CN109456195A - A kind of method of substep catalysis preparation high-purity propyl ester - Google Patents
A kind of method of substep catalysis preparation high-purity propyl ester Download PDFInfo
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- CN109456195A CN109456195A CN201811230476.9A CN201811230476A CN109456195A CN 109456195 A CN109456195 A CN 109456195A CN 201811230476 A CN201811230476 A CN 201811230476A CN 109456195 A CN109456195 A CN 109456195A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
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Abstract
The present invention provides a kind of methods that substep is catalyzed preparation high-purity propyl ester, the following steps are included: using gallic acid and normal propyl alcohol as raw material, successively under the catalytic action of perchloric acid and sulfamic acid, or under the catalytic action of p-methyl benzenesulfonic acid and sulfamic acid, it is reacted, obtains propyl ester.Through detecting, the propyl ester that the above method provided by the invention synthesizes meets 2015 editions pharmacopoeial quality requirements, and purity is up to 99.9% or more, and gallic acid impurity peaks are not detected.
Description
Technical field
The present invention relates to the sides of technical field of organic synthesis more particularly to a kind of substep catalysis preparation high-purity propyl ester
Method.
Background technique
Propyl ester chemical name is propylgallate, molecular formula C10H12O5, molecular weight 212.20, with inhibition (thrombus
Plain A2) platelet aggregation caused by TXA2；Whole blood viscosity and plasma viscosity can be reduced, erythrocyte electrophoresis speed is accelerated,
Can also relax vascular smooth muscle, increase blood flow coronarius；There is significant protective effect to myocardial ischemia.In expansion brain blood
Pipe while improving Brain circlulation, can also mitigate the lipid mistake of brain tissue by improving brain tissue SOD, GSH-PX and CAT activity
Oxidation reaction inhibits brain edema to be formed, and protects brain tissue Na+, K+Atpase activity effectively mitigates cerebral ischemia re-pouring damage
Wound, to preventing from cerebral ischemia re-pouring injured having good application prospect.
The preparation of propyl ester carries out esterification generally using gallic acid as raw material.Due to gallic acid and product Gallate third
Ester chemical property is close, therefore reacts the more difficult removing after the completion of reaction of incomplete gallic acid on a small quantity, to purifying bring compared with
Big difficulty, so that the purity of propyl ester is affected.
As people's living standard is constantly promoted, drug safety is more and more paid attention to, to drug pharmacopeia impurity mark
Alignment request also correspondinglys increase, and primary raw material gallic acid impurity must not in the related substance of 2010 editions States Pharmacopoeia specifications propyl ester detections
Always miscellaneous to be not greater than 0.5% greater than 0.1%, this is to much also according to the propyl ester of common single step catalytic esterification processes production
Producer produces very big challenge, is difficult to produce the propyl ester of gallic acid content qualification according to common synthesis technology.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is that providing a kind of substep catalysis preparation high-purity propyl ester
Method, the propyl ester of preparation purity with higher.
In order to solve the above problem, the present invention provides a kind of methods that substep is catalyzed preparation high-purity propyl ester, including with
Lower step:
Using gallic acid and normal propyl alcohol as raw material, successively under the catalytic action of perchloric acid and sulfamic acid, or right
It under the catalytic action of toluenesulfonic acid and sulfamic acid, is reacted, obtains propyl ester.
The present invention is carried out substep catalysis, is made not having using perchloric acid and sulfamic acid or p-methyl benzenesulfonic acid and sulfamic acid
The esterification of gallate-based and normal propyl alcohol is abundant, remains without raw material gallic acid.
The equation of above-mentioned reaction is as follows:
In some embodiments of the invention, use a water gallic acid for raw material.
Specifically, the method for the above substep catalysis the following steps are included:
Using gallic acid and normal propyl alcohol as raw material, under the catalytic action of perchloric acid or p-methyl benzenesulfonic acid, counterflow condition
Under, carry out catalysis reaction for the first time；
Reach theoretical value to reaction system water yield, sulfamic acid is added, carries out second of catalysis reaction, obtain Gallate third
Ester.
In the gallic acid and normal propyl alcohol, preferably normal propyl alcohol is excessive, it is preferred that the gallic acid and normal propyl alcohol rub
You are than being 1:(2~3).
The molar ratio of the perchloric acid or p-methyl benzenesulfonic acid and gallic acid is preferably (0.1~0.3): 1, it is further excellent
It is selected as 0.2:1.
The water entrainer of the reaction is preferably benzene.
The present invention is to the dosage of the benzene and is not particularly limited, and can be carried out according to the universal experience of those skilled in the art
It adjusts.
