CN105237491B - Isoxazole compounds and its synthetic method - Google Patents
Isoxazole compounds and its synthetic method Download PDFInfo
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- 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
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- 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
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- 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
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Abstract
The present invention relates to a kind of isoxazole compounds and its synthetic method.The structural formula of the compound is：Wherein, R1For chlorphenyl, aminomethyl phenyl or acetylphenyl；R2For hydrogen or methyl formate；R3For methyl formate, Ethyl formate or Phenoxymethyl.The substituted isoxazole compounds of the present invention are a kind of important organic reaction intermediates, by different types of organic chemical reactionses, such as ring-opening reaction, addition reaction, substitution reaction, can quickly and easily synthesize a series of Fang isoxazole derivants.The inventive method raw material is simple and easy to get, and using nitrogen source and oxygen source of the Gerhardite as novelty, there is best reactivity under the promotion of copper, and use conventional reaction dissolvent, it is simple to operate, mild condition, reaction environmental protection, when outstanding in yield, there is good development prospect in the industrial production.
Description
Technical field
The present invention relates to a kind of isoxazole compounds and its synthetic method.
Background technology
Isoxazole compounds are a kind of with compared with high bioactivity and potential physiology, the nitrogen heterocyclic ring chemical combination of pharmacological activity
Thing, get more and more people's extensive concerning for a long time.For example, the medicine containing isoxazole skeleton is a kind of effective antitumour medicine
（See reference document：Iranpoor, N.et al.Tetrahedron Lett. 2006, 47, 8247）.Isoxazole chemical combination
Most of Grain-positives and negative bacterium are had inhibitory action by thing or a kind of effective broad spectrum antibiotic（See reference document：
Costanzi, S. et al. Bioorg. Med. Chem. 2012, 20, 5254）.In addition to the application in medicine,
Isoxazole compounds are also a kind of important herbicide（See reference document：Rhone-Poulenc Agriculture Ltd.
Patent: US5552367 A1, 1996）.In addition, this kind of compound is also used as isoxazole semisynthetic penicillin, example
Such as Cloxacillin, infection caused by the staphylococcus of production penicillase is included for treating gram-positive cocci（See reference document：
Doyle, F. P. et al. J. Am. Chem. Soc. 1963, 5838）.
, isoxazole compounds or a kind of highly useful organic synthesis building block in addition, available for building structure
Other organic compounds more complicated and changeable.For example, Cosimelli et al. utilizes various substituted isoxazole derivativeses and uncle
Acid amides reacts, and having obtained one kind can be as the acid amides isoxazole compound of the probe of transport protein（See reference document：
Cosimelli, B. et al. Eur. J. Med. Chem. 2011, 46, 4506）.
The method for the synthesizing isoxazole class compound reported in document mainly has following several：
（One）In 2003, Barbachyn et al. reported [3+2] cycloaddition reaction of bromo oxime and alkynol.Pass through this
Kind method, they have synthesized the isoxazole of 3- p-bromophenyl -5- hydroxyls -, and can have been synthesized a series of by functional group conversions
Isoxazole compounds（See reference document：Barbachyn. R. M.et al.J. Med. Chem. 2003, 46,
284）.
（Two）2012, Rowbottom seminars reported the work of cyano compound and hydroxylamine hydrochloride in sodium hydroxide
Under, with water as solvent, disubstituted isoxazole compound is can obtain under conditions of 100 DEG C.But this method is equally deposited
It is more complicated in Material synthesis, the shortcomings of being not easy to obtain polysubstituted product（See reference document：Rowbottom. M. W. et al.J. Med. Chem. 2012, 55, 1082)。
（Three）Itoh et al. occurs three groups then by the use of acetone or acetophenone as solvent under the promotion of ammonium ceric nitrate, with alkynes
Divide reaction, synthesis of acetyl base or benzoyl substitution isoxazole compounds.But this method have to the scope of substrate it is larger
Limitation, and big content of starting materials causes to waste（See reference document：Itoh, K. et al. Tetrahedron Lett. 2002,43, 7035）.
