CN107935912A - A kind of preparation process of Amlodipine intermediate - Google Patents
A kind of preparation process of Amlodipine intermediate Download PDFInfo
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- CN107935912A CN107935912A CN201711453154.6A CN201711453154A CN107935912A CN 107935912 A CN107935912 A CN 107935912A CN 201711453154 A CN201711453154 A CN 201711453154A CN 107935912 A CN107935912 A CN 107935912A
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- Prior art keywords
- safe
- efficient method
- compound
- rapid
- preparing amlodipine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The present invention relates to a kind of safe and efficient method for preparing Amlodipine intermediate：
Description
Technical field
The present invention relates to medicinal chemistry art, more particularly, to a kind of preparation process of Amlodipine intermediate.
Background technology
Amlodipine is cerebrocrast, (individually or with other drugs is merged available for treatment all kinds hypertension
Using) and angina pectoris, especially spontaneous angina pectoris (merging individually or with other drugs use).This product has kidney certain guarantor
Shield acts on.
Amlodipine feature is slower with acceptor association and dissociation speed, therefore holding time late occurs in drug effect
It is long.Nifedipine is more than to the selectively acting of vascular smooth muscle.It can increase cardiac output and coronary artery in myocardial ischemia person this product
Flow, increases myocardial oxygen delivery and lowers oxygen consumption, improve locomitivity.In addition, this product may activate ldl receptor, reduce fat and exist
Arterial wall is accumulated and suppresses collage synthesis, thus has anti arteriosclerosis effect.
In synthetic route according to the literature, following route is one of main industrial method.
The route technics comparing is simple, and multi-step, which need not purify, can be directly used for the next step, and overall yield is high, and
Special installation is not required.But step 2 uses substantial amounts of sodium hydride, has been short of in security.So find one effectively
Alternative, be of great value work.
Then and chloroacetyl acetacetic ester according to reaction mechanism, it is necessary first to take out the hydrogen of hydroxyl with highly basic, form sodium alkoxide,
Reaction, sloughs sodium chloride, obtains target product.Therefore, the method for document report is in accordance with this mechanism, uses a limited number of kind
Highly basic reacts.
Method 1
Method disclosed in Chinese patent CN106749187, in THF solution, using sodium hydride as highly basic, with N- ethoxys
Phthalimide and the reaction of 4- chloroacetyl acetacetic esters, can obtain target compound.
As above-mentioned statement, water is met due to sodium hydride and is caught fire, and releases a large amount of hydrogen in the reaction so that was produced
There are obvious security risk in journey.
Method 2
Method disclosed in US2012022251, using sodium tert-butoxide and THF systems, can also complete similar conversion.
The sodium tert-butoxide that this method uses is expensive, and meets water vigorous reaction, also there is the danger caught fire.
Method 3
Method disclosed in US4120956, using sodium ethoxide/THF systems, can also complete similar conversion.
But our repetition tests, it is as a result all undesirable.Some conditions are even without obtaining target product.
The shortcomings that in order to overcome above method, the present invention provide a kind of safe and efficient side for preparing Amlodipine intermediate
Method, the method raw material is cheap and easy to get, and production operation is simple, is suitable for industrialized production.
The content of the invention
The purpose of the present invention is overcome defect existing in the prior art, there is provided one kind is safely and efficiently prepared in Amlodipine
The method of mesosome, easily prepared, high income and implementation cost is relatively low.
The technical solution adopted by the present invention to solve the technical problems is：
A kind of safe and efficient method for preparing Amlodipine intermediate：
Concretely comprise the following steps：
Step 1, using 4- chloroacetyl acetacetic esters and paratoluenesulfonic acid sodium salt as raw material, in reaction dissolvent, heating, reacts
To compound 2；
Step 2, compound 2 and N- ethoxy phthalimides, addition alkali compounds is catalyst, while adds phase transfer
Catalyst, heating, obtains compound 1.
