CN110256387B - Preparation method of medical intermediate - Google Patents
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Abstract
The invention discloses a preparation method of a medical intermediate, belonging to the technical field of pharmaceutical chemicals. The preparation method of the medical intermediate provided by the invention takes dehydroacetic acid and aromatic amine as raw materials, takes 1, 3, 6-naphthalene trisulfonic acid as a catalyst, and carries out condensation reaction in an isopropanol aqueous solution reaction solvent to directly prepare and obtain the high-purity 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivative without further purification treatment. The invention has simple production process, and the synthesized product has high purity and high yield.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of a pharmaceutical intermediate.
Background
As one of Schiff base compounds, pyrone derivatives are widely distributed in nature, are intermediates or basic skeletons for synthesis of many natural product molecules or pharmaceutical drugs, have numerous physiological activities, and exert important effects on various physiological processes, such as analgesic activity, antifungal activity, antiviral activity, anticancer activity, properties against invasion by other organisms, diuretic activity, and the like. Based on the above properties, pyrone derivatives are important biosynthetic intermediates in biological medicine. The pyrone derivative contains 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivatives with pyrone structures, and is also an important medical intermediate applied to the aspects of pharmacology and biological activity.
The preparation of Schiff base compounds is usually carried out by a series of steps including condensation, addition, rearrangement, elimination, coupling, etc., while the base compounds in the general sense are usually products formed by the condensation of aldehydes or ketones with primary amines. With the progress of science and technology, people begin to select different reaction raw materials according to actual needs to achieve different purposes. For example, in recent years, researchers have begun to prepare 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivatives by coupling reaction of dehydroacetic acid with amines and derivatives thereof as reaction raw materials, and organic bases or acids are often required as catalysts in the preparation process.
A series of 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivatives (Preparation of antibacterial and chemical, 2009, 57: 1399-1399) are synthesized by using dehydroacetic acid (α, gamma-diacetyl acetoacetate) and aromatic amine as reaction raw materials, triethylamine as a reaction catalyst and 1, 4-dioxan as a reaction solvent by Antonio J.DeMuner et al, but the method has the problems that the reaction time of the Preparation process is long and the reaction time is 16H, the purity of the prepared product is low, further purification operation is needed, the reaction catalyst and the solvent cannot be recycled, and the method is limited in practical application.
Subsequently, Guohongjun et al still started from dehydroacetic acid with aromatic amines, but used acidic ionic liquids [ BMIM-SO3H]HSO4As catalyst, ultrasonic radiation is adopted under water bath at 40 ℃ for assistance, after the reaction is ended, the organic solvent is removed by rotary evaporation, the obtained residue is washed by ethanol, and the product is purified by silica gel column chromatography if necessary to obtain a pure product, and a series of 4-hydroxy-6-methyl- [1- (phenylimino) ethyl products are prepared by reaction]The (E) -2H-pyran-2-one derivative greatly shortens the reaction time, has high product yield, and can be repeatedly used (the catalyst is used for synthesizing the 4-hydroxy-6-methyl- [1- (phenylimino) ethyl by the catalysis of the ionic liquid under the ultrasonic radiation]-2H-pyran-2-one derivative [ J]Organic chemistry, 2012, 32: 2193 to 2197). However, the method still has the following problems: firstly, the obtained product still needs further treatment to improve the purity; secondly, substances which can be recycled are limited, only the catalyst can be recycled, the catalyst recycling process is complex, and the cost is high; at present, the preparation cost of the acidic ionic liquid containing parent structures of imidazole, pyridine and the like is relatively high, the biodegradability is poor, and in addition, as further researches on the ionic liquid are carried out, the ionic liquid also has certain toxicity。
Therefore, the development of a green, efficient, convenient and fast synthetic method of the high-purity medical intermediate 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivative has practical significance.
Disclosure of Invention
1. Problems to be solved
The invention provides a preparation method of a medical intermediate 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivative, aiming at the problems that the method for preparing the 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivative in the prior art has low yield, a reaction solvent cannot be recycled, and the prepared product needs to be purified by other technical means.
