CN103242284A - Palladium-catalyzed 5-trifluoromethylpiperonal synthesis method - Google Patents
Palladium-catalyzed 5-trifluoromethylpiperonal synthesis method Download PDFInfo
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- CN103242284A CN103242284A CN2012100223903A CN201210022390A CN103242284A CN 103242284 A CN103242284 A CN 103242284A CN 2012100223903 A CN2012100223903 A CN 2012100223903A CN 201210022390 A CN201210022390 A CN 201210022390A CN 103242284 A CN103242284 A CN 103242284A
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- piperonylaldehyde
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- trifluoromethyl
- cuprous
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- CWPJHCMWEGNRLP-UHFFFAOYSA-N O=Cc(cc1C(F)(F)F)cc2c1OCO2 Chemical compound O=Cc(cc1C(F)(F)F)cc2c1OCO2 CWPJHCMWEGNRLP-UHFFFAOYSA-N 0.000 description 1
- PRYDNEPQUGCULA-UHFFFAOYSA-N O=Cc(cc1I)cc2c1OCO2 Chemical compound O=Cc(cc1I)cc2c1OCO2 PRYDNEPQUGCULA-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a palladium-catalyzed 5-trifluoromethylpiperonal synthesis method. The method comprises the following steps: heating 1.0 part of 5-iodopiperonal, 5.0-10.0 parts of FSO2CF2COOCH3, 2.5-5.0 parts of a halogenated cuprous salt, and 0.1-0.2 parts of a palladium catalyst in a solvent N,N-dimethylformamide to 100DEG C under the protection of nitrogen, and reacting for 8-16h; and filtering the obtained reaction solution through diatomite, drying the obtained filtrate, separating the dried filtrate through column chromatography through using a petroleum ether-ethyl acetate mixed liquor as an eluate according to a volume ratio of 10:1 to obtain a white solid which is 5-trifluoromethylpiperonal.
Description
Technical field
The present invention relates to pharmaceutical intermediate organic synthesis field, particularly, the present invention relates to a kind of synthetic method of pharmaceutical intermediate 5-trifluoromethyl piperonylaldehyde.
Background technology
The piperonylaldehyde derivative is a kind of important organic intermediate, in field of fine chemical such as perfume, spices, agricultural chemicals, medicine purposes is widely arranged, and they provide important component part for the compound of developing new biologically active.As: the amino piperonylaldehyde of 6-is exactly a kind of important medicine intermediate, in anti-malaria medicaments, anti senile dementia drug, hypertension and antipsychotics application is arranged; Piperine with calmness, anti-epileptic and antidepressant effect also can be synthetic by piperonylaldehyde.So the synthetic of piperonylaldehyde derivative paid close attention to by people always.
Piperonylaldehyde has good using value at 5 derivatives with the functional group of leaving away, the present invention designs a kind of new piperonylaldehyde derivative: 5-trifluoromethyl piperonylaldehyde, because the trifluoromethyl on 5 has more intense activity, this compound can be used as intermediate for the preparation of any derivative that contains piperonylaldehyde.Trifluoromethyl has specific functions such as high electronegativity, high stability, strong liposoluble perviousness, is introduced into and can significantly improves its polarity, stability and lipotropy in the piperonylaldehyde, obviously strengthens biological activity.The trifluoromethyl piperonylaldehyde has characteristics such as consumption is few, toxicity is low, drug effect is high, metabolic capacity is strong, and having very in fields such as biological chemistry, medicine, agricultural chemicals, functional materials and dyestuff, important use is worth.
Yet, in the preparation process of 5-trifluoromethyl piperonylaldehyde, run into difficulty, because trifluoromethylation reaction is subjected to the influence of factors such as trifluoromethyl reagent, reaction conditions and by product are many, trifluoromethyl piperonylaldehyde derivative synthetic remains an important topic.
The present invention finds the method for a 5-trifluoromethyl piperonylaldehyde by research, is raw material with 5-iodine piperonylaldehyde, and in the presence of palladium and copper, the iodine with in 5 of the trifluoromethyl replacements obtains 5-trifluoromethyl piperonylaldehyde.Reaction raw materials of the present invention is cheap and easy to get, and conversion unit is simple, can high yield make 5-trifluoromethyl piperonylaldehyde, be suitable for industrialization production.
