CN101525278A - New synthetic method of guaiacol glycerin ether - Google Patents
New synthetic method of guaiacol glycerin ether Download PDFInfo
- Publication number
- CN101525278A CN101525278A CN200910097547A CN200910097547A CN101525278A CN 101525278 A CN101525278 A CN 101525278A CN 200910097547 A CN200910097547 A CN 200910097547A CN 200910097547 A CN200910097547 A CN 200910097547A CN 101525278 A CN101525278 A CN 101525278A
- Authority
- CN
- China
- Prior art keywords
- reaction
- guaiacol
- synthetic method
- glycerol ether
- ether
- 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.)
- Granted
Links
Abstract
The invention discloses a new synthetic method of guaiacol glycerin ether with a structure as shown in a formula (IV), isopropylidene glycerol-4-methanol with a structure as shown in formula (I) and guaiacol with a structure as shown in a formula (II) are taken as raw materials, Mitsunobu reaction occurs in organic solvent under the effect of triphenylphosphine and diisopropyl azodicarboxylate to generate intermediate product guaiacol isopropylidene glycerol ether with the structure as shown in formual (III); after full reaction, the obtained intermediate product crude product from separation witnesses hydrolysis reaction directly under acid conditions without purification; after separation and purification of the reaction liquid, the target product guaiacol glycerin with the structure as shown in (IV) ether is obtained. The synthetic method of the invention features application of clean raw material with low cost and easy availability, moderate reaction conditions, simple post treatment processes and adaptability to industrialized production.
Description
(1) technical field
The present invention relates to a kind of new synthetic method of guaiacol glycerol ether, belong to pharmaceutical chemistry technical field.
(2) background technology
Guaiacol glycerol ether (chemical name: 3-o-methoxyphenyl-1,2-propylene glycol) is a kind of expectorant, has effects such as antibechic, spasmolysis.Because this medicine has advantages such as divided dose is accurate, convenient, the drug effect performance is quick, is widely used as nonprescription drugs in daily life.Simultaneously, it also is a kind of bioactive medicine intermediate that has, and is used for the synthetic of beta-blocker.In the last few years, discovered that this medicine also can be used for reducing thrombocyte viscosity, relaxed muscle and narcotic for animals etc., the application prospect of having deepened this medicine greatly.
The method of the synthesizing guaiacol glyceryl ether of having reported at present has four kinds.
Method one condensation under alkaline condition by epoxy chloropropane and methyl catechol (hydroxyanisole), acid-catalyzed hydrolysis gets target product then, perhaps epoxy chloropropane is hydrolyzed into behind the glycerin chlorohydrin and methyl catechol condensation under alkaline condition gets target product.The shortcoming of this method is that used raw material epoxy chloropropane is mainly from the Nonrenewable resources petroleum cracking.
Method two is reacted under the catalysis of triethylamine or pyridine by Racemic glycidol and methyl catechol, and the shortcoming of this method is to remove residual be difficult to of catalyzer in product, and is bigger to the injury of environment and human body.
Method three is asymmetric synthesis methods, generates intermediate product methyl catechol allyl ethers by alpha-halogen propylene and methyl catechol under salt of wormwood catalysis, and the methyl catechol allyl ethers is at K then
3Fe (CN)
6, K
2CO
3, (DHQD)
2-PHAL, t-BuOH/H
2O, OsO
4Condition under be hydrolyzed into target product.The shortcoming of this method is catalyzer and solvent costliness, and aftertreatment is loaded down with trivial details.
Method four by tosic acid isopropylidene glycerol-4-methanol ester and methyl catechol at N, dinethylformamide is that solvent, sodium hydroxide are the O-alkylated reaction to take place under the condition of basic catalyst generate intermediate product methyl catechol isopropylidene glycerol-4-methanol ether, intermediate product methyl catechol isopropylidene glycerol-4-methanol ether again under acidic conditions hydrolysis get target product.The used raw material tosic acid isopropylidene glycerol-4-methanol ester of this method is reacted by isopropylidene glycerol-4-methanol and Tosyl chloride, and step is various, and the boiling point height of solvent DMF, and it is big to remove institute's consumption energy consumption, and small amount of residual all has detrimentally affect to environment and human body.
