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Synlett 2007(18): 2855-2858  
DOI: 10.1055/s-2007-991083
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Macrocyclic Urea Kinase Inhibitors

Zhi-Fu Tao*, Thomas J. Sowin, Nan-Horng Lin
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA
Fax: +1(847)9355165; e-Mail: Zhi-Fu.Tao@abbott.com;
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Publication History

Received 19 June 2007
Publication Date:
12 October 2007 (online)

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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

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

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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).