CN105237491A - Isoxazole compounds and synthetic method thereof - Google Patents
Isoxazole compounds and synthetic method thereof Download PDFInfo
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- CN105237491A CN105237491A CN201510590026.0A CN201510590026A CN105237491A CN 105237491 A CN105237491 A CN 105237491A CN 201510590026 A CN201510590026 A CN 201510590026A CN 105237491 A CN105237491 A CN 105237491A
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- isoxazole
- isoxazole compounds
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- 150000002545 isoxazoles Chemical class 0.000 title claims abstract description 22
- 238000010189 synthetic method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- -1 acetylphenyl Chemical group 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims abstract description 4
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Chemical group CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 239000012043 crude product Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 13
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- 150000001345 alkine derivatives Chemical class 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 235000002639 sodium chloride Nutrition 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 abstract description 2
- 238000007259 addition reaction Methods 0.000 abstract description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 2
- 239000007806 chemical reaction intermediate Substances 0.000 abstract description 2
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 2
- 125000000068 chlorophenyl group Chemical group 0.000 abstract description 2
- 229910052802 copper Inorganic materials 0.000 abstract description 2
- 239000010949 copper Substances 0.000 abstract description 2
- SXTLQDJHRPXDSB-UHFFFAOYSA-N copper;dinitrate;trihydrate Chemical compound O.O.O.[Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O SXTLQDJHRPXDSB-UHFFFAOYSA-N 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000006053 organic reaction Methods 0.000 abstract description 2
- 239000001301 oxygen Substances 0.000 abstract description 2
- 229910052760 oxygen Inorganic materials 0.000 abstract description 2
- 238000007142 ring opening reaction Methods 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical group COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 abstract 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
- 229910052757 nitrogen Inorganic materials 0.000 abstract 1
- 125000003944 tolyl group Chemical group 0.000 abstract 1
- 125000004494 ethyl ester group Chemical group 0.000 description 14
- 150000008359 benzonitriles Chemical class 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- FMVJYQGSRWVMQV-UHFFFAOYSA-N ethyl propiolate Chemical class CCOC(=O)C#C FMVJYQGSRWVMQV-UHFFFAOYSA-N 0.000 description 5
- 150000002823 nitrates Chemical class 0.000 description 5
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KBIAVTUACPKPFJ-UHFFFAOYSA-N 1-ethynyl-4-methoxybenzene Chemical group COC1=CC=C(C#C)C=C1 KBIAVTUACPKPFJ-UHFFFAOYSA-N 0.000 description 1
- UJJFTIBNCODKOS-UHFFFAOYSA-N 3-ethynyl-1h-indole Chemical class C1=CC=C2C(C#C)=CNC2=C1 UJJFTIBNCODKOS-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- RNZWXMWCMSSQAE-UHFFFAOYSA-N OC1=C(Br)C(=NO1)C1=CC=CC=C1 Chemical compound OC1=C(Br)C(=NO1)C1=CC=CC=C1 RNZWXMWCMSSQAE-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- XQFARSXVMYNQRL-UHFFFAOYSA-N acetylene chlorobenzene Chemical group C#C.ClC1=CC=CC=C1 XQFARSXVMYNQRL-UHFFFAOYSA-N 0.000 description 1
- BLJLOSJXZCESDI-UHFFFAOYSA-N acetylene toluene Chemical group C#C.CC1=CC=CC=C1 BLJLOSJXZCESDI-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002774 b raf kinase inhibitor Substances 0.000 description 1
- 150000008366 benzophenones Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 1
- 229960003326 cloxacillin Drugs 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229960005081 diclofenamide Drugs 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- ZTRKRZNHEYBVHX-UHFFFAOYSA-N ethynylbenzene pentan-3-one Chemical class C(C)C(=O)CC.C(#C)C1=CC=CC=C1 ZTRKRZNHEYBVHX-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229950009506 penicillinase Drugs 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- AIQRJSXKXVZCJO-UHFFFAOYSA-N prop-2-ynoxybenzene Chemical compound C#CCOC1=CC=CC=C1 AIQRJSXKXVZCJO-UHFFFAOYSA-N 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- FAGLEPBREOXSAC-UHFFFAOYSA-N tert-butyl isocyanide Chemical compound CC(C)(C)[N+]#[C-] FAGLEPBREOXSAC-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention relates to a kind of isoxazole compounds and a synthetic method thereof. The structural formula of the compounds is shown in the specification, R1 is chlorophenyl, methylphenyl or acetylphenyl, R2 is hydrogen or methyl formate, and R3 is methyl formate, ethyl formate or phenoxymethyl. The substituted isoxazole compounds are a kind of important organic reaction intermediates, and can be used to conveniently rapidly synthesize a series of aromatic isoxazole derivatives through different types of organic chemical reactions, such as ring-opening reaction, addition reaction, substitution reaction and the like. The method raw materials are simple and easy to obtain. Cupric nitrate trihydrate is employed as a novel nitrogen source and oxygen source, and possesses best reaction activity under promotion effect of copper. Also, routine reaction solvents are employed, operation is simple, conditions are mild, the reaction is friendly to environment, the yield is medium to excellent, and extremely good development prospect in industrial production is provided.
