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CAS No. : | 59277-89-3 | MDL No. : | MFCD00057880 |
Formula : | C8H11N5O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MKUXAQIIEYXACX-UHFFFAOYSA-N |
M.W : | 225.20 | Pubchem ID : | 135398513 |
Synonyms : |
Aciclovir;Acycloguanosine;NSC 645011;ACV;BW 248U
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.38 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 55.68 |
TPSA : | 119.05 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.78 cm/s |
Log Po/w (iLOGP) : | 0.24 |
Log Po/w (XLOGP3) : | -1.56 |
Log Po/w (WLOGP) : | -1.48 |
Log Po/w (MLOGP) : | -1.83 |
Log Po/w (SILICOS-IT) : | -0.57 |
Consensus Log Po/w : | -1.04 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.41 |
Solubility : | 88.5 mg/ml ; 0.393 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.43 |
Solubility : | 83.2 mg/ml ; 0.369 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.28 |
Solubility : | 11.9 mg/ml ; 0.0528 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.47 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With pyridine; | EXAMPLE 20 9-(2-(3-Carboxypropionyloxy)ethoxymethyl)guanine A mixture of 9-(2-hydroxyethoxymethyl)guanine (0.25 g), succinic anhydride (0.55 g) and pyridine (50 ml) was heated under anhydrous conditions on a steam bath overnight. The solvent was evaporated under reduced pressure at <40 C., the last trace being removed azeotropically with toluene. The residue was triturated with acetone and the product removed by filtration. Recrystallization from methanol afforded 9-{2-(3-carboxypropionyloxy)ethoxymethyl} guanine, m.p. 203-207 C. (sinter 190 C.), in 44% yield. |
With pyridine; at 120℃; for 10h; | A mixture of acyclovir (10 mmol) and anhydride (20 mmol) in pyridine (20 ml) was stirred and heated in an oil bath at 120 C for 10 h. The completion of the reaction was monitored by thin layer chromatography (TLC). After the mixture was cooled to 0-5 C, the crystalline solid that separated out was collected by filtration, thoroughly washed with acetone, and dried in vacuo at 40 C. An analytical sample was obtained by crystallization from methanol as a white solid in 76% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichlorophosphate; In triethyl phosphate; at 0 - 4℃; for 12h; | EXAMPLE 1 Preparation of acyclovir monophosphate (ACVMP) ACVMP was prepared using a procedure adapted from Yoshikawa et al. Tetrahedron Lett. 1967, 50, 5065. A mixture of 1 g acyclovir (4.3 mmol) and 6 ml triethylphosphate was gradually added to a mixture of 4 ml triethylphosphate and 860 mul phosphorus oxychloride (8.6 mmol) at 00C. The mixture was maintained at 0-40C for 12 h under stirring. Then 100 ml of diethyl ether were added to precipitate the acyclovir-delta'-phosphorodichloridate. The precipitate was filtered and dissolved in 25 ml of ice-cold 5% NaHCO3 in water. After stirring at O0C for 1 h and at room temperature for 8 h, the pH was adjusted to 7.0 with NaOH 1M. After further 12 h under stirring, the mixture was evaporated to dryness, dissolved in the minimum volume of water and loaded onto a DEAE-cellulose column. The column was eluted with a linear gradient (0.05-0.8 M) of triethylammonium bicarbonate, pH 7.5. Appropriate fractions were evaporated under vacuum. Ethanol was added and evaporated again to remove triethylammonium bicarbonate obtaining ACVMP as triethylammonium salt (1.28 g, 2.53 mmol, yield = 59%). 1H-NMR (D2O, pH 7.5, 200MHz) delta (ppm): 1.17-1.21 (t, J = 7.3, 18H), 3.06-3.17 (q, J = 7.3, 12H), 3.69-3.77 (m, 2H), 3.85-3.94 (m, 2H), 5.51(s, 1 H), 7.93 (s, 1 H). 31P-NMR (D2O, pH 7.5-; 80MHz) delta (ppm): 3.79 (s). | |
With triethyl phosphate; trichlorophosphate; at -18℃; for 4h; | General procedure: Phosphorus oxychloride (1.50 mol/equiv) was added to a suspension of ACV (1.00 mol/equiv) in triethylphosphate (1 ml) pre-cooled to -18 C. The mixture was kept at -18 C for 4 h. Then, it was treated with the amidating agent (amine (3.00 mol/equiv) and N,N-diisopropylethylamine (6.00 mol/equiv) in 1% aqueous dioxane (1 ml)). The reaction was maintained at +4 C for 2 h, neutralised by a saturated NaHCO3 solution (10 ml) pre-cooled to +4 C, and extracted with ether (10 ml). The aqueous extract was applied onto a D-Toyopearl column (20 × 175 mm) and eluted with a linear gradient of NH4HCO3 (0 ? 0.25 M, 600 ml). The target fraction was concentrated by evaporation under vacuum; the residue was diluted with water, re-evaporated (2 × 30 ml) and additionally chromatographed on a RP-18 column (15 × 140 mm) and eluted with a linear gradient of acetonitrile (0 ? 30%, 400 ml) in 0.05 M NH4HCO3. The fraction containing the target product was freeze-dried from water. | |
With trimethyl phosphite; trichlorophosphate; at -5℃; for 4h;Inert atmosphere; | General procedure: To a stirring solution of the desired nucleoside (1.00 mol/eq) in trimethylphosphate or triethylphosphate, POCl3 (1.00 mol/eq) was added dropwise at 5C under an argon atmosphere. The reaction mixture was stirred at 5C for 4-5 h, or at 5C for 16 h. Anhydrous CH2Cl2 and the appropriate amino acid ester salt (5.0 mol/eq) were added, followed by dropwise addition of anhydrous Et3N (10.0 mol/eq) at 0C, or anhydrous DIPEA (10.0 mol/eq) at 78C. The reaction mixture was stirred at 78C for 30 min and then at room temperature for 16-45 h. After this period, H2O was added and the aqueous phase was extracted with CH2Cl2. The organic phase was washed with brine, dried over anhydrous Na2SO4 orMgSO4, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography using different eluent systems. |
With trichlorophosphate; In tetrahydrofuran; dichloromethane; at -20 - 15℃;Inert atmosphere; | (0075) 4.5 g of anhydrous acyclovir was added to 100 ml of dry THF, and purged with nitrogen, and the reaction mixture was stirred and cooled to 15 C. to -20 C. A solution of 2.8 g of phosphorus oxychloride and 8 ml of anhydrous dichloromethane was added dropwise with stirring, and the temperature of the reaction mixture was kept from -15 C. to -20 C., stirring was continued until acyclovir was completely reacted, and the reaction solution was evaporated under reduced pressure to dryness to obtain dichlorophosphate derivatives II1 of acyclovir. | |
With trichlorophosphate; In tetrahydrofuran; dichloromethane; at -20 - -15℃;Inert atmosphere; | 4.5 g of anhydrous acyclovir was added to 100 ml of dry THF, and purged with nitrogen, and the reaction mixture was stirred and cooled to -15 C. to -20 C. A solution of 2.8 g of phosphorus oxychloride and 8 ml of anhydrous dichloromethane was added dropwise with stirring, and the temperature of the reaction mixture was kept from -15 C. to -20 C., stirring was continued until acyclovir was completely reacted, and the reaction solution was evaporated under reduced pressure to dryness to obtain dichlorophosphate derivatives II1of acyclovir. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydroxide; | Example 4 Synthesis of acyclovir from 9-((2-acetoxyethoxy) methyl)-N2 -acetylguanine. To 5.0 g of 9-((2-acetoxyethoxy)methyl)-N2 -acetylguanine was added 50 ml of an aqueous 5% sodium hydroxide solution, and the mixture was sitrred for 24 hours at room temperature for reaction. The resulting reaction solution was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration, whereby 3.2 g of acyclovir was obtained. Yield, 92%. 1 H NMR (300 MHz, DMSO-d6) analytical values: delta, 3.47 (4H, brs, H-3' & 4'), 4.66 (1H, brs, OH), 5.35 (2H, s, H-1'), 6.49 (2H, brs, NH2), 7.81 (1H, s. H-8). Mass spectral analytical value: MH+ =226. |
92% | With sodium hydroxide; | Example 4 Synthesis of Acyclovir from 9-((2-acetoxyethoxy)methyl)-N2 -acetylguanine To 5.0 g of 9-((2-acetoxyethoxy)methyl)-N2 -acetylguanine was added 50 ml of an aqueous 5% sodium hydroxide solution, and the mixture was sitrred for 24 hours at room temperature for reaction. The resulting reaction solution was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration, whereby 3.2 g of acyclovir was obtained. Yield, 92%. 1 H NMR (300 MHz, DMSO-d6) analytical values: delta, 3.47 (4H, brs, H-3' & 4'), 4.66 (1H, brs, OH), 5.35 (2H, s, H-1'), 6.49 (2H, brs, NH2), 7.81 (1H, s, H-8), 10.65 (1H, brs, NH). Mass spectral analytical value: MH+ =226. |
86% | With methanol; potassium hydroxide; at 20℃; for 12h; | 5 mmol of acetyl-protected acyclovir (3) 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 acyclovir (5), and the product yield was 86%. |
EXAMPLE 3 By operating as described in Example 1, from 17.5 g of N2-acetyl-9-(2-acetoxyethoxymethyl)guanine 18.9 g of acyclovir, wet of acetone, are obtained. By drying under vacuum at 80C up to constant weight, 12.650 g of acyclovir with a purity of 99.25% are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With bromine; In water; at 20℃; | To a suspension of acyclovir 6 (1 g, 4.4 mmol) in water (7.4 mL) bromine water [34.2 mL (bromine water was obtained by dropwise addition of 1mLof bromine into the 100mL of water during stirring the solution for15 minutes)] was added dropwise at intervals of every 2 - 3 seconds. The resulting white precipitate was filtered off rapidly and washed first with 30mL of cold water and then with 30mL of cold acetone to give 8-bromo acyclovir7 (1.28 g, 95%) as a white solid homogeneous by TLC: mp>300 C dec (from water-acetone, 1:1 v/v); Rf = 0.7 (CH2Cl2/MeOH 3:1);UV (MeOH): lambdamax/nm 261, log epsilon/dm3mol-1cm-1 3.98; IR (KBr) nu/cm-1:3489 (m), 3391 (m), 3265 (m), 3240 (m), 3178 (m), 2949 (w), 1711 (s),1630 (s), 1605 (s), 1570 (s), 1520 (m), 1460 (m), 1402 (w), 1360 (w), 1350(w), 1327 (w), 1302 (w), 1279 (m), 1254 (w), 1178 (w), 1130 (m), 1107 (w),1076 (m); 1H NMR (DMSO-d6) delta/ppm: 10.74 (bs, 1H, NH-1), 6.62 (bs,2H, NH2), 5.30 (s, 2 H, CH2-1'), 4.68 (t, 1H, J 5.3 Hz, OH-'), 3.47 (m,4H, CH2-3?, CH2-4'); 13C NMR (DMSO-d6) delta/ppm: 155.6 (C-6), 154.2(C-2), 152.9 (C-4), 120.9 (C-8), 116.6 (C-5), 72.4 (C-1'), 70.8 (C-3'),59.8 (C-4'). HRMS: m/z: 304.0036 [M+H]+; Calcd. for C8H10BrN5O3H: 304.0045. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 84% 2: 4% | With dmap In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | The compound was synthesized according to literature procedure[51,52]. Acyclovir (1.0 g, 4.44 mmol, 1.0 equiv.) was suspended inanhydrous pyridine (25 mL) and the suspension was cooled to 0 C.Chlorotrimethylsilane (3.4 mL, 26.6 mmol, 6.0 equiv.) were addeddropwise and the suspension was left to stir for 15 min. Then, DMAP(0.1 g, 0.9 mmol, 0.2 equiv.) and 4-methoxytrityl chloride (1.65 g,5.3 mmol, 1.2 equiv.) were added in one scoop. The reaction was left to stir at r.t. overnight. The reaction mixture is cooled to 0C, water(10 mL) and a 25% NH4OH solution (10 mL) is added and the mixtureis left to stir for 30 min. The crude mixture is filtered, and the solvent isremoved under reduced pressure. The crude product is purified viacolumn chromatography over silica gel with CH2Cl2:MeOH (100:00 to100:07) and isolated as colorless solid (1.3 g, 2.6 mmol, 59%). Thespectral data matches the reported. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With pyridine for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.2% | EXAMPLE 1 Preparation of 2-[(2-AMINO-1,6-DIHYDRO-6-OXO-9H-PURIN-9YL)METHOXY] ETHYL N-[(BENZYLOXY)CARBONYL] L-VALINATE (Formula IV) 50 g of N-[(benzyloxy)carbonyl] L-valine (CBZ-L-valine) of Formula III and 500 ml of dimethyl formamide (DMF) were charged into a round bottom flask followed by stirring with simultaneous cooling to 15 C. over a period of 10 minutes. To the obtained clear solution 68.6 g of dicyclohexyl carbodiimide dissolved in 100 ml of dimethyl formamide was slowly added over a period of 45 minutes followed by stirring for 15 minutes at 15 C. 50 g of 9-((2-hyroxyethoxy)methyl)-2-amino-1H-purin-6(9H)-one (acyclovir) of Formula II and 4.066 g of dimethylaminopyridine were charged into the reaction mass and subjected to stirring for about 6 hours at 15 C. After completion of the reaction, the reaction mass was filtered and the solids washed with 100 ml of dimethyl formamide. The resultant filtrate was subjected to distillation under vacuum at 80 C. until 80% of the volume was distilled. The resultant filtrate was transferred into another flask and 300 ml of water was added at 30 C. followed by heating to 70 C. for a period of 30 minutes. The mixture was cooled to 20 C. and the separated solid was filtered, followed by washing the solid with 100 ml of water. The solid material was subjected to suction drying to afford the 256 g of wet solid title compound. 256 g of the above-obtained wet material was taken into a round bottom flask along with 750 ml of methanol and 225 ml of water, followed by heating to 80 C. with simultaneous stirring for 4 hours. The obtained mass was cooled to a temperature of 35 C. with simultaneous stirring. The solid obtained was filtered and washed with a mixture of 338 ml methanol and 178 ml water. Finally the obtained solid material was subjected to suction drying followed by drying under vacuum at 55 C. to afford 88.7 g (87.2%) of the title compound. Purity: 99.3 weight % by HPLC. | |
EXAMPLE 2 To a 250 mL reaction flask, as described in Example 1, was charged under nitrogen 13.8 grams of Z-valine, 11.3 grams of dry acyclovir and 50 mL of DMF. (The acyclovir was dried in a vacuum oven at 80-85 C. and at less than 5 Torr vacuum for 4 hours.) The mixture in the reaction flask was stirred and cooled to approximately 0-2 C. Benzene sulfonyl chloride (12.4 grams) was added all at once to the cooled mixture and the reaction mixture stirred for 10 minutes. 1-methyl imidazole (12.6 grams) was added drop wise to the reaction mixture over a period of 1 hour and the mixture stirred at 0-5 C. for 4 hours, and then overnight at room temperature. HPLC analysis of the reaction mixture indicated that the esterification reaction was incomplete. Additional 2.2 grams of benzene sulfonyl chloride was added drop wise to the reaction mixture with stirring. The reaction mixture was stirred at 18-20 C. for 2.5 hours. HPLC analysis of the reaction mixture indicated that approximately 2% of the acyclovir remained unreacted. An additional 1 gram of benzene sulfonyl chloride was added all at once to the reaction mixture, which was stirred for 1 additional hour. Water (75 mL) was added to the reaction mixture and the slurry obtained was heated to 80-85 C. whereat a substantial portion of the solids in the reaction mixture dissolved. The solution was cooled gradually to room temperature. The crystals obtained were recovered by filtration and washed twice with approximately 50 mL portions of water. The wet cake was stirred in 60 mL of 95% ethanol and heated to reflux. The mixture in the flask was cooled with stirring overnight to room temperature. The solids that formed were recovered by filtration and washed with 50 mL ethanol and dried in vacuo. The dried product was slurried in a mixture of 50 mL water and 50 mL methanol at 60-65 C., cooled to room temperature, filtered, washed with methanol and dried in vacuo. The product yield was 19.0 grams. HPLC analysis of the recovered product revealed it to be 98.5% Z-valacyclovir (area percent). | ||
With 1-methyl-1H-imidazole; p-toluenesulfonyl chloride; In N,N-dimethyl-formamide; at 10 - 20℃;Product distribution / selectivity; | EXAMPLE 4 A 250 mL reaction flask, as described in Example 1, was charged with 11.3 grams of dry acyclovir, 13.8 grams of Z-valine, 30 mL of DMF and 13.8 grams of 1-methyl imidazole. The mixture was cooled to temperatures of 10-12 C., and a solution of 14.3 grams of p-toluene sulfonyl chloride in 20 mL of DMF was added drop wise over one hour while the mixture was at a temperature of 10-15 C. The mixture was stirred at 10-15 C. for 2 hours and then overnight at room temperature. Water (50 mL) was then added to the reaction flask and the reaction mixture heated to 90-95 C. The resultant solution was cooled over 4 hours to room temperature and the solid crystalline product that formed was recovered by filtration. The crystals were washed three times with 100 mL portions of water, followed by washing two times with 50 mL portions of ethanol. The washed crystals were dried in a vacuum oven at 95-100 C. and 20-25 Torr. 18.2 grams of solid Z-valine acyclovir product were obtained, which by HPLC analysis was found to be greater than 97% pure. |
With 4-methyl-morpholine; 1-methyl-1H-imidazole; benzenesulfonyl chloride; In N,N-dimethyl-formamide; at 5 - 10℃; for 5h;Product distribution / selectivity; | EXAMPLE 6 A mixture of 11.8 grams of dry acyclovir, 13.8 grams of Z-valine and 50 mL of DMF was cooled in a reaction flask to 5 C. and 13.4 grams of benzene sulfonyl chloride was added to the cooled mixture. Over a period of 1 hour, a mixture of 10.2 grams of N-methyl morpholine and 4.7 grams of 1-methyl imidazole was added to the contents of the reaction flask, while maintaining the contents at 5-10 C. The contents of the reaction flask were stirred for 4 hours at that temperature. HPLC analysis of the reaction mixture showed that 10% of acyclovir remained unreacted. Additional benzene sulfonyl chloride (3.4 grams) and 1-methyl imidazole (5 grams) were added to the reaction flask and the contents stirred overnight at room temperature. Water (50 mL) was added to the reaction mixture and the mixture heated to 90 C. Thereafter, the contents of the reaction flask were cooled to room temperature and crystals that formed were recovered by filtration. The recovered crystals were washed three times with 50 mL portions of water. The wet cake was mixed with 100 mL of 95% ethanol and heated to reflux. The resulting mixture was cooled to room temperature and the crystals that formed were recovered by filtration. The filtered solids were washed twice with 95% ethanol and dried in a vacuum oven at 60-65 C. and 20-25 Torr. 19.5 grams of Z-valacyclovir product were recovered. HPLC analysis of the product showed it to have a purity of 97.3%. | |
With 1-methyl-1H-imidazole; benzenesulfonyl chloride; In N,N-dimethyl-formamide; at 10 - 15℃; for 1.75h;Product distribution / selectivity; | EXAMPLE 3 To a 250 mL reaction flask, as described in Example 1, was charged 11.9 grams of acyclovir containing approximately 5% water, 13.8 grams of Z-valine, 13.8 grams of 1-methyl imidazole and 50 mL of DMF. The mixture was cooled to 10 C. with stirring under nitrogen and 13.4 grams of benzene sulfonyl chloride was added drop wise over 1 hour and 45 minutes while maintaining the temperature of the reaction mixture at 10-15 C. Thereafter, the reaction mixture was stirred for an additional 30 minutes at 10-15 C. and then allowed to warm to room temperature. HPLC analysis did not show the presence of any acyclovir. Water (40mL) was added to the reaction flask and the contents of the flask heated to 85-90 C. to dissolve the precipitate that had formed. The solution was cooled gradually over approximately 2 hours to ambient (room) temperature. The solids that formed were recovered by filtration, and washed three times with 100 mL portions of water. The product was dried in a vacuum oven at approximately 100 C. and 20-25 Torr. The dried product (20.1 grams) was analyzed by HPLC and found to be greater than 99% Z-valacyclovir. | |
With 1-methyl-1H-imidazole; benzenesulfonyl chloride; In N,N-dimethyl-formamide; at 10℃; for 5.5h;Product distribution / selectivity; | EXAMPLE 12 A 500 mL automated reactor flask equipped with a thermocouple, agitator, nitrogen inlet, bubbler and addition lines was charged with 150 mL DMF, 34.8 grams of acyclovir (4.4% water) and 41.4 grams of Z-valine. The slurry in the reactor was cooled to 10 C. and the addition of 44.3 grams of 1-methyl imidazole (NMI) to the reactor at a rate of 0.738 g/min was begun. After 3 minutes, the addition of 47.6 grams of benzene sulfonyl chloride (BSC) was begun at a rate of 1.06 g/min. The total addition time for NMI was 60 minutes, and the total addition time for BSC was 45 minutes. The temperature within the reactor was maintained at 10 C. during the addition of the NMI and BSC. Progress of the reaction was monitored by HPLC. After 5.5 hours, 150 mL of water was added all at once to the yellow homogeneous reaction mixture, which resulted in the formation of a slurry of white granules. The slurry was heated to 85 C., held at that temperature for 10 minutes, and then cooled to room temperature (about 20 C.) at a rate of 1.0 C./minute. The resulting crude reaction slurry was stirred overnight at room temperature. The crude reaction slurry was filtered and the crystals recovered were washed two times with 150 mL of water. The wet cake was charged to a 500 mL 3-necked flask equipped with agitator, nitrogen inlet/bubbler and thermocouple. Water (150 mL) was added to the flask and the resultant slurry heated to 80 C. for one hour. The slurry was allowed to cool to room temperature, and the crystals in the slurry filtered. The filter cake was washed two times with 150 mL of water and one time with 150 mL of 95% ethanol. The washed filter cake was allowed to dry in air for approximately 2 hours, and was returned to the 3-necked flask. Isopropanol (300 mL) was added to the flask, and the resultant slurry heated to 74 C. for 0.5 hours before allowing it to cool to room temperature. The crystals were filtered and washed two times with 150 mL of isopropanol. The wet cake product was dried at 70-75 C. at 20-25 Torr for 3 hours to obtain a yield of 58.15 grams. HPLC analyses showed the product to be 98.2% (area percent normalized) Z-valacyclovir. | |
With 1-methyl-1H-imidazole; benzenesulfonyl chloride; In acetonitrile; at 10 - 20℃; for 3.25h;Product distribution / selectivity; | EXAMPLE 5 A 100 mL reaction flask equipped with mechanical stirrer and thermometer was charged with 5.65 grams of dry acyclovir, 6.9 grams of Z-valine, 6.9 grams of 1-methyl imidazole and 25 mL of acetonitrile. The mixture was stirred magnetically and cooled with stirring to 10 C. Benzene sulfonyl chloride (6.7 grams) was added drop wise over 15 minutes to the reaction mixture, which was then stirred for 1 hour at 10-15 C., followed by stirring for 2 hours at room temperature. HPLC analysis indicated that the esterification reaction was incomplete. Additional 1-methyl imidazole (0.43 grams) and benzene sulfonyl chloride (0.67 grams) was added to the reaction flask and the contents stirred for 2 hours at room temperature. HPLC analysis of the reaction mixture indicated that the reaction was substantially complete. Water (25 mL) was added to the reaction mixture, which was warmed to approximately 40 C. and stirred at that temperature for 30 minutes. The mixture was cooled to room temperature and the crystals that formed were recovered by filtration. The crystals were washed with water and then with ethanol, and then dried under vacuum (20-25 Torr) to obtain 9.8 grams of product, which by HPLC analysis was 98.5% Z-valacyclovir. | |