2. Technical scheme
In order to solve the problems, the technical scheme adopted by the invention is as follows:
a process for preparing the medical intermediate from dehydroacetic acid and aromatic amine includes catalytic condensation in isopropanol aqueous solution in the presence of catalyst to obtain 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivative. Only trace amount of by-products are produced in the reaction process, the 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivative with higher purity is directly formed after the reaction is finished, the further purification by silica gel column chromatography is not needed, and the yield of the product is high; the 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-ketone derivative is separated to obtain residual filtrate, the residual filtrate is not required to be treated, the residual filtrate can be directly added into the raw materials to carry out the next round of condensation reaction, and the filtrate (the isopropanol aqueous solution solvent and the catalyst) can be simply and conveniently recycled.
Preferably, the ratio of isopropanol in the aqueous isopropanol solution: the volume ratio concentration of the water is 46-55%.
Preferably, the ratio of isopropanol in the aqueous isopropanol solution: the volume ratio concentration of the water is 50-54%.
Preferably, the ratio of isopropanol in the aqueous isopropanol solution: the volume ratio concentration of the water is 41-53%.
Preferably, the ratio of isopropanol in the aqueous isopropanol solution: the volume ratio concentration of the water is 52-53%.
Further, the preparation method of the medical intermediate comprises the following specific steps: adding dehydroacetic acid, aromatic amine and a catalyst into an isopropanol aqueous solution, uniformly mixing, heating and refluxing for 50-100 min, directly cooling and standing to separate out a solid product, separating and washing the solid product, and drying in vacuum to obtain the high-purity 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivative. The purification is carried out without other means such as silica gel column chromatography or recrystallization, and the experimental steps are simplified.
In order to further remove impurities and ensure the purity of the product, the separated solid product is washed by absolute ethyl alcohol.
And separating the solid product to obtain a filtrate, wherein the obtained filtrate can be recycled. Few byproducts are generated in the reaction process, so that the filtrate almost has no residual impurities and can be directly recycled, and the influence on the next reaction caused by the impurities is avoided; in addition, the loss of the solvent and the catalyst in the reaction process is almost negligible, and the influence on the next reaction due to the change of the solvent amount and the catalyst concentration is avoided; and multiple circulation experiments prove that after the filtrate is repeatedly and continuously recycled for 5 or 6 times, the purity of the prepared 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivative is still more than 98 percent, and the yield is still more than 60 percent.
Further, the catalyst is 1, 3, 6-naphthalene trisulfonic acid. 1, 3, 6-naphthalene trisulfonic acid and isopropanol aqueous solution jointly form a reaction-catalysis solvent system for chemical synthesis of raw materials, the reaction-catalysis solvent system and the isopropanol aqueous solution generate a synergistic effect, and the isopropanol aqueous solution can change the catalysis mode of the 1, 3, 6-naphthalene trisulfonic acid (H is supplied)+Mode), by-products in the reaction process are reduced, and the 1, 3, 6-naphthalene trisulfonic acid can provide enough active catalytic groups, so that the product yield is improved.
The raw material proportion, the type of catalyst, the amount of catalyst, the reaction solvent and the like jointly form a final reaction system, and the whole body is usually dragged and moved for any chemical synthesis or production, wherein the change of any aspect can cause the purity and yield of the later-stage product to be reduced and the generation amount of byproducts in the reaction process to be increased, thereby influencing the effect, on the basis that:
preferably, the addition molar ratio of the aromatic amine to the dehydroacetic acid is (1.0-1.2): 1.
preferably, the volume of the isopropanol aqueous solution in milliliters is 7 to 10 times the amount of dehydroacetic acid in millimoles.
Preferably, the addition molar ratio of the 1, 3, 6-naphthalene trisulfonic acid to the dehydroacetic acid is (0.04-0.07): 1.
preferably, the 1, 3, 6-naphthalenetrisulfonic acid described above has the following structural formula:
the reaction formula for preparing 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivatives by catalytic dehydrogenation of acetic acid and aromatic amine using 1, 3, 6-naphthalenetrisulfonic acid is as follows:
wherein the aromatic amine is any one of 4-nitroaniline, benzylamine, 4-chloroaniline, 2-chloroaniline, 3-chloroaniline, 4-fluoroaniline, 4-methyl-3-chloroaniline, 4-methylaniline and 4-methoxyaniline.
