CN107011285A - A kind of preparation method of isradipine impurity III - Google Patents
A kind of preparation method of isradipine impurity III Download PDFInfo
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- CN107011285A CN107011285A CN201710337693.7A CN201710337693A CN107011285A CN 107011285 A CN107011285 A CN 107011285A CN 201710337693 A CN201710337693 A CN 201710337693A CN 107011285 A CN107011285 A CN 107011285A
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- isradipine
- preparation
- impurity iii
- impurity
- iii
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- 0 CC(C)NCCC(*)=O Chemical compound CC(C)NCCC(*)=O 0.000 description 1
- ANUAJLDSIJZQSG-SVFXKOTRSA-N N=C(C(C=O)=CC=C1)/C1=N\O Chemical compound N=C(C(C=O)=CC=C1)/C1=N\O ANUAJLDSIJZQSG-SVFXKOTRSA-N 0.000 description 1
Classifications
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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
Abstract
The invention discloses a kind of preparation method of isradipine impurity III, it is characterised in that：Using benzene, simultaneously the formaldehyde of oxadiazole 4 and the base methyl acrylate of 2 acetyl group, 3 benzofuraxan 4, as raw material, occur condensation reaction under alkalescent, organic conditions, are isolated to isradipine impurity III, 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 III.
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, and compound 1 and compound 3 are using piperidines and glacial acetic acid as catalysis
Agent can produce a kind of impurity and (be to be distinguished with other impurity, the impurity is referred to as into isradipine impurity during being reacted
Ⅲ).Isradipine impurity III is by Ben Bing oxadiazole -4- formaldehyde (compound 1) and 2- acetyl group -3- benzofuraxan -4- bases-the third
E pioic acid methyl ester (compound 2) dehydration condensation is generated, and its structural formula is as follows：
Isradipine impurity III is produced during prepare compound 2, and may be remained in most product isradipine
Go, influence the quality of final products isradipine, also, separation is difficult.Obviously, the higher isradipine impurity of purity is prepared
III and its feature and property are studied, this is very necessary for the synthetic route and technique for optimizing or simplifying isradipine.
Also, isradipine impurity III is used for the methodological study of isradipine process exploitation process, and is used for her as reference substance
Draw the quality research of Horizon key intermediate (compound 2) 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 III, gained isradipine impurity III
Purity can be used for the quality research of isradipine key intermediate (compound 2) as reference substance, be drawn for her up to more than 98%
The process optimization of Horizon provides theories integration.
In order to solve the above technical problems, technical scheme is as follows：
A kind of preparation method of isradipine impurity III, it is characterised in that：With Ben Bing oxadiazole -4- formaldehyde and 2- acetyl
Base -3- benzofuraxans -4- bases-methyl acrylate is raw material, occurs condensation reaction under alkalescent, organic conditions, through separating
To isradipine impurity III, reaction equation is as follows：
Further, the preparation method of the isradipine impurity III, specifically includes following steps：
S1,5-10g 2- acetyl group -3- benzofuraxans -4- bases-methyl acrylate is added to 100-180ml organic solvents
5-7g Ben Bing oxadiazole -4- formaldehyde, 0.3-1.1g glacial acetic acid and 0.1-0.5g catalyst are added after middle stirring, fully dissolving, is entered
Row temperature rising reflux reacts；
Reaction solution obtained by S2, filtration step S1, obtains filtrate；
S3, the addition 10-30ml organic solvents in filtrate obtained by step S2, are heated to reflux 1-2h, cooling filtering；
S4, will step S3 filtering gained 60 DEG C of drying of filtrate after obtain isradipine impurity III.
Further, the organic solvent in the step S1 is dimethyl sulfoxide, DMF, N, N- dimethyl
Acetamide, tetrahydrofuran, isopropyl ether, absolute ethyl alcohol, absolute methanol, 1,4- dioxane or acetone.
Further, the organic solvent in the step S1 is isopropyl ether or tetrahydrofuran.
Further, the catalyst in the step S1 is in pyridine, triethylamine, piperidines, DIPEA
It is one or more of.
Further, the temperature rising reflux reaction time is 2-5h in the step S1.
Further, the organic solvent added in the step S3 is absolute methanol, absolute ethyl alcohol, ethyl acetate, dichloro
Methane or acetone.
