CN103087015A - Preparation method of sorbitan oleate servicing as medicinal auxiliary material - Google Patents
Preparation method of sorbitan oleate servicing as medicinal auxiliary material Download PDFInfo
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- CN103087015A CN103087015A CN2012105540384A CN201210554038A CN103087015A CN 103087015 A CN103087015 A CN 103087015A CN 2012105540384 A CN2012105540384 A CN 2012105540384A CN 201210554038 A CN201210554038 A CN 201210554038A CN 103087015 A CN103087015 A CN 103087015A
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Abstract
The invention relates to a preparation method of sorbitan oleate servicing as a medicinal auxiliary material. The preparation method is characterized by comprising the following steps: adding powdered solid sorbitol into a reactor; stirring; heating to 80-105 DEG C to melt the powdered solid sorbitol; adding an acidic catalyst; agitating; dewatering at 90-110 DEG C at a vacuum condition; neutralizing the rest acidic catalyst after the reaction; filtering; decolouring; filtering; concentrating; drying to obtain 1,4-sorbitan; adding oleic acid into the reactor, the prepared 1, 4-sorbitan and a basic catalyst, wherein the mass ratio of the 1, 4-sorbitan to the oleic acid is 1:(2.06-2.41); pouring nitrogen and removing the oxygen; stirring and heating; carrying out esterification reaction at 190 to 210 DEG C; and then carrying out cooling, decolouring and filtering after the reaction so as to obtain the sorbitan oleate. The preparation method is simple in process and short in reaction time; the prepared product which is the sorbitan oleate is light in colour and high in purity; and the physicochemical performance of the sorbitan oleate meets the requirement of Section II of Pharmacopeia, Edition 2010.
Description
Technical field
The present invention relates to a kind of chemical industry synthetic method, relate in particular to a kind of preparation method of pharmaceutical excipient Sorbitan Oleate.
Background technology
Sorbitan Oleate (also claiming sorbitan monooleate or sorbester p17) is a kind of important nonionogenic tenside, is commonly used for the w/o type emulsifying agent.Due to its excellent emulsification, dispersion and the surfactivity such as wetting, and nontoxic, non-stimulated, low volatilization, the characteristics such as micelle-forming concentration is higher and the micella free energy is lower, extensive in sector applications such as oil, food, makeup and medicine.
In preparation about Sorbitan Oleate, a traditional step base catalysis method be with sorbyl alcohol and oleic acid under basic catalyst exists, carry out simultaneously etherificate and esterification in 190 ℃-260 ℃.The production technique of the synthetic Sorbitan Oleate of single stage method is disclosed as patent CN102260228A, it be with sorbyl alcohol and oleic acid under efficient composite catalyst exists, at 190-240 ℃, carry out simultaneously etherificate and esterification 5-8h.Although this method is simple, but because esterification and etherification reaction carry out simultaneously, often occur that esterification carries out better, and etherificate becomes ring not enough, makes the interior etherificate degree in the Sorbitan Oleate molecule low, and the content of the sorbitol ester of straight chain is larger, final result is that the inside regularity of product is poor, the performance of outward appearance is poor fluidity, and muddiness is solidified etc.Simultaneously, sorbyl alcohol can further dewater under higher temperature, long reaction times act on, multiple reaction is carried out under same temperature of reaction, causes that the reaction product color and luster is dark, poor transparency, and by product is many, quality is unstable, and What is more, and coking is serious, and its application prospect is restricted.
At " impact of catalyzer on synthetic sorbitan monooleate esterification " (Feng Xiping; " Information "; The 17th phase in 2010) propose the two step synthesis Sorbitan Oleate, namely at first under the basic catalyst effect, sorbyl alcohol and fatty acid ester are changed into sorbitan fatty acid monoesters or dibasic acid esters; Then sorbitan fatty acid monoesters and dibasic acid esters are dehydrated into acid anhydride under an acidic catalyst effect.The first esterification of the method, then etherificate, the ester group that esterification is introduced is sterically hindered large, causes later stage etherificate difficulty; And unsaturated fatty acids residual in the early stage esterification process is easily oxidized in etherification procedure, and the product color that obtains is brown to dark-brown, even blackout.
