CN112094182A - Green synthesis method of medical intermediate benzocyclohexanone compound - Google Patents
Green synthesis method of medical intermediate benzocyclohexanone compound Download PDFInfo
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Abstract
The invention provides a green synthesis method of a benzocyclohexanone compound, belonging to the technical field of organic synthesis. The method provided by the invention comprises the steps of taking a 4-phenylbutyric acid compound as a raw material, carrying out reflux reaction with oxalyl chloride in dichloromethane, evaporating to dryness in vacuum to obtain a crude 4-phenylbutyryl chloride compound, dissolving the crude product in a solvent, adding a metal-doped modified molecular sieve catalyst to start reaction, stirring at different temperatures to carry out ring closing reaction, and carrying out suction filtration, solvent washing, column chromatography purification and other operations after the reaction is finished to obtain a target product, namely a benzocyclohexanone compound. The synthesis method disclosed by the invention is environment-friendly in reaction, simple and convenient to operate, and suitable for green synthesis of the benzocyclohexanone compound, and the catalyst can be recycled.
Description
Technical Field
The invention relates to a synthetic method of a medical intermediate, namely a benzocyclohexanone compound, and belongs to the technical field of organic synthesis.
Background
The benzo cyclohexanone structure is an important medical intermediate, can be used for the synthesis of various chemical drugs, and has very important functions in drug design and functional group modification. Therefore, the development of the synthesis method of the benzocyclohexanone compounds is increasingly emphasized by the industry, wherein the method for obtaining the benzocyclohexanone compound by heating, dehydrating and cyclizing the 4-phenylbutyric acid compound in the presence of strong acidic reagents such as polyphosphoric acid, phosphorus pentoxide, and eaton reagent is a common method, but the method needs to use a large excess of strong acid, even uses the strong acid for solvation reaction, and not only can harm the personal health of operators and corrode equipment in the high-temperature reaction and post-treatment processes, but also can easily cause serious environmental pollution due to a large amount of strong acid wastewater generated in post-treatment. The other improved method is that 4-phenylbutyric acid compound is first converted into corresponding acyl chloride, and then Friedel-crafts acylation reaction is carried out under the catalysis of Lewis acid such as aluminum trichloride, stannic chloride and the like to obtain the benzocyclohexanone compound through cyclization.
The invention provides a green synthesis method of a benzocyclonone compound, which is characterized in that a 4-phenylbutyric acid compound is taken as a raw material, the 4-phenylbutyryl chloride compound and oxalyl chloride are firstly prepared, then heterogeneous catalytic hydrolysis is carried out on a metal-doped modified molecular sieve, the benzocyclonone compound is obtained, and the metal-doped modified molecular sieve is recovered. The method realizes green synthesis of the benzo cyclohexanone compounds, has the advantages of environmental friendliness, simplicity and convenience in operation and high product yield, and has a good application prospect.
Disclosure of Invention
In order to solve the technical problems, the invention provides a green synthesis method of a benzocyclohexanone compound, which overcomes the defects of serious pollution, equipment corrosion, complex operation and the like in the traditional synthesis method, and adopts the following technical scheme:
the invention provides a green synthesis method of a benzocyclohexanone compound shown as a formula (III), which comprises the following steps: refluxing and reacting the 4-phenylbutyric acid compound shown in the formula (I) in the step (1) with oxalyl chloride in dichloromethane for 2 hours to generate a crude 4-phenylbutyryl chloride compound shown in the formula (II), and performing ring closure on the crude product in the step (2) in a solvent by catalysis of a metal-doped modified molecular sieve catalyst to obtain a benzocyclohexanone compound shown in the formula (III).
