CN104710348B - Preparation method of 3,5-dicyano-4-p-fluorophenyl-2,6-dioxopiperidine - Google Patents
Preparation method of 3,5-dicyano-4-p-fluorophenyl-2,6-dioxopiperidine Download PDFInfo
- Publication number
- CN104710348B CN104710348B CN201510169133.6A CN201510169133A CN104710348B CN 104710348 B CN104710348 B CN 104710348B CN 201510169133 A CN201510169133 A CN 201510169133A CN 104710348 B CN104710348 B CN 104710348B
- Authority
- CN
- China
- Prior art keywords
- fluorophenyl
- methyl
- dicyano
- water
- fluorobenzaldehyde
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention discloses a method for preparing 3,5-dicyano-4-p-fluorophenyl-2,6-dioxopiperidine by using p-fluorobenzaldehyde, methyl cyanoacetate, cyanoacetamide and ammonia water which serve as the raw materials through the steps of one-pot reaction, acidification and filtration, wherein 3,5-dicyano-4-p-fluorophenyl-2,6-dioxopiperidine prepared by the method is an intermediate of paroxetine which serves as an antidepressant drug. The method has the characteristics of cheap and easily-available in raw materials, simplicity in operation, mild conditions, high yield, low cost and low energy consumption, and has a good industrialization prospect.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate 3,5- dicyanos -4- p-fluorophenyl -2,6- piperidine diones.
Background technology
3,5- dicyano -4- p-fluorophenyl -2,6- piperidine diones are important fine-chemical intermediates, and its Jing is hydrolyzed, taken off
Carboxylic can be obtained the intermediate 3- p-fluorophenyl glutaric acids of antidepressants Paxil, such as Scott（WO 2009/005647）With
Chaubey etc.（Tetrahedron:Asymmetry 2012,23,1206- 1212）, therefore 3,5- dicyano -4- is to fluorobenzene
Base -2,6- piperidine diones are important organic synthesis targets.
The synthesis of 3,5- dicyano -4- p-fluorophenyl -2,6- piperidine diones is detected in Wu etc.（Heterocycles 2009,
78(4),977-982）Report, 4-Fluorobenzaldehyde and two molecule ethyl cyanoacetates in absolute methanol, lithium nitride Li3N is ammonia
Source Jing one pot reactions obtain target product, yield 74%.Although reaction is carried out at room temperature, anhydrous, closed, reaction is required
Time is longer, and yield is low, particularly lithium nitride and water vigorous reaction, can burn in atmosphere, and dangerous big, price height is difficult
, usage amount is big, it is difficult to realize industrialization.
The content of the invention
Lithium nitride price height is not easy to obtain in order to overcome existing process, reaction condition is more harsh, yield is low, cost is high etc.
Shortcoming, the invention provides a kind of low cost, easy-operating 3,5- dicyanos -4- p-fluorophenyl -2, the preparation of 6- piperidine diones
Method.
The present invention is molten by 4-Fluorobenzaldehyde, methyl cyanoacetate, cyanoacetamide and catalyst with secondary amine or tertiary amine as catalyst
In solvent, ammoniacal liquor is added dropwise under conditions of not higher than 15 DEG C of control, reaction 7-10h is stirred at room temperature, be diluted with water, be acidified, filtering,
Washing, dry prepared 3,5- dicyano -4- p-fluorophenyl -2,6- piperidine diones.Product yield more than 83%, content in crude product 95% with
On.
Wherein secondary amine catalyst includes piperidines, morpholine, piperazine, pyrrolidines and di-n-propylamine, and wherein tertiary amine catalyst includes
N- methyl piperidines, N-methylmorpholine, 1- methyl piperazines, 1,4- lupetazins, N- crassitudes and triethylamine.
Wherein solvent is methyl alcohol or ethanol or isopropanol or water, or the mixture of water and aforementioned any one alcohol.
Wherein 4-Fluorobenzaldehyde:Methyl cyanoacetate:The mol ratio of cyanoacetamide preferably 1:1.1:1 to 1:1:1.2 between.
The one pot reaction of the present invention, including 4-Fluorobenzaldehyde and the Knoevenagel condensations of methyl cyanoacetate, are condensed and produce
The molecule inner ring condensation of the Michael additions of thing and cyanoacetamide, ester and acid amides, into the steps such as salt, acidifying, the following institute of reaction equation
Show.
The methyl cyanoacetate of the present invention can also be ethyl cyanoacetate, cyanoacetic acid isopropyl ester etc., but methyl cyanoacetate disappears
Consumption and price are minimum, with industrial production prospect.
