CN104356010A - Improved preparation method of propranolol - Google Patents
Improved preparation method of propranolol Download PDFInfo
- Publication number
- CN104356010A CN104356010A CN201410567296.5A CN201410567296A CN104356010A CN 104356010 A CN104356010 A CN 104356010A CN 201410567296 A CN201410567296 A CN 201410567296A CN 104356010 A CN104356010 A CN 104356010A
- Authority
- CN
- China
- Prior art keywords
- preparation
- proprasylyte
- reaction
- isopropylamine
- propranolol
- Prior art date
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- QYYCPWLLBSSFBW-UHFFFAOYSA-N C(C1OC1)Oc1c(cccc2)c2ccc1 Chemical compound C(C1OC1)Oc1c(cccc2)c2ccc1 QYYCPWLLBSSFBW-UHFFFAOYSA-N 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N CC(C)NCC(COc1cccc2ccccc12)O Chemical compound CC(C)NCC(COc1cccc2ccccc12)O AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses an improved preparation method of propranolol, which comprises the following step: in an organic solvent, 3-(1-naphthoxy)-1,2-propylene oxide reacts with isopropylamine under the action of a catalyst so as to obtain the propranolol. Compared with an existing preparation method, the method has the advantages that the preparation method is simple and convenient, reaction conditions are mild, the process is easy to control and the preparation method has small side effects; the catalyst has high catalytic activity and selectivity, is environmental-friendly and can be repeatedly used; a product is easy to separate and purify, the finished product with high purity can be obtained, yield is high, a small quantity of three wastes are generated, and the preparation method has low pollution and is suitable for industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to a kind of improvement preparation method of Proprasylyte.
Background technology
Propranolol hydrochloride is first and is applied to clinical beta-blockers, has made huge contribution to treatment hypertension and stenocardia.Scientist James Bu Laike wins Nobel Prizes in medicine in 1988 and Queen of England prize for this reason.
Propranolol hydrochloride chemical name: 1-isopropylamino-3-(1-naphthyloxy)-2-propanol hydrochloride.Its levo form activity comparatively dextrorotation is eager to excel, and clinically uses its racemic modification.Its structural formula is as follows:
Propranolol hydrochloride is clinical conventional receptor,β retarding agent, the effect of energy competitive inhibition catecholamine (catecholamine), be usually used in preventing and treating the various diseases such as irregular pulse, stenocardia, hypertension, myocardial infarction, coronary heart disease, hyperthyroidism, clinical application is extensive.Discovered in recent years, this medicine has much new purposes, thus expands clinical application range, is mainly used in treating the sinus tachycardia, migraine, restless leg syndrome, psychotic disorder, the prevention esophageal varix that occur in anesthesia and breaks.
Prior art [Hunan Industrial Professional Technology Academe journal, 2003,3 (3): 18-19] and [chapter think rule, Zhang Wei. fine chemicals and intermediate handbook last volume. Chemical Industry Press, 1510] disclose the most frequently used preparation method of propranolol hydrochloride, wherein operational path is as follows:
1-naphthols and epoxy chloropropane generation etherification reaction obtain 3-(1-naphthyloxy)-1,2 epoxy prapane; Then Proprasylyte is obtained with Isopropylamine amination reaction; Last and hydrochloric acid salt-forming reaction, obtains propranolol hydrochloride.
3-(1-naphthyloxy) amination reaction of-1,2 epoxy prapane and Isopropylamine, need the Isopropylamine of use more than 3.5 times, need after reaction terminates to reclaim Isopropylamine; And Isopropylamine boiling point is lower, easily lose in reaction process, recovering effect is poor, and the rate of recovery is low.For reducing the loss of Isopropylamine, accelerated reaction is carried out, and has bibliographical information to react in confined conditions, needs carrying out higher than under condition of normal pressure.Reaction generally needs comparatively high temps, the long period, and aftertreatment is loaded down with trivial details, needs to use the high toxicity solvent such as dimethylbenzene.Overall yield of reaction is not high.Certain drawback is there is in suitability for industrialized production.
The improvement preparation method of exploitation Proprasylyte, reduce the consumption of Isopropylamine, optimum synthesis technique and aftertreatment technology, improve transformation efficiency and the selectivity of reaction, improve quality and yield, the suitability for industrialized production reduced costs for propranolol hydrochloride has great importance.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of improvement preparation method of Proprasylyte.Compare with existing preparation method, it is easy that present method has preparation method, reaction conditions is gentle, catalyst activity and selectivity high, environmental protection is reusable, and product is easy to separation and purification, equipment corrosion and environmental pollution little, can obtain the end product that purity is higher, yield is high, is suitable for the advantages such as suitability for industrialized production.
For overcoming the weak point of existing preparation method, the invention provides following technical scheme.
An improvement preparation method for Proprasylyte, in organic solvent, 3-(1-naphthyloxy)-1,2 epoxy prapane (II) and Isopropylamine, under H beta-molecular sieve catalyzer exists, aminolysis reaction occurs, and obtain Proprasylyte (I), reaction equation is as follows:
。
An improvement preparation method for Proprasylyte, the SiO of described H beta-molecular sieve catalyzer
2/ Al
2o
3=55 ~ 65; The ratio of described catalyzer and the weight consumption of formula II is 0.1:1 ~ 0.5:1.
An improvement preparation method for Proprasylyte, described organic solvent is methylene dichloride; The volumetric usage of described organic solvent and the ratio of formula II weight consumption are 5:1 ~ 8:1.
An improvement preparation method for Proprasylyte, the ratio of described Isopropylamine and the molar weight of formula II is 1.0:1 ~ 1.5:1.
An improvement preparation method for Proprasylyte, described aminolysis reaction temperature is 25 ~ 35 DEG C.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Raw materials used and the reagent of the present invention all commercially.
The present invention compared with prior art tool has the following advantages:
1) preparation method is easy, and reaction conditions is gentle, and process easily controls, and side reaction is few, and feed stock conversion is high;
2) adopt environmental protection reusable H beta-molecular sieve to be catalyzer, catalytic activity and selectivity high, environmental protection is reusable.
3) product is easy to separation and purification, and can obtain the end product that purity is higher, yield is high, and the three wastes are few, pollutes little, is suitable for suitability for industrialized production.
Embodiment
Following examples further illustrate of the present invention, but should not be regarded as the restriction to this patent.
Embodiment 1:
Take 3-(1-naphthyloxy)-1,2 epoxy prapane 200.2g, Isopropylamine 70.9g, H beta-molecular sieve (SiO
2/ Al
2o
3=60) 4.0g and methylene dichloride 1200ml, is placed in reaction flask.30-35 DEG C of stirring reaction.TLC monitors response situation.After 110 minutes, stopped reaction.Filtration of catalyst, filtrate decompression evaporate to dryness, residue normal hexane recrystallization obtains Proprasylyte 239.4 g, yield 92.3%, HPLC purity 99.2%.
Embodiment 2:
Take 3-(1-naphthyloxy)-1,2 epoxy prapane 200.2g, Isopropylamine 76.8g, H beta-molecular sieve (SiO
2/ Al
2o
3=60) 2.0g and methylene dichloride 1400ml, is placed in reaction flask.25-30 DEG C of stirring reaction.TLC monitors response situation.After 120 minutes, stopped reaction.Filtration of catalyst, filtrate decompression evaporate to dryness, residue normal hexane recrystallization obtains Proprasylyte 241.2 g, yield 93.0%, HPLC purity 99.1%.
Embodiment 3:
Take 3-(1-naphthyloxy)-1,2 epoxy prapane 200.2g, Isopropylamine 59.1g, H beta-molecular sieve (SiO
2/ Al
2o
3=60) 4.0g and methylene dichloride 1200ml, is placed in reaction flask.25-30 DEG C of stirring reaction.TLC monitors response situation.After 130 minutes, stopped reaction.Filtration of catalyst, filtrate decompression evaporate to dryness, residue normal hexane recrystallization obtains Proprasylyte 240.4 g, yield 92.7%, HPLC purity 99.2%.
Embodiment 4:
Take 3-(1-naphthyloxy)-1,2 epoxy prapane 200.2g, Isopropylamine 88.7g, H beta-molecular sieve (SiO
2/ Al
2o
3=60) 6.0g and methylene dichloride 1000ml, is placed in reaction flask.30-35 DEG C of stirring reaction.TLC monitors response situation.After 115 minutes, stopped reaction.Filtration of catalyst, filtrate decompression evaporate to dryness, residue normal hexane recrystallization obtains Proprasylyte 240.9 g, yield 92.9%, HPLC purity 99.1%.
Embodiment 5:
Take 3-(1-naphthyloxy)-1,2 epoxy prapane 200.2g, Isopropylamine 82.8g, H beta-molecular sieve (SiO
2/ Al
2o
3=60) 10.0g and methylene dichloride 1600ml, is placed in reaction flask.25-30 DEG C of stirring reaction.TLC monitors response situation.After 105 minutes, stopped reaction.Filtration of catalyst, filtrate decompression evaporate to dryness, residue normal hexane recrystallization obtains Proprasylyte 242.2 g, yield 93.4%, HPLC purity 99.2%.
Embodiment 6-10:
H beta-molecular sieve (SiO
2/ Al
2o
3=60) the repeatability test of catalyzer
Upper crowd H beta-molecular sieve (SiO
2/ Al
2o
3=60) catalyzer is by after filtration in reaction solution, directly drops in lower batch reaction liquid and carries out catalyzed reaction.Often criticize test all to carry out according to following proportioning.