The temperature of the first time catalysis reaction is preferably 80~90 DEG C, and the reaction time is preferably 12~14h.
In first time catalytic reaction process, reaction system switchs to dark red solution by pulpous state.
It is currently preferred, while carrying out back flow reaction, the water that benzene is taken out of is collected and measured using water segregator.When anti-
When the system water yield of answering reaches theoretical value, sulfamic acid is added, carries out second of catalysis reaction, obtains propyl ester.
The molar ratio of the sulfamic acid and gallic acid is preferably (0.05~0.1): 1, further preferably 0.05:1.
It is currently preferred, system temperature is reduced when sulfamic acid is added, it is preferred that when sulfamic acid is added, system
Temperature is 50~60 DEG C.Sulfamic acid addition finishes, and system temperature restores to reflux temperature.
Preferably, the temperature of second of the catalysis reaction is preferably 80~90 DEG C, and the reaction time is preferably 1~2h.
After reaction, reaction system is concentrated into the half of total volume, obtains propyl ester crude product concentrate.
It is currently preferred, the propyl ester crude product is purified, preferably specifically:
Water is added to be crystallized, solid filtering, water washing to neutrality, active carbon decoloring, it is pure to obtain propyl ester for water recrystallization
Product.
The water that purification step uses is preferably purified water.
Through detecting, the propyl ester that the above method provided by the invention synthesizes meets 2015 editions pharmacopoeial quality requirements, and pure
Degree up to 99.9% or more, is not detected gallic acid impurity peaks.
Detailed description of the invention
Fig. 1 is the HPLC map of gallic acid and propyl ester mixed solution；
Fig. 2 is the HPLC map of propyl ester prepared by the embodiment of the present application 2.
Specific embodiment
In order to further illustrate the present invention, preparation high-purity Gallate is catalyzed to substep provided by the invention below with reference to embodiment
The method of propyl ester is described in detail.
Embodiment 1
A water gallic acid 37.6g (0.2mol) is accurately weighed, is added in 500mL three-necked flask, successively measures perchloric acid
1.6mL (0.02mol), benzene 40mL take normal propyl alcohol 45mL (0.6mol), are added in three-necked flask, three-necked flask is placed in 1L electricity and adds
In hot jacket, three-necked flask Single port is inserted into thermometer, and another port connects water segregator, and water segregator upper end takes back flow tube, and middle port is used
Long handle is clamping fixed, and tape splicing seals tetrafluoro agitating paddle, opens stirring motor, electric heating cover and condensed water, keeps temperature 80 DEG C~90
It DEG C is stirred at reflux reaction, is reacted 12 hours~14 hours or so.
When having collected about 7.2mL (0.4mol) condensed water in water segregator, 0.97g (0.01mol) sulfamic acid is added, continues
It is concentrated under reduced pressure into the half of total volume after being stirred at reflux reaction 1 hour, obtains propyl ester crude product concentrate.
After the purified water crystallization of propyl ester concentrate, gallic acid raw material, propyl ester crude product are not measured in crude crystalline
With purifying water washing to neutrality, active carbon decoloring, filtering drying after purified water recrystallizes obtains fine work propyl ester 28.4g, yield is about
66.98%, purity 99.6%.
Embodiment 2
Water gallic acid (0.2mol) 37.6g is accurately weighed, is added in 500mL three-necked flask, successively measures perchloric acid
3.2 (0.04mol) mL, benzene 40mL, take normal propyl alcohol 45mL (0.6mol), are added in three-necked flask, three-necked flask is placed in 1L electricity and adds
In hot jacket, three-necked flask Single port is inserted into thermometer, and another port connects water segregator, and water segregator upper end takes back flow tube, and middle port is long
Spindle clamp is clamped, and tetrafluoro agitating paddle is connect, and opens stirring motor, electric heating cover and condensed water, is kept for 80 DEG C~90 DEG C of temperature and stirred back
Stream reaction, reacts 12 hours~14 hours or so.
When having collected about 7.2mL (0.4mol) condensed water in water segregator, 0.97g (0.01mol) sulfamic acid is added, continues
It is concentrated under reduced pressure into the half of total volume after being stirred at reflux reaction 1 hour, obtains propyl ester crude product concentrate.
After the purified water crystallization of propyl ester concentrate, gallic acid raw material, propyl ester crude product are not measured in crude crystalline
With purifying water washing to neutrality, active carbon decoloring, filtering drying after purified water recrystallizes obtains fine work propyl ester 34.6g, yield is about
81.60%, purity 99.9%.
