* 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.
Adenine (40g) was first added to the flask, liquid bromine (107 ml) was added under mechanical stirring, the addition process was slow, and then stirred at room temperature for 3 hours;After the completion of the reaction, the excess liquid bromine was removed by adding sodium hydrogen sulfite solution, and the reaction liquid was adjusted to neutrality with ammonia water to precipitate a white powdery solid. Filtration, the solid was washed with ice water to give 8-bromo adenine, pale yellow solid 54 g, yield 85.7percent;
74%
at 20℃;
Example 8Preparation of 2-(3-(6-amino-9-(pent-4-ynyl)-9H-purin-8-ylthio)phenoxy)-N-hydroxyacetamide (Compound 14)Step 8a. 8-Bromo-9H-purin-6-amine (compound 302); Bromine (9.36 g, 58.5 mmol) was added to H2O (25 mL) with stirring, then the compound 301 (1.1 g, 8.1 mmol) was added into the solution. The mixture was stirred at room temperature overnight. The excess bromine was removed and the solvent was evaporated to give compound 302 as a light yellow solid (1.28 g, 74percent). The crude product was used without further purification: LC-MS: 214 [M+1]+.
Reference:
[1] Patent: CN108503643, 2018, A, . Location in patent: Paragraph 0023; 0036; 0037; 0038
[2] Patent: US2008/234297, 2008, A1, . Location in patent: Page/Page column 33; 38
[3] Synthetic Communications, 2013, vol. 43, # 11, p. 1469 - 1476
[4] Journal of Medicinal Chemistry, 2009, vol. 52, # 19, p. 5974 - 5989
[5] Collection of Czechoslovak Chemical Communications, 2000, vol. 65, # 7, p. 1126 - 1144
[6] Collection of Czechoslovak Chemical Communications, 2000, vol. 65, # 7, p. 1109 - 1125
[7] Chemistry - An Asian Journal, 2011, vol. 6, # 8, p. 2048 - 2054
[8] Journal of Medicinal Chemistry, 2005, vol. 48, # 8, p. 2892 - 2905
[9] Patent: WO2015/23976, 2015, A2, . Location in patent: Paragraph 0270
[10] Journal of Medicinal Chemistry, 2015, vol. 58, # 9, p. 3922 - 3943
(8-bromo-9-(pent-4-ynyl)-9H-purin-6-yl)amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With caesium carbonate; In N,N-dimethyl-formamide; at 85℃;
Step 8b. 8-Bromo-9-(pent-4-ynyl)-9H-purin-6-amine (Compound 303-14); A mixture of compound 302 (1.7 g, 8.1 mmol), 5-chloropent-1-yne (1.7 g, 16.2 mmol), Cs2CO3 (5.8 g, 17.8 mmol) and 25 mL of DMF was heated to 85 C. and stirred overnight. Then DMF was removed in vacuo. The residue was purified by column chromatography (dichloromethane: methanol=40:1) to give compound 303-14 (512 mg, 23%) as a white solid: LC-MS: 280 [M+1], 1H NMR (DMSO-d6) delta 1.91 (m, 2H), 2.22 (m, 2H), 2.79 (t, J=2.4 Hz, 1H), 4.18 (t, J=7.2 Hz, 2H), 7.36 (s, 2H), 8.11 (s, 1H).
23%
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere;
A mixture of 6 (2.0 g, 9.4 mmol), CS2CO3 (4.6 g, 14.1 mmol) and 5-chloropent-l-yne (1.92 ml, 18.8 mmol) in DMF (25 mL) under nitrogen protection was heated at 80 C for 3 h. Following solvent removal, the crude material was purified by preparatory TLC (CH2Cl3:MeOH:AcOH, 20: 1 :0.1) to provide 0.52 g (23 %) of 7. H NMR (500 MHz, CDCl3/MeOH-i delta 8.29 (s, 1H), 4.33 (t, J= 7.2 Hz, 2H), 2.28-2.33 (m, 2H), 2.09 (pentet, J= 7.0 Hz, 2H), 2.02 (t, J= 2.6 Hz, 1H); 13C NMR (125 MHz, CDCl3/MeOH-i) delta 154.4, 153.1, 151.3, 127.4, 1 19.9, 82.4, 69.7, 43.8, 28.2, 16.1 ; MS (ESI): m/z 280.1/282.2 [M + H]+.
With hydrazine; In tetrahydrofuran; at 100℃; for 1.33333h;Microwave irradiation;
A suspension of <strong>[6974-78-3]8-bromoadenine</strong> (0.0859 g, 0.4 mmol) and anhydrous hydrazine (1 mL) in THF (5 mL) is microwaved at 100 0C for 80 min (normal setting) . The solvent is evaporated, and EtOH (2 mL) is added: some white solid precipitates. The white solid is isolated by vacuum filtration, rinsed with EtOH and dried under vaccum to afford 0.07 g (100%) of product 8- Hydrazino-9H-purin-6-ylamine as a white solid. LC/MS Calculated for C5H7N7: m/z = 165. Found: m/z = 166 [M+H]+.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 95℃;Inert atmosphere;
A flask charged with <strong>[6974-78-3]8-bromo-9H-purin-6-amine</strong> (500 mg, 2.3 mmol), phenylboronic acid (427 mg, 3.5 mmol), Pd(dppf)Cl2 (84 mg, 0.115 mmol), and K2C03 (952 mg, 6.9 mmol) in dioxane (20 mL ) and water (4 mL) was degassed and filled with N2. The reaction was stirred at 95 C under nitrogen atmosphere overnight. Solvent was removed and the residue was purified by prep-TLC (DCM/MeOH = 10/1 ) to give 8-phenyl-9H-purin-6-amine (170 mg, yield: 35 %) as a brown solid. MS: m/z 212.1 (M+H+).
<i>N</i>-[3-(6-amino-9<i>H</i>-purin-8-ylamino)-propyl]-<i>N</i>'-(1-{1-[1-(1-carbamoyl-4-guanidino-butylcarbamoyl)-4-guanidino-butylcarbamoyl]-4-guanidino-butylcarbamoyl}-4-guanidino-butyl)-succinamide[ No CAS ]
With potassium tert-butylate; In N,N-dimethyl-formamide; at 20 - 130℃; for 12h;
Intermediate 13 : 8-[(7-Chloro-l ,3-benzothiazol-2-yl)thio]-9H-purin-6-amine; To a suspension of 8-bromoadenine (0.15 g, 0.701 mmol) and 7-chloro- benzothiazole-2-thiol (0.17 g, 0.841 mmol) in DMF was added potassium t-butoxide (0.094 mul, 0.841 mmol) at room temperature. The reaction mixture was heated at 130 0C for 12 h, then the reaction was cooled to room temperature and the crude was purified by silica gel flash column to give 8-(7-chloro-benzothiazol-2-ylsulfanyl)-9H- purin-6-ylamine (0.058 g, 25percent); LC-MS [M+H]+ 335.0.