Synthesis of (4′R)-Azido-(2′R)-2′-Deoxy-2′-C-Methyluridine and Its Esters by Direct Iodide Displacement

Cyril Benhaim; Sébastien Lemaire; Tim Gaekens; Tom Govaerts; Ioannis N. Houpis; Peter Reniers; Anja Van Looy; Wim A. A. Vermeulen; Sebastian Bernhardt; Coura Diène; Paul Knochel; Vittorio Farina

doi:10.1055/s-0033-1339293

Synlett, Inhaltsverzeichnis

Synlett 2013; 24(13): 1697-1701
DOI: 10.1055/s-0033-1339293

letter

Synthesis of (4′R)-Azido-(2′R)-2′-Deoxy-2′-C-Methyluridine and Its Esters by Direct Iodide Displacement

Cyril Benhaim*

^aJanssen Chemical Development, Turnhoutseweg 30, 2340 Beerse, Belgium Fax: +32(14)605755 eMail: cbenhaim@its.jnj.com eMail: slemaire@its.jnj.com

,

Sébastien Lemaire*

^aJanssen Chemical Development, Turnhoutseweg 30, 2340 Beerse, Belgium Fax: +32(14)605755 eMail: cbenhaim@its.jnj.com eMail: slemaire@its.jnj.com

,

Tim Gaekens

^aJanssen Chemical Development, Turnhoutseweg 30, 2340 Beerse, Belgium Fax: +32(14)605755 eMail: cbenhaim@its.jnj.com eMail: slemaire@its.jnj.com

,

Tom Govaerts

^aJanssen Chemical Development, Turnhoutseweg 30, 2340 Beerse, Belgium Fax: +32(14)605755 eMail: cbenhaim@its.jnj.com eMail: slemaire@its.jnj.com

,

Ioannis N. Houpis

^aJanssen Chemical Development, Turnhoutseweg 30, 2340 Beerse, Belgium Fax: +32(14)605755 eMail: cbenhaim@its.jnj.com eMail: slemaire@its.jnj.com

,

Peter Reniers

^aJanssen Chemical Development, Turnhoutseweg 30, 2340 Beerse, Belgium Fax: +32(14)605755 eMail: cbenhaim@its.jnj.com eMail: slemaire@its.jnj.com

,

Anja Van Looy

^aJanssen Chemical Development, Turnhoutseweg 30, 2340 Beerse, Belgium Fax: +32(14)605755 eMail: cbenhaim@its.jnj.com eMail: slemaire@its.jnj.com

,

Wim A. A. Vermeulen

^aJanssen Chemical Development, Turnhoutseweg 30, 2340 Beerse, Belgium Fax: +32(14)605755 eMail: cbenhaim@its.jnj.com eMail: slemaire@its.jnj.com

,

Sebastian Bernhardt

^bDepartment Chemie und Biochemie, Ludwig-Maximilian Universität München, Butenandtstr. 5-12, Haus F, 81377 München, Germany

,

Coura Diène

^bDepartment Chemie und Biochemie, Ludwig-Maximilian Universität München, Butenandtstr. 5-12, Haus F, 81377 München, Germany

,

Paul Knochel

^bDepartment Chemie und Biochemie, Ludwig-Maximilian Universität München, Butenandtstr. 5-12, Haus F, 81377 München, Germany

,

Vittorio Farina

^aJanssen Chemical Development, Turnhoutseweg 30, 2340 Beerse, Belgium Fax: +32(14)605755 eMail: cbenhaim@its.jnj.com eMail: slemaire@its.jnj.com

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Abstract

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Abstract

The synthesis of an anti-infective nucleoside intermediate was accomplished through direct iodine displacement at C-5′ by a tetrabutylammonium carboxylate. This approach constitutes a more efficient alternative to the traditional oxidative displacement.

