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Design and preparation method of novel rofecoxib derivative

A technology of rofecoxib and derivatives, which is applied in the field of preparation of rofecoxib furan analogs, and can solve problems such as increasing the risk of heart disease or stroke

Inactive Publication Date: 2022-06-21
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But taking rofecoxib can increase the risk of heart disease or stroke, and rofecoxib has been withdrawn due to cardiovascular safety risks

Method used

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  • Design and preparation method of novel rofecoxib derivative
  • Design and preparation method of novel rofecoxib derivative
  • Design and preparation method of novel rofecoxib derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Embodiment 2: The reaction steps of the method for preparing novel rofecoxib derivative TW-2:

[0019] Add 4 mL of solvent MeCN, compound 4-thiamphenicol phenyl-β-chloro-ethylene-1,3-dithiane (167 mg) and 4-thiamphenicol benzaldehyde (53 mg) into the reaction flask, and add KOH ( 34 mg), reacted at room temperature for 10 minutes, added dilute acid to adjust the pH to neutral, separated and purified to obtain the target compound TW-2 (151 mg, 75%).

[0020] The structure of embodiment 2 gained product TW-2, nuclear magnetic data are as follows:

[0021] 1H NMR (400MHz, Chloroform-d) δ7.90 (d, J=8.5Hz, 2H), 7.60-7.55(m, 2H), 7.51-7.46(m, 2H), 7.41-7.38(m, 2H), 7.28(dd, J=8.6, 1.9Hz, 1H), 6.68(s, 1H), 3.09(s, 3H), 3.00(t, J=7.0Hz, 2H), 2.75–2.68(m, 2H), 1.99 (q,J=7.0Hz,2H),1.37(t,J=8.1Hz,1H).

[0022] Embodiment 3: The reaction steps of the method for preparing novel rofecoxib derivative TW-3:

Embodiment 2

[0023] TW-1 (81 mg) was dissolved in 10 mL of methanol and placed in a reaction flask, and Raney nickel (290 mg) was added to react for 24 h for reduction to obtain the target compound TW-3 (53 mg, 89%).

[0024] The structure of embodiment 3 gained product TW-3, nuclear magnetic data are as follows:

[0025] 1H NMR (400MHz, Chloroform-d) δ7.88–7.76(m,2H),7.75–7.66(m,2H),7.57(d,J=1.8Hz,1H),7.47–7.33(m,5H), 6.65– 6.52(m,1H),3.05(s,4H).13C NMR(101MHz,Chloroform-d)δ146.34, 142.91,138.54,136.19,133.56,128.96,128.81,128.72,128.62,127.92, 1226.20, ,126.09,125.62,114.82,44.48.

[0026] Embodiment 4: The reaction steps of the method for preparing novel rofecoxib derivative TW-4:

[0027] TW-2 (83 mg) was dissolved in 10 mL ethanol and placed in a reaction flask, and Raney nickel (297 mg) was added to react for 24 h for reduction to obtain the target compound TW-4 (54 mg, 89%).

Embodiment 3

[0029] 1H NMR (400MHz, Chloroform-d) δ7.97–7.80(m,2H),7.69–7.43(m,4H),7.38–7.20(m,3H),6.58(d,J=2.1Hz,1H), 3.08(s, 3H).13C NMR(101MHz,CDCl3)δ146.34,142.91,138.54,136.19,133.56, 128.96,128.81,128.72,128.62,128.09,127.92,127.56,126.20,126.09, 125.62,114.82,77.36,77.04, 76.73, 44.48.

[0030] Embodiment 5: The reaction steps of the method for preparing novel rofecoxib derivative TW-6:

[0031] Add 4mL DMSO, compound 4-thiamphenylphenyl-β-chloro-ethylene-1,3-dithiane (167mg) and 4-fluorobenzaldehyde (62mg) into the reaction flask, add tBuOK (67mg) under stirring, React at room temperature for 10 minutes, add dilute hydrochloric acid to adjust the pH to neutral, separate and purify to obtain TW-5 compound, spin to dry the solvent, add methanol, add Raney nickel (299mg), react for 24h, and obtain TW-6 (41mg, 65% )

[0032] The structure of embodiment 5 gained product TW-6, nuclear magnetic data are as follows:

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Abstract

The invention provides a design and preparation method of a novel rofecoxib derivative, and the novel rofecoxib furan derivatives TW-1, TW-2, TW-3, TW-4, TW-5 and TW-6 are designed and synthesized by changing the structure and position of a five-membered ring and adjusting and changing the position of a 4-methylsulfone benzene ring. The novel rofecoxib derivative provides possibility for searching rofecoxib similar drug molecules with higher pharmacological activity or lower toxicity.

Description

technical field [0001] The invention belongs to the field of medicines, in particular to a preparation method of rofecoxib furan analogs. Background technique [0002] Rofecoxib (Refocoxib) is a non-steroidal anti-inflammatory drug and a representative drug of cyclooxygenase inhibitors. Its excellent analgesic and anti-inflammatory activity has great research value and wide application. However, taking rofecoxib can increase the risk of heart disease or stroke, and rofecoxib has been withdrawn from the market due to cardiovascular safety risks. Therefore, looking for rofecoxib derivatives with higher pharmacological activity or lower toxic and side effects has become a research hotspot for a time. According to the structure-activity relationship of substituents in the structure of rofecoxib, the present invention designs a furan type lead compound of rofecoxib. [0003] The structure of rofecoxib: [0004] Derivatives with the structure of rofecoxib have been reported...

Claims

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Application Information

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IPC IPC(8): C07D307/64C07D307/38
CPCC07D307/64C07D307/38
Inventor 唐寿初吴志华李嘉董康王晓磊刘剑
Owner LANZHOU UNIVERSITY
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