CN105061341A - Acyl triazole compound and acetophenone-substituted phenyl methyl sulfoxide compound and preparing methods and application thoseof - Google Patents
Acyl triazole compound and acetophenone-substituted phenyl methyl sulfoxide compound and preparing methods and application thoseof Download PDFInfo
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- CN105061341A CN105061341A CN201510516237.XA CN201510516237A CN105061341A CN 105061341 A CN105061341 A CN 105061341A CN 201510516237 A CN201510516237 A CN 201510516237A CN 105061341 A CN105061341 A CN 105061341A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
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- C07C317/00—Sulfones; Sulfoxides
- C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses an acyl triazole compound, an acetophenone-substituted phenyl methyl sulfoxide compound and preparing methods and application thoseof. The structural formula (1) of the acyl triazole compound is as shown in the specification. In the structural formula (1), X is Cl or Br or I or OSO2R3; the R3 is C1-C4 alkyl groups or phenyl groups or substituted phenyl groups; the R1 and R2 separately are H or halogen or CN or NO2 or C1-C6 alkyl groups or C1-C6 alkoxy or C1-C6 alkyl sulphanyl or NR4R5, the R4 and R5 separately are C1-C6 alkyl groups. Polmacoxib midbody is formed by means of the compounds in a synthesis mode, and the compounds are high in yield, low in cost, free of byproduct cyanogen compound, safe, environmentally friendly and suitable for industrial production.
Description
Technical field
The present invention relates to the field of a kind of midbody compound of chemical synthetic drug and preparation method thereof, specifically, the present invention relates to midbody compound of preparation pool horse former times cloth (Polmacoxib) and preparation method thereof.
Background technology
2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H) furanone (compound 01) and 2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methyl sulfoxide base) phenyl]-3 (2H) furanone (compound 02) are the important intermediate of synthesizing new antiphlogiston pool horse former times cloth (compound 03).
Bibliographical information: compound 02 is obtained through oxidation by compound 01, and compound 01, is obtained through cyclisation by structural formula VII compound:
Cyclizing agent used is 2-bromine isobutyl acyl cyanide (compound 04) (Bioorg.Med.Chem.2002,10:1137-42; CN201410364152.X; WO2015080435),
There are two shortcomings in this reaction: (1) by product is prussiate, severe toxicity, and waste water is difficult; (2) prussic acid of severe toxicity can be discharged after compound 04 moisture absorption.Require very high to packaging, storage and production environment.In producing, have minority specioz 04 unreacted complete, aftertreatment is by abnormally dangerous.
Also have report once to use 2-bromine isobutyl acylbromide (compound 05) to make cyclizing agent (Bioorg.Med.Chem.2002,10:1137-42), but effect is bad, yield only has 33%.Be badly in need of improving.
Summary of the invention
The invention provides a kind of acyl group triazole compound, phenyl methyl sulfoxide compound and its preparation method and application that methyl phenyl ketone replaces; when adopting this acyl group triazole compound for the preparation of pool horse former times cloth intermediate; avoid the use of toxic agent; meanwhile, reaction yield is higher.
A kind of acyl group triazole compound, structure is as shown in formula I:
In formula I, X is Cl, Br, I or OSO
2r
3; R
3for C
1~ C
4alkyl, phenyl or substituted-phenyl;
R
1and R
2be separately H, F, Cl, Br, I, CN, NO
2, C
1~ C
6alkyl, C
1~ C
6alkoxyl group, C
1~ C
6alkylthio or NR
4r
5, wherein, R
4and R
5be separately C
1~ C
6alkyl.
This compound can be used for preparing compound 01 or 02.
The reaction formula preparing compound 01 is as follows:
The reaction formula preparing compound 02 is as follows:
Wherein, it is relatively stable that described acyl group triazole compound meets water, reacts can not discharge prussic acid with water, for the preparation of compound 01 or 02 time can not by-product prussiate, and reaction yield is higher, is a kind of environmental protection industrial chemicals.
As preferably, X is Cl or Br.
As preferably, R
1and R
2separately be selected from H or C
1~ C
4alkyl.
As preferably, X is Cl or Br, R
1and R
2be H simultaneously.
