CN103848726B - A kind of high-purity dihydroxy dibutyl ethers and preparation method thereof - Google Patents
A kind of high-purity dihydroxy dibutyl ethers and preparation method thereof Download PDFInfo
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- CN103848726B CN103848726B CN201210523118.3A CN201210523118A CN103848726B CN 103848726 B CN103848726 B CN 103848726B CN 201210523118 A CN201210523118 A CN 201210523118A CN 103848726 B CN103848726 B CN 103848726B
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- dibutyl ethers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/09—Preparation of ethers by dehydration of compounds containing hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
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Abstract
The invention discloses a kind of preparation method of new dihydroxy dibutyl ethers, i.e., 1, after 3 butanediols are handled through acidic cationic resin, dihydroxy dibutyl ethers crude product is obtained through vacuum distillation, crude product is handled and rectification under vacuum through petroleum ether, and high-purity dihydroxy dibutyl ethers are made.The process route overcomes the corrosion caused using sulfuric acid to equipment, with reactions steps are short, mild condition, simple to operate, high income and the features such as high product purity, is an environment-friendly and easy industrialized synthetic route.
Description
Technical field
The present invention relates to dihydroxy dibutyl ethers（Dyskinebyl）Preparation method, belong to chemicals synthesis field.
Background technology
Dihydroxy dibutyl ethers soft capsule, English entitled Dihydroxydibutylether Soft Capsules, trade name
It is a kind of disease in the liver and gallbladder adjuvant drug for the strong elements of Bao Dan.Succeeded in developing and put on market first by French Laphal pharmaceutical factories, China
The approved medicine import is used to treat disease in the liver and gallbladder.The medicine belongs to the two-way accelerator of choleresis, with cholagogic, anti-inflammatory, spasmolysis,
Protect liver, lipid-loweringing, row's masonry are used, and are real efficiently preferable cholagogs.
Dihydroxy dibutyl ethers（The strong elements of Bao Dan）It is a kind of mixture for having a pharmacological activity, it is by several isomerisms each other
The hydroxy ether composition of body.Document report it mainly contain 3 isomers：4- (3- hydroxybutoxies) -2- butanol (I), 3- (3- hydroxyls
Base butoxy)-n-butyl alcohol (II), 3- (3- hydroxyl -1- methyl propoxyl group)-n-butyl alcohol (III).Compound structure is as shown below：
Its preparation method mainly has three kinds：（1）BE 709336A are reported, using 1,3-BDO as starting material, it is dissolved
In dioxane solvent, add sodium hydride and paratoluensulfonyl chloride, primary hydroxyl is optionally reacted, prepare with（Ⅰ）For
The dihydroxy dibutyl ethers of principal component.（2）Nippon Zohki drugmakers, using Alpha-Methyl-γ-methoxypropanol as raw material, lead to
Over cure acid catalysis bimolecular condensation, hydroiodic acid dealkylation reaction be prepared for（Ⅲ）Based on dihydroxy dibutyl ethers.（3）
US4584321 with 1,3 butanediol be initiation material, be condensed by sulfuric acid catalysis bimolecular, be prepared for（Ⅱ）Based on dihydroxy
Dibutyl ethers.
In above-mentioned three kinds of methods, first method has used expensive and activity very strong sodium hydride, and cost is high, potential safety hazard
Greatly；In addition, also using poisonous reagent dioxane.Second method has used relatively expensive Alpha-Methyl-γ-methoxy propyl
Alcohol be starting material and the concentrated sulfuric acid as catalyst, the former causes production cost high, and the latter is strong to the corrosivity of equipment.The third side
Method, although it is starting material to have used 1,3 cheap butanediols, but still has used the concentrated sulfuric acid as catalyst.
Therefore, find raw material to be easy to get, the safety coefficient high production work for preparing dihydroxy dibutyl ethers small to equipment corrosion
Skill has great importance.
The content of the invention
China's approved Dyskinebyl import is used for clinic, but up to the present domestic also without the imitated registration of producer's proposition
Apply, one of its major reason is probably that dihydroxy dibutyl ethers are the high boiling liquid mixture that a variety of isomers are constituted,
The high purity product that acquisition unknown impuritie is less than or reached foreign level has certain difficulty.Therefore suitable synthetic route is developed
High-purity dihydroxy dibutyl ethers are obtained, the production domesticization of the medicine is realized as early as possible, cost is reduced, many patients are benefited, with important society
Can meaning and economic interests.