Embodiment 3
Water gallic acid (0.2mol) 37.6g is accurately weighed, is added in 500mL three-necked flask, successively measures perchloric acid
4.8 (0.06mol) mL, benzene 40mL, take normal propyl alcohol 45mL (0.6mol), are added in three-necked flask, three-necked flask is placed in 1L electricity and adds
In hot jacket, three-necked flask Single port is inserted into thermometer, and another port connects water segregator, and water segregator upper end takes back flow tube, and middle port is long
Spindle clamp is clamped, and tetrafluoro agitating paddle is connect, and opens stirring motor, electric heating cover and condensed water, is kept for 80 DEG C~90 DEG C of temperature and stirred back
Stream reaction, reacts 12 hours~14 hours or so.
When having collected about 7.2mL (0.4mol) condensed water in water segregator, 0.97g (0.01mol) sulfamic acid is added, continues
It is concentrated under reduced pressure into the half of total volume after being stirred at reflux reaction 1 hour, obtains propyl ester crude product concentrate.
After the purified water crystallization of propyl ester concentrate, gallic acid raw material, propyl ester crude product are not measured in crude crystalline
With purifying water washing to neutrality, active carbon decoloring, filtering drying after purified water recrystallizes obtains fine work propyl ester 31.3g, yield is about
73.80%, purity 99.6%.
Embodiment 4
Water gallic acid (0.2mol) 37.6g is accurately weighed, is added in 500mL three-necked flask, successively measures perchloric acid
3.2 (0.04mol) mL, benzene 40mL, take normal propyl alcohol 45mL (0.6mol), are added in three-necked flask, three-necked flask is placed in 1L electricity and adds
In hot jacket, three-necked flask Single port is inserted into thermometer, and another port connects water segregator, and water segregator upper end takes back flow tube, and middle port is long
Spindle clamp is clamped, and tetrafluoro agitating paddle is connect, and opens stirring motor, electric heating cover and condensed water, is kept for 80 DEG C~90 DEG C of temperature and stirred back
Stream reaction, reacts 12 hours~14 hours or so.
When having collected about 7.2mL (0.4mol) condensed water in water segregator, 1.94g (0.02mol) sulfamic acid is added, continues
It is concentrated under reduced pressure into the half of total volume after being stirred at reflux reaction 1 hour, obtains propyl ester crude product concentrate.
After the purified water crystallization of propyl ester concentrate, gallic acid raw material, propyl ester crude product are not measured in crude crystalline
With purifying water washing to neutrality, active carbon decoloring, filtering drying after purified water recrystallizes obtains fine work propyl ester 32.1g, yield is about
75.70%, purity 99.7%.
Comparative example 1
A water gallic acid 37.6g (0.2mol) is accurately weighed, is added in 500mL three-necked flask, successively measures perchloric acid
3.2mL (0.04mol), benzene 40mL take normal propyl alcohol 45mL (0.6mol), are added in three-necked flask, three-necked flask is placed in 1L electricity and adds
In hot jacket, three-necked flask Single port is inserted into thermometer, and another port connects water segregator, and water segregator upper end takes back flow tube, and middle port is long
Spindle clamp is clamped, and tetrafluoro agitating paddle is connect, and opens stirring motor, electric heating cover and condensed water, is kept for 80 DEG C~90 DEG C of temperature and stirred back
Stream reaction, reacts 12 hours~14 hours or so.
When having collected about 7.2mL (0.4mol) condensed water in water segregator, it is concentrated under reduced pressure into the half of total volume, obtains propyl ester
Crude product concentrate.
After the purified water crystallization of propyl ester concentrate, the suction of about 0.25% chromatography of gallic acid raw material is measured in crude crystalline
It receives, propyl ester crude product purifying water washing to neutrality, active carbon decoloring, filtering drying after purified water recrystallization obtains fine work Gallate third
Ester 27.1g, yield about 63.920%, purity 99.1%.
Embodiment 5
A water gallic acid 37.6g (0.2mol) is accurately weighed, 3.8g (0.02mol) water p-methyl benzenesulfonic acid is added
In 500mL three-necked flask, benzene 40mL is successively measured, is taken normal propyl alcohol 45mL (0.6mol), is added in three-necked flask, three-necked flask is set
In 1L electric heating cover, three-necked flask Single port is inserted into thermometer, and another port connects water segregator, and water segregator upper end takes back flow tube,
The long spindle clamp of middle port is clamped, and tetrafluoro agitating paddle is connect, and opens stirring motor, electric heating cover and condensed water, keeps temperature 80 DEG C~90
It DEG C is stirred at reflux reaction, is reacted 12 hours~14 hours or so.
