CN101318909B - Benzoyl fluoride benzene salicylamide compounds, preparation and application thereof - Google Patents

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

A kind of benzoyl fluorophenyl salicylamide compound and its preparation and application

(1) Technical field

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

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 incorporate biomacromolecules , leading to lethal synthesis. When fluorine atoms are introduced into the drug molecule, its electrical effect and analog effect not only change the distribution of electron density inside the molecule, but also improve the fat solubility and permeability of the compound, and the solubility on the biomembrane is enhanced. The speed of absorption and transmission in organisms changes the physiological effects. Therefore, fluorine-containing drugs have the characteristics of less dosage, low toxicity, high efficacy, and strong metabolism. Because fluorine-containing drugs have excellent, unique and valuable properties, they are favored by medical researchers and related companies.

The research and development of fluorine-containing drugs mainly focus on the research and development of fluorine-containing aromatic and heterocyclic compounds, such as diflunisal (flunyl salicylic acid), which has good anti-inflammatory activity. 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 Modification and preparation of diflunisal prodrugs with good solubility, few side effects and strong anti-inflammatory activity are of great significance and will certainly attract the attention of more and more scientific workers.

(3) Contents of the invention

The object of the present invention is to provide a new benzoyl fluoride phenyl salicylamide anti-inflammatory drugs - benzoyl fluoride phenyl salicylamide compounds and preparation methods thereof, and the derivatives in anti-inflammatory, analgesic drugs in the application.

The technical scheme adopted in the present invention is:

A kind of benzoyl fluorophenyl salicylamide compound, structure is as shown in formula (I):

In formula (I):

R ₁ and R ₂ are independently H, C1-C6 alkyl or substituted alkyl, C3-C6 cycloalkyl, C6-C10 aryl or substituted aryl, and the substituents of the substituted alkyl are: Phenyl, halogen, nitro or C1-C3 alkoxy, the substituents of the substituted aryl are: halogen, nitro, C1-C3 alkoxy, C1-C3 alkyl; or R ₁ , R ₂ They are connected to form a ring, and the N connected to R ₁ and R ₂ constitutes a C4-C10 heterocyclic group.

Preferably, in the formula (I): R ₁ is H or C1-C4 alkyl, R ₂ is C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, benzyl, 1-2 C1~C3 alkyl substituted phenyl, halogen substituted phenyl, C1~C3 alkoxy substituted phenyl, or R ₁ and R ₂ are connected to form a ring, and N connected to R ₁ and R ₂ forms N- Methylpiperazinyl or morpholinyl.

More preferably, in the formula (I): _R is H, methyl or ethyl, methyl, ethyl, propyl, cyclohexane, benzyl, phenyl, o-tolyl, m-toluene base, p-tolyl, 2,5-dimethylphenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, p-methoxyphenyl, or R ₁ and R ₂ are connected to form a ring, and the same N Constitute N-methylpiperazinyl or morpholinyl.

More preferably, the benzoyl fluoride phenyl salicylamide compound is one of the following:

The present invention also relates to a method for preparing the benzoyl fluoride phenyl salicylic amide compound, the method comprising: using benzoyl fluoride phenyl salicyloyl chloride represented by formula (III) as a raw material, and R ₁ R ₂ NH is subjected to a substitution reaction in an organic solvent at 0 to 160°C to obtain the benzoyl fluorophenyl salicylamide compound, and R ₁ and R ₂ are as defined above;

The organic solvent is one of the following: C3-C8 ketones, C4-C8 ethers, C2-C4 nitriles, C1-C3 halogenated hydrocarbons, C6-C8 aromatic hydrocarbons, C4-C8 alkanes or C2-C8 C5 amides;

The ratio of the amount of benzoyl fluoride benzene salicyloyl chloride to the R ₁ R ₂ NH substance is 1:0.5-5.

The substitution reaction temperature for preparing the benzoyl fluorophenyl salicylamide compound is preferably carried out at room temperature, and the reaction time is preferably 0.5-5 hours.

Preferably, the organic solvent is one of the following: acetone, ether, acetonitrile, methylene chloride, dimethyl sulfoxide, benzene, cyclohexane, N, N-dimethylformamide or chloroform, the organic solvent mass The dosage is 4 to 20 times the mass of benzoyl fluoride phenylsalicyloyl chloride.