The purpose of the present invention is using 1,3-BDO as starting material, by the corrosive catalysts in reaction system（Sulfuric acid）Change
For non-corrosiveness catalyst, there is provided a kind of high-purity dihydroxy dibutyl ethers and preparation method thereof.
High-purity dihydroxy dibutyl ethers of the present invention are to contain 4- (3- hydroxybutoxies) -2- butanol 8%-20%, 3- (3-
Hydroxybutoxy)-n-butyl alcohol 50%-65%, 3- (3- hydroxyl -1- methyl propoxyl group)-n-butyl alcohol 20%-35%, three's content it
Be not less than 96.0%.
Ion exchange resin have it is reusable and to equipment corrosion it is small the characteristics of, experiment has been surprisingly found that, with appropriate
The alternative sulphuric acid catalysis of ion exchange resin completes 1,3-BDO and is condensed into the reaction of ether, and obtains the dihydroxy two of high-purity
Butyl ether.The preparation method of high-purity dihydroxy dibutyl ethers of the present invention is to exchange 1,3-BDO acid cation to set
Fat processing, obtains dihydroxy dibutyl ethers crude product, then be made through petroleum ether and rectification under vacuum through vacuum distillation.Reaction equation
It is as follows：
1,3-BDO can be smoothly completed with acid cation exchange resin under proper proportion to react and obtains high-purity
Dihydroxy dibutyl ethers are spent, test result indicates that the quality of 1,3-BDO and storng-acid cation exchange resin（Gram）Volume（In the least
Rise）Than being 1：0.1~0.3.
Acid cation exchange resin can select storng-acid cation exchange resin and weak-acid cation-exchange resin,
Two kinds of resins can complete this reaction.
Storng-acid cation exchange resin can select model be 001 × 1,001 × 2,001 × 3,001 × 4,001 × 7,
002×7、003×7、004×7、001×8、001×7×7、D072、D061、D001-CC、NKA-9、HD-8、D001、
JK006、HZ016。
Weak-acid cation-exchange resin can select model be 110, D151, D152, D113, DLT-1, D155, HZD-2,
HZD-5、DK110、JK110、HD-1。
According to gas chromatography, (specific method of testing sees below assay to the high-purity dihydroxy dibutyl ethers that this method is obtained
With relevant substance-measuring) content and relevant substance-measuring have been carried out respectively, as a result show：High-purity dihydroxy dibutyl ethers content is
98.26%（More than 96%）, as a result see accompanying drawing 1 and accompanying drawing 2；1,3 butylene glycol is not detected in relevant material（Less than 2.0%）, it is single
Impurity is respectively 0.015%, 0.17%, 0.31%, 0.22% and 0.41%, no more than 0.5%, and total impurities is 1.13%（It is less than
4.0%）, as a result see accompanying drawing 4.This result shows that high-purity thing is substantially better than the product quality of listing preparation.Using identical method pair
Import listing preparation carries out content and relevant substance-measuring respectively, and it is 89.61% as a result to show content, as a result sees accompanying drawing 3；It is relevant
1,3 butylene glycol is not detected in material（Less than 2.0%）, single contaminant is respectively 0.21%, 0.49%, 0.23%, 2.71%, 2.95%
With 4.21%, total impurities reaches 10.8%, as a result sees accompanying drawing 5.
Assay shines gas chromatography（Two annex VE of Chinese Pharmacopoeia version in 2000）Determine
Chromatographic condition uses FFAP type capillary columns with system suitability test：Temperature programming, initial temperature is 140
DEG C, 3min is kept, then 180 DEG C are warming up to 20 DEG C per minute of speed, is kept for 30 minutes, theoretical cam curve presses the fourth of dihydroxy two
The separating degree that Ji Mifeng calculating is not less than 2000,1.3- butanediols peak and dihydroxy dibutyl ethers peak should be greater than 2.0.
The preparation of inner mark solution takes n-octyl alcohol 2ml, puts in 100ml measuring bottles, plus acetone solution and is diluted to scale, shakes up,
Produce.
Determination method takes test sample appropriate（It is approximately equivalent to dihydroxy dibutyl ethers 0.25g）, it is accurately weighed, put in 10ml measuring bottles,
Plus inner mark solution dissolves and is diluted to scale, precision measures 1 μ l, injects gas chromatograph, records chromatogram.Separately take the fourth of dihydroxy two
Base ether reference substance (self-control) is in right amount, accurately weighed, plus inner mark solution and quantifies dilution solution in every 1ml containing about 25mg is made,
It is measured in the same method, by internal standard method with calculated by peak area, produces.