When having collected about 7.6mL (0.42mol) condensed water in water segregator, 0.97g sulfamic acid is added, continues to be stirred at reflux
Reaction is concentrated under reduced pressure into the half of total volume after 1 hour, obtain propyl ester crude product concentrate.
After the purified water crystallization of propyl ester concentrate, does not measure the chromatography of gallic acid raw material about in crude crystalline and inhale
It receives, propyl ester crude product purifying water washing to neutrality, active carbon decoloring, filtering drying after purified water recrystallization obtains fine work Gallate third
Ester 28.9g, yield about 68.16%, purity 99.6%.
Embodiment 6
A water gallic acid 37.6g (0.2mol) is accurately weighed, 7.6g (0.04mol) water p-methyl benzenesulfonic acid is added
In 500mL three-necked flask, benzene 40mL is successively measured, is taken normal propyl alcohol 45mL (0.6mol), is added in three-necked flask, three-necked flask is set
In 1L electric heating cover, three-necked flask Single port is inserted into thermometer, and another port connects water segregator, and water segregator upper end takes back flow tube,
The long spindle clamp of middle port is clamped, and tetrafluoro agitating paddle is connect, and opens stirring motor, electric heating cover and condensed water, keeps temperature 80 DEG C~90
It DEG C is stirred at reflux reaction, is reacted 12 hours~14 hours or so.
When having collected about 7.9mL (0.44mol) condensed water in water segregator, 0.97g sulfamic acid is added, continues to be stirred at reflux
Reaction is concentrated under reduced pressure into the half of total volume after 1 hour, obtain propyl ester crude product concentrate.
After the purified water crystallization of propyl ester concentrate, the chromatographic absorption of gallic acid raw material is not measured in crude crystalline,
Propyl ester crude product purifying water washing to neutrality, active carbon decoloring, filtering drying after purified water recrystallizes obtain fine work propyl ester
32.2g, yield about 75.95%, purity 99.7%.
Embodiment 7
A water gallic acid 37.6g (0.2mol) is accurately weighed, 11.4g (0.06mol) water p-methyl benzenesulfonic acid is added
In 500mL three-necked flask, benzene 40mL is successively measured, is taken normal propyl alcohol 45mL (0.6mol), is added in three-necked flask, three-necked flask is set
In 1L electric heating cover, three-necked flask Single port is inserted into thermometer, and another port connects water segregator, and water segregator upper end takes back flow tube,
The long spindle clamp of middle port is clamped, and tetrafluoro agitating paddle is connect, and opens stirring motor, electric heating cover and condensed water, keeps temperature 80 DEG C~90
It DEG C is stirred at reflux reaction, is reacted 12 hours~14 hours or so.
When having collected about 8.3mL (0.46mol) condensed water in water segregator, 0.97g sulfamic acid is added, continues to be stirred at reflux
Reaction is concentrated under reduced pressure into the half of total volume after 1 hour, obtain propyl ester crude product concentrate.
After the purified water crystallization of propyl ester concentrate, the chromatographic absorption of gallic acid raw material is not measured in crude crystalline,
Propyl ester crude product purifying water washing to neutrality, active carbon decoloring, filtering drying after purified water recrystallizes obtain fine work propyl ester
29.3g, yield about 69.10%, purity 99.5%.
Embodiment 8
A water gallic acid 37.6g (0.2mol) is accurately weighed, 7.6g (0.04mol) water p-methyl benzenesulfonic acid is added
In 500mL three-necked flask, benzene 40mL is successively measured, is taken normal propyl alcohol 45mL (0.6mol), is added in three-necked flask, three-necked flask is set
In 1L electric heating cover, three-necked flask Single port is inserted into thermometer, and another port connects water segregator, and water segregator upper end takes back flow tube,
The long spindle clamp of middle port is clamped, and tetrafluoro agitating paddle is connect, and opens stirring motor, electric heating cover and condensed water, keeps temperature 80 DEG C~90
It DEG C is stirred at reflux reaction, is reacted 12 hours~14 hours or so.
When having collected about 7.9mL (0.44mol) condensed water in water segregator, 1.94g (0.02mol) sulfamic acid is added, after
Continue the half for being concentrated under reduced pressure into total volume after being stirred at reflux reaction 1 hour, obtains propyl ester crude product concentrate.
