CN106146424A - A kind of preparation method of 5-methyl-3,4-diphenyl isoxazole - Google Patents
A kind of preparation method of 5-methyl-3,4-diphenyl isoxazole Download PDFInfo
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- CN106146424A CN106146424A CN201510128243.8A CN201510128243A CN106146424A CN 106146424 A CN106146424 A CN 106146424A CN 201510128243 A CN201510128243 A CN 201510128243A CN 106146424 A CN106146424 A CN 106146424A
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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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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a kind of 5-methyl-3, the preparation method of 4-diphenyl isoxazole, it comprises the steps of in first alcohol and water, in the presence of an inorganic base, compound 2 is carried out dehydration, prepares 5-methyl-3,4-diphenyl isoxazole.
Description
Technical field
The present invention relates to the preparation method of a kind of medicine intermediate, be specifically related to a kind of 5 methyl 3,4 hexichol
The preparation method of base isoxazole.
Background technology
5 methyl 3,4 diphenyl isoxazoles, its structural formula is:This compound is synthesis
The key intermediate of Parecoxib Sodium (Parecoxib Sodium).Parecoxib Sodium is by the Pfizer of the U.S.
The cox 2 inhibitor of company's research and development, listed in European Union in 2002, trade name Dynastat, is used for
The short term therapy of postoperative pain.
Leonardo Di Nunno etc. reports synthesis (the Journal of of 5 methyl 3,4 diphenyl isoxazoles
Medicinal Chemistry, 2004,47,4881-4889): aqueous sodium carbonate is joined 4,5-dihydro
-5-methyl-3, in the tetrahydrofuran solution of 4-diphenyl-5-isoxazole, are heated to reflux one hour, obtain two
Phase solution, ethyl acetate extracts, and organic facies is dried with anhydrous sodium sulfate, obtains product after concentration, receives
Rate is 80%.The main defect of this technique is that yield is on the low side, and the product purity that obtain is found through experiments
Only 85%.
Leterdre LJ etc. describes 5 methyl 3,4 diphenyl isoxazoles in patent WO 2005123701
Synthesis: by 4,5-dihydro-5-methyl-3,4-diphenyl-5-isoxazole joins in the solution of trifluoroacetic acid,
It is dehydrated at 35 DEG C, obtains 5 methyl 3,4 diphenyl isoxazoles, yield 74%, purity 89%.
Therefore, this area is needed a kind of high yield, high product purity badly, is prone to 5 methyl of industrialized production
The preparation method of 3,4 diphenyl isoxazoles.
Summary of the invention
The technical problem to be solved is different in order to solve existing preparation 5 methyl 3,4 diphenyl
The method yield of azoles is low, purity difference, be difficult to the defects such as industrialized production, and provides a kind of 5
The preparation method of methyl 3,4 diphenyl isoxazole.The preparation method of the present invention is simple to operate, productivity is high,
Product purity up to more than 99%, low cost, be prone to industrialized production.
The invention provides a kind of 5-methyl-3, the preparation method of 4-diphenyl isoxazole, it comprises following step
Rapid: in first alcohol and water, in the presence of an inorganic base, compound 2 is carried out dehydration, prepares 5-
Methyl-3,4-diphenyl isoxazole；
In the present invention, described first alcohol and water, can be ability with the volume mass ratio of described compound 2
The volume mass ratio that this type of reaction of territory is conventional, preferably 1mL/g～50mL/g, be more preferably
5mL/g～30mL/g, such as 20mL/g.
In the present invention, in described first alcohol and water, the volume ratio of described methanol and described water can be this
The volume ratio that this type of reaction of field is conventional, preferably 7:3～3:7, is more preferably 4:6～6:4, such as 1:1.
In the present invention, described inorganic base can be the inorganic base that this type of reaction of this area is conventional, preferably
Alkali carbonate, is more preferably one or more in sodium carbonate, potassium carbonate and cesium carbonate.
In the present invention, described inorganic base and the mol ratio of described compound 2 can be that this type of is anti-in this area
Mol ratio that should be conventional, preferably 1.5～2, such as 1.8.
In the present invention, it is preferred that described inorganic base and described water are first dissolved as the aqueous solution of inorganic base
After feed intake again；The concentration of described inorganic base aqueous solution can be that the quality of this type of reaction routine of this area is dense
Degree, preferably 1%～32.9%, be more preferably 3%～31.5%, such as 7.7%.
In the present invention, the temperature of described dehydration can be the temperature that this type of reaction of this area is conventional, relatively
It is 50 DEG C～80 DEG C goodly, such as 70 DEG C.
In the present invention, the time of described dehydration can be the time that this type of reaction of this area is conventional, one
As no longer react with compound 2 or after testing till (such as TLC) reaction completely, preferably 2～
12 hours, be more preferably 2～6 hours.
