CN102276504A - Synthesis method of bromisoval - Google Patents
Synthesis method of bromisoval Download PDFInfo
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- CN102276504A CN102276504A CN2010102070481A CN201010207048A CN102276504A CN 102276504 A CN102276504 A CN 102276504A CN 2010102070481 A CN2010102070481 A CN 2010102070481A CN 201010207048 A CN201010207048 A CN 201010207048A CN 102276504 A CN102276504 A CN 102276504A
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Abstract
The invention discloses a synthesis method of bromisoval, comprising the steps of: 1, reacting isovaleric acid and bromine to generate alpha-bromo isovaleric acid under the catalysis of phosphorus tribromide; 2, directly pressing a product obtained after the reaction in the step 1 into an acylation and bromination tank, adding the phosphorus tribromide and the bromine for continuous reaction to generate alpha-bro-moisopentanoyl bromide, reducing the pressure and heating after the reaction, distilling and collecting 85-95 DEG C/20-30mmHG fractions to obtain the alpha-bro-moisopentanoyl bromide; and 3, condensing the alpha-bro-moisopentanoyl bromide with urea to obtain bromisoval. The synthesis method of the bromisoval disclosed by the invention has the advantages of high product yield, high purity, fewer impurities, low cost and easiness for production control, in addition, a bromine hydride gas generated in the production process is absorbed with water to obtain hydrobromic acid for comprehensive utilization, therefore, three-waste discharge is reduced.
Description
Technical field
The present invention relates to a kind of synthetic method of bromisoval.Belong to technical field of medicine synthesis.
Background technology
Bromisoval is an old sedative hypnotic, belongs to straight chain ureide derivative sedative hypnotic, because its determined curative effect, and advantage such as side effect is little, still application in clinical at present.Its preparation has tablet, injection and other compound preparation.Its traditional synthetic method is that isovaleric acid generates alpha-brominated isoamyl acylbromide with the bromine reaction under red phosphorus catalysis, promptly gets bromisoval with urea condensation again, this law yield low (29%), cost height; It is that raw material and urea condensation obtain bromisoval that the day disclosure special permission clear 54-39019 of communique and two patents of clear 54-27527 adopt alpha-brominated isoveryl chloride, though this law synthesis yield is high, but play the alpha-brominated isoveryl chloride of real raw material is to obtain with alpha-brominated isovaleric acid and sulfur oxychloride reaction, this method easily produces alpha-chloro isovalerylurea impurity, cause final product quality to descend, and carry out that with sulfur oxychloride the potential explosion hazard is arranged when chloride is produced, and produce a large amount of sulfurous gas and hydrogen chloride gas, be unfavorable for the disposal of three wastes.
Summary of the invention
The purpose of this invention is to provide a kind of synthesis yield height, cost is low, and does not contain the bromisoval new synthetic process of alpha-chloro isovalerylurea impurity.
Technical scheme of the present invention is: the first step: isovaleric acid generates alpha-brominated isovaleric acid with the bromine reaction under the catalysis of phosphorus tribromide; Second step: after the first step had been reacted, product directly entered the acylbromide jar without separation, added phosphorus tribromide and bromine, continued reaction, generated alpha-brominated isoamyl acylbromide, and after having reacted, straight run distillation obtains the alpha-brominated isoamyl acylbromide of high purity; The 3rd step: alpha-brominated isoamyl acylbromide and urea condensation obtain bromisoval.
The invention has the beneficial effects as follows: product yield height, purity height, impurity is few, cost is low, produce the bromize hydrogen gas be easy to control, produce in the production process obtains Hydrogen bromide after water absorbs, and can fully utilize, and has reduced three waste discharge.
Embodiment
1, alpha-brominated isovaleric acid is synthetic
Isovaleric acid and phosphorus tribromide are dropped in the retort, slowly drip bromine then, so that there is not the color of bromine to be as the criterion in the reflux exchanger, insulation refluxes, till no hydrogen bromide is emitted (the hydrogen bromide water absorbs the preparation Hydrogen bromide), reaction finishes, and reaction solution directly is pressed in the acylbromide jar.
2, alpha-brominated isoamyl acylbromide is synthetic
Alpha-brominated isovaleric acid is dropped in the acylbromide jar, drop into phosphorus tribromide again, be heated to about 40 ℃ and drip bromine, till no bromize hydrogen gas is emitted, feed liquid is evacuated in the retort, carry out underpressure distillation and collect 85-95 ℃/20-30mmHg cut, get alpha-brominated isoamyl acylbromide (above two step yields are 96%).
3, bromisoval is synthetic
Urea and ethylene dichloride are added in the condensation reaction jar, be warming up to 60 ℃, begin to drip alpha-brominated isoamyl acylbromide, maintain the temperature at about 60～65 ℃, dropwise, be warming up to 70～72 ℃, insulation reaction 3.5 hours is cooled to room temperature, adds the aqueous sodium hydroxide solution for preparing, make reaction solution be neutral, ethylene dichloride is reclaimed in distillation then, till no ethylene dichloride steams, crystallisation by cooling, centrifugal, washing, get the slightly wet product of bromisoval, can be directly used in refining.
4, refining
Bromisoval crude product, ethanol, activated carbon are added in the decoloring reaction jar, and heating makes its dissolving, and insulation decolouring 5 minutes, press filtration are to crystallizer, and crystallisation by cooling filters, and cold washing with alcohol, drying, packing promptly get (3,4 liang of step yields are more than 76%).
