CN110256362A - A kind of preparation method of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates - Google Patents
A kind of preparation method of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates Download PDFInfo
- Publication number
- CN110256362A CN110256362A CN201910725343.7A CN201910725343A CN110256362A CN 110256362 A CN110256362 A CN 110256362A CN 201910725343 A CN201910725343 A CN 201910725343A CN 110256362 A CN110256362 A CN 110256362A
- Authority
- CN
- China
- Prior art keywords
- ethyl
- methyl butyl
- barbiturates
- alcohol
- purity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/62—Barbituric acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to it is a kind of prepare for calmness, hypnosis, preanesthetic medication and anticonvulsant drug amobarbital (I) preparation method.The present invention provides one kind to be prepared the new preparation process of high-purity amobarbital (I) by ethyl malonic acid diethylester.Including three steps: A, bromination；B, it is alkylated；C, cyclization, acidification, purifying.Advantage is: easy to operate, with short production cycle, low energy consumption, and Recycling Mother Solution is applied, and the three wastes are few, process stabilizing, good product quality, and purity is high, isomer impurities content is less than 0.1%, and high income, production cost is low, is suitble to industrialized production.
Description
Technical field
The invention belongs to chemicals preparation fields, and in particular to it is a kind of prepare for calmness, hypnosis, preanesthetic medication and
The preparation method of anticonvulsant drug 5- ethyl -5- (1- methyl butyl) barbiturates.
Background technique
The preparation method of relevant document report amobarbital has following several；Chemical reagent 2011,33 (9), 857~
The paper " synthesising process research of yellow Jackets " of 858 reports, is acted on using 2 bromo pentane and ethyl malonic acid diethylester, system
Standby 2- ethyl -2- (1- methyl butyl)-diethyl malonate, then prepare with urea effect the synthetic process of amobarbital.
Due to the analytical reagents that the 2 bromo pentane used is the production of Beijing blueness limitless blessing Science and Technology Ltd., mark >=99.0% contains
Amount, is only 95% or so through gas chromatography analysis 2 bromo pentane content, wherein 3- bromo pentane silane content accounts for 5% or so.So system
Its isomers 2- ethyl -2- (2- ethyl propyl)-malonic acid two in standby 2- ethyl -2- (1- methyl butyl)-diethyl malonate
Ethyl ester is difficult to be separated off, and is more difficult to be separated off after the isomers of generation target compound in subsequent reaction.
There are also a kind of luminals for preparing disclosed in China Patent Publication No. CN102311394A for relevant report
The study on the synthesis etc. of the phenobarbital of method and " Anhui chemical industry " report of volume 33 the 20070430,42nd~43.Chemical reagent
2011,33 (9), the specific method of the paper " synthesising process research of yellow Jackets " of 857~858 reports, step (1) will
160ml dehydrated alcohol is added in there-necked flask, 12.7g (0.55mol) metallic sodium is added portionwise under stirring, to sodium fully reacting
Afterwards, temperature is controlled at 45 DEG C hereinafter, 94.0g (0.5mol) ethyl malonic acid diethylester is slowly added dropwise, and is finished, after reacting 0.5h,
Again slowly be added dropwise 90.0g (0.6mol) 2 bromo pentane, be warming up to back flow reaction 4h, ethyl alcohol be evaporated off under decompression, be cooled to 40 DEG C with
After lower, residue is dissolved in water, and separates oil reservoir, and water layer twice, merges organic phase, anhydrous sodium sulfate is dry, mistake with extracted by ether
Filter, recycles ether, and b.p123~126 DEG C/2.66*104Pa fraction 86.1g is collected in residue vacuum distillation；Step (2) will
100ml dehydrated alcohol is added in there-necked flask, and 4.1g (0.18mol) metallic sodium is added portionwise under stirring, after sodium fully reacting,
9.5g (0.16mol) urea is added, is completely dissolved to urea, after reacting 0.5h, 38.0g (0.15mol) 2- ethyl -2- is added dropwise
(1- methyl butyl)-diethyl malonate, finishes, and after back flow reaction 6h, steams ethyl alcohol, under cooling that residue into water is molten
