21 (Table 1). Bromination using NBS in MeCN gave bromide 22, but the reaction did not go to completion and a considerable amount of 3 remained unreacted. Other attempts at bromination or oxidation of 3 using various oxidants other than selenium dioxide were not successful. Oxidation with selenium dioxide was not feasible for large scale production due to the usage of a stoichiometric amount of toxic selenium dioxide, the sticking of byproducts derived from selenium dioxide to the reactors, and a high reaction temperature (140 °C). We therefore decided to further investigate functionalization of the methyl moiety of 3. We next examined alternative transformation of the functionality of the methyl group 3 other than by direct oxidation. After extensive exploration, we finally found that the

Figure 1. Dolutegravir sodium.

many synthetic steps and chromatographic purification procedures were required for its preparation in the medicinal chemistry stage, resulting in difficulty for large-scale synthesis. We report herein exploration for improvement of the synthetic route, process development, and manufacturing procedure for practical scale production of dolutegravir sodium (1).1

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RESULTS AND DISCUSSION Construction of the highly functionalized tricyclic structure of dolutegravir sodium (1) has been a key issue since its discovery in the medicinal chemistry stage. The synthetic route at that stage required numerous synthetic steps (17 steps) along with chromatographic purification operations, leading to a low total © XXXX American Chemical Society

Special Issue: Japanese Society for Process Chemistry Received: November 30, 2018

A

DOI: 10.1021/acs.oprd.8b00409 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Scheme 1. Synthetic Route for Dolutegravir Sodium (1) in the Medicinal Chemistry Stage

enolate derived from 3 could react with benzaldehyde to provide aldol-type adduct 24 (Table 2).4

Scheme 2. Retrosynthetic Analysis of Dolutegravir Sodium (1)

Table 2. Aldol-Type Condensation of 3 with Benzaldehyde

Table 1. Direct Oxidation of the Methyl Group of 3

entry

conditions

results

1 2 3 4 5 6 7 8

NBS/MeCN, 60 °C NBS/AIBN/CCl4 Bu4NBr3/MeCN 60 °C NaIO4/LiBr/AcOH, 100 °C NaClO/NaOH aq KMnO4/CHCl3−H2O RuCl3/NaClO aq SeO2/PhBr, 140 °C, 13 h

22: ∼50% decomposition no reaction no reaction no reaction no reaction no reaction 23: 6570%

entry

base

solvent

temperature

yield of 24 (%)

1 2 3 4 5 6 7 8

t-BuOK t-BuOLi MeOLi i-PrMgBr DBN LiN(SiMe3)2 LiN(SiMe3)2 LiN(SiMe3)2

THF THF MeOH THF DMSO THF THF THF

0 °Cr.t. 0 °Cr.t. 0 °Cr.t. −78 °C−r.t. r.t.−90 °C −60 °C −50 °C −40 °C

decomposition 4050 no reaction trace trace 74 73 49

Use of alkoxide, Grignard reagent, or an amine base provided a small or only trace amount of 24 (entries 1−5); however, yields of 24 were improved by employing lithium bis(trimethylsilylamide) (LiN(SiMe3)2) as a base (entries 6− 8). Additionally, the temperature for enolate formation was found to be important, since the adduct 24 could be obtained in satisfactory yield below −50 °C (entries 6 and 7), whereas the yield decreased considerably at −40 °C, indicating decomposition of the enolate of 3 at higher temperatures (entry 8). B

DOI: 10.1021/acs.oprd.8b00409 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Scheme 3. Synthetic Route to Pyrone Carboxylic Acid 21a

(a) BnBr, K2CO3, MeCN, (b) (1) LiN(SiMe3)2, (2) PhCHO, THF, −65 °C (83%, 2 steps), (c) (1) MsCl, Et3N, (2) DBU, N-methylpyrrolidone (95%), (d) (1) RuCl3−NaIO4, (2) TEMPO-NaClO, MeCN aq (70%).

