N-[9-[[2-(Acetyloxy)-1-[(acetyloxy)methyl]ethoxy]methyl]-6,9-dihydro-6-oxo-1H-purin-2-yl]acetamide

Light Brown Solid

In the first step, 20.0-diacetylguanine 50.0 g (0.21 mol, 1.0 eq), 1, 3-diacetoxy-2-(acetoxymethoxy)propane 104.2 g (0.42 mol, 2.0 eq ), 3.0 g (0.021 mol, 0.1 eq) of boron trifluoride etherate and 200 g of N, N-dimethylformamide were placed in a microwave reactor, and the mixture was heated to 100 ° C for 10 hours.The solvent was distilled off under reduced pressure, and the mixture was cooled to room temperature. 450 g of ethyl acetate was added and refluxed for 1 hour, and the temperature was lowered to 0 to 5 ° C for 1 hour.After suction filtration and drying, the triacetyl ganciclovir compound (2) 68.3 g, the yield was 85.3percent, The purity was 95.6percent, and the compound (3) was 3.1percent.Example 7 Ganciclovir (1.0 g, 4.0 mmol), acetic anhydride (5.0 ml, 53 mmol), and pyridine (10.0 ml) were heated together, under reflux, for 6 hours. Initially, the reaction mixture was not homogeneous but once reaction completed, all were in the solution. The reaction was cooled, treated with methanol (5.0 ml), stirred for 30 minutes at 25° C., and then concentrated under reduced pressure. The crude gummy product was purified by silica gel column chromatography using 4-6percent methanol/ dichloromethane 4 to provide tri-acetylated ganciclovir, 2 (1.2 g, 3.14 mmol, yield 80percent) as a colorless powdered. Example 8 Preparation of 9-(1, 3-dihydroxy-2-propoxymethyl)guanine 12 and 7-(1, 3-dihydroxy-2-propoxymethyl)guanine 11 Compound 9 (8.0 g) was dissolved in 100 ml of aqueous methylamine (40percent) and gently refluxed for 1.5 hours, and then was evaporated to dryness to give a white solid. The solid was crystallized from 50 ml of water and 10 drops of acetic acid (to neutralize amine and remove the color) to give a white crystalline product 12 (4.63 g, 87percent). mp>300° (dec.); Rf 0.62 (CH3 OH:CHCl3 =1:1); UV (H2 O) pH7 lambdamax 251.5 (epsilon 10180), 272.0 (sh, epsilon 7500), pH2 lambdamax 253.5 (epsilon9840), pH 11 lambdamax 265.6 (epsilon 8060); 1 H NMR (DMSO-d6) delta 10.64 (s, 1H, AcNH, D2 O exchangeable), 7.80 (s, 1H, 8-H), 6.49 (s, 2H, NH2 D2 O exchangeable), 5.43 (s, 2H, 1'-H), 4.61 (t, 2H, OH, D2 O exchangeable), 3.55-3.28 (m, 5H, 4'-H, 5'-H, 3'-H).In the second step, the above-mentioned triacetyl ganciclovir compound (2) 67.1 g and 10percent potassium hydroxide solution 200 g are put into a microwave reactor.The temperature was raised to 70 ° C for 0.5 hour, cooled to room temperature, sulfuric acid was added to adjust the pH to neutrality, 3.3 g of activated carbon was added, and then dissolved.The mixture was decolorized by reflux at elevated temperature for 1 hour, filtered, and the filtrate was cooled to 10 ° C for crystallization.Filtration and drying gave 37.5 g of crude ganciclovir, the yield was 84.2percent, and the purity was 97.1percent. In the third step, 37.5 g of crude ganciclovir and 187 g of DMF were added to the reaction flask, and the mixture was heated to 90 ° C until stirred.Then cooled to 40 ° C, added 561g of methanol, and continued to cool to 20 ° C for 5 hours.Filtration, methanol washing, drying to obtain pure