CN112812029A - Preparation method of benzene crotonate compound - Google Patents
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- CN112812029A CN112812029A CN202110091981.5A CN202110091981A CN112812029A CN 112812029 A CN112812029 A CN 112812029A CN 202110091981 A CN202110091981 A CN 202110091981A CN 112812029 A CN112812029 A CN 112812029A
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The application relates to the technical field of organic synthesis, in particular to a preparation method of a benzene crotonic acid ester compound, which comprises the following steps: s1, carrying out a Willgenod-Kindler reaction on a p-acetophenone substance-compound II under the catalysis of alkali to obtain a thiophenylacetic acid amide substance-compound III; s2, coupling the compound III with an ester of bromo-acid (compound IV) to generate a compound V through Eschenmoser coupling under the catalysis of alkali; s3, removing the protecting group on the amino group of the compound V under the action of an amino compound and alkali to finally obtain the benzene crotonate compound. According to the technical scheme, the acetophenone compound is used as the raw material in the synthesis process, the reaction conditions are mild, the raw material is cheap and easy to obtain, the economic effect of an enterprise is improved, and the method is suitable for large-scale production.
Description
Technical Field
The application relates to the technical field of organic synthesis, in particular to a preparation method of a benzene crotonic acid ester compound.
Background
The benzene crotonic acid ester compound is a compound with a phenyl butenoic acid ester structure, and has wide application in the fields of medicines, pesticides, electronic materials and the like.
At present, the benzene crotonic acid ester compound is prepared by condensation reaction of a benzene acetic acid compound and an acetate compound, wherein the benzene acetic acid compound is high in price, and the preparation process and the purification process are difficult, so that the price is high, and the benzene acetic acid compound belongs to a compound easy to prepare toxin, is limited in purchase and use, and is not beneficial to large-scale production of enterprises.
Disclosure of Invention
In order to avoid the use of phenylacetic acid, reduce the production cost of enterprises and provide a new idea for the synthesis of the benzene crotonate compounds, the application provides a preparation method of the benzene crotonate compounds.
The preparation method of the benzene crotonic acid ester compound adopts the following technical scheme:
the preparation method of the benzene crotonate compound comprises the following steps:
s1, carrying out a Willgenodt-Kindler reaction on a p-acetophenone substance-compound II under the catalysis of alkali to obtain a thioacetic acid amide substance-compound III, wherein the reaction formula is shown as a formula I;
wherein the compound VI is primary amine or secondary amine, and the compound VI is added into the reaction system in the form of amine or ammonium salt;
s2, coupling the compound III with an ester of bromo-acid (compound IV) to generate a compound V by Eschenmoser coupling under the catalysis of alkali, wherein the reaction formula is shown as formula II;
s3, removing R from the compound V61And R62In the formula II, a group which is not hydrogen is used to obtain a compound I, namely, the compound I is a benzene crotonate compound, and the reaction formula is shown as a formula III:
wherein R is1、R2、R3、R4、R5Each independently selected from fluorine, chlorine, bromine, trifluoromethyl or hydrogen, and not simultaneously hydrogen; when R is1、R2、R3、R4And when one or more of R is fluorine, the remainder are not all H. R61And R62Is hydrogen or saturated alkyl.
In the technical scheme, the phenylcrotonate compound is prepared by taking the acetophenone compound as a raw material through three steps, and the use of the phenylacetic acid compound is discharged in the process, so that the method is a novel synthetic method of the phenylcrotonate compound and has a good application prospect.
In step S2, Eschenmoser coupling is performed via bromate, during which process the amino group on compound III is subjected to R in step S161And R62The protection of (2) is not easy to generate side reaction, and is helpful for improving the purity, and in the process, the reaction can be completed only by adding a certain amount of alkali, compared with the common ester exchange reaction, the whole reaction is easier to generate, and the reaction selectivity is better.
In the above reactions, the reaction with different substituents on the benzene ring has a good reaction effect, so the method has a wide application range and a good synthesis effect on various different crotonic ester compounds.
Alternatively, in step S1, compound VI is selected from one of dimethylamine hydrochloride and diethylamine hydrochloride, and step S1 is performed in N, N-dimethylformamide.
In the experiment, the hydrochloride of the secondary amine is selected, so that the dispersibility of the hydrochloride is good, and side reactions are not easy to occur in subsequent reactions, so that the amino can be protected well, and the probability of ester exchange reaction on the amino is reduced. When the amino compound exists in the form of ammonium salt, the rearrangement reaction is facilitated, and the purity of the final product is better. In the reaction process, raw materials are easy to obtain, the overall cost is low, and the N, N-dimethylformamide is used as a solvent, so that the toxicity and the pollution are low, and the pressure on the environment is low.