Key words

nucleosides - iodine - azides - carboxylic acids - solvent effects

Volltext

Referenzen

References and Notes
1 Maag H, Rydzewski RM, McRoberts MJ, Crawford-Ruth D, Verheyden JP. H, Prisbe EJ. J. Med. Chem. 1992; 35: 1440
2 Wang Q, Hu W, Wang S, Pan Z, Tao L, Guo X, Qian K, Chen C.-H, Lee K.-H, Chang J. Eur. J. Med. Chem. 2011; 4178
3 Klumpp K, Kalayanov G, Ma H, Pogam SL, Leveque V, Jiang W.-R, Inocencio N, De Witte A, Rajyaguru S, Tai E, Chanda S, Irwin MR, Sund C, Winqvist A, Maltseva T, Eriksson S, Usova E, Smith M, Alker A, Najera I, Cammack N, Martin JA, Johansson NG, Smith DB. J. Biol. Chem. 2008; 283: 2167
4 Smith DB, Kalayanov G, Sund C, Winqvist A, Pinho P, Maltseva T, Morisson V, Leveque V, Rajyaguru S, Pogam SL, Najera I, Benkestock K, Zhou X.-X, Maag H, Cammack N, Martin JA, Swallow S, Johansson NG, Klumpp K, Smith M. J. Med. Chem. 2009; 52: 219
5 Smith DB, Kalayanov G, Sund C, Winqvist A, Maltseva T, Leveque V, Rajyaguru S, Pogam SL, Najera I, Benkestock K, Zhou X.-X, Kaiser AC, Maag H, Cammack N, Martin JA, Swallow S, Klumpp K, Smith M. J. Med. Chem. 2009; 52: 2971
6 Nilsson M, Kalayanov G, Winqvist A, Pinho P, Sund C, Zhou X.-X, Wähling H, Belfrage H.-K, Pelcman M, Agback T, Benckestock K, Wikström K, Boothee M, Lindqvist A, Rydegård C, Jonckers TH. M, Vandyck K, Raboisson P, Lin T.-I, Lachau-Durand S, De Kock H, Smith DB, Martin JA, Klumpp K, Simmen K, Vrang L, Terelius Y, Samuelsson B, Rosenquist A, Johansson NG. Bioorg. Med. Chem. Lett. 2012; 22: 3265
7 Lemaire S, Houpis I, Wechselberger R, Langens J, Vermeulen WA. A, Smets N, Nettekoven U, Wang Y, Xiao T, Qu H, Liu R, Jonckers TH. M, Raboisson P, Vandyck K, Nilsson KM, Farina V. J. Org. Chem. 2011; 76: 297

8a Perrone P, Daverio F, Valente R, Rajyaguru S, Martin JA, Lévêque V, Le Pogam S, Najera I, Klumpp K, Smith DB, McGuigan C. J. Med. Chem. 2007; 50: 5463
8b Campeau L.-C, O’Shea PD. Synlett 2011; 57

9 Houpis IN, Lemaire S, Farina V, Xiao T, Liu R, Nettekoven U, Wang Y. Synlett 2012; 23: 313
10 Communication from the Belgian Federal Public Service Employment, Labour and Social Dialogue.
11 Compound 2a (10 g, 44.64 mmol) was dissolved in THF (40 mL) at r.t. A suspension of benzyltriethylammonium azide in MeCN (1.4 equiv, 1.5 M) was added, followed by N-methylmorpholine (710 mg). After cooling to 0 °C, an iodine solution in THF (1.3 equiv, 1.5 M) was added dropwise, and the reaction mixture was stirred for 4 h at 0 °C. N-Methylmorpholine (7.4 g) and DMAP (500 mg) were added followed by dropwise addition of isobutyric anhydride (1.75 equiv, 13 mL). After 1 h, the reaction mixture was quenched with aq Na₂SO₃ (160 mL, 50 mg/mL), and H₂O (7 mL) and EtOAc (80 mL) were added. The organic phase was separated and then washed with 1 M aq citric acid solution (20 mL), sat. NaHCO₃ (150 mL), and brine (150 mL). The organic phase was concentrated under reduced procedure, and the crude product was crystallized from 2-PrOH–H₂O (6:1, v/v, 200 mL) at 0 °C to afford 16.8 g (86%) of compound 6 as white solid. ¹H NMR (360 MHz, CDCl₃): δ = 1.01 (d, J = 7.3 Hz, 3 H), 1.22 (d, J = 6.9 Hz, 3 H), 1.23 (d, J = 6.9Hz, 3 H), 2.66 (sept, J = 6.9 Hz, 1 H), 3.03 (sext, J = 7.3 Hz, 1 H), 3.67 (d, J = 11.3 Hz, 1 H), 3.79 (d, J = 11.3 Hz, 1 H), 5.23 (br, 1 H), 5.84 (dd, J = 2.2, 8.05 Hz, 1 H), 6.40 (br, 1 H), 7.65 (br, 1 H), 9.71 (s, 1 H) ppm. ¹³C NMR (60 MHz, CDCl₃): δ = 5.52, 11.87, 18.81, 33.74, 40.41, 78.47, 102.60, 149.94, 162.40, 166.87, 176.46 ppm. Compound 6′ (Figure 1) was isolated by column chromatography (Chiralcel OJ 20 μm) with EtOH as eluent. Characterization of Compound 6′ ¹H NMR (400 MHz,DMSO-d ₆): δ = 0.82–0.73 (m, 3 H), 1.12–0.85 (m, 6 H), 2.90–2.74 (m, 1 H), 3.36 (d, J = 11.6 Hz, 1 H), 3.58 (d, J = 11.3 Hz, 1 H), 5.26 (d, J = 6.5 Hz, 1 H), 5.69–5.47 (m, 1 H), 5.96 (d, J = 7.6 Hz, 1 H), 7.45 (d, J = 8.1 Hz, 1 H), 11.33 (s, 1 H) ppm. ¹³C NMR (90 MHz, DMSO-d ₆): δ 10.95, 18.41, 18.56, 33.14, 41.21, 80.00, 88.39, 96.85, 101.94 ppm.
12 Smith DB, Martin JA, Klumpp K, Baker SJ, Blomgren PA, Devos R, Granycome C, Hang J, Hobbs CJ, Jiang W.-R, Laxton C, Le Pogam S, Leveque V, Ma H, Maile G, Merrett JH, Pichota A, Sarma K, Smith M, Swallow S, Symons J, Vesey D, Najera I, Cammack N. Bioorg. Med. Chem. Lett. 2007; 17: 2570

