Synthesis of Naltrexone and (R)-Methylnaltrexone from Oripavine via Direct Oxidation of Its Quaternary Salts

Abstract

(R)-Methylnaltrexone and naltrexone were each prepared in four steps from oripavine in practical yields. The procedure involved quaternization of oripavine with cyclopropylmethyl halides, singlet oxygen oxidation of the quaternary salts, and the reduction of endo per­oxides to 14-hydroxyketone functionalities. (R)-Methylnaltrexone was prepared from the corresponding R-diastereomer of the oripavine salt. All diastereomeric mixtures of the quaternary salts were subjected to N-demethylation with sodium thiolate to yield cyclopropyl methylnororipavine, which was converted into naltrexone by peracid oxidation and hydrogenation according to established procedures.

Key words

photochemical oxidation - singlet oxygen - naltrexone synthesis - (R)-methylnaltrexone synthesis - N-demethylation of oripavine quaternary salts

• References and Notes


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• 20 Key Experimental Procedures N-Cyclopropylmethyl Nororipavine Methyl Bromide (7b)A. From Chloride Salt 7aCompound 7a (0.150 g, 0.39 mmol) was dissolved in a minimum amount of aq MeOH (H₂O–MeOH, 3:1). The solution was filtered through a column packed with Dowex^®-1 resin (Sigma, strongly basic bromine loaded, 50–100 mesh) and eluted with distilled H₂O (500 mL). The majority of the solvent was removed under reduced pressure. The residue was lyophilized to give the title compound 7b as a white solid (0.16 g, 95%). ¹H NMR and ¹³C NMR spectra were identical to the spectra of compound 7a. MS–FAB⁺: m/z = 785 [(C₂₂H₂₆NO₃)₂Br]⁺.B. From Oripavine and Cyclopropylmethyl BromideA flame-dried, argon-purged round-bottomed flask with an attached reflux condenser was charged a suspension of oripavine (1.84 g, 6.18 mmol) in anhydrous DMF (10 mL). Cyclopropylmethyl bromide (1.8 mL, 18.5 mmol, 3.0 equiv) was added to the vigorously stirred suspension of oripavine in one portion and at r.t. The flask was immersed in an 80 °C oil bath, and the mixture was stirred under argon atmosphere for 12 h. After cooling, an aliquot was analyzed by HPLC (285 nm) and determined to contain approximately 3.6% (integration, area under curve) oripavine (as the HBr salt). NaHCO₃ (0.02 g, 0.24 mmol, 4 mol%) was added to the reaction mixture, which was stirred for 1 h prior to the addition of additional cyclopropylmethyl bromide (0.30 mL, 3.1 mmol, 0.5 equiv) at r.t. The reaction mixture was immersed in the 80 °C oil bath for an additional 8 h. Analysis by HPLC (285 nm) revealed that approximately 1% oripavine remained in the reaction mixture. The reaction mixture (fine beige slurry) was cooled to r.t. and filtered through a fine-fritted funnel. The residue was washed with MeOH (1.5 mL), and the product precipitated after slow addition of the filtrate to a vigorously stirred volume of toluene (ca. 100 mL). After the precipitate was filtered and washed with toluene (2 × 10 mL), it was dried under vacuum