Specifically, the method is as follows:

(1), by fluorophenyl salicylic acid and benzoyl chloride in chloroform or dichloromethane, react to obtain the benzoyl fluorophenyl salicylic acid shown in formula (II); The quality of described chloroform or dichloromethane It is 4 to 20 times the mass of Fluorben salicylic acid;

The reaction formula is as follows:

(2), benzoyl fluorophenyl salicylic acid shown in formula (II) and sulfur oxychloride in chloroform or methylene chloride, react to obtain benzoyl fluorophenyl salicylic acid chloride shown in formula (III); The quality of described chloroform or dichloromethane is 4～20 times of the quality of benzoyl fluorophenyl salicylic acid;

The reaction formula is as follows:

(3), using benzoyl fluoride phenyl salicyloyl chloride represented by formula (III) as a raw material, and R ₁ R ₂ NH in an organic solvent, carry out a substitution reaction at normal temperature to obtain the benzoyl fluoride phenyl salicylate Amide compounds (I); the organic solvent is one of the following: acetone, ether, acetonitrile, methylene chloride, dimethyl sulfoxide, benzene, toluene, cyclohexane, N,N-dimethylformamide or chloroform , the ratio of the amount of said benzoyl fluoride phenyl salicyloyl chloride to R ₁ R ₂ NH substance is 1: 0.5～5; 20 times.

The reaction formula is as follows:

The present invention also relates to the application of the benzoyl fluoride phenyl salicylamide compound in the preparation of anti-inflammatory drugs. Experimentally confirmed that compounds (I-1), (I-2), (I-4), (I-5), (I-8), (I-9), (I-10), (I- 12), (I-13), (I-15), (I-16), (I-17) all have certain anti-inflammatory effects, among which: compound (I-16) has better anti-inflammatory activity, Compounds (I-1), (I-5) have significant anti-inflammatory activity.

Application of the benzoyl fluorophenyl salicylamide compound in the preparation of analgesics. Experimentally confirmed that compounds (I-1), (I-2), (I-3), (I-4), (I-6), (I-7), (I-8), (I- 9), (I-10), (I-12), (I-13), (I-15), (I-16), (I-17), (I-18) all have certain analgesic effects effect, wherein: compounds (I-1), (I-7) and (I-18) have better analgesic activity, compounds shown in formula (I-16), (I-17) have significant analgesic active.

Benzoyl fluoride phenyl salicylic amide compound derivatives of the present invention and the beneficial effects of preparation and application are mainly reflected in: (1), providing a new anti-inflammatory, Analgesic drugs provide a research basis for new drug screening; (2), compounds shown in formulas (I-1), (I-5) have particularly significant anti-inflammatory effects; (3), formulas (I-16), The compound shown in (I-17) has a particularly significant analgesic effect; (4), the compound of the present invention has a simple preparation process and is easy for industrial production.

(4) Specific implementation methods

The present invention is further described below in conjunction with specific embodiment, but protection scope of the present invention is not limited thereto:

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

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;

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=7.5Hz, 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);

EIMS: m/z (%) = 354 (M ⁺ , 1.02).

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

Add 3.54 g (0.01 mol) of the crude product of benzoylfluorophenylsalicylic acid prepared in Example 1, 1.8 g of thionyl chloride and 30 ml of CH ₂ Cl ₂ into the reaction flask, and react under reflux 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: Preparation of N-methylbenzoyl fluorophenyl salicylamide (I-1)

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);

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);

EIMS: m/z (%) = 367 (M ⁺ , 1.36).

Embodiment 4: Preparation of N-ethylbenzoyl fluorophenyl salicylamide (I-2)

Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add 1.4g of 60-70% ethylamine solution dropwise, and react at room temperature for 2-4h. Evaporate to dryness under reduced pressure and recrystallize to obtain 2.8 g of N-ethylbenzoylfluorophenylsalicylamide, melting point: 128-131°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ(ppm): 1.00(t, 3H, J=7.2Hz, CH ₃ ), 3.37(q, 2H, J=6.4Hz, CH ₂ ), 6.31(s, 1H , NH), 6.94(t, 1H, J=8.4Hz, 3′-H), 6.98(t, 1H, J=8.4Hz, 5′-H), 7.31(d, 1H, J=8.4Hz, 5 -H), 7.45(m, 1H, 6'-H), 7.55(t, 2H, J=7.6Hz, 3", 5"-H), 7.65(d, 1H, J=8.4Hz, 6-H ), 7.69(t, 1H, J=7.2Hz, 4″-H), 7.95(s, 1H, 2-H), 8.22(d, 2H, J=7.2Hz, 2″, 6″-H);

EIMS: m/z (%) = 381 (M ⁺ , 2.19).

