Efficient Strategy to Prepare Water-Soluble Prodrugs of Ketones

Abstract

A novel method for the synthesis of water-soluble ­ketoxime phosphate prodrugs avoiding the unwanted Beckmann rearrangement is developed. In the first step, a novel in situ prepared phosphorochloridic acid bis-(2-trimethylsilyl-ethyl) (TMSE) ester 1 reacts with the hydroxyimine 2. In the second step, the formed TMSE-phosphate triester 3 undergoes a tetrabutylammonium ­fluoride mediated microwave-assisted conversion into the corresponding ketoxime phosphate salt 4 without further Beckmann ­rearrangement.

imines - ketones - prodrugs - Beckmann rearrangement - protecting groups

References and Notes

1 Stella VJ. Adv. Drug Deliv. Rev.  1996,  19:  111 

2a Fleisher D. Bong R. Stewart BH. Adv. Drug Deliv. Rev.  1996,  19:  115 

2b Krise JP. Stella VJ. Adv. Drug Deliv. Rev.  1996,  19:  287 

2c Schultz C. Bioorg. Med. Chem.  2003,  11:  885 

3a Kearney AS. Stella VJ. Pharm. Res.  1992,  9:  497 

3b Safadi M. Oliyai R. Stella VJ. Pharm. Res.  1993,  10:  1350 

3c Krise JP. Zygmunt J. Georg GI. Stella VJ. J. Med. Chem.  1999,  42:  3094 

4a Jousserandot A. Boucher J.-L. Desseaux C. Delaforge M. Mansuy D. Bioorg. Med. Chem. Lett.  1995,  5:  423 

4b Venhuis BJ. Dijkstra D. Wustrow D. Meltzer LT. Wise LD. Johnson SJ. Wikström HV. J. Med. Chem.  2003,  46:  4136 

4c Kumpulainen H. Mähönen N. Laitinen M.-L. Jaurakkajärvi M. Raunio H. Juvonen RO. Vepsäläinen J. Järvinen T. Rautio J. J. Med. Chem.  2006,  in press 

5a Jones B. Chem. Rev.  1944,  35:  335 

5b Li D. Shi F. Guo S. Deng Y. Tetrahedron Lett.  2004,  46:  671 

6 Green TW. Wuts PGM. Protective Groups in Organic Synthesis   3rd ed.:  John Wiley and Sons, Inc; New York: 1999.  Chap. 9.

7 Wu M. Chen R. Huang Y. Synthesis  2004,  15:  2441 

8 Naik R. Pasha MA. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  2005,  44:  778 

9 Wada T. Sekine M. Tetrahedron Lett.  1994,  35:  757 

10a Ross KC. Rathbone DL. Thomson W. Freeman S. J. Chem. Soc., Perkin Trans. 1  1995,  4:  421 

10b Chao H.-G. Bernatowicz MS. Klimas CE. Matsueda GR. Tetrahedron Lett.  1993,  34:  3377 

