CN107011322B - Preparation and purification method of dehydrophenylahistine compound - Google Patents
Preparation and purification method of dehydrophenylahistine compound Download PDFInfo
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Abstract
The invention provides a preparation and purification method of a high-purity dehydrophenylalsteine compound, which mainly aims at removing trans-isomer. The invention relates to the preparation of high purity (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione monohydrate and (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) deuterated methylene) piperazine-2, 5-dione monohydrate, the purity of the prepared product being greater than 99.5%, the trans isomer content being less than 0.1%; meanwhile, the invention relates to the preparation and purification of related important intermediates of 5- (tert-butyl) -1H-imidazole-4-ethyl formate and 1, 4-diacetyl piperazine-2, 5-diketone, thereby reducing the production cost, reducing the post-treatment difficulty and enabling the process to better meet the requirements of industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and relates to a preparation and purification method of a dehydrophenylahistine compound.
Background
The structural formula of dehydrophenylalsteine compound (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) methylene) piperazine-2, 5-diketone is as follows:
the compound is also called Plinabulin (KPU-2, NPI-2358), a tubulin binding agent, a synthetic derivative of the low molecular cyclic dipeptide phenylahistin or halimide derived from Aspergillus marinus. It binds to tubulin near the colchicine binding site and has good antitumor activity, especially in non-small cell lung cancer, the drug has been in clinical phase three in the united states for the next half year 2015, where the drug named plinabulin is also applied clinically in china as a concentration solution of injectable plinabulin, currently under examination.
The (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione has strong photosensitivity, especially in solution, so more ((3E, 6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione isomers are generated in the preparation method reported in the original research patent, are not easy to remove, bring problems to subsequent preparations, and influence the declaration and clinical safety of the medicine, thereby preparing the high-purity (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) methylene) piperazine The (E) -2, 5-diketones have important meanings.
The deuterated dehydrophenylalsteine compound (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) deuterated methylene) piperazine-2, 5-diketone is a novel tubulin binding agent, and the applicant of the invention has applied for an invention patent with the patent application number of 201510293269.8 aiming at a preparation method and application thereof in preparing anti-tumor drugs. However, the preparation method provided by the method can generate a certain content of ((3E, 6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) deuterated methylene) piperazine-2, 5-diketone isomer.
Meanwhile, the preparation and purification method reported about (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) methylene) piperazine-2, 5-diketone at present is complex, and the column chromatography purification of a part of intermediates restricts the industrial production of the medicine, so that the establishment of a set of process significance suitable for industrial production is important.
Disclosure of Invention
The invention aims to provide a preparation and purification method of a dehydrophenylahistine compound, and particularly relates to a purification process of high-purity (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione and (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) deuterated methylene) piperazine-2, 5-dione and a preparation and purification method of an important intermediate thereof.
In order to realize the purpose of the invention, the invention adopts the following technical scheme to realize:
a method for preparing and purifying dehydrophenylalsteines compound, the dehydrophenylalsteines compound has a structure shown in general formula (I),
r in the general formula (I)1Is a polysubstitution group which is different from one to five substitutions on a benzene ring, and the substituent is selected from hydrogen atoms, deuterium atoms, halogen atoms, hydroxyl groups, methoxy groups, amino groups, phenyl groups, aminomethyl phenyl groups, C1-C24 alkyl groups, C2-C24 alkenyl groups, C2-C24 alkynyl groups, aryl alkyl groups, heterocyclic aryl alkyl groups, acyl groups of C1-C24, alkoxy groups of C1-C24, carboxyl groups, carboxylic ester groups, amide groups, N-mono-substituted or N, N-di-substituted amide groups, sulfonic ester groups, sulfonamide groups, N-substituted sulfonamide groups, alkoxy groups, aryl alkoxy groups, alkylthio groups, cyano groups, amino groups, substituted amino groups and nitro groups; cycloalkyl, cycloalkenyl, aryl, substituted aryl, aromatic heterocyclic, aryloxy, aroyl, epoxy, cycloacyl, aromatic thio, aromatic sulfonyl;
R2is a hydrogen atom or a deuterium atom, R3Is a hydrogen atom or a deuterium atom;
X1is an oxygen atom or a sulfur atom, X2Is an oxygen atom or a sulfur atom;
X3is-NH, an oxygen atom or a sulfur atom;
the preparation and purification method comprises the following steps: putting the crude product of the compound shown in the general formula (I) into a brown bottle, adding isopropanol or ethanol or n-butanol under the heating condition until the crude product is completely dissolved, adding water without crystal precipitation, putting the mixture at 15-30 ℃, stirring, cooling and crystallizing, and performing suction filtration, washing and drying to obtain the high-purity dehydrophenylacetin compound.
