CN106380405B - A kind of synthetic method of 2- (3- nitrobenzal) isopropyl acetoacetate - Google Patents
A kind of synthetic method of 2- (3- nitrobenzal) isopropyl acetoacetate Download PDFInfo
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- CN106380405B CN106380405B CN201610707888.1A CN201610707888A CN106380405B CN 106380405 B CN106380405 B CN 106380405B CN 201610707888 A CN201610707888 A CN 201610707888A CN 106380405 B CN106380405 B CN 106380405B
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- nitrobenzal
- isopropyl acetoacetate
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- thionyl chloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
Abstract
The invention discloses a kind of synthetic methods of 2- (3- nitrobenzal) isopropyl acetoacetate: solvent is put into reaction kettle, m-nitrobenzaldehyde is put under conditions of 10 ~ 40 DEG C, stirring and dissolving, put into isopropyl acetoacetate, it is sufficiently mixed, under conditions of 20 ~ 25 DEG C, thionyl chloride is added dropwise；Under conditions of 20 ~ 25 DEG C, the reaction was continued 1 ~ 10 hour, after reaction, reaction solution is centrifuged, disposing mother liquor, Washing of Filter Cake to neutrality, and drying obtains 2- (3- nitrobenzal) isopropyl acetoacetate；Present invention employs thionyl chlorides as catalyst, due to generating water in the synthetic reaction, water and thionyl chloride generate hydrochloric acid and sulfurous acid, two acid and can be catalyzed, for this reaction, catalytic performance is moderate, strong unlike the concentrated sulfuric acid, and catalytic performance is much stronger than acetic acid and piperidines again, production cost is low, strong operability, post-processing is simple and pollution level reduces, and is suitable for industrialized production.
Description
Technical field
The present invention relates to organic chemistry fileds, and in particular to a kind of conjunction of 2- (3- nitrobenzal) isopropyl acetoacetate
At method.
Background technique
Cardiovascular disease is a kind of disease for seriously endangering human health, Nimodipine as cardiovascular and cerebrovascular common medicine have with
Lower effect: (1) for the blood circulation of acute cerebrovascular disease convalescence improve.Brain after the subarachnoid hemorrhage of a variety of causes
Vasopasm and its caused ischemic neurologic deficits hypertension, migraine etc..(2) it is protected used also as ischaemic neuronal
With the treatment of vascular dementia.(3) also there is certain curative effect to sudden deafness.Due in Nimodipine intermediate 2- (3- nitro
Benzal) in isopropyl acetoacetate production, a large amount of spent acid are generated, during waste acid treatment, the direct very big cost of increase,
If processing is not in place, very big pollution is easily caused, in view of the situation, has carried out the research and development of method
The Chinese chemical name of compound is known as: 2- (3- nitrobenzal) isopropyl acetoacetate, molecule C14H15NO5
;CAS registration number: 39562-25-9, chemical structure are as follows:
, as Nimodipine intermediate, 2- (3- nitrobenzal) acetoacetate is different
Propyl ester preparation method is currently to be reacted using m-nitrobenzaldehyde and isopropyl acetoacetate as starting material by catalysis,
Main is the difference for selecting catalyst.
Middle figure classification number R972+.4 Document code A, article are numbered: 1001-8255(2001) 01-0008-02 is disclosed
The preparation method that 2- (3- nitrobenzal) acetoacetate methoxy acrylate is reported in document duplicates in target substance, uses
Acetic anhydride and the concentrated sulfuric acid are as catalyst, and in practical operation, post-processing is difficult, and target yield is low.
Middle figure classification number: O625.1 Document code: A article is numbered: 1001-8225(2002) 08-0374-01 is disclosed
The preparation method that 2- (3- nitrobenzal) ethyl acetoacetate is reported in document duplicates in target product, and this method uses
Sulfuric acid is as catalyst, and has that post-processing is difficult, and product yield is low, seriously polluted
The Chinese patent of application number 201110307671.9 discloses 2- (3- nitrobenzal) isopropyl acetoacetate system
Preparation Method, and using sulfuric acid as catalyst is only the dosage for optimizing sulfuric acid, reduces certain pollution, does not also have
It tackles the problem at its root, in addition the preparation method, increases the dosage of isopropyl acetoacetate, molar ratio is m-nitro
Two times of formaldehyde, considerably increase production cost.
The Chinese patent of application number 201110389598.4 uses acetic acid and piperidines as catalyst, it is necessary to increase temperature
It could react thorough, it is evident that the catalyst has the reacting catalytic performance certain limitation, and increasing temperature potential must largely increase
Add energy consumption, increase cost, moreover after temperature raising, also promotes the generation of side reaction.
