Formal Synthesis of Tamiflu: Conversion of Tamiflu into Tamiphosphor

Abstract

A short, enantiomeric, synthesis of Shibasaki’s 3rd generation intermediate to form (-)-oseltamivir phosphate (Tamiflu^®) has been achieved in eight steps with the use of inexpensive starting materials. A formal synthetic route to convert tamiflu into tamiphosphor via Fang’s tamiphosphor intermediate has been accomplished.

Key words

hydrolysis - epoxide - oxidation - amides - enantioselectivity

References and Notes

• 1 Molinari NA. Ortega-Sanchez IR. Messonnier ML. Thompson WW. Wortley PM. Weintraub E. Bridges CB. Vaccine  2007,  25:  5086 
• 2 Cheam AL. Barr IG. Hampson AW. Mosse J. Hurt AC. Antiviral Res.  2004,  63:  177 
• 3 Smith BJ. McKimm-Breshkin JL. McDonald M. Fernley RT. Varghese JN. Colman PM. J. Med. Chem.  2002,  45:  2207 
• 4 De Clercq E. Nat. Rev. Drug Discov.  2006,  5:  1015 
• 5a Johnson DS. Li JJ. The Art of Drug Synthesis   John Wiley & Sons; Hoboken, NJ: 2007.  p.95 
• 5b Werner L. Machara A. Sullivan B. Carrera I. Moser M. Adams DR. Hudlicky T. J. Org. Chem.  2011,  76:  10050 
• 6 Thorlund K. Awad T. Boivin G. Thabane L. BMC Infectious Diseases  2011,  11:  134 
• 7 Shie JJ. Fang JM. Wang SY. Tsai KC. Cheng YS. Yang AS. Hsiao SC. Su CY. Wong CH. J. Am. Chem. Soc.  2007,  129:  11892 
• 8 Shie JJ. Fang JM. Wong CH. Angew. Chem. Int. Ed.  2008,  47:  5788 
• 9 Yamatsugu K. Kamijo S. Suto Y. Kanai M. Shibasaki M. Tetrahedron Lett.  2007,  48:  1403 
• 10 Shibasaki M. Kanai M. Eur. J. Org. Chem.  2008,  1839 
• 11 Tanaka T. Tan Q. Kawakubo H. Hayashi M. J. Org. Chem.  2011,  76:  5477 
• 12a Brandsma L. Vansoolingen J. Andringa H. Synth. Commun.  1990,  20:  2165 
• 12b Ruggles E. Deker P. Hondal R. Tetrahedron  2009,  65:  1257 
• 13 Tan QT. Hayashi M. Org. Lett.  2009,  11:  3314 
• 14 Sabitha G. Babu RS. Rajkumar M. Yadav JS. Org. Lett.  2002,  4:  343 
• 15 Ittah Y. Sasson Y. Shahak I. Tsaroom S. Blum J. J. Org. Chem.  1978,  43:  4271 
• 16 Ballereau S. McCort I. Dureault A. Depezay JC. Tetrahedron  2001,  57:  1935 
• 19 Naskar D. Roy S. Tetrahedron  2000,  56:  1369 
• 20 Hartung J. Schwarz M. Synlett  2000,  371 
• 21 Paquette LA. Dahnke K. Doyon J. He W. Wyant K. Friedrich D. J. Org. Chem.  1991,  56:  6199 