11 Li J. Luo X. Wang Q. Zheng L.-M. King I. Doyle TW. Chen S.-H. Bioorg. Med. Chem. Lett.  1998,  8:  3159 

12

Phosphorous Acid Bis(2-trimethylsilylethyl) Ester ( 7). Freshly distilled PCl₃ (2.4 mL, 27.5 mmol) in anhyd Et₂O (50 mL) was added dropwise to a solution of 2-(trimethyl-silyl)ethanol (11.8 mL, 82.5 mmol) and anhyd Et₃N (11.5 mL, 82.5 mmol) in Et₂O (250 mL) at 0 °C over 2 h under an N₂ flow. The vigorously stirred reaction mixture was allowed to warm to r.t. during 1 h. The precipitate was filtered out of the mixture under an N₂ atmosphere and washed thoroughly with Et₂O (200 mL) followed by H₂O (100 mL). The separated organic phase was stirred with H₂O (100 mL) at 35 °C for 1 h, dried over Na₂SO₄, and concentrated in vacuo to obtain the phosphite 7 as a colourless fluid (7.6 g, 98%). ¹H NMR: δ = 0.05 (s, 18 H), 1.090 (m, ² J _HH = 13.72 Hz, J = 11.52, 5.78 Hz, 2 H), 1.091 (m, ² J _HH = 13.72 Hz, J = 11.40, 5.60 Hz, 2 H), 4.149 (m, ² J _HH = 10.27 Hz, J = 11.52, 5.60 Hz, ³ J _HP = 8.26 Hz, 2 H), 4.169 (m, ² J _HH = 10.27 Hz, J = 11.40, 5.78 Hz, ³ J _HP = 8.40 Hz, 2 H), 6.787 (d, ^¹ J _HP = 687.77 Hz, 1 H). ¹³C NMR: δ = -1.42 (q), 19.82 (td, ³ J _CP = 5.9 Hz), 64.28 (td, ² J _CP = 5.9 Hz). ³¹P NMR: δ = 7.56 (s). Anal. Calcd for C₁₀H₂₇O₃PSi₂·0.1Et₂O: C, 43.09; H, 9.74. Found: C, 43.20; H, 10.12.

13

Phosphorochloric Acid Bis(2-trimethylsilylethyl) Ester ( 1) The phosphine 7 (1.0 g, 3.5 mmol) in anhyd toluene (10 mL) was dropped to a solution of N-chlorosuccinimide (0.47 g, 3.5 mmol) in anhyd toluene (10 mL) at -10 °C under an argon atmosphere. After the addition, the reaction mixture was stirred for 2 h at r.t. The mixture was filtered and the filtrate containing the chlorophosphate 1 (0.97 g, 86%) was used immediately for the phosphorylation of the ketoxime 2. ¹H NMR: δ = 0.02 (s, 18 H), 1.168 (m, ² J _HH = 13.49 Hz, J = 11.32, 5.90 Hz, 2 H), 1.176 (m, ² J _HH = 13.49 Hz, J = 11.33, 5.88 Hz, 2 H), 4.292 (m, ² J _HH = 10.06 Hz, J = 11.33, 5.90 Hz, ³ J _HP = 8.47 Hz, 2 H), 4.333 (m, ² J _HH = 10.06 Hz, J = 11.32, 5.88 Hz, ³ J _HP = 8.46 Hz, 2 H). ¹³C NMR: δ = -1.46 (q), 19.27 (td, ³ J _CP = 6.7 Hz), 68.72 (td, ² J _CP = 7.9 Hz). ³¹P NMR: δ = 4.59 (s). Anal. Calcd for C₁₀H₂₆ClO₃PSi₂·3HCl: C, 28.18; H, 6.86. Found: C, 28.59; H, 6.60.