In the present invention, the post processing of described dehydration can be the rear place that this type of reaction of this area is conventional
Reason, such as, after having reacted, be extracted with ethyl acetate reactant liquor, collect organic facies, be dried, concentrate,
I.e. prepare 5-methyl-3,4-diphenyl isoxazole；It is preferred that also include recrystallization after aforesaid operations.Described
The solvent of recrystallization can be the solvent of the conventional recrystallization in this area, preferably normal hexane and acetic acid second
The mixed solvent of ester, more preferably for normal hexane and mixed solvent that ethyl acetate volume ratio is 1～5, most preferably
Ground is the mixed solvent of 3 for normal hexane and ethyl acetate volume ratio.The solvent of described recrystallization is with described
The volume mass of compound 2 than be the conventional volume mass ratio of this type of reaction of this area, be preferably
4mL/g～40mL/g.
From comparative example 1,2 and 4 it can be seen that the reaction the present invention is the most sensitive to solvent,
When THF replaces with ethanol, DMF, yield reduces；But, through substantial amounts of screening, invention
After people creatively finds THF is replaced with methanol, yield, purity are significantly increased, and lead to further
Cross recrystallization and improve the purity of product, make it easy to industrialized production.
On the premise of common sense in the field, above-mentioned each preferred feature can independent assortment, with
Each preferred embodiments to the present invention.
In addition to specified otherwise, the abbreviation THF used in the present invention refers to that oxolane, DMF refer to
DMF, TLC refers to that thin layer chromatography, m.p. refer to that fusing point, MS refer to mass spectral analysis,
NMR refers to nuclear magnetic spectrum analysis.
The most progressive effect of the present invention is: the preparation method of the present invention is simple to operate, productivity is high, product
Thing purity up to more than 99%, low cost, be prone to industrialized production.
Detailed description of the invention
Further illustrate the present invention by embodiment below, but the present invention is not intended to be limited thereto.
The embodiment of the present invention uses HPLC to test purity, and design parameter is as follows:
Chromatographic column: Dionet Acclaim C184.6*250mm, 5 μm；
Flowing phase: acetonitrile: phosphate buffer (PH 3.0)=40:60；
Detection wavelength: 215nm.
Embodiment 1
In four mouthfuls of round-bottomed flasks of a 1L add compound 2 (40g), methanol (400mL), 7.7%
Aqueous sodium carbonate (400mL), is heated to 70 DEG C, after stirring reaction 2h, and TLC plate monitoring raw material
Fundamental reaction is complete, and solution is divided into solid-liquid biphase, is extracted with ethyl acetate, collected organic layer, with anhydrous
Sodium sulfate is dried, and vacuum obtains white solid, HPLC purity: 94.9% after being spin-dried for.
White solid uses 40ml ethyl acetate and the mixed solvent recrystallization of 120ml normal hexane (1:3) again,
Obtaining target compound is white solid 34.2g, yield 92%, HPLC purity: 99.7%.m.p.97-98℃；
MS(m/z):236(M+H)+；1H NMR(400MHz,CDCl3)
δ:2.43(s,3H,-CH3), 7.19-7.43 (m, 10H ,-CH=).
Embodiment 2
Addition compound 2 (5g) in four mouthfuls of round-bottomed flasks of a 250mL, methanol (50mL),
7.7% wet chemical (50mL), is heated to 70 DEG C, and after stirring reaction 2h, solution is divided into solid-liquid
Biphase, it is extracted with ethyl acetate, collected organic layer, is dried with anhydrous sodium sulfate, vacuum obtains after being spin-dried for
White solid, HPLC purity: 97.7%.
White solid uses 50ml ethyl acetate and the mixed solvent recrystallization of 150ml normal hexane (1:3) again,
Obtaining target compound is white solid 4.17g, yield 90%, HPLC purity: 99.6%.
Comparative example 1
Addition compound 2 (6g) in four mouthfuls of round-bottomed flasks of a 250mL, ethanol (60mL),
7.7% aqueous sodium carbonate (60mL), is heated to 70 DEG C, and after stirring reaction 6h, solution is divided into solid-liquid
Biphase, it is extracted with ethyl acetate, collected organic layer, is dried with anhydrous sodium sulfate, vacuum obtains after being spin-dried for
White solid.Again with ethyl acetate and the mixed solvent recrystallization of normal hexane (1:3), obtain target compound
For white solid 3.34g, yield 60%, HPLC purity: 99.2%.
Comparative example 2
Addition compound 2 (6g) in four mouthfuls of round-bottomed flasks of a 250mL, DMF (60mL),
7.7% aqueous sodium carbonate (60mL), is heated to 70 DEG C, and after stirring reaction 12h, solution is divided into solid
Liquid is biphase, is extracted with ethyl acetate, and collected organic layer is dried with anhydrous sodium sulfate, and vacuum obtains after being spin-dried for
To white solid.Again with ethyl acetate and the mixed solvent recrystallization of normal hexane (1:3), obtain target chemical combination
Thing is white solid 2.79g, yield 50%, HPLC purity: 99.1%.
