91702-61-3

Usage

Uses

Used in Pharmaceutical Industry:
Acyclovir IMpurity C is used as a reference standard for quality control and analytical testing in the pharmaceutical industry. It helps ensure the purity, potency, and safety of the antiviral drug Acyclovir, which is used to treat various viral infections, including herpes simplex and varicella-zoster virus.
Additionally, Acyclovir IMpurity C may be used in research and development for the study of the synthesis, properties, and potential applications of Acyclovir and its related compounds. This can contribute to the advancement of antiviral therapies and the development of new drugs to combat viral infections.

Synthetic route

7-<(2-acetoxyethoxy)methyl>-N2-acetylguanine (91702-60-2) → 7-(2-Hydroxyethoxymethyl)guanine (91702-61-3)

Conditions	Yield
With methylamine at 80℃; for 0.5h;	82%

7-[[2-(p-methoxyphenyloxy)ethoxy]methyl]guanine (374678-34-9) → 7-(2-Hydroxyethoxymethyl)guanine (91702-61-3)

Conditions	Yield
With ammonium cerium(IV) nitrate In water; acetonitrile at 0 - 25℃; for 1h;	70%
With NH4Ca(NO3)3 In water; acetonitrile	70%

2-acetoxyethyl acetoxymethyl ether (59278-00-1) + acetic anhydride (108-24-7) + G (118-00-3) → acycloguanosine (59277-89-3) + 7-(2-Hydroxyethoxymethyl)guanine (91702-61-3)

Conditions	Yield
With sodium hydroxide; toluene-4-sulfonic acid 1.) 100 deg C, 20 h, 2.) room temperature, overnight; Yield given. Multistep reaction;	A n/a B 0.5%

2-amino-1,9-dihydro-6H-purin-6-one (73-40-5) → 7-(2-Hydroxyethoxymethyl)guanine (91702-61-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: (NH4)2SO4 / 24 h / Heating 2: 3.54 g / acetonitrile / 7 h / 25 °C 3: 88 percent / dimethylformamide / 8 h / 25 °C 4: 82 percent / dimethylformamide / 25 °C 5: 70 percent / ceric ammonium nitrate / acetonitrile; H2O / 1 h / 0 - 25 °C View Scheme

6-Trimethylsilanyloxy-9H-purin-2-ylamine (890044-83-4) → 7-(2-Hydroxyethoxymethyl)guanine (91702-61-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 3.54 g / acetonitrile / 7 h / 25 °C 2: 88 percent / dimethylformamide / 8 h / 25 °C 3: 82 percent / dimethylformamide / 25 °C 4: 70 percent / ceric ammonium nitrate / acetonitrile; H2O / 1 h / 0 - 25 °C View Scheme

7-[(2-chloroethoxy)methyl]guanine (146828-69-5) → 7-(2-Hydroxyethoxymethyl)guanine (91702-61-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 82 percent / dimethylformamide / 25 °C 2: 70 percent / ceric ammonium nitrate / acetonitrile; H2O / 1 h / 0 - 25 °C View Scheme

9-(triphenylmethyl)guanine (374678-33-8) → 7-(2-Hydroxyethoxymethyl)guanine (91702-61-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 88 percent / dimethylformamide / 8 h / 25 °C 2: 82 percent / dimethylformamide / 25 °C 3: 70 percent / ceric ammonium nitrate / acetonitrile; H2O / 1 h / 0 - 25 °C View Scheme

2,9-diacetylguanine (3056-33-5) → 7-(2-Hydroxyethoxymethyl)guanine (91702-61-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) p-toluenesulfonic acid / 1.) AcOH, 2.) toluene, reflux, 16 h 2: 82 percent / aq. MeNH2 / 0.5 h / 80 °C View Scheme
Multi-step reaction with 2 steps 1: 22 percent / p-toluenesulfonic acid / 1.) 120-125 deg C, 2.) 150 deg C, 45 min 2: 82 percent / aq. MeNH2 / 0.5 h / 80 °C View Scheme

7-(2-Hydroxyethoxymethyl)guanine (91702-61-3) → 7-[(2-chloroethoxy)methyl]guanine (146828-69-5)

Conditions	Yield
With thionyl chloride In N,N,N,N,N,N-hexamethylphosphoric triamide at 20℃; for 24h;	61.9%

7-(2-Hydroxyethoxymethyl)guanine (91702-61-3) + methyl iodide (74-88-4) → 7-(2-Hydroxyethoxymethyl)-9-methylguaninium Hydroiodide (124321-53-5)

Conditions	Yield
In N,N-dimethyl-formamide at 20℃;	31%

N-ethyl-N-(2,3-dihydro-1,4-phthalazinedion-6-yl)-{4-[1,5-bis(4-N,N-dimethylaminophenyl)-5-(4-N-ethyl-N-(2,3-dihydro-1,4-phthalazinedion-6-yl)aminophenyl)-2,4-pentadienylidene]-2,5-cyclohexadien-1-ylidene}ammonium perchlorate (760974-67-2) + 7-(2-Hydroxyethoxymethyl)guanine (91702-61-3) → C61H63N13O7

