Vol. 63, No. 2143 Chem. Pharm. Bull. 63, 143–146 (2015)
Note
An Improved Efficient Synthesis of the Antibacterial Agent Torezolid Gang Li,# Bao-Kun Yuan,# Wu Tang, Hong-Yi Zhao, Zi-Yun Lin, and Hai-Hong Huang* State Key Laboratory of Bioactive Substances and Function of Natural Medicine and Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences; Beijing 100050, P. R. China. Received November 3, 2014; accepted November 28, 2014; advance publication released online December 10, 2014 An improved and efficient method for the preparation of torezolid based on Suzuki cross-coupling reaction as the key step was developed on a gram scale in five steps. The total yield was 44% and the optical purity of torezolid by the improved method was above 99%. Key words
synthesis; torezolid; Suzuki cross-coupling; optical purity
Oxazolidinones are an interesting class of antibacterials with good antimicrobial activity. Among them, torezolid (TR-700), a novel second-generation oxazolidinone is the active ingredient of the prodrug torezolid phosphate1) (TR-701, Fig. 1), which was launched in the U.S. in June 2014 for treatment of acute bacterial skin and skin structure infections (ABSSSI). Torezolid is active against all clinically relevant Gram-positive pathogens, some fastidious Gram-negative pathogens, and the atypical Chlamydia spp.2,3) Moreover, torezolid retains activity against linezolid-resistant strains of S. aureus including cfr-harboring strains.4,5) Therefore, torezolid is an attractive target for efficient synthesis. Despite the potential of torezolid to be developed and approved by FDA for clinical use, only two synthetic routes have been reported on the synthesis of torezolid.6) The first route was disclosed by Rhee and Im7,8) (Chart 1, Path A), using 3-fluoroaniline as the starting material, with a total yield of 6.2% in a five-step procedure.8) Subsequently, another synthetic route was disclosed by Costello in the patent literature in 2010 (Chart 1, Path B), where 4-bromo-3-fluoroaniline was used as starting material to torezolid in 46% yield over 4 steps.9) In the first synthetic protocol, the cross-coupling step of organostannane 6 with aryl bromide 10 gave a poor yield of 26%, and the residual tin impurity contained in the active pharmaceutical ingredient (API) is not desirable for pharmaceutical use. Furthermore, the iodination of 4 is a costly reaction using I2 and CF3COOAg. Although Costello’s protocol was in good overall yield, the conversion of intermediate 8 into 9 used cryogenic condition such as −72°C, and the starting material 7 was more expensive compared to Path A. Taking these aspects into consideration, our efforts were focused on developing a facile, economical, and environmentally benign approach to torezolid from cheap and commercially available starting materials. Encouraged by the promising result of good yield from 10 to 12 under mild reaction conditions, herein we have developed a convenient and efficient five-step approach to the synthesis of torezolid, which involves the construction the pivotal C–C bond between the pyridyl and phenyl groups through a Suzuki cross-coupling reaction of organoboronate ester 12 with aryl iodide 5 as the key step to afford torezolid. #
These authors contributed equally to this work.
Results and Discussion
Torezolid was synthesized by a convenient five-step procedure as described in Chart 2. In this convergent route, the critical step is the Suzuki cross-coupling reaction of aryl iodide 5 with aryl boronate ester 12 to construct the biaryl moiety. Instead of using expensive and toxic hexabutyldistannane, bis(pinacolato)diboron was employed to obtain the boronate ester 12 easily under mild reaction conditions.10–13) Several catalysts were screened for the construction of C–C bond to afford compound 1. The results were summarized in Table 1. It was found that the Suzuki coupling proceeded smoothly with high yield using Pd(OAc)2 as the catalyst and the reaction in a sealed tube was more effective, which gave a higher yield at lower temperature (Table 1, entry 4). In addition, treatment of 4 with N-iodosuccinimide (NIS) in the presence of trifluoroacetic acid (TFA) afforded 5 in 83% yield within 3 h. In comparison, the use of I2 and CF3COOAg, an expensive reagent, yielded compound 5 for 24 h in Path A.14) In this fashion, the total yield was increased from 6.2% to 44% compared to the method of Im’s group.8) The enantiomer of torezolid was also synthesized by our improved method. (S)-(+)-Glycidyl butylate was used to construct the oxazolidinone intermediate. The optical purity was measured by HPLC equipment with AD-Hs column (Fig. 2). The optical purity of torezolid was above 99%.15) Overall, this synthetic route was efficient and easy to scale-up on gram scale.
