CN104800226A - Applications of O-phenylacetyl-(4-trifluoromethyl) salicylamide compound in preparing drugs used for treating intestinal cancer - Google Patents

Abstract

The invention discloses an O-phenylacetyl-(4-trifluoromethyl) salicylamide compound represented by formula (I), and applications thereof in preparing drugs used for treating intestinal cancer.

Description

The application of a kind of O-phenylacetyl-(4-trifluoromethyl) salicylamide compounds in preparation treatment bowelcancer medicine

(1) technical field

The application of the concrete a kind of O-phenylacetyl of the present invention-(4-trifluoromethyl) salicylamide compounds in preparation treatment bowelcancer medicine.

(2) background technology

Chinese patent CN 201210055341.X " (4-substituted benzene formyl) fluorobenzene salicylamide compound is preparing the application in medicament for resisting cervical cancer ", CN201210055273.7 " phenylacetyl fluorobenzene salicylamide compound is preparing the application in medicament for resisting cervical cancer " describe the O-benzoyl of diflunisal prepared by salicylic acid parent, the application of O-phenylacetyl fluorobenzene salicylamide compound in anti-cervical cancer respectively.Consider trifluoromethyl (CF ₃) there is electron-withdrawing, the characteristic such as lipotropy and stable C-F key equally by force, effectively can change the acidity of compound, dipole moment, polarity and lipotropy after introduce trifluoromethyl in drug effect molecule, the metabolic stability of biomolecule can be strengthened simultaneously; And trifluoromethyl salicylic acid is relatively cheap, be easy to get.

It is active that this patent has anti-intestinal cancer by O-phenylacetyl-(4-trifluoromethyl) the salicylamide compounds obtained after carrying out structural modification to trifluoromethyl salicylic acid, and tool has very great significance.

(3) summary of the invention

The object of the invention is to provide the application of a kind of O-phenylacetyl-(4-trifluoromethyl) salicylamide compounds in preparation treatment bowelcancer medicine.

O-phenylacetyl of the present invention-(4-trifluoromethyl) salicylamide compounds is such as formula shown in (I):

In formula I, R is halogen; R ₁for hydrogen or chlorine; R ₂for H or ethyl; R ₃for cyclohexyl, benzyl or structure are such as formula the substituted-phenyl shown in (A):

In formula (A), Q ₁~ Q ₅respective is independently H, methyl, fluorine, chlorine, nitro, methoxyl group, ethyoxyl.

Preferably, described R is fluorine or chlorine; R1 is hydrogen or chlorine; R ₂for H, R ₃for structure is such as formula the substituted-phenyl shown in (A), corresponding described O-phenylacetyl-(4-trifluoromethyl) salicylamide compounds is such as formula shown in (II):

Further, the O-phenylacetyl of structure as shown in formula I-(4-trifluoromethyl) salicylamide compounds is one of compound in table 1:

Table 1:

Compound

R

R 1

R 2

R 3

Q 1

Q 2

Q 3

Q 4

Q 5

Ⅰ-1

F

H

H

/

H

H

H

H

H

Ⅰ-2

F

H

H

/

CH 3

H

H

H

H

Ⅰ-3

F

H

H

/

H

CH 3

H

H

H

Ⅰ-4

F

H

H

/

H

H

CH 3

H

H

Ⅰ-5

F

H

H

/

H

H

F

H

H

Ⅰ-6

F

H

H

/

Cl

H

H

H

H

Ⅰ-7

F

H

H

/

H

Cl

H

H

H

Ⅰ-8

F

H

H

/

H

H

Cl

H

H

Ⅰ-9

F

H

H

/

OCH 3

H

H

H

H

Ⅰ-10

F

H

H

/

H

H

OCH 3

H

H

Ⅰ-11

F

H

H

/

OC 2H 5

H

H

H

H

Ⅰ-12

F

H

H

/

F

H

F

H

H

Ⅰ-13

F

H

H

/

Cl

H

Cl

H

H

Ⅰ-14

F

H

H

/

Cl

H

H

Cl

H

Ⅰ-15

F

H

H

/

H

Cl

Cl

H

H

Ⅰ-16

F

H

H

/

Cl

H

NO 2

H

H

Ⅰ-17

F

H

H

/

NO 2

H

Cl

H

H

Ⅰ-18

F

H

H

CH 2C 6H 5

/

/

/

/

/

Ⅰ-19

F

H

H

Cyclohexyl

/

/

/

/

/

Ⅰ-20

Cl

H

H

/

H

H

H

H

H

Ⅰ-21

Cl

H

H

/

CH 3

H

H

H

H

Ⅰ-22

Cl

H

H

/

H

CH 3

H

H

H

Ⅰ-23

Cl

H

H

/

H

H

CH 3

H

H

Ⅰ-24

Cl

H

H

/

H

H

F

H

H

Ⅰ-25

Cl

H

H

/

Cl

H

H

H

H

Ⅰ-26

Cl

H

H

/

H

Cl

H

H

H

Ⅰ-27

Cl

H

H

/

H

H

Cl

H

H

Ⅰ-28

Cl

H

H

/

OCH 3

H

H

H

H

Ⅰ-29

Cl

H

H

/

H

H

OCH 3

H

H

Ⅰ-30

Cl

H

H

/

H

H

NO 2

H

H

Ⅰ-31

Cl

H

H

/

OC 2H 5

H

H

H

H

Ⅰ-32

Cl

H

H

/

F

H

F

H

H

Ⅰ-33

Cl

H

H

/

Cl

H

H

Cl

H

Ⅰ-34

Cl

H

H

/

Cl

H

NO 2

H

H

Ⅰ-35

Cl

H

H

/

NO 2

H

Cl

H

H

Ⅰ-36

Cl

H

H

/

H

CF 3

NO 2

H

H

Ⅰ-37

Cl

H

H

Cyclohexyl

/

/

/

/

/

Ⅰ-38

Cl

H

C 2H 5

/

H

H

H

H

H

Ⅰ-39

Cl

Cl

H

/

H

H

H

H

H

Ⅰ-40

Cl

Cl

H

/

CH 3

H

H

H

H

Ⅰ-41

Cl

Cl

H

/

H

CH 3

H

H

H

Ⅰ-42

Cl

Cl

H

/

H

H

CH 3

H

H

Ⅰ-43

Cl

Cl

H

/

H

H

F

H

H

Ⅰ-44

Cl

Cl

H

/

Cl

H

H

H

H

Ⅰ-45

Cl

Cl

H

/

H

Cl

H

H

H

Ⅰ-46

Cl

Cl

H

/

H

H

Cl

H

H

Ⅰ-47

Cl

Cl

H

/

OCH 3

H

H

H

H

Ⅰ-48

Cl

Cl

H

/

H

H

OCH 3

H

H

Ⅰ-49

Cl

Cl

H

/

H

H

NO 2

H

H

Ⅰ-50

Cl

Cl

H

/

OC 2H 5

H

H

H

H

Ⅰ-51

Cl

Cl

H

/

F

H

F

H

H

Ⅰ-52

Cl

Cl

H

/

Cl

H

H

Cl

H

Ⅰ-53

Cl

Cl

H

/

Cl

H

NO 2

H

H

Ⅰ-54

Cl

Cl

H

/

NO 2

H

Cl

H

H

Ⅰ-55

Cl

Cl

H

/

H

CF 3

NO 2

H

H

。

Preferred, described O-phenylacetyl-(4-trifluoromethyl) salicylamide compounds is I-5 ~ I-45.

The preparation method of O-phenylacetyl-(4-trifluoromethyl) salicylamide compounds as shown in formula I of the present invention is as follows: the trifluoromethyl salicylic acid as shown in formula III and the substituted benzene excess acetyl chloride shown in formula IV, obtain the O-phenylacetyl shown in formula (V)-(4-trifluoromethyl) salicylic acid; Then, with SOCl ₂the O-phenylacetyl shown in formula VI-(4-trifluoromethyl) bigcatkin willow acyl chlorides is obtained through chloride; Finally, with aminated compounds formula (VII) Suo Shi through amidation process, obtained O-phenylacetyl-(4-trifluoromethyl) salicylamide compounds Ru shown in (I).The equation of described reaction is shown below.

In formula IV, formula (V), formula VI, R is halogen, preferred fluorine or chlorine; R ₁for hydrogen or chlorine;

In formula (VII), R ₂for H or ethyl; R ₃for cyclohexyl, benzyl or structure are such as formula the substituted-phenyl shown in (A):

In formula (A), Q ₁~ Q ₅respective is independently H, methyl, fluorine, chlorine, nitro, methoxyl group, ethyoxyl.

