6-(Benzyloxy)-9-((1S,3S)-4-(benzyloxy)-3-((benzyloxy)methyl)-2-methylenecyclopentyl)-N-((4-methoxyphenyl)diphenylmethyl)-9H-purin-2-amine Chemical Properties

Density 

1.19

storage temp. 

Keep in dark place,Inert atmosphere,Room temperature

pka

3.08±0.30(Predicted)

InChI

InChI=1S/C53H49N5O4/c1-38-46(36-60-33-39-18-8-3-9-19-39)48(61-34-40-20-10-4-11-21-40)32-47(38)58-37-54-49-50(58)55-52(56-51(49)62-35-41-22-12-5-13-23-41)57-53(42-24-14-6-15-25-42,43-26-16-7-17-27-43)44-28-30-45(59-2)31-29-44/h3-31,37,46-48H,1,32-36H2,2H3,(H,55,56,57)/t46-,47-,48-/m0/s1

InChIKey

OXHGMTPGAFKZHK-QQVWZEJNSA-N

SMILES

N1C2C(=NC(NC(C3=CC=C(OC)C=C3)(C3=CC=CC=C3)C3=CC=CC=C3)=NC=2OCC2=CC=CC=C2)N([C@H]2C[C@H](OCC3=CC=CC=C3)[C@@H](COCC3=CC=CC=C3)C2=C)C=1

CAS DataBase Reference

142217-80-9(CAS DataBase Reference)

Safety Information

HS Code 

29335990

6-(Benzyloxy)-9-((1S,3S)-4-(benzyloxy)-3-((benzyloxy)methyl)-2-methylenecyclopentyl)-N-((4-methoxyphenyl)diphenylmethyl)-9H-purin-2-amine Usage And Synthesis

Chemical Properties

White powder

Definition

6-(Benzyloxy)-9-((1S,3S)-4-(benzyloxy)-3-((benzyloxy)methyl)-2-methylenecyclopentyl)-N-((4-methoxyphenyl)diphenylmethyl)-9H-purin-2-amine is also known as Entecavir Impurity 3. Entecavir belongs to the family of medicines called antivirals. Entecavir is used to treat liver infections caused by hepatitis B virus.

Synthesis

Step (1) Preparation of Intermediate IX: In a 20L sealed and nitrogen-filled reaction flask, 3.8kg of zinc powder and 10wt% hydrochloric acid (12.5L) were added sequentially and stirred at room temperature for 10-15 minutes, followed by diafiltration, and washed with purified water to neutral. Next, it was washed with 3.0 L of ethanol and 4.5 L of tetrahydrofuran and dried under vacuum at 40±2°C for 4-4.5 hours to obtain about 3 kg of activated zinc powder. The activated zinc powder needs to be sealed and stored under vacuum for backup. In a 100L reactor, after evacuation and replacement of nitrogen, add 40L of tetrahydrofuran dried by A-type molecular sieve. Under stirring, 3 kg of dry activated zinc powder and 1.3 L of dibromomethane were added, and the mixture was cooled to -70~-55°C. Then 1140 ml of titanium tetrachloride was added dropwise with continuous stirring for 1 hour. The temperature was then increased and the reaction was carried out for 48±0.5 h. The reaction was kept sealed during the reaction. The prepared enolization reagent was cooled to -20°C and a solution of 1.2 kg of Intermediate VIII dissolved in 20 L of dichloromethane was slowly added dropwise at -30°C. After the dropwise addition, the temperature was raised to 15-20 °C and the reaction was continued with stirring for 180 ± 10 min. The end point of the reaction was monitored by TLC. The reaction solution was transferred to a 200 L reaction vessel (containing a mixed system of 30 L of dichloromethane, 100 L of pure water and 10 kg of sodium bicarbonate) and stirred for 60-70 min. The mixture was separated using a stainless steel centrifuge and the filter cake was washed twice with dichloromethane (16L). The filtrates were combined and the aqueous phase was subjected to secondary extraction with dichloromethane (16L x 2). The combined organic phases were concentrated to dryness under vacuum at 25-30°C to afford 6-benzyloxy-9-((1S,3R,3S)-4-benzyloxy-3-benzyloxymethyl-2-methylenecyclopentyl)-N-((4-methoxyphenyl)diphenylmethyl)-9H-purin-2-amine (Intermediate IX) as a yellow powder in a single-step yield of 88% and purity of 93.6%.

References

[1] Patent: CN108148061, 2018, A. Location in patent: Paragraph 0028; 0029; 0030; 0031; 0032; 0033; 0034

6-(Benzyloxy)-9-((1S,3S)-4-(benzyloxy)-3-((benzyloxy)methyl)-2-methylenecyclopentyl)-N-((4-methoxyphenyl)diphenylmethyl)-9H-purin-2-amine(142217-80-9)Related Product Information

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