The method of above synthesizing guaiacol glyceryl ether, or raw materials cost height, or environment had pollution, or step is various, or the aftertreatment complexity, for its preparation has proposed new problem demanding prompt solution.
(3) summary of the invention
The technical problem to be solved in the present invention provide a kind of raw material cleaning, cheap and easy to get, reaction conditions is gentle, the synthetic method of the simple guaiacol glycerol ether of aftertreatment.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A kind of structure is suc as formula the synthetic method of the guaiacol glycerol ether shown in (IV), be that the methyl catechol shown in (II) is a raw material suc as formula isopropylidene glycerol-4-methanol shown in (I) and structure with structure, Mitsunobu reaction generating structure takes place under the effect of triphenylphosphine (TPP) and diisopropyl azodiformate (DIAD) in organic solvent suc as formula the intermediate product methyl catechol isopropylidene glycerol-4-methanol ether shown in (III), fully the reaction back separates that the intermediate product crude product that obtains is not purified directly to issue unboiled water at acidic conditions and separate reaction, and reaction solution obtains structure suc as formula the target product guaiacol glycerol ether shown in (IV) through separation and purification;
Reaction formula is as follows:
Mitsunobu of the present invention is reflected in the organic solvent and carries out, it is one of following that described organic solvent can be selected from: methylene dichloride, tetrahydrofuran (THF), benzene, toluene, N, dinethylformamide, methylformamide, N-N-methyl-2-2-pyrrolidone N-(NMP), dioxane.Be preferably tetrahydrofuran (THF) or toluene.Tetrahydrofuran (THF) more preferably.
It is 1: 1～3: 1～3: 1～3 that the present invention recommends the molar ratio of described isopropylidene glycerol-4-methanol, methyl catechol, triphenylphosphine, diisopropyl azodiformate, be preferably 1: 1～1.5: 1～1.5: 1～1.5, more preferably 1: 1.1～1.5: 1.1～1.5: 1.1～1.5.
The present invention recommends described volume of organic solvent consumption to count 8～15mL/g with the quality of isopropylidene glycerol-4-methanol.
The present invention recommends described Mitsunobu to be reflected under 25～110 ℃ of temperature condition to carry out 2～48h.Preferably under 60～110 ℃ of temperature condition, carry out 4～24h, more preferably under 60～67 ℃ of temperature condition, carry out 8～12h.
Mitsunobu reaction of the present invention generates intermediate product methyl catechol isopropylidene glycerol-4-methanol ether, can separate by the following method after fully reacting and obtain the intermediate product crude product: unreacted raw material methyl catechol is removed through alkali cleaning earlier in abundant reaction back, then drying, the concentrated intermediate product crude product that obtains.The alkali that described alkali cleaning is used can be selected sodium hydroxide solution for use, and its mass concentration is generally 5～20%.General intermediate product crude product can be more successively with saturated aqueous common salt and clear water washing, with further removal of impurities after alkali cleaning.
Mitsunobu reaction of the present invention specifically can be carried out according to following: isopropylidene glycerol-4-methanol, methyl catechol, triphenylphosphine mix under room temperature in organic solvent, slowly inwardly splash into diisopropyl azodiformate then, dropwise the back in 25～110 ℃ of reaction 2～48h, through alkali cleaning, drying, the concentrated intermediate product crude product that obtains.
Hydrolysis reaction of the present invention is to carry out under acid catalysis, and it is one of following that employed acid can be selected from: hydrochloric acid, sulfuric acid, Glacial acetic acid, perchloric acid, tosic acid.Be preferably hydrochloric acid, the massfraction of its aqueous solution is 5～37%, is preferably 5～10%.The volumetric usage of described aqueous acid is counted 5～20mL/g with the quality of isopropylidene glycerol-4-methanol.
