Convenient and Efficient Synthesis of Pyrazole-Based DHODase Inhibitors from 3-Aryl-4-cyanosydnone

Abstract

Pyrazole-based DHODase inhibitors have been efficient and conveniently synthesized in 51-60% yield from 3-(p-aryl)-4-cyanosydnone via regioselective 1,3-diploar cycloaddition followed by an amidation and a Ritter reaction.

Key words

sydnones - 1,3-dipolar cycloaddition - propargylic ester - pyrazole - DHODase inhibitors

References and Notes

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• 3 Copeland RA. Marcinkeviciene J. Haque TS. Kopcho LM. Jing W. Wang K. Ecret LD. Sizemore C. Amsler KA. Foster L. Tadesse S. Combs AP. Stern AM. Trainor GL. Slee A. Rogers MJ. Hobbs F. J. Biol. Chem.  2000,  275:  33373 
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• 5 Lam PY, Clark CG, Dominguez C, Fevig JM, Han Q, Li R, Pinto DJ.-P, Pruitt JR, and Quan ML. inventors; The Du Pont Merck Pharmaceutical Company U.S.A.  W09857951. 
• 6 Danishefsky SJ. Pearson WH. Segmuller BE. J. Am. Chem. Soc.  1985,  107:  1280 
• 7 Haque TS. Tadesse S. Marcinkeviciene J. Rogers MJ. Sizemore C. Kopcho LM. Amsler K. Ecret LD. Zhan DL. Hobbs F. Slee A. Trainor GL. Stern AM. Copeland RA. Combs AP. J. Med. Chem.  2002,  45:  4669 
• For the preparation of sydnones, see:
• 9a Yeh M.-Y. Tien H.-J. Huang L.-Y. Chen M.-H. J. Chin. Chem. Soc.  1983,  30:  29 
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8

1,3-Dipolar Cycloaddition; General Procedure. Ethyl, tert-butyl, benzyl, or diphenylmethyl propiolate (0.25 g, 2.0 equiv) was added to a solution of 3-(p-ethoxyphenyl)-4-cyanosydnone (2, 0.23 g, 1.0 equiv) in chlorobenzene (10 mL) and heated to reflux under N₂ for 48 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to remove chlorobenzene. The residue was dissolved in CH₂Cl₂ (2.0 mL) and purified by gravity column chromatography (silica, EtOAc-hexanes, 15:85) to provide the corresponding products 5a-d and 6a-c.
5d: IR (KBr): 3031 (s), 2980 (s), 2229 (m, CN), 1726 (m, C=O) cm^-1; ¹H NMR (CDCl₃, 300 MHz): δ = 1.35 (t, J = 10.4 Hz, 3 H, CH₃), 3.98 (q, J = 10.4 Hz, 2 H, CH₂), 6.92 (d, J = 7.7 Hz, 2 H, ArH), 7.08 (s, 1 H, Ph₂CH), 7.15 (s, 1 H, pyrazole-H), 7.20-7.35 (m, 8 H, ArH), 7.41 (d, J = 7.7 Hz, 2 H, ArH), 7.47-7.54 (m, 2 H, ArH); ¹³C NMR (CDCl₃, 75 MHz): δ = 14.66, 63.95, 77.92, 110.11, 115.15, 115.65, 117.82, 124.92, 124.97, 127.22, 128.15, 128.57, 128.62, 130.95, 139.53, 139.59, 144.21, 159.65, 159.99; Anal. Calcd for C₂₆H₂₁N₃O₃: C, 73.74; H, 5.00; N, 9.92. Found: C, 73.65; H, 5.12; N, 9.96.
9: IR (KBr): 3020 (s), 2985 (s), 2932 (m, C=N), 1736 (m, C=O) cm^-1; ¹H NMR (CDCl₃, 300 MHz): δ = 6.90 (d, J = 7.7 Hz, 2 H, ArH), 7.07 (s, 1 H, Ph₂CH), 7.13 (s, 1 H, pyrazole-H), 7.21-7.37 (m, 8 H, ArH), 7.41 (d, J = 7.7 Hz, 2 H, ArH), 7.47-7.54 (m, 3 H, ArH); ¹³C NMR (CDCl₃, 75 MHz): δ = 77.89, 110.11, 115.13, 115.64, 117.80, 124.90, 124.95, 126.45, 127.19, 128.15, 128.56, 128.59, 130.92, 139.49, 139.55, 144.20, 159.97; Anal. Calcd for C₂₄H₁₇N₃O₂: C, 75.97; H, 4.52; N, 11.08. Found: C, 75.92; H, 4.56; N, 11.12.

