6-Chloro-9-beta-D-(2,3-isopropylidene)ribofuranosylpurine

Pale Yellow Solid

((3aR, 4R, 6R, 6aR)-6-(6-chloro-9H-purin-9-yl)-2, 2-dimethyltetrahydrofuro[3, 4- d][l, 3]dioxol-4-yl)methanol-Toluenesulfonic acid monohydrate (19.8 g, 104 mmol) was added to a stirred suspension of (2R, 3R, 4S, 5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran- 3, 4-diol (3.0 g, 10.5 mmol) in dried acetone (300 mL). The solid dissolved 15 min later. 2 h later, the solution was poured into stirred aqueous NaHC0Compound 356l-(4-(tert-butyl)phenyl)-3-(3-((((2R, 3S, 4R, 5R)-5-(6-(dimethylamino)-9H-purin-9-yl)-3, 4- dihydroxytetrahydrofuran-2-yI)methyl)(isopropyl)amino)propyl)ureaStep 1. Preparation of ((3aR, 4R, 6R, 6aR)-6-(6-chloro-9H-purin-9-yl)-2, 2- dimethyltetrahydrofuro[3, 4-d][l, 3]dioxol-4-yl)methanolp-Toluenesulfonic acid monohydrate (134 g, 700 mmol) was added to a stirred suspension of (2R, 3R, 4S, 5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran- 3, 4-diol (20 g, 70 mmol) in acetone (100 mL). After stirred at 25° C for 6 h, the reaction mixture was poured into stirred aqueous NaHC0200 mg (0.7 mmol) of the commercial precursor 6-chloropurine riboside and acetone (10 mL)were mixed under agitation at room temperature for 30 min. This was followed by the slowaddition of p-toluensulfonic acid (5.57 mmol). The solution was kept under stirring conditionsat room temperature for 3 h. The progress of the reaction was monitored by TLC. Sodiumbicarbonate (1.5 g) was added and maintained under agitation. Once the reaction was finished, the solid phase was removed and washed with ethyl acetate (2). The product was thenpurified by column chromatography with mixtures of CH2Cl2-MeOH, obtaining the compound[6-(6-Chloro-purin-9-yl)-2, 2-dimethyl-tetrahydro-furo[3, 4-d][1, 3]dioxol-4-yl]-methanol (A); Yellow solid, 74.1percent yield; m.p. 155–158 °C 1H–NMR (CDCl3, 400.1 MHz) δ 8.72 (s, 1H, CH-Ar purine); 8.31 (s, 1H, CH-Ar purine); 6.01 (d, J = 8.0 Hz, 1H, CH-1'); 5.16 (m, 1H, CH-2'); 4.97 (d, J = 7.83 Hz, 1H, CH-3');4.52 (d, J = 1.22 Hz, 1H, CH-4'); 3.83 (m, 2H, CH2-5'); 5.06 (m, 1 OH); 1.62 (s, 3H, ketal); 1.35 (s, 3H, ketal). 13C–NMR (CDCl3, 100.6 MHz) δ 151.6, 151.4, 148.8, 144.4, 132.5, 114.0, 93.4, 86.2, 83.2, 81.1, 62.7, 27.1, 24.8. IR (KBr) λ/cm1 3320, 2906, 2863, 959, 733. Anal. Cal. C13H15ClN4O4: C = 47.75percent, H = 4.59percent, Cl = 10.85percent, N = 17.14percent.To a solution of 2 (20.0 g, 65.2 mmol) in dry dichloromethane was dropwise added TMCS (57.7 ml, 456.1 mmol) under argon atmosphere at room temperature, after short time. To the solution was dropwis added tert-butyl nitrite (59.6 ml, 547.3 mmol), then stirred at room temperature for overnight. The mixture was quenched with saturated NaHCO20 g of 2 ', 3'-isopropylideneuridine (compound of formula II) was dissolved in anhydrous dichloromethane, In the argon protection, In the dark and under normal conditions, 63.4 ml of trimethylchlorosilane was slowly added dropwise, After stirring for 15 min, 59.3 ml of n-butyl nitrite was slowly added dropwise, Stir the reaction after overnight stirring.The organic phase was collected by extraction with chloroform. The organic phase was combined, dried over anhydrous NaSO4, filtered and evaporated to dryness. The residue was separated by silica gel column chromatography (eluent: dichloromethane: methanol = 10: 1v / V) to give 12.7 g of the white product (compound represented by the formula III) in a yield of 60percent. EI: 326.((2RTo a stirred solution of chloropurine 23 (15.0 g, 52.2 mmol) in 175 mL of acetone was 2, 2-dimethoxypropane (63.0mL, 538 mmol) followed by p-toluenesulfonic acid (10.9 g, 60 mmol). The resulting heterogeneous mixture wasstirred for 2.5 h at rt during which time the solution become homogenous and bright yellow. The volatiles were removed in vacuo to give a thick yellow oil. The oil was dissolved in 150 mL of EtOAc followed by the addition of 150 mL of saturated NaHCO3 over a period of 5 minutes during which time the yellow color disappeared. The resulting layers were separated and the aqueous layer was extracted with 2 × 150 mL of EtOAc. The combined organic layers were washed with 200 mL of brine, dried (Na2SO4) and concentrated in vacuo to give the acetonide S12Next, electrophilic AMP analogs with two significantly different substituents at N6-position (i.e. a propargyl and phenyl alkyne) were synthesized following Scheme 2 and Scheme 