Conditions	Yield
Stage #1: 7-(2-Hydroxyethoxymethyl)guanine With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 3h; Stage #2: N-ethyl-N-(2,3-dihydro-1,4-phthalazinedion-6-yl)-{4-[1,5-bis(4-N,N-dimethylaminophenyl)-5-(4-N-ethyl-N-(2,3-dihydro-1,4-phthalazinedion-6-yl)aminophenyl)-2,4-pentadienylidene]-2,5-cyclohexadien-1-ylidene}ammonium perchlorate In dimethyl sulfoxide; mineral oil at 20℃; for 2h;

Upstream product

• 3056-33-5 2,9-diacetylguanine 
• 374678-33-8 9-(triphenylmethyl)guanine 
• 73-40-5 2-amino-1,9-dihydro-6H-purin-6-one 
• 374678-34-9 7-[[2-(p-methoxyphenyloxy)ethoxy]methyl]guanine 
• 59278-00-1 2-acetoxyethyl acetoxymethyl ether 
• 108-24-7 acetic anhydride 
• 118-00-3 G 
• 91702-60-2 7-<(2-acetoxyethoxy)methyl>-N²-acetylguanine 
• 146828-69-5 7-[(2-chloroethoxy)methyl]guanine 
• 890044-83-4 6-Trimethylsilanyloxy-9H-purin-2-ylamine 

Relevant academic research and scientific papers

Antiviral compounds

This invention relates to purine compounds of formula (I): R1 is NH2 or OH; R2 is H or NH2; R3 is H or alkyl; each of m and n, independently, is 1, 2, 3, or 4; X is O, S, or NH; and Y is H, halogen, ORa, P(O)(ORa)2, or P(O)(ORa)(ORb), in which Ra is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, and Rb is wherein A is adenine, guanine, cytosine, uracil, or thymine; Rc is H or OH; Rd is H or alkyl; Re is H, alkyl, or 5-ethylidene-(3,4-dialkoxyl)-furan-2-one; provided that if R1 is NH2, R2 is H; and if R1 is OH, R2 is NH2.

Design, synthesis, and biological evaluation of novel nucleoside and nucleotide analogues as agents against DNA viruses and/or retroviruses

A novel strategy was developed for the synthesis of N7-purine acyclic nucleosides 9 and 14. The key step involved the reaction between [2-(p- methoxyphenyloxy)ethoxy]methyl chloride and N9-tritylated nucleobases 6 or 11 followed by concomitant self-detritylation. N7-Guanine acyclic nucleoside 9 exhibited antiviral activity, but was phosphorylated by both HSV and Vero cell thymidine kinases. Thus, it showed more potent cellular toxicity than acyclovir (2). N7-Adenine acyclic nucleoside 14 was found to be an excellent antiviral agent as well as a good inhibitor of calf mucosal adenosine deaminase. This inhibitory property allows for a greater expression of antiviral activity of antiviral agents, such as N9-adenine acyclic nucleoside 1 and ara-A (3). Compound 14 was phosphorylated neither by herpes simplex virus (HSV) thymidine kinase nor by Vero cell thymidine kinase, yet it enhanced the rate constant for the monophosphorylation of acyclovir (2) by HSV thymidine kinase. Consequently, the combination of acyclovir (2) and 14 exhibited greater antiviral activity than acyclovir alone. 7-[2(Phosphonomethoxy)ethyl] adenine (20) was also synthesized. The key step involved the reaction of 9-(2-cyanoethyl)adenine (15) with methyl iodoacetate in the presence of lithium 2,2,6,6-tetramethylpiperidine in THF. Unlike 9-[2- (phosphonomethoxy)ethyl] adenine (PMEA, 4), the N7-isomer 20 was not phosphorylated effectively by 5-phosphoribosyl 1-pyrophosphate synthetase (PRPP synthetase). Thus, it did not exhibit pronounced antiviral activity. Dinucleotide 5′-monophosphate 24 and its butenolide ester 25 were also synthesized. Compound 24 showed substrate activity toward PRPP synthetase and exhibited notable activity against DNA viruses. The antiviral activity of the ester derivative 25 was found to be higher than that of the parent molecule 24. Dinucleotide 5′-monophosphate 24 is suseptible to degradation by snake venom and spleen phosphodiesterases. However, its respective butenolide ester derivative 25 was completely resistant to snake venom and spleen enzymes. Butenolide ester derivatives 28 and 29 were also synthesized and exhibited notable anti-DNA virus and anti-retrovirus activity in vitro. Compounds 2, 4, 9, 14, 20, 24, 25, and 28 were also evaluated for their inhibitory effect on HSV-1-induced mortality in NMRI mice. N7-adenine acyclic nucleoside 14 [LD50 (intraperitoneal, ip) 950 mg/kg], nucleotide-containing butenolide 25 [LD50 (ip) 675 mg/kg], and butenolide 28 [LD50 (ip) 710 mg/kg] were found to be potent anti-HSV-1 agents in vivo. In addition, butenolide 28 efficiently decreased tumor formation induced by Moloney murine sarcoma virus (MSV) in NMRI mice while significantly increasing the survival time of MSV-infected mice.

Synthesis of 9-(2-hydroxyethoxymethyl)guanine (acyclovir) from guanosine

A convenient synthesis of 9-(2-hydroxyethoxymethyl)guanine (acyclovir) from guanosine by chemical transpurination was developed. The isomerization of the 7-isomer to the desired 9-isomer and the purification of the 9- isomer was achieved simply by concentration, heating and further crystallization.