Synthesis of Macrocyclic Urea Kinase Inhibitors

Abstract

An efficient and convergent route was developed for the synthesis of a novel class of urea-based macrocyclic kinase inhibitors. The synthesis is featured with an efficient urea formation by using a key carbamate intermediate and with a smooth ring-closure olefin metathesis. Furthermore, the hydrogenations of the resulting olefins were investigated in this complex macrocyclic ring system.

Key words

metathesis - urea - macrocycles - hydrogenations - kinase inhibitors

References and Notes

• For reviews, see:
• 1a Meggers E. Atilla-Gokcumen GE. Bregman H. Maksimoska J. Mulcahy SP. Pagano N. Williams D. Synlett  2007,  1177 
• 1b Noble MEM. Endicott JA. Johnson LN. Science  2004,  303:  1800 
• For reviews, see:
• 2a Dumas J. Smith RA. Lowinger TB. Curr. Opin. Drug Discovery Dev.  2004,  7:  600 
• 2b Dumas J. Curr. Opin. Drug Discovery Dev.  2002,  5:  718 
• 3 Chen Z. Xiao Z. Gu W.-Z. Xue J. Bui M. Kovar P. Li G. Wang G. Tao Z.-F. Tong Y. Lin N.-H. Sham HL. Wang JY. Sowin TJ. Rosenberg SH. Zhang HY. Int. J. Cancer  2006,  119:  2784 
• 4 For a review, see: Tao Z.-F. Lin N.-H. Anticancer Agents Med. Chem.  2006,  6:  377 
• 5 For a review, see: Chen X. Wang W. Ann. Rep. Med. Chem.  2003,  38:  333 
• 7 Grabowski EJ, Tristram EW, and Tull RJ. inventors; US  3625944. 
• 10a Miller SJ. Grubbs RH. J. Am. Chem. Soc.  1995,  117:  5855 
• 10b Fürstner A. Angew. Chem. Int. Ed.  2000,  39:  3012 
• 10c Martin WHC. Blechert S. Curr. Top. Med. Chem.  2005,  5:  1521 
• 12 The green color could be removed by following a recently reported method: Ahn YM. Yang K. Georg GI. Org. Lett.  2001,  3:  1411 
• 14 VanRheenen V. Kelly RC. Cha DY. Tetrahedron Lett.  1976,  17:  1973 
• 15 Johnson RA. Sharpless KB. Comprehensive Organic Synthesis   Vol. 7:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  p.389 
• 16 Bloch R. Abecassis J. Hassan D. J. Org. Chem.  1985,  50:  1544 

6

All compounds were unambiguously characterized by ¹H NMR, MS, and analytical LC-MS.

8

A Typical Procedure for the Preparation of Phenyl Chloroformate To a suspension of 15b (200 mg, 1.05 mmol) in pyridine (0.17 mL, 2.1 mmol) and CH₂Cl₂ (10 mL) at 0 °C was injected phenyl chloroformate (0.145 mL, 2.1 mmol) dropwise. The reaction mixture was stirred at r.t. for 3 h and directly applied to flash chromatography eluted with CH₂Cl₂. Compound 16b was obtained in 86% yield; mp 140-141 °C (CH₂Cl₂). MS (DCI/NH₃): m/z = 328.13 [M + NH₄]. ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.56 (q, J = 6.71 Hz, 2 H), 4.49 (t, J = 6.71 Hz, 2 H), 5.11 (dd, J = 10.22, 1.68 Hz, 1 H), 5.19 (dd, J = 17.24, 1.68 Hz, 1 H), 5.88 (m, 1 H), 7.27 (d, J = 7.63 Hz, 2 H), 7.31 (t, J = 7.32 Hz, 1 H), 7.47 (t, J = 7.93 Hz, 2 H), 8.73 (s, 1 H), 11.62 (s, 1 H) ppm.

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Typical Procedures for the Preparation of Acyclic Ureas
Preparation of Compound 17a
2-(Allyloxy)-5-chloroaniline (108.8 mg, 0.59 mmol) and 16b (116 mg, 0.37 mmol) in toluene (10 mL) were heated at 90 °C for 24 h. The reaction mixture was concentrated and the residue was purified by flash chromatograghy eluting with hexane-EtOAc (3:1) to give the title compound (86 mg, 58%) as colorless solid; mp 138-139 °C (EtOAc). MS (DCI/NH₃): m/z = 400.09 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.53 (q, J = 6.65 Hz, 2 H), 4.45 (t, J = 6.60 Hz, 2 H), 4.70 (m, 2 H), 5.10 (dd, J = 10.28, 1.99 Hz, 1 H), 5.17 (m, 1 H), 5.30 (m, 1 H), 5.42 (m, 1 H), 5.85 (m, 1 H), 6.07 (m, 1 H), 7.06 (d, J = 2.15 Hz, 1 H), 7.06 (s, 1 H), 8.19 (d, J = 2.15 Hz, 1 H), 8.86 (s, 1 H), 9.05 (s, 1 H), 10.69 (s, 1 H) ppm.
Preparation of Compound 17d
A mixture of 16b (1.925g, 6.21 mmol) and 2c (2.049g, 6.21 mmol) in DMF (25 mL) was stirred at 70 °C for 6 h. The DMF was then removed by evaporation, and the residue was suspended in a mixture of hexane and EtOAc. The precipitates were collected by filtration and dried in vacuo. The desired product (3 g, 88%) was obtained as colorless solid; mp 167-168 °C (EtOAc). MS (DCI/NH₃): m/z = 546.18 [M + H]⁺. ¹H NMR (500 MHz, DMSO-d ₆): δ = 0.00 (s, 9 H) 0.90-0.93 (m, 2 H), 2.56 (q, J = 6.76 Hz, 2 H), 3.75-3.79 (m, 2 H), 4.47 (t, J = 6.55 Hz, 2 H), 4.71 (d, J = 5.30 Hz, 2 H), 5.13 (d, J = 10.29 Hz, 1 H), 5.19 (dd, J = 17.31, 1.72 Hz, 1 H), 5.31 (s, 2 H), 5.33 (dd, J = 10.45, 1.40 Hz, 1 H), 5.46 (dd, J = 17.31, 1.40 Hz, 1 H), 5.89 (m, 1 H), 6.09 (m, 1 H), 7.02 (s, 1 H), 8.13 (s, 1 H), 8.85 (s, 1 H), 8.94 (s, 1 H), 10.59 (s, 1 H) ppm. Compounds 17c and 18 were prepared using a procedure similar to that described for 17d.