to provide a slightly off-white solid in greater than quantitative yield. This material was stirred in acetone (50 mL) at r.t. for 2 h prior to a second filtration. The solid was collected and dried under vacuum to yield 2.60 g (94% yield) of N-cyclopropylmethyl oripavine ammonium bromide salt (7b) as a white, free-flowing solid; mp 194–200 °C; isomeric ratio determined by HPLC (S/R = 2.6:1). R-IsomerMp 219–221 °C (EtOH); R_f = 0.30 (CH₂Cl₂–MeOH, 5:1); [α]_D ²⁰ –109.38 (c 1, MeOH). ¹H NMR (600 MHz, DMSO): δ = 9.37 (s, 1 H), 6.62 (d, J = 8.1 Hz, 1 H), 6.55 (d, J = 8.1 Hz, 1 H), 6.01 (d, J = 6.6 Hz, 1 H), 5.42 (s, 1 H), 5.29 (d, J = 6.6 Hz, 1 H), 4.67 (d, J = 7.2 Hz, 1 H) 3.71 (m, 1 H), 3.70 (m, 1 H), 3.61 (s, 3 H), 3.45 (dd, J = 13.5, 4.6 Hz, 1 H), 3.39 (dd, J = 13.7, 7.6 Hz, 1 H), 3.29 (ddd, J = 13.2, 13.2, 4.0 Hz, 1 H) 3.19 (s, 3 H), 3.06 (dd, J = 19.4, 7.2 Hz, 1 H), 2.59 (ddd, J = 14.1, 14.1, 5.1 Hz, 1 H), 1.86 (dd, J = 14.2, 2.9 Hz, 1 H), 1.21 (m, 1 H), 0.75 (m, 2 H), 0.51 (m, 1 H), 0.44 (m, 1 H). ¹³C NMR (150 MHz, DMSO): δ = 154.6, 143.5, 140.4, 132.6, 124.1, 122.5, 120.2, 119.8, 117.6, 96.1, 87.2, 68.1, 67.1, 55.6, 54.0, 46.1, 44.2, 31.5, 30.4, 5.1, 4.4, 4.2. S-IsomerMp 195–197 °C (MeOH–i-PrOH); R_f = 0.28 (CH₂Cl₂–MeOH, 5:1); [α]_D ²⁰ –43.73 (c 1.0, MeOH). ¹H NMR (600 MHz, DMSO): δ = 9.37 (s, 1 H), 6.63 (d, J = 8.0 Hz, 1 H), 6.57 (d, J = 8.0 Hz, 1 H), 5.98 (d, J = 6.6 Hz, 1 H), 5.39 (s, 1 H), 5.26 (d, J = 6.6 Hz, 1 H), 4.75 (d, J = 6.9 Hz, 1 H), 3.77 (d, J = 19.6 Hz, 1 H), 3.64 (dd, J = 13.4, 6.1 Hz, 1 H), 3.60 (s, 3 H), 3.49 (dd, J = 13.4, 3.2 Hz, 1 H), 3.35 (m, 1 H), 3.29 (s, 3 H), 3.28 (m, 1 H), 3.06 (dd, J = 19.5, 7.0 Hz, 1 H), 2.56 (ddd, J = 14.0, 14.0, 4.5 Hz, 1 H), 1.79 (d, J = 11.9 Hz, 1 H), 1.21 (m, 1 H), 0.72 (m, 2 H), 0.52 (m, 1 H), 0.39 (m, 1 H). ¹³C NMR (150 MHz, DMSO): δ = 154.6, 143.4, 140.4, 132.6, 124.1, 122.6, 120.2, 119.7, 117.6, 96.0, 87.3, 68.6, 63.9, 55.6, 54.0, 48.6, 43.7, 31.3, 30.6, 4.9, 4.6, 4.3. MS–FAB⁺: m/z (%) = 55 (31), 98 (24), 112 (38), 239 (12), 352 (100). HRMS: m/z calcd for C₂₂H₂₆N0₃ ⁺: 352.1907; found: 352.1898. N-Cyclopropylmethyl Nororipavine (8)To a slurry of NaOt-Bu (0.88 g, 9.20 mmol) in freshly distilled DMSO (6 mL) was added tert-dodecanethiol (1.86 g, 9.20 mmol, distilled) in one portion. The vigorously stirred mixture was purged with argon for 3 min. The flask was immersed in a 90 °C oil bath for 10 min, then the oil bath (and the mixture) was allowed to cool to 80 °C. A solution of N-cyclopropylmethyl oripavine ammonium bromide (7b, 1.32 g, 3.07 mmol; R/S ratio = 66:34) in DMSO (6 mL) at r.t. was added to the preformed mixture of tert-dodecanethiolate in DMSO at 80 °C over 10 min. A sharp color change from a clear, slightly yellow solution to a black-colored mixture occurred after the addition of the first few drops of the N-cyclopropylmethyl oripavine ammonium bromide solution. The reaction mixture was stirred at 80 °C for 45 min following the addition and monitored by HPLC (285 nm). After complete consumption of