CN101591338A - The synthetic method of indene - Google Patents
The synthetic method of indene Download PDFInfo
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- CN101591338A CN101591338A CNA2009101042072A CN200910104207A CN101591338A CN 101591338 A CN101591338 A CN 101591338A CN A2009101042072 A CNA2009101042072 A CN A2009101042072A CN 200910104207 A CN200910104207 A CN 200910104207A CN 101591338 A CN101591338 A CN 101591338A
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Abstract
The present invention relates to a kind of synthetic method of indene; described method is a starting raw material with 3-aminoacetophenone cheap and easy to get; 3-aminoacetophenone and acetic anhydride are transformed into 3-acetamido methyl phenyl ketone; gained 3-acetamido methyl phenyl ketone elder generation and Powdered potassium hydroxide effect; change N-methyl-N-(3-acetylphenyl) ethanamide with iodomethane reaction again, gained N-methyl-N-(3-acetylphenyl) ethanamide under the effect of sodium ethylate with ethyl formate react basic metal 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enolate.Gained basic metal 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enolate and (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone condensation synthesizing Indiplon.This method cost is low, reaction conditions is gentle, safety and environmental protection, be easy to suitability for industrialized production, and the gained indene can be used as soporific and is used for the insomnia treatment.
Description
Technical field
The present invention relates to the new synthetic method of indene; specifically; be a kind of be raw material with the 3-aminoacetophenone, through the method for basic metal 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enolate and (3-amino-1H-pyrazoles-4-yl)-efficient synthesizing Indiplon of 2-thiophene ketone condensation.
Technical background
" insomnia " is meant that the patient does not have enough sleep or feels all relevant uncomfortable states with sleep.Insomnia is a kind of common disease.The most direct consequence of insomnia causes the metabolic disorder of human body exactly, reduces production efficiency, causes that mood, behavior and psychomotor function aspects change; Insomnia and some other disease-related comprise the obstacle of dysthymia disorders, anxiety disorder, gi tract and cardiovascular systems etc. in addition.Last century, the long run test of the nineties Chicago University proved absolutely this point: the crowd of reception test, only allow to sleep 4 hours every night, and the test period span is 6 days.Found that their internal secretion ability and the response capacity of Regular Insulin descended 30% respectively, and the reduction significantly of these indexs, the early stage sign of diabetes often.Other has report, and long-term insomniac's serious mishap and wound incidence are obviously than normal people height.It is reported, the survey showed that for of carrying out in the adult of Los Angeles, in the field of investigation, there is 32% grownup to suffer from insomnia approximately, the result that same investigation is carried out Florida Alachua prefecture is at least 45% suffered from sleeping by investigation adult population report or keep the sleep state difficulty, in the investigated population in gondola San Marino, there is 13% crowd to suffer from insomnia approximately.The data of WHO shows that the whole world has nearly 1/4 people to be subjected to the insomnia puzzlement.Insomnia is relevant with individual age and sex, and sickness rate is than higher in more old individuality and women.Insomnia is a very general problem in China, and epidemiology survey shows that the sickness rate of adult's insomnia is 30～35%, and is particularly in the majority with women and old man.The survey data of Chinese Medical Association shows that China's somnopathy morbidity reaches 42.7%, has 300,000,000 middle-aged peoples to suffer from somnopathy approximately.
Insomnia is dealt with improperly, is a medical care problem, also is a social concern.On the traditional sense, the processing of insomnia is comprised the treatment and the alleviation of nosetiology factor, improve sleep quality and use soporific.At present, the treatment means of insomnia is mainly taked two kinds of pharmacological agent and non-drug therapies: the First Principles of non-drug therapy is " Sleep hygiene " (sleep hygiene), and this insomnia that a variety of causes is caused all is necessary; When Sleep hygiene and non-drug therapy were invalid when having a sleepless night serious, pharmacological agent just became first-selection.
The clinical medicine that is used for the treatment of insomnia mainly contains veronal and non-barbiturates, benzodiazepines, antihistaminic, antipsychotics and other tranquilizer at present, and wherein benzodiazepines is most widely used.Benzodiazepine mainly by with GABA (γ-An Jidingsuan) receptors bind, regulate the release of inhibitory nerve mediator GABA, weaken neuronic activity and play a role.But simultaneously since benzodiazepine to the GABA receptor subtype in conjunction with lacking selectivity, thereby often cause the generation of untoward reaction, as dysmnesia, next day still residual sedative effect, the place phenomenon etc. of sleeping being arranged.Therefore, develop that a kind of determined curative effect, untoward reaction are light, the medicine of quick acting has seemed very necessary.
