Efficient Strategy to Prepare Water-Soluble Prodrugs of Ketones

Kristiina M. Huttunen; Hanna Kumpulainen; Jukka Leppänen; Jarkko Rautio; Tomi Järvinen; Jouko Vepsäläinen

doi:10.1055/s-2006-933115

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Synlett 2006(5): 0701-0704
DOI: 10.1055/s-2006-933115

LETTER

Efficient Strategy to Prepare Water-Soluble Prodrugs of Ketones

Kristiina M. Huttunen*^a, Hanna Kumpulainen^a, Jukka Leppänen^a, Jarkko Rautio^a, Tomi Järvinen^a, Jouko Vepsäläinen^b
^a Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, 70211 Kuopio, Finland
Fax: +358(17)162456; e-Mail: Kristiina.Huttunen@uku.fi;
^b Department of Chemistry, University of Kuopio, P.O. Box 1627, 70211 Kuopio, Finland

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Publication History

Received 21 December 2005
Publication Date:
09 March 2006 (online)

Abstract
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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.

Key words

imines - ketones - prodrugs - Beckmann rearrangement - protecting groups

References and Notes

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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.