Relevant synthetic method, can refer to Chinese patent CN102010366A and in Bioorg.Med.Chem.Lett.19 (2), content disclosed in 516-519 is upper.Concrete, described method recommends to carry out according to following steps:

(1) in toluene solvant, under catalyst A exists, acyl chloride reaction will be carried out such as formula the A of substituted phenylacetic acid chloride reagent (VIII) Suo Shi (preferably 80 DEG C) at 60 ~ 100 DEG C of temperature, usually reaction 3-8 hour; Reaction terminates rear steaming and desolventizes, and obtains the substituted benzene chloroacetic chloride as shown in formula IV, dissolves, obtain solution of acid chloride A stand-by by organic solvent A;

In formula (VIII), R is halogen; R ₁for hydrogen or chlorine;

Described catalyst A is: DMF, pyridine, DMA; Described chloride reagent A is: thionyl chloride, phosphorus oxychloride, phosphorus pentachloride; Described organic solvent A is: oxolane, butanone, toluene;

Described substituted phenylacetic acid is 1:1 ~ 3 with the ratio of the amount of substance of chloride reagent A, preferred 1:2.

(2) the 4-trifluoromethyl salicylic acid organic solvent B such as shown in formula III is dissolved, add organic amine A, then the solution of acid chloride A that step (1) is obtained is added, esterification is carried out under room temperature, usual reaction 6-16 hour, reaction terminates rear reactant liquor a separating treatment, obtains such as formula the O-phenylacetyl shown in (V)-(4-trifluoromethyl) salicylic acid;

Described organic amine A is: triethylamine, pyridine; Described organic solvent B is: oxolane, butanone, toluene;

The ratio of the amount of substance of described 4-trifluoromethyl salicylic acid as shown in formula III, the substituted benzene chloroacetic chloride in solution of acid chloride A is 1:1.The amount of substance of the substituted benzene chloroacetic chloride in solution of acid chloride A measures with the amount of substance of substituted phenylacetic acid.

The ratio of the amount of substance of described trifluoromethyl salicylic acid as shown in formula III, organic amine A is 1:1.

The method of described reactant liquor a separating treatment is: after reaction terminates, reactant liquor a filters, in filtrate, add dilute hydrochloric acid, stirring, crystallization, filter, filter cake washing with alcohol, drying, obtains the O-phenylacetyl shown in formula (V)-(4-trifluoromethyl) salicylic acid.

(3) in toluene solvant, under catalyst B exists, O-phenylacetyl-(4-trifluoromethyl) salicylic acid chloride reagent B (preferably 80 DEG C) at 60 ~ 100 DEG C of temperature that step (2) is obtained carries out acyl chloride reaction, usually reacts 3 ~ 10 hours; Reaction terminates rear steaming and desolventizes, and obtains the O-phenylacetyl shown in formula VI-(4-trifluoromethyl) bigcatkin willow acyl chlorides, dissolves, obtain solution of acid chloride B stand-by with organic solvent C;

Described catalyst B is: DMF, pyridine, DMA; Described chloride reagent B is: thionyl chloride, phosphorus oxychloride, phosphorus pentachloride; Described organic solvent C is: oxolane, acetone, butanone, toluene;

The ratio of the amount of substance of described O-phenylacetyl-(4-trifluoromethyl) salicylic acid, chloride reagent B is 1:1 ~ 3, preferred 1:2.

(4) aminated compounds formula (VII) Suo Shi is joined in organic solvent D, then the solution of acid chloride B that step (3) is obtained is added, carry out condensation reaction under room temperature, reaction terminates rear reactant liquor b separating treatment and obtains the O-phenylacetyl shown in formula I-(4-trifluoromethyl) salicylamide compounds.

Described organic solvent D is: oxolane, acetone, butanone, toluene; Described.

Shown in O-phenylacetyl shown in formula VI in described solution of acid chloride B-(4-trifluoromethyl) bigcatkin willow acyl chlorides and formula (VII), the ratio of the amount of substance of aminated compounds is 1:2.The amount of substance of the O-phenylacetyl shown in the formula VI in described solution of acid chloride B-(4-trifluoromethyl) bigcatkin willow acyl chlorides measures with O-phenylacetyl-(4-trifluoromethyl) salicylic amount of substance.

The method of described reactant liquor b separating treatment is: after reaction terminates, reactant liquor b filters, and adds water to filtrate, stirring, crystallization, filter, use butanone recrystallization after filter cake washing with alcohol, obtain the O-phenylacetyl shown in formula I-(4-trifluoromethyl) salicylamide compounds.

After tested, O-phenylacetyl of the present invention-(4-trifluoromethyl) salicylamide compounds obviously can suppress the growth of multiple colon-cancer cell under finite concentration, can be used as the treatment that antitumor drug is applied to intestinal cancer.

(4) detailed description of the invention

Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this:

Embodiment 1: preparation O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylic acid (V-1)

15.4g (0.1mol) para-fluorophenylacetic acid, 24.0g (0.2mol) thionyl chloride, 60ml toluene and 4 DMF are dropped in reaction bulb, back flow reaction 6 hours, evaporated under reduced pressure, obtains pink liquid, uses 20ml acetone diluted, for subsequent use.

15.9g (0.077mol) 4-trifluoromethyl salicylic acid, 6.2g (0.077mol) pyridine, 50ml acetone is added in another reaction bulb, stir 30min, under ice bath, slowly add the solution of acid chloride obtained by previous step, stirring at normal temperature is spent the night.

Filter, 100ml water is added to filtrate, steaming is revolved after separatory, obtain faint yellow solid, with toluene wash, drying, obtain white powder, obtain O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylic acid crude product, yield: 75.76%, fusing point: 94-97 DEG C (correction).

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,DMSO,δppm):4.00(s,2H,-CH ₂),7.19(t,2H,J＝9.0Hz,3′,5′-H),7.40(dd,2H,J＝7.5Hz,2′,6′-H),7.71(s,1H,3-H),7.78(d,1H,J＝9.0Hz,5-H),8.13(d,1H,J＝8.0Hz,6-H),13.71(s,1H,-COOH)。

Embodiment 2: preparation O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylic acid (V-2)

The para-fluorophenylacetic acid in embodiment 1 is replaced with 0.1mol 4-Chlorophenylacetic acid, other operations are with embodiment 1, obtain O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylic acid crude product, yield: 81.67%, fusing point: 119-121 DEG C (correction).

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃δppm):3.93(s,2H,-CH ₂),7.33(d,2H,J＝8.5Hz,3′,5′-H),7.36(d,2H,J＝8.5Hz,2′,6′-H),7.41(s,1H,3-H),7.66(d,1H,J＝8.5Hz,5-H),8.26(d,1H,J＝8.0Hz,6-H),13.75(s,1H,-COOH)。

Embodiment 3: preparation O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylic acid (V-3)

Replace the para-fluorophenylacetic acid in embodiment 1 with 0.1mol 2,4-fenac, other operations are with embodiment 1, obtain O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylic acid crude product, yield: 76.67%, fusing point: 131-132 DEG C (correction).

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):4.10(s,2H,-CH ₂),7.27(d,1H,J＝8.5Hz,6′-H),7.36(d,1H,J＝8.0Hz,5′-H),7.45(s,1H,3-H),7.47(d,1H,3′-H),7.66(d,1H,J＝8.0Hz,5-H),8.25(d,1H,J＝8.5Hz,6-H),13.75(s,1H,-COOH)。

Embodiment 4: preparation N-phenyl-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-1)

5.1g (0.015mol) O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylic acid crude product (V-1), 3.6g (0.03mol) thionyl chloride, 50ml toluene and 2 DMF are dropped in reaction bulb, react 6 hours under 80 DEG C (correction), evaporated under reduced pressure, obtain yellow liquid, add 40ml acetone solution, obtained O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) bigcatkin willow acyl chlorides (VI-1) solution, for subsequent use.

Under ice bath, the mixed liquor of 2.8g (0.03mol) aniline/10ml acetone is joined in VI-1 solution made, normal-temperature reaction 10h; Filter, 100ml water is added to filtrate, stirring, crystallization, filter, washing with alcohol, butanone recrystallization, obtains white N-phenyl-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-1), fusing point: 125-127 DEG C (correction), yield: 72.35%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.87(s,2H,-CH ₂),6.89(t,2H,J＝8.0Hz,3′,5′-H),7.17(t,H,J＝7.5Hz,4″-H),7.21(d d,2H,J＝7.5Hz,2′,6′-H),7.35(t,2H,J＝7.5Hz,3″,5″-H),7.43(d,2H,J＝6.5Hz,2″,6″-H),7.43(s,1H,3-H),7.23(d,1H,J＝8.5Hz,5-H),7.65(s,1H,-NH),7.89(d,1H,J＝8.0Hz,6-H)。

Embodiment 5: preparation N-(2-aminomethyl phenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-2)

The aniline in embodiment 4 is replaced with 0.03mol ortho-aminotoluene, other operations are with embodiment 4, obtain N-(2-aminomethyl phenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-2), fusing point: 142-144 DEG C (correction), yield: 69.9%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):2.16(s,3H,-CH ₃),3.87(s,2H,-CH ₂),6.86(t,2H,J＝8.5Hz,3′,5′-H),7.18(dd,2H,J＝8.5Hz,2′,6′-H),7.19(d,2H,J＝7.5Hz,3″-H),7.21(t,1H,J＝8.0Hz,5″-H),7.26(t,1H,J＝7.5Hz,4″-H),7.75(d,1H,J＝8.0Hz,6″-H),7.44(s,1H,-NH),7.44(s,1H,3-H),7.65(d,1H,J＝7.5Hz,5-H),7.93(d,1H,J＝7.5Hz,6-H)。

