Benzoyl fluoride benzene salicylamide compounds, preparation and application thereof

A technology of benzoyl phenylsalicylamide and benzoyl fluoride, which is applied in the field of preparation of anti-inflammatory and analgesic drugs, and can solve diflunisal poor solubility, side effects, and application limitations and other problems, to achieve the effect of easy industrial production, significant analgesic effect, and simple preparation process

Inactive Publication Date: 2008-12-10
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although diflunisal has been used clinically as a non-steroidal anti-inflammatory drug, the poor solubility of diflunisal and certain toxic and side effects limit its application. Therefore, by structuralizing diflunisal It is of great significance to prepare diflunisal prodrugs with good solubility, small side effects and strong anti-inflammatory activity, and will certainly attract the attention of more and more scientific workers.

Method used

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  • Benzoyl fluoride benzene salicylamide compounds, preparation and application thereof
  • Benzoyl fluoride benzene salicylamide compounds, preparation and application thereof
  • Benzoyl fluoride benzene salicylamide compounds, preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: Preparation of benzoyl fluorophenyl salicylic acid (II)

[0037]

[0038] Add 15g (0.06mol) of diflunisal, 50ml of dichloromethane, and 4.8g (0.06mol) of pyridine in sequence in the reaction flask, stir, add dropwise 8.5g (0.06mol) of benzoyl chloride, stir, and react at room temperature for 4h. After the reaction is completed, wash with dilute hydrochloric acid, suction filter, and dry to obtain 20.1 g of white solid, which is the crude product of benzoylfluorophenylsalicylic acid (II) (purity ≥ 85%), melting point: 167-172°C, and set aside;

[0039] 1 H NMR (500MHz, CDCl 3 ): δ (ppm): 6.96 (t, 1H, J = 8.0Hz, 3'-H), 7.00 (t, 1H, J = 8.0Hz, 5'-H), 7.35 (d, 1H, J = 7.5 Hz, 5-H), 7.46(m, 1H, 6'-H), 7.50(t, 2H, J=8.0Hz, 3", 5"-H), 7.65(t, 1H, J=7.6Hz, 4″-H), 7.80(d, 1H, J=8.0Hz, 6-H), 8.21(d, 2H, J=7.5Hz, 2″, 6″-H), 8.25(s, 1H, 2- H), 11.24(s, 1H, -COOH);

[0040] EIMS: m / z(%)=354(M + , 1.02).

Embodiment 2

[0041] Embodiment 2: Preparation of benzoyl fluoride benzene salicyloyl chloride (III)

[0042]

[0043] The benzoyl fluorophenylsalicylic acid crude product 3.54g (0.01mol), sulfur oxychloride 1.8g and 30m1CH prepared in Example 1 2 Cl 2 Added to the reaction bottle, reflux reaction for 4 hours. After the reaction was completed, evaporate to dryness under reduced pressure to obtain a light yellow solid, which is the crude product of benzoyl fluoride phenylsalicyloyl chloride (III) (purity ≥ 80%), and set aside.

Embodiment 3

[0044] Embodiment 3: Preparation of N-methylbenzoyl fluorophenyl salicylamide (I-1)

[0045]

[0046] Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add dropwise 2.6g of 30% methylamine aqueous solution, and react at room temperature for 4h. Evaporate to dryness under reduced pressure and recrystallize to obtain 2.9 g of N-methylbenzoylfluorophenylsalicylamide, melting point: 147-150°C (uncorrected);

[0047] 1 H NMR (400MHz, CDCl 3 ): δ (ppm): 2.89 (d, 3H, J=4.8Hz, CH 3 ), 6.36(s, 1H, NH), 6.94(t, 1H, J=8.4Hz, 3′-H), 7.00(t, 1H, J=8.2Hz, 5′-H), 7.31(d, 1H , J=8.4Hz, 5-H), 7.45(m, 1H, 6′-H), 7.56(t, 2H, J=7.6Hz, 3″, 5″-H), 7.65(d, 1H, J =8.4Hz, 6-H), 7.69(t, 1H, J=7.6Hz, 4″-H), 7.94(s, 1H, 2-H), 8.27(d, 2H, J=6.8Hz, 2″ , 6″-H);

[0048] EIMS: m / z(%)=367(M + , 1.36).

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Abstract

The invention provides a benzoyl fluorobenzene salicylamide compound and a preparation method and an application thereof. The benzoyl fluorobenzene salicylamide compound with a structure shown in a formula (I) is formed by the substitution reaction of benzoyl fluorobenzene salicyloylchloride as shown in a formula (III) and R1R2NH in an organic solvent at a temperature of between 0 and 160 DEG C. Derivatives of the benzoyl fluorobenzene salicylamide compound and the preparation method and the application thereof of the invention have the advantages of: (1) providing a novel anti-inflammatory and analgesic drug with remarkable anti-inflammatory and analgesic activities, and providing a research basis for selecting novel drugs; (2) simple preparation process and applicability industrialized production.

Description

(1) Technical field [0001] The present invention relates to a new substance with anti-inflammatory and analgesic activity—benzoyl fluorophenyl salicylic amide compound and its preparation method, as well as its application in the preparation of anti-inflammatory and analgesic drugs. (2) Background technology [0002] Benzoyl fluorophenyl salicylamide derivatives are compounds containing fluorine atoms. Due to the small radius of the fluorine atom and the largest electronegativity, the energy of the formed C-F bond is much greater than that of the C-H bond, which increases the stability of fluorine-containing organic compounds; and because of the small size of the fluorine atom, it is often considered to be The non-classical electron isostere of H atom is easy to produce antagonism, that is, it does not interfere with the interaction between fluorine-containing drugs and corresponding cell receptors, can replace normal metabolic drugs at the molecular level, and deceptively i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/58C07C231/02C07D295/192A61K31/616A61K31/625A61P29/00
Inventor 钟光祥陈路路李建
Owner ZHEJIANG UNIV OF TECH
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