CN106748695A - The preparation method of m-trifluoromethyl cinnamic acid - Google Patents
The preparation method of m-trifluoromethyl cinnamic acid Download PDFInfo
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- CN106748695A CN106748695A CN201611065709.5A CN201611065709A CN106748695A CN 106748695 A CN106748695 A CN 106748695A CN 201611065709 A CN201611065709 A CN 201611065709A CN 106748695 A CN106748695 A CN 106748695A
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- cinnamic acid
- trifluoromethylbenzaldehyde
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
- C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
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Abstract
The invention discloses a kind of preparation method of m-trifluoromethyl cinnamic acid, it is obtained through a step aldol reaction in the presence of base catalyst with acetaldehyde by m-Trifluoromethylbenzaldehyde；Wherein, base catalyst is DBU, triethylamine or diisopropyl ethyl amine, and DBU is 1: 10~3: 5 with the mol ratio of m-Trifluoromethylbenzaldehyde；Acetaldehyde is 1: 1~5: 1 with the mol ratio of the m-Trifluoromethylbenzaldehyde；Condensation reaction is carried out in the presence of methyl alcohol, methyl tertiary butyl ether(MTBE) or tetrahydrofuran.Method of the present invention synthetic route is short, and reaction condition is gentle, simple to operate, especially by suitable base catalyst is selected, can obtain product of the purity more than 98% with preferable yield, so that it is adapted to large-scale industrial production, with larger application value.
Description
Technical field
The invention belongs to technology of fine chemicals, and in particular to a kind of preparation method of m-trifluoromethyl cinnamic acid.
Background technology
M-trifluoromethyl cinnamic acid is the important intermediate of synthetic hydrochloric acid cinacalcet.
The preparation method of m-trifluoromethyl cinnamic acid mainly has following several disclosed in prior art：
（One）With m-Trifluoromethylbenzaldehyde as initiation material, first m-TrifluoromethylcinnaAcid Acid is condensed to yield with acetic anhydride, then with
Piperidines is condensed to yield amide intermediate, is most obtained through red aluminium reducing afterwards.Its synthetic route is as follows：
。
（Two）With m-Trifluoromethylbenzaldehyde as initiation material, m-TrifluoromethylcinnaAcid Acid first is condensed to yield with malonic acid,
Activated ester intermediate is condensed to yield with carbonyl dimidazoles again, is most obtained through red aluminium reducing afterwards.Its synthetic route is as follows：
。
The deficiency of above two method is：（1）Synthetic route is more long, and total recovery is relatively low.（2）Reduction reaction is needed to use
Expensive red aluminum, does not only result in that production cost is higher, and the accessory substance post processing of red aluminum is more difficult.
（Three）With m-TrifluoromethylcinnaAcid Acid as initiation material, mixed anhydride first is condensed into ethyl chloroformate, then use hydroboration
Sodium reduction obtains m-trifluoromethyl cinnamyl alcohol, is finally aoxidized with manganese dioxide or TEMPO and obtained.Its synthetic route is as follows：
。
The deficiency of the method is：（1）Synthetic route is more long, and total recovery is relatively low, and production cost is higher.（2）Using boron hydrogen
Change sodium reduction to be difficult to control to.（3）More harmful solid waste can be produced using manganese dioxide.
（Four）With m-Trifluoromethylbenzaldehyde as initiation material, with acetaldehyde in the mixed solvent that aqueous slkali and ethanol are formed
Condensation reaction is carried out to obtain【Referring to Chinese patent literature CN104592037A】.Wherein, aqueous slkali be sodium hydrate aqueous solution or
Person's potassium hydroxide aqueous solution, its mass fraction is 1~3%；Aqueous slkali is 5~10: 1 with the volume ratio of ethanol；M-trifluoromethyl benzene
Formaldehyde is 1: 3.5~4.5 with the mol ratio of acetaldehyde；Setting-up point is 25~30 DEG C, and the reaction time is 5~10h.
The deficiency of the method is：Found using m-trifluoromethyl cinnamic acid obtained in the method through applicant's many experiments
Purity is relatively low, less than 90%.
The content of the invention
It is an object of the invention to solve the above problems, there is provided a kind of purity and yield m-trifluoromethyl Chinese cassia tree higher
The preparation method of aldehyde.
Realizing the technical scheme of above-mentioned purpose of the present invention is：A kind of preparation method of m-trifluoromethyl cinnamic acid, it be by
M-Trifluoromethylbenzaldehyde is obtained in the presence of base catalyst with acetaldehyde through a step aldol reaction.
Applicant is had found by numerous studies：The inorganic weak bases that the condensation reaction is commonly used using aldol condensation, such as sodium carbonate,
Potassium carbonate etc., reactionless phenomenon occurs；And the inorganic strong alkali commonly used using aldol condensation, such as NaOH, potassium hydroxide, hydrogen-oxygen
Change barium etc., the product of generation is more miscellaneous and is difficult to separate, and causes purity very low, less than 90%；And use conventional organic base, such as pyrrole
Pyridine, DMAP（DMAP）, 1,4- diazabicylos [2.2.2] octane（DABCO）Occur Deng same reactionless phenomenon.
