CN102584831A - Preparation method for zaleplon - Google Patents
Preparation method for zaleplon Download PDFInfo
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- CN102584831A CN102584831A CN2011104610101A CN201110461010A CN102584831A CN 102584831 A CN102584831 A CN 102584831A CN 2011104610101 A CN2011104610101 A CN 2011104610101A CN 201110461010 A CN201110461010 A CN 201110461010A CN 102584831 A CN102584831 A CN 102584831A
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- aminoacetophenone
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- zaleplone
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- propenyl
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Abstract
The invention relates to a preparation method for zaleplon. The method comprises the following steps of: (1) making 3-aminoacetophenone react with acetic anhydride to obtain 3-(N-acetyl) aminoacetophenone; (2) making 3-(N-acetyl)aminoacetophenone react with iodoethane to obtain 3-(N-ethyln-acetamino) acetophenone; (3) making 3-(N-ethyl-N-acetamino)acetophenone react with N,N-dimethylformamide dimethyl acetal under a refluxing action to obtain N-[3-(3-dimethylamino-1-oxygen-2-allyl-phenyl)]-N-ethyl acetamide; and (4) making N-[3-(3-]dimethylamino-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide react with 3-aminopyrazole-4-nitrile to obtain crude zaleplon, and refining to obtain the zaleplon. The preparation method has the advantages of small adding amount of solvent, easiness for operating, capability of saving expensive N,N-dimethylformamide dimethyl acetal, no need of special process conditions, and suitability of mass production.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of preparation method of zaleplone.
Background technology
Insomnia is clinical common illness, and benzodiazepines (BZD) pharmacological agent insomnia is effective, but is prone to produce some like untoward reactions such as withdrawal syndrome and residual sedative effects.Zaleplone is novel non-BZD class soporific, is selectivity ω 1 receptor stimulant, and some pharmacological property of BZD class medicine is arranged, and has tranquilizing soporific, flaccidity, anxiety and anticonvulsant action.Characteristics are rapid-action, can obviously shorten the sleeping preceding waiting time, and the transformation period is short, and after effect is light, and it is little to bring out the disturbance of perception effect, and good safety is arranged.Fugitive medicine as adult's insomnia.
Zaleplone Zaleplon, trade(brand)name Sonata, by the exploitation of U.S. AHP company, be used for the short of grownup insomnia first in Denmark and Sweden's listing in July, 1999.
At present, the compound method that relates to the document record of product zaleplone of the present invention is:
3-aminoacetophenone and acetic acid and acetic anhydride generate 3-(N-ethanoyl) aminoacetophenone, this product and N, and the condensation of dinethylformamide dimethylacetal is reacted with iodoethane then.The N that second step consumed, dinethylformamide dimethylacetal amount is big, and reaction product need make with extra care, complex operation, cost is high, is difficult to mass production.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of solvent less investment, simple to operate, zaleplone that cost is low.
The preparation method of zaleplone of the present invention comprises the steps:
(1) 3-aminoacetophenone and acetic acid and acetic anhydride make 3-(N-ethanoyl) aminoacetophenone;
(2) with the 3-that makes (N-ethanoyl) aminoacetophenone and iodoethane reaction, make 3-(N-ethyl-N-kharophen) methyl phenyl ketone;
(3) with the 3-that makes (N-ethyl-N-kharophen) methyl phenyl ketone and N, the reaction of dinethylformamide dimethylacetal makes N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide;
(4) with the N-that makes [3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 3-amino-pyrazol-4-nitrile reaction, make the zaleplone bullion, refining, get zaleplone.
Wherein, in step (1), 3-aminoacetophenone, acetic acid and diacetyl oxide mixed reacted under the room temperature 0.5～1 hour, product is cooled to 0～3 ℃ of crystallization, 3-(N-ethanoyl) aminoacetophenone; Wherein, the mol ratio of 3-aminoacetophenone, acetic acid and diacetyl oxide is (1～2): (2～2.5): (1～1.5).
In addition, in step (2), be solvent with acetone, dissolving 3-(N-ethanoyl) aminoacetophenone and iodoethane, regulating the pH of mixed value is 7～8, the reaction down that refluxes, reaction finishes the back with the dichloromethane extraction product, obtains 3-(N-ethyl-N-kharophen) methyl phenyl ketone; Wherein, the mol ratio of 3-(N-ethanoyl) aminoacetophenone and iodoethane is (1～1.5): (2～2.5); The consumption of said solvent is 3-(N-ethanoyl) aminoacetophenone and iodoethane gross weight 3～4 times.
In addition, in step (3), with 3-(N-ethyl-N-kharophen) methyl phenyl ketone and N, the dinethylformamide dimethylacetal mixes, and refluxes 5～6 hours, makes N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide; 3-(N-ethyl-N-kharophen) methyl phenyl ketone and N wherein, the mol ratio of dinethylformamide dimethylacetal is (1～1.5): (1.5～2).
In addition; In said step (4), N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 3-amino-pyrazol-4-nitrile be dissolved in 30～35% the acetum, refluxed 5～6 hours; Product is cooled to 0～2 ℃ of crystallization, gets zaleplone; Wherein, the mol ratio of N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 3-amino-pyrazol-4-nitrile is (0.8～1): (0.6～0.75); The consumption of acetum is N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 3-amino-pyrazol-4-nitrile gross weight 6～8 times.
In addition, the mol ratio of said 3-aminoacetophenone, acetic acid and diacetyl oxide preferred (1.2～1.4): (2.25～2.42): (1.32～1.42);
The mol ratio of said 3-(N-ethanoyl) aminoacetophenone and iodoethane preferred (1.13～1.19): (2.31～2.38);
Said 3-(N-ethyl-N-kharophen) methyl phenyl ketone and N, the mol ratio of dinethylformamide dimethylacetal preferred (1.17～1.22): (1.6～1.8);
The mol ratio of said N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 3-amino-pyrazol-4-nitrile preferred (0.81～0.83): (0.69～0.74).
In addition, described in the step (4) refining for the zaleplone dissolving crude product in 90～95% ethanolic soln, be heated to 70～80 ℃ of insulation 20～40min after-filtration, filtrating is cooled to 0～2 ℃ of crystallization, drying, zaleplone.In addition, said refining can carrying out once or twice.Carry out making with extra care for twice and can obtain purer zaleplone.
In addition, zaleplone is dissolved in ethanolic soln after, in ethanolic soln, add gac earlier and decolour and refilter.
In addition, with Pottasium Hydroxide or sodium hydrate regulator solution pH value.
The synthetic route of zaleplone of the present invention is:
The invention has the advantages that:
(1) in preparation route of the present invention; Generate 3-(N-ethyl-N-kharophen) methyl phenyl ketone through 3-(N-ethyl) aminoacetophenone and iodoethane reaction; The product that generates need not refining can the input in next step reaction, but the N of conserve expensive, the dinethylformamide dimethylacetal.And simple to operate, can reduce the solvent input, reduce cost, reduce industrial pollution, be suitable for scale operation.
(2) respectively to go on foot yield all higher for synthetic route, and raw material is easy to get, and need not the special process condition, and production cost is lower, and expectation can obtain favorable economic benefit and social benefit.
Description of drawings
Fig. 1 is the infrared spectrum of standard zaleplone.
The infrared spectrum of the zaleplone that Fig. 2 makes for embodiment 1.
Fig. 3 is the performance liquid spectrogram of standard zaleplone.
The performance liquid spectrogram of the zaleplone that Fig. 4 makes for embodiment 1.
Embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.
One, preparation zaleplone
The zaleplone method for detecting purity is following in the embodiments of the invention:
Get the about 25mg of zaleplone, the accurate title, decide, and puts in the 50ml measuring bottle, with 60% dissolve with methanol, is diluted to scale, and the accurate 3ml that draws puts in the 100ml measuring bottle, is diluted to scale with 60% methyl alcohol, as need testing solution.It is an amount of that precision takes by weighing reference substance in addition, processes the reference substance solution that concentration is 0.015mg/ml with method.Precision is measured need testing solution and each 10 μ l of reference substance solution, measures according to HPLC in accordance with the law, calculates content.Performance liquid chromatography external standard method calculation formula:
In the formula:
C
X: trial-product concentration; C
R: reference substance concentration; A
X: the trial-product peak area; A
R: the reference substance peak area.
1, the preparation of 3-(N-ethanoyl) aminoacetophenone:
With 162.19g 3-aminoacetophenone, stir in the 135.11g acetic acid adding flask, add the 144.97g diacetyl oxide; Heat is given birth in reaction, the solid dissolving, and stirring reaction is after 50 minutes; Placed 4 hours for 0 ℃, add the about 600ml washed product of water, filter; 50 ℃ of vacuum dryings of solid get 192.9g white solid product 3-(N-ethanoyl) aminoacetophenone, yield 91%.
2, the preparation of 3-(N-ethyl-N-kharophen) methyl phenyl ketone:
192.9g 3-(N-ethanoyl) aminoacetophenone and acetone 2340ml are added stirring in the bottle, add the 347.8g iodoethane again, regulating pH value with the 55%KOH aqueous solution is 7.5, and reflux stirred 3.5 hours, steams solvent to the greatest extent, adds 1170ml water dissolution product.Divide the extraction aqueous solution three times with the 1170ml methylene dichloride, extracting solution merges, and methylene dichloride is to the greatest extent steamed in decompression, remains 230g oily 3-(N-ethyl-N-kharophen) methyl phenyl ketone (product is 223g in theory), need not make with extra care, and product directly is used for step reaction down.
3, the preparation of N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide:
With 230g oily 3-(N-ethyl-N-kharophen) methyl phenyl ketone product and 108.85g N, the dinethylformamide dimethylacetal adds in the bottle, and reflux stirred 5.5 hours.Low-boiling-point substance is to the greatest extent steamed in decompression then, after residual residue is cold slightly, adds 160ml methylene dichloride, the backflow of 470ml sherwood oil 2 minutes; Put cold after, solidify, filter; Get 265g N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide orange powder, yield 95%.
4, the preparation of zaleplone (G):
In 265g N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 100.32g 3-amino-pyrazol-4-nitrile and 2370ml 33% acetum adding bottle, refluxed 5 hours, stir cooling; Placed 4 hours for 0 ℃; Filter,, use 300ml 95% washing with alcohol filter cake again with 300ml water washing filter cake; In 70 ℃ of vacuum dryings, get 249g bullion Zha Lapulong.
5, zaleplone is refining
249g zaleplone bullion joins in 1350ml 95% ethanol, and heating for dissolving is cold slightly, adds the 9g gac; In 70 ℃ the insulation half a hour, take advantage of hot suction filtration, filtrate 0 ℃ the placement 6 hours; Filter, solid gets finished product 190.32g at last in 70 ℃ of vacuum dryings; Yield 72%, purity 99.5%, fusing point 184.6.
Embodiment 2
1, the preparation of 3-(N-ethanoyl) aminoacetophenone:
With 189.22g 3-aminoacetophenone, stir in the 135.11g acetic acid adding flask, add the 134.76g diacetyl oxide; Heat is given birth in reaction, the solid dissolving, and stirring reaction is after 45 minutes; Placed 5 hours for 3 ℃, add the about 600ml washed product of water, filter; 45 ℃ of vacuum dryings of solid get 223.72g white solid product 3-(N-ethanoyl) aminoacetophenone, yield 90%.
2, the preparation of 3-(N-ethyl-N-kharophen) methyl phenyl ketone:
223.72g 3-(N-ethanoyl) aminoacetophenone and 2330ml acetone are added stirring in the bottle, add the 393.04g iodoethane again, regulating pH value with the 60%KOH aqueous solution is 8, and reflux stirred 4 hours, steams solvent to the greatest extent, adds 1200ml water dissolution product.Divide the extraction aqueous solution three times with the 1200ml methylene dichloride, extracting solution merges, and methylene dichloride is to the greatest extent steamed in decompression, remains 270g oily 3-(N-ethyl-N-kharophen) methyl phenyl ketone (product is 259g in theory), need not make with extra care, and product directly is used for step reaction down.
3, the preparation of N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide:
With 270g oily 3-(N-ethyl-N-kharophen) methyl phenyl ketone and 135.89gN, the dinethylformamide dimethylacetal adds in the bottle, and reflux stirred 5 hours.Low-boiling-point substance is to the greatest extent steamed in decompression then, after residual residue is cold slightly, adds 160ml methylene dichloride, the backflow of 470ml sherwood oil 2 minutes; Put cold after, solidify, filter; Get 308.34g N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide orange powder, productive rate 94%.
4, the preparation of zaleplone (G):
In 308.34g N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 114.15g 3-amino-pyrazol-4-nitrile and 2400ml 30% acetum adding bottle, refluxed 5 hours, stir cooling; Placed 5 hours for 2 ℃; Filter,, use 350ml95% washing with alcohol filter cake again with 300ml water washing filter cake; In 70 ℃ of vacuum dryings, get 256g bullion Zha Lapulong.
5, zaleplone is refining
For the first time: 256g zaleplone bullion joins in the 1350ml90% ethanol, and heating for dissolving is cold slightly, adds the 9g gac; In 80 ℃ of insulations 40 minutes, take advantage of hot suction filtration, filtrate 2 ℃ and placed 6 hours; Filter, solid gets finished product 241.83g at last in 70 ℃ of vacuum dryings; Yield 75%, purity 99.3%, fusing point 184.6.
Embodiment 3
1, the preparation of 3-(N-ethanoyl) aminoacetophenone:
With 175.71g 3-aminoacetophenone, stir in the 138.72g acetic acid adding flask, add the 140.88g diacetyl oxide; Heat is given birth in reaction, the solid dissolving, and stirring reaction is after 55 minutes; Placed 3 hours for 3 ℃, add the about 600ml washed product of water, filter; 45 ℃ of vacuum dryings of solid get 211.93g white solid product 3-(N-ethanoyl) aminoacetophenone, yield 92%.
2, the preparation of 3-(N-ethyl-N-kharophen) methyl phenyl ketone:
211.93g 3-(N-ethanoyl) aminoacetophenone and 2350ml acetone are added stirring in the bottle, add the 379.63g iodoethane again, regulating pH value with the 55%KOH aqueous solution is 7, and reflux stirred 4 hours, steams solvent to the greatest extent, adds 1170ml water dissolution product.Divide the extraction aqueous solution three times with the 1170ml methylene dichloride, extracting solution merges, and methylene dichloride is to the greatest extent steamed in decompression, remains 260.38g oily 3-(N-ethyl-N-kharophen) methyl phenyl ketone (product is 245g in theory), need not make with extra care, and product directly is used for step reaction down.
3, the preparation of N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide:
With 260.38g 3-(N-ethyl-N-kharophen) methyl phenyl ketone and 123.54gN, the dinethylformamide dimethylacetal adds in the bottle, and reflux stirred 6 hours.Low-boiling-point substance is to the greatest extent steamed in decompression then, after residual residue is cold slightly, adds 160ml methylene dichloride, the backflow of 470ml sherwood oil 2 minutes; Put cold after, solidify, filter; Get 280.22g N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide orange powder, productive rate 90%.
4, the preparation of zaleplone (G):
In 280.22g N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 102.15g 3-amino-pyrazol-4-nitrile and 2390ml 35% acetum adding bottle, refluxed 6 hours, stir cooling; Placed 4 hours for 0 ℃; Filter,, use 300ml95% washing with alcohol filter cake again with 300ml water washing filter cake; In 70 ℃ of vacuum dryings, get 212.9g bullion Zha Lapulong.
5, zaleplone is refining
For the first time: 212.9g zaleplone bullion joins in the 1350ml95% ethanol, and heating for dissolving is cold slightly, adds the 9g gac, 70 ℃ of insulation half a hour, takes advantage of hot suction filtration, and filtrate 0 ℃ and placed 6 hours, filtration, solid is in 70 ℃ of vacuum dryings.
For the second time: refining identical with for the first time, get finished product 204.76g, yield 71%, purity 99.4%, fusing point 185.7 at last.
Embodiment 4
1, the preparation of 3-(N-ethanoyl) aminoacetophenone:
With 135.16g 3-aminoacetophenone, stir in the 150.13g acetic acid adding flask, add the 102.09g diacetyl oxide; Heat is given birth in reaction, the solid dissolving, and stirring reaction is after 50 minutes; Placed 4 hours for 0 ℃, add the about 600ml washed product of water, filter; 50 ℃ of vacuum dryings of solid get 154.16g white solid product 3-(N-ethanoyl) aminoacetophenone, yield 87%.
2, the preparation of 3-(N-ethyl-N-kharophen) methyl phenyl ketone:
154.16g 3-(N-ethanoyl) aminoacetophenone and acetone 2340ml are added stirring in the bottle, add the 329.23g iodoethane again, regulating pH value with the 55%KOH aqueous solution is 7.5, and reflux stirred 3.5 hours, steams solvent to the greatest extent, adds 1170ml water dissolution product.Divide the extraction aqueous solution three times with the 1170ml methylene dichloride, extracting solution merges, and methylene dichloride is to the greatest extent steamed in decompression, remains 203.2g oily 3-(N-ethyl-N-kharophen) methyl phenyl ketone (product is 178.56g in theory), need not make with extra care, and product directly is used for step reaction down.
3, the preparation of N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide:
With 203.2g oily 3-(N-ethyl-N-kharophen) methyl phenyl ketone and 95.39gN, the dinethylformamide dimethylacetal adds in the bottle, and reflux stirred 5.5 hours.Low-boiling-point substance is to the greatest extent steamed in decompression then, after residual residue is cold slightly, adds 160ml methylene dichloride, the backflow of 470ml sherwood oil 2 minutes; Put cold after, solidify, filter; Get 208.37g N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide orange powder, yield 92%.
4, the preparation of zaleplone (G):
In 208.37g N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 81.08g 3-amino-pyrazol-4-nitrile and 2370ml 33% acetum adding bottle, refluxed 5 hours, stir cooling; Placed 4 hours for 0 ℃; Filter,, use 300ml95% washing with alcohol filter cake again with 300ml water washing filter cake; In 70 ℃ of vacuum dryings, get 180g bullion Zha Lapulong.
5, zaleplone is refining
For the first time: 180g zaleplone bullion joins in the 1350ml95% ethanol, and heating for dissolving is cold slightly, adds the 9g gac, 70 ℃ of insulation half a hour, takes advantage of hot suction filtration, and filtrate 0 ℃ and placed 6 hours, filtration, solid is in 70 ℃ of vacuum dryings.
For the second time: refining identical with for the first time, get finished product 160.3g, yield 70%, purity 99.2%, fusing point 184.6 at last.
Embodiment 5
1, the preparation of 3-(N-ethanoyl) aminoacetophenone:
With 270.32g 3-aminoacetophenone, stir in the 120.1g acetic acid adding flask, add the 153.14g diacetyl oxide; Heat is given birth in reaction, the solid dissolving, and stirring reaction is after 55 minutes; Placed 3 hours for 3 ℃, add the about 600ml washed product of water, filter; 45 ℃ of vacuum dryings of solid get 228.59g white solid product 3-(N-ethanoyl) aminoacetophenone, yield 86%.
2, the preparation of 3-(N-ethyl-N-kharophen) methyl phenyl ketone:
228.59g 3-(N-ethanoyl) aminoacetophenone and 2350ml acetone are added stirring in the bottle, add the 268.27g iodoethane again, regulating pH value with the 55%KOH aqueous solution is 8, and reflux stirred 4 hours, steams solvent to the greatest extent, adds 1170ml water dissolution product.Divide the extraction aqueous solution three times with the 1170ml methylene dichloride, extracting solution merges, and methylene dichloride is to the greatest extent steamed in decompression, remains 283.4g oily 3-(N-ethyl-N-kharophen) methyl phenyl ketone (product is 265g in theory), need not make with extra care, and product directly is used for step reaction down.
3, the preparation of N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide:
With 283.4g oily 3-(N-ethyl-N-kharophen) methyl phenyl ketone and 125.73gN, the dinethylformamide dimethylacetal adds in the bottle, and reflux stirred 6 hours.Low-boiling-point substance is to the greatest extent steamed in decompression then, after residual residue is cold slightly, adds 160ml methylene dichloride, the backflow of 470ml sherwood oil 2 minutes; Put cold after, solidify, filter; Get 305.61g N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide orange powder, yield 91%.
4, the preparation of zaleplone (G):
In 305.61g N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 75.87g 3-amino-pyrazol-4-nitrile and 2390ml 35% acetum adding bottle, refluxed 6 hours, stir cooling; Placed 4 hours for 0 ℃; Filter,, use 300ml 95% washing with alcohol filter cake again with 300ml water washing filter cake; In 70 ℃ of vacuum dryings, get 175g bullion Zha Lapulong.
5, zaleplone is refining
For the first time: 175g zaleplone bullion joins in the 1350ml95% ethanol, and heating for dissolving is cold slightly, adds the 9g gac, 70 ℃ of insulation half a hour, takes advantage of hot suction filtration, and filtrate 0 ℃ and placed 6 hours, filtration, solid is in 70 ℃ of vacuum dryings.
For the second time: refining identical with for the first time, get finished product 156.47g, yield 73%, purity 99.2%, fusing point 185.7 at last.
Two, the zaleplone that makes is analyzed.
With the standard zaleplone is reference substance, and the zaleplone that makes with the embodiment of the invention 1 is measured ir spectra and liquid chromatography as sample, result such as Fig. 1～and shown in Figure 4.
By Fig. 1 and shown in Figure 2, ir spectra shows the pyrimidine ring that 2 adjacent H are arranged in the molecule, and the aromatic ring of 3 adjacent H is arranged, and the characteristic groups such as carbonyl of itrile group and acid amides are consistent with standard substance.
Wherein, By the performance liquid spectrogram, the RT of chromatographic peak is 5.368min among Fig. 3, and the RT of chromatographic peak is 5.542min among Fig. 4; Promptly represent zaleplone sample and reference substance chromatographic peak RT basically identical, prove that the product that the present invention makes is a zaleplone.
The zaleplone that the present invention makes shows 2 methyl H through the test proton nmr spectra, and 1 methylene radical H is arranged, and 2 pyrimidine ring H is arranged, 1 pyrazoles ring H, 4 aromatic ring H.The carbon spectrum shows 17 carbon atom peaks, 2 primary carbon atoms is wherein arranged, 1 secondary carbon(atom), 7 tertiary carbon atoms, 7 quaternary carbon atoms.
13C-
1H COSY spectrum shows except 7 quaternary carbon atom C
18, C
7, C
10, C
8, C
14, C
3, C
3aOutside all the other 9 carbon atoms all link to each other with relevant Wasserstoffatoms, meet the structure of zaleplone, meet the structure of zaleplone.
These article of powder X ray diffractogram proof crystallization and gained crystallization in methylene dichloride in ethanol, crystal formation is consistent, does not find polymorphism.
In sum, each item analysis indexes shows that the zaleplone that the present invention makes is consistent with the standard substance zaleplone.
Claims (9)
1. the preparation method of a zaleplone is characterized in that, comprises the steps:
(1) 3-aminoacetophenone and acetic acid and acetic anhydride make 3-(N-ethanoyl) aminoacetophenone;
(2) with the 3-that makes (N-ethanoyl) aminoacetophenone and iodoethane reaction, make 3-(N-ethyl-N-kharophen) methyl phenyl ketone;
(3) with the 3-that makes (N-ethyl-N-kharophen) methyl phenyl ketone and N, the reaction of dinethylformamide dimethylacetal makes N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide;
(4) with the N-that makes [3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 3-amino-pyrazol-4-nitrile reaction, make the zaleplone bullion, refining, get zaleplone.
2. method according to claim 1 is characterized in that, in step (1), 3-aminoacetophenone, acetic acid and diacetyl oxide is mixed reacted under the room temperature 0.5～1 hour, and product is cooled to 0～3 ℃ of crystallization, 3-(N-ethanoyl) aminoacetophenone;
Wherein, the mol ratio of 3-aminoacetophenone, acetic acid and diacetyl oxide is (1～2): (2～2.5): (1～1.5).
3. according to the described method of claim 1, it is characterized in that, in step (2); With acetone is solvent; Dissolving 3-(N-ethanoyl) aminoacetophenone and iodoethane, regulating the pH of mixed value is 7～8, reaction down refluxes; Reaction finishes the back with the dichloromethane extraction product, obtains 3-(N-ethyl-N-kharophen) methyl phenyl ketone;
Wherein, the mol ratio of 3-(N-ethanoyl) aminoacetophenone and iodoethane is (1～1.5): (2～2.5); The consumption of said solvent is 3-(N-ethanoyl) aminoacetophenone and iodoethane gross weight 3～4 times.
4. method according to claim 1; It is characterized in that; In step (3), with 3-(N-ethyl-N-kharophen) methyl phenyl ketone and N, the dinethylformamide dimethylacetal mixes; Refluxed 5～6 hours, and made N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide;
3-(N-ethyl-N-kharophen) methyl phenyl ketone and N wherein, the mol ratio of dinethylformamide dimethylacetal is (1～1.5): (1.5～2).
5. method according to claim 1; It is characterized in that; In said step (4), N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 3-amino-pyrazol-4-nitrile be dissolved in 30～35% the acetum, refluxed 5～6 hours; Product is cooled to 0～2 ℃ of crystallization, gets zaleplone;
Wherein, the mol ratio of N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 3-amino-pyrazol-4-nitrile is (0.8～1): (0.6～0.75); The consumption of acetum is N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 3-amino-pyrazol-4-nitrile gross weight 6～8 times.
6. according to the arbitrary described method of claim 1～5, it is characterized in that,
The mol ratio of said 3-aminoacetophenone, acetic acid and diacetyl oxide is (1.2～1.4): (2.25～2.42): (1.32～1.42);
The mol ratio of said 3-(N-ethanoyl) aminoacetophenone and iodoethane is (1.13～1.19): (2.31～2.38);
Said 3-(N-ethyl-N-kharophen) methyl phenyl ketone and N, the mol ratio of dinethylformamide dimethylacetal is (1.17～1.22): (1.6～1.8);
The mol ratio of said N-[3-(3-dimethylin-1-oxygen-2-propenyl-phenyl)]-N-ethyl acetamide and 3-amino-pyrazol-4-nitrile is (0.81～0.83): (0.69～0.74).
7. method according to claim 1 is characterized in that, described in the step (4) refining for the zaleplone dissolving crude product in 90～95% ethanolic soln; Be heated to 70～80 ℃ of insulation 20～40min after-filtration; Filtrating is cooled to 0～2 ℃ of crystallization, and drying gets zaleplone.
8. method according to claim 7 is characterized in that, zaleplone is dissolved in ethanolic soln after, in ethanolic soln, add earlier gac and decolour and refilter.
9. method according to claim 3 is characterized in that, with Pottasium Hydroxide or sodium hydrate regulator solution pH value.
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