In conclusion presence different degrees of in existing intermediate preparation process post-processes difficulty, it is seriously polluted, or
The defects of energy consumption is high, high production cost.
Summary of the invention
Aiming at the problems existing in the prior art, the present invention provides a kind of 2- (3- nitrobenzal) isopropyl acetoacetate
Synthetic method, post-processing is simple, at low cost.
In order to solve the above technical problems, the invention adopts the following technical scheme:
A kind of synthetic method of 2- (3- nitrobenzal) isopropyl acetoacetate, steps are as follows:
(1) solvent is put into reaction kettle, m-nitrobenzaldehyde is put under conditions of 10 ~ 40 DEG C, stirring and dissolving is thrown
Enter isopropyl acetoacetate, be sufficiently mixed, under conditions of 20 ~ 25 DEG C, thionyl chloride is added dropwise；
(2) after thionyl chloride is added dropwise, under conditions of 20 ~ 25 DEG C, the reaction was continued 1 ~ 10 hour, preferably 10 hours；
(3) after reaction, reaction solution is centrifuged, disposing mother liquor, Washing of Filter Cake to neutrality, drying obtains 2- (3- nitro
Benzal) isopropyl acetoacetate.
Preparation route is as follows: 。
The m-nitrobenzaldehyde, isopropyl acetoacetate, solvent and thionyl chloride mass ratio be 40:40 ~ 50:36:8
~15。
The m-nitrobenzaldehyde, isopropyl acetoacetate, solvent and thionyl chloride mass ratio be 40:43:36:10.
Solvent used is at least one of isopropanol, ethyl alcohol, methanol, propyl alcohol, butanol.
The time for adding of thionyl chloride is 1 ~ 3 hour in the step (1), preferably 2 hours.
Drying in the step (3) is dried 10 ~ 12 hours under conditions of 50 ~ 65 DEG C (preferably 60 DEG C).
Centrifuging temperature in the step (3) is 0 ~ 30 DEG C, preferably 20 DEG C.
Beneficial effects of the present invention: the reaction used catalyst of m-nitrobenzaldehyde and isopropyl acetoacetate mainly utilizes
Hydrogen ion in catalyst carries out catalytic action, and therefore, by largely testing, present invention employs thionyl chloride conducts
Catalyst, due to generating water in the synthetic reaction, water and thionyl chloride generate hydrochloric acid and sulfurous acid, two acid and can urge
Change, for this reaction, catalytic performance is moderate (basic normal-temperature reaction), strong unlike the concentrated sulfuric acid (necessary low-temp reaction), catalysis
Performance is much stronger than acetic acid and piperidines (must increase thermotonus) again, and production cost is low, strong operability, post-processing it is simple and
Pollution level reduces, and is suitable for industrialized production.
Specific embodiment
Combined with specific embodiments below, the present invention will be further described.It should be understood that following embodiment is merely to illustrate this
The person skilled in the art of the range of invention and is not intended to limit the present invention, the field can make one according to the content of foregoing invention
A little nonessential modifications and adaptations.
Embodiment 1
The synthetic method of 2- (3- nitrobenzal) isopropyl acetoacetate of the present embodiment, steps are as follows:
(1) 36 grams of isopropanol are put into the glass reaction bottle that capacity is 500 mL, stir lower investment m-nitrobenzaldehyde
40 grams, 43 grams of isopropyl acetoacetate are put into again, are stirred at room temperature until dissolution completely, can be heated slightly；Reaction solution cools to
20 ~ 25 DEG C, 10 grams of thionyl chlorides are slowly added dropwise, controls rate of addition, is added dropwise within 1.5 ~ 2 hours；
(2) 20 ~ 25 DEG C of temperature are controlled, is reacted 10 hours；
(3) after reaction, reaction solution is centrifuged under conditions of 20 DEG C and is separated by solid-liquid separation, disposing mother liquor, filter cake is used
Originally water washing is to neutrality；Filter cake is dried 10 ~ 12 hours between 50 ~ 65 DEG C, obtains 2- (3- nitrobenzal) acetoacetate
68 grams of isopropyl ester, yield actual production/theoretical yield * 100/100=68/73*100/100=93.1%, testing product fusing point 89.5
~90.2℃；It is detected with HPLC: column type number c-18 mobile phase methanol-acetonitrile-water (35:38:27, V:V:V) area normalization method
Product content 98.46% is obtained, map sees attached list 1.