a

Scheme 4. Attempts to Prepare Aldehyde 20

Scheme 5. Successful Preparation of Aldehyde 20 as Its Hydrate Form 31 Using 3-Amino-1,2-propanediola

a

(a) 3-amino-1,2-propanediol, EtOH (83%), (b) Me2SO4, NaHCO3, N-methylpyrrolidone (82%), (c) NaIO4, MeCN aq (89%).

methyl ester 26, but oxidation of primary alcohol of 26 did not proceed (TEMPO, Swern, or Dess-Martin oxidation, etc.). Moreover, 26 was quite unstable and easily cyclized to lactone 27. The lactone formation was not suppressed even if the ester moiety was changed to tert-butyl ester. Next, we tried using aminoacetaldehyde dimethyl acetal, but acid-catalyzed hydrolysis of the acetal moiety of 28 did not proceed. After extensive exploration, we finally developed a synthetic method using 3amino-1,2-propanediol. The lactone formation of the resulting ester 30 was effectively suppressed and the diol moiety of 30 was oxidatively cleaved to give the desired aldehyde 20 in good yield as a hydrate form 31 (Scheme 5). Conversion of aldehyde equivalent 31 to dolutegravir sodium (1) was accomplished by the synthetic scheme shown in Scheme 6. Diastereoselective tricyclic scaffold formation was accomplished using (R)-3-aminobutan-1-ol under acidic conditions. In the medicinal chemistry stage, cyclization was conducted in dichloromethane under microwave conditions. Examining the reaction conditions revealed that toluene-acetic acid was a suitable solvent system for preparative scale synthesis of 19. The cyclization reaction proceeded in high diastereoselectivity (>20:1) and the further improvement of the diastereoselectivity was accomplished by the subsequent crystallization to provide the tricyclic product 19 (>200:1). The high diastereoselectivity would be due to the difference of the reaction rate of the intramolecular aminolysis between the intermediary diastereomeric aminals 33 and 34, which are in

The adduct 24 was dehydrated to give styrene 25, whose double bond was oxidatively cleaved to give the desired carboxylic acid 21 (Scheme 3). In the initial manufacturing campaign from 25 to 21, NaClO2 was used for the oxidation of intermediary aldehyde 23 to carboxylic acid 21. However, there was a safety concern that an explosive chlorine dioxide (ClO2) would be formed by the reaction between HClO generated and reagent NaClO2 (eq 1). Therefore, hydrogen peroxide was added to eliminate NaClO (eq 2), and the evolving oxygen gas was diluted to a concentration of less than 5%, the explosive limit concentration of oxygen gas, by introducing nitrogen gas through the reactor in the first campaign. 2NaClO2 + HClO → 2ClO2 + NaCl + NaOH

(1)

NaClO + H 2O2 → NaCl + H 2O + O2

(2)

For a safer and more scalable process, we established an oxidation method using the combination of TEMPO (2,2,6,6tetramethylpiperidine 1-oxyl) and NaClO instead of NaClO2/ H2O2 and conducted the manufacturing of 21 in the multihundred mole scale in the next campaign.5 In the medicinal stage synthetic method, osmium reagent was used for oxidation of the allyl moiety of 15 to obtain the aldehyde intermediate. To avoid the toxic osmium reagent, the method for preparing aldehyde intermediate 20 was explored (Scheme 4). We first used ethanolamine for pyridone formation. The resulting pyridone was transformed into C

DOI: 10.1021/acs.oprd.8b00409 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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withdrawing bromide or amide substituents. Formation of the debenzylated byproduct 18 would presumably arise from benzylation of PPh3; that is, PPh3 attacks at the benzylic position of 17, leaving debenzylated 18 as a good leaving group.8 The electron deficiency of the tricyclic scaffold is considered to contribute to the formation of the byproducts. Removal of the benzyl protecting group of 17 and the following sodium salt formation gave the desired dolutegravir sodium (1) as previously reported.1b The impurity 35 was removed during the isolation step of debenzylation and salt formation, and 1 with high purity was obtained (99.9 HPLC peak area%). The amount of residual palladium was reduced to less than 4 ppm in 18 (free form of 1) by treatment with activated charcoal and crystallization after debenzylation of 17. After sodium salt formation and crystallization, the residual palladium was further reduced to less than 1 ppm in the final API, thus achieving the successful development of a preparative scale manufacturing method of 1 (Scheme 7).