The present invention post-processing approach, be simply diluted with water after the completion of reaction, hydrochloric acid acidifying, filter, washing, be dried,
Whole process is simple and convenient, and consumption is saved during section, and it is anti-that consersion unit includes that reactor and pipeline etc. directly carry out next group without the need for drying
Should, the step of relevant device must be dehydrated after every batch reaction in prior art is solved, improve production efficiency.
The present invention proposes 3,5- dicyano -4- p-fluorophenyl -2, the preparation method of 6- piperidine diones, and its key character is：
（1）It is ammonia source that ammoniacal liquor substitutes lithium nitride, and cheap and easy to get, easy to use, reaction system is not required to strictly control anhydrous, airtight condition,
Security is good；（2）Reaction time is short, product yield high, three-waste pollution are few；（3）The post processing of reaction is simple and convenient, reaction system
Without the need for being dried, consumption is saved during section, production efficiency is high.
The present invention with 4-Fluorobenzaldehyde, methyl cyanoacetate, cyanoacetamide, ammoniacal liquor as raw material, under secondary amine or tertiary amine catalytic,
One pot reaction, acidifying, filtration etc. in the mixture of methyl alcohol or ethanol or isopropanol or water or water with aforementioned any one alcohol
3,5- dicyano -4- p-fluorophenyl -2,6- piperidine diones, with raw material is cheap and easy to get, simple to operate, mild condition, receipts is obtained
The advantages of rate height, low cost, energy-saving are consumed, with higher industrial production value.
Specific embodiment
Following examples are raw materials used, solvent etc. is technical grade product, without being further purified.Assay uses high
Effect liquid phase chromatogram（HPLC）Normalization method.Infrared, nuclear-magnetism and mass spectroscopy structural are characterized and use respectively infrared spectrometer, nuclear magnetic resoance spectrum
Instrument and mass spectrograph.
Embodiment 1
The synthesis of 3,5- dicyano -4- p-fluorophenyl -2,6- piperidine diones
4-Fluorobenzaldehyde 24.8g (0.20mol), cyanoacetamide 20.2g (0.24mol), cyanoacetic acid are added in four-hole bottle
Methyl esters 19.8g (0.20mol), morpholine 1.0g and methyl alcohol 120mL, stirring is lower to be added dropwise ammoniacal liquor 170g (1.98mol), is added dropwise program control
Temperature processed is below 15 DEG C.Drip off and reaction 7h is stirred at room temperature, addition water 120mL, hydrochloric acid are acidified to pH below 5.Filter, wash,
Ecru is dried to obtain to off-white color powdered product 3,5- dicyano -4- p-fluorophenyl -2,6- piperidine dione 45.6g, yield
83.2%, content 96.8%.
Embodiment 2
The synthesis of 3,5- dicyano -4- p-fluorophenyl -2,6- piperidine diones
4-Fluorobenzaldehyde 24.8g (0.20mol), cyanoacetamide 17.6g (0.21mol), cyanoacetic acid are added in four-hole bottle
Methyl esters 19.8g (0.20mol), piperidines 0.85g, ethanol 80mL, water 20mL, stirring is lower to be added dropwise ammoniacal liquor 160g (1.65mol), is added dropwise
Process control temp is below 10 DEG C.Drip off and reaction 9h is stirred at room temperature, addition water 160mL, hydrochloric acid are acidified to pH below 5.Cross
Filter, wash, being dried to obtain ecru to off-white color powdered product 3,5- dicyano -4- p-fluorophenyl -2,6- piperidine diones
47.5g, yield 86.7%, content 96.2%.
Embodiment 3
The synthesis of 3,5- dicyano -4- p-fluorophenyl -2,6- piperidine diones
4-Fluorobenzaldehyde 24.8g (0.20mol), cyanoacetamide 16.8g (0.20mol), cyanoacetic acid are added in four-hole bottle
Methyl esters 19.8g (0.20mol), triethylamine 1.2g and isopropanol 100mL, stirring is lower to be added dropwise ammoniacal liquor 100g (1.65mol), is added dropwise
Process control temperature is below 10 DEG C.Drip off and reaction 8h is stirred at room temperature, addition water 300mL, hydrochloric acid are acidified to pH below 5.Filter,
Wash, be dried to obtain ecru to off-white color powdered product 3,5- dicyano -4- p-fluorophenyl -2,6- piperidine dione 46.9g, receive
Rate 85.5%, content 97.1%.
