Chiral synthesis of combined protein deacetylated enzyme inhibitor

A technology of deacetylase and chiral synthesis, applied in the direction of organic chemistry, etc., can solve the problems of low overall yield, expensive, poor stability of intermediates, etc.

Inactive Publication Date: 2007-04-04
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route not only uses expensive chiral source 3-hydroxy-2-methylpropionate methyl ester and many more expensive reagents, but also has poor stability of intermediates, strict experimental operation requirements, long synthesis steps, and low overall yield. High (6.1%)

Method used

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  • Chiral synthesis of combined protein deacetylated enzyme inhibitor
  • Chiral synthesis of combined protein deacetylated enzyme inhibitor
  • Chiral synthesis of combined protein deacetylated enzyme inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment one: compound 2a and 2b Preparation of:

[0061] Dissolve 1.51g of p-nitrobenzaldehyde in 35mL of DMF, add 230mg of L-proline, and then add 1.44mL of propionaldehyde, stir at room temperature for 7 hours, and follow the complete reaction by TLC. Add 100mL of water, extract three times with ethyl acetate, combine the organic layers, dry over magnesium sulfate, and dry the solvent with a vacuum pump to obtain 2a and 2b The crude product was directly put into the next step.

[0062] compound 2a The hydrogen spectrum:

[0063] 1 HNMR (300MHz, CDCl 3 ): δ9.802 (1H, d, J = 0.9Hz), 8.224 (2H, d, J = 6.6Hz), 7.548 (2H, d, J = 6.3Hz), 4.974 (1H, d, J = 6.0Hz ), 3.409 (1H, br), 2.774 (1H, m), 0.996 (3H, d, J=5.7Hz).

Embodiment 2

[0064] Embodiment two: compound 3a and 3b Preparation of:

[0065] will contain 2a and 2b The crude product was added with 30 mL of methanol, 3.00 g of trimethyl orthoformate and 380 mg of p-toluenesulfonic acid monohydrate, and stirred at room temperature for 30 minutes. Add 10 mL of saturated sodium bicarbonate solution and 100 mL of water, extract three times with ethyl acetate, combine the organic layers, dry over magnesium sulfate, and drain the solvent to obtain a crude product. The compound was purified by column chromatography 3a and 3b A total of 2.26g ( 1 Proof of HNMR analysis 3a : 3b =11:1), the two-step total yield was 88.6%.

[0066] compound 3a The hydrogen spectrum:

[0067] 1 HNMR (300MHz, CDCl 3 ): δ8.202 (2H, d, J = 8.7Hz), 7.513 (2H, d, J = 8.7Hz), 4.719 (1H, d, J = 8.4Hz), 4.313 (1H, d, J = 5.7Hz ), 3.497(3H, s), 3.416(3H, s), 2.114(1H, m), 0.686(3H, d, J=7.2Hz);

[0068] compound 3b The hydrogen spectrum:

[0069] 1 HNMR (400MHz, CDCl...

Embodiment 3

[0073] Embodiment three: compound 4a and 4b Preparation of:

[0074] 3.63g 4a and 4b The mixture was dissolved in 25 mL DMF with 4.28 g TBSCl and 2.90 g imidazole, and stirred at room temperature for 20 hours. Add 80mL of water, extract with ethyl acetate, and the organic layer is dried with magnesium sulfate and pumped dry to obtain 4a and 4b crude product. Separation by column chromatography 4a and 4b , to get the compound 4a A total of 3.75 g, as a light yellow solid, yield 71.4%.

[0075] 1 HNMR (300MHz, CDCl 3 ): 68.173 (2H, d, J = 8.7Hz), 7.467 (2H, d, J = 8.7Hz), 4.804 (1H, d, J = 6.6Hz), 4.152 (1H, d, J = 5.4Hz), 3.376(3H, s), 3.365(3H, s), 0.883(9H, s), 0.689(3H, d, J=6.9Hz), 0.053(3H, s), -0.236(3H, s);

[0076] MS(EI)m / z(%): 369[M + ], 266(35), 240(100), 89(11);

[0077] [α] D 22 +35.3° (c=2.20, CHCl 3 ).

[0078] Mp 35-36°C.

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Abstract

Chiral synthesis of Trichostatin A has better intermediate stability and more product yield. It's simple and cheap.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a new chiral total synthesis method of histone deacetylase inhibitor Trichostatin A. Background technique [0002] Trichostatin A is a natural product isolated from a species of Streptomyces hygroscopicus by Japanese scientist Tsuji in 1976. Tsuji found that the natural product has antifungal effects. In 1985, Yoshida and Morioka found that Trichostatin A can induce differentiation of various tumor cells such as human leukemia and human head and neck tumors, and cause tumor cell apoptosis. In 1990, Yoshida et al. discovered Trichostatin A. It is a strong HDAC (histidine deacetylase) inhibitor. Trichostatin A can affect transcription, interfere with cell cycle, and inhibit the proliferation of tumor cells. At the same time, Yoshida et al. also found that the S configuration of Trichostatin A (the natural Trichostatin A is the R configuration) has no differentiation-inducing effect, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C259/06
Inventor 段文虎张土磊
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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