Scheme 6. Synthetic Scheme for Dolutegravir Sodium 1 from Aldehyde Hydrate 31a

a

(a) (R)-3-aminobutan-1-ol, AcOH, toluene (83%), (b) NBS, DCM (85%), (c) 2,4-difluorobenzylamine, Pd(PPh3)4, diisopropylethylamine, CO, DMSO (90%), (d) Pd−C, H2, THF−H2O (74%), (e) NaOH aq, EtOH (95%).

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an equilibrium, in the same manner as reported elsewhere;6 that is, intermediate 33 with a methyl moiety at the axial position is sterically favored for cyclization over 34 due to its lesser steric hindrance between the methyl and the ester moiety (see Figure 2).

CONCLUSION The synthetic method for preparing dolutegravir sodium (1) was explored, and a practical and scalable method was established. Construction of a highly functionalized tricyclic scaffold was the key issue to establishing a practical synthetic route to 1. We were able to do this by developing efficient and practical methods for functionalization and functional group transformation starting from maltol (2). The synthetic route developed herein gives quite high yields at each conversion step and with the purity of the 1 obtained being up to 99.9%, thus enabling the supply large amounts of 1 of high purity.

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Figure 2. Intermediary aminals for intramolecular aminolysis.

EXPERIMENTAL SECTION General. All materials were purchased from commercial suppliers. Unless otherwise specified, all reagents and solvents were used without further purification. 1H NMR and 13C NMR spectra were recorded in the solvent indicated on Varian Mercury NMR spectrometer or Varian Unity INOVA 500 spectrometer, and FAB mass spectra were recorded on a JEOL JMS-SX/SX102A spectrometer. 3-(Benzyloxy)-2-(2-hydroxy-2-phenylethyl)-4H-pyran-4one (24). To a solution of maltol (2) (55.0 kg, 436 mol) in acetonitrile (606 kg) was added potassium carbonate (72.3 kg, 523 mol) and benzyl bromide (78.3 kg, 458 mol), and the whole solution was stirred at 70 °C for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and to the concentrate was added toluene (240 kg) and water (275 L). After being stirred for 5 min, the organic layer was separated, washed with 3% NaCl aq (275 L), and concentrated under reduced pressure to the volume of 110 L. To the concentrate was added THF (670 kg), cooled to −65 °C, added lithium bis(trimethylsilylamide) (87.6 kg, 524 mmol) in THF solution, and stirred for 0.5 h. Benzaldehyde (55.5 kg, 524 mol) was added and stirred at −65 °C for an additional 2 h. The reaction mixture was added to the mixture of water (540 L), HCl aq (136 kg), and ethyl acetate (970 L) at 0 °C, and the organic layer was separated, washed with 3% NaCl aq, and concentrated under reduced pressure. To the residue was added toluene (285 kg) and concentrated. The concentrate was cooled to 5 °C, and precipitate was collected by centrifugation to give 24 (116.6 kg, 83%) as a white to light yellowish white solid.

Bromination of 19 was accomplished using N-bromosuccinimide, and the resulting bromide 32 was converted to amide 17 by applying palladium-catalyzed amidation7 using Pd(PPh3)4 catalyst and 2,4-difluorobenzylamine under carbon monoxide atmosphere. Amidation proceeded smoothly and chromatographic purification was eliminated by examining the workup procedure. The desired amidated product 17 was obtained in good yield along with a small amount of impurity 35 (1.5%) and debenzylated byproduct of 18 (free form of 1, 4.0%) (Figure 3). The byproduct 35 was identified as a product having one more 2,4-difluorobenzylamine moiety by nucleophilic aromatic substitution of 2,4-difluorobenzylamine for benzyl alcohol, and its formation was competitive with that of 32 to 17 in the reaction course. This nucleophilic substitution of difluorobenzylamine is considered to be attributed to the electron-deficient nature of the tricyclic scaffold with electron-