About the measure of material
This product about 1.0g is taken, it is accurately weighed, it is placed in 10ml measuring bottles, plus inner mark solution dissolves and is settled to scale, shakes up,
It is used as need testing solution；Accurately weighed 1.3- butanediols reference substance about 120mg, is placed in 100ml measuring bottles, plus inner mark solution dilution
To scale, shake up, be used as reference substance solution.According to the chromatographic condition under assay, precision measures need testing solution, reference substance
Each 1 μ l of solution, inject gas chromatograph, record to 3 times of principal component retention time.As aobvious in the chromatogram of need testing solution
Impurity peaks, by internal standard method with calculated by peak area.
Simple to operate, obtained good product quality of the invention（Preparation is listed better than foreign countries）, high income, and avoid sulphur
Corrosion of the acid to equipment, reduces three-waste pollution, also repeats use again as the resin of catalyst in addition.
Brief description of the drawings
Fig. 1：Dihydroxy dibutyl ethers reference substance（Self-control）The gas chromatogram of assay
Fig. 2：The gas chromatogram of the high-purity thing assay of dihydroxy dibutyl ethers
Fig. 3：Marketed products（Dyskinebyl）The gas chromatogram of assay
Fig. 4；Gas chromatogram of the high-purity thing of dihydroxy dibutyl ethers about substance-measuring
Fig. 5；Marketed products（Dyskinebyl）About the gas chromatogram of substance-measuring
Embodiment
In the examples below in order to remove contained oligomer, organic matter and harmful ion in resin, to ensure resin
Activity is, it is necessary to which it is pre-processed and used after regeneration with water and acid-base pair.
Contribute to understand the present invention by following examples, but present disclosure is not limited in example：
Embodiment 1
300ml1,3- butanediols, pretreated 001 × 7 type highly acidic cation are added in 1000ml four-hole boiling flasks
Exchanger resin 40g, heating stirring, reaction water removal 4h.Resin is filtered to remove after cooling, pH value of solution about 5~6 is measured, with a little
NaOH solution is adjusted to neutrality.Vacuum distillation obtains crude product, crude product again after petroleum ether and rectification under vacuum, collect 156 ~ 161 DEG C/
20mmHg cuts, obtain 55.4g, gas phase purity 98.4%.
Embodiment 2
300ml1,3- butanediols, pretreated 001 × 7 type highly acidic cation are added in 1000ml four-hole boiling flasks
Exchanger resin 60g, heating stirring, reaction water removal 3.5h.It is filtered to remove resin after cooling, surveys pH value of solution about 5~6, with a little
NaOH solution is adjusted to neutrality.Vacuum distillation obtains crude product, and crude product after petroleum ether and rectification under vacuum, collects 156 ~ 161 again
DEG C/20mmHg cuts, obtain 58.3g, gas phase purity 98.5%.
Embodiment 3
300ml1,3- butanediols, pretreated 001 × 7 type highly acidic cation are added in 1000ml four-hole boiling flasks
Exchanger resin 60g, heating stirring, reaction water removal 4h is filtered to remove resin, surveys pH value of solution about 5~6, use a little NaOH after cooling
Solution is adjusted to neutrality.Vacuum distillation obtains crude product, crude product again after petroleum ether and rectification under vacuum, collect 156 ~ 161 DEG C/
20mmHg cuts, obtain 59.0g, gas phase purity 98.5%.
Embodiment 4
300ml1,3- butanediols, pretreated 001 × 8 type highly acidic cation are added in 1000ml four-hole boiling flasks
Exchanger resin 50g, heating stirring, reaction water removal 4h is filtered to remove resin, surveys pH value of solution about 5~6, use a little NaOH after cooling
Solution is adjusted to neutrality.Vacuum distillation obtains crude product, crude product again after petroleum ether and rectification under vacuum, collect 156 ~ 161 DEG C/
20mmHg cuts, obtain 57.1g, gas phase purity 98.2%.
Embodiment 5
300ml1,3- butanediols, pretreated D001-CC types highly acidic cation are added in 1000ml four-hole boiling flasks
Exchanger resin 50g, heating stirring, reaction water removal 4h is filtered to remove resin, surveys pH value of solution about 5~6, use a little NaOH after cooling
Solution is adjusted to neutrality.Vacuum distillation obtains crude product, crude product again after petroleum ether and rectification under vacuum, collect 156 ~ 161 DEG C/
20mmHg cuts, obtain 55.2g, gas phase purity 98.0%.
