CN105061341B - Acyl group triazole compound, phenyl methyl sulfoxide compound of acetophenone substitution and its preparation method and application - Google Patents
Acyl group triazole compound, phenyl methyl sulfoxide compound of acetophenone substitution and its preparation method and application Download PDFInfo
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- CN105061341B CN105061341B CN201510516237.XA CN201510516237A CN105061341B CN 105061341 B CN105061341 B CN 105061341B CN 201510516237 A CN201510516237 A CN 201510516237A CN 105061341 B CN105061341 B CN 105061341B
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- YOCIJWAHRAJQFT-UHFFFAOYSA-N CC(C)(C(Br)=O)Br Chemical compound CC(C)(C(Br)=O)Br YOCIJWAHRAJQFT-UHFFFAOYSA-N 0.000 description 1
- XBHPAQWQSFPQRD-UHFFFAOYSA-N CC(C)(C(C#N)=O)Br Chemical compound CC(C)(C(C#N)=O)Br XBHPAQWQSFPQRD-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- 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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- C—CHEMISTRY; METALLURGY
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- 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
- C07D307/58—One oxygen atom, e.g. butenolide
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Abstract
Phenyl methyl sulfoxide compound replaced the invention discloses a kind of acyl group triazole compound, acetophenone and its preparation method and application; shown in the structure of the acyl group triazole compound such as formula (I); in formula (I), X is Cl, Br, I or OSO2R3；R3For C1~C4Alkyl, phenyl or substituted phenyl；R1And R2It is separately H, halogen, CN, NO2、C1~C6Alkyl, C1~C6Alkoxy, C1~C6Alkylthio group or NR4R5, wherein, R4And R5It is separately C1~C6Alkyl.Horse former times cloth intermediate is moored using the compound synthesis, high income, cost is low, not by-product cyanogen compound safety and environmental protection, be adapted to industrialization production.
Description
Technical field
The present invention relates to a kind of field of midbody compound of chemical synthetic drug and preparation method thereof, specifically,
The present invention relates to midbody compound for preparing pool horse former times cloth (Polmacoxib) and preparation method thereof.
Background technology
2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl mercapto) phenyl] -3 (2H) furanones (compound 01) and 2,
2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl sulfoxide base) phenyl] -3 (2H) furanones (compound 02) are synthesizing news
The important intermediate of anti-inflammatory agent pool horse former times cloth (compound 03).
Document report：Compound 02 is obtained by compound 01 is oxidized, compound 01, by structural formula VII compounds through ring
Change is obtained：
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 the reaction：(1) accessory substance is cyanide, and severe toxicity, waste water is difficult；(2) moisture absorption of compound 04
The hydrogen cyanide of severe toxicity can be discharged afterwards.Very high is required to packaging, storage and production environment.There is minority specioz 04 in such as producing
Unreacted is complete, and post processing will be abnormally dangerous.
Also have been reported that once used 2- bromine isobutyl acylbromides (compound 05) make cyclizing agent (Bioorg.Med.Chem.2002,10:
1137-42), but effect is bad, yield only has 33%.It need to improve.
The content of the invention
The invention provides a kind of acyl group triazole compound, acetophenone replace phenyl methyl sulfoxide compound and
Its preparation method and application, when being used to prepare pool horse former times cloth intermediate using the acyl group triazole compound, it is to avoid
The use of toxic agent, meanwhile, reaction yield is higher.
A kind of acyl group triazole compound, shown in structure such as formula (I)：
In formula (I), X is Cl, Br, I or OSO2R3；R3For C1~C4Alkyl, phenyl or substituted-phenyl；
R1And R2It is separately H, F, Cl, Br, I, CN, NO2、C1~C6Alkyl, C1~C6Alkoxy, C1~C6Alkane sulphur
Base or NR4R5, wherein, R4And R5It is separately C1~C6Alkyl.
The compound can be used for prepare compound 01 or 02.
The reaction equation of prepare compound 01 is as follows：
The reaction equation of prepare compound 02 is as follows：
Wherein, described acyl group triazole compound is met water and relatively stablized, and hydrogen cyanide will not be discharged with water reaction,
During for prepare compound 01 or 02 will not by-product cyanide, and reaction yield is higher, is a kind of environmental protection industrial chemicals.