After the purified water crystallization of propyl ester concentrate, the chromatographic absorption of gallic acid raw material is not measured in crude crystalline,
Propyl ester crude product purifying water washing to neutrality, active carbon decoloring, filtering drying after purified water recrystallizes obtain fine work propyl ester
30.0g, yield about 70.75%, purity 99.6%.
Comparative example 2
A water gallic acid 37.6g (0.2mol) is accurately weighed, 7.6g (0.04mol) water p-methyl benzenesulfonic acid is added
In 500mL three-necked flask, benzene 40mL is successively measured, is taken normal propyl alcohol 45mL (0.6mol), is added in three-necked flask, three-necked flask is set
In 1L electric heating cover, three-necked flask Single port is inserted into thermometer, and another port connects water segregator, and water segregator upper end takes back flow tube,
The long spindle clamp of middle port is clamped, and tetrafluoro agitating paddle is connect, and opens stirring motor, electric heating cover and condensed water, keeps temperature 80 DEG C~90
It DEG C is stirred at reflux reaction, is reacted 12 hours~14 hours or so.
When having collected about 7.9mL (0.44mol) condensed water in water segregator, it is concentrated under reduced pressure into the half of total volume, obtains Gallate third
Ester crude product concentrate.
After the purified water crystallization of propyl ester concentrate, the chromatography of gallic acid raw material about 0.30% is measured in crude crystalline
It absorbs, propyl ester crude product purifying water washing to neutrality, active carbon decoloring, filtering drying after purified water recrystallization obtains fine work Gallate
Propyl ester 26.9g, yield about 63.44%, purity 99.1%.
By above-described embodiment and comparative example it is found that the present invention using perchloric acid and sulfamic acid or p-methyl benzenesulfonic acid and
Sulfamic acid system carries out substep catalysis reaction, the propyl ester of preparation purity with higher.
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims (7)
1. a kind of method of substep catalysis preparation high-purity propyl ester, comprising the following steps:
Using gallic acid and normal propyl alcohol as raw material, successively under the catalytic action of perchloric acid and sulfamic acid, or to toluene
It under the catalytic action of sulfonic acid and sulfamic acid, is reacted, obtains propyl ester.
2. the method according to claim 1, wherein specifically includes the following steps:
Using gallic acid and normal propyl alcohol as raw material, under the catalytic action of perchloric acid or p-methyl benzenesulfonic acid, under counterflow condition, into
Row catalysis reaction for the first time；
Reach theoretical value to reaction system water yield, sulfamic acid is added, carries out second of catalysis reaction, obtain propyl ester.
3. according to the method described in claim 2, it is characterized in that, the reaction system water yield is measured by water segregator.
4. according to the method described in claim 2, it is characterized in that, the first time catalysis reaction temperature be 80~90 DEG C,
Reaction time is 12~14h；The temperature of second of the catalysis reaction is 80~90 DEG C, and the reaction time is 1~2h.
5. method according to claim 1 or 2, which is characterized in that the perchloric acid or p-methyl benzenesulfonic acid and galla turcica
The molar ratio of acid is (0.1~0.3): 1；The molar ratio of the sulfamic acid and gallic acid is (0.05~0.1): 1.
6. the method according to claim 1, wherein the water entrainer of the reaction is benzene.
7. the method according to claim 1, wherein after reaction, further includes:
Reaction system is concentrated into the half of total volume, and water is added and is crystallized, solid filtering, water washing to neutrality, and active carbon is de-
Color, water recrystallization, obtains propyl ester sterling.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1371899A (en) * | 2001-02-28 | 2002-10-02 | 罗伟 | Process for preparing propyl gallate |
| CN101643418A (en) * | 2009-09-07 | 2010-02-10 | 湖南先伟实业有限公司 | Preparation method of gallic acid alcohol ester |
| CN102964252A (en) * | 2012-11-27 | 2013-03-13 | 湖南先伟实业有限公司 | Technology for preparing propyl gallate by utilizing mixed catalyst |
-
2018
- 2018-10-22 CN CN201811230476.9A patent/CN109456195A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1371899A (en) * | 2001-02-28 | 2002-10-02 | 罗伟 | Process for preparing propyl gallate |
| CN101643418A (en) * | 2009-09-07 | 2010-02-10 | 湖南先伟实业有限公司 | Preparation method of gallic acid alcohol ester |
| CN102964252A (en) * | 2012-11-27 | 2013-03-13 | 湖南先伟实业有限公司 | Technology for preparing propyl gallate by utilizing mixed catalyst |
Non-Patent Citations (2)
| Title |
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| 伍焜贤和陈永清: "《没食子酸丙醋制备工艺改进》", 《中国医药工业杂志》 * |
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