CN101811932A - Preparation method of Aliskiren intermediate trans-1,4-dibromo-2-butylene - Google Patents
Preparation method of Aliskiren intermediate trans-1,4-dibromo-2-butylene Download PDFInfo
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- CN101811932A CN101811932A CN201010162477A CN201010162477A CN101811932A CN 101811932 A CN101811932 A CN 101811932A CN 201010162477 A CN201010162477 A CN 201010162477A CN 201010162477 A CN201010162477 A CN 201010162477A CN 101811932 A CN101811932 A CN 101811932A
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- butylene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/013—Preparation of halogenated hydrocarbons by addition of halogens
- C07C17/02—Preparation of halogenated hydrocarbons by addition of halogens to unsaturated hydrocarbons
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Abstract
The invention provides a new method for preparing high-purity trans-1,4-dibromo-2-butylene, in particular an effective method which reduces the content of transition bromination impurities 1,2,3,4-tetrabromobutane in the trans-1,4-dibromo-2-butylene. The method is characterized in that fractions containing the trans-1,4-dibromo-2-butylene are collected by using a decompression and distillation method.
Description
Technical field
It is anti--1 to the present invention relates to the intermediate of angiotonin enzyme inhibitors aliskiren (aliskiren), the preparation and the method for purification thereof of 4-two bromo-2-butylene.
Background technology
Aliskiren is a non-peptide class feritin blocade of new generation, be to use the designed a kind of novel cpd that comes out of the crystal structure analysis of early stage feritin blocade mixture and robot calculator pattern, not with the structure of the similar amino acid that contracts that extends in the prorenin blocade.Be a kind of strong effectively, the feritin blocade of lower molecular weight (relative molecular weight is 610), non-peptide class, high selectivity.Get permission listing in the U.S. at first in March, 2007, separately or coupling in hypertensive control; In January, 2008, the compound preparation of being made up of aliskiren and two hydrogen thiazines has also obtained the listing of FDA and has permitted.
Aliskiren can reduce renin activity in first link blocking-up RAS system, reduces the generation of AngII and aldosterone, does not influence the metabolism of bradykinin and prostaglandin(PG), plays effect hypotensive and the treatment cardiovascular disorder.From present research aliskiren is potent, high selectivity, orally active, long lasting antihypertensive drug of new generation.Though the same with the mechanism of action of aldosterone receptor blocker with angiotensin-convertion enzyme inhibitor, angiotensin II receptor antagonists, different is that the direct acting position of aliskiren is a feritin.The II clinical trial phase that carries out in Ireland confirms that aliskiren can effectively reduce light moderate hypertension patient's blood pressure level; In the III clinical trial phase, the experimenter tangible antihypertensive effect just occurred in 2 weeks of begin treatment.In addition, the simultaneous test of aliskiren and irbesartan has also confirmed the curative effect of aliskiren to light moderate hypertension patient.
Because aliskiren has the effect of good clinical treatment hypertension and chronic nephropathy, enjoy attracting attention of each big drugmaker at present, and intermediate is anti--1,4-two bromo-2-butylene are key intermediates of synthetic aliskiren.
Present disclosed preparation is anti--1, and the synthetic method of 4-two bromo-2-butylene has a variety of.
Reported among the US7470822 divinyl is dissolved in the tetracol phenixin, be added dropwise to the liquid bromine, reaction finishes the back distillation except that desolvating, and will distill substrate again and obtain 1 with the normal hexane recrystallization, 4-two bromo-2-butylene.(Journal of AmericanChemical Society such as Hurd, nineteen thirty-nine, 61 volumes, 249 pages) and (Journal of American ChemicalSociety, nineteen fifty, 72 volumes such as SKINNER, 1648 pages) also mention divinyl and bromine reaction and finish after, reaction solvent and lower boiling impurity are removed in distillation, will distill substrate then and obtain 1 with solvent crystallization, 4-two bromo-2-butylene.
US4626544 reported with suitable-1, and it is suitable-1 that the 4-butylene glycol is that raw material and phosphorus tribromide reaction generate, 4-butylene dibromo, the back generates anti--1 with the iodine isomerization, 4-two bromo-2-butylene, this patent further report purify anti--1, the method for 4-two bromo-2-butylene, can generate more isomer impurities suitable-1 in this route experimentation, 4-two bromo-2-butylene, and a spot of 1,2,3, the 4-tetrabromobutane.