Preferably, in step 1, the molar ratio of 4- chloroacetyl acetacetic esters and paratoluenesulfonic acid sodium salt is 1:1-1:1.3.It is preferred that
, in step 1,4- chloroacetyl acetacetic esters and paratoluenesulfonic acid sodium salt rub
You are than being 1:1.16.
Preferably, in step 1, reaction temperature is 100-105 DEG C.
Preferably, in step 1, reaction dissolvent is selected any in absolute ethyl alcohol, isopropanol, dioxane, DMF or THF.
Preferably, in step 2, the molar ratio of compound 2 and N- ethoxy phthalimides is 1:1-1:1.3.
Preferably, in step 2, the molar ratio of compound 2 and N- ethoxy phthalimides is 1:1.2.
Preferably, in step 2, the alkali compounds is sodium hydroxide.
Preferably, in step 2, reaction dissolvent is selected any in toluene, dioxane, DMF or acetonitrile.
Preferably, in step 2, the phase transfer catalyst is selected from neopelex, PEG-400 or tetrabutyl bromine
Change any of ammonium.
Beneficial effect：The present invention solves defect present in background technology,
1st, the 4- hydroxyl ethyl acetoacetates that Amlodipine midbody compound 2 is protected using p-methyl benzenesulfonic acid, due to adopting
With paratoluenesulfonic acid sodium salt so that the condition of etherification step substantially reduces, while avoids using dangerous or expensive reagent so that raw
Production security greatly improves.
2nd, by contrast experiment, the yield for adding paratoluenesulfonic acid sodium salt is substantially greater than addition p-methyl benzenesulfonic acid/triethylamine
Reaction.
3rd, by contrast experiment, in step 2, the purity for adding phase transfer catalyst product greatly improves.
Embodiment
Presently preferred embodiments of the present invention is described in detail below, so that advantages and features of the invention can be more easy to by this
Field personnel understanding, so as to make a clearer definition of the protection scope of the present invention.
The embodiment of the present invention includes：
Embodiment 1：The preparation of compound 2
350ml DMF, 49.5g 4- chloroacetyl acetacetic esters and 67.9g paratoluenesulfonic acid sodium salts, heating are added in flask
To 105 DEG C of reaction 5.5h.Decompression evaporates about 2/3 solvent, obtains solidliquid mixture.It is cooled to room temperature, adds 500ml water stirring 1h.
Filter, washing, obtains Light brown solid.Step 2 reaction is directly used in without purifying.Yield：88.5%.
Embodiment 2：The preparation of compound 2
350ml DMF, 49.5g 4- chloroacetyl acetacetic esters and 67.9g paratoluenesulfonic acid sodium salts, heating are added in flask
To 105 DEG C of reaction 5.5h.It is cooled to room temperature, reactant is poured into 1000ml water, stir 1h, filter, washing, obtains light brown and consolidate
Body.Step 2 reaction is directly used in without purifying.Yield：86.1%.
Embodiment 3：
The contrast experiment of the preparation of compound 2, investigates and substitutes paratoluenesulfonic acid sodium salt to anti-with p-methyl benzenesulfonic acid and triethylamine
The influence answered.
350ml DMF, 49.5g 4- chloroacetyl acetacetic esters and 60.2g p-methyl benzenesulfonic acid are added in flask, is cooled to
5-10℃.35.4g triethylamines are slowly added dropwise, 1h is kept the temperature after adding, then heat to 105 DEG C of reaction 5.5h.Decompression evaporates about 2/3
Solvent, obtains solidliquid mixture.It is cooled to room temperature, adds 500ml water stirring 1h.There is grease to stick in bottle wall, outwell water layer, add
Enter 40ml ethyl acetate to be stirred overnight.Filter, washing, obtains Light brown solid.Yield：26.7%.
From yield, 4- chloroacetyl acetacetic esters add p-methyl benzenesulfonic acid, triethylamine prepare compound 2, and yield is significantly
Less than 4- chloroacetyl acetacetic esters and the yield of paratoluenesulfonic acid sodium salt reaction.