Conclusion
In summary, we have developed a convenient and efficient method for preparation of torezolid in overall yield of 44% over 5 steps. This convergent process started from commercially available and inexpensive materials. Moreover, the Suzuki cross-coupling reaction was used as a key step to avoid expensive and toxic tin reagent. This significantly improved efficient method could potentially be useful in scale-up on gram scale and it is complementary to the existing methods for the synthesis of torezolid.
Experimental 1
H- and 13C-NMR spectra were recorded on Mercury-400 spectrometer. Chemical shifts are referenced to the residual solvent peak and reported in ppm (δ scale) and all coupling
To whom correspondence should be addressed. e-mail: [email protected] * © 2015 The Pharmaceutical Society of Japan
Chem. Pharm. Bull.
144
Fig. 1.
Vol. 63, No. 2 (2015)
Torezolid and Torezolid Phosphate
Reagents and conditions: (a) NaHCO3, Cbz-Cl, THF, 0°C, 2 h, 60%; (b) n-BuLi, (R)-(−)-glycidyl butylate, THF, −78°C to r.t., 26 h, 70%; (c) CF3COOAg, I 2, MeCN, r.t., 24 h, 93%; (d) (Bu)3Sn-Sn(Bu)3, Pd(PPh 3)2Cl 2, 1,4-dioxane, 100°C, 2 h, 61%; (e) Pd(PPh3)2Cl 2, LiCl, N-methyl pyrrolidone, 120°C, 4 h, 26%; (f) NaHCO3, Cbz-Cl, THF, 0°C, 2 h, 92%; (g) triisopropyl borate, n-BuLi, THF, −72°C, 66%; (h) K 2CO3, Pd 2(dba)3, tricyclohexylphosphine, 1,4-dioxane/H 2O, 70°C, 1 h, 87%; (j) LiHMDS, DMPU, (R)(−)-glycidyl butylate, THF, 0°C to r.t., 17 h, 89%.
Chart 1
Reagents and conditions: (i) NaHCO3, Cbz-Cl, THF, 0°C, 2 h, 88%; (ii) n-BuLi, (R)-(−)-glycidyl butylate, THF, −78°C to r.t., 26 h, 91%; (iii) N-iodosuccinimide, TFA, r.t., 3 h, 83%; (iv) CH3COOK, bis(pinacolato)diboron, Pd (dppf) Cl 2; l,4-dioxane, 80°C, 3 h, 86%; (v) K 2CO3, Pd(OAc)2, DMF/H 2O, 90°C, 6 h, 78%.
Chart 2 The Exploration of Catalysts for the Synthesis of Torezolid 1
Table 1.
Entry a)
1 2a) 3a) 4a) 5b)
c)
d)
Catalyst
Yield
Pd(PPh3)4 Pd(PPh3)2Cl2 Pd(dppf)Cl2 Pd(OAc)2 Pd(OAc)2
60% 36% 32% 78% 65%
a) Reaction of coupling reagents 5 (1.0 eq.) and 12 (1.2 eq.) was run in a sealed tube under argon, using K2CO3 (3.0 eq.) as the base in the presence of DMF/H2O (1 : 1) at 90°C for 6 h. b) Reaction of coupling reagents 5 (1.0 eq.) and 12 (1.2 eq.) was run with a condenser under argon, using K2CO3 (3.0 eq.) as the base in the presence of DMF/H2O (1 : 1) at 110°C for 6 h. c) Using 10 mol% of the catalyst. d) Isolated yield.
