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A Concise and Efficient Synthesis of Dapagliflozin Jun Yu,* Ying Cao, HaiZhou Yu, and JinJia Wang The Research Academy of Jiangsu Hansoh Pharmaceutical Co., LTD, Dongjin Road, Huaguoshan Avenue, Lianyungang, Jiangsu 222069, P. R. China
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the solvent, the crude product 9 was obtained as an oil, for which purification was a great challenge. After screening of solvents,6 we found that the crude oil could be efficiently crystallized from a mixture of n-propanol and n-heptane to generate 9 in >98.5% purity as the crystalline n-propanol solvate (78% yield for two steps). The next step, entailing the reduction of ethyl C-aryl glycoside 9, was also optimized. In general, the reduction of tetra-O-protected methyl C-aryl glycosides to the corresponding β-C-aryl glycosides with a Lewis acid and silane proceeds with high diastereoselectivity.7−10 Wang et al. found that tetraO-unprotected methyl C-aryl glycosides could be successfully reduced using AlCl3 or BF3·Et2O and Et3SiH with very high diastereoselectivity (β:α > 99:1).11 Therefore, the direct reduction of tetra-O-unprotected ethyl C-aryl glycoside 9 was investigated. When a mixture of 9 and Et3SiH in CH3CN/ CH2Cl2 was treated with BF3·OEt2, the reaction proceeded smoothly at −15 °C, and crude β-C-aryl glycoside 1 was obtained with very high diastereoselectivity (β:α > 99:1). However, furanoside byproducts 10a/b were generated in up to 20% yield as a 1:1 mixture of α/β anomers (Scheme 3). This side reaction is mainly attributed to the water content of the reaction mixture.11 Raising the water content from 0.1% to 1.95% and 3.82% substantially enhanced the formation of impurities 10a/b (Table 1). Therefore, a low water content (98.5%). The tetra-O-unprotected compound 9 could be directly reduced to crude dapagliflozin with high diastereoselectivity. The final pure API product 1 was isolated and purified with high purity (>99.7%). The process has been implemented on a multikilogram scale. KEYWORDS: dapagliflozin, ethyl C-aryl glycoside, crystalline n-propanol solvate, diastereoselectivity
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INTRODUCTION Dapagliflozin (1) is a selective SGLT-2 inhibitor for the treatment of type 2 diabetes.1,2 It was approved by the U.S. Food and Drug Administration on Jan 8, 2014. However, the method for the synthesis of dapagliflozin has been rarely reported.1−4The general synthetic pathway for dapagliflozin is outlined in Scheme 1.1−3 Trimethylsilyl (TMS)-protected gluconolactone 3 is added to the aryllithium formed by Br/Li exchange of aryl bromide 2 with n-BuLi. The resulting mixture is then treated with methanesulfonic acid in methanol to give methyl C-aryl glycoside 4. Compound 4 is acetylated with Ac2O to generate 5, which is subsequently reduced to 6 with triethylsilane (Et3SiH) and BF3·Et2O. Hydrolysis of 6 with lithium hydroxide generates 1. In this process, compound 4 is hard to isolate and purify because of its syrupy nature. Because tetra-acetylated compounds 5 and 6 are stable crystalline solids, their isolation is ideal to effect a necessary purification. However, the undesired protection and deprotection strategy makes the process unattractive and economically inefficient on the industrial level. We report herein a concise and practical route to 1.
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RESULTS AND DISCUSSION The improved synthetic route for dapagliflozin is outlined in Scheme 2. Persilylated gluconolactone 3 was prepared in quantitative yield by addition of trimethylsilyl chloride to gluconolactone 7 in N-methylmorpholine and THF.5 Aryl bromide 2 was treated with n-BuLi and, when the Br/Li exchange was complete, persilylated lactone 3 was added. Then trifluoroacetic acid in water was added to the resulting reaction mixture to obtain the intermediate lactol 8. Compound 8 was subsequently treated with methanesulfonic acid in EtOH to yield ethyl C-aryl glycoside 9. After workup and distillation of © XXXX American Chemical Society
Received: April 2, 2019 Published: June 27, 2019 A
DOI: 10.1021/acs.oprd.9b00141 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Communication
Scheme 1. Synthetic Approach to Dapagliflozin (1) from the Literature1
Scheme 2. Improved Route to 1
Scheme 3. Impurities 10a/b
n-propanol solvate. A low content of water and n-propanol was necessary to suppress the formation of furanoside side products during the reduction of compound 9. Dapagliflozin could be obtained in >99.7% purity upon crystallization from ethyl acetate/heptane.