17

(1 S ,5 R ,6 S )-5-Azido-6-hydroxycyclohex-2-en-1-yl 4-Nitrobenzoate(4): CeCl₃˙7H₂O (1 mmol) and NaN₃ (1.1 mmol) were added to epoxide 3 (1 mmol) in a mixture of MeCN and H₂O (9:1, 10 mL). The reaction mixture was stirred at reflux temperature until the disappearance of starting material as indicated by TLC. The reaction mixture was extracted with EtOAc, and the combined organic layers were washed with H₂O and brine, dried over anhyd Na₂SO₄, and evaporated under reduced pressure. The residue was subjected to flash chromatography on silica gel (hexane-EtOAc) to provide the pure azidohydrin 4 in 74% yield as a white foam; [α]^²6 _D +27 (c = 0.05, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 8.20-8.33 (m, 4 H), 5.81-5.90 (m, 1 H), 5.62-5.75 (m, 2 H), 3.94 (dd, J = 10.4, 7.5 Hz, 1 H), 3.76 (td, J = 10.4, 5.9 Hz, 1 H), 2.93 (s, 1 H), 2.61 (dt, J = 17.6, 5.5 Hz, 1 H), 2.23 (ddd, J = 17.8, 10.3, 2.5 Hz, 1 H). ^¹³C NMR (400 MHz, CDCl₃): δ = 164.94, 158.39, 150.93, 135.12, 130.93, 127.81, 124.86, 123.57, 76.79, 74.22, 61.22, 30.39. HRMS (CI): m/z [M + H] calcd for C₁₃H₁₂N₄O₅: 305.0886; found: 305.0883.
(1 S ,2 S ,6 S )-7-Acetyl-7-azabicyclo[4.1.0]hept-3-en-2-yl 4-Nitrobenzoate (5): A solution of 4 (0.82 g, 2.6 mmol) and triphenylphosphine (0.85 g, 2.9 mmol) in anhyd MeCN (5.2 mL) was refluxed for 2 h. After cooling to r.t., the solvent was removed under reduced pressure, and pyridine (5.2 mL) and Ac₂O (490 µL, 5.2 mmol, 2 equiv) were added at r.t. After 5 h, the reaction mixture was concentrated in vacuum. The residue was purified by column chromatography (silica gel, hexane-EtOAc, 3:1 → 1:1) to afford 5 (60 mg, 0.976 mmol) in 76% yield as a pale yellow semisolid; [α]^²6 _D +36 (c = 0.11, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 8.26 (d, J = 4.1 Hz, 4 H), 5.70-5.95 (m, 2 H), 5.50-5.70 (m, 1 H), 3.13-3.38 (m, 1 H), 2.88-3.15 (m, 1 H), 2.64 (dd, J = 19.9, 4.4 Hz, 1 H), 2.29-2.54 (m, 1 H), 2.07 (s, 3 H). ^¹³C NMR (400 MHz, CDCl₃): δ = 182.74, 164.35, 150.96, 135.20, 131.07, 126.69, 123.66, 122.15, 68.22, 37.37, 34.79, 24.51, 23.31. HRMS (CI): m/z [M + H] calcd for C₁₅H₁₄N₂O₅: 303.0981; found: 303.0986.
(1 S ,5 R ,6 S )-6-Acetamido-5-azidocyclohex-2-en-1-yl 4-Nitrobenzoate (6): To a solution of 5 (2.11 g, 6.98 mmol) in MeCN (4.2 mL), tetramethylguanidinium azide (TMGA; 2.18 g, 13.96 mmol, 2 equiv) was added and the mixture was stirred at 60 ˚C for 13 h. After completion of the reaction, MeCN was removed under reduced pressure. HCl (5%, 20 mL) was added and the solution was extracted with Et₂O (3 × 15 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated and purified by column chromatography (hexane-EtOAc) to afford 6 (2.23 g) in 83% yield as a white solid; mp 181-183 ˚C; [α]^²6 _D +42 (c = 0.12, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 8.23 (dd, J = 51.0, 8.8 Hz, 4 H), 5.89-6.17 (m, 2 H), 5.66 (d, J = 3.3 Hz, 2 H), 4.35-4.73 (m, 1 H), 3.74-4.04 (m, 1 H), 2.71 (dd, J = 18.1, 4.0 Hz, 1 H), 2.36 (dd, J = 18.1, 9.0 Hz, 1 H), 2.01 (s, 3 H). ^¹³C NMR (400 MHz, CDCl₃): δ = 170.25, 163.83, 150.74, 135.25, 130.73, 123.73, 70.37, 56.34, 50.82, 30.93, 23.59. HRMS (ESI): m/z [M + Na] calcd for C₁₅H₁₅N₅O₅: 368.0971; found: 368.0974.
(1 S ,5 R ,6 S )-6-Acetamido-5- tert -butoxycarbonylamino-2-en-1-yl 4-Nitrobenzoate(7): To a solution of 6 (1.24 g, 3.6 mmol) in MeCN (6 mL), Ph₃P (1.16 g, 3.96 mmol, 1.1 equiv) was added and the mixture was stirred at 60 ˚C for 3 h. H₂O (2 mL) was added and the reaction mixture was stirred at 45 ˚C for 2 h. Solvent was removed under reduced pressure followed by the addition of CH₂Cl₂ (6 mL), Et₃N (1.5 mL, 10.8 mmol), and Boc₂O (1.57 g, 7.2 mmol), and the mixture was stirred at r.t. for 2 h. Deionised H₂O (6 mL) was added and the aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL) and the combined organic layer was dried over Na₂SO₄. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, hexane-EtOAc, 1:1) to afford 7 (1.27 g, 3.28 mmol) in 91% yield (2 steps) as a white solid; mp 196-198 ˚C; [α]^²6 _D +154 (c = 0.16, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 8.09-8.46 (m, 4 H), 6.38 (d, J = 7.7 Hz, 1 H), 5.98 (s, 2 H), 5.59 (s, 1 H), 4.73 (d, J = 7.5 Hz, 2 H), 3.89-4.43 (m, 2 H), 2.65 (d, J = 18.7 Hz, 1 H), 2.10 (dd, J = 17.6, 9.6 Hz, 1 H), 1.91 (s, 3 H), 1.44 (s, 9 H). ^¹³C NMR (400 MHz, CDCl₃): δ = 170.51, 163.77, 156.90, 150.57, 135.19, 131.99, 130.80, 123.56, 80.08, 70.50, 53.54, 45.56, 32.65, 28.21, 23.13. HRMS (ESI): m/z [M + H] calcd for C₂₀H₂₅N₃O₇: 420.1771; found: 420.1774.
tert -Butyl [(1 R ,6 S )-6-Acetamido-5-oxocyclohex-3-en-1-yl]carbamate (8): To a solution of 7 (635 mg, 1.63 mmol) in MeOH (3.26 mL) was added solid NaOMe (44 mg, 0.81 mmol) under argon atmosphere. After stirring at r.t. for 1 h, glacial AcOH (47 µL) was added to quench the reaction. MeOH was removed by rotary evaporation and CH₂Cl₂ (3 mL) was added to the residue. After cooling to 4 ˚C Dess-Martin periodinane (1.03 g, 2.44 mmol, 1.5 equiv) was added. After 1 h, sat. aq Na₂S₂O₃ was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layer was washed with sat. aq NaHCO₃ and brine, and then dried over Na₂SO₄. The solvent was removed under reduced pressure and was purified by column chromatography (silica gel, hexane-EtOAc, 2:1) to afford 8 (332.4 mg, 1.4 mmol) in 86% yield as a white solid; mp 143-144 ˚C; [α]^²6 _D -132 (c = 0.08, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 6.85-7.08 (m, 1 H), 6.38 (d, J = 6.4 Hz, 1 H), 6.12 (dd, J = 10.1, 3.0 Hz, 1 H), 5.70 (d, J = 7.8 Hz, 1 H), 4.59 (dd, J = 13.0, 7.1 Hz, 1 H), 3.75-4.03 (m, 1 H), 2.93 (dt, J = 18.7, 5.5 Hz, 1 H), 2.29-2.52 (m, 1 H), 2.07 (s, 3 H), 1.40 (s, 9 H). ^¹³C NMR (101 MHz, CDCl₃): δ = 194.98, 172.50, 156.09, 148.65, 128.51, 79.73, 59.70, 53.49, 34.11, 28.31, 23.11. HRMS (CI): m/z [M⁺] calcd for C₁₃H₂₀N₂O₄: 268.1423; found: 268.1425.