constant (J) values are given in Hz. High-resolution mass spectra were measured on a Theromo Extractive Orbitrap plus mass spectrometer (ESI). The optical rotation was measured on a PerkinElmer, Inc. 241MC polarimeter. All solvents were dried before use. All other reagents were obtained from com-
mercial suppliers and used without further purification. Typical Procedure for the Preparation of N-Carbobenzyloxy-3-fluoroaniline (3) To a stirred solution of 3-fluoroaniline 2 (20.00 g, 180 mmol) and NaHCO3 (30.24 g, 360 mmol) in tetrahydrofuran (THF) (100 mL) was slowly added N-carbobenzyloxy chloride (30.8 mL, 216 mmol) at 0°C. After being stirred for 2 h at 0°C, the solvent was removed under reduced pressure and the residue was taken up with water (100 mL) and extracted with EtOAc (100 mL×2). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was washed with petroleum ether to obtain the title compound (39.16 g, 88.7%). The 1 H-NMR spectra were in accordance with the literature data.8) 1 H-NMR (400 MHz, CDCl3) δ: 7.31–7.40 (m, 6H), 7.19–7.23 (m, 1H), 7.01 (d, 1H, J=8.0 Hz), 6.73–6.77 (m, 2H), 5.20 (s, 2H). Typical Procedure for the Preparation of (R)-3-(3Fluorophenyl)-2-oxo-5-oxazolidinylmethanol (4) To a solution of N-carbobenzyloxy-3-fluoroaniline 3 (39.00 g, 159 mmol) in anhydrous THF (200 mL) at −78°C was slowly
Chem. Pharm. Bull. Vol. 63, No. 2 (2015)145
Fig. 2.
The Optical Purity Analysis by HPLC Equipment with AD-Hs Column
Chromatogram of torezolid and its enantiomer synthesized by our improved method (A). Chromatogram of torezolid synthesized by our improved method (B).
added n-butyllithium 2.5 M in n-hexane (71.3 mL, 178 mmol) under argon condition. After the solution was stirred at −78°C for 10 min, (R)-(−)-glycidyl butylate (24.9 mL, 178 mmol) was slowly added. The mixture was stirred at −78°C for 2 h and stirred at room temperature for 24 h. After completion of the reaction, an aqueous saturated ammonium chloride solution (150 mL) was added and the mixture was extracted with ethyl acetate (200 mL×2). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was recrystallized from 20% ethyl acetate in petroleum ether to give the title compound (30.75 g, 91.6%). The 1H-NMR spectra were in accordance with the literature data.8) 1H-NMR (400 MHz, DMSO-d6 ) δ: 7.51–7.54 (m, 1H), 7.38–7.42 (m, 1H), 7.31–7.34 (m, 1H), 6.91–6.96 (m, 1H), 5.21 (t, 1H, J=5.6 Hz), 4.68–4.73 (m, 1H), 4.08 (t, 1H, J=9.2 Hz), 3.81–3.85 (m, 1H), 3.65–3.67 (m, 1H), 3.56–3.57 (m, 1H). Typical Procedure for the Preparation of (R)-3-(4Iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol (5) A solution of 4 (11.00 g, 52.08 mmol) in trifluoroacetic acid (50 mL) was treated with N-iodosuccinimide (NIS, 12.30 g, 54.69 mmol) at room temperature. After being stirred for 3 h at room temperature, the solvent was concentrated in vacuo. The residue was taken up with 10% Na2S2O3(50 mL) and extracted with ethyl acetate (50 mL×4). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was washed with 20% ethyl acetate in petroleum ether to obtain the title compound (14.6 g, 83.2%). The 1H-NMR spectra were in accordance with the literature data.8) 1H-NMR (400 MHz, DMSO-d6 ) δ: 7.79–7.83 (m, 1H), 7.57 (dd, 1H, J=11.0 Hz, 2.4 Hz), 7.21 (dd, 1H, J=8.8 Hz, 2.4 Hz), 5.20 (t, 1H, J=5.6 Hz), 4.68–4.74 (m, 1H), 4.06 (t, 1H, J=9.2 Hz), 3.79–3.83 (m, 1H), 3.64–3.68 (m, 1H), 3.55–3.57 (m, 1H). Typical Procedure for the Preparation of 2-(2-Methyltetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)pyridine (12) To a solution of 10 (1.00 g, 4.17 mmol) in dry degassed l,4-dioxane (15 mL) was added bis(pinacolato)diboron (1.27 g, 5.00 mmol), potassium acetate (1.35 g, 13.75 mmol), and Pd(dppf)Cl2 (0.26 g, 0.35 mmol). The reaction mixture was heated at 80°C for 3 h in a sealed tube under argon. The reaction mixture was filtered through silica gel flash column with CH2Cl2 and the organic layer was evaporated under reduced pressure, and the residue was washed with n-hexane to obtain the title compound (1.03 g, 86.3%). 1 H-NMR (400 MHz, CDCl3) δ: 9.14 (s, 1H), 8.30 (m, 2H), 4.48
(s, 3H), 1.38 (s, 12H). Typical Procedure for the Preparation of (R)-3-(4-(2-(2Methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl Oxazolidin-2-one (1) To a solution of 5 (1.03 g, 3.06 mmol) and potassium carbonate (1.27g, 9.18 mmol) in degassed N,N-dimethylformamide (DMF) (5 mL) and H2O (5 mL) was added 12 (1.05 g, 3.67 mmol) followed by palladium acetate (0.07 g, 0.31 mmol) and the reaction mixture was heated at 90°C for 6 h in a sealed tube under argon. The reaction mixture was cooled to room temperature, poured into the ice water. The crude solid was filtered and purified by column chromatography (2% CH3OH in CH2Cl2) to obtain the title compound (0.88 g, 77.6%). ee>99%. mp: 199–201°C. [α]D20=−46 (c=0.5, DMSO). The 1H-NMR and 13C-NMR spectra were in accordance with the literature data.8) 1H-NMR (400 MHz, DMSO-d6) δ: 8.93 (s, 1H), 8.19–8.23 (m, 2H), 7.68–7.76 (m, 2H), 7.51–7.53 (m, 1H), 5.24 (t, 1H J=5.6 Hz), 4.75–4.76 (m, 1H), 4.47 (s, 3H), 4.15 (t, 1H, J=8.6 Hz), 3.90–3.92 (m, 1H), 3.69–3.72 (m, 1H), 3.60–3.63 (m, 1H). 13 C-NMR (100 MHz, DMSO-d6) δ: 163.9, 159.3 (J=244 Hz), 154.3, 149.4, 145.1, 140.5, 137.2, 131.6, 130.9, 122.1, 118.6 (J=13 Hz), 114.0, 105.4 (J=28 Hz), 73.5, 61.6, 46.0. ESI-HRMS m/z: Calcd for C17H16F N6O3 (M+H)+: 371.1262. Found: 371.1254. Typical Procedure for the Preparation of the Enantiomer of Torezolid The enantiomer of torezolid was prepared according to that described for 1 in 61% yield as an off-white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.94 (s, 1H), 8.19–8.25 (m, 2H), 7.70–7.78 (m, 2H), 7.53–7.55 (m, 1H), 5.25 (t, 1H, J=5.6 Hz), 4.76–4.77 (m, 1H), 4.48 (s, 3H), 4.16 (t, 1H, J=8.6 Hz), 3.91–3.93 (m, 1H), 3.70–3.73 (m, 1H), 3.61–3.64 (m, 1H). 13C-NMR (100 MHz, DMSO-d6) δ: 163.9, 159.3 (J=244 Hz), 154.3, 149.4, 145.1, 140.5, 137.2, 131.6, 130.9, 122.1, 118.6 (J=13 Hz), 114.0, 105.4 (J=28 Hz), 73.5, 61.6, 46.0. mp: 199–201°C. ESI-HR-MS m/z: Calcd for C17H16F N6O3 (M+H)+: 371.1262. Found: 371.1247. [α]D20=+45 (c=0.5, DMSO). Conflict of Interest interest.
References and Notes
The authors declare no conflict of
1) Liapikou A., Cilloniz C., Mensa J., Torres A., Pulm. Pharmacol. Ther.: ‹http://dx.doi.org/10.1016/j.pupt.2014.05.003›, (2014) in press. 2) Prokocimer P., Bien P., Surber J., Mehra P., DeAnda C., Bulitta J., Corey G. R., Antimicrob. Agents Chemother., 55, 583–592 (2011).
