AU2016102185A4 - Celiprolol pharmaceutical intermediate 3- (4-ethoxyphenyl) -1, 1-diethyl-urea synthesis method - Google Patents
Celiprolol pharmaceutical intermediate 3- (4-ethoxyphenyl) -1, 1-diethyl-urea synthesis method Download PDFInfo
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- AU2016102185A4 AU2016102185A4 AU2016102185A AU2016102185A AU2016102185A4 AU 2016102185 A4 AU2016102185 A4 AU 2016102185A4 AU 2016102185 A AU2016102185 A AU 2016102185A AU 2016102185 A AU2016102185 A AU 2016102185A AU 2016102185 A4 AU2016102185 A4 AU 2016102185A4
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- ethoxyphenyl
- diethyl
- celiprolol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Celiprolol pharmaceutical intermediate 3- (4-ethoxyphenyl) -1,1-diethyl-urea synthesis method, comprising the following steps: equipped with a stiffer and a dropping funnel, the reaction vessel was added 0.22 mol p-aminophenyl ether (2), 0.45- 0.47mol sodium bisulfite solution, 80- 90ml tetrahydrofuran solution, controlling the stirring speed 130-160rpm, control temperature of the solution 35-40 C, added 0.25-0.27mol solution of N, N- diethylamino-carboxamide (3), control add dropwise time to 4-5 h, the reaction continued stirring 30-35h, added 300 - 350ml sodium chloride solution, solution of oxalic acid solution was used to adjust pH to 4-5, the reaction was continued to 4-5h, solid separated, the temperature of the solution is reduced to 10 - 15 C, filtered, washed with saline solution, dehydrated with dehydrating agent, recrystallized from hexane solution, got 3- (4-ethoxyphenyl) -1, 1-diethyl-urea.
Description
Celiprolol pharmaceutical intermediate 3- (4-ethoxyphenyl) -1, 1-diethyl-urea synthesis method
TECHNICAL FIELD
The present invention relates to celiprolol pharmaceutical intermediate 3- (4-ethoxyphenyl) -1, 1-diethyl-urea synthesis method.
BACKGROUND ART
Celiprolol have intrinsic sympathomimetic activity, and does not increase airway resistance, can help peripheral expansion, improve blood circulation. The product has no stabilizing effect film and does not inhibit myocardial contractility, is better than other non-endogenous sympathomimetic activity of β-blockers which can cause sinus bradycardia possibility to be small. The goods can get through the placental barrier. It can be used for mild to moderate hypertension. The product is a highly selective β- blockers, by blocking βι receptors, dilation of blood vessels, lowers blood pressure. The goods is on the high selectivity and myocardial cell membrane βΐ receptor binding affinity receptor 20 to 30 times stronger than the bronchial and vascular smooth muscle β2· 3- (4-ethoxyphenyl) -1,1-diethyl-urea as celiprolol drug intermediates, its synthesis method is of great economic significance for improving drug synthesis product quality, reducing the by-product content.
SUMMARY OF THE INVENTION
Object of the present invention is to provide celiprolol pharmaceutical intermediate 3- (4-ethoxyphenyl) -1,1-diethyl-urea synthesis method, comprising the following steps: (i) equipped with a stirrer and a dropping funnel, the reaction vessel was added 0.22 mol p-aminophenyl ether (2), 0.45- 0.47mol sodium bisulfite solution, 80- 90ml tetrahydrofuran solution, controlling the stirring speed 130-160rpm, control temperature of the solution 35-40°C, added 0.25-0.27mol solution of N, N- diethylamino-carboxamide (3), control add dropwise time to 4-5 h, the reaction continued stirring 30-35h, added 300 - 350ml sodium chloride solution, solution of oxalic acid solution was used to adjust pH to 4-5, the reaction was continued to 4-5h, solid separated, the temperature of the solution is reduced to 10 - 15°C, filtered, washed with saline solution, dehydrated with dehydrating agent, recrystallized from hexane solution, got 3- (4-ethoxyphenyl) -1,1-diethyl-urea (1); wherein sodium chloride solution in step (i) has a mass fraction of 10-15%, oxalic acid solution in step (i) has a mass fraction of 25-30%, saline solution in step (i) is any one of potassium nitrate solution or sodium sulfate solution ; dehydrating agent in step (i) is any one of activated alumina or phosphoms pentoxide.
The throughout reaction process can be summarized using the following reaction formula:
Advantage of the present invention is that: the reaction intermediate links are reduced, reducing the reaction temperature and reaction time, improving the reaction yield.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION
Embodiment 1
Equipped with a stirrer and a dropping funnel, the reaction vessel was added 0.22 mol p-aminophenyl ether (2), 0.45 mol sodium bisulfite solution, 80 ml tetrahydrofuran solution, controlling the stirring speed 130 rpm, control temperature of the solution 35 °C, added 0.25 mol solution of N, N- diethylamino-carboxamide (3), control add dropwise time to 4 h, the reaction continued stirring 30 h, added 300 ml sodium chloride solution with a mass fraction of 10%, solution of oxalic acid solution with a mass fraction of 25%was used to adjust pH to 4-5, the reaction was continued to 4-5h, solid separated, the temperature of the solution is reduced to 10 °C, filtered, washed with potassium nitrate solution, dehydrated with activated alumina dehydrating agent, recrystallized from hexane solution, got 3- (4-ethoxyphenyl) -1,1-diethyl-urea 43.09 g, yield 83%.