EXAMPLE 7 A 250 mL reaction flask equipped with a mechanical stirrer and thermometer was charged with 10.6 grams of acyclovir (5.6% water), 13.4 grams of N-benzyloxycarbonyl-L-valine (Z-valine), 0.55 grams of dimethylamino pyridine (DMAP) and 40 mL of DMF. Triethyl amine (22.4 grams) was added to the slurry at room temperature over 25 minutes. The resulting slurry was cooled to 0-5 C. Diethyl chlorophosphate (DECP, 15.3 grams) was added drop wise to the cooled slurry over 25 minutes, while maintaining the slurry at approximately 0-10 C. The reaction mixture was stirred for 2 hours at 5-10 C. and then overnight at room temperature. HPLC analysis showed that approximately 2% of the added-acyclovir remained unreacted. DECP (1.53 grams) was added to the reaction flask at room temperature and the contents stirred for an additional 2.5 hours. Water (100 mL) was then added slowly to the reaction mixture. A white solid precipitated. The resulting white slurry was heated to 100 C. and maintained at that temperature for approximately 20 minutes. The reaction mixture was then cooled to room temperature and stirred overnight. Precipitated solids in the reaction mixture were isolated by filtration and washed once with 40 mL of water and two times with 40 mL of methanol. The washed solids were dried over 4 hours in a vacuum oven at 65 C. and 20 Torr. 20.9 grams of product were recovered, which HPLC analysis showed to be 99% pure Z-valacyclovir by area percent. EXAMPLE 9 A 250 mL reaction flask equipped with a mechanical stirrer and thermometer was charged with 10.6 grams of acyclovir (5.6% water), 12.3 grams of Z-valine, 0.55 grams of N,N-dimethylamino pyridine (DMAP) and 40 mL of DMF. Triethylamine (15.7 grams) was added to the contents of the reaction flask at room temperature and over 6 minutes. The resultant slurry was cooled to 3 C., and 11.5 grams of diethyl chlorophosphate (DECP) added drop wise to the cooled slurry over 1-hour while maintaining the slurry at 0-10 C. The reaction mixture was stirred for 3 hours at 5-10 C. and then overnight at room temperature. Additional DECP (1.5 grams) was added to the reaction mixture at room temperature, which was then stirred for 22 hours at room temperature. Water (100 mL) was added to the reaction mixture and the resulting white slurry heated to 97 C. and kept at that temperature for 5 minutes. The reaction mixture was then cooled to room temperature and solids in the mixture isolated by filtration. The recovered solids were washed once with water (40 mL) and then twice with 40 mL portions of methanol. The washed white solids were vacuum dried at 65 C. and 25 Torr for 6 hours. 18.2 grams of dried product were recovered. HPLC analysis of the dried product showed it to be 99.2% pure Z-valacyclovir by area percent. | ||
EXAMPLE 11 A 250 mL reaction flask was charged with 10.6 grams of acyclovir (5.6% water), 12.3 grams of Z-valine, 0.55 grams-of DMAP and 40 mL of DMF. N,N-diisopropyl ethylamine (20.1 grams) was added to the-reaction flask at room temperature over 8 minutes. The resulting slurry was cooled to 3 C. and 13.1 grams of DECP added drop wise to the cooled slurry over 23 minutes while maintaining the slurry within the range of 3-7 C. The reaction mixture was stirred for 1.75 hours at 4-5 C. and then for 4 days at room temperature. Water (80 mL) was added to the reaction mixture and the resulting white slurry heated to 100 C. and maintained at that temperature for 20 minutes. The resulting solution was cooled to room temperature, and solids that formed were isolated by filtration. The recovered solids were washed once with water (40 mL) and twice with 40 mL portions of 95% ethanol. The washed white solid was vacuum dried at 65 C. and 25 Torr for 6 hours. The dried solid product (22.0 grams) was analyzed by HPLC and found to be 98.2% pure Z-valacyclovir by area percent. | ||
EXAMPLE 10 A 250 mL reaction flask was charged with 10.6 grams of acyclovir (5.6% water), 12.3 grams of Z-valine, 0.55 grams of DMAP and 40 mL of DMF. N-methyl morpholine (NMM, 15.7 grams) was added to the reactions flask at room temperature over 10 minutes. The resulting slurry was cooled to 2 C., and diethyl chlorophosphate (DECP, 11.5 grams) was added drop wise to the cooled slurry over 15 minutes while maintaining the slurry at 1-10 C. The reaction mixture was stirred for 3 hours at 3 C., and then overnight at room temperature. Additional DECP (3.83 grams) was added to the reaction mixture at room temperature. The reaction mixture was then stirred for 6 hours followed by the addition of 4.5 grams of NMM at room temperature. After 17 hours additional stirring, more DECP (1.5 grams) was added at room temperature. The reaction mixture was then stirred for 4.25 hours at room temperature, and thereafter 100 mL of water was added to the mixture. The resulting white slurry was heated to 95 C. and kept at that temperature for 15 minutes. The resulting solution was cooled to room temperature and solids that formed were isolated by filtration. The recovered solids were washed once with water (40 mL) and twice with 40 mL of methanol. The washed white solids were vacuum dried at 65 C. and 25 Torr. HPLC analysis of the product (19.6 grams) showed it to be 98% pure Z-valacyclovir by area percent. | ||
EXAMPLE 13 A 250 mL reaction flask equipped with mechanical stirrer and thermometer was charged with 10.5 grams of acyclovir (5.6% water), 13.4 grams of Z-valine, and 40 mL of DMF. The resulting slurry was cooled to 3 C. and 6.2 grams of N-methyl imidazole (NMI) was added drop wise to the cooled slurry over 5 minutes while maintaining the slurry at 3 C. The reaction mixture was cooled to -2 C., followed by the addition of 8.65 grams of methane sulfonyl chloride (MSC) over approximately 1.5 hours, while maintaining the temperature of the reaction mixture at 0-1 C. Additional NMI (6.2 grams) was then added to the reaction mixture over 1.5 hours at 1-5 C. The reaction mixture was stirred for 1 hour 50 minutes, and an additional 1.1 grams of NMI was added to the mixture at 5 C. The reaction mixture was stirred for 1 hour 35 minutes at 4-7 C., and 0.36 grams of additional NMI was added to the mixture. The reaction mixture was stirred for 16 hours and 35 minutes in an ice-bath (1-5 C.). Water (40 mL) was added to the reaction mixture and the resulting slurry was then heated to 103 C., thereby to form a light yellow solution. A white solid was observed in the solution after it was cooled to room temperature. The solid was recovered by filtration and washed once with water (50 mL) and two times with 50 mL of a water/ethanol mixture (1:1, v/v). The wet cake was placed in a 250 mL flask containing 100 mL of a water/ethanol mixture (15/85, v/v). The resulting slurry was heated to 79 C. and kept at that temperature for 5 minutes. The resulting solution was cooled to 30 C. The solids that formed upon cooling were recovered by filtration and washed two times with 50 mL of an ethanol/water mixture (3/1, v/v). The white solid was air-dried overnight and then vacuum dried at 65 C. and 25 Torr for 6 hours. The dried solid product (17.8 grams) was analyzed by HPLC and found to be 97.2% pure Z-valacyclovir by area percent. | ||
EXAMPLE 8 A 250 mL reaction flask equipped with a mechanical stirrer and thermometer was charged with 10.6 grams of acyclovir (5.6% water), 13.4 grams of Z-valine and 40 mL of DMF. 1-methyl imidazole (18.6 grams) was added to the reaction flask at room temperature over 10 minutes. The resulting slurry was cooled to 0-5 C. and diethyl chlorophosphate (15.3 grams) was added drop wise to the slurry over 30 minutes while maintaining the slurry at 0-10 C. The reaction mixture was stirred for 5 hours at 10 C. and then overnight at room temperature. Water (100 mL) was added to the reaction mixture and the resulting white slurry was heated to approximately 100 C. The resulting solution was cooled to room temperature and the solids that formed were isolated by filtration. Recovered solids were washed with water (40 mL) and twice with 40 mL portions of methanol. The washed solids were vacuum dried at 65 C. and 25 Torr for 6 hours. The dried product (20.2 grams) was analyzed by HPLC and found to be 99.4% Z-valacyclovir by area percent). | ||
With dmap; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃; for 48h; | The starting material of the process, N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, (the compound of formula II) is a known compound and can be prepared by a person skilled in the art by following the processes disclosed in the literature. For example, the compound of formula II may be prepared by following the process disclosed in the U.S. Pat. No. 4,957,924, which is incorporated herein by reference. The process involves addition of N-(benzyloxy)carbonyl-L-valine (CBZ-L-valine), dimethylformamide (DMF), 4-dimethylaminopyridine (DMAP) and dicyclohexylcarbodimide (DCC) to the warm solution of acyclovir in DMF to obtain a faint yellow solution. The resulting faint yellow solution was allowed to cool to room temperature and stirred overnight to obtain white precipitate. The reaction mixture was again recharged with the same amounts of CBZ-L-valine, DMAP and DCC, the cloudy suspension obtained is stirred at room temperature for 2 days. The suspension is filtered to remove the solid and the filtrate is concentrated to obtain a light yellow oil. The oil is purified by flash chromatography on silica gel to yield the compound of formula II. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h; | A solution of acyclovir (96.8 mg, 0,43 mmmol) in dimethylformamide (1.5 mL), was treated with acetic anhidride (122. 7 J-, 1.29 MMOL) and 4-dimethylaminopirydine (DMAP) (5.3 mg, 0.04 MMOL). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated to dryness to give 1 (91 % yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With dmap; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h; | [00468] A solution of acyclovir (100 mg, 0.44 mmol), dimethylaminopyridine (5.4 mg, 0.044 mmol) and chloroacetic anhydride (226 mg, 1.32 mmol) in dimethylformamide (9 mL) was stirred at room temperature for 18 h. The dimethylformamide was removed by evaporation. The crude product was purified by reverse-phase HPLC (22 mm×250 mm C-18 column, a 5-25% CH3CN/H2O gradient with 0.1% trifluoroacetic acid, 214 and 254 nm UV detection) and lyophilized. The product was obtained as a white powder (62 mg, 47%). 