Embodiment 5: Preparation of N-propylbenzoyl fluorophenyl salicylamide (I-3)

Add all the crude benzoyl fluoride phenylsalicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add 1.2g of n-propylamine dropwise, and react at room temperature for 3h. Evaporate to dryness under reduced pressure and recrystallize to obtain 3.0 g of N-n-propylbenzoylfluorophenylsalicylicamide, melting point: 145-150°C (uncorrected).

¹ H NMR (400MHz, CDCl ₃ ): δ(ppm): 0.81(t, 3H, J=7.6Hz, CH ₃ ), 1.40(m, 2H, CH ₂ ), 3.30(q, 2H, J=6.0Hz , CH ₂ ), 6.37(s, 1H, NH), 6.95(t, 1H, J=8.4Hz, 3'-H), 6.99(t, 1H, J=8.4Hz, 5'-H), 7.31( d, 1H, J=8.4Hz, 5-H), 7.46(m, 1H, 6'-H), 7.56(t, 2H, J=7.6Hz, 3", 5"-H), 7.66(d, 1H, J=8.4Hz, 6-H), 7.70(t, 1H, J=7.2Hz, 4″-H), 7.96(s, 1H, 2-H), 8.23(d, 2H, J=7.6Hz , 2″, 6″-H);

EIMS: m/z (%) = 395 (M ⁺ , 1.73).

Embodiment 6: Preparation of N, N-dimethylbenzoyl fluorophenyl salicylamide (I-4)

Add all the crude benzoyl fluoride phenylsalicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add dropwise 2.8g of 33% dimethylamine aqueous solution, and react at room temperature for 2.5h. Evaporate to dryness under reduced pressure and recrystallize to obtain 2.9 g of N,N-dimethylbenzoylfluorophenylsalicylamide, melting point: 123-128°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ(ppm): 2.95, 3.03 (s, s, 6H, J=4.80Hz, CH ₃ ), 6.93 (t, 1H, J=8.4Hz, 3′-H) , 6.97(t, 1H, J=8.2Hz, 5′-H), 7.42(d, 1H, J=8.0Hz, 5-H), 7.42(m, 1H, 6′-H), 7.51(s, 1H, 2-H), 7.51(t, 2H, J=7.6Hz, 3", 5"-H), 7.59(d, 1H, J=8.0Hz, 6-H), 7.65(t, 1H, J =7.6Hz, 4″-H), 8.17(d, 2H, J=7.6Hz, 2″, 6″-H);

EIMS: m/z (%) = 381 (M ⁺ , 15.57).

Embodiment 7: Preparation N, N-diethylbenzoyl fluorophenyl salicylamide (I-5)

Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add 1.7g of diethylamine dropwise, and react at room temperature for 3.5h. Evaporate to dryness under reduced pressure and recrystallize to obtain 3.1 g of N,N-diethylbenzoylfluorophenylsalicylamide, melting point: 125-128°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm): 1.02, 1.08 (t, t, 6H, J=7.2Hz, CH ₃ ), 3.24 (m, 4H, CH ₂ ), 6.94 (t, 1H, J=8.4Hz, 3'-H), 6.98(t, 1H, J=8.4Hz, 5'-H), 7.43(d, 1H, J=8.4Hz, 5-H), 7.43(m, 1H, 6'-H), 7.50(t, 3H, J=7.6Hz, 2, 3", 5"-H), 7.58(d, 1H, J=8.0Hz, 6-H), 7.64(t, 1H, J=8.0Hz, 4″-H), 8.18(d, 2H, J=7.2Hz, 2″, 6″-H);

EIMS: m/z (%) = 409 (M ⁺ , 4.78).