3. Compound 2 that has a small hydrophobic group (propargyl alkyne) at the N6-position was prepared by coupling 2-chloroethanesulfonyl chloride with the 5-amino adenine moiety, followed by the deprotection of the acid labile acetonide (Scheme 2). The synthesis of compound 3, which has a large hydrophobic group (phenyl alkyne) at the N6-position, required tert-butyldimethylsilane (TI3DMS) protection and deprotection steps on the 5’ alcohol and Hoc protection on the N6-amine due to the instability of the reaction intermediates during the Mitsunobu reaction. Subsequent treatment with 2-chloroethanesulfonyl chloride and global deprotection of the acid labile protecting groups led to the formation of compound 3.(2R, 5R) -2- (6- chloro -9H- purin-9-yl) -5- (hydroxymethyl) tetrahydrofuran-3, 4-diol (4.8 g, 16.74 mmol) and 2, 2 - dimethoxy-propane (10.26 mL, 83.71 mmol) toIn a nitrogen stream, and then p- toluene sulfonic acid monohydrate (3.18 g, 16.74 mmol) was dissolved in anhydrous acetone (120 mL) to It was added dropwise then stirred at room temperature for 4 hours.The completion of the reactionA check after the reaction with saturated aqueous sodium hydrogen carbonate solutionIt concludes.The reaction solutionThe organic layer was concentrated under reduced pressure with chloroform (4 X 20 mL) Extracted and washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate.Intermediate compound by separating the resulting residue was then concentrated under reduced pressure, by column chromatography ((3aR, 4R, 6R, 6aR)-6-(6-chloro-9H-purin-9-yl)-2, 2-dimethyl-tetrahydrofuro[3, 4-d] [1, 3]dioxol-4-yl)methanol (4.87 g, 89.03percent a)Obtained.Step 1 (2R, 3R, 4S, 5R)-2-(6-Chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3, 4-diol (5.47 g, yield: 72percent) was obtained according to the process described in the known method [Journal of Organic Chemistry (J. Org. Chem.), 2002, vol. 67, pp. 6788-6796] using (2R, 3R, 4R, 5R)-2-(acetoxymethyl)-5-(6-chloro-9H-purin-9-yl)tetrahydrofuran-3, 4-diyl diacetate (10.9 g, 26.4 mmol) synthesized by the method described in the known method [Journal of Medicinal Chemistry (J. Med. Chem.), 2012, vol. 55, pp. 1478-1489]. To a 200-L reactor with moderate stirring were charged acetone (115 L, 23 vol) and 6-chloropurine-9-riboside (5.0 kg, 17.4 mol, 1.0 wt/1.0 vol). Subsequently, p- TsOHA mixture of 6-chloropurine riboside (1) (1.0 g, 3.5 mmol), p-toluenesulfonic acid monohydrate (1.0 g, 5.3 mmol) and 2, 2-dimethoxypropane (10 mL) in acetone (20 mL) was stirred at room temperature under N2 for 3 h. Another portion of 2, 2-dimethoxypropane (10 mL) was added, and the mixture was stirred for another 1 h. The mixture was concentrated by rotary evaporation under reduced pressure. The residue was diluted with CH2C12, and extracted with water. The aqueous phase was washed with CH2C12, and the combined organic layers were washed with saturated NaHCO3 and brine. The organic phase was dried over MgSO4, filtered, concentrated by rotatory evaporation under reduced pressure, and purified by column chromatography (silica gel, EtOAc/hexane gradients from 3:7 to 1:0) to give compound 23 (870 mg, 76percent yield). C, 3H, 5C1N404; [cx]D25 = —112.6 (CHC13, c = 2); JR Vx (neat) 1592, 1563, 1490, 1438, 1419, 1400, 1384, 1337, 1259, 1202, 1154, 1136, 1108, 1080 cm-’; ‘H NMR (CDC13, 600 MHz) ö 8.79 (1 H, s), 8.25 (1 H, s), 6.00 (1 H, d, J= 4.6 Hz), 5.24—5.21 (1 H, m), 5.14 (1 H, dd, J 5.6, 1.5 Hz), 4.93 (1 H, dd, J 10.6, 2.0 Hz), 4.57 (1 H, d, J= 1.5 Hz), 4.00 (1 H, dt, J 12.7, 2.0 Hz), 3.84 (1 H, ddd, J 12.7, 10.6, 2.3 Hz), 1.68 (3 H, s), 1.41 (3 H, s); ‘3C NMR (CDC13, 150 MHz) ö 152.4, 151.7, 150.4, 144.7, 133.4, 114.5, 94.1, 86.3, 83.2, 81.5, 63.2, 27.6, 25.2; ESJ—HRMS calcd. for C13H1635C1N404: 327.0855, found: m/z327.0868 [M + Hj.First step, 6-chloropurine riboside (2.0 g) and 2, 2-dimethoxypropane (5.80 g) in dry acetone (100 ml), (1S)-(+)-camphor-10-sulfonic acid (1.60 g) was added as a catalyst. The reaction mixture was stirred at room temperature for 11 h. After evaporating the solvent, the mixture was dissolved in chloroform (200 ml), and a NaHCO

Molecular Weight:326.73
XLogP3:0.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:2
Exact Mass:326.0781827
Monoisotopic Mass:326.0781827
Topological Polar Surface Area:91.5
Heavy Atom Count:22
Complexity:442
Defined Atom Stereocenter Count:4
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes