CN104974042A - Preparation method of compound - Google Patents
Preparation method of compound Download PDFInfo
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- CN104974042A CN104974042A CN201410140148.5A CN201410140148A CN104974042A CN 104974042 A CN104974042 A CN 104974042A CN 201410140148 A CN201410140148 A CN 201410140148A CN 104974042 A CN104974042 A CN 104974042A
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Abstract
The invention discloses a preparation method of a compound. A synthetic method of a compound with a structure of formula I shown in the specification is provided. The method comprises the step of reacting 2,3-dichlorobenzaldehyde with methyl acetoacetate to form the compound with the structure of formula I.
Description
Technical field
The present invention relates to a kind of preparation method of compound, more specifically relate to the preparation method of the compound with following formula I structure.
Background technology
The formula II compound (butyrate clevidipine) shown below is the forth generation dihydropyridine calcium channel blocade used for intravenous injection for Astrazeneca AB's exploitation.The intravenous injection antihypertensive drug of its first approval listing of the Shi Shinianlai U.S..It has fugitive, quick-acting features, different through the antihypertensive drug of kidney and (or) hepatic metabolism from current many intravenous injections, and its metabolism in blood and tissue, does not thus accumulate in vivo.
Pharmacological research shows, butyrate clevidipine is as a kind of up-to-date Horizon class antihypertensive drug, can selectivity blocking calcium ions, bring out calcium ion flowing, reduce intracellular calcium concentration, reduce the tension force of vascular smooth muscle and the reaction to endogenous pressor substance thereof, thus vasodilator, reduce blood pressure.Butyrate clevidipine can be injectable emulsion, and for reducing unsuitable oral administration or the invalid hypertension of oral administration, it has rapid-action, effect and eliminates also fast, can accurately control the advantage of blood pressure by ascending-dose.From many antihypertensive drugs used for intravenous injection through kidney and (or) hepatic metabolism are different at present, butyrate clevidipine metabolism in blood and tissue, does not thus accumulate in vivo.
Carrying out in efficient liquid phase chromatographic analysis to butyrate clevidipine product, find a kind of major impurity peak, it has structure shown in following formula I:
The domestic Study of synthesis method for butyrate clevidipine is more, but to the less research of the preparation of its impurity, and the requirement that current medicine is declared for impurity research is higher, impurity research is conducive to improving for medicinal substances quantifier elimination and raising.
Although patent WO2010014234A1 reports the more impurity of butyrate clevidipine, it fails to provide the preparation method of these impurity.
Therefore, the synthetic method providing a kind of above-mentioned specific impurities of butyrate clevidipine is badly in need of in this area, and it is easy and simple to handle, product purity is higher, is suitable for drug quality research.
Summary of the invention
An object of the present invention is just to provide the synthetic method of specific impurities in a kind of butyrate clevidipine, to make this route can obtain this impurity, to be applicable to medicinal substances quantifier elimination.
One aspect of the present invention provides a kind of synthetic method with the compound of following formula I structure, said method comprising the steps of:
Make 2,3 dichloro benzaldehyde and methyl acetoacetate reaction, form the compound with following formula I structure:
In a preferred embodiment of the present invention, described reaction is carried out in a solvent; Preferably, described solvent is organic solvent, water or its combination; Preferably, described organic solvent is selected from alcohol, ester, ether, ketone and combination thereof; Preferably, described organic solvent is selected from tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol, the trimethyl carbinol, sec-butyl alcohol, methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, acetone, butanone, acetonitrile, propionitrile and combination thereof; Preferably, described organic solvent is selected from acetone, the trimethyl carbinol or its combination; Preferably, described reaction is not carried out in a solvent.
In a preferred embodiment of the present invention, described reaction is carried out in the presence of a base; Preferably, described alkali is selected from organic bases, mineral alkali and combination thereof; Preferably, described organic bases is selected from amine, an alkali metal salt of alcohol, metal alkylide lithium compound, amido lithium compound and combination thereof; Preferably, described amine is selected from piperidines, triethylamine, DMA and combination thereof; Preferably, an alkali metal salt of described alcohol is selected from sodium methylate, potassium ethylate, potassium tert.-butoxide and combination thereof; Preferably, described metal alkylide lithium compound is selected from butyllithium, phenyl lithium and combination thereof; Preferably, described amido lithium compound is selected from lithium diisopropyl amido, hexamethyldisilazane lithium and combination thereof; Preferably, described mineral alkali is selected from salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide or its combination; Preferably, described alkali is potassium tert.-butoxide.
In a preferred embodiment of the present invention, temperature of reaction is negative 10 DEG C to 100 DEG C, preferred 0-90 DEG C, more preferably 10-60 DEG C, most preferably 20-30 DEG C.
In a preferred embodiment of the present invention, the mol ratio of described 2,3 dichloro benzaldehyde and methyl acetoacetate is 2:1-1:8, is preferably 1:1-1:5, is more preferably 1:1.5-1:3, most preferably is 1:1.8-1:2.5.
In a preferred embodiment of the present invention, the consumption of described alkali is the 1-50% of 2,3 dichloro benzaldehyde mole number, is preferably 5-30%, is more preferably 6-20%, most preferably is 8-15%.
Method of the present invention is easy and simple to handle, product purity is higher, is suitable for the quality standard research of butyrate clevidipine impurity of the drug.
Embodiment
In the present invention, if do not illustrated especially, percentage ratio (%) or part all refer to weight percentage relative to composition or weight part.
In the present invention, if do not illustrated especially, involved each component or its preferred ingredient can be combined to form new technical scheme mutually.
In the present invention, if do not illustrated especially, all embodiments mentioned in this article and preferred implementation can be combined to form new technical scheme mutually.
In the present invention, if do not illustrated especially, all technical characteristics mentioned in this article and preferred feature can be combined to form new technical scheme mutually.
In the present invention, if do not have contrary explanation, in composition, the content sum of each component is 100%.
In the present invention, if do not have contrary explanation, in composition, the number sum of each component can be 100 weight parts.
In the present invention, unless otherwise indicated, the breviary of any real combinings that numerical range " a-b " represents between a to b represents, wherein a and b is real number.Such as numerical range " 0-5 " represents the whole real numbers all listed between " 0-5 " herein, and the breviary of " 0-5 " just these combinations of values represents.
In the present invention, unless otherwise indicated, the breviary of the arbitrary integer combination that integer numerical range " a-b " represents between a to b represents, wherein a and b is integer.Such as integer numerical range " 1-N " represents 1,2 ... N, wherein N is integer.
In the present invention, unless otherwise indicated, " its combination " represents the multicomponent mixture of described each element, such as two kinds, three kinds, four kinds and until the multicomponent mixture of maximum possible.
If do not particularly not pointed out, this specification sheets term " one " used refers to " at least one ".
If do not particularly not pointed out, the benchmark of percentage ratio of the present invention (comprising weight percentage) is all the gross weight of described composition.
" scope " disclosed herein is with the form of lower limit and the upper limit.One or more lower limit can be respectively, and one or more upper limit.Given range is limited by a selected lower limit and a upper limit.Selected lower limit and the upper limit define the border of special scope.All scopes that can carry out by this way limiting comprise and may be combined with, and namely any lower limit can be combined to form a scope with any upper limit.Such as, list the scope of 60-120 and 80-110 for special parameter, be interpreted as that the scope of 60-110 and 80-120 also expects.In addition, if the minimum extent value listed 1 and 2, and if list maximum range value 3,4 and 5, then the scope below can all expect: 1-3,1-4,1-5,2-3,2-4 and 2-5.
In this article, except as otherwise noted, the ratio of each component or weight all refer to dry weight.
In this article, except as otherwise noted, each reaction is carried out all at normal temperatures and pressures.
In this article, except as otherwise noted, each reactions steps can sequentially be carried out, and also can not carry out in order.Such as, between each reactions steps, other steps can be comprised, and also can reversed order between reactions steps.Preferably, reaction method is herein that order is carried out.
One aspect of the present invention provides a kind of synthetic method with the compound of following formula I structure, said method comprising the steps of:
Make 2,3 dichloro benzaldehyde and methyl acetoacetate reaction, form the compound with following formula I structure:
In the present invention, described reaction is preferably carried out in a solvent.In a preferred embodiment of the present invention, described solvent can be any solvent conventional in organic chemistry filed, as long as it can solubilizing reaction reagent and do not cause adverse influence to reaction.In a preferred embodiment of the present invention, described solvent can be organic solvent, water or its combination.In a preferred embodiment of the present invention, described organic solvent is selected from alcohol, ester, ether, ketone and combination thereof.In another preferred embodiment of the present invention, described organic solvent is selected from tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol, the trimethyl carbinol, sec-butyl alcohol, methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, acetone, butanone, acetonitrile, propionitrile and combination thereof.In another preferred embodiment of the present invention, described organic solvent is selected from acetone, the trimethyl carbinol or its combination.Certainly, reaction of the present invention also can not be carried out in a solvent.
In a preferred embodiment of the present invention, described reaction is carried out in the presence of a base.In another preferred embodiment of the present invention, described alkali can be any alkali used in organic reaction, as long as it can provide alkaline environment to reaction and can not cause disadvantageous effect to reaction.In a preferred embodiment of the present invention, described alkali is selected from organic bases, mineral alkali and combination thereof.In another preferred embodiment of the present invention, described organic bases is selected from amine, an alkali metal salt of alcohol, metal alkylide lithium compound, amido lithium compound and combination thereof.In another preferred embodiment of the present invention, described amine is selected from piperidines, triethylamine, DMA and combination thereof.In another preferred embodiment of the present invention, an alkali metal salt of described alcohol is selected from sodium methylate, potassium ethylate, potassium tert.-butoxide and combination thereof.In a preferred embodiment of the present invention, described metal alkylide lithium compound is selected from butyllithium, phenyl lithium and combination thereof.In a preferred embodiment of the present invention, described amido lithium compound is selected from lithium diisopropyl amido (LDA), hexamethyldisilazane lithium (LiHMDS) and combination thereof.In another preferred embodiment of the present invention, described mineral alkali is selected from salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide or its combination.In the most preferred example of the present invention, described alkali is potassium tert.-butoxide.
In a preferred embodiment of the present invention, described temperature of reaction is negative 10 degree to 100 DEG C, preferred 0-90 DEG C, more preferably 10-60 DEG C, most preferably 20-30 DEG C.
In the present invention, the mol ratio of described 2,3 dichloro benzaldehyde and methyl acetoacetate can be arbitrary.But, in order to save cost and obtain better purity, described 4-(2,3-dichlorobenzene) mol ratio of butyl-3-alkene-2-ketone and methyl acetoacetate is 2:1-1:8, be preferably 1:1-1:5, be more preferably 1:1.5-1:3, most preferably be 1:1.8-1:2.5.
In the present invention, the consumption of described alkali is conventional.But in order to save cost and obtain better purity, the consumption of described alkali is the 1-50% of 2,3 dichloro benzaldehyde mole number, is preferably 5-30%, is more preferably 6-20%, most preferably is 8-15%.
Describe the present invention in detail by the following examples, but following examples are only exemplary, scope of the present invention is not limited thereto.
Embodiment
Embodiment 1
By 2,3-dichloromethane benzaldehyde (10g, 57.1mmol) and methyl acetoacetate (13.27g, 114mmol) be fully uniformly mixed at round-bottomed bottle, add piperidines (0.566ml, 5.71mmol) under room temperature, reactant at room temperature stirs 24 hours.After adding 200 milliliters of methylene dichloride dissolvings, then add piperidines (2.83ml, 28.6mmol).After reaction solution at room temperature stirs 4 days, reaction solution water and saturated salt washing, anhydrous sodium sulfate drying, drains to obtain crude product.It is yellow oil (700mg, 2.235mmol, 3.91%yield) that column chromatography obtains compd A.
Spectral data:
1H NMR(500MHz,Acetone-d6)δ7.52(dd,J=8.0,1.5Hz,1H),7.48(dd,J=7.9,1.5Hz,1H),7.38(t,J=7.9Hz,1H),6.04(s,1H),4.29(ddd,J=10.2,8.9,5.4Hz,1H),3.99(ddd,J=8.9,2.2,1.2Hz,1H),3.64(s,3H),2.71–2.58(m,2H),2.01(s,3H)；
13C NMR(126MHz,Acetone)δ196.05,172.13,156.95,142.53,133.95,132.38,130.31,129.16,128.70,127.71,52.71,52.50,42.01,41.78,22.61；
MS(ESI):312.93(M+H)
Embodiment 2
By 2,3-dichloromethane benzaldehyde (10g, 57.1mmol) with methyl acetoacetate (13.27g, 114mmol) be fully uniformly mixed at round-bottomed bottle, sodium hydroxide (5.71mmol) is added under room temperature, after reactant at room temperature stirs 2 days, reaction solution water and saturated salt washing, anhydrous sodium sulfate drying, drains to obtain crude product.It is yellow oil (100mg, 0.335mmol, 0.56%yield) that column chromatography obtains compd A.
Spectral data:
1H NMR(500MHz,Acetone-d6)δ7.52(dd,J=8.0,1.5Hz,1H),7.48(dd,J=7.9,1.5Hz,1H),7.38(t,J=7.9Hz,1H),6.04(s,1H),4.29(ddd,J=10.2,8.9,5.4Hz,1H),3.99(ddd,J=8.9,2.2,1.2Hz,1H),3.64(s,3H),2.71–2.58(m,2H),2.01(s,3H)；
13C NMR(126MHz,Acetone)δ196.05,172.13,156.95,142.53,133.95,132.38,130.31,129.16,128.70,127.71,52.71,52.50,42.01,41.78,22.61；
MS(ESI):312.93(M+H)
Embodiment 3
By 2,3-dichloromethane benzaldehyde (10g, 57.1mmol) with methyl acetoacetate (13.27g, 114mmol) be fully uniformly mixed at round-bottomed bottle, salt of wormwood (5.71mmol) is added under room temperature, after reactant at room temperature stirs 36 days, reaction solution water and saturated salt washing, anhydrous sodium sulfate drying, drains to obtain crude product.It is yellow oil (350mg, 1.118mmol, 1.95%yield) that column chromatography obtains compd A.
Spectral data:
1H NMR(500MHz,Acetone-d6)δ7.52(dd,J=8.0,1.5Hz,1H),7.48(dd,J=7.9,1.5Hz,1H),7.38(t,J=7.9Hz,1H),6.04(s,1H),4.29(ddd,J=10.2,8.9,5.4Hz,1H),3.99(ddd,J=8.9,2.2,1.2Hz,1H),3.64(s,3H),2.71–2.58(m,2H),2.01(s,3H)；
13C NMR(126MHz,Acetone)δ196.05,172.13,156.95,142.53,133.95,132.38,130.31,129.16,128.70,127.71,52.71,52.50,42.01,41.78,22.61；
MS(ESI):312.93(M+H)
Claims (6)
1. there is a synthetic method for the compound of following formula I structure, said method comprising the steps of: make 2,3 dichloro benzaldehyde and methyl acetoacetate reaction, form the compound with following formula I structure:
2. the method for claim 1, is characterized in that, described reaction is carried out in a solvent; Preferably, described solvent is organic solvent, water or its combination; Preferably, described organic solvent is selected from alcohol, ester, ether, ketone and combination thereof; Preferably, described organic solvent is selected from tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol, the trimethyl carbinol, sec-butyl alcohol, methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, acetone, butanone, acetonitrile, propionitrile and combination thereof; Preferably, described organic solvent is selected from acetone, the trimethyl carbinol or its combination; Preferably, described reaction is not carried out in a solvent.
3. the method for claim 1, is characterized in that, described reaction is carried out in the presence of a base; Preferably, described alkali is selected from organic bases, mineral alkali and combination thereof; Preferably, described organic bases is selected from amine, an alkali metal salt of alcohol, metal alkylide lithium compound, amido lithium compound and combination thereof; Preferably, described amine is selected from piperidines, triethylamine, DMA and combination thereof; Preferably, an alkali metal salt of described alcohol is selected from sodium methylate, potassium ethylate, potassium tert.-butoxide and combination thereof; Preferably, described metal alkylide lithium compound is selected from butyllithium, phenyl lithium and combination thereof; Preferably, described amido lithium compound is selected from lithium diisopropyl amido, hexamethyldisilazane lithium and combination thereof; Preferably, described mineral alkali is selected from salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide or its combination; Preferably, described alkali is potassium tert.-butoxide.
4. the method for claim 1, is characterized in that, temperature of reaction is negative 10 DEG C to 100 DEG C, preferred 0-90 DEG C, more preferably 10-60 DEG C, most preferably 20-30 DEG C.
5. the method for claim 1, is characterized in that, the mol ratio of described 2,3 dichloro benzaldehyde and methyl acetoacetate is 2:1-1:8, is preferably 1:1-1:5, is more preferably 1:1.5-1:3, most preferably is 1:1.8-1:2.5.
6. the method for claim 1, is characterized in that, the consumption of described alkali is the 1-50% of 2,3 dichloro benzaldehyde mole number, is preferably 5-30%, is more preferably 6-20%, most preferably is 8-15%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744258A (en) * | 2015-03-27 | 2015-07-01 | 上海馨平医药科技发展有限公司 | Clevidipine butyrate specific decarboxylation impurity and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101613280A (en) * | 2009-05-13 | 2009-12-30 | 合肥立方制药有限公司 | Felodipine synthetic intermediate 2, the preparation method of 3-dichlorin benzylidene methyl acetoacetate |
| WO2010014727A1 (en) * | 2008-08-01 | 2010-02-04 | The Medicines Company | Pharmaceutical compositions and methods for producing low impurity concentrations of the same |
| CN102432527A (en) * | 2011-11-04 | 2012-05-02 | 浙江九旭药业有限公司 | Method for preparing clevidipine butyrate |
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2014
- 2014-04-09 CN CN201410140148.5A patent/CN104974042A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010014727A1 (en) * | 2008-08-01 | 2010-02-04 | The Medicines Company | Pharmaceutical compositions and methods for producing low impurity concentrations of the same |
| CN101613280A (en) * | 2009-05-13 | 2009-12-30 | 合肥立方制药有限公司 | Felodipine synthetic intermediate 2, the preparation method of 3-dichlorin benzylidene methyl acetoacetate |
| CN102432527A (en) * | 2011-11-04 | 2012-05-02 | 浙江九旭药业有限公司 | Method for preparing clevidipine butyrate |
Non-Patent Citations (1)
| Title |
|---|
| DHEVALAPALLY B. RAMACHARY ET.: "Organocatalytic Cascade Reactions Based on Push-Pull Dienamine Platform: Synthesis of Highly Substituted Anilines", 《J. ORG. CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744258A (en) * | 2015-03-27 | 2015-07-01 | 上海馨平医药科技发展有限公司 | Clevidipine butyrate specific decarboxylation impurity and preparation method thereof |
| CN104744258B (en) * | 2015-03-27 | 2016-09-14 | 上海馨平医药科技发展有限公司 | A kind of butyrate clevidipine specific decarboxylation impurity and preparation method thereof |
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Application publication date: 20151014 |