CN102382006A - Synthesis method of 2-[2-(4-fluorophenyl)-2-oxa-1-phenylethyl]-4-methyl-3-oxa-N-phenylpentanamide - Google Patents
Synthesis method of 2-[2-(4-fluorophenyl)-2-oxa-1-phenylethyl]-4-methyl-3-oxa-N-phenylpentanamide Download PDFInfo
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Abstract
The invention discloses a synthesis method of 2-[2-(4-fluorophenyl)-2-oxa-1-phenylethyl]-4-methyl-3-oxa-N-phenylpentanamide. The method is characterized by comprising the following steps: firstly preparing methyl isobutyryl acetate from toluene, sodium hydride, dimethyl cabonate, methyl isopropyl ketone and the like as raw materials; then preparing isobutyryl acetanilide from toluene, methyl isobutyl acetate, HCl, sodium bicarbonate and the like as raw materials; preparing 4-fluorophenylacetophenone from aluminium choride, phenylacetyl chloride and the like as raw materials; preparing 2-chloro-1-(4-fluorophenyl)-acetophenone from 4-fluorophenylacetophenone, dichloromethane, chlorine and the like as raw materials; and finally preparing the finished product from isobutyryl acetanilide, potassium carbonate and 2-chloro-1-(4-fluorophenyl)-acetophenone. The raw materials of the synthesis method are inexpensive and easily available, the reaction has five steps and the yield of each step is high, thus the production cost can be greatly reduced; and the reaction conditions are mild, the method can be controlled easily, the process is simple, the pollution is low and the method is suitable for industrial production.
Description
Technical field
The present invention relates to the compound method of a kind of medicine intermediate 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide.
Background technology
2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide is the key intermediate of synthetic A Fatating, and A Fatating is a reductase inhibitor, is the efficient hypolipidemic of a new generation.This medicine can not only reducing cholesterol, and can triglyceride reducing, and its effect is far superior to other statinses, has vast market prospect.
The synthetic route of public reported 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide is more; The wherein industriallization or three routes that mainly contain: be to be that raw material carries out the Knoevenagel condensation with phenyl aldehyde under the catalysis of Beta-alanine 1, with the isobutyryl Acetanilide with industrial applications prospect; Condensation product carries out the Stetter addition with p-Fluorobenzenecarboxaldehyde under 4-methyl-3-ethyl-5-thiazoleethanol bromination quaternary ammonium salt catalysis can obtain the targeted product; The p-Fluorobenzenecarboxaldehyde price of using in this method is more expensive; Be not suitable for scale operation, and the used catalyzer of Stetter addition is difficult to also obtain; 2, be to obtain α-bromo-4-fluorophenyl methyl phenyl ketone through Friedel-Crafts reaction and bromo-reaction by phenyllacetyl chloride and fluorobenzene; Under the sodium ethylate effect, obtain 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide with the condensation of isobutyryl Acetanilide; This method raw material is easy to get, and it is higher that each goes on foot reaction yield.But condensation reaction uses sodium ethylate to be highly basic, requires anhydrous condition, and reaction conditions is relatively harsher, and by product is many, is not easy to purify.The raw material isobutyryl Acetanilide that uses is to be starting raw material with ethyl isobutyryl in two kinds of methods; Aminolysis obtains under quadrol catalysis with aniline; This reaction needed 24h could accomplish, and yield is also on the low side, and ethyl isobutyryl is domestic does not also have a supply of commodities; 3, be the synthetic ethyl isobutyryl of raw material with the isopropylformic acid, each goes on foot reaction yield neither be very high, and aminolysis reaction does not add quadrol; Replace toluene to make solvent with dimethyl benzene, reaction 2h can accomplish, and yield is good slightly than second method; Condensation reaction is used salt of wormwood instead as highly basic, replaces DMF with acetone.(East China University of Science's chemistry and pharmacy institute, Shanghai 200237) reduced cost though reduce relative method 2, simplified step, but its productive rate is still not high.
Summary of the invention
Technical problem to be solved by this invention is the deficiency to prior art, and the compound method of the 2-that a kind of method is more reasonable, workable, productive rate is high [2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide is provided.
Technical problem to be solved by this invention is to realize through following technical scheme.The present invention is the compound method of a kind of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide, is characterized in that its step is following:
(1) preparation of isobutyryl methyl acetate:
Under the nitrogen protection, suction toluene in reaction flask adds sodium hydride, and described sodium hydride is scattered in the MO, and its quality solubility is 40-60%; Under agitation, the suction methylcarbonate is warmed up to 50-60 ℃; It is 40-60% that Methyl isobutyl ketone is dissolved in the dense thing of toluene to its quality, and beginning slowly drips the toluene mixing solutions of Methyl isobutyl ketone, after dropwising, is incubated 1-3 hour; Sampling TLC follows the tracks of, and reaction cools to 15-20 ℃ after finishing, and slowly drips water, and after dropwising, pouring reaction solution into mass concentration is in the 50-70% hydrochloric acid soln, has great amount of carbon dioxide gas to produce; The mass ratio of described toluene (the toluene amount that adds does not for the first time contain the amount that adds in the follow-up mixing solutions), sodium hydride, methylcarbonate, Methyl isobutyl ketone, water and hydrochloric acid soln is 1000:100-120: 300-310:120-140:190-210:700-900;
After the layering, water layer merges organic layer with an amount of methylbenzene extraction 2-3 time, washs organic layer with suitable quantity of water, uses an amount of saturated common salt water washing organic layer again; Underpressure distillation obtains the isobutyryl methyl acetate;
(2) preparation of isobutyryl Acetanilide:
Under nitrogen protection, suction toluene in reaction flask, the isobutyryl methyl acetate is warming up to 70-80 ℃, collects toluene and methanol azeotrope, reaction 11-12h; Be cooled to 10-20 ℃, regulate pH to 1-2 with 10-20%HCl; Stir 20-40min, leave standstill 20-40min, layering; Organic layer is washed once with an amount of, and organic layer adds the 3-4% sodium hydrogen carbonate solution, stirs 20-40min, leaves standstill 20-40min, layering, and organic layer is evaporated to the dried isobutyryl Acetanilide that obtains;
The mass ratio of described toluene, isobutyryl methyl acetate, HCl and sodium hydrogen carbonate solution is 1100-1200:295-305: 110-120:4-6;
(3) preparation of 4-fluorophenyl methyl phenyl ketone:
In reaction flask, add aluminum chloride, fluorobenzene, under ice-water bath, drip phenyllacetyl chloride, temperature is controlled at below 40 ℃; Be warming up to 80 ℃, insulated and stirred 3-5 hour, it is complete that TLC analyzes raw material reaction, reduces to room temperature, gets dark green solution; In the mixture of the hydrochloric acid of impouring trash ice and 2mol/L, controlled temperature is below 60 ℃, layering; Organic layer adds saturated sodium bicarbonate and regulates pH, layering; Water layer is carried with an amount of fluorobenzene is counter, merges organic layer, is concentrated into driedly, adds an amount of sherwood oil recrystallization, 4-fluorophenyl methyl phenyl ketone;
The mass ratio of described aluminum chloride, fluorobenzene (the fluorobenzene amount that adds for the first time, the amount that adds when not containing follow-up counter carrying), phenyllacetyl chloride, trash ice, hydrochloric acid and saturated sodium bicarbonate is 150:600-630:210-230:550-650:340-380:110-130;
(4) preparation of 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone:
In reaction flask, add 4-fluorophenyl methyl phenyl ketone, methylene dichloride feeds chlorine under the room temperature, when 4-fluorophenyl methyl phenyl ketone has reacted, in reaction kettle, adds the sodium sulfite solution of 8-15%, adds saturated sodium bicarbonate and regulates pH; Layering, organic layer add suitable quantity of water washing again, concentrate oily matter 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone;
The mass ratio of described 4-fluorophenyl methyl phenyl ketone, methylene dichloride, chlorine, sodium sulfite solution and saturated sodium bicarbonate is 260-280:2100-2500:90-120: 650-680;
(5) preparation of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide:
The isobutyryl Acetanilide is added in the reaction vessel, add Virahol again, ice-water bath is cooled to 0-5 ℃, adds salt of wormwood; Temperature remains on 0-5 ℃, drips and presses 2-chloro-1-(4-the fluorophenyl)-methyl phenyl ketone of 1:0.9-1.1 mixed and the mixing solutions of Virahol, is warming up to 60-65 ℃ after dripping off, insulated and stirred 10-15 hour; The mass ratio of described isobutyryl Acetanilide, Virahol (the Virahol amount that adds does not for the first time contain the amount that adds in the follow-up mixing solutions), salt of wormwood and 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone is 350-400:650-750:120-160:270-300;
TLC analyzes 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone and reacts completely; Reaction solution is concentrated into dried, adds suitable quantity of water and ETHYLE ACETATE, layering; Water layer once merges organic layer and is concentrated into driedly with counter the carrying of an amount of ETHYLE ACETATE, adds the making beating of an amount of Virahol, filters, and solid adds an amount of recrystallizing methanol, 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide.
In the compound method technical scheme of the present invention:
1, in step (1): the mass ratio of described toluene (the toluene amount that adds does not for the first time contain the amount that adds in the follow-up mixing solutions), sodium hydride, methylcarbonate, Methyl isobutyl ketone, water and hydrochloric acid soln is preferably 1000:112: 305:130:200:800.
2, in step (2): the mass ratio of described toluene, isobutyryl methyl acetate, HCl and sodium hydrogen carbonate solution is preferably 1170:301: 117:5.
3, in step (3): the mass ratio of described aluminum chloride, fluorobenzene (the fluorobenzene amount that adds for the first time, the amount that adds when not containing follow-up counter carrying), phenyllacetyl chloride, trash ice, hydrochloric acid and saturated sodium bicarbonate is 150:613:219:600:360:120.
4, in step (4): the mass ratio of described 4-fluorophenyl methyl phenyl ketone, methylene dichloride, chlorine, sodium sulfite solution and saturated sodium bicarbonate is preferably 278:2300:105: 665.
5, in step (5): the mass ratio of described isobutyryl Acetanilide, Virahol (the Virahol amount that adds does not for the first time contain the amount that adds in the follow-up mixing solutions), salt of wormwood and 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone is preferably 375:700:140:283.8.
The synthetic route of compound method of the present invention is following:
Compared with prior art, the present invention has the following advantages:
(1) adopting Methyl isobutyl ketone and methylcarbonate is raw material, and synthetic ethyl isobutyryl uses chlorine to substitute the bromine in original technology in Synthetic 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone; Be convenient to operation; And cost reduces, and raw material is cheap and easy to get, and reaction has five steps; But per step yield is all very high, greatly reduces production cost;
(2) reaction conditions is gentle, is easy to control, and technology is simple, pollutes for a short time, helps realizing suitability for industrialized production;
(3) in last condensation reaction, replace sodium ethylate, avoided anhydrous condition, be convenient to control, and avoided the use of costliness or highly toxic substance with yellow soda ash.
Embodiment
Below further describe concrete technical scheme of the present invention,, and do not constitute restriction its right so that those skilled in the art understands the present invention further.
Embodiment 1, the compound method of a kind of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide, and its step is following:
(1) preparation of isobutyryl methyl acetate:
Under the nitrogen protection, suction toluene in reaction flask adds sodium hydride, and described sodium hydride is scattered in the MO, and its quality solubility is 40%; Under agitation, the suction methylcarbonate is warmed up to 50 ℃; It is 40% that Methyl isobutyl ketone is dissolved in the dense thing of toluene to its quality, and beginning slowly drips the toluene mixing solutions of Methyl isobutyl ketone, after dropwising, is incubated 1 hour; Sampling TLC follows the tracks of, and reaction cools to 15 ℃ after finishing, and slowly drips water, and after dropwising, pouring reaction solution into mass concentration is in 50% hydrochloric acid soln, has great amount of carbon dioxide gas to produce; The mass ratio of described toluene, sodium hydride, methylcarbonate, Methyl isobutyl ketone, water and hydrochloric acid soln is 1000:100: 300:120:190:700;
After the layering, water layer merges organic layer with an amount of methylbenzene extraction 2 times, washs organic layer with suitable quantity of water, uses an amount of saturated common salt water washing organic layer again; Underpressure distillation obtains the isobutyryl methyl acetate;
(2) preparation of isobutyryl Acetanilide:
Under nitrogen protection, suction toluene in reaction flask, the isobutyryl methyl acetate is warming up to 70 ℃, collects toluene and methanol azeotrope, reaction 11h; Be cooled to 10 ℃, regulate pH to 1 with 10%HCl; Stir 20min, leave standstill 20min, layering; Organic layer is washed once with an amount of, and organic layer adds 3% sodium hydrogen carbonate solution, stirs 20min, leaves standstill 20min, layering, and organic layer is evaporated to the dried isobutyryl Acetanilide that obtains;
The mass ratio of described toluene, isobutyryl methyl acetate, HCl and sodium hydrogen carbonate solution is 1100:295: 110:4;
(3) preparation of 4-fluorophenyl methyl phenyl ketone:
In reaction flask, add aluminum chloride, fluorobenzene, under ice-water bath, drip phenyllacetyl chloride, temperature is controlled at below 40 ℃; Be warming up to 80 ℃, insulated and stirred 3 hours, it is complete that TLC analyzes raw material reaction, reduces to room temperature, gets dark green solution; In the mixture of the hydrochloric acid of impouring trash ice and 2mol/L, controlled temperature is below 60 ℃, layering; Organic layer adds saturated sodium bicarbonate and regulates pH, layering; Water layer is carried with fluorobenzene is counter, merges organic layer, is concentrated into driedly, adds an amount of sherwood oil recrystallization, 4-fluorophenyl methyl phenyl ketone;
The mass ratio of described aluminum chloride, fluorobenzene, phenyllacetyl chloride, trash ice, hydrochloric acid and saturated sodium bicarbonate is 150:600:210:550:340:110;
(4) preparation of 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone:
In reaction flask, add 4-fluorophenyl methyl phenyl ketone, methylene dichloride feeds chlorine under the room temperature, when 4-fluorophenyl methyl phenyl ketone has reacted, in reaction kettle, adds 8% sodium sulfite solution, adds saturated sodium bicarbonate and regulates pH; Layering, organic layer add suitable quantity of water washing again, concentrate oily matter 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone;
The mass ratio of described 4-fluorophenyl methyl phenyl ketone, methylene dichloride, chlorine, sodium sulfite solution and saturated sodium bicarbonate is 260:2100:90: 650;
(5) preparation of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide:
The isobutyryl Acetanilide is added in the reaction vessel, add Virahol again, ice-water bath is cooled to 0 ℃, adds salt of wormwood; Temperature remains on 0 ℃, drips and presses 2-chloro-1-(4-the fluorophenyl)-methyl phenyl ketone of 1:0.9 mixed and the mixing solutions of Virahol, is warming up to 60 ℃ after dripping off, insulated and stirred 10 hours; The mass ratio of described isobutyryl Acetanilide, Virahol, salt of wormwood and 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone is 350:650:120:270;
TLC analyzes 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone and reacts completely; Reaction solution is concentrated into dried, adds suitable quantity of water and ETHYLE ACETATE, layering; Water layer once merges organic layer and is concentrated into driedly with counter the carrying of an amount of ETHYLE ACETATE, adds the making beating of an amount of Virahol, filters, and solid adds an amount of recrystallizing methanol, 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide.
Embodiment 2, the compound method of a kind of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide, and its step is following:
(1) preparation of isobutyryl methyl acetate:
Under the nitrogen protection, suction toluene in reaction flask adds sodium hydride, and described sodium hydride is scattered in the MO, and its quality solubility is 60%; Under agitation, the suction methylcarbonate is warmed up to 60 ℃; It is 60% that Methyl isobutyl ketone is dissolved in the dense thing of toluene to its quality, and beginning slowly drips the toluene mixing solutions of Methyl isobutyl ketone, after dropwising, is incubated 3 hours; Sampling TLC follows the tracks of, and reaction cools to 20 ℃ after finishing, and slowly drips water, and after dropwising, pouring reaction solution into mass concentration is in 70% hydrochloric acid soln, has great amount of carbon dioxide gas to produce; The mass ratio of described toluene, sodium hydride, methylcarbonate, Methyl isobutyl ketone, water and hydrochloric acid soln is 1000:120: 310:140:210:900;
After the layering, water layer merges organic layer with an amount of methylbenzene extraction 3 times, washs organic layer with suitable quantity of water, uses an amount of saturated common salt water washing organic layer again; Underpressure distillation obtains the isobutyryl methyl acetate;
(2) preparation of isobutyryl Acetanilide:
Under nitrogen protection, suction toluene in reaction flask, the isobutyryl methyl acetate is warming up to 80 ℃, collects toluene and methanol azeotrope, reaction 12h; Be cooled to 20 ℃, regulate pH to 2 with 20%HCl; Stir 40min, leave standstill 20-40min, layering; Organic layer is washed once with an amount of, and organic layer adds 4% sodium hydrogen carbonate solution, stirs 40min, leaves standstill 40min, layering, and organic layer is evaporated to the dried isobutyryl Acetanilide that obtains;
The mass ratio of described toluene, isobutyryl methyl acetate, HCl and sodium hydrogen carbonate solution is 1200:305: 120:6;
(3) preparation of 4-fluorophenyl methyl phenyl ketone:
In reaction flask, add aluminum chloride, fluorobenzene, under ice-water bath, drip phenyllacetyl chloride, temperature is controlled at below 40 ℃; Be warming up to 80 ℃, insulated and stirred 5 hours, it is complete that TLC analyzes raw material reaction, reduces to room temperature, gets dark green solution; In the mixture of the hydrochloric acid of impouring trash ice and 2mol/L, controlled temperature is below 60 ℃, layering; Organic layer adds saturated sodium bicarbonate and regulates pH, layering; Water layer is carried with fluorobenzene is counter, merges organic layer, is concentrated into driedly, adds an amount of sherwood oil recrystallization, 4-fluorophenyl methyl phenyl ketone;
The mass ratio of described aluminum chloride, fluorobenzene, phenyllacetyl chloride, trash ice, hydrochloric acid and saturated sodium bicarbonate is 150:630:230:650:380:130;
(4) preparation of 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone:
In reaction flask, add 4-fluorophenyl methyl phenyl ketone, methylene dichloride feeds chlorine under the room temperature, when 4-fluorophenyl methyl phenyl ketone has reacted, in reaction kettle, adds 15% sodium sulfite solution, adds saturated sodium bicarbonate and regulates pH; Layering, organic layer add suitable quantity of water washing again, concentrate oily matter 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone;
The mass ratio of described 4-fluorophenyl methyl phenyl ketone, methylene dichloride, chlorine, sodium sulfite solution and saturated sodium bicarbonate is 280:2500:120: 680;
(5) preparation of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide:
The isobutyryl Acetanilide is added in the reaction vessel, add Virahol again, ice-water bath is cooled to 5 ℃, adds salt of wormwood; Temperature remains on 5 ℃, drips and presses 2-chloro-1-(4-the fluorophenyl)-methyl phenyl ketone of 1:1.1 mixed and the mixing solutions of Virahol, is warming up to 65 ℃ after dripping off, insulated and stirred 15 hours; The mass ratio of described isobutyryl Acetanilide, Virahol, salt of wormwood and 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone is 400:750:160:300;
TLC analyzes 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone and reacts completely; Reaction solution is concentrated into dried, adds suitable quantity of water and ETHYLE ACETATE, layering; Water layer once merges organic layer and is concentrated into driedly with counter the carrying of an amount of ETHYLE ACETATE, adds the making beating of an amount of Virahol, filters, and solid adds an amount of recrystallizing methanol, 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide.
Embodiment 3,2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide compound experiment.
1, the preparation of isobutyryl methyl acetate:
Under the nitrogen protection, suction 1000g toluene in reaction flask adds 112 g sodium hydrides and (is scattered in the MO; Content 50%), stir down suction 305 g methylcarbonates; Be warmed up to 50-60 ℃, the 130g Methyl isobutyl ketone is dissolved in the 260g toluene, and beginning slowly drips the toluene mixing solutions of Methyl isobutyl ketone; About 5 hours of the dropping time of control, after dropwising, be incubated 1 hour.Sampling TLC follows the tracks of, and reaction cools to 15-20 ℃ after finishing, and slowly drips 200g water, after dropwising, pours reaction solution in the mixing solutions of 300g concentrated hydrochloric acid and 500g water, has great amount of carbon dioxide gas to produce.Layering, water layer merge organic layer with 4010g methylbenzene extraction twice, with 400g water washing organic layer, use 400g saturated common salt water washing organic layer again.Underpressure distillation obtains isobutyryl methyl acetate 199.6 Kg, yield 91.5%.
2, the preparation of isobutyryl Acetanilide
Under nitrogen protection, suction 1170g toluene in reaction flask, 301 g isobutyryl methyl acetates are warming up to 70-80 ℃, collect toluene and methanol azeotrope, and reaction 11-12h is qualified to middle control.Be cooled to 10-20 ℃, regulate PH to 1-2 with 117g 15%HCl, repetition measurement PH behind the 15min is until qualified; Stir 30min, leave standstill 30min, layering, organic layer is with the 300g washing once; Organic layer adds 5 g, 3% sodium hydrogencarbonate, stirs 30min, leaves standstill 30min; Layering, organic layer are evaporated to dried isobutyryl Acetanilide 407g, the yield 95% of obtaining.
3, the preparation of 4-fluorophenyl methyl phenyl ketone
In reaction flask, add 150 g aluminum chlorides, 613 g fluorobenzene under ice-water bath, drip 219 g phenyllacetyl chlorides, and temperature is controlled at below 40 ℃, drips off in about 5 hours.Be warming up to 80 ℃, insulated and stirred 3-5 hour, it is complete that TLC analyzes raw material reaction, reduces to room temperature, gets dark green solution, and in the mixture of the hydrochloric acid of impouring 600 g trash ices and 360Lg 2mol/L, heat release is obvious, and temperature is controlled at (it is orange that solution is) below 60 ℃.Layering, organic layer add the 120g saturated sodium bicarbonate and regulate PH, layering.The g fluorobenzene is counter carries with 50 for water layer, merges organic layer, is concentrated into driedly, adds 400g sherwood oil recrystallization, 4-fluorophenyl methyl phenyl ketone 289 g, yield 95.1%.
4, the preparation of 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone
In reaction flask, add 4-fluorophenyl methyl phenyl ketone 278 g, methylene dichloride 2300g feeds 105 g chlorine under the room temperature; The consumption of strict control chlorine when middle control 4-fluorophenyl methyl phenyl ketone has reacted, adds the sodium sulfite solution of 665g10% in reaction kettle; Add the 665g saturated sodium bicarbonate and regulate PH, layering, organic layer adds the 500g water washing again; Concentrate oily matter 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone 317.5 g, yield 97%.
5, the preparation of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide
375g isobutyryl Acetanilide is added in the reaction flask, add 700 g Virahols again, ice-water bath is cooled to 0-5 ℃, adds 140 g salt of wormwood.Temperature remains on 0-5 ℃, drips the aqueous isopropanol (283.8 g 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketones and 300 g Virahol mixed solutions) of 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone, drips off in about 3 hours, is warming up to 60-65 ℃, insulated and stirred 12 hours.TLC analyzes 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone and reacts completely, and reaction solution is concentrated into dried, adds 500 g water and 1000 g ETHYLE ACETATE; Layering, water layer once merges organic layer and is concentrated into driedly with counter the carrying of 500 g ETHYLE ACETATE, adds 500 g Virahols making beating; Filter; Solid adds 800 g recrystallizing methanol, gets 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide 415.9 g, yield 87.2%
Claims (6)
1. the compound method of a 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide is characterized in that its step is following:
(1) preparation of isobutyryl methyl acetate:
Under the nitrogen protection, suction toluene in reaction flask adds sodium hydride, and described sodium hydride is scattered in the MO, and its quality solubility is 40-60%; Under agitation, the suction methylcarbonate is warmed up to 50-60 ℃; It is 40-60% that Methyl isobutyl ketone is dissolved in the dense thing of toluene to its quality, and beginning slowly drips the toluene mixing solutions of Methyl isobutyl ketone, after dropwising, is incubated 1-3 hour; Sampling TLC follows the tracks of, and reaction cools to 15-20 ℃ after finishing, and slowly drips water, and after dropwising, pouring reaction solution into mass concentration is in the 50-70% hydrochloric acid soln, has great amount of carbon dioxide gas to produce; The mass ratio of described toluene, sodium hydride, methylcarbonate, Methyl isobutyl ketone, water and hydrochloric acid soln is 1000:100-120: 300-310:120-140:190-210:700-900;
After the layering, water layer merges organic layer with an amount of methylbenzene extraction 2-3 time, washs organic layer with suitable quantity of water, uses an amount of saturated common salt water washing organic layer again; Underpressure distillation obtains the isobutyryl methyl acetate;
(2) preparation of isobutyryl Acetanilide:
Under nitrogen protection, suction toluene in reaction flask, the isobutyryl methyl acetate is warming up to 70-80 ℃, collects toluene and methanol azeotrope, reaction 11-12h; Be cooled to 10-20 ℃, regulate pH to 1-2 with 10-20%HCl; Stir 20-40min, leave standstill 20-40min, layering; Organic layer is washed once with an amount of, and organic layer adds the 3-4% sodium hydrogen carbonate solution, stirs 20-40min, leaves standstill 20-40min, layering, and organic layer is evaporated to the dried isobutyryl Acetanilide that obtains;
The mass ratio of described toluene, isobutyryl methyl acetate, HCl and sodium hydrogen carbonate solution is 1100-1200:295-305: 110-120:4-6;
(3) preparation of 4-fluorophenyl methyl phenyl ketone:
In reaction flask, add aluminum chloride, fluorobenzene, under ice-water bath, drip phenyllacetyl chloride, temperature is controlled at below 40 ℃; Be warming up to 80 ℃, insulated and stirred 3-5 hour, it is complete that TLC analyzes raw material reaction, reduces to room temperature, gets dark green solution; In the mixture of the hydrochloric acid of impouring trash ice and 2mol/L, controlled temperature is below 60 ℃, layering; Organic layer adds saturated sodium bicarbonate and regulates pH, layering; Water layer is carried with an amount of fluorobenzene is counter, merges organic layer, is concentrated into driedly, adds an amount of sherwood oil recrystallization, 4-fluorophenyl methyl phenyl ketone;
The mass ratio of described aluminum chloride, fluorobenzene, phenyllacetyl chloride, trash ice, hydrochloric acid and saturated sodium bicarbonate is 150:600-630:210-230:550-650:340-380:110-130;
(4) preparation of 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone:
In reaction flask, add 4-fluorophenyl methyl phenyl ketone, methylene dichloride feeds chlorine under the room temperature, when 4-fluorophenyl methyl phenyl ketone has reacted, in reaction kettle, adds the sodium sulfite solution of 8-15%, adds saturated sodium bicarbonate and regulates pH; Layering, organic layer add suitable quantity of water washing again, concentrate oily matter 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone;
The mass ratio of described 4-fluorophenyl methyl phenyl ketone, methylene dichloride, chlorine, sodium sulfite solution and saturated sodium bicarbonate is 260-280:2100-2500:90-120: 650-680;
(5) preparation of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide:
The isobutyryl Acetanilide is added in the reaction vessel, add Virahol again, ice-water bath is cooled to 0-5 ℃, adds salt of wormwood; Temperature remains on 0-5 ℃, drips and presses 2-chloro-1-(4-the fluorophenyl)-methyl phenyl ketone of 1:0.9-1.1 mixed and the mixing solutions of Virahol, is warming up to 60-65 ℃ after dripping off, insulated and stirred 10-15 hour; The mass ratio of described isobutyryl Acetanilide, Virahol, salt of wormwood and 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone is 350-400:650-750:120-160:270-300;
TLC analyzes 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone and reacts completely; Reaction solution is concentrated into dried, adds suitable quantity of water and ETHYLE ACETATE, layering; Water layer once merges organic layer and is concentrated into driedly with counter the carrying of an amount of ETHYLE ACETATE, adds the making beating of an amount of Virahol, filters, and solid adds an amount of recrystallizing methanol, 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl valeramide.
2. compound method according to claim 1 is characterized in that, in step (1): the mass ratio of described toluene, sodium hydride, methylcarbonate, Methyl isobutyl ketone, water and hydrochloric acid soln is 1000:112: 305:130:200:800.
3. compound method according to claim 1 is characterized in that, in step (2): the mass ratio of described toluene, isobutyryl methyl acetate, HCl and sodium hydrogen carbonate solution is 1170:301: 117:5.
4. compound method according to claim 1 is characterized in that, in step (3): the mass ratio of described aluminum chloride, fluorobenzene, phenyllacetyl chloride, trash ice, hydrochloric acid and saturated sodium bicarbonate is 150:613:219:600:360:120.
5. compound method according to claim 1 is characterized in that, in step (4): the mass ratio of described 4-fluorophenyl methyl phenyl ketone, methylene dichloride, chlorine, sodium sulfite solution and saturated sodium bicarbonate is 278:2300:105: 665.
6. compound method according to claim 1 is characterized in that, in step (5): the mass ratio of described isobutyryl Acetanilide, Virahol, salt of wormwood and 2-chloro-1-(4-fluorophenyl)-methyl phenyl ketone is 375:700:140:283.8.
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