14

4-(6-Methoxy-2-naphthyl)-2-butanone Oxime ( 2). Nabumetone (5.0 g, 21.9 mmol), hydroxylamine hydro-chloride (3.0 g, 43.8 mmol) and pyridine (3.5 mL, 43.8 mmol) were refluxed in EtOH (100 mL) overnight. The mixture was concentrated in vacuo and the residue was dissolved in Et₂O (150 mL), washed with sat. Na₂CO₃ (150 mL) and H₂O (3 × 70 mL), dried over Na₂SO₄ and evap-orated in vacuo to provide the ketoxime 2 (5.0 g, 94%) as a white solid mixture of two isomers. ¹H NMR (major isomer): δ = 1.93 (s, 3 H), 2.58 (dd, 2 H), 2.96 (dd, J = 10.4, 5.8 Hz, 2 H), 3.90 (s, 3 H), 7.10 (d, ⁴ J _HH = 2.6 Hz, 1 H), 7.12 (dd, J = 8.8, 2.6 Hz, 1 H), 7.29 (dd, J = 8.6, 1.8 Hz, 1 H), 7.55 (d, ⁴ J _HH = 1.8 Hz, 1 H), 7.662 (d, J = 8.8 Hz, 1 H), 7.664 (d, J = 8.6 Hz, 1 H), 8.20 (1 H, br s). ¹H NMR (minor isomer): δ = 1.83 (s, 3 H), 2.75 (dd, 2 H), 2.97 (dd, J = 9.9, 6.3 Hz, 2 H), 3.91 (s, 3 H), 7.11 (d, ⁴ J _HH = 2.6 Hz, 1 H), 7.12 (dd, J = 9.0, 2.6 Hz, 1 H), 7.34 (dd, J = 8.4, 1.7 Hz, 1 H), 7.59 (d, ⁴ J _HH = 1.7 Hz, 1 H), 7.674 (d, J = 9.0 Hz, 1 H), 7.674 (d, J = 8.4 Hz, 1 H), 8.01 (1 H, br s). ¹³C NMR (major isomer): δ = 13.76 (q), 32.59 (t), 37.73 (t), 55.30 (q), 105.71 (d), 118.77 (d), 126.28 (d), 126.93 (d), 127.54 (d), 128.96 (d), 129.12 (s), 133.15 (s), 136.26 (s), 157.30 (s), 158.03. ¹³C NMR (minor isomer): δ = 20.36 (q), 30.62 (t), 31.51 (t), 55.30 (q), 105.71 (d), 118.76 (d), 126.23 (d), 126.90 (d), 127.57 (d), 128.99 (d), 129.11 (s), 131.17 (s), 136.40 (s), 157.31 (s), 158.54 (s). ESI-MS: m/z = 244.0 [M + H]⁺. Anal. Calcd for C₁₅H₁₇NO₂·0.1H₂O: C, 73.50; H, 7.07; N, 5.71. Found: C, 73.45; H, 7.19; N, 5.81.

15

Phosphoric Acid Triester ( 3). NaH (0.12 g, 3.1 mmol) was added to a solution of the ketoxime 2 (0.74 g, 3.1 mmol) in anhyd THF (10 mL) and the mixture was stirred at r.t. for 2 h. The chlorophosphate 1 (3.1 mmol) was filtered directly to the reaction mixture at -70 °C under an argon atmosphere and the mixture was allowed to warm to r.t. After 20 h, the mixture was concentrated in vacuo and dissolved in Et₂O (40 mL). The solution was washed with H₂O (2 × 20 mL), dried over Na₂SO₄, and evaporated in vacuo. Because the compound partially decomposed by using the silica gel flash chromato-graphy, the residue was purified by the preparative HPLC on reversed phase Kromasil^® 100 Å (C8) column using MeCN-H₂O (9:1 v/v) as an eluent to obtain the triester 3 (0.4 g, 25%) as a light yellow oil. ¹H NMR (major isomer): δ = 0.03 (s, 18 H), 1.09 (m, 4 H), 2.01 (s, 3 H), 2.66-2.70 (m, 1 H), 2.78-2.82 (m, 1 H), 2.96-3.00 (m, 2 H), 3.91 (s, 3 H), 4.17-4.30 (m, 4 H), 7.09-7.14 (m, 2 H), 7.26-7.32 (m, 1 H), 7.54-7.58 (m, 1 H), 7.64-7.69 (m, 2 H). ¹H NMR (minor isomer): δ = 0.03 (s, 18 H), 1.09 (m, 4 H), 1.91 (s, 3 H), 2.66-2.70 (m, 1 H), 2.87-2.82 (m, 1 H), 2.96-3.00 (m, 2 H), 3.91 (s, 3 H), 4.17-4.30 (m, 4 H), 7.09-7.14 (m, 2 H), 7.26-7.32 (m, 1 H), 7.54-7.58 (m, 1 H), 7.64-7.69 (m, 2 H). ¹³C NMR (major isomer): δ = -1.37 (q), 15.46 (q), 19.63 (td, ³ J _CP = 6.0 Hz), 32.38 (t), 37.52 (t), 55.40 (q), 67.01 (td, ² J _CP = 3.1 Hz), 105.75 (d), 119.02 (d), 126.48 (d), 127.13 (d), 127.53 (d), 129.05 (d), 129.14 (s), 133.31 (s), 135.72 (s), 157.49 (s), 166.45 (d, ³ J _CP = 12.6 Hz). ¹³C NMR (minor isomer): δ = -1.37 (q), 19.68 (td, ³ J _CP = 6.0 Hz), 20.38 (q), 31.77 (t), 32.06 (t), 55.40 (q), 66.96 (td, ² J _CP = 3.1 Hz), 105.75 (d), 119.05 (d), 126.41 (d), 127.21 (d), 127.45 (d), 129.08 (d), 129.11 (s), 133.38 (s), 135.47 (s), 157.53 (s), 167.07 (d, ³ J _CP = 12.6 Hz). ³¹P NMR (major isomer): δ = 0.54 (s). ³¹P NMR (minor isomer): δ = 0.64 (s). Anal. Calcd for C₂₅H₄₂NO₅PSi₂·0.1H₂O: C, 57.13; H, 8.09; N, 2.67. Found: C, 56.80; H, 8.07; N, 2.73.

