CN112250634B - Preparation method of 4-phenylimidazole - Google Patents
Preparation method of 4-phenylimidazole Download PDFInfo
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
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Abstract
The invention discloses a preparation method of 4-phenylimidazole, which comprises the following steps: reacting the compound 1A and the compound 1B with a nitrogen-containing compound to obtain an intermediate; and reacting the intermediate with a reducing agent to obtain a 4-phenylimidazole crude product, and purifying to obtain a 4-phenylimidazole refined product. According to the invention, a reagent with a low price is used as an initial raw material, a final product is obtained through two-step reaction, the reaction condition of each step is mild, the yield of the obtained 4-phenylimidazole is high, and the cost can be greatly reduced.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 4-phenylimidazole.
Background
4-phenylimidazole with CAS number of 670-95-1 and molecular structural formula of
Is an epoxy curing imidazole accelerator and an organic synthesis intermediate. 4-phenylimidazole is used as a basic raw material of medicines with central nervous system and metabolic disorder, is widely applied in the medical industry, but is relatively expensive, and at present, the literature reports on the synthesis of 4-phenylimidazole are few.
In patent CN103450089B, α -bromoacetophenone and formamidine acetate are subjected to substitution reaction in ethylene glycol, and then subjected to cyclization reaction with acid-binding agent potassium carbonate, and then post-treatment to obtain 4-phenylimidazole, but the yield is low.
Therefore, the method for preparing the 4-phenylimidazole has great significance for seeking a new method for preparing the 4-phenylimidazole, optimizing the preparation process, reducing the production cost and improving the yield.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides the preparation method of the 4-phenylimidazole, which uses a reagent with lower price as an initial raw material, has mild reaction conditions, and can obtain the 4-phenylimidazole with high yield and greatly reduce the cost; the crude product of 4-phenylimidazole obtained by the preparation method is purified to obtain a refined product of 4-phenylimidazole.
The invention is realized by adopting the following technical scheme:
a preparation method of 4-phenylimidazole comprises the following preparation steps:
preparation step S1: reacting the compound 1A and the compound 1B with a nitrogen-containing compound to obtain an intermediate;
compound 1A is a compound of the general structure shown in formula i:
in the formula I, Z is one of hydrogen atom, hydroxyl, SH, OR, SR, OM, SM and halogen;
chemical combinationThe compound 1B is a carbonyl reagent,
Triphosgene, N' -carbonyldiimidazole, (NH) 4 ) 2 CO 3 、NH 4 HCO 3 One or more combinations of (a); x 1 、X 2 Are respectively halogen, hydroxyl and NH 2 SH, OR, SR, OM, SM;
wherein R in OR and SR is one of saturated OR unsaturated, straight-chain OR branched-chain, heteroatom-containing OR heteroatom-free C1-C30 hydrocarbon groups; m in OM and SM is metal element cation, inorganic ammonium salt cation, organic ammonium salt cation, phosphorus salt cation,
One of a salt positive ion and an onium salt positive ion;
preparation step S2: and reacting the intermediate with a reducing agent to obtain the 4-phenylimidazole.
The reaction equation of the preparation step S1 is shown by the following formula (1):
the reaction equation of the preparation step S2 is shown in the following formula (2):
further, the intermediate is at least one structure of intermediate 2A, intermediate 2B, intermediate 2C and intermediate 2D;
wherein, the intermediate 2A is a compound with a general structure shown in a formula II:
intermediate 2B is a compound of the general structure shown in formula iii:
the intermediate 2C is a compound with a general structure shown in a formula IV:
intermediate 2D is a compound of the general structure shown in formula v:
further, the nitrogen-containing compound is one or a combination of a plurality of cyanide, ammonia gas, ammonia water and ammonium salt. Preferably, the nitrogen-containing compound is sodium cyanide, potassium cyanide, hydrocyanic acid, ammonia gas, ammonia water, (NH) 4 ) 2 CO 3 、NH 4 HCO 3 One or a combination of several of them;
further, the reducing agent is one or more of hydrogen, lithium aluminum hydride, iron, zinc, magnesium, sulfite, ferrous salt, stannous salt, potassium borohydride, sodium borohydride, hydrazine, sulfur dioxide and hydrogen sulfide.
Further, the molar ratio of the compound 1A to the compound 1B is 1: 0.1-10; the molar ratio of the compound 1A to the nitrogen-containing compound is 1: 0.1-10; the molar ratio of the intermediate to the reducing agent is 1: 0.1-10.
Further, the reaction conditions in the preparation step S1 are: the reaction temperature is-50 ℃ to 200 ℃, the reaction pressure is-0.05 MPa to 1MPa, and the reaction time is 0.1h to 72 h; the reaction conditions in the preparation step S2 were: the reaction temperature is-50 ℃ to 200 ℃, the reaction pressure is-0.05 MPa to 1MPa, and the reaction time is 0.1h to 72 h.
Further, an auxiliary agent is added in the preparation step S1, wherein the auxiliary agent is POCl 3 、PCl 5 、P 2 S 5 、P 2 O 5 One or a combination of several of them.
Further, a catalyst is added in the preparation step S2, the catalyst is one or a combination of a simple substance, an oxide and a hydroxide containing platinum, palladium, ruthenium, rhodium and nickel, or the catalyst is loaded by activated carbon or Al 2 O 3 One or more of simple substances, oxides and hydroxides of loaded platinum, palladium, ruthenium, rhodium and nickel.
Further, the reaction of the preparation step S1 is carried out in a first reaction solvent; the first reaction solvent is one or a combination of more of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, 1, 2-dichloroethane, dioxane, N-dimethylformamide, dimethyl sulfoxide and water;
the reaction of preparation step S2 is carried out in a second reaction solvent; the second reaction solvent is one or a combination of more of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, 1, 2-dichloroethane, dioxane, N-dimethylformamide, dimethyl sulfoxide and water.
Preferably, the preparation method of the 4-phenylimidazole further comprises the following preparation steps:
under the drying condition, dissolving the crude 4-phenylimidazole obtained by the preparation method in a purification solvent, recrystallizing at low temperature, filtering to remove insoluble substances, and then performing rotary evaporation and drying on the filtrate to obtain refined 4-phenylimidazole; wherein the purifying solvent is one or more of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide, dimethyl sulfoxide and water.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, a reagent with a low price is used as an initial raw material, a final product is obtained through two-step reaction, the reaction condition of each step is mild, the yield of the obtained 4-phenylimidazole is high, and the cost can be greatly reduced.
The whole preparation method is simple and easy to control, is favorable for enlarging production, shortens the reaction production period, can obtain the 4-phenylimidazole with higher purity through conventional recrystallization purification, and can effectively improve the yield of the product.
Detailed Description
The invention will now be further described with reference to specific embodiments, which are intended to illustrate the invention in more detail by way of some non-limiting examples. It should be noted that these examples should not be construed as limiting the scope of the invention, which can be implemented in any manner described in the summary of the invention. The pressure values mentioned in the patent of the invention are gauge pressures unless otherwise specified. The yield in the invention refers to the percentage ratio of the actual product quality to the theoretical product quality; wherein, the theoretical product quality is calculated by the raw materials which are not excessive in the reaction equation. The purification yield in the examples of the present invention refers to the number of moles of the purified 4-phenylimidazole divided by the number of moles of the crude 4-phenylimidazole before purification.
The following are specific examples of the present invention, and raw materials, equipment, and the like used in the following examples can be obtained by purchasing, unless otherwise specified.
Example 1
The preparation method of the 4-phenylimidazole comprises the following preparation steps:
106g of benzaldehyde (compound 1A) and 1B (NH) were sequentially added to a stainless steel reaction vessel 4 ) 2 CO 3 The molar ratio of the compound 1A to the compound 1B to the nitrogen-containing compound is 1:1.1:1.1, the mixture is uniformly stirred and reacts for 24 hours at the temperature of 100 ℃ and the pressure of 0.5MPa to obtain an intermediate;
introducing a reducing reagent sodium borohydride into the intermediate, reacting for 48 hours at the temperature of 60 ℃ and the pressure of 0MPa, wherein the molar ratio of the intermediate to the reducing reagent is 1:3, so as to obtain crude 4-phenylimidazole, and the total yield is about 78.6%;
under the drying condition, 100g of crude 4-phenylimidazole is dissolved in 400ml of ethanol, low-temperature recrystallization is carried out, filtration is carried out again to remove insoluble substances, then the filtrate is added into a rotary evaporator, rotary evaporation is carried out for 1h at about 100 ℃, and then drying is carried out for 2h in a blast oven at 100 ℃ to obtain refined 4-phenylimidazole, wherein the purification yield is about 85.4%.