The advantageous effects of the present invention：The preparation technology of isradipine impurity III of the present invention is simple, and route is short, without crossing post
Purify, and raw material is easy to get, products obtained therefrom purity height (HPLC >=98%), can be directly used for isradipine key intermediate (chemical combination
Thing 2) quality research.
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 III, it is characterised in that：With Ben Bing oxadiazole -4- first
Aldehyde and 2- acetyl group -3- benzofuraxans -4- bases-methyl acrylate are raw material, condensation occur under alkalescent, organic conditions anti-
Should, isradipine impurity III is isolated to, reaction equation is as follows：
Further, the preparation method of the isradipine impurity III, specifically includes following steps：
S1,5-10g 2- acetyl group -3- benzofuraxans -4- bases-methyl acrylate is added to 100-180ml organic solvents
Ben Bing oxadiazole -4- formaldehyde 5-7g, glacial acetic acid 0.3-1.1g and catalyst 0.1-0.5g are added after middle stirring, fully dissolving, is entered
Row temperature rising reflux reacts；
Reaction solution obtained by S2, filtration step S1, obtains filtrate；
S3, the addition 10-30ml organic solvents in filtrate obtained by step S2, are heated to reflux 1-2h, cooling filtering；
S4, will step S3 filtering gained 60 DEG C of drying of filtrate after obtain isradipine impurity III.
Further, the organic solvent in the step S1 is dimethyl sulfoxide, DMF, N, N- dimethyl
Acetamide, tetrahydrofuran, isopropyl ether, absolute ethyl alcohol, absolute methanol, 1,4- dioxane or acetone.
Further, the organic solvent in the step S1 is isopropyl ether or tetrahydrofuran.
Further, the catalyst in the step S1 is in pyridine, triethylamine, piperidines, DIPEA
It is one or more of.
Further, the temperature rising reflux reaction time is 2-5h in the step S1.
Further, the organic solvent added in the step S3 is absolute methanol, absolute ethyl alcohol, ethyl acetate, dichloro
Methane or acetone.
Embodiment 1
130mL isopropyl ethers are sequentially added into reaction bulb, 8.31g compounds 2 are sufficiently stirred for after dissolving adding 5g compounds
1,0.6g glacial acetic acid and 0.2g piperidines, temperature rising reflux reaction 4h；Filtering reacting liquid obtains filtrate, and 15mL is added into filtrate
Ethyl acetate, stirs and is heated to reflux 1h, and cooling filtering, 60 DEG C of dried screenings obtain isradipine impurity III, and purity is
99.5%, weight 6.75g.
Mass spectrometric data and the nuclear magnetic data detection of the present embodiment products obtained therefrom are as follows：ESI-MS：377.30[M+H]+；1H-
NMR:(δ-DMSO), δ 3.814 (3H, s), δ 7.515~7.542 (1H, d), δ 7.578~7.627 (2H, m), δ 7.831~
7.858 (1H, d), δ 7.905~7.916 (1H, d), δ 7.986~7.995 (1H, d), δ 8.041~8.079 (1H, m), δ
8.079~8.091 (1H, d), δ 8.229 (1H, s).
Embodiment 2
100mL tetrahydrofurans are sequentially added into reaction bulb, 5g compounds 2 are sufficiently stirred for after dissolving adding 5g compounds
1,0.4g glacial acetic acid and 0.1g piperidines, temperature rising reflux reaction 2h；Filtering reacting liquid obtains filtrate, and 10mL is added in filtrate
Acetone, stirs and is heated to reflux 2h, and cooling filtering, 60 DEG C of dried screenings obtain isradipine impurity III, and purity is 98.9%, weight
Measure 5.81g.
Embodiment 3
150mL isopropyl ethers are sequentially added into reaction bulb, 10g compounds 2 are sufficiently stirred for after dissolving adding 5g compounds 1,
1.0g glacial acetic acid and 0.5g pyridines, temperature rising reflux reaction 5h；Filtering reacting liquid obtains filtrate, and 30mL second is added in filtrate
Acetoacetic ester, stirs and is heated to reflux 2h, and cooling filtering, 60 DEG C of dried screenings obtain isradipine impurity III, and purity is 99.1%,
Weight 6.26g.
Embodiment 4
125mL absolute methanols are sequentially added into reaction bulb, 8g compounds 2 are sufficiently stirred for after dissolving adding 6g compounds
1,0.6g glacial acetic acid and 0.3g triethylamines, temperature rising reflux reaction 4h；Filtering reacting liquid obtains filtrate, is added in filtrate
18mL dichloromethane, stirs and is heated to reflux 2h, and cooling filtering, 60 DEG C of dried screenings obtain isradipine impurity III, and purity is
99.2%, weight 7.04g.
Embodiment 5
120mL DMAs are sequentially added into reaction bulb, 9.25g compounds 2 are sufficiently stirred for after dissolving
Add 7g compounds 1,0.5g glacial acetic acid and 0.4g piperidines, temperature rising reflux reaction 4h；Filtering reacting liquid obtains filtrate, in filtering
25mL ethyl acetate is added in thing, stirs and is heated to reflux 2h, cooling filtering, 60 DEG C of dried screenings obtain isradipine impurity
III, purity is 99.3%, weight 6.45g.
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 (7)
1. a kind of preparation method of isradipine impurity III, it is characterised in that：With Ben Bing oxadiazole -4- formaldehyde and 2- acetyl group -
3- benzofuraxans -4- bases-methyl acrylate is raw material, occurs condensation reaction under alkalescent, organic conditions, is isolated to her
Horizon impurity III is drawn, reaction equation is as follows：
2. the preparation method of isradipine impurity III as claimed in claim 1, it is characterised in that：The isradipine impurity III
Preparation method, specifically includes following steps：
S1, by 5-10g 2- acetyl group -3- benzofuraxans-methyl acrylate be added in 100-180ml organic solvents stir, fill
Divide and 5-7g Ben Bing oxadiazole -4- formaldehyde, 0.3-1.1g glacial acetic acid and 0.1-0.5g catalyst are added after dissolving, heat up back
Stream reaction；
Reaction solution obtained by S2, filtration step S1, obtains filtrate；
S3, the addition 10-30ml organic solvents in filtrate obtained by step S2, are heated to reflux 1-2h, cooling filtering；
S4, will step S3 filtering gained 60 DEG C of drying of filtrate after obtain isradipine impurity III.
3. the preparation method of isradipine impurity III as claimed in claim 2, it is characterised in that：It is organic molten in the step S1
Agent is dimethyl sulfoxide, DMF, DMA, tetrahydrofuran, isopropyl ether, absolute ethyl alcohol, anhydrous
Methanol, 1,4- dioxane or acetone.
4. the preparation method of isradipine impurity III as claimed in claim 2, it is characterised in that：It is organic molten in the step S1
Agent is isopropyl ether or tetrahydrofuran.
5. the preparation method of isradipine impurity III as claimed in claim 2, it is characterised in that：Catalyst in the step S1
For pyridine, triethylamine, piperidines, N, the one or more in N- diisopropylethylamine.
6. the preparation method of isradipine impurity III as claimed in claim 2, it is characterised in that：Temperature rising reflux in the step S1
Reaction time is 2-5h.
7. the preparation method of isradipine impurity III as claimed in claim 2, it is characterised in that：What is added in the step S3 has
Machine solvent is absolute methanol, absolute ethyl alcohol, ethyl acetate, dichloromethane or acetone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201710337693.7A CN107011285A (en) | 2017-05-15 | 2017-05-15 | A kind of preparation method of isradipine impurity III |
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| CN201710337693.7A CN107011285A (en) | 2017-05-15 | 2017-05-15 | A kind of preparation method of isradipine impurity III |
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| CN201710337693.7A Pending CN107011285A (en) | 2017-05-15 | 2017-05-15 | A kind of preparation method of isradipine impurity III |
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Citations (1)
| 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 |
-
2017
- 2017-05-15 CN CN201710337693.7A patent/CN107011285A/en active Pending
Patent Citations (1)
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 何勇 等: ""伊拉地平有关物质的合成"", 《中国医药工业杂志》 * |
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Address after: North District 401122 Chongqing City No. 101 garden Jinyu Road Applicant after: Chongqing kangkere Pharmaceutical Co., Ltd Address before: North District 401122 Chongqing City No. 101 garden Jinyu Road Applicant before: CHONGQING CONQUER PHARMACEUTICAL Co.,Ltd. |
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Application publication date: 20170804 |