CN103539753B - A kind of synthetic method of the isoxazole carboxylic acid of 3 substitution 4 - Google Patents
A kind of synthetic method of the isoxazole carboxylic acid of 3 substitution 4 Download PDFInfo
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- 238000006467 substitution reaction Methods 0.000 title claims abstract description 28
- 238000010189 synthetic method Methods 0.000 title claims abstract description 11
- UBNWPQXLFRMMEI-GQCTYLIASA-N 5-[3-[(e)-3-(3-hydroxy-2-methoxycarbonylphenoxy)prop-1-enyl]phenyl]-1,2-oxazole-3-carboxylic acid Chemical compound COC(=O)C1=C(O)C=CC=C1OC\C=C\C1=CC=CC(C=2ON=C(C=2)C(O)=O)=C1 UBNWPQXLFRMMEI-GQCTYLIASA-N 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- -1 dimethylamino methylene Chemical group 0.000 claims abstract description 28
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002585 base Substances 0.000 claims abstract description 10
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 230000007062 hydrolysis Effects 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000000977 initiatory effect Effects 0.000 claims abstract description 4
- 150000002576 ketones Chemical class 0.000 claims abstract description 4
- 150000002596 lactones Chemical class 0.000 claims abstract description 4
- 239000000463 material Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 4
- 150000005840 aryl radicals Chemical class 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000003851 azoles Chemical class 0.000 claims 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 claims 1
- 230000007935 neutral effect Effects 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 14
- 239000002253 acid Substances 0.000 abstract description 5
- 150000002148 esters Chemical class 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- 238000011084 recovery Methods 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 8
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- 238000012423 maintenance Methods 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 238000007670 refining Methods 0.000 description 4
- 150000002240 furans Chemical class 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- SZKVGVRLYVFVFP-UHFFFAOYSA-N 3-phenyl-1,2-oxazole-4-carboxylic acid Chemical class OC(=O)C1=CON=C1C1=CC=CC=C1 SZKVGVRLYVFVFP-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- YBLSBWHFPXDRHC-UHFFFAOYSA-N 3-methyl-1,2-oxazole-4-carboxylic acid Chemical class CC1=NOC=C1C(O)=O YBLSBWHFPXDRHC-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 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
- 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
- C07D413/04—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 directly linked by a ring-member-to-ring-member bond
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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of high-purity, the synthetic method of the isoxazole carboxylic acid of 3 substitution of regioselectivity high 4.This method is simple to operation, and reaction is gentle, in high yield, solves the severe reaction conditions that existing preparation method is present, and has isomers to generate, and separates difficult；Total recovery is low, is not easy to the technical problem of large-scale production.Preparation process：With the oxopropanoic acid ester of 3 substitution 3（I）It is initiation material, carrying out ring-closure reaction in water with hydroxylamine hydrochloride and alkali is obtained the ketone of 3 substitution, 4 isoxazole 5（II）；Compound（II）And the reaction of N, N dimethylformamide dimethyl acetal prepares the ketone of 4 dimethylamino methylene, 3 substitution, 4 hydrogen isoxazole 5（III）；Compound（III）In the basic conditions, lactone hydrolysis, again cyclization are experienced；Acidifying obtains the isoxazole carboxylic acid of 3 substitution 4.The present invention is prepared for the method exploitation of the isoxazole carboxylic acid of 3 substitution base 4 and large-scale.
Description
Technical field
The present invention relates to the synthetic method that a kind of 3- replaces -4- isoxazole carboxylic acids.
Background technology
3- substitution -4- isoxazole carboxylic acid class compounds are in the middle of important medicine and pesticide intermediate, at present, are taken on 3-
The synthetic method of generation -4- isoxazole carboxylic acid class compounds, it is as described below：
1st, document monthly chemistry and Eurasian Chemical Engineering magazine（Monatshefte fuer Chemie, 2008, 139 (6), 685-689 andEurasian Chemico-Technological Journal, 2006,8 (3), 189-195）
Report, base -3- oxopropanoic acid esters are replaced as raw material with 3-, at high temperature with former carboxylic acid triethyl reaction generation its substituent 2- second
Epoxide methylene -3- replaces base -3- oxygen propionic esters, obtains 3- substitution -4- isoxazole carboxylic acid esters with hydroxylamine hydrochloride cyclization afterwards,
Then corresponding carboxylic acid is obtained by hydrolysis, shown in following reaction equation：
There is following defect in the method：Cyclization has isomers, and yield is relatively low.