16

Ketoxime Phosphate TBA Salt 4
The phosphoric acid triester (3, 0.30 g, 0.57 mmol) and TBAF (0.72 g, 2.3 mmol) were irradiated in MeOH (5 mL) at 160 °C (17 bar, 35-135 W) in a microwave reactor for 6 h. The mixture was evaporated in vacuo and the residue was purified by the preparative HPLC on resin-based Supelcogel ODP-50 column using 0.05% Et₃N solution and MeCN (3:7 v/v) as an eluent to yield the brownish oily ketoxime phos-phate 4 (0.4 g, 87%) as a salt of TBA⁺. ¹H NMR (major isomer): δ = 1.99 (s, 3 H), 2.61-2.64 (m, 2 H), 2.97-3.08 (m, 2 H), 3.92 (s, 3 H), 7.11-7.14 (m, 2 H), 7.29-7.33 (m, 1 H), 7.58-7.61 (m, 1 H), 7.66-7.69 (m, 2 H). ¹H NMR (minor isomer): δ = 1.85 (s, 3 H), 2.61-2.64 (m, 2 H), 2.97-3.08 (m, 2 H), 3.92 (s, 3 H), 7.11-7.14 (m, 2 H), 7.29-7.33 (m, 1 H), 7.58-7.61 (m, 1 H), 7.66-7.69 (m, 2 H). ¹H NMR (TBA⁺ salt): δ = 1.01 (t, J = 7.5 Hz, 12 H), 1.45 (sext, J = 7.5 Hz, 8 H), 1.67 (m, 8 H), 3.35 (t, J = 8.5 Hz, 8 H). ¹³C NMR (major isomer): δ = 15.02 (q), 32.97 (t), 38.07 (t), 55.40 (q), 105.75 (d), 118.76 (d), 126.32 (d), 126.92 (d), 127.81 (d), 129.08 (d), 129.21 (s), 133.14 (s), 136.96 (s), 157.29 (s), 160.73 (d, ³ J _CP = 12.1 Hz). ¹³C NMR (minor isomer): δ = 20.65 (q), 31.67 (t), 31.89 (t), 55.40 (q), 105.75 (d), 118.68 (d), 126.36 (d), 126.85 (d), 127.95 (d), 129.12 (d), 129.19 (s), 133.14 (s), 136.85 (s), 157.25 (s), 161.06 (d, ³ J _CP = 12.4 Hz). ¹³C NMR (TBA⁺salt): δ = 13.84 (q), 19.87 (t), 24.24 (t), 58.89 (t). ³¹P NMR (major isomer): δ = 2.55 (s). ³¹P NMR (minor isomer): δ = 2.58 (s). ESI-MS: anionic m/z = 322.6 [M + H]^-. Anal. Calcd for C₁₅H₁₇NO₅P·2.3C₁₆H₃₆N·4.3H₂O): C, 65.05; H, 11.32; N, 4.83. Found: C, 64.63; H, 11.68; N, 4.56.