starting material the reaction mixture was allowed to cool to r.t. with stirring, then it was poured into H₂O (80 mL). The pH of the aqueous mixture was adjusted to pH 2 with HCl (6 M) and washed with hexanes (1 × 20 mL, 1 × 10 mL). The pH of the aqueous mixture (milky yellow suspension) was readjusted to pH 8 with NaOH (aq, 15%). The fine, white precipitate was observed upon pH adjustment and dissolved upon extraction with EtOAc (1 × 20 mL, 1 × 15 mL). The pH of the aqueous phase was adjusted again to pH 8 (white precipitate was observed) and extracted with EtOAc (3 × 10 mL). The organic layers were combined and washed with H₂O (1 × 10 mL) and brine (1 × 10 mL), then dried over MgSO₄, filtered, and concentrated to provide crude material, which was crystallized from acetone–cyclohexane mixture (1:1) to afford 0.61 g (59% yield) of N-cyclopropylmethyl nororipavine (8) as a pale-yellow crystalline solid. Column chromatography (MeOH–EtOAc, 1:5) of mother liquor afforded 0.07 g (6% yield) of title compound. R_f = 0.25 (MeOH–EtOAc, 1:5); mp 165–166 °C (CH₂Cl₂), 166–167 °C (MeOH); [α]_D ²⁰ –168.60 (c 1, CHCl₃). IR (KBr): ν = 3445, 2908, 1630, 1458, 1234, 1046, 1016, 926, 868 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 6.65 (d, J = 8.4 Hz, 1 H), 6.55 (d, J = 8.4 Hz, 1 H), 5.59 (d, J = 6.6 Hz, 1 H), 5.29 (s, 1 H), 5.07 (d, J = 6.6 Hz, 1 H), 4.02 (d, J = 6.6 Hz, 1 H), 3.61 (s, 3 H), 3.29 (d, J = 18.0 Hz, 1 H), 3.00 (dd, J = 12.6, 4.2 Hz, 1 H), 2.90 (m, 1 H), 2.76 (dd, J = 18.0, 7.2 Hz, 1 H), 2.55 (m, 2 H), 2.24 (m, 1 H), 1.71 (d, J = 11.4 Hz, 1 H), 0.97 (m, 1 H), 0.56 (d, J = 8.4 Hz, 2 H), 0.19 (d, J = 8.4 Hz, 2 H). ¹³C NMR (150 MHz, CDCl₃): δ = 152.2, 143.1, 138.8, 133.2, 132.6, 126.7, 119.7, 116.5, 112.1, 96.4, 89.4, 58.6, 58.6, 55.0, 46.8, 43.8, 36.2, 31.2, 9.2, 3.9 (2 × CH₂). MS (EI⁺): m/z (%) = 43 (100), 58(19), 84 (56), 227 (8), 282 (12), 337 (41). HRMS: m/z calcd for C₂₁H₂₃NO₃: 337.1678; found: 337.1681.Naltrexone (1)A solution of N-methylcyclopropyl nororipavine (8, 0.52 g, 1.52 mmol) in H₂O–AcOH (1:1 v/v) was chilled to 5 °C with stirring. A solution of peracetic acid (0.40 g, 1.67 mmol; 32 wt%) in AcOH was added dropwise over 2 min. The mixture was stirred at 5 °C for 10 min prior to warming to r.t. Monitoring of the reaction by TLC (MeOH–EtOAc = 1:10) showed consumption of starting material 35 min after addition of peracetic acid. The reaction mixture at r.t. was diluted with i-PrOH (2.5 mL), then Pd/C (0.05 g, 10 wt%) was added, and the reaction mixture was subjected to a hydrogen atmosphere (Parr shaker, 3.45 bar) for 15 h. The mixture was filtered through a pad of Celite, which was subsequently washed with i-PrOH. AcOH was removed as an azeotrope with toluene prior to concentration to dryness. Naltrexone (0.51 g, 95% yield) was obtained after further drying under vacuum; R_f  = 0.55 (CHCl₃–MeOH, 92:8); mp 167–169 °C [CHCl₃, lit.