Further: putting a crude product of (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) deuterated methylene) piperazine-2, 5-dione into a brown bottle, adding isopropanol as a solvent, heating to completely dissolve the crude product,adding water, wherein the volume ratio of the isopropanol to the water is VIsopropanol (I-propanol)∶VWater (W)Placing the mixture at 15-30 ℃, stirring, cooling and crystallizing, filtering, washing and drying to obtain a light yellow solid which is a high-purity (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) deuterated methylene) piperazine-2, 5-diketone monohydrate with the isomer content of less than 0.1%.
Further: the volume ratio of the isopropanol to the water is VIsopropanol (I-propanol)∶VWater (W)＝5∶2。
Further: the preparation method of the crude product of the compound (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) methylene) piperazine-2, 5-diketone comprises the following steps:
under the alkaline condition, cyclizing isocyano ethyl acetate and trimethyl acetic anhydride to obtain 5- (tert-butyl) oxazole-4-ethyl formate;
heating 5- (tert-butyl) oxazole-4-ethyl formate with a formamide solvent, converting the heated solution into an imidazole ring, reducing the imidazole ring with lithium aluminum hydride, and oxidizing manganese dioxide to obtain 5- (tert-butyl) -1H-imidazole-4-formaldehyde; dissolving glycine anhydride in acetic anhydride solvent to obtain 1, 4-diacetyl piperazine-2, 5-diketone;
under the alkaline condition, condensing 5- (tert-butyl) -1H-imidazole-4-formaldehyde with 1, 4-diacetyl piperazine-2, 5-diketone and then condensing with benzaldehyde to obtain a crude product of (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) methylene) piperazine-2, 5-diketone.
Further: putting a crude product of (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) methylene) piperazine-2, 5-dione in a brown bottle, adding isopropanol serving as a solvent, heating to completely dissolve the crude product, and adding water, wherein the volume ratio of the isopropanol to the water is VIsopropanol (I-propanol)∶VWater (W)Stirring and cooling at 15-30 ℃ for crystallization, and performing suction filtration, washing and drying to obtain a light yellow solid which is a high-purity (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) methylene) piperazine-2, 5-diketone monohydrate with the isomer content of less than 0.1%.
Further: the volume ratio of the isopropanol to the water is VIsopropanol (I-propanol)∶VWater (W)＝5∶2。
Further: the ethyl 5- (tert-butyl) -1H-imidazole-4-carboxylate was purified by the following steps: heating 5- (tert-butyl) -1H-oxazole-4-ethyl formate to react with formamide, cooling mother liquor after the reaction is finished, extracting with sodium carbonate and petroleum ether, removing petroleum ether layer impurities, extracting with ethyl acetate, combining organic phases, washing with water, drying, concentrating under reduced pressure to obtain concentrated solution, pouring the concentrated solution into water while the concentrated solution is hot, stirring and pulping, separating out solids, and performing suction filtration, washing and vacuum drying to obtain a purified product of the 5- (tert-butyl) -1H-imidazole-4-ethyl formate.
