CN104961642A - Novel propranolol synthesis method - Google Patents
Novel propranolol synthesis method Download PDFInfo
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- CN104961642A CN104961642A CN201510360594.1A CN201510360594A CN104961642A CN 104961642 A CN104961642 A CN 104961642A CN 201510360594 A CN201510360594 A CN 201510360594A CN 104961642 A CN104961642 A CN 104961642A
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- proprasylyte
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- isopropylamine
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- propranolol
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Abstract
The invention discloses a novel propranolol synthesis method. The method includes the following steps that 3-(1-naphthoxy)-1, 2-epoxypropane and isopropylamine generate a ring-opening reaction in the presence of a catalyst, propranolol is obtained, the yield is larger than or equal to 93%, and the purity is larger than or equal to 99%. Compared with an existing preparation method, the method has the advantages that the method is easy and convenient to implement, the reaction condition is mild, the catalytic activity and selectivity of the catalyst are high, few side reactions happen, products can be separated and purified easily, less device corrosion and less pollution to the environment are caused, end products with the high purity can be obtained, the yield is high, and the method is suitable for industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to a kind of novel method of synthesizing 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 hydrocarbyl reaction obtain 3-(1-naphthyloxy)-1,2 epoxy prapane; Then Proprasylyte is obtained with Isopropylamine ring-opening reaction; Last and hydrochloric acid salt-forming reaction, obtains propranolol hydrochloride.
3-(1-naphthyloxy) ring-opening reaction of-1,2 epoxy prapane and Isopropylamine, yield only has an appointment 50%, usually needs the Isopropylamine of use more than 3.5 times, needs to reclaim Isopropylamine after reaction terminates; 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 side reaction is more, and aftertreatment is loaded down with trivial details, and yield is lower.Need during recovery 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 novel method of exploitation synthesis Proprasylyte, improves reaction yield, reduces the consumption of Isopropylamine, optimum synthesis technique; Improve transformation efficiency and the selectivity of reaction, reduce the generation of side reaction, improve quality; Reduce environmental pollution, 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 novel method of synthesizing Proprasylyte.Compare with existing preparation method, it is easy that present method has preparation method, and reaction conditions is gentle, catalyst activity and selectivity high, product is easy to separation and purification, equipment corrosion and environmental pollution little, can obtain the end product that purity is higher, product 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.
Synthesize a novel method for Proprasylyte, 3-(1-naphthyloxy)-1,2 epoxy prapane (II) and Isopropylamine, take methylene dichloride as solvent, under triethylamine exists, ring-opening reaction occurs, and obtain Proprasylyte (I), reaction equation is as follows:
。
Synthesize a novel method for Proprasylyte, the ratio of the molar weight of Isopropylamine and formula II is 1.0:1 ~ 1.4:1.
Synthesize a novel method for Proprasylyte, the ratio of the weight consumption of triethylamine and formula II is 0.01:1 ~ 0.02:1.
Synthesize a novel method for Proprasylyte, the volumetric usage of methylene dichloride and the ratio of formula II weight consumption are 5:1 ~ 9:1.
Synthesize a novel method for Proprasylyte, described ring-opening reaction temperature is 20 ~ 30 DEG C.
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) method is easy, and reaction conditions is gentle, and process easily controls, and side reaction is few, and feed stock conversion is high, and product yield is high;
2) adopt triethylamine be catalyzer, catalytic activity and selectivity high.
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
Embodiment 1:
Take 3-(1-naphthyloxy)-1,2 epoxy prapane 200.2g, Isopropylamine 70.9g and methylene dichloride 1800ml, be placed in reaction flask.Temperature control less than 30 DEG C, stirs lower slowly dropping triethylamine 4.0g.Drip off rear insulation 25-30 DEG C of stirring reaction.TLC monitors response situation.After 5 hours, stopped reaction.Evaporated under reduced pressure, residue toluene/normal hexane recrystallization obtains Proprasylyte 243.3 g, yield 93.8%, HPLC purity 99.3%.
Embodiment 2:
Take 3-(1-naphthyloxy)-1,2 epoxy prapane 200.2g, Isopropylamine 76.8g and methylene dichloride 1000ml, be placed in reaction flask.Temperature control less than 30 DEG C, stirs lower slowly dropping triethylamine 2.3g.Drip off rear insulation 25-30 DEG C of stirring reaction.TLC monitors response situation.After 5.5 hours, stopped reaction.Evaporated under reduced pressure, residue toluene/normal hexane recrystallization obtains Proprasylyte 244.0 g, yield 94.1%, HPLC purity 99.2%.
Embodiment 3:
Take 3-(1-naphthyloxy)-1,2 epoxy prapane 200.2g, Isopropylamine 59.1g and methylene dichloride 1600ml, be placed in reaction flask.Temperature control less than 30 DEG C, stirs lower slowly dropping triethylamine 2.5g.Drip off rear insulation 25-30 DEG C of stirring reaction.TLC monitors response situation.After 6 hours, stopped reaction.Evaporated under reduced pressure, residue toluene/normal hexane recrystallization obtains Proprasylyte 241.2 g, yield 93.0%, HPLC purity 99.1%.