3. Advantageous effects
Compared with the prior art, the invention has the beneficial effects that:
(1) according to the preparation method of the medical intermediate, the isopropanol aqueous solution is used as a reaction solvent, the catalysis mode of the catalyst can be changed, and the byproducts generated in the reaction process are reduced, so that on one hand, the effective generation rate of the raw materials to the product can be ensured, the product yield is high, on the other hand, the product purity can be improved, and further chromatography or recrystallization purification is not needed;
(2) according to the preparation method of the medical intermediate, the filtrate after the product is separated can be recycled, the preparation method is green and environment-friendly, the yield and the purity of the product can still be guaranteed after repeated recycling, the filtrate can be recycled without any treatment during recycling, and the recycling is simple;
(3) the preparation method of the medical intermediate provided by the invention takes 1, 3, 6-naphthalene trisulfonic acid as a catalyst to form a reaction catalysis system together with an isopropanol aqueous solution, the two generate a synergistic effect, and the isopropanol aqueous solution changes the catalysis mode of the 1, 3, 6-naphthalene trisulfonic acid (H is supplied)+Mode), by-products in the reaction process are reduced, the selectivity of the product is improved, more products can be obtained under the condition of the same raw material consumption (taking dehydroacetic acid as a metering reference), and the whole preparation method is economical, efficient, green and environment-friendly.
Drawings
FIG. 1 is a graph showing the change in the yield of the product when the catalyst system comprising 1, 3, 6-naphthalenetrisulfonic acid and an aqueous isopropanol solution is recycled in the catalytic preparation of 3- [1- (4-nitrophenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-one in example 10 of the present invention;
FIG. 2 is a graph showing the change in the product yield when the catalyst system comprising 1, 3, 6-naphthalenetrisulfonic acid and an aqueous isopropanol solution is recycled in the reaction for catalytically preparing 3- [1- (phenylmethylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-one in example 11 of the present invention;
FIG. 3 is a graph showing the change in the yield of the product when the catalyst system comprising 1, 3, 6-naphthalenetrisulfonic acid and an aqueous isopropanol solution is recycled in the reaction for catalytically preparing 3- [1- (3-chloro-4-methylphenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-one in example 12 of the present invention.
Detailed Description
The essential features and the remarkable effects of the present invention can be obtained from the following examples, which are not intended to limit the present invention in any way, and those skilled in the art who have the benefit of this disclosure will be able to make numerous insubstantial modifications and adaptations to the present invention without departing from the scope of the present invention.
The invention is further illustrated by the following specific examples in which infrared spectroscopic measurements of the reaction products are characterized by the use of an EQUINOX 55 infrared spectrometer (KBr pellet) from Bruker, Germany; the nuclear magnetic resonance instrument of AVANCE 300MHz of Germany Bruker company is adopted for the characterization of the hydrogen spectrum nuclear magnetic resonance; the melting point of the reaction product was determined by the capillary method.
Example 1
Adding 1.2mmol of 4-nitroaniline, 1.0mmol of dehydroacetic acid and 0.07mmol of 1, 3, 6-naphthalene trisulfonic acid catalyst into a 50mL single-neck flask containing 9mL of 52% isopropanol aqueous solution in volume ratio and provided with a condenser tube and a stirring magneton, magnetically stirring and uniformly mixing at room temperature, heating until reflux is generated, keeping the reflux reaction time to be 91min, detecting by TLC (thin-plate chromatography), allowing the raw material point to disappear, cooling to room temperature after the reaction is finished, precipitating a large amount of solid, standing, performing suction filtration, washing filter residues for 3 times (3mL of × 3) by using 3mL of absolute ethyl alcohol, and performing vacuum drying at 80 ℃ to obtain 3- [1- (4-nitrophenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-one, determining the purity of the filter residues to be 98.9% by high performance liquid chromatography, calculating the yield to be 72%, and directly adding the 4-nitroaniline and the dehydroacetic acid into the filtrate for reuse.