18

Tamiflu^® was purchesed from Hangzhou DayangChem Co. Ltd. and LGM Pharma.

22

(3 R ,4 R ,5 S )-4-Acetamido-5-[( tert -butoxycarbonyl)-amino]-3-(pentan-3-yloxy)cyclohex-1-enecarboxylic Acid (9): Solid 1 (163 mg, 0.413 mmol) was dissolved in sat. NaHCO₃ (10 mL) and was extracted with EtOAc (2 × 10 mL). The combined organic layer was dried with Na₂SO₄. After complete removal of the solvent, the residue was dissolved in H₂O-MeOH (1 mL; 1:1) mixture and solid KOH (46.3 mg, 0.826 mmol) was added, and the mixture was stirred at r.t. overnight. After most of the MeOH was removed under reduced pressure, H₂O was removed by azeotropic evaporation with benzene. The residue was dissolved in CH₂Cl₂ (1 mL) and treated with Et₃N (287 uL, 2.06 mmol, 5 equiv), and Boc₂O (180 mg, 8826 mmol, 2 equiv), and the mixture was stirred at r.t. for 4 h. The reaction mixture was quenched with a sat. aq NH₄Cl solution and extracted with EtOAc (3 × 5 mL). The organic extracts were combined, washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give pure product 9 as a white solid in 97% yield; mp 206-208 ˚C; [α]^²6 _D -53 (c = 0.12, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 6.82 (s, 1 H), 6.75 (d, J = 8.3 Hz, 1 H), 5.78 (d, J = 9.6 Hz, 1 H), 3.86-4.10 (m, 2 H), 3.66-3.84 (m, 1 H), 3.26-3.34 (m, 1 H), 2.69 (dd, J = 17.6, 4.7 Hz, 1 H), 2.24 (dd, J = 17.4, 10.8 Hz, 1 H), 1.98 (s, 3 H), 1.46 (t, J = 6.6 Hz, 4 H), 1.40 (s, 9 H), 0.77 -0.93 (m, 6 H). ^¹³C NMR (400 MHz, CDCl₃): δ= 171.36, 169.00, 156.72, 139.30, 128.92, 82.08, 79.65, 76.00, 55.10, 49.27, 30.72, 28.34, 26.15, 25.49, 23.22, 9.63, 9.00. HRMS (ESI): m/z [M + Na] calcd for C₁₉H₃₂N₂O₆: 407.2158; found: 407.2153.