Description
Technical field
The present invention relates to a kind of isoxazole compounds and synthetic method thereof.
Background technology
Isoxazole compounds is the nitrogen-containing heterocycle compound that a class has compared with high biological activity and potential physiology, pharmacologically active, gets more and more people's extensive concerning for a long time.Such as, the medicine containing isoxazole skeleton is that (see reference a kind of effective antitumour medicine document: Iranpoor, N.etal.
tetrahedronLett. 2006,
47, 8247).Isoxazole compounds or a kind of effective broad spectrum antibiotic, (see reference document: Costanzi, S.etal. to have restraining effect to most of gram-positive and negative bacterium
bioorg.Med.Chem.
2012,
20, 5254).Except the application in medicine, ， isoxazole compounds is also the important weedicide (see reference document: Rhone-PoulencAgricultureLtd.Patent:US5552367A1,1996) of a class.In addition, this compounds can also such as, as isoxazole semisynthetic penicillin, cloxacillin, is used for the treatment of gram positive coccus and comprises the infection that the staphylococcus that produces penicillinase causes (see reference document: Doyle, F.P.etal.
j.Am.Chem.Soc. 1963, 5838).
， isoxazole compounds or the very useful organic synthesis building block of a class in addition, can be used for building structure other organic compound more complicated and changeable.Such as, the people such as Cosimelli utilize various replacement Isoxazole derivative and teritary amide reaction, obtain that a class can (see reference document: Cosimelli, B.etal. as the acid amides isoxazole compound of the probe of translocator
eur.J.Med.Chem.
2011,
46, 4506).
The method of the synthesizing isoxazole compounds reported in document mainly contains following several:
(1) in 2003, the people such as Barbachyn report [3+2] cycloaddition reaction of bromo oxime and alkynol.By this method, they have synthesized 3-to bromophenyl-5-hydroxyl-isoxazole, and by functional group conversions, (see reference document: Barbachyn.R.M.etal. to have synthesized a series of isoxazole compounds
j.Med.Chem.
2003,
46, 284).
(2) 2012 years, Rowbottom seminar reported cyano compound and oxammonium hydrochloride under the effect of sodium hydroxide, uses water as solvent, can obtain disubstituted isoxazole compound under the condition of 100 DEG C.But it is more complicated that the method exists Material synthesis equally, (see reference document: Rowbottom.M.W.etal. not easily to obtain the shortcomings such as polysubstituted product
j.Med.Chem.
2012,
55, 1082).
(3) people such as Itoh then with acetone or methyl phenyl ketone as solvent under the promotion of ceric ammonium nitrate, react with alkynes generation three components, synthesis of acetyl base or benzoyl replace isoxazole compounds.But the scope of the method to substrate has larger restriction, and large content of starting materials causes waste, and (see reference document: Itoh, K.etal.
tetrahedronLett. 2002,
43, 7035).
(4) Odom seminar reports the three components reaction of 3,5-dichlorphenamide bulk powder and benzo alkynes and tert-butyl isonitrile, optionally can generate two Zhong isoxazole compounds through two-step reaction.But this method productive rate is not high, and (see reference document: Odom.A.etal.
tetrahedron 2012,
68, 807).
In sum, the synthetic method of isoxazole compounds has above several, but the substrate of these reactions is all comparatively complicated, generally needs just can be obtained by a few step reaction, and these reactions often need strong acid or highly basic etc. to compare exacting terms.
Summary of the invention
The object of the present invention is to provide a kind of isoxazole compound, particularly the synthetic method of 3-acyl substituted isoxazole compound.
For achieving the above object, the reaction mechanism that the inventive method adopts is:
R
1=chloro-phenyl-, aminomethyl phenyl or acetylphenyl;
R
2=hydrogen or methyl-formiate;
R
3=methyl-formiate, ethyl formate or Phenoxymethyl.