Summary of the invention
One of purpose of the present invention is to provide a kind of new compound 5-trifluoromethyl piperonylaldehyde, and structural formula is as follows.
The physical parameter of this compound:
Molecular formula: C
9H
5F
3O
3
Chinese named: 5-trifluoromethyl piperonylaldehyde; 3,4-dioxy methylene radical-5-trifluoromethylated benzaldehyde
English name: 3,4-methylenedioxy-5-(trifluoromethyl)-benzaldehyde
Molecular weight: 218.0
Outward appearance: white solid
1H?NMR(CDCl
3，400MHz)：δ9.87(1H，s，CHO)，7.62(1H，s，ArH)，7.49(1H，d，J＝1.2Hz，ArH)，6.25(2H，s，OCH
2O)；
13C?NMR(CDCl
3，100MHz)δ189.06，150.34，131.59，124.64，124.60，124.56，124.52，109.33，103.69；
19F?NMR(CDCl
3，400MHz)：δ-61.71；
Two of purpose of the present invention is to provide a kind of synthetic method of 5-trifluoromethyl piperonylaldehyde.This method raw material is easy to get, and cost is low, and the yield height is suitable for industrialization production.
5-trifluoromethyl piperonylaldehyde of the present invention, the preparation method is as follows:
Be raw material with 5-iodine piperonylaldehyde, in the presence of palladium and copper, the iodine on replacing 5 with trifluoromethyl obtains 5-trifluoromethyl piperonylaldehyde.
Reaction formula is as follows:
Preferred method of the present invention adopts N, and dinethylformamide is solvent, is reflected under the nitrogen protection to carry out, and trifluoromethyl reagent is selected from: FSO
2CF
2COOCH
3, being reflected under the heating condition and carrying out, the reaction times is 8-16 hour, preferred 10 hours, palladium and copper were divalence palladium salt and cuprous salt.
Particularly preferred method of the present invention adopts N, and dinethylformamide is solvent, be reflected under the nitrogen protection to carry out, wherein:
5-iodine piperonylaldehyde consumption is 1.0 equivalents,
FSO
2CF
2COOCH
3Consumption is the 5.0-10.0 equivalent, preferred 5.0 equivalents
The consumption of cuprous halide salt is the 2.5-5.0 equivalent, preferred 5.0 equivalents
The consumption of palladium catalyst is the 0.1-0.2 equivalent,
Reaction is heated to 100 ℃ and carries out.
After reaction finished, reaction solution was through diatomite filtration, and the filtrate evaporate to dryness is by column chromatography for separation, and elutriant is the mixed solution of 10: 1 sherwood oil of volume ratio and ethyl acetate, and getting white solid is 5-trifluoromethyl piperonylaldehyde.
Wherein used cuprous halide salt is cuprous iodide or cuprous bromide, is preferably cuprous iodide; Used palladium catalyst is PdCl
2Or Pd (OAc)
2, be preferably PdCl
2
Raw material of the present invention is 5-iodine piperonylaldehyde, belongs to prior art, can buy from the market to obtain, and also can obtain with prior art for preparing.
Description of drawings
Fig. 1 5-trifluoromethyl piperonylaldehyde
1H NMR spectrogram (CDCl
3, 400M Hz)
Fig. 2 5-trifluoromethyl piperonylaldehyde
13C NMR spectrogram (CDCl
3, 100M Hz)
Fig. 3 5-trifluoromethyl piperonylaldehyde
19F NMR spectrogram (CDCl
3, 400M Hz)
Embodiment
Further specify the present invention below by specific embodiment.Following embodiment is that essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out for explanation the present invention rather than limitation of the present invention.
Embodiment 1
The preparation of 5-iodine piperonylaldehyde:
With N, dinethylformamide is solvent, adds the 5-iodo-3 of 1.0 equivalents in reaction vessel, 4-Dihydroxy benzaldehyde, the CH of 1.5-3.0 equivalent
2I
2K with the 2.0-4.0 equivalent
2CO
3, be heated to 120 ℃ of reactions 6-10 hour; Reacting liquid filtering rear filtrate evaporate to dryness, through column chromatography for separation, elutriant is the mixed solution of 10: 1 sherwood oil of volume ratio and ethyl acetate, getting white solid is 5-iodine piperonylaldehyde.