In being used for the treatment of the patent drug of insomnia, the patent of the market leader Ambien of first non-benzodiazepine-present expired in 2007, and this will provide a huge market opportunity for the brand medicine of new generation after the improvement.Second non-benzodiazepine is Zaleplon (Zaleplone).The 3rd non-benzodiazepine is promptly by the common indene of developing (indiplon) of Pfizer and Neurocrine company, as a kind of novel Pyrazolopyrimidines type medicine, optionally with GABA
AAcceptor α
1The hypotype effect, this specific specificity is in conjunction with the generation that can reduce the untoward reaction that the benzodiazepines medicine had.The non-benzodiazepines that the indene conduct is developed recently is sedative hypnotic safely and effectively, rapid-action, action time is short, there are not the effect of obviously being still drank after a night, knock-on aypnia and Withrawal symptom, evident in efficacy and better tolerance, action time is of short duration also correspondingly to reduce untoward reaction, is insomniac's Gospel.Indene may become the gold standard (Gold standard) of sleep medicine.At present, indene has been finished III phase clinical study experiment, estimates and will at first go on the market in the U.S. in the near future.
Existing indene synthetic method, shortcoming such as reagent costliness, poor stability, long reaction time are arranged, yield is low, aftertreatment is loaded down with trivial details, as: the methylation reaction of acetamido, adopting sodium hydride usually is alkali, reagent costliness, dangerous, long reaction time; The enamine synthesis method is owing to use DMF-DMA, reagent costliness; Condensation reaction is Glacial acetic acid with an organic solvent, and sodium bicarbonate is used in aftertreatment, produces great amount of carbon dioxide gas, not only dangerous but also not environmental protection, and aftertreatment is loaded down with trivial details, it is extensive synthetic etc. to be difficult to.
The compound patent of indene sees the United States Patent (USP) (US Pat.NO.4521422) of the Dusza of American Cyanamid Co. application in 1985 the earliest, this patent report aryl and heterocyclic aryl [7-(aryl and heterocyclic aryl)-pyrazoles [1,5-a] pyrimidine] ketone compounds (II) as Mammals is had active new compound of calming soporific, anxiety and skeletal muscle relaxation and synthetic method thereof.Can get with replacing 3-dimethylin-2-propylene-1-ketone (b) condensation by substituted pyrazolecarboxylic (a).
Especially; at aryl and heterocyclic aryl [7-(aryl and heterocyclic aryl)-pyrazoles [1; 5-a] pyrimidine] in the ketone compounds (II), work as R2=H, the R3=thienyl; R5=H; R6=H, during R7=2-(N-methyl-N-ethanoyl amido) phenyl, the structure of II is an indene; its chemical name is N-methyl-N-[3-[3-(2-thiophene carbonyl)-pyrazoles-[1,5-α] pyrimidin-7-yl] phenyl] ethanamide.
The United States Patent (USP) (US Pat.NO.4626538) of the Dusza of American Cyanamid Co. in 1986 application is addressed key intermediate N-methyl-N-[3-[3-(dimethylin)-1-ketone-2-propenyl] phenyl] ethanamide 7 synthetic:
3-kharophen methyl phenyl ketone 2 generates N-[3-[3-(dimethylamino)-1-ketone-2-propenyl with the DMF-DMA reaction]-phenyl]-ethanamide 6, again under the NaH effect, with methyl iodide methylate key intermediate N-methyl-N-[3-[3-(the dimethylamino)-1-ketone-2-propenyl of synthesizing Indiplon]-phenyl] ethanamide 7.
The Tomcufcik of American Cyanamid Co. in 1996 reports the synthetic of another key intermediate (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone 5 in United States Patent (USP) (US Pat.NO.4900836):
Acetyl thiophene 8 generates 3-(N with the DMF-DMA reaction, the N-dimethyl) amino-1-(2-thiophene)-2-propylene-1-ketone 9,9 generate 5-(2-thiophene) isoxzzole 10 with the oxammonium hydrochloride reaction again, 5-(2-thiophene) isoxzzole 10 generates the 3-[(dimethylamino with the DMF-DMA reaction) methylene radical]-β-ketone-2-thiophene vinyl cyanide 11,11 and aminoguanidine nitrate reaction generate another key intermediate (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone 5 of synthesizing Indiplon.
The Dusza of the American Cyanamid Co. synthetic route that the reported first indene is complete in United States Patent (USP) (US Pat.NO.6399621) in 2002 and as sedative hypnotics, anxiolytic and skeletal muscle relaxant.The method that indene synthetic press the United States Patent (USP) (US Pat.NO.4900836) of the United States Patent (USP) (US Pat.NO.4626538) of Dusza and Tomcufcik be first two the key intermediate N-methyl-N-[3-[3-(dimethylamino) of synthesizing of raw material-1-ketone-2-propenyl with 3-kharophen methyl phenyl ketone 2 and 2-acetyl thiophene 8 respectively]-phenyl] ethanamide 7 and (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone 5,7 and 5 these two key intermediates condensation synthesizing Indiplon under the effect of Glacial acetic acid has been established indene synthetic basic line.
Brave (the Fan Shiyong of scholar Fan in 2006, the rice spring, what Xinhua, Li Song, Zheng Zhibing. synthesizing of novel sedative hypnotic indene. Chinese pharmaceutical chemistry magazine, 2006,16 (6), 363-365.) and Shao Qiurong (Shao Qiurong, Wu Jingchang. the synthesis technique of indene improves. Chinese practical medical magazine, 2006,6 (20), 1855-1857) synthetic this method of mainly continuing to use of report indene.
Lippa was synthetic at the indene of United States Patent (USP) (US Pat.NO.20080045547A) report in 2008, only at synthetic key intermediate N-methyl-N-[3-[3-(dimethylamino)-1-ketone-2-propenyl]-phenyl] during ethanamide 7, the order that methylates changes and reagent changes, 2 methylate earlier generates 3,3 form enamine 7 with the DMA-DMF reaction again, methylating reagent is a methyl tosylate, the synthetic same United States Patent (USP) of indene rest part (US Pat.NO.6399621).
The Gross of U.S. Neurocrine Biosciences company in 2002 has reported the novel method of seven kinds of synthesizing Indiplons in United States Patent (USP) (US Pat.NO.006472528B1): first method is, amino-pyrazol 12 generates bromo amino-pyrazol 13 with bromine reaction, 13 get bromo Pyrazolopyrimidine compound 14 with enamine 7 condensations in acetic acid, in the presence of zinc or magnesium 2-thiophene chloride 15 generate 2-thiophene zincons or Grignard reagent and 14 react indene, perhaps bromo Pyrazolopyrimidine compound 14 carries out Suzuki linked reaction synthesizing Indiplon with the 2-thienyl boric acid under carbon monoxide and palladium catalysis.
Second method is that amino-pyrazol 12 gets Pyrazolopyrimidine compound 17,17 with enamine 7 condensations and carries out the Friedel-Crafts synthesizing Indiplon with 2-thiophene chloride 15 under the aluminum chloride effect again in acetic acid.
The third method is that oxyethyl group methylene radical third dicyan 18 gets cyano group amino-pyrazol 19,19 with the hydrazine cyclization and exists
Acetic acid exists down and enamine 7 condensations get in the Pyrazolopyrimidine compound 20,20 cyano group and Grignard reagent thiophene magnesium bromide or the addition of 2-thiophene lithium, hydrolysis gets indene.
The 4th kind of method is amino-pyrazol ethyl formate 21 and 3-aldehyde radical methyl propionate or 3, and the condensation in the presence of acetic acid of 3-dimethoxy ethyl propionate generates Pyrazolopyrimidine compound 22,22 and gets the chloro pyrrole with phosphorus oxychloride reaction
Azoles and pyrimidine compound 23,23 and phenyl boronate 24 are carried out standard Suzuki linked reaction synthesizing pyrazole and pyrimidine methyl compound 25,25 and Grignard reagent thiophene magnesium bromide or the addition of 2-thiophene lithium, hydrolysis gets indene.
The 5th kind of method is the one kettle way synthesizing Indiplon; be 3-acetamido methyl phenyl ketone 2 elder generations and sodium hydride effect; change N-methyl-N-(3-acetylphenyl) ethanamide 3 with iodomethane reaction again; 3 mix with cyano compound 26, use dilution with toluene, add excessive DMF-DMA; back flow reaction; steam toluene and remove DMF-DMA and disappear to raw material, enamine 11 and 7 mixed solution, add aminoguanidine nitrate and sodium hydroxide and react to alkene
Amine 11 disappears, and adds acetic acid at reaction mixture, reacting by heating, and the product separation and purification gets indene, and in entire reaction course, reaction intermediate 11,7 does not need to separate from reaction system with 5 etc.
The new method that the 6th kind of method is key intermediate (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone 5 is synthetic,
Be methoxyl group propylene cyanogen 26; get amino-pyrazol 12 with hydrazine reaction; again with 2-thiophene chloride 15 react 12 amino acylate acid amides, acid amides adds thermal rearrangement and gets (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone 5,5 and get indene with enamine 7 condensation in acetic acid.
The 7th kind of method made the key intermediate of synthetic indene for selecting enamine Equivalent enol ether.3-kharophen methyl phenyl ketone 2 and triethyl orthoformate react enamine Equivalent enol ether 28; 28 under the sodium hydride effect; get key intermediate 29 with iodomethane reaction; another key intermediate carries out the Friedel-Crafts acylation reaction by thiophene and chloro-acetyl chloride and gets chloro acetyl thiophene 30, with potassium cyanide S takes place again
N2 react cyano group thing 26,26 and DMF-DMA or triethyl orthoformate reaction respectively enamine 11 or enol ether 31,11 or 31 and aminoguanidine nitrate react key intermediate 5,5 and 29 in acetic acid, reflux indene.
In sum, in the known synthetic method of indene, the place that synthetic route and synthesis technique come with some shortcomings is as long reaction time, severe reaction conditions, reagent costliness, severe toxicity, dangerous and environmental pollution etc.Therefore, the synthetic route of, safety low, efficient for cost of indene exploitation, environmental protection is being fit to scale operation, to the market development of indene with promote significant.
Summary of the invention
Purpose of the present invention provides a kind of indene synthetic method.The inventive method aftertreatment is simple, and cost is low, and the reaction times is short, reaction temperature and, be fit to suitability for industrialized production, also have the advantage of safety, environmental protection.
Technical scheme of the present invention is as follows:
Indene (I) synthetic method mainly comprises following steps:
1) temperature of reaction is under 0～room temperature, and 3-aminoacetophenone and acetic anhydride obtain 3-acetamido methyl phenyl ketone;
2) in the organic solvent, the 3-acetamido methyl phenyl ketone that obtains in the step 1) reacts with alkali metal hydroxide earlier, obtains N-methyl-N-(3-acetylphenyl) ethanamide with the methylating reagent reaction again;
3) temperature of reaction is 0～75 ℃, reaction conditions is anhydrous, with step 2) N-methyl-N-(3-acetylphenyl) ethanamide of obtaining earlier with the alkali metal alkoxide reaction, with the manthanoate reaction, obtain basic metal 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enolate again;
4) with water as reaction medium; temperature of reaction is under 5～65 ℃; the resulting basic metal 3-of step 3) (N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enolate obtains indene with (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone condensation under acidic conditions; the acid of adopting in the acidic conditions is concentrated hydrochloric acid or acetic acid, water: sour weight ratio is 2～15: 1.
The mass ratio of 3-aminoacetophenone described in the step 1) and diacetyl oxide is 1.3～2: 1.
Step 2) organic solvent described in is tetrahydrofuran (THF) or ether or trimethyl carbinol methyl ether or toluene.
Step 2) the described alkali metal hydroxide described in is Powdered potassium hydroxide; Described methylating reagent is methyl iodide or methyl-sulfate.
The weight ratio of 3-acetamido methyl phenyl ketone step 2) and Powdered potassium hydroxide, methyl iodide is 2～3: 1: 2～4.
Organic solvent described in the step 3) is ethanol or methyl alcohol.
Alkali metal alkoxide described in the step 3) is sodium ethylate or sodium methylate.
Manthanoate described in the step 3) is ethyl formate or methyl-formiate.
The weight ratio of described water of step 4) and concentrated hydrochloric acid is 3～15: 1, and the weight ratio of described water and acetic acid is 2～10: 1.
The synthetic method that indene of the present invention is new is the improvement to the existing synthetic method of indene.3-acetamido methyl phenyl ketone and DMF-DMA that this method changes existing route form enamine earlier; after the methylate order of condensation again; and after taking 3-acetamido methyl phenyl ketone to methylate earlier to generate N-methyl-N-(3-acetylphenyl) ethanamide 3; be transformed into basic metal 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enolate 4; enolate 4 again with the method for (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone 5 condensation synthesizing Indiplons, make the synthetic cost of indene lower; the reaction conditions milder; operate simpler; safety and environmental protection; be easier to suitability for industrialized production.
Compare with existing indene synthetic method, the present invention is a raw material with 3-aminoacetophenone 2, as solvent and acylating reagent, when preparation 3-acetamido methyl phenyl ketone, 0 ℃ is reacted to room temperature with the acetyl acid anhydride, no longer add other organic solvent, directly water is removed unreacted acetic acid, re-crystallizing in ethyl acetate, and the reaction times is short, the reaction conditions gentleness, aftertreatment is simple; 3-acetamido methyl phenyl ketone is in tetrahydrofuran (THF) or toluene, under the effect of Powdered potassium hydroxide, methylate and generate N-methyl-N-(3-acetylphenyl) ethanamide with iodomethane reaction, adopt Powdered potassium hydroxide to replace sodium hydride in the existing indene synthetic method, reagent cost is reduced greatly, and avoid using the unsafe factor of sodium hydride a large amount of releasing hydrogen gas in suitability for industrialized production and excellent yield; N-methyl-N-(3-acetylphenyl) ethanamide is elder generation and alkali metal alkoxide effect in alcoholic solution; react with manthanoate again; be transformed into basic metal 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enolate; adopt cheap ethyl formate to substitute expensive DMF-DMA; reagent cost is reduced greatly; and 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enol sodium salt is soluble in water; be difficult for the moisture absorption; stable; be easy to preserve; generating in the condensation reaction of indene with (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone condensation; use water as solvent; can avoid with an organic solvent reducing the consumption of acetic acid as far as possible; and in the condensation reaction generative process; the indene that generates is directly separated out from reaction system; destroy molecular balance; make condensation reaction towards the direction that generates indene, reaction is carried out more easily, and aftertreatment only needs filtration washing; recrystallization purifying is operated more simple effective; safety and environmental protection.
The synthesis material 3-aminoacetophenone that relates among the present invention is an important chemical material, and is with low cost, is easy to obtain.
Adopt diacetyl oxide under ice bath, the 3-aminoacetophenone to be carried out acetylize among the present invention; slowly drip diacetyl oxide; solved the problem of a large amount of heat releases of acetylization reaction; diacetyl oxide is not only made solvent but also make reaction reagent; remove excessive acetic anhydride via with frozen water; reaction product is through simple recrystallization purifying, simple to operate, environmental protection.
Adopt Powdered potassium hydroxide to make highly basic among the present invention, methyl-sulfate or methyl iodide are methylating reagent, reagent cheapness, reaction temperature and, aftertreatment simply, shortened the reaction times greatly, excellent yield.
Relate to the new key intermediate of synthesizing Indiplon among the present invention---the synthetic method of 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enol sodium salt; greatly improved the combined coefficient of key intermediate, had that cost is low, route is short, aftertreatment is simple, yield is high, be suitable for characteristics such as suitability for industrialized production.A large amount of synthetic of 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enol sodium salt are realized, are the synthetic solid foundation of having laid of indene.
The indene that relates among the present invention can be used as soporific and is used for the insomnia treatment.
The synthetic method that indene involved in the present invention is new has been simplified reactions steps, has that cost is low, reaction conditions is gentle, simple to operate, safety and environmental protection, more is applicable to the advantage of suitability for industrialized production.
Embodiment
Technical scheme of the present invention is:
With 3-aminoacetophenone cheap and easy to get is starting raw material; 3-aminoacetophenone and acetyl anhydride reactant are transformed into 3-acetamido methyl phenyl ketone; gained 3-acetamido methyl phenyl ketone elder generation and alkali metal hydroxide effect; particularly Powdered potassium hydroxide; again with methylating reagent; particularly iodomethane reaction changes N-methyl-N-(3-acetylphenyl) ethanamide; gained N-methyl-N-(3-acetylphenyl) ethanamide is in alkali metal alkoxide, particularly the existence of sodium ethylate down and manthanoate react described basic metal enolate.Basic metal 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enolate is synthetic with (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone condensation.
Method of the present invention is the preparation of indene:
(1) the 3-aminoacetophenone slowly drips the acetyl acid anhydride under 0～room temperature, reacts to be transformed into 3-acetamido methyl phenyl ketone in 2～5 hours, removes unreacted acetic acid with big water gaging, gets pure product with ethanol or re-crystallizing in ethyl acetate; Yield 90～99%.
(2) 3-acetamido methyl phenyl ketone is dissolved in tetrahydrofuran (THF) or the toluene, with Powdered potassium hydroxide reaction, changes N-methyl-N-(3-acetylphenyl) ethanamide in 5～12 hours with iodomethane reaction more earlier; the elimination inorganic salt; water washing is removed micro-product, the yield 85～95% of getting with toluene.Product can be directly used in next step reaction without being further purified.
(3) N-methyl-N-(3-acetylphenyl) ethanamide is dissolved in the alcohol; with the sodium ethylate reaction, with the ethyl formate reaction, be transformed into 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enol sodium salt more earlier; through dry pure product, the yield 80～92% of getting of absolute ethanol washing.
(4) amido-β-ketone phenylpropionaldehyde enol sodium salt is soluble in water for basic metal 3-(N-methyl-N-ethanoyl); under the effect of concentrated hydrochloric acid or 36% acetic acid; in room temperature with (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone condensation; reacted 2～5 hours; change indene into; with the frozen water washing, dry pure product, the yield 88～95% of getting.
Adopt method of the present invention can obtain the 3-aminoacetophenone of following structure:
Adopt method of the present invention can obtain N-methyl-N-(3-acetylphenyl) ethanamide of following structure:
Adopt method of the present invention can obtain 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enol sodium salt of following structure:
Adopt method of the present invention can obtain N-methyl-N-[3-[3-(2-thienyl carbonyl)-pyrazoles [1, the 5-a]-pyrimidin-7-yl of following structure]-phenyl] ethanamide (indene):
Help further to understand the present invention by following embodiment.
Material therefor, reagent and instrument
Agents useful for same is analytical pure in the present embodiment;
Institute responds and all follows the tracks of with thin-layer chromatography, the efficient tlc silica gel plate (model C F-254) that uses the yellow affair silica gel of Yantai City's Zhifu development experiments factory to be produced, phospho-molybdic acid, ammonium molybdate, potassium permanganate or iodine colour developing.
With the pre-treatment of sodium silk, the time spent all is back to blueness with sodium and benzophenone and steams stand-by tetrahydrofuran (THF) under nitrogen protection with preceding.
Fusing point is measured with the WRR fusing point instrument that Shanghai Precision Scientific Apparatus Co., Ltd produces.
All compounds
1HNMR is measured by the Mercury Plus-400 nuclear magnetic resonance spectrometer that U.S. Varian company produces, and mark in TMS does without specified otherwise, is all used CDCl
3Make solvent, δ value unit is ppm.
Embodiment 1Preparation 3-kharophen methyl phenyl ketone
In the 1000ml Erlenmeyer flask, add 318g m-aminophenyl ethyl ketone (2.356mol), under the ice bath, stir and slowly drip 166ml acetic anhydride (2.452mol) in following 2 hours, have a large amount of solids to separate out.TLC shows that raw material disappears, and with reaction mixture impouring 2500ml frozen water, suction filtration is washed with distilled water to neutrality, and is dry that light yellow solid 381.6 restrains.Fusing point: 125.6.～127.3 ℃; With 2000ml ethyl acetate heating for dissolving, elimination impurity while hot, filtrate is reduced to room temperature naturally.Separate out a large amount of solids, the ethyl acetate washing of suction filtration, ice, dry colourless granular crystalline 3-kharophen methyl phenyl ketone 351.9, the yield 96% of getting.Fusing point: 127.0.～128.4 ℃.
Product is through magnetic resonance detection, and data are as follows:
1HNMR (4OOMHz, CDCl
3) δ
Ppm: 2.220 (s, 3H, NHCOCH
3), 2.601 (s, 3H, COCH
3), 7.431 (t, 1H, J=7.6Hz, 3 '-H), 7.610 (br, H ,-NH), 7.691 (H, d, J=7.6Hz, 4 '-H), 7.925 (d, H, J=7.6Hz, 2 '-H), 8.004 (s, H, 6 '-H).
Embodiment 2Preparation N-methyl-N-(3-acetylphenyl) ethanamide
In the 250ml round-bottomed flask, add magneton, vacuum flame drying is chilled to room temperature, feeds N
2, add 11.128 gram Powdered KOH (0.199mol) fast, add tetrahydrofuran solution and 15ml methyl iodide (0.244mol) that 160ml contains 17.295 gram 3-acetamido methyl phenyl ketones (0.098mol), stirred overnight at room temperature.The elimination inorganic salt, 3 * 30ml water washing concentrates.40ml toluene is removed N-methyl-N-(3-acetylphenyl) ethanamide 17.593 grams that minor amount of water gets colorless oil, yield 94%.
Product is through magnetic resonance detection, and data are as follows:
1HNMR (400MHz, CDCl
3) δ
Ppm: 1.872 (s, 3H, COC
H 3), 2.625 (s, 3H, NCOCH
3), 3.280 (s, 3H, NCH
3), 7.402 (d, 2H, J=7.6Hz, 2 '-H), 7534 (t, 1H, J=7.6Hz, 3 '-H), 7.7.791 (s, H, 6 '-H), 7.913 (d, 1H, J=7.6Hz, 4 '-H);
Embodiment 3Preparation 3-(N-methyl N-ethanoyl) amido-β-ketone phenylpropionaldehyde enol sodium salt
Contain in ethanol (168.478mmol) solution of 11.457 gram sodium ethylates at 76ml; add 12.533 gram N-methyl-N-(3-acetylphenyl) ethanamides (65.618mmol); under room temperature; drip 8ml ethyl formate (98.246mmol), separate out a large amount of solids, stirred overnight at room temperature; suction filtration; use the 50ml absolute ethanol washing, get white powder solid 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enol sodium salt 13.916 grams, yield 88% in 40～45 ℃ of following vacuum-dryings.Fusing point: 246.4～247.9 ℃;
Product is through magnetic resonance detection, and data are as follows:
1HNMR (400MHz, DMSO) δ ppm:1.745 (s, 3H, COC
H 3), 3.138 (s, 3H, NCH
3), 7.256 (d, 1H, J=7.6Hz, 2 '-H), 7.367 (t, 1H, J=7.6Hz, 3 '-H), 7.567 (s, 1H, 6 '-H), 7.645 (d, 1H, J=7.6Hz, 4 '-H), 8.493 (s, 1H, 2-H), 9.364 (br, 1H, 1-H).
Embodiment 4Preparation (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone
United States Patent (USP) (US Pat.NO.4900836) and document (Fan Shiyong with reference to Tomcufcik, the rice spring, what Xinhua, Li Song, Zheng Zhibing. synthesizing of novel sedative hypnotic indene. Chinese pharmaceutical chemistry magazine, 2006,16 (6), 363-365.) with (Shao Qiurong, Wu Jingchang. the synthesis technique of indene improves. Chinese practical medical magazine, 2006,6 (20), 1855-1857) the report method is synthetic
1. prepare β-dimethylamino-1-(2-thiophene)-2-propylene-1-ketone
In the eggplant type bottle of 100ml, add the methanol solution 63.635g (0.143mol) of 13.039g acetyl thiophene (0.103mol) and DMF-DMA, the about 35h of reflux, concentrated except that desolvate the dark oil thing.Get yellowish brown rhombus shaped solid with re-crystallizing in ethyl acetate, dry β-dimethylamino-1-(2-thiophene)-2-propylene-1-ketone 15.486g, productive rate: 83.3%, Mp:113.3～114.9 ℃.
Product is through magnetic resonance detection, and data are as follows:
1HNMR (400MHz, CD
3Cl) δ
Ppm: 2.930 (s, 3H ,-CH
3), 3.138 (s, 3H ,-CH
3), 5.628 (d, 1H, J=12.4Hz ,-CHCO-), 7.073 (dd, 1H, J
1=3.6Hz, J
2=3.6Hz, 4-H), 7.479and 7.4665 (dd, 1H, J
1=0.8Hz, J
2=1.2Hz, 5-H), 7.63 (dd, 1H, J
1=1.2Hz, J
2=1.2Hz, CHN), 7.806 (d, 1H, J=12Hz, 3-H).
2. prepare 5-(2-thiophene) isoxzzole
In the 100ml eggplant type bottle, the mixture that adds 3.857g β-dimethylamino-1-(2-thiophene)-2-propylene-1-ketone (0.021mol) and 1.609g oxammonium hydrochloride (0.023mol), add 23ml methyl alcohol stirring and dissolving again, reflux 2.3h, be cooled to concentrate after the room temperature the solid oily matter of yellowish brown, add ethyl acetate, there are a large amount of solids to separate out, filter, wash solid with ethyl acetate, again it is concentrated and remove ethyl acetate, get orange-yellow oily thing 5-(2-thiophene) isoxzzole 3.224g, yield: 99.6%.
Product is through magnetic resonance detection, and data are as follows:
1HNMR (400MHz, CD
3Cl) δ
Ppm: 6.376 (d, 1H, J=2Hz, 2-H), 7.125 (dd, 1H, J
1=3.4Hz, J
2=5Hz, 4 '-H), 7.447 (dd, 1H, J
1=1.2Hz, J
2=4.6Hz, 5 '-H), 7.520 (dd, 1H, J
1=1.2Hz, J
2=3Hz, 3 '-H), 8.249 (d, 1H, J=2Hz,, 3-H).
3. prepare α-[(dimethylamino) methylene radical]-β-ketone-2-thiophene vinyl cyanide
The mixture that adds the methanol solution 19.379g (0.044mol) of 3.224g5-(2-thiophene) isoxzzole (0.021mol) and DMF-DMA in the 100ml eggplant type bottle, reflux 6h, in ice-water bath cooling down, there are a large amount of solids to separate out, add after a certain amount of petroleum ether and stirring staticly, filter, get orange/yellow solid, after the drying α-[(dimethylamino) methylene radical]-β-ketone-2-thiophene vinyl cyanide 3.834g, productive rate: 87.2%, Mp:144.4～146.8 ℃.
Product is through magnetic resonance detection, and data are as follows:
1HNMR (400MHz, CD
3Cl) δ
Ppm: 3.313 (s, 3H ,-CH
3), 3.504 (s, 3H ,-CH
3), 7.120 and 7.107 (dd, 1H, J
1=3.91Hz, J
2=3.9Hz, 4-H), 7.582 (dd, 1H, J
1=0.97Hz, J
2=0.97Hz, 5-H), 8.045 (S, 1H, CHN), 8.2065 (dd, 1H, J
1=0.97Hz, J
2=0.97Hz, 3-H)
4. prepare (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone
Add 1.028g α-[(dimethylamino) methylene radical]-β-ketone-2-thiophene vinyl cyanide (0.005mol) and 1.237g sulfuric acid aminoguanidine salt (0.005mol) mixture in the 50ml eggplant type bottle, add dehydrated alcohol 20ml, stir not exclusively dissolving, add 0.429g (0.01mol) sodium hydroxide reflux 14h, concentrate to remove and desolvate, add 10ml distilled water, stir, there are a large amount of solids to separate out, filter, dry (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone 0.868g, productive rate: 90.1%, Mp:141.4～143.8 ℃.
Product is through magnetic resonance detection, and data are as follows:
1HNMR (400MHz, CD
3OD) δ
Ppm: 7.1955 (d, 1H, J=3.6Hz, 7-H), 7.2085 (d, 1H, J=3.6Hz, 4-H), 7.7495 (d, 1H, J=1.2Hz ,-NH
2), 7.7615 (d, 1H, J=1.2Hz, NH
2), 7.8515 (d, 1H, J=1.2Hz, 2-H), 7.8605 (d, 1H, J=1.2Hz, 3-H), 7.873 (s, 1H, NH)
Embodiment 5Preparation N-methyl-N-[3-[3-(2-thienyl carbonyl)-pyrazoles [1,5-a]-pyrimidin-7-yl]-phenyl] ethanamide (indene)
2.552 gram (3-amino-1H-pyrazoles-4-yl)-2-thienyl ketone (13.22mmol); be dissolved in 36ml 36% acetate, under the room temperature, dropping contains the aqueous solution that 10ml contains 3.657 gram 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enol sodium salts (15.17mmol); stirring at room 2～5 hours; there are a large amount of light yellow solids to separate out, add the 30ml frozen water, stir half an hour; suction filtration; with the washing of 20ml frozen water, dry that light yellow granular crystalline indene 4.237 restrains yield 85%.Fusing point: 179.5～183.6 ℃.
Product is through magnetic resonance detection, and data are as follows:
1HNMR (400MHz, CDCl
3) δ
Ppm: 2.015 (s, 3H ,-COCH
3), 3.363 (s, 3H ,-NCH
3), 7.1645 (d, 1H, J=4.4Hz, 13-H), 7.224 and 7.2115 (dd, 1H, J
1=4Hz, J
2=3.6Hz, 14-H), 7.475 (d, 1H, J=8Hz, 15-H), 7.680 (t, 1H, J=8Hz, 16-H), 7.7215 (dd, 1H, J
1=1.2Hz, J
2=1.2Hz, 3-H), 7.9946 (t, 2H, J=1.6Hz, 4-H or 9-H), 8.104and 8.0945 (dd, 1H, J
1=0.8Hz, J
2=1.2Hz, 2-H), 8.729 (s, 1H, 11-H), 8.8485 (d, H, J=2.2Hz, 10-H)
Conclusion: adopt the indene of the inventive method preparation, structure is correct, the recovery rate height.It is simple that the inventive method has aftertreatment, and the reaction times is short, and cost is lower, reaction conditions milder, operation are simpler, safety and environmental protection, be easier to the advantage of suitability for industrialized production.
Should be realized that,, can under the situation that does not break away from principle of the present invention and scope, carry out various improvement although narrated specific embodiment of the present invention at this for illustrative purposes.Therefore.The present invention is unrestricted except appended claim.
Claims (9)
1. the synthetic method of an indene is characterized in that comprising following steps:
1) temperature of reaction is under 0～room temperature, and 3-aminoacetophenone and acetic anhydride obtain 3-acetamido methyl phenyl ketone;
2) in the organic solvent, the 3-acetamido methyl phenyl ketone that obtains in the step 1) reacts with Powdered potassium hydroxide earlier, obtains N-methyl-N-(3-acetylphenyl) ethanamide with the methylating reagent reaction again;
3) temperature of reaction is 0～75 ℃, reaction conditions is anhydrous, with step 2) N-methyl-N-(3-acetylphenyl) ethanamide of obtaining earlier with the alkali metal alkoxide reaction, with the manthanoate reaction, obtain basic metal 3-(N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enolate again;
4) with water as reaction medium; temperature of reaction is under 5～65 ℃; the resulting basic metal 3-of step 3) (N-methyl-N-ethanoyl) amido-β-ketone phenylpropionaldehyde enolate obtains indene with (3-amino-1H-pyrazoles-4-yl)-2-thiophene ketone condensation under acidic conditions; the acid of adopting in the acidic conditions is concentrated hydrochloric acid or acetic acid, water: sour weight ratio is 2～15: 1.
2. method according to claim 1, the weight ratio that it is characterized in that 3-aminoacetophenone described in the step 1) and diacetyl oxide is 1.3～2: 1.
3. method according to claim 1 is characterized in that step 2) described in organic solvent be tetrahydrofuran (THF) or ether or trimethyl carbinol methyl ether or toluene.
4. method according to claim 1 is characterized in that step 2) described in described methylating reagent be methyl iodide or methyl-sulfate.
5. method according to claim 1 is characterized in that step 2) described in 3-acetamido methyl phenyl ketone and the weight ratio of Powdered potassium hydroxide, methyl iodide be 2～3: 1: 2～4.
6. method according to claim 1 is characterized in that the organic solvent described in the step 3) is ethanol or methyl alcohol.
7. method according to claim 1 is characterized in that the alkali metal alkoxide described in the step 3) is sodium ethylate or sodium methylate.
8. method according to claim 1 is characterized in that the manthanoate described in the step 3) is ethyl formate or methyl-formiate.
9. method according to claim 1, the weight ratio that it is characterized in that water described in the step 4) and concentrated hydrochloric acid is 3～15: 1, the weight ratio of described water and acetic acid is 2～10: 1.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101870700A (en) * | 2010-05-24 | 2010-10-27 | 中国人民解放军第三军医大学 | Method for synthesizing Indiplon |
| CN102516250A (en) * | 2011-12-22 | 2012-06-27 | 安润医药科技（苏州）有限公司 | Synthesizing method of compound zaleplon |
| CN102675320A (en) * | 2011-03-16 | 2012-09-19 | 中国人民解放军军事医学科学院毒物药物研究所 | Process for synthesizing indiplon serving as sedative hypnotic medicine suitable for industrial production |
| CN103922947A (en) * | 2014-04-21 | 2014-07-16 | 江西师范大学 | New method for synthesizing N,N-disubstituted enaminone compound |
| CN104016988A (en) * | 2014-06-05 | 2014-09-03 | 临海市利民化工有限公司 | Preparation method of indiplon |
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2009
- 2009-06-30 CN CN2009101042072A patent/CN101591338B/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101870700A (en) * | 2010-05-24 | 2010-10-27 | 中国人民解放军第三军医大学 | Method for synthesizing Indiplon |
| CN101870700B (en) * | 2010-05-24 | 2012-05-23 | 中国人民解放军第三军医大学 | Method for synthesizing Indiplon |
| CN102675320A (en) * | 2011-03-16 | 2012-09-19 | 中国人民解放军军事医学科学院毒物药物研究所 | Process for synthesizing indiplon serving as sedative hypnotic medicine suitable for industrial production |
| CN102516250A (en) * | 2011-12-22 | 2012-06-27 | 安润医药科技（苏州）有限公司 | Synthesizing method of compound zaleplon |
| CN103922947A (en) * | 2014-04-21 | 2014-07-16 | 江西师范大学 | New method for synthesizing N,N-disubstituted enaminone compound |
| CN103922947B (en) * | 2014-04-21 | 2015-06-17 | 江西师范大学 | New method for synthesizing N,N-disubstituted enaminone compound |
| CN104016988A (en) * | 2014-06-05 | 2014-09-03 | 临海市利民化工有限公司 | Preparation method of indiplon |
| CN104016988B (en) * | 2014-06-05 | 2016-04-13 | 临海市利民化工有限公司 | A kind of preparation method of indene |
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| Publication number | Publication date |
|---|---|
| CN101591338B (en) | 2011-07-20 |
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