Table 1. Effect of Water Content on the Formation of Impurities 10a/b entry
equiv of water
% water
1 (%)
10a/b (%)
1 2 3
0.025 0.5 1.0
0.1 1.9 3.82
96.51 78.57 48.19
1.60 19.88 49.84
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Table 2. Effect of n-Propanol Content on the Formation of Impurities 10a/b entry
equiv of n-PrOH
% n-PrOH
1 (%)
10a/b (%)
1 2 3
2.0 0.5 0.2
20.9 6.24 2.58
35.92 79.77 96.5
61.28 16.00 1.64
EXPERIMENTAL SECTION
General Information. All of the reagents and compound 2 were purchased from commercial suppliers and used without further purification. NMR data were collected on a Bruker Avance 400 NMR spectrometer at 400 MHz for 1H and 100 MHz for 13C. IR spectra were recorded on a Nicolet FT IR200 spectrometer in KBr pellets. Mass spectral analyses were performed on an Agilent 6224Q-TOF mass spectrometer equipped with an electrospray ionization source and on a Thermo Scientific LTQ XL mass spectrometer equipped with an electrospray ionization source. Differential scanning calorimetry was performed on a PerkinElmer Pyris 1 instrument. X-ray diffraction data were recorded on a Bruker D8 Advance X-ray powder diffractometer.
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CONCLUSION We have developed a concise and efficient process for the production of the SGLT-2 inhibitor dapagliflozin (1). Crystallization from n-PrOH/heptane yielded the key ethyl C-aryl glycoside intermediate 9 as a highly purified crystalline B
DOI: 10.1021/acs.oprd.9b00141 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Communication
layers were passed through a Celite filter and then concentrated to give an oil. The product was dissolved in nPrOH (12 L) at 40 °C and treated with n-heptane (60 L) and water (300 mL). The mixture was stirred for 6 h at 15 °C, and then the crystals were filtered and washed with n-heptane (6 L). The product was dried to constant weight under vacuum at 45 °C to give compound 9 (3.24 kg, 78% yield over two steps) as a white solid. The HPLC purity was 98.6%. The content of n-PrOH was 10.1%. 1H NMR (400 MHz, DMSO-d6): δ 7.51 (m, 1H), 7.38−7.40 (m, 2H), 7.06−7.08 (d, J = 8.8 Hz, 2H), 6.81−6.83 (d, J = 8.8 Hz, 2H), 4.95−4.97 (d, J = 5.6 Hz, 1H), 4.71−4.73 (m, 2H), 4.50−4.52 (m, 1H), 3.92−3.98 (m, 4H), 3.74−3.76 (m, 1H), 3.57−3.61 (m, 2H), 3.45 (m, 1H), 3.26− 3.28 (m, 2H), 2.95 (m, 1H), 2.87 (m, 1H), 1.27−1.31 (m, 3H), 1.04−1.08 (m, 3H). 13C NMR (100 MHz, DMSO-d6): δ 157.34, 139.69, 137.79, 132.78, 131.69, 130.99, 129.96, 128.76, 127.65, 114.74, 100.94, 77.30, 74.62, 74.49, 70.59, 63.35, 61.36, 56.63, 38.27, 15.40, 15.14. MS (m/z): 470.37 [M + NH4]+ (2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-ethoxybenzyl)phenyl)6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (1). Compound 9 (3 kg, 6.6 mol) was dissolved in CH2Cl2 (10 L) and then concentrated to give an oil. The product was dissolved in CH2Cl2 (5 L) and then concentrated to give an oil. This operation was repeated another three times. Then the product was dissolved in CH2Cl2 (15 L) and CH3CN (5 L) and dried with molecular sieves (3 kg) for 14 h. The organic layers were filtered, and CH3CN (10 L) and Et3SiH (2.3 kg, 19.8 mol) were added to the filtrate. The reaction mixture was cooled to −20 °C under the protection of argon gas and treated with boron trifluoride diethyl etherate (1.9 kg, 13.2 mol) while temperature was maintained below −10 °C.The mixture was stirred for 4 h in the −10 °C range and then for 1 h at 0 °C. Aqueous saturated NaHCO3 