Example 2
The preparation method of the 4-phenylimidazole comprises the following preparation steps:
sequentially adding 122g of a mixture of a compound 1A benzoic acid, a compound 1B triphosgene, a nitrogen-containing compound hydrocyanic acid and ammonia water into a stainless steel reaction kettle, wherein the molar ratio of the compound 1A to the compound 1B to the nitrogen-containing compound is 1:1.3:1.3, uniformly stirring, and reacting for 24 hours at the temperature of 80 ℃ and the pressure of 0.3MPa to obtain an intermediate;
introducing a reducing reagent hydrogen into the intermediate, reacting for 48 hours at the temperature of 60 ℃ and the pressure of 0.6MPa, wherein the molar ratio of the intermediate to the reducing reagent is 1:8, and the total yield of the crude product 4-phenylimidazole is about 80.5%;
under the drying condition, 100g of crude 4-phenylimidazole is dissolved in 400ml of ethanol, low-temperature recrystallization is carried out, filtration is carried out again to remove insoluble substances, then the filtrate is added into a rotary evaporator and rotary evaporation is carried out for 1h at about 100 ℃, and then drying is carried out for 2h in a blast oven at 100 ℃ to obtain refined 4-phenylimidazole, wherein the purification yield is about 86.2%.
Example 3
The preparation method of the 4-phenylimidazole comprises the following preparation steps:
138g of a compound 1A benzaldehyde and a compound 1B NH are sequentially added into a stainless steel reaction kettle 4 HCO 3 The molar ratio of the compound 1A to the compound 1B to the nitrogen-containing compound is 1:1.1:1.1, the mixture is uniformly stirred at the temperature of 120 ℃ and the pressure ofReacting for 24 hours under the condition of 0.3MPa to obtain an intermediate;
introducing a reducing reagent potassium borohydride into the intermediate, wherein the molar ratio of the intermediate to the reducing reagent is 1:3, and reacting for 48 hours at 50 ℃ and 0.1MPa to obtain crude 4-phenylimidazole, wherein the total yield is about 76.3%;
under the drying condition, 100g of crude 4-phenylimidazole is dissolved in 400ml of ethanol, low-temperature recrystallization is carried out, filtration is carried out again to remove insoluble substances, then the filtrate is added into a rotary evaporator and rotary evaporation is carried out for 1h at about 100 ℃, and then drying is carried out for 2h in a blast oven at 100 ℃ to obtain refined 4-phenylimidazole, wherein the purification yield is about 82.1%.
Example 4
The preparation method of the 4-phenylimidazole comprises the following preparation steps:
139g of compound 1A methyl benzoate and compound 1B (NH) were sequentially added to a stainless steel reaction vessel 4 ) 2 CO 3 The molar ratio of the compound 1A to the compound 1B to the nitrogen-containing compound is 1:1.5:1.5, the mixture is uniformly stirred and reacts for 24 hours at the temperature of 120 ℃ and the pressure of 0.8MPa to obtain an intermediate;
introducing a reducing reagent hydrogen into the intermediate, wherein the molar ratio of the intermediate to the reducing reagent is 1:6, reacting for 48 hours at the temperature of 550 ℃ and under the pressure of 0.6MPa to obtain crude 4-phenylimidazole, and the total yield is about 78.9%;
under the drying condition, 100g of crude 4-phenylimidazole is dissolved in 400ml of ethanol, low-temperature recrystallization is carried out, filtration is carried out again to remove insoluble substances, then the filtrate is added into a rotary evaporator and rotary evaporation is carried out for 1h at about 100 ℃, and then drying is carried out for 2h in a blast oven at 100 ℃ to obtain refined 4-phenylimidazole, wherein the purification yield is about 81.4%.
Example 5
The preparation method of the 4-phenylimidazole comprises the following preparation steps:
2000ml of ethanol, 139g of compound 1A ammonium benzoate and compound 1B formyl are sequentially added into a stainless steel reaction kettleAmine, ammonium cyanide, a nitrogenous compound, 10g PCl 5 The molar ratio of the compound 1A to the compound 1B to the nitrogen-containing compound is 1:1.2:1.2, the mixture is uniformly stirred and reacts for 24 hours at the temperature of 120 ℃ and the pressure of 0.8MPa to obtain an intermediate;
uniformly mixing the intermediate with 5g of platinum catalyst loaded by active carbon and 1000ml of ethanol, introducing a reduction reagent hydrogen, reacting for 48 hours at the temperature of 120 ℃ and the pressure of 0.7MPa, wherein the molar ratio of the intermediate to the reduction reagent is 1:7, and the total yield of the 4-phenylimidazole is about 80.1%;
under the drying condition, 100g of crude 4-phenylimidazole is dissolved in 400ml of ethanol, low-temperature recrystallization is carried out, filtration is carried out again to remove insoluble substances, then the filtrate is added into a rotary evaporator and rotary evaporation is carried out for 1h at about 100 ℃, and then drying is carried out for 2h in a blast oven at 100 ℃ to obtain refined 4-phenylimidazole, wherein the purification yield is about 84.5%.
The above embodiments are only a part of the preferred embodiments of the present invention, and the embodiments are described only for illustrating the principle of the present invention, and thus the scope of the present invention is not limited by the embodiments. As will be apparent to those skilled in the art, numerous changes, modifications and variations can be made in the present invention without departing from the spirit, principles and scope of the invention, the invention resides in the claims hereinafter appended, and the invention includes all such changes, modifications and variations.
Claims (7)
1. The preparation method of 4-phenylimidazole is characterized by comprising the following preparation steps:
preparation step S1: reacting the compound 1A and the compound 1B with a nitrogen-containing compound to obtain an intermediate;
compound 1A is a compound of the general structure shown in formula i:
in the formula I, Z is one of hydrogen atom, hydroxyl, OR and OM;
the compound 1B is
Triphosgene, (NH) 4 ) 2 CO 3 、NH 4 HCO 3 One of (a) and (b); x 1 Is NH 2 ；
Wherein R in OR is methyl; m in OM is one of inorganic ammonium salt positive ions and organic ammonium salt positive ions;
the nitrogen-containing compound is one or a combination of more of cyanide, ammonia gas, ammonia water and ammonium salt;
preparation step S2: reacting the intermediate with a reducing agent to obtain 4-phenylimidazole; the reducing agent is one or a combination of hydrogen, lithium aluminum hydride, potassium borohydride and sodium borohydride.
2. The process for preparing 4-phenylimidazole according to claim 1, wherein the molar ratio of compound 1A to compound 1B is 1: 0.1-10; the molar ratio of the compound 1A to the nitrogen-containing compound is 1: 0.1-10; the molar ratio of the intermediate to the reducing agent is 1: 0.1-10.
3. The process for producing 4-phenylimidazole according to claim 1, wherein the reaction conditions in the production step S1 are: the reaction temperature is-50 ℃ to 200 ℃, the reaction pressure is-0.05 MPa to 1MPa, and the reaction time is 0.1h to 72 h; the reaction conditions in the preparation step S2 were: the reaction temperature is-50 ℃ to 200 ℃, the reaction pressure is-0.05 MPa to 1MPa, and the reaction time is 0.1h to 72 h.
4. The method according to claim 1, wherein an auxiliary agent is further added in step S1, wherein the auxiliary agent is POCl 3 、PCl 5 One or a combination of both.
5. The method according to claim 1, wherein a catalyst is further added in step S2, and the catalyst is platinum supported on activated carbon.
6. The process for producing 4-phenylimidazole according to claim 1, wherein the reaction of production step S1 is carried out in a first reaction solvent; the first reaction solvent is one or the combination of two of methanol and ethanol;
the reaction of preparation step S2 is carried out in a second reaction solvent; the second reaction solvent is one or two of methanol and ethanol.
7. The process for the preparation of 4-phenylimidazole according to any one of claims 1 to 6, further comprising the steps of:
under the drying condition, dissolving the crude 4-phenylimidazole obtained in the preparation step S2 in a purification solvent, recrystallizing at low temperature, filtering to remove insoluble substances, and then performing rotary evaporation and drying on the filtrate to obtain refined 4-phenylimidazole; wherein, the purifying solvent is one or the combination of two of methanol and ethanol.
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