* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 0.25 h; Stage #2: With N-Bromosuccinimide In DMF (N,N-dimethyl-formamide) at 20℃; for 0.5 h;
To a solution of (E)-5- (2-CARBOXYVINYL)-2 -DEOXYURIDINE (5.777 g, 19.37 mmol) in dimethylforamide (29 mL) was added K2CO3 (5.890 g, 42.61 mmol) and the suspension stirred at room temperature for 15 mins. A solution of N-bromosuccinimide (3.655 g, 20.53 mmol) was added dropwise over 30 mins at 20°C. The resulting suspension was filtered and the solid washed with DMF. The combined filtrate and washings were evaporated to dryness in vacuo and the residue dissolved in MEOH. To this silica gel was added and the suspension evaporated to dryness and the solid applied to the top of chromatographic column. The column was eluted with CHLOROFORM/METHANOL 92/8 to give a white solid (5787g, 71.9percent). Crystallisation from water gave a white powder. IH-NMR (DMSO-d6 ; 300 MHz) 8 11.59 (1H, bs, NH-3), 8.08 (1H, s, H-6), 7.25 (1H, d, 3J=13. 6 Hz, H-5B), 6.85 (1H, D, J=13. 6 Hz, H-5A), 6.13 (1H, T, 3J=6. 5 Hz, H-L ), 5.29 (1H, bs, OH-3'), 5. 13 (1H, bs, OH-5'), 4.24 (1H, M, H-3'), 3.79 (1H,m, H-4'), 3.66 (2H, M, H-5'), 2. 51 (1H, m, H-2'), 2.14 (1H, M, H-2 ). 13C-NMR (DMSO-D6 ; 75 MHz): 6 40.2 (C-2'), 61.3 (C-5), 70.3 (C-4'), 84.8 (C-3'), 87.8 (C-1'), 108.9 (C-5B), 110. 0 (C-5), 130.3 (C-5A), 149.6, 162.1 (C-2, C4).
67%
With N-Bromosuccinimide; potassium carbonate In N,N-dimethyl-formamide
E-5-(2-Bromovinyl)-2'-deoxy-L-uridine (7). To a solution of 6 (200 mg, 0.67 mmol) in DMF (mL) was added potassium carbonate (190 mg, 1.48 mmol) and the suspension was stirred at rt for 15 min. A solution of N-bromosuccinimide (130 mg, 0.73 mmol) in DMF (I mL) was added dropwise over min). The resulting suspension was immediately filtered under suction and the solid was thoroughly washed with DMF. The combined filtrate and washings were evaporated to dryness in vacuo to remove completely DMF and the residue was purified by flash-chromatography on silica gel (methanol-chloroform 1:10) to yield 150 mg (67percent) of 7 as a white solid: mp 156° C. (dec.); [α]D-19.4(c 0.20, MeOH); UV (MeOH) λmax 245.0 nm (ε 1889) (pH 2), 243 nm (ε 2145) (pH 7), 253.5 nm (ε 2079) (pH 11
Reference：
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 24, p. 6663 - 6671
[2] RSC Advances, 2015, vol. 5, # 31, p. 24558 - 24563
[3] Patent: WO2005/12327, 2005, A2, . Location in patent: Page/Page column 24-25
[4] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5640 - 5642
[5] Patent: US6653318, 2003, B1,
[6] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 23, p. 5618 - 5623
2
[ 73446-74-9 ]
[ 69304-47-8 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1981, p. 1665 - 1670
[2] Patent: US4424211, 1984, A,
3
[ 951-78-0 ]
[ 69304-49-0 ]
[ 66-22-8 ]
[ 69304-47-8 ]
Reference：
[1] Journal of Molecular Catalysis B: Enzymatic, 2013, vol. 95, p. 16 - 22
4
[ 1006597-31-4 ]
[ 69304-47-8 ]
Yield
Reaction Conditions
Operation in experiment
84.6%
Stage #1: With water; sodium hydroxide In ethanol for 2.5 h; Heating; Reflux Stage #2: With hydrogenchloride In ethanol; water
20.07 g (47.87 mmol) 2,3'-anhydro-2'-deoxy-5'-O-benzoyl-5-(E)-bromovinyluridine are suspended in 400 ml ethanol and mixed with a solution of 4.78 g (120 mmol) sodium hydroxide in 95 ml water. This is heated for 2.5 h to boiling, thereafter the reaction is terminated (DC-control with dichloromethane/methanol 10:1). After neutralisation with hydrochloric acid, the solvent is distilled off until dry and the residue is extracted several times with acetone/acetic ester mixture (1:1). 13.5 g (84.6percent) product are obtained.