Take 3-(1-naphthyloxy)-1,2 epoxy prapane 200.2g, Isopropylamine 65.0g, H beta-molecular sieve (SiO
2/ Al
2o
3=60) 5.0g and methylene dichloride 1000ml, is placed in reaction flask.20-25 DEG C of stirring reaction.TLC monitors response situation.After about 100 ~ 120 minutes, stopped reaction.Filtration of catalyst, filtrate decompression evaporate to dryness, residue normal hexane recrystallization obtains Proprasylyte.
| Embodiment | Product/g | Yield/% | Purity/% |
| 6 | 241.4 | 93.1 | 99.1 |
| 7 | 239.6 | 92.4 | 99.3 |
| 8 | 242.0 | 93.3 | 99.0 |
| 9 | 239.1 | 92.2 | 99.2 |
| 10 | 242.2 | 93.4 | 99.1 |
Embodiment recited above is only be described the preferred embodiment for the present invention; not the spirit and scope of the present invention are limited; under the prerequisite not departing from design philosophy of the present invention; the various distortion that in this area, common engineering technical personnel make technical scheme of the present invention and improvement, all should belong to protection scope of the present invention.
Claims (5)
1. an improvement preparation method for Proprasylyte, is characterized in that: in organic solvent, 3-(1-naphthyloxy)-1,, under H beta-molecular sieve catalyzer exists, there is aminolysis reaction in 2-propylene oxide (II) and Isopropylamine, obtain Proprasylyte (I), reaction equation is as follows:
。
2. the improvement preparation method of a kind of Proprasylyte as claimed in claim 1, is characterized in that: the SiO of described H beta-molecular sieve catalyzer
2/ Al
2o
3=55 ~ 65; The ratio of described catalyzer and the weight consumption of formula II is 0.1:1 ~ 0.5:1.
3. the improvement preparation method of a kind of Proprasylyte as claimed in claim 1, is characterized in that: described organic solvent is methylene dichloride; The volumetric usage of described organic solvent and the ratio of formula II weight consumption are 5:1 ~ 8:1.
4. the improvement preparation method of a kind of Proprasylyte as claimed in claim 1, is characterized in that: the ratio of described Isopropylamine and the molar weight of formula II is 1.0:1 ~ 1.5:1.
5. the improvement preparation method of a kind of Proprasylyte as claimed in claim 1, is characterized in that: described aminolysis reaction temperature is 25 ~ 35 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410567296.5A CN104356010A (en) | 2014-10-23 | 2014-10-23 | Improved preparation method of propranolol |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410567296.5A CN104356010A (en) | 2014-10-23 | 2014-10-23 | Improved preparation method of propranolol |
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| CN104356010A true CN104356010A (en) | 2015-02-18 |
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| CN201410567296.5A Pending CN104356010A (en) | 2014-10-23 | 2014-10-23 | Improved preparation method of propranolol |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104961642A (en) * | 2015-06-26 | 2015-10-07 | 华中药业股份有限公司 | Novel propranolol synthesis method |
| CN109839444A (en) * | 2017-11-27 | 2019-06-04 | 武汉科福新药有限责任公司 | The separation method of naphthol derivative and its application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0050885B1 (en) * | 1980-10-16 | 1984-07-18 | BLASCHIM S.p.A. | Process for preparing 1-amino-3-aryloxy-2-propanols and 1-amino-2-aryl-2-ethanols |
-
2014
- 2014-10-23 CN CN201410567296.5A patent/CN104356010A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0050885B1 (en) * | 1980-10-16 | 1984-07-18 | BLASCHIM S.p.A. | Process for preparing 1-amino-3-aryloxy-2-propanols and 1-amino-2-aryl-2-ethanols |
Non-Patent Citations (3)
| Title |
|---|
| ASIT K. CHAKRABORTI, ET AL.: "Scope and limitations of montmorillonite K 10 catalysed opening of epoxide rings by amines", 《TETRAHEDRON》 * |
| SAGAR P. PATHARE, ET AL.: "An efficient protocol for regioselective ring opening of epoxides using sulfated tungstate: application in synthesis of active pharmaceutical ingredients atenolol, propranolol and ranolazine", 《TETRAHEDRON LETTERS》 * |
| SAGAR P. PATHARE, ET AL.: "An efficient protocol for regioselective ring opening of epoxides using sulfated tungstate: application in synthesis of active pharmaceutical ingredients atenolol, propranolol and ranolazine", 《TETRAHEDRON LETTERS》, vol. 54, 21 September 2013 (2013-09-21), pages 6455 - 6459, XP028751830, DOI: doi:10.1016/j.tetlet.2013.09.065 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104961642A (en) * | 2015-06-26 | 2015-10-07 | 华中药业股份有限公司 | Novel propranolol synthesis method |
| CN109839444A (en) * | 2017-11-27 | 2019-06-04 | 武汉科福新药有限责任公司 | The separation method of naphthol derivative and its application |
| CN109839444B (en) * | 2017-11-27 | 2022-03-15 | 武汉科福新药有限责任公司 | Process for separating naphthol derivatives and their use |
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Application publication date: 20150218 |