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Entecavir intermediate and preparation method thereof
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A technology of entecavir and intermediates, applied in the field of entecavir intermediates and their preparation, can solve the problems of harsh reaction conditions, unsuitable for industrial production, environmental pollution and the like
Active Publication Date: 2017-12-05
HSING PHARMACEUTICALS CO LTD
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[0009] The technical problem to be solved by the present invention is to overcome the relatively expensive reaction raw materials of the existing entecavir preparation method, difficult to obtain, harsh reaction conditions, low product yield, cumbersome post-processing operations, low atom utilization, serious environmental pollution and unsuitable for industrialization. Production and other defects, but provide entecavir intermediates and preparation methods thereof
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Embodiment 1
[0152]
[0153] Example 1-1 in compound 2 (R 1 for ) (30.1g, 86.5mmol) in water (6500mL) was added potassiumbicarbonate (260g, 2600mmol), potassiumfluoride (100g, 1720mmol). 30% hydrogenperoxide (550 g, 4320 mmol) was slowly added to the obtained mixed solution at 70 degrees Celsius. After the dropwise addition, the mixed solution was incubated at 70 degrees Celsius and stirred for 3 hours, then added acetic acid (1150 mL), and continued to be incubated at 70 degrees Celsius and stirred for 30 minutes. The mixture was filtered through diatomaceous earth and then slowly cooled to 5°C. The powdery crystals collected by filtration were washed with distilled water at 5°C, redispersed in 2500mL of distilled water, and heated to 95°C to dissolve them completely. The obtained supernatant was slowly cooled to 5°C. The obtained powdery crystals were collected by filtration and dried to obtain 121.3 g of the desired target compound, with a yield of 89%.
[0154] 1 H NMR (40...
Embodiment 2
[0161]
Embodiment 2-1
[0163] Compound 3-1 (R 2 for P 2 Concentrated sulfuric acid (8.2ml, 98%) was added to a solution of benzyl) (82.0g, 165mmol) in dichloromethane (82mL). The resulting brown liquid was stirred at 25°C for 2 hours and then slowly dropped into an aqueous potassiumhydroxide solution (2M, 1.6L). After the obtained mixed solution was evaporated to dryness of the organic solvent, acetic acid was added to adjust the pH=6-7. The solid obtained is collected by filtration and dried to obtain the desired target compound 2-1 (R 1 for ) 50g, yield 87%.
[0164] 1 H NMR (400MHz, CDCl 3 ):δ7.64(s,1H),5.30(s,2H),5.16-5.10(m,1H),3.88-3.72(m,2H),3.56-3.46(m,1H),2.52-2.38(m ,1H),2.17-1.92(m,2H),1.90-1.75(m,1H),1.73-1.54(m,4H),1.00-0.70(m,4H);
[0167] Example 2-2 to Example 2-8 were prepared according to the same method as ...
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Abstract
The invention discloses an entecavir intermediate and a preparation method thereof. The present invention provides a method for preparing an entecavir intermediate compound 10, which comprises the following steps: reducing the ester compound 11 in an organic solvent under the action of a reducing agent to obtain compound 10. The present invention also provides a method for preparing an entecavir intermediate compound 11, which comprises the following steps: in an organic solvent, under the condition of the presence of an acid, reacting compound 12 with a hydroxyl-protecting reagent on a hydroxyl-protecting group to obtain compound 11 . The preparation method of the invention has cheap and easy-to-obtain raw materials, mild reaction conditions and high product yield. The atomic economy is good, the environment is friendly, and it is suitable for industrial production.
Description
technical field [0001] The invention relates to an entecavir intermediate and a preparation method thereof. Background technique [0002] As an important class of compounds, nucleotide analogues have received extensive attention in the field of medicinal chemistry. Research related to it has produced a large number of important drugs, especially in the field of antiviral drugs. A considerable number of anti-AIDS drugs and anti-hepatitis B drugs have benefited from in-depth research in this field. [0003] There are 350 million to 400 million hepatitis B virus (HBV) infected people in the world, and nearly 1 million patients die of liver cirrhosis and liver cancer caused by HBV infection every year. There are more than 120 million HBV infections in my country, accounting for more than 1 / 3 of the world's total, ranking first in the world, and 30 million patients with chronic hepatitis B (hepatitis B), and this number is currently on the rise. Chronic hepatitis B virus infec...
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