(4) Odom seminars report three component reactions of 3,5- dichloroanilines and benzo alkynes and tert-butyl isonitrile,
Two Zhong isoxazole compounds can be selectively generating by two-step reaction.But the method yield is not high（See reference document：
Odom. A. et al. Tetrahedron 2012, 68, 807）.
The synthetic method of , isoxazole compounds has that the above is several in summary, but substrates of these reactions are all relative
Complex, generally requiring can just be obtained by the reaction of several steps, and to generally require strong acid or highly basic etc. more severe for these reactions
The condition at quarter.
The content of the invention
It is an object of the invention to provide a kind of isoxazole compound, particularly 3- acyl groups substitution isoxazole compounds
Synthetic method.
To reach above-mentioned purpose, the reaction mechanism that the inventive method uses for：
R1=chlorphenyl, aminomethyl phenyl or acetylphenyl；
R2=hydrogen or methyl formate；
R3=methyl formate, Ethyl formate or Phenoxymethyl.
According to above-mentioned reaction mechanism, present invention employs following technical scheme：
A kind of isoxazole compounds, it is characterised in that the structural formula of the compound is：
Wherein, R1For chlorphenyl, aminomethyl phenyl or acetylphenyl；R2For hydrogen or formic acid
Methyl esters；R3For methyl formate, Ethyl formate or Phenoxymethyl.
A kind of synthetic method of above-mentioned isoxazole compounds, it is characterised in that this method has following steps：Lazy
Property atmosphere protection under, by alkynes, the second component alkynes, copper nitrate press 1：（1.0~8.0）：（2.0~8.0）Mol ratio add
Into benzonitrile solvent, stirring reaction to reaction raw materials disappear at 50~80 DEG C；After reaction terminates, with water and saturated common salt
Water washs respectively, and product is extracted with ethyl acetate, and organic phase obtains crude product after drying and removing solvent；The crude product carries through separation
It is pure to obtain isoxazole compounds；The structural formula of described alkynes is：；The structure of the second described component alkynes
Formula is：。
The substituted isoxazole compounds of the present invention are a kind of important organic reaction intermediates, by different types of
Organic chemical reactionses, such as ring-opening reaction, addition reaction, substitution reaction, it can quickly and easily synthesize a series of Fang Yi Evil
Azole derivative.Fluorescence can be used for pass for example, the product that such compound obtains by aminating reaction and nucleophilic addition is one kind
The intermediate of the material of sensor（See reference document: Martorana. A.; Pace. A.; Buscemi. S.;
Piccionello. A.,Org. Lett.2012, 14, 3240)；The BRAF kinase inhibitors of Se Falong companies of U.S. exploitation
The amide backbone containing isoxazole ring substituted after the deprotection that medicine also includes such compound（See reference document：
Rowbottom. M. W.; Faraoni. R.; Chao, Q.; Campbell, B.T.; Lai,A.G.,et al. J. Med. Chem. 2012, 55, 1082）.
The inventive method raw material is simple and easy to get, and using nitrogen source and oxygen source of the Gerhardite as novelty, in copper
There is best reactivity under promotion, and use conventional reaction dissolvent, simple to operate, mild condition, reaction environmental protection, yield
In when outstanding, have good development prospect in the industrial production.
Embodiment
Embodiment one：3- (the chloro- benzoyls of 4-) -4,5- isoxazolyl -5- carboxylic acid, ethyl esters
3- (the chloro- benzoyls of 4-) -4,5- isoxazolyl -5- carboxylic acid, ethyl esters use following step：It is 1. anti-at 1000 milliliters
Answer in bottle by 1：1.5：2.0 mol ratio 14.7 grams of ethyl propiolates of addition, 30.8 grams of 4- chlorobenzene acetylene, 72.5 grams of copper nitrates,
750 milliliters of benzonitriles are added, are heated to 70 DEG C.Tracked and reacted with thin-layer chromatography method, disappeared to reaction raw materials；2. react
After end, into system plus water quenching is gone out reaction, and product is extracted with ethyl acetate, with saturated common salt water washing, with rotating after drying
Evaporimeter removes solvent, obtains crude product；3. crude product column chromatography（Petroleum ether:Ethyl acetate=50: 1）Purifying, is obtained
35.15 grams of 3- (the chloro- benzoyls of 4-) -4,5- isoxazolyl -5- carboxylic acid, ethyl esters, yield 84%.Fusing point：64℃.