Active carbon decoloring, filtering is added in solution, and filtrate is placed in 25 DEG C of PH to 2~3 with hydrochloric acid regulating solution, and what filter collection was precipitated consolidates
Body, solid is washed twice, dry, obtains 23.3g amobarbital crude product, yield 68.7%.M.p.139~131 DEG C.In addition, to state
The 2 bromo pentane product of inside and outside other mark content >=99.0% is analyzed, and the content of isomers 3- bromo pentane silane is also 5%
Left and right.Using the method for rectifying, it is also difficult to remove isomers 3- bromo pentane silane.And 2 bromo pentane is found in distillation process
3- bromo pentane silane can be converted into.Report 2 bromo pentane preparation method at present, the isomers 3- bromine penta in the preparation process of 2 bromo pentane
It is generated while alkane is inevitable.And 2 bromo pentane and 3- bromo pentane silane physicochemical property are almost close, and only poor 1 DEG C of boiling point,
And boiling range has intersection, so being difficult to be separated off by the method for rectifying.It is generated in reacting with ethyl malonic acid diethylester
2- ethyl-(1- ethyl propyl) diethyl malonate and isomers 2- ethyl-(2- ethyl propyl) diethyl malonate.2- second
Base-(1- methyl butyl) diethyl malonate is same as isomers to be difficult to rectifying removing, penta bar generated in subsequent reaction
It is more difficult to be separated off than appropriate isomer products.Lead to isomers in final goal 5- ethyl -5- (1- methyl butyl) barbiturates
(impurity) content at least 0.5% or more；In addition, this report step (1) its post-processing approach there are many defects, not only needs to use
Extracted by ether, it is also dry with sodium sulphate.The water in organic phase can only be taken away with sodium sulphate drying, it can not be wherein water-soluble
Property impurity and alkaline matter are taken away.Alkaline matter therein has stayed in organic phase, since the target compound of preparation is in alkalinity
Under the conditions of it is unstable, subsequent recycling ether and residue vacuum distillation in target compound can be destroyed generation by-product.
Chemical reagent 2011,33 (9), the paper " synthesising process research of yellow Jackets " of 857~858 reports.This report step (2)
Equally exist many defects.Free alkali (i.e. sodium hydroxide) is inevitably generated during it is in the sodium ethoxide of production,
Due to the presence of free alkali, reactant ethyl-(1- methyl butyl) diethyl malonate and free alkali are acted on, and a part is broken
It is bad.In addition it matches urea and sodium alkoxide dosage is inadequate, and leads to reaction not exclusively, therefore seriously affected product purity, secondary
Product is more, and yield is lower, cumbersome, and the reaction time is long, and energy consumption is high, products obtained therefrom poor appearance, and big carbon content active is needed to decolourize, and three
It is useless more, it is at high cost.
Summary of the invention
The object of the present invention is to provide a kind of new works for preparing high-purity 5- ethyl -5- (1- methyl butyl) barbiturates
Skill.The 2 bromo pentane content of preparation is greater than 99.8%, and isomers 3- bromo pentane silane content is less than 0.1%, target compound 5- ethyl-
The 5- single maximum contaminant of (1- methyl butyl) barbiturates (isomers) is less than 0.1%.The process stabilizing, synthetic reaction are to steam
It is completed during evaporating, and to alcohol na concn without particular/special requirement, reaction condition is easily controllable, and the reaction time is short, easy to operate, the three wastes
It is few, the generation of isomers is greatly reduced, good product quality, high income, production cost is low, is more suitable for industrialized production.
The object of the present invention is achieved like this:
2- amylalcohol acts in the presence of the carbonate of anhydrous alkali metal with phosphorus tribromide, is distilled, is fractionated obtained 2- bromine penta
The mixture of alkane and 2- amylalcohol.
Ethyl malonic acid diethylester acts on 2 bromo pentane and ethyl-(1- methyl fourth is made in the presence of the alcoholic solution of sodium alkoxide
Base) diethyl malonate.
Ethyl-(1- methyl butyl) diethyl malonate acts on, acidified system in the presence of the alcoholic solution of sodium alkoxide with urea
Obtain the crude product of 5- ethyl -5- (1- methyl butyl) barbiturates.
5- ethyl -5- (1- methyl butyl) barbiturates crude product is recrystallized through ethanol water, filtration washing, vacuum drying
Prepare the new process of 5- ethyl -5- (1- methyl butyl) barbiturates finished product.
Its reaction equation is as follows:
The present invention provides a kind of preparation method of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates, this method packets
Include three steps:
A, 2- amylalcohol acts in the presence of the anhydrous carbonate of alkali metal with phosphorus tribromide, is distilled, is fractionated obtained 2- bromine
The mixture of pentane and 2- amylalcohol；
B, ethyl malonic acid diethylester acts on 2 bromo pentane and ethyl-(1- methyl is made in the presence of the alcoholic solution of sodium alkoxide
Butyl) diethyl malonate；
C, by ethyl-obtained in step B (1- methyl butyl) diethyl malonate in the presence of the alcoholic solution of sodium alkoxide, with
Urea effect, the crude product of acidified obtained 5- ethyl -5- (1- methyl butyl) barbiturates；5- ethyl -5- (1- methyl butyl)
Barbiturates) crude product recrystallizes to obtain 5- ethyl -5- (1- methyl butyl) barbiturates finished product in purified water.
The preparation method of a kind of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates, it is characterized in that: step A
The anhydrous carbonate of middle alkali metal is sodium carbonate or potassium carbonate；The matter of the anhydrous carbonate and phosphorus tribromide of 2- amylalcohol and alkali metal
Measure ratio=1:0.02~0.06:0.25~0.3；Dropwise reaction time 2 h, -10 DEG C~-15 DEG C of temperature；Reaction temperature is by -10
DEG C~-15 DEG C be to slowly warm up to room temperature in 3 hours；110~113 DEG C of temperature of normal pressure still top gas, obtain 2 bromo pentane and 2- amylalcohol
Mixture, the content of 2 bromo pentane is 30~35% (w/w).
The preparation method of a kind of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates, it is characterized in that: step B
The alcoholic solution of middle sodium alkoxide is the ethanol solution of sodium ethoxide, content 18%~40% (w/w)；The alcoholic solution of sodium alkoxide is first in step C
The methanol solution of sodium alkoxide, content are 29%~31% (w/w)；The suitable ethyl acetate of the sodium alkoxide alcoholic solution of step B and step C
Free alkali therein is eliminated under micro- reflux.
The preparation method of a kind of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates, it is characterized in that: step B
The molar ratio of middle reactant are as follows: ethyl malonic acid diethylester: sodium ethoxide: 2 bromo pentane=1:1.01~1.05:1.1~1.15；
Reaction is completed during the adition process of 2 bromo pentane and steaming alcohol, and the addition time of 2 bromo pentane is 2~3 hours, steams alcohol
Process time is 2 hours, steams the control of alcohol process reaction outlet temperature at 135 DEG C.
The preparation method of a kind of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates, it is characterized in that: step C
The molar ratio of reactant are as follows: ethyl-(1- methyl butyl) diethyl malonate: sodium methoxide: urea=1.0:2.0~2.5:1.5
~2.0；Reaction is completed during steaming alcohol, steams the control of alcohol outlet temperature at 135~140 DEG C；10 DEG C are cooled to hereinafter, being added
Ice water dissolution, ethyl-(1- methyl butyl) diethyl malonate: mass ratio=1:4~6 with ice water, temperature are 0~5 DEG C, mistake
Filter, filtrate hydrochloric acid acidification crystallization, be centrifuged 5- ethyl -5- (1- methyl butyl) barbiturates crude product；5- ethyl -5- (1- first
Base butyl) crude product of barbiturates recrystallizes through ethanol water, be made 5- ethyl -5- (1- methyl butyl) barbiturates at
Product.
The invention has the advantages that the process stabilizing, the 2 bromo pentane content of preparation is greater than 99.8%, isomers 3- bromo pentane silane
For content less than 0.1%, reaction condition is mild, easily controllable, and gained target compound product purity is high, and single maximum contaminant is (different
Structure body impurity) less than 0.1%, high income, post-processing is easy, and low energy consumption, and solvent recycles, and the three wastes are few, and production cost is low, fits
Close industrialized production.
The present invention is further elaborated with reference to embodiments:
Embodiment 1:
Step A: being added the 700g2- amylalcohol and 18g natrium carbonicum calcinatum of dosage in 2000L reaction flask, stirs lower cooling
To -10 DEG C~-15 DEG C, 200g phosphorus tribromide is slowly added dropwise in control temperature -10 ± 5 DEG C, about needs drip off within 2 hours.The lower control of stirring
Reaction temperature, which is to slowly warm up to room temperature about by -10 DEG C, to be needed 3 hours, and then gradually heating distillation to interior temperature is no more than 150 DEG C, is stopped
Distillation.The stirring drying of alkanol anhydrous sodium sulfate is steamed, the stirring of 20g natrium carbonicum calcinatum is added and neutralizes 5~10min (alkane at this time
Alcoholic solution pH value should be neutral), it filters immediately, filtrate carries out normal pressure fractionation, collects 110~113 DEG C of capital temperature of fraction, obtains
To the mixture 793.84g of 2 bromo pentane and 2- amylalcohol.The content of 2 bromo pentane is 33.74%.
Step B: content is added in tetra- mouthfuls of reaction flasks of 1000ml equipped with blender, thermometer and reflux condenser
Alcohol sodium alcohol solution 362g and the 5g ethyl acetate of 18.99% (W/W), heating steams ethyl alcohol to ethyl alcohol na concn and reaches under stirring
To 40% (W/W), 100 DEG C of addition 188.2g ethyl malonic acid diethylesters are cooled to, temperature reaction process steams ethyl alcohol to interior temperature
Reach 125 DEG C or so, stop heating, then depressurizes and steam alcohol to 75 DEG C of interior temperature.Start the 2 bromo pentane and 2- penta of a dropping step A preparation
The mixture 176.5g of alcohol, the fractionation of dropwise addition process steam alcohol, and maximum temperature is no more than 76 DEG C.With alcohol constantly separate interior temperature by
Gradually rise, not more than 118 DEG C, about 3h is needed to add.After adding, back flow reaction 2h, then alcohol is steamed to 135 DEG C of interior temperature, cooling
To 40 DEG C hereinafter, the dissolution of 200ml water is added, with 50% sulfuric acid tune PH6.7~7.0, stratification, organic phase vacuum fractionation obtains second
Base-(1- methyl butyl) diethyl malonate 217.3g, content 98.73%.
Step C: the methanol solution of 139.7g content 29% (W/W) sodium methoxide and 2.5g ethyl acetate are added to reaction flask
In, heating 60~85 DEG C elimination reaction 30 minutes.60.6g urea and 129.2g ethyl-(1- methyl butyl) malonic acid two is added
Ethyl ester, heating is distilled to recover first, ethyl alcohol to 135~140 DEG C, then evaporated under reduced pressure (about needing 2~3 hours).Be cooled to 20 DEG C hereinafter,
517g cold-water solution is added.Active carbon decoloring, filtering is added, hydrochloric acid is acidified to PH3~4, filters, dry 107.2g5- second
The crude product of base -5- (1- methyl butyl) barbiturates.The water of the crude product ethyl alcohol of 5- ethyl -5- (1- methyl butyl) barbiturates
Solution recrystallization, filtration washing are dried in vacuo to obtain 99.6g5- ethyl -5- (1- methyl butyl) barbiturates finished product, HPLC content
99.87%.
Embodiment 2
Step A: being added the 700g2- amylalcohol and 14g natrium carbonicum calcinatum of dosage in 2000L reaction flask, stirs lower cooling
To -10 DEG C~-15 DEG C, 175g phosphorus tribromide is slowly added dropwise in control temperature -10 ± 5 DEG C, about needs drip off within 2 hours.The lower control of stirring
Reaction temperature, which is to slowly warm up to room temperature about by -10 DEG C, to be needed 3 hours, and then gradually heating distillation to interior temperature is no more than 150 DEG C, is stopped
Distillation.The stirring drying of alkanol anhydrous sodium sulfate is steamed, the stirring of 20g natrium carbonicum calcinatum is added and neutralizes 5~10min (alkane at this time
Alcoholic solution pH value should be neutral), it filters immediately, filtrate carries out normal pressure fractionation, collects 110~113 DEG C of capital temperature of fraction, obtains
To the mixture 756.65g of 2 bromo pentane and 2- amylalcohol.The content of 2 bromo pentane is 30.67%.
Step B: content is added in tetra- mouthfuls of reaction flasks of 1000ml equipped with blender, thermometer and reflux condenser
Alcohol sodium alcohol solution 376.3g and the 5.5g ethyl acetate of 18.99% (W/W), it is dense to sodium ethoxide to steam ethyl alcohol for heating under stirring
Degree reaches 40% (W/W), is cooled to 100 DEG C of addition 188.2g ethyl malonic acid diethylesters, temperature reaction process steams ethyl alcohol extremely
Interior temperature reaches 125 DEG C or so, stops heating, then depressurizes and steam alcohol to 75 DEG C of interior temperature.Start a dropping step A preparation 2 bromo pentane and
The mixture 203g of 2- amylalcohol, the fractionation of dropwise addition process steam alcohol, and maximum temperature is no more than 76 DEG C.Interior temperature is constantly separated with alcohol
It is gradually increasing, not more than 118 DEG C, about 3h is needed to add.After adding, back flow reaction 2h, then alcohol is steamed to 135 DEG C of interior temperature, drop
Temperature is to 40 DEG C hereinafter, the dissolution of 200ml water is added, with 50% sulfuric acid tune PH6.7~7.0, stratification, organic phase vacuum fractionation is obtained
Ethyl-(1- methyl butyl) diethyl malonate 220.9g, content 98.82%.
Step C: the methanol solution of 180g content 30% (W/W) sodium methoxide and 3g ethyl acetate are added in reaction flask,
Heating 60~85 DEG C elimination reaction 30 minutes.45.5g urea and 129.2g ethyl-(1- methyl butyl) malonic acid diethyl is added
Ester, heating is distilled to recover first, ethyl alcohol to 135~140 DEG C, then evaporated under reduced pressure (about needing 2~3 hours).Be cooled to 20 DEG C hereinafter, plus
Enter 646g cold-water solution.Active carbon decoloring, filtering is added, hydrochloric acid is acidified to PH3~4, filters to obtain 104g5- ethyl -5- (1- first
Base butyl) barbiturates crude product.The aqueous solution of the crude product ethyl alcohol of 5- ethyl -5- (1- methyl butyl) barbiturates is tied again
Crystalline substance, filtration washing are dried in vacuo to obtain 99.3g5- ethyl -5- (1- methyl butyl) barbiturates finished product, HPLC content 99.91%.
Embodiment 3:
Step A: being added the 700g2- amylalcohol and 42g natrium carbonicum calcinatum of dosage in 2000L reaction flask, stirs lower cooling
To -10 DEG C~-15 DEG C, 210g phosphorus tribromide is slowly added dropwise in control temperature -10 ± 5 DEG C, about needs drip off within 2 hours.The lower control of stirring
Reaction temperature, which is to slowly warm up to room temperature about by -10 DEG C, to be needed 3 hours, and then gradually heating distillation to interior temperature is no more than 150 DEG C, is stopped
Distillation.The stirring drying of alkanol anhydrous sodium sulfate is steamed, the stirring of 20g natrium carbonicum calcinatum is added and neutralizes 5~10min (alkane at this time
Alcoholic solution pH value should be neutral), it filters immediately, filtrate carries out normal pressure fractionation, collects 110~113 DEG C of capital temperature of fraction, obtains
To the mixture 800.38g of 2 bromo pentane and 2- amylalcohol.The content of 2 bromo pentane is 34.98%.
Step B: content is added in tetra- mouthfuls of reaction flasks of 1000ml equipped with blender, thermometer and reflux condenser
Alcohol sodium alcohol solution 362g and the 5g ethyl acetate of 18.99% (W/W), heating steams ethyl alcohol to ethyl alcohol na concn and reaches under stirring
To 40% (W/W), 100 DEG C of addition 188.2g ethyl malonic acid diethylesters are cooled to, temperature reaction process steams ethyl alcohol to interior temperature
Reach 125 DEG C or so, stop heating, then depressurizes and steam alcohol to 75 DEG C of interior temperature.Start the 2 bromo pentane and 2- penta of a dropping step A preparation
The mixture 177.98g of alcohol, the fractionation of dropwise addition process steam alcohol, and maximum temperature is no more than 76 DEG C.Interior temperature is constantly separated with alcohol
It is gradually increasing, not more than 118 DEG C, about 3h is needed to add.After adding, back flow reaction 2h, then alcohol is steamed to 135 DEG C of interior temperature, drop
Temperature is to 40 DEG C hereinafter, the dissolution of 200ml water is added, with 50% sulfuric acid tune PH6.7~7.0, stratification, organic phase vacuum fractionation is obtained
Ethyl-(1- methyl butyl) diethyl malonate 223.1g, content 98.52%.
Step C: the methanol solution of 130.7g content 31% (W/W) sodium methoxide and 2g ethyl acetate are added to reaction flask
In, heating 60~85 DEG C elimination reaction 30 minutes.45.5g urea and 129.2g ethyl-(1- methyl butyl) malonic acid two is added
Ethyl ester, heating is distilled to recover first, ethyl alcohol to 135~140 DEG C, then evaporated under reduced pressure (about needing 2~3 hours).Be cooled to 20 DEG C hereinafter,
517g cold-water solution is added.Active carbon decoloring, filtering is added, hydrochloric acid is acidified to PH3~4, filters to obtain 109g5- ethyl -5- (1-
Methyl butyl) barbiturates crude product.The aqueous solution of the crude product ethyl alcohol of 5- ethyl -5- (1- methyl butyl) barbiturates is tied again
Crystalline substance, filtration washing are dried in vacuo to obtain 104.6g5- ethyl -5- (1- methyl butyl) barbiturates finished product, HPLC content
99.89%.
Embodiment 4:
Step A: being added the 700g2- amylalcohol and 42g natrium carbonicum calcinatum of dosage in 2000L reaction flask, stirs lower cooling
To -10 DEG C~-15 DEG C, 200g phosphorus tribromide is slowly added dropwise in control temperature -10 ± 5 DEG C, about needs drip off within 2 hours.The lower control of stirring
Reaction temperature, which is to slowly warm up to room temperature about by -10 DEG C, to be needed 3 hours, and then gradually heating distillation to interior temperature is no more than 150 DEG C, is stopped
Distillation.The stirring drying of alkanol anhydrous sodium sulfate is steamed, the stirring of 20g natrium carbonicum calcinatum is added and neutralizes 5~10min (alkane at this time
Alcoholic solution pH value should be neutral), it filters immediately, filtrate carries out normal pressure fractionation, collects 110~113 DEG C of capital temperature of fraction, obtains
To the mixture 794.66g of 2 bromo pentane and 2- amylalcohol.The content of 2 bromo pentane is 34.46%.
Step B: content is added in tetra- mouthfuls of reaction flasks of 1000ml equipped with blender, thermometer and reflux condenser
Alcohol sodium alcohol solution 376.3g and the 5.5g ethyl acetate of 18.99% (W/W), it is dense to sodium ethoxide to steam ethyl alcohol for heating under stirring
Degree reaches 40% (W/W), is cooled to 100 DEG C of addition 188.2g ethyl malonic acid diethylesters, temperature reaction process steams ethyl alcohol extremely
Interior temperature reaches 125 DEG C or so, stops heating, then depressurizes and steam alcohol to 75 DEG C of interior temperature.Start a dropping step A preparation 2 bromo pentane and
The mixture 172.8g of 2- amylalcohol, the fractionation of dropwise addition process steam alcohol, and maximum temperature is no more than 76 DEG C.As constantly separating for alcohol is interior
Temperature is gradually increasing, and not more than 118 DEG C, about 3h is needed to add.After adding, back flow reaction 2h, then steam alcohol to 135 DEG C of interior temperature,
40 DEG C are cooled to hereinafter, the dissolution of 200ml water is added, with 50% sulfuric acid tune PH6.7~7.0, stratification, organic phase vacuum fractionation
Obtain ethyl-(1- methyl butyl) diethyl malonate 224.2g, content 98.77%.
Step C: the methanol solution of 174.2g content 31% (W/W) sodium methoxide and 3g ethyl acetate are added to reaction flask
In, heating 60~85 DEG C elimination reaction 30 minutes.60.6g urea and 129.2g ethyl-(1- methyl butyl) malonic acid two is added
Ethyl ester, heating is distilled to recover first, ethyl alcohol to 135~140 DEG C, then evaporated under reduced pressure (about needing 2~3 hours).Be cooled to 20 DEG C hereinafter,
775g cold-water solution is added.Active carbon decoloring, filtering is added, hydrochloric acid is acidified to PH3~4, filters to obtain 111.2g5- ethyl -5-
The crude product of (1- methyl butyl) barbiturates.The aqueous solution of the crude product ethyl alcohol of 5- ethyl -5- (1- methyl butyl) barbiturates
Recrystallization, filtration washing are dried in vacuo to obtain 105.8g5- ethyl -5- (1- methyl butyl) barbiturates finished product, HPLC content
99.83%.
Claims (5)
1. a kind of preparation method of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates, it is characterized in that: this method includes three
Step:
A, 2- amylalcohol acts in the presence of the anhydrous carbonate of alkali metal with phosphorus tribromide, is distilled, is fractionated obtained 2 bromo pentane
With the mixture of 2- amylalcohol；
B, ethyl malonic acid diethylester acts on 2 bromo pentane and ethyl-(1- methyl fourth is made in the presence of the alcoholic solution of sodium alkoxide
Base) diethyl malonate；
C, by ethyl-obtained in step B (1- methyl butyl) diethyl malonate in the presence of the alcoholic solution of sodium alkoxide, with urea
Effect, the crude product of acidified obtained 5- ethyl -5- (1- methyl butyl) barbiturates；5- ethyl -5- (1- methyl butyl) bars of ratio
Appropriate acid) crude product recrystallizes to obtain 5- ethyl -5- (1- methyl butyl) barbiturates finished product in purified water.
2. a kind of preparation method of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates described in accordance with the claim 1, special
Sign is: the anhydrous carbonate of alkali metal is sodium carbonate or potassium carbonate in step A；The anhydrous carbonate and three of 2- amylalcohol and alkali metal
Mass ratio=1:0.02~0.06:0.25~0.3 of phosphonium bromide；Dropwise reaction time 2 h, -10 DEG C~-15 DEG C of temperature；Instead
Temperature is answered to be to slowly warm up to room temperature in 3 hours by -10 DEG C~-15 DEG C；110~113 DEG C of temperature of normal pressure still top gas, obtain 2- bromine penta
The mixture of alkane and 2- amylalcohol, the content of 2 bromo pentane are 30~35% (w/w).
3. a kind of preparation method of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates described in accordance with the claim 1, special
Sign is: the alcoholic solution of sodium alkoxide is the ethanol solution of sodium ethoxide, content 18%~40% (w/w) in step B；Sodium alkoxide in step C
Alcoholic solution is the methanol solution of sodium methoxide, and content is 29%~31% (w/w)；The sodium alkoxide alcoholic solution of step B and step C is in right amount
Ethyl acetate free alkali therein is eliminated under micro- reflux.
4. according to a kind of preparation method of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates described in claim 1 or 3,
It is characterized in that: in step B reactant molar ratio are as follows: ethyl malonic acid diethylester: sodium ethoxide: 2 bromo pentane=1:1.01~
1.05:1.1~1.15；Reaction is completed during the adition process of 2 bromo pentane and steaming alcohol, the addition time of 2 bromo pentane
It is 2~3 hours, steaming alcohol process time is 2 hours, steams the control of alcohol process reaction outlet temperature at 135 DEG C.
5. a kind of preparation method of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates described in accordance with the claim 1, special
Sign is: the molar ratio of step C reactant are as follows: ethyl-(1- methyl butyl) diethyl malonate: sodium methoxide: urea=1.0:2.0
~2.5:1.5~2.0；Reaction is completed during steaming alcohol, steams the control of alcohol outlet temperature at 135~140 DEG C；It is cooled to 10 DEG C
Hereinafter, ice water dissolution is added, ethyl-(1- methyl butyl) diethyl malonate: mass ratio=1:4~6 with ice water, temperature are
0~5 DEG C, filtering, filtrate hydrochloric acid acidification crystallization, be centrifuged 5- ethyl -5- (1- methyl butyl) barbiturates crude product；5- second
The crude product of base -5- (1- methyl butyl) barbiturates is recrystallized through ethanol water, is made 5- ethyl -5- (1- methyl butyl) bar
Than the finished product of appropriate acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910725343.7A CN110256362A (en) | 2019-08-07 | 2019-08-07 | A kind of preparation method of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910725343.7A CN110256362A (en) | 2019-08-07 | 2019-08-07 | A kind of preparation method of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110256362A true CN110256362A (en) | 2019-09-20 |
Family
ID=67912104
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910725343.7A Withdrawn CN110256362A (en) | 2019-08-07 | 2019-08-07 | A kind of preparation method of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110256362A (en) |
-
2019
- 2019-08-07 CN CN201910725343.7A patent/CN110256362A/en not_active Withdrawn
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106278862B (en) | A kind of new technique for synthesizing of 2,4 dichlorophenoxyacetic acid | |
| CN102417498B (en) | The synthetic method of 3-(α-methoxyl group) methene cumarone-2 (3H)-one | |
| CN104177250A (en) | Process for producing glycollic acid from methyl glycolate | |
| CN106220532B (en) | A kind of method of separation of extractive distillation acetonitrile and triethylamine | |
| CN103694119A (en) | Preparation method of ethyl 4,4,4-trifluoroacetoacetate | |
| EP2534130A2 (en) | Method for producing astaxanthin dimethyl disuccinate | |
| CN108976164A (en) | The preparation method of chiral piperidine amine compounds and the recovery method of chiral resolving agent | |
| CN110256362A (en) | A kind of preparation method of high-purity 5- ethyl -5- (1- methyl butyl) barbiturates | |
| CN102311394B (en) | Preparation method for 5-ethyl-5-phenyl barbituric acid | |
| CN101260092B (en) | Method for preparing cinepazide maleate | |
| CN101508678A (en) | Process for preparing 2-methyl-4-amino-5-acetyl aminomethyl pyrimidine | |
| CN114736144B (en) | Industrial preparation method of docusate calcium | |
| CN109776300A (en) | The synthetic method of loxoprofen sodium | |
| CN115124417A (en) | Method and equipment for refining lactic acid monomer | |
| CN108675919A (en) | A kind of method that double trimethylolpropane is extracted in trimethylolpropane heavy constituent | |
| CN105541712B (en) | The preparation method of Solifenacin intermediate | |
| CN104098438B (en) | A kind of method of Separation and Recovery Pentyl alcohol from pimelinketone by-product lightweight oil | |
| CN100506775C (en) | New technology of producing chloral from chlorine oil | |
| CN117623911A (en) | Refining method of valproic acid | |
| CN106496089B (en) | A method of preparing Oxiracetam | |
| CN106957235B (en) | A kind of preparation method of tamoxifen | |
| CN105622350A (en) | Synthesis method of resveratrol | |
| CN110003119A (en) | A kind of preparation method of 5- methyl -5- phenyl barbiturates | |
| AT502144A1 (en) | PROCESS FOR THE PRODUCTION OF HIGH-PURITY, HALOGEN-FREE O-PHTHALALDEHYDE | |
| CN111056997A (en) | Synthetic method of benzamide compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20190920 |
|
| WW01 | Invention patent application withdrawn after publication |