Further: the 1, 4-diacetylpiperazine-2, 5-dione is purified by: and (2) carrying out reflux reaction on glycine anhydride and acetic anhydride, after the reaction is finished, cooling mother liquor to room temperature, concentrating under reduced pressure to evaporate the solvent, dissolving the concentrated solution by using dichloromethane, filtering by using kieselguhr, concentrating under reduced pressure to remove the dichloromethane, recrystallizing by using ethyl acetate, crystallizing at low temperature, filtering, and drying to obtain the purified 1, 4-diacetyl piperazine-2, 5-diketone.
The invention has the advantages and technical effects that: aiming at the problem that a trans-isomer generated in the preparation process of the dehydrophenylacetin compound is difficult to remove, the invention provides a method for purifying the dehydrophenylacetin compound, in particular to a method for preparing and purifying (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) methylene) piperazine-2, 5-diketone and (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) deuterated methylene) piperazine-2, 5-diketone, the solvent used in the method is obtained by a large amount of experimental screening, and the method has the characteristics of easy obtainment of the solvent, simple operation, high yield, good reproducibility and the like, the prepared trans-isomer is less than 0.1%, which has important significance for drug declaration and safety evaluation of the compound.
Meanwhile, the invention also provides a preparation and purification process of 5- (tert-butyl) -1H-imidazole-4-ethyl formate and N, N-diacetyl piperazine-2, 5-diketone which are used as intermediates for preparing the dehydrophenyl acissidine compounds, solves the problem of column purification of the two intermediates, is more favorable for industrial production of the compounds, improves the yield and reduces the cost.
Drawings
FIG. 1 is an HPLC spectrum of (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) deuteromethylene) piperazine-2, 5-dione monohydrate at 254nm wavelength of the present invention;
FIG. 2 is a thermogravimetric analysis of (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) deuterated methylene) piperazine-2, 5-dione monohydrate of the present invention;
FIG. 3 is an HPLC spectrum of (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione monohydrate at 254nm wavelength of the present invention;
FIG. 4 is a thermogravimetric analysis of (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione monohydrate of the present invention.
Detailed Description
The technical solution of the present invention will be described in further detail with reference to specific examples.
Example 1
Preparation of crude (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) deuterated methylene) piperazine-2, 5-dione
The specific preparation process comprises the following steps:
1) preparation of (Z) -1-acetyl-3- ((5- (tert-butyl) -1H-imidazol-4-yl) deuterated methylene) piperazine-2, 5-dione
10.00g (65.29mmol) of 5- (tert-butyl) -1H-imidazole-4-deuterated formaldehyde is added to 50ml DMF, 25.88g (130.59mmol) of N, N-diacetylpiperazine-2, 5-dione are added and exhausted three times under nitrogen protection, 31.91g (97.94mmol) of cesium carbonate are added and exhausted three times under nitrogen protection, and the mixture is stirred at room temperature for 20 hours in the dark. The reaction mixture was poured into ice water (400mL), filtered, the filter cake was washed with water (200mL × 2), petroleum ether and ethyl acetate (8: 1) (200mL) in that order, the filter cake was ultrasonically dispersed with ethanol and dichloromethane, the insoluble matter was filtered off, concentrated under reduced pressure, and anhydrous ethanol was used with water. Slurried with ethyl acetate (250 mL). To obtain brown yellow solid (Z) -1-acetyl-3- ((5- (tert-butyl) -1H-imidazole-4-yl) deuterated methylene) piperazine-2, 5-dione 8.96g with the yield of 47.11%.
2) Preparation of crude (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) deuterated methylene) piperazine-2, 5-dione
8.84g (30.33mmol) of (Z) -1-acetyl-3- ((5- (tert-butyl) -1H-imidazol-4-yl) deuterated methylene) piperazine-2, 5-dione are added to 25mL of DMF, 4.83g (45.51mmol) of benzaldehyde are added with nitrogen blanketing and cesium carbonate 14.82g (45.49mmol) with nitrogen blanketing are added, and the reaction is stirred for 24H at 50 ℃. The reaction mixture was poured into ice water (300mL), filtered, the cake was washed with 200mL × 2 water, 200mL petroleum ether and ethyl acetate (8: 1) in this order, the cake was ultrasonically dispersed with ethanol (50mL) and ethyl acetate (160mL), the insoluble matter was filtered off, and the mixture was concentrated under reduced pressure to leave anhydrous ethanol with water. 150mL was sonicated with ethyl acetate and left to stand at-30 ℃ overnight. Suction filtration is carried out, and a filter cake is washed by ethyl glacial acetate (50mL) to obtain 6.66g of yellow-green solid with the yield of 65.09%.