Optionally, in step S1, the alkali is sodium acetate, and the ratio of the amount of the compound I, the sulfur, the compound VI and the sodium acetate is 1 (1.5-5) to 1.5 (1.5-3).
Sodium acetate is selected as alkali instead of other strong alkali, so that the catalytic reaction can be realized, and the thioamide generated in the reaction can be inhibited from being hydrolyzed, so that the subsequent reaction can be more smoothly realized. In addition, the weak alkali can ensure that the halogen substituent on the benzene ring in the compound II is not easy to generate nucleophilic substitution reaction and is not easy to be substituted by nitrogen atoms or other substances with larger electron cloud density in the reaction process of the compound VI, thereby further reducing the loss of raw materials. Meanwhile, sodium acetate has better solubility in organic solvent, which is beneficial to the smooth reaction.
Alternatively, in step S1, compound VI is morpholine, and step S1 is performed directly in morpholine.
In the process, morpholine is a solvent, is a substance participating in the reaction and is a base used for catalytic reaction, and morpholine is well dispersed in compound II, so that morpholine is used as the solvent to directly participate in the reaction, the conversion rate of compound II can be further improved, the waste of raw materials is reduced, and the operation is more convenient.
Optionally, in step S1, the reaction temperature is higher than 50 ℃, and does not exceed the reflux temperature of the reaction system, and the reaction time is 3-18 h.
Among the above reaction conditions, a higher temperature contributes to the occurrence of the rearrangement reaction, and also can improve the efficiency of the reaction. The reaction time is within 3-18 h, and the reaction can be fully carried out.
Optionally, in step S2, compound IV is selected from any one of the following compounds (IVa, IVb, IVc, IVd, IVe):
in step S2, the ratio of the amounts of compound III and compound IV is 1 (2-4).
The coupling of the compounds IVa to IVe has higher coupling efficiency, and after the coupling reaction is finished, impurities can be easily separated from the system, so that the reaction step has higher yield and better purity.
Optionally, in step S2, the alkali is any one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine and DBU, or a combination of any number of the above materials, and the amount ratio of the compound III to the added alkali is 1 (3-5).
In the process, weaker inorganic base and organic base are selected to participate in the reaction, which is beneficial to further reducing hydrolysis of thioamide groups and ester groups generated subsequently in the reaction process, and reducing deprotection phenomenon caused by hydrolysis of protected amino groups in the reaction process, thereby further improving the purity and yield of the final product.
Optionally, in step S3, the amino deprotection reaction is performed in an amino compound and an alcohol solvent, where the amino compound is any one or a combination of any several of liquid ammonia, ammonium acetate, and ammonia water, and the alcohol compound is selected from one of methanol and ethanol, or a compound system of methanol and ethanol in any ratio.
In the technical scheme, the amino compound and the dissolved compound system are selected, so that the protective group on the nitrogen atom in the compound V can be thoroughly and efficiently removed in the reaction process. The reaction conditions are mild, and after the reaction is finished, the residual substances except the target product are liquid and can be directly removed by reduced pressure distillation, so that the separation of the substances is convenient.
Optionally, in step S3, liquid ammonia is used as the amino compound.
In the reaction, liquid ammonia is selected as a system, the reaction condition is mild, and the efficiency and the yield of amino deprotection are further improved.
Optionally, in step S3, deamination is performed with an organic amine, where the organic amine is triethylamine, and a solvent system of the reaction is chloroform or acetonitrile.
Organic amine is selected to participate in the reaction, and an aprotic solvent is adopted to participate in the reaction, so that the occurrence of side reactions in the reaction process is further reduced, the overall conditions are also mild, and the purity of the finally obtained product is high.
In summary, the present application includes at least one of the following advantages:
1. in the application, acetophenone compounds are selected as raw materials, Willgeodt-Kindler reaction, Eschenmoser coupling and amino deprotection are carried out in sequence to finally prepare the benzene crotonate compounds, the use of phenylacetic acid which is an easily toxic compound is discharged in the reaction process, the overall reaction cost is low, the yield is high, and the method has a good industrial application prospect.
2. In the present application, a weak base is used in both step S1 and step S2, and functions to protect the amino group and to suppress hydrolysis of the system and reduce the occurrence of side reactions.
Detailed Description
The present application will be described in further detail with reference to examples.