solution (20 L) and EtOAc (30 L) were added to the reaction mixture. The layers were separated, and the aqueous layer was extracted with EtOAc (30 L). The organic layers were combined and washed with brine (10 L × 2) and then with water (10 L × 2). The organic layer was dried with Na2SO4, filtered, and evaporated to give an oil. The oil was dissolved in EtOAc (24 L), and then n-heptane (30 L) was added within about 20 min at 25 °C. The resulting clear solvent mixture was stirred at 25 °C for 24 h, and then the crystals were filtered and washed with n-heptane (6 L) under the protection of nitrogen gas. The product was dried to constant weight under vacuum at 45 °C to give compound 1 (2.1 kg, 79% yield) as a white solid. The HPLC purity was 99.78%. Compound 1 has a melting point of 88.3 °C. The MsOH solution should be used immediately to avoid sulfonate formation, and we have no data on the presence of sulfonates in the API. 1H NMR (400 MHz, DMSO-d6): δ 7.32−7.37 (m, 2H), 7.22−7.24 (m, 1H), 7.08−7.10 (m, 2H), 6.80−6.84 (m, 2H), 4.94−4.96 (m, 2H), 4.82−4.83 (d, J = 5.6 Hz, 1H), 4.43−4.46 (m, 1H), 3.93−4.02 (m, 5H), 3.68−3.73 (m, 1H), 3.42−3.48 (m, 1H), 3.10−3.28 (m, 4H), 1.27−1.30 (m, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 157.38, 140.14, 138.27, 132.40, 131.69, 131.27, 130.03, 129.13, 127.81, 114.78, 81.67, 81.18, 78.80, 75.19, 70.80, 63.37, 61.86, 38.14, 15.15. IR (KBr): 3415, 2979, 2918, 1617, 1512, 1475, 1391, 1242, 1103, 1045, 913, 825 cm−1. MS (m/z): 431.12 [M + Na]+.
(3R,4S,5R,6R)-3,4,5-Tris((trimethylsilyl)oxy)-6(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (3). Gluconolactone (7) (2.5 kg, 14.0 mol) in THF (25 L) was treated with N-methylmorpholine (11.2 kg, 110.7 mol), and the slurry was cooled to 0 °C. Trimethylsilyl chloride (8.4 kg, 77.3 mol) was introduced, and the slurry was stirred for 17 h at 20 °C. The reaction mixture was cooled to 0 °C, and the reaction was quenched with water (14 L) below 20 °C. The phases were separated, and n-heptane (20 L) was added to the aqueous layer for washing and extraction. The combined organic layers were washed with aqueous saturated KH2PO4 solution (25 L × 2) and then with brine (12 L × 1). The organic layer was dried with Na2SO4, filtered, and evaporated under vacuum to give compound 3 (6.6 kg, 100% yield) as a yellow liquid. (3R,4S,5S,6R)-2-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-6(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol (8). A reactor equipped with a liquid nitrogen cryostat was purged with argon gas and charged sequentially with 4-(5-bromo-2chlorobenzyl)phenyl ethyl ether (2) (3 kg, 9.2 mol), anhydrous THF (6 L), and toluene (12 L). The solution was cooled to −80 °C and treated with n-BuLi (3.3 kg, 12.0 mol, 2.5 M in hexane) while the temperature was maintained at −80 °C. The mixture was stirred for 30 min. A solution of 3 (6.6 kg, 14.0 mol) in toluene (6 L) was charged while the temperature of the reaction mixture was maintained below −70 °C. The mixture was stirred for another 60 min. A solution of TFA (2.1 kg, 18.4 mol) in water (9 L) was charged while the temperature of the reaction mixture was maintained below −30 °C. Then the reaction mixture was stirred for 2 h at 15 °C. To the mixture were added water (3 L) and EtOAc (3 L), and the layers were separated. The aqueous layer was extracted with EtOAc (15 L × 1), and the organic layers were combined and washed with aqueous saturated NaHCO3 solution (12 L × 1) and then with water (12 