CN103351300A - Preparation method of aliskiren intermediate side chain ((s)-methyl-2-bromoisovalerate) - Google Patents
Preparation method of aliskiren intermediate side chain ((s)-methyl-2-bromoisovalerate) Download PDFInfo
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- CN103351300A CN103351300A CN2013102673853A CN201310267385A CN103351300A CN 103351300 A CN103351300 A CN 103351300A CN 2013102673853 A CN2013102673853 A CN 2013102673853A CN 201310267385 A CN201310267385 A CN 201310267385A CN 103351300 A CN103351300 A CN 103351300A
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Abstract
The invention belongs to the field of medicine chemistry, and relates to a preparation method of aliskiren intermediate side chain ((s)-methyl-2-bromoisovalerate). The preparation method comprises following steps: dimethyl isopropylmalonate hydrolyzes in the presence of alkali and converts to an acid; separated isopropylmalonic acid reacts with diethylamine in a formaldehyde solution and generates isopropyl acrylic acid; isopropyl acrylic acid reacts with hydrogen bromide organic acid solution and generates ethyl 2-bromo-3-methylbutyrate; ethyl 2-bromo-3-methylbutyrate is subjected to the processes of salification and de-salification in sequence and generates (s)-ethyl 2-bromo-3-methylbutyrate; (s)-ethyl 2-bromo-3-methylbutyrate is subjected to an esterification reaction and generates (s)-methyl-2-bromoisovalerate. The preparation method has the advantages of simple operation, extremely high purity, high yield, mild reaction conditions, and no side reactions.
Description
Technical field
The invention belongs to chemical field, relate to the preparation method who prepares aliskiren intermediate side chain (S)-2-bromo methyl isovalerate (formula I).
I
Background technology
Aliskiren is that the antihypertensive drug with novel pharmacological mechanism of Novartis Co.,Ltd's exploitation is the s-generation renin inhibitor that acts on RAAS.2007 respectively in the U.S. and European Union's approval listing.In January, 2008, the compound preparation that is comprised of aliskiren and hydrochlorothiazide has also obtained the listing license of FDA.Compare with depressor common on the market, this medical instrument has high selectivity, the escalated dose administration can not cause the blood pressure rapid drawdown, in the numerous synthetic routes of numerous aliskirens, in general (S)-2-bromo methyl isovalerate one of intermediate that is absolutely necessary, this intermediate synthetic causes a large amount of concerns, the document of delivering is more, by consulting pertinent literature, we develop the method for synthetic (S)-2-bromo methyl isovalerate in the aliskiren synthetic work, the method is simple to operate, based on very high purity, yield is high, and reaction conditions is gentle, does not have the generation of side reaction.
Summary of the invention
The invention provides a kind of method for preparing aliskiren intermediate side chain (S)-2-bromo methyl isovalerate, its step is, the isopropyl-malonic acid dimethyl ester is generated isopropyl-malonic acid by basic hydrolysis, isolated isopropyl-malonic acid is reacted into isopropylacrylic acid with diethylamine in formaldehyde solution, obtain 2-bromo isovaleric acid with the reaction of hydrogen bromide organic acid soln again, obtain (S)-2-bromo isovaleric acid by resolving agent salify solution salt, obtain (S)-2-bromo methyl isovalerate through over-churning again.The method has raw material and is simple and easy to, and reaction conditions is gentle, is easy to control, characteristics that product yield is high.
Wherein said alkali comprises sodium hydroxide and potassium hydroxide, wherein preferred potassium hydroxide.Described organic acid comprises formic acid and acetic acid, wherein preferred acetic acid.Described resolving agent comprises (S)-α-phenylethylamine and quinine, wherein first-selected (S)-α-phenylethylamine.Employed resolution solvent is ether.The used catalyzer of described esterification is TMSCHN
2, solvent is toluene.
Embodiment
Further specify by the following examples the present invention, but not as limitation of the present invention.
Embodiment 1:
In the 1L there-necked flask, add 201.6ml water and 201.6g sodium hydroxide, be made into 50% aqueous sodium hydroxide solution.Be heated with stirring to 80 ℃, weighing 174.19g isopropyl-malonic acid dimethyl ester is in the 250ml dropping funnel, and 80 ℃ of droppings keep 1d/s.Stirring reaction 5 hours obtains isopropyl-malonic acid through aftertreatment, yield 52.92%.
Embodiment 2:
In the 1L there-necked flask, add 201.6ml water and 201.6g potassium hydroxide, be made into 50% potassium hydroxide aqueous solution.Be heated with stirring to 80 ℃, weighing 174.19g isopropyl-malonic acid dimethyl ester is in the 250ml dropping funnel, and 80 ℃ of droppings keep 1d/s.Stirring reaction 5 hours obtains isopropyl-malonic acid through aftertreatment, yield 55.69%.
Embodiment 3:
In 1L single port bottle, add successively the 81.78g isopropyl-malonic acid, 115.38ml diethylamine and 224.9ml formaldehyde solution (37%).Be heated with stirring to backflow, back flow reaction 5 hours obtains water white transparency oily thing 54.4g, yield 85% through aftertreatment.
Embodiment 4:
Add 122.18ml hydrogen bromide formic acid solution (containing hydrogen bromide 0.68mol) in the 500ml round-bottomed flask, drip the 54.4g isopropylacrylic acid under 0 ℃ in the formic acid solution of hydrogen bromide, stirring reaction is one day under the room temperature, the treated light orange oily matter of 82.26g that obtains.
Embodiment 5:
Add 122.18ml hydrogen bromide acetic acid solution (containing hydrogen bromide 0.68mol) in the 500ml round-bottomed flask, drip the 54.4g isopropylacrylic acid under 0 ℃ in the acetic acid solution of hydrogen bromide, stirring reaction is one day under the room temperature, the treated light orange oily matter of 87.33g that obtains.
Embodiment 6:
In the 1L there-necked flask, add 30.7g2-bromo isovaleric acid, add the 307ml anhydrous diethyl ether, stir under 40 ℃ of reflux conditionss.Weighing 51g quinine adds in the bottle, stirs 2 hours, stops to stir, and adds a small amount of crystal seed, is cooled to the room temperature standing over night.Second day has the needle-like white solid to separate out, 5 ℃ of crystallizatioies 2 hours, and suction filtration gets the 16.24g solid, and ether recrystallization three times gets qualified (the S)-2-bromo isovaleric acid quinine salt of optics, accumulative total yield 20.3%.
Embodiment 7:
In the 1L there-necked flask, add 30.7g2-bromo isovaleric acid, add the 307ml anhydrous diethyl ether, stir under 40 ℃ of reflux conditionss.Weighing 19.06gS-α-phenylethylamine slowly drops in the bottle in constant pressure funnel, drips to finish, and stirs 5 minutes, stops to stir, and adds a small amount of crystal seed, is cooled to the room temperature standing over night.Second day has the needle-like white solid to separate out, 5 ℃ of crystallizatioies 2 hours, and suction filtration gets the 12.98g solid, and ether recrystallization three times gets qualified (the S)-2-bromo isovaleric acid phenylethylamine salt of optics, accumulative total yield 21.13%.
Embodiment 8:
In the 50ml there-necked flask, add 0.2g(S)-2-bromo isovaleric acid phenylethylamine salt, add 2.258ml 1N HCl, stirring reaction is 3 hours under the room temperature, treated 0.121g colorless oil (S)-2-bromo isovaleric acid, the yield 98% of obtaining.
Embodiment 9:
In 50ml single port bottle, add 0.11g(S)-2-bromo isovaleric acid, add 1.138ml methyl alcohol, 3.983ml toluene, stirring reaction under the room temperature.Pipette 0.427ml TMSCHN
2, dropping in the reaction solution, stirring at room reaction 1 hour obtains faint yellow oily thing after treatment.
Claims (10)
1. method for preparing aliskiren intermediate side chain (S)-2-bromo methyl isovalerate, it is characterized in that, (1) the isopropyl-malonic acid dimethyl ester is hydrolyzed in the presence of alkali and generates isopropyl-malonic acid, (2) isopropyl-malonic acid is reacted into isopropylacrylic acid with diethylamine in formaldehyde solution, (3) reaction of isopropylacrylic acid and hydrogen bromide organic acid soln obtains 2-bromo isovaleric acid, (4) 2-bromo isovaleric acid obtains (S)-2-bromo isovaleric acid by resolving agent salify solution salt, (5) (S)-2-bromo isovaleric acid obtains (S)-2-bromo methyl isovalerate through over-churning.
2. according to claim 1 method is characterized in that, the alkali of (1) one-step hydrolysis reaction usefulness is selected from sodium hydroxide and potassium hydroxide.
3. according to claim 1 method is characterized in that, the alkali of (1) one-step hydrolysis reaction usefulness is potassium hydroxide.
4. according to claim 1 method is characterized in that, the organic acid of (3) step usefulness is selected from formic acid and acetic acid.
5. according to claim 1 method is characterized in that, the organic acid of (3) step usefulness is acetic acid.
6. according to claim 1 method is characterized in that, the resolving agent of (4) step usefulness is selected from (S)-α-phenylethylamine and quinine.
7. according to claim 1 method is characterized in that, the resolving agent of (4) step usefulness is (S)-α-phenylethylamine.
8. according to claim 1 method is characterized in that, the solvent of the fractionation of (4) step usefulness is ether.
9. according to claim 1 method is characterized in that, the used catalyzer of (5) step esterification is TMSCHN
2
10. according to claim 1 method is characterized in that, the used solvent of (5) step esterification is toluene.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110066835A (en) * | 2019-03-21 | 2019-07-30 | 浙江工业大学 | A kind of application of lipase in resolution of racemic 2- bromo ethyl isovalerate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030181765A1 (en) * | 2000-07-25 | 2003-09-25 | Stefan Stutz | Process for the preparation of substituted octanoyl amides |
| US20060041169A1 (en) * | 1999-07-29 | 2006-02-23 | Peter Herold | Preparation of n-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amides |
| CN102001920A (en) * | 2010-11-09 | 2011-04-06 | 常州制药厂有限公司 | Preparation method of medicine intermediate |
| CN102432466A (en) * | 2011-09-22 | 2012-05-02 | 武汉武药制药有限公司 | Preparation method of aliskiren intermediate |
-
2013
- 2013-06-30 CN CN2013102673853A patent/CN103351300A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060041169A1 (en) * | 1999-07-29 | 2006-02-23 | Peter Herold | Preparation of n-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amides |
| US20030181765A1 (en) * | 2000-07-25 | 2003-09-25 | Stefan Stutz | Process for the preparation of substituted octanoyl amides |
| CN102001920A (en) * | 2010-11-09 | 2011-04-06 | 常州制药厂有限公司 | Preparation method of medicine intermediate |
| CN102432466A (en) * | 2011-09-22 | 2012-05-02 | 武汉武药制药有限公司 | Preparation method of aliskiren intermediate |
Non-Patent Citations (2)
| Title |
|---|
| 吴勇等: "阿利克仑的合成", 《中国药科大学学报》 * |
| 钟嫄等: "阿利克仑合成路线图解", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110066835A (en) * | 2019-03-21 | 2019-07-30 | 浙江工业大学 | A kind of application of lipase in resolution of racemic 2- bromo ethyl isovalerate |
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Application publication date: 20131016 |