CN105503658A - Synthesis method of celiprolol drug intermediate 3-(4-enthoxyphenyl)-1,1-diethylurea - Google Patents
Synthesis method of celiprolol drug intermediate 3-(4-enthoxyphenyl)-1,1-diethylurea Download PDFInfo
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- CN105503658A CN105503658A CN201510976438.8A CN201510976438A CN105503658A CN 105503658 A CN105503658 A CN 105503658A CN 201510976438 A CN201510976438 A CN 201510976438A CN 105503658 A CN105503658 A CN 105503658A
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- celiprolol
- ethoxyl phenenyl
- diethyl urea
- synthetic method
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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
- 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
- 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
A synthesis method of celiprolol drug intermediate 3-(4-enthoxyphenyl)-1,1-diethylurea comprises steps as follows: 0.22 mol of p-phenetidine, 0.45-0.47 mol of sodium hydrogen sulfite and 80-90 ml of tetrahydrofuran are added to a reaction container provided with a stirrer and a dropping funnel, the stirring speed is controlled within 130-160 rpm, the solution temperature is controlled within 35-40 DEG C, 0.25-0.27 mol of N,N-diethylamino formamide is dropwise added, the addition time is controlled within 4-5 h, the solution is stirred continuously to react for 30-35 h, 300-350 ml of a sodium chloride solution is added, the pH of the solution is adjusted to range from 4 to 5 with an oxalic acid, the solution reacts continuously for 4-5 h, solids are separated out, the solution is cooled to the temperature of 10-15 DEG C, filtration, washing with a salt solution, dehydration with a dehydrating agent and recrystallization in hexane are performed, and 3-(4-enthoxyphenyl)-1,1-diethylurea is obtained.
Description
Technical field
The present invention relates to the synthetic method of a kind of celiprolol pharmaceutical intermediate 3-(4-ethoxyl phenenyl)-1,1-diethyl urea.
Background technology
Celiprolol has intrinsic sympathomimetic acitivity, does not increase resistance of respiratory tract, and expansion peripheral blood vessel, improves blood circulation.These product also do not suppress myocardial contraction without film static stabilization, cause the possibility of sinus bradycardia little than other beta-blockers without endogenous sympathomimetic activity.These product are by placental barrier.Be applicable to light, moderate hypertension.These product are a kind of highly selective beta-blockers, and by retardance β1receptor, vasodilation, reduces blood pressure.On this product highly selective and myocardial cell membrane, β1receptor combines, its avidity than segmental bronchus and vascular smooth muscle beta 2 receptor strong 20 ~ 30 times.Heart rate when having a rest and move and cardiac output can be reduced, reduce systolic pressure during motion, suppress the tachycardia of Racemic isoproterenol induction.To Healthy People, these product can not reverse the vasodilator effect of the Racemic isoproterenol of beta 2 receptor mediation.These product have intrinsic sympathomimetic acitivity, do not increase resistance of respiratory tract, and expansion peripheral blood vessel, improves blood circulation.These product also do not suppress myocardial contraction without film static stabilization, cause the possibility of sinus bradycardia little than other beta-blockers without endogenous sympathomimetic activity.3-(4-ethoxyl phenenyl)-1,1-diethyl urea is as celiprolol pharmaceutical intermediate, and its synthetic method is good and bad for raising pharmaceutical synthesis quality product, reduces by-products content and has Important Economic meaning.
Summary of the invention
The object of the present invention is to provide the synthetic method of a kind of celiprolol pharmaceutical intermediate 3-(4-ethoxyl phenenyl)-1,1-diethyl urea, comprise the steps:
I () is being provided with agitator, in the reaction vessel of dropping funnel, add p-phenetidine (2) 0.22mol, sodium bisulfite 0.45-0.47mol, tetrahydrofuran (THF) 80-90ml, control stirring velocity 130-160rpm, control solution temperature at 35--40 DEG C, drip N, N-diethylin methane amide (3) 0.25-0.27mol, time for adding controls at 4-5h, continue stirring reaction 30-35h, add sodium chloride solution 300-350ml, with oxalic acid solution regulator solution pH to 4-5, continue reaction 4-5h, solid is had to separate out, reduce solution temperature to 10--15 DEG C, filter, brine, dewatering agent dewaters, recrystallization in hexane, obtain 3-(4-ethoxyl phenenyl)-1, 1-diethyl urea (1), wherein, the massfraction of the sodium chloride solution described in step (i) is 10-15%, and the massfraction of the oxalic acid solution described in step (i) is 25-30%,
Salts solution described in step (i) is any one in saltpetre, sodium sulfate, and the dewatering agent described in step (i) is any one in activated alumina, Vanadium Pentoxide in FLAKES.
Whole reaction process can represent with following reaction formula:
The invention has the advantages that: the middle-chain decreasing reaction, reduce temperature of reaction and reaction times, improve reaction yield.
Embodiment
Below in conjunction with concrete embodiment, the invention will be further described:
A kind of synthetic method of celiprolol pharmaceutical intermediate 3-(4-ethoxyl phenenyl)-1,1-diethyl urea
Example 1:
Agitator is being installed, in the reaction vessel of dropping funnel, add p-phenetidine (2) 0.22mol, sodium bisulfite 0.45mol, tetrahydrofuran (THF) 80ml, control stirring velocity 130rpm, control solution temperature at 35 DEG C, drip N, N-diethylin methane amide (3) 0.25mol, time for adding controls at 4h, continue stirring reaction 30h, adding massfraction is 10% sodium chloride solution 300ml, be 25% oxalic acid solution regulator solution pH to 4 with massfraction, continue reaction 4h, solid is had to separate out, reduce solution temperature to 10 DEG C, filter, potassium nitrate solution washs, activated alumina dewaters, recrystallization in hexane, obtain 3-(4-ethoxyl phenenyl)-1, 1-diethyl urea (1) 43.09g, yield 83%.