Embodiment 4：The preparation of compound 1
420ml dioxane, 33.0g compounds 2,25.6g N- ethoxys phthalimides and 55.0g are added in flask
Sodium hydroxide, adds 5.5g PEG-400.Back flow reaction 3h is warming up to, is cooled to room temperature, is filtered.Filtrate decompression is concentrated into closely
It is dry, add 300ml water stirring 1h, it is impossible to cure.Toluene extraction (50ml x 3) is added, combining methylbenzene, is washed, dry.Evaporate
Solvent, obtains light brown thick liquid.Yield：89.1%, purity：92.5% (presses high performance liquid chromatography areas of peak normalization method
Meter).
Embodiment 5：The preparation of compound 1
420ml dioxane, 33.0g compounds 2,25.6g N- ethoxys phthalimides and 55.0g are added in flask
Sodium hydroxide, adds 5.5g tetrabutylammonium bromide.Back flow reaction 3h is warming up to, is cooled to room temperature, is filtered.Filtrate decompression concentrates
To near dry, addition 300ml water stirrings 1h, it is impossible to cure.Toluene extraction (50ml x 3) is added, combining methylbenzene, is washed, dry.
Solvent is evaporated, obtains light brown thick liquid.Yield：82.7%, purity：83.9% (is normalized by high-efficient liquid phase color spectral peak area
Method meter).
Embodiment 6：
The contrast experiment of the preparation of compound 1, investigation are added without influence of the phase transfer catalyst to reaction.
420ml dioxane, 33.0g compounds 2,25.6g N- ethoxys phthalimides and 55.0g are added in flask
Sodium hydroxide.Back flow reaction 3h is warming up to, is cooled to room temperature, is filtered.Filtrate decompression is concentrated near dry, addition 300ml water stirrings
1h, it is impossible to cure.Toluene extraction (50ml x 3) is added, combining methylbenzene, washing, is repeated 3 times, dry.Solvent is evaporated, is obtained light brown
Color thick liquid.Yield：86.5%, purity：59.6% (based on high performance liquid chromatography areas of peak normalization method).
From the purity of reaction product, in the preparation of compound 1, it is added without phase transfer catalyst and is urged than adding phase transfer
Agent PEG-400, tetrabutylammonium bromide purity are low.
It should be appreciated that specific embodiment described above is only used for explaining the present invention, it is not intended to limit the present invention.By
Among the obvious changes or variations that the spirit of the present invention is extended out is still in protection scope of the present invention.
Claims (10)
- A kind of 1. safe and efficient method for preparing Amlodipine intermediate, it is characterised in that：Its reactions steps is：Concretely comprise the following steps：Step 1, using 4- chloroacetyl acetacetic esters and paratoluenesulfonic acid sodium salt as raw material, in reaction dissolvent, heating, reactionization Compound 2；Step 2, compound 2 and N- ethoxy phthalimides, addition alkali compounds is catalyst, while adds phase transfer catalysis (PTC) Agent, heating, obtains compound 1.
- A kind of 2. safe and efficient method for preparing Amlodipine intermediate according to claim 1, it is characterised in that：Step In rapid 1, the molar ratio of 4- chloroacetyl acetacetic esters and paratoluenesulfonic acid sodium salt is 1:1-1:1.3.
- A kind of 3. safe and efficient method for preparing Amlodipine intermediate according to claim 2, it is characterised in that：Step In rapid 1, the molar ratio of 4- chloroacetyl acetacetic esters and paratoluenesulfonic acid sodium salt is 1:1.16.
- A kind of 4. safe and efficient method for preparing Amlodipine intermediate according to claim 1, it is characterised in that：Step In rapid 1, reaction temperature is 100-105 DEG C.
- A kind of 5. safe and efficient method for preparing Amlodipine intermediate according to claim 1, it is characterised in that：Step In rapid 1, reaction dissolvent is selected any in absolute ethyl alcohol, isopropanol, dioxane, DMF or THF.
