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Novel purification processing process for R-9-(2-hydroxypropyl)adenine

An R-9-, hydroxypropyl technology, applied in the field of organic synthesis, can solve the problems of increasing the difficulty of separation, waste of raw materials, difficult separation of isomers, etc., and achieves the effect of high practical value and reduced separation cost.

Inactive Publication Date: 2015-09-09
LUOYANG DESHENG BIO TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the poor selectivity of this reaction, the reaction itself will inevitably generate about 5-10% isomers. Since the isomers are difficult to separate, most of the literature and patents are not purified in this step, and the crude product is directly dried and put into the next step. Not only increases the difficulty of separation in the next step, but also the isomers can participate in the next reaction, waste the raw materials in the next step, and increase the production cost

Method used

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  • Novel purification processing process for R-9-(2-hydroxypropyl)adenine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Step 1: Obtain R-9-(2-hydroxypropyl)adenine crude product

[0025] Add 100 g of adenine (0.74 mol) and 2.35 g (0.058 mol) of sodium hydroxide to 500 ml of DMF respectively, stir at room temperature for 20 min, add 96.5 g (0.946 mol) of R-propylene carbonate, and raise the temperature to 120 ~130℃ heat preservation reaction for 16 hours;

[0026] After the reaction was detected by HPLC, steam the solution of R-9-(2-hydroxypropyl)adenine under reduced pressure to remove about 70-80% of the DMF solvent, add 300ml of toluene, stir evenly, and keep warm at 0°C for 2 h, filtered, and dried to obtain 136 g of R-9-(2-hydroxypropyl)adenine crude product, with a crude yield of 95.7%, a purity of 90.8%, and an isomer of 8.0%.

[0027] Step 2: Column packing and pretreatment

[0028] Weigh one 150g of PRP-6A resin, pour it into a glass chromatography column, wash it with ethanol repeatedly 3 times to make the column compact and free of air bubbles, the resin height is 28c...

Embodiment 2

[0042] Step 1: Obtain R-9-(2-hydroxypropyl)adenine crude product

[0043] The amount of adenine was changed to 500 g, and the operation was the same as step 1 of Example 1 to obtain 675 g of R-9-(2-hydroxypropyl) adenine crude product, with a crude product yield of 95.1%, a purity of 91.9%, and an isomer of 7.8%.

[0044] Step 2: Column packing and pretreatment

[0045] Weigh 1.5kg of PRP-6A resin, pour it into a glass chromatography column, wash it repeatedly with methanol 3 times to make the column compact and free of air bubbles, the height of the resin is 50 cm, and the column is uniform, then wash it repeatedly with ethyl acetate 3 times , and finally replace ethyl acetate with methanol until no ethyl acetate is tested, and the chromatographic column is ready for use.

[0046] Step 3: Sample loading

[0047] Dissolve 60 g of crude R-9-(2-hydroxypropyl)adenine in a small amount of water (200ml), pour it into the PRP-6A resin chromatographic column, and complete the sampl...

Embodiment 3

[0059] Step 1: Obtain R-9-(2-hydroxypropyl)adenine crude product

[0060] The amount of adenine was changed to 5 kg, and the operation was the same as in step 1 of Example 1 to obtain 6.85 kg of R-9-(2-hydroxypropyl) adenine crude product, with a crude product yield of 96.4%, a purity of 90.7%, and an isomer of 8.2%. .

[0061] Step 2: Column packing and pretreatment

[0062] The quality of PRP-6A resin is 25 kg. The operation procedure is the same as that of step 2 of Example 1.

[0063] Step 3: Sample loading

[0064] The amount of sample loaded was 1 kg, and the operation was the same as Step 3 of Example 1.

[0065] Step 4: Elution

[0066] Prepare 80% ethanol water as the eluent, pour it into the resin chromatographic column, use the air pump to pressurize the elution, the flow rate is controlled at 150ml / min, use the receiving bottle to receive the eluent every 500ml in turn, and HPLC detects the product in each bottle content.

[0067] Step Five: Concentrate ...

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Abstract

The invention relates to a novel purification processing process for R-9-(2-hydroxypropyl)adenine. R-9-(2-hydroxypropyl)adenine is prepared from adenine and R-propylene carbonate under alkaline conditions. According to the process, a solvent DMF after reacting is subjected to reduced-pressure distillation for mechanically applying, toluene is added into the residue so as to precipitate a crude product, and the yield of the crude product is higher than 90%; and then, the crude product is subjected to chromatographic separation by using resin PRP-6A, ethanol water serves as an eluant, an isomer II is eluted firstly, R-9-(2-hydroxypropyl)adenine I is then eluted, eluates of the two kinds of products are respectively collected, depressurized concentration evaporation is carried out so as to obtain white crystalline powder R-9-(2-hydroxypropyl)adenine I which has the purity higher than 99% and the separation yield higher than 90%, the purity of the isomer II is higher than 99%, and the separation yield of the isomer II is higher than 90%. According to the process disclosed by the invention, the processing is simple, a resin chromatographic column can be reused repeatedly without affecting the separating effect, and the eluant can be repeatedly applied mechanically, so that the separation cost is greatly reduced; two kinds of products are obtained, the product purity is high, the overall yield is higher than 80%, and the volume of the generated wastewater is small, so that the process is applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and relates to the technical field of a purification process for preparing R-9-(2-hydroxypropyl) adenine from adenine and R-propylene carbonate. Background technique [0002] R-9-(2-hydroxypropyl) adenine is a key intermediate in the synthesis of tenofovir dipivoxil, a nucleotide reverse transcriptase inhibitor used to treat HIV-1 infection. Its consumption is increasing and its use is becoming more and more extensive. At present, there are many patents and literature reports about R-9-(2-hydroxypropyl) adenine: the patent has CN103408548, and the method is to react adenine and acetic anhydride to generate diacetyl adenine, and then combine with R-propylene carbonate The final product is obtained by ester reaction and hydrolysis of acetyl groups under alkaline conditions. The acetyl protection method has a yield of 90%. However, this method produces a large amount of waste acid and ino...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/34
CPCC07D473/34
Inventor 王育才苏华强韩建星刘爱香
Owner LUOYANG DESHENG BIO TECH CO LTD
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