Example 1, a method for preparing a benzocrotonate compound, wherein 2, 4-dichloroacetophenone is selected as the compound II, and the specific reaction steps are as follows.
S1, Willgenodt-Kindler reaction: 189.0g (1mol) of compound IIs, 48.1g (1.5mol) of elemental sulfur and 261.4g (namely compound VI and 3mol) of morpholine are weighed, mixed uniformly, heated to 120 ℃, kept to reflux for 6 hours, the point of the raw material of the 2, 4-dichloroacetophenone disappears in the TLC point plate detection reaction, then the reaction system is added into an ice-water mixture, filtered, a filter cake is washed by water, and the disease is recrystallized in absolute ethyl alcohol to obtain 252.5g of sulfo-2, 4-dichlorophenylacetamide (compound III), wherein the yield is 87%, and the purity is 99.2%.
The reaction formula of step S1 is as follows:
s2, Eschenmoser coupling reaction, weighing 252.5g (0.87mol) of compound IIIIII, weighing 1.74mol of ethyl bromoacetate (compound IV, 290.6g), weighing 3.0mol of sodium carbonate (322.8g) as a base, dissolving in 10000mL of dichloromethane, stirring at 25 +/-5 ℃ for 8h, and detecting disappearance of the raw material point of compound III in the reaction by TLC point plate. The reaction solution was cooled to 0 ℃, filtered, and recrystallized in absolute ethanol to give compound v249.3g, with a yield of 83%, content of 98.8%.
The reaction formula of step S2 is as follows:
s3, amino deprotection: compound V49.3g was weighed, added to 300mL of a saturated ethanol solution of liquid ammonia, and after sufficient dissolution, stirred at 25 ± 5 ℃ for 20h, disappearance of the starting material spot of compound V in the reaction was detected by TLC spot plate, and then the above system was vacuum distilled to remove the solvent to give compound I as a yellow solid, 36.8g, yield 94%, content 99.1%.
The reaction formula of step S3 is as follows:
example 2, a method for producing a benzocrotonate-based compound, which is different from example 1, is as follows in step S1:
s1, Willgenodt-Kindler reaction: 189.0g (1mol) of compound III, 48.1g (1.5mol) of elemental sulfur, 122.2g (1.5mol) of dimethylamine hydrochloride and 123g (1.5mol) of sodium acetate are weighed, dissolved in 400 mLN' N-dimethylformamide and fully mixed uniformly, heated to 100 ℃ for reaction for 10 hours, the point of the 2, 4-dichloroacetophenone raw material disappears in the detection reaction through a TLC point plate, then the reaction system is added into an ice water mixture, filtered, the filter cake is washed by water and recrystallized in absolute ethyl alcohol, and 235.1g of sulfo-2, 4-dichlorophenylacetamide (compound III) is obtained, the yield is 81%, and the purity is 99.2%.
Example 3, a method for preparing a benzocrotonate-based compound, which is different from example 2, is that dimethylamine hydrochloride was replaced with diethylamine hydrochloride in an equal amount, the reaction temperature was changed to 50 ℃ and the reaction time was changed to 18 hours.
Example 4, a method for preparing a benzocrotonate-based compound, which is different from example 1, is that, in step S1, the reaction temperature is 45 ℃ and the reaction time is 25 hours.
Example 5, a method for producing a benzocrotonate-based compound, which is different from example 2, is that sodium acetate is replaced with sodium hydroxide in an equivalent amount.
Example 6, a process for producing a benzocrotonate-based compound, which is different from example 2, is that in step S1, sulfur, ethyl bromoacetate (compound IV) and sodium acetate are added in amounts of 5mol each.
Example 7A process for producing a benzocrotonate-based compound, which is different from example 2, in that, in step S1, 5mol of each of sulfur and ethyl bromoacetate (compound IV) and 3mol of sodium acetate are added.
Example 8, a process for producing a isocrotonate-based compound, which is different from example 2, in that sulfur and dimethylamine hydrochloride were added in an amount of 1.2mol each and that the reaction time was 18 hours.
Example 9, a process for producing a benzocrotonate-based compound, which is different from example 2 in that 5mol of sodium acetate was added.
Examples 10 to 13, the difference between the methods for producing a benzocrotonate-based compound and example 1 is that in step S2, the amounts of the substances such as compound IV are replaced with those shown in table 11.