²³ 174–176 °C (acetone)]; [α]_D ²⁰ –84.8 (c 1.0, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 6.73 (d, J = 7.6 Hz, 1 H), 6.59 (d, J = 7.6 Hz, 1 H), 5.66 (s, 2 H), 4.76 (s, 1 H), 3.22 (d, J = 5.6 Hz, 1 H), 3.12–3.03 (m, 2 H), 2.73 (dd, J = 4.1, 11.6 Hz, 1 H), 2.58 (dd, J = 5.8, 18.6 Hz, 1 H), 2.52–2.30 (m, 4 H), 2.16 (td, J = 5.9, 3.0 Hz, 1 H), 1.92 (d, J = 12.0 Hz, 1 H), 1.75–1.50 (m, 3 H), 0.87 (m, 2 H), 0.56 (d, J = 7.4 Hz, 2 H), 0.16 (d, J = 4.4 Hz, 2 H).General Procedure for the Photooxygenation Reactions ¹⁸To a solution of the quaternized morphine alkaloid (0.25–0.30 mmol) in CH₂Cl₂–MeOH (4:1, 8 mL) in a double-glass wall mini reactor was added tetraphenylporphyrin (0.02 g). Oxygen was bubbled through the reaction mixture for 4 h, while irradiated from a distance of 30 cm with a street lamp (500 W) at a reaction temperature of 5–15 °C. The strongly colored solution was transferred to an Erlenmeyer flask, and the corresponding endoperoxide was precipitated by the addition of Et₂O. The slightly purple solid was dissolved in MeOH and precipitated with Et₂O to afford the endoperoxide as slightly colored solid. Because of the instability of the endoperoxide intermediates, only ¹H NMR data were obtained.General Procedure for the Reduction of Endoperoxide IntermediatesTo a solution of the endoperoxide intermediate (0.20–0.30 mmol) dissolved in a mixture of H₂O–i-PrOH–formic acid (1:1:1, 2.4 mL) was added Pd/C (10%, 10 wt%). The reaction mixture was flushed three times with H₂ and then stirred at 1 atm of H₂ for 24 h. The suspension was filtered through a short plug of Celite, and the plug was washed with MeOH. The filtrate was concentrated in vacuo, and the residue was lyophilized. Flash column chromatography on silica (eluent CH₂Cl₂–MeOH, 9:1) provided the corresponding product.Methylnaltrexone Bromide (5b)A. From Chloride Salt by Ion ExchangeCompound 5a (0.05 g, 0.13 mmol) dissolved in a minimum amount aq MeOH (H₂O–MeOH, 3:1), and the solution was filtered through a column packed with Dowex^®-1 resin (Sigma, strongly basic bromine loaded, 50–100 mesh) and eluted with distilled H₂O (400 mL). The majority of the solvent was removed under reduced pressure, then the residue was lyophilized to give the title compound 5b as a white solid (0.054 g, 98%). ¹H NMR and ¹³C NMR spectra were identical to the spectra of 5b obtained from compound 11b. MS–FAB⁺: m/z = 793 ­[(C₂₁H₂₆NO₄)₂Br]⁺.B. By Reduction of Endoperoxide 11bFollowing the general procedure for the reduction of endoperoxide intermediates, compound 11b (0.10 g, 0.22 mmol) yielded methylnaltrexone bromide salt 5b as a colorless solid (0.08 g, 74%). MS–FAB⁺: m/z = 793 [(C₂₁H₂₆NO₄)₂Br]⁺.C. By Reduction of Enone 12bTo a solution of the enone 12b (0.20 g, 0.46 mmol) dissolved in MeOH (3 mL) was added Pd/C (0.02 g; 10 wt%). The reaction mixture was hydrogenated in Parr shaker at 40 psi for 12 h. The suspension was filtered through a short plug of Celite, and the plug was washed with MeOH. The evaporation of MeOH furnished 0.19 g of essentially pure product (checked by HPLC and by ¹H NMR).
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