Embodiment 8: Preparation of N-cyclohexylbenzoyl fluorophenyl salicylamide (I-6)

Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add dropwise 2.0g of cyclohexylamine, and react at room temperature for 4h. Evaporate to dryness under reduced pressure and recrystallize to obtain 3.9 g of N-cyclohexylbenzoyl phenyl salicylamide, melting point: 154-157°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ(ppm): 0.98 (m, 2H, 3″′, 5″′-CH ₂ ), 1.06 (m, 2H, 4″′-CH ₂ ), 1.28 (m , 2H, 3″′, 5″′-CH ₂ ), 1.56 (m, 2H, 2″′, 6″′-CH ₂ ), 1.80 (m, 2H, 2″′, 6″′-CH ₂ ) , 3.86(m, 1H, 1"'-CH), 6.23(d, 1H, J=8.0Hz, NH), 6.93(t, 1H, J=8.0Hz, 3'-H), 6.97(t, 1H , J=8.0Hz, 5'-H), 7.28(d, 1H, J=8.4Hz, 5-H), 7.45(m, 1H, 6'-H), 7.55(t, 2H, J=8.0Hz , 3″, 5″-H), 7.64 (d, 1H, J=8.0Hz, 6-H), 7.69 (t, 1H, J=7.6Hz, 4″-H), 7.93 (s, 1H, 2 -H), 8.22(d, 2H, J=7.6Hz, 2″-H);

EIMS: m/z (%) = 435 (M ⁺ , 1.64).

Embodiment 9: Preparation of N-benzylbenzoyl fluorophenyl salicylamide (I-7)

Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add 2.2g of benzylamine dropwise, and react at room temperature for 4h. Evaporate to dryness under reduced pressure and recrystallize to obtain 3.8 g of N-benzylbenzoyl fluorophenylsalicylamide, melting point: 150-154°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ(ppm): 4.52(d, 2H, J=5.2Hz, CH ₂ ), 6.66(s, 1H, NH), 6.94(t, 1H, J=8.0Hz, 3'-H), 6.98(t, 1H, J=8.0Hz, 5'-H), 7.14(m, 5H, Ar"'H), 7.29(d, 1H, J=8.4Hz, 5-H) , 7.46(m, 1H, 6'-H), 7.47(t, 2H, J=7.6Hz, 3", 5"-H), 7.66(t, 1H, J=7.2Hz, "-H), 7.67 (d, 1H, J=7.6Hz, 6-H), 8.03(s, 1H, 2-H), 8.07(d, 2H, J=7.2Hz, 2″, 6″-H);

EIMS: m/z (%) = 443 (M ⁺ , 1.00).

Embodiment 10: Preparation of N-phenylbenzoyl fluorophenyl salicylamide (I-8)

Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add 2.2g of aniline dropwise, and react at room temperature for 4h. Evaporate to dryness under reduced pressure and recrystallize to obtain 3.8 g of N-phenylbenzoyl fluorophenylsalicylic acid amide, melting point: 139-140°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ(ppm): 6.96 (t, 1H, J=8.4Hz, 3′-H), 7.00 (t, 1H, J=8.4Hz, 5′-H), 7.08 (t, 1H, J=7.6Hz, 4"'-H), 7.26(t, 2H, J=8.0Hz, 3"', 5"'-H), 7.37(d, 1H, J=8.0Hz, 5-H), 7.45(d, 2H, J=7.6Hz, 2"', 6"'-H), 7.47(m, 1H, 6'-H), 7.55(t, 2H, J=7.6Hz, 3", 5"-H), 7.69(t, 1H, J=7.6Hz, 4"-H), 7.72(d, 1H, J=8.0Hz, 6-H), 8.10(s, 1H, 2- H), 8.23(s, 1H, NH), 8.24(d, 2H, J=7.2Hz, 2″, 6″-H);

EIMS: m/z (%) = 429 (M ⁺ , 0.89).

Example 11: Preparation of N-(o-tolyl)-benzoyl fluorophenyl salicylamide (I-9)

Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add 2.2g of o-toluidine dropwise, and react at room temperature for 4h. Evaporate to dryness under reduced pressure and recrystallize to obtain 4.0 g of N-(o-tolyl)-benzoylfluorophenylsalicylamide, melting point: 165-168°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ(ppm): 2.18(s, 3H, CH ₃ ), 6.96(t, J=8.4Hz, 1H, 3′-H), 7.00(t, 1H, J= 8.0Hz, 5'-H), 7.07(t, 1H, J=7.2Hz, 4"'-H), 7.14(d, 1H, J=7.6Hz, 3"'-H), 7.20(t, 1H , J=6.8Hz, 5"'-H), 7.36(d, 1H, J=8.4Hz, 5-H), 7.48(m, 1H, 6'-H), 7.53(t, 2H, J=7.6 Hz, 3″, 5″-H), 7.68(t, 1H, J=7.6Hz, 4″-H), 7.72(d, 1H, J=8.4Hz, 6-H), 7.85(d, 1H, J=8.4Hz, 6"'-H), 7.90(s, 1H, -NH), 8.09(s, 1H, 2-H), 8.22(d, 2H, J=7.2Hz, 2", 6"- H);

EIMS: m/z (%) = 443 (M ⁺ , 0.33).