Claims (6)
1. the synthetic method of a bromisoval may further comprise the steps: the first step: isovaleric acid generates alpha-brominated isovaleric acid with the bromine reaction under the catalysis of phosphorus tribromide; Second step: after the first step had been reacted, product directly was pressed in the acylbromide jar without separation, added phosphorus tribromide and bromine, continued reaction, generated alpha-brominated isoamyl acylbromide, and after having reacted, distillation obtains alpha-brominated isoamyl acylbromide; The 3rd step: alpha-brominated isoamyl acylbromide and urea condensation obtain the bromisoval crude product.The bromisoval crude product gets elaboration with ethyl alcohol recrystallization;
2. the synthetic method of bromisoval according to claim 1, it is characterized in that: the first step: isovaleric acid generates alpha-brominated isovaleric acid with the bromine reaction under the catalysis of phosphorus tribromide, its proportioning is: isovaleric acid: phosphorus tribromide: bromine=1: 0.01-0.02: 1.8-2.0, be preferably in 1: 0.017: 1.96, temperature of reaction is 20-60 ℃, is preferably in about 40 ℃ reaction till do not have bromize hydrogen gas and emit;
3. the synthetic method of bromisoval according to claim 1, it is characterized in that: second step: after the first step has been reacted, product is without separation, directly be pressed in the acylbromide jar, add phosphorus tribromide and bromine, continue reaction, generate alpha-brominated isoamyl acylbromide, after having reacted, distillation obtains alpha-brominated isoamyl acylbromide, its proportioning is: isovaleric acid: phosphorus tribromide: bromine=1: 1.1-1.2: 0.5-0.7, be preferably in 1: 1.15: 0.6, temperature of reaction is 20-40 ℃, is preferably in about 40 ℃ reaction till do not have bromize hydrogen gas and emit, 85-95 ℃/20-30mmHg cut is collected in the underpressure distillation that heats up then, gets alpha-brominated isoamyl acylbromide;
4. the synthetic method of bromisoval according to claim 1, it is characterized in that: the 3rd step: alpha-brominated isoamyl acylbromide and urea condensation obtain the bromisoval crude product, its proportioning is: alpha-brominated isoamyl acylbromide: urea: ethylene dichloride=1: 0.58-0.64: 0.4-0.7, be preferably in 1: 0.62: 0.53, urea and ethylene dichloride are dropped in the condensation jar, be warming up to 30～60 ℃, be preferably in 60 ℃, begin to drip alpha-brominated isoamyl acylbromide, maintain the temperature at about 60～65 ℃, dropwise, be warming up to 70～72 ℃, insulation reaction 1～4 hour is preferably in 3.5 hours, and reaction finishes, be cooled to room temperature, slowly add the aqueous sodium hydroxide solution for preparing, making reaction solution pH is 6～8, preferably is neutral pH 7, ethylene dichloride is reclaimed in distillation then, till no ethylene dichloride steams, crystallisation by cooling, centrifugal, washing, get the slightly wet product of bromisoval, the slightly wet product of bromisoval can be directly used in refining, also can make with extra care dry back;
5. the synthetic method of bromisoval according to claim 4, it is characterized in that: the 3rd step condensation used aqueous sodium hydroxide solution also can be potassium hydroxide aqueous solution, sodium bicarbonate aqueous solution, aqueous sodium carbonate or other inorganic metal alkaline solutions etc.;
6. the synthetic method of bromisoval according to claim 1, it is characterized in that: the bromisoval crude product gets elaboration with ethyl alcohol recrystallization, and its proportioning is: bromisoval crude product: ethanol: gac=1: 2-3: an amount of, be preferably in 1: 2.5: 0.01.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102070481A CN102276504A (en) | 2010-06-12 | 2010-06-12 | Synthesis method of bromisoval |
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| CN2010102070481A CN102276504A (en) | 2010-06-12 | 2010-06-12 | Synthesis method of bromisoval |
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| CN102276504A true CN102276504A (en) | 2011-12-14 |
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| CN2010102070481A Pending CN102276504A (en) | 2010-06-12 | 2010-06-12 | Synthesis method of bromisoval |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110204460A (en) * | 2019-06-04 | 2019-09-06 | 华润双鹤利民药业（济南）有限公司 | A kind of bromisoval fabrication processing |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5032588A (en) * | 1989-12-08 | 1991-07-16 | Abbott Laboratories | Thiazole lipoxygenase-inhibiting compounds derived from non-steroidal antiinflammatory carboxylic acids |
-
2010
- 2010-06-12 CN CN2010102070481A patent/CN102276504A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5032588A (en) * | 1989-12-08 | 1991-07-16 | Abbott Laboratories | Thiazole lipoxygenase-inhibiting compounds derived from non-steroidal antiinflammatory carboxylic acids |
Non-Patent Citations (1)
| Title |
|---|
| EVTUSHENKO, N. S.; KLYUEV, N. A.: "Gas chromatographic-mass spectrometric investigation of initial, intermediate and final products in N-(a-bromoisovaleryl)urea synthesis.", 《KHIMIKO-FARMATSEVTICHESKII ZHURNAL》, vol. 20, no. 8, 31 December 1986 (1986-12-31), pages 1004 - 1009 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110204460A (en) * | 2019-06-04 | 2019-09-06 | 华润双鹤利民药业（济南）有限公司 | A kind of bromisoval fabrication processing |
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Address after: 274500 the Yellow River Road, Shandong County, Dongming Applicant after: Shandong Fangming Pharmaceutical Group Co., Ltd. Address before: 274500 the Yellow River Road, Shandong County, Dongming Applicant before: Shandong Fangming Pharmaceutical Co., Ltd. |
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Free format text: CORRECT: APPLICANT; FROM: SHANDONG FANGMING PHARMACEUTICAL CO., LTD. TO: SHANDONG FANGMING PHARMACEUTICAL GROUP CO., LTD. |
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Application publication date: 20111214 |