According to above-mentioned reaction mechanism, present invention employs following technical scheme:
A kind of isoxazole compounds, is characterized in that the structural formula of this compound is:
wherein, R
1for chloro-phenyl-, aminomethyl phenyl or acetylphenyl; R
2for hydrogen or methyl-formiate; R
3for methyl-formiate, ethyl formate or Phenoxymethyl.
A kind of synthetic method of above-mentioned isoxazole compounds, it is characterized in that the method has following steps: under inert atmosphere protection, by alkynes, second component alkynes, cupric nitrate by 1:(1.0 ~ 8.0): the mol ratio of (2.0 ~ 8.0) joins in cyanobenzene solvent, and at 50 ~ 80 DEG C, stirring reaction disappears to reaction raw materials; After reaction terminates, wash respectively, be extracted with ethyl acetate product with water and saturated aqueous common salt, organic phase drying obtains crude product after removing solvent; This crude product obtains isoxazole compounds through separating-purifying; The structural formula of described alkynes is:
; The structural formula of described second component alkynes is:
.
Replacement isoxazole compounds of the present invention is the important organic reaction intermediate of a class, by dissimilar organic chemical reactions, as ring-opening reaction, addition reaction, substitution reaction etc., a series of Fang isoxazole derivant can be synthesized quickly and easily.Such as, this compounds is that a class can be used for the intermediate of the material of fluorescent optical sensor (see reference document: Martorana.A. through the product that amination reaction and nucleophilic addition(Adn) obtain; Pace.A.; Buscemi.S.; Piccionello.A.,
org.Lett. 2012,
14, 3240); (see reference the amide backbone containing isoxazole ring replaced after the BRAF kinase inhibitor drug that Se Falong company of the U.S. develops also comprises the deprotection of this compounds document: Rowbottom.M.W.; Faraoni.R.; Chao, Q.; Campbell, B.T.; Lai, A.G., etal.
j.Med.Chem. 2012,
55, 1082).
The inventive method raw material is simple and easy to get, and adopt Gerhardite as the nitrogenous source of novelty and oxygen source, best reactive behavior is had under the promotion of copper, and use conventional reaction solvent, simple to operate, mild condition, reaction environmental protection, by the time outstanding in productive rate, there is good development prospect in the industrial production.
Embodiment
Embodiment one: 3-(the chloro-benzoyl of 4-)-4,5-isoxazolyl-5-carboxylic acid, ethyl ester
3-(the chloro-benzoyl of 4-)-4; 5-isoxazolyl-5-carboxylic acid, ethyl ester adopts following step: 1. in 1000 milliliters of reaction flasks, add 14.7 grams of ethyl propiolates by the mol ratio of 1:1.5:2.0; 30.8 grams of 4-chlorobenzene acetylene; 72.5 gram cupric nitrate; add 750 milliliters of cyanobenzenes again, be heated to 70 DEG C.Follow the tracks of reaction by thin-layer chromatography method, disappear to reaction raw materials; 2., after reaction terminates, the cancellation that adds water in system is reacted, and is extracted with ethyl acetate product, uses saturated common salt water washing, remove solvent, obtain crude product after drying with Rotary Evaporators; 3. crude product column chromatography (sherwood oil: ethyl acetate=50:1) purifying, obtain 35.15 grams of 3-(the chloro-benzoyl of 4-)-4,5-isoxazolyl-5-carboxylic acid, ethyl ester, productive rate is 84%.Fusing point: 64 DEG C.
IR(KBr,cm-1):1741,1656,1581,1239,1177,890,761.
1 HNMR(CDCl 3 ,500MHz): δ8.28(d,
J=8.5Hz,2H),7.51(d,
J=8.5Hz,2H),7.42(s,1H),4.47(q,
J=7.0Hz,2H),1.43(t,3H).
13 CNMR(CDCl 3 ,125MHz): δ183.1,162.0,161.2,156.1,141.2,133.4,132.1,129.1,110.0,62.7,14.1.
LC-MS(ESI)m/z:282[M
+(
37Cl)+H],280[M
+(
35Cl)+H].
HRMS(ESI)m/z:calcdforC
13H
11ClNO
4[M
+H]280.0377,found280.0369.