Perisobutyric acid was freshly prepared using the reported conditions:

13a Krasutsky PA, Kolomitsyn IV, Botov EM, Carlson RM, Semenova IG, Fokin AA. Tetrahedron Lett. 2002; 8687
13b Evans FW, Sehon AH. Can. J. Chem. 1963; 41: 1826

14a As the reaction slows down, the proportion of double structure 14 increased. The double structure resulted from the deprotonation of the uridine N–H bond followed by nucleophilic substitution at the iodine.
14b TBAE and TBAA were prepared and used as organic ionic bases in cross-coupling reactions: Yang C.-T, Fu Y, Huang Y.-B, Yi J, Guo Q.-X, Liu L. Angew. Chem. Int. Ed. 2009; 48: 7398

15 Preparation of Compound 12 TBAOH solution in MeOH (44.77 g, 53.94 mmol, 1 M) was added to a solution of isobutyric acid (4.75 g, 53.94 mmol) in MeOH (430 mL) at r.t. The mixture was stirred for 6 h then concentrated down. Co-evaporation with toluene to remove H₂O resulted in 19.42 g of colorless solid 12 (>99% yield). ¹H NMR (360 MHz, CDCl₃): δ = 0.99 (t, J = 7.2 Hz, 12 H, CH₃), 1.12 (d, J = 3.6 Hz, 6 H, CH₃), 1.45 (br, 8 H, CH₂), 1.65 (br, 8 H, CH₂), 2.35 (br, 1 H, CH) 3.40 (br, 8 H, NCH₂, each, 3-H) ppm. ¹³C NMR (90 MHz, CDCl₃): δ = 14.1 (CH₃), 20.2 (CH₂), 21.4 (CH₃), 24.5 (CH₂), 38.1 (CH), 59.2 (NCH₂) ppm.
16 The hygroscopic solid was stored under nitrogen.
17 Compound 13 was isolated by column chromatography from the reaction mixture: eluent 0.5% aq (NH₄)₂CO₃–MeCN (70:30). ¹H NMR (300 MHz, acetone-d ₆): δ = 0.88 (t, J = 7.30 Hz, 3 H), 0.88 (d, J = 7.30 Hz, 3 H), 1.11 (d, J = 7.05 Hz, 6 H), 1.14 (d, J = 6.80 Hz, 6 H), 1.26 (sext, J = 7.40 Hz, 2 H), 1.49 (quin, J = 7.37 Hz, 2 H), 2.58 (quin, J = 6.80 Hz, 2 H), 2.63 (quin, J = 7.10 Hz, 1 H), 2.89–3.08 (m, 1 H), 3.80 (t, J = 7.30 Hz, 2 H), 4.44 (d, J = 12.09 Hz, 1 H), 4.53 (d, J = 12.10 Hz, 1 H), 5.42 (br s, 1 H), 5.80 (d, J = 8.06 Hz, 1 H), 6.32 (br s, 1 H), 7.72 (d, J = 8.06 Hz, 1 H) ppm. ¹³C NMR (101 MHz, DMSO-d ₆): δ = 10.63, 13.59, 18.47, 18.50, 18.53, 18.58, 19.48, 29.03, 33.05, 33.08, 65.40, 101.15, 150.39, 161.60, 175.24, 175.53 ppm.