Preferably, X is Cl or Br.
Preferably, R1And R2Separately it is selected from H or C1~C4Alkyl.
Preferably, X is Cl or Br, R1And R2It is simultaneously H.
Present invention also offers a kind of preparation method of described acyl group triazole compound, as the change shown in formula (II)
Compound carries out acylation reaction with the compound shown in formula (III) and obtained；
In formula (II), X is Cl, Br, I or OSO2R3, R3For C1~C4Alkyl, phenyl or substituted-phenyl, preferably X be Cl or
Br.X' is Cl, Br or I, and preferably X' is Cl or Br.Most preferably X, X ' are while being Cl or while being Br.
In formula (III), R1And R2It is separately H, F, Cl, Br, I, CN, NO2、R4、OR4、SR4Or NR4R5, R4And R5
It is separately C1~C6Alkyl.Preferably, R1And R2It is separately H, C1~C4Alkyl, most preferably R1And R2
It is simultaneously H.
The detailed process of the preparation method is as follows：In the presence of acid binding agent, by the compound and formula shown in formula (II)
(III) the compound reaction shown in, the described acyl group triazole compound of generation.
Described acid binding agent be preferably in potassium carbonate, sodium carbonate, pyridine, niacinamide and formula II I at least
One kind, most preferably formula II I.
The solvent of the reaction is preferably ethers, esters, ketone, alkyl halide hydro carbons, nitrile and amide-type；Further preferred first
Base tertbutyl ether, isopropyl ether, positive propyl ether, tetrahydrofuran, 1,4- dioxane, ethyl acetate, butyl acetate, acetone, butanone, first
Base isobutyl ketone, dichloromethane, chloroform, acetonitrile, DMF or dimethyl sulfoxide (DMSO) etc., most preferably tetrahydrochysene furan
Mutter, 1,4- dioxane or DMAC N,N' dimethyl acetamide.
Preferably -30~100 DEG C of the temperature of the reaction, preferably 0~40 DEG C, most preferably room temperature.
Described acyl group triazole compound can also be adopted to be prepared with the following method：
Formula (VI) compound is reacted with the compound shown in formula (V), the described acyl group triazole chemical combination of generation
Thing；
In formula (IV), X is Cl, Br, I or OSO2R3, R3For C1~C4Alkyl, phenyl or substituted-phenyl, preferably X be Cl or
Br。
In formula (V), R1And R2It is separately H, F, Cl, Br, I, CN, NO2、R4、OR4、SR4Or NR4R5, R4And R5Point
C independently is not it1~C6Alkyl.It is preferred that R1And R2It is separately H, C1~C4Alkyl, most preferably R1And R2It is simultaneously H.
The solvent of the reaction is preferably ethers, esters, ketone, alkyl halide hydro carbons, nitrile or amide solvent, more preferably first
Base tertbutyl ether, isopropyl ether, positive propyl ether, tetrahydrofuran, 1,4- dioxane, ethyl acetate, butyl acetate, acetone, butanone, first
Base isobutyl ketone, dichloromethane, chloroform, acetonitrile, DMF or dimethyl sulfoxide (DMSO) etc., most preferably tetrahydrochysene furan
Mutter, 1,4- dioxane or DMAC N,N' dimethyl acetamide.
The temperature of the reaction is preferably -30~100 DEG C, most preferably 40~60 DEG C.
Present invention also offers a kind of phenyl methyl sulfoxide compound of acetophenone substitution, shown in structure such as formula (VI)：
The compound it is chemical entitled：2- (3- fluorophenyls) -1- [4- (methyl sulfoxide base) phenyl] ethyl ketone.
A kind of preparation method of the phenyl methyl sulfoxide compound replaced present invention also offers described acetophenone, by
Compound of the structure as shown in formula (VII) carries out oxidation reaction and obtained；
Reaction equation is as follows：
The preferred Iodosobenzene of oxidant, hydrogen peroxide, peroxy acid such as Peracetic acid, benzoyl peroxide, m-chloro peroxide benzene
Formic acid, as most preferably, the oxidant used in oxidation reaction is metachloroperbenzoic acid.
The solvent of the reaction is preferably ketone, alkyl halide hydro carbons, nitrile or amide-type, and more preferably acetone, butanone, methyl is different
Butyl ketone, dichloromethane, chloroform, acetonitrile, DMA etc., most preferably dichloromethane.
Preferably -50~100 DEG C, most preferably -20~30 DEG C of reaction temperature.
Oxidant and the mol ratio of formula (VII) compound, preferably 1~3, most preferably 1~1.5.
Described acyl group triazole compound can be used for (2H) Furanones compound (structure of synthesis 2,2- dimethyl -3
Formula VIII), it is preferred for synthesis 2, (structural formula VIII, G1, G2 are virtue to 2- dimethyl -4,5- diaryl -3 (2H) furanone
Base), it is most preferably for synthesis 2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl mercapto) phenyl] -3 (2H) furanone (chemical combination
Thing 01) and 2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl sulfoxide) phenyl] -3 (2H) furanones (compound 02).
Reaction equation is as follows：
In formula (I), X is Cl, Br, I or OSO2R3, R3For C1~C4Alkyl, phenyl or substituted-phenyl, preferably X be Cl
Or Br.
R1And R2It is separately H, F, Cl, Br, I, CN, NO2、R4、OR4、SR4Or NR4R5, R4And R5Separately
For C1~C6Alkyl.It is preferred that R1And R2It is separately H, C1~C4Alkyl, most preferably R1And R2It is simultaneously H.
In formula (VIII) and (IX), G1And G2It is separately H, alkyl, replaces alkyl, aryl, substituted aryl, preferably
Aryl and substituted aryl, most preferably G1For 3- fluorophenyls, G2For 4- (first sulfydryl) phenyl or 4- (methyl sulfoxide base) phenyl.
When described acyl group triazole compound synthesizes 2,2- -3 (2H) Furanones compounds of dimethyl, preferably in nothing
Highly basic is added under water condition.Highly basic is generally metal hydride, metal alkyl compound, metal alkoxide, metal amine
Based compound and metallic silicon compounds, preferably sodium hydride, lithium hydride, calcium hydride, butyl lithium, ethylmagnesium bromide, sodium methoxide, ethanol
Double silicon amine lithiums of magnesium, tert-butyl alcohol lithium, diisopropylamine lithium, hexamethyl etc..
The preferred ethers of reaction dissolvent, alkyl halide hydro carbons, nitrile and amide-type, preferably methyl tertiary butyl ether(MTBE), isopropyl ether, positive third
Ether, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, dichloromethane, chloroform, acetonitrile, DMF, dimethyl sulfoxide (DMSO) etc., most
It is preferred that tetrahydrofuran, 1,4- dioxane and DMAC N,N' dimethyl acetamide.
Preferably -30~100 DEG C of reaction temperature, preferably 0~40 DEG C, most preferably room temperature.
Described acyl group triazole compound can use the pure compound separated, and can also directly use reaction solution.
It is preferred that directly using reaction solution.
Present invention also offers a kind of application of described acyl group triazole compound, including：The described nitrogen of acyl group three
The phenyl methyl sulfoxide compound that azole compounds replace with described acetophenone reacts, and obtains mooring horse former times cloth intermediate
(compound 02)；
Compared with the existing technology, beneficial effects of the present invention are embodied in：Pool is synthesized using acyl group triazole compound
When horse former times cloth intermediate, the larger accessory substance of toxicity will not be produced, environmentally friendly, reaction yield is higher, with reality
Industrial application value.
Embodiment
With reference to specific embodiment, the present invention is described further.
Embodiment 1：The preparation of 1- (2- bromines isobutyryl) -1,2,4- triazoles
1,2,4- triazole 1.38g (20mmol) is mixed with tetrahydrofuran 13.9ml, stirred, pure 2- bromines isobutyryl is added dropwise
Bromine 2.29g (10mmol), is dripped off for about 30 minutes, continues to stir 2 hours, and filtering filters out insoluble matter, filtrate decompression is concentrated to dryness.