Embodiment two: 3-(4-Methyl-benzoyl)-4,5-isoxazolyl-5-carboxylic acid, ethyl esters
3-(4-Methyl-benzoyl)-4; 5-isoxazolyl-5-carboxylic acid, ethyl ester adopts following step: 1. in 1000 milliliters of reaction flasks, add 11.8 grams of ethyl propiolates by the mol ratio of 1:4.0:4.0; 56.0 grams of 4-methylbenzene acetylene; 116.0 grams of cupric nitrates; add 600 milliliters of cyanobenzenes again, be heated to 60 DEG C.Follow the tracks of reaction by thin-layer chromatography method, disappear to reaction raw materials; 2., after reaction terminates, the cancellation that adds water in system is reacted, and is extracted with ethyl acetate product, uses saturated common salt water washing, remove solvent, obtain crude product after drying with Rotary Evaporators; 3. crude product column chromatography (sherwood oil: ethyl acetate=50:1) purifying, obtains 25.6 grams of 3-(4-Methyl-benzoyl)-4,5-isoxazolyl-5-carboxylic acid, ethyl esters, productive rate is 93%.Fusing point: 70 DEG C.
IR(KBr,cm-1):1737,1660,1605,1316,1252,894,763.
1 HNMR(CDCl 3 ,500MHz): δ8.20(d,
J=8.0Hz,2H),7.40(s,1H),7.32(d,
J=8.0Hz,2H),4.46(q,
J=7.0Hz,2H),2.45(s,3H),1.43(t,3H).
13 CNMR(CDCl 3 ,125MHz): δ184.0,162.3,160.9,156.3,145.6,132.7,130.8,129.4,110.1,62.6,21.8,14.1.
LC-MS(ESI)m/z:260[M
+H].
HRMS(ESI)m/z:calcdforC
14H
14NO
4[M
+H]260.0923,found260.0915.
Embodiment three: 3-(4-acetylbenzene formyl radical)-4,5-isoxazolyl-5-carboxylic acid, ethyl esters
3-(4-acetylbenzene formyl radical)-4; 5-isoxazolyl-5-carboxylic acid, ethyl ester adopts following step: 1. in 1000 milliliters of reaction flasks, add 14.7 grams of ethyl propiolates by the mol ratio of 1:4.0:8.0; 86.7 grams of 4-acetylenylbenzene ethyl ketones; 290.0 grams of cupric nitrates; add 750 milliliters of cyanobenzenes again, be heated to 50 DEG C.Follow the tracks of reaction by thin-layer chromatography method, disappear to reaction raw materials; 2., after reaction terminates, the cancellation that adds water in system is reacted, and is extracted with ethyl acetate product, uses saturated common salt water washing, remove solvent, obtain crude product after drying with Rotary Evaporators; 3. crude product column chromatography (sherwood oil: ethyl acetate=30:1) purifying, obtains 33.65 grams of 3-(4-acetylbenzene formyl radicals)-4,5-isoxazolyl-5-butyl carboxylates, productive rate is 77%.Fusing point: 73 DEG C.
IR(KBr,cm-1):1742,1688,1656,1582,1259,1204,904,858.
1 HNMR(CDCl 3 ,500MHz): δ8.41(d,
J=8.5Hz,2H),8.10(d,
J=8.5Hz,2H),7.46(s,1H),4.50(q,
J=7.0Hz,2H),2.69(s,3H),1.46(t,3H).
13 CNMR(CDCl 3 ,125MHz): δ197.3,183.9,161.9,161.4,156.1,140.9,138.2,130.9,128.4,109.9,62.7,26.9,14.1.
LC-MS(ESI)m/z:288[M
+H].
HRMS(ESI)m/z:calcdforC
15H
14NO
5[M
+H]288.0872,found288.0864.
Embodiment four: 3-(4-anisoyl)-4,5-isoxazolyl-5-carboxylic acid, ethyl esters
3-(4-anisoyl)-4; 5-isoxazolyl-5-carboxylic acid, ethyl ester adopts following step: 1. in 1000 milliliters of reaction flasks, add 9.8 grams of ethyl propiolates by the mol ratio of 1:2.0:4.0; 26.5 grams of 4-Methoxy-phenylacetylene; 96.6 gram cupric nitrate; add 500 milliliters of cyanobenzenes again, be heated to 80 DEG C.Follow the tracks of reaction by thin-layer chromatography method, disappear to reaction raw materials; 2., after reaction terminates, the cancellation that adds water in system is reacted, and is extracted with ethyl acetate product, uses saturated common salt water washing, remove solvent, obtain crude product after drying with Rotary Evaporators; 3. crude product column chromatography (sherwood oil: ethyl acetate=50:1) purifying, obtains 22.1 grams of 3-(4-anisoyl)-4,5-isoxazolyl-5-carboxylic acid, ethyl esters, productive rate is 80%.Fusing point: 91 DEG C.
IR(KBr,cm-1):1744,1597,1431,1249,1185,1012,889,764.
1 HNMR(CDCl 3 ,500MHz): δ8.33(d,
J=9.0Hz,2H),7.39(s,1H),7.00(d,
J=9.0Hz,2H),4.46(q,
J=7.0Hz,2H),3.90(s,3H),1.43(t,
J=7.0Hz,3H).
13 CNMR(CDCl 3 ,125MHz): δ182.6,164.7,162.4,160.8,156.3,133.2,128.1,114.0,110.2,62.6,55.6,14.1.
LC-MS(ESI)m/z:276[M
+H].
HRMS(ESI)m/z:calcdforC
14H
14NO
5[M
+H]276.0872,found276.0863.
Embodiment five: 3-(1-(4-tosyl group)-1
h-indoles-3-acyl group)-4,5-isoxazolyl-5-carboxylic acid, ethyl esters
3-(1-(4-tosyl group)-1
h-indoles-3-acyl group)-4,5-isoxazolyl-5-carboxylic acid, ethyl esters adopt following step: 1. in 1000 milliliters of reaction flasks, add 14.7 grams of ethyl propiolates by the mol ratio of 1:3.0:6.0,133.0 grams of 1-(4-tosyl groups) 3-ethynyl-1
h-indoles, 217.5 grams of cupric nitrates, then add 750 milliliters of cyanobenzenes, be heated to 70 DEG C.Follow the tracks of reaction by thin-layer chromatography method, disappear to reaction raw materials; 2., after reaction terminates, the cancellation that adds water in system is reacted, and is extracted with ethyl acetate product, uses saturated common salt water washing, remove solvent, obtain crude product after drying with Rotary Evaporators; 3. crude product column chromatography (sherwood oil: ethyl acetate=10:1) purifying, obtains 34.1 grams of 3-(1-(4-tosyl group)-1
h-indoles-3-acyl group)-4,5-isoxazolyl-5-carboxylic acid, ethyl esters, productive rate is 52%.Fusing point: 141 DEG C.
IR(KBr,cm-1):3148,1741,1645,1529,1443,1378,1296,1203,1012,960,842,757,662,574.
1 HNMR(CDCl 3 ,500MHz): δ9.03(s,1H),8.43-8.41(m,1H),8.00-7.98(m,1H),7.88(d,
J=8.5Hz,2H),7.43(s,1H),7.42-7.39(m,2H),7.29(d,
J=8.5Hz,2H),4.49(q,
J=7.0Hz,2H),2.36(s,3H),1.45(t,
J=7.0Hz,3H).
13 CNMR(CDCl 3 ,125MHz): δ178.2,162.7,161.2,156.2,146.1,136.6,134.6,134.4,130.3,127.8,127.3,126.1,125.2,122.9,118.4,113.2,109.2,62.6,21.6,14.1.
LC-MS(ESI)m/z:439[M
+H].
HRMS(ESI)m/z:calcdforC
22H
19N
2O
6S[M
+H]439.0964,found439.0952.
Embodiment six: 3-benzoyl-4,5-isoxazolyl-4,5-dimethyl dicarboxylate
3-benzoyl-4; 5-isoxazolyl-4; 5-dimethyl dicarboxylate adopts following step: 1. in 1000 milliliters of reaction flasks, add 17.04 grams of dimethyl butyns by the mol ratio of 1:2.0:4.0; 24.5 gram phenylacetylene; 116.0 grams of cupric nitrates; add 600 milliliters of cyanobenzenes again, be heated to 80 DEG C.Follow the tracks of reaction by thin-layer chromatography method, disappear to reaction raw materials; 2., after reaction terminates, the cancellation that adds water in system is reacted, and is extracted with ethyl acetate product, uses saturated common salt water washing, remove solvent, obtain crude product after drying with Rotary Evaporators; 3. crude product column chromatography (sherwood oil: ethyl acetate=30:1) purifying, obtain 26.1 grams of 3-benzoyl-4,5-isoxazolyl-4,5-dimethyl dicarboxylates, productive rate is 75%.Fusing point: 92 DEG C.
IR(KBr,cm-1):1749,1658,1598,1451,1286,1216,1097,902,688.
1 HNMR(CDCl 3 ,500MHz): δ8.16(d,
J=8.5Hz,2H),7.68(t,
J=7.5Hz,1H),7.53(t,
J=7.5Hz,2H),4.03(s,1H),3.90(s,1H).