Embodiment 6: preparation N-(3-aminomethyl phenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-3)

The aniline in embodiment 4 is replaced with 0.03mol meta-aminotoluene, other operations are with embodiment 4, obtain N-(3-aminomethyl phenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-3), fusing point: 116-118 DEG C (correction), yield: 77.6%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹HNMR(500MHz,CDCl ₃,δppm):2.37(s,3H,-CH ₃),3.88(s,2H,-CH ₂),6.92(t,2H,J＝9.0Hz,3′,5′-H),7.02(d,1H,J＝6.5Hz,4″-H),7.24(dd,2H,J＝8.5Hz,2′,6′-H),7.25(t,1H,J＝5.0Hz,5″-H),7.26(d,1H,J＝8.0Hz,6″-H),7.28(s,1H,2″-H),7.43(s,1H,3-H),7.63(d,1H,J＝8.0Hz,5-H),7.63(s,1H,-NH),7.89(d,1H,J＝8.0Hz,6-H)。

Embodiment 7: preparation N-(4-aminomethyl phenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-4)

The aniline in embodiment 4 is replaced with 0.03mol para-totuidine, other operations are with embodiment 4, obtain N-(4-aminomethyl phenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-4), fusing point: 142-145 DEG C (correction), yield: 79.2%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):2.37(s,3H,-CH ₃),3.87(s,2H,-CH ₂),6.91(t,2H,J＝8.5Hz,3′,5′-H),7.16(d,2H,J＝8.0Hz,3″,5″-H),7.23(dd,2H,J＝8.5Hz,2′,6′-H),7.33(d,2H,J＝8.0Hz,2″,6″-H),7.42(s,1H,3-H),7.61(d,1H,J＝8.0Hz,5-H),7.67(s,1H,-NH),7.89(d,1H,J＝8.0Hz,6-H)。

Embodiment 8: preparation N-(4-fluorophenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-5)

The aniline in embodiment 4 is replaced with 0.03mol para-fluoroaniline, other operations are with embodiment 4, obtain N-(4-fluorophenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-5), fusing point: 134-136 DEG C (correction), yield: 87.1%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.88(s,2H,-CH ₂),6.92(t,2H,J＝8.5Hz,3′,5′-H),7.05(t,2H,J＝8.5Hz,3″,5″-H),7.4(d d,2H,J＝8.5Hz,2′,6′-H),7.37(dd,2H,J＝8.5Hz,2″,6″-H),7.44(s,1H,3-H),7.63(d,1H,J＝7.5Hz,5-H),7.64(s,1H,-NH),7.90(d,1H,J＝8.0Hz,6-H)。

Embodiment 9: preparation N-(2-chlorphenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-6)

The aniline in embodiment 4 is replaced with 0.03mol o-chloraniline, other operations are with embodiment 4, obtain N-(2-chlorphenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-6), fusing point: 108-110 DEG C (correction), yield: 72.4%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.92(s,2H,-CH ₂),6.91(t,2H,J＝8.5Hz,3′,5′-H),7.14(t,1H,J＝7.5Hz,4″-H),7.25(dd,2H,J＝6.5Hz,2′,6′-H),7.35(t,1H,J＝7.5Hz,5″-H),7.42(d,1H,J＝6.0Hz,3″-H),7.46(s,1H,3-H),7.66(d,1H,J＝7.5Hz,6″-H),8.01(d,1H,J＝8.0Hz,5-H),8.35(d,1H,-NH),8.40(d,1H,J＝8.0Hz,6-H)。

Embodiment 10: preparation N-(3-chlorphenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-7)

The aniline in embodiment 4 is replaced with 0.03mol m-chloroaniline, other operations are with embodiment 4, obtain N-(3-chlorphenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-7), fusing point: 112-114 DEG C (correction), yield: 79.8%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.98(s,2H,-CH ₂),6.94(t,2H,J＝8.5Hz,3′,5′-H),7.19(t,1H,J＝6.0Hz,5″-H),7.25(dd,2H,J＝8.5Hz,2′,6′-H),7.27(d,2H,J＝6.0Hz,4″,6″-H),7.44(s,1H,2″-H),7.53(s,1H,3-H),7.64(d,1H,J＝8.5Hz,5-H),7.68(s,1H,-NH),7.88(d,1H,J＝8.5Hz,6-H)。

Embodiment 11: preparation N-(4-chlorphenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-8)

The aniline in embodiment 4 is replaced with 0.03mol parachloroanilinum, other operations are with embodiment 4, obtain N-(4-chlorphenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-8), fusing point: 144-147 DEG C (correction), yield: 69.5%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.87(s,2H,-CH ₂),6.92(t,2H,J＝8.5Hz,3′,5′-H),7.22(dd,2H,J＝8.5Hz,2′,6′-H),7.31(d,2H,J＝9.0Hz,3″,5″-H),7.37(d,2H,J＝9.0Hz,2″,6″-H),7.43(s,1H,3-H),7.61(d,1H,J＝8.0Hz,5-H),7.77(s,1H,-NH),7.86(d,1H,J＝8.0Hz,6-H)。

Embodiment 12: preparation N-(2-methoxyphenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-9)

The aniline in embodiment 4 is replaced with 0.03mol 2-aminoanisole, other operations are with embodiment 4, obtain N-(2-methoxyphenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-9), fusing point: 113-115 DEG C (correction), yield: 68.7%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.87(s,2H,-CH ₂),3.91(s,3H,-OCH ₃),6.93(t,2H,J＝8.5Hz,3′,5′-H),6.95(d,1H,J＝7.5Hz,6″-H),7.06(t,1H,J＝7.5Hz,4″-H),7.16(t,1H,J＝7.5Hz,5″-H),7.26(dd,2H J＝8.5Hz,2′,6′-H),7.44(s,1H,3-H),7.64(d,1H,J＝8.5Hz,5-H),7.99(d,1H,J＝8.5Hz,6-H),8.47(d,1H,J＝8.0Hz,3″-H),8.53(s,1H,-NH)。

Embodiment 13: preparation N-(4-methoxyphenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-10)

The aniline in embodiment 4 is replaced with 0.03mol 4-aminoanisole, other operations are with embodiment 4, obtain N-(4-methoxyphenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-10), fusing point: 133-135 DEG C (correction), yield: 76.1%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.84(s,2H,-CH ₂),3.88(s,3H,-OCH ₃),6.90(t,2H,J＝8.5Hz,3′,5′-H),6.93(d,2H,J＝8.5Hz,2″,6″-H),7.24(dd,2H,J＝8.5Hz,2′,6′-H),7.34(d,2H,J＝8.5Hz,3″,5″-H),7.42(s,1H,3-H),7.61(d,1H,J＝7.5Hz,5-H),7.66(s,1H,-NH),7.89(d,1H,J＝7.5Hz,6-H)。

Embodiment 14: preparation N-(2-ethoxyl phenenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-11)

The aniline in embodiment 4 is replaced with 0.03mol 2-phenetidine, other operations are with embodiment 4, obtain N-(2-ethoxyl phenenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-11), fusing point: 93-95 DEG C (correction), yield: 69.4%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):1.05(t,3H,J＝6.0Hz,-CH ₃),3.89(s,2H,-CH ₂),4.11(q,2H,J＝6.0Hz,-OCH ₂),6.89(t,2H,J＝8.5Hz,3′,5′-H),6.91(d,1H,J＝8.5Hz,6″-H),7.04(t,1H,J＝8.0Hz,5″-H),7.13(t,1H,J＝8.0Hz,4″-H),7.22(dd,2H,J＝8.5Hz,2′,6′-H),7.44(s,1H,3-H),7.65(d,1H,J＝8.0Hz,5-H),7.95(d,1H,J＝8.0Hz,3″-H),8.45(d,1H,J＝8.5Hz,6-H),8.47(s,1H,-NH)。

Embodiment 15: preparation N-(2,4 difluorobenzene base)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-12)

With 0.03mol 2,4-difluoroaniline replaces the aniline in embodiment 4, other operations are with embodiment 4, obtain N-(2,4-difluorophenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-12), fusing point: 129-132 DEG C (correction), yield: 72.16%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.94(s,2H,-CH ₂),6.91(t,2H,J＝8.5Hz,3″-H),6.92(t,2H,J＝8.5Hz,5″-H),6.97(t,2H,J＝8.5Hz,3′,5′-H),7.30(dd,2H,J＝8.5Hz,2′,6′-H),7.45(s,1H,3-H),7.66(d,1H,J＝8.0Hz,5-H),8.06(d,1H,J＝8.0Hz,6-H),8.13(s,1H,-NH),8.30(q,1H,J＝7.5Hz,6″-H)。

Embodiment 16: preparation N-(2,4-Dichlorobenzene base)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-13)