1H NMR (300 MHz, DMSO-d6) delta 10.67 (s, 1H), 7.88 (s, 1H), 6.53 (s, 1H), 5.27 (s, 2H), 4.35 (s, 2H), 4.21 (t, J=3 Hz, 2H), 3.70 (t, J=3 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) delta 168.1, 157.6, 154.8, 152.3, 138.6, 117.1, 72.7, 67.1, 65.2, 41.8; TOF-MS (m/z): 302.0 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With ammonia; In N,N-dimethyl-formamide; | EXAMPLE 3 Synthesis of 3-(2-acetoxy-ethoxymethyl)-6-(4-chlorophenyl)-3,5-dihydro-1,3,4,5,7a-s-indacen-8-one (Compound 3) A solution of 1.4 g (6.22 mmol) acyclovir, 30 mL DMF, and 400 mg sodium hydride (80%) was stirred at room temperature for 30 min, then 0.7 mL 2-bromo-4'-chloroacetophenone was added dropwise into the solution. Changing to orange color, the solution was added 17 mL ammonia, and continuously stirred for 5 hr. The solvent was removed to obtain a residue, which was washed with water. The product, 3-(2-hydroxy-ethoxymethyl)-6-(4-chlorophenyl)-3,5-dihydro-1,3,4,5,7a-pentaaza-s-indacen-8-one, was produced and weighted 1.62 g (white solid, yield 72 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With trimethylsilyl trifluoromethanesulfonate; acetic acid; 1,1,1,3,3,3-hexamethyl-disilazane; | EXAMPLE 3 Alternative Preparation of a Compound of Formula (I) A mixture of guanine (25 g), hexamethyldisilazane (HMDS, 125 ml), and trimethylsilyl trifluoromethanesulfonate (1 ml) was heated to reflux (130-135 C.) for 24 hours. The resulting mixture was cooled to 70 C., 1,3-dioxolane (25 ml) added, and the resulting mixture refluxed for 16 hours. Excess HMDS and 1,3-dioxolane were removed by distillation under reduced pressure. The reaction mixture was cooled to 70 C., and poured into a mixture of 600 ml of 10% aqueous acetic acid. The mixture was heated to give a solution. The hot solution was treated with a small amount of activated carbon (1.25 g) to remove any color, filtered, and the filtrate slowly cooled to 5 C. The white crystalline solid thus produced was filtered off, to yield pure 9-(2-hydroxyethoxymethyl)guanine (29 g, 78%). 1 H NMR: 3.38 (4H, singlet); 4.64 (1H, broad singlet); 5.26 (2H, singlet); 6.54 (2H, broad singlet); 7.68 (1H, singlet). |
73% | With trifluorormethanesulfonic acid; 1,1,1,3,3,3-hexamethyl-disilazane; In water; acetic acid; | EXAMPLE 5 Alternative Preparation of a Compound of Formula (I) A mixture of guanine (25 g), hexamethyldisilazane (HMDS, 135 ml), and trifluoromethanesulfonic acid (0.75 ml) was heated to reflux (130-135 C.) for 24 hours. The resulting mixture was cooled to 70 C., and excess HMDS removed by distillation (0.1 to 1 mm Hg), slowly raising the bath temperature back to 110 C. The resulting mixture was cooled to 50 C., 1,3-dioxolane (36 ml) added, and the resulting mixture refluxed for 16 hours. The mixture was then cooled to 60 C., 300 ml of water and 2 ml of acetic acid added, and then low boiling solvent was removed by distillation at atmospheric pressure. The reaction mixture was cooled, and the yellow solid filtered off, which was then dissolved in a mixture of 450 ml water and 24 ml of acetic acid at 80 C. The hot solution was treated with a small amount of activated carbon (2 g) to remove any color, filtered, and the filtrate slowly cooled to 5 C., to yield pure 9-(2-hydroxyethoxymethyl)guanine (27.4 g, 73%). 1 NMR: 3.38 (4H, singlet); 4.64 (1H, broad singlet); 5.26 (2H, singlet); 6.54 (2H, broad singlet); 7.68 (1H, singlet). |
72% | With ammonium hydroxide; sodium hydroxide; trifluorormethanesulfonic acid; acetic acid; 1,1,1,3,3,3-hexamethyl-disilazane; In water; toluene; | EXAMPLE 8 Alternative Preparation of a Compound of Formula (I) A mixture of guanine (25 g), hexamethyldisilazane (HMDS, 125 ml), and trifluoromethanesulfonic acid (0.75 ml) was heated to reflux (130-135 C.) for 18 hours. The resulting mixture was cooled to 70 C., and excess HMDS removed by distillation (0.1 to 1 mm Hg). The resulting mixture was cooled, and toluene (250 ml) and 1,3-dioxolane (18 ml) added, and the resulting mixture refluxed for 10 hours at 105 C. The mixture was then cooled and 250 ml of water containing sodium hydroxide (7 g) added, and the aqueous layer separated. The toluene layer was washed with water (150 ml), and the combined aqueous layers were heated at atmospheric pressure to distill off low boiling organic material. The solution was cooled, and acetic acid (10.5 g) added to give a white precipitate. To this was added 29% ammonium hydroxide (6 g), the mixture heated to dissolve the solid, and the hot solution treated with a small amount of activated carbon (3 g) to remove any color. The slurry thus obtained was heated to redissolve the solid, filtered, and the filtrate slowly cooled to 5 C. The white crystalline solid thus produced was filtered off, to yield pure 9-(2-hydroxyethoxymethyl)guanine (26.8 g, 72%) 1 NMR: 3.38 (4H, singlet); 4.64 (1H, broad singlet); 5.26 (2H, singlet); 6.54 (2H, broad singlet); 7.68 (1H, singlet). |
66.6% | With trifluorormethanesulfonic acid; acetic acid; 1,1,1,3,3,3-hexamethyl-disilazane; In methanol; water; | EXAMPLE 4 Alternative Preparation of a Compound of Formula (I) A mixture of guanine (25 g), hexamethyldisilazane (HMDS, 125 ml), and trifluoromethanesulfonic acid (0.75 ml) was heated to reflux (130-135 C.) for 16 hours. The resulting mixture was cooled to 70 C., and excess HMDS removed by distillation (0.1 to 1 mm Hg), slowly raising the bath temperature back to 130 C. The resulting mixture was cooled to 60 C., 1,3-dioxolane (20 ml) added, and the resulting mixture refluxed for 16 hours. The mixture was then cooled to 45 C., 200 ml of methanol added, and then low boiling solvent was removed by distillation at atmospheric pressure. The reaction mixture was cooled, and poured into a mixture of 500 ml water and 10 ml of acetic acid. The mixture was heated to 80 C., removing low boiling material, to give a solution. The hot solution was treated with a small amount of activated carbon (2.5 g) to remove any color, and 100 ml of water added. The slurry thus obtained was heated to 75 C. to redissolve the solid, filtered, and the filtrate slowly cooled to 5 C. The white crystalline solid thus produced was filtered off, and recrystallized from 525 ml of 5% aqueous acetic acid, to yield pure 9-(2-hydroxyethoxymethyl)guanine (24.8 g, 66.6%). 1 NMR,: 3.38 (4H, singlet); 4.64 (1H, broad singlet); 5.26 (2H, singlet); 6.54 (2H, broad singlet); 7.68 (1H, singlet). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In methanol | 3.C Preparation of Compounds of Formula (I) where R1 is Hydrogen 3C. Preparation of Formula I Where R1 is Hydrogen 9-(2-Acetoxyethoxy)methyl-N2 -acetylguanine (1.3 gm, 4.2 mmol) was dissolved in 10 ml of methanol and 10 ml of concentrated ammonium hydroxide, and the solution was heated at 50° C. for a period of 4 hours. The solvents were evaporated off, yielding a solid. The solid was recrystallized from methanol, yielding 0.85 gm of 9-(2-hydroxyethoxy)methylguanine (90% yield). Characteristic analytical data are as follows: 1 H NMR(DMSO-d6), δ3.16 (4H, singlet, --OCH2 CH2 O--), 4.6 (1H, br singlet, --OH), 5.26 (2H, singlet, --NCH2 --), 6.45 (2H, br singlet, --NH2), 7.76 (1H, singlet, --N=CH--N--). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With acetic acid; In water; | EXAMPLE 2 Preparation of a Compound of Formula (I) A mixture of 9-(2-trimethylsilylethoxymethyl)guanine (15.8 g), water (250 ml), and acetic acid (20 ml) was heated to reflux, giving a solution. The hot solution was treated with a small amount of Montmorillonite K10 (an acidic clay) to remove any color, filtered, and the filtrate slowly cooled to 5 C. The white crystalline solid thus produced was filtered off, to yield 9-(2-hydroxyethoxymethyl)guanine (8.8 g, 69%). 1 H NMR 3.38 (4H, singlet); 4.64 (1H, broad singlet); 5.26 (2H, singlet); 6.54 (2H, broad singlet); 7.68 (1H, singlet). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium hydroxide; In water; | EXAMPLE 4 87.5 g (125 ml, apparent d-0.7) of strong basic resin (AMBERLITE IRA-400) were suspended in deionized water and loaded into a chromatographic column (diameter=4 cm, h=40 cm). After the usual regeneration treatments (subsequent elution with 2M NaOH, 2M HCl, 2M NaOH and deionized water till neutrality) a solution obtained by dissolving 50 g of acyclovir into 100 ml of a 10% NaOH solution, diluted up to 200 ml with water, was loaded. The solution was then eluted with a flow of 250 ml/hour (4.2 ml/min). After eluding the above solution, the column was eluted with the same flow rate with 900 ml of a 1:1 v/v MeOH/1M NaOH mixture. The so obtained elude was adjusted to pH 5-6 with aqueous HCl. The precipitated solid was filtered, washed with water and dried. 45 g of acyclovir (90% yield) free from guanine were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.7% | With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In N,N-dimethyl-formamide; at 20℃; | Combine acyclovir (0.50 g, 2.22 mmol) with t-Boc-aminocyclopropyl carboxylic acid (0.58 g, 2.89 mmol), l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0.64 g, 3.33 mmol) and 4-dimethylaminopyridine (0.05 g, 0.36 mmol) in dry N,N-dimethylformamide (3 mL). Add triethylamine (0.31 g, 3.11 mmol) and stir the resulting suspension at room temperature under nitrogen overnight. Cool to 0C and add 10 mL of a 0.3 M solution of hydrochloric acid to precipitate a white solid. Collect by vacuum filtration and wash with ether. The resulting solid is recrystallized from isopropanol to give product as a white solid. Yield: 93.7 % MS (LC-MS): 409.3 (M+l). MS (LC-MS): 407.3 (M-I) 1HNMR (d6-DMSO): delta 0.97 (s 2H); 1.23-1.24 (d, 2H); 1.33 (s, 9H); 3.60 (s, 2H); 4.07 (s, 2H); 5.32 (s, 2H); 6.50 (s, 2H); 7.50 (s, IH); 7.78 (s, IH); 10.65 (s, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | dmap; In pyridine; | To a solution of 1.0 g (4.4 mmol) of acyclovir in 25 mL of freshly distilled dry pyridine were added 2.27 g (4.4 mmol) of trigonelline anhydride diiodide and a catalytic amount (5.4 mg. 4 mmol) of 4-(dimethylamino)pyridine (DMAP). The resultant suspension was stirred for 4 days under argon at room temperature. As the reaction proceeded, the orange color of the anhydride was replaced with a yellow color. When all of the acyclovir had been consumed, the reaction was stopped, the precipitate (containing the product ester plus the trigonelline formed as a by-product) was removed by filtration and washed with acetone and ether to remove DMAP. The yellow solid was then stirred in dry methanol at room temperature to remove trigonelline, unreacted anhydride and acyclovir. The title compound was obtained in 87% yield (1.82 g), melting at 201-202 C. NMR and UV analyses confirmed that the product had the formula: STR132 |
87% | dmap; In pyridine; | To a solution of 1.0 g (4.4 mmol) of acyclovir in 25 mL of freshly distilled dry pyridine were added 2.27 g (4.4 mmol) of trigonelline anhydride diiodide and a catalytic amount (5.4 mg, 4 mmol) of 4-(dimethylamino)pyridine (DMAP). The resultant suspension was stirred for 4 days under argon at room temperature. As the reaction proceeded, the orange color of the anhydride was replaced with a yellow color. When all of the acyclovir had been consumed, the reaction was stopped, the precipitate (containing the product ester plus the trigonelline formed as a by-product) was removed by filtration and washed with acetone and ether to remove DMAP. The yellow solid was then stirred in dry methanol at room temperature to remove trigonelline, unreacted anhydride and acyclovir. The title compound was obtained in 87% yield (1.82 g), melting at 201-202 C. NMR and UV analyses confirmed that the product had the formula: STR131 |