Table 1 analyzes result table.
| Peak number | Peak name | Retention time | Peak height | Peak area | Content |
| 1 | Impurity | 1.332 | 86.869 | 810.550 | 0.0180 |
| 2 | Impurity | 2.490 | 1684.026 | 16647.051 | 0.3688 |
| 3 | Impurity | 2.940 | 1218.333 | 8028.200 | 0.1778 |
| 4 | Main peak | 4.182 | 616883.000 | 4444541.500 | 98.4620 |
| 5 | Impurity | 4.607 | 1157.438 | 7980.500 | 0.1768 |
| 6 | Impurity | 5.007 | 1351.750 | 9670.200 | 0.2142 |
| 7 | Impurity | 8.282 | 1768.402 | 20705.801 | 0.4587 |
| 8 | Impurity | 12.332 | 325.713 | 5584.300 | 0.1237 |
| It amounts to | 624475.531 | 4514068.102 | 100.000 |
Embodiment 2
A kind of synthetic method of 2- (3- nitrobenzal) isopropyl acetoacetate, steps are as follows:
(1) 36g isopropanol is put into reaction kettle, 40g m-nitrobenzaldehyde is put under conditions of 10 DEG C, stirred molten
Solution puts into 50g isopropyl acetoacetate, is sufficiently mixed, and under conditions of 20 DEG C, thionyl chloride 15g is added dropwise, controls thionyl chloride
Time for adding be 1 hour；
(2) after thionyl chloride is added dropwise, under conditions of 25 DEG C, the reaction was continued 1 hour；
(3) after reaction, reaction solution is centrifuged under conditions of 0 DEG C, disposing mother liquor, Washing of Filter Cake to neutrality, 50
It is dried under conditions of DEG C and obtains within 12 hours 2- (3- nitrobenzal) isopropyl acetoacetate.
Embodiment 3
A kind of synthetic method of 2- (3- nitrobenzal) isopropyl acetoacetate, steps are as follows:
(1) mixture of 36g ethyl alcohol and propyl alcohol is put into reaction kettle, nitro between 40g is put under conditions of 40 DEG C
Benzaldehyde, stirring and dissolving put into 40g isopropyl acetoacetate, are sufficiently mixed, and under conditions of 25 DEG C, thionyl chloride 8g is added dropwise,
The time for adding for controlling thionyl chloride is 2 hours；
(2) after thionyl chloride is added dropwise, under conditions of 20 DEG C, the reaction was continued 10 hours；
(3) after reaction, reaction solution is centrifuged under conditions of 30 DEG C, disposing mother liquor, Washing of Filter Cake to neutrality, 65
It is dried under conditions of DEG C and obtains within 10 hours 2- (3- nitrobenzal) isopropyl acetoacetate.
Embodiment 4
A kind of synthetic method of 2- (3- nitrobenzal) isopropyl acetoacetate, steps are as follows:
(1) 36g propyl alcohol is put into reaction kettle, 40g m-nitrobenzaldehyde is put under conditions of 30 DEG C, stirred molten
Solution puts into 48g isopropyl acetoacetate, is sufficiently mixed, and under conditions of 24 DEG C, thionyl chloride 12g is added dropwise, controls thionyl chloride
Time for adding be 1.5 hours；
(2) after thionyl chloride is added dropwise, under conditions of 24 DEG C, the reaction was continued 8 hours；
(3) after reaction, reaction solution is centrifuged under conditions of 20 DEG C, disposing mother liquor, Washing of Filter Cake to neutrality, 60
It is dried under conditions of DEG C and obtains within 11 hours 2- (3- nitrobenzal) isopropyl acetoacetate.
Embodiment 5
A kind of synthetic method of 2- (3- nitrobenzal) isopropyl acetoacetate, steps are as follows:
(1) 36g butanol is put into reaction kettle, 40g m-nitrobenzaldehyde is put under conditions of 20 DEG C, stirred molten
Solution puts into 45g isopropyl acetoacetate, is sufficiently mixed, and under conditions of 22 DEG C, thionyl chloride 10g is added dropwise, controls thionyl chloride
Time for adding be 2 hours；
(2) after thionyl chloride is added dropwise, under conditions of 22 DEG C, the reaction was continued 5 hours；
(3) after reaction, reaction solution is centrifuged under conditions of 10 DEG C, disposing mother liquor, Washing of Filter Cake to neutrality, 55
It is dried under conditions of DEG C and obtains within 12 hours 2- (3- nitrobenzal) isopropyl acetoacetate.
Embodiment 6
A kind of synthetic method of 2- (3- nitrobenzal) isopropyl acetoacetate, steps are as follows:
(1) mixture of 36g ethyl alcohol and butanol is put into reaction kettle, nitro between 40g is put under conditions of 25 DEG C
Benzaldehyde, stirring and dissolving put into 42g isopropyl acetoacetate, are sufficiently mixed, and under conditions of 23 DEG C, thionyl chloride is added dropwise
14g, the time for adding for controlling thionyl chloride is 2.5 hours；
(2) after thionyl chloride is added dropwise, under conditions of 24 DEG C, the reaction was continued 10 hours；
(3) after reaction, reaction solution is centrifuged under conditions of 25 DEG C, disposing mother liquor, Washing of Filter Cake to neutrality, 62
It is dried under conditions of DEG C and obtains within 10 hours 2- (3- nitrobenzal) isopropyl acetoacetate.
Basic principles and main features and advantages of the present invention of the invention have been shown and described above.The skill of the industry
Art personnel it should be appreciated that the present invention is not limited to the above embodiments, the above embodiments and description only describe
The principle of the present invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these
Changes and improvements all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and
Its equivalent thereof.
Claims (5)
1. a kind of synthetic method of 2- (3- nitrobenzal) isopropyl acetoacetate, it is characterised in that steps are as follows:
(1) solvent is put into reaction kettle, m-nitrobenzaldehyde is put under conditions of 10 ~ 40 DEG C, stirring and dissolving puts into second
Ethyl acetoacetic acid isopropyl ester, is sufficiently mixed, and under conditions of 20 ~ 25 DEG C, thionyl chloride is added dropwise；
(2) after thionyl chloride is added dropwise, under conditions of 20 ~ 25 DEG C, the reaction was continued 1 ~ 10 hour；
(3) after reaction, reaction solution is centrifuged, disposing mother liquor, Washing of Filter Cake to neutrality, drying obtains 2- (3- nitro benzal
Base) isopropyl acetoacetate；
Preparation route is as follows:
；
The m-nitrobenzaldehyde, isopropyl acetoacetate, solvent and thionyl chloride mass ratio be 40:43:36:10.
2. 2- (3- nitrobenzal) isopropyl acetoacetate synthetic method according to claim 1, it is characterised in that: institute
It is at least one of ethyl alcohol, methanol, propyl alcohol, butanol with solvent.
3. 2- (3- nitrobenzal) isopropyl acetoacetate synthetic method according to claim 1, it is characterised in that: institute
The time for adding for stating thionyl chloride in step (1) is 1 ~ 3 hour.
4. 2- (3- nitrobenzal) isopropyl acetoacetate synthetic method according to claim 1, it is characterised in that: institute
Stating the drying in step (3) is dried 10 ~ 12 hours under conditions of 50 ~ 65 DEG C.
5. 2- (3- nitrobenzal) isopropyl acetoacetate synthetic method according to claim 1, it is characterised in that: institute
Stating the centrifuging temperature in step (3) is 0 ~ 30 DEG C.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4044141A (en) * | 1975-02-26 | 1977-08-23 | Bayer Aktiengesellschaft | 1,4-Dihydropyridines |
| US4675329A (en) * | 1984-07-03 | 1987-06-23 | Bayer Aktiengesellschaft | Isopropyl 2-(3-trifluoromethylphenoxy)-ethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate as vaso-dilators |
| CN102503833A (en) * | 2011-10-12 | 2012-06-20 | 北京汉典中西药研究开发中心 | Preparation method of isopropyl 2-(3-nitrobenzal) acetoacetate |
-
2016
- 2016-08-24 CN CN201610707888.1A patent/CN106380405B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4044141A (en) * | 1975-02-26 | 1977-08-23 | Bayer Aktiengesellschaft | 1,4-Dihydropyridines |
| US4675329A (en) * | 1984-07-03 | 1987-06-23 | Bayer Aktiengesellschaft | Isopropyl 2-(3-trifluoromethylphenoxy)-ethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate as vaso-dilators |
| CN102503833A (en) * | 2011-10-12 | 2012-06-20 | 北京汉典中西药研究开发中心 | Preparation method of isopropyl 2-(3-nitrobenzal) acetoacetate |
Non-Patent Citations (2)
| Title |
|---|
| Efficient Condensation of Cycloketones and Acetone Using SOCl2/EtOH;Zhiguo Hu等;《Journal of the Korean Chemical Society》;20051231;第49卷(第5期);第1-3页 |
| 阿折地平的合成工艺改进;刘剑峰;《中国药物化学杂志》;20100630;第20卷(第3期);第192-194页 |
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