Table 1 selection of Compounds IV in examples 10-13 and the structural formula of the finally prepared Compound I
Example 14, a process for producing a benzocrotonate-based compound, which is different from example 10, is that in step S2, potassium carbonate is used as a base in place of sodium carbonate in an equivalent amount.
Example 15, a method for producing a benzocrotonate-based compound, which is different from example 10, is that sodium carbonate is replaced with sodium bicarbonate in an equal amount as a base in step S2.
Example 16, a method for producing a benzocrotonate-based compound, which is different from example 10, is that potassium hydrogencarbonate in an equivalent amount is used as a base in place of sodium carbonate in step S2.
Example 17, a method for producing a benzocrotonate-based compound, which is different from example 10, is that triethylamine in an equivalent amount is used as a base in place of sodium carbonate in step S2.
Example 18, a method for producing a benzocrotonate-based compound, which is different from example 10, is that, in step S2, equal amounts of DBU are used instead of sodium carbonate as a base.
Example 19 a process for producing a benzocrotonate-based compound, which is different from example 10, in that in step S2, sodium carbonate is used in an amount of 2.61mol (three times equivalent as much as compound III).
Example 20, a process for producing a benzocrotonate-based compound, which is different from example 10, is that sodium carbonate is used in an amount of 4.35mol (five equivalent times as much as compound III) in step S2.
Example 21 a process for producing a benzocrotonate-based compound, which is different from example 10, in that, in step S2, sodium carbonate is used in an amount of 6.96mol (eight-fold equivalent to compound III).
Example 22, a process for producing a benzocrotonate-based compound, which is different from example 10, is that in step S2, sodium carbonate is used in an amount of 1.74mol (twice equivalent as compared with compound III).
Example 23, a process for producing a benzocrotonate-based compound, which is different from example 10, is that in step S2, compound IV is added in an amount of 3.48mol (four times equivalent as much as compound III).
The yields, total yields and target product contents of examples 1 to 23 in the respective steps are shown in Table 2.
Table 2, data table of yield and target product content in each step of examples 1 to 23
According to the experimental data, the compound I, namely 1- (2, 4-dichlorophenyl) -2-amino-ethyl crotonate (or methyl ester), prepared by using 2, 4-dichloroacetophenone as a substrate by the method has better yield, the final yield is closer and the purity is higher compared with a phenylacetic acid coupling mode, a complex separation mode is not adopted in the whole step process, most of materials can be removed by direct evaporation, a small part of materials can be directly removed by simple recrystallization, and the purity of the final product is high. In addition, the material source is cheaper, any easily-made toxic/easily-made explosive medicine is not used in the whole process, and the method has obvious benefits for reducing the production cost of enterprises.
Examples 10 to 14, in which the compound IV is replaced, show that when the compound IV is prepared by using diethyl 2-bromo-1, 3-malonate to participate in the transesterification reaction, the yield of step S2 is higher, and the effect is better.
Examples 24 to 37, methods for producing benzocrotonate-based compounds, which are different from example 1, are shown in table 3 for compound II and compound I finally obtained.
Table 3, structural formulas of Compound II and Compound I finally obtained in examples 24 to 37
The yields of steps S1, S2 and S3 and the content of compound I in the final product of examples 24 to 37 are shown in Table 4.
Table 4, data table of yield and target product content in each step of examples 24 to 37
| Numbering | S1 yield | S2 yield | S3 yield | Overall yield of | Content (wt.) |
| Example 24 | 88％ | 81％ | 93％ | 66.3％ | 99.0％ |
| Example 25 | 81％ | 72％ | 92％ | 53.7％ | 98.3％ |
| Example 26 | 87％ | 83％ | 94％ | 67.9％ | 98.9％ |
| Example 27 | 87％ | 82％ | 92％ | 65.6％ | 98.8％ |
| Example 28 | 89％ | 84％ | 91％ | 68.0％ | 98.7％ |
| Example 29 | 90％ | 86％ | 95％ | 73.5％ | 99.1％ |
| Example 30 | 83％ | 79％ | 87％ | 57.0％ | 98.1％ |
| Example 31 | 89％ | 82％ | 90％ | 65.7％ | 98.4％ |
| Example 32 | 90％ | 87％ | 90％ | 70.5％ | 98.5％ |
| Example 33 | 84％ | 81％ | 88％ | 59.9％ | 98.2％ |
| Example 34 | 88％ | 83％ | 91％ | 66.5％ | 98.6％ |
| Example 35 | 89％ | 84％ | 93％ | 69.5％ | 98.9％ |
| Example 36 | 91％ | 84％ | 95％ | 72.6％ | 99.1％ |
| Example 37 | 86％ | 83％ | 93％ | 66.4％ | 99.0％ |
According to the experimental data, the method provided by the application can ensure the yield of the compound with different substitutions on the benzene ring to be at least more than 50%, and has great applicability.