With 0.03mol 2,4-dichloroaniline replaces the aniline in embodiment 4, other operations are with embodiment 4, obtain N-(2-chloro-4 nitrophenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-13), fusing point: 127-129 DEG C (correction), yield: 76.5%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.88(s,2H,-CH ₂),6.97(t,2H,J＝8.5Hz,3′,5′-H),7.25(dd,2H,J＝8.5Hz,2′,6′-H),7.26(d,1H,J＝9.0Hz,5″-H),7.40(s,1H,J＝8.5Hz,6″-H),7.45(s,1H,3-H),7.62(s,1H,3″-H),7.65(d,1H,J＝8.0Hz,5-H),7.68(s,1H,-NH),7.88(d,1H,J＝8.0Hz,6-H)。

Embodiment 17: preparation N-(2,5-Dichlorobenzene base)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-14)

With 0.03mol 2,5-dichloroaniline replaces the aniline in embodiment 4, other operations are with embodiment 4, obtain N-(2,5-Dichlorobenzene base)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-14), fusing point: 131-133 DEG C (correction), yield: 41.3%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.91(s,2H,-CH ₂),6.95(t,2H,J＝8.5Hz,3′,5′-H),7.13(d,1H,J＝9.0Hz,4″-H),7.27(dd,2H,J＝8.5Hz,2′,6′-H),7.33(d,1H,J＝9.0Hz,3″-H),7.46(s,1H,3-H),7.66(d,1H,J＝8.0Hz,5-H),7.97(d,1H,J＝8.0Hz,6-H),8.31(s,1H,-NH),8.49(s,1H,6″-H)。

Embodiment 18: preparation N-(3,4-Dichlorobenzene base)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-15)

With 0.03mol 3,4-dichloroaniline replaces the aniline in embodiment 4, other operations are with embodiment 4, obtain N-(3,4-Dichlorobenzene base)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-15), fusing point: 146-148 DEG C (correction), yield: 85.5%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.91(s,2H,-CH ₂),6.95(t,2H,J＝8.5Hz,3′,5′-H),7.26(dd,2H,J＝8.5Hz,2′,6′-H),7.33(d,1H,J＝9.0Hz,5″-H),7.43(s,1H,2″-H),7.45(s,1H,3-H),7.66(d,1H,J＝8.0Hz,5-H),7.99(d,1H,J＝8.0Hz,6-H),8.28(s,1H,-NH),8.35(s,1H,J＝9.0Hz,2″-H)。

Embodiment 19: preparation N-(2-chloro-4 nitrophenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-16)

The aniline in embodiment 4 is replaced with the chloro-4-nitroaniline of 0.03mol 2-, other operations are with embodiment 4, obtain N-(2-chloro-4 nitrophenyl)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-16), fusing point: 130-132 DEG C (correction), yield: 53.8%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.92(s,2H,-CH ₂),6.93(t,2H,J＝8.5Hz,3′,5′-H),7.26(dd,2H,J＝8.5Hz,2′,6′-H),7.48(s,1H,3-H),7.70(d,1H,J＝8.0Hz,5-H),8.00(d,1H,J＝8.0Hz,6-H),8.24(d,1H,J＝9.0Hz,6″-H),8.33(s,1H,3″-H),8.58(s,1H,-NH),8.68(d,1H,J＝9.0Hz,5″-H)。

Embodiment 20: preparation N-(the chloro-2-nitrobenzophenone of 4-)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-17)

The aniline in embodiment 4 is replaced with 0.03mol 4-chloro-2-nitroaniline, other operations are with embodiment 4, obtain N-(the chloro-2-nitrobenzophenone of 4-)-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-17), fusing point: 109-111 DEG C (correction), yield: 60.5%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.19(s,2H,-CH ₂),6.93(t,2H,J＝8.5Hz,3′,5′-H),7.26(dd,2H,J＝8.5Hz,2′,6′-H),7.48(s,1H,3-H),7.66d,1H,J＝8.5Hz,5″-H),7.67(s,1H,3″-H),8.01(d,1H,J＝8.5Hz,6″-H),8.23(d,1H,J＝7.5Hz,5-H),8.74(d,1H,J＝9.0Hz,6-H),10.08(s,1H,-NH)。

Embodiment 21: preparation N-benzyl-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-18)

The aniline in embodiment 4 is replaced with 0.03mol benzylamine, other operations are with embodiment 4, obtain N-benzyl-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-18), fusing point: 101-103 DEG C (correction), yield: 41.8%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.69(S,2H,-CH ₂),4.51(d,2H,J＝6.5Hz,-CH ₂),6.45(s,1H,-NH),7.04(t,2H,J＝8.5Hz,3′,5′-H),7.21(d d,2H,J＝8.5Hz,2′,6′-H),7.27(m,5H,Ar″-H),7.39(s,1H,3-H),7.58(d,1H,J＝7.5Hz,5-H),7.21(d,1H,J＝8.5Hz,6-H)。

Embodiment 22: preparation N-cyclohexyl-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-19)

The aniline in embodiment 4 is replaced with 0.03mol cyclohexylamine, other operations are with embodiment 4, obtain N-cyclohexyl-O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-19), fusing point: 124-127 DEG C (correction), yield: 31.5%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):1.07(m,1H,4″-CH ₂),1.18(m,2H,3″,5″-CH ₂),1.44(m,2H,3″,5″-CH ₂),1.68(m,1H,4″-CH ₂),1.75(m,2H,2″,6″-CH ₂),1.93(m,2H,2″,6″-CH ₂),3.88(m,1H,1″-CH),3.89(s,2H,-CH ₂),5.93(d,1H,J＝6.0Hz,-NH),7.10(t,2H,J＝8.5Hz,3′,5′-H),7.35(s,1H,3-H),7.36(d d,2H,J＝8.5Hz,2′,6′-H),7.56(d,1H,J＝8.0Hz,5-H),7.76(d,1H,J＝8.0Hz,6-H)。

Embodiment 23: preparation N-phenyl-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-20)

(0.015mol) O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylic acid in embodiment 4 is replaced with 0.015mol O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylic acid, other operations are with embodiment 4, obtain N-phenyl-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-20), fusing point: 138-140 DEG C (correction), yield: 72.40%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.88(s,2H,-CH ₂),7.19(m,5H,Ar″-H),7.39(d,2H,J＝7.5Hz,3′,5′-H),7.42(d,2H,J＝8.0Hz,2′,6′-H),7.44(s,1H,3-H),7.65(d,1H,J＝8.5Hz,5-H),7.66(s,1H,-NH),7.90(d,1H,J＝8.0Hz,6-H)。

Embodiment 24: preparation N-(2-aminomethyl phenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-21)

The aniline in embodiment 23 is replaced with 0.03mol ortho-aminotoluene, other operations are with embodiment 23, obtain N-(2-aminomethyl phenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-21), fusing point: 149-151 DEG C (correction), yield: 62.68%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,DMSO,δppm):2.21(s,3H,-CH ₃),3.98(s,2H,-CH ₂),7.19(t,1H,J＝7.0Hz,4″-H),7.23(t,1H,J＝7.0Hz,5″-H),7.27(d,1H,J＝7.5Hz,6″-H),7.30(d,1H,J＝7.5Hz,3″-H),7.35(m,4H,Ar′-H),7.78(s,1H,3-H),7.82(d,1H,J＝8.0Hz,5-H),7.95(d,1H,J＝8.0Hz,6-H),9.99(s,1H,-NH)。

Embodiment 25: preparation N-(3-aminomethyl phenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-22)

The aniline in embodiment 23 is replaced with 0.03mol meta-aminotoluene, other operations are with embodiment 23, obtain N-(3-aminomethyl phenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-22), fusing point: 139-141 DEG C (correction), yield: 61.19%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,DMSO,δppm):2.32(s,3H,-CH ₃),3.94(s,2H,-CH ₂),6.97(d,1H,J＝7.5Hz,4″-H),7.25(t,1H,J＝8.0Hz,5″-H),7.26(d,2H,J＝8.5Hz,3′,5′-H),7.30(d,2H,J＝8.5Hz,2′,6′-H),7.44(d,1H,J＝8.5Hz,6″-H),7.50(s,1H,2″-H),7.78(s,1H,3-H),7.80(d,1H,J＝9.5Hz,5-H),7.88(d,1H,J＝8.0Hz,6-H),10.41(s,1H,-NH)。

Embodiment 26: preparation N-(4-aminomethyl phenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-23)

The aniline in embodiment 23 is replaced with 0.03mol para-totuidine, other operations are with embodiment 23, obtain N-(4-aminomethyl phenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-23), fusing point: 143-145 DEG C (correction), yield: 43.28%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):2.38(s,3H,-CH ₃),3.87(s,2H,-CH ₂,7.12(d,2H,J＝8.0Hz,3″,5″-H),7.18(m,4H,Ar′-H),7.30(d,2H,J＝8.0Hz,2″,6″-H),7.43(s,1H,3-H),7.61(s,1H,-NH),7.63(d,1H,J＝7.5Hz,5-H),7.89(d,1H,J＝7.5Hz,6-H)。

Embodiment 27: preparation N-(4-fluorophenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-24)