2nd, document Germany applied chemistry（Angew .Chem. Int. Ed. 2008, 47,8285–8287）Report is with propine
There are 1,3 Dipolar Cycloadditions and obtain 3- substitution -4- isoxazole carboxylic acid esters, so in acid esters and nitrile oxide under heavy metal catalyst
Corresponding carboxylic acid is obtained by hydrolysis afterwards, shown in following reaction equation：
There are the following problems for the method：The method uses heavy metal catalyst, high cost, inconvenient operation；And region
Selectivity is influenceed very big by the nitrile oxide of different substituents.
3rd, patent WO 2008011453 to be reported and prepare 3- substitution -4- isoxazole carboxylics with propiolate and the reaction of halo oxime
Acid esters, then obtains corresponding carboxylic acid, shown in following reaction equation by hydrolysis：
Through improving after WO 2010051549, propiolate is prepared into 3- pyrroles（Or morpholine）Base acrylate, then with halo oxime
Reaction prepares 3- substitution -4- isoxazole carboxylic acid esters
There is following defect in the method：Halo oxime prepares difficulty, and yield is not high.
In addition, there is following common issue in above-mentioned all methods：Regioselectivity is poor, and isomer separation is difficult, and reaction is difficult
To control, total recovery is low, is not suitable for extensive preparation or industrialized production.
The content of the invention
It is an object of the invention to provide a kind of green, mild condition, to possess the extensive 3- substitutions -4- for preparing value different
The synthetic method of oxazole carboxylic acid compound.The severe reaction conditions that existing preparation method is present mainly are solved, there is isomers to produce
Raw, product separates difficult, the low technical problem for being not suitable for large-scale production of total recovery.
Technical scheme：
3- replaces -4- isoxazole carboxylic acid class compounds, shown under its structure：
Wherein, R is alkyl, aryl radical, the one kind in fragrant heterocyclic radical.When R is that aliphatic alkyl replaces base, or
Aryl radical containing electron donating group, and the fragrant heterocyclic radical containing electron donating group, synthesis are easier, and yield is higher.
More preferably R is the one kind in methyl, phenyl, methoxyphenyl or pyridine radicals.
Shown in the following reaction equation of specific synthetic route of the invention：
In above-mentioned route, -3- oxopropanoic acid esters are replaced with 3-（I）It is initiation material, with hydroxylamine hydrochloride and alkali in water
Carry out intermolecularization reaction and 3- substitution -4- hydrogen-isoxazole -5- ketone is obtained（II）；Compound（II）And N,N-dimethylformamide
Dimethylacetal reaction prepares 4- dimethylamino methylene -3- substitution -4- hydrogen-isoxazole -5- ketone（III）；Compound
（III）In the basic conditions, lactone hydrolysis, again cyclization are experienced；Acidifying obtains compound（IV）3- replaces -4- isoxazoles
Carboxylic acid.The present invention is prepared for the method exploitation of 3- substitution -4- isoxazole carboxylic acids and large-scale.
Wherein, 3- substitutions -3- oxopropanoic acid esters（I）In the basic conditions with hydroxylamine hydrochloride cyclization prepare compound（II）,
Wherein alkali can be sodium carbonate, potassium carbonate, NaOH, and potassium hydroxide etc., its consumption is 0.5~2 equivalent of hydroxylamine hydrochloride, instead
It is 0~50 DEG C to answer temperature.
Above-claimed cpd（II）React and prepare 4- with N,N-dimethylformamide dimethylacetal in organic solvent
Dimethylamino methylene -3- substitution -4- hydrogen-isoxazole -5- ketone（III）.Wherein, DMF dimethylacetal is used
It is compound to measure（II）1 ~ 5 equivalent, reaction need to carry out in a solvent, and the solvent for being used is toluene, ethyl acetate or tetrahydrochysene
One kind in furans, reaction temperature is -10~80 DEG C.