Example 38, a method for producing a benzocrotonate-based compound, which is different from example 37, in that step S1 is specifically as follows:
s1, Willgenodt-Kindler reaction: weighing 1mol of compound II, 48.1g (1.5mol) of elemental sulfur, 122.2g (1.5mol) of dimethylamine hydrochloride and 123g (1.5mol) of sodium acetate, dissolving in 400 mLN' N-dimethylformamide, fully mixing, heating to 100 ℃, reacting for 10h, detecting by TLC (thin layer chromatography) dot plate that the raw material of 2, 4-dichloroacetophenone disappears, adding the reaction system into an ice water mixture, filtering, washing filter cakes with water, and recrystallizing in absolute ethyl alcohol to obtain compound III.
Example 39 a method for producing a benzocrotonate-based compound, which is different from example 38 in that dimethylamine hydrochloride was replaced with an equal amount of diethylamine hydrochloride in step S1.
Examples 40 to 43, the difference between the method for producing a benzocrotonate-based compound and example 37 is that in step S2, compound IV is selected in the amounts shown in Table 5.
Table 5 selection of Compounds IV and structural formulas of the finally prepared Compounds I in examples 40 to 43
Example 44, a process for producing a benzocrotonate-based compound, which is different from example 42, is that in step S2, sodium carbonate is replaced with triethylamine as a base, and the amount of triethylamine added is 2.5 times the equivalent of compound III.
Example 45, a method for producing a benzocrotonate-based compound, which is different from example 37, is that in step S3, an equal amount of a methanol solution of saturated liquid ammonia is used instead of an ethanol solution of saturated liquid ammonia.
Example 46, a method for producing a benzocrotonate-based compound, which is different from example 37, is such that, in step S3, a mixed system of 150mL of a saturated liquid ammonia methanol solution and 150mL of a methanol solution containing 1.5 equivalents of ammonium acetate per equivalent of the compound V is used instead of the saturated liquid ammonia ethanol solution.
Example 47, a method for producing a benzocrotonate-based compound, which is different from example 37, is carried out by replacing the saturated liquid ammonia ethanol solution with 300mL of an ethanol solution containing 1.5 times the equivalent of ammonium acetate to the compound V.
Example 48A process for producing a benzocrotonate-based compound, which is different from example 37, comprises preparing a mixed solution of 150mL of an ethanol solution containing saturated liquid ammonia and 150mL of an ethanol solution containing one equivalent of triethylamine as the compound V, instead of the saturated ethanol solution containing liquid ammonia.
Example 49, a process for producing a benzocrotonate-based compound, different from example 37, in that a solution of saturated liquid ammonia in ethanol was replaced with 300mL of a solution of triethylamine in acetonitrile, in which the amount of the substance of triethylamine was 1.5 times the amount of the substance of compound V.
Example 50, a process for the preparation of a benzocrotonate-based compound, differing from example 37 in that a solution of saturated liquid ammonia in ethanol is replaced with 300mL of a solution of triethylamine in chloroform, the amount of the substance of triethylamine being 1.5 times the amount of the substance of compound V.
Example 51A method for producing a benzocrotonate-based compound, which is different from example 37, includes replacing 300mL of a 32% strength by mass concentrated aqueous ammonia solution with an ethanol solution of saturated liquid ammonia.
The yields of steps S1, S2 and S3 and the content of compound I in the final product of examples 38 to 51 are shown in Table 6.