Embodiment 4:
Take 3-(1-naphthyloxy)-1,2 epoxy prapane 200.2g, Isopropylamine 65.0g and methylene dichloride 1200ml, be placed in reaction flask.Temperature control less than 30 DEG C, stirs lower slowly dropping triethylamine 3.0g.Drip off rear insulation 25-30 DEG C of stirring reaction.TLC monitors response situation.After 5 hours, stopped reaction.Evaporated under reduced pressure, residue toluene/normal hexane recrystallization obtains Proprasylyte 245.1 g, yield 94.5%, HPLC purity 99.4%.
Embodiment 5:
Take 3-(1-naphthyloxy)-1,2 epoxy prapane 200.2g, Isopropylamine 82.8g and methylene dichloride 1400ml, be placed in reaction flask.Temperature control less than 30 DEG C, stirs lower slowly dropping triethylamine 2.0g.Drip off rear insulation 25-30 DEG C of stirring reaction.TLC monitors response situation.After 4.5 hours, stopped reaction.Evaporated under reduced pressure, residue toluene/normal hexane recrystallization obtains Proprasylyte 246.2 g, yield 94.9%, HPLC purity 99.2%.
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. synthesize a novel method for Proprasylyte, it is characterized in that: 3-(1-naphthyloxy)-1,2 epoxy prapane (II) and Isopropylamine, take methylene dichloride as solvent, under triethylamine exists, ring-opening reaction occurs, obtain Proprasylyte (I), reaction equation is as follows:
。
2. a kind of novel method of synthesizing Proprasylyte as claimed in claim 1, is characterized in that: the ratio of the molar weight of Isopropylamine and formula II is 1.0:1 ~ 1.4:1.
3. a kind of novel method of synthesizing Proprasylyte as claimed in claim 1, is characterized in that: the ratio of the weight consumption of triethylamine and formula II is 0.01:1 ~ 0.02:1.
4. a kind of novel method of synthesizing Proprasylyte as claimed in claim 1, is characterized in that: the volumetric usage of methylene dichloride and the ratio of formula II weight consumption are 5:1 ~ 9:1.
5. a kind of novel method of synthesizing Proprasylyte as claimed in claim 1, is characterized in that: described ring-opening reaction temperature is 20 ~ 30 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510360594.1A CN104961642A (en) | 2015-06-26 | 2015-06-26 | Novel propranolol synthesis method |
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| CN201510360594.1A CN104961642A (en) | 2015-06-26 | 2015-06-26 | Novel propranolol synthesis method |
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| CN104961642A true CN104961642A (en) | 2015-10-07 |
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| CN201510360594.1A Pending CN104961642A (en) | 2015-06-26 | 2015-06-26 | Novel propranolol synthesis method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111253267A (en) * | 2019-12-23 | 2020-06-09 | 常州市天华制药有限公司 | Method for synthesizing propranolol hydrochloride |
| CN113336656A (en) * | 2021-05-28 | 2021-09-03 | 常州康普药业有限公司 | Method for synthesizing propranolol hydrochloride |
| CN113511979A (en) * | 2021-07-05 | 2021-10-19 | 天津力生制药股份有限公司 | Synthesis method and application of propranolol |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964259A (en) * | 2012-12-11 | 2013-03-13 | 上海奥博生物医药技术有限公司 | Preparation method of related substance E of metoprolol |
| WO2014121040A8 (en) * | 2013-02-04 | 2015-02-12 | Janssen Pharmaceutica Nv | Flap modulators |
| CN104356010A (en) * | 2014-10-23 | 2015-02-18 | 华中药业股份有限公司 | Improved preparation method of propranolol |
-
2015
- 2015-06-26 CN CN201510360594.1A patent/CN104961642A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964259A (en) * | 2012-12-11 | 2013-03-13 | 上海奥博生物医药技术有限公司 | Preparation method of related substance E of metoprolol |
| WO2014121040A8 (en) * | 2013-02-04 | 2015-02-12 | Janssen Pharmaceutica Nv | Flap modulators |
| CN104356010A (en) * | 2014-10-23 | 2015-02-18 | 华中药业股份有限公司 | Improved preparation method of propranolol |
Non-Patent Citations (2)
| Title |
|---|
| TAKUYA KUMAMOTO等: "Synthesis of enantiomeric 4-hydroxypropranolols from 1,4-dihydroxynaphthalene", 《TETRAHEDRON: ASYMMETRY》 * |
| 张英: "盐酸普萘洛尔的合成研究工艺", 《工程科技I辑》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111253267A (en) * | 2019-12-23 | 2020-06-09 | 常州市天华制药有限公司 | Method for synthesizing propranolol hydrochloride |
| CN113336656A (en) * | 2021-05-28 | 2021-09-03 | 常州康普药业有限公司 | Method for synthesizing propranolol hydrochloride |
| CN113336656B (en) * | 2021-05-28 | 2022-03-01 | 常州康普药业有限公司 | Method for synthesizing propranolol hydrochloride |
| CN113511979A (en) * | 2021-07-05 | 2021-10-19 | 天津力生制药股份有限公司 | Synthesis method and application of propranolol |
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Inventor after: Feng Xuan Inventor after: Liu Yuting Inventor after: Wang Yong Inventor after: Fu Lin Inventor after: Liao Jun Inventor after: Wei Xuli Inventor before: Feng Xuan Inventor before: Fu Lin Inventor before: Liao Jun Inventor before: Wei Xuli Inventor before: Wang Yong |
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Application publication date: 20151007 |