Synthesis intermediate of Entecavir and preparation method thereof

A compound and selected technology, applied in the preparation of hydroxyl compounds, organic compounds, chemical instruments and methods, etc., can solve the problems of harsh reaction conditions, large environmental pollution, and high equipment requirements

Active Publication Date: 2013-09-18
ZHEJIANG AUSUN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The problem of this preparation method is that the reaction is complicated, and the cost of some reagents is high. For example, the starting material needs to use expensive chiral boron reagents, and the synthesis of some intermediates is difficult, and the reaction conditions are harsh. The final debenzylation uses highly toxic boron reagents. Boron trichloride has great environmental pollution and high equipment requirements
[0011] In addition, WO2010 / 074534 utilizes the following reaction to prepare entecavir through intermediate II, but the reaction conditions are harsh, the reagents used are expensive, and it is difficult to apply to industrial production

Method used

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  • Synthesis intermediate of Entecavir and preparation method thereof
  • Synthesis intermediate of Entecavir and preparation method thereof
  • Synthesis intermediate of Entecavir and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0209] Example 1: Preparation of (2R, 3S)-2-(prop-1-en-2-yl)hex-5-ene-1,3-diol (compound 2)

[0210]

[0211] Suspend 1.0g CuI (5mmol) in 50ml of anhydrous ether, cool to -20°C, add isopropene Grignard reagent 0.5M 100ml THF solution (50mmol) dropwise under the protection of argon, and stir at -20°C for 25min , cooled to -78°C, added dropwise a 15ml THF solution containing 1.6g (14.2mmol) of compound 1, heated to -20°C and stirred for 16 hours, then added saturated NH 4 Cl 200ml, the organic layer was separated, and the aqueous layer was extracted with EtOAc 100ml x 2. The organic layers were combined, washed with water, and evaporated to dryness to obtain 2.63g of an oily substance. Add 20ml THF, 30ml H 2 O, add 3.0g NaIO under stirring 4 , stirred at room temperature for 3h. Saturated with Na 2 SO 3 , separate the organic layer, extract the aqueous layer with EtOAc 20ml x 2, combine the extracts, wash with saturated NaCl, wash with anhydrous NaCl 2 SO 4 After dryin...

Embodiment 2

[0215] Example 2: Preparation of (3R, 4S)-3-((tert-butyldimethylsilyloxy)methyl)-2-methylhept-1,6-dien-4-ol (compound 3, wherein R'=t-Bu(Me) 2 Si-)

[0216]

[0217] Add 232mg of 2 to 7.5ml CH 2 Cl 2 Dissolve, add 202mg of imidazole, cool to 0°C, add 245mg of TBSCl under stirring, and add 0°C to room temperature for 10 hours. Add 10ml of water, separate the organic layer, wash with water, anhydrous Na 2 SO 4 It was dried, filtered and purified by a short column of silica gel eluting with petroleum ether / EtOAc (50 / 1) to give the product 290 mg (72.3%), Rf=0.75 (petroleum ether / EtOAc (20 / 1)).

[0218] [α] D 20 =-25 (c 0.5, CHCl 3 );

[0219] 1 H NMR (300M, CDCl 3 , ppm) δ5.98-5.86 (m, 1H), 5.12 (d, 1H, J=6.3Hz), 5.07 (s, 1H), 4.86 (s, 1H), 4.76 (s, 1H), 3.94-3.77 (m, 3H), 2.09-2.35(m, 3H), 1.71(s, 3H), 0.90(s, 9H), 0.08(s, 6H);

[0220] 13 C NMR (100M, CDCl 3 , ppm) δ143.6, 135.5, 116.9, 113.4, 74.0, 66.9, 53.3, 39.8, 25.8, 22.0, 18.1.

[0221] HR-MS (ESI) cal...

Embodiment 3

[0222] Example 3: Preparation of (1S, 2R)-2-((tert-butyldimethylsilyloxy)methyl)-3-methylcyclopent-3-en-1-ol (compound 4, wherein R' =t-Bu(Me) 2 Si-)

[0223]

[0224] 820 mg of compound 3 was dissolved in 20 ml of dichloromethane, and 50 mg of Grubbs second-generation catalyst (2%) was added in an argon atmosphere, heated to reflux and stirred for 2 hours in an argon atmosphere, concentrated under reduced pressure, and the residue was purified by a short silica gel column, petroleum ether / Elution with EtOAc (20 / 1) gave 600 mg (81.5%) of the product, Rf = 0.35 (petroleum ether / EtOAc (10 / 1)).

[0225] [α] D 20 =+34 (c 0.25, CHCl 3 );

[0226] 1 H NMR (300M, CDCl 3 , ppm) δ5.32 (s, 1H), 4.34-4.29 (m, 1H), 3.85 (dd, 1H, J=9.9, 4.8Hz) 3.46 (t, J=8.4Hz), 2.64-2.56 (m, 2H), 2.21-2.16(m, 1H), 1.66(s, 3H), 0.9(s, 9H), 0.10(s, 6H).

[0227] 13 C NMR (125M, CDCl 3 , ppm) δ138.1, 123.4, 64.1, 59.2, 39.9, 25.9, 18.2, 15.3, -5.5, -5.5.

[0228]HR-MS (ESI) calculated value C...

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Abstract

The invention relates to a synthesis intermediate of Entecavir and a preparation method thereof. Specifically, the invention relates to a synthesis intermediate shown as formula II for preparation of Entecavir, a preparation method of the intermediate, and a method for preparing Entecavir from the intermediate shown in formula II, wherein R and R' are as defined in the specification.

Description

technical field [0001] The invention relates to a synthetic intermediate of medicine and a preparation method thereof, in particular to a new synthetic intermediate for preparing entecavir and a preparation method of the intermediate. Background of the invention [0002] Entecavir, the compound shown in the following formula I, 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxyl-3-(hydroxymethyl)-2-methylene Cyclopentyl]-6H-purin-6-one is a new nucleoside antiviral drug. [0003] [0004] Entecavir is the third anti-hepatitis B virus (HBV) drug on the market after lamivudine and adefovir dipivoxil, and it is also the most effective anti-HBV drug currently on the market. The anti-HBV effect of entecavir is 100 times that of lamivudine and more than 30 times that of adefovir dipivoxil; its side effects are very low, the selection index is greater than 8000, and it is also very effective against lamivudine-resistant HBV viruses. Good curative effect, is one of the most important ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C33/02C07C29/36C07F7/18C07D473/18
CPCC07C29/36C07D303/18C07D473/18C07F7/1804C07C33/02
Inventor 郑志国
Owner ZHEJIANG AUSUN PHARMA
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