Present invention also offers a kind of preparation method of described acyl group triazole compound, carry out acylation reaction by the compound shown in the compound shown in formula (II) and formula (III) and obtain;
In formula (II), X is Cl, Br, I or OSO
2r
3, R
3for C
1~ C
4alkyl, phenyl or substituted-phenyl, preferred X is Cl or Br.X' is Cl, Br or I, and preferred X' is Cl or Br.Most preferably X, X ' is Cl simultaneously or is Br simultaneously.
In formula (III), R
1and R
2be separately H, F, Cl, Br, I, CN, NO
2, R
4, OR
4, SR
4or NR
4r
5, R
4and R
5be separately C
1~ C
6alkyl.As preferably, R
1and R
2be separately H, C
1~ C
4alkyl, most preferably R
1and R
2be H simultaneously.
The detailed process of this preparation method is as follows: under the existence of acid binding agent, is reacted by the compound shown in the compound shown in formula (II) and formula (III), the acyl group triazole compound described in generation.
Described acid binding agent is preferably at least one in salt of wormwood, sodium carbonate, pyridine, niacinamide and formula II I, most preferably is formula II I.
The solvent of this reaction is preferably ethers, ester class, ketone, haloalkane hydro carbons, nitrile and amides; Further preferable methyl tertbutyl ether, isopropyl ether, positive propyl ether, tetrahydrofuran (THF), 1,4-dioxane, ethyl acetate, butylacetate, acetone, butanone, methyl iso-butyl ketone (MIBK), methylene dichloride, chloroform, acetonitrile, N, dinethylformamide or dimethyl sulfoxide (DMSO) etc., most preferably be tetrahydrofuran (THF), 1,4-dioxane or N,N-dimethylacetamide.
The temperature of this reaction preferably-30 ~ 100 DEG C, is preferably 0 ~ 40 DEG C, most preferably room temperature.
Described acyl group triazole compound can also be adopted and prepare with the following method:
Compound shown in formula (VI) compound and formula (V) is reacted, the acyl group triazole compound described in generation;
In formula (IV), X is Cl, Br, I or OSO
2r
3, R
3for C
1~ C
4alkyl, phenyl or substituted-phenyl, preferred X is Cl or Br.
In formula (V), R
1and R
2be separately H, F, Cl, Br, I, CN, NO
2, R
4, OR
4, SR
4or NR
4r
5, R
4and R
5be separately C
1~ C
6alkyl.Preferred R
1and R
2be separately H, C
1~ C
4alkyl, most preferably R
1and R
2be H simultaneously.
The solvent of this reaction is preferably ethers, ester class, ketone, haloalkane hydro carbons, nitrile or amide solvent, more preferably methyl tertiary butyl ether, isopropyl ether, positive propyl ether, tetrahydrofuran (THF), 1,4-dioxane, ethyl acetate, butylacetate, acetone, butanone, methyl iso-butyl ketone (MIBK), methylene dichloride, chloroform, acetonitrile, N, dinethylformamide or dimethyl sulfoxide (DMSO) etc., most preferably be tetrahydrofuran (THF), 1,4-dioxane or N,N-dimethylacetamide.
The temperature of this reaction is preferably-30 ~ 100 DEG C, most preferably 40 ~ 60 DEG C.
Present invention also offers the phenyl methyl sulfoxide compound that a kind of methyl phenyl ketone replaces, structure is such as formula shown in (VI):
The chemistry of this compound is called: 2-(3-fluorophenyl)-1-[4-(methyl sulfoxide base) phenyl] ethyl ketone.
Present invention also offers the preparation method of the phenyl methyl sulfoxide compound that a kind of described methyl phenyl ketone replaces, carry out oxidizing reaction by structure such as formula the compound shown in (VII) and obtain;
Reaction formula is as follows:
Oxygenant preferential oxidation iodobenzene, hydrogen peroxide, peroxy acid are as Peracetic Acid, benzoyl peroxide, metachloroperbenzoic acid, and as most preferably, oxidizing reaction oxygenant used is metachloroperbenzoic acid.
The solvent of this reaction is preferably ketone, haloalkane hydro carbons, nitrile or amides, and more preferably acetone, butanone, methyl iso-butyl ketone (MIBK), methylene dichloride, chloroform, acetonitrile, N,N-dimethylacetamide etc., most preferably be methylene dichloride.
Temperature of reaction preferably-50 ~ 100 DEG C, most preferably-20 ~ 30 DEG C.