17

Amidation; General Procedure. Benzylamine (8.0 mmol) was added to a solution of 3-aryl-4-cyanosydnone (5d or 9, 2.0 mmol) in xylene (15 mL) and the resulting solution was heated to reflux for 72 h under N₂. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove xylene. The residue was dissolved in CH₂Cl₂ (2.0 mL) and purified by column chromatography (silica, EtOAc-hexanes, 4:1) to provide the corresponding product 10a or 10b in 93% and 91% yields, respectively.
10a: Mp 142-144 °C; IR (KBr): 3331 (s, NH), 2237 (m, CN), 1655 (m, C=O) cm^-1; ¹H NMR (CDCl₃, 300 MHz): δ = 1.34 (t, J = 6.8 Hz, 3 H, CH₃), 4.10 (q, J = 6.8 Hz, 2 H, CH₂), 4.44 (d, J = 6.3 Hz, 2 H, NCH₂), 7.13 (d, J = 9.0 Hz, 2 H, ArH), 7.20-7.26 (m, 1 H, ArH), 7.29-7.31 (m, 4 H, ArH), 7.66 (s, 1 H, pyrazole-H), 7.71 (d, J = 9.0 Hz, 2 H, ArH), 9.14 (t, J = 6.3 Hz, 1 H, NH); ¹³C NMR (CDCl₃, 75 MHz): δ = 15.83, 43.51, 65.01, 111.99, 116.38, 117.03, 117.28, 126.94, 128.15, 128.67, 169.59, 131.97, 140.63, 148.63, 160.70, 160.93; Anal. Calcd for C₂₀H₁₈N₄O₂: C, 69.35; H, 5.24; N, 16.17. Found: C, 69.40; H, 5.35; N, 16.02.
10b: Mp 95-96 °C; IR (KBr): 3281 (s, NH), 2232 (m, CN), 1649 (m, C=O) cm^-1; ¹H NMR (CDCl₃, 300 MHz): δ = 4.45 (d, J = 6.2 Hz, 2 H, NCH₂), 7.20-7.27 (m, 1 H, ArH), 7.29-7.31 (m, 4 H, ArH), 7.55-7.65 (m, 3 H, ArH), 7.77 (s, 1 H, pyrazole-H), 7.79 (d, J = 9.0 Hz, 2 H, ArH), 9.18 (t, J = 6.2 Hz, 1 H, NH); ¹³C NMR (CDCl₃, 75 MHz): δ = 43.52, 11.94, 116.90, 117.83, 125.17, 128.18, 128.68, 129.61, 131.05, 131.21, 139.03, 140.55, 148.98, 160.90; Anal. Calcd for C₁₈H₁₄N₄O: C, 71.51; H, 4.67; N, 18.53. Found: C, 71.54; H, 4.74; N, 18.44.

20

Ritter Reaction; General Procedure A solution of cyclohexanol (4.0 mmol) and BF₃·OEt₂ (4.0 mmol) in chlorobenzene was stirred at r.t. for 0.5 h. Compound 10a or 10b (1.0 mmol) was added to the reaction mixture, which was heated to reflux for 72 h. The solution was neutralized with Et₃N and the reaction mixture was concentrated under reduced pressure to remove chlorobenzene. The residue was dissolved in CH₂Cl₂ (2.0 mL) and purified by column chromatography (silica, EtOAc-hexanes, 1:4) to provide the corresponding product 11a or 11b as light-yellow solids in 76% and 70% yields, respectively.
11a: Mp 146-148 °C; IR (KBr); 3322 (s, NH), 2929 (m), 2852 (m), 1647 (m) cm^-1; ¹H NMR (CDCl₃, 300 MHz): δ = 1.09-1.21 (m, 4 H), 1.33 (t, J = 6.9 Hz, 3 H, CH₃), 1.52-1.73 (m, 6 H), 3.57 (m, 1 H, NCH), 4.09 (q, J = 10.1 Hz, 2 H, CH₂), 4.42 (d, J = 5.9 Hz, 2 H, NCH₂), 6.99 (d, J = 8.6 Hz, 2 H, ArH), 7.22 (d, J = 8.6 Hz, 2 H, ArH), 7.30 (d, J = 3.7 Hz, 4 H, ArH), 7.33 (s, 1 H, ArH), 7.36 (s, 1 H, pyrazole-H), 8.47 (d, J = 7.7 Hz, 1 H, NH), 8.89 (t, J = 5.9 Hz, 1 H, NH); ¹³C NMR (CDCl₃, 75 MHz): δ = 15.02, 25.06, 25.55, 32.45, 42.47, 48.54, 63.88, 108.50, 114.58, 126.68, 127.15, 127.72, 128.66, 133.18, 139.35, 140.10, 146.33, 158.28, 158.72, 161.22; Anal. Calcd for C₂₆H₃₀N₄O₃: C, 69.93; H, 6.77; N, 12.55. Found: C, 69.79; H, 6.85; N, 12.40.
11b: Mp 142-143 °C; IR (KBr): 3281 (s, NH), 2927 (s), 1644 (m, C=O) cm^-1; ¹H NMR (CDCl₃, 300 MHz): δ = 1.07-1.29 (m, 4 H), 1.53-1.75 (m, 6 H), 3.59 (m, 1 H, NCH), 4.44 (d, J = 6.1 Hz, 2 H, NCH₂), 7.20-7.25 (m, 2 H, ArH), 7.30 (d, J = 4.2 Hz, 4 H, ArH), 7.42-7.46 (m, 4 H, ArH), 7.51 (s, 1 H, pyrazole-H), 8.54 (d, J = 7.8 Hz, 1 H, NH), 8.92 (t, J = 6.1 Hz, 1 H, NH); ¹³C NMR (CDCl₃, 75 MHz): δ = 25.91, 26.39, 33.26, 43.37, 49.49, 109.67, 126.01, 128.08, 128.60, 129.56, 129.67, 130.04, 140.36, 140.86, 140.96, 147.57, 159.24, 162.10; Anal. Calcd for C₂₄H₂₆N₄O₂: C, 71.62; H, 6.51; N, 13.92. Found: C, 71.42; H, 6.60; N, 13.77.