CN107151234A - A kind of preparation method of isradipine impurity I - Google Patents
A kind of preparation method of isradipine impurity I Download PDFInfo
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- CN107151234A CN107151234A CN201710337691.8A CN201710337691A CN107151234A CN 107151234 A CN107151234 A CN 107151234A CN 201710337691 A CN201710337691 A CN 201710337691A CN 107151234 A CN107151234 A CN 107151234A
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- isradipine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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Abstract
The invention discloses a kind of preparation method of isradipine impurity I, it is characterised in that：Using the base methyl acrylate of 2 acetyl group, 3 benzofuraxan 4 as raw material, occur deacetylation under alkaline organic conditions, be isolated to isradipine impurity I, reaction equation is as follows：
Description
Technical field
The invention belongs to technical field of organic synthesis, it is related to a kind of preparation method of isradipine impurity I.
Background technology
Isradipine is a kind of new dihydropyridine calcium channel blocker, is opened by Switzerland Shandeshi (Sandoz) company
Hair, ratifies listing in 2 months 1989 first by Britain's Ciba-Geigy (Ciba-Geigy) company.Isradipine by expanding blood vessel,
Peripheral vascular resistance is reduced, increases coronary blood flow, improves myocardial oxygen delivery function and reaches the purpose reduced blood pressure.Isradipine
With stronger vasorelaxation action, and acardia inhibitory action, hardly cause reflex tachycardia.Clinical and animal is real
Checking is bright, and the medical instrument has obvious antihypertensive effect and study of anti-atherogenic effect, by remaining or recovering left ventricle subendothelial
Blood flow, prevent ischemic injuries, improve the amount of exercise of angina pectoris and congestive heart failure patients, in treatment hypertension
While, there is protective effect to heart.Isradipine can increase the excretion of sodium ion and water, there is diuresis, and energy nephrectasia is defeated
Go out artery, reduce capillary of kidney pressure, have protective effect to kidney.It has been reported that researcher has found treatment hypertension agents, she draws ground
It is flat to delay, even stop the Parkinson's disease state of an illness.
Isradipine is benzofuraxan dihydropyridine compounds, and its synthesis is more complicated, and the purifying of particularly raw material is outstanding
For difficulty.United States Patent (USP) US7329756 is disclosed using Ben Bing oxadiazole -4- formaldehyde (compound 1), and methyl acetoacetate (is changed
Compound 3), and the 3- amino crotons isopropyl propionates (compound 4) that in the market is easy to buy are Material synthesis isradipine, are mesh
Before be relatively easy to the Industrialized synthesis method realized, specific synthetic route is as follows：
Patent US7329756 has carried out detailed elaboration to the synthetic method, passes through theory deduction and efficient liquid in research
The means such as phase chromatogram and mass spectrum are found, according to said synthesis route compound 1 and compound 3 using piperidines and glacial acetic acid as catalyst
A kind of impurity can be produced during progress dehydration (to be to distinguish with other impurity, the impurity is referred to as into isradipine impurity
I), the isradipine impurity I is generated by Ben Bing oxadiazole -4- formaldehyde (compound 1) and glacial acetic acid condensation dehydration, its
Structural formula is as follows：
Isradipine impurity I is produced during prepare compound 2, and may be remained in final products isradipine
Go, influence the quality of final products isradipine, also, separation is difficult.
Obviously, prepare the higher isradipine impurity I of purity and its feature and property are studied, this is for optimization
Or the synthetic route and process conditions of simplified isradipine are very necessary.Also, isradipine impurity I is used for isradipine work
The methodological study of skill development process, and the quality research as reference substance for isradipine key intermediate (compound 2)
It is all very necessary.
The content of the invention
It is an object of the invention to provide a kind of preparation method of isradipine impurity I, gained isradipine impurity I it is pure
Degree can be used for the quality research of isradipine key intermediate (compound 2) as reference substance, draw ground for her up to more than 98%
Flat process optimization provides theories integration.
In order to solve the above technical problems, technical scheme is as follows：
A kind of preparation method of isradipine impurity I, it is characterised in that：With 2- acetyl group -3- benzofuraxan -4- bases-the third
E pioic acid methyl ester is raw material, occurs deacetylation under alkaline organic conditions, is isolated to isradipine impurity I, reaction
Formula is as follows：
Further, the preparation method of the isradipine impurity I, specifically includes following steps：
S1,5-10g 2- acetyl group -3- benzofuraxans -4- bases-methyl acrylate is added to 120-250ml organic solvents
10-30ml aqueous slkalis are added after middle stirring, fully dissolving, temperature rising reflux reaction is carried out；
Reaction solution obtained by S2, the step that is concentrated under reduced pressure S1, removes low boiling component；
S3, with concentrated hydrochloric acid regulating step S2 concentrate to PH=3, add the extraction of 30-80ml ethyl acetate, organic layer point
From, 5-10g anhydrous sodium sulfate drying organic layers are added, are filtered, concentration filtrate；
S4, concentrate obtained by step S3 crossed into column separating purification；Wherein, isolate and purify eluent for ethyl acetate and just oneself
Alkane composition, and the volume proportion of ethyl acetate and n-hexane composition is 2:1；
The refined solution that S5, concentration step S4 are obtained, adds rising temperature for dissolving in organic solvent, rear decrease temperature crystalline, filtering, 60 DEG C
Dry isradipine impurity I.
Further, the organic solvent in the step S1 is dimethyl sulfoxide, DMF, N, N- dimethyl
Acetamide, tetrahydrofuran, absolute ethyl alcohol, absolute methanol, 1,4- dioxane or acetone.
Further, the organic solvent in the step S1 is methanol or acetone.
Further, the aqueous slkali in the step S1 is solution of potassium carbonate, sodium carbonate liquor, sodium bicarbonate solution, hydrogen
Sodium hydroxide solution or potassium hydroxide solution.
Further, the aqueous slkali in the step S1 is sodium hydroxide solution or potassium hydroxide solution.
Further, alkaline concentration is 5% by percentage to the quality in the step S1.
Further, the temperature rising reflux reaction time is 10-12h in the step S1.
Further, the organic solvent added in the step S5 be tetrahydrofuran, absolute ethyl alcohol, absolute methanol, Isosorbide-5-Nitrae-
Dioxane, acetone, ethyl acetate, isopropyl acetate or petroleum ether, addition are 5-10mL.
Further, the organic solvent added in the step S5 is acetone or ethyl acetate.
Further, crystallization temperature is 0-10 DEG C in the step S5.
The advantageous effects of the present invention：The preparation technology of isradipine impurity I of the present invention is simple, and raw material is easy to get, gained production
Product purity height (HPLC >=98%), can be directly used for the quality research of isradipine key intermediate (compound 2).
Embodiment
To further appreciate that the technical characteristic of the present invention, below in conjunction with specific embodiment, the present invention will be described in detail.
The invention provides a kind of preparation method of isradipine impurity I, it is characterised in that：With 2- acetyl group -3- benzos
Furazan -4- bases-methyl acrylate is raw material, occurs deacetylation under alkaline organic conditions, is isolated to Yi Ladi
Flat impurity I, reaction equation is as follows：
Further, the preparation method of the isradipine impurity I, specifically includes following steps：
S1,5-10g 2- acetyl group -3- benzofuraxans -4- bases-methyl acrylate is added to 120-250ml organic solvents
10-30ml aqueous slkalis are added after middle stirring, fully dissolving, temperature rising reflux reaction is carried out；
Reaction solution obtained by S2, the step that is concentrated under reduced pressure S1, removes low boiling component；
S3, with concentrated hydrochloric acid regulating step S2 concentrate to PH=3, add the extraction of 30-80ml ethyl acetate, organic layer point
From, 5-10g anhydrous sodium sulfate drying organic layers are added, are filtered, concentration filtrate；
S4, concentrate obtained by step S3 crossed into column separating purification；Wherein, isolate and purify eluent for ethyl acetate and just oneself
Alkane composition, and the volume proportion of ethyl acetate and n-hexane composition is 2:1；
The refined solution that S5, concentration step S4 are obtained, adds rising temperature for dissolving in organic solvent, rear decrease temperature crystalline, filtering, 60 DEG C
Dry isradipine impurity I.
Further, the organic solvent in the step S1 is dimethyl sulfoxide, DMF, N, N- dimethyl
Acetamide, tetrahydrofuran, absolute ethyl alcohol, absolute methanol, 1,4- dioxane or acetone.
Further, the organic solvent in the step S1 is methanol or acetone.
Further, the aqueous slkali in the step S1 is solution of potassium carbonate, sodium carbonate liquor, sodium bicarbonate solution, hydrogen
Sodium hydroxide solution or potassium hydroxide solution.
Further, the aqueous slkali in the step S1 is sodium hydroxide solution or potassium hydroxide solution.
Further, alkaline concentration is 5% by percentage to the quality in the step S1.
Further, the temperature rising reflux reaction time is 10-12h in the step S1.
Further, the organic solvent added in the step S5 be tetrahydrofuran, absolute ethyl alcohol, absolute methanol, Isosorbide-5-Nitrae-
Dioxane, acetone, ethyl acetate, isopropyl acetate or petroleum ether, addition are 5-10mL.
Further, the organic solvent added in the step S5 is acetone or ethyl acetate.
Further, crystallization temperature is 0-10 DEG C in the step S5.
Embodiment 1
10mL5% hydrogen is added after 5g compounds 2, fully 125mL absolute methanol stirring and dissolvings, dissolving are added into reaction bulb
Sodium hydroxide solution, temperature rising reflux reaction 10h, be concentrated under reduced pressure removing low boiling component；Concentrate is adjusted to PH=3 with concentrated hydrochloric acid,
The extraction of 30mL ethyl acetate is added, point liquid obtains organic layer, add 5g anhydrous sodium sulfate dryings, filtering concentrates filtrate；Concentrate
Crossing column separating purification, (eluent is ethyl acetate and n-hexane composition, ethyl acetate：N-hexane=2:1)；Concentrate and purify liquid,
5mL ethyl acetate rising temperature for dissolving is added, 5 DEG C of crystallizations are cooled to, filtering, 60 DEG C of dry impurity I.The purity 99.2% of impurity I, weight
2.28g is measured, yield is 59.1%.
Mass spectrometric data and the nuclear magnetic data detection of the present embodiment products obtained therefrom are as follows：ESI-MS：189.16[M-H]-；1H-
NMR:(δ-DMSO), and δ 7.076~7.102 (1H, d), δ 7.637~7.664 (1H, dd), δ 7.793~7.820 (1H, d), δ
7.898~7.909 (1H, d), δ 8.080~8.095 (1H, d), δ 12.806 (1H, s)；1D-NMR:(δ-DMSO), δ 7.057~
7.084 (1H, d), δ 7.608~7.634 (1H, dd), δ 7.761~7.788 (1H, d), δ 7.857~7.868 (1H, d), δ
8.044~8.059 (1H, d).
Embodiment 2
Added after 5g compounds 2,150mLN, fully dinethylformamide stirring and dissolving, dissolving are added into reaction bulb
15mL5% potassium hydroxide solutions, temperature rising reflux reaction 12h, be concentrated under reduced pressure removing low boiling component；Concentrate is adjusted with concentrated hydrochloric acid
To PH=3, the extraction of 30mL ethyl acetate is added, point liquid obtains organic layer, add 10g anhydrous sodium sulfate dryings, filtering, concentration filter
Liquid；Concentrate crosses column separating purification, and (eluent is ethyl acetate and n-hexane composition, ethyl acetate：N-hexane=2:1)；It is dense
Contracting refined solution, adds 5mL tetrahydrofuran rising temperature for dissolving, is cooled to 0 DEG C of crystallization, filtering, 60 DEG C of dry impurity I.The purity of impurity I
99%, weight 2.56g, yield is 66.3%.
Embodiment 3
8g compounds 2 are added into reaction bulb, 16mL5% hydrogen is added after the dissolving of 160mL absolute ethyl alcohol and stirrings, fully dissolving
Potassium oxide solution, temperature rising reflux reaction 10h, be concentrated under reduced pressure removing low boiling component；Concentrate is adjusted to PH=3 with concentrated hydrochloric acid,
The extraction of 55mL ethyl acetate is added, point liquid obtains organic layer, add 10g anhydrous sodium sulfate dryings, filtering concentrates filtrate；Concentration
Thing crosses column separating purification, and (eluent is ethyl acetate and n-hexane composition, ethyl acetate：N-hexane=2:1)；Concentrate and purify
Liquid, adds 10mL acetone rising temperature for dissolving, is cooled to 10 DEG C of crystallizations, filtering, 60 DEG C of dry impurity I.The purity 98.2% of impurity I,
Weight 3.92g, yield is 63.4%.
Embodiment 4
25mL5% is added after 10g compounds 2, fully 250mL tetrahydrofuran stirring and dissolvings, dissolving are added into reaction bulb
Sodium hydroxide solution, temperature rising reflux reaction 10h, be concentrated under reduced pressure removing low boiling component；Concentrate is adjusted to PH=with concentrated hydrochloric acid
3, the extraction of 60mL ethyl acetate is added, point liquid obtains organic layer, add 10g anhydrous sodium sulfate dryings, filtering concentrates filtrate；It is dense
Contracting thing crosses column separating purification, and (eluent is ethyl acetate and n-hexane composition, ethyl acetate：N-hexane=2:1)；Concentration is pure
Change liquid, add 10mL1,4- dioxane rising temperature for dissolving is cooled to 5 DEG C of crystallizations, filtering, 60 DEG C of dry impurity I.Impurity I is pure
Degree 99.1%, weight 4.55g, yield is 58.9%.
Embodiment 5
Added after 5g compounds 2, fully 125mL DMA stirring and dissolvings, dissolving are added into reaction bulb
12mL5% sodium hydroxide solutions, temperature rising reflux reaction 12h, be concentrated under reduced pressure removing low boiling component；Concentrate is adjusted with concentrated hydrochloric acid
To PH=3, the extraction of 30mL ethyl acetate is added, point liquid obtains organic layer, add 5g anhydrous sodium sulfate dryings, filtering, concentration filter
Liquid；Concentrate crosses column separating purification, and (eluent is ethyl acetate and n-hexane composition, ethyl acetate：N-hexane=2:1)；It is dense
Contracting refined solution, adds 6mL isopropyl acetate rising temperature for dissolving, is cooled to 5 DEG C of crystallizations, filtering, 60 DEG C of dry impurity I.Impurity I is pure
Degree 99.3%, weight 2.12g, yield is 54.9%.
Embodiment 6
30mL5% hydrogen-oxygens are added after 10g compounds 2, fully 250mL acetone stirring and dissolvings, dissolving are added into reaction bulb
Change sodium solution, temperature rising reflux reacts 10h, and be concentrated under reduced pressure removing low boiling component；Concentrate is adjusted to PH=3 with concentrated hydrochloric acid, plus
Enter the extraction of 80mL ethyl acetate, point liquid obtains organic layer, add 10g anhydrous sodium sulfate dryings, filtering concentrates filtrate；Concentrate
Crossing column separating purification, (eluent is ethyl acetate and n-hexane composition, ethyl acetate：N-hexane=2:1)；Concentrate and purify liquid,
10mL1 is added, 4- dioxane rising temperature for dissolving is cooled to 5 DEG C of crystallizations, filtering, 60 DEG C of dry impurity I.The purity of impurity I
99%, weight 4.63g, yield is 60.1%.
The preferred embodiments of the present invention are the foregoing is only, are not intended to limit the invention, for the skill of this area
For art personnel, within the spirit and principles of the invention, any modification, equivalent substitution and improvements made etc. all should be included
Within protection scope of the present invention.
Claims (10)
1. a kind of preparation method of isradipine impurity I, it is characterised in that：With 2- acetyl group -3- benzofuraxans -4- bases-propylene
Sour methyl esters is raw material, occurs deacetylation under alkaline organic conditions, is isolated to isradipine impurity I, reaction equation
It is as follows：
2. the preparation method of isradipine impurity I as claimed in claim 1, it is characterised in that：The system of the isradipine impurity I
Preparation Method, specifically includes following steps：
S1,5-10g 2- acetyl group -3- benzofuraxans -4- bases-methyl acrylate is added in 120-250ml organic solvents and stirred
Mix, fully add 10-30ml aqueous slkalis after dissolving, carry out temperature rising reflux reaction；
Reaction solution obtained by S2, the step that is concentrated under reduced pressure S1, removes low boiling component；
S3, with concentrated hydrochloric acid regulating step S2 concentrate to PH=3, add the extraction of 30-80ml ethyl acetate, organic layer separation,
5-10g anhydrous sodium sulfate drying organic layers are added, filtering concentrates filtrate；
S4, concentrate obtained by step S3 crossed into column separating purification；Wherein, eluent is isolated and purified for ethyl acetate and n-hexane group
Compound, and the volume proportion of ethyl acetate and n-hexane composition is 2:1；
The refined solution that S5, concentration step S4 are obtained, adds rising temperature for dissolving in organic solvent, rear decrease temperature crystalline, filtering, 60 DEG C of dryings
Obtain isradipine impurity I.
3. the preparation method of isradipine impurity I as claimed in claim 2, it is characterised in that：It is organic molten in the step S1
Agent be dimethyl sulfoxide, DMF, DMA, tetrahydrofuran, absolute ethyl alcohol, absolute methanol, 1,
4- dioxane or acetone.
4. the preparation method of isradipine impurity I as claimed in claim 2, it is characterised in that：Aqueous slkali in the step S1
For solution of potassium carbonate, sodium carbonate liquor, sodium bicarbonate solution, sodium hydroxide solution or potassium hydroxide solution.
5. the preparation method of isradipine impurity I as claimed in claim 2, it is characterised in that：Aqueous slkali in the step S1
For sodium hydroxide solution or potassium hydroxide solution.
6. the preparation method of isradipine impurity I as claimed in claim 2, it is characterised in that：Aqueous slkali is dense in the step S1
Degree is 5% by percentage to the quality.
7. the preparation method of isradipine impurity I as claimed in claim 2, it is characterised in that：Temperature rising reflux in the step S1
Reaction time is 10-12h.
8. a kind of preparation method of isradipine impurity I as claimed in claim 2, it is characterised in that：Add in the step S5
The organic solvent entered is tetrahydrofuran, absolute ethyl alcohol, absolute methanol, Isosorbide-5-Nitrae-dioxane, acetone, ethyl acetate, isopropyl acetate
Ester or petroleum ether, addition are 5-10mL.
9. a kind of preparation method of isradipine impurity I as claimed in claim 8, it is characterised in that：Add in the step S5
The organic solvent entered is acetone or ethyl acetate.
10. a kind of preparation method of isradipine impurity I as claimed in claim 2, it is characterised in that：Tied in the step S5
Brilliant temperature is 0-10 DEG C.
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| CN201710337691.8A CN107151234A (en) | 2017-05-15 | 2017-05-15 | A kind of preparation method of isradipine impurity I |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1918139A (en) * | 2004-02-25 | 2007-02-21 | 活跃生物技术有限公司 | Cinnamic amides, process for their preparation, and pharmaceutical compositions containing them |
| US7329756B2 (en) * | 2003-07-15 | 2008-02-12 | Shasun Chemicals And Drugs Limited | Process for the manufacture of Isradipine |
| CN104478745A (en) * | 2014-11-03 | 2015-04-01 | 陕西嘉禾植物化工有限责任公司 | Synthetic method for 4-amino-3-phenylbutyric acid hydrochloride |
-
2017
- 2017-05-15 CN CN201710337691.8A patent/CN107151234A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7329756B2 (en) * | 2003-07-15 | 2008-02-12 | Shasun Chemicals And Drugs Limited | Process for the manufacture of Isradipine |
| CN1918139A (en) * | 2004-02-25 | 2007-02-21 | 活跃生物技术有限公司 | Cinnamic amides, process for their preparation, and pharmaceutical compositions containing them |
| CN104478745A (en) * | 2014-11-03 | 2015-04-01 | 陕西嘉禾植物化工有限责任公司 | Synthetic method for 4-amino-3-phenylbutyric acid hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| ŠTEFAN MARCHALÍN等: ""Synthesis of 3-(5-Alkyl-4-acetyl(ethoxycarbonyl))-2-propenoates from Derivatives of 3-Phenoxy-2-furylmethylene"", 《COLLECT. CZECH. CHEM. COMMUN.》 * |
| 常雁红: "《有机化学》", 30 September 2016, 冶金工业出版社 * |
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Application publication date: 20170912 |