The invention provides a synthesis method of a benzocyclohexanone compound shown in a formula (III), which comprises the following steps: refluxing and reacting the 4-phenylbutyric acid compound shown in the formula (I) with oxalyl chloride in dichloromethane for 2 hours, after the reaction is finished, evaporating to dryness in vacuum to obtain a crude 4-phenylbutyryl chloride compound shown in the formula (II), dissolving the crude product in a solvent, adding a metal-doped modified molecular sieve catalyst to start the reaction, stirring at 0-110 ℃ for 10-24 hours, after the reaction is finished, returning to room temperature, performing suction filtration, washing with the solvent and recovering the molecular sieve catalyst, combining filtrates, evaporating to dryness in vacuum, and purifying the residue through silica gel column chromatography to obtain the benzocyclohexanone compound shown in the formula (III).
Wherein R is1And R2Each independently selected from H, halogen, C1-C20Alkyl radical, C1-C20Alkoxy radical, C3-C20Cycloalkyl radical, C5-C20Aryl or substituted C5-C20Aryl, or R1And R2Together with the carbon atoms to which they are bonded, form a ring structure.
In the synthesis method of the present invention, further, R1And R2Each independently selected from H, C1-C6Alkyl radical, C1-C6Alkoxy radical, C5-C6Aryl or substituted C5-C6Aryl, or R1And R2Together with the carbon atoms to which they are bonded, form a ring structure.
In the synthesis method of the present invention, further, R1And R2Each independently selected from H, methyl, methoxy, ethyl, ethoxy, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or n-hexyl, phenyl, 4-methylphenyl or 3-chlorophenyl.
In the synthesis method of the present invention, the substituted substituent is selected from halogen, C1-C20Alkyl radical, C1-C20Alkoxy or C5-C20And (4) an aryl group. Or further, the substituted substituent is selected from halogen, C1-C6Alkyl radical, C1-C6Alkoxy or C5-C6And (4) an aryl group.
In the synthesis method of the present invention, the C1-C6Alkyl or alkoxy means a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as, but not limited to, methyl, methoxy, ethyl, ethoxy, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl, and the like.
In the synthesis method of the present invention, the aryl group or substituted aryl group means an aryl group or substituted aryl group having 5 to 6 carbon atoms, and may be, for example, a phenyl group, a 4-methylphenyl group, a 3-chlorophenyl group, or the like, without limitation.
In the synthesis method of the present invention, the halogen refers to F, Cl, Br, I, and the like.
In the synthesis method of the invention, the solvent is any one or a mixture of several of dichloromethane, 1, 2-dichloroethane, carbon tetrachloride, benzene, toluene and xylene, and most preferably toluene. The amount of the organic solvent is not strictly limited, and can be appropriately selected and determined by those skilled in the art according to actual conditions, for example, the amount is determined to facilitate the reaction and the post-treatment, and will not be described in detail herein.
In the synthesis method, the catalyst is a metal-doped modified molecular sieve selected from any one of an Al-MCM-41 molecular sieve, a Fe-Al-MCM-41 molecular sieve, a Mg-Al-MCM-41 molecular sieve or a Cu-Al-MCM-41 molecular sieve. Among them, the most preferable is Fe-Al-MCM-41 molecular sieve, the load of iron on the molecular sieve is 2%, and the silica-alumina ratio is 50. In the synthesis method, the addition amount of the metal-doped modified molecular sieve is 0.05-0.06 g per 1mmol of 4-phenylbutyric acid compound.
The metal-doped modified molecular sieve is prepared from sodium silicate, aluminum sulfate, hexadecyl trimethyl ammonium bromide, metal salt and deionized water through a hydrothermal synthesis method, drying and roasting, wherein the metal salt is a halide of iron, magnesium or copper, the doping load weight of the iron, magnesium or copper in the Al-MCM-41 molecular sieve is 2%, and the silica-alumina ratio of the Al-MCM-41 molecular sieve is 50.
In the synthesis process of the present invention, the reaction temperature for catalytic ring closure is 0 to 110 ℃, for example 50 to 60 ℃.
In the synthesis method of the present invention, the reaction time for catalytic ring closure is 10 to 24 hours, for example 15 to 20 hours.
In the synthesis method, the catalyst is recovered, and the circulation sleeve is used for the next reaction.
In the synthesis method, a 4-phenylbutyric acid compound shown in the formula (I) and oxalyl chloride react in dichloromethane under reflux for 2 hours, the reaction is completed and then vacuum-evaporated to dryness to obtain a crude 4-phenylbutyryl chloride compound shown in the formula (II), the crude 4-phenylbutyryl chloride compound is dissolved in a solvent, a metal-doped modified molecular sieve catalyst is added to start the reaction, the reaction is stirred at the temperature of 0-110 ℃ for 10-24 hours, the reaction is recovered to room temperature after the reaction is completed, the reaction is filtered, the solvent is used for washing and recovering the molecular sieve catalyst, the filtrate is combined and vacuum-evaporated to dryness, and the residue is purified by silica gel column chromatography to obtain the benzocyclohexanone compound shown in.
The invention has the following beneficial effects:
the invention provides a method for synthesizing a benzocyclohexanone compound, which successfully realizes the green heterogeneous synthesis of the benzocyclohexanone compound by replacing a strongly acidic dehydrating agent, aluminum trichloride and other Lewis acids with serious pollution through the catalytic action of a metal-doped modified molecular sieve catalyst, is environment-friendly in reaction, high in product yield and simple and convenient to operate, and meanwhile, the molecular sieve catalyst can be recycled for multiple times, so that the method has good practical application prospect and large-scale production potential.
Detailed Description
The present invention is further illustrated by the following examples, but the use and purpose of these exemplary embodiments are only to exemplify the present invention, and do not constitute any limitation to the actual scope of the present invention in any form, and do not limit the scope of the present invention.
The materials, reagents, apparatus and methods used in the following examples, unless otherwise specified, are all conventional in the art and are commercially available or prepared by conventional methods to those skilled in the art.
Example 1
Adding 10mmol of the compound shown in the formula (I) and 20mL of dichloromethane into a reactor in sequence, dropwise adding 20mmol of oxalyl chloride into the reactor under ice bath, heating up and refluxing for 2 hours after dropwise adding, evaporating to dryness in vacuum after the reaction is finished to obtain a crude product of the 4-phenylbutyryl chloride compound shown in the formula (II), dissolving the crude product in 20mL of toluene, adding a Fe-Al-MCM-41 molecular sieve to start the reaction, stirring for 18 hours at 60 ℃, recovering to room temperature after the reaction is finished, performing suction filtration, washing with toluene and recovering a molecular sieve catalyst, combining filtrates, evaporating to dryness in vacuum, and purifying the residue by silica gel column chromatography to obtain the benzocyclohexanone compound shown in the formula (III), wherein the yield is 95.2%.1H NMR(CDCl3,400MHz):8.05-8.00(m,1H),7.52-7.43(m,1H),7.35-7.19(m,2H),2.97(t,2H,J＝6.4Hz),2.66(t,2H,J＝6.4Hz),2.19-2.09(m,2H)。
Example 2
Into a reactorAdding 10mmol of the compound shown in the formula (I) and 20mL of dichloromethane in sequence, dropwise adding 20mmol of oxalyl chloride into a reactor under ice bath, heating up and refluxing for 2 hours after dropwise adding, evaporating to dryness in vacuum after the reaction is finished to obtain a crude product of the 4-phenylbutyryl chloride compound shown in the formula (II), dissolving the crude product in 20mL of toluene, adding a Fe-Al-MCM-41 molecular sieve to start the reaction, stirring for 18 hours at 60 ℃, recovering to room temperature after the reaction is finished, performing suction filtration, washing with toluene and recovering a molecular sieve catalyst, combining filtrates, evaporating to dryness in vacuum, and purifying the residue by silica gel column chromatography to obtain the benzocyclohexanone compound shown in the formula (III), wherein the yield is 92.7%.1H NMR(CDCl3,400MHz):7.87(s,1H),7.34(d,1H,J＝8.0Hz),7.17(d,1H,J＝8.0Hz),2.91(t,2H,J＝6.0Hz),2.73-2.60(m,4H),2.19-2.06(m,2H),1.24(t,3H,J＝7.6Hz)。
Example 3
Adding 10mmol of the compound shown in the formula (I) and 20mL of dichloromethane into a reactor in sequence, dropwise adding 20mmol of oxalyl chloride into the reactor under ice bath, heating up and refluxing for 2 hours after dropwise adding, evaporating to dryness in vacuum after the reaction is finished to obtain a crude product of the 4-phenylbutyryl chloride compound shown in the formula (II), dissolving the crude product in 20mL of toluene, adding a Fe-Al-MCM-41 molecular sieve to start the reaction, stirring for 18 hours at 60 ℃, recovering to room temperature after the reaction is finished, performing suction filtration, washing with toluene and recovering a molecular sieve catalyst, combining filtrates, evaporating to dryness in vacuum, and purifying the residue by silica gel column chromatography to obtain the benzocyclohexanone compound shown in the formula (III), wherein the yield is 98.8%.1H NMR(CDCl3,400MHz):7.71(s,1H),7.15(s,1H),2.82(t,2H,J＝6.0Hz),2.61(t,2H,J＝6.4Hz),2.33(s,3H),2.28(s,3H),2.16-2.04(m,2H)。
Example 4
10mmol of the compound of the formula (I) and 20mL of dichloromethane are sequentially added into a reactor,dropwise adding 20mmol of oxalyl chloride into a reactor under ice bath, heating up and carrying out reflux reaction for 2 hours after the oxalyl chloride is completely dripped, carrying out vacuum evaporation to obtain a 4-phenylbutyryl chloride compound crude product of the formula (II) after the reaction is completed, dissolving the crude product in 20mL of toluene, adding a Fe-Al-MCM-41 molecular sieve to start the reaction, stirring for 18 hours at 60 ℃, recovering to room temperature after the reaction is completed, carrying out suction filtration, washing with toluene and recovering a molecular sieve catalyst, combining filtrates, carrying out vacuum evaporation to dryness, and purifying the residue through silica gel column chromatography to obtain the benzocyclohexanone compound of the formula (III), wherein the yield is 85.7%.1H NMR(CDCl3,400MHz):7.88(s,1H),7.34(d,1H,J＝8.0Hz),7.18(d,1H,J＝8.0Hz),2.93(t,2H,J＝6.0Hz),2.66(t,2H,J＝6.4Hz),2.55-2.43(m,1H),2.19-2.05(m,2H),1.94-1.65(m,5H),1.50-1.18(m,5H)。
Example 5
Adding 10mmol of the compound shown in the formula (I) and 20mL of dichloromethane into a reactor in sequence, dropwise adding 20mmol of oxalyl chloride into the reactor under ice bath, heating up and refluxing for 2 hours after dropwise adding, evaporating to dryness in vacuum after the reaction is finished to obtain a crude product of the 4-phenylbutyryl chloride compound shown in the formula (II), dissolving the crude product in 20mL of toluene, adding a Fe-Al-MCM-41 molecular sieve to start the reaction, stirring for 18 hours at 60 ℃, recovering to room temperature after the reaction is finished, performing suction filtration, washing with toluene and recovering a molecular sieve catalyst, combining filtrates, evaporating to dryness in vacuum, and purifying the residue by silica gel column chromatography to obtain the benzocyclohexanone compound shown in the formula (III), wherein the yield is 98.4%.1H NMR(CDCl3,400MHz):7.50(s,1H),7.12(d,1H,J＝8.4Hz),7.05(d,1H,J＝8.4Hz),3.75(s,3H),2.91(t,2H,J＝6.4Hz),2.66(t,2H,J＝6.4Hz),2.20-2.08(m,2H)。