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3) Schaadt R., Sweeney D., Shinabarger D., Zurenko G., Antimicrob. Agents Chemother., 53, 3236–3239 (2009). 4) Shaw K. J., Poppe S., Schaadt R., Brown-Driver V., Finn J., Pillar C. M., Shinabarger D., Zurenko G., Antimicrob. Agents Chemother., 52, 4442–4447 (2008). 5) Prokocimer P., Bien P., DeAnda C., Pillar C. M., Bartizal K., Antimicrob. Agents Chemother., 56, 4608–4613 (2012). 6) Moellering R. C. Jr., Clin. Infect. Dis., 58 (Suppl. 1), S1–S3 (2014). 7) Rhee J. K., Im W. B., Cho C. H., Choi S. H., Lee T. H., PCT Int. Patent WO 2005/058886 A1 (2005). 8) Im W. B., Choi S. H., Park J.-Y., Choi S. H., Finn J., Yoon S.-H., Eur. J. Med. Chem., 46, 1027–1039 (2011). 9) Costello C. A., Simson J. A., Duguid R. J., Phillipson D., PCT Int. Patent WO 2010/042887 A2 (2010). 10) Reck F., Zhou F., Eyermann C. J., Kern G., Carcanague D., Ioan-
11) 12) 13)
14) 15)
Vol. 63, No. 2 (2015)
nidis G., Illingworth R., Poon G., Gravestock M. B., J. Med. Chem., 50, 4868–4881 (2007). Gordeev M. F., Yuan Z., Liu J., PCT Int. Patent WO 2008/108988 A1 (2008). Haydon D. J., Czaplewski L. G., PCT Int. Patent WO 2009/074812 A1 (2009). Siddiqui A., Nan Y., Patel M. F., Reddy P. A. P., Mansoor U. F., Meng Z., Vitharana L. D., Zhao L., Mandal A. K., Liu D., PCT Int. Patent WO 2011/090935 A1 (2011). Chen S., Lou R., Wu Y., Zhou J., Hanselmann R., U. S. Patent US 2010/0234615 A1 (2010). The optical purity was measured by Shimadzu LC 20 with UV detector SPD-20 A HPLC equipment with AD-Hs column. Column size: 0.46 cm i.d.×15 cm L. Mobile phase: n-hexane/isopropyl alcohol/diethylamine=70/30/0.1 (v/v/v). Flow rate: 1.0 mL/min.
Note
An Improved Efficient Synthesis of the Antibacterial Agent Torezolid Gang Li,# Bao-Kun Yuan,# Wu Tang, Hong-Yi Zhao, Zi-Yun Lin, and Hai-Hong Huang* State Key Laboratory of Bioactive Substances and Function of Natural Medicine and Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences; Beijing 100050, P. R. China. Received November 3, 2014; accepted November 28, 2014; advance publication released online December 10, 2014 An improved and efficient method for the preparation of torezolid based on Suzuki cross-coupling reaction as the key step was developed on a gram scale in five steps. The total yield was 44% and the optical purity of torezolid by the improved method was above 99%. Key words
synthesis; torezolid; Suzuki cross-coupling; optical purity
Oxazolidinones are an interesting class of antibacterials with good antimicrobial activity. Among them, torezolid (TR-700), a novel second-generation oxazolidinone is the active ingredient of the prodrug torezolid phosphate1) (TR-701, Fig. 1), which was launched in the U.S. in June 2014 for treatment of acute bacterial skin and skin structure infections (ABSSSI). Torezolid is active against all clinically relevant Gram-positive pathogens, some fastidious Gram-negative pathogens, and the atypical Chlamydia spp.2,3) Moreover, torezolid retains activity against linezolid-resistant strains of S. aureus including cfr-harboring strains.4,5) Therefore, torezolid is an attractive target for efficient synthesis. Despite the potential of torezolid to be developed and approved by FDA for clinical use, only two synthetic routes have been reported on the synthesis of torezolid.6) The first route was disclosed by Rhee and Im7,8) (Chart 1, Path A), using 3-fluoroaniline as the starting material, with a total yield of 6.2% in a five-step procedure.8) Subsequently, another synthetic route was disclosed by Costello in the patent literature in 2010 (Chart 1, Path B), where 4-bromo-3-fluoroaniline was used as starting material to torezolid in 46% yield over 4 steps.9) In the first synthetic protocol, the cross-coupling step of organostannane 6 with aryl bromide 10 gave a poor yield of 26%, and the residual tin impurity contained in the active pharmaceutical ingredient (API) is not desirable for pharmaceutical use. Furthermore, the iodination of 4 is a costly reaction using I2 and CF3COOAg. Although Costello’s protocol was in good overall yield, the conversion of intermediate 8 into 9 used cryogenic condition such as −72°C, and the starting material 7 was more expensive compared to Path A. Taking these aspects into consideration, our efforts were focused on developing a facile, economical, and environmentally benign approach to torezolid from cheap and commercially available starting materials. Encouraged by the promising result of good yield from 10 to 12 under mild reaction conditions, herein we have developed a convenient and efficient five-step approach to the synthesis of torezolid, which involves the construction the pivotal C–C bond between the pyridyl and phenyl groups through a Suzuki cross-coupling reaction of organoboronate ester 12 with aryl iodide 5 as the key step to afford torezolid. #
These authors contributed equally to this work.