The present invention recommends described hydrolysis reaction to carry out 1～24h under 25～100 ℃ of temperature condition.Preferably under 80～100 ℃ of temperature condition, carry out 1～4h.
The present invention is behind hydrolysis reaction, reaction solution can carry out separation and purification by the following method and obtain final product: reaction solution is cooled to room temperature, add the alkali lye neutralization, the acetone of generation is removed in distillation, cooling is filtered, and filtrate is used dichloromethane extraction, the extraction liquid drying, concentrate thick product, thick product gets the final product guaiacol glycerol ether through recrystallization.Described alkali lye can use solution commonly used such as sodium hydroxide solution, potassium hydroxide solution, and the employed solvent of recrystallization can be the mixed solvent of toluene, ether, ethyl acetate and sherwood oil.
Hydrolysis reaction of the present invention specifically can carry out according to following: add aqueous acid in the intermediate product crude product, in 25～100 ℃ of reaction 1～24h, reaction solution is cooled to room temperature, add the alkali lye neutralization, the acetone of generation is removed in distillation, cooling, filter, filtrate is used dichloromethane extraction, the extraction liquid drying, concentrate thick product, thick product gets the final product guaiacol glycerol ether through recrystallization.
Guaiacol glycerol ether synthetic method of the present invention, its beneficial effect is mainly reflected in:
(1) the raw material isopropylidene glycerol-4-methanol can be formed by glycerine and condensation of acetone, and method is simple, with low cost and clean environment firendly.
(2) choosing diisopropyl azodiformate and triphenylphosphine is the Mitsunobu reaction reagent, and reaction conditions gentleness, easy and simple to handle, less energy consumption, yield height are fit to suitability for industrialized production.
(3) aftertreatment of the present invention is simple.The intermediate product that the Mitsunobu reaction obtains need not purifying, has simplified operation greatly; It is extraction agent that the after product of hydrolysis simultaneously separates the lower boiling methylene dichloride of selection, less energy consumption, and the yield height is fit to suitability for industrialized production.
(4) concrete embodiment
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
Embodiment 1
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 1.24g (0.010mol) methyl catechol, 2.62g (0.010mol) triphenylphosphine, the 10mL tetrahydrofuran (THF), slowly inwardly drip 2.0mL (0.010mol) diisopropyl azodiformate under the room temperature, be warming up to 60 ℃ after dropwising, behind the reaction 12h, divide with 5% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and wash for 2 times, and is dry then, concentrate and obtain the intermediate product crude product.In above-mentioned crude product, add 10% hydrochloric acid 20mL, be heated to 80 ℃ of reaction 4h.Cooling, the sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 0.75g, productive rate 38%, fusing point: 78～79 ℃.
Embodiment 2
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 3.72g (0.030mol) methyl catechol, 7.86g (0.030mol) triphenylphosphine, the 30mL tetrahydrofuran (THF), slowly inwardly drip 6.0mL (0.030mol) diisopropyl azodiformate under the room temperature, be warming up to 60 ℃ after dropwising, behind the reaction 12h, divide with 20% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and wash for 2 times, and is dry then, concentrate and obtain the intermediate product crude product.In above-mentioned crude product, add 10% hydrochloric acid 20mL, be heated to 80 ℃ of reaction 4h.Cooling, the sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 1.58g, productive rate 80%.
Embodiment 3
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 1.36g (0.011mol) methyl catechol, 2.88g (0.011mol) triphenylphosphine, the 20mL tetrahydrofuran (THF), slowly inwardly drip 2.2mL (0.011mol) diisopropyl azodiformate under the room temperature, be warming up to 60 ℃ after dropwising, behind the reaction 12h, divide with 20% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and wash for 2 times, and is dry then, concentrate and obtain the intermediate product crude product.In above-mentioned crude product, add 10% hydrochloric acid 20mL, be heated to 80 ℃ of reaction 4h.Cooling, the sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 1.54g, productive rate 78%.