Example 2:
Agitator is being installed, in the reaction vessel of dropping funnel, add p-phenetidine (2) 0.22mol, sodium bisulfite 0.46mol, tetrahydrofuran (THF) 85ml, control stirring velocity 150rpm, control solution temperature at 37 DEG C, drip N, N-diethylin methane amide (3) 0.26mol, time for adding controls at 4h, continue stirring reaction 33h, adding massfraction is 12% sodium chloride solution 320ml, be 27% oxalic acid solution regulator solution pH to 4 with massfraction, continue reaction 4h, solid is had to separate out, reduce solution temperature to 13 DEG C, filter, metabisulfite solution washs, Vanadium Pentoxide in FLAKES dewaters, recrystallization in hexane, obtain 3-(4-ethoxyl phenenyl)-1, 1-diethyl urea (1) 44.65g, yield 86%.
Example 3:
Agitator is being installed, in the reaction vessel of dropping funnel, add p-phenetidine (2) 0.22mol, sodium bisulfite 0.47mol, tetrahydrofuran (THF) 90ml, control stirring velocity 160rpm, control solution temperature at 40 DEG C, drip N, N-diethylin methane amide (3) 0.27mol, time for adding controls at 5h, continue stirring reaction 35h, adding massfraction is 15% sodium chloride solution 350ml, be 30% oxalic acid solution regulator solution pH to 5 with massfraction, continue reaction 5h, solid is had to separate out, reduce solution temperature to 15 DEG C, filter, potassium nitrate solution washs, activated alumina dewaters, recrystallization in hexane, obtain 3-(4-ethoxyl phenenyl)-1, 1-diethyl urea (1) 47.25g, yield 91%.
Claims (4)
1. a celiprolol pharmaceutical intermediate 3-(4-ethoxyl phenenyl)-1, the synthetic method of 1-diethyl urea, it is characterized in that, comprise the steps: that (i) is being provided with agitator, in the reaction vessel of dropping funnel, add p-phenetidine (2) 0.22mol, sodium bisulfite 0.45-0.47mol, tetrahydrofuran (THF) 80-90ml, control stirring velocity 130-160rpm, control solution temperature at 35--40 DEG C, drip N, N-diethylin methane amide (3) 0.25-0.27mol, time for adding controls at 4-5h, continue stirring reaction 30-35h, add sodium chloride solution 300-350ml, with oxalic acid solution regulator solution pH to 4-5, continue reaction 4-5h, solid is had to separate out, reduce solution temperature to 10--15 DEG C, filter, brine, dewatering agent dewaters, recrystallization in hexane, obtain 3-(4-ethoxyl phenenyl)-1, 1-diethyl urea (1), wherein, the massfraction of the sodium chloride solution described in step (i) is 10-15%.
2. the synthetic method of a kind of celiprolol pharmaceutical intermediate 3-(4-ethoxyl phenenyl)-1,1-diethyl urea according to claim 1, it is characterized in that, the massfraction of the oxalic acid solution described in step (i) is 25-30%.
3. the synthetic method of a kind of celiprolol pharmaceutical intermediate 3-(4-ethoxyl phenenyl)-1,1-diethyl urea according to claim 1, is characterized in that, the salts solution described in step (i) is any one in saltpetre, sodium sulfate.
4. a kind of celiprolol pharmaceutical intermediate 3-(4-ethoxyl phenenyl)-1 according to claim 1, the synthetic method of 1-diethyl urea, it is characterized in that, the dewatering agent described in step (i) is any one in activated alumina, Vanadium Pentoxide in FLAKES.
Priority Applications (3)
| 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 |
| CN201610813956.2A CN106397274A (en) | 2015-12-23 | 2016-09-11 | Synthetic method of celiprolol drug intermediate 3-(4-ethoxyphenyl)-1,1-diethylurea |
| AU2016102185A AU2016102185A4 (en) | 2015-12-23 | 2016-12-22 | Celiprolol pharmaceutical intermediate 3- (4-ethoxyphenyl) -1, 1-diethyl-urea synthesis method |
Applications Claiming Priority (1)
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105503658A true CN105503658A (en) | 2016-04-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510976438.8A Pending CN105503658A (en) | 2015-12-23 | 2015-12-23 | Synthesis method of celiprolol drug intermediate 3-(4-enthoxyphenyl)-1,1-diethylurea |
| CN201610813956.2A Pending CN106397274A (en) | 2015-12-23 | 2016-09-11 | Synthetic method of celiprolol drug intermediate 3-(4-ethoxyphenyl)-1,1-diethylurea |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610813956.2A Pending CN106397274A (en) | 2015-12-23 | 2016-09-11 | Synthetic method of celiprolol drug intermediate 3-(4-ethoxyphenyl)-1,1-diethylurea |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN105503658A (en) |
| AU (1) | AU2016102185A4 (en) |
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2015
- 2015-12-23 CN CN201510976438.8A patent/CN105503658A/en active Pending
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2016
- 2016-09-11 CN CN201610813956.2A patent/CN106397274A/en active Pending
- 2016-12-22 AU AU2016102185A patent/AU2016102185A4/en not_active Ceased
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| Publication number | Publication date |
|---|---|
| CN106397274A (en) | 2017-02-15 |
| AU2016102185A4 (en) | 2017-02-23 |
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Application publication date: 20160420 |