Example 2
Preparation of (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) deuterated methylene) piperazine-2, 5-dione monohydrate
2.0g of the crude product from example 1 was placed in a brown bottle, heated and dissolved completely by adding 125mL of isopropanol, 50mL of water was added and no crystal precipitated, the mixture was placed at room temperature, cooled and crystallized under stirring, filtered, the cake was washed with isopropanol and water at 1: 1 and dried to give 1.642g of a yellow powdery solid with a yield of 78.13% and a product purity of 99.94% at 254nm, wherein the isomer ((3E, 6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) deuteromethylene) piperazine-2, 5-dione was 0.06%, as shown in fig. 1.1H NMR(500MHz，dmso)δ12.22(brs，2H)，10.00(brs，1H)，7.82(d，J＝12.7Hz，1H)，7.51(d，J＝7.6Hz，2H)，7.40(t，J＝7.7Hz，2H)，7.30(t，J＝7.4Hz，1H)，6.73(s，1H)，1.37(s，9H)。MS(ESI)m/z 338.1715(M+H)+(calcd for C19H20DN4O2)。
The resulting product was the monohydrate of (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) deuterated methylene) piperazine-2, 5-dione, tested at a moisture content of 5.314%, with fig. 2 being a data support for thermogravimetric analysis. The elemental analysis is shown in table 1 below:
TABLE 1 elemental analysis data for (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) deuterated methylene) piperazine-2, 5-dione monohydrate
Example 3
Preparation method of (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) methylene) piperazine-2, 5-diketone crude product
The specific preparation process comprises the following steps:
1) preparation of ethyl 5- (tert-butyl) oxazole-4-carboxylate
90g (796mmol) of ethyl isocyanoacetate are added to 1000mL of tetrahydrofuran, 145g (955mmol) of DBU are slowly added dropwise, then 178g (955mmol) of trimethylacetic anhydride are added dropwise, and the reaction is stirred at room temperature for 48h after completion of the dropwise addition. After the reaction, the mixture was concentrated under reduced pressure. Extracting, adding a proper amount of 1500mL of dichloromethane, washing with 800mL of 10% sodium carbonate, 800mL of 10% citric acid and 800mL of saturated salt water in sequence, and back-extracting the aqueous phase twice with 1000mL of dichloromethane. The organic phases are combined, dried over anhydrous sodium sulfate, filtered after half an hour, and concentrated under reduced pressure. And (3) passing through a silica gel (200-300 meshes) column (EA: PE is 1: 10, 1: 8 and 1: 5) to obtain 177g of yellow liquid which is 5- (tert-butyl) oxazole-4-ethyl formate, wherein the yield is 113%.
2) Preparation of ethyl 5- (tert-butyl) -1H-imidazole-4-carboxylate
157g (796mmol) of 5- (tert-butyl) -1H-oxazole-4-carboxylic acid ethyl ester were added to 717g (15.914mmol) of formamide and the reaction was stirred at reflux for 30H at 180 ℃ in an oil bath. Cooled to room temperature, extracted, added with 800mL 10% sodium carbonate, added with 500mL petroleum ether extracted and the organic layer discarded, extracted three times with ethyl acetate (1000mL x 3), the organic phases were combined and washed twice with saturated brine (800mL x 2), the aqueous phase was back-extracted twice with ethyl acetate (500mL x 2), the combined organic phases were dried over anhydrous sodium sulfate. Filtering, and concentrating under reduced pressure. Pulping, adding 1000mL of water, stirring, filtering, washing a filter cake with water, and drying in vacuum at 50 ℃.71 g of an earthy yellow solid was obtained as the ethyl 5- (tert-butyl) -1H-imidazole-4-carboxylate in a yield of 45%.
3) Preparation of 5- (tert-butyl) -1H-imidazole-4-methanol
40g (1054mmol) of lithium aluminium hydride are added to 300mL of dry tetrahydrofuran at-10 ℃ in cold hydrazine, 70g (357mmol) of ethyl 5- (tert-butyl) -1H-imidazole-4-carboxylate dissolved in 200mL of tetrahydrofuran are slowly added dropwise to the suspension of lithium aluminium hydride, and the reaction is stirred at room temperature for 3H after dropwise addition. Quenching the reaction by ice water, measuring a proper amount of ice by using a measuring cup, and dropwise adding the reaction solution. Suction filtration, filter cake washed twice with water (1000mL x 2), twice with tetrahydrofuran (500mL x 2), twice with absolute ethanol (500mL x 2), reduced pressure concentration, absolute ethanol with water. 51g of a pale yellow solid was obtained as the 5- (tert-butyl) -1H-imidazole-4-methanol in 93% yield.
4) Preparation of 5- (tert-butyl) -1H-imidazole-4-carbaldehyde
50g (324mmol) of 5- (tert-butyl) -1H-imidazole-4-methanol are added to 500mL of dichloromethane, 282g (3242mmol) of manganese dioxide are added and the reaction is stirred at room temperature for 24H. Suction filtration, adding diatomite, filter cake washing with anhydrous ethanol (500mL x 3) three times, decompression concentration. 43g of a pale yellow solid was obtained as the 5- (tert-butyl) -1H-imidazole-4-carbaldehyde in a yield of 87%.
5) Preparation of N, N-diacetylpiperazine-2, 5-dione
50g (438mmol) of glycine anhydride were added to 179g (1753mmol) of acetic anhydride, and the reaction was stirred under reflux in an oil bath at 155 ℃ for 30h and concentrated under reduced pressure. Dissolving the mixture with dichloromethane, spreading diatomite and silica gel solution for filtration, leaching a filter cake with dichloromethane, concentrating under reduced pressure, dissolving the filter cake with ethyl acetate at 70 ℃ for recrystallization to obtain 74g of brown solid which is the N, N-diacetyl piperazine-2, 5-diketone with the yield of 85%.
6) Preparation of (Z) -1-acetyl-3- ((5- (tert-butyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
1g (6.5mmol) of 5- (tert-butyl) -1H-imidazole-4-carbaldehyde was added to 7mL of DMF, and then 2.59g (13mmol) of N, N-diacetylpiperazine-2, 5-dione were added under nitrogen to purge three times, 3.19g (9.8mmol) of cesium carbonate were added under nitrogen to purge three times, and the reaction was stirred at room temperature in the dark for 20H. The reaction mixture was poured into (100mL) ice water, filtered, the filter cake was washed with water (100mL × 2), petroleum ether and ethyl acetate (8: 1) (90mL) in this order, the filter cake was ultrasonically dispersed with ethanol and dichloromethane, the insoluble matter was filtered off, concentrated under reduced pressure, and anhydrous ethanol was used with water. Then, the mixture was slurried with ethyl acetate (50mL) to give 0.89g of (Z) -1-acetyl-3- ((5- (tert-butyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione as a brown yellow solid in a yield of 46.9%.
7) Preparation of crude (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione
0.85g (2.9mmol) of (Z) -1-acetyl-3- ((5- (tert-butyl) -1H-imidazol-4-yl) methylene) piperazine-2, 5-dione are added to DMF, 0.56g (5.25mmol) of benzaldehyde are added and the mixture is degassed under nitrogen, 0.95g (2.9mmol) of cesium carbonate is added and the mixture is degassed under nitrogen, the temperature is programmed to 80 ℃ and the reaction is stirred for 24H in the dark. The reaction mixture was poured into ice water (100mL), filtered, the cake was washed with 100mL × 2 water, 90mL petroleum ether and ethyl acetate (8: 1) in this order, the cake was ultrasonically dispersed with ethanol (30mL) and ethyl acetate (100mL), the insoluble matter was filtered off, and the mixture was concentrated under reduced pressure, and anhydrous ethanol was used to carry water. 50mL of the product was dispersed in ethyl acetate, allowed to stand at-30 ℃ overnight, filtered with suction, and the filter cake was washed with ethyl glacial acetate (5mL) to give 0.73g of crude product.
Example 4
Preparation of (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione monohydrate
Placing 0.73g of the crude product in a brown bottle, adding 45mL of isopropanol under heating to dissolve completely, adding 18mL of water without crystal precipitation, placing at room temperature, stirring and coolingPerforming cooling crystallization, performing suction filtration, washing a filter cake with isopropanol and water at a ratio of 1: 1, and drying to obtain 0.59g of yellow powdery solid, wherein the yield is 76.71%, and the purity of the product at 254nm is 99.91%, and the content of an isomer ((3E, 6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione is 0.09%, which is shown in figure 3;1H NMR(400MHz，DMSO-d6)δ12.31(s，1H)，12.22(s，1H)，10.00(s，1H)，7.84(s，1H)，7.52(d，J＝8Hz，2H)，7.39(t，J＝8Hz，2H)，7.32(t，J＝8Hz，1H)，6.86(s，1H)，6.73(s，1H)，1.37(s，9H)；MS(ESI)m/z 337.1659(M+H)+(calcd for C19H21N4O2)。
the resulting product was the monohydrate of (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) methylene) piperazine-2, 5-dione, tested at a moisture content of 5.326%, and fig. 4 is the data supported by thermogravimetric analysis spectra.
Example 5
Preparation of intermediate ethyl 5- (tert-butyl) -1H-imidazole-4-carboxylate
157g (796mmol) of 5- (tert-butyl) -1H-oxazole-4-carboxylic acid ethyl ester were added to 717g (15.91mmol) of formamide and the reaction was stirred under reflux for 30H at 180 ℃ in an oil bath. Cooled to room temperature, extracted, added 800mL 10% sodium carbonate, added 500mL petroleum ether extraction and discarded organic layer, again using ethyl acetate (1000mL 3) extraction three times, combined organic phase and saturated saline (800 x 2) washed twice, aqueous phase with ethyl acetate (500mL 2) back extraction two times, combined organic phase anhydrous sodium sulfate drying. Filtering, and concentrating under reduced pressure. Pulping, adding 1000mL of water, stirring, filtering, washing a filter cake with water, and drying in vacuum at 50 ℃.71 g of solid yellowish brown 5- (tert-butyl) -1H-imidazole-4-carboxylic acid ethyl ester was obtained in a yield of 45%.
Example 6
Preparation of intermediate N, N-diacetylpiperazine-2, 5-dione
50g (438mmol) of glycine anhydride were added to 179g (1753mmol) of acetic anhydride, and the reaction was stirred under reflux in an oil bath at 155 ℃ for 30h and concentrated under reduced pressure. Dissolving the mixture by using dichloromethane, spreading diatomite and silica gel solution for filtration, leaching a filter cake by using dichloromethane, concentrating the filter cake under reduced pressure, dissolving the filter cake by using ethyl acetate at 70 ℃ for recrystallization, and obtaining 74g of brown solid N, N-diacetylpiperazine-2, 5-diketone with the yield of 85 percent.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions.
Claims (3)
1. A method for preparing and purifying dehydrophenylahistine compounds is characterized in that: the dehydrophenylalsteine compound has a structure shown in a general formula (I):
（I）
r in the general formula (I)1Is a substituent on a benzene ring, and the substituent is selected from a hydrogen atom and a deuterium atom;
R2is a hydrogen atom or a deuterium atom, R3Is a hydrogen atom or a deuterium atom;
X1is an oxygen atom, X2Is an oxygen atom;
X3is-NH;
the preparation and purification method comprises the following steps: putting the crude product of the compound shown in the general formula (I) into a brown bottle, adding isopropanol or ethanol or n-butanol under heating until the crude product is completely dissolved, adding water without crystal precipitation, putting the mixture at 15-30 ℃, stirring, cooling and crystallizing, and performing suction filtration, washing and drying to obtain the dehydrophenylacetin compound.
2. The method for producing and purifying dehydrophenylalsteines as claimed in claim 1, wherein: preparing (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazol-4-yl) deuterated methylene) piperazinePutting the crude product of the-2, 5-diketone in a brown bottle, adding isopropanol serving as a solvent, heating until the crude product is completely dissolved, and then adding water, wherein the volume ratio of the isopropanol to the water is VIsopropanol (I-propanol)：VWater (W)And (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) deuterated methylene) piperazine-2, 5-diketone monohydrate with the trans-isomer content of less than 0.1% is obtained through stirring, cooling and crystallizing at the temperature of 15-30 ℃, suction filtration, washing and drying.
3. The method for producing and purifying dehydrophenylalsteines as claimed in claim 1, wherein:
putting a crude product of (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) methylene) piperazine-2, 5-dione in a brown bottle, adding isopropanol serving as a solvent, heating to completely dissolve the crude product, and adding water, wherein the volume ratio of the isopropanol to the water is VIsopropanol (I-propanol)：VWater (W)=5: and 2, stirring, cooling and crystallizing at 15-30 ℃, and performing suction filtration, washing and drying to obtain a light yellow solid which is (3Z,6Z) -3-benzylidene-6- ((5-tert-butyl-1H-imidazole-4-yl) methylene) piperazine-2, 5-diketone monohydrate with the trans-isomer content of less than 0.1%.
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| CN201610664088.6A CN107011322B (en) | 2016-08-12 | 2016-08-12 | Preparation and purification method of dehydrophenylahistine compound |
| US16/325,166 US10851086B2 (en) | 2016-08-12 | 2017-07-24 | Polycrystalline form of dehydrophenylahistin-like compound, and manufacturing and purification method and application thereof |
| EP17838550.6A EP3498702B1 (en) | 2016-08-12 | 2017-07-24 | Polycrystalline form of dehydrophenylahistin-like compound, and manufacturing and purification method and application thereof |
| PCT/CN2017/094066 WO2018028420A1 (en) | 2016-08-12 | 2017-07-24 | Polycrystalline form of dehydrophenylahistin-like compound, and manufacturing and purification method and application thereof. |
| CN202111486744.5A CN114276332B (en) | 2016-08-12 | 2017-07-24 | Polymorphic form of dehydrogenated phenyl-achyranthes and its preparing and purifying process and application |
| EP22175200.9A EP4089085B1 (en) | 2016-08-12 | 2017-07-24 | Manufacturing and purification method of polycrystalline form of dehydrophenylahistin-like compound |
| CN201780049392.2A CN109563079B (en) | 2016-08-12 | 2017-07-24 | Polymorphic form of dehydrophenylahistine compound, preparation and purification method and application thereof |
| US16/995,098 US11608325B2 (en) | 2016-08-12 | 2020-08-17 | Polycrystalline form of dehydrophenylahistin-like compound, and manufacturing and purification method and application thereof |
| US16/995,045 US11578057B2 (en) | 2016-08-12 | 2020-08-17 | Polycrystalline form of dehydrophenylahistin-like compound, and manufacturing and purification method and application thereof |
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| Synthesis and Structure-Activity Relationship Study of Antimicrotubule Agents Phenylahistin Derivatives with a Didehydropiperazine-2,5-dione Structure;Yuri Yamazaki等;《J. Med. Chem.》;20111220;第55卷;第1056-1071页 * |
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