Embodiment 4
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 1.86g (0.015mol) methyl catechol, 3.93g (0.015mol) triphenylphosphine, the 20mL tetrahydrofuran (THF), slowly inwardly drip 3.0mL (0.015mol) diisopropyl azodiformate under the room temperature, be warming up to 60 ℃ after dropwising, behind the reaction 12h, divide with 20% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and wash for 2 times, and is dry then, concentrate and obtain the intermediate product crude product.In above-mentioned crude product, add 10% hydrochloric acid 20mL, be heated to 80 ℃ of reaction 4h.Cooling, the sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 1.58g, productive rate 80%.
Embodiment 5
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 1.86g (0.015mol) methyl catechol, 3.93g (0.015mol) triphenylphosphine, 20mL toluene, slowly inwardly drip 3.0mL (0.015mol) diisopropyl azodiformate under the room temperature, be warming up to 60 ℃ after dropwising, behind the reaction 12h, divide with 20% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and wash for 2 times, and is dry then, concentrate and obtain the intermediate product crude product.In above-mentioned crude product, add 10% hydrochloric acid 20mL, be heated to 80 ℃ of reaction 4h.Cooling, the sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 1.42g, productive rate 72%.
Embodiment 6
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 1.86g (0.015mol) methyl catechol, 3.93g (0.015mol) triphenylphosphine, 20mL toluene, slowly inwardly drip 3.0mL (0.015mol) diisopropyl azodiformate under the room temperature, be warming up to 110 ℃ after dropwising, behind the reaction 2h, divide with 20% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and wash for 2 times, and is dry then, concentrate and obtain the intermediate product crude product.In above-mentioned crude product, add 10% hydrochloric acid 20mL, be heated to 80 ℃ of reaction 4h.Cooling, the sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 1.09g, productive rate 55%.
Embodiment 7
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 1.86g (0.015mol) methyl catechol, 3.93g (0.015mol) triphenylphosphine, 20mL toluene, slowly inwardly drip 3.0mL (0.015mol) diisopropyl azodiformate under the room temperature, be warming up to 110 ℃ after dropwising, behind the reaction 4h, divide with 20% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and wash for 2 times, and is dry then, concentrate and obtain the intermediate product crude product.In above-mentioned crude product, add 10% hydrochloric acid 20mL, be heated to 80 ℃ of reaction 4h.Cooling, the sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 1.35g, productive rate 68%.
Embodiment 8
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 1.86g (0.015mol) methyl catechol, 3.93g (0.015mol) triphenylphosphine, the 20mL tetrahydrofuran (THF), slowly inwardly drip 3.0mL (0.015mol) diisopropyl azodiformate under the room temperature, dropwise the back in 25 ℃ of reaction 48h, divide with 20% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and washes dry then, the concentrated intermediate product crude product that obtains for 2 times.In above-mentioned crude product, add 10% hydrochloric acid 20mL, be heated to 80 ℃ of reaction 4h.Cooling, the sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 0.55g, productive rate 28%.
Embodiment 9
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 1.86g (0.015mol) methyl catechol, 3.93g (0.015mol) triphenylphosphine, the 20mL tetrahydrofuran (THF), slowly inwardly drip 3.0mL (0.015mol) diisopropyl azodiformate under the room temperature, be warming up to 60 ℃ after dropwising, behind the reaction 24h, divide with 20% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and wash for 2 times, and is dry then, concentrate and obtain the intermediate product crude product.In above-mentioned crude product, add 10% hydrochloric acid 20mL, be heated to 80 ℃ of reaction 4h.Cooling, the sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 1.54g, productive rate 78%.