The common shortcoming of aforesaid method is excessive brominated product, promptly 1,2,3, and the 4-tetrabromobutane is difficult to remove by the crystalline method, still contains at least 1% excessive brominated product behind the recrystallization.And anti--1,4-two bromo-2-butylene are having very strict requirement qualitatively as the key intermediate of aliskiren, and it is anti--1 therefore to develop a kind of preparation high purity, and the method for 4-two bromo-2-butylene highly significant.
Summary of the invention
It is highly purified anti--1 that order of the present invention provides a kind of preparation, and the novel method of 4-two bromo-2-butylene particularly provides a kind of effective ways to reduce instead-1, contained excessive bromination impurity 1,2,3 in the 4-two bromo-2-butylene, 4-tetrabromobutane.
Particularly, it is anti--1 to the invention provides a kind of preparation high purity, the method for 4-two bromo-2-butylene, and this method may further comprise the steps:
(a) divinyl and bromine react in solvent;
(b) after reaction finishes, by underpressure distillation collect be rich in anti--1, the cut of 4-two bromo-2-butylene;
(c) be rich in instead-1 with collected, the cut of 4-two bromo-2-butylene carries out crystallization with solvent.
In the aforesaid method, wherein the solvent of step (a) reaction is preferably the mixed solvent of any or they in methylene dichloride, trichloromethane, the ethyl acetate, more preferably methylene dichloride; Temperature of reaction is preferably-25 ℃～60 ℃, more preferably-15 ℃～20 ℃; Reaction times is preferably 0.5～20 hour, more preferably 1～8 hour.
After reaction finishes, at first remove reaction solvent by distillation, more then underpressure distillation collect be rich in anti--1, the cut of 4-two bromo-2-butylene.In the process of above-mentioned underpressure distillation, preferably control vacuum tightness in 1000 handkerchiefs～1500 handkerchief scopes, collect the cut in 60 ℃～90 ℃ scopes; More preferably control vacuum tightness in 1000 handkerchiefs～1500 handkerchief scopes, collect the cut in 70～80 ℃ of scopes.
Being rich in of collecting is anti--1, and the cut of 4-two bromo-2-butylene carries out crystallization in appropriate solvent, and wherein recrystallisation solvent is preferably methyl alcohol, ethanol, propyl alcohol, toluene, normal hexane or hexanaphthene, more preferably ethanol.
As another aspect of the present invention, the present invention also provides a kind of reduction anti--1, contained impurity 1,2,3 in the 4-two bromo-2-butylene, and the method for 4-tetrabromobutane is characterized in that collecting with the method for underpressure distillation and contains instead-1, the cut of 4-two bromo-2-butylene.
The present invention compared with prior art, the product purity height for preparing, isomer impurities is suitable-1,4-two bromo-2-butylene, 1,2-dibromo butene, particularly excessive bromination impurity 1,2,3, the 4-tetrabromobutane is all below 0.2%; And method provided by the invention, simple to operate, environmental friendliness, total recovery are higher, are fit to very much suitability for industrialized production.
Embodiment
Embodiment 1
70.0g divinyl joins in the 1200ml methylene dichloride, is cooled to-10～10 ℃, adds 172.6g liquid bromine, be incubated-5～-15 ℃ and stirred 5 hours, reaction finishes the back air distillation except that desolvating, and obtains the 228.4g solid crude product.Crude product is carried out underpressure distillation, and control vacuum tightness is collected the cut in 70～80 ℃ of scopes in 1000Pa～1500Pa scope, obtain the 187.5g white solid.The 280ml dehydrated alcohol is joined in the above-mentioned white solid, be heated to 70 ℃ under stirring and make its dissolving, cool to room temperature is separated out precipitation, obtains the 168.7g white solid behind the filtering drying, and total recovery is 73.1%.
Anti--1 in the product, 4-two bromo-2-butylene GC purity: 99.86%, single maximum contaminant 0.13%.
Embodiment 2
70.0g divinyl joins in the 1200ml methylene dichloride, is cooled to-10～10 ℃, adds 172.6g liquid bromine, is incubated-5～-15 ℃ and stirs 5 hours, reaction has finished the back air distillation except that desolvating, and obtains the 228.4g solid crude product.Crude product is carried out underpressure distillation, and control vacuum tightness is collected the cut in 70～80 ℃ of scopes in 1000Pa～1500Pa scope, obtain the 187.5g white solid.The 560ml normal hexane is joined in the above-mentioned white solid, be heated to 70 ℃ under stirring and make its dissolving, cool to room temperature is separated out precipitation, obtains the 150.0g white solid behind the filtering drying, and total recovery is 65%.