87% | dmap; In pyridine; | To a solution of 1.0 g (4.4 mmol) of acyclovir in 25 mL of freshly distilled dry pyridine were added 2.27 g (4.4 mmol) of trigonelline anhydride diiodide and a catalytic amount (5.4 mg, 4 mmol) of 4-(dimethylamino)pyridine (DMAP). The resultant suspension was stirred for 4 days under argon at room temperature As the reaction proceeded, the orange color of the anhydride was replaced with a yellow color. When all of the acyclovir had been consumed, the reaction was stopped, the precipitate (containing the product ester plus the trigonelline formed as a by-product) was removed by filtration and washed with acetone and ether to remove DMAP. The yellow solid was then stirred in dry methanol at room temperature to remove trigonelline, unreacted anhydride and acyclovir. The title compound was obtained in 87% yield (1.82 g), melting at 201-202 C. NMR and UV analyses confirmed that the product had the formula: STR130 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With ammonia; In methanol; | 9-(benzoyloxyethoxymethyl)guanine (0.58g) and methanol (80ml) saturated with ammonia were heated in a bomb at 80 C. for 16 hours. The reaction mixture was removed from the bomb and the solvent evaporated under reduced pressure. The residue was thoroughly washed with ether and then recrystallized from methanol to give 9-(2-hydroxyethoxymethyl)guanine (0.31g., 75% of theoretical), m.p. 256.5-257 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 2.08333h; | To a suspension of acyclovir (6.67 mmol) in 60 mL CH2CI2 at 0 CC and under argon, DMAP (5 equivalents) and triethylamine (5 equivalents) were added. The resulting mixture was stirred for a few minutes and valproyl chloride (5 equivalents) in 20 mL CH2CI2 was added dropwise over the course of 5 minutes. The yellowish solution was brought to room temperature and then stirred for 2 hours. The mixture was quenched with water and diluted with CH2CI2. The resulting mixture was washed thrice with 5 % HCI solution (50 mL), twice with saturated NaHCO3 solution (50 mL) and once with brine (50 mL). The organic layer was dried over MgSO4 and evaporated.The resulting off-white solid was re-crystallized from ethanol, to give AN-446 as white crystals (850 mg, 27 % yield). m.p. = 113-115 C. 1H-NMR (CDCI3): delta = 9.38 (s, 1H1 H-1), 8.14 (s, 1H, H-8), 5.54 (s, 2H, H-T)1 4.26 (t, J=5.1 Hz1 2H1 H^1), 3.78 (t, J =5.1 Hz, 2H, H-31), 2.54 (m, 1H, H-3"), 2.35 (m, 1 H1 H-71), 1.97 (m, 2H, H-3), 1.69+1.53 (m, 4H, H-4"+ 4H, H-81), 1.39+1.29 (m, 4H, H-5"+ 4H, H-91), 0.92 (t, J = 6.98 Hz, 3H1 H-6"), 0.83 (t, J = 7.9 Hz, 3H, H-101) ppm.13C-NMR (CDCI3): delta = 178.3 (C-211), 176.5 (C-61), 154.9 (C-6), 148.3 (C-2), 139.1 (C- 8), 120.2 (C-5), 118.0 (C-4), 73.22 (C-T), 67.72 (C-31), 62.23 (C-41), 48.28(C-3"), 45.11 (C-71), 34.64 (C-4"), 34.49 (C-81), 20.60 (C-5"), 20.54 (C-91). 13.95 (C-6"+C-10') ppm.HRMS: calculated for C24H40N5O5 (MH+, DCI/CH4) 478.3029; found 478.3034. Elemental analysis: calculated for C24H40N5O5 (477.295) C1 60.36; H1 8.23; N, 14.66; 0,16.75; found C, 60.45; H, 8.77; N1 15.07; 0,17.26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With dmap; In tetrahydrofuran; | 250 mg (2.05 mmol) of DMAP (4-dimethylaminopyridine) in 10 mL tetrahydrofuran (THF) was added to a suspension of acyclovir (225 mg, 1 mmol) under argon. The resulting suspension was stirred for a few minutes and valproyl chloride (0.35 mL, 2.05 mmol) was added dropwise over the course of 5 minutes. The suspension then became thicker and was stirred overnight. The solvent was removed and the resulting yellowish solid residue was re- crystallized in ethanol to give AN-452 (230 mg, 65 % yield) as white crystals, m.p. = 219-2220C. 1H-NMR (DMSOd6): delta = 10.66 (s, 1H, H-1), 7.80 (s, 1H, H-8), 6.53 (s, 2H, H-10),5.34 (S, 2H, H-11), 4.11 (m, 2H, H-4'), 3.65 (m, 2H, H-31), 2.26 (m, 1 H, H-71), 1.36 (m, 4H, H- 8'), 1.16 (sex, J =7.2 Hz, 4H, H-91), 0.81 (t, J =7.2 Hz, 6H, H-10') ppm. 13C-NMR (DMSO-d6): delta = 175.4 (C-61), 156.8 (C-6), 153.9 (C-2), 151.4 (C-4), 137.6 (C-8), 71.7 (C-11), 66.7 (C-41), 62.4 (C-31), 44.3 (C-71), 35.0 (C-81), 19.9 (C-91), 13.8 (C-101) ppm. Elemental analysis: calculated for C16H25N5O4 (351.4) C, 54.69; H, 7.17; N, 19.93; found C, 51.70; H, 7.26; N1 19.58. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Acyclovir (0.5 gram, 2.22 mmol) was suspended in pyridine (50 mL) and trimethylsilyl chloride (1.2 mL, 9.4 mmol) was added. The mixture was stirred for 15 minutes, after which a clear solution formed, and valproyl chloride (0.5 mL, 2.95 mmol) was then added over the course of 3 minutes. The yellowish clear solution was stirred overnight at room temperature. The solution was then cooled to 0-(-5) 0C and distilled water (10 mL) was added. The slightly yellowish, clear solution was stirred overnight at room temperature. The solvent was then removed and the residue was suspended in distilled water (50 mL). The aqueous suspension was extracted with ethyl acetate:ether solution (3x30 mL). The organic layer that contained a pink precipitate was separated and evaporated to give a pink powder. The solid was washed thrice with n-hexane (10 mL) and dried under vacuum. The solid was then re-crystallized in methanol to give AN-463 (560 mg, 72 % yield) as pink crystals.1H-NMR (MeOD): delta = 8.16 (s, 1H, H-8), 5.62 (s, 2H, H-1'), 3.67 (m, 4H, H-4'+H-3'), 2.26 (m, 1H, H-3"), 1.72+1.52 (m, 4H, H-4"), 1.38 (m, 4H, H-5"), 0.97 (t, J = Hz, 6H, H-6") ppm.13C-NMR (MeOD): delta = 182.1 (C-2"), 158.3 (C-6), 151.8 (C-2), 150.6 (C-4), 142.5 (C- 8), 121.7 (C-5) 75.2 (C-11), 73.1 (C-41), 62.74 (C-31), 49.2 (C-3"), 36.8 (C-4"), 22.5 (C-5"), 15.2 (C-6") ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pivaloyl chloride; In pyridine; at -15 - 20℃; for 2h; | Acyclovir (200 mg, 0.89 mmol) and compound A3 [See Compound 5 of Example 2] (674.2 mg, 1.15 mmol) were coevaporated together with anhydrous pyridine and dissolved in this solvent (13.3 mL). Pivaloyl chloride (162 muL, 1.15 mmol) was added drop wise at - 15C and the solution was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane and neutralized with an aqueous solution OfNH4Cl 0.5M. The mixture was partitioned between dichloromethane and aqueous NH4Cl 0.5M, the organic phases were combined, dried over Na2SO4 evaporated under reduced pressure (bath temperature not exceeding 30 C) and coevaporated twice with toluene. The crude mixture was filtered on a silica gel plug eluting with a gradient 0-15% methanol in dichloromethane + 0.2% acetic acid) to afford the desired product Fl (602 mg, 98%).Compound F1:LR LC/MS (M+H+) 691.9 (M-H-) 690.0 (4.82 min)._UV: lambdamax = 254 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Prodrug synthesis Amino acid ester prodrugs of ACV - ACV-Arg, ACV-Gly, ACV-Ile, ACV-Phe, ACV-Trp and ACV-Val, were prepared by a two-step synthesis as outlined in Scheme 1 starting from ACV using a method adapted from the literature [15,19,20]. Briefly, N-Boc protected l-arginine, l-glycine, l-isoleucine, l-phenylalanine, l-tryptophan or l-valine (3.55 * 10-3 mol), DIC (0.48 g, 3.80 * 10-3 mol) and HOBt (0.48 g, 3.55 * 10-3 mol) were dissolved in DMF (10 ml) under N2. The mixture was stirred for 2 h at 0 C, and was then added dropwise to a solution of ACV (0.8 g, 3.55 * 10-3 mol) and DMAP (0.005 g, 0.4 * 10-3 mol) in DMF (110 ml) at room temperature. The solution was stirred continuously and warmed up to 50 C. The reaction ran overnight. DMF was removed by rotary evaporation using a Rotavapor (Buechi Labortechnik AG; Flawil, Switzerland) and the residue was placed on a silica gel column and eluted with 8:1:0.1-15:1:0.1 mixture of dichloromethane, methanol and acetic acid to give the desired intermediate as a white solid. De-protection of the intermediates was carried out using a 1:1 mixture of dichloromethane and trifluoroacetic acid (30 ml) in an ice bath for 2 h. After removal of the solvent by rotary evaporation, the resulting oil was then added dropwise to vigorously stirred cold diethyl ether (20 ml) and ACV-X prodrug was immediately precipitated. The precipitate was filtered with a Buechner funnel and then washed with cold diethyl ether (20 ml). The filter cake was dissolved in 10 ml of H2O and lyophilized for 30 h using an Alpha 2-4 LD Plus freeze dryer (Martin Christ GmbH; Osterode am Harz, Germany). A hygroscopic, fluffy white solid with a purity of >95% (HPLC-UV, wavelength 254 nm) was obtained. The 1H NMR spectrum of each prodrug was recorded on a Varian Gemini NMR spectrometer (300 MHz) at ambient temperature. The high resolution mass spectrum of each prodrug was acquired using an API QSTAR Pulsar, ESI-Qtof mass spectrometer (Applied Biosystems; Rotkreuz, Switzerland). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water at 37℃; aq. phosphate buffer; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Prodrug synthesis Amino acid ester prodrugs of ACV - ACV-Arg, ACV-Gly, ACV-Ile, ACV-Phe, ACV-Trp and ACV-Val, were prepared by a two-step synthesis as outlined in Scheme 1 starting from ACV using a method adapted from the literature [15,19,20]. Briefly, N-Boc protected l-arginine, l-glycine, l-isoleucine, l-phenylalanine, l-tryptophan or l-valine (3.55 * 10-3 mol), DIC (0.48 g, 3.80 * 10-3 mol) and HOBt (0.48 g, 3.55 * 10-3 mol) were dissolved in DMF (10 ml) under N2. The mixture was stirred for 2 h at 0 C, and was then added dropwise to a solution of ACV (0.8 g, 3.55 * 10-3 mol) and DMAP (0.005 g, 0.4 * 10-3 mol) in DMF (110 ml) at room temperature. The solution was stirred continuously and warmed up to 50 C. The reaction ran overnight. DMF was removed by rotary evaporation using a Rotavapor (Buechi Labortechnik AG; Flawil, Switzerland) and the residue was placed on a silica gel column and eluted with 8:1:0.1-15:1:0.1 mixture of dichloromethane, methanol and acetic acid to give the desired intermediate as a white solid. De-protection of the intermediates was carried out using a 1:1 mixture of dichloromethane and trifluoroacetic acid (30 ml) in an ice bath for 2 h. After removal of the solvent by rotary evaporation, the resulting oil was then added dropwise to vigorously stirred cold diethyl ether (20 ml) and ACV-X prodrug was immediately precipitated. The precipitate was filtered with a Buechner funnel and then washed with cold diethyl ether (20 ml). The filter cake was dissolved in 10 ml of H2O and lyophilized for 30 h using an Alpha 2-4 LD Plus freeze dryer (Martin Christ GmbH; Osterode am Harz, Germany). A hygroscopic, fluffy white solid with a purity of >95% (HPLC-UV, wavelength 254 nm) was obtained. The 1H NMR spectrum of each prodrug was recorded on a Varian Gemini NMR spectrometer (300 MHz) at ambient temperature. The high resolution mass spectrum of each prodrug was acquired using an API QSTAR Pulsar, ESI-Qtof mass spectrometer (Applied Biosystems; Rotkreuz, Switzerland). | ||