Figure 3. Structure of the process impurities formed in palladiumcatalyzed amidation. D

DOI: 10.1021/acs.oprd.8b00409 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Scheme 7. Overview of the Preparative Synthetic Scheme for the Preparation of Dolutegravir Sodium (1)

H NMR (300 MHz, CDCl3) δ 7.62 (d, J = 5.7 Hz, 1H), 7.5−7.2 (m, 10H), 6.38 (d, J = 5.7 Hz, 1H), 5.16 (d, J = 11.4 Hz, 1H), 5.09 (d, J = 11.4 Hz, 1H), 4.95 (dd, J = 4.8, 9.0 Hz, 1H), 3.01 (dd, J = 9.0, 14.1 Hz, 1H), 2.84 (dd, J = 4.8, 14.1 Hz, 1H). (E)-3-(Benzyloxy)-2-styryl-4H-pyran-4-one (25). To a solution of 24 (116.6 kg, 362 mol) and triethylamine (54.9 kg, 543 mol) in THF (1036 kg) was added methanesulfonyl chloride (53.9 kg, 471 mol) and stirred at room temperature for 1 h. To the reaction mixture was added N-methylpyrrolidone (60 kg) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 154 kg) and stirred for 1 h. To the reaction mixture was added H2SO4−NaCl aq, and the organic layer was separated and concentrated under reduced pressure. To the concentrate was added acetonitrile (137 kg), cooled to 5 °C, and stirred for 30 min. The precipitate was collected by centrifugation to give 25 (107.7 kg, 95%) as a white to light yellowish white solid. 1 H NMR (300 MHz, CDCl3) δ 7.69 (d, J = 5.7 Hz, 1H), 7.50−7.25 (m, 10H), 7.22 (d, J = 16.2 Hz, 1H), 7.03 (d, J = 16.2 Hz, 1H), 6.41 (d, J = 5.7 Hz, 1H), 5.27 (s, 2H). 3-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (21). To a solution of 25 (104 kg, 342 mol), ruthenium chloride (142 g, 0.68 mol) in acetonitrile (778 kg) and water (104 L) was added a solution of sulfuric acid (75 kg) and sodium periodate (161 kg) in water (1610 L) at room temperature. After completion of the reaction, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (312 L × 2). The combined extract was washed successively with aqueous sodium hydrogen sulfite and 2 M aqueous sodium hydroxide solution. To this was added TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl, 2.7 kg, 0.017 mol) and 5% sodium hydrogen carbonate solution (615 L) and added dropwise a solution of sodium hypochlorite at room temperature. After completion of the reaction, the reaction mixture was washed with aqueous sodium hydrogen sulfite, and the aqueous layer was extracted with ethyl acetate. To the combined organic layer was added aqueous 12% sulfuric acid aq (227 L), and the precipitate was 1