The aniline in embodiment 23 is replaced with 0.03mol 4-fluoroaniline, other operations are with embodiment 23, obtain N-(4-fluorophenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-24), fusing point: 151-153 DEG C (correction), yield: 59.02%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,DMSO,δppm):3.94(s,2H,-CH ₂),7.22(t,2H,J＝8.5Hz,3″,5″-H),7.28(d,2H,J＝8.5Hz,3′,5′-H),7.31(d,2H,J＝8.5Hz,2′,6′-H),7.66(dd,2H,J＝9.0Hz,2″,6″-H),7.76(s,1H,3-H),7.81(d,1H,J＝9.0Hz,5-H),7.90(d,1H,J＝7.5Hz,6-H),11.53(s,1H,-NH)。

Embodiment 28: preparation N-(2-chlorphenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-25)

The aniline in embodiment 23 is replaced with 0.03mol o-chloraniline, other operations are with embodiment 23, obtain N-(2-chlorphenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-25), fusing point: 121-123 DEG C (correction), yield: 78.57%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.92(s,2H,-CH ₂),7.15(t,H,J＝8.0Hz,4″-H),7.19(t,2H,J＝8.5Hz,3′,5′-H),7.23(d,2H,J＝8.5Hz,2′,6′-H),7.37(t,1H,J＝8.0Hz,5″-H),7.42(d,1H,J＝8.0Hz,3″-H),7.46(s,1H,3-H),7.66(d,1H,J＝8.0Hz,5-H),8.00(d,1H,J＝8.5Hz,6-H),8.32(d,1H,-NH),8.38(d,1H,J＝8.5Hz,6″-H)。

Embodiment 29: preparation N-(3-chlorphenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-26)

The aniline in embodiment 23 is replaced with 0.03mol m-chloroaniline, other operations are with embodiment 23, obtain N-(3-chlorphenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-26), fusing point: 133-135 DEG C (correction), yield: 75.65%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.88(s,2H,-CH ₂),7.18(d,2H,J＝8.0Hz,4″-H),7.20(m,4H,Ar′-H),7.23(d,1H,J＝8.0Hz,6″-H),7.28(t,2H,J＝8.0Hz,5″-H),7.44(s,1H,3-H),7.54(s,1H,2″-H),7.63(d,1H,J＝8.0Hz,5-H),7.69(s,1H,-NH),7.86(d,1H,J＝8.0Hz,6-H)。

Embodiment 30: preparation N-(4-chlorphenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-27)

The aniline in embodiment 23 is replaced with 0.03mol parachloroanilinum, other operations are with embodiment 23, obtain N-(4-chlorphenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-27), fusing point: 153-155 DEG C (correction), yield: 71.37%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.87(s,2H,-CH ₂),7.19(m,4H,Ar′-H),7.32(d,2H,J＝8.5Hz,3″,5″-H),7.34(d,2H,J＝9.0Hz,2″,6″-H),7.43(s,1H,3-H),7.63(d,1H,J＝8.0Hz,5-H),7.67(s,1H,-NH),7.87(d,1H,J＝8.0Hz,6-H)。

Embodiment 31: preparation N-(2-methoxyphenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-28)

The aniline in embodiment 23 is replaced with 0.03mol 2-aminoanisole, other operations are with embodiment 23, obtain N-(2-methoxyphenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-28), fusing point: 114-116 DEG C (correction), yield: 64.20%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.86(s,3H,-OCH ₃),3.90(s,2H,-CH ₂),6.94(d,1H,J＝8.0Hz,6″-H),7.07(t,1H,J＝8.0Hz,5″-H),7.16(t,1H,J＝8.0Hz,4″-H),7.26(m,4H,Ar′-H),7.44(s,1H,3-H),7.64(d,1H,J＝8.5Hz,5-H),7.98(d,1H,J＝8.0Hz,6-H),8.46(d,1H,J＝8.0Hz,3″-H),8.50(s,1H,-NH)。

Embodiment 32: preparation N-(4-methoxyphenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-29)

The aniline in embodiment 23 is replaced with 0.03mol 4-aminoanisole, other operations are with embodiment 23, obtain N-(4-methoxyphenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-29), fusing point: 140-142 DEG C (correction), yield: 64.78%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.84(s,3H,-OCH ₃),3.87(s,2H,-CH ₂),6.89(d,2H,J＝9.0Hz,3″,5″-H),7.20(m,4H,Ar′-H),7.31(d,2H,J＝8.5Hz,2″,6″-H),7.42(s,1H,3-H),7.60(d,1H,J＝8.0Hz,5-H),7.64(s,1H,-NH),7.87(d,1H,J＝8.0Hz,6-H)。

Embodiment 33: preparation N-(3-nitrobenzophenone)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-30)

The aniline in embodiment 23 is replaced with 0.03mol 3-nitroaniline, other operations are with embodiment 23, obtain N-(3-nitrobenzophenone)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-30), fusing point: 156-158 DEG C (correction), yield: 73.91%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.89(s,2H,-CH ₂),7.16(d,2H,J＝8.0Hz,3′,5′-H),7.23(d,2H,J＝8.0Hz,2′,6′-H),7.48(s,1H,3-H),7.53(t,1H,J＝8.0Hz,5″-H),7.67(d,1H,J＝8.0Hz,5-H),7.75(d,1H,J＝8.5Hz,6″-H),7.81(s,1H,-NH),7.91(d,1H,J＝8.0Hz,6-H),8.06(d,1H,J＝8.0Hz,4″-H),8.24(s,1H,2″-H)。

Embodiment 34: preparation N-(2-methoxyphenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-31)

The aniline in embodiment 23 is replaced with 0.03mol 2-aminoanisole, other operations are with embodiment 23, obtain N-(2-methoxyphenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-31), fusing point: 102-104 DEG C (correction), yield: 38.76%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):1.42(t,3H,J＝7.0Hz,-CH ₃),3.89(s,2H,-CH ₂),4.10(q,2H,J＝7.0Hz,-OCH ₂),6.89(d,1H,J＝8.5Hz,3″-H),7.05(t,1H,J＝8.0Hz,4″-H),7.13(t,1H,J＝8.0Hz,5″-H),7.19(m,4H,Ar′-H),7.44(s,1H,3-H),7.65(d,1H,J＝8.0Hz,5-H),7.94(d,1H,J＝8.0Hz,6-H),8.44(s,1H,-NH),8.45(d,1H,J＝8.5Hz,6″-H)。

Embodiment 35: preparation N-(2,4 difluorobenzene base)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-32)

With 0.03mol 2,4-difluoroaniline replaces the aniline in embodiment 23, other operations are with embodiment 23, obtain N-(2,4-difluorophenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-32), fusing point: 136-138 DEG C (correction), yield: 73.91%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,DMSO,δppm):3.96(s,1H,-CH ₂),7.14(t,1H,J＝8.5Hz,3″-H),7.33(m,4H,Ar′-H),7.37(t,1H,J＝8.5Hz,5″-H),7.64(q,1H,J＝8.5Hz,6″-H),7.79(s,1H,3-H),7.82(d,1H,J＝8.0Hz,6-H),7.92(d,1H,J＝8.0Hz,5-H),10.32(s,1H,-NH)。

Embodiment 36: preparation N-(2,5-Dichlorobenzene base)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-33)

With 0.03mol 2,5-dichloroaniline replaces the aniline in embodiment 23, other operations are with embodiment 23, obtain N-(2,5-difluorophenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-33), fusing point: 160-162 DEG C (correction), yield: 54.66%

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.91(s,2H,-CH ₂),7.14(d,1H,J＝9.0Hz,4″-H),7.23(m,4H，Ar′-H),7.33(d,1H,J＝8.5Hz,3″-H),7.46(s,1H,3-H),7.67(d,1H,J＝8.0Hz,5-H),7.98(d,1H,J＝8.0Hz,6-H),8.28(s,1H,-NH),8.49(s,1H,6″-H)。

Embodiment 37: preparation N-(2-chloro-4 nitrophenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-34)

The aniline in embodiment 23 is replaced with the chloro-4-nitroaniline of 0.03mol 2-, other operations are with embodiment 23, obtain N-(2-chloro-4 nitrophenyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-34), fusing point: 138-140 DEG C (correction), yield: 67.70%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.91(s,2H,-CH ₂),7.16(d,J＝8.5Hz,3′,5′-H),7.22(d,2H,J＝8.5Hz,2′,6′-H),7.49(s,1H,3-H),7.70(d,1H,J＝8.0Hz,5-H),7.98(d,1H,J＝8.0Hz,6-H),8.23(d,1H,J＝9.0Hz,6″-H),8.31(s,1H,3″-H),8.49(s,1H,-NH),8.62(d,1H,J＝9.0Hz,5″-H)。

Embodiment 38: preparation N-(the chloro-2-nitrobenzophenone of 4-)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-35)