(E)-5-(2-bromovinyl)-2’-deoxyuridine-5’-(1-phenylbenzyloxy-L-alaninyl)phosphate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With 1-methyl-1H-imidazole In tetrahydrofuran at -80℃;
21.9%
With 1-methyl-1H-imidazole In tetrahydrofuran at -78 - 20℃; for 12.5167h; Inert atmosphere;
General experimental procedure for the preparation of BVdU ProTides (8-53);
BVdU phosphoramidates (8-53) were prepared applying the extensively described phosphochloridate chemistry.To a Stirring of solution of (E)-5-(2-bromovinyl)-2’-deoxyuridine, BVdU or 5-(2-carboxymethoxyvinyl)-2’-deoxyuridine, 2, (1.0mol eq.) and the appropriate phosphochloridate (3.0 mol eq.) in anhydrous THF at -78 °C; NMI (5.0 mol eq.) was added dropwise over 1 min. After 30 min the reaction was left to rise to room temperature and stirred for 12 h. The solvent was removed under reduced pressure and the yellow oil obtained was dissolved in DCM, washed with 0.5 M HCl and water. The organic layer was dried over MgSO4, filtered, reduced to dryness and purified by flash chromatography. (E)-5-(2-bromovinyl)-2’-deoxyuridine-5’-(1-phenyl(benzyloxy-L-alaninyl) phosphate (8) Purified by column chromatography (CH2Cl2/MeOH from 100/0 to 97/3), white solid, yield 21.9%. 31P NMR (202MHz, MeOD) δ 4.31, 3.84. 1H-NMR (500 MHz; MeOD) δ 7.78-7.71 (m, 1H, H-6), 7.42-7.29 (m, 8H, ArH, H-5b), 7.28-7.16 (m, 3H, ArH), 6.87-6.78 (m, 1H, H-5a), 6.29-6.19 (m, 1H, H-1’), 5.18-5.12 (m, 2H, CH2Ph), 4.47-4.31 (m, 3H, H-3’, H-5’), 4.13-4.07 (m, 2H, CH3CH, H-4’), 2.34-2.24 (m, 1H, H-2’), 2.13-2.03 (m, 1H, H-2’), 1.39-1.31 (m, 3H, CH3). 13C-NMR (125 MHz; MeOD) δ 174.73, 174.70 (C=O ester), 163.64 (C-4), 151.14 (C-2), 140.01 (C-6), 147.01, 137.38, 130.91, 130.53, 129.79, 129.36, 126.41, 121.56, 116.41 (C-5a, Ph, C-5), 109.36 (C-5b), 87.26, 86.98 (C-1’), 86.30 (C-4’), 72.21 (C-3’), 71.77 (PhCH2 ester), 67.88 (C-5’), 51.85 (CH3CH), 41.40 (C-2’), 20.60, 20.49 (CH3). MS [ESI, m/z]: 672.06 [M+Na]. tR = 13.48 min.
With potassium carbonate In aq. phosphate buffer at 20℃; for 3h; Enzymatic reaction;
2.7. Transglycosylation: general protocol
General procedure: To a solution of phosphate buffer (10 mM) at pH 7.5 (10 mL) containing 2′-deoxyuridine (1, 45.6 mg, 20 mM) and the 5-substituted base (8-13, 13-22 mg, 10 mM), 10 IU of immobilized enzyme (EcTP or BsPyNP) were added and the suspension was kept under mechanical stirring at room temperature. In the case of 5-bromovinyluracil (13), pH was set to 10 by using a 10 mM phosphate buffer containing 13.8 mg of potassium carbonate (final concentration 10 mM). Aliquots (0.2 mL) were periodically withdrawn, filtered through a pipette filter device to remove the biocatalyst and analyzed by HPLC (see below for chromatographic conditions and Rt). When the highest conversion was achieved, the reaction was stopped by filtration of the immobilized biocatalyst on a Büchner funnel with a sintered glass disc under reduced pressure. The produced nucleosides (2 and 14-18) were identified by comparison of their HPLC Rt with that of authentic samples.
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