ganciclovir 31.0g, yield 82.8percent, purity 99.0percent, 5 mmoles of acetyl-protected ganciclovir (4) and 20 mmol of KOH were stirred in 20 ml of methanol at room temperature for 12 hours, decolorized by activated carbon, filtered, and the solvent was distilled off under reduced pressure to obtain a viscous material. Recrystallization from water gave a white powder which was ganciclovir (6). The product yield was 78percent.C. 9-(1, 3-Dihydroxy-2-propoxymethyl)guanine A solution of 838 mg (2.2 mmole) of 5 mmol of N9-methyl-N2-acetylguanine (2) was dissolved in 20 mL of anhydrous toluene, 0.5 mmol of palladium acetate was added, and 6 mmol of PhI (OPiv) 2 and 6 mmol were added.1, 3-Acetylglycerol, the reaction was stirred at 120 ° C for 24 hours, then the reaction temperature was lowered to room temperature, 20 ml of ethyl acetate was added, stirred well, transferred to a separatory funnel, and washed twice with water. The organic phase was washed once with saturated brine and dried over anhydrous sodium sulfate. The yield was 64percent.In the first step, 20.0-diacetylguanine 50.0 g (0.21 mol, 1.0 eq), 1, 3-diacetoxy-2-(acetoxymethoxy)propane 104.2 g (0.42 mol, 2.0 eq ), 3.0 g (0.021 mol, 0.1 eq) of boron trifluoride etherate and 200 g of N, N-dimethylformamide were placed in a microwave reactor, and the mixture was heated to 100 ° C for 10 hours.The solvent was distilled off under reduced pressure, and the mixture was cooled to room temperature. 450 g of ethyl acetate was added and refluxed for 1 hour, and the temperature was lowered to 0 to 5 ° C for 1 hour.After suction filtration and drying, the triacetyl ganciclovir compound (2) 68.3 g, the yield was 85.3percent, The purity was 95.6percent, and the compound (3) was 3.1percent.To a suspension of acetylated ganciclovir, 2 (0.38 g, 1.0 mmol) in dry THF (10 mL) were subsequently added under stirring triphenylphosphane (0.314 g, 1.2 mmol) and acetyl protected thiopropanol (0.268 g, 2.0 mmol). Reaction was not clear. After 10 min DIAD (0.4 mL, 2 mmol) dissolved in THF (1 mL) was added dropwise and the mixture become clear and then stirred at 25° C. for 10 hours. THF was evaporated under reduced pressure and the crude reaction mixture was extracted with DCM (3×30 mL) from water. The combined organic layer was washed with brine and dried over anhydrous sodium sulphate, filtered and evaporated to get yellowish oil. The crude product was dissolved in a minimum volume of DCM and added dropwise to cold mixture of ether and hexane (20percent hexane). The phosphine oxide stays in ether and product crushed out from ether, centrifuged and dissolved in DCM/MeOH, TLC showed little phosphine oxide and product and unreacted ganciclovir. The crude product loaded on silica gel column and purified by 1-2percent Methanol/Dichloromethane (0.098 g, yield 20percent). 1H NMR (CDCl3, 400 MHz): delta 8.10 (s, 1H), 7.97 (m, 1H), 5.65 (s, 2H), 4.59 (t, 2H, J=6.2 Hz), 4.12 (m, 5H), 3.07 (t, 2H, J=7.1 Hz), 2.58 (s, 3H), 2.34 (s, 3H), 2.17 (m, 2H), 1.98 (m, 6H). 