BOC L-Valine (120 g) was dissolved in 300 ml dimethylformamide (DMF) at 25- 30C. The solution was cooled to -5C and DCC solution (137.47 g DCC in 350 ml DMF) was added at -5 to -10C in 90 min followed by stirring for 10 min at -5 to 10C. Acyclovir (100 g) was added to the obtained solution of Boc-Valine, followed by 4-dimethylaminopyridine (DMAP) (7g) was added at -5 to -10C. After completion of the reaction, residue was washed with DMF (100 ml) and DMF was distilled out under vacuum at 55-60C. Preheated DM water (2 lit) was added to the above residue at 70-75C and stirred for 60 min at 70-75C and cooled to 30- 35C. The product was filtered and washed with 300 ml DM water at 35-45C; and further washed with 150 ml ethanol and dried the product at 45-50C. Yield: Dry- 205 g crude Purity: 97.5 to 98% (by HPLC) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Prodrug synthesis Amino acid ester prodrugs of ACV - ACV-Arg, ACV-Gly, ACV-Ile, ACV-Phe, ACV-Trp and ACV-Val, were prepared by a two-step synthesis as outlined in Scheme 1 starting from ACV using a method adapted from the literature [15,19,20]. Briefly, N-Boc protected l-arginine, l-glycine, l-isoleucine, l-phenylalanine, l-tryptophan or l-valine (3.55 * 10-3 mol), DIC (0.48 g, 3.80 * 10-3 mol) and HOBt (0.48 g, 3.55 * 10-3 mol) were dissolved in DMF (10 ml) under N2. The mixture was stirred for 2 h at 0 C, and was then added dropwise to a solution of ACV (0.8 g, 3.55 * 10-3 mol) and DMAP (0.005 g, 0.4 * 10-3 mol) in DMF (110 ml) at room temperature. The solution was stirred continuously and warmed up to 50 C. The reaction ran overnight. DMF was removed by rotary evaporation using a Rotavapor (Buechi Labortechnik AG; Flawil, Switzerland) and the residue was placed on a silica gel column and eluted with 8:1:0.1-15:1:0.1 mixture of dichloromethane, methanol and acetic acid to give the desired intermediate as a white solid. De-protection of the intermediates was carried out using a 1:1 mixture of dichloromethane and trifluoroacetic acid (30 ml) in an ice bath for 2 h. After removal of the solvent by rotary evaporation, the resulting oil was then added dropwise to vigorously stirred cold diethyl ether (20 ml) and ACV-X prodrug was immediately precipitated. The precipitate was filtered with a Buechner funnel and then washed with cold diethyl ether (20 ml). The filter cake was dissolved in 10 ml of H2O and lyophilized for 30 h using an Alpha 2-4 LD Plus freeze dryer (Martin Christ GmbH; Osterode am Harz, Germany). A hygroscopic, fluffy white solid with a purity of >95% (HPLC-UV, wavelength 254 nm) was obtained. The 1H NMR spectrum of each prodrug was recorded on a Varian Gemini NMR spectrometer (300 MHz) at ambient temperature. The high resolution mass spectrum of each prodrug was acquired using an API QSTAR Pulsar, ESI-Qtof mass spectrometer (Applied Biosystems; Rotkreuz, Switzerland). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | A solution of N-acetyl-S-(4-nitroxybutyroyl)cisteine (2.8 g, 9.6 mmoles) and 1,1-carbonyldiimidazol (1.55 g, 9.6 mmoles) in tetrahydrofuran (50 ml) is prepared and left under stirring at room temperature for 1 hour. The reaction mixture is treated with aciclovir (2.16 g, 9.6 mmoles). After 6 hours of reaction at room temperature, the solution is evaporated at reduced pressure, the obtained residue treated with ethyl acetate and washed with brine. The organic phase is anhydrified with sodium sulphate and then dried under vacuum. The obtained residue is purified by chromatography on silica gel column eluting with ethyl acetate. 9-[[2-[N-acetyl-S-(4-nitroxybutyroyl)cisteinyl-]ethoxy]methyl]guanine is obtained. Yields: 9%.Elementary analysis Calculated C: 35.25% H: 3.95% N: 13.76% S: 47.05% Found C: 35.38% H: 3.99% N: 13.84% S: 47.20% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | dmap; In N,N-dimethyldecanoamide; at 25℃; for 48h;Inert atmosphere;Product distribution / selectivity; | Example 1; Synthesis of acyclovir hexanoate using N,N-dimethylamide of decanoic acid Under argon atmosphere, acyclovir (25 mM) and hexanoic anhydride (75 mM) were placed in 1 200 ml 3-necked flask and 3.5 ml of the solvent N,N-dimethyldecanoamide were added. Once 2 mM of the catalyst 4-N,N-dimethylaminopyridine were added, the mixture was stirred at 25C for 48h. Subsequently the reaction mixture was washed with water to remove the unreacted acid and anhydride. The yield obtained as the isolated product was 90%. The ester was characterized by NMR, IR and TLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Commercially available <strong>[1679-53-4]10-hydroxydecanoic acid</strong> (500 mg, 2.66 mmol) was dissolved in DMF (5 mL). EDC (1019.89 mg, 5.32 mmol) was added and stirred it for 1 hour at room temperature. In a separate reaction flask, acyclovir (599.06 mg, 2.66 mmol) was dissolved in DMF and DMAP (487.46 mg, 3.99 mmol) was added and continued stirring for 10 minutes at room temperature under inert atmosphere to activate the hydroxyl group of the acyclovir. This mixture was added into the reaction mixture containing <strong>[1679-53-4]10-hydroxydecanoic acid</strong> through a syringe and continued stirring for 72 hours at room temperature. A small portion of the reaction mixture was taken out and injected into LC/MS to ensure the complete conversion of the starting material to product. The reaction mixture was filtered and solvent was evaporated at room temperature under reduced pressure to get crude product. Compound 1 was purified by silica column chromatography using 10% MeOH/DCM as eluent with 53% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | For the synthesis, commercially available ricinoleicacid (100 mg, 0.33 mmol) was dissolved in dry dimethyl formaldehyde ("DMF") (2 mL), l-(3-demethylaminopropyl)-3- ethyl carbodiimide ("EDC") (126 mg, 0.66 mmol) was added to the reaction mixture, and stirred for one hour at room temperature under inert atmosphere. In a separate reaction flask, ACV (110 mg, 0.49 mmol) was dissolved in DMF and 4-dimethyl aminopyridine ("DMAP") (60 mg, 0.49 mmol) added to it. This reaction mixture was stirred continuously for 10 minutes at room temperature under inert atmosphere to activate the hydroxyl group of acyclovir. It was then added to the reaction mixture (ricinoleicacid and EDC dissolved in DMF) through a syringe and stirring was continued for about 72 hours. A small portion of this reaction mixture was taken out and injected into LC/MS to ensure complete conversion of the starting material to product. The reaction mixture was filtered and the solvent was evaporated at room temperature at reduced pressure to obtain a crude product Ricinoleicacid- ACV ("R-ACV"). This crude product 3 was purified by silica column chromatography using 6% MeOH/ DCM as the eluent with 47% yield (Scheme 1).For the synthesis of the final conjugated compound Biotin-<strong>[141-22-0]Ricinoleic acid</strong>- ACV ("B-R-ACV") (5), biotin (29 mg, 0.11 mmol) was dissolved in DMF (1 ml). The <n="25"/>coupling agent EDC (23 mg, 0.11 mmol) was added and stirred for about one hour at room temperature. In a separate reaction flask, the intermediate R-ACV (30 mg, 0.05 mmol) was placed in DMF and the base DMAP (10 mg, 0.075 mmol) was added. The mixture was stirred for about 10 minutes at room temperature under an inert atmosphere. The biotin mixture was added to the R-ACV mixture through a syringe and the reaction was stirred for about 72 hours at room temperature. The reaction mixture was filtered and the solvent was evaporated at room temperature under a reduced pressure to get the crude product. The final product B-R-ACV 5 was purified by silica column chromatography using 20% MeOH/DCM as eluent with 79% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap In dimethyl sulfoxide for 0.166667h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium chloride; potassium hydroxide; In water; at 25℃; for 0.0833333h;pH 12.0; | General procedure: Hydrolysis of the compounds (3-13) was performed in acidic ( 2, KCl and HCl, 25 ml of 0.2 M KCl and 6.5 ml of 0.2 M HCl diluted to 100 ml), neutral ( 7.4, phosphate buffer, 25 ml of 0.2 M KH2PO4 and 19.5 ml of 0.2 M KOH diluted to 100 ml) and basic ( 12, KCl and KOH, 25 ml of 0.2 KCl and 6 ml of 0.2 KOH diluted to 100 ml) conditions at 25 C and with 0.02 mM of the studied compounds. The samples were taken (10 mul) at regular intervals and were analysed by TLC in a system of dioxane:ammonia (8:2). Substance containing zones were cut out and washed with aqueous dioxane. The amount of product was estimated by their UV-absorption at 250 nm.The experiments were performed three times for each phosphoramidate. The averaged data are presented in Table 1; the experimental error did not exceed 20%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium dihydrogenphosphate; potassium hydroxide; In aq. phosphate buffer; water; at 25℃; for 120h;pH 7.4; | General procedure: Hydrolysis of the compounds (3-13) was performed in acidic ( 2, KCl and HCl, 25 ml of 0.2 M KCl and 6.5 ml of 0.2 M HCl diluted to 100 ml), neutral ( 7.4, phosphate buffer, 25 ml of 0.2 M KH2PO4 and 19.5 ml of 0.2 M KOH diluted to 100 ml) and basic ( 12, KCl and KOH, 25 ml of 0.2 KCl and 6 ml of 0.2 KOH diluted to 100 ml) conditions at 25 C and with 0.02 mM of the studied compounds. The samples were taken (10 mul) at regular intervals and were analysed by TLC in a system of dioxane:ammonia (8:2). Substance containing zones were cut out and washed with aqueous dioxane. The amount of product was estimated by their UV-absorption at 250 nm.The experiments were performed three times for each phosphoramidate. The averaged data are presented in Table 1; the experimental error did not exceed 20%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 80% | With potassium chloride; potassium hydroxide; In water; at 25℃;pH 12.0; | General procedure: Hydrolysis of the compounds (3-13) was performed in acidic ( 2, KCl and HCl, 25 ml of 0.2 M KCl and 6.5 ml of 0.2 M HCl diluted to 100 ml), neutral ( 7.4, phosphate buffer, 25 ml of 0.2 M KH2PO4 and 19.5 ml of 0.2 M KOH diluted to 100 ml) and basic ( 12, KCl and KOH, 25 ml of 0.2 KCl and 6 ml of 0.2 KOH diluted to 100 ml) conditions at 25 C and with 0.02 mM of the studied compounds. The samples were taken (10 mul) at regular intervals and were analysed by TLC in a system of dioxane:ammonia (8:2). Substance containing zones were cut out and washed with aqueous dioxane. The amount of product was estimated by their UV-absorption at 250 nm.The experiments were performed three times for each phosphoramidate. The averaged data are presented in Table 1; the experimental error did not exceed 20%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 80% | With potassium chloride; potassium hydroxide; In water; at 25℃; for 120h;pH 12.0; | General procedure: Hydrolysis of the compounds (3-13) was performed in acidic ( 2, KCl and HCl, 25 ml of 0.2 M KCl and 6.5 ml of 0.2 M HCl diluted to 100 ml), neutral ( 7.4, phosphate buffer, 25 ml of 0.2 M KH2PO4 and 19.5 ml of 0.2 M KOH diluted to 100 ml) and basic ( 12, KCl and KOH, 25 ml of 0.2 KCl and 6 ml of 0.2 KOH diluted to 100 ml) conditions at 25 C and with 0.02 mM of the studied compounds. The samples were taken (10 mul) at regular intervals and were analysed by TLC in a system of dioxane:ammonia (8:2). Substance containing zones were cut out and washed with aqueous dioxane. The amount of product was estimated by their UV-absorption at 250 nm.The experiments were performed three times for each phosphoramidate. The averaged data are presented in Table 1; the experimental error did not exceed 