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Synlett 2002(1): 0093-0096
DOI: 10.1055/s-2002-19358
LETTER
© Georg Thieme Verlag Stuttgart · New York

Solid-Phase Synthesis of 6-Sulfonylamino Morphinan Libraries

Hiroshi Ohnoa, Kuniaki Kawamuraa, Atsushi Otakea, Hiroshi Nagase*a, Hiroshi Tanakab, Takashi Takahashi*b
Department of Medicinal Chemistry, Pharmaceutical Research Laboratory, Toray Industries, Inc.,, 1111 Tebiro, Kamakura, Kanagawa 248-8555, Japan
Fax: +81(467)324791; e-Mail: hiroshi_nagase@nts.toray.co.jp;
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8552, Japan
Fax: +81(3)57342884; e-Mail: ttakashi@o.cc.titech.ac.jp;
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Publikationsverlauf

Received 19 October 2001
Publikationsdatum:
01. Februar 2007 (online)

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Abstract

A solid-phase synthesis of 6-sulfonylamino morphinan has been developed. The morphinan derivatives were designed as selective opioid ligands. The sulfonamide moiety was introduced by reductive amination of a ketone on solid phase, followed by sulfonylation of the resulting amine. Using this methodology, the synthesis of three combinatorial libraries was accomplished to prepare 339 morphinan derivatives with over 70% purity.

Key words

opioid - morphinan - solid-phase synthesis - ketones - sulfonamides

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    IRORI, P.O. Box 502778, San Diego, CA 92150-2778, www.irori.com.
7

Column: HYPERSIL ODS 5 µm, 4.6 × 150 mm; mobile phase: 20 mM AcONH4:MeOH = 70:30 (0 min)-10:90 (6-12 min); UV: 254 nm.

13

General procedure for the solid phase synthesis of 6-sulfonamido-morphinans 2: To a mixture of Wang resin (NOVA; 0.72 mmol/g, 4.00 g, 2.88 mmol), naltrexone (5) (4.37 g, 12.8 mmol) and PPh3 (1.78 g, 6.8 mmol) in THF was slowly added a 40% toluene solution of DEAD (3.10 mL, 6.8 mmol). The resulting suspension was shaken at room temperature for 19 h. The solvents were then removed by filtration and the resulting beads were washed with THF, DMF, MeOH, THF, and CH2Cl2, and dried in vacuo to give resin-supported naltrexone 4 (5.26 g). The beads (31 mg) were packed in Microkans, and 14 Microkans in DMF-MeOH-HOAc (100:10:1) (14 mL) were treated with methylamine hydrochloride (143 mg, 2.1 mmol) and NaBH3CN (267 mg, 4.06 mmol). After being shaken for 28 h, the mixture was filtered, washed with DMF, MeOH, THF, and CH2Cl2, and dried in vacuo to give resin 8a. To one of the resulting Microkans in CH2Cl2 (1 mL), DIEA (188 µL, 1.08 mmol) and p-toluenesulfonyl chloride (107 mg, 0.54 mmol) were added. The mixture was shaken for 2 h, filtered, washed with THF, DMF, MeOH, THF, and CH2Cl2, and dried in vacuo. The resulting Microkan was treated with 10% TFA/CH2Cl2 (2 mL) for 30 min, filtered, and then washed with CH2Cl2. The combined filtrates were evaporated, and dried in vacuo to give 14.6 mg of morphinan compound 2aA TFA salt with 96% purity determined by reversed-phase HPLC. MS m/z 511 ((M + H)+). a-2c 1H NMR (270 MHz, CDCl3) δ 0.09-0.15 (1H, m), 0.50-0.57 (2H, m), 0.80-0.90 (2H, m), 1.04-1.14 (1 H, m), 1.38 (1 H, dd, J = 8.6, 14.9 Hz), 1.55-1.69 (2 H, m), 2.18-2.32 (3 H, m), 2.35-2.44 (1 H, m), 2.41 (3 H, s), 2.50-2.59 (1 H, m), 2.62-2.67 (1 H, m), 2.88 (3 H, s), 3.01 (1 H, d, J = 18.8 Hz), 3.08 (1 H, d, J = 6.6 Hz), 4.49 (1 H, ddd, J = 3.8, 3.8, 13.1 Hz), 4.79-4.81 (1 H, m), 6.51 (1 H, d, J = 7.9 Hz), 6.70 (1 H, d, J = 7.9 Hz), 7.29 (2 H, d, J = 7.9 Hz), 7.74 (2 H, d, J = 8.6 Hz); 13C NMR (67.8 MHz, CDCl3) δ 3.8, 4.2, 9.4, 17.5, 21.6, 22.9, 29.8, 30.2, 31.7, 33.7, 43.1, 48.2, 53.1, 59.7, 62.0, 69.5, 94.4, 117.2, 119.2, 126.0, 127.1, 129.8, 130.8, 136.5, 137.4, 143.2, 145.4; IR(neat) 3355, 2928, 1616, 1463, 1337, 1152, 940, 859, 757, 666 cm-1. HRMS (ESI) 511 (M + H+), calcd 511.2267, found 511.2280. b-2c 1H NMR (270 MHz, CDCl3) δ 0.09-0.14 (2 H, m), 0.49-0.55 (2 H, m), 0.77-0.90 (2 H, m), 1.13-1.23 (1 H, m), 1.33-1.60 (3 H, m), 1.93-2.26 (3 H, m), 2.36 (2 H, d, J = 6.6 Hz), 2.41 (3 H, s), 2.53-2.66 (2 H, m), 2.85 (3 H, s), 3.00 (1 H, d, J = 10.6 Hz), 3.05 (1 H, s), 3.75 (1 H, ddd, J = 4.6, 8.3, 12.9 Hz), 4.50 (1 H, d, J = 7.9 Hz), 6.59 (1 H, d, J = 9.3 Hz), 6.75 (1 H, d, J = 8.3 Hz), 7.27 (2 H, d, J = 8.3 Hz), 7.67 (2 H, d, J = 8.6 Hz); 13C NMR (67.8 MHz, CDCl3) δ 3.9, 3.9, 9.5, 21.6, 22.0, 22.7, 29.6, 30.5, 30.8, 44.0, 48.1, 58.8, 59.2, 62.4, 70.1, 89.4, 117.7, 119.4, 124.5, 127.3, 129.6, 131.2, 137.3, 140.3, 142,2, 143.2; IR(neat) 3350, 2831, 1622, 1394, 1337, 1157, 918, 875, 758, 657 cm-1. HRMS (ESI) 511 (M + H+), calcd 511.2267, found 511.2266.