The aniline in embodiment 23 is replaced with 0.03mol 4-chloro-2-nitroaniline, other operations are with embodiment 23, obtain N-(the chloro-2-nitrobenzophenone of 4-)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-35), fusing point: 124-126 DEG C (correction), yield: 74.21%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.90(s,2H,-CH ₂),7.17(t,2H,J＝8.5Hz,3′,5′-H),7.23(d,2H,J＝8.5Hz,2′,6′-H),7.50(s,1H,3-H),7.67(d,1H,J＝9.0Hz,5″-H),7.68(d,1H,J＝8.0Hz,5-H),8.00(d,1H,J＝8.0Hz,6-H),8.22(s,1H,3″-H),8.70(d,1H,J＝8.0Hz,6″-H),10.82(s,1H,-NH)。

Embodiment 39: preparation N-(4-nitro-3-trifluoromethyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-36)

The aniline in embodiment 23 is replaced with 0.03mol 4-nitro-3-trifluoromethylaniline, other operations are with embodiment 23, obtain N-(4-nitro-3-trifluoromethyl)-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-36), fusing point: 157-159 DEG C (correction), yield: 54.49%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.87(s,2H,-CH ₂),7.19(d,2H,J＝9.0Hz,3′,5′-H),7.22(d,2H,J＝9.0Hz,2′,6′-H),7.49(s,1H,3-H),7.66(d,1H,J＝7.5Hz,5-H),7.86(d,1H,J＝8.0Hz,6-H),7.87(d,1H,J＝9.0Hz,6″-H),7.91(s,1H,2″-H),7.99(d,1H,J＝9.0Hz,5″-H),8.62(s,1H,-NH)。

Embodiment 40: preparation N-cyclohexyl-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-37)

The aniline in embodiment 23 is replaced with 0.03mol cyclohexylamine, other operations are with embodiment 23, obtain N-cyclohexyl-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-37), fusing point: 145-147 DEG C (correction), yield: 45.52%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):1.13(m,2H,3″,5″-CH ₂),1.23(m,1H,4″-CH ₂),1.44(m,2H,3″,5″-CH ₂),1.68(m,1H,4″-CH ₂),1.75(m,2H,2″,6″-CH ₂),1.93(m,2H,2″,6″-CH ₂),3.87(m,1H,1″-CH),3.89(s,2H,-CH ₂),5.88(d,1H,J＝6.0Hz,-NH),7.33(d,2H,J＝8.5Hz,3′,5′-H),7.34(s,1H,3-H),7.38(d,2H,J＝8.5Hz,2′,6′-H),7.57(d,1H,J＝7.5Hz,5-H),7.76(d,1H,J＝8.0Hz,6-H)。

Embodiment 41: preparation N-ethyl, N-phenyl-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-38)

The aniline in embodiment 23 is replaced with 0.03mol N-ethylaniline, other operations are with embodiment 23, obtain N-ethyl, N-phenyl-O-(4-chlorobenzene acetyl)-(4-trifluoromethyl) salicylamide (I-38), fusing point: 89-93 DEG C (correction), yield: 44.83%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):1.18(t,3H,J＝7.0Hz,-CH ₃),3.92(q,2H,J＝7.0Hz,- CH ₂ -CH ₃),3.92(s,2H,-CH ₂),7.04(d,2H,J＝7.0Hz,5,6-H),7.11(t,1H,J＝7.0Hz,4″-H),7.18(m,4H,Ar″-H),7.30(s,1H,3-H),7.37(m,4H,Ar′-H)。

Embodiment 42: preparation N-phenyl-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-39)

With 0.015mol O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylic acid replaces in embodiment 4 (0.015mol) O-(4-fluorobenzene acetyl)-(4-trifluoromethyl) salicylic acid, other operations are with embodiment 4, obtain N-phenyl-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-39), fusing point: 160-162 DEG C (correction), yield: 61.38%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):4.03(s,2H,-CH ₂),7.14(t,1H,J＝8.5Hz,6′-H),7.22(d,1H,J＝8.0Hz,5′-H),7.23(t,1H,J＝7.5Hz,4″-H),7.32(s,1H,3′-H),7.40(t,2H,J＝7.5Hz,3″,5″-H),7.47(s,1H,3-H),7.51(d,2H,J＝8.0Hz,2″,6″-H),7.65(d,1H,J＝8.0Hz,5-H),7.72(s,1H,-NH),7.91(d,1H,J＝8.0Hz,6-H)。

Embodiment 43: preparation N-(2-aminomethyl phenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-40)

The aniline in embodiment 42 is replaced with 0.03mol ortho-aminotoluene, other operations are with embodiment 42, obtain N-(2-aminomethyl phenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-40), fusing point: 167-168 DEG C (correction), yield: 59.59%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):2.18(s,2H,-CH ₃),4.02(s,2H,-CH ₂),7.10(d,1H,J＝8.0Hz,6′-H),7.19(t,1H,J＝6.0Hz,4″-H),7.20(d,1H,J＝8.5Hz,5′-H),7.24(d,1H,J＝6.0Hz,6″-H),7.28(t,1H,J＝6.0Hz,5″-H),7.28(s,1H,3′-H),7.48(s,1H,3-H),7.50(s,1H,-NH),7.64(d,1H,J＝8.0Hz,5-H),7.79(d,1H,J＝8.0Hz,6-H),7.93(d,1H,J＝7.5Hz,3″-H)。

Embodiment 44: preparation N-(3-aminomethyl phenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-41)

The aniline in embodiment 42 is replaced with 0.03mol meta-aminotoluene, other operations are with embodiment 42, obtain N-(3-aminomethyl phenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-41), fusing point: 130-132 DEG C (correction), yield: 73.45%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):2.39(s,2H,-CH ₃),4.03(s,2H,-CH ₂),7.03(d,1H,J＝6.0Hz,4″-H),7.14(d,1H,J＝8.5Hz,6′-H),7.21(d,1H,J＝8.5Hz,5′-H),7.28(t,1H,J＝8.0Hz,5″-H),7.30(d,1H,J＝8.0Hz,6″-H),7.33(s,1H,3′-H),7.34(s,1H,2″-H),7.46(s,1H,3-H),7.64(d,1H,J＝8.0Hz,5-H),7.65(s,1H,-NH),7.90(d,1H,J＝8.0Hz,6-H)。

Embodiment 45: preparation N-(4-aminomethyl phenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-42)

The aniline in embodiment 42 is replaced with 0.03mol para-totuidine, other operations are with embodiment 42, obtain N-(4-aminomethyl phenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-42), fusing point: 165-167 DEG C (correction), yield: 66.52%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):1.56(s,2H,-CH ₃),4.02(s,2H,-CH ₂),7.14(d,1H,J＝8.0Hz,6′-H),7.19(d,2H,J＝8.0Hz,3″,5″-H),7.22(d,1H,J＝8.0Hz,5′-H),7.32(s,1H,3′-H),7.38(d,2H,J＝8.0Hz,2″,6″-H),7.46(s,1H,3-H),7.62(d,1H,J＝7.5Hz,5-H),7.64(s,1H,-NH),7.91(d,1H,J＝8.0Hz,6-H)。

Embodiment 46: preparation N-(4-fluorophenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-43)

The aniline in embodiment 42 is replaced with 0.03mol para-fluoroaniline, other operations are with embodiment 42, obtain N-(4-fluorophenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-43), fusing point: 164-166 DEG C (correction), yield: 61.38%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):4.03(s,2H,-CH ₂),7.09(t,2H,J＝8.5Hz,3″,5″-H),7.23(d,1H,J＝8.0Hz,6′-H),7.24(d,1H,J＝8.5Hz,5′-H),7.32(s,1H,3′-H),7.46(dd,2H,J＝9.0Hz,2″,6″-H),7.47(s,1H,3-H),7.64(d,1H,J＝8.0Hz,5-H),7.70(s,1H,-NH),7.91(d,1H,J＝8.0Hz,6-H)。

Embodiment 47: preparation N-(2-chlorphenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-44)

The aniline in embodiment 42 is replaced with 0.03mol o-chloraniline, other operations are with embodiment 42, obtain N-(2-chlorphenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-44), fusing point: 135-137 DEG C (correction), yield: 77.18%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):4.07(s,2H,-CH ₂),7.15(t,1H,J＝8.0Hz,4″-H),7.10(d,1H,J＝7.5Hz,6′-H),7.25(d,1H,J＝8.5Hz,5′-H),7.33(s,1H,3′-H),7.38(t,1H,J＝8.0Hz,5″-H),7.44(d,1H,J＝8.0Hz,3″-H),7.51(s,1H,3-H),7.67(d,1H,J＝7.5Hz,5-H),8.01(d,1H,J＝8.0Hz,6″-H),8.37(s,1H,-NH),8.46(d,1H,J＝8.0Hz,6-H)。

Embodiment 48: preparation N-(3-chlorphenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-45)

The aniline in embodiment 42 is replaced with 0.03mol m-chloroaniline, other operations are with embodiment 42, obtain N-(3-chlorphenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-45), fusing point: 126-127 DEG C (correction), yield: 78.51%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):4.03(s,2H,-CH ₂),7.18(d,1H,J＝8.0Hz,4″-H),7.19(d,1H,J＝8.5Hz,6′-H),7.24(d,1H,J＝8.5Hz,5′-H),7.34(s,1H,3′-H),7.31(d,1H,J＝8.0Hz,6″-H),7.32(t,1H,J＝8.0Hz,5″-H),7.47(s,1H,3-H),7.62(s,1H,2″-H),7.64(d,1H,J＝8.5Hz,5-H),7.74(s,1H,-NH),7.88(d,1H,J＝7.5Hz,6-H)。