Example 6
10mmol of the above compound of formula (I) and 20mL of dichloromethane were sequentially added to the reactor under ice bathDropping 20mmol of oxalyl chloride into a reactor, heating and refluxing for 2 hours after the oxalyl chloride is dropped, evaporating to dryness in vacuum after the reaction is completed to obtain a 4-phenylbutyryl chloride compound crude product of the formula (II), dissolving the crude product in 20mL of toluene, adding a Fe-Al-MCM-41 molecular sieve to start the reaction, stirring at 60 ℃ for 18 hours, recovering to room temperature after the reaction is completed, performing suction filtration, washing with toluene and recovering a molecular sieve catalyst, combining filtrates, evaporating to dryness in vacuum, and purifying the residue by silica gel column chromatography to obtain the benzocyclohexanone compound of the formula (III), wherein the yield is 84.0%.1H NMR(CDCl3,400MHz):8.11(s,1H),7.55(d,1H,J＝8.4Hz),7.10(d,1H,J＝8.4Hz),2.90(t,2H,J＝6.0Hz),2.64(t,2H,J＝6.4Hz),2.20-2.05(m,2H)。
Example 7
Adding 10mmol of the compound shown in the formula (I) and 20mL of dichloromethane into a reactor in sequence, dropwise adding 20mmol of oxalyl chloride into the reactor under ice bath, heating up and refluxing for 2 hours after dropwise adding, evaporating to dryness in vacuum after the reaction is finished to obtain a crude product of the 4-phenylbutyryl chloride compound shown in the formula (II), dissolving the crude product in 20mL of toluene, adding a Fe-Al-MCM-41 molecular sieve to start the reaction, stirring for 18 hours at 60 ℃, recovering to room temperature after the reaction is finished, performing suction filtration, washing with toluene and recovering a molecular sieve catalyst, combining filtrates, evaporating to dryness in vacuum, and purifying the residue by silica gel column chromatography to obtain the benzocyclohexanone compound shown in the formula (III), wherein the yield is 90.5%.1H NMR(CDCl3,400MHz):8.09(s,1H),7.59-7.06(m,6H),2.96(t,2H,J＝6.4Hz),2.69(t,2H,J＝6.4Hz),2.25-2.08(m,2H)。
Examples 8 to 10
The catalyst Fe-Al-MCM-41 molecular sieves in example 1 were replaced with Al-MCM-41, Mg-Al-MCM-41, and Cu-Al-MCM-41 molecular sieves, respectively, and the other operations were the same, thereby obtaining examples 8 to 10.
The results are shown in Table 1 below.
TABLE 1
| Numbering | Catalyst and process for preparing same | Product yield (%) |
| Example 8 | Al-MCM-41 molecular sieve | 86.1 |
| Example 9 | Mg-Al-MCM-41 molecular sieve | 92.5 |
| Example 10 | Cu-Al-MCM-41 molecular sieve | 94.6 |
The above results show that when Fe-Al-MCM-41 molecular sieve is used as catalyst, the reaction can obtain the highest yield of the benzocyclohexanone product (see example 1), other catalysts such as Mg-Al-MCM-41 and Cu-Al-MCM-41 molecular sieve can also obtain higher product yield, and the yield of the Al-MCM-41 molecular sieve is slightly lower, which indicates that metal elements such as iron and copper can have a certain synergistic effect on the cyclization reaction.
Examples 11 to 13
The catalyst Fe-Al-MCM-41 molecular sieve recovered by suction filtration in example 1 is washed by dichloromethane and diethyl ether in sequence, and is circularly used for the next reaction after being dried in vacuum at 70 ℃ for 12 hours, and other operations are the same as those in example 1, so that examples 11-13 are obtained.
The results are shown in Table 2 below.
TABLE 2
| Numbering | Number of times of application | Product yield (%) |
| Example 11 | 1 | 94.7 |
| Example 12 | 2 | 94.4 |
| Example 13 | 3 | 92.5 |
The results show that the Fe-Al-MCM-41 molecular sieve still can keep higher catalytic activity under the condition of recycling for 3 times.