Embodiment 4
The synthesis of 3,5- dicyano -4- p-fluorophenyl -2,6- piperidine diones
4-Fluorobenzaldehyde 24.8g (0.20mol), cyanoacetamide 16.8g (0.20mol), cyanoacetic acid are added in four-hole bottle
Methyl esters 21.8g (0.22mol), di-n-propylamine 1.0g, ethanol 100mL, stirring is lower to be added dropwise ammoniacal liquor 90g (1.48mol), and process is added dropwise
Control temperature is below 15 DEG C.Drip off and reaction 10h is stirred at room temperature, addition water 280mL, hydrochloric acid are acidified to pH below 5.Filtration, water
Wash, be dried to obtain ecru to off-white color powdered product 3,5- dicyano -4- p-fluorophenyl -2,6- piperidine dione 47.9g, yield
87.4%, content 97.5%.
Embodiment 5
The synthesis of 3,5- dicyano -4- p-fluorophenyl -2,6- piperidine diones
4-Fluorobenzaldehyde 24.8g (0.20mol), cyanoacetamide 17.6g (0.21mol), cyanoacetic acid are added in four-hole bottle
Methyl esters 19.8g (0.20mol), N- crassitude 0.9g, water 100mL, stirring is lower to be added dropwise ammoniacal liquor 120g (1.98mol), is added dropwise
Process control temp is below 5 DEG C.Drip off and reaction 8h is stirred at room temperature, addition water 260mL, hydrochloric acid are acidified to pH below 5.Filter,
Wash, be dried to obtain ecru to off-white color powdered product 3,5- dicyano -4- p-fluorophenyl -2,6- piperidine dione 46.2g, receive
Rate 84.3%, content 95.4%.
Embodiment 6
The synthesis of 3,5- dicyano -4- p-fluorophenyl -2,6- piperidine diones
4-Fluorobenzaldehyde 24.8g (0.20mol), cyanoacetamide 16.8g (0.20mol), cyanoacetic acid are added in four-hole bottle
Methyl esters 21.8g (0.22mol), 1- methyl piperazine 1.0g, methyl alcohol 120mL, water 20mL, stirring is lower to be added dropwise ammoniacal liquor 110g
(1.32mol), dropwise addition process control temp is below 0 DEG C.Drip off and reaction 7h is stirred at room temperature, add water 230mL, hydrochloric acid to be acidified to
Below pH 5.Filter, wash, being dried to obtain ecru to off-white color powdered product 3,5- dicyano -4- p-fluorophenyl -2,6- piperazines
Pyridine diketone 46.9g, yield 85.6%, content 96.6%.
The characterize data of product is as follows：IR（KBr）/cm-1：3315（NH）, 2274（Cyano group）,1726,1702（Carbonyl）.1H
NMR(DMSO-d6,300MHz)/ppm:12.08(s,1H,NH),7.20-6.92(m,4H, ArH),4.73-4.69(m,2H,
CH),4.34-4.28(m,1H,CH).MS（m/z）：258 [M+H]+。
The industry it is to be understood by the skilled artisans that the present invention is not restricted to the described embodiments, above-described embodiment and explanation
It is described in book simply to illustrate that the principle of the present invention.Without departing from the spirit and scope of the present invention, the present invention goes back
Various changes and modifications are had, these are both fallen within the scope of protection of present invention.
Claims (1)
1. one kind 3,5- dicyano -4- p-fluorophenyl -2, the preparation method of 6- piperidine diones, it is characterised in that：With secondary amine or uncle
Amine is catalyst, and 4-Fluorobenzaldehyde, methyl cyanoacetate, cyanoacetamide and catalyst are dissolved in solvent, not higher than 15 DEG C of control
Under conditions of ammoniacal liquor is added dropwise, reaction 7-10h is stirred at room temperature, be diluted with water, be acidified, filtering, washing, being dried prepared 3,5- dicyan
Base -4- p-fluorophenyl -2,6- piperidine diones；
The secondary amine catalyst is piperidines, morpholine, piperazine, pyrrolidines and di-n-propylamine one kind therein；
The tertiary amine catalyst is N- methyl piperidines, N-methylmorpholine, 1- methyl piperazines, 1,4- lupetazins, N- methyl pyrroles
Cough up alkane and triethylamine one kind therein；
The solvent is methyl alcohol or ethanol or isopropanol or water, or the mixture of water and aforementioned any one alcohol；
The 4-Fluorobenzaldehyde of methods described：Methyl cyanoacetate：The mol ratio of cyanoacetamide is 1:1.1:1 to 1:1:1.2 between.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510169133.6A CN104710348B (en) | 2015-04-13 | 2015-04-13 | Preparation method of 3,5-dicyano-4-p-fluorophenyl-2,6-dioxopiperidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510169133.6A CN104710348B (en) | 2015-04-13 | 2015-04-13 | Preparation method of 3,5-dicyano-4-p-fluorophenyl-2,6-dioxopiperidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104710348A CN104710348A (en) | 2015-06-17 |