Methyl tertiary butyl ether(MTBE) 5ml is added, is stirred 30 minutes, filtering, filter cake drying obtains product 2.05g, yield 94%.
1H-NMR(CDCl3, 400MHz)：δ 2.18 (S, 6H), 8.07 (S, 1H), 8.97 (S, 1H)
Embodiment 2：The preparation of 1- (2- chlorine isobutyryl) -1,2,4- triazoles
N, (1,2, the 4- triazole) 1.64g of N '-carbonyl two (10mmol) are mixed with tetrahydrofuran 16.4ml, 2- chlorine is added
Isobutyric acid 1.23g (10mmol), 50 DEG C of stirring reactions 2 hours, cooling is concentrated under reduced pressure into dry.Methyl tertiary butyl ether(MTBE) 10ml is added,
Stirring 30 minutes, filtering, filter cake drying obtains product 1.55g, yield 89.3%.
1H-NMR(CDCl3, 400MHz)：δ1.97(S,6H),δ7.93(S,1H),δ8.84(S,1H)
Embodiment 3：1- (2- bromines isobutyryl) -3- methyl isophthalic acids, the preparation of 2,4- triazoles
By 3- methyl isophthalic acids, 2,4- triazole 1.66g (20mmol) are mixed with tetrahydrofuran 16.6ml, stirring, and pure 2- is added dropwise
Bromine isobutyl acylbromide 2.29g (10mmol), is dripped off for about 30 minutes, continues to stir 2 hours, and filtering filters out insoluble matter, filtrate decompression is dense
It is reduced to dry.Methyl tertiary butyl ether(MTBE) 5ml is added, is stirred 30 minutes, filtering, filter cake drying obtains product 2.09g, yield 90%.
1H-NMR(CDCl3, 400MHz)：δ2.17(S,6H),δ2.32(S,3H),δ8.77(S,1H)
Embodiment 4：The preparation of 1- (2- bromines isobutyryl) -3,5- dimethyl -1,2,4- triazoles
3,5- dimethyl-1,2,4-triazols 1.94g (20mmol) is mixed with tetrahydrofuran 19.4ml, stirred, is added dropwise
Pure 2- bromine isobutyl acylbromides 2.29g (10mmol), drips off for about 30 minutes, continues to stir 2 hours, and filtering filters out insoluble matter, filtrate subtracts
Pressure is concentrated to dryness.Methyl tertiary butyl ether(MTBE) 5ml is added, is stirred 30 minutes, filtering, filter cake drying obtains product 2.12g, yield 86%.
1H-NMR(CDCl3, 400MHz)：δ2.17(S,6H),δ2.39(S,6H)
Embodiment 5：The preparation of the chloro- 1,2,4- triazoles of 1- (2- bromines isobutyryl) -3-
The triazole 2.06g (10mmol) of 3- chloro- 1,2,4- are mixed with tetrahydrofuran 20.6ml, stirred, pure 2- chlorine is added dropwise
Isobutyryl chloride 2.29g (10mmol), is dripped off for about 30 minutes, continues to stir 8 hours, filtering, filters out insoluble matter, filtrate decompression concentration
It is extremely dry.Methyl tertiary butyl ether(MTBE) 5ml is added, is stirred 30 minutes, filtering, filter cake drying obtains product 2.15g, yield 85%.
1H-NMR(CDCl3, 400MHz)：δ2.19(S,6H),δ9.06(S,1H)
Embodiment 6：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl mercapto) phenyl] -3 (2H) furanone (compounds
01) preparation
By 2- (3- fluorophenyls) -1- (4- first mercaptophenyl-) ethyl ketone 1.30g (5mmol), tetrahydrofuran 15ml stirring mixing is cold
To 0 DEG C, 60%NaH 0.6g (15mmol) are added, are kept for 0~5 DEG C, are stirred 1.0 hours.
The triazole 1.09g (5mmol) of 1- (2- bromines isobutyryl) -1,2,4- are dissolved in tetrahydrofuran 10.9ml, instillation
State about 1.0 hours in reaction bulb and drip off, be stirred overnight at room temperature.2N hydrochloric acid 20ml are added, are concentrated under reduced pressure, tetrahydrofuran is removed, to
Residue adds water 30ml, suction filtration, and filter cake is washed with water twice, with ethyl alcohol recrystallization, obtains product 1.35g, yield 82.2%.