Embodiment 49: preparation N-(4-chlorphenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-46)

The aniline in embodiment 42 is replaced with 0.03mol parachloroanilinum, other operations are with embodiment 42, obtain N-(4-chlorphenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-46), fusing point: 151-153 DEG C (correction), yield: 71.85%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):4.02(s,2H,-CH ₂),7.17(d,1H,J＝8.0Hz,5′-H),7.23(d,1H,J＝8.5Hz,6′-H),7.32(d,2H,J＝8.0Hz,3″,5″-H),7.35(s,1H,3′-H),7.44(d,2H,J＝8.0Hz,2″,6″-H),7.47(s,1H,3-H),7.63(d,1H,J＝7.5Hz,5-H),7.72(s,1H,-NH),7.87(d,1H,J＝8.0Hz,6-H)。

Embodiment 50: preparation N-(2-methoxyphenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-47)

The aniline in embodiment 42 is replaced with 0.03mol 2-aminoanisole, other operations are with embodiment 42, obtain N-(2-methoxyphenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-47), fusing point: 130-132 DEG C (correction), yield: 71.08%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.88(s,3H,-CH ₃),4.06(s,2H,-CH ₂),6.94(d,1H,J＝8.0Hz,3″-H),7.07(t,1H,J＝7.0Hz,5″-H),7.13(d,1H,J＝7.5Hz,6′-H),7.15(t,1H,J＝8.0Hz,4″-H),7.23(d,1H,J＝8.5Hz,5′-H),7.34(s,1H,3′-H),7.49(s,1H,3-H),7.65(d,1H,J＝7.0Hz,5-H),8.00(d,1H,J＝7.5Hz,6-H),8.48(d,1H,J＝8.5Hz,6″-H),8.56(s,1H,-NH)。

Embodiment 51: preparation N-(4-methoxyphenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-48)

The aniline in embodiment 42 is replaced with 0.03mol 4-aminoanisole, other operations are with embodiment 42, obtain N-(4-methoxyphenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-48), fusing point: 154-155 DEG C (correction), yield: 87.18%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):3.85(s,3H,-CH ₃),4.03(s,2H,-CH ₂),6.92(d,2H,J＝8.5Hz,3″,5″-H),7.16(d,1H,J＝8.5Hz,5′-H),7.23(d,1H,J＝8.5Hz,6′-H),7.33(s,1H,3′-H),7.40(d,2H,J＝9.0Hz,2″,6″-H),7.46(s,1H,3-H),7.61(s,1H,-NH),7.63(d,1H,J＝8.0Hz,5-H),7.92(d,1H,J＝8.0Hz,6-H)。

Embodiment 52: preparation N-(3-nitrobenzophenone)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-49)

The aniline in embodiment 42 is replaced with 0.03mol 3-nitroaniline, other operations are with embodiment 42, obtain N-(3-nitrobenzophenone)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-49), fusing point: 171-172 DEG C (correction), yield: 82.02%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):4.05(s,2H,-CH ₂),7.19(d,1H,J＝8.0Hz,5′-H),7.27(d,1H,J＝6.5Hz,6′-H),7.28(s,1H,3′-H),7.50(s,1H,3-H),7.57(t,1H,J＝8.0Hz,5″-H),7.67(d,1H,J＝7.5Hz,5-H),7.88(d,1H,J＝8.0Hz,6-H),7.92(d,1H,J＝8.0Hz,6″-H),8.61(s,1H,-NH),8.07(s,1H,J＝7.0Hz,4″-H),8.35(s,1H,2″-H)。

Embodiment 53: preparation N-(2-ethoxyl phenenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-50)

The aniline in embodiment 42 is replaced with 0.03mol 2-phenetidine, other operations are with embodiment 42, obtain N-(2-ethoxyl phenenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-50), fusing point: 121-123 DEG C (correction), yield: 62.61%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):1.43(t,3H,J＝6.0Hz-CH ₃),4.05(s,2H,-CH ₂),4.11(q,2H,J＝8.5Hz,-OCH ₂),6.92(d,1H,J＝8.0Hz,5′-H),7.04(t,1H,J＝7.5Hz,5″-H),7.11(d,1H,J＝8.0Hz,3″-H),7.13(t,1H,J＝7.5Hz,6″-H)，7.19(d,1H,J＝8.5Hz,6′-H),7.33(s,1H,3′-H),7.48(s,1H,3-H),7.66(d,1H,J＝8.0Hz,5-H),7.96(d,1H,J＝8.0Hz,6-H),8.50(s,1H,-NH),8.48(d,1H,J＝8.0Hz,5″-H)。

Embodiment 54: preparation N-(2,4 difluorobenzene base)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-51)

With 0.03mol 2,4-difluoroaniline replaces the aniline in embodiment 42, other operations are with embodiment 42, obtain N-(2,4-difluorophenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-51), fusing point: 164-165 DEG C (correction), yield: 70.24%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):4.08(s,2H,-CH ₂),6.94(t,1H,J＝8.0Hz,3″-H),6.98(t,1H,J＝8.5Hz,5″-H),7.21(d,1H,J＝8.0Hz,5′-H),7.29(d,1H,J＝8.5Hz,6′-H),7.36(s,1H,3′-H),7.51(s,1H,3-H),7.67(d,1H,J＝7.5Hz,5-H),8.06(d,1H,J＝8.0Hz,6-H),8.14(s,1H,-NH),8.35(q,1H,J＝8.5Hz,6″-H)。

Embodiment 55: preparation N-(2,5-Dichlorobenzene base)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-52)

With 0.03mol 2,5-dichloroaniline replaces the aniline in embodiment 42, other operations are with embodiment 42, obtain N-(2,5-Dichlorobenzene base)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-52), fusing point: 153-155 DEG C (correction), yield: 67.29%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):4.08(s,2H,-CH ₂),7.14(d,1H,J＝8.5Hz,6′-H),7.20(d,1H,J＝8.5Hz,5′-H),7.27(d,1H,J＝7.5Hz,4″-H),7.35(d,1H,J＝7.5Hz,3″-H),7.35(s,1H,3′-H),7.51(s,1H,3-H),7.68(d,1H,J＝7.5Hz,5-H),7.99(d,1H,J＝8.0Hz,6-H),8.35(s,1H,-NH),8.57(s,1H,6″-H)。

Embodiment 56: preparation N-(2-chloro-4 nitrophenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-53)

The aniline in embodiment 42 is replaced with the chloro-4-nitroaniline of 0.03mol 2-, other operations are with embodiment 42, obtain N-(2-chloro-4 nitrophenyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-53), fusing point: 148-150 DEG C (correction), yield: 87.18%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):4.07(s,2H,-CH ₂),7.18(d,1H,J＝8.0Hz,6′-H),7.27(d,1H,J＝8.5Hz,5′-H),7.31(s,1H,3′-H),7.54(s,1H,3-H),7.71(d,1H,J＝8.0Hz,5-H),8.01(d,1H,J＝8.0Hz,6-H),8.27(d,1H,J＝9.0Hz,6″-H)，8.35(s,1H,3″-H),8.61(s,1H,-NH),8.76(d,1H,J＝9.0Hz,5″-H)。

Embodiment 57: preparation N-(the chloro-2-nitrobenzophenone of 4-)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-54)

The aniline in embodiment 42 is replaced with 0.03mol 4-chloro-2-nitroaniline, other operations are with embodiment 42, obtain N-(the chloro-2-nitrobenzophenone of 4-)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-54), fusing point: 151-152 DEG C (correction), yield: 79.36%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,CDCl ₃,δppm):4.06(s,2H,-CH ₂),7.18(d,1H,J＝8.5Hz,5′-H),7.29(d,1H,J＝8.0Hz,6′-H),7.30(s,1H,3′-H),7.48(s,1H,3-H),7.69(d,1H,J＝8.5Hz,6″-H),7.71(d,1H,J＝9.0Hz,5″-H),8.01(d,1H,J＝8.0Hz,5-H),8.26(s,1H,3″-H)，8.82(d,1H,J＝9.0Hz,6-H),10.91(s,1H,-NH)。

Embodiment 58: preparation N-(4-nitro-3-trifluoromethyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-55)

The aniline in embodiment 42 is replaced with 0.03mol 4-nitro-3-trifluoromethylaniline, other operations are with embodiment 42, obtain N-(4-nitro-3-trifluoromethyl)-O-(2,4-dichloro-benzenes acetyl)-(4-trifluoromethyl) salicylamide (I-55), fusing point: 176-177 DEG C (correction), yield: 62.06%.