The mol ratio of oxygenant and formula (VII) compound, preferably 1 ~ 3, most preferably 1 ~ 1.5.
Described acyl group triazole compound can be used for synthesis 2, 2-dimethyl-3 (2H) Furanones compound (structural formula VIII), be preferred for synthesis 2, 2-dimethyl-4, 5-diaryl-3 (2H) furanone (structural formula VIII, G1, G2 is aryl), most preferably for the synthesis of 2, 2-dimethyl-4-(3-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H) furanone (compound 01) and 2, 2-dimethyl-4-(3-fluorophenyl)-5-[4-(methyl sulfoxide) phenyl]-3 (2H) furanone (compound 02).
Reaction formula is as follows:
In formula (I), X is Cl, Br, I or OSO
2r
3, R
3for C
1~ C
4alkyl, phenyl or substituted-phenyl, preferred X is Cl or Br.
R
1and R
2be separately H, F, Cl, Br, I, CN, NO
2, R
4, OR
4, SR
4or NR
4r
5, R
4and R
5be separately C
1~ C
6alkyl.Preferred R
1and R
2be separately H, C
1~ C
4alkyl, most preferably R
1and R
2be H simultaneously.
In formula (VIII) and (IX), G
1and G
2be separately H, alkyl, substituted alkyl, aryl, substituted aryl, preferred aryl groups and substituted aryl, most preferably G
1for 3-fluorophenyl, G
2for 4-(first sulfydryl) phenyl or 4-(methyl sulfoxide base) phenyl.
When described acyl group triazole compound synthesizes 2,2-dimethyl-3 (2H) Furanones compound, preferably add highly basic in anhydrous conditions.Highly basic is generally metal hydride, metal alkyl compound, metal alkoxide, metal amine based compound and metallic silicon compounds, the two silicon amine lithiums of preferred sodium hydride, lithium hydride, hydrolith, butyllithium, ethylmagnesium bromide, sodium methylate, magnesium ethylate, trimethyl carbinol lithium, diisopropylamine lithium, hexamethyl etc.
The preferred ethers of reaction solvent, haloalkane hydro carbons, nitrile and amides, preferable methyl tertbutyl ether, isopropyl ether, positive propyl ether, tetrahydrofuran (THF), 1,4-dioxane, methylene dichloride, chloroform, acetonitrile, N, dinethylformamide, dimethyl sulfoxide (DMSO) etc., most preferably tetrahydrofuran (THF), 1,4-dioxane and N,N-dimethylacetamide.
Temperature of reaction preferably-30 ~ 100 DEG C, preferably 0 ~ 40 DEG C, most preferably room temperature.
Described acyl group triazole compound with the pure compound separated, also directly can use reaction solution.Preferably directly use reaction solution.
Present invention also offers a kind of application of described acyl group triazole compound, comprise: the phenyl methyl sulfoxide compound that described acyl group triazole compound and described methyl phenyl ketone replace reacts, obtain pool horse former times cloth intermediate (compound 02);
Compared with the existing technology; beneficial effect of the present invention is embodied in: when adopting acyl group triazole compound to synthesize pool horse former times cloth intermediate, can not produce the by product that toxicity is larger, environmentally friendly; reaction yield is higher, has actual industrial application value.
Embodiment
Below in conjunction with specific embodiment, the present invention is described further.
The preparation of embodiment 1:1-(2-bromine isobutyryl)-1,2,4-triazoles
1,2,4-triazole 1.38g (20mmol) is mixed with tetrahydrofuran (THF) 13.9ml, stirs, drip pure 2-bromine isobutyl acylbromide 2.29g (10mmol), within about 30 minutes, drip off, continue stirring 2 hours, filter, filtering insolubles, filtrate reduced in volume is to dry.Add methyl tertiary butyl ether 5ml, stir 30 minutes, filter, filter cake is dried, and obtains product 2.05g, yield 94%.
1H-NMR(CDCl
3，400MHz)：δ2.18(S,6H)，8.07(S,1H)，8.97(S,1H)
The preparation of embodiment 2:1-(2-chlorine isobutyryl)-1,2,4-triazoles
By N, N '-carbonyl diurethane (1,2,4-triazole) 1.64g (10mmol) mixes with tetrahydrofuran (THF) 16.4ml, adds 2-chlorine isopropylformic acid 1.23g (10mmol), and 50 DEG C of stirring reactions 2 hours, cooling, is evaporated to dry.Add methyl tertiary butyl ether 10ml, stir 30 minutes, filter, filter cake is dried, and obtains product 1.55g, yield 89.3%.