Example 12: Preparation of N-(m-tolyl)-benzoyl fluorophenyl salicylamide (I-10)

Add all the crude product of benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add 2.2g of m-toluidine dropwise, and react at room temperature for 4h. Evaporate to dryness under reduced pressure and recrystallize to obtain 4.1 g of N-(m-tolyl)-benzoylfluorophenylsalicylamide, melting point: 130-133°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ(ppm): 2.28(s, 3H, CH ₃ ), 6.90(d, 1H, J=7.6Hz, 4″′-H), 6.96(t, J=8.4 Hz, 3'-H), 7.00(t, 1H, J=8.0Hz, 5'-H), 7.14(t, 1H, J=8.0Hz, 5"'-H), 7.24(d, 1H, J =8.0Hz, 6"'-H), 7.25(s, 1H, 2"'-H), 7.38(d, 1H, J=8.4Hz, 5-H), 7.48(m, 1H, 6'-H ), 7.55(t, 2H, J=8.4Hz, 3″, 5″-H), 7.68(t, 1H, J=7.6Hz, 4″-H), 7.71(d, 1H, J=8.4Hz, 6-H), 8.11(s, 1H, 2-H), 8.20(s, 1H, NH), 8.25(d, 2H, J=7.2Hz, 2″, 6″-H);

EIMS: m/z (%) = 443 (M ⁺ , 1.25).

Example 13: Preparation of N-(p-tolyl)-benzoyl fluorophenyl salicylamide (I-11)

Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add 2.2g of p-toluidine dropwise, and react at room temperature for 4h. Evaporate to dryness under reduced pressure and recrystallize to obtain 4.1 g of N-(p-tolyl)-benzoylfluorophenylsalicylamide, melting point: 178-180°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ(ppm): 2.28(s, 3H, CH ₃ ), 6.96(t, 1H, J=8.4Hz, 3′-H), 7.00(t, 1H, J= 8.4Hz, 5'-H), 7.07(d, 2H, J=8.4Hz, 3"', 5"'-H), 7.33(d, 2H, J=8.4Hz, 2"', 6"'- H), 7.37(d, 1H, J=8.4Hz, 5-H), 7.48(m, 1H, 6'-H), 7.54(t, 2H, J=8.0Hz, 3", 5"-H) , 7.69(t, 1H, J=7.2Hz, 4″-H), 7.71(d, 1H, J=6.0Hz, 6-H), 8.10(s, 1H, 2-H), 8.18(s, 1H , NH), 8.24 (d, 2H, J=8.0Hz, 2″, 6″-H);

EIMS: m/z (%) = 443 (M ⁺ , 2.48).

Example 14: Preparation of N-(2,5-dimethylphenyl)-benzoyl fluorophenyl salicylamide (I-12)

Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add 2.4g of 2,5-dimethylaniline dropwise, and react at room temperature for 4h. Evaporate to dryness under reduced pressure and recrystallize to obtain 4.1 g of N-(2,5-dimethylphenyl)-benzoylfluorophenylsalicylamide, melting point: 174-176°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm): 2.10 (s, 3H, 2″′-CH ₃ ), 2.27 (s, 3H, 5″′-CH ₃ ), 6.87 (d, 1H, J =7.6Hz, 4"'-H), 6.96(t, 1H, J=8.4Hz, 3'-H), 6.99(t, 1H, J=8.0Hz, 5'-H), 7.00(d, 1H , J=7.2Hz, 3"'-H), 7.35(d, 1H, J=8.4Hz, 5-H), 7.48(m, 1H, 6'-H), 7.51(t, 2H, J=8.0 Hz, 3″, 5″-H), 7.61 (s, 1H, 6″′-H), 7.66 (t, 1H, J=7.6Hz, 4″-H), 7.71 (d, 1H, J=7.6 Hz, 6-H), 7.83(s, 1H, NH), 8.07(s, 1H, 2-H), 8.212(d, 2H, J=7.2Hz, 2″, 6″-H);

EIMS: m/z (%) = 457 (M ⁺ , 0.88).

