Preparation method of 6-substitute-5,6-dihydro phenanthridine derivative

A technology for dihydrophenanthridine and derivatives, which is applied in the field of preparation of 6-substituted-5,6-dihydrophenanthridine derivatives, can solve problems such as difficulty in the source of biphenyl derivatives 1, and achieve a wide range of substrate adaptation , high yield and easy access to raw materials

Active Publication Date: 2013-11-27
CHINA PHARM UNIV
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0005] The above method has the following disadvantages: (1) The source of biphenyl derivative 1 is difficult; (2) Two kinds of noble metal catalysts are used

Method used

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  • Preparation method of 6-substitute-5,6-dihydro phenanthridine derivative
  • Preparation method of 6-substitute-5,6-dihydro phenanthridine derivative
  • Preparation method of 6-substitute-5,6-dihydro phenanthridine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Synthesis of 6-(3-oxopropyl)-5-(4-toluenesulfonyl)-5,6-dihydrophenanthridine (I-1):

[0020]

[0021] In a 500ml three-necked bottle, (E)-2-(3-oxo-1-butenyl) phenylboronic acid pinacol ester (II-1: R=CH 3 ) (2.72g, 0.01mol), N-(4-toluenesulfonyl)-2-bromoaniline (3.24g, 0.01mol), tetrakis (triphenylphosphine) palladium (1.16g, 0.001mol) and 2mol / L Sodium carbonate aqueous solution (6.36g, 0.06mol) was completely dissolved in 300mL of ethylene glycol dimethyl ether, protected by nitrogen gas, heated to reflux for 6h, after the completion of the reaction monitored by TLC, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, the residue Separation by column chromatography gave yellow oily product I-1, weighing 2.76 g, with a yield of 84.9%.

[0022] 1 H-NMR (300MHz, CDCl3) δ7.74 (dd, J=7.6, 1.4Hz, 1H), 7.57 (dd, J=7.4, 1.7Hz, 1H), 7.43–7.29 (m, 2H), 7.23–7.13 (m,2H),7.13–7.02(m,2H),6.88(d,J=8.2Hz,2H),6.65(d J=8.1Hz,2H),5.82(t...

Embodiment 2

[0025] Synthesis of 2-methyl-6-(3-oxopropyl)-5-(4-toluenesulfonyl)-5,6-dihydrophenanthridine (I-2):

[0026] With (E)-2-(3-oxo-1-butenyl) phenylboronic acid pinacol ester (II-1: R=CH 3 ) and 4-methyl-N-(4-toluenesulfonyl)-2-bromoaniline as raw materials, and the operation was the same as in Example 1 to obtain yellow oily product I-2 with a yield of 92%.

[0027]

[0028] 1 H-NMR (300MHz, CDCl3) δ7.66(d, J=8.2Hz, 1H), 7.40(s, 1H), 7.26–7.17(m, 3H), 7.16–7.20(m, 2H), 6.94(d ,J=8.3Hz,2H),6.70(d,J=8.0Hz,2H),5.81(t,J=7.2Hz,1H),2.71(dd,J=16.2,7.4Hz,1H),2.50(dd ,J=16.1,7.2Hz,1H),2.44(s,3H),2.16(s,3H),2.14(s,3H).

[0029] 13 C-NMR (75MHz, CDCl 3 )δ204.61,142.32,137.00,133.89,133.52,130.03,129.37,129.16,129.02,128.75,127.81,127.26,127.04,126.78,126.60,126.45,123.61,122.62,122.02,54.95,48.37,29.88,20.91,20.72.

Embodiment 3

[0031] Synthesis of 2-fluoro-6-(3-oxopropyl)-5-(4-toluenesulfonyl)-5,6-dihydrophenanthridine (I-3):

[0032] With (E)-2-(3-oxo-1-butenyl) phenylboronic acid pinacol ester (II-1: R=CH 3 ) and 4-fluoro-N-(4-toluenesulfonyl)-2-bromoaniline as raw materials, and the operation was the same as in Example 1 to obtain yellow solid product I-3 with a yield of 83% and a melting range of 123-125°C.

[0033]

[0034] 1 H-NMR (300MHz, CDCl 3 )δ7.75(dd, J=8.9,5.3Hz,1H),7.26(dd,J=9.33,3.0Hz,1H),7.21(s,1H),7.19–7.06(m,4H),6.91(d ,J=8.3Hz,2H),6.69(d,J=8.0Hz,2H),5.84(t,J=7.2Hz,1H),2.68(dd,J=16.2,7.3Hz,1H),2.50(dd ,J=16.2,7.3Hz,1H),2.14(s,3H),2.12(s,3H).

[0035] 13 C-NMR (75MHz, CDCl 3 )δ204.10,163.02,159.84,142.70,133.94,133.12,131.42,131.31,130.90,130.77,128.15,127.95,127.28,126.59,122.88,115.28,115.01,109.82,109.51,54.70,48.37,29.31,20.82.

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Abstract

The invention relates to the field of organic synthesis, and particularly relates to a preparation method of a 6-substitute-5,6-dihydro phenanthridine derivative. The preparation method disclosed by the invention comprises the following steps of: carrying out Suzuki-Miyaura reaction and Michael addition reaction on phenylboronic acid ester II and an o-bromoaniline derivative III which used as raw materials in the presence of a palladium catalyst in a one-pot manner. The method has the advantages of easily available raw material, wide substrate application range, high yield, and the like.

Description

technical field [0001] The present invention relates to the field of organic synthesis. It specifically relates to a preparation method of 6-substituted-5,6-dihydrophenanthridine derivatives. Background technique [0002] 5,6-dihydrophenanthridine derivatives are the core structure of various natural products, and their derivatives have various biological activities. The literature (Bioorg Med Chem Lett, 2012, 22, 3095–3099) reported a class of derivatives containing 5,6-dihydrophenanthridine structure, and found that they have bradykinin B1 receptor antagonistic activity. [0003] Document (J Org Chem, 1998,63,5211-5215) reported 5, the synthetic route of 6-dihydrophenanthridine derivatives is as follows: [0004] [0005] The above method has the following disadvantages: (1) The source of biphenyl derivative 1 is difficult; (2) Two kinds of noble metal catalysts are used. Contents of the invention [0006] The object of the present invention is to find a method for...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/12
Inventor 徐云根朱启华姚魏
Owner CHINA PHARM UNIV
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