collected by centrifugation to give 21 (59.1 kg, 70%) as a white to light yellowish white solid. 1 H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 5.7 Hz, 1H), 7.54−7.46 (m, 2H), 7.40−7.26 (m, 3H), 6.48 (d, J = 5.7 Hz, 1H), 5.6 (brs, 1H), 5.31 (s, 2H). 3-(Benzyloxy)-1-(2,3-dihydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid (29). To a solution of 21 (32.2 kg, 131 mol) in ethanol (76 kg) was added a solution of 3-amino1,2-propanediol (29.8 kg, 327 mol) in ethanol (51 kg) at 65 °C and stirred at 75 °C for 3.5 h. After cooling to 40 °C, the reaction mixture was concentrated under reduced pressure and to the concentrate was added ethyl acetate (161 L) and water (193 L). The organic layer was separated, and to the organic layer was added 12% sulfuric acid aq. The precipitate was collected by centrifugation, washed, and dried to give 29 (34.87 kg, 83%) as a white to light yellowish white solid. 1 H NMR (300 MHz, DMSO-d6) δ 7.67 (d, J = 7.5 Hz, 1H), 7.5−7.2 (m, 5H), 6.40 (d, J = 7.5 Hz, 1H), 5.07 (s, 2H), 4.2− 4.0 (m, 1H), 3.9−3.6 (m, 2H), 3.38 (dd, J = 4.2, 10.8 Hz, 1H), 3.27 (dd, J = 6.0, 10.8 Hz, 1H). FAB-MS m/z 320 [M + H]+ Methyl 3-(benzyloxy)-1-(2,3-dihydroxypropyl)-4-oxo-1,4dihydropyridine-2-carboxylate (30). To a solution of 29 (8.0 kg, 25.1 mol) and sodium hydrogen carbonate (6.3 kg) in N-methylpyrrolidone (41 kg) and water (0.43 kg) was added dimethyl sulfate (4.73 kg, 37.5 mol) at 30 °C. After cooling to 5 °C, 2 N HCl aq and 20% aqueous sodium chloride solution were successively added and stirred at 5 °C for 30 min. The precipitate was collected by filtration, washed, and dried to give 30 (6.80 kg, 81%) as a white to light yellowish brownish white solid. 1 H NMR (500 MHz, DMSO-d6) δ 7.59 (d, J = 7.5 Hz, 1H), 7.4−7.3 (m, 5H), 6.28 (d, J = 7.5 Hz, 1H), 5.21 (d, J = 5.4 Hz, 1H), 5.12 (d, J = 10.8 Hz, 1H), 5.07 (d, J = 10.8 Hz, 1H), 4.84 (t, J = 5.7 Hz, 1H), 3.97 (dd, J = 2.4, 14.1 Hz, 1H), 3.79 (s, 3H), 3.71 (dd, J = 9.0, 14.4 Hz, 1H), 3.65−3.55 (m, 1H), 3.40−3.30 (m, 1H), 3.24−3.17 (m, 1H). FAB-MS m/z 334 [M + H]+ Methyl 3-(benzyloxy)-1-(2,2-dihydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylate (31). To a solution of 30 (6.80 E