¹h nuclear magnetic resonance map is analyzed as follows:

¹H NMR(500MHz,DMSO,δppm):4.09(s,2H,-CH ₂),7.32(d,1H,J＝8.0Hz,5′-H),7.44(s,1H,2″-H),7.46(d,1H,J＝8.5Hz,6′-H),7.83(s,1H,3-H),7.87(d,1H,J＝8.0Hz,5-H),7.96(d,1H,J＝8.0Hz,6-H),8.11(d,1H,J＝9.0Hz,6″-H),8.27(d,1H,J＝8.5Hz,5″-H),8.33(s,1H,3′-H),11.25(s,1H,-NH)。

Embodiment 59 ~ 99:O-phenylacetyl-anti-intestinal cancer active testing of (4-trifluoromethyl) salicylamide compounds

A. principle: the succinate dehydrogenase in living cells mitochondrion can make exogenous Thiazolyl blue (MTT) be reduced to water-insoluble bluish violet crystallization first a ceremonial jade-ladle, used in libation (Formazan) and be deposited in cell, and dead cell is without this function.First a ceremonial jade-ladle, used in libation in dimethyl sulfoxide (DMSO) energy dissolved cell, measures first a ceremonial jade-ladle, used in libation light absorption value with enzyme-linked immunosorbent assay instrument at 490nm wavelength place, indirectly can reflect proliferative conditions and the number change of cell.Within the scope of certain cell number, the amount that MTT crystallization is formed is directly proportional to cell number.

B. cell: people's colon-cancer cell strain (HCT-116), people's colon-cancer cell strain (DLD-1), the strain of people's colon-cancer cell (Colo-320) (all purchased from Shanghai Inst. of Life Science, CAS).

C. experimental procedure

1) preparation of sample: Compound I-5 ~ I-45 prepared by Example 8 ~ 48, every 1mg sample 20 μ L DMSO dissolve, get 2 μ L, 1000 μ L culture fluid (preparation see culture fluid in the cultivation of step (2) cell below) dilution again, be made into the sample liquid of 100 μ g/mL, then use culture fluid serial dilution to working concentration 10 μ g/mL and 1 μ g/mL.

The preparation of 5mg/mLMTT: with normal saline configuration MTT solution, concentration is 5mg/mL.

2) cultivation of cell

The preparation of culture fluid: containing 800,000 units of Penicillin, 1.0g streptomycin, 10% inactivated fetal bovine serum in every 1000mL RPMI-1640 culture fluid (Hangzhou Ji Nuo company).

The cultivation of cell: colon-cancer cell HCT-116, DLD-1, Colo-320 are inoculated in respectively in culture fluid, puts 37 DEG C (corrections), 5%CO ₂cultivate in incubator, 3 ~ 5d goes down to posterity.

3) working sample is to the inhibitory action of each growth of tumour cell

By cell ethylenediaminetetraacetic acid (EDTA)-trypsinization liquid (0.25% pancreatin, 0.02%EDTA, with the configuration of Hank ' s buffer) digestion, and to be diluted to cell concentration with culture fluid be 3 × 10 ⁴/ mL, is added in 96 porocyte culture plates, and every hole 100 μ L, puts 37 DEG C (corrections), 5%CO ₂after cultivating 24h in incubator, incline culture fluid, and add the sample with culture fluid dilution, every hole 200 μ L, each concentration adds 3 holes, puts 37 DEG C (corrections), 5%CO ₂cultivate in incubator, in cell culture well, the MTT of 5mg/mL is added after 72h, every hole 10 μ L, puts 37 DEG C (corrections) and hatches 3h, add DMSO, every hole 150 μ L, with agitator (Haimen kylin Medical Instruments factory, QL-9001) vibration, first a ceremonial jade-ladle, used in libation is dissolved completely, light absorption value is detected at 490nm wavelength place with enzyme-linked immunosorbent assay instrument (BIO-RAD company of the U.S., 680 types).The culture fluid cultured cells of cisplatin control sample and same concentration DMSO is contained as blank under similarity condition, according to formula (1) calculation sample to the suppression ratio of growth of tumour cell, and the suppression ratio of compounds on cell growth under each concentration, the half-inhibition concentration (IC of each sample is calculated with SPSS software (purchased from American SPSS Inc.) ₅₀), result is as shown in table 2:

Computing formula: suppression ratio (%)=(OD _blank-OD _sample)/OD _blank× 100% formula (1)

Table 2: each compound is to the IC of HCT-116, DLD-1, Colo-320 ₅₀(mg/L)

Claims (4)

1. the application of the O-phenylacetyl as shown in formula I-(4-trifluoromethyl) salicylamide compounds in preparation treatment bowelcancer medicine,

In formula I, R is halogen; R ₁for hydrogen or chlorine; R ₂for H or ethyl; R ₃for cyclohexyl, benzyl or structure are such as formula the substituted-phenyl shown in (A):

In formula (A), Q ₁~ Q ₅respective is independently H, methyl, fluorine, chlorine, nitro, methoxy or ethoxy.

2. apply as claimed in claim 1, in wherein said formula I O-phenylacetyl-(4-trifluoromethyl) salicylamide compounds, R is fluorine or chlorine; R ₁for hydrogen or chlorine; R ₂for H, R ₃for structure is such as formula the substituted-phenyl shown in (A), described O-phenylacetyl-(4-trifluoromethyl) salicylamide compounds is such as formula shown in (II):

In formula II, Q ₁~ Q ₅respective is independently H, methyl, fluorine, chlorine, nitro, methoxy or ethoxy.

3. apply as claimed in claim 1, wherein said O-phenylacetyl-(4-trifluoromethyl) salicylamide compounds one of compound listed by table 1:

Table 1:

Compound R R ₁ R ₂ R ₃ Q ₁ Q ₂ Q ₃ Q ₄ Q ₅ Ⅰ-1 F H H / H H H H H Ⅰ-2 F H H / CH ₃ H H H H Ⅰ-3 F H H / H CH ₃ H H H Ⅰ-4 F H H / H H CH ₃ H H Ⅰ-5 F H H / H H F H H Ⅰ-6 F H H / Cl H H H H Ⅰ-7 F H H / H Cl H H H

Ⅰ-8 F H H / H H Cl H H Ⅰ-9 F H H / OCH ₃ H H H H Ⅰ-10 F H H / H H OCH ₃ H H Ⅰ-11 F H H / OC ₂H ₅ H H H H Ⅰ-12 F H H / F H F H H Ⅰ-13 F H H / Cl H Cl H H Ⅰ-14 F H H / Cl H H Cl H Ⅰ-15 F H H / H Cl Cl H H Ⅰ-16 F H H / Cl H NO ₂ H H Ⅰ-17 F H H / NO ₂ H Cl H H Ⅰ-18 F H H CH ₂C ₆H ₅ / / / / / Ⅰ-19 F H H Cyclohexyl / / / / / Ⅰ-20 Cl H H / H H H H H Ⅰ-21 Cl H H / CH ₃ H H H H Ⅰ-22 Cl H H / H CH ₃ H H H Ⅰ-23 Cl H H / H H CH ₃ H H Ⅰ-24 Cl H H / H H F H H Ⅰ-25 Cl H H / Cl H H H H Ⅰ-26 Cl H H / H Cl H H H Ⅰ-27 Cl H H / H H Cl H H Ⅰ-28 Cl H H / OCH ₃ H H H H Ⅰ-29 Cl H H / H H OCH ₃ H H Ⅰ-30 Cl H H / H H NO ₂ H H Ⅰ-31 Cl H H / OC ₂H ₅ H H H H Ⅰ-32 Cl H H / F H F H H Ⅰ-33 Cl H H / Cl H H Cl H Ⅰ-34 Cl H H / Cl H NO ₂ H H Ⅰ-35 Cl H H / NO ₂ H Cl H H Ⅰ-36 Cl H H / H CF ₃ NO ₂ H H Ⅰ-37 Cl H H Cyclohexyl / / / / / Ⅰ-38 Cl H C ₂H ₅ / H H H H H Ⅰ-39 Cl Cl H / H H H H H Ⅰ-40 Cl Cl H / CH ₃ H H H H Ⅰ-41 Cl Cl H / H CH ₃ H H H

Ⅰ-42 Cl Cl H / H H CH ₃ H H Ⅰ-43 Cl Cl H / H H F H H Ⅰ-44 Cl Cl H / Cl H H H H Ⅰ-45 Cl Cl H / H Cl H H H Ⅰ-46 Cl Cl H / H H Cl H H Ⅰ-47 Cl Cl H / OCH ₃ H H H H Ⅰ-48 Cl Cl H / H H OCH ₃ H H Ⅰ-49 Cl Cl H / H H NO ₂ H H Ⅰ-50 Cl Cl H / OC ₂H ₅ H H H H Ⅰ-51 Cl Cl H / F H F H H Ⅰ-52 Cl Cl H / Cl H H Cl H Ⅰ-53 Cl Cl H / Cl H NO ₂ H H Ⅰ-54 Cl Cl H / NO ₂ H Cl H H Ⅰ-55 Cl Cl H / H CF ₃ NO ₂ H H

。

4. apply as claimed in claim 3, wherein said O-phenylacetyl-(4-trifluoromethyl) salicylamide compounds is compounds I-5 ~ I-45.