Results and Discussion
Torezolid was synthesized by a convenient five-step procedure as described in Chart 2. In this convergent route, the critical step is the Suzuki cross-coupling reaction of aryl iodide 5 with aryl boronate ester 12 to construct the biaryl moiety. Instead of using expensive and toxic hexabutyldistannane, bis(pinacolato)diboron was employed to obtain the boronate ester 12 easily under mild reaction conditions.10–13) Several catalysts were screened for the construction of C–C bond to afford compound 1. The results were summarized in Table 1. It was found that the Suzuki coupling proceeded smoothly with high yield using Pd(OAc)2 as the catalyst and the reaction in a sealed tube was more effective, which gave a higher yield at lower temperature (Table 1, entry 4). In addition, treatment of 4 with N-iodosuccinimide (NIS) in the presence of trifluoroacetic acid (TFA) afforded 5 in 83% yield within 3 h. In comparison, the use of I2 and CF3COOAg, an expensive reagent, yielded compound 5 for 24 h in Path A.14) In this fashion, the total yield was increased from 6.2% to 44% compared to the method of Im’s group.8) The enantiomer of torezolid was also synthesized by our improved method. (S)-(+)-Glycidyl butylate was used to construct the oxazolidinone intermediate. The optical purity was measured by HPLC equipment with AD-Hs column (Fig. 2). The optical purity of torezolid was above 99%.15) Overall, this synthetic route was efficient and easy to scale-up on gram scale.
Conclusion
In summary, we have developed a convenient and efficient method for preparation of torezolid in overall yield of 44% over 5 steps. This convergent process started from commercially available and inexpensive materials. Moreover, the Suzuki cross-coupling reaction was used as a key step to avoid expensive and toxic tin reagent. This significantly improved efficient method could potentially be useful in scale-up on gram scale and it is complementary to the existing methods for the synthesis of torezolid.
Experimental 1
H- and 13C-NMR spectra were recorded on Mercury-400 spectrometer. Chemical shifts are referenced to the residual solvent peak and reported in ppm (δ scale) and all coupling
To whom correspondence should be addressed. e-mail: [email protected] * © 2015 The Pharmaceutical Society of Japan
Chem. Pharm. Bull.
144
Fig. 1.
Vol. 63, No. 2 (2015)
Torezolid and Torezolid Phosphate
Reagents and conditions: (a) NaHCO3, Cbz-Cl, THF, 0°C, 2 h, 60%; (b) n-BuLi, (R)-(−)-glycidyl butylate, THF, −78°C to r.t., 26 h, 70%; (c) CF3COOAg, I 2, MeCN, r.t., 24 h, 93%; (d) (Bu)3Sn-Sn(Bu)3, Pd(PPh 3)2Cl 2, 1,4-dioxane, 100°C, 2 h, 61%; (e) Pd(PPh3)2Cl 2, LiCl, N-methyl pyrrolidone, 120°C, 4 h, 26%; (f) NaHCO3, Cbz-Cl, THF, 0°C, 2 h, 92%; (g) triisopropyl borate, n-BuLi, THF, −72°C, 66%; (h) K 2CO3, Pd 2(dba)3, tricyclohexylphosphine, 1,4-dioxane/H 2O, 70°C, 1 h, 87%; (j) LiHMDS, DMPU, (R)(−)-glycidyl butylate, THF, 0°C to r.t., 17 h, 89%.
Chart 1
Reagents and conditions: (i) NaHCO3, Cbz-Cl, THF, 0°C, 2 h, 88%; (ii) n-BuLi, (R)-(−)-glycidyl butylate, THF, −78°C to r.t., 26 h, 91%; (iii) N-iodosuccinimide, TFA, r.t., 3 h, 83%; (iv) CH3COOK, bis(pinacolato)diboron, Pd (dppf) Cl 2; l,4-dioxane, 80°C, 3 h, 86%; (v) K 2CO3, Pd(OAc)2, DMF/H 2O, 90°C, 6 h, 78%.
Chart 2 The Exploration of Catalysts for the Synthesis of Torezolid 1
Table 1.