3- [1- (4-Nitrophenylimino) ethyl]-4-hydroxy-6-methyl-2H-pyran-2-one: a white solid; m.p.154-156 ℃; ir (kbr) v: 3396, 3033, 2925, 1698, 1647, 1562, 1468, 1379, 1066, 942, 835, 762cm-1；1H NMR(300MHz，CDCl3)：δ＝2.18(s，3H，CH3)，2.36(s，3H，CH3)，2.55(s，3H，CH3)，5.73(s，1H，CH)，7.02(d，J＝6.5Hz，2H，ArH)，7.21(d，J＝6.1Hz，2H，ArH)，15.64(s，1H，OH)。
Example 2
Adding 1.0mmol of benzylamine, 1.0mmol of dehydroacetic acid and 0.04mmol of 1, 3, 6-naphthalene trisulfonic acid catalyst into a 50ml single-neck flask containing 7ml of isopropanol water solution with the volume ratio concentration of 46%, carrying out magnetic stirring and uniform mixing at room temperature, heating until reflux is generated, keeping the reflux reaction time to be 54min, detecting by TLC (thin-plate chromatography), allowing the raw material point to disappear, cooling to room temperature after the reaction is finished, precipitating a large amount of solid, standing, carrying out suction filtration, washing filter residues with anhydrous ethanol (3ml × 3), and carrying out vacuum drying at 80 ℃ to obtain 3- [1- (phenylmethylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-ketone, wherein the purity is 98.6% by high performance liquid chromatography, and the calculated yield is 86%.
3- [1- (Phenylmethylimino) ethyl]-4-hydroxy-6-methyl-2H-pyran-2-one: a light yellow solid; m.p.79-81 ℃; ir (kbr) v: 3439, 3055, 2914, 1696, 1641, 1568, 1470, 1384, 1057, 993, 872, 725cm-1；1H NMR(300MHz，CDCl3)：δ＝2.14(s，3H，CH3)，2.66(s，3H，CH3)，4.65(d，J＝5.4Hz，2H，CH2)，5.69(s，1H，CH)，7.24～7.29(m，2H，ArH)，7.35(d，J＝6.6Hz，1H，ArH)，7.37(t，J＝7.5Hz，2H，ArH)，14.52(s，1H，OH)。
Example 3
Adding 1.1mmol of 4-chloroaniline, 1.0mmol of dehydroacetic acid and 0.06mmol of 1, 3, 6-naphthalene trisulfonic acid catalyst into a 50ml single-neck flask containing 8ml of isopropanol aqueous solution with the volume ratio concentration of 50%, carrying out magnetic stirring and uniform mixing at room temperature, heating until reflux is generated, keeping the reflux reaction time to be 79min, detecting by TLC (thin-plate chromatography), allowing the raw material point to disappear, cooling to room temperature after the reaction is finished, precipitating a large amount of solid, standing, carrying out suction filtration, washing filter residues with anhydrous ethanol (3ml × 3), and carrying out vacuum drying at 80 ℃ to obtain the 3- [1- (4-chlorophenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-ketone, wherein the purity is 99.1% by high performance liquid chromatography, and the yield is calculated to be 79%.
3- [1- (4-chlorophenylimino) ethyl]-4-hydroxy-6-methyl-2H-pyran-2-one: a white solid; m.p.138-140 ℃; ir (kbr) v: 3401, 3077, 2723, 1714, 1649, 1563, 1462, 1326, 1088, 947, 839, 716cm-1；1H NMR(300MHz，CDCl3)：δ＝2.11(s，3H，CH3)，2.46(s，3H，CH3)，5.75(s，1H，CH)，7.39(d，J＝8.5Hz，2H，ArH)，7.52(d，J＝8.5Hz，2H，ArH)，15.69(s，1H，OH)
Example 4
Adding 1.1mmol of 2-chloroaniline, 1.0mmol of dehydroacetic acid and 0.07mmol of 1, 3, 6-naphthalene trisulfonic acid catalyst into a 50ml single-neck flask containing 8ml of isopropanol aqueous solution with the volume ratio concentration of 50%, wherein the flask is provided with a condenser tube and a stirring magneton, magnetically stirring and uniformly mixing at room temperature, heating until reflux is generated, keeping the reflux reaction time to be 84min, detecting by TLC (thin-plate chromatography), allowing the raw material point to disappear, cooling to room temperature after the reaction is finished, precipitating a large amount of solid, standing, performing suction filtration, washing filter residues with anhydrous ethanol (3ml × 3), and performing vacuum drying at 80 ℃ to obtain 3- [1- (2-chlorophenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-one, wherein the purity is 99.2% by high performance liquid chromatography, and the yield is 74%.