Embodiment 10
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 1.86g (0.015mol) methyl catechol, 3.93g (0.015mol) triphenylphosphine, the 20mL tetrahydrofuran (THF), slowly inwardly drip 3.0mL (0.015mol) diisopropyl azodiformate under the room temperature, be warming up to 67 ℃ after dropwising, behind the reaction 8h, divide with 20% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and wash for 2 times, and is dry then, concentrate and obtain the intermediate product crude product.In above-mentioned crude product, add 10% hydrochloric acid 20mL, be heated to 80 ℃ of reaction 4h.Cooling, the sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 1.56g, productive rate 79%.
Embodiment 11
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 1.86g (0.015mol) methyl catechol, 3.93g (0.015mol) triphenylphosphine, the 20mL tetrahydrofuran (THF), slowly inwardly drip 3.0mL (0.015mol) diisopropyl azodiformate under the room temperature, be warming up to 60 ℃ after dropwising, behind the reaction 12h, divide with 20% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and wash for 2 times, and is dry then, concentrate and obtain the intermediate product crude product.In above-mentioned crude product, add 10% acetic acid 20mL, be heated to 80 ℃ of reaction 4h.Cooling, the sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 1.48g, productive rate 75%.
Embodiment 12
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 1.86g (0.015mol) methyl catechol, 3.93g (0.015mol) triphenylphosphine, the 20mL tetrahydrofuran (THF), slowly inwardly drip 3.0mL (0.015mol) diisopropyl azodiformate under the room temperature, be warming up to 60 ℃ after dropwising, behind the reaction 12h, divide with 20% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and wash for 2 times, and is dry then, concentrate and obtain the intermediate product crude product.In above-mentioned crude product, add 5% hydrochloric acid 20mL, be heated to 80 ℃ of reaction 4h.Cooling, the sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 1.54g, productive rate 78%.
Embodiment 13
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 1.86g (0.015mol) methyl catechol, 3.93g (0.015mol) triphenylphosphine, the 20mL tetrahydrofuran (THF), slowly inwardly drip 3.0mL (0.015mol) diisopropyl azodiformate under the room temperature, be warming up to 60 ℃ after dropwising, behind the reaction 12h, divide with 20% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and wash for 2 times, and is dry then, concentrate and obtain the intermediate product crude product.In above-mentioned crude product, add 37% hydrochloric acid 20mL, be heated to 80 ℃ of reaction 4h.Cooling, the sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 1.56g, productive rate 79%.
Embodiment 14
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 1.86g (0.015mol) methyl catechol, 3.93g (0.015mol) triphenylphosphine, the 20mL tetrahydrofuran (THF), slowly inwardly drip 3.0mL (0.015mol) diisopropyl azodiformate under the room temperature, be warming up to 60 ℃ after dropwising, behind the reaction 12h, divide with 20% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and wash for 2 times, and is dry then, concentrate and obtain the intermediate product crude product.In above-mentioned crude product, add 10% hydrochloric acid 20mL, be heated to 100 ℃ of reaction 1h.Cooling, the sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 1.48g, productive rate 75%.
Embodiment 15
In the 50mL there-necked flask, add 1.32g (0.010mol) isopropylidene glycerol-4-methanol, 1.86g (0.015mol) methyl catechol, 3.93g (0.015mol) triphenylphosphine, the 20mL tetrahydrofuran (THF), slowly inwardly drip 3.0mL (0.015mol) diisopropyl azodiformate under the room temperature, be warming up to 60 ℃ after dropwising, behind the reaction 12h, divide with 20% sodium hydroxide solution 80mL successively wash for 4 times, saturated aqueous common salt 60mL divide wash for 3 times, clear water 40mL divides and wash for 2 times, and is dry then, concentrate and obtain the intermediate product crude product.In above-mentioned crude product, add 10% hydrochloric acid 20mL, behind 25 ℃ of reaction 24h.The sodium hydroxide solution 25mL neutralization of adding 10%.Acetone is removed in distillation.Cooling is filtered, and filtrate is used dichloromethane extraction.The extraction liquid drying, concentrate, the toluene recrystallization gets guaiacol glycerol ether 1.31g, productive rate 66%.