1H-NMR(CDCl3, 400MHz)：δ 1.55 (S, 6H), δ 2.50 (S, 3H) δ 7.02~7.10 (m, 3H), δ 7.18 (d,
2H) δ 7.29~7.33 (m, 1H), δ 7.55 (d, 2H)
Embodiment 7：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl mercapto) phenyl] -3 (2H) furanone (compounds
01) preparation
By 2- (3- fluorophenyls) -1- (4- first mercaptophenyl-) ethyl ketone 1.30g (5mmol), tetrahydrofuran 15ml stirring mixing is cold
To 0 DEG C, 60%NaH 0.6g (15mmol) are added, are kept for 0~5 DEG C, are stirred 1.0 hours.
The triazole 0.868g (5mmol) of 1- (2- chlorine isobutyryl) -1,2,4- are dissolved in tetrahydrofuran 8.7ml, instillation
State about 1.0 hours in reaction bulb and drip off, be stirred overnight at room temperature.2N hydrochloric acid 20ml are added, are concentrated under reduced pressure, tetrahydrofuran is removed, to
Residue adds water 30ml, suction filtration, and filter cake is washed with water twice, with ethyl alcohol recrystallization, obtains product 1.28g, yield 78%.
Embodiment 8：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl mercapto) phenyl] -3 (2H) furanone (compounds
01) preparation
By 2- (3- fluorophenyls) -1- (4- first mercaptophenyl-) ethyl ketone 1.30g (5mmol), tetrahydrofuran 15ml stirring mixing is cold
To 0 DEG C, 60%NaH 0.6g (15mmol) are added, are kept for 0~5 DEG C, are stirred 1.0 hours.
By 1- (2- bromines isobutyryl) -3- methyl isophthalic acids, 2,4- triazole 1.16g (5mmol) dissolve in tetrahydrofuran 11.6ml,
Instill about 1.0 hours in above-mentioned reaction bulb and drip off, be stirred overnight at room temperature.2N hydrochloric acid 20ml are added, are concentrated under reduced pressure, tetrahydrochysene furan is removed
Mutter, 30ml, suction filtration added water to residue, filter cake is washed with water twice, with ethyl alcohol recrystallization, obtains product 1.37g, yield
83.4%.
Embodiment 9：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl mercapto) phenyl] -3 (2H) furanone (compounds
01) preparation
By 2- (3- fluorophenyls) -1- (4- first mercaptophenyl-) ethyl ketone 1.30g (5mmol), tetrahydrofuran 15ml stirring mixing is cold
To 0 DEG C, 60%NaH 0.6g (15mmol) are added, are kept for 0~5 DEG C, are stirred 1.0 hours.
1- (2- bromines isobutyryl) -3,5- dimethyl -1,2,4- triazoles 1.23g (5mmol) are dissolved in into tetrahydrofuran
12.3ml, instills and is dripped off within about 1.0 hours in above-mentioned reaction bulb, is stirred overnight at room temperature.2N hydrochloric acid 20ml are added, is concentrated under reduced pressure, removes
Tetrahydrofuran is removed, 30ml, suction filtration are added water to residue, filter cake is washed with water twice, with ethyl alcohol recrystallization, obtains product 1.41g, is received
Rate 85.9%.
Embodiment 10：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl mercapto) phenyl] -3 (2H) furanone (chemical combination
Thing 01) preparation
By 2- (3- fluorophenyls) -1- (4- first mercaptophenyl-) ethyl ketone 1.30g (5mmol), tetrahydrofuran 15ml stirring mixing is cold
To 0 DEG C, 60%NaH 0.6g (15mmol) are added, are kept for 0~5 DEG C, are stirred 1.0 hours.
