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(a) Synthesis of 8-methoxymethoxy-1-naphthalene carbaldehyde STR83 9.5 g of 8-hydroxy-1-naphthol was dissolved in 210 ml of acetone, to which 22.7 g of hydrous potassium carbonate and 5.43 ml of chloromethyl methyl ether were added and refluxed for one hour under heating. The reaction solution was filtered and the filtrate was concentrated. 12.2 g of thus obtained yellow oily product was dissolved with no further purification into 250 ml of dichloromethane, to which 4.3 g of pyridinium trifluoro acetate and 18.3 g of pyridinium dichromate were added and stirred at a room temperature for 12 hours. After filtering off insoluble matters, the filtrate was concentrated and then purified on silica gel column chromatography (10% ethyl acetatemexane), to obtain in 5.1 g of the above-captioned compound as colorness crystals. m.p.; 56~57 C. 1 H-NMR(90 MHz, CDCl3)delta; 3.50(s,3H), 5.35(s,2H), 7.16~8.00 (m,6H), 11.11(s,1H)
With tert-butylamine; In water; acetonitrile; at 15.0℃;
To a solution of DMT-2'-OMe-Bz-adenosine-CE phosphoramidite 2a (1.0 g, 1.13 mmol) and water (40.6 mg, 2.25 mmol) in dry CH3CN (4 mL) was added pyridinium trifluoroacetate (261.0 mg, 1.35 mmol) at 15 C. To the reaction mixture was added t-butylamine (4 mL). The mixture was concentrated to afford 1 g of the crude compound 2b as a white solid, which was co-evaporated with DCM (3x) and used directly for the next step. ESI-MS: m/z=450.0 [M+1]+. (DMT = 4,4'-dimethoxytrityl).
To a solution of compound 1a (4.3 g, 4.51 mmol) and water (156.8 mg, 8.7 mmol) in dry CH3CN (16 mL) was added pyridinium trifluoroacetate (1.0 g, 5.2 mmol) at room temperature. After 1 min, t-butylamine (4 mL) was added. The resulting mixture was stirred at 15 C for 20 min. The mixture was concentrated for 2 h to afford the crude product 1b as a white solid (4.0 g). The crude product was used directly for the next step.
N-[9-[(2R,3R,4R,5R)-5-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-[tert-butyl(dimethyl)silyl]oxy-3-[2-cyanoethoxy-(diisopropylamino)phosphanyl]oxy-tetrahydrofuran-2-yl]-6-oxo-1H-purin-2-yl]-2-methyl-propanamide[ No CAS ]
[ 464-05-1 ]
3'-O-[tert-butyl(dimethyl)silyl]-2'-O-[hydroxy(oxido)-λ5-phosphanyl]-N-(2-methylpropanoyl)guanosine pyridine salt[ No CAS ]
N-[9-[(2R,3R,4R,5R)-5-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-4-[tert-butyl(dimethyl)silyl]oxy-3-[2-cyanoethoxy-(diisopropylamino)phosphanyl]oxy-tetrahydrofuran-2-yl]-6-oxo-1H-purin-2-yl]-2-methyl-propanamide[ No CAS ]
[ 464-05-1 ]
C5H5N*C41H52N5O10PSi[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
941.1 mg
[55] Example 3 Step 1: preparation of compound 3a To a solution DMT-3'-O-TBDMS-G(iBu)-CE phosphoramidite compound 2d (1 g, 1.03 mmol) and water (37.1 mg, 2.06 mmol) in CH3CN (4 mL) was added <strong>[464-05-1]pyridinium trifluoroacetate</strong> (238.9 mg, 1.2 mmol) at room temperature. To the reaction mixture was added tert-butylamine (4 mL). The resulting mixture was stirred at room temperature for 20 min. The mixture was concentrated to afford compound 3a (941.1 mg) as a white solid, which was co-evaporated with DCM (3x) and used directly for the next step.
To a solution compound 3m (1.0 g, 1.031 mmol, 1.0 eq) and water (37.138 mg, 2.061 mmol, 2.0 eq) in MeCN (5.0 mL) was added <strong>[464-05-1]pyridinium trifluoroacetate</strong> (238.872 mg, (0321) 1.237 mmol, 1.2 eq) at 25 C. The reaction mixture was stirred at 25 C for 5 min. After 5 min, t-butylamine (5.0 mL) was added. The reaction mixture was stirred at 25 C for 15 min. The mixture was then concentrated under reduced pressure to form a foam. The residue was dissolved in CH3CN (5.0 mL) and concentrated under reduced pressure to afford a foam again. This process was repeated one more time to afford compound 3n (0322) (859.79 mg, crude) as a white foam. The crude product was used directly for the next step without further purification.