Claims (10)
1, a kind of structure is suc as formula the synthetic method of the guaiacol glycerol ether shown in (IV), be that the methyl catechol shown in (II) is a raw material suc as formula isopropylidene glycerol-4-methanol shown in (I) and structure with structure, Mitsunobu reaction generating structure takes place under the effect of triphenylphosphine and diisopropyl azodiformate in organic solvent suc as formula the intermediate product methyl catechol isopropylidene glycerol-4-methanol ether shown in (III), fully the reaction back separates that the intermediate product crude product that obtains is not purified directly to issue unboiled water at acidic conditions and separate reaction, and reaction solution obtains structure suc as formula the target product guaiacol glycerol ether shown in (IV) through separation and purification; It is one of following that described organic solvent is selected from: methylene dichloride, tetrahydrofuran (THF), benzene, toluene, N, dinethylformamide, methylformamide, N-N-methyl-2-2-pyrrolidone N-, dioxane;
2, the synthetic method of guaiacol glycerol ether as claimed in claim 1 is characterized in that described organic solvent is tetrahydrofuran (THF) or toluene.
3, the synthetic method of guaiacol glycerol ether as claimed in claim 1, the molar ratio that it is characterized in that described isopropylidene glycerol-4-methanol, methyl catechol, triphenylphosphine, diisopropyl azodiformate is 1: 1～3: 1～3: 1～3.
4, the synthetic method of guaiacol glycerol ether as claimed in claim 1, it is characterized in that described Mitsunobu is reflected under 25～110 ℃ of temperature condition carries out 2～48h.
5, the synthetic method of guaiacol glycerol ether as claimed in claim 1, it is characterized in that described Mitsunobu is reflected under 60～110 ℃ of temperature condition carries out 4～24h.
6, the synthetic method of guaiacol glycerol ether as claimed in claim 1, it is one of following to it is characterized in that the acid that adds in the described hydrolysis reaction is selected from: hydrochloric acid, sulfuric acid, Glacial acetic acid, perchloric acid, tosic acid.
7, the synthetic method of guaiacol glycerol ether as claimed in claim 1 is characterized in that described hydrolysis reaction carries out 1～24h under 25～100 ℃ of temperature condition.
8, the synthetic method of guaiacol glycerol ether as claimed in claim 1, it is characterized in that described Mitsunobu is reflected to separate by the following method after the abundant reaction obtains the intermediate product crude product: fully unreacted raw material methyl catechol is removed through alkali cleaning earlier in the reaction back, and is dry then, concentrate and obtain the intermediate product crude product.
9, the synthetic method of guaiacol glycerol ether as claimed in claim 1, it is characterized in that described Mitsunobu reaction is specific as follows: isopropylidene glycerol-4-methanol, methyl catechol, triphenylphosphine mix under room temperature in organic solvent, slowly inwardly splash into diisopropyl azodiformate then, dropwise the back in 25～110 ℃ of reaction 2～48h, through alkali cleaning, drying, the concentrated intermediate product crude product that obtains.。
10, the synthetic method of guaiacol glycerol ether as claimed in claim 9, it is characterized in that described hydrolysis reaction is specific as follows: in the intermediate product crude product, add aqueous acid, in 25～100 ℃ of reaction 1～24h, reaction solution is cooled to room temperature, add the alkali lye neutralization, the acetone of generation is removed in distillation, cooling is filtered, and filtrate is used dichloromethane extraction, the extraction liquid drying, concentrate thick product, thick product gets the final product guaiacol glycerol ether through recrystallization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100975477A CN101525278B (en) | 2009-04-09 | 2009-04-09 | New synthetic method of guaiacol glycerin ether |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100975477A CN101525278B (en) | 2009-04-09 | 2009-04-09 | New synthetic method of guaiacol glycerin ether |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101525278A true CN101525278A (en) | 2009-09-09 |
