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Synlett 2008(11): 1703-1705  
DOI: 10.1055/s-2008-1078494
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Pharmacologically Active Apomorphines by Direct N-Substitution on the Aporphine Backbone

Attila Sipos*, Sándor Berényi*
Department of Organic Chemistry, University of Debrecen, P. O. Box 20, 4010 Debrecen, Hungary
Fax: +36(52)512836; e-Mail: asipos@puma.unideb.hu;
Further Information

Publication History

Received 1 April 2008
Publication Date:
11 June 2008 (online)

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Abstract

A method has been developed for the direct N-substitution of aporphines comprising the N-oxidation-N-deprotection-N-alkylation sequence. This methodology was found to be insensitive to the change in the substitution pattern of rings A or D, therefore it is presumed to be applicable also for aporphines derived from total synthesis and natural sources.

Key words

alkaloids - transition metals - protecting groups - me­dicinal chemistry - oxidations

17

General Procedure for the N-Substitution of Aporphines
Apocodeine base (2.92 mmol) and Na2WO4 (300 mg, 1.02 mmol) was dissolved in H2O-1,4-dioxane (1:2, 10 mL) and cooled to 0 °C for the dropwise addition of H2O2 (30% w/v, 12 mmol). The reaction mixture was stirred at r.t. for 3.5 h. The excess H2O2 was quenched by addition of small portions of MnO2 at 0 °C and the presence of the peroxide determined by KI-starch paper. The reaction mixture, containing some overoxidized product as dark precipitation, was then vacuum filtered through a short pad of Celite. Solvent was removed in vacuo to give the crude product as a pale brown solid. It was immediately turned into hydrochloride salt by dissolving in a few drops of CHCl3 and dropping some EtOH sat. with HCl gas. After filtration, the mixture of minor apocodeine·HCl and major apocodeine N-oxide·HCl was dissolved in MeOH (10 mL) followed by the addition of FeSO4·7H2O (2 equiv) at 0 °C. The reaction mixture was then left to stir at r.t. for 1 h. Conversion was followed by TLC (80% CH2Cl2-20% MeOH). The reaction solvent was removed in vacuo and the residue redissolved in a 0.1 M EDTA solution adjusted to pH 10 by addition of NH3 (70 mL). The aqueous phase was then extracted with CHCl3 (3 × 30 mL). The combined organic phase was dried over MgSO4, filtered, and the solvent removed in vacuo to give dark brown mixture of apocodeine and norapocodeine. Norapocodeine was isolated by means of silica column chromatography (eluent: 80% CH2Cl2-20% MeOH).
Physical and spectral data of the products of the synthetic route from (-)-(R)-2-bromoapocodeine (14) to (-)-(R)-N-propyl-2-bromonorapomorphine (10) are detailed to represent the described method.
(-)-( R )-2-Bromoapocodeine N -Oxide Hydrochloride (24·HCl)
Off-white, plate-shape crystals; mp >250 °C (Et2O); [α]D 25 -168 (c 0.1, DMSO); R f base = 0.21 (CHCl3-MeOH, 8:2). HRMS (EI): m/z (%) calcd for C18H18BrNO3 +: 375.0470 [M+]; found: 375.0482 (100) [M+]. 1H NMR (400 MHz, DMSO-d 6): δ = 7.44 (1 H, s, C1-H), 7.14 (1 H, s, C3-H), 6.77-6.70 (2 H, 2 d, C8-H, C9-H, J 8-9 = 8.1 Hz), 6.14 (1 H, br s, OH), 5.32 (1 H, td, C6a-H, J 6a-7a 9.4 Hz, J 6a-7b 2.7 Hz), 3.77 (3 H, s, C10-OCH3), 3.70-2.94 (6 H, m, C4-Ha, C4-Hb, C5-Ha, C5-Hb, C7-Ha, C7-Hb), 2.91 (3 H, s, NCH3). 13C NMR (100 MHz, DMSO-d 6): δ = 146.61 (C10), 144.43 (C9), 136.19-114.78 (10 C, arom.), 75.09 (C6a), 60.56 (C5), 56.23 (C10-OCH3), 54.51 (N-CH3), 37.39 (C7), 25.81 (C4).
(-)-( R )-2-Bromonorapocodeine Hydrochloride (34·HCl)
White, cubic crystals; mp >250 °C (Et2O); [α]D 25 -78 (c 0.1, DMSO); R f base = 0.17 (CHCl3-MeOH, 8:2). HRMS (EI): m/z (%) calcd for C17H17BrNO2 +: 346.0437 [M+ + 1]; found: 346.0444 (100) [M+ + 1]. 1H NMR (400 MHz, DMSO-d 6): d = 7.41 (1 H, s, C1-H), 7.07 (1 H, s, C3-H), 6.69-6.62 (2 H, 2 d, C8-H, C9-H, J 8-9 = 8.0 Hz), 6.09 (1 H, br s, OH), 4.13 (1 H, td, C6a-H, J 6a-7a = 9.1 Hz, J 6a-7b = 2.5 Hz), 3.83 (3 H, s, C10-OCH3), 3.09-2.18 (7 H, m, C4-Ha, C4-Hb, C5-Ha, C5-Hb, C7-Ha, C7-Hb, NH). 13C NMR (100 MHz, DMSO-d 6): d = 147.12 (C10), 144.76 (C9), 137.28-113.19 (10 C, arom.), 56.47 (C10-OCH3), 53.71 (C6a), 43.56 (C5), 37.18 (C7), 26.66 (C4).
(-)-(R)-N-Propyl-2-bromonorapocodeine (44) and (-)-(R)-N-propyl-2-bromonorapomorphine (10) are characterized in ref. 16a.