In " synthesizing of High Quality Sorbitan Monoleate " (mao Lianshan Mountain, " printing during chemical industry ", the 19th the 5th phase of volume in 2005) mention in and adopt that the method for esterification prepares sorbitan monooleate after first etherificate, but the temperature of its etherificate is higher, be 160-180 ℃, may cause the excessive dehydration of sorbyl alcohol and be exposed to for a long time coking occurs in hot environment, and then cause the color of product darker.Except this, adopt in its esterification reaction process and vacuumize the method for getting rid of oxygen, also taken a part of oleic acid away when vacuumizing, cause the loss of material, wherein the molar ratio of acid alcohol reaches more than 1.5 and just can obtain qualified product.
Summary of the invention
Technical problem to be solved by this invention is that a kind of preparation method of pharmaceutical excipient Sorbitan Oleate is provided for the deficiencies in the prior art.This preparation method's technique is simple, and the reaction times is short, the product Sorbitan Oleate lighter color for preparing, and purity is high, and physico-chemical property meets the requirement of 2010 editions two ones of pharmacopeia.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A kind of preparation method of pharmaceutical excipient Sorbitan Oleate is characterized in that, it comprises the following steps:
(1) add the Neosorb powder in reactor, stir, be warming up to 80 ℃-105 ℃, make its melting, then add an acidic catalyst, stir, in 90 ℃ of-110 ℃ of dehydrations, after reaction was completed, remaining an acidic catalyst neutralized under vacuum condition, filter, then through decolouring, filter, concentrated, drying obtains Isosorbide-5-Nitrae-anhydrous sorbitol;
(2) add in reactor oleic acid, above-mentioned prepare 1,4-anhydrous sorbitol and basic catalyst, the mass ratio of described Isosorbide-5-Nitrae-anhydrous sorbitol and oleic acid are 1:2.06-2.41, letting nitrogen in and deoxidizing, then stir to heat up, carry out esterification in 190 ℃-210 ℃, after reaction is completed, cooling, decolouring is filtered, and obtains Sorbitan Oleate.
Press such scheme, an acidic catalyst in described step (1) is the sulfuric acid of phosphoric acid, phosphorous acid, tosic acid, 5-35wt% or the solid acid that is rich in the hydrogen proton, and the consumption of described catalyzer is the 0.5wt%-3wt% of sorbyl alcohol quality.
Press such scheme, the dehydration temperaturre in described step (1) is preferably 95 ℃-110 ℃, and dewatering time is preferably 2h-4h, and the vacuum tightness value must not be higher than 0.01MPa.
Press such scheme, the neutralization reagent in described step (1) is the aqueous solution of calcium hydroxide, magnesium hydroxide or hydrated barta, is preferably saturated aqua calcis.
Press such scheme, the decolouring in described step (1) is to add gac to carry out, and described gac is preferably the pharmaceutical grade gac.
Press such scheme, the oleic acid in described step (2) is preferably the vegetable oil acid of oleic acid content 〉=78wt%; Described Neosorb is preferably the pharmaceutical grade sorbitol powder.
Press such scheme, the basic catalyst in described step (2) is sodium carbonate, sodium bicarbonate, magnesium oxide or zinc oxide, and the consumption of described catalyzer is the 0.5wt%-3wt% of Isosorbide-5-Nitrae-anhydrous sorbitol and oleic acid total mass.
Press such scheme, the esterification reaction temperature in described step (2) is preferably 190 ℃-200 ℃; Reaction time of esterification is 3h-8h.