L× 1). The organic layer was dried with Na2SO4, filtered, and evaporated under vacuum to give compound 8 as a yellow liquid. The liquid was used directly in the next step without further purification. The following characterization data for purified compound 8 were obtained: 1H NMR (400 MHz, DMSO-d6): δ 7.57 (m, 1H), 7.40−7.42 (m, 1H), 7.31−7.33 (m, 1H), 7.06−7.08 (d, J = 8.4 Hz, 2H), 6.78−6.80 (d, J = 8.4 Hz, 2H), 6.29 (s, 1H), 4.84−4.85 (d, J = 5.2 Hz, 1H), 4.66−4.67 (d, J = 4.8 Hz, 1H), 4.47−4.49 (m, 1H), 4.34−4.36 (m, 1H), 3.91− 3.97 (m, 4H), 3.64−3.67 (m, 2H), 3.52−3.58 (m, 2H), 3.24− 3.25 (m, 1H), 2.94−2.98 (m, 1H), 1.25−1.28 (m, 3H). 13C NMR (100 MHz, DMSO-d6): δ 157.31, 143.90, 137.41, 132.49, 131.78, 130.47, 129.97, 128.45, 127.23, 114.66, 97.84, 77.15, 74.82, 73.72, 70.85, 63.36, 61.59, 38.41, 15.15. MS (m/ z): 447.34 [M + Na]+ (3R,4S,5S,6R)-2-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-2ethoxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (9). Compound 8 obtained above was dissolved in EtOH (21 L) at 40 °C. Then the solution was cooled to 15 °C and treated with MsOH (1.8 kg, 18.4 mol) in EtOH (9 L). The reaction mixture was stirred for 9 h and then added to aqueous saturated NaHCO3 solution (30 L), and the resulting mixture was charged with water (30 L) and EtOAc (30 L). The layers were separated, and the aqueous layer was extracted with EtOAc (30 L). The organic layers were combined and washed with brine (15 L × 2). The organic layer was dried with Na2SO4 and then evaporated to give an oil. The product was dissolved in EtOAc (10 L) and dried with Na2SO4. The EtOAc C
DOI: 10.1021/acs.oprd.9b00141 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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Communication
(b) Juaristi, E.; Cuevas, G. Recent Studies of the Anomeric Effect. Tetrahedron 1992, 48, 5019. (c) Czernecki, S.; Ville, G. C-Glycosides. 7. Stereospecific C-glycosylation of aromatic and heterocyclic rings. J. Org. Chem. 1989, 54, 610. (9) (a) Pulley, S. R.; Carey, J. P. C-Arylglycosides via a Benzannulation Mediated by Fischer Chromium Carbene Complexes. J. Org. Chem. 1998, 63, 5275. (b) Dondoni, A.; Scherrmann, M.-C. Thiazole-Based Synthesis of Formyl C-Glycosides. J. Org. Chem. 1994, 59, 6404. (c) Dondoni, A.; Scherrmann, M.-C. Thiazole-Based Synthesis of C-Glycosyl Aldehydes. Tetrahedron Lett. 1993, 34, 7319. (10) (a) Sakamaki, S.; Kawanishi, E.; Nomura, S.; Ishikawa, T. Arylβ-C-glucosidation using glucal boronate: application to the synthesis of tri-O-methylnorbergenin. Tetrahedron 2012, 68, 5744. (b) Terauchi, M.; Abe, H.; Tovey, S. C.; Dedos, S. G.; Taylor, C. W.; Paul, M.; Trusselle, M.; Potter, B. V. L; Matsuda, A.; Shuto, S. A Systematic Study of C-Glucoside Trisphosphates as myo-Inositol Trisphosphate Receptor Ligands. Synthesis of β-C-Glucoside Trisphosphates Based on the Conformational Restriction Strategy. J. Med. Chem. 2006, 49, 1900. (11) Wang, X.-j.; Zhang, L.; Byrne, D.; Nummy, L.; Weber, D.; Krishnamurthy, D.; Yee, N.; Senanayake, C. H. Efficient Synthesis of Empagliflozin, an Inhibitor of SGLT-2, Utilizing an AlCl3-Promoted Silane Reduction of a β-Glycopyranoside. Org. Lett. 2014, 16, 4090. (12) Gougoutas, J. Z.; Lobinger, H.; Ramakrishnan, S.; Deshpande, P. P.; Bien, J. T.; Lai, C.; Wang, C.; Riebel, P.; Grosso, J. A.; Nirschl, A. A.; Singh, J.; DiMarco, J. D. Crystal Structures of SGLT2 Inhibitors and Processes for Preparing Same. US 8501698 B2, 2013. (13) One reviewer thought that we should carry out extensive work on crystallization solvent screening for compound 1. The solvents screened included MeOH, EtOH, ethyl formate, ethyl acetate, isopropyl acetate, and n-butyl acetate. It was found that only ethyl acetate/n-heptane solvent mixtures produced crystalline material.