(3 R ,4 R ,5 S )-4-Methyl-2-thioxothiazol-3 (2 H )-yl-4-acetamido-5-[( tert -butoxycarbonyl)amino]-3-(pentan-3-loxy)cyclohex-1-enecarboxylate (10): DABCO (112 mg, 1.43 mmol) and thiohydroxamic acid (12; 84 mg, 0.572 mmol) were added to a cold (0 ˚C), magnetically stirred solution of 9 (110 g, 0.286 mmoL) in anhyd CH₂Cl₂ (1.43 mL), and the reaction mixture was stirred for 45 min at 0-5 ˚C, and treated with propane phosphonic acid anhydride [PPAA; 0.5 mL, 50% (w/w) solution of PPAA in DMF]. The reaction mixture was stirred for 5 h at r.t. All volatiles were removed at 20 ˚C under reduced pressure to afford a residue which was taken up in Et₂O (2 mL) and H₂O (2 mL). The combined ethereal layers were washed with H₂O (2 mL), dried with anhyd Na₂SO₄, filtered, and evaporated. Column chromatography (elution with 25-50% Et₂O and hexane) gave the ester 10 (119 mg, 81%) as a semisolid; [α]^²6 _D -59 (c = 0.06, CHCl₃). ^¹H NMR (400 MHz, MeOD): δ = 6.61 (s, 1 H), 4.24 (d, J = 7.5 Hz, 1 H), 3.95 (t, 1 H), 3.84 (td, J = 10.3, 5.4 Hz, 1 H), 3.40-3.52 (m, 1 H), 2.84 (d, J = 17.4 Hz, 1 H), 2.31-2.59 (m, 1 H), 2.19 (s, 3 H), 1.98 (s, 3 H), 1.48-1.63 (m, 6 H), 1.45 (s, 9 H), 0.92 (dt, J = 15.4, 7.4 Hz, 6 H). ^¹³C NMR (400 MHz, MeOD): δ = 182.38, 173.72, 157.96, 138.94, 126.34, 104.20, 83.72, 80.41, 77.15, 55.87, 49.99, 31.62, 28.71, 27.22, 26.72, 22.99, 13.14, 9.94, 9.59. HRMS (ESI): m/z [M + Na] calcd for C₂₃H₃₅N₃O₆S₂: 536.1865; found: 536.1873.
tert -Butyl-[(1 S ,5 R ,6 R )-6-acetamido-3-bromo-5-(pentan-3-yloxy)cyclohex-3-en-1-yl]carbamate (11): Thiohydroxamic ester 10 (96 mg, 0.187 mmol) and AIBN (1.5 mg) were dissolved in bromotrichloromethane (935 µL) and heated to 70 ˚C. The reaction was stirred for an additional 1 h, cooled, and chromatographed directly on silica gel (hexane-EtOAc) to give 21 (59 mg, 76%) as a white solid; mp 153-155 ˚C; [α]^²6 _D -42 (c = 0.32, CHCl₃). All spectroscopic data was identical to the previously reported data of 11. ^¹H NMR (400 MHz, CDCl₃): δ = 6.05 (s, 1 H), 5.65 (d, J = 9.0 Hz, 1 H), 5.36 (d, J = 8.9 Hz, 1 H), 4.08 (q, J = 9.2 Hz, 1 H), 3.74-3.92 (m, 2 H), 3.19-3.34 (m, 1 H), 2.76 (dd, J = 17.8, 5.2 Hz, 1 H), 2.57 (dd, J = 15.7, 8.1 Hz, 1 H), 1.97 (s, 3 H), 1.36-1.53 (m, 13 H), 0.87 (t, J = 6.4 Hz, 6 H). ^¹³C NMR (400 MHz, CDCl₃): δ = 170.66, 155.91, 129.25, 121.57, 81.89, 79.71, 76.37, 52.74, 49.52, 40.41, 28.30, 26.15, 25.87, 23.35, 9.61, 9.43. HRMS (ESI): m/z [M + H] calcd for C₁₈H₃₁BrN₂O₄: 419.1545; found: 419.1550.