1H-NMR(CDCl
3，400MHz)：δ1.97(S,6H),δ7.93(S,1H),δ8.84(S,1H)
Embodiment 3:1-(2-bromine isobutyryl)-3-methyl isophthalic acid, the preparation of 2,4-triazole
By 3-methyl isophthalic acid, 2,4-triazole 1.66g (20mmol) mixes with tetrahydrofuran (THF) 16.6ml, stirs, drip pure 2-bromine isobutyl acylbromide 2.29g (10mmol), within about 30 minutes, drip off, continue stirring 2 hours, filter, filtering insolubles, filtrate reduced in volume is to dry.Add methyl tertiary butyl ether 5ml, stir 30 minutes, filter, filter cake is dried, and obtains product 2.09g, yield 90%.
1H-NMR(CDCl
3，400MHz)：δ2.17(S,6H),δ2.32(S,3H),δ8.77(S,1H)
The preparation of embodiment 4:1-(2-bromine isobutyryl)-3,5-dimethyl-1,2,4-triazols
3,5-dimethyl-1,2,4-triazol 1.94g (20mmol) is mixed with tetrahydrofuran (THF) 19.4ml, stir, drip pure 2-bromine isobutyl acylbromide 2.29g (10mmol), within about 30 minutes, drip off, continue stirring 2 hours, filter, filtering insolubles, filtrate reduced in volume is to dry.Add methyl tertiary butyl ether 5ml, stir 30 minutes, filter, filter cake is dried, and obtains product 2.12g, yield 86%.
1H-NMR(CDCl
3，400MHz)：δ2.17(S,6H),δ2.39(S,6H)
The preparation of chloro-1,2, the 4-triazole of embodiment 5:1-(2-bromine isobutyryl)-3-
Chloro-for 3-1,2,4-triazole 2.06g (10mmol) is mixed with tetrahydrofuran (THF) 20.6ml, stirs, drip pure 2-chlorine isobutyryl chloride 2.29g (10mmol), within about 30 minutes, drip off, continue stirring 8 hours, filter, filtering insolubles, filtrate reduced in volume is to dry.Add methyl tertiary butyl ether 5ml, stir 30 minutes, filter, filter cake is dried, and obtains product 2.15g, yield 85%.
1H-NMR(CDCl
3，400MHz)：δ2.19(S,6H),δ9.06(S,1H)
The preparation of embodiment 6:2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H) furanone (compound 01)
By 2-(3-fluorophenyl)-1-(4-first mercaptophenyl-) ethyl ketone 1.30g (5mmol), tetrahydrofuran (THF) 15ml is uniformly mixed, and is chilled to 0 DEG C, adds 60%NaH0.6g (15mmol), keeps 0 ~ 5 DEG C, stirs 1.0 hours.
1-(2-bromine isobutyryl)-1,2,4-triazole 1.09g (5mmol) is dissolved in tetrahydrofuran (THF) 10.9ml, instills in above-mentioned reaction flask about 1.0 hours and drip off, stirred overnight at room temperature.Add 2N hydrochloric acid 20ml, concentrating under reduced pressure, removing tetrahydrofuran (THF), to add water 30ml to residue, suction filtration, filter cake washes twice with water, with ethyl alcohol recrystallization, obtains product 1.35g, yield 82.2% again.
1H-NMR(CDCl
3，400MHz)：δ1.55(S,6H),δ2.50(S,3H)δ7.02～7.10(m,3H),δ7.18(d,2H)δ7.29～7.33(m,1H),δ7.55(d,2H)
The preparation of embodiment 7:2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H) furanone (compound 01)
By 2-(3-fluorophenyl)-1-(4-first mercaptophenyl-) ethyl ketone 1.30g (5mmol), tetrahydrofuran (THF) 15ml is uniformly mixed, and is chilled to 0 DEG C, adds 60%NaH0.6g (15mmol), keeps 0 ~ 5 DEG C, stirs 1.0 hours.