5-iodo-3, the preparation method of 4-Dihydroxy benzaldehyde: be solvent with 1,2-ethylene dichloride, add the 5-iodo-vanillin food grade,1000.000000ine mesh of 1.0 equivalents in reaction vessel, ice bath is cooled to 0 ℃, adds the AlCl of 2.5 equivalents
3With the pyridine of 10.0 equivalents, be heated to back flow reaction 2-4 hour; Add 20% hydrochloric acid in the reaction solution, tell organic phase, the water ethyl acetate extraction gets 5-iodo-3, the 4-Dihydroxy benzaldehyde behind the merging organic phase evaporate to dryness.
Synthesizing of embodiment 2:5-trifluoromethyl piperonylaldehyde
Under the nitrogen protection, add N in the 50ml there-necked flask, dinethylformamide 30ml, 1.0 gram 5-iodine piperonylaldehydes, 6.9 gram FSO
2CF
2COOCH
3, 3.4 gram cuprous iodides, 0.12 gram Palladous chloride is heated to 100 ℃ of reactions 10 hours; Reaction solution is through diatomite filtration, and the filtrate evaporate to dryness is by column chromatography for separation, and elutriant is the mixed solution of 10: 1 sherwood oil of volume ratio and ethyl acetate, and getting white solid is 5-trifluoromethyl piperonylaldehyde 0.7 gram (87%).
Synthesizing of embodiment 3:5-trifluoromethyl piperonylaldehyde
Under the nitrogen protection, add N in the 50ml there-necked flask, dinethylformamide 30ml, 1.0 gram 5-iodine piperonylaldehydes, 3.45 gram FSO
2CF
2COOCH
3, 1.7 gram cuprous iodides, 0.06 gram Palladous chloride is heated to 100 ℃ of reactions 10 hours; Reaction solution is through diatomite filtration, and the filtrate evaporate to dryness is by column chromatography for separation, and elutriant is the mixed solution of 10: 1 sherwood oil of volume ratio and ethyl acetate, and getting white solid is 5-trifluoromethyl piperonylaldehyde 0.65 gram (83%).
Synthesizing of embodiment 4:5-trifluoromethyl piperonylaldehyde
Under the nitrogen protection, add N in the 500ml there-necked flask, dinethylformamide 300ml, 17.5 gram 5-iodine piperonylaldehydes, 121 gram FSO
2CF
2COOCH
3, 61 gram cuprous iodides, 2.2 gram Palladous chlorides are heated to 100 ℃ of reactions 10 hours; Reaction solution is through diatomite filtration, and the filtrate evaporate to dryness is by column chromatography for separation, and elutriant is the mixed solution of 10: 1 sherwood oil of volume ratio and ethyl acetate, and getting white solid is 5-trifluoromethyl pepper 11 grams (81%).
Synthesizing of embodiment 5:5-trifluoromethyl piperonylaldehyde
Under the nitrogen protection, add N in the 50ml there-necked flask, dinethylformamide 30ml, 1.0 gram 5-iodine piperonylaldehydes, 6.9 gram FSO
2CF
2COOCH
3, 3.4 gram cuprous iodides, 0.15 gram Pd (OAc)
2Be heated to 100 ℃ of reactions 10 hours; Reaction solution is through diatomite filtration, and the filtrate evaporate to dryness is by column chromatography for separation, and elutriant is the mixed solution of 10: 1 sherwood oil of volume ratio and ethyl acetate, and getting white solid is 5-trifluoromethyl piperonylaldehyde 0.63 gram (80.7%).
Synthesizing of embodiment 6:5-trifluoromethyl piperonylaldehyde
Under the nitrogen protection, add N in the 50ml there-necked flask, dinethylformamide 30ml, 1.0 gram 5-iodine piperonylaldehydes, 6.9 gram FSO
2CF
2COOCH
3, 2.5 gram cuprous bromides, 0.12 gram Palladous chloride is heated to 100 ℃ of reactions 10 hours; Reaction solution is through diatomite filtration, and the filtrate evaporate to dryness is by column chromatography for separation, and elutriant is the mixed solution of 10: 1 sherwood oil of volume ratio and ethyl acetate, and getting white solid is 5-trifluoromethyl piperonylaldehyde 0.58 gram (74%).