-1 1741, 1656, 1581, 1239, 1177, 890, 761.
1H NMR (CDCl3, 500 MHz): δ 8.28 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5
Hz, 2H), 7.42 (s, 1H), 4.47 (q, J = 7.0 Hz, 2H), 1.43 (t, 3H).
13C NMR (CDCl3, 125 MHz): δ 183.1, 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: calcd for C13H11ClNO4 [M+H] 280.0377, found 280.0369.
Embodiment two： 3-（4- Methyl-benzoyls）- 4,5- isoxazolyl -5- carboxylic acid, ethyl esters
3-（4- Methyl-benzoyls）- 4,5- isoxazolyl -5- carboxylic acid, ethyl esters use following step：1. at 1000 milliliters
1 is pressed in reaction bulb：4.0：4.0 mol ratio adds 11.8 grams of ethyl propiolates, 56.0 grams of 4- methyl phenylacetylenes, 116.0 grams of nitre
Sour copper, 600 milliliters of benzonitriles are added, are heated to 60 DEG C.Tracked and reacted with thin-layer chromatography method, disappeared to reaction raw materials；②
After reaction terminates, into system plus water quenching is gone out reaction, and product is extracted with ethyl acetate, and with saturated common salt water washing, is used after drying
Rotary Evaporators remove solvent, obtain crude product；3. crude product column chromatography（Petroleum ether:Ethyl acetate=50: 1）Purifying,
Obtain 25.6 grams of 3-（4- Methyl-benzoyls）- 4,5- isoxazolyl -5- carboxylic acid, ethyl esters, yield 93%.Fusing point：70℃.
-1 1737, 1660, 1605, 1316, 1252, 894, 763.
1H NMR (CDCl3, 500 MHz): δ 8.20 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H),
7.32 (d, J = 8.0 Hz, 2H), 4.46 (q, J = 7.0 Hz, 2H), 2.45 (s, 3H), 1.43 (t,
3H).
13C NMR (CDCl3, 125 MHz): δ 184.0, 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: calcd for C14H14NO4 [M+H] 260.0923, found 260.0915.
Embodiment three： 3-（4- acetylbenzene formoxyls）- 4,5- isoxazolyl -5- carboxylic acid, ethyl esters
3-（4- acetylbenzene formoxyls）- 4,5- isoxazolyl -5- carboxylic acid, ethyl esters use following step：1. at 1000 milliliters
1 is pressed in reaction bulb：4.0：8.0 mol ratio 14.7 grams of ethyl propiolates of addition, 86.7 grams of 4- acetylenylbenzene ethyl ketones, 290.0 grams
Copper nitrate, 750 milliliters of benzonitriles are added, are heated to 50 DEG C.Tracked and reacted with thin-layer chromatography method, disappeared to reaction raw materials；
2. after reaction terminates, into system plus water quenching is gone out reaction, and product is extracted with ethyl acetate, with saturated common salt water washing, after drying
Remove solvent with Rotary Evaporators, obtain crude product；3. crude product column chromatography（Petroleum ether:Ethyl acetate=30: 1）It is pure
Change, obtain 33.65 grams of 3-（4- acetylbenzene formoxyls）- 4,5- isoxazolyl -5- butyl carboxylates, yield 77%.Fusing point：73
℃。
-1 1742, 1688, 1656, 1582, 1259, 1204, 904, 858.
1H NMR (CDCl3, 500 MHz): δ 8.41 (d, J = 8.5 Hz, 2H), 8.10 (d, J = 8.5
Hz, 2H), 7.46 (s, 1H), 4.50 (q, J = 7.0 Hz, 2H), 2.69 (s, 3H), 1.46 (t, 3H).
13C NMR (CDCl3, 125 MHz): δ 197.3, 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: calcd for C15H14NO5 [M+H] 288.0872, found 288.0864.