1-(2-chlorine isobutyryl)-1,2,4-triazole 0.868g (5mmol) is dissolved in tetrahydrofuran (THF) 8.7ml, instills in above-mentioned reaction flask about 1.0 hours and drip off, stirred overnight at room temperature.Add 2N hydrochloric acid 20ml, concentrating under reduced pressure, removing tetrahydrofuran (THF), to add water 30ml to residue, suction filtration, filter cake washes twice with water, with ethyl alcohol recrystallization, obtains product 1.28g, yield 78% again.
The preparation of embodiment 8:2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H) furanone (compound 01)
By 2-(3-fluorophenyl)-1-(4-first mercaptophenyl-) ethyl ketone 1.30g (5mmol), tetrahydrofuran (THF) 15ml is uniformly mixed, and is chilled to 0 DEG C, adds 60%NaH0.6g (15mmol), keeps 0 ~ 5 DEG C, stirs 1.0 hours.
By 1-(2-bromine isobutyryl)-3-methyl isophthalic acid, 2,4-triazole 1.16g (5mmol) dissolves in tetrahydrofuran (THF) 11.6ml, instills in above-mentioned reaction flask about 1.0 hours and drips off, stirred overnight at room temperature.Add 2N hydrochloric acid 20ml, concentrating under reduced pressure, removing tetrahydrofuran (THF), to add water 30ml to residue again, suction filtration, and filter cake washes twice with water, with ethyl alcohol recrystallization, obtains product 1.37g, yield 83.4%.
The preparation of embodiment 9:2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H) furanone (compound 01)
By 2-(3-fluorophenyl)-1-(4-first mercaptophenyl-) ethyl ketone 1.30g (5mmol), tetrahydrofuran (THF) 15ml is uniformly mixed, and is chilled to 0 DEG C, adds 60%NaH0.6g (15mmol), keeps 0 ~ 5 DEG C, stirs 1.0 hours.
1-(2-bromine isobutyryl)-3,5-dimethyl-1,2,4-triazol 1.23g (5mmol) is dissolved in tetrahydrofuran (THF) 12.3ml, instills in above-mentioned reaction flask about 1.0 hours and drip off, stirred overnight at room temperature.Add 2N hydrochloric acid 20ml, concentrating under reduced pressure, removing tetrahydrofuran (THF), to add water 30ml to residue, suction filtration, filter cake washes twice with water, with ethyl alcohol recrystallization, obtains product 1.41g, yield 85.9% again.
The preparation of embodiment 10:2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H) furanone (compound 01)
By 2-(3-fluorophenyl)-1-(4-first mercaptophenyl-) ethyl ketone 1.30g (5mmol), tetrahydrofuran (THF) 15ml is uniformly mixed, and is chilled to 0 DEG C, adds 60%NaH0.6g (15mmol), keeps 0 ~ 5 DEG C, stirs 1.0 hours.
Chloro-for 1-(2-bromine isobutyryl)-3-1,2,4-triazole 1.26g (5mmol) is dissolved in tetrahydrofuran (THF) 12.6ml, instills in above-mentioned reaction flask about 1.0 hours and drip off, stirred overnight at room temperature.Add 2N hydrochloric acid 20ml, concentrating under reduced pressure, removing tetrahydrofuran (THF), to add water 30ml to residue, suction filtration, filter cake washes twice with water, with ethyl alcohol recrystallization, obtains product 1.33g, yield 81% again.
The preparation of embodiment 11:2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H) furanone (compound 01)
By 2-(3-fluorophenyl)-1-(4-first mercaptophenyl-) ethyl ketone 2.60g (10mmol), tetrahydrofuran (THF) 26ml is uniformly mixed, and is chilled to 0 DEG C, adds 60%NaH1.20g (30mmol), keep 0 ~ 5 DEG C, stir 1.0 hours.
By 1,2,4-triazole 1.38g (20mmol) mixes with tetrahydrofuran (THF) 13.8ml, stirs, and drips 2-bromine isobutyl acylbromide 2.29g (10mmol), within about 30 minutes, drip off, continue stirring 2 hours, filter, filtering insolubles, filtrate is instilled in above-mentioned reaction flask about 1.0 hours to drip off, stirred overnight at room temperature.Add 2N hydrochloric acid 40ml, concentrating under reduced pressure, removing tetrahydrofuran (THF), to add water 60ml to residue, suction filtration, filter cake washes twice with water, with ethyl alcohol recrystallization, obtains product 2.65g, yield 80.7% again.