20%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 80% | With potassium chloride; potassium hydroxide; In water; at 25℃;pH 12.0; | General procedure: Hydrolysis of the compounds (3-13) was performed in acidic ( 2, KCl and HCl, 25 ml of 0.2 M KCl and 6.5 ml of 0.2 M HCl diluted to 100 ml), neutral ( 7.4, phosphate buffer, 25 ml of 0.2 M KH2PO4 and 19.5 ml of 0.2 M KOH diluted to 100 ml) and basic ( 12, KCl and KOH, 25 ml of 0.2 KCl and 6 ml of 0.2 KOH diluted to 100 ml) conditions at 25 C and with 0.02 mM of the studied compounds. The samples were taken (10 mul) at regular intervals and were analysed by TLC in a system of dioxane:ammonia (8:2). Substance containing zones were cut out and washed with aqueous dioxane. The amount of product was estimated by their UV-absorption at 250 nm.The experiments were performed three times for each phosphoramidate. The averaged data are presented in Table 1; the experimental error did not exceed 20%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 80% | With potassium chloride; potassium hydroxide; In water; at 25℃;pH 12.0; | General procedure: Hydrolysis of the compounds (3-13) was performed in acidic ( 2, KCl and HCl, 25 ml of 0.2 M KCl and 6.5 ml of 0.2 M HCl diluted to 100 ml), neutral ( 7.4, phosphate buffer, 25 ml of 0.2 M KH2PO4 and 19.5 ml of 0.2 M KOH diluted to 100 ml) and basic ( 12, KCl and KOH, 25 ml of 0.2 KCl and 6 ml of 0.2 KOH diluted to 100 ml) conditions at 25 C and with 0.02 mM of the studied compounds. The samples were taken (10 mul) at regular intervals and were analysed by TLC in a system of dioxane:ammonia (8:2). Substance containing zones were cut out and washed with aqueous dioxane. The amount of product was estimated by their UV-absorption at 250 nm.The experiments were performed three times for each phosphoramidate. The averaged data are presented in Table 1; the experimental error did not exceed 20%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 80% | With potassium chloride; potassium hydroxide; In water; at 25℃;pH 12.0; | General procedure: Hydrolysis of the compounds (3-13) was performed in acidic ( 2, KCl and HCl, 25 ml of 0.2 M KCl and 6.5 ml of 0.2 M HCl diluted to 100 ml), neutral ( 7.4, phosphate buffer, 25 ml of 0.2 M KH2PO4 and 19.5 ml of 0.2 M KOH diluted to 100 ml) and basic ( 12, KCl and KOH, 25 ml of 0.2 KCl and 6 ml of 0.2 KOH diluted to 100 ml) conditions at 25 C and with 0.02 mM of the studied compounds. The samples were taken (10 mul) at regular intervals and were analysed by TLC in a system of dioxane:ammonia (8:2). Substance containing zones were cut out and washed with aqueous dioxane. The amount of product was estimated by their UV-absorption at 250 nm.The experiments were performed three times for each phosphoramidate. The averaged data are presented in Table 1; the experimental error did not exceed 20%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 80% | With potassium chloride; potassium hydroxide; In water; at 25℃;pH 12.0; | General procedure: Hydrolysis of the compounds (3-13) was performed in acidic ( 2, KCl and HCl, 25 ml of 0.2 M KCl and 6.5 ml of 0.2 M HCl diluted to 100 ml), neutral ( 7.4, phosphate buffer, 25 ml of 0.2 M KH2PO4 and 19.5 ml of 0.2 M KOH diluted to 100 ml) and basic ( 12, KCl and KOH, 25 ml of 0.2 KCl and 6 ml of 0.2 KOH diluted to 100 ml) conditions at 25 C and with 0.02 mM of the studied compounds. The samples were taken (10 mul) at regular intervals and were analysed by TLC in a system of dioxane:ammonia (8:2). Substance containing zones were cut out and washed with aqueous dioxane. The amount of product was estimated by their UV-absorption at 250 nm.The experiments were performed three times for each phosphoramidate. The averaged data are presented in Table 1; the experimental error did not exceed 20%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 80% | With potassium chloride; potassium hydroxide; In water; at 25℃;pH 12.0; | General procedure: Hydrolysis of the compounds (3-13) was performed in acidic ( 2, KCl and HCl, 25 ml of 0.2 M KCl and 6.5 ml of 0.2 M HCl diluted to 100 ml), neutral ( 7.4, phosphate buffer, 25 ml of 0.2 M KH2PO4 and 19.5 ml of 0.2 M KOH diluted to 100 ml) and basic ( 12, KCl and KOH, 25 ml of 0.2 KCl and 6 ml of 0.2 KOH diluted to 100 ml) conditions at 25 C and with 0.02 mM of the studied compounds. The samples were taken (10 mul) at regular intervals and were analysed by TLC in a system of dioxane:ammonia (8:2). Substance containing zones were cut out and washed with aqueous dioxane. The amount of product was estimated by their UV-absorption at 250 nm.The experiments were performed three times for each phosphoramidate. The averaged data are presented in Table 1; the experimental error did not exceed 20%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With hydrogenchloride; In isopropyl alcohol; at 20℃; for 0.5h; | Acyclovir (3.00 g, 13.3 mmol) was suspended in 30 mL isopropanol. A solution of concentrated HCI (0.486 g, 13.3 mmol; 1.32 mL HCI 37 % was used) in 15 mL isopropanol was added to this suspension and the reaction mixture was stirred for 30 min at room temperature. The solvent was evaporated using a Rotavapor and the solid obtained was further dried using high vacuum with no heating. The product was obtained as a white solid in a 94% yield. 1H- NMR (500 MHz, DMSO-d6) delta (ppm) = 11.68 (s, 1H); 8.99 (s, 1H); 7.31 (s, 2H); 5.51 (s, 2H); 3.58 (t, 2H); 3.47 (t, 2H); 13C-NMR (125 MHz, DMSO-d6) delta (ppm) =155.92; 154.56; 150.56; 138.02; 110.28; 74.13; 71.68; 60.30. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.16% | With triethylamine In N,N-dimethyl-formamide at 60℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; diisopropyl-carbodiimide / N,N-dimethyl-formamide / 2 h / 0 °C / Inert atmosphere 1.2: 20 - 50 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 2 h / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: Boc-Arg(Boc)2OH With benzotriazol-1-ol; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 2h; Inert atmosphere; Stage #2: acycloguanosine With dmap In N,N-dimethyl-formamide at 20 - 50℃; Inert atmosphere; | 2.2. Prodrug synthesis General procedure: Prodrug synthesis Amino acid ester prodrugs of ACV - ACV-Arg, ACV-Gly, ACV-Ile, ACV-Phe, ACV-Trp and ACV-Val, were prepared by a two-step synthesis as outlined in Scheme 1 starting from ACV using a method adapted from the literature [15,19,20]. Briefly, N-Boc protected l-arginine, l-glycine, l-isoleucine, l-phenylalanine, l-tryptophan or l-valine (3.55 * 10-3 mol), DIC (0.48 g, 3.80 * 10-3 mol) and HOBt (0.48 g, 3.55 * 10-3 mol) were dissolved in DMF (10 ml) under N2. The mixture was stirred for 2 h at 0 °C, and was then added dropwise to a solution of ACV (0.8 g, 3.55 * 10-3 mol) and DMAP (0.005 g, 0.4 * 10-3 mol) in DMF (110 ml) at room temperature. The solution was stirred continuously and warmed up to 50 °C. The reaction ran overnight. DMF was removed by rotary evaporation using a Rotavapor (Büchi Labortechnik AG; Flawil, Switzerland) and the residue was placed on a silica gel column and eluted with 8:1:0.1-15:1:0.1 mixture of dichloromethane, methanol and acetic acid to give the desired intermediate as a white solid. De-protection of the intermediates was carried out using a 1:1 mixture of dichloromethane and trifluoroacetic acid (30 ml) in an ice bath for 2 h. After removal of the solvent by rotary evaporation, the resulting oil was then added dropwise to vigorously stirred cold diethyl ether (20 ml) and ACV-X prodrug was immediately precipitated. The precipitate was filtered with a Büchner funnel and then washed with cold diethyl ether (20 ml). The filter cake was dissolved in 10 ml of H2O and lyophilized for 30 h using an Alpha 2-4 LD Plus freeze dryer (Martin Christ GmbH; Osterode am Harz, Germany). A hygroscopic, fluffy white solid with a purity of >95% (HPLC-UV, wavelength 254 nm) was obtained. The 1H NMR spectrum of each prodrug was recorded on a Varian Gemini NMR spectrometer (300 MHz) at ambient temperature. The high resolution mass spectrum of each prodrug was acquired using an API QSTAR Pulsar, ESI-Qtof mass spectrometer (Applied Biosystems; Rotkreuz, Switzerland). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide; at 20 - 55℃; for 18h; | Step 1 : 7-([l,l'-biphenyl]-4-ylmethyl)-2-amino-9-((2-hydroxyethoxy)methyl)-9H-purin-7- ium-6-olate The alkylation of acycloguanosine (Sigma- Aldrich No. A4669) was carried out following general procedure B. LC-MS method 1 Rt = 0.95 mins; MS m/z [M+H]+ 392.2. [0091] Method B: In a 2-dram vial, a 0.1 M solution of GMP or GDP triethyl- or tributylammonium salt in DMSO was treated with the bromide alkylating reagent (4 equiv.). The solution was stirred at room temperature or 55 C for 18 h and then direclty subjected to purification by reversed phase column chromatography (ISCO Teledyne C18aq. Eluent: 0.1 M triethylammonium bicarbonate (pH=8.0) to MeCN 0-100%). Fractions that contained the desired product were pooled, and the solvent was removed by lyophilzation to obtain the pure products as tributylammonium salts as colorless solids or foams. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; isopropyl alcohol; | 0.384 g of Acyclovir (1 .705 mmol) and 0.298 g of L-<strong>[3081-61-6]theanine</strong> (1 .71 1 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 34a, while the FTIR spectrum is shown in Figure 34b. The DSC melting endotherm of the product was characterized by a peak maximum at 1 19C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | 13 (124?mg; 0.3?mmol) and DCC (68?mg; 0.3?mmol) were dissolved in 0.3?mL DMF and cooled to 0?C. The reaction was stirred at this temperature for 1?h during which time a white precipitate was formed. A solution of acyclovir (50?mg; 0.2?mmol) and DMAP (10?mg; 0.1?mmol) in 1.5?mL DMF was then added. The suspension was warmed to room temperature and stirred for 24?h during which time the suspension changed from orange-brown to a brown-purple colour. The suspension was filtered and the filtrate washed with the minimum of DCM. The liquor was concentrated and the residue purified by flash column chromatography (95:5 CHCl3:MeOH ? 9:1 CHCl3:MeOH) to give the title compound as a brown solid (123?mg; 96%). Rf (CHCl3:CH3OH, 9:1): 0.46. [alpha]D25 (CHCl3; c = 0.98): +7.20. upsilonmax (thin film): 3311, 3107, 2982, 2941, 1696, 1602, 1534, 1484, 1371, 1254, 1157, 1102, 1057, 845, 758. deltaH (CD3OD, 300?MHz): 1.41 (3H, d, J?=?6.8), 1.49-1.63 (18H, m), 2.88-3.03 (2H, m), 3.71-3.80 (2H, m), 4.14-4.22 (2H, m), 4.41-4.48 (1H, m), 5.23-5.28 (1H, m), 5.49 (2H, s), 7.88 (1H, s). deltaC (CD3OD, 75?MHz): 22.2, 28.5, 29.1, 36.1, 56.2, 57.5, 65.2,65.2, 68.7, 68.7, 74.1, 79.9, 84.2, 118.7, 140.2, 153.2, 156.0, 156.9, 159.6, 170.3, 172.0, 206.5. MS: C24H38N7O8S m/z (ES+) 584.1 [M + Na+]. HRMS: Calculated C24H38N7O8SNa: 584.2497, found: 584.2503. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | General procedure: A mixture of bile acids (0.480 g, 2 mmol) and DCC (0.191 g,2 mmol) in DMF was stirred for 1 h at 0 C under nitrogen atmosphere (Fig. 1). A solution of ACV (0.225 g, 1 mmol)and DMAP (0.244 g, 2 mmol) in DMF was added to the reaction mixture and stirred for 24 h. Then DMF was evaporated in vacuo, and the residue was purified on silica gel chromatography, using gradient of MeOH/CH2Cl2 (1:4).For the identification of the three analogues NMR and mass spectrometry were applied. The 1H, 13C NMR spectra were obtained on a Bruker Avance DRX-500 spectrometer, operating at 500.13 MHz. The ESI mass spectra were obtained on Bruker EVOQ Elite ER TQ. The IR spectra were obtainedon a Thermo Scientific Nicolet iS10 FT-IR. ACV-cholate (500 MHz NMR, DMSO-d6, 25 C): delta0.69 (3H, s, H-18), 0.86 (3H, s, H-19), 1.01 (3H, s, H-21),2.53 (4H, d, J = 3.5 Hz, CH2), 3.23 (1H, m, 3alpha-OH),3.42 (1H, s, 7alpha-OH), 4.01 (1H, s, 12alpha-OH); 4.21 (m, 2H,CH2OC(O), ACV), 5.01 (s, 2H, N-CH2-O, ACV), 6.43 (s,2H, 2-NH2, ACV), 7.13 (s, 1H, H-8, ACV), 10.78 (s, 1H,ACV-NH); 13C-NMR (500 MHz, DMSO-d6, 25 C) (35.25--CH2), (31.0 -CH2), (71.4-CH), (39.9 -CH2), (41.9 -C),(35.7 -CH2), (70.8 -CH), (41.7 -CH), (26.6 -CH), (34.8-C), (27.6 -CH2), (72 -CH), (46.2 -C), (39.85 -CH), (23.1-CH2), (28.9 -CH2), (46.4 -CH), (12.7 -CH3), (22.9 -CH3),(35.25 -CH), (17.3 -CH3), (30.9 -CH2), (30.8 -CH2), (62.9-C Acycl), (67.0 -C Acycl), (116.9 -C Acycl), (137.9 -CAcycl), (151.8 -C Acycl), (154.3 -C Acycl), (157.1 -CAcycl), (173.6 -C); IR, functional groups: OH (3334 cm-1),C-H (2931 cm-1), C-H (2866 cm-1), ester group (1688 cm-1), NH2(1628 cm-1), C-H (1487 cm-1), C-H(1447 cm-1), Ether C-O (1308 cm-1), N-H (1221 cm-1);ESI MS: [M+H]+ was found 616, calculated 615.78;yield = 0.117 g (19%, white powder). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | General procedure: A mixture of bile acids (0.480 g, 2 mmol) and DCC (0.191 g,2 mmol) in DMF was stirred for 1 h at 0 C under nitrogen atmosphere (Fig. 1). A solution of ACV (0.225 g, 1 mmol)and DMAP (0.244 g, 2 mmol) in DMF was added to the reaction mixture and stirred for 24 h. Then DMF was evaporated in vacuo, and the residue was purified on silica gel chromatography, using gradient of MeOH/CH2Cl2 (1:4).For the identification of the three analogues NMR and mass spectrometry were applied. The 1H, 13C NMR spectra were obtained on a Bruker Avance DRX-500 spectrometer, operating at 500.13 MHz. The ESI mass spectra were obtained on Bruker EVOQ Elite ER TQ. The IR spectra were obtainedon a Thermo Scientific Nicolet iS10 FT-IR |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | General procedure: A mixture of bile acids (0.480 g, 2 mmol) and DCC (0.191 g,2 mmol) in DMF was stirred for 1 h at 0 C under nitrogen atmosphere (Fig. 1). A solution of ACV (0.225 g, 1 mmol)and DMAP (0.244 g, 2 mmol) in DMF was added to the reaction mixture and stirred for 24 h. Then DMF was evaporated in vacuo, and the residue was purified on silica gel chromatography, using gradient of MeOH/CH2Cl2 (1:4).For the identification of the three analogues NMR and mass spectrometry were applied. The 1H, 13C NMR spectra were obtained on a Bruker Avance DRX-500 spectrometer, operating at 500.13 MHz. The ESI mass spectra were obtained on Bruker EVOQ Elite ER TQ. The IR spectra were obtainedon a Thermo Scientific Nicolet iS10 FT-IR |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With [(NH-C3H5)Tr(NHP(iPr)2)2CoCl2]; In toluene; at 80℃;Inert atmosphere; Green chemistry; | In a 250 ml three-necked flask, guanine (6.00 g, 39.7 mmol) was added in order.2-(Hydroxymethylmethoxy)-ethanol (4.328 g, 47.64 mmol), [(NH-C3H5)Tr(NHP(iPr)2)2CoCl2] (0.468 g, 1.0 mmol),Toluene (80 mL); heated to 80 C under nitrogen atmosphere for 24 hours.At the end of the reaction, the temperature was lowered to room temperature, quenched with water, and extracted repeatedly with toluene.The solvent was dried under reduced pressure and dried. Recrystallization from ethanol gave a white solid. Yield: 85%. Acyclovir (7.58 g) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 48h; | Triethylamine (15 mL, 108 mmol, 8 equiv.) was added dropwise to asolution of acyclovir (3.04 g, 13.5 mmol, 1 equiv.) in dry DMF (400 mL)at 0 C. 4-nitrophenyl chloroformate (6.26 g, 31.1 mmol, 2.3 equiv.)dissolved in dry DCM (20 mL) was added dropwise to the reaction mixtureat 0 C, upon which the reaction was allowed to heat up to roomtemperature. The reaction was stirred at room temperature for two days,the volume was reduced in vacuo, and the solution filtered. The precipitatewas washed with DCM and the product isolated as an off-whitesolid (2.73 g, 7.01 mmol, 52%) 1H NMR (400 MHz, CDCl3) delta 8.31 (d,J=9.1 Hz, 2H), 7.87 (s, 1H), 7.53 (d, J=9.1 Hz, 2H), 6.54 (s, 2H), 5.40(s, 2H), 4.33 (s, 2H), 3.77 (s, 2H). 13C NMR (100 MHz, CDCl3) delta 156.78,155.21, 153.96, 152.01, 151.45, 145.18, 137.75, 125.48, 122.60,116.47, 71.84, 67.80, 66.16. HRMS (ESI): calc. [C15H16N6O7+H+]:391.0997; found 391.0997, calc. [C15H16N6O7+Na+]: 413.0816; found413.0814, calc. [C15H16N6O7+K+]: 429.0556; found 429.0561. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: (S)-N-(benzyloxycarbonyl)valine; acycloguanosine With 4-dimethylaminopyridine In N,N-dimethyl-formamide at 5℃; Stage #2: With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 10℃; for 30h; | 1.1 1) synthesis of CBZ-L-valine-acyclovir 44.8 g of N,N-dimethylformamide was sequentially added to a 200 ml reaction flask.N-benzyloxycarbonyl-L-proline 7.7 g, 4-dimethylaminopyridine 0.43 g andAcyclovir 5.6g, stirred, cooled to 5 ° C and then addedN,N-dicyclohexylcarbodiimideThe solution of N,N-dimethylformamide was 23.1 g, and the addition was completed in 1 h. Reaction 2h.Then, the temperature was raised to 10 ° C for 21 h.Additional N-benzyloxycarbonyl-L-proline 0.78g, 4-dimethylaminopyridine 0.045g andN,N-dicyclohexylcarbodiimide 1.02 g, temperature control 10 ° C, continued reaction for 6 h.Filtration, washing and drying gave CBZ-L-valine-acyclovir 10.0 g in a yield of 88%. |
82% | With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 24h; | (3) Preparation of compound 3c: The operation was as follows: Compound 1 (acyclovir 225.2 mg, 1.0 mmol), N-Cbz-L-valine 2c (301.5 mg, 1.2 mmol), and EDCI (286.8 mg, 1.5 mmol) were added to a dry 25 mL reaction flask in sequence. mmol), DMAP (12.2 mg, 0.1 mmol) and DMF (2.0 mL), and the reaction mixture was allowed to react at room temperature for 24 h. After the reaction is complete, add cold water to the reaction solution to precipitate the product, filter with suction, wash with water three times, take the filter cake and dry to obtain a crude product, transfer the crude product to a 100 mL round-bottomed flask, add silica gel (300-400 2 g, dissolved in DCM, dried by a rotary evaporator and a circulating water vacuum pump, the sample was subjected to a dry loading method, separated and collected by a silica gel column with THF as the eluent to obtain the target compound 3c ( 376.7mg, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | To a stirred solution of heptadecanoic acid (2.0 g, 0.0073 mol) in DMF (20 mL) was added DMAP (1.35 g, 0.011 mol) and EDC.HC1 (2.83 g, 0.0147 mol) at 0C. The resulting reaction mixture was stirred for lh at rt, and then compound A-5 (3.5 g, 0.0188 mol) was added slowly at 0C. The resulting reaction mixture was stirred at room temperature for 72h. The reaction mass was filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel (100-200 mesh) chromatography to afford Compound 3 (0.343 g, 10%) as an off-white solid. MS (ESI) m/z 478.50 [M+H]+; 1H NMR (400 MHz, DMSO-i) delta 10.62 (s, 1H), 7.81 (s, 1H), 6.50 (s, 2H), 5.34 (s, 2H), 4.09-4.07 (m, 2H), 3.66-3.64 (m, 2H), 2.23-2.20 (m, 2H), 1.47-1.44 (m, 2H), 1.23 (m, 26H), 0.87-0.83 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 16h; | 3.2.3. General Method for the Synthesis of ACV Derivatives General procedure: A mixture of the corresponding [2,6-dioxo-3-[(2-benzoylphenoxy)ethyl)]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (0.5 mmol) and ACV (0.5 mmol) was twice evaporated in DMF, then dissolved in DMF (5 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.2 eq) and dimethyl-aminopyridine (0.5 eq) were added. The reaction mixture was allowed to mix for 16 h at room temperature. The progress of the reaction was monitored by TLC. The solvent was then evaporated and the residue was purified by column chromatography on silica gel eluting with a 9:1 chloroform-methanol mixture. The yield of the target products was 26-39%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 16h; | 3.2.3. General Method for the Synthesis of ACV Derivatives General procedure: A mixture of the corresponding [2,6-dioxo-3-[(2-benzoylphenoxy)ethyl)]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (0.5 mmol) and ACV (0.5 mmol) was twice evaporated in DMF, then dissolved in DMF (5 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.2 eq) and dimethyl-aminopyridine (0.5 eq) were added. The reaction mixture was allowed to mix for 16 h at room temperature. The progress of the reaction was monitored by TLC. The solvent was then evaporated and the residue was purified by column chromatography on silica gel eluting with a 9:1 chloroform-methanol mixture. The yield of the target products was 26-39%. [2,6-Dioxo-3-[(2-benzoylphenoxy)ethyl]-6-methyl-3,6-dihydropyrimidine-1(2H)-yl]acetate of ACV (2a). Purified on a silica gel column using chloroform:methanol (9:1) as eluent in 33% yield. Rf 0.57 (chloroform:methanol, 95:5).1H-NMR (CD3OD:CDCl3): 1.97 (3H, s, CH3), 3.88-3.91 (2H, m, CH2O), 4.04-4.07 (2H, m, CH2N), 4.24-4.37 (4H, m, 2 × CH2CH2C=O), 4.58 (2H, s, NCH2C=O), 5.29 (1H, d, H5Ura), 5.64 (2H, s, OCH2N), 7.06-7.12 (2H, m, Ph), 7.24-7.28 (1H, d, Ph), 7.40-7.52 (3H, m, Ph), 7.54-7.60 (1H, m, Ph), 7.73-7.76 (2H, d, Ph), 9.02 (1H, s, H8).13C-NMR (DMSO-d6): 19.9, 41.9, 44.6, 64.3, 66.1, 66.7, 72.3, 100.6, 113.25, 117.0, 121.7, 129.0, 129.1, 129.2, 129.7, 132.3, 134.1, 136.9, 138.0, 151.6, 151.9, 153.9, 154.6, 155.6, 155.6, 157.2, 161.0, 168.3, 196. HRMS:m/z[M + H]+calcd for C30H29N7O8: 616.2150, found: 616.2136. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 24h; | (6) Preparation of compound 3f: The operation was as follows: Compound 1 (acyclovir 225.2 mg, 1.0 mmol), N-Cbz-L-proline 2f (299.1 mg, 1.2 mmol), and EDCI (286.8 mg, 1.5 mmol) were added to a dry 25 mL reaction flask in sequence. mmol), DMAP (12.2 mg, 0.1 mmol) and DMF (2.0 mL), and the reaction mixture was allowed to react at room temperature for 24 h. After the reaction is complete, add cold water to the reaction solution to precipitate the product, filter with suction, wash with water three times, take the filter cake and dry to obtain a crude product, transfer the crude product to a 100 mL round-bottomed flask, add silica gel (300-400 2g, dissolved in DCM, dried by a rotary evaporator and a circulating water vacuum pump, the sample was taken by dry method, and the target compound 3f ( 389.8mg, 85%). |
Tags: 59277-89-3 synthesis path| 59277-89-3 SDS| 59277-89-3 COA| 59277-89-3 purity| 59277-89-3 application| 59277-89-3 NMR| 59277-89-3 COA| 59277-89-3 structure
A311430[ 69657-51-8 ]
Sodium 2-amino-9-((2-hydroxyethoxy)methyl)-9H-purin-6-olate
Reason: Free-salt
A147424[ 261506-45-0 ]
Sodium 2-((2-amino-6-oxo-1H-purin-9(6H)-yl)methoxy)ethanolate dihydrate
Reason: Free-salt
A2667493[ 69657-51-8 ]
Sodium 2-amino-9-((2-hydroxyethoxy)methyl)-9H-purin-6-olate
Reason: Free-salt
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H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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