Synthesizing of embodiment 7:5-trifluoromethyl piperonylaldehyde
Under the nitrogen protection, add N in the 50ml there-necked flask, dinethylformamide 30ml, 1.0 gram 5-iodine piperonylaldehydes, 6.9 gram FSO
2CF
2COOCH
3, 2.5 gram cuprous bromides, 0.15 gram palladium is heated to 100 ℃ of reactions 10 hours; Reaction solution is through diatomite filtration, and the filtrate evaporate to dryness is by column chromatography for separation, and elutriant is the mixed solution of 10: 1 sherwood oil of volume ratio and ethyl acetate, and getting white solid is 5-trifluoromethyl piperonylaldehyde 0.55 gram (70%).
Claims (9)
1. compound that structure is following:
2. the preparation method of claim 1 compound is characterized in that, is raw material with 5-iodine piperonylaldehyde, and the iodine on replacing 5 with trifluoromethyl obtains 5-trifluoromethyl piperonylaldehyde.
3. according to the preparation method of claim 2, it is characterized in that reaction formula is as follows:
4. according to the preparation method of claim 3, it is characterized in that adopt N, dinethylformamide is solvent, is reflected under the nitrogen protection to carry out, divalence palladium salt and cuprous salt are respectively palladium catalyst and cuprous halide salt.
5. according to the preparation method of claim 4, it is characterized in that wherein said cuprous halide salt is cuprous iodide or cuprous bromide, palladium catalyst is PdCl
2Or Pd (OAc)
2
6. according to the preparation method of claim 3, it is characterized in that be reflected under the heating condition and carry out, the reaction times is 8-16 hour.
7. according to the preparation method of claim 6, it is characterized in that the reaction times is 10 hours.
8. according to the preparation method of claim 3, it is characterized in that wherein, 5-iodine piperonylaldehyde consumption is 1.0 equivalents, FSO
2CF
2COOCH
3Consumption is the 5.0-10.0 equivalent, and the consumption of cuprous halide salt is the 2.5-5.0 equivalent, and the consumption of palladium catalyst is the 0.1-0.2 equivalent, and reaction is heated to 100 ℃ and carries out.
9. according to the preparation method of claim 3, it is characterized in that after reaction finished, reaction solution was through diatomite filtration, the filtrate evaporate to dryness is by column chromatography for separation, and the mixed solution wash-out with 10: 1 sherwood oil of volume ratio and ethyl acetate gets 5-trifluoromethyl piperonylaldehyde.
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|---|---|---|---|
| CN201210022390.3A CN103242284B (en) | 2012-02-01 | 2012-02-01 | A kind of synthetic method of 5-trifluoromethyl piperonylaldehyde of palladium chtalyst |
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|---|---|---|---|
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850317A (en) * | 2011-06-27 | 2013-01-02 | 天士力制药集团股份有限公司 | Substituted cinnamide derivative, its preparation method and application |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850317A (en) * | 2011-06-27 | 2013-01-02 | 天士力制药集团股份有限公司 | Substituted cinnamide derivative, its preparation method and application |
Non-Patent Citations (2)
| Title |
|---|
| JING NIE，ET AL.: "Asymmetric Construction of Stereogenic Carbon Centers Featuring a Trifluoromethyl Group from Prochiral Trifluoromethylated Substrates", 《CHEM. REV.》 * |
| 蒋海珍等: "含氟砌块的分子设计合成及其在合成含氟杂环化合物中的应用", 《上海大学学报（自然科学版）》 * |
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Address after: 300410 Tianjin city Beichen District Huaihe road and road intersection Dingjiang tianzhijiao Park forensic Center for Intellectual Property Department Patentee after: Tasly Pharmaceutical Group Limited by Share Ltd Address before: 300410 Tianjin city Beichen District Huaihe road and road intersection Dingjiang tianzhijiao Park forensic Center for Intellectual Property Department Patentee before: Tasly Pharmaceutical Group Co., Ltd. |
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