The preparation of embodiment 12:2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H) furanone (compound 01)
By 2-(3-fluorophenyl)-1-(4-first mercaptophenyl-) ethyl ketone 2.60g (10mmol), N,N-dimethylacetamide 20.8ml is uniformly mixed, be chilled to 0 DEG C, add 60%NaH2.0g (50mmol), keep 0 ~ 5 DEG C, stir 1.0 hours.
By 1,2,4-triazole 1.38g (20mmol) mixes with N,N-dimethylacetamide 13.8ml, stir, drip 2-bromine isobutyl acylbromide 2.29g (10mmol), within about 30 minutes, drip off, continue stirring 2 hours, filter, filtering insolubles, instills in above-mentioned reaction flask about 1.0 hours and drips off, stirred overnight at room temperature by filtrate.Add 2N hydrochloric acid 60ml, be evaporated near dry, to add water 60ml to residue, suction filtration, filter cake washes twice with water, with ethyl alcohol recrystallization, obtains product 2.85g, yield 86.8% again.
The preparation of embodiment 13:2-(3-fluorophenyl)-1-[4-(methyl sulfoxide base) phenyl] ethyl ketone (structural formula IV)
Metachloroperbenzoic acid 1.22g (6.3mmol) is dissolved in cold methylene dichloride 12ml for subsequent use.
2-(3-fluorophenyl)-1-(4-first mercaptophenyl-) ethyl ketone 1.30g (5mmol) is dissolved in methylene dichloride 13ml, is chilled to less than-5 DEG C.Drip above-mentioned metachloroperbenzoic acid solution.Control rate of addition, make temperature be no more than 0 DEG C, complete between-5 ~ 5 DEG C stir 2 hours, add 10% sodium carbonate solution 25ml, stir 1 hour, separate aqueous phase, organic phase washed with water secondary, each 20ml.By the organic phase anhydrous sodium sulfate drying after washing, filter, leach sodium sulfate, filtrate reduced in volume, to dry, obtains product 1.35g, yield 97.8%.The pure recrystallization of structural analysis sample first.
1H-NMR(CDCl
3，400MHz)：δ2.76(S,3H),δ4.31(S,2H),δ6.95～7.05(m,3H),δ7.28～7.32(m,1H),δ7.74(d,2H),δ8.14(d,2H)
The preparation of embodiment 14:2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methyl sulfoxide base) phenyl]-3 (2H) furanone (compound 02)
By 2-(3-fluorophenyl)-1-[4-(methyl sulfoxide base) phenyl] ethyl ketone 1.38g (5mmol), tetrahydrofuran (THF) 15ml is uniformly mixed, and is chilled to 0 DEG C, adds 60%NaH0.6g (15mmol), keep 0 ~ 5 DEG C, stir 1.0 hours.
1-(2-bromine isobutyryl)-1,2,4-triazole 1.09g (5mmol) is dissolved in tetrahydrofuran (THF) 10.9ml, instills in above-mentioned reaction flask about 1.0 hours and drip off, stirred overnight at room temperature.Add 2N hydrochloric acid 20ml, concentrating under reduced pressure, removing tetrahydrofuran (THF), to add water 30ml to residue, suction filtration, filter cake washes twice with water, with ethyl alcohol recrystallization, obtains product 1.52g, yield 92.6% again.
1H-NMR(CDCl
3，400MHz)：δ1.55(S,6H),δ2.50(S,3H)δ7.02～7.10(m,3H),δ7.18(d,2H)δ7.29～7.33(m,1H),δ7.55(d,2H)
The preparation of embodiment 15:2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methyl sulfoxide base) phenyl]-3 (2H) furanone (compound 02)
By 2-(3-fluorophenyl)-1-[4-(methyl sulfoxide base) phenyl] ethyl ketone 1.38g (5mmol), tetrahydrofuran (THF) 15ml is uniformly mixed, and is chilled to 0 DEG C, adds 60%NaH0.6g (15mmol), keep 0 ~ 5 DEG C, stir 1.0 hours.