18 Compound 14 was isolated by column chromatography from the reaction mixture: eluent 0.5% aq (NH₄)₂CO₃–MeCN (70:30). ¹H NMR (300 MHz, acetone-d ₆): δ = 1.02 (d, J = 7.3 Hz, 6 H), 1.13–1.23 (m, 18 H), 2.51–2.75 (m, 3 H), 2.88–3.04 (m, 1 H), 3.05–3.21 (m, 1 H), 4.47 (d, J = 12.2 Hz, 1 H), 4.58 (d, J = 12.2 Hz, 1 H), 4.57–4.70 (m, 2 H), 5.13–5.55 (m, 2 H), 5.75 (d, J = 8.2 Hz, 1 H), 5.88 (d, J = 8.2 Hz, 1 H), 6.24–6.66 (m, 2 H), 7.68 (d, J = 8.2 Hz, 1 H), 7.78 (d, J = 8.2 Hz, 1 H), 10.35 (br s, 1 H) ppm. ¹³C NMR (101 MHz, acetone-d ₆): δ = 11.40, 11.87, 19.12, 19.21, 19.25, 34.41, 34.44, 34.47, 34.52, 40.83, 41.64, 41.41, 77.23, 80.03, 81.33, 96.76, 97.01, 102.29, 102.81, 151.29, 152.17, 162.68, 163.59, 176.08, 176.14, 176.57, 206.32 ppm.
19 Khalafi-Nezhad A, Zare A, Parhami A, Hasaninejad A, Moosavi Zare AR. J. Iran. Chem. Soc. 2008; S40
20 The analogue of the doubly substituted uridine 14 with the iodide still at one of the C-6′ positions was never detected.
21 Preparation of Compound 3 A mixture of 6 (463 g, 1.0 mol) and compound 12 (3–10 mol, Table 2, entries 10–13) was heated in 2-MeTHF (0.04 mol L^–1) for 16 h at reflux. The reaction mixture was then cooled down to r.t. and washed with aq HCl (1 M), followed by aq Na₂CO₃ (2.5 w/w% solution). The organic layer was then concentrated down. Final crystallization from a mixture of 2-MeTHF and diisopropyl ether (1:5) gave 3 in a range of 62–95% yield (Table 2, entries 10–13); mp 148.6 °C. ¹H NMR (360 MHz, acetone-d ₆): δ = 0.99–1.10 (m, 3 H), 1.12–1.30 (m, 12 H), 2.05–2.13 (m, 3 H), 2.58–2.77 (m, 2 H), 3.23–3.04 (m, 1 H), 4.48 (d, J = 12.09 Hz, 1 H), 4.57 (d, J = 12.10 Hz, 1 H), 5.73 (d, J = 8.40 Hz, 1 H), 6.44 (br s, 1 H), 7.74 (d, J = 8.00 Hz, 1 H), 10.22 (br s, 1 H) ppm. ¹³C NMR (90 MHz, acetone-d ₆): δ = 11.71, 19.24, 19.34, 34.17, 34.42, 40.31, 64.29, 75.73, 96.05, 103.16, 150.68, 163.18, 176.10, 176.66 ppm.
22 Preparation of Compound 8 from 3 Compound 3 was successfully deprotected to furnish the sodium derivative 8. Compound 3 (500 mg) was suspended in MeOH (2.5 mL) at r.t. MeONa (1.1 equiv, 0.24 mL, 30 w%) in MeOH was added dropwise. After 30 min stirring, the solvent was reduced by half with a flow of nitrogen. Compound 8 was crystallized by dropwise addition of MBTE (15 mL) in 82% yield as sodium salt (292 mg). ¹H NMR (360 MHz, DMSO): δ = 7.39 (d, J = 7.3 Hz, 1 H), 6.32 (d, J = 8 Hz, 1 H), 5.30 (d, J = 7.7 Hz, 1 H), 3.95 (d, J = 10.6 Hz, 1 H), 3.70 (s, 2 H), 2.46–2.39 (m, 1 H), 0.77 (d, J = 6.5 Hz, 3 H) ppm. ¹³C NMR (90 MHz, DMSO): δ = 174.1, 157.9, 138.2, 102.1, 98.7, 84.8, 74.7, 60.8, 40.8, 11.4 ppm.