the present invention is by carrying out raw material preferably, select the Neosorb powder, be preferably the pharmaceutical grade sorbitol powder to carry out etherification reaction, need to be to its pretreated step of dewatering in the time of can saving conventional use liquid sorbitol, simplified technique, carry out further dehydration reaction under vacuum condition, can reduce the dehydration reaction temperature, improve dehydration reaction efficient, the coking phenomenon of avoiding the excessive dehydration of sorbyl alcohol and excess Temperature and may causing, to complete 1 within the time faster, the preparation of 4-anhydrous sorbitol, the crude product 1 that then will prepare and get, the 4-anhydrous sorbitol can reach lighter color through aftertreatment, purity high 1, the preparation of 4-anhydrous sorbitol, then again with itself and oleic acid, be preferably the vegetable oil acid of oleic acid content 〉=78%, under certain mol ratio consumption, in carrying out esterification under the katalysis of basic catalyst again under the condition of letting nitrogen in and deoxidizing, so can guarantee on the one hand carrying out smoothly of esterification, also can avoid on the other hand adopting the oleic acid loss that vacuumizes the deoxygenation processing and bring, at last with the esterification products that makes through decolouring, filter, obtain lighter color, purity is high, and physico-chemical property meets the Sorbitan Oleate of the requirement of 2010 editions two ones of pharmacopeia.
Beneficial effect of the present invention:
Technique is simple, and is controlled, and the reaction times is short, the product Sorbitan Oleate lighter color of preparation, and purity is high, and physico-chemical property meets the requirement of 2010 editions two ones of pharmacopeia.
Embodiment
Embodiment 1:
In the 250mL there-necked flask of thermometer is housed, add Neosorb powder 100g, stir, be warming up to 95 ℃ of meltings, adding the 1g massfraction is 20% sulfuric acid, is evacuated to 0.01MPa, is warming up to 105 ℃ of dehydration 2.5h.Then be cooled to 30 ℃, with saturated aqua calcis neutralization, filter, remove excessive catalyst sulfuric acid.Add activated carbon decolorizing, remove by filter gac, concentrated, drying obtains Isosorbide-5-Nitrae-anhydrous sorbitol.
In the 250mL there-necked flask of thermometer, prolong and nitrogen ingress pipe is housed, adding 36g Isosorbide-5-Nitrae-anhydrous sorbitol, 74.3g massfraction is 80% vegetable oil acid (both mol ratios are 1:1.2) and 1.1g sodium carbonate, logical nitrogen 30min, stirring is warming up to 200 ℃, esterification 4h.Cooling adds activated carbon decolorizing, filters, and removes gac, obtains Sorbitan Oleate.
Embodiment 2:
In the 250mL there-necked flask of thermometer is housed, add pharmaceutical grade Neosorb powder 100g, stir, be warming up to 100 ℃ of meltings, adding the 1.5g massfraction is 10% sulfuric acid, is evacuated to 0.01MPa, is warming up to 110 ℃ of dehydration 2h.Then be cooled to 30 ℃, with saturated aqua calcis neutralization, filter, remove excessive catalyst sulfuric acid.Add the pharmaceutical grade activated carbon decolorizing, remove by filter gac, concentrated, drying obtains Isosorbide-5-Nitrae-anhydrous sorbitol.
In the 250mL there-necked flask of thermometer, prolong and nitrogen ingress pipe is housed, add 36g 1,4-anhydrous sorbitol, 80.4g massfraction are 80% vegetable oil acid (both mol ratios are 1:1.3) and 1.16g sodium carbonate, logical nitrogen 30min, stirring is warming up to 200 ℃, esterification 4h.Cooling adds the pharmaceutical grade activated carbon decolorizing, filters, and removes gac, obtains Sorbitan Oleate.
Embodiment 3:
In the 250mL there-necked flask of thermometer is housed, add Neosorb powder 100g, stir, be warming up to 100 ℃ of meltings, adding the 3g massfraction is 30% sulfuric acid, is evacuated to 0.01MPa, is cooled to 90 ℃ of dehydration 4h.Then cooling with saturated aqua calcis neutralization, is filtered, and removes excessive catalyst sulfuric acid.Add activated carbon decolorizing, remove by filter gac, concentrated, drying obtains Isosorbide-5-Nitrae-anhydrous sorbitol.
In the 250mL there-necked flask of thermometer, prolong and nitrogen ingress pipe is housed, add 36g Isosorbide-5-Nitrae-anhydrous sorbitol, 86.7g oleic acid (both mol ratios are 1:1.4) and 1.23g sodium carbonate, letting nitrogen in and deoxidizing stirs and is warming up to 200 ℃, esterification 4h.Cooling adds activated carbon decolorizing, filters, and removes gac, obtains Sorbitan Oleate.