| CN104710348B true CN104710348B (en) | 2017-04-26 |
Family
ID=53410138
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510169133.6A Expired - Fee Related CN104710348B (en) | 2015-04-13 | 2015-04-13 | Preparation method of 3,5-dicyano-4-p-fluorophenyl-2,6-dioxopiperidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104710348B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554010B (en) * | 2013-11-05 | 2015-11-04 | 衢州学院 | 1-alkyl-4-is to fluorophenyl-2,6-dioxopiperidine-3-manthanoate synthesis technique |
| CN104311536A (en) * | 2014-10-24 | 2015-01-28 | 上海应用技术学院 | Method for preparing lenalidomide |
-
2015
- 2015-04-13 CN CN201510169133.6A patent/CN104710348B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN104710348A (en) | 2015-06-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Shaabani et al. | Cellulose sulfuric acid as a bio-supported and recyclable solid acid catalyst for the one-pot three-component synthesis of α-amino nitriles | |
| Augustine et al. | An efficient one-pot synthesis of coumarins mediated by propylphosphonic anhydride (T3P) via the Perkin condensation | |
| Rasheed et al. | Sulphuric acid immobilized on silica gel (H 2 SO 4–SiO 2) as an eco-friendly catalyst for transamidation | |
| CN108424388B (en) | Preparation method of medicine for treating chronic anemia | |
| Amore et al. | Fast, easy, solvent-free, microwave-promoted Michael addition of anilines to α, β-unsaturated alkenes: synthesis of N-aryl functionalized β-amino esters and acids | |
| Mansoor et al. | ZrOCl2· 8H2O: an efficient and recyclable catalyst for the three-component synthesis of amidoalkyl naphthols under solvent-free conditions | |
| Ghosh et al. | Synthesis of functionalized benzimidazoles and quinoxalines catalyzed by sodium hexafluorophosphate bound Amberlite resin in aqueous medium | |
| KR101472686B1 (en) | Method for preparation of benzimidazole derivatives | |
| Hamstra et al. | Poly (methylhydrosiloxane) as a green reducing agent in organophosphorus-catalysed amide bond formation | |
| An et al. | H8-BINOL chiral imidodiphosphoric acids catalyzed cyclization reactions of β, γ-unsaturated α-ketoesters, arylamines and 1, 3-dicarbonyl compounds: enantioselective synthesis of 1, 4-dihydropyridines | |
| CN105037381A (en) | Green catalytic preparation method of pyrano[4,3-b]pyran derivative | |
| Zhang et al. | Iron-catalyzed carbonylative cyclization of γ, δ-unsaturated aromatic oxime esters with amines | |
| Wagh et al. | Metal-free N-iodosuccinimide-catalyzed mild oxidative C–H bond amination of benzoxazoles | |
| Ge et al. | Synthesis of novel carbohydrate-based valine-derived formamide organocatalysts by CuAAC click chemistry and their application in asymmetric reduction of imines with trichlorosilane | |
| Wang et al. | nBu4NI-catalyzed oxidative amidation of aldehydes with tertiary amines | |
| Bhattacharjee et al. | One-pot three component synthesis of 3, 5-disubstituted 2, 6-dicyanoaniline derivatives using 4-dimethylaminopyridine (DMAP) as a catalyst | |
| CN103420860A (en) | Method for compounding amino-substituted arylate compound | |
| Liu et al. | A simple and novel amide ligand based on quinoline derivative used for palladium-catalyzed Suzuki coupling reaction | |
| Song et al. | Synthesis of chiral sultams with two adjacent stereocenters via palladium-catalyzed dynamic kinetic resolution | |
| CN104710348B (en) | Preparation method of 3,5-dicyano-4-p-fluorophenyl-2,6-dioxopiperidine | |
| CN103664631B (en) | Preparation method of naftifine hydrochloride | |
| CN106748966A (en) | A kind of synthetic method of Ramipril key intermediate | |
| Du et al. | A convenient synthesis of polysubstituted 2-amino-4, 5-dihydrofuran-3-nitriles from benzoins or benzaldehydes | |
| CN107868033B (en) | Preparation method of phenylalanine compound | |
| Li et al. | A facile method for synthesis of polysubstituted naphthalene derivatives through pyrrolidine catalyzed domino reaction |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170426 Termination date: 20200413 |