Entry a)
1 2a) 3a) 4a) 5b)
c)
d)
Catalyst
Yield
Pd(PPh3)4 Pd(PPh3)2Cl2 Pd(dppf)Cl2 Pd(OAc)2 Pd(OAc)2
60% 36% 32% 78% 65%
a) Reaction of coupling reagents 5 (1.0 eq.) and 12 (1.2 eq.) was run in a sealed tube under argon, using K2CO3 (3.0 eq.) as the base in the presence of DMF/H2O (1 : 1) at 90°C for 6 h. b) Reaction of coupling reagents 5 (1.0 eq.) and 12 (1.2 eq.) was run with a condenser under argon, using K2CO3 (3.0 eq.) as the base in the presence of DMF/H2O (1 : 1) at 110°C for 6 h. c) Using 10 mol% of the catalyst. d) Isolated yield.
constant (J) values are given in Hz. High-resolution mass spectra were measured on a Theromo Extractive Orbitrap plus mass spectrometer (ESI). The optical rotation was measured on a PerkinElmer, Inc. 241MC polarimeter. All solvents were dried before use. All other reagents were obtained from com-
mercial suppliers and used without further purification. Typical Procedure for the Preparation of N-Carbobenzyloxy-3-fluoroaniline (3) To a stirred solution of 3-fluoroaniline 2 (20.00 g, 180 mmol) and NaHCO3 (30.24 g, 360 mmol) in tetrahydrofuran (THF) (100 mL) was slowly added N-carbobenzyloxy chloride (30.8 mL, 216 mmol) at 0°C. After being stirred for 2 h at 0°C, the solvent was removed under reduced pressure and the residue was taken up with water (100 mL) and extracted with EtOAc (100 mL×2). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was washed with petroleum ether to obtain the title compound (39.16 g, 88.7%). The 1 H-NMR spectra were in accordance with the literature data.8) 1 H-NMR (400 MHz, CDCl3) δ: 7.31–7.40 (m, 6H), 7.19–7.23 (m, 1H), 7.01 (d, 1H, J=8.0 Hz), 6.73–6.77 (m, 2H), 5.20 (s, 2H). Typical Procedure for the Preparation of (R)-3-(3Fluorophenyl)-2-oxo-5-oxazolidinylmethanol (4) To a solution of N-carbobenzyloxy-3-fluoroaniline 3 (39.00 g, 159 mmol) in anhydrous THF (200 mL) at −78°C was slowly
Chem. Pharm. Bull. Vol. 63, No. 2 (2015)145
Fig. 2.
The Optical Purity Analysis by HPLC Equipment with AD-Hs Column
Chromatogram of torezolid and its enantiomer synthesized by our improved method (A). Chromatogram of torezolid synthesized by our improved method (B).
added n-butyllithium 2.5 M in n-hexane (71.3 mL, 178 mmol) under argon condition. After the solution was stirred at −78°C for 10 min, (R)-(−)-glycidyl butylate (24.9 mL, 178 mmol) was slowly added. The mixture was stirred at −78°C for 2 h and stirred at room temperature for 24 h. After completion of the reaction, an aqueous saturated ammonium chloride solution (150 mL) was added and the mixture was extracted with ethyl acetate (200 mL×2). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was recrystallized from 20% ethyl acetate in petroleum ether to give the title compound (30.75 g, 91.6%). The 1H-NMR spectra were in accordance with the literature data.8) 1H-NMR (400 MHz, DMSO-d6 ) δ: 7.51–7.54 (m, 1H), 7.38–7.42 (m, 1H), 7.31–7.34 (m, 1H), 6.91–6.96 (m, 1H), 5.21 (t, 1H, J=5.6 Hz), 4.68–4.73 (m, 1H), 4.08 (t, 1H, J=9.2 Hz), 3.81–3.85 (m, 1H), 3.65–3.67 (m, 1H), 3.56–3.57 (m, 1H). Typical Procedure for the Preparation of (R)-3-(4Iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol (5) A solution of 4 (11.00 g, 52.08 mmol) in trifluoroacetic acid (50 mL) was treated with N-iodosuccinimide (NIS, 12.30 g, 54.69 mmol) at room temperature. After being stirred for 3 h at room temperature, the solvent was concentrated in vacuo. The residue was taken up with 10% Na2S2O3(50 mL) and extracted with ethyl acetate (50 mL×4). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was washed with 20% ethyl acetate in petroleum ether to obtain the title compound (14.6 g, 83.2%). The 1H-NMR spectra were in accordance with the literature data.8) 1H-NMR (400 MHz, DMSO-d6 ) δ: 7.79–7.83 (m, 1H), 7.57 (dd, 1H, J=11.0 Hz, 2.4 Hz), 7.21 (dd, 1H, J=8.8 Hz, 2.4 Hz), 5.20 (t, 1H, J=5.6 Hz), 4.68–4.74 (m, 1H), 4.06 (t, 1H, J=9.2 Hz), 3.79–3.83 (m, 1H), 3.64–3.68 (m, 1H), 3.55–3.57 (m, 1H). Typical Procedure for the Preparation of 2-(2-Methyltetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)pyridine (12) To a solution of 10 (1.00 g, 4.17 mmol) in dry degassed l,4-dioxane (15 mL) was added bis(pinacolato)diboron (1.27 g, 5.00 mmol), potassium acetate (1.35 g, 13.75 mmol), and Pd(dppf)Cl2 (0.26 g, 0.35 mmol). The reaction mixture was heated at 80°C for 3 h in a sealed tube under argon. The reaction mixture was filtered through silica gel flash column with CH2Cl2 and the organic layer was evaporated under reduced pressure, and the residue was washed with n-hexane to obtain the title compound (1.03 g, 86.3%). 1 H-NMR (400 MHz, CDCl3) δ: 9.14 (s, 1H), 8.30 (m, 2H), 4.48
(s, 3H), 1.38 (s, 12H). Typical Procedure for the Preparation of (R)-3-(4-(2-(2Methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl Oxazolidin-2-one (1) To a solution of 5 (1.03 g, 3.06 mmol) and potassium carbonate (1.27g, 9.18 mmol) in degassed N,N-dimethylformamide (DMF) (5 mL) and H2O (5 mL) was added 12 (1.05 g, 3.67 mmol) followed by palladium acetate (0.07 g, 0.31 mmol) and the reaction mixture was heated at 90°C for 6 h in a sealed tube under argon. The reaction mixture was cooled to room temperature, poured into the ice water. The crude solid was filtered and purified by column chromatography (2% CH3OH in CH2Cl2) to obtain the title compound (0.88 g, 77.6%). ee>99%. mp: 199–201°C. [α]D20=−46 (c=0.5, DMSO). The 1H-NMR and 13C-NMR spectra were in accordance with the literature data.8) 1H-NMR (400 MHz, DMSO-d6) δ: 8.93 (s, 1H), 8.19–8.23 (m, 2H), 7.68–7.76 (m, 2H), 7.51–7.53 (m, 1H), 5.24 (t, 1H J=5.6 Hz), 4.75–4.76 (m, 1H), 4.47 (s, 3H), 4.15 (t, 1H, J=8.6 Hz), 3.90–3.92 (m, 1H), 3.69–3.72 (m, 1H), 3.60–3.63 (m, 1H). 13 C-NMR (100 MHz, DMSO-d6) δ: 163.9, 159.3 (J=244 Hz), 154.3, 149.4, 145.1, 140.5, 137.2, 131.6, 130.9, 122.1, 118.6 (J=13 Hz), 114.0, 105.4 (J=28 Hz), 73.5, 61.6, 46.0. ESI-HRMS m/z: Calcd for C17H16F N6O3 (M+H)+: 371.1262. Found: 371.1254. Typical Procedure for the Preparation of the Enantiomer of Torezolid The enantiomer of torezolid was prepared according to that described for 1 in 61% yield as an off-white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.94 (s, 1H), 8.19–8.25 (m, 2H), 7.70–7.78 (m, 2H), 7.53–7.55 (m, 1H), 5.25 (t, 1H, J=5.6 Hz), 4.76–4.77 (m, 1H), 4.48 (s, 3H), 4.16 (t, 1H, J=8.6 Hz), 3.91–3.93 (m, 1H), 3.70–3.73 (m, 1H), 3.61–3.64 (m, 1H). 13C-NMR (100 MHz, DMSO-d6) δ: 163.9, 159.3 (J=244 Hz), 154.3, 149.4, 145.1, 140.5, 137.2, 131.6, 130.9, 122.1, 118.6 (J=13 Hz), 114.0, 105.4 (J=28 Hz), 73.5, 61.6, 46.0. mp: 199–201°C. ESI-HR-MS m/z: Calcd for C17H16F N6O3 (M+H)+: 371.1262. Found: 371.1247. [α]D20=+45 (c=0.5, DMSO). Conflict of Interest interest.
References and Notes
The authors declare no conflict of
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