Example 15: Preparation of N-(o-chlorophenyl)-benzoyl fluorophenyl salicylamide (I-13)

Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add 2.6g of o-chloroaniline dropwise, and react at room temperature for 4h. Evaporate to dryness under reduced pressure and recrystallize to obtain 4.0 g of N-(o-chlorophenyl)-benzoylfluorophenylsalicylamide, melting point: 139-141°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ(ppm): 6.96 (t, 1H, J=8.4Hz, 3′-H), 6.99 (t, 1H, J=8.0Hz, 5′-H), 7.03 (t, 1H, J=7.2Hz, 4"'-H), 7.26(d, 1H, J=7.2Hz, 3"'-H), 7.29(t, 1H, J=8.0Hz, 5"'- H), 7.37(d, 1H, J=8.4Hz, 5-H), 7.49(m, 1H, 6'-H), 7.51(t, 2H, J=7.6Hz, 3", 5"-H) , 7.66(t, 1H, J=7.2Hz, 4″-H), 7.74(d, 1H, J=8.4Hz, 6-H), 8.14(s, 1H, 2-H), 8.23(d, 2H , J=7.6Hz, 2", 6"-H), 8.47(d, 1H, J=7.6Hz, 6"'-H), 8.67(s, 1H, NH);

EIMS: m/z (%) = 463 (M ⁺ , 0.37).

Example 16: Preparation of N-(m-chlorophenyl)-benzoyl fluorophenyl salicylamide (I-14)

Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add 2.6g of m-chloroaniline dropwise, and react at room temperature for 4h. Evaporate to dryness under reduced pressure and recrystallize to obtain 4.2 g of N-(m-chlorophenyl)-benzoylfluorophenylsalicylamide, melting point: 157-159°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ(ppm): 6.97 (t, 1H, J=8.4Hz, 3'-H), 7.00 (t, 1H, J=8.4Hz, 5'-H), 7.05 (d, 1H, J=8.0Hz, 4"'-H), 7.17(t, 1H, J=8.0Hz, 5"'-H), 7.28(d, 1H, J=8.0Hz, 5-H) , 7.38(d, 1H, J=8.4Hz, 6"'-H), 7.47(m, 1H, 6'-H), 7.54(s, 1H, 2"'-H), 7.57(t, 2H, J=7.6Hz, 3″, 5″-H), 7.69(t, 1H, J=8.0Hz, 4″-H), 7.73(d, 1H, J=8.0Hz, 6-H), 8.10(s , 1H, 2-H), 8.25(d, 2H, J=7.6Hz, 2″-H), 8.30(s, 1H, NH);

EIMS: m/z (%) = 463 (M ⁺ , 16.55).

Example 17: Preparation of N-(p-chlorophenyl)-benzoyl fluorophenyl salicylamide (I-15)

Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add 2.6g of p-chloroaniline dropwise, and react at room temperature for 4h. Evaporate to dryness under reduced pressure and recrystallize to obtain 4.1 g of N-(p-chlorophenyl)-benzoylfluorophenylsalicylamide, melting point: 172-175°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm): 6.97 (t, 1H, J=8.4Hz, 3′-H), 7.01 (t, 1H, J=8.0Hz, 5′-H), 7.23 (d, 2H, J=7.6Hz, 3″′, 5″′-H), 7.39 (d, 2H, J=8.4Hz, 2″′, 6″′-H), 7.41 (d, 1H, J =8.0Hz, 5-H), 7.49(m, 1H, 6'-H), 7.56(t, 2H, J=7.6Hz, 3", 5"-H), 7.72(t, 1H, J=8.0 Hz, 4″-H), 7.74 (d, 1H, J=8.0Hz, 6-H), 8.12 (s, 1H, 2-H), 8.24 (d, 2H, J=7.6Hz, 2″, 6 "-H), 8.30(s, 1H, NH);

EIMS: m/z (%) = 463 (M ⁺ , 0.61).