Example IV： 3-（4- methoxybenzoyl bases）- 4,5- isoxazolyl -5- carboxylic acid, ethyl esters
3-（4- methoxybenzoyl bases）- 4,5- isoxazolyl -5- carboxylic acid, ethyl esters use following step：1. at 1000 milliliters
1 is pressed in reaction bulb：2.0：4.0 mol ratio 9.8 grams of ethyl propiolates of addition, 26.5 grams of 4- Methoxy-phenylacetylenes, 96.6 grams of nitre
Sour copper, 500 milliliters of benzonitriles are added, are heated to 80 DEG C.Tracked and reacted with thin-layer chromatography method, disappeared to reaction raw materials；②
After reaction terminates, into system plus water quenching is gone out reaction, and product is extracted with ethyl acetate, and with saturated common salt water washing, is used after drying
Rotary Evaporators remove solvent, obtain crude product；3. crude product column chromatography（Petroleum ether:Ethyl acetate=50: 1）Purifying,
Obtain 22.1 grams of 3-（4- methoxybenzoyl bases）- 4,5- isoxazolyl -5- carboxylic acid, ethyl esters, yield 80%.Fusing point：91℃.
-1 1744, 1597, 1431, 1249, 1185, 1012, 889, 764.
1H NMR (CDCl3, 500 MHz): δ 8.33(d, J = 9.0 Hz, 2H), 7.39 (s, 1H), 7.00
(d, J = 9.0 Hz, 2H), 4.46 (q, J = 7.0 Hz, 2H), 3.90 (s, 3H), 1.43 (t, J = 7.0
Hz, 3H).
13C NMR (CDCl3, 125 MHz): δ 182.6, 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: calcd for C14H14NO5 [M+H] 276.0872, found 276.0863.
Embodiment five： 3-（1- (4- tosyls) -1H- indoles -3- acyl groups）- 4,5- isoxazolyl -5- carboxylic acid, ethyl esters
3-（1- (4- tosyls) -1H- indoles -3- acyl groups）- 4,5- isoxazolyl -5- carboxylic acid, ethyl esters use following steps
Suddenly：1. 1 is pressed in 1000 milliliters of reaction bulbs：3.0：6.0 mol ratio adds 14.7 grams of ethyl propiolates, 133.0 grams of 1-（4- first
Benzenesulfonyl）3- acetenyls -1H- indoles, 217.5 grams of copper nitrates, 750 milliliters of benzonitriles are added, are heated to 70 DEG C.With thin
Layer chromatography method tracking reaction, disappears to reaction raw materials；After 2. reaction terminates, into system plus water quenching is gone out reaction, with acetic acid second
Ester extracts product, with saturated common salt water washing, removes solvent with Rotary Evaporators after drying, obtains crude product；3. crude product post
Chromatography（Petroleum ether:Ethyl acetate=10: 1）Purifying, obtains 34.1 grams of 3-（1- (4- tosyls) -1H- indoles -3-
Acyl group）- 4,5- isoxazolyl -5- carboxylic acid, ethyl esters, yield 52%.Fusing point：141℃.
-1 3148, 1741, 1645, 1529, 1443, 1378, 1296, 1203, 1012, 960, 842,
757, 662, 574.
1H NMR (CDCl3, 500 MHz): δ 9.03 (s, 1H), 8.43-8.41 (m, 1H), 8.00-7.98
(m, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.43 (s, 1H), 7.42-7.39 (m, 2H), 7.29 (d,J = 8.5 Hz, 2H), 4.49 (q, J = 7.0 Hz, 2H), 2.36 (s, 3H), 1.45 (t, J= 7.0 Hz,
3H).
13C NMR (CDCl3, 125 MHz): δ 178.2, 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: calcd for C22H19N2O6S [M+H] 439.0964, found 439.0952.
