CN103102267A - Preparation method of pharmaceutic adjuvant grade Glyceryl Behenate - Google Patents

Preparation method of pharmaceutic adjuvant grade Glyceryl Behenate Download PDF

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CN103102267A
CN103102267A CN2011103550090A CN201110355009A CN103102267A CN 103102267 A CN103102267 A CN 103102267A CN 2011103550090 A CN2011103550090 A CN 2011103550090A CN 201110355009 A CN201110355009 A CN 201110355009A CN 103102267 A CN103102267 A CN 103102267A
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glyceryl behenate
behenic acid
acid
add
glycerine
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CN103102267B (en
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缪志毅
黄云生
刘飞
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JIANGXI ALPHA HI-TECH PHARMACEUTICAL Co Ltd
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JIANGXI ALPHA HI-TECH PHARMACEUTICAL Co Ltd
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Abstract

本发明涉及药物合成领域,具体地涉及一种药用辅料级山嵛酸甘油酯的制备方法。根据本发明的方法包括步骤:(1)在反应器中加入山嵛酸和甘油搅拌均匀;(2)直接升温脱水酯化反应;(3)加入活性炭脱色、趁热过滤;(4)加纯化水冷却结晶,离心,干燥,粉碎得到药用辅料级山嵛酸甘油酯。本发明采用山嵛酸和甘油直接脱水酯化制备山嵛酸甘油酯,无需像常规酯化反应时加入催化剂,如:浓硫酸、对甲苯磺酸、固体酸等;也无需加入其它反应溶剂;此外产品精制较为方便。该工艺“三废”产生少,操作简单,收率可达89%以上,适宜工业化生产,质量可满足药用辅料级要求。The invention relates to the field of drug synthesis, in particular to a preparation method of pharmaceutical excipient grade glyceryl behenate. The method according to the present invention comprises the steps: (1) adding behenic acid and glycerin in the reactor and stirring evenly; (2) directly raising the temperature for dehydration esterification reaction; (3) adding activated carbon for decolorization and filtering while hot; (4) adding purification Cooling with water for crystallization, centrifugation, drying, and crushing to obtain pharmaceutical excipient grade glyceryl behenate. The present invention uses behenic acid and glycerin to directly dehydrate and esterify glyceryl behenate to prepare glyceryl behenate, without adding catalysts such as concentrated sulfuric acid, p-toluenesulfonic acid, solid acid, etc.; and without adding other reaction solvents; In addition, product refining is more convenient. The process produces less "three wastes", is simple to operate, and has a yield of more than 89%, which is suitable for industrial production, and the quality can meet the requirements of pharmaceutical excipients.