Example 18: Preparation of N-(p-methoxyphenyl)-benzoyl fluorophenyl salicylamide (I-16)

Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add 2.5g of p-methoxyaniline dropwise, and react at room temperature for 4h. Evaporate to dryness under reduced pressure and recrystallize to obtain 3.8 g of N-(p-methoxyphenyl)-benzoylfluorophenylsalicylamide, melting point: 184-185°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm): 3.79 (s, 3H, -CH ₃ ), 6.79 (d, 2H, J=8.4Hz, 3″′, 5″′-H), 6.95 ( t, 1H, J=8.4Hz, 3'-H), 6.99(t, 1H, J=7.6Hz, 5'-H), 7.34(d, 1H, J=8.0Hz, 5-H), 7.35( d, 3H, J=8.0Hz, 2"', 6"'-H), 7.47(m, 1H, 6'-H), 7.54(t, 2H, J=7.6Hz, 3", 5"-H ), 7.69(t, 1H, J=8.0Hz, "-H), 7.70(d, 1H, J=8.4Hz, 6-H), 8.09(s, 1H, 2-H), 8.12(s, 1H , NH), 8.24 (d, 2H, J=8.0Hz, 2″, 6″-H);

EIMS: m/z (%) = 459 (M ⁺ , 6.79).

Example 19: Preparation of N-(4-methylpiperazinyl)-benzoyl fluorophenyl salicylamide (I-17)

Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add 2.0g of N-methylpiperazine dropwise, and react at room temperature for 4h. Evaporate to dryness under reduced pressure and recrystallize to obtain 3.8 g of N-(4-methylpiperazinyl)-benzoylfluorophenylsalicylamide, melting point: 154-157°C (uncorrected);

¹ H NMR (500MHz, CDCl ₃ ): δ(ppm): 2.20(s, 3H, -CH ₃ ), 2.28(t, 4H, J=4.2Hz, 3″'-CH ₂ ), 3.38, 3.720(t , t, 4H, J=4.8Hz, 2″′-CH ₂ ), 6.94 (t, 1H, J=8.0Hz, 3′-H), 6.97 (t, 1H, J=8.0Hz, 5′-H ), 7.42(d, 1H, J=8.4Hz, 5-H), 7.42(m, 1H, 6'-H), 7.49(s, 1H, 2-H), 7.51(t, 2H, J=8.0 Hz, 3", 5"-H), 7.60(d, 1H, J=8.0Hz, 6-H), 7.65(t, 1H, J=7.6Hz, 4"-H), 8.18(d, 2H, J=8.0,2"-H);

EIMS: m/z (%) = 436 (M ⁺ , 6.91).

Example 20: Preparation of N-(4-morpholinyl)-benzoyl fluorophenyl salicylamide (I-18)

Add all the crude benzoyl fluoride benzene salicyloyl chloride and 30ml of dichloromethane into the reaction flask, stir, add dropwise 1.8g of morpholine, and react at room temperature for 3.5h. Evaporate to dryness under reduced pressure and recrystallize to obtain 3.7 g of N-(4-morpholinyl)-benzoylfluorophenylsalicylamide, melting point: 169-172°C (uncorrected);

¹ H NMR (400MHz, CDCl ₃ ): δ(ppm): 3.45 (m, 4H, 2″′, 6″′-CH ₂ ), 3.60 (m, 4H, 3″′, 5″′-CH ₂ ) , 6.95(t, 1H, J=8.0Hz, 3'-H), 7.00(t, 1H, J=8.0Hz, 5'-H), 7.42(d, 1H, J=8.4Hz, 5-H) , 7.43(m, 1H, 6'-H), 7.53(s, 1H, 2-H), 7.55(t, 2H, J = 7.6, 3", 5"-H), 7.63(d, 1H, J =8.0Hz, 6-H), 7.69(t, 1H, J=7.6Hz, 4″-H), 8.21(d, 2H, J=7.6Hz, 2″, 6″-H);

EIMS: m/z (%) = 423 (M ⁺ , 6.70).

Example 21: Anti-inflammatory activity test

(1) Screening model: xylene-induced ear swelling in mice

Experimental animals: Kunming mice, both male and female, 18-24g;

(2), sample processing

1. First weigh a certain amount of sample and add a small amount of 1% (w/w) CMC (sodium carboxymethylcellulose) to grind, then add 1% CMC to make a 4 mg/ml suspension. Inject at a volume of 0.1ml/10g body weight, shake and mix well before injection.

