Preparation method of (R)-(+)-9-(2-hydroxypropyl) adenine

A technology of hydroxypropyl and adenine, which is applied in the field of --9-adenine and its preparation, and can solve problems such as limiting industrial value

Active Publication Date: 2015-06-17
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] J.Am.Chem.Soc.1996,118,7420 reported the use of achiral propylene oxide as a raw material to prepare (R)-(+)-9-(2-hydroxypropyl)adenine in five steps In the method of nucleophilic substitution between propylene oxide and azide group, the self-made selen / Cr ligand was used together to obtain chiral amino alcohols with enantioselectivity as high as 97%. High stability, but the key step requires the use of self-made selen / Cr reagents, which limits the industrial value of this route

Method used

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  • Preparation method of (R)-(+)-9-(2-hydroxypropyl) adenine
  • Preparation method of (R)-(+)-9-(2-hydroxypropyl) adenine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Add 1mmol of 6-chloropurine and 3mmol of potassium carbonate successively to 6mL of DMF (dimethylformamide, the same below), stir for 10 minutes under ice-bath conditions, add bromoacetone 0.168mL (2mmol), and react for 1 hour under ice-bath. Add appropriate amount of water, extract 3 to 5 times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and separate by column chromatography to obtain 6-chloro-9-(acetonyl)purine. Yield 96%.

[0036] Add 5 mol% prolinol ligand and 1 mol% ruthenium catalyst into 0.5 mL acetonitrile, stir at room temperature for 1 hour, then add HCOONa·2H 2 O (1mmol), after stirring for ten minutes, add 0.1mol of 6-chloro-9-(acetonyl)purine, react at room temperature for 24 hours, separate and purify by column chromatography to obtain 6-chloro-9-(acetonyl)purine, produce Yield 12%, enantioselectivity 98%.

[0037] At 0°C, add 0.5mmol of 6-chloro-9-(acetonyl)purine into 50ml of newly prepared ammonia methanol solution, react ...

Embodiment 2

[0039] Add 1 mmol of 6-chloropurine and 3 mmol of potassium carbonate to 6 mL of DMF in sequence, stir for 10 minutes under ice-bath conditions, add bromoacetone 0.168 mL (2 mmol), react for 1 hour under ice-cooling, add appropriate amount of water, and use ethyl acetate Extract 3 to 5 times, dry the organic phase with anhydrous sodium sulfate, and separate by column chromatography to obtain 6-chloro-9-(acetonyl)purine. Yield 96%.

[0040] Add 5 mol% prolinol ligand and 5 mol% ruthenium catalyst into 0.5 mL acetonitrile, stir at room temperature for 1 hour, then add HCOONa·2H 2 O (1mmol), after stirring for ten minutes, add 0.1mol of 6-chloro-9-(acetonyl)purine, room temperature for 24 hours, column chromatography separation, get 6-chloro-9-(acetonyl)purine, yield 99%, enantioselectivity 98%.

[0041] At 0°C, add 0.5mmol of 6-chloro-9-(acetonyl)purine into 50ml of newly prepared ammonia methanol solution, react at 60°C for 48 hours, and separate by column chromatography to o...

Embodiment 3

[0043] Add 1 mmol of 6-chloropurine and 3 mmol of potassium carbonate to 6 mL of DMF in sequence, stir for 10 minutes under ice-bath conditions, add bromoacetone 0.168 mL (2 mmol), react for 1 hour under ice-cooling, add appropriate amount of water, and use ethyl acetate Extract 3 to 5 times, dry the organic phase with anhydrous sodium sulfate, and separate by column chromatography to obtain 6-chloro-9-(acetonyl)purine. Yield 96%.

[0044] Add 2 mol% prolinol ligand and 5 mol% ruthenium catalyst into 0.5 mL acetonitrile, stir at room temperature for 1 hour, then add HCOONa·2H 2 O (1mmol), after stirring for ten minutes, add 0.1mol of 6-chloro-9-(acetonyl)purine, room temperature for 24 hours, column chromatography separation, get 6-chloro-9-(acetonyl)purine, yield 95%, enantioselectivity 45%.

[0045] At 0°C, add 0.5mmol of 6-chloro-9-(acetonyl)purine into 50ml of newly prepared ammonia methanol solution, react at 60°C for 48 hours, and separate by column chromatography to o...

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Abstract

The invention discloses a preparation method of (R)-(+)-9-(2-hydroxypropyl) adenine, which is a key intermediate for tenofovir disoproxil fumarate. The method comprises the following steps: (1) reacting 6-chloropurine and bromopropanone to obtain 6-chloro-9-(acetonyl)-purine; (2) performing an asymmetric hydrogenation reduction reaction of the resultant 6-chloro-9-(acetonyl)-purine to obtain (R)-(+)-6-chloro-9-(2-hydroxypropyl) adenine; and (3) performing an aminolysis reaction of the resultant (R)-(+)-6-chloro-9-(2-hydroxypropyl) adenine to obtain (R)-(+)-9-(2-hydroxypropyl) adenine. An achiral compound, cheap and easy to obtain, is taken as a raw material in the method; the reaction steps are small; the reaction is easy to deal with; the enantioselectivity of the product is high; and the yield is high, and thus the preparation method has industrialization value.

Description

technical field [0001] The invention belongs to the fields of chemistry and medicine, and in particular relates to (R)-(+)-9-(2-hydroxypropyl)adenine and a preparation method thereof. Background technique [0002] Tenofovir disoproxil fumarate (TDF) is an antiviral drug, the chemical name is (R)-9-(2-phosphomethoxypropyl) adenine bis(isopropoxycarbonyloxymethyl) ) ester, developed by Gilead Corporation of the United States, its structural formula is as shown in formula IA. Tenofovir disoproxil fumarate is a novel acyclic nucleotide analog that can significantly inhibit HBV in vitro and exhibit anti-HIV-1 and HIV-2 activity. After being hydrolyzed in vivo, the medicinal ingredient tenofovir (IB) is obtained, which can inhibit the activity of reverse transcriptase and inhibit the replication of viruses. At present, it has been approved by the European Union and the US FDA for the treatment of hepatitis B, and the FDA has also approved it as a drug for the treatment of HIV. ...

Claims

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Application Information

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IPC IPC(8): C07D473/34
CPCC07B2200/07C07D473/34
Inventor 张倩马佰位郭海明王鑫渠桂荣
Owner HENAN NORMAL UNIV
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