TABLE 6 data table of yield and target product content in each step of examples 38 to 50
| Numbering | S1 yield | S2 yield | S3 yield | Overall yield of | Content (wt.) |
| Example 38 | 88％ | 81％ | 92％ | 65.6％ | 99.1％ |
| Example 39 | 82％ | 76％ | 94％ | 58.6％ | 98.9％ |
| Example 40 | 86％ | 86％ | 90％ | 66.6％ | 98.7％ |
| EXAMPLE 41 | 86％ | 82％ | 89％ | 62.8％ | 98.8％ |
| Example 42 | 86％ | 44％ | 91％ | 34.4％ | 98.2％ |
| Example 43 | 86％ | 83％ | 90％ | 64.2％ | 99.1％ |
| Example 44 | 86％ | 69％ | 89％ | 52.8％ | 98.6％ |
| Example 45 | 86％ | 83％ | 86％ | 61.4％ | 98.9％ |
| Example 46 | 86％ | 83％ | 84％ | 60.0％ | 98.4％ |
| Example 47 | 86％ | 83％ | 88％ | 62.8％ | 98.6％ |
| Example 48 | 86％ | 83％ | 92％ | 65.7％ | 99.0％ |
| Example 49 | 86％ | 83％ | 90％ | 64.2％ | 98.8％ |
| Example 50 | 86％ | 83％ | 91％ | 65.0％ | 99.7％ |
| Example 51 | 86％ | 83％ | 79％ | 56.4％ | 98.9％ |
The experimental data show that the method is also suitable for synthesizing different benzene crotonate compounds by using the trifluoro-substituted acetophenone as the raw material, and has better yield. In addition, in step S3, the selection of triethylamine as the amino compound and the selection of the aprotic solvent system help to greatly improve the purity of the finally obtained compound I, and help to improve the yield. In addition, if the selected amino compound is inorganic ammonium, the solution of liquid ammonia and methanol or ethanol has better reaction effect.
In conclusion, in the application, the acetophenone is used as the raw material to synthesize the benzene crotonate compound, so that the application range is better. Compared with the reaction in a phenylacetic acid condensation mode, the preparation method avoids the use of strong acid and strong base, most of the whole reaction process can be carried out at a state close to room temperature, the post-treatment is more convenient, and the application prospect is wide.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (10)
1. The preparation method of the benzene crotonic acid ester compound is characterized by comprising the following steps:
s1, carrying out a Willgenodt-Kindler reaction on a p-acetophenone substance-compound II under the catalysis of alkali to obtain a thioacetic acid amide substance-compound III, wherein the reaction formula is shown as a formula I;
wherein the compound VI is primary amine or secondary amine, and the compound VI is added into the reaction system in the form of amine or ammonium salt;
s2, coupling the compound III with an ester of bromo-acid (compound IV) to generate a compound V by Eschenmoser coupling under the catalysis of alkali, wherein the reaction formula is shown as formula II;
s3, removing R from the compound V61And R62In the formula II, a group which is not hydrogen is used to obtain a compound I, namely, the compound I is a benzene crotonate compound, and the reaction formula is shown as a formula III:
wherein R is1、R2、R3、R4、R5Each independently selected from fluorine, chlorine, bromine, trifluoromethyl or hydrogen, and not simultaneously hydrogen; when R is1、R2、R3、R4And when one or more of R is fluorine, the remainder are not all H, R61And R62Is hydrogen or saturated alkyl.
2. The method of producing a benzocrotonate-based compound according to claim 1, wherein in step S1, the compound VI is one selected from dimethylamine hydrochloride and diethylamine hydrochloride, and in step S1, the compound is produced in N, N-dimethylformamide.
3. The method of claim 2, wherein in step S1, the alkali is sodium acetate, and the ratio of the compound I, the compound S, the compound VI and the sodium acetate is 1 (1.5-5) to 1.5-5 (1.5-3).
4. The method of claim 1, wherein in step S1, compound VI is morpholine and step S1 is performed directly in morpholine.
5. The method for producing a benzocrotonate-based compound according to any one of claims 2 to 4, wherein in step S1, the reaction temperature is higher than 50 ℃ and does not exceed the reflux temperature of the reaction system, and the reaction time is 3 to 18 hours.
6. The method for producing a benzocrotonate compound according to claim 1, wherein in step S2, compound IV is any one of the following compounds (IVa, IVb, IVc, IVd, IVe):
in step S2, the ratio of the amounts of compound III and compound IV is 1 (2-4).
7. The method of claim 1, wherein in step S2, the base is selected from any one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, DBU, or a combination thereof, and the ratio of the amount of the compound III to the amount of the base added is 1 (3-5).
8. The method for preparing a benzocrotonate compound according to claim 1, wherein in step S3, an amino deprotection reaction is performed in an amino compound and an alcohol solvent, the amino compound is selected from any one or a combination of any several of liquid ammonia, ammonium acetate and ammonia water, and the alcohol compound is selected from one of methanol and ethanol or a compound system of methanol and ethanol in any proportion.
9. The method of producing a benzocrotonate-based compound according to claim 8, wherein in step S3, liquid ammonia is used as the amino compound.
10. The method of claim 1, wherein the step S3 comprises deaminating with an organic amine, wherein the organic amine is triethylamine, and the solvent system of the reaction is chloroform or acetonitrile.
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