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Synthetic method of entecavir

A technology of entecavir and a synthesis method, which is applied in the field of synthesis of pharmaceutical intermediates and entecavir, can solve the problems such as difficulty in obtaining raw materials, low yield, complicated reaction and the like

Active Publication Date: 2013-02-13
苏州市玮琪生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Nevertheless, previously published patents and documents always encounter problems of one kind or another, such as defects such as difficult access to raw materials, low yield, high cost, complex reactions, and poor purity.

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment one: the preparation of compound III-1

[0050]

[0051] Dissolve (+)-Corey diol (17.2g, 1eq) in 100mL tetrahydrofuran, add 4-methylbenzenesulfonic acid (760mg, 0.04eq), then slowly add acetaldehyde diethyl acetal (23.6g, 2eq). After stirring for 15 minutes, heat to reflux and continue stirring for 4 hours. Remove from heat and cool to room temperature. Add 20 ml of saturated sodium bicarbonate and extract with ethyl acetate. The organic phase was concentrated to 50ml, and 150ml of petroleum ether was slowly added under stirring, and a solid was precipitated to obtain compound III-1 (16.8g, 85% yield). 1 H NMR (CDCl 3 , 400 MHz) δ 1.36 (d, J=5.2 Hz ,3H, CH 3 ), 1.64-1.73 (m, 1H), 1.83-1.90 (m, 1H), 2.30-2.44 (m, 2H), 2.62-2.73 (m, 2H), 3.38-3.45 (m, 1H), 3.58 (t , J=10.8 Hz, 1H), 4.28 (dd, J=4.4Hz, 10.8 Hz, 1H), 4.70(q, J=4.8 Hz, 1H), 4.88-4.92 (m, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 20.6,32.4, 36.6, 36.9, 45.3, 70.4, 79.7, 80.5, 99.7,176.0; Ms (+C,...

Embodiment 2

[0052] Embodiment two: the preparation of compound III-2

[0053]

[0054] (+)-Corey diol (17.2 g, 1 eq) was dissolved in 100 mL of toluene, 4-methylbenzenesulfonic acid (760 mg, 0.04 eq) was added, followed by the slow addition of benzaldehyde (21.2 g, 2 eq) at room temperature. Then it was heated to reflux temperature, and the water was separated by reflux through a water separator, and stirred for 6 hours. Remove from heat and cool to room temperature. Add 20 ml of saturated sodium bicarbonate and extract with ethyl acetate. The organic phase was concentrated to 50ml, and 150ml of petroleum ether was slowly added under stirring, and a solid was precipitated to obtain compound III-1 (18.5g, 71% yield). 1 H NMR (CDCl 3 , 400 MHz) δ1.72-1.75 (m, 1H), 2.14-2.19 (m, 1H), 2.39-2.53 (m, 2H), 2.81-2.88 (m, 1H), 3.36-3.38 (m, 1H) , 4.13 (d, J=14.8 Hz, 1H), 4.25 (d, J=14.8 Hz, 1H), 4.48(dd, J=3.2 Hz, J=4.4 Hz, 1H), 5.15-5.18 (m, 1H) , 5.48 (s, 1H), 7.36-7.41 (m, ArH, 3H), 7.4...

Embodiment 3

[0055] Embodiment three: the preparation of compound IV-1

[0056]

[0057] Compound III (19.8g, 1eq) was dissolved in 400mL of anhydrous tetrahydrofuran at 0 o Add Lithium Aluminum Hydride (3.8g, 1eq) in batches at 0°C, keeping the internal temperature below 10 o C, the addition was completed within 30 min, and after the addition was completed, it was slowly raised to room temperature and continued to stir for 3 hours. Then, the reaction solution was cooled to 0 o C, slowly drop 30% sodium hydroxide solution to quench the reaction. Filter and wash the filter residue with ethyl acetate. The crude compound IV-1 from the concentrated filtrate (19 g, 95% yield, can be directly used in the next step). 1 H NMR (CDCl 3 , 400 MHz) δ1.36 (d, J=4.8 Hz , 3H, CH 3 ), 1.45-1.61 (m, 3H), 1.70-1.75 (m, 1H), 1.84-1.90 (m, 1H), 2.51-2.58 (m, 1H), 3.29-3.34 (m, 1H), 3.50 (t , J=10.8 Hz, 1H), 3.55-3.61 (m, 1H), 3.77-3.80 (m, 1H), 4.19 (dd, J=4Hz, 10.4 Hz, 1H), 4.30 (q, J=6.8 Hz, 1H),...

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Abstract

The invention discloses a synthetic method of entecavir. The synthetic method of the entecavir is characterized in that Corey lactone diol serves as initial raw materials, hydroxy group is used for protection, lithium aluminium hydride is used for reduction, then dimethyl tertiary butyl chlorosilane is used to selectively protect the primary hydroxy group, mitsunobu reaction is carried out, 6-substituted guanine is used for condensation, silicon substrate protecting group is removed, alkene is eliminated, then ozone is cut off and reduced, the alkene is eliminated through the hydroxy group, and at last the entecavir is obtained after the protection is removed. The reaction of the synthetic method of the entecavir is easy to control and simple, the raw materials are cheap and easy to obtain, the operation is simple, convenient and environment-friendly, and therefore the synthetic method of the entecavir is suitable for industrialized production.

Description

technical field [0001] The present invention relates to a synthesis method of medicine, in particular to a synthesis method of entecavir and a medicine intermediate used in the synthesis. Background technique [0002] Entecavir, whose chemical name is (2-amino-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-1H-purine-6(9H) - Ketone, its structure is shown in the following formula: [0003] [0004] Entecavir is a guanosine nucleoside analog, which can effectively inhibit the replication of hepatitis B virus and is used for the treatment of hepatitis B. It was developed by Bristol-Myers Squibb in the United States and officially announced by the FDA on March 30, 2005, becoming the third nucleoside drug for the treatment of hepatitis B (HBV). It has strong antiviral ability and high selectivity, and its cytotoxicity is one-eight thousandth of the anti-hepatitis B virus activity, and the drug resistance produced by long-term use is relatively low. [0005]...

Claims

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Application Information

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IPC IPC(8): C07D473/18C07D319/08
CPCY02P20/55
Inventor 顾瑜蔡荣华孙希栋朱虹赵懿
Owner 苏州市玮琪生物科技有限公司
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