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Typical Procedures for Ring-Closure Metathesis
The Grubbs II catalyst was used to provide the reported yields of 19a-e.
Preparation of Compound 19a
Compound 17a (60 mg, 0.15 mmol) in CH₂Cl₂ (66 mL) was treated with the Grubbs II catalyst (20 mg, 0.024 mmol). The reaction mixture was stirred at 50 °C overnight. Then, the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with hexane-EtOAc (1:1). The title compound was obtained in 76% yield. MS (DCI/NH₃): m/z = 389.09 [M + NH₄]⁺. ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.71 (q, J = 7.49 Hz, 2 H), 4.68 (t, J = 7.05 Hz, 2 H), 4.70 (d, J = 6.86 Hz, 2 H), 6.02 (m, 1 H), 6.09 (m, 1 H), 7.12 (dd, J = 8.89, 2.65 Hz, 1 H), 7.22 (d, J = 9.04 Hz, 1 H), 7.98 (s, 1 H), 8.12 (d, J = 2.49 Hz, 1 H), 10.35 (s, 1 H), 10.97 (s, 1 H) ppm. HRMS: m/z calcld for C₁₇H₁₅ClN₅O₃: 372.0863; found: 372.0871.
Compounds 19b,c,d were prepared using a procedure similar to that described for 19a.
Compound 19d: mp 170-171 °C (EtOAc). MS (DCI/NH₃): m/z = 535.14 [M + NH₄]⁺. ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.00 (s, 9 H), 0.90-0.94 (m, 2 H), 2.73 (q, J = 7.36 Hz, 2 H), 3.76-3.80 (m, 2 H), 4.66-4.73 (m, 4 H), 5.36 (s, 2 H), 5.99-6.14 (m, 2 H), 7.13 (s, 1 H), 7.99 (s, 1 H), 8.07 (s, 1 H), 10.24 (s, 1 H), 10.93 (s, 1 H) ppm.

Preparation of Compound 19e
A mixture of 17e (2.93 g, 7.06 mmol) and the Grubbs II catalyst (0.6 g, 0.71 mmol) in CH₂Cl₂ (3.6 L) was stirred at r.t. overnight, and then DMSO (10 mL, 141 mmol) was added. The resulting mixture was further stirred 24 h and concentrated. The residue was purified by flash chromatography eluting with 9% EtOAc in CH₂Cl₂ to provide the desired product (2.1 g, 77%) as yellow solid; mp 240 °C (dec.; EtOAc). MS (DCI/NH₃): m/z = 404.08 [M + NH₄]⁺. ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.71 (q, J = 7.70 Hz, 2 H), 4.58 (d, J = 6.86 Hz, 2 H), 4.65 (t, J = 7.64 Hz, 2 H), 5.17 (s, 2 H), 5.95-6.07 (m, 2 H), 6.64 (s, 1 H), 7.81 (s, 1 H), 7.96 (s, 1 H), 10.10 (s, 1 H), 10.79 (s, 1 H) ppm; DMSO was used to facilitate the removal of the green color as previously described in ref. 12.

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Typical Procedure for the Hydrogenation - Preparation of Compound 20d
A mixture of 19d (2 g, 3.86 mmol) and 10% Pd/C (160 mg, 0.151 mmol) in THF was stirred under H₂ atmosphere for 3 h, and the insoluble material was filtered off. The filtrate was concentrated, and the residue was purified by flash chromatography eluting with 9% of EtOAc in CH₂Cl₂. The desired product (1.83 g, 91%) was obtained as colorless solid; mp 203-204 °C (EtOAc). MS (DCI/NH₃): m/z = 537.20 [M + NH₄]⁺. ¹H NMR (500 MHz, DMSO-d ₆): δ = 0.00 (s, 9 H), 0.90-0.94 (m, 2 H), 1.59-1.65 (m, 2 H), 1.83-1.87 (m, 2 H), 1.94-2.01 (m, 2 H), 3.77-3.80 (m, 2 H), 4.19-4.21 (m, 2 H), 4.60-4.63 (m, 2 H), 5.35 (s, 2 H), 7.05 (s, 1 H), 8.00 (s, 1 H), 8.17 (s, 1 H), 9.84 (s, 1 H), 10.90 (s, 1 H).