13 CNMR(CDCl 3 ,125MHz): δ183.7,160.2,159.9,159.0,155.9,134.8,134.8,130.5,128.8,117.6,53.6,53.3.
LC-MS(ESI)m/z:290[M
+H].
HRMS(ESI)m/z:calcdforC
14H
11NO
6[M
+H]290.0665,found290.0656.
Embodiment seven: 5-(phenoxymethyl) isoxazole-3-base phenyl ketone
5-(phenoxymethyl) isoxazole-3-base phenyl ketone adopts following step: 1. in 1000 milliliters of reaction flasks, add 19.8 grams of phenyl-2-propynyl ether by the mol ratio of 1:1.5:2.0,23.0 gram phenylacetylene, 72.5 grams of cupric nitrates, then add 750 milliliters of cyanobenzenes, be heated to 50 DEG C.Follow the tracks of reaction by thin-layer chromatography method, disappear to reaction raw materials; 2., after reaction terminates, the cancellation that adds water in system is reacted, and is extracted with ethyl acetate product, uses saturated common salt water washing, remove solvent, obtain crude product after drying with Rotary Evaporators; 3. crude product column chromatography (sherwood oil: ethyl acetate=50:1) purifying, obtain 36.50 grams of 5-(phenoxymethyl) isoxazole-3-base phenyl ketones, productive rate is 87%.Fusing point: 76 DEG C.
IR(KBr,cm-1):3136,1657,1592,1495,1455,1246,1068,889,835,723,679.
1 HNMR(CDCl 3 ,500MHz): δ8.29-8.31(m,2H),7.65(t,
J=7.5Hz,1H),7.52(t,
J=7.5Hz,2H),7.33(t,
J=7.5Hz,2H),7.03(t,
J=7.5Hz,1H),6.99(d,
J=7.5Hz,5.0Hz,2H),6.88(s,1H),5.24(s,2H).
13 CNMR(CDCl 3 ,125MHz): δ185.4,168.9,161.8,157.6,135.6,134.1,130.6,129.7,128.6,122.0,114.8,104.3,61.0.
LC-MS(ESI)m/z:280[M
+H].
HRMS(ESI)m/z:calcdforC
17H
14NO
3[M
+H]280.0974,found280.0965.
Claims (2)
1. an isoxazole compounds, is characterized in that the structural formula of this compound is:
wherein, R
1for chloro-phenyl-, aminomethyl phenyl or acetylphenyl; R
2for hydrogen or methyl-formiate; R
3for methyl-formiate, ethyl formate or Phenoxymethyl.
2. the synthetic method of an isoxazole compounds according to claim 1, it is characterized in that the method has following steps: under inert atmosphere protection, by alkynes, second component alkynes, cupric nitrate by 1:(1.0 ~ 8.0): the mol ratio of (2.0 ~ 8.0) joins in cyanobenzene solvent, and at 50 ~ 80 DEG C, stirring reaction disappears to reaction raw materials; After reaction terminates, wash respectively, be extracted with ethyl acetate product with water and saturated aqueous common salt, organic phase drying obtains crude product after removing solvent; This crude product obtains isoxazole compounds through separating-purifying; The structural formula of described alkynes is:
; The structural formula of described second component alkynes is:
.
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| CN111196786A (en) * | 2019-11-09 | 2020-05-26 | 上海大学 | Trifluoromethanesulfonyl substituted isoxazole compound and synthesis method thereof |
| CN113149926A (en) * | 2021-04-30 | 2021-07-23 | 华侨大学 | Preparation method of 3, 5-disubstituted isoxazole derivative |
| CN113149923A (en) * | 2021-03-26 | 2021-07-23 | 上海大学 | 3-cyano-N-oxidoisoxazoline compound and synthetic method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111196786A (en) * | 2019-11-09 | 2020-05-26 | 上海大学 | Trifluoromethanesulfonyl substituted isoxazole compound and synthesis method thereof |
| CN113149923A (en) * | 2021-03-26 | 2021-07-23 | 上海大学 | 3-cyano-N-oxidoisoxazoline compound and synthetic method thereof |
| CN113149926A (en) * | 2021-04-30 | 2021-07-23 | 华侨大学 | Preparation method of 3, 5-disubstituted isoxazole derivative |
| CN113149926B (en) * | 2021-04-30 | 2023-05-26 | 华侨大学 | Preparation method of 3, 5-disubstituted isoxazole derivative |
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