The triazole 1.26g (5mmol) of 1- (2- bromines isobutyryl) -3- chloro- 1,2,4- are dissolved in into tetrahydrofuran 12.6ml, dripped
Enter about 1.0 hours in above-mentioned reaction bulb and drip off, be stirred overnight at room temperature.2N hydrochloric acid 20ml are added, are concentrated under reduced pressure, tetrahydrochysene furan is removed
Mutter, 30ml, suction filtration are added water to residue, filter cake is washed with water twice, with ethyl alcohol recrystallization, obtains product 1.33g, yield 81%.
Embodiment 11：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl mercapto) phenyl] -3 (2H) furanone (chemical combination
Thing 01) preparation
By 2- (3- fluorophenyls) -1- (4- first mercaptophenyl-) ethyl ketone 2.60g (10mmol), tetrahydrofuran 26ml stirrings are mixed,
It is cooled to 0 DEG C, adds 60%NaH 1.20g (30mmol), kept for 0~5 DEG C, stirs 1.0 hours.
1,2,4- triazole 1.38g (20mmol) is mixed with tetrahydrofuran 13.8ml, stirred, 2- bromine isobutyl acylbromides are added dropwise
2.29g (10mmol), is dripped off for about 30 minutes, continues to stir 2 hours, and filtering filters out insoluble matter, filtrate is instilled into above-mentioned reaction bulb
Drip off within middle about 1.0 hours, be stirred overnight at room temperature.2N hydrochloric acid 40ml are added, are concentrated under reduced pressure, tetrahydrofuran are removed, to residue again
Add water 60ml, suction filtration, and filter cake is washed with water twice, with ethyl alcohol recrystallization, obtains product 2.65g, yield 80.7%.
Embodiment 12：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl mercapto) phenyl] -3 (2H) furanone (chemical combination
Thing 01) preparation
By 2- (3- fluorophenyls) -1- (4- first mercaptophenyl-) ethyl ketone 2.60g (10mmol), DMA 20.8ml
Stirring mixing, is cooled to 0 DEG C, adds 60%NaH 2.0g (50mmol), is kept for 0~5 DEG C, stirs 1.0 hours.
1,2,4- triazole 1.38g (20mmol) is mixed with DMA 13.8ml, stirred, 2- bromines are added dropwise
Isobutyl acylbromide 2.29g (10mmol), is dripped off for about 30 minutes, continues to stir 2 hours, and filtering filters out insoluble matter, filtrate is instilled
State about 1.0 hours in reaction bulb and drip off, be stirred overnight at room temperature.2N hydrochloric acid 60ml are added, is concentrated under reduced pressure into and closely does, to residue again
Add water 60ml, suction filtration, and filter cake is washed with water twice, with ethyl alcohol recrystallization, obtains product 2.85g, yield 86.8%.
Embodiment 13：The preparation of 2- (3- fluorophenyls) -1- [4- (methyl sulfoxide base) phenyl] ethyl ketone (structural formula IV)
Metachloroperbenzoic acid 1.22g (6.3mmol) is dissolved in standby in cold dichloromethane 12ml.
2- (3- fluorophenyls) -1- (4- first mercaptophenyl-) ethyl ketone 1.30g (5mmol) is dissolved in dichloromethane 13ml, is cooled to -5
Below DEG C.Above-mentioned metachloroperbenzoic acid solution is added dropwise.Rate of addition is controlled, temperature heating is no more than 0 DEG C, finish -5~
Stirred 2 hours between 5 DEG C, add 10% sodium carbonate liquor 25ml, stirred 1 hour, separate aqueous phase, organic phase be washed with water it is secondary,
Each 20ml.By the organic phase anhydrous sodium sulfate drying after washing, filtering filters out sodium sulphate, filtrate decompression is concentrated to dryness, and is obtained
Product 1.35g, yield 97.8%.The structural analysis sample pure recrystallization of first.
1H-NMR(CDCl3, 400MHz)：δ 2.76 (S, 3H), δ 4.31 (S, 2H), δ 6.95~7.05 (m, 3H), δ 7.28~
7.32(m,1H),δ7.74(d,2H),δ8.14(d,2H)
Embodiment 14：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl sulfoxide base) phenyl] -3 (2H) furanones
The preparation of (compound 02)
2- (3- fluorophenyls) -1- [4- (methyl sulfoxide base) phenyl] ethyl ketone 1.38g (5mmol), tetrahydrofuran 15ml are stirred
Mixing is mixed, is cooled to 0 DEG C, 60%NaH 0.6g (15mmol) are added, is kept for 0~5 DEG C, is stirred 1.0 hours.