Embodiment six：3- benzoyl -4,5- isoxazolyl -4,5- dimethyl dicarboxylates
3- benzoyl -4,5- isoxazolyls -4,5- dimethyl dicarboxylate uses following step：1. in 1000 milliliters of reactions
1 is pressed in bottle：2.0：4.0 mol ratio 17.04 grams of dimethyl butyns of addition, 24.5 grams of phenylacetylenes, 116.0 grams of copper nitrates,
600 milliliters of benzonitriles are added, are heated to 80 DEG C.Tracked and reacted with thin-layer chromatography method, disappeared to reaction raw materials；2. react
After end, into system plus water quenching is gone out reaction, and product is extracted with ethyl acetate, with saturated common salt water washing, with rotating after drying
Evaporimeter removes solvent, obtains crude product；3. crude product column chromatography（Petroleum ether:Ethyl acetate=30: 1）Purifying, is obtained
26.1 gram 3- benzoyl -4,5- isoxazolyl -4,5- dimethyl dicarboxylates, yield 75%.Fusing point：92℃.
-1 1749, 1658, 1598, 1451, 1286, 1216, 1097, 902, 688.
1H NMR (CDCl3, 500 MHz): δ 8.16 (d, J = 8.5 Hz, 2H), 7.68 (t, J = 7.5
Hz, 1H), 7.53 (t, J = 7.5 Hz, 2H), 4.03 (s, 1H), 3.90 (s, 1H).
13C NMR (CDCl3, 125 MHz): δ 183.7, 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: calcd for C14H11NO6 [M+H] 290.0665, found 290.0656.
Embodiment seven： 5-（Phenoxymethyl）Isoxazole -3-base phenyl ketone
5-（Phenoxymethyl）Isoxazole -3-base phenyl ketone uses following step：1. pressed in 1000 milliliters of reaction bulbs
1：1.5：2.0 mol ratio adds 19.8 grams of phenyl -2-propynyl ether, 23.0 grams of phenylacetylenes, 72.5 grams of copper nitrates, adds
750 milliliters of benzonitriles, are heated to 50 DEG C.Tracked and reacted with thin-layer chromatography method, disappeared to reaction raw materials；After 2. reaction terminates,
Into system plus water quenching is gone out reaction, and product is extracted with ethyl acetate, and with saturated common salt water washing, is gone after drying with Rotary Evaporators
Fall solvent, obtain crude product；3. crude product column chromatography（Petroleum ether:Ethyl acetate=50: 1）Purifying, obtains 36.50 grams of 5-
（Phenoxymethyl）Isoxazole -3-base phenyl ketone, yield 87%.Fusing point：76℃.
-1 3136, 1657, 1592, 1495, 1455, 1246, 1068, 889, 835, 723, 679.
1H NMR (CDCl3, 500 MHz): δ 8.29-8.31 (m, 2H), 7.65 (t, J = 7.5 Hz,1H),
7.52 (t, J = 7.5 Hz,2H), 7.33 (t, J = 7.5 Hz,2H), 7.03 (t, J = 7.5 Hz, 1H),
6.99 (d, J = 7.5Hz, 5.0 Hz, 2H), 6.88 (s, 1H), 5.24 (s, 2H).
13C NMR (CDCl3, 125 MHz): δ 185.4, 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: calcd for C17H14NO3 [M+H] 280.0974, found 280.0965.
Claims (1)
1. a kind of synthetic method of isoxazole compounds, the structural formula of the compound are：
Wherein, R1For chlorphenyl, aminomethyl phenyl or acetylphenyl；R2For hydrogen or methyl formate；
R3For methyl formate, Ethyl formate or Phenoxymethyl；It is characterized in that this method has following steps：In inert atmosphere protection
Under, alkynes, the second component alkynes, copper nitrate are pressed 1：（1.0~8.0）：（2.0~8.0）Mol ratio to be added to benzonitrile molten
In agent, stirring reaction to reaction raw materials disappear at 50~80 DEG C；After reaction terminates, washed respectively with water and saturated aqueous common salt,
Product is extracted with ethyl acetate, organic phase obtains crude product after drying and removing solvent；The crude product obtains Yi Evil through separating-purifying
Azole compounds；The structural formula of described alkynes is：；The structural formula of the second described component alkynes is：。
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