Description

A kind of preparation method of pharmaceutical excipient level Glyceryl Behenate
Technical field
The present invention relates to medicine and synthesize the field, relate to particularly a kind of preparation method of pharmaceutical excipient level Glyceryl Behenate.
Background technology
Glyceryl Behenate is nonionogenic tenside, has emulsification, dispersion, froth breaking and lubrication; Can be used as emulsifying agent and emulsion stabilizer, for the preparation of emulsion, ointment, salve.The main application of Glyceryl Behenate in medicament is to be used as lubricant in tablet, pill, granule and capsule manufacturing; Make dispersion agent, also have been widely used in solid, semisolid and liquid preparation; Also can be used for slow releasing tablet, and as the skeleton of water-soluble drug sustained-release preparation.
The method of at present synthetic Glyceryl Behenate has: 1, make isopropylidene glycerol-4-methanol with glycerine and acetone reaction, react to get the different acetonylidene glyceryl ester of behenic acid with behenic acid again, further with its hydrolysis single Glyceryl Behenate (universal will, Huang Tianhe, " study on the synthesis of single Glyceryl Behenate ", " chemical reagent ", 2009,31); 2, the one-pot synthesis of protecting with acetone; namely make isopropylidene glycerine by glycerine and acetone reaction; (Gu Yujie, horse are firm etc. to have prepared glyceryl monolaurate, single tetradecanoic acid glyceryl ester, monopalmitin, glyceryl monostearate, 5 kinds of monoglycerides of single Glyceryl Behenate with fatty acid response under the Catalyzed by p-Toluenesulfonic Acid effect; " synthesizing series high purity monoglyceride "; " daily chemical industry "; 2006,36).
Above-mentioned synthetic method is all synthetic single Glyceryl Behenate or mixes Glyceryl Behenate, and the pharmaceutical grade Glyceryl Behenate is a kind of mixture that contains behenic acid monoglyceride, dibasic acid esters and three esters, wherein single Glyceryl Behenate content should be 12%~18%, and acid number must be below 4.Therefore, above-mentioned literature method can not be used for directly preparing pharmaceutical excipient level Glyceryl Behenate.
Have no at present document and the patent report of pharmaceutical grade Glyceryl Behenate production technique both at home and abroad, the synthetic of similar derivative only arranged.
Summary of the invention
The present inventor proposes and has completed the present invention in order to address the above problem.
Purpose of the present invention is for providing a kind of preparation method of pharmaceutical excipient level Glyceryl Behenate.
Preparation method according to pharmaceutical excipient level Glyceryl Behenate of the present invention said method comprising the steps of:
(1) add behenic acid and glycerine to stir in reactor, wherein, the molar ratio of behenic acid and glycerine is 1~2.5: 1;
(2) the dehydration esterification that directly heats up does not need catalyzer, and temperature of reaction is 105~200 ℃, and the reaction times is 5-12 hour;
(3) add activated carbon decolorizing, filtered while hot;
(4) crystallisation by cooling, centrifugal, drying is pulverized and is obtained pharmaceutical excipient level Glyceryl Behenate.
The present invention is take behenic acid and glycerine as raw material, and the Direct Dehydration esterification obtains the requirement of pharmaceutical excipient level Glyceryl Behenate, and its reaction scheme is as follows:
The method according to this invention, wherein, in the esterification process of step (1), the molar ratio of behenic acid and glycerine is 1.35~1.9: 1, is preferably 1.6~1.9: 1.Behenic acid and glycerine ratio control can be produced the qualified product of behenic acid direactive glyceride content well under these processing condition.
The method according to this invention, wherein, in step (2) directly heated up the dehydration esterification, temperature of reaction was 120~180 ℃, is preferably 140~160 ℃; Reaction times is 6-10 hour, is preferably 7-8 hour.The high temperature dehydration esterification temperature is too high can affect product color, and too low reaction not exclusively.
According to power method of the present invention, wherein, in step (3), add the gac of behenic acid weight ratio 1% to decolour, elimination discoloring agent gac should be while hot.
According to method of the present invention, wherein, in step (4), add the purified water cooling crystallization of 2~5 times of amounts of behenic acid weight, be preferably 3~4 times of amounts, purified water is good.
According to method of the present invention, wherein, the recrystallization temperature of step (4) is 10~40 ℃, is preferably 20~30 ℃.
The consumption of gac is too low can affect product color, does not reach decolorizing effect.As too high in consumption, adsorb excessively, yield reduces.
The method according to this invention wherein, is selected the normal pressure forced air drying when dry in step (4).
The present invention adopts behenic acid and the esterification of glycerine Direct Dehydration to prepare Glyceryl Behenate, adds catalyzer when need not as conventional esterification, as: the vitriol oil, tosic acid, solid acid etc.; Also need not to add other reaction solvent; Product purification more in addition.This technique " three wastes " produces few, and simple to operate, yield can reach more than 89%, suitability for industrialized production, but the requirement of quality fulfilling medicinal auxiliary material level.
Embodiment
Embodiment 1
Drop into 50.1kg behenic acid and 13.5kg glycerine (mol ratio is 1: 1) in glassed steel reaction vessels, being warming up to 105 ℃ of dehydration reactions 10 hours (controls acid number<4.0=, adds the 5.0kg activated carbon decolorizing, filtered while hot, add the 250.0kg purified water in filtrate, be cooled to 40 ℃ of crystallizatioies 24 hours, centrifugal rejection filter, forced air drying, pulverize, cross 80 mesh sieves, obtain 57.2kg pharmaceutical excipient level Glyceryl Behenate, molar yield: 89.9%.Acid number 1.7; Saponification value 147.3; Behenic acid direactive glyceride 17.8% (by the two ministerial standard tests of 2010 editions Chinese Pharmacopoeias), warp 1H-NMR; 13C-NMR; The C-H Correlated Spectroscopy; Long-range C-H Correlated Spectroscopy conclusive evidence is the mixture of monoesters, diester, three esters.