3- [1- (2-chlorophenylimino) ethyl]-4-hydroxy-6-methyl-2H-pyran-2-one: a white solid; m.p.159-161 ℃; ir (kbr) v: 3430, 3079, 2925, 1696, 1644, 1567, 1459, 1362, 1060, 945, 857, 754cm-1；1H NMR(300MHz，CDCl3)：δ＝2.15(s，3H，CH3)，2.49(s，3H，CH3)，5.77(s，1H，CH)，7.23(t，J＝7.5Hz，1H，ArH)，7.29～7.35(m，2H，ArH)，7.55(dd，J1＝1.5Hz，J2＝7.1Hz，1H，ArH)，15.93(s，1H，OH)
Example 5
Adding 1.1mmol of 3-chloroaniline, 1.0mmol of dehydroacetic acid and 0.06mmol of 1, 3, 6-naphthalene trisulfonic acid catalyst into a 50ml single-neck flask containing 9ml of an isopropanol aqueous solution with the volume ratio concentration of 52 percent and provided with a condenser tube and a stirring magneton, magnetically stirring and uniformly mixing at room temperature, heating until reflux is generated, keeping the reflux reaction time to be 68min, detecting by TLC (thin-plate chromatography), allowing the raw material point to disappear, cooling to room temperature after the reaction is finished, precipitating a large amount of solid, standing, performing suction filtration, washing filter residues with anhydrous ethanol (3ml × 3), and performing vacuum drying at 80 ℃ to obtain the 3- [1- (3-chlorophenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-ketone, wherein the purity is 98.9 percent by high performance liquid chromatography, and the yield is 80 percent.
3- [1- (3-chlorophenylimino) ethyl]-4-hydroxy-6-methyl-2H-pyridinePyran-2-one: a white solid; m.p.116-118 ℃; ir (kbr) v: 3427, 3061, 2644, 1703, 1651, 1564, 1462, 1383, 1068, 996, 837, 792cm-1；1H NMR(300MHz，CDCl3)：δ＝2.13(s，3H，CH3)，2.56(s，3H，CH3)，5.75(s，1H，CH)，7.04(d，J＝7.5Hz，1H，ArH)，7.18(s，1H，ArH)，7.31～7.38(m，2H，ArH)，15.90(s，1H，OH)
Example 6
Adding 1.1mmol of 4-fluoroaniline, 1.0mmol of dehydroacetic acid and 0.06mmol of 1, 3, 6-naphthalene trisulfonic acid catalyst into a 50ml single-neck flask containing 9ml of an isopropanol aqueous solution with the volume ratio concentration of 52 percent and provided with a condenser tube and a stirring magneton, magnetically stirring and uniformly mixing at room temperature, heating until reflux is generated, keeping the reflux reaction time to be 81min, detecting by TLC (thin-plate chromatography), allowing the raw material point to disappear, cooling to room temperature after the reaction is finished, precipitating a large amount of solid, standing, performing suction filtration, washing filter residues with anhydrous ethanol (3ml × 3), and performing vacuum drying at 80 ℃ to obtain 3- [1- (4-fluorophenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-ketone, wherein the purity is 98.7 percent by high performance liquid chromatography, and calculating the yield to be 76 percent.
3- [1- (4-fluorophenylimino) ethyl]-4-hydroxy-6-methyl-2H-pyran-2-one: a white solid; m.p.146-148 ℃; ir (kbr) v: 3425, 3083, 2929, 1728, 1664, 1579, 1481, 1333, 1067, 1005, 836, 774cm-1；1H NMR(300MHz，CDCl3)：δ＝2.14(s，3H，CH3)，2.55(s，3H，CH3)，5.76(s，1H，CH)，7.17(d，J＝6.5Hz，4H，ArH)，15.73(s，1H，OH)
Example 7
Adding 1.0mmol of 4-methyl-3-chloroaniline, 1.0mmol of dehydroacetic acid and 0.05mmol of 1, 3, 6-naphthalene trisulfonic acid catalyst into a 50ml single-neck flask containing 9ml of an isopropanol aqueous solution with the volume ratio concentration of 52 percent and provided with a condenser tube and a stirring magneton, magnetically stirring and uniformly mixing at room temperature, heating until reflux is generated, keeping the reflux reaction time to be 59min, detecting by TLC (thin-plate chromatography), removing raw material points, cooling to room temperature after the reaction is finished to separate out a large amount of solid, standing, performing suction filtration, washing filter residues by absolute ethyl alcohol (3ml × 3) and performing vacuum drying at 80 ℃ to obtain 3- [1- (3-chloro-4-methylphenyl imino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-one, determining the purity by high performance liquid chromatography to be 98.4 percent, calculating the yield to be 84 percent, and directly adding the 4-methyl-3-chloroaniline and the dehydroacetic acid into the filtrate for repeated use.
