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Substituted (3S, 4R)/(3R, 4S)-Statines compound and preparation method thereof

A compound and said technology are applied in the field of key fragment substitution/-Statines compounds and their preparation, which can solve the problems of harsh preparation conditions, lack of universality, and difficulties in Statine preparation, and achieve high yield, simple route, and easy operation. simple effect

Inactive Publication Date: 2018-05-29
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, practice shows that the preparation of (3R,4S)-Statine and its enantiomer (3S,4R)-Statine is difficult. Although there are many international research papers on the synthesis of (3S,4R) and (3R,4S)-Statine The methods are publicly reported, but these known methods are not universal, and most of the preparation conditions are harsh, so they are not suitable for large-scale production

Method used

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  • Substituted (3S, 4R)/(3R, 4S)-Statines compound and preparation method thereof
  • Substituted (3S, 4R)/(3R, 4S)-Statines compound and preparation method thereof
  • Substituted (3S, 4R)/(3R, 4S)-Statines compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Synthesis of (2S,3R)-tert-butoxycarbonyl 2-ethyl 3-tert-butyldimethylsilyloxy 5-carbonylpyrrole (compound 2a)

[0024] The initial material 1 was prepared according to our previous literature (Org. Lett. 2014, 16, 4328-4331, Org. Chem. Front. 2015, 2, 1485–1499). Compound 1 (1g, 2.86mmol) was dissolved in 12mL of tetrahydrofuran, magnesium powder (224mg, 9.16mmol) was added at 0°C, bromoethane (935mg, 8.58mmol) was added dropwise, and the temperature was naturally raised to react for 12 hours. After quenching with ammonium chloride, extract with ethyl acetate, dry, and concentrate to obtain a crude product, which is dissolved in 10 mL of dichloromethane and added to Boc 2 O (1.25g, 5.72mmol), DMAP (350mg, 2.86mmol) and triethylamine (2.0mL, 14.30mmol) were reacted for 24 hours, concentrated and purified by silica gel column to give white solid 2a (384mg, 39%). 1 H NMR (400MHz, CDCl 3 )δ4.09(d, J=5.2Hz, 1H), 3.87(dd, J=9.6, 3.8Hz, 1H), 2.77(dd, J=17.6, 5.3Hz, 1H), 2.34...

Embodiment 2

[0032]Synthesis of (2S,3R)-tert-butoxycarbonyl-2-(4-methylphenyl)-3-tert-butyldimethylsilyloxy 5-carbonylpyrrole (compound 2b)

[0033] Compound 1 (1g, 2.86mmol) was dissolved in 12mL of tetrahydrofuran, magnesium powder (224mg, 9.16mmol) was added at 0°C, 4-bromotoluene (1.47g, 8.58mmol) was added dropwise, and then the temperature was naturally raised for 3 hours. After quenching with saturated ammonium chloride, extract with ethyl acetate, dry, and concentrate to obtain a crude product, which is dissolved in 10 mL of dichloromethane and added to Boc 2 O (1.25g, 5.72mmol), DMAP (350mg, 2.86mmol) and triethylamine (2.0mL, 14.30mmol) were reacted for 24 hours, concentrated and purified by silica gel column to give white solid 2a (615mg, 53%). 1 H NMR (600MHz, CDCl 3 )δ7.19-7.15(m,2H),7.08-7.04(m,2H),4.96-4.92(m,1H),4.08(ddd,J=5.5,2.2,1.2Hz,1H),2.85(dd, J=17.5,5.6Hz,1H),2.39(ddd,J=17.5,1.9,0.8Hz,1H),2.35(s,3H),1.32(s,9H),0.89(s,9H),0.08(s ,3H),0.05(s,3H).

[0034] Synthesis...

Embodiment 3

[0041] Synthesis of (2S,3R)-tert-butoxycarbonyl-2-(3-methylphenyl)-3-tert-butyldimethylsilyloxy 5-carbonylpyrrole (compound 2c)

[0042] Compound 1 (1g, 2.86mmol) was dissolved in 12mL of tetrahydrofuran, magnesium powder (224mg, 9.16mmol) was added at 0°C, 3-bromotoluene (1.47g, 8.58mmol) was added dropwise, and the temperature was naturally raised for 3 hours. After quenching with saturated ammonium chloride, extract with ethyl acetate, dry, and concentrate to obtain a crude product, which is dissolved in 10 mL of dichloromethane and added to Boc 2 O (1.25g, 5.72mmol), DMAP (350mg, 2.86mmol) and triethylamine (2.0mL, 14.30mmol) were reacted for 24 hours, concentrated and purified by silica gel column to give white solid 2c (696mg, 60%). 1 H NMR (400MHz, CDCl 3 )δ7.28-7.22(m,1H),7.15-7.08(m,1H),7.01-6.93(m,2H),4.98-4.88(m,1H),4.10(ddd,J=5.6,2.4,1.5 Hz,1H),2.86(dd,J=17.4,5.7Hz,1H),2.40(ddd,J=17.5,2.1,0.8Hz,1H),2.34(s,3H),1.31(s,9H),0.89 (s,9H),0.08(s,3H),0.05(s,3H).

[004...

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Abstract

Belonging to the field of chemical synthesis, the invention relates to a key segment substituted (3S, 4R) / (3R, 4S)-Statines compound of natural products with important activity and a preparation method thereof. The synthesis of the preparation method of the substituted (3S, 4R) / (3R, 4S)-Statines includes conversion of intermediates 1-5, and the synthesis method includes steps 1-4. The technical route for preparation of the substituted (3R, 4S)-statines and the enantiomer (3S, 4R)-Statines thereof has the advantages of simple operation, concise course, high yield, and use of common reagents, also is suitable for large-scale preparation. And the obtained target product can be used for diversity synthesis study of a plurality of natural products with important physiological activity.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and relates to a key fragment substituted (3S, 4R) / (3R, 4S)-Statines compound with important active natural products and a preparation method thereof. Background technique [0002] Statine, namely β-hydroxy γ-amino-4-substituted butyric acid, is a key fragment of a variety of natural products and drug molecules with important physiological activities. It was first discovered in 1970 by Japanese scientists from the structure of the aspartyl protease inhibitor pepstain It was discovered that the skeleton was found in many natural products such as Hapolasin, Dolastatins and Symplocin A. Now medicinal chemistry studies show that many drugs have proved that (3R,4S)-Statine plays a key active role. For example, Dolastatins containing a (3R,4S)-Statine skeleton has multiple analogues entering clinical research, and Hapolasin containing a (3R,4S)-Statine skeleton has a great effect on multi-drug resist...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/22C07C229/34C07C227/20
CPCC07C229/22C07C229/34
Inventor 魏邦国司长梅孙逊邵路平周雯毛卓亚周倩茹
Owner FUDAN UNIV