Embodiment 6
300ml1 is added in 1000ml four-hole boiling flasks, 3- butanediols, pretreated D072 types highly acidic cation is handed over
Resin 50g is changed, heating stirring, reaction water removal 4h is filtered to remove resin, surveys pH value of solution about 5~6 after cooling, molten with a little NaOH
Liquid is adjusted to neutrality.Vacuum distillation obtains crude product, crude product again after petroleum ether and rectification under vacuum, collect 156 ~ 161 DEG C/
20mmHg cuts, obtain 54.6g, gas phase purity 98.1%.
Embodiment 7
300ml1 is added in 1000ml four-hole boiling flasks, 3- butanediols, pretreated 110 type Subacidity cation is exchanged
Resin 60g, heating stirring, reaction water removal 4h is filtered to remove resin, vacuum distillation obtains crude product, and crude product is again through oil after cooling
Ether is washed with after rectification under vacuum, is collected 156 ~ 161 DEG C/20mmHg cuts, is obtained 37.8g, gas phase purity 97.8%.
Embodiment 8
300ml1 is added in 1000ml four-hole boiling flasks, 3- butanediols, pretreated D072 types Subacidity cation is handed over
Resin 60g is changed, heating stirring, reaction water removal 4h is filtered to remove resin, vacuum distillation obtains crude product, and crude product is again through stone after cooling
After oily ether washing and rectification under vacuum, 156 ~ 161 DEG C/20mmHg cuts are collected, 41.3g, gas phase purity 97.6% is obtained.
Claims (5)
1. a kind of high-purity dihydroxy dibutyl ethers, it is characterised in that contain 4- (3- hydroxybutoxies) -2- butanol 8%-20%, 3-
(3- hydroxybutoxies)-n-butyl alcohol 50%-65%, 3- (3- hydroxyl -1- methyl propoxyl group)-n-butyl alcohol 20%-35%, three's content it
Be not less than 96.0%, its preparation method is to handle 1,3-BDO with acid cation exchange resin, is obtained through vacuum distillation
After dihydroxy dibutyl ethers crude product, it is made through petroleum ether and rectification under vacuum.
2. high-purity dihydroxy dibutyl ethers according to claim 1, it is characterized in that 1,3-BDO is exchanged with acid cation
The volume mass ratio of resin is 1ml：0.1~0.3g.
3. high-purity dihydroxy dibutyl ethers according to claim 1, it is characterized in that acid cation exchange resin selects strong acid
Property cationic ion-exchange resin and weak-acid cation-exchange resin.
4. high-purity dihydroxy dibutyl ethers according to claim 1, it is characterized in that storng-acid cation exchange resin is selected from type
Number be 001 × 1,001 × 2,001 × 3,001 × 4,001 × 7,002 × 7,003 × 7,004 × 7,001 × 8,001 × 7 × 7,
D072, D061, D001-CC, NKA-9, HD-8, D001 and JK006, HZ016 cationic ion-exchange resin.
5. high-purity dihydroxy dibutyl ethers according to claim 1, it is characterized in that weak-acid cation-exchange resin is selected from type
Number it is 110, D151, D152, D113, DLT-1, D155, HZD-2, HZD-5, DK110, JK110 and HD-1 cation exchange tree
Fat.
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| CN201210523118.3A CN103848726B (en) | 2012-12-09 | 2012-12-09 | A kind of high-purity dihydroxy dibutyl ethers and preparation method thereof |
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| CN107266293B (en) * | 2016-04-08 | 2022-05-13 | 河北凯盛医药科技有限公司 | Dihydroxydibutyl ether synthesized by catalysis of dry hydrogen resin and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4584321A (en) * | 1983-05-30 | 1986-04-22 | Istituto Luso Farmaco D'italia S.P.A. | 3-(3-Hydroxybutoxy)-1-butanol in pharmaceutical compositions |
-
2012
- 2012-12-09 CN CN201210523118.3A patent/CN103848726B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4584321A (en) * | 1983-05-30 | 1986-04-22 | Istituto Luso Farmaco D'italia S.P.A. | 3-(3-Hydroxybutoxy)-1-butanol in pharmaceutical compositions |
Non-Patent Citations (2)
| Title |
|---|
| "Thermally stable ion-exchange resins as catalysts for the liquid-phase dehydration of 1-pentanol to di-n-pentyl ether (DNPE)";Roger Bringué et al.;《Journal of Catalysis》;20060928;第244卷;33-42 * |
| "阳离子交换树脂的有机催化进展";冯新亮等;《有机化学》;20031231;第23卷(第12期);1348-1355 * |
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