(2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluorotetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite[ No CAS ]
C38H35FN5O8P*C5H5N[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91.0%
[63] example 5 Step 1: preparation of compound 5b To a solution of DMT-2'-F-dA(Bz)-CE phosphoramidite 5a (2.20 g, 2.51 mmol) in CH3CN (12.0 mL) was added water (90.5 mg, 5.02 mmol, 2.0 eq) and <strong>[464-05-1]pyridinium trifluoroacetate</strong> (582.1 mg, 3.01 mmol, 1.2 eq). The mixture was stirred at 25 C for 5 min. Then tert-butylamine (12.0 mL) was added and the reaction mixture was stirred at 25 C for 15 min. The mixture was concentrated under reduced pressure to give a foam, which was dissolved in CH3CN (10.0 mL) and concentrated again to afford compound 5b (1.69 g, 2.29 mmol, 91.0% yield) as a white foam. ESI-MS: m/z 740.2 [M + H]+.
(2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluorotetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite[ No CAS ]
To a solution of le (9.5 g, 10.92 mmol) and water (393.464 mg, 21.84 mmol) in dry CH3CN (38 mL) was added <strong>[464-05-1]pyridinium trifluoroacetate</strong> (2.531 g, 13.10 mmol) at room temperature. t-Butylamine (38 mL) was added. The resulting mixture was stirred at 15 C for 20 min. The mixture was concentrated to afford If (8.876 g, crude) as a white solid. The crude product was used directly for the next step.
To a solution of compound 11(1.76 g, 1.783 mmol) in CH3CN (10.0 mL) and water (64.236 uL, 3.56 mmol) was added <strong>[464-05-1]pyridinium trifluoroacetate</strong> (413.16 mg, 2.14 mmol).After 5 mi tert-butylamine (10.0 mL) was added and the reaction mixture was stirred for15 mm at room temperature. The mixture was concentrated under reduced pressure toafford a white foam. The residue was dissolved in CH3CN (10.0 mL) and concentrated to afford a foam, and this process was repeated one more time to give compound im (1.82 g, crude) as a white foam, which was used for the next step without further purification.
To a solution of 2n (813 mg, 0.898 mmol) in water and acetonitrile was added <strong>[464-05-1]pyridinium trifluoroacetate</strong> (208.18 mg, 1.078 mmol) at room temperature. t-Butylamine (3.44 mL) was added. The resulting mixture was stirred at room temperature for 20 mm.The mixture was concentrated to afford the crude product 2o (836.39 mg, 0.898 mmol, crude) as a yellow solid, which was co-evaporated with CH2C12 (3x) and used directly for the following step.
(2R,3R,4R,5R)-5-[6-(benzoylamino)-9H-purin-9-yl]-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ylhydrogenphosphonate[ No CAS ]
(1S,2R,3S,5R)-5-(6-benzamido-9H-purin-9-yl)-3-(bis(4-methoxyphenyl)(phenyl)methoxy)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl (2-cyanoethyl) diisopropylphosphoramidite[ No CAS ]
[ 464-05-1 ]
[ 1066-33-7 ]
(2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((((((1S,2R,3S,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((tert-butyldimethylsilyl)oxy)-3-hydroxycyclopentyl)oxy)(2-cyanoethoxy)phosphorothioyl)oxy)methyl)-4-fluorotetrahydrofuran-3-yl hydrogen phosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
Step 1: Synthesis of (2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((((((1S,2R,3S,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((tert-butyldimethylsilyl)oxy)-3-hydroxycyclopentyl)oxy)(2-cyanoethoxy)phosphorothioyl)oxy)methyl)-4-fluorotetrahydrofuran-3-yl hydrogen phosphonate (C-1) To a round bottom flask, equipped with a magnetic stirbar, was added the H-phosphonate B-4 (1.0 g, 2.29 mmol) and <strong>[464-05-1]pyridinium trifluoroacetate</strong> (1.77 g, 9.15 mmol). The solids were taken up in anhydrous MeCN (10 mL*2) and concentrated under vacuum. The residue was re-dissolved in anhydrous MeCN (30 mL) and 3 A molecular sieves (4.0 g) were added. The solution was stirred for 30 minutes at which point phosphoramidite A-7 (2.67 g, 2.74 mmol) was added. The reaction was stirred at rt for 1.5 hours during which a homogeneous solution was obtained. To the reaction was added DDTT (493 mg, 2.40 mmol) and the reaction was allowed to stir at rt overnight. The reaction was filtered and the solids washed with MeOH/DCM (1:1). The filtrate was concentrated under vacuum followed by trituration with n-hexane/TBME (1:1). The crude residue thus obtained was purified via preparatory high performance liquid chromatography (Phenomenex Synergi Max-RP 150*50 mm*10 mum, 20% MeCN/H2O with 10 mM NH4HCO3 to 50% MeCN/H2O with 10 mM NH4HCO3, 120 mL/min) to afford C-1 (390 mg, 13%) as a white solid. LCMS [M+H]=1038 observed; 31P NMR (162 MHz, METHANOL-d4) delta ppm=68.24 (s, 1P), 67.74 (s, 1P), 2.95 (s, 1P), 2.71 (s, 1P).
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