2. Use 1% CMC as solvent control.

(3), experimental steps

The mice were randomly divided into groups, and the solvent control 1% CMC or the test compound 40 mg/kg was orally administered respectively. 45 minutes after the administration, 0.05 ml of xylene was slowly dripped on the right ear shell of the mice, and the left ear shell was used as a control. Two hours later, the mice were killed by dislocation of the neck, and the left and right ear shells were cut off from each mouse, and the left and right ear pieces were cut off at the same position with a punch, and weighed with an electronic balance. The mouse (right ear weight-left ear weight) is the degree of swelling. (Swelling degree of mice in the control group−swelling degree of mice in the administration group)/swelling degree of mice in the control group×100% is the swelling inhibition % of the test compound.

(4) Evaluation criteria

Ineffective: swelling inhibition rate <30%;

Weak effect: swelling inhibition rate > 40%;

Markedly effective: swelling inhibition rate > 60%

(5) Anti-inflammatory activity test results

The anti-inflammatory activity of the benzoyl fluoride phenyl salicylamide compounds prepared in Examples 3-20 was tested. Anti-inflammatory test results are as follows:

Table 1: Compounds inhibit the swelling of the mouse ear shell (%)

compound Dose (mg/kg) Number of mice (only) Swelling inhibition rate (%) I-1 40 8 68.86 I-2 40 8 35.90 I-3 40 8 0

I-4 40 8 34.07 I-5 40 8 65.20 I-6 40 8 0 I-7 40 8 0 I-8 40 6 19.79 I-9 40 6 21.40 I-10 40 6 12.30 I-11 40 6 0 I-12 40 6 23.74 I-13 40 6 11.14 I-14 40 6 0 I-15 40 6 5.36 I-16 40 8 43.22

I-17 40 8 27.47 I-18 40 8 0 II 40 6 16.06

According to the anti-inflammatory activity evaluation standard, compounds (I-1) and (I-5) have significant anti-inflammatory activity, and (I-16) has better anti-inflammatory activity.

Example 22: Analgesic Activity Test

(1) Screening model: acetic acid writhing reaction

Experimental animals: Kunming mice, both male and female, 18-24g;

(2), sample processing

1. First weigh a certain amount of sample, add a small amount of 1% CMC to grind, then add 1% CMC to make a 4mg/ml suspension. Inject at a volume of 0.1ml/10g body weight, shake and mix well before injection.

2. Use 1% CMC as solvent control.

(3), experimental steps

The mice were divided into random groups, respectively orally administered with solvent control 1% CMC or test compound 40mg/kg, 45min after the administration, intraperitoneally injected 0.7% (v/v) acetic acid 0.1ml/10g, tested after 5min, and recorded each group within 5min. The number of writhing in mice. (Writhing number of mice in the control group−Writhing number of mice in the administration group)/Writhing number of mice in the control group×100% is the percentage of inhibition of the writhing response of the test compound.

(4) Evaluation criteria

Ineffective: inhibition of writhing response%<30%;

Weak effect: inhibition of writhing reaction%>40%;

Significantly effective: inhibition of writhing reaction% > 60%

(5), analgesic activity test

The analgesic activity of the benzoyl fluoride phenyl salicylamide compounds prepared in Examples 3-20 was tested. The results of the analgesic test are as follows:

Table 2: Compounds inhibit the writhing response to acetic acid in mice (%)

compound Dose (mg/kg) Number of mice (only) Twisting inhibition rate (%) I-1 40 8 47.50 I-2 40 8 15.83 I-3 40 8 9.16 I-4 40 8 37.50 I-5 40 8 0

I-6 40 8 33.33 I-7 40 8 52.50 I-8 40 6 5.57 I-9 40 6 20.79 I-10 40 6 3.26 I-11 40 6 0 I-12 40 6 13.78

I-13 40 6 0.74 I-14 40 6 0 I-15 40 6 4.13 I-16 40 8 92.50 I-17 40 8 88.33 I-18 40 8 57.50 II 40 6 7.97

According to the evaluation criteria of analgesic activity, compounds (I-16) and (I-17) have significant analgesic activity, and compounds (I-1), (I-7) and (I-18) have better analgesic activity active.

Claims (3)

1. benzoyl fluoride benzene salicylamide compounds, it is characterized in that: described compound is:

2. compound (I-1) or (I-5) application in the preparation anti-inflammatory drug:

3. compound (I-16) or (I-17) application in the preparation analgesic: