Summary of the invention
To the objective of the invention is in order addressing the above problem, synthetic alpha-ararin technique for producing raw material to be provided, synthetics purity height does not contain the carcinogenic substance safrole, and quality is better than the product that extract.
In order to address the above problem, the present invention is achieved in that it comprises the following production phase:
Fs is the acetylization reaction stage, at acetylization reaction in the stage:
(1), the proportioning raw materials of acetylization reaction such as following table:
Material name | Specification | Proportional quantity (kg) |
Para benzoquinone | Content 〉=89% | ????1 |
Acetic anhydride | Content 〉=94% | ????3 |
Sulfuric acid | Content 〉=97% | ????0.2 |
Water | | ????8 |
(2), the technological process of acetylization reaction is as follows:
Enamel reactor is scrubbed clean oven dry, check that the bottom valve door closes, the vacuum suction meets the acetic anhydride of acetylization reaction proportioning raw materials, stir the back and add the sulfuric acid that meets the acetylization reaction proportioning raw materials, adjusting a jar interior temperature of charge is 37 ℃-44 ℃, add the para benzoquinone that meets the acetylization reaction proportioning raw materials then, controlled temperature finishes the nature cooling at 38 ℃-50 ℃, adding refrigerated water is hydrolyzed, temperature of charge is 4 ℃-10 ℃, and discharging dries, be washed to PH neutrality, oven dry promptly gets 1.2.4. triacetyl oxygen base benzene, and is stand-by;
Subordinate phase is the methylation reaction stage, at methylation reaction in the stage:
(1), the proportioning raw materials of methylation reaction such as following table:
Material name | Specification | Proportional quantity (kg) |
1.2.4. triacetyl oxygen base benzene | | ????1 |
Methyl-sulfate | Content 〉=90% | ????3.5 |
Liquid caustic soda | Content 45% | ????2.2 |
Methyl alcohol | Industrial goods | ????6 |
(2), the technological process of methylation reaction is as follows:
This process using methyl alcohol is solvent, also can form homogeneous reaction system for 1.2.4. triacetyl oxygen base benzene, methyl-sulfate, liquid caustic soda can dissolve other solvent wherein jointly, finishes methylation reaction under this stable reaction conditions;
Operating process: in enamel reaction still, add the 1.2.4. triacetyl oxygen base benzene that meets the methylation reaction proportioning raw materials, take by weighing the methyl-sulfate that meets the methylation reaction proportioning raw materials and under agitation slowly add the methyl alcohol that meets the methylation reaction proportioning raw materials, under agitation slowly add, in stir adjusting jar temperature 35-45 ℃ the time, beginning slowly drips the liquid caustic soda that meets the methylation reaction proportioning raw materials, temperature is noted being controlled between 45-50 ℃, finish, be incubated into ripening reaction 0.5-2 hour, cooling adds water makes its material layering, and shunting discards water layer, use ether extraction, washing, drying, underpressure distillation, collect 110-170 ℃ of fraction, vacuum tightness is 0.08-0.1Mpa, and getting light brown oily thing is that finished product is the 1.2.4.-trimethoxy-benzene, stand-by;
Phase III is the aldehyde radical step of reaction, in the aldehyde radical step of reaction:
(1), the proportioning raw materials of aldehyde radical reaction is as follows:
Material name | Specification | Proportional quantity (kg) |
1.2.4. trimethoxy-benzene | | ????1 |
The N.N.-dimethyl formamide | Technical grade 95% | ????1.7 |
Phosphorus oxychloride | Technical grade 95% | ????1.38 |
Water | | ????30 |
(2), the technological process of aldehyde radical reaction is as follows:
The 300L enamel pot is dried, to meet with vacuum in the N.N.-dimethyl formamide suction jar of aldehyde radical reaction raw materials proportioning, opening chilled brine is cooled between 3-15 ℃, the phosphorus oxychloride that begins to meet aldehyde radical reaction raw materials proportioning slowly drips, finish and continue to stir the stand-by 1.2.4.-trimethoxy-benzene that meets aldehyde radical reaction raw materials proportioning of suction, in 40 ℃-80 ℃ insulations 5-9 hour, be hydrolyzed, separate out crystallization very soon, the freezing temperature down of icy salt solution is washed to neutrality below 12 ℃, dry, go into to dry by the fire the 2.4.5-TMB that gets product, for light yellow needle-like crystal, stand-by;
The quadravalence section is the vinylation step of reaction, in the vinylation step of reaction:
(1), the proportioning raw materials such as the following table of vinylation reaction:
Material name | Specification | Proportional quantity (kg) |
2.4.5-TMB | | ????1 |
Propionic anhydride | Technical grade is more than 95% | ????1.75 |
Sodium Propionate | Technical grade is anhydrous | ????0.5 |
(2), the technological process of vinylation reaction is as follows:
In stainless steel cauldron, add the stand-by 2.4.5-TMB that meets vinylation reaction raw materials proportioning, propionic anhydride, Sodium Propionate stirs, be warming up to 140 ℃-190 ℃ back flow reaction 5-9 hour, cooling adds the water hydrolysis, stirs to add Na
2CO
3Neutralize, extract respectively with ether, water layer extracts again, and the combined ether layer is washed and stirred, and is static, shunting, and drying, distillation, normal pressure boils off the ether recycling, and underpressure distillation 140-180 ℃, vacuum tightness is 0.08-0.1Mpa, collects fraction, gets thick alpha-ararin;
Five-stage is the recrystallization stage, at recrystallization in the stage:
(1) proportioning raw materials in recrystallization stage is as follows:
Material name | Specification | Proportional quantity (kg) |
Thick alpha-ararin | | ????1 |
Ethanol | Industrial goods preparation 60%-75% | ????1.5-1.6 |
(2) recrystallization stage process process is as follows:
The 60%-75% ethanol that has prepared is dissolved, drop in the crystallizer, thick alpha-ararin is dropped in the crystallizer, stir a little in below 3-10 ℃, kept 20-60 minute, discharging dries, wash once with ethanol, discharging, oven dry, mother liquor reclaims, ethanol utilizes again, and the mother liquor recrystallize promptly gets alpha-ararin.
Advantage of the present invention and effect are: the present invention adopts the method for synthetic to produce alpha-ararin, improved the output of propenyl-2,4,5-trimethoxy beozene greatly, reduced cost, solved the carcinogenic substance safrole that contains in the volatile oil, nontoxic, have no side effect, to satisfy the needs of clinical application, synthetics purity can reach 98.5%, and quality is better than the product that extract.
Embodiment
Below in conjunction with embodiment the present invention is elaborated:
Embodiment one
Concrete production technique of the present invention comprises following several stages:
1, the acetylization reaction stage
(1), the proportioning raw materials of acetylization reaction such as following table:
Material name | Specification | Proportional quantity (kg) |
Para benzoquinone | Content 〉=89% | ????1 |
Acetic anhydride | Content 〉=94% | ????3 |
Sulfuric acid | Content 〉=97% | ????0.2 |
Water | | ????8 |
(2), the technological process of acetylization reaction is as follows:
The 300L enamel reactor is scrubbed oven dry; check that the bottom valve door closes; the vacuum suction is the acetic anhydride 90kg of amount accurately; stir and add sulfuric acid 3.3L down; adjusting a jar interior temperature of charge is 40 ℃ or 42 ℃, begins to add the para benzoquinone that meets the acetylization reaction proportioning raw materials, and it is evenly uninterrupted that feed rate is wanted; controlled temperature is at 45 ℃; finish nature cooling 1 hour 20 minutes, add refrigerated water and be hydrolyzed, temperature of charge is 8-5 ℃; discharging; dry, be washed to PH6-7, oven dry; promptly get 1.2.4-triacetyl oxygen base benzene, stand-by.
(3), the chemical equation of acetylization reaction:
Para benzoquinone acetic anhydride 1.2.4-triacetyl oxygen base toluylic acid
2, the methylation reaction stage
(1), the proportioning raw materials of methylation reaction such as following table:
Material name | Specification | Proportional quantity (kg) |
1.2.4-triacetyl oxygen base benzene | | ????1 |
Methyl-sulfate | Content 〉=90% | ????3.5 |
Liquid caustic soda | Content 34-50% | ????2.2 |
Methyl alcohol | Industrial goods | ????6 |
(2), the technological process of methylation reaction is as follows:
This process using methyl alcohol is solvent, also can form homogeneous reaction system for 1.2.4-triacetyl oxygen base benzene, methyl-sulfate, liquid caustic soda can dissolve other solvent wherein jointly, finishes methylation reaction under this stable reaction conditions;
Operating process: in the 500L enamel reaction still, add the stand-by 1.2.4-triacetyl oxygen base benzene that meets the methylation reaction proportioning raw materials, accurately take by weighing the methyl-sulfate that meets the methylation reaction proportioning raw materials and under agitation slowly add the methyl alcohol that meets the methylation reaction proportioning raw materials, under agitation slowly add, stir adjusted in 10 minutes jar in when 40 ℃ of temperature or 42 ℃, beginning slowly drips the liquid caustic soda that meets the methylation reaction proportioning raw materials, temperature notes being controlled at 47 ℃, finish, be incubated into ripening reaction 1 hour, cooling adds water makes its material layering, and shunting discards water layer, extract 3 times with ether (benzene or toluene), wash 3 times, drying is removed ether, underpressure distillation, collect 133 ℃ of fractions, vacuum tightness is 0.1Mpa, and getting light brown oily thing is that finished product is the 1.2.4.-trimethoxy-benzene, stand-by.
(3), the chemical equation of methylation reaction:
1.2.4.-trimethoxy-benzene methyl sodium sulphate sodium-acetate
3, aldehyde radical step of reaction
(1), the proportioning raw materials of aldehyde radical reaction is as follows:
Material name | Specification | Proportional quantity (kg) |
1.2.4. trimethoxy-benzene | | ????1 |
The N.N.-dimethyl formamide | Technical grade 95% | ????1.7 |
Phosphorus oxychloride | Technical grade 95% | ????1.38 |
Water | | ????30 |
(2), the technological process of aldehyde radical reaction is as follows:
The 300L enamel pot is dried, weighing is met accurately in the N.N.-dimethyl formamide suction jar of aldehyde radical reaction raw materials proportioning with vacuum, opening chilled brine is cooled to below 6 ℃, beginning accurately to measure the phosphorus oxychloride that meets aldehyde radical reaction raw materials proportioning slowly drips, finish and continue to stir the stand-by 1.2.4.-trimethoxy-benzene that meets aldehyde radical reaction raw materials proportioning of suction in 20 minutes, be incubated 7 hours in 55 ℃ or 60 ℃, be hydrolyzed, separate out crystallization very soon, the freezing temperature down of icy salt solution is washed to neutrality below 12 ℃, dry, go into to dry by the fire finished product 2.4.5-TMB, for light yellow needle-like crystal, stand-by.
(3), the chemical equation of aldehyde radical reaction:
N.N-dimethylformamide phosphorus oxychloride 2.4.5.-TMB
4, vinylation step of reaction
(1), the proportioning raw materials such as the following table of vinylation reaction:
Material name | Specification | Proportional quantity (kg) |
2.4.5-TMB | | ????1 |
Propionic anhydride | Technical grade is more than 95% | ????1.75 |
Sodium Propionate | Technical grade is anhydrous | ????0.5 |
(2), the technological process of vinylation reaction is as follows:
In the stainless steel cauldron of 100L, add the 2.4.5-TMB that meets vinylation reaction raw materials proportioning, propionic anhydride, Sodium Propionate stirs, and is warming up to 167 ℃ of back flow reaction 7 hours, and cooling adds the water hydrolysis, stirs to add Na
2CO
3Neutralize, extract with ether (benzene or toluene), extract respectively 3 times, water layer extracts again, and the washing of combined ether layer stirred, and be static, shunting, and drying, distillation, normal pressure boils off the ether recycling, 167 ℃ of underpressure distillation, vacuum tightness is 0.1Mpa.Collect fraction and get finished product, promptly thick alpha-ararin.
(3), the chemical equation of vinylation reaction is as follows:
2.4.5.-trimethoxy-1-propenylbenzene propionic acid Sodium Propionate
5, the recrystallization stage
(3) proportioning raw materials in recrystallization stage is as follows:
Material name | Specification | Proportional quantity (kg) |
Thick alpha-ararin | | ????1 |
Ethanol | Industrial goods preparation 60-75% | ????1.5-1.6 |
(4) recrystallization stage process process is as follows:
70% ethanol that has prepared is dissolved, drop in the crystallizer, thick alpha-ararin is dropped in the crystallizer, stir a little in below 5 ℃, kept 30 minutes, discharging dries, and washes once discharging, oven dry with ethanol.Mother liquor reclaims, and ethanol utilizes again, and it is alpha-ararin that mother liquor is recrystallised to finished product.
Embodiment two
The technological process of methylation reaction can also be in the following method, and other stage is with embodiment one:
Suction gauge water in the 500L enamel reaction still, add the 1.2.4-triacetyl oxygen base benzene that meets the methylation reaction proportioning raw materials, stirred 10 minutes, and added the liquid caustic soda that meets the methylation reaction proportioning raw materials, drip the methyl-sulfate that meets the methylation reaction proportioning raw materials then, drip off back adjusting pH value and remain on 8 or 9 reactions 2 hours, extract, standing demix divides oil-yielding stratum, water layer extracts again, merge oil reservoir and add extract phase, be washed to neutrality, discard water layer, reclaim solvent, continue distillation, collect 145 ℃ of fractions, vacuum is 0.1MPA, get yellow or light yellow transparent liquid, i.e. 1.2.4-trimethoxy-benzene.
Embodiment three,
The technological process of methylation reaction can also be in the following method, and other stage is with embodiment one:
The quantitative water of suction in the 500L enamel reaction still, add the 1.2.4-triacetyl oxygen base benzene that meets the methylation reaction proportioning raw materials, stirred 10 minutes, dropwise liquid is quantitative, the dropping methyl-sulfate is quantitative, dropwise liquid drips methyl-sulfate, again dropwise liquid more again, the liquid caustic soda and the methyl-sulfate that meet the methylation reaction proportioning raw materials alternately drip until reacting completely, remain stable temperature of reaction, stable pH value state becomes ripening reaction 2 hours, extract, standing demix divides oil-yielding stratum, and water layer extracts again, merge oil reservoir and extract phase, be washed to neutrality, discard water layer, reclaim solvent, continue distillation and collect 145 ℃ of fractions, vacuum is 0.1Mpa, gets yellow or yellowish transparent liquid, i.e. 1.2.4-trimethoxy-benzene.
Embodiment four: i.e. grignard reaction
The technological process of vinylation reaction can also be in the following method, and other stage is with embodiment one:
In drying, in the clean stainless steel cauldron, vacuum suction tetrahydrofuran (THF) stirs and drops into exsiccant magnesium powder (sheet) down, the an amount of monobromethane that meets is looked temperature situation heat a little, and it is steady to adjust temperature then, naturally heat up and heat up until 50 ℃ of stable no longer continuation, dripping bromine ethane kept 2.5 hours at 50 ℃, treated magnesium powder (sheet) off-bottom, and beginning slowly drips tetrahydrofuran solution, after dripping, slowly heat up, the backflow phenomenon timing occurs, back flow reaction 8 hours, cooling, add dilute acetic acid and be neutralized to neutrality, boil off tetrahydrofuran (THF), a jar interior thing adds water and is hydrolyzed, divide oil-yielding stratum, water layer extracts merging again, extract and oil reservoir, washing, alkali cleaning, be washed to and reclaim toluene under the neutral low temperature, distill, collect fraction white or faint yellow thing, promptly get thick alpha-ararin 2.4.5-trimethoxy-1-propenylbenzene.Each raw material should meet the proportioning raw materials of vinylation reaction in present method.