DOI: 10.1021/acs.oprd.8b00409 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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sulfoxide (18.6 kg) was added tetrakis(triphenylphosphine) palladium (466 g) and stirred at 90 °C under carbon monoxide atmosphere for 5 h. After cooling to room temperature, ethyl acetate (61 kg) and water (48 kg) were added and insoluble material was filtered off. Organic layer was separated and ethyl acetate (91 kg) added. The organic layer was washed with 0.5 N HCl aq and concentrated. To the residue was added 2propanol (26.5 kg) and concentrated. The precipitate was collected by filtration, washed, and dried to give 17 (3.70 kg, 90%) as a solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.40 (t, J = 6.0 Hz, 1H), 8.59 (s, 1H), 7.60−7.56 (m, 2H), 7.45−7.30 (m, 4H), 7.24 (td, J = 10.5, 2.5 Hz, 1H), 7.06 (td, J = 8.5, 1.5 Hz, 1H), 5.35 (dd, J = 5.5, 4.0 Hz, 1H), 5.06 (s, 2H), 4.82−4.75 (m, 1H), 4.60−4.52 (m, 3H), 4.36 (dd, J = 13.5, 6.0 Hz, 1H), 3.96 (t, J = 10.5 Hz, 1H), 3.9−3.8 (m, 1H), 2.0−1.9 (m, 1H), 1.51 (dd, J = 13.5, 1.5 Hz, 1H), 1.27 (d, J = 7.0 Hz, 3H). FAB-MS m/z 510 [M + H]+, 1019 [2M + H]+ Dolutegravir Sodium (1). To a solution of 17 (3.70 kg, 7.26 mol) in tetrahydrofuran (55.9 kg) and water (1.9 kg) was added 5% Pd−C (2.96 kg) in water (7.8 kg) under nitrogen atmosphere. After replacing the atmosphere with hydrogen, the whole was stirred at 40 °C under hydrogen atmosphere for 2 h. The reaction mixture was filtered, and to the filtrate was added activated carbon (0.37 kg) and stirred at 40 °C for 2 h and filtered. The filtrate was concentrated under reduced pressure and to the concentrate was added water (74 kg) dropwise and stirred for 1 h. The precipitate formed was collected by filtration, washed with ethanol, and dried under reduced pressure to give 18 (2.22 kg), which was dissolved in ethanol (94.6 kg) and water (13.3 kg) at 70 °C. To the solution was added a solution of sodium hydroxide (212 g) in water (2.6 kg) at 60 °C and stirred at 25 °C for 3 h. The precipitate was collected by filtration, washed with ethanol (8.8 kg), and dried under reduced pressure to give 1 (2.22 kg, 69%, 99.9 HPLC peak area %). 1 H NMR (500 MHz, DMSO-d6) δ 10.70 (t, J = 6.0 Hz, 1H), 7.89 (s, 4H), 7.35 (td, J = 8.7, 6.8 Hz, 1H), 7.20 (ddd, J = 10.4, 4.9, 4.2 Hz, 1H), 7.02 (m, 1H), 5.17 (dd, J = 5.1, 3.4 Hz, 1H), 4.81 (m, 1H), 4.51 (d, J = 6.0 Hz, 2H), 4.31 (dd, J = 14.0, 3.4 Hz, 1H), 4.16 (dd, J = 14.0, 5.1 Hz, 1H), 3.97 (td, J = 11.9, 2.3 Hz, 1H), 3.81 (m, 1H), 1.87 (m, 1H), 1.38 (m, 1H), 1.24 (d, J = 7.1 Hz, 3H). 13C NMR (125 MHz, DMSO-d6) δ 177.84, 167.00, 165.94, 161.20 (dd, J = 244.6, 11.9 Hz), 161.01, 159.93 (dd, J = 246.7, 12.0 Hz), 134.21, 130.46 (dd, J = 9.8, 6.3 Hz), 122.85 (dd, J = 15.0, 3.5 Hz), 114.76, 111.14 (dd, J = 20.9, 4.0 Hz), 108.62, 103.57 (t, J = 25.9 Hz), 75.52, 61.81, 53.05, 42.87, 35.22, 29.13, 15.25. FAB-MS m/z 464 [M + Na]+, 442 [M + H]+