Therefore, applicant finally found that by numerous studies：The condensation reaction is in the carbon -7- alkene of 1,8- diazabicylos 11
（DBU）, triethylamine or diisopropyl ethyl amine these three organic bases can obtain product of the purity more than 98%.
However, slower using triethylamine and diisopropyl ethyl amine reaction speed, the time is more long, and yield is relatively
It is low, therefore, base catalyst is preferably DBU.
Above-mentioned DBU is 1: 10~3: 5, preferably 1: 5 with the mol ratio of m-Trifluoromethylbenzaldehyde.
Above-mentioned acetaldehyde is 1: 1~5: 1, preferably 2.5: 1 with the mol ratio of m-Trifluoromethylbenzaldehyde.
Above-mentioned condensation reaction is carried out in presence of organic solvent；The organic solvent is methyl alcohol, methyl tertbutyl
Ether or tetrahydrofuran.
However, it is equally relatively low using methyl alcohol and methyl tertiary butyl ether(MTBE) yield, therefore, organic solvent is preferably tetrahydrochysene furan
Mutter.
The good effect that the present invention has：Method of the present invention synthetic route is short, and reaction condition is gentle, simple to operate, especially
It is, by selecting suitable base catalyst, can to obtain product of the purity more than 98% with preferable yield, so as to be adapted to
Large-scale industrial production, with larger application value.
Specific embodiment
（Embodiment 1）
The preparation method of the m-trifluoromethyl cinnamic acid of the present embodiment is as follows：
The m-Trifluoromethylbenzaldehyde of 17.41g is added in four-hole boiling flask（0.1mol）, 68.0mL tetrahydrofuran and
The DBU of 3.04g（0.02mol）, the 11.01g acetaldehyde of the lower fresh distillation of addition of stirring（0.25mol）, at room temperature（20~25 DEG C）
Stirring 48h, sampling is controlled in HPLC, is disappeared to raw material, terminates reaction.
Temperature of charge vacuum distillation less than 30 DEG C is kept, excessive acetaldehyde and solvent is removed, then adds that 1mol/L's is dilute
It is 3~5 that hydrochloric acid is neutralized to pH, is extracted with dichloromethane, and organic phase is concentrated under reduced pressure to remove solvent, and rectification under vacuum obtains colorless oil
Thing 15.0g, yield is 75.0%, and purity is 98.5%（HPLC）.
（2~embodiment of embodiment 7）
The preparation method of each embodiment is substantially the same manner as Example 1, and difference is shown in Table 1.
Table 1
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 | |
| M-Trifluoromethylbenzaldehyde | 17.41g | 17.41g | 17.41g | 17.41g | 17.41g | 17.41g | 17.41g |
| Acetaldehyde | 11.01g | 11.01g | 11.01g | 11.01g | 11.01g | 11.01g | 11.01g |
| DBU | 3.04g | / | / | 3.04g | 3.04g | 1.52g | 9.12g |
| Triethylamine | / | 2.02g | / | / | / | / | / |
| Diisopropyl ethyl amine | / | / | 2.58g | / | / | / | / |
| Tetrahydrofuran | 68.0mL | 68.0mL | 68.0mL | / | / | 68.0mL | 68.0mL |
| Methyl alcohol | / | / | / | 68.0mL | / | / | / |
| Methyl tertiary butyl ether(MTBE) | / | / | / | / | 68.0mL | / | / |
| Weight | 15.0g | 11.4g | 12.4g | 10.8g | 13.6g | 14.0g | 14.8g |
| Purity | 98.5% | 98.1% | 98.2% | 98.0% | 98.3% | 98.4% | 98.6% |
| Yield | 75.0% | 57.0% | 62.0% | 54.0% | 68.0% | 70.0% | 74.0% |
（Comparative example 1 and comparative example 2）
Method according to Chinese patent literature CN104592037A embodiments 1 and embodiment 2 prepares m-trifluoromethyl cinnamic acid, knot
Fruit yield is respectively 70.3% and 69.7%, purity（HPLC）Respectively 87.2% and 85.9%.
（3~comparative example of comparative example 8）
The preparation method of each comparative example is substantially the same manner as Example 1, and difference is shown in Table 2.