The triazole 1.09g (5mmol) of 1- (2- bromines isobutyryl) -1,2,4- are dissolved in tetrahydrofuran 10.9ml, instillation
State about 1.0 hours in reaction bulb and drip off, be stirred overnight at room temperature.2N hydrochloric acid 20ml are added, are concentrated under reduced pressure, tetrahydrofuran is removed, to
Residue adds water 30ml, suction filtration, and filter cake is washed with water twice, with ethyl alcohol recrystallization, obtains product 1.52g, yield 92.6%.
1H-NMR(CDCl3, 400MHz)：δ 1.55 (S, 6H), δ 2.50 (S, 3H) δ 7.02~7.10 (m, 3H), δ 7.18 (d,
2H) δ 7.29~7.33 (m, 1H), δ 7.55 (d, 2H)
Embodiment 15：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl sulfoxide base) phenyl] -3 (2H) furanones
The preparation of (compound 02)
2- (3- fluorophenyls) -1- [4- (methyl sulfoxide base) phenyl] ethyl ketone 1.38g (5mmol), tetrahydrofuran 15ml are stirred
Mixing is mixed, is cooled to 0 DEG C, 60%NaH 0.6g (15mmol) are added, is kept for 0~5 DEG C, is stirred 1.0 hours.
The triazole 0.868g (5mmol) of 1- (2- chlorine isobutyryl) -1,2,4- are dissolved in tetrahydrofuran 13.0ml, instillation
State about 1.0 hours in reaction bulb and drip off, be stirred overnight at room temperature.2N hydrochloric acid 20ml are added, are concentrated under reduced pressure, tetrahydrofuran is removed, to
Residue adds water 30ml, suction filtration, and filter cake is washed with water twice, with ethyl alcohol recrystallization, obtains product 1.44g, yield 87.7%.
Embodiment 16：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl sulfoxide base) phenyl] -3 (2H) furanones
The preparation of (compound 02)
2- (3- fluorophenyls) -1- [4- (methyl sulfoxide base) phenyl] ethyl ketone 1.38g (5mmol), tetrahydrofuran 15ml are stirred
Mixing is mixed, is cooled to 0 DEG C, 60%NaH 0.6g (15mmol) are added, is kept for 0~5 DEG C, is stirred 1.0 hours.
By 1- (2- bromines isobutyryl) -3- methyl isophthalic acids, 2,4- triazole 1.16g (5mmol) dissolve in tetrahydrofuran 11.6ml,
Instill about 1.0 hours in above-mentioned reaction bulb and drip off, be stirred overnight at room temperature.2N hydrochloric acid 20ml are added, are concentrated under reduced pressure, tetrahydrochysene furan is removed
Mutter, 30ml, suction filtration are added water to residue, filter cake is washed with water twice, with ethyl alcohol recrystallization, obtains product 1.47g, yield
89.5%.
Embodiment 17：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl sulfoxide base) phenyl] -3 (2H) furanones
The preparation of (compound 02)
2- (3- fluorophenyls) -1- [4- (methyl sulfoxide base) phenyl] ethyl ketone 1.38g (5mmol), tetrahydrofuran 15ml are stirred
Mixing is mixed, is cooled to 0 DEG C, 60%NaH 0.6g (15mmol) are added, is kept for 0~5 DEG C, is stirred 1.0 hours.
1- (2- bromines isobutyryl) -3,5- dimethyl -1,2,4- triazoles 1.23g (5mmol) are dissolved in into tetrahydrofuran
12.3ml, instills and is dripped off within about 1.0 hours in above-mentioned reaction bulb, is stirred overnight at room temperature.2N hydrochloric acid 20ml are added, is concentrated under reduced pressure, removes
Tetrahydrofuran is removed, 30ml, suction filtration are added water to residue, filter cake is washed with water twice, with ethyl alcohol recrystallization, obtains product 1.45g, is received
Rate 88.3%.