Embodiment 4, and is substantially the same manner as Example 1, but following change is arranged:
Described an acidic catalyst is phosphoric acid;
Described basic catalyst is sodium bicarbonate;
The quality of added oleic acid is 77.4g, and sodium bicarbonate is 3.4g.
Embodiment 5, and is substantially the same manner as Example 1, but following change is arranged:
Described an acidic catalyst is phosphorous acid;
Described neutralization reagent is barium hydroxide solution.
Embodiment 6, and is substantially the same manner as Example 1, but following change is arranged:
Described an acidic catalyst is tosic acid;
Described neutralization reagent is magnesium hydroxide solution;
Described basic catalyst is magnesium oxide.
Embodiment 7, and is substantially the same manner as Example 1, but following change is arranged:
Described an acidic catalyst is the solid acid SO that is rich in the hydrogen proton
4 2-/ ZrO
2
Described basic catalyst is zinc oxide;
Described reaction time of esterification is 3h.
Embodiment 8, and is substantially the same manner as Example 1, but following change is arranged:
The quality of added oleic acid is 83.6g, and sodium carbonate is 2.58g;
Described esterification reaction temperature is 190 ℃, and the reaction times is 8h.
Embodiment 9, and is substantially the same manner as Example 1, but following change is arranged:
Added sodium carbonate is 0.675g;
Described esterification reaction temperature is 210 ℃, and the reaction times is 4h.
The hydroxyl value of the prepared Isosorbide-5-Nitrae-anhydrous sorbitol of embodiment 1-9 is at 1200-1400.Prepared Sorbitan Oleate is transparent faint yellow, acid number≤8, and hydroxyl value 190-215, saponification value 145-160, iodine number 62-76, peroxide value≤10 meet the requirement of 2010 editions two ones of pharmacopeia.
Claims (8)
1. the preparation method of a pharmaceutical excipient Sorbitan Oleate, is characterized in that, it comprises the following steps:
(1) add the Neosorb powder in reactor, stir, be warming up to 80 ℃-105 ℃, make its melting, then add an acidic catalyst, stir, in 90 ℃ of-110 ℃ of dehydrations, after reaction was completed, remaining an acidic catalyst neutralized under vacuum condition, filter, then through decolouring, filter, concentrated, drying obtains Isosorbide-5-Nitrae-anhydrous sorbitol;
(2) add in reactor oleic acid, above-mentioned prepare 1,4-anhydrous sorbitol and basic catalyst, the mass ratio of described Isosorbide-5-Nitrae-anhydrous sorbitol and oleic acid are 1:2.06-2.41, letting nitrogen in and deoxidizing, then stir to heat up, carry out esterification in 190 ℃-210 ℃, after reaction is completed, cooling, decolouring is filtered, and obtains Sorbitan Oleate.
2. the preparation method of pharmaceutical excipient Sorbitan Oleate described according to claim, it is characterized in that: an acidic catalyst in described step (1) is the sulfuric acid of phosphoric acid, phosphorous acid, tosic acid, 5-35wt% or the solid acid that is rich in the hydrogen proton, and the consumption of described catalyzer is the 0.5wt%-3wt% of sorbyl alcohol quality.
3. the preparation method of pharmaceutical excipient Sorbitan Oleate described according to claim, it is characterized in that: the dehydration temperaturre in described step (1) is 95 ℃-110 ℃, and dewatering time is 2h-4h, and the vacuum tightness value must not be higher than 0.01MPa.
4. the preparation method of pharmaceutical excipient Sorbitan Oleate described according to claim, it is characterized in that: the neutralization reagent in described step (1) is the aqueous solution of calcium hydroxide, magnesium hydroxide or hydrated barta.
5. the preparation method of pharmaceutical excipient Sorbitan Oleate described according to claim, it is characterized in that: the decolouring in described step (1) is to add gac to carry out, and described gac is the pharmaceutical grade gac.