- A kind of 6. safe and efficient method for preparing Amlodipine intermediate according to claim 1, it is characterised in that：Step In rapid 2, the molar ratio of compound 2 and N- ethoxy phthalimides is 1:1-1:1.3.
- A kind of 7. safe and efficient method for preparing Amlodipine intermediate according to claim 6, it is characterised in that：Step In rapid 2, the molar ratio of compound 2 and N- ethoxy phthalimides is 1:1.2.
- A kind of 8. safe and efficient method for preparing Amlodipine intermediate according to claim 1, it is characterised in that：Step In rapid 2, the alkali compounds is sodium hydroxide.
- A kind of 9. safe and efficient method for preparing Amlodipine intermediate according to claim 1, it is characterised in that：Step In rapid 2, reaction dissolvent is selected any in toluene, dioxane, DMF or acetonitrile.
- A kind of 10. safe and efficient method for preparing Amlodipine intermediate according to claim 1, it is characterised in that： In step 2, the phase transfer catalyst is selected from any of neopelex, PEG-400 or tetrabutylammonium bromide.
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| CN201711453154.6A CN107935912B (en) | 2017-12-28 | 2017-12-28 | Preparation process of amlodipine intermediate |
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| CN201711453154.6A CN107935912B (en) | 2017-12-28 | 2017-12-28 | Preparation process of amlodipine intermediate |
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| CN107935912B CN107935912B (en) | 2022-08-19 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111303006A (en) * | 2020-04-03 | 2020-06-19 | 常州大学 | Preparation method of amlodipine key intermediate |
| CN111620806A (en) * | 2020-06-12 | 2020-09-04 | 史卫明 | Preparation method of amlodipine intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6057322A (en) * | 1995-01-30 | 2000-05-02 | Hoechst Aktiengesellschaft | Basically-substituted benzoylguanidines, a process for preparing them, their use as a medicament or diagnostic agent, and a medicament containing them |
| US20070260065A1 (en) * | 2006-05-03 | 2007-11-08 | Vijayabhaskar Bolugoddu | Process for preparing amlodipine |
| CN102010361A (en) * | 2010-12-28 | 2011-04-13 | 山东新华制药股份有限公司 | Method for preparing amlodipine intermediate |
| CN106749187A (en) * | 2016-12-29 | 2017-05-31 | 千辉药业（安徽）有限责任公司 | A kind of synthetic method of phthalyl Amlodipine |
-
2017
- 2017-12-28 CN CN201711453154.6A patent/CN107935912B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6057322A (en) * | 1995-01-30 | 2000-05-02 | Hoechst Aktiengesellschaft | Basically-substituted benzoylguanidines, a process for preparing them, their use as a medicament or diagnostic agent, and a medicament containing them |
| US20070260065A1 (en) * | 2006-05-03 | 2007-11-08 | Vijayabhaskar Bolugoddu | Process for preparing amlodipine |
| CN102010361A (en) * | 2010-12-28 | 2011-04-13 | 山东新华制药股份有限公司 | Method for preparing amlodipine intermediate |
| CN106749187A (en) * | 2016-12-29 | 2017-05-31 | 千辉药业（安徽）有限责任公司 | A kind of synthetic method of phthalyl Amlodipine |
Non-Patent Citations (2)
| Title |
|---|
| 俞陆军，等: "苯磺酸氨氯地平的合成", 《辽宁化工》 * |
| 濮荷妹，等: "氨氯地平中间体的合成", 《广东化工》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111303006A (en) * | 2020-04-03 | 2020-06-19 | 常州大学 | Preparation method of amlodipine key intermediate |
| CN111303006B (en) * | 2020-04-03 | 2021-10-12 | 常州大学 | Preparation method of amlodipine key intermediate |
| CN111620806A (en) * | 2020-06-12 | 2020-09-04 | 史卫明 | Preparation method of amlodipine intermediate |
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| CN107935912B (en) | 2022-08-19 |
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