CN106748695B - Preparation method of m-trifluoromethyl cinnamaldehyde - Google Patents
Preparation method of m-trifluoromethyl cinnamaldehyde Download PDFInfo
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- CN106748695B CN106748695B CN201611065709.5A CN201611065709A CN106748695B CN 106748695 B CN106748695 B CN 106748695B CN 201611065709 A CN201611065709 A CN 201611065709A CN 106748695 B CN106748695 B CN 106748695B
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- 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 preparation method of m-trifluoromethyl cinnamaldehyde, which is prepared by one-step aldol condensation reaction of m-trifluoromethyl benzaldehyde and acetaldehyde in the presence of an alkaline catalyst; wherein the basic catalyst is DBU, triethylamine or diisopropylethylamine, and the molar ratio of DBU to m-trifluoromethylbenzaldehyde is 1: 10-3: 5; the molar ratio of acetaldehyde to m-trifluoromethylbenzaldehyde is 1: 1-5: 1; the condensation reaction is carried out in the presence of methanol, methyl tert-butyl ether or tetrahydrofuran. The method has the advantages of short synthetic route, mild reaction conditions and simple operation, and particularly, a product with the purity of more than 98 percent can be obtained with better yield by selecting a proper alkaline catalyst, so that the method is suitable for large-scale industrial production and has higher application value.
Description
Technical Field
The invention belongs to the technical field of fine chemicals, and particularly relates to a preparation method of m-trifluoromethyl cinnamaldehyde.
Background
The m-trifluoromethyl cinnamaldehyde is an important intermediate for synthesizing cinacalcet hydrochloride.
The preparation method of m-trifluoromethyl cinnamaldehyde disclosed by the prior art mainly comprises the following steps:
the method comprises the following steps of (I) condensing m-trifluoromethyl benzaldehyde serving as a starting raw material with acetic anhydride to obtain m-trifluoromethyl cinnamic acid, condensing with piperidine to obtain an amide intermediate, and finally reducing with red aluminum to obtain the intermediate. The synthetic route is as follows:
and (II) m-trifluoromethyl benzaldehyde is used as a starting material, is condensed with malonic acid to obtain m-trifluoromethyl cinnamic acid, is condensed with carbonyl diimidazole to obtain an active ester intermediate, and is finally reduced by red aluminum to obtain the intermediate. The synthetic route is as follows:
the two methods have the following defects: (1) the synthesis route is longer, and the total yield is lower. (2) The reduction reaction needs the use of expensive red aluminum, which not only results in higher production cost, but also makes the post-treatment of the by-product of the red aluminum difficult.
And (III) taking m-trifluoromethyl cinnamic acid as a starting material, condensing with ethyl chloroformate to obtain mixed anhydride, reducing with sodium borohydride to obtain m-trifluoromethyl phenyl propenyl alcohol, and oxidizing with manganese dioxide or TEMPO to obtain the m-trifluoromethyl phenyl propenyl alcohol. The synthetic route is as follows:
the method has the following disadvantages: (1) the synthesis route is longer, the total yield is lower, and the production cost is higher. (2) Reduction with sodium borohydride is difficult to control. (3) Oxidation with manganese dioxide produces more hazardous solid waste.
(IV) m-trifluoromethyl benzaldehyde is used as a starting material, and is subjected to condensation reaction with acetaldehyde in a mixed solvent formed by an alkali solution and ethanol [ see Chinese patent document CN104592037A ]. Wherein the aqueous alkali is a sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution, and the mass fraction of the aqueous alkali is 1-3%; the volume ratio of the alkali solution to the ethanol is 5-10: 1; the mol ratio of the m-trifluoromethyl benzaldehyde to the acetaldehyde is 1: 3.5-4.5; the condensation reaction temperature is 25-30 ℃, and the reaction time is 5-10 h.
The method has the following disadvantages: through a plurality of experiments of the applicant, the purity of the m-trifluoromethyl cinnamaldehyde prepared by the method is lower than 90%.
Disclosure of Invention
The invention aims to solve the problems and provides a preparation method of m-trifluoromethyl cinnamaldehyde with high purity and yield.
The technical scheme for realizing the above purpose of the invention is as follows: a process for preparing meta-trifluoromethyl cinnamaldehyde by one-step aldol condensation reaction between meta-trifluoromethyl benzaldehyde and acetaldehyde in the presence of basic catalyst.
The applicant has found through a large number of studies that: the condensation reaction uses inorganic weak base commonly used in aldol condensation, such as sodium carbonate, potassium carbonate and the like, and no reaction phenomenon occurs; inorganic strong base commonly used for aldol condensation, such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, is used, and the generated product is relatively impurity and difficult to separate, so that the purity is very low and is less than 90%; the same applies to the use of conventional organic bases, such as pyridine, 4-Dimethylaminopyridine (DMAP), 1, 4-diazabicyclo [2.2.2] octane (DABCO), etc.
For this reason, the applicant finally found through a large amount of studies: the condensation reaction can obtain a product with the purity of more than 98 percent by using three organic bases, namely 1, 8-diazabicycloundecen-7-ene (DBU), triethylamine or diisopropylethylamine.
However, the reaction using triethylamine and diisopropylethylamine is slow, long, and relatively low in yield, and thus the basic catalyst is preferably DBU.
The molar ratio of DBU to m-trifluoromethylbenzaldehyde is 1: 10-3: 5, preferably 1: 5.
The molar ratio of the acetaldehyde to the m-trifluoromethylbenzaldehyde is 1: 1-5: 1, and preferably 2.5: 1.
The above condensation reaction is carried out in the presence of an organic solvent; the organic solvent is methanol, methyl tert-butyl ether or tetrahydrofuran.
However, the yield is also relatively low with methanol and methyl tert-butyl ether, and therefore the organic solvent is preferably tetrahydrofuran.
The invention has the following positive effects: the method has the advantages of short synthetic route, mild reaction conditions and simple operation, and particularly, a product with the purity of more than 98 percent can be obtained with better yield by selecting a proper alkaline catalyst, so that the method is suitable for large-scale industrial production and has higher application value.
Detailed Description
(example 1)
The preparation method of m-trifluoromethyl cinnamaldehyde in this example is as follows:
17.41g of m-trifluoromethylbenzaldehyde (0.1 mol), 68.0mL of tetrahydrofuran and 3.04g of DBU (0.02 mol) were put into a four-necked flask, and 11.01g of freshly distilled acetaldehyde (0.25 mol) was added thereto with stirring, and the mixture was stirred at room temperature (20 to 25 ℃) for 48 hours, followed by sampling and HPLC control until the starting material disappeared, thereby terminating the reaction.
And (3) carrying out reduced pressure distillation at the material temperature below 30 ℃ to remove excessive acetaldehyde and solvent, then adding 1mol/L diluted hydrochloric acid to neutralize until the pH value is 3-5, extracting with dichloromethane, carrying out reduced pressure concentration on the organic phase to remove the solvent, and carrying out reduced pressure rectification to obtain 15.0g of colorless oily matter, wherein the yield is 75.0%, and the purity is 98.5% (HPLC).
(examples 2 to 7)
The preparation method of each example is basically the same as that of example 1 except for the differences shown in Table 1.
TABLE 1
| Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 | Example 7 | |
| Meta-trifluoromethyl benzaldehyde | 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 | / | / | / | / | / |
| Diisopropylethylamine | / | / | 2.58g | / | / | / | / |
| Tetrahydrofuran (THF) | 68.0mL | 68.0mL | 68.0mL | / | / | 68.0mL | 68.0mL |
| Methanol | / | / | / | 68.0mL | / | / | / |
| Methyl tert-butyl ether | / | / | / | / | 68.0mL | / | / |
| Weight (D) | 15.0g | 11.4g | 12.4g | 10.8g | 13.6g | 14.0g | 14.8g |
| Purity of | 98.5% | 98.1% | 98.2% | 98.0% | 98.3% | 98.4% | 98.6% |
| Yield of | 75.0% | 57.0% | 62.0% | 54.0% | 68.0% | 70.0% | 74.0% |
(comparative example 1 and comparative example 2)
The m-trifluoromethyl cinnamaldehyde was prepared according to the methods of chinese patent document CN104592037A example 1 and example 2, resulting in yields of 70.3% and 69.7%, respectively, and purity (HPLC) of 87.2% and 85.9%, respectively.
(comparative examples 3 to 8)
The comparative examples were prepared substantially the same as in example 1, except that the differences are shown in Table 2.
TABLE 2
| Example 1 | Comparative example 3 | Comparative example 4 | Comparative example 5 | Comparative example 6 | Comparative example 7 | Comparative example 8 | |
| Meta-trifluoromethyl benzaldehyde | 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 | / | / | / | / | / |
| Sodium hydroxide | / | / | 0.8g | 0.8g | / | / | / |
| Potassium hydroxide | / | / | / | / | 1.12g | / | / |
| Potassium carbonate | / | / | / | / | / | 2.76g | / |
| DMAP | / | / | / | / | / | / | 2.44g |
| Tetrahydrofuran (THF) | 68.0mL | / | / | 68.0mL | 68.0mL | 68.0mL | 68.0mL |
| Ethanol | / | 68.0mL | 68.0mL | / | / | / | / |
| Product weight | 15.0g | 14.1g | 14.4g | 11.7g | 12.0g | Is free of | Is free of |
| Purity of | 98.5% | 94.4% | 88.2% | 87.0% | 84.3% | / | / |
| Yield of | 75.0% | 70.5% | 72.0% | 58.5% | 60.0% | / | / |
Claims (3)
1. A preparation method of m-trifluoromethyl cinnamaldehyde is provided, which is prepared by one-step aldol condensation reaction of m-trifluoromethyl benzaldehyde and acetaldehyde in the presence of an alkaline catalyst; the method is characterized in that: the basic catalyst is 1, 8-diazabicycloundecen-7-ene; the condensation is carried out in the presence of an organic solvent; the organic solvent is tetrahydrofuran; the molar ratio of the acetaldehyde to the m-trifluoromethylbenzaldehyde is 2.5: 1; the aldol condensation reaction temperature is 20-25 ℃; the aldol condensation reaction time is 48 hours;
and after the reaction is finished, keeping the temperature of the material below 30 ℃, distilling under reduced pressure to remove excessive acetaldehyde and solvent, adding 1mol/L diluted hydrochloric acid to neutralize until the pH value is 3-5, extracting with dichloromethane, concentrating the organic phase under reduced pressure to remove the solvent, and rectifying under reduced pressure.
2. The method for preparing m-trifluoromethyl cinnamaldehyde according to claim 1, wherein: the molar ratio of the 1, 8-diazabicycloundecen-7-ene to the m-trifluoromethylbenzaldehyde is 1: 10-3: 5.
3. The method for preparing m-trifluoromethyl cinnamaldehyde according to claim 2, wherein: the molar ratio of the 1, 8-diazabicycloundecen-7-ene to the m-trifluoromethylbenzaldehyde is 1: 5.
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