Embodiment 2
Drop into 50.0kg behenic acid and 10.0kg glycerine (mol ratio is 1.35: 1) in glassed steel reaction vessels, being warming up to 120 ℃ of dehydration reactions 8 hours (controls acid number<4.0=, adds the 5.0kg activated carbon decolorizing, filtered while hot, add the 200.0kg purified water in filtrate, be cooled to 30 ℃ of crystallizatioies 24 hours, centrifugal rejection filter, forced air drying, pulverize, cross 80 mesh sieves, obtain 54.5kg pharmaceutical excipient level Glyceryl Behenate, molar yield: 90.8%.Acid number 2.5; Saponification value 150.6; Behenic acid direactive glyceride 16.1% (by the two ministerial standard tests of 2010 editions Chinese Pharmacopoeias), warp 1H-NMR; 13C-NMR; The C-H Correlated Spectroscopy; Long-range C-H Correlated Spectroscopy conclusive evidence is the mixture of monoesters, diester, three esters.
Embodiment 3
Drop into 51.2kg behenic acid and 8.6kg glycerine (mol ratio is 1.6: 1) in glassed steel reaction vessels, be warming up to 140 ℃ of dehydration reactions 8 hours (controlling acid number<4.0), add the 5.1kg activated carbon decolorizing, filtered while hot, add the 150.0kg purified water in filtrate, be cooled to 20 ℃ of crystallizatioies 24 hours, centrifugal rejection filter, forced air drying, pulverize, cross 80 mesh sieves, obtain 54.8kg pharmaceutical excipient level Glyceryl Behenate, molar yield: 91.6%.Acid number 2.6; Saponification value 154.5; Behenic acid direactive glyceride 15.3% (by the two ministerial standard tests of 2010 editions Chinese Pharmacopoeias), warp 1H-NMR; 13C-NMR; The C-H Correlated Spectroscopy; Long-range C-H Correlated Spectroscopy conclusive evidence is the mixture of monoesters, diester, three esters.
Embodiment 4
Drop into 50.5kg behenic acid and 7.2kg glycerine (mol ratio is 1.9: 1) in glassed steel reaction vessels, being warming up to 160 ℃ of dehydration reactions 7 hours (controls acid number<4.0=, adds the 5.0kg activated carbon decolorizing, filtered while hot, add the 128.0kg purified water in filtrate, be cooled to 10 ℃ of crystallizatioies 24 hours, centrifugal rejection filter, forced air drying, pulverize, cross 80 mesh sieves, obtain 52.6kg pharmaceutical excipient level Glyceryl Behenate, molar yield: 911%.White powder; 69.5 ℃~72.1 ℃ of fusing points; Acid number 3.1; Saponification value 155.1; Behenic acid direactive glyceride 14.8% (by the two ministerial standard tests of 2010 editions Chinese Pharmacopoeias), warp 1H-NMR; 13C-NMR; The C-H Correlated Spectroscopy; Long-range C-H Correlated Spectroscopy conclusive evidence is the mixture of monoesters, diester, three esters.
Embodiment 5
Drop into 51.0kg behenic acid and 6.6kg glycerine (mol ratio is 2.1: 1) in glassed steel reaction vessels, be warming up to 180 ℃ of dehydration reactions 8 hours (controlling acid number<4.0), add the 5.0kg activated carbon decolorizing, filtered while hot, add the 120.0kg purified water in filtrate, be cooled to 20 ℃ of crystallizatioies 24 hours, centrifugal rejection filter, forced air drying, pulverize, cross 80 mesh sieves, obtain 51.8kg pharmaceutical excipient level Glyceryl Behenate, molar yield: 90%.Acid number 2.5; Saponification value 158.5; Behenic acid direactive glyceride 14.6% (by the two ministerial standard tests of 2010 editions Chinese Pharmacopoeias), warp 1H-NMR; 13C-NMR; The C-H Correlated Spectroscopy; Long-range C-H Correlated Spectroscopy conclusive evidence is the mixture of monoesters, diester, three esters.
Embodiment 6
Drop into 50.1kg behenic acid and 5.4kg glycerine (mol ratio is 2.5: 1) in glassed steel reaction vessels, be warming up to 200 ℃ of dehydration reactions 6 hours (controlling acid number<4.0), add the 5.0kg activated carbon decolorizing, filtered while hot, add the 100.0kg purified water in filtrate, be cooled to 25 ℃ of crystallizatioies 24 hours, centrifugal rejection filter, forced air drying, pulverize, cross 80 mesh sieves, obtain 50.6kg pharmaceutical excipient level Glyceryl Behenate, molar yield: 91%.Acid number 3.5; Saponification value 160.5; Behenic acid direactive glyceride 13.5% (by the two ministerial standard tests of 2010 editions Chinese Pharmacopoeias), warp 1H-NMR; 13C-NMR; The C-H Correlated Spectroscopy; Long-range C-H Correlated Spectroscopy conclusive evidence is the mixture of monoesters, diester, three esters.
Embodiment 7
Drop into 51.5kg behenic acid and 8.5kg glycerine (mol ratio is 1.6: 1) in glassed steel reaction vessels, be warming up to 140 ℃ of dehydration reactions 5 hours (controlling acid number<4.0), add the 5.1kg activated carbon decolorizing, filtered while hot, add the 130.0kg purified water in filtrate, be cooled to 25 ℃ of crystallizatioies 24 hours, centrifugal rejection filter, forced air drying, pulverize, cross 80 mesh sieves, obtain 52.9kg pharmaceutical excipient level Glyceryl Behenate, molar yield: 88.0%.Acid number 3.4; Saponification value 156.5; Behenic acid direactive glyceride 14.5% (by the two ministerial standard tests of 2010 editions Chinese Pharmacopoeias), warp 1H-NMR; 13C-NMR; The C-H Correlated Spectroscopy; Long-range C-H Correlated Spectroscopy conclusive evidence is the mixture of monoesters, diester, three esters.
Embodiment 8
Drop into 51.7kg behenic acid and 8.6kg glycerine (mol ratio is 1.6: 1) in glassed steel reaction vessels, being warming up to 140 ℃ of dehydration reactions 12 hours (controls acid number<4.0=, adds the 5.1kg activated carbon decolorizing, filtered while hot, add the 130.0kg purified water in filtrate, be cooled to 25 ℃ of crystallizatioies 24 hours, centrifugal rejection filter, forced air drying, pulverize, cross 80 mesh sieves, obtain 50.7kg pharmaceutical excipient level Glyceryl Behenate, molar yield: 84.0%.Acid number 2.1; Saponification value 158.5; Behenic acid direactive glyceride 15.3% (by the two ministerial standard tests of 2010 editions Chinese Pharmacopoeias), warp 1H-NMR; 13C-NMR; The C-H Correlated Spectroscopy; Long-range C-H Correlated Spectroscopy conclusive evidence is the mixture of monoesters, diester, three esters.