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.9b00141. NMR, IR, and mass spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jun Yu: 0000-0002-8262-0689 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank LeiLei Wang for analytical support. Jiangsu Hansoh Pharmaceutical Co., LTD is highly appreciated. REFERENCES
(1) Meng, W.; Ellsworth, B. A.; Nirschl, A. A.; McCann, P. J.; Patel, M.; Girotra, R. N.; Wu, G.; Sher, P. M.; Morrison, E. P.; Biller, S. A.; Zahler, R.; Deshpande, P. P.; Pullockaran, A.; Hagan, D. L.; Morgan, N.; Taylor, J. R.; Obermeier, M. T.; Humphreys, W. G.; Khanna, A.; Discenza, L.; Robertson, J. G.; Wang, A.; Han, S.; Wetterau, J. R.; Janovitz, E. B.; Flint, O. P.; Whaley, J. M.; Washburn, W. N. Discovery of Dapagliflozin: A Potent, Selective Renal SodiumDependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes. J. Med. Chem. 2008, 51, 1145. (2) Ellsworth, B.; Washburn, W. N.; Sher, P. M.; Wu, G.; Meng, W. C-Aryl Glucoside SGLT2 Inhibitors and Method. US 6515117 B2, 2003. (3) Deshpande, P. P.; Ellsworth, B. A.; Singh, J.; Denzel, T.; Lai, C.; Crispino, G.; Randazzo, M. E.; Gougoutas, J. Z. Methods of Producing C-Aryl Glucoside SGLT2 Inhibitors. US 7375213 B2, 2008. (4) Zhu, F.; Rodriguez, J.; Yang, T.; Kevlishvili, I.; Miller, E.; Yi, D.; O’Neill, S.; Rourke, M. J.; Liu, P.; Walczak, M. A. Glycosyl CrossCoupling of Anomeric Nucleophiles: Scope, Mechanism, and Applications in the Synthesis of Aryl C-Glycosides. J. Am. Chem. Soc. 2017, 139, 17908. (5) Horton, D.; Priebe, W. Synthetic Routes to Higher-Carbon Sugars. Reaction of Lactones with 2-Lithio-1,3-Dithiane. Carbohydr. Res. 1981, 94, 27. (6) One reviewer thought that we should carry out extensive work on crystallization solvent screening for compound 9. We had screened many solvents such as alcohols like MeOH, EtOH, n-PrOH, i-PrOH, and n-BuOH; esters like ethyl acetate, ethyl formate, methyl formate, and isopropyl acetate; ethers like THF, MTBE, and 1,4-dioxane; and hydrocarbons like toluene, n-hexane, and n-heptane. We found that compound 9 could crystallize from n-PrOH as a crystalline n-propanol solvate, whereas the others were still oils. Compound 9 is a single anomer (probably the thermodynamically stable α anomer) according to its NMR spectra. The reduction of 9 is stereospecific. (7) (a) Ellsworth, B. A.; Doyle, A. G.; Patel, M.; Caceres-Cortes, J.; Meng, W. W.; Deshpande, P. P.; Pullockaran, A.; Washburn, W. N. CArylglucoside synthesis: triisopropylsilane as a selective reagent for the reduction of an anomeric C-phenyl ketal. Tetrahedron: Asymmetry 2003, 14, 3243. (b) Kraus, G. A.; Molina, M. T. A Direct Synthesis of C-Glycosyl Compounds. J. Org. Chem. 1988, 53, 752. (c) Lewis, M. D.; Cha, K.; Kishi, Y. Highly Stereoselective Approaches to α and βC-Glycopyranosides. J. Am. Chem. Soc. 1982, 104, 4976. (8) (a) Terauchi, M.; Abe, H.; Matsuda, A.; Shuto, S. An Efficient Synthesis of β-C-Glycosides Based on the Conformational Restriction Strategy: Lewis Acid Promoted Silane Reduction of the Anomeric Position with Complete Stereoselectivity. Org. Lett. 2004, 6, 3751. D
DOI: 10.1021/acs.oprd.9b00141 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
