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Synthetic method for chiral carbocyclic ring intermediate of abacavir

A synthesis method and intermediate technology, applied in the field of enzymatic synthesis, can solve the problems of long synthesis steps, high synthesis cost, low yield and optical purity, etc., and achieve the effects of short reaction time, high yield and high optical purity

Active Publication Date: 2010-06-16
苏州国镝医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This carbocycle contains two asymmetric centers. At present, chemical methods are mainly used to synthesize this intermediate with high optical purity, but the synthesis steps are quite long, the yield and optical purity are very low, and the synthesis cost is very high.

Method used

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  • Synthetic method for chiral carbocyclic ring intermediate of abacavir
  • Synthetic method for chiral carbocyclic ring intermediate of abacavir
  • Synthetic method for chiral carbocyclic ring intermediate of abacavir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024]

[0025] Step 1: Add acetic anhydride (3.0 mol) dropwise to a THF solution (500 ml) of compound A (1.5 mol) and triethylamine (4.5 mol). With stirring, the system was heated to reflux for 23 hours. Activated carbon (37.5 g) was added, the system was stirred for 20 minutes, and filtered. The system was concentrated in vacuo, water (1000 ml) was added to the residue, and the aqueous phase was extracted 3 times with cyclohexane (1000 ml each). The organic phases were combined, washed once with saturated brine (500 mL), and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation and dried under vacuum to obtain compound 1 as a light brown oil (yield 74%).

[0026] Step 2: Dissolve compound 1 (1 mole) in 1200 milliliters of ethanol, add the above-mentioned organic solution to the phosphate buffer solution of subtilisin cross-linking enzyme crystals (20 grams of wet weight subtilisin cross-linking enzyme crystals are suspended in In 1800 ml of...

Embodiment 2

[0028]

[0029] Step 1: Boc anhydride (3.0 mol) was added dropwise to a mixed solution of compound A (1.5 mol) and triethylamine (4.5 mol) in THF (250 ml) / water (250 ml). Under stirring, the system reacted overnight at room temperature. The system was concentrated in vacuo, water (1000 ml) was added to the residue, and the aqueous phase was extracted 3 times with ethyl acetate (1000 ml each). The organic phases were combined, washed once with saturated brine (500 mL), and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation and dried under vacuum to obtain compound 3 as a light brown oil (yield 85%).

[0030] Step 2: Dissolve compound 3 (1 mole) in 1500 milliliters of isopropanol, add the above-mentioned organic solution to the phosphate buffer solution of subtilisin cross-linking enzyme crystals (20 grams of wet weight of subtilisin cross-linking enzyme crystals suspended in 1800 ml of phosphate buffer solution, pH equal to 8). Keep the sys...

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Abstract

The invention discloses a method for synthesizing a chiral carbon ring intermediate of Abacavir. The steps are as follows: firstly, an intermediate 1 is prepared by 2-azabicyclo[2.2.1]hept-5- en-3-one, 1 mol of intermediate 1 is dissolved into 500 to 2000ml of organic solvent, the organic solvent is added into phosphate buffer solution of bacillus subtilis proteinase cross-linked enzyme crystals;the system is maintained between 15 and 35 DEG C and is mechanically stirred for 5 to 10 hours, the stirring speed is between 100 and 500r / m; the reaction is stopped, and the bacillus subtilis proteinase cross-linked enzyme crystals are reclaimed after the filtration; another 1000 to 2000ml of organic solvent is used to extract the filtrate for 3 to 6 times; organic phases are merged and dried bydrying agent; and the target compound is obtained through reduced pressure distillation or column chromatography. The method has the advantages that: the method has short reaction time and high yield,the obtained product has high optical purity, and the catalyst can be reclaimed and reused.

Description

technical field [0001] The invention relates to the enzymatic synthesis of key chiral carbocyclic intermediates of abacavir, and belongs to the application field of enzymes in chiral synthesis. Background technique [0002] Since the first AIDS patient was diagnosed in 1981, the HIV virus has been spreading at an alarming rate around the world. According to the "2004 Global AIDS Epidemic Annual Report" released by the Joint United Nations Program on HIV / AIDS and the World Health Organization (WHO) in July 2004, there are currently 38 million HIV / AIDS patients worldwide. , 30 million people have died of AIDS so far. [0003] In 1985, my country's Peking Union Medical College Hospital detected the first AIDS patient. Since 1995, the number of HIV-infected people and patients in my country has risen linearly at a 45° angle. Experts estimate that due to the rapid development of AIDS, the actual number of infected people in my country has exceeded 1 million, and this number is ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/16C07D209/52
CPCY02P20/584
Inventor 袁方姚亦明韩国霞李锐
Owner 苏州国镝医药科技有限公司
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