Embodiment 18：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl sulfoxide base) phenyl] -3 (2H) furanones
The preparation of (compound 02)
2- (3- fluorophenyls) -1- [4- (methyl sulfoxide base) phenyl] ethyl ketone 1.38g (5mmol), tetrahydrofuran 15ml are stirred
Mixing is mixed, is cooled to 0 DEG C, 60%NaH 0.6g (15mmol) are added, is kept for 0~5 DEG C, is stirred 1.0 hours.
The triazole 1.26g (5mmol) of 1- (2- bromines isobutyryl) -3- chloro- 1,2,4- are dissolved in into tetrahydrofuran 12.6ml, dripped
Enter about 1.0 hours in above-mentioned reaction bulb and drip off, be stirred overnight at room temperature.2N hydrochloric acid 20ml are added, are concentrated under reduced pressure, tetrahydrochysene furan is removed
Mutter, 30ml, suction filtration are added water to residue, filter cake is washed with water twice, with ethyl alcohol recrystallization, obtains product 1.36g, yield
82.8%.
Embodiment 19：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl sulfoxide base) phenyl] -3 (2H) furanones
The preparation of (compound 02)
By 2- (3- fluorophenyls) -1- [4- (methyl sulfoxide base) phenyl] ethyl ketone 2.76g (10mmol), tetrahydrofuran 27.6ml
Stirring mixing, is cooled to 0 DEG C, adds 60%NaH 1.20g (30mmol), is kept for 0~5 DEG C, stirs 1.0 hours.
1,2,4- triazole 1.38g (20mmol) is mixed with tetrahydrofuran 13.8ml, stirred, 2- bromine isobutyl acylbromides are added dropwise
2.29g (10mmol), is dripped off for about 30 minutes, continues to stir 2 hours, and filtering filters out insoluble matter, filtrate is instilled into above-mentioned reaction bulb
Drip off within middle about 1.0 hours, be stirred overnight at room temperature.2N hydrochloric acid 40ml are added, are concentrated under reduced pressure, tetrahydrofuran are removed, to residue again
Add water 60ml, suction filtration, and filter cake is washed with water twice, with ethyl alcohol recrystallization, obtains product 3.06g, yield 93.2%.
Embodiment 20：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl sulfoxide base) phenyl] -3 (2H) furanones
The preparation of (compound 02)
By 2- (3- fluorophenyls) -1- [4- (methyl sulfoxide base) phenyl] ethyl ketone 2.76g (10mmol), N, N- dimethylacetamides
Amine 22.1ml stirring mixing, is cooled to 0 DEG C, adds 60%NaH 2.0g (50mmol), kept for 0~5 DEG C, stir 1.0 hours.
1,2,4- triazole 1.38g (20mmol) is mixed with DMA 13.8ml, stirred, 2- bromines are added dropwise
Isobutyl acylbromide 2.29g (10mmol), is dripped off for about 30 minutes, continues to stir 2 hours, and filtering filters out insoluble matter, filtrate is instilled
State about 1.0 hours in reaction bulb and drip off, be stirred overnight at room temperature.2N hydrochloric acid 60ml are added, is concentrated under reduced pressure into and closely does, to residue again
Add water 60ml, suction filtration, and filter cake is washed with water twice, with ethyl alcohol recrystallization, obtains product 3.11g, yield 94.7%.
Claims (2)
1. a kind of phenyl methyl sulfoxide compound of acetophenone substitution, it is characterised in that shown in structure such as formula (VI)：
2. a kind of application of the phenyl methyl sulfoxide compound of acetophenone substitution as claimed in claim 1, it is characterised in that
The phenyl methyl sulfoxide type that structure replaces such as the acetophenone as shown in formula (VI) of acyl group triazole compound and structure of formula (I)
Compound reacts, and obtains pool horse former times cloth intermediate (compound 02)；
In formula (I), X is Cl, Br or I；
R1And R2It is separately H, F, Cl, Br, I or C1~C6Alkyl.
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| "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";Song Seok Shin等;《J. Med. Chem.》;20041231;第47卷;第792－804页 * |
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