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Precursor of key intermediate of AG 7088 class compound and its sythetic process

A technique for the synthesis of AG7088, which is applied in the direction of organic chemistry, can solve the problems of low selectivity and low yield, and achieve the effects of high yield, easy availability of raw materials, and simple post-treatment

Inactive Publication Date: 2005-01-12
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Summarizing the synthetic routes of the above literature, all have the defects of low selectivity and low yield

Method used

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  • Precursor of key intermediate of AG 7088 class compound and its sythetic process
  • Precursor of key intermediate of AG 7088 class compound and its sythetic process
  • Precursor of key intermediate of AG 7088 class compound and its sythetic process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1: Coupling

[0050] Under the protection of argon at -78°C, 2.5ml (4mmol) of BuLi was slowly added dropwise to 0.67ml (4.8mmol) of diisopropylamine dissolved in 6ml of THF, and after stirring for half an hour, 0.46ml was slowly added dropwise. (4mmol) of ethyl propiolate, reacted for half an hour, slowly added 593mg (2.1mmol) of N-dibenzyl galenaldehyde dissolved in 4ml TFH, and added saturated NH 4 Aqueous Cl solution quenched the reaction. The temperature of the reaction system was allowed to slowly rise to room temperature. Then add 10ml of 1M aqueous citric acid solution, then extract the product with 15ml of ether, and then use saturated NaHCO 3 Wash the organic phase with NaCl aqueous solution, separate the organic layer, anhydrous NaCl 2 SO 4 Drying, concentration, and column chromatography yielded 489 mg of a yellow viscous liquid with a yield of 73%. At the same time, 94 mg of another isomer was obtained, and the ratio betw...

Embodiment 2

[0055] Example 2: Hydrogenation

[0056] 437 mg of the product obtained in the first step was dissolved in 5 ml EtOAc, and 512 mg of (Boc) 2 O 175 mg of Pd(OH) 2 , hydrogenated at 40° C. under 50 atm pressure for one day, evaporated the solvent under reduced pressure, and obtained 315 mg of the product by flash column chromatography, with a yield of 90%.

[0057]

[0058] The spectrogram data is as follows:

[0059] 1 H NMR: δ0.93(d, 3H, J=6.6), 1.26(d, 3H, J=6.6), 1.26(t, 3H, J=7.2), 1.45(s, 9H), 1.56-1.67(m , 1H), 1.77-1.93(m, 2H), 2.50-2.56(ddd, J 1 =2,7,J 2 =6.9, J3=9.0), 2.92 (d, 1H, J=6.3) 3.53-3.46 (m, 1H), 3.61-3.71 (m, 1H), 4.14 (q, J=7.2), 4.45, (d, J=9.3).

[0060] ESI-Ms: [M+1]=304.2

[0061] Optical rotation: CHCl 3 , c=1.070, [α]=-9.3

Embodiment 3

[0062] Example 3: Hydroxyl Flip Ring Closure

[0063] Dissolve 91 mg of the product from the previous step in 2.5 ml of CH 2 Cl 2 208 μl of NEt were sequentially cooled in an ice-salt bath under the protection of argon 3 , 58μl of MsCl was added to it, reacted for half an hour, and added 5ml of CH 2 Cl 2 Dilute sequentially with 1M HCl, saturated NaHCO 3 and NaCl aqueous solution, the organic layer was separated, anhydrous NaSO 4 Dry and concentrate. The obtained product was dissolved in 4 ml of DMF and heated to 65° C. for one day without isolation. DMF was distilled off under reduced pressure and flash column chromatography was used to obtain 59 mg of the product, with a two-step yield of 86%.

[0064]

[0065] The spectrogram data is as follows:

[0066] 1 H NMR δ 0.93 (d, 3H, J=5.4), 0.95 (d, 3H, J=5.4), 1.27 (t, 3H, J=7.2), 1.67-1.79 (m, 1H), 1.92-2.04 ( m, 2H), 2.53(t, 2H, J=4.2), 3.19(t, 1H, J=5.1), 4.15(q, 2H, J=7.2), 4.32-4.36(m, 1H), ...

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Abstract

This invention relates to synthesis of precursor of intermediate of AG7088 type compounds, with its constructural formula as shown. Under N protection, coupling reaction of amino-aldehyde and propiolate is proceeded. Said product is hydrogenized with N protection base being substituted by Boc or other nucleophilic protection base. Said product is then hydroxylated activated. Then it is proceeded inner molecular SN2 reaction to produce oxazolon ane, then being reverse turning its hydroxy structure, adding N protection base, opening the ring of oxazolidone, under acid condition to close penta internal ester ring to obtain intermediate of AG7088. In this invention natural amino acid is used as raw material, with short synthesis process, high yield, good stereoselectivity.

Description

technical field [0001] The invention relates to a precursor of a key intermediate of the AG7088 compound and a synthesis method thereof. technical background [0002] The AG7088 compound is an inhibitor of rhinovirus protease, and is clinically used as a medicine for treating common cold. And may have inhibitory effect on SARS virus. The AG7088 compound molecule contains two peptide bonds, which bind to the target protein in the form of hydrogen bonds. On the right side, the Michael addition receptor is covalently bonded to the sulfhydryl group of cysteine ​​in the target protein. And the amino acid structure in the middle is ketomethylene dipeptide isoesters (ketomethylene dipeptide isoesters). [0003] Several main synthetic routes of its key intermediates are as follows: [0004] 1: J. Org. Chem. 2003, 5, 2042 [0005] [0006] 2: Jean-Francios, etc, Tetrahedron Lett. 1995, 2757 [0007] [0008] 3: Jeffrey A. Compbell, etc., J. Org. Chem. 1995, 14, 4602 [0...

Claims

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Application Information

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IPC IPC(8): C07D263/24C07D413/06
Inventor 马大为谢卫青邹斌
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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