In conclusion, the invention provides a green synthesis method of a benzocyclohexanone compound, which realizes green, simple and efficient synthesis of the benzocyclohexanone compound, and the catalyst can be recycled and reused, so that the method has a good practical application prospect.
It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes, modifications and/or alterations to the present invention may be made by those skilled in the art after reading the technical disclosure of the present invention, and all such equivalents may fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A green synthesis process of a benzocyclohexanone compound represented by formula (III), the process comprising: refluxing and reacting the 4-phenylbutyric acid compound shown in the formula (I) and oxalyl chloride in dichloromethane for 2 hours to generate a crude 4-phenylbutyryl chloride compound shown in the formula (II), and performing ring closure on the crude product in the step (2) in a solvent by catalysis of a metal-doped modified molecular sieve catalyst to obtain a benzocyclohexanone compound shown in the formula (III),
wherein R is1And R2Each independently selected from H, halogen, C1-C20Alkyl radical, C1-C20Alkoxy radical, C3-C20Cycloalkyl radical, C5-C20Aryl or substituted C5-C30Aryl, or R1And R2Together with the carbon atoms to which they are bonded, form a ring structure.
2. The method of synthesis of claim 1, wherein: r1And R2Each independently selected from H, C1-C6Alkyl radical, C1-C6Alkoxy radical, C5-C6Aryl or substituted C5-C6Aryl, or R1And R2Together with the carbon atoms to which they are bonded, form a ring structure.
3. The method of synthesis of claim 1, wherein: r1And R2Each independently selected from H, methyl, methoxy, ethyl, ethoxy, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or n-hexyl, phenyl, 4-methylphenyl or 3-chlorophenyl.
4. The method of synthesis of claim 1, wherein: the solvent is selected from any one or a mixture of more of dichloromethane, 1, 2-dichloroethane, carbon tetrachloride, benzene, toluene and xylene, and toluene is most preferable.
5. The method of synthesis of claim 1, wherein: the metal-doped modified molecular sieve catalyst is any one of an Al-MCM-41 molecular sieve, a Fe-Al-MCM-41 molecular sieve, a Mg-Al-MCM-41 molecular sieve or a Cu-Al-MCM-41 molecular sieve.
6. The method of synthesis of claim 1, wherein: the metal-doped modified molecular sieve is prepared from sodium silicate, aluminum sulfate, hexadecyl trimethyl ammonium bromide, metal salt and deionized water through a hydrothermal synthesis method, drying and roasting, wherein the metal salt is a halide of iron, magnesium or copper, the doping load weight of the iron, magnesium or copper in the Al-MCM-41 molecular sieve is 2%, and the silica-alumina ratio of the Al-MCM-41 molecular sieve is 50.
7. The method of synthesis of claim 1, wherein: the addition amount of the metal-doped modified molecular sieve is 0.05g-0.06g of the metal-doped modified molecular sieve added in each 1mmol of 4-phenylbutyric acid compound.
8. The method of synthesis of claim 1, wherein: the reaction temperature of the step (2) is 0-110 ℃.
9. The method of synthesis of claim 1, wherein: the reaction time of the step (2) is 10 to 24 hours.
10. The method of synthesis according to any one of claims 1 to 8, wherein: refluxing and reacting the 4-phenylbutyric acid compound shown in the formula (I) with oxalyl chloride in dichloromethane for 2 hours, after the reaction is finished, evaporating to dryness in vacuum to obtain a crude 4-phenylbutyryl chloride compound shown in the formula (II), dissolving the crude product in a solvent, adding a metal-doped modified molecular sieve catalyst to start the reaction, stirring at 0-110 ℃ for 10-24 hours, after the reaction is finished, returning to room temperature, performing suction filtration, washing with the solvent and recovering the molecular sieve catalyst, combining filtrates, evaporating to dryness in vacuum, and purifying the residue through silica gel column chromatography to obtain the benzocyclohexanone compound shown in the formula (III).
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