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Efficiently synthesized gamma-aminobutyrate derivative with weak activated cyclopropane and alcohol intermolecular carbonylation coupling

A technology of carbonylation coupling and aminobutyrate, applied in the field of application, can solve the problems of poor substrate diversity and applicability, cumbersome synthesis steps, etc., and achieve the effects of good reaction applicability, wide range of substrates, and easy operation

Inactive Publication Date: 2019-06-21
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In summary, although the research on weakly activated cyclopropane has made some progress, the existing strategies require the introduction of capture functional groups in the substrate molecule, which makes the synthesis steps cumbersome, and the diversity and applicability of the substrate are poor, so The intermolecular reactions of weakly activated cyclopropane, an important intermediate in organic synthesis, urgently need to be developed and utilized

Method used

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  • Efficiently synthesized gamma-aminobutyrate derivative with weak activated cyclopropane and alcohol intermolecular carbonylation coupling
  • Efficiently synthesized gamma-aminobutyrate derivative with weak activated cyclopropane and alcohol intermolecular carbonylation coupling
  • Efficiently synthesized gamma-aminobutyrate derivative with weak activated cyclopropane and alcohol intermolecular carbonylation coupling

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: Synthesis of 2-Oxo-2-phenylethyl 4-(1,3,3-Trimethylureido)butanoate

[0025]

[0026] Add raw materials 1a (142mg, 1.0mmol), 2a (272mg, 2.0mmol), [Rh(CO) 2 Cl] 2 (14.5mg, 0.0375mmol), P(C 6 f 5 ) 3 (80mg, 0.15mmol), 1,2-dichlorobenzene (5mL), 130°C, carbon monoxide for 36 hours. After the reaction was completed, silica gel column chromatography was carried out with eluent (ethyl acetate / petroleum ether=1 / 1) to obtain 244 mg of product 3a (colorless oily liquid), with a yield of 80%. 1 H NMR (400MHz, CDCl 3 )δ7.91(d, J=7.2Hz, 2H), 7.61(t, J=7.4Hz, 1H), 7.49(t, J=7.4Hz, 2H), 5.35(s, 2H), 3.25(t, J=7.3Hz, 2H), 2.83(s, 3H), 2.80(s, 6H), 2.50(t, J=7.4Hz, 2H), 2.0-1.93(m, 2H). 13 C NMR (101MHz, CDCl 3 )δ191.97, 172.44, 165.28, 133.93, 133.74, 128.70, 127.55, 65.85, 49.23, 38.48, 36.56, 30.91, 22.59. HRMS (ESI) calcd.for C 16 h 23 N 2 o 4 (M+H) + : 307.1652, Found: 307.1651.

Embodiment 2

[0027] Embodiment 2: the synthesis of Formestane Product

[0028]

[0029] Add raw material 1a (14.2mg, 0.1mmol), 2b (60mg, 0.2mmol), [Rh(CO) 2 Cl] 2 (1.45mg, 0.00375mmol), P(C 6 f 5 ) 3 (8mg, 0.015mmol), 1,2-dichlorobenzene (0.5mL), 130°C, carbon monoxide for 96 hours. After the reaction was completed, silica gel column chromatography was performed with eluent (ethyl acetate / petroleum ether=2 / 1) to obtain 26 mg of product 3b (colorless oily liquid), with a yield of 55%. 1 H NMR (400MHz, CDCl 3 )δ3.23(t, J=7.3Hz, 2H), 2.80(s, 3H), 2.77(s, 6H), 2.71-2.67(m, 1H), 2.51-2.41(m, 5H), 2.12-1.99 (m, 3H), 1.96-1.91(m, 4H), 1.86-1.67(m, 4H), 1.58-1.52(m, 1H), 1.44-1.38(m, 1H), 1.30-1.23(m, 5H) , 1.09-1.02(m, 2H), 0.89(s, 3H). 13 C NMR (101MHz, CDCl 3 )δ220.29,190.45,171.10,165.54,155.17,139.29,53.87,50.81,49.44,47.53,39.23,38.75,36.88,35.81,34.74,34.66,33.41,31.32,30.96,29.83,23.94,22.84,21.79,20.34 , 17.76, 13.78.HRMS(ESI)calcd.forC 27 h 41 N 2 o 5 (M+H) + : 473.3010...

Embodiment 3

[0030] Embodiment 3: Synthesis of 16a-Hydroxyestrone Product

[0031]

[0032] Add raw material 1a (14.2mg, 0.1mmol), 2c (57mg, 0.2mmol), [Rh(CO) 2 Cl] 2 (1.9mg, 0.005mmol), P(C 6 f 5 ) 3 (10.6mg, 0.02mmol), 1,2-dichlorobenzene (0.5mL), 130°C and carbon monoxide for 96 hours. After the reaction was completed, silica gel column chromatography was performed with eluent (ethyl acetate / petroleum ether=2 / 1) to obtain 30 mg of product 3c (colorless oily liquid), with a yield of 65%. 1 H NMR (400MHz, CDCl 3)δ7.12(d, J=8.4Hz, 1H), 6.66(dd, J=8.4, 2.6Hz, 1H), 6.60(d, J=2.6Hz, 1H), 6.31-6.27(br, 1H), 5.47(d, J=8.3Hz, 1H), 3.23(td, J=7.1, 3.1Hz, 2H), 2.86-2.78(m, 11H), 2.41-2.36(m, 3H), 2.27-2.20(m, 1H), 2.17-2.10(m, 1H), 1.95-1.87(m, 4H), 1.82-1.74(m, 2H), 1.60-1.54(m, 2H), 1.52-1.37(m, 2H), 0.99( s, 3H). 13 C NMR (101MHz, CDCl 3 )δ213.98,172.55,165.64,154.88,137.46,130.48,126.21,115.44,113.13,72.47,49.44,47.95,47.65,43.75,38.75,38.26,36.81,31.30,31.27,29.39,29.19,26.30,25....

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Abstract

The invention provides a method for efficiently synthesizing a gamma-aminobutyrate derivative through weak activated cyclopropane and alcohol intermolecular carbonylation coupling, belongs to the technical field of application and aims to solve the problem that intermolecular carbonylation coupling of weak activated cyclopropane and a compound of a keto-alcohol or glycol structure is achieved fora first time by using a newly developed double-orientation catalytic system. As gamma-aminobutyric acid has certain bioactivity, the method can be directly applied to later functional group modification on natural products and medicine micromolecules.

Description

technical field [0001] The invention provides a method for efficiently synthesizing gamma-aminobutyrate derivatives through carbonylation coupling between weakly activated cyclopropane and alcohol molecules, and belongs to the field of application technology. Background technique [0002] Cyclopropane compounds are an important class of intermediates in organic synthesis. The release of ring tension is the main driving force for carbon-carbon bond cleavage, and the metal intermediates produced at the same time can realize multiple transformations, so the development of simple and efficient synthetic methods has high application value. Activated cyclopropanes mainly include alkylene cyclopropanes and vinyl cyclopropanes. There are many studies on this type of cyclopropanes, while studies on weakly activated substrates such as cyclopropanones, amides, amino groups, and alkyl cyclopropanes Relatively small. [0003] Narasaka's group previously reported the (3+1+2) cycloadditi...

Claims

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Application Information

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IPC IPC(8): C07C273/18C07C275/16C07J1/00C07D281/02C07D211/34
Inventor 王晓晨张雅林郭瑞婷
Owner NANKAI UNIV
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