Anti--1 in the product, 4-two bromo-2-butylene GC purity: 99.52%, single maximum contaminant 0.2%.
Claims (9)
- One kind to prepare high purity anti--1, the method for 4-two bromo-2-butylene may further comprise the steps:(a) divinyl and bromine react in solvent;(b) after reaction finishes, by underpressure distillation collect be rich in anti--1, the cut of 4-two bromo-2-butylene;(c) be rich in instead-1 with collected, the cut of 4-two bromo-2-butylene carries out crystallization with solvent.
- 2. method according to claim 1, wherein the solvent of step (a) is selected from the mixed solvent of methylene dichloride, trichloromethane, ethyl acetate any or they.
- 3. method according to claim 1, wherein the temperature of reaction of step (a) is-25 ℃～60 ℃, more preferably-15 ℃～20 ℃.
- 4. method according to claim 1, wherein step (a) reaction times is 0.5～20 hour, more preferably 1～8 hour.
- 5. method according to claim 1 wherein in the described vacuum distillation process of step (b), is preferably controlled vacuum tightness in 1000Pa～1500Pa scope, collects 50 ℃～90 ℃ cuts.
- 6. method according to claim 5 wherein in the described vacuum distillation process of step (b), is preferably controlled vacuum tightness in 1000Pa～1500Pa scope, the cut in collecting 70～80 ℃.
- 7. method according to claim 1, wherein the recrystallisation solvent of step (c) is preferably methyl alcohol, ethanol, propyl alcohol, toluene, normal hexane or hexanaphthene.
- 8. method according to claim 7, wherein the recrystallisation solvent of step (c) is preferably ethanol.
- One kind reduce anti--1, contained impurity 1,2,3 in the 4-two bromo-2-butylene, the method for 4-tetrabromobutane is characterized in that collecting with the method for underpressure distillation and contains instead-1, the cut of 4-two bromo-2-butylene.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010162477A CN101811932A (en) | 2010-04-10 | 2010-04-10 | Preparation method of Aliskiren intermediate trans-1,4-dibromo-2-butylene |
| PCT/CN2011/070564 WO2011124098A1 (en) | 2010-04-10 | 2011-01-25 | Process for preparing aliskiren intermediate trans-1, 4-dibromo-2-butylene |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010162477A CN101811932A (en) | 2010-04-10 | 2010-04-10 | Preparation method of Aliskiren intermediate trans-1,4-dibromo-2-butylene |
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| Publication Number | Publication Date |
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| CN101811932A true CN101811932A (en) | 2010-08-25 |
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| CN201010162477A Pending CN101811932A (en) | 2010-04-10 | 2010-04-10 | Preparation method of Aliskiren intermediate trans-1,4-dibromo-2-butylene |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1956759A (en) * | 2004-05-07 | 2007-05-02 | 韦恩诺利特两合公司 | Method for the distillation of product mixtures |
| CN101058551A (en) * | 2006-04-18 | 2007-10-24 | 北京大学 | Method of synthesizing hexa-2,4-dienedinitrile from 1,4-dihalogen-1,3-butadiene and cuprous cyanide |
| US20080262271A1 (en) * | 2004-10-05 | 2008-10-23 | Sangho Koo | C10 Dialdehyde, Synthetic Method Thereof, and Synthetic Method of Beta-Carotene Using the Same |
-
2010
- 2010-04-10 CN CN201010162477A patent/CN101811932A/en active Pending
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2011
- 2011-01-25 WO PCT/CN2011/070564 patent/WO2011124098A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1956759A (en) * | 2004-05-07 | 2007-05-02 | 韦恩诺利特两合公司 | Method for the distillation of product mixtures |
| US20080262271A1 (en) * | 2004-10-05 | 2008-10-23 | Sangho Koo | C10 Dialdehyde, Synthetic Method Thereof, and Synthetic Method of Beta-Carotene Using the Same |
| US7470822B2 (en) * | 2004-10-05 | 2008-12-30 | Myongji University Industry And Academia Cooperation | C10 dialdehyde, synthetic method thereof, and synthetic method of beta-carotene using the same |
| CN101058551A (en) * | 2006-04-18 | 2007-10-24 | 北京大学 | Method of synthesizing hexa-2,4-dienedinitrile from 1,4-dihalogen-1,3-butadiene and cuprous cyanide |
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| WO2011124098A1 (en) | 2011-10-13 |
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Application publication date: 20100825 |