| CN101525278B CN101525278B (en) | 2011-12-28 |
Family
ID=41093377
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100975477A Expired - Fee Related CN101525278B (en) | 2009-04-09 | 2009-04-09 | New synthetic method of guaiacol glycerin ether |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101525278B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104138765A (en) * | 2014-07-10 | 2014-11-12 | 浙江海洲制药有限公司 | Solid base catalyst, preparation of solid base catalyst as well as application of solid base catalyst to preparation of guaifenesin |
| CN109651103A (en) * | 2017-10-10 | 2019-04-19 | 中石化石油工程技术服务有限公司 | A kind of method of purification of laruyl alcohol alkyl ether |
-
2009
- 2009-04-09 CN CN2009100975477A patent/CN101525278B/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104138765A (en) * | 2014-07-10 | 2014-11-12 | 浙江海洲制药有限公司 | Solid base catalyst, preparation of solid base catalyst as well as application of solid base catalyst to preparation of guaifenesin |
| CN104138765B (en) * | 2014-07-10 | 2016-07-13 | 浙江海洲制药有限公司 | A kind of solid base catalyst and preparation and the application in preparing guaifenesin |
| CN109651103A (en) * | 2017-10-10 | 2019-04-19 | 中石化石油工程技术服务有限公司 | A kind of method of purification of laruyl alcohol alkyl ether |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101525278B (en) | 2011-12-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102936248A (en) | Method for preparing doxofylline | |
| CN101525278B (en) | New synthetic method of guaiacol glycerin ether | |
| CN105753721A (en) | Synthesis method of levalbuterol | |
| CN101353296B (en) | Method for preparing (Z)-3'-hydroxy-3,4,4',5-tetramethoxy diphenyl ethylene from regenerative natural plant resource | |
| CN101402555A (en) | Method of preparing (Z)-3'-hydroxyl-3,4,4',5-tetramethoxy toluylene | |
| CN106928226B (en) | A kind of preparation method of bromoacetaldehyde condensed ethandiol | |
| CN1297557C (en) | Preparation of spirocyclic template compound | |
| CN104774174B (en) | A kind of method of asymmetric syntheses S carbinoxamines | |
| CN103435505A (en) | Method for synthesizing (R)-salmeterol | |
| CN103214421B (en) | The industrialized preparing process of 2-sulfydryl-1-Methylimidazole | |
| CN103497157A (en) | 2-imidazolidone synthesis method | |
| CN102491953A (en) | Method for synthesizing florfenicol midbody RT0131 | |
| CN102399231A (en) | Galanthamine preparation method | |
| CN103012215B (en) | Azo dodecanedioic acid dialkyl ester preparation method | |
| CN101531660A (en) | Industrialization production process of entecavir-monohydrate | |
| CN105884625A (en) | Synthesis method of R-salmeterol | |
| CN101985446B (en) | Method for synthesizing (+/-)-9-O-demethyl-alpha-dihydrotetrabenazine | |
| CN102503806A (en) | Method for synthesis of 1,3,5,7-tetra(4-acrylatophenyl)adamantine compound | |
| CN100355746C (en) | Synthesis of 1, 4-dioxo spiro [4, 5] decane-8-one | |
| CN102807516A (en) | Intermediate in amisulpride and method for preparing amisulpride by using intermediate | |
| CN103288650A (en) | Hydrochloric acid 1-amino-3, 5-dimethyl adamantane preparation method | |
| CN1086187C (en) | Method for preparing bicyclohexyl-18-crown-6 | |
| CN100430376C (en) | Improved method for preparing N-methyl-3-phenyl-3-hydroxy-propylamine | |
| CN101962320B (en) | Method for preparing intermediate 1,2-dicarboxylicacid of antidiabetic medicine gliclazide | |
| CN100999478A (en) | Process of preparing serine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20111228 Termination date: 20180409 |