3- [1- (3-chloro-4-methylphenylimino) ethyl]-4-hydroxy-6-methyl-2H-pyran-2-one: a light yellow solid; m.p.167-169 ℃; ir (kbr) v: 3437, 3078, 2981, 1704, 1652, 1559, 1468, 1356, 1063, 950, 832 and 763cm-1；1H NMR(300MHz，CDCl3)：δ＝2.12(s，3H，CH3)，2.35(s，3H，CH3)，2.52(s，3H，CH3)，5.70(s，1H，CH)，6.93(d，J＝8.0Hz，1H，ArH)，7.13(s，1H，ArH)，7.24(d，J＝8.0Hz，1H，ArH)，15.74(s，1H，OH)
Example 8
Adding 1.1mmol of 4-methylaniline, 1.0mmol of dehydroacetic acid and 0.06mmol of 1, 3, 6-naphthalene trisulfonic acid catalyst into a 50ml single-neck flask containing 9ml of 54 volume percent isopropanol aqueous solution with a condenser tube and a stirring magneton, magnetically stirring and uniformly mixing at room temperature, heating until reflux is generated, keeping the reflux reaction time for 66min, detecting by TLC (thin-plate chromatography), allowing the raw material point to disappear, cooling to room temperature after the reaction is finished, precipitating a large amount of solid, standing, performing suction filtration, washing filter residues with anhydrous ethanol (3ml × 3), and performing vacuum drying at 80 ℃ to obtain 3- [1- (4-methylphenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-ketone, wherein the purity is 99.0 percent by high performance liquid chromatography, and the calculated yield is 81 percent.
3- [1- (4-Methylphenylimino) ethyl]-4-hydroxy-6-methyl-2H-pyran-2-one: a white solid; m.p.154-156 ℃; ir (kbr) v: 3402, 3038, 2932, 1704, 1655, 1569, 1477, 1386, 1071, 950, 841, 768cm-1；1H NMR(300MHz，CDCl3)：δ＝2.15(s，3H，CH3)，2.37(s，3H，CH3)，2.56(s，3H，CH3)，5.71(s，1H，CH)，7.01(d，J＝6.2Hz，2H，ArH)，7.20(d，J＝6.1Hz，2H，ArH)，15.63(s，1H，OH)
Example 9
Adding 1.2mmol of 4-methoxyaniline, 1.0mmol of dehydroacetic acid and 0.07mmol of 1, 3, 6-naphthalene trisulfonic acid catalyst into a 50ml single-neck flask containing 55% by volume of isopropanol aqueous solution with a condenser tube and a stirring magneton, magnetically stirring and uniformly mixing at room temperature, heating until reflux is generated, keeping the reflux reaction time to be 87min, detecting by TLC (thin-plate chromatography), allowing the raw material point to disappear, cooling to room temperature to precipitate a large amount of solid after the reaction is finished, standing, performing suction filtration, washing filter residues with anhydrous ethanol (3ml × 3), and performing vacuum drying at 80 ℃ to obtain 3- [1- (4-methoxyphenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-one, wherein the purity is 98.8% as determined by high performance liquid chromatography, and the calculated yield is 72%.
4- [1- (4-Methoxyphenylimino) ethyl]-4-hydroxy-6-methyl-2H-pyran-2-one: a yellow solid; m.p.180-182 ℃; ir (kbr) v: 3437, 3085, 2927, 1692, 1615, 1561, 1474, 1328, 1066, 942, 830, 712cm-1；1H NMR(300MHz，CDCl3)：δ＝2.17(s，3H，CH3)，2.54(s，3H，CH3)，3.81(s，3H，CH3)，5.74(s，1H，CH)，6.93(d，J＝8.6Hz，2H，ArH)，7.08(d，J＝8.6Hz，2H，ArH)，15.56(s，1H，OH)
Example 10
Example 1 after the completion of the reaction, the filtrate was subjected to the next batch of preparative reactions according to the amounts of the raw materials charged and the reaction conditions in example 1 without any treatment, which was repeated 6 times, and the product, 3- [1- (4-nitrophenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-one, had a liquid chromatography purity of more than 98.5% and the calculated yield varied as shown in fig. 1.
Example 11
Example 2 after the completion of the reaction, the filtrate was subjected to the next batch of preparative reactions according to the amounts of the raw materials charged and the reaction conditions in example 2 without any treatment, which was repeated 5 times, and the liquid chromatographic purities of the products, 3- [1- (phenylmethylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-one, were each more than 98.2%, and the calculated yield was varied as shown in FIG. 2.
Example 12
Example 7 the next batch of preparative reactions was carried out according to the amounts of the starting materials charged and the reaction conditions in example 7 without any treatment of the filtrate after the end of the reaction, and this was repeated 6 times, and the product 3- [1- (3-chloro-4-methylphenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-one showed a liquid chromatographic purity of more than 98.0%, and the calculated yield varied as shown in fig. 3.
Comparative example 1
To a 50ml single neck flask with a condenser and stirring magnetons containing 9ml of analytically pure isopropanol, 1.2mmol of 4-nitroaniline, 1.0mmol of dehydroacetic acid and 0.07mmol of 1, 3, 6-naphthalenetrisulfonic acid catalyst were added and mixed by magnetic stirring at room temperature. Heating until reflux is generated, keeping the reflux reaction for 91min, detecting by TLC (thin-plate chromatography), and detecting to find that the raw material point of the synthesized product still exists. After the reaction was completed, no solid precipitated after cooling to room temperature. Then, it was found by investigation that the products were all dissolved in the reaction liquid (filtrate), and the content of 3- [1- (4-nitrophenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-one was only 43.3% (external standard method) by detecting the reaction liquid by high performance liquid chromatography, and the calculated yield was only 24%.
Comparative example 2
Adding 1.2mmol of 4-nitroaniline, 1.0mmol of dehydroacetic acid and 0.07mmol of 1, 3, 6-naphthalene trisulfonic acid catalyst into a 50ml single-neck flask containing 9ml of 52 percent ethanol aqueous solution with a condenser tube and a stirring magneton, magnetically stirring and uniformly mixing at room temperature, heating until reflux is generated, keeping the reflux reaction time to be 91min, detecting by TLC (thin-plate chromatography), not completely disappearing the raw material point, cooling to room temperature after the reaction is finished, only precipitating a small amount of solid, standing, performing suction filtration, washing filter residues by absolute ethyl alcohol (3ml × 3), and performing vacuum drying at 80 ℃ to obtain the 3- [1- (4-nitrophenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-ketone, wherein the purity is 92.4 percent by high performance liquid chromatography, and the calculated yield is only 38 percent.
Comparative example 3
Adding 1.2mmol of 4-nitroaniline, 1.0mmol of dehydroacetic acid and 0.07mmol of 1, 3, 6-naphthalene trisulfonic acid catalyst into a 50ml single-neck flask containing 9ml of an isopropanol aqueous solution with the volume ratio concentration of 26%, wherein the condensation tube and a stirring magneton are arranged, the raw materials cannot be completely dissolved, uniformly mixing by magnetic stirring at room temperature, heating until reflux is generated, keeping the reflux reaction time to be 91min, detecting by TLC (thin-plate chromatography), the raw material points are not completely disappeared, cooling to room temperature after the reaction is finished, so that a large amount of solid is formed, standing, carrying out suction filtration, washing filter residues by absolute ethyl alcohol (3ml × 3), carrying out vacuum drying at 80 ℃ to obtain a light yellow solid, and obtaining the 3- [1- (4-nitrophenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-ketone with the content of only 78.6% (external standard method) by high performance liquid chromatography, wherein the calculated yield is 43%.