Embodiment 2
Equipped with a stirrer and a dropping funnel, the reaction vessel was added 0.22 mol p-aminophenyl ether (2), 0.46 mol sodium bisulfite solution, 85 ml tetrahydrofuran solution, controlling the stirring speed 150 rpm, control temperature of the solution 37 °C, added 0.26 mol solution of N, N- diethylamino-carboxamide (3), control add dropwise time to 4 h, the reaction continued stirring 33 h, added 320 ml sodium chloride solution with a mass fraction of 12%, solution of oxalic acid solution with a mass fraction of 27%was used to adjust pH to 4, the reaction was continued to 4h, solid separated, the temperature of the solution is reduced to 13 °C, filtered, washed with potassium nitrate solution, dehydrated with phosphorus pentoxide dehydrating agent, recrystallized from hexane solution, got 3- (4-ethoxyphenyl) -1,1-diethyl-urea 44.65 g, yield 86% .
Embodiment 3
Equipped with a stirrer and a dropping funnel, the reaction vessel was added 0.22 mol p-aminophenyl ether (2), 0.47 mol sodium bisulfite solution, 90 ml tetrahydrofuran solution, controlling the stirring speed 160 rpm, control temperature of the solution 40 °C, added 0.27 mol solution of N, N- diethylamino-carboxamide (3), control add dropwise time to 5 h, the reaction continued stirring 35 h, added 350 ml sodium chloride solution with a mass fraction of 15%, solution of oxalic acid solution with a mass fraction of 30% was used to adjust pH to 5, the reaction was continued to 5h, solid separated, the temperature of the solution is reduced to 13 °C, filtered, washed with potassium nitrate solution, dehydrated with activated alumina dehydrating agent, recrystallized from hexane solution, got 3- (4-ethoxyphenyl) -1,1-diethyl-urea 47.25 g, yield 91%. .
While a number of preferred embodiments have been described, it will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.
Claims (4)
1. Celiprolol pharmaceutical intermediate 3- (4-ethoxyphenyl) -1,1-diethyl-urea synthesis method, comprising the following steps: (i) equipped with a stirrer and a dropping funnel, the reaction vessel was added 0.22 mol p-aminophenyl ether (2), 0.45- 0.47mol sodium bisulfite solution, 80- 90ml tetrahydrofuran solution, controlling the stirring speed 130-160rpm, control temperature of the solution 35-40°C, added 0.25-0.27mol solution of N, N-diethylamino-carboxamide (3), control add dropwise time to 4-5 h, the reaction continued stirring 30-35h, added 300 - 350ml sodium chloride solution, solution of oxalic acid solution was used to adjust pH to 4-5, the reaction was continued to 4-5h, solid separated, the temperature of the solution is reduced to 10 - 15 °C, filtered, washed with saline solution, dehydrated with dehydrating agent, recrystallized from hexane solution, got 3- (4-ethoxyphenyl) -1,1-diethyl-urea (1); wherein sodium chloride solution in step (i) has a mass fraction of 10-15%.
2. Celiprolol pharmaceutical intermediate 3- (4-ethoxyphenyl) -1,1-diethyl-urea synthesis method according to claim 1 wherein oxalic acid solution in step (i) has a mass fraction of 25-30%.
3. Celiprolol pharmaceutical intermediate 3- (4-ethoxyphenyl) -1,1-diethyl-urea synthesis method according to claim 1 wherein saline solution in step (i) is any one of potassium nitrate solution or sodium sulfate solution.
4. Celiprolol pharmaceutical intermediate 3- (4-ethoxyphenyl) -1,1-diethyl-urea synthesis method according to claim 1 wherein dehydrating agent in step (i) is any one of activated alumina or phosphorus pentoxide.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510976438.8A CN105503658A (en) | 2015-12-23 | 2015-12-23 | Synthesis method of celiprolol drug intermediate 3-(4-enthoxyphenyl)-1,1-diethylurea |
| CN2015109764388 | 2015-12-23 | ||
| CN201610813956.2A CN106397274A (en) | 2015-12-23 | 2016-09-11 | Synthetic method of celiprolol drug intermediate 3-(4-ethoxyphenyl)-1,1-diethylurea |
| CN2016108139562 | 2016-09-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2016102185A4 true AU2016102185A4 (en) | 2017-02-23 |
Family
ID=55712030
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2016102185A Ceased AU2016102185A4 (en) | 2015-12-23 | 2016-12-22 | Celiprolol pharmaceutical intermediate 3- (4-ethoxyphenyl) -1, 1-diethyl-urea synthesis method |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN105503658A (en) |
| AU (1) | AU2016102185A4 (en) |
-
2015
- 2015-12-23 CN CN201510976438.8A patent/CN105503658A/en active Pending
-
2016
- 2016-09-11 CN CN201610813956.2A patent/CN106397274A/en active Pending
- 2016-12-22 AU AU2016102185A patent/AU2016102185A4/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| CN105503658A (en) | 2016-04-20 |
| CN106397274A (en) | 2017-02-15 |
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| FGI | Letters patent sealed or granted (innovation patent) | ||
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