Claims (7)

1. the preparation method of a pharmaceutical excipient level Glyceryl Behenate, is characterized in that, said method comprising the steps of:
(1) add behenic acid and glycerine to stir in reactor, wherein, the molar ratio of behenic acid and glycerine is 1~2.5: 1;
(2) the dehydration esterification that directly heats up, temperature of reaction is 105~200 ℃, the reaction times is 5-12 hour;
(3) add activated carbon decolorizing, filtered while hot;
(4) crystallisation by cooling, centrifugal, drying is pulverized and is obtained pharmaceutical excipient level Glyceryl Behenate.
2. method according to claim 1, is characterized in that, in the esterification process of step (1), the molar ratio of behenic acid and glycerine is 1.35~1.9: 1, is preferably 1.6~1.9: 1.
3. method according to claim 1, is characterized in that, in step (2) directly heated up the dehydration esterification, temperature of reaction was 120~180 ℃, is preferably 140~160 ℃; Reaction times is 6-10 hour, is preferably 7-8 hour.
4. according to method claimed in claim 1, it is characterized in that, in step (3), add the gac of behenic acid weight ratio 1% to decolour.
5. according to method claimed in claim 1, it is characterized in that, in step (4), add the purified water cooling crystallization of 2~5 times of amounts of behenic acid weight, be preferably 3~4 times of amounts.
6. according to method claimed in claim 1, it is characterized in that, the recrystallization temperature of step (4) is 10~40 ℃, is preferably 20~30 ℃.
7. method according to claim 1, is characterized in that, selects the normal pressure forced air drying when dry in step (4).
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104557525A (en) * 2013-10-21 2015-04-29 广东东阳光药业有限公司 Method for preparing ester
CN107417522A (en) * 2017-05-22 2017-12-01 武汉桀升生物科技有限公司 A kind of method for catalyzing and synthesizing the Compritol 888 ATO for pharmaceutic adjuvant

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4098706A (en) * 1975-05-07 1978-07-04 Sapchim-Fournier-Cimag Lubricating agents for thermoplastic materials and process for preparing the same
CN101495538A (en) * 2006-07-28 2009-07-29 日清奥利友集团株式会社 Esterification reaction product, gelling agent containing the product, and cosmetic preparation containing them

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4098706A (en) * 1975-05-07 1978-07-04 Sapchim-Fournier-Cimag Lubricating agents for thermoplastic materials and process for preparing the same
CN101495538A (en) * 2006-07-28 2009-07-29 日清奥利友集团株式会社 Esterification reaction product, gelling agent containing the product, and cosmetic preparation containing them

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104557525A (en) * 2013-10-21 2015-04-29 广东东阳光药业有限公司 Method for preparing ester
CN104557525B (en) * 2013-10-21 2019-01-04 广东东阳光药业有限公司 A kind of preparation method of ester
CN107417522A (en) * 2017-05-22 2017-12-01 武汉桀升生物科技有限公司 A kind of method for catalyzing and synthesizing the Compritol 888 ATO for pharmaceutic adjuvant

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