1-(2-chlorine isobutyryl)-1,2,4-triazole 0.868g (5mmol) is dissolved in tetrahydrofuran (THF) 13.0ml, instills in above-mentioned reaction flask about 1.0 hours and drip off, stirred overnight at room temperature.Add 2N hydrochloric acid 20ml, concentrating under reduced pressure, removing tetrahydrofuran (THF), to add water 30ml to residue, suction filtration, filter cake washes twice with water, with ethyl alcohol recrystallization, obtains product 1.44g, yield 87.7% again.
The preparation of embodiment 16:2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methyl sulfoxide base) phenyl]-3 (2H) furanone (compound 02)
By 2-(3-fluorophenyl)-1-[4-(methyl sulfoxide base) phenyl] ethyl ketone 1.38g (5mmol), tetrahydrofuran (THF) 15ml is uniformly mixed, and is chilled to 0 DEG C, adds 60%NaH0.6g (15mmol), keep 0 ~ 5 DEG C, stir 1.0 hours.
By 1-(2-bromine isobutyryl)-3-methyl isophthalic acid, 2,4-triazole 1.16g (5mmol) dissolves in tetrahydrofuran (THF) 11.6ml, instills in above-mentioned reaction flask about 1.0 hours and drips off, stirred overnight at room temperature.Add 2N hydrochloric acid 20ml, concentrating under reduced pressure, removing tetrahydrofuran (THF), to add water 30ml to residue, suction filtration, filter cake washes twice with water, with ethyl alcohol recrystallization, obtains product 1.47g, yield 89.5% again.
The preparation of embodiment 17:2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methyl sulfoxide base) phenyl]-3 (2H) furanone (compound 02)
By 2-(3-fluorophenyl)-1-[4-(methyl sulfoxide base) phenyl] ethyl ketone 1.38g (5mmol), tetrahydrofuran (THF) 15ml is uniformly mixed, and is chilled to 0 DEG C, adds 60%NaH0.6g (15mmol), keep 0 ~ 5 DEG C, stir 1.0 hours.
1-(2-bromine isobutyryl)-3,5-dimethyl-1,2,4-triazol 1.23g (5mmol) is dissolved in tetrahydrofuran (THF) 12.3ml, instills in above-mentioned reaction flask about 1.0 hours and drip off, stirred overnight at room temperature.Add 2N hydrochloric acid 20ml, concentrating under reduced pressure, removing tetrahydrofuran (THF), to add water 30ml to residue, suction filtration, filter cake washes twice with water, with ethyl alcohol recrystallization, obtains product 1.45g, yield 88.3% again.
The preparation of embodiment 18:2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methyl sulfoxide base) phenyl]-3 (2H) furanone (compound 02)
By 2-(3-fluorophenyl)-1-[4-(methyl sulfoxide base) phenyl] ethyl ketone 1.38g (5mmol), tetrahydrofuran (THF) 15ml is uniformly mixed, and is chilled to 0 DEG C, adds 60%NaH0.6g (15mmol), keep 0 ~ 5 DEG C, stir 1.0 hours.
Chloro-for 1-(2-bromine isobutyryl)-3-1,2,4-triazole 1.26g (5mmol) is dissolved in tetrahydrofuran (THF) 12.6ml, instills in above-mentioned reaction flask about 1.0 hours and drip off, stirred overnight at room temperature.Add 2N hydrochloric acid 20ml, concentrating under reduced pressure, removing tetrahydrofuran (THF), to add water 30ml to residue, suction filtration, filter cake washes twice with water, with ethyl alcohol recrystallization, obtains product 1.36g, yield 82.8% again.
The preparation of embodiment 19:2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methyl sulfoxide base) phenyl]-3 (2H) furanone (compound 02)
By 2-(3-fluorophenyl)-1-[4-(methyl sulfoxide base) phenyl] ethyl ketone 2.76g (10mmol), tetrahydrofuran (THF) 27.6ml is uniformly mixed, and is chilled to 0 DEG C, adds 60%NaH1.20g (30mmol), keep 0 ~ 5 DEG C, stir 1.0 hours.