Table 2
| Embodiment 1 | Comparative example 3 | Comparative example 4 | Comparative example 5 | Comparative example 6 | Comparative example 7 | Comparative example 8 | |
| M-Trifluoromethylbenzaldehyde | 17.41g | 17.41g | 17.41g | 17.41g | 17.41g | 17.41g | 17.41g |
| Acetaldehyde | 11.01g | 11.01g | 11.01g | 11.01g | 11.01g | 11.01g | 11.01g |
| DBU | 3.04g | 3.04g | / | / | / | / | / |
| NaOH | / | / | 0.8g | 0.8g | / | / | / |
| Potassium hydroxide | / | / | / | / | 1.12g | / | / |
| Potassium carbonate | / | / | / | / | / | 2.76g | / |
| DMAP | / | / | / | / | / | / | 2.44g |
| Tetrahydrofuran | 68.0mL | / | / | 68.0mL | 68.0mL | 68.0mL | 68.0mL |
| Ethanol | / | 68.0mL | 68.0mL | / | / | / | / |
| Products weight | 15.0g | 14.1g | 14.4g | 11.7g | 12.0g | Nothing | Nothing |
| Purity | 98.5% | 94.4% | 88.2% | 87.0% | 84.3% | / | / |
| Yield | 75.0% | 70.5% | 72.0% | 58.5% | 60.0% | / | / |
Claims (8)
1. a kind of preparation method of m-trifluoromethyl cinnamic acid, it is in base catalyst by m-Trifluoromethylbenzaldehyde and acetaldehyde
In the presence of through a step aldol reaction be obtained；It is characterized in that：The base catalyst is 1,8- diazabicylos 11
Carbon -7- alkene, triethylamine or diisopropyl ethyl amine.
2. the preparation method of m-trifluoromethyl cinnamic acid according to claim 1, it is characterised in that：The base catalyst
It is the carbon -7- alkene of 1,8- diazabicylos 11.
3. the preparation method of m-trifluoromethyl cinnamic acid according to claim 1 and 2, it is characterised in that：The 1,8- bis-
Carbon -7- the alkene of azabicyclic 11 is 1: 10~3: 5 with the mol ratio of the m-Trifluoromethylbenzaldehyde.
4. the preparation method of m-trifluoromethyl cinnamic acid according to claim 3, it is characterised in that：The 1,8- diazas
Carbon -7- the alkene of two ring 11 is 1: 5 with the mol ratio of the m-Trifluoromethylbenzaldehyde.
5. the preparation method of m-trifluoromethyl cinnamic acid according to claim 1 and 2, it is characterised in that：The acetaldehyde with
The mol ratio of the m-Trifluoromethylbenzaldehyde is 1: 1~5: 1.
6. the preparation method of m-trifluoromethyl cinnamic acid according to claim 5, it is characterised in that：The acetaldehyde with it is described
The mol ratio of m-Trifluoromethylbenzaldehyde is 2.5: 1.
7. the preparation method of m-trifluoromethyl cinnamic acid according to claim 1 and 2, it is characterised in that：The condensation is
Carry out in presence of organic solvent；The organic solvent is methyl alcohol, methyl tertiary butyl ether(MTBE) or tetrahydrofuran.
8. the preparation method of m-trifluoromethyl cinnamic acid according to claim 7, it is characterised in that：The organic solvent is
Tetrahydrofuran.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112830879A (en) * | 2019-11-22 | 2021-05-25 | 北京泰德制药股份有限公司 | Preparation method of cinacalcet hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102718638A (en) * | 2012-05-09 | 2012-10-10 | 湖北远成药业有限公司 | Industrial preparation method of high-yield cinnamaldehyde |
| CN104592037A (en) * | 2015-01-08 | 2015-05-06 | 浙江大学 | Synthesis method of cinacalcet |
| CN105646215A (en) * | 2008-04-09 | 2016-06-08 | 杜邦公司 | Method for preparing 3-trifluoromethyl chalcones |
-
2016
- 2016-11-28 CN CN201611065709.5A patent/CN106748695B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646215A (en) * | 2008-04-09 | 2016-06-08 | 杜邦公司 | Method for preparing 3-trifluoromethyl chalcones |
| CN102718638A (en) * | 2012-05-09 | 2012-10-10 | 湖北远成药业有限公司 | Industrial preparation method of high-yield cinnamaldehyde |
| CN104592037A (en) * | 2015-01-08 | 2015-05-06 | 浙江大学 | Synthesis method of cinacalcet |
Non-Patent Citations (3)
| Title |
|---|
| IULIANA COTA等: "The DBU-H2O complex as a new catalyst for aldol condensation reactions", 《CATALYSIS COMMUNICATIONS》 * |
| TAO SHEN等: "Production of liquid hydrocarbon fuels with 3-pentanone and platform molecules derived from lignocellulose", 《RSC ADV.》 * |
| YUJIRO HAYASHI等: "One-Pot Synthesis of (S)-Baclofen via Aldol Condensation of Acetaldehyde with Diphenylprolinol Silyl Ether Mediated Asymmetric Michael Reaction as a Key Step", 《ORG. LETT.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112830879A (en) * | 2019-11-22 | 2021-05-25 | 北京泰德制药股份有限公司 | Preparation method of cinacalcet hydrochloride |
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