6. the preparation method of pharmaceutical excipient Sorbitan Oleate described according to claim, it is characterized in that: the oleic acid in described step (2) is the vegetable oil acid of oleic acid content 〉=78%; Described Neosorb is the pharmaceutical grade sorbitol powder.
7. the preparation method of pharmaceutical excipient Sorbitan Oleate described according to claim, it is characterized in that: the basic catalyst in described step (2) is sodium carbonate, sodium bicarbonate, magnesium oxide or zinc oxide, the consumption of described catalyzer is the 0.5wt%-3wt% of Isosorbide-5-Nitrae-anhydrous sorbitol and oleic acid total mass.
8. the preparation method of pharmaceutical excipient Sorbitan Oleate described according to claim, it is characterized in that: the esterification reaction temperature in described step (2) is 190 ℃-210 ℃; Reaction time of esterification is 3h-8h.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230859A (en) * | 2014-08-28 | 2014-12-24 | 安庆市中创生物工程有限公司 | Preparation technique of sorbitan monooleate |
| CN106045946A (en) * | 2016-06-28 | 2016-10-26 | 江苏省海安石油化工厂 | Preparation method of sorbitan tristearate |
| CN106167476A (en) * | 2016-07-20 | 2016-11-30 | 广州嘉德乐生化科技有限公司 | A kind of preparation method of Sorbitan Oleate |
| CN106349467A (en) * | 2016-08-31 | 2017-01-25 | 浙江皇马科技股份有限公司 | Preparation method of easy-to-degrade adipic acid polyethylene glycol polyester |
| CN106749118A (en) * | 2016-11-23 | 2017-05-31 | 张家港格瑞特化学有限公司 | The smooth caprylate emulsifying agent of sorb |
| CN113289547A (en) * | 2020-06-10 | 2021-08-24 | 广州市品然生物科技有限公司 | Preparation method of dehydrated mannitol oleate emulsifier |
| CN114349720A (en) * | 2022-01-24 | 2022-04-15 | 抚顺东科新能源科技有限公司 | Preparation method of colorless sorbitan |
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| CN101983977A (en) * | 2010-08-17 | 2011-03-09 | 南京威尔化工有限公司 | Method for synthesizing polysorbate-80 for injection |
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Patent Citations (1)
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| CN101983977A (en) * | 2010-08-17 | 2011-03-09 | 南京威尔化工有限公司 | Method for synthesizing polysorbate-80 for injection |
Non-Patent Citations (1)
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| 倪永全: "失水山梨醇单油酸酯质量改进的研究", 《日用化学工业》, no. 2, 31 December 1996 (1996-12-31), pages 2 - 4 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230859A (en) * | 2014-08-28 | 2014-12-24 | 安庆市中创生物工程有限公司 | Preparation technique of sorbitan monooleate |
| CN106045946A (en) * | 2016-06-28 | 2016-10-26 | 江苏省海安石油化工厂 | Preparation method of sorbitan tristearate |
| CN106167476A (en) * | 2016-07-20 | 2016-11-30 | 广州嘉德乐生化科技有限公司 | A kind of preparation method of Sorbitan Oleate |
| CN106349467A (en) * | 2016-08-31 | 2017-01-25 | 浙江皇马科技股份有限公司 | Preparation method of easy-to-degrade adipic acid polyethylene glycol polyester |
| CN106349467B (en) * | 2016-08-31 | 2018-06-05 | 浙江皇马科技股份有限公司 | A kind of preparation method of degradable type adipic acid polyethylene glycol polyester |
| CN106749118A (en) * | 2016-11-23 | 2017-05-31 | 张家港格瑞特化学有限公司 | The smooth caprylate emulsifying agent of sorb |
| CN113289547A (en) * | 2020-06-10 | 2021-08-24 | 广州市品然生物科技有限公司 | Preparation method of dehydrated mannitol oleate emulsifier |
| CN114349720A (en) * | 2022-01-24 | 2022-04-15 | 抚顺东科新能源科技有限公司 | Preparation method of colorless sorbitan |
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