Comparative example 4
1.2mmol of 4-nitroaniline, 1.0mmol of dehydroacetic acid and 0.07mmol of 1, 3, 6-naphthalenetrisulfonic acid catalyst are added into a 50ml single-neck flask containing 9ml of 78% isopropanol aqueous solution by volume ratio and provided with a condenser tube and a stirring magneton, the raw materials are completely dissolved, and the mixture is magnetically stirred and uniformly mixed at room temperature. Heating until reflux is generated, keeping the reflux reaction time to be 91min, detecting by TLC (thin-plate chromatography), not completely disappearing the raw material point, and cooling to room temperature after the reaction is finished without solid precipitation. The content of 3- [1- (4-nitrophenylimino) ethyl ] -4-hydroxy-6-methyl-2H-pyran-2-one determined by high performance liquid chromatography in the reaction solution is only 56.9% (external standard method), and the calculated yield is 35%.
Claims (8)
1. A process for producing a pharmaceutical intermediate which is a 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivative, characterized in that: dehydroacetic acid and aromatic amine are taken as raw materials, and are catalyzed and condensed by a catalyst in an isopropanol water solution to obtain a 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivative;
the volume ratio concentration of the isopropanol aqueous solution is 46-55%; the catalyst is 1, 3, 6-naphthalene trisulfonic acid.
2. The process for producing a pharmaceutical intermediate according to claim 1, characterized in that: the method comprises the following specific steps: adding dehydroacetic acid, aromatic amine and catalyst into isopropanol water solution, mixing, heating and refluxing, cooling and standing, separating solid product, and vacuum drying to obtain 4-hydroxy-6-methyl- [1- (phenylimino) ethyl ] -2H-pyran-2-one derivative.
3. The process for producing a pharmaceutical intermediate according to claim 1, characterized in that: before vacuum drying, the solid product separated out by standing is washed by absolute ethyl alcohol.
4. The process for producing a pharmaceutical intermediate according to claim 1, characterized in that: separating out a solid product to obtain a filtrate; the filtrate can be recycled, and when the filtrate is recycled, raw materials are directly added into the filtrate for the next reaction.
5. The process for producing a pharmaceutical intermediate according to claim 1, characterized in that: the addition molar ratio of the aromatic amine to the dehydroacetic acid is (1.0-1.2): 1.
6. The process for producing a pharmaceutical intermediate according to claim 1, characterized in that: the addition molar ratio of the 1, 3, 6-naphthalene trisulfonic acid to the dehydroacetic acid is (0.04-0.07): 1.
7. The process for producing a pharmaceutical intermediate according to claim 1, characterized in that: the volume of the isopropanol water solution in milliliters is 7-10 times of the amount of dehydroacetic acid in millimoles.
8. The process for producing a pharmaceutical intermediate according to claim 1, characterized in that: the aromatic amine is any one of 4-nitroaniline, benzylamine, 4-chloroaniline, 2-chloroaniline, 3-chloroaniline, 4-fluoroaniline, 4-methyl-3-chloroaniline, 4-methylaniline and 4-methoxyaniline.
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| CN1646467A (en) * | 2002-04-02 | 2005-07-27 | 南密西西比研究基金会大学 | Process for making butenyl esters from butadiene |
| CN1683353A (en) * | 2005-03-11 | 2005-10-19 | 河南省科学院化学研究所 | New process for producing liquid methyl tetrahydro phthalic anhydride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1646467A (en) * | 2002-04-02 | 2005-07-27 | 南密西西比研究基金会大学 | Process for making butenyl esters from butadiene |
| CN1683353A (en) * | 2005-03-11 | 2005-10-19 | 河南省科学院化学研究所 | New process for producing liquid methyl tetrahydro phthalic anhydride |
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| A novel and convenient synthesis of 4-hydroxy-6-methyl-3-(1-(phenylimino)ethyl)-2H-pyran-2-one derivatives under ultrasound irradiation;Huiyan Wang 等;《Ultrasonics Sonochemistry》;20110120;第18卷(第5期);第1048-1051页，尤其是第1049页流程图1以及第1050页表2中化合物3d的常规制备 * |
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