By 1,2,4-triazole 1.38g (20mmol) mixes with tetrahydrofuran (THF) 13.8ml, stirs, and drips 2-bromine isobutyl acylbromide 2.29g (10mmol), within about 30 minutes, drip off, continue stirring 2 hours, filter, filtering insolubles, filtrate is instilled in above-mentioned reaction flask about 1.0 hours to drip off, stirred overnight at room temperature.Add 2N hydrochloric acid 40ml, concentrating under reduced pressure, removing tetrahydrofuran (THF), to add water 60ml to residue, suction filtration, filter cake washes twice with water, with ethyl alcohol recrystallization, obtains product 3.06g, yield 93.2% again.
The preparation of embodiment 20:2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methyl sulfoxide base) phenyl]-3 (2H) furanone (compound 02)
By 2-(3-fluorophenyl)-1-[4-(methyl sulfoxide base) phenyl] ethyl ketone 2.76g (10mmol), N, N-N,N-DIMETHYLACETAMIDE 22.1ml is uniformly mixed, be chilled to 0 DEG C, add 60%NaH2.0g (50mmol), keep 0 ~ 5 DEG C, stir 1.0 hours.
By 1,2,4-triazole 1.38g (20mmol) mixes with N,N-dimethylacetamide 13.8ml, stir, drip 2-bromine isobutyl acylbromide 2.29g (10mmol), within about 30 minutes, drip off, continue stirring 2 hours, filter, filtering insolubles, instills in above-mentioned reaction flask about 1.0 hours and drips off, stirred overnight at room temperature by filtrate.Add 2N hydrochloric acid 60ml, be evaporated near dry, to add water 60ml to residue, suction filtration, filter cake washes twice with water, with ethyl alcohol recrystallization, obtains product 3.11g, yield 94.7% again.
Claims (10)
1. an acyl group triazole compound, is characterized in that, structure is as shown in formula I:
In formula I, X is Cl, Br, I or OSO
2r
3; R
3for C
1~ C
4the phenyl of alkyl, phenyl or replacement;
R
1and R
2be separately H, F, Cl, Br, I, CN, NO
2, C
1~ C
6alkyl, C
1~ C
6alkoxyl group, C
1~ C
6alkylthio or NR
4r
5, wherein, R
4and R
5be separately C
1~ C
6alkyl.
2. acyl group triazole compound according to claim 1, is characterized in that, X is Cl or Br.
3. acyl group triazole compound according to claim 1 and 2, is characterized in that, R
1and R
2separately be selected from H or C
1~ C
4alkyl.
4. acyl group triazole compound according to claim 1, is characterized in that, X is Cl or Br, R
1and R
2be H simultaneously.
5. a preparation method for the acyl group triazole compound as described in any one of Claims 1 to 4, is characterized in that, carries out acylation reaction obtain by the compound shown in the compound shown in formula (II) and formula (III);
Or, carry out acylation reaction by the compound shown in formula (IV) compound and formula (V) and obtain;
Wherein, X, R
1and R
2definition as described in any one of Claims 1 to 4;
X' is independently selected from Cl, Br or I.
6. the preparation method of acyl group triazole compound according to claim 5, is characterized in that, in formula (II), X and X' is Cl or Br simultaneously.
7. a phenyl methyl sulfoxide compound for methyl phenyl ketone replacement, it is characterized in that, structure is such as formula shown in (VI):
8. a preparation method for the phenyl methyl sulfoxide compound of methyl phenyl ketone replacement as claimed in claim 7, is characterized in that, carry out oxidizing reaction obtain by structure such as formula the compound shown in (VII);
9. the preparation method of phenyl methyl sulfoxide compound that replaces of methyl phenyl ketone according to claim 8, is characterized in that, oxidizing reaction oxygenant used is metachloroperbenzoic acid.
10. the application of the acyl group triazole compound as described in any one of Claims 1 to 4, it is characterized in that, the phenyl methyl sulfoxide compound that described acyl group triazole compound and methyl phenyl ketone according to claim 7 replace reacts, and obtains pool horse former times cloth intermediate (compound 02);
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| CN1348447A (en) * | 1999-04-14 | 2002-05-08 | 株式会社太平洋 | 4,5-diaryl-3(i(2H))-furanone derivatives as cyclooxygenase-2 inhibitors |
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| Title |
|---|
| SONG SEOK SHIN等: ""In Vitro Structure-Activity Relationship and in Vivo Studies for a Novel Class of Cyclooxygenase-2 Inhibitors: 5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone Derivatives"", 《J. MED. CHEM.》 * |
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