A kind of method of synthesizing thiophene inhibitor TPCA-1

A TPCA-1 and inhibitor technology, applied in the direction of organic chemistry, can solve the problems of cumbersome synthesis steps, harsh conditions, and inconvenient use, and achieve the effects of high yield, mild reaction conditions, and easy-to-obtain reaction raw materials

Active Publication Date: 2020-04-10
HENAN NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In the above reaction, the starting material 2,5-dihydroxy-1,4-dithiane has a foul smell, which is extremely inconvenient to use. At the same time, the steps of the synthesis method are cumbersome and the required conditions are relatively harsh, so the synthesis method still needs to be carried out. development optimization

Method used

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  • A kind of method of synthesizing thiophene inhibitor TPCA-1
  • A kind of method of synthesizing thiophene inhibitor TPCA-1
  • A kind of method of synthesizing thiophene inhibitor TPCA-1

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Optimization of ring expansion reaction conditions:

[0027]

[0028]

[0029] During the screening of reaction conditions, the effects of different catalysts, bases, solvents and temperatures on the reaction were investigated. Finalized Yb(OTf) 3 It is the best catalyst, dichloroethane is the best solvent, rubidium carbonate is the best base, and the reaction temperature is 90°C.

Embodiment 2

[0031] Step 1: Add 1(50.4mg, 0.2mmol), 2(30.4mg, 0.4mmol), Rb in turn to the reaction tube 2 CO 3 (9.2mg, 0.04mmol), Yb(OTf) 3 (25mg, 0.04mmol), and dichloroethane 3mL. The mixture was warmed to 90°C and stirred for 8 hours. Monitored by TLC. The reaction mixture was concentrated in vacuo, followed by column chromatography to obtain product 3 as a white solid, yield 72%, 36.4 mg.

[0032] 1 H NMR (400MHz, CDCl 3 ):δ7.41-7.34(m,2H),7.04-6.95(m,2H),6.12(br,2H),4.81(t,J=8.0,1H),3.69(s,3H),3.39(dd ,J=14.0,8.4Hz,1H),3.10(dd,J=14.4,7.2Hz,1H);

[0033] 13 C NMR (150MHz, CDCl 3 ): δ166.7, 163.2, 162.3, 161.5, 137.6 (d, J C-F =3.0Hz), 128.9(d, J C-F =9.0Hz), 115.7(d, J C-F =21.0Hz), 90.6, 50.7, 41.8.

[0034] HRMS: exact mass calcd for C12H12FNO2S(M+H)+: requires m / z 254.0646, found m / z 264.0645.

[0035] Step 2: Add 3 (50.6 mg, 0.2 mmol) and 2 mL of dichloromethane into the reaction tube. The mixture was moved to -20°C and stirred, and DDQ (34 mg, 0.15 mol) was weighed ...

Embodiment 3

[0047] Step 1: Add 1 (50.4 mg, 0.2 mmol), 2 (30.4 mg, 0.4 mmol), Na 2 CO 3 (4.2mg, 0.04mmol), Yb(OTf) 3 (25mg, 0.04mmol), and dichloroethane 3mL. The mixture was warmed to 90°C and stirred for 8 hours. Monitored by TLC. The reaction mixture was concentrated in vacuo, followed by column chromatography to obtain product 3 as a white solid, yield 61%, 30.8 mg.

[0048] 1 H NMR (400MHz, CDCl 3 ):δ7.41-7.34(m,2H),7.04-6.95(m,2H),6.12(br,2H),4.81(t,J=8.0,1H),3.69(s,3H),3.39(dd ,J=14.0,8.4Hz,1H),3.10(dd,J=14.4,7.2Hz,1H);

[0049] 13 C NMR (150MHz, CDCl 3 ): δ166.7, 163.2, 162.3, 161.5, 137.6 (d, J C-F =3.0Hz), 128.9(d, J C-F =9.0Hz), 115.7(d, J C-F =21.0Hz), 90.6, 50.7, 41.8.

[0050] HRMS: exact mass calcd for C12H12FNO2S(M+H)+: requires m / z 254.0646, found m / z 264.0645.

[0051] Step 2: Add 3 (50.6 mg, 0.2 mmol) and 2 mL of dichloromethane into the reaction tube. The mixture was moved to -20°C and stirred, and DDQ (34 mg, 0.15 mol) was weighed and slowly added to the...

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Abstract

The invention relates to a method for synthesizing a thiophenes inhibitor TPCA-1, and belongs to the field of organic chemical drug synthesis. The method comprises the following steps: taking thioureaand 2-(4-fluorophenyl) cyclopropane-1,1-dimethyl isophthalate as starting raw materials, and the TPCA-1 is obtained through a multi-step reaction including a ring enlargement reaction, an oxidation reaction, an addition reaction and an amidation reaction in sequence. In the used route of the method, the reaction raw materials are easily obtained, the yield is high, and the TPCA-1 can be obtainedsuccessfully.

Description

technical field [0001] The invention relates to a method for synthesizing TPCA-1, which contains thiophene inhibitors, and belongs to the field of organic chemical drug synthesis. Background technique [0002] TPCA-1 (Chinese name: 5-(4-fluorophenyl)-2-ureidothiophene-3-carboxamide, CAS: 507475-17-4) is a novel and effective selective inhibitor of human IKK-2 . IκB kinase 2 (IKK-2) has been shown to play a key role in nuclear factor κB-regulated production of pro-inflammatory molecules by stimulating tumor necrosis factor-α (TNF-α) and interleukin (IL-1), suggesting that inhibition of IKK- 2 may be beneficial to the treatment of rheumatoid arthritis. [0003] At present, the synthesis method of this compound is less reported in the literature. For example, in the existing method, it is prepared after five steps of reaction. The reaction equation is as follows: [0004] [0005] In the above reaction, the starting material 2,5-dihydroxy-1,4-dithiane has a foul smell, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/42
CPCC07D333/42
Inventor 谢明胜秦涛郭海明王东超李建平渠桂荣
Owner HENAN NORMAL UNIV
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