Comparative example 3
Addition compound 2 (5g) in four mouthfuls of round-bottomed flasks of a 50mL, trifluoroacetic acid (5mL),
Dichloromethane solution (20mL), is heated to 35 DEG C, after stirring reaction 3h, is cooled to-5 DEG C, dropping
Water 15ml cancellation, dichloromethane extracts, and collected organic layer is dried with anhydrous sodium sulfate, and vacuum is spin-dried for
After obtain white solid.Again with ethyl acetate and mixed solvent (1:3) recrystallization of normal hexane, obtain target
Compound is white solid 3.33g, yield 72%, HPLC purity: 99.2%.
Comparative example 4
Addition compound 2 (6g) in four mouthfuls of round-bottomed flasks of a 250mL, THF (60mL),
7.7% aqueous sodium carbonate (60mL), is heated to 70 DEG C, and after stirring reaction 2h, solution is divided into solid-liquid
Biphase, it is extracted with ethyl acetate, collected organic layer, is dried with anhydrous sodium sulfate, vacuum obtains after being spin-dried for
White solid, yield 80%, HPLC purity: 85%.
Claims (10)
1. 5-methyl-3, the preparation method of 4-diphenyl isoxazole, it comprises the steps of in first
In alcohol and water, in the presence of an inorganic base, compound 2 is carried out dehydration, prepare 5-methyl-3,4-
Diphenyl isoxazole；
2. preparation method as claimed in claim 1, it is characterised in that described first alcohol and water, with
The volume mass of described compound 2 is than for 1mL/g～50mL/g.
3. preparation method as claimed in claim 1, it is characterised in that in described first alcohol and water,
The volume ratio of described methanol and described water is 7:3～3:7.
4. preparation method as claimed in claim 1, it is characterised in that described inorganic base is alkali gold
Belong to carbonate.
5. preparation method as claimed in claim 1, it is characterised in that described inorganic base is with described
The mol ratio of compound 2 be 1.5～2.
6. preparation method as claimed in claim 1, it is characterised in that described inorganic base is with described
Water be first dissolved as the aqueous solution of inorganic base after feed intake again.
7. preparation method as claimed in claim 6, it is characterised in that described inorganic base aqueous solution
Mass concentration be 1%～32.9%.
8. preparation method as claimed in claim 1, it is characterised in that the temperature of described dehydration
Degree is 50 DEG C～80 DEG C.
9. preparation method as claimed in claim 1, it is characterised in that described dehydration time
Between be 2～12 hours.
10. preparation method as claimed in claim 1, it is characterised in that after described dehydration
It is processed as: after having reacted, is extracted with ethyl acetate reactant liquor, collect organic facies, be dried, concentrate,
Recrystallization.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510128243.8A CN106146424A (en) | 2015-03-23 | 2015-03-23 | A kind of preparation method of 5-methyl-3,4-diphenyl isoxazole |
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| CN201510128243.8A CN106146424A (en) | 2015-03-23 | 2015-03-23 | A kind of preparation method of 5-methyl-3,4-diphenyl isoxazole |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112409284A (en) * | 2020-11-28 | 2021-02-26 | 南京艾普特生物医药有限公司 | Synthetic method of 5-methyl-3, 4-diphenyl isoxazole |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1578774A (en) * | 2001-10-02 | 2005-02-09 | 法玛西雅公司 | Method for preparing benzenesulfonyl compounds |
| WO2005123701A1 (en) * | 2004-06-14 | 2005-12-29 | Pharmacia Corporation | Method for the preparation of diarylisoxazole sulfonamide compounds and intermediates |
| CN104447600A (en) * | 2013-09-22 | 2015-03-25 | 江苏奥赛康药业股份有限公司 | Preparation method of parecoxib sodium compound as well as intermediate impurity and application of parecoxib sodium compound |
-
2015
- 2015-03-23 CN CN201510128243.8A patent/CN106146424A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1578774A (en) * | 2001-10-02 | 2005-02-09 | 法玛西雅公司 | Method for preparing benzenesulfonyl compounds |
| WO2005123701A1 (en) * | 2004-06-14 | 2005-12-29 | Pharmacia Corporation | Method for the preparation of diarylisoxazole sulfonamide compounds and intermediates |
| CN104447600A (en) * | 2013-09-22 | 2015-03-25 | 江苏奥赛康药业股份有限公司 | Preparation method of parecoxib sodium compound as well as intermediate impurity and application of parecoxib sodium compound |
Non-Patent Citations (2)
| Title |
|---|
| LEONARDO DI NUNNO ET AL: "Novel Synthesis of 3,4-Diarylisoxazole Analogues of Valdecoxib: Reversal Cyclooxygenase-2 Selectivity by Sulfonamide Group Removal", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| SHIBING TANG ET AL: "Efficient and Regioselective One-Pot Synthesis of 3-Substituted and 3,5-Disubstituted Isoxazoles", 《ORGANIC LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112409284A (en) * | 2020-11-28 | 2021-02-26 | 南京艾普特生物医药有限公司 | Synthetic method of 5-methyl-3, 4-diphenyl isoxazole |
| CN112409284B (en) * | 2020-11-28 | 2022-04-22 | 上海彩迩文生化科技有限公司 | Synthetic method of 5-methyl-3, 4-diphenyl isoxazole |
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Application publication date: 20161123 |