kg, 20.4 mol), acetic anhydride (0.12 kg) in acetonitrile (54 kg), and water (3.4 kg) was added dropwise a solution of sodium periodate (5.24 kg) in water (68 kg) at 30 °C. After completion of the reaction, a solution of ascorbic acid (12.9 kg) in water (116 kg) was added and concentrated under reduced pressure. To the concentrate was added water (27 kg) at 5 °C and the whole was allowed to stand at 5 °C for 1 h. The precipitate was collected by filtration, washed, and dried to give 31 (5.78 kg, 89%) as a solid. 1 H NMR (500 MHz, DMSO-d6) δ 7.61 (d, J = 7.6 Hz, 1H), 7.32−7.36 (m, 5H), 6.31 (d, J = 6.9 Hz, 2H), 6.29 (d, J = 7.6 Hz, 1H), 5.09 (s, 2H), 4.91 (m, 1H), 3.80 (s, 3H), 3.73 (d, J = 5.3 Hz, 2H).13C NMR (125 MHz, DMSO-d6) δ 172.42, 162.31, 144.72, 141.24, 137.01, 135.21, 128.14, 128.13, 127.86, 116.87, 87.86, 72.61, 59.05, 53.03. FAB-MS m/z 320 [M + H]+ (4R,12aS)-7-(Benzyloxy)-4-methyl-3,4,12,12a-tetrahydro2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione (19). A solution of 31 (590 g, 1.85 mol) in methanol (5.9 L) was stirred at 70 °C for 30 min, then concentrated under reduced pressure. To the residue was added toluene (3.0 L), acetic acid (380 mL), and (R)-3-aminobutan-1-ol (139 g), and the whole was stirred at 90 °C for 2 h. After cooled to 50 °C, the reaction mixture was concentrated under reduced pressure and to the residue was added water (3.0 L) and extracted with chloroform (3.0 L × 2). The combined extract was concentrated and ethyl acetate (3.0 L) was added. The precipitate was collected by filtration, washed with ethyl acetate, and dried to give 19 (504.4 g, 80%) as a solid. 1 H NMR (500 MHz, DMSO-d6) δ 7.69 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.4−7.3 (m, 3H), 6.32 (d, J = 7.5 Hz, 1H), 5.29 (dd, J = 5.7, 5.5 Hz, 1H), 5.03 (d, J = 10.5 Hz, 1H), 5.02 (d, J = 10.5 Hz, 1H), 4.8−4.7 (m, 1H), 4.32 (dd, J = 13.5 4.0 Hz, 1H), 4.11 (dd, J = 13.5, 8.0 Hz, 1H), 4.0−3.8 (m, 2H), 2.0−1.9 (m, 1H), 1.5−1.4 (m, 1H), 1.27 (d, J = 7.0 Hz, 3H). FAB-MS m/z 341 [M + H]+ (4R,12aS)-7-(Benzyloxy)-9-bromo-4-methyl-3,4,12,12atetrahydro-2H-pyrido [1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine6,8-dione (32). To a solution of N-bromosuccinimide (1.85 kg, 10.4 mol) in dichloromethane (8.5 kg) was added dropwise a solution of 19 (3.22 kg, 9.46 mol) in dichloromethane (34.1 kg) at room temperature and stirred for 30 min. After completion of the reaction, 5% aqueous sodium hydrogen sulfite solution was added and organic layer was separated. The organic layer was washed with water (13 kg) and concentrated. To the residue was added N-methylpyrrolidone (13 kg) and concentrated. To the residue was added water (35 kg) and the precipitate was collected by filtration, washed, and dried to give 32 (3.38 kg, 85%) as a solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.56 (d, J = 7.7 Hz, 2H), 7.4−7.3 (m, 2H), 7.31 (t, J = 7.3 Hz, 1H), 5.32 (dd, J = 5.4, 3.8 Hz, 1H), 5.05 (d, J = 10.9 Hz, 1H), 5.03 (d, J = 10.9 Hz, 1H), 4.82−4.74 (m, 1H), 4.39 (dd, J = 13.6, 3.7 Hz, 1H), 4.18 (dd, J = 13.6, 5.4 Hz, 1H), 3.96 (td, J = 11.8, 8.2 Hz, 1H), 3.84 (ddd, J = 11.8, 4.9, 2.4 Hz, 1H), 1.90−1.98 (m, 1H), 1.49 (dq, J = 13.6, 2.4 Hz, 1H), 1.27 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, DMSO-d6) δ 169.26, 155.56, 148.54, 139.83, 137.31, 129.83, 128.26, 127.91, 127.65, 112.43, 75.60, 72.84, 61.72, 51.44, 44.32, 29.13, 15.60. FAB-MS m/z 419 [M + H]+ (4R,12aS)-7-(Benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2’:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (17). To a solution of 32 (3.38 kg, 8.06 mol), diisopropylethylamine (2.6 kg) and 2,4-difluorobenzylamine (1.73 kg) in dimethyl

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yasunori Aoyama: 0000-0003-1932-6396 Tatsuro Yasukata: 0000-0002-9625-0957 Notes

The authors declare no competing financial interest.

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REFERENCES

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DOI: 10.1021/acs.oprd.8b00409 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

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DOI: 10.1021/acs.oprd.8b00409 Org. Process Res. Dev. XXXX, XXX, XXX−XXX