Above-claimed cpd（III）In the basic conditions, lactone hydrolysis, again cyclization are experienced；Acidifying obtain 3- substitution-
4- isoxazole carboxylic acids（IV）.Alkali in alkalescence condition is sodium carbonate, potassium carbonate, NaOH, potassium hydroxide one kind therein, its
It is 14- dimethylamino methylene -3- substitution -4- hydrogen-isoxazole -5- ketone to measure（III）1~5 equivalent, the solvent for being used is
Water, reaction temperature is 20~60 DEG C.
Beneficial effects of the present invention：The present invention relates to one kind synthesis 3- substitution -4- isoxazole carboxylic acids, the method has following
Advantage：
1）Initiation material beta- ketone esters are mostly simple and easy to get, and major part is for commercially available or by simple chemical reaction
Can prepare；
2）The high income of reaction, one-step reaction yield is basic more than 80%, and total recovery is in 60-70%；
3）Mild condition, it is not harsh to consersion unit requirement.This approach avoid in the height required for common synthetic methods
Temperature or metal recall reaction；
4）Reaction time is short, and operation and post processing are easy, and intermediate can be applied to down without purifying or simple recrystallization
Step reaction, can be prepared on a large scale.
Specific embodiment
Hereinafter reaction example is used to illustrate the present invention that the present invention to be including but not limited to following relevant content, all sides herein
On the basis of method simple modification belong to the present invention protection technology within：
Embodiment 1, step 1
The synthesis of 3- methyl -4- hydrogen-isoxazole -5- ketone
By in sodium carbonate (53 g, 0.5 mol) 1.5 L water of addition, half an hour is stirred, treat that sodium carbonate is completely molten
By hydroxylamine hydrochloride after solution（69.5 g, 1 mol）It is dividedly in some parts.Stirring half an hour, after after bubble-free releasing, by acetyl second
Acetoacetic ester (130 g, 1 mol) is slowly added drop-wise in above-mentioned reaction solution.Completion of dropping, is stirred at room temperature overnight.Reaction
After finishing, reaction solution ethyl acetate（500 mL×3）Extract.Merge organic layer, drying be concentrated to give colorless oil 3- methyl-
4- hydrogen-isoxazole -5- ketone（95 g, yield 95.9%）, purity> 95%.
1H NMR (400 MHz, CDCl3): d 3.49 (s, 2 H), 2.41 (s, 3 H)。
Step 2
The synthesis of 4- dimethylamino methylene -3- methyl -4- hydrogen-isoxazole -5- ketone
3- methyl -4- hydrogen-ketone of isoxazole -5 (49.5 g, 0.5 mol) is added in 500 mL tetrahydrofurans, is opened
Open stirring, by reaction system cool down -5 DEG C after, slowly be added dropwise DMF dimethylacetal（65.5 g,
0.55 mol）, dropwise addition process maintenance reaction stable system is below 0 DEG C.After being added dropwise to complete, reaction system stabilization is slowly carried
Room temperature is raised to, and is stirred at room temperature overnight.After completion of the reaction, decompression boils off tetrahydrofuran, obtains yellow crude, crude product tetrahydrochysene
The sterling 4- dimethylamino methylene -3- methyl -4- hydrogen-isoxazoles-of furans and methyl tertbutyl mixed solution recrystallizing and refining
5- ketone（63.5 g, the % of yield 82.4）.
1H NMR (400 MHz, CDCl3): d 7.06 (s, 1 H), 3.68 (s, 3 H), 3.33 (s, 3
H), 2.54 (s, 3 H)。
Step 3
The synthesis of 3- methyl -4- isoxazole carboxylic acids
By 4- dimethylamino methylene -3- methyl -4- hydrogen-isoxazole -5- ketone (50 g, 0.32 mol) and hydroxide
Sodium（12.8 g, 0.32 mol）Add in 500 mL water, open stirring, stirred after reaction system is warmed up into 40 DEG C
1 hour.After question response terminates, water is concentrated to dryness, obtains 3- methyl -4- isoxazoles-carboxylic acid sodium salt.Then 6 are slowly added dropwise
N concentrated hydrochloric acids, 2-3 is transferred to by pH value, uses ethyl acetate（500 mL×3）Extract.Merge organic layer, drying is concentrated to give 3- first
Base -4- isoxazoles-carboxylic acid（36.5 g, yield 89.9%）.
1H NMR (400 MHz, DMSO): d 9.02 (s, 1 H), 2.52 (s, 3 H)。
Embodiment 2, step 1
The synthesis of 3- phenyl -4- hydrogen-ketone of isoxazole -5
By in sodium carbonate (53 g, 0.5 mol) 1.5 L water of addition, half an hour is stirred, treat that sodium carbonate is completely molten
By hydroxylamine hydrochloride after solution（69.5 g, 1 mol）It is dividedly in some parts.Stirring half an hour, after bubble-free releasing after, by 3- phenyl-
3- propionic acid methyl esters (178 g, 1 mol) are slowly added drop-wise in above-mentioned reaction solution.Completion of dropping, was stirred at room temperature
Night.After completion of the reaction, reaction solution ethyl acetate（500 mL×3）Extract.Merge organic layer, drying be concentrated to give 3- phenyl-
4- hydrogen-isoxazole -5- ketone（135 g, yield 83.8%）, purity> 95%
1H NMR (400 MHz, CDCl3): d 7.66-7.68 (d, J = 8 Hz, 2 H), 7.56-7.61 (m,
3 H), 3.81 (s, 2 H)。
Step 2
The synthesis of 4- dimethylamino methylene -3- phenyl -4- hydrogen-isoxazole -5- ketone
3- phenyl -4- hydrogen-isoxazole -5- ketone (49.5 g, 0.5 mol) is added in 500 mL tetrahydrofurans,
Stirring is opened, DMF dimethylacetal will be slowly added dropwise after -5 DEG C of reaction system cooling（65.5 g,
0.55 mol）, be added dropwise process maintenance reaction stable system at 0 DEG C once.After being added dropwise to complete, reaction system stabilization is slowly carried
Room temperature is raised to, and is stirred at room temperature overnight.After completion of the reaction, decompression boils off tetrahydrofuran, obtains yellow crude, crude product tetrahydrochysene furan
The sterling 4- dimethylamino methylene -3- phenyl -4- hydrogen-isoxazole -5- muttered with methyl tertbutyl mixed solution recrystallizing and refining
Ketone（56.1 g, the % of yield 84.6）.
1H NMR (400 MHz, CDCl3): d 7.41-7.47 (m, 5 H), 7.05 (s, 1 H), 3.78 (s,
3 H), 3.27 (s, 3 H)。
Step 3
The synthesis of 3- phenyl -4- isoxazole carboxylic acids
By 4- dimethylamino methylene -3- phenyl -4- hydrogen-isoxazole -5- ketone（50 g, 0.32 mol）And NaOH
（12.8 g, 0.32 mol）Add in 500 mL water, open stirring, 1 is stirred after reaction system is warmed up into 40 DEG C
Hour.After question response terminates, water is concentrated to dryness, obtains 3- phenyl -4- isoxazoles-carboxylic acid sodium salt.Then 6 N are slowly added dropwise dense
Hydrochloric acid, 2-3 is transferred to by pH value, uses ethyl acetate（500 mL×3）Extract.Merge organic layer, drying is concentrated to give 3- phenyl -4-
Isoxazole-carboxylic acid（39.5 g, yield 90.5%）.
1H NMR (400 MHz, CDCl3): d 9.13 (s, 1 H), 7.31-7.39 (m, 5 H)。
Embodiment 3, step 1
The synthesis of 3- (4- methoxyphenyls) -4- hydrogen-isoxazole -5- ketone
By sodium carbonate（53 g, 0.5 mol）Add in 1.5 L water, stir half an hour, will after sodium carbonate is completely dissolved
Hydroxylamine hydrochloride（69.5 g, 1 mol）It is dividedly in some parts.Stirring half an hour, after bubble-free releasing after, by 3- (4- methoxyphenyls)-
3- propionic acid methyl esters（282 g, 1 mol）Slowly it is added drop-wise in above-mentioned reaction solution.Completion of dropping, is stirred at room temperature overnight.
After completion of the reaction, reaction solution ethyl acetate（500 mL×3）Extract.Merge organic layer, drying is concentrated to give 3- (4- methoxyl groups
Phenyl) -4- hydrogen-isoxazole -5- ketone（178 g, yield 93.5%）, purity> 95%.
1H NMR (400 MHz, CDCl3): d 7.61-7.63 (d, J = 8 Hz, 2 H), 6.96-6.98 (d,J = 8 Hz, 2 H), 3.87 (s, 3 H), 3.78 (s, 2 H)。
Step 2
The synthesis of 4- dimethylamino methylene -3- (4- methoxyphenyls) -4- hydrogen-isoxazole -5- ketone
3- (4- methoxyphenyls) -4- hydrogen-ketone of isoxazole -5 (49.5 g, 0.5 mol) is added into 500 mL tetrahydrochysenes
In furans, open stirring, by reaction system cool down -5 DEG C after, slowly be added dropwise DMF dimethylacetal
（65.5 g, 0.55 mol）, be added dropwise process maintenance reaction stable system at 0 DEG C once.It is after being added dropwise to complete, reaction system is steady
Fixed slow lifting is stirred at room temperature overnight to room temperature.After completion of the reaction, decompression boils off tetrahydrofuran, obtains yellow crude, crude product
With tetrahydrofuran and sterling 4- dimethylamino methylene -3- (the 4- methoxybenzenes of methyl tertbutyl mixed solution recrystallizing and refining
Base) -4- hydrogen-isoxazole -5- ketone（50.6 g, the % of yield 79.5）.
1H NMR (400 MHz, CDCl3): d 7.37-7.39 (d, J = 8 Hz, 2 H), 7.04 (s, 1
H), 6.95-6.97 (d, J = 8 Hz, 2 H), 3.83 (s, 3 H), 3.74 (s, 3 H), 3.26 (s, 3
H)。
Step 3
The synthesis of 3- (4- methoxyphenyls) -4- isoxazole carboxylic acids
By 4- dimethylamino methylene -3- (4- methoxyphenyls) -4- hydrogen-isoxazole -5- ketone（50 g, 0.32 mol）
And NaOH（12.8 g, 0.32 mol）Add in 500 mL water, stirring is opened, after reaction system is warmed up into 40 DEG C
Stirring 1 hour.After question response terminates, water is concentrated to dryness, obtains 3- (4- methoxyphenyls) -4- isoxazoles-carboxylic acid sodium salt.
Then 6 N concentrated hydrochloric acids are slowly added dropwise, pH value is transferred to 2-3, use ethyl acetate（500 mL×3）Extract.Merge organic layer, dry
It is concentrated to give 3- (4- methoxyphenyls)- 4- isoxazoles-carboxylic acid（36.5 g, yield 82.0%）.
1H NMR (400 MHz, DMSO): d 9.11 (s, 1 H), 7.87-7.89 (d, J = 8 Hz, 2
H), 6.92-6.94 (d, J = 8 Hz, 2 H), 3.75 (s, 3 H)。
Embodiment 4, step 1
The synthesis of 3- (3- pyridine radicals) -4- hydrogen-isoxazole -5- ketone
By in sodium carbonate (5.3 g, 0.05 mol) 200 mL water of addition, half an hour is stirred, treat that sodium carbonate is complete
By hydroxylamine hydrochloride after dissolving（6.95 g, 0.1 mol）It is dividedly in some parts.Stirring half an hour, after after bubble-free releasing, by 3-
(3- pyridine radicals) -3- oxygen methyl propionate (17.9 g, 0.1 mol) is slowly added drop-wise in above-mentioned reaction solution.Completion of dropping,
It is stirred overnight at room temperature.After completion of the reaction, reaction solution ethyl acetate（100 mL×3）Extract.Merge organic layer, dry concentration
Obtain 3- (3- pyridine radicals) -4- hydrogen-isoxazole -5- ketone（12.1 g, yield 75.3%）, purity> 95%.
1H NMR (400 MHz, CDCl3): d 8.83-8.84 (d, J = 2 Hz, 1 H), 8.77-8.78 (d,J = 4 Hz, 1 H), 8.09-8.11 (d, J = 8 Hz, 1 H), 7.44-7.47 (m, 1 H), 3.84 (s, 2
H)。
Step 2
The synthesis of 4- dimethylamino methylene -3- (3- pyridine radicals) -4- hydrogen-isoxazole -5- ketone
By 3- (3- pyridine radicals) -4- hydrogen-isoxazole -5- ketone（8.1 g, 0.05 mol）Add 80 mL tetrahydrofurans
In, open stirring, by reaction system cool down -5 DEG C after, slowly be added dropwise DMF dimethylacetal（6.55
G, 0.055 mol）, be added dropwise process maintenance reaction stable system at 0 DEG C once.It is after being added dropwise to complete, reaction system stabilization is slow
Slow lifting is stirred at room temperature overnight to room temperature.After completion of the reaction, decompression boils off tetrahydrofuran, obtains yellow crude.Crude product uses four
Hydrogen furans and methyl tertbutyl mixed solution recrystallizing and refining obtain sterling 4- dimethylamino methylene -3- (3- pyridine radicals) -4 hydrogen -
Isoxazole -5- ketone（6.35 g, the % of yield 62.4）.
1H NMR (400 MHz, CDCl3): d 8.73-8.73 (d, J = 4 Hz, 1 H), 8.70(s, 1 H),
7.86-7.88 (d, J = 8 Hz, 1 H), 7.43-7.45 (m, 1 H), 7.03 (s, 1 H), 3.80 (s, 3
H), 3.31 (s, 3 H)。
Step 3
The synthesis of 3- (3- pyridine radicals) -4- isoxazole carboxylic acids
By 4- dimethylamino methylene -3- (3- pyridine radicals) -4- hydrogen-isoxazole -5- ketone（5.0 g, 0.032 mol）With
NaOH（1.28 g, 0.032 mol）Add in 50 mL water, open stirring, after reaction system is warmed up into 40 DEG C,
Stirring 1 hour.After question response terminates, water is concentrated to dryness, obtains 3- (3- pyridine radicals) -4- isoxazoles-carboxylic acid sodium salt.Then
6 N concentrated hydrochloric acids are slowly added dropwise, ethyl acetate is used（50 mL×3）Extract.Merge organic layer, drying is concentrated to give 3- (3- pyridines
Base) -4- isoxazole carboxylic acids（3.65 g, yield 83.5%）.
1H NMR (400 MHz, DMSO): d 9.14 (s, 1 H), 8.97 (s, 1 H), 8.54-8.55 (d,J = 4 Hz, 1 H), 8.22 (s, 1 H), 7.38-7.41 (m, 1 H)。
Claims (4)
1. a kind of 3- replaces the synthetic method of -4- isoxazole carboxylic acids, it is characterized in that comprise the following steps, the first step, with 3- substitutions -
3- oxopropanoic acids ester is initiation material, and carrying out ring-closure reaction in water with hydroxylamine hydrochloride and alkali is obtained 3- substitution -4- isoxazoles -5-
Ketone；Second step, 3- substitution -4- isoxazole -5- ketone and the reaction of DMF dimethylacetal prepare 4- diformazans
Amido methylene -3- substitution -4- hydrogen-isoxazole -5- ketone；3rd step, 4- dimethylamino methylene -3- substitution -4- hydrogen-different evil
Azoles -5- ketone in the basic conditions, experiences lactone hydrolysis, again cyclization；Acidifying obtains 3- substitution -4- isoxazole carboxylic acids, closes
Chemical structure of general formula into compound is as follows：
Wherein group R is：Alkyl, aryl radical, the one kind in fragrant heterocyclic radical；Reaction equation is as follows：
。
2. synthetic method according to claim 1, it is characterized in that alkali is sodium carbonate in the first step, potassium carbonate, NaOH,
One kind in potassium hydroxide, base amount is 0.5~2 equivalent of hydroxylamine hydrochloride, and reaction temperature is 0~50 DEG C.
3. synthetic method according to claim 1, it is characterized in that, 3- replace -4- isoxazole -5- ketone in organic solvent and
DMF dimethylacetal reacts, wherein, DMF dimethylacetal consumption is 3- substitutions -4-
1 ~ 5 equivalent of isoxazole -5- ketone, organic solvent is the one kind in toluene, ethyl acetate or tetrahydrofuran, and reaction temperature is -10
~80 DEG C.
4. synthetic method according to claim 1, it is characterized in that, the alkali of the 3rd step neutral and alkali condition is sodium carbonate, carbonic acid
Potassium, NaOH, potassium hydroxide one kind therein, base amount is 4- dimethylamino methylene -3- substitution -4- hydrogen-isoxazole -5-
1~5 equivalent of ketone, the solvent for being used is water, and reaction temperature is 20~60 DEG C.
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