13C NMR (101 MHz, CDCl3): delta 195.6, 170.5, 161.0, 153.3, 152.6, 141.5, 132.0, 128.6, 74.8, 71.9 66.1, 63.0, 28.9, 25.7, 25.7, 20.6. ESI-LC/MS: Expected [M+H]+ for C20H27N5O8S is 498.16, found m/z: 498.08 [M+H]+.To a suspension of acetylated ganciclovir, 2 (0.382 g, 1.0 mmol) in dry THF (5.0 mL) were subsequently added under stirring triphenylphosphine (0.393 g, 1.5 mmol) and alcohol, 3 (0.616 g, 2.0 mmol) under nitrogen atmosphere. Initially, reaction mixture was not clear but after 15 min when diethyl azodicarboxylate (DEAD) (0.261 g, 1.5 mmol) in dry THF (2.0 mL) was added drop wise, the reaction mixture turned yellow and started to become clear. The reaction was continued to stir at 25° C. for 10 hours. THF was evaporated under reduced pressure and the crude reaction mixture was extracted with DCM (3×30 mL) from water. The combined organic layer was washed with brine and dried over anhydrous sodium sulphate, filtered and evaporated to get yellowish oil. The crude product loaded on silica gel column and purified by 2-4percent Methanol/Dichloromethane. Desired product, 4 was less polar than starting compound 2. The expected product was eluted in 3percent MeOH/DCM solvent system as a colorless oil (0.403 g, 0.6 mmol, yield 60percent). 1H NMR (400 MHz, CDCl3): delta 8.13 (S, 1H), 7.96 (s, 1H), 5.66 (s, 2H), 4.68 (t, J=3.5 Hz, 2H), 4.21-4.14 (m, 2H), 4.11-4.02 (m, 2H), 3.93 (t, J=3.0 Hz, 2H), 3.79-3.72 (m, 5H), 3.69-3.67 (m, 6H), 3.54 (t, J=3.0 Hz, 2H), 2.56 (s, 3H), 1.97 (s, 6H), 0.88 (s, 9H), 0.06 (s, 6H). 13C NMR (CDCl3, 100 MHz): delta 170.5, 161.0, 153.3, 152.5, 141.9, 117.4, 74.7, 72.6, 71.8, 70.8, 70.7, 70.66, 70.6, 68.9, 66.7, 62.9, 62.6, 25.9, 25.2, 20.6, '5.2. ESI-LC/MS: Expected [M+H]+ for C29H49N5O11Si is 672.32, found m/z: 672.51 [M+H]+.To a suspension of compound 5 (0.11 g, 0.2 mmol) and acetylated ganciclovir, 2 (0.152 g, 0.4 mmol) in dry THF (6.0 mL) were subsequently added under stirring triphenylphosphine (0.078 g, 0.03 mmol) under nitrogen atmosphere. The reaction mixture was cloudy initially but after 15 min when diethyl azodicarboxylate (DEAD) (0.069 g, 0.4 mmol) in dry THF (1.0 mL) was added drop wise, the reaction mixture turned yellow and became clear. The reaction was continued to stir at 25° C. for 12 hours. THF was evaporated under reduced pressure and the crude reaction mixture was evaporated under reduced pressure to get yellowish colored oil. The crude product loaded on silica gel column and purified by 10-20percent Methanol/Ethyl Acetate solvent system to elute unreacted 2 then using 4-6percent Methanol/Dichloromethane expected dimeric ganciclovir, 7 was eluted to provide colorless oil (0.09 g, yield 49percent). 1H NMR (400 MHz, CD3OD): delta 7.97 (s, 1H), 5.65 (s, 2H), 4.66 (t, J=4.0 Hz, 2H), 4.23-4.02 (m, 5H), 3.90 (t, J=4.0 Hz, 2H), 3.67 (m, 2H), 3.62 (m, 2H), 2.68 (bs, 2H), 2.49 (s, 3H), 1.95 (s, 6H). 13C NMR (CD3OD, 100 MHz): delta 170.7, 160.8, 153.1, 152.5, 141.7, 117.3, 74.8, 71.9, 70.7, 70.5, 68.9, 66.6, 62.9, 29.6, 20.5. Expected [M+H]+ for C38H52N10O17 is 921.35, found m/z: 921.44 [M+H]+

Ganciclovir derivative.

Molecular Weight:381.34
XLogP3:-1.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:9
Rotatable Bond Count:10
Exact Mass:381.12844796
Monoisotopic Mass:381.12844796
Topological Polar Surface Area:150
Heavy Atom Count:27
Complexity:620
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes