CN104710348A - 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
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- CN104710348A CN104710348A CN201510169133.6A CN201510169133A CN104710348A CN 104710348 A CN104710348 A CN 104710348A CN 201510169133 A CN201510169133 A CN 201510169133A CN 104710348 A CN104710348 A CN 104710348A
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- fluorophenyl
- dioxopiperidine
- dicyano
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- fluorobenzenecarboxaldehyde
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- 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
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- Hydrogenated Pyridines (AREA)
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 medicine intermediate 3,5-dicyano-4-to the preparation method of fluorophenyl-2,6-dioxopiperidine.
Background technology
3,5-dicyano-4-is to fluorophenyl-2,6-dioxopiperidine is important fine-chemical intermediate, it can obtain the intermediate 3-of thymoleptic paroxetine to fluorophenyl pentanedioic acid, as (Tetrahedron:Asymmetry 2012,23 such as (WO 2009/005647) and Chaubey such as Scott through hydrolysis, decarboxylation, 1206-1212), therefore 3,5-dicyano-4-are important organic synthesis targets to fluorophenyl-2,6-dioxopiperidine.
The synthesis of 3,5-dicyano-4-to fluorophenyl-2,6-dioxopiperidine is detected in the report of (Heterocycles 2009,78 (4), 977-982) such as Wu, p-Fluorobenzenecarboxaldehyde and two molecule ethyl cyanoacetates in anhydrous methanol, lithium nitride Li
3n is that ammonia source obtains target product through one pot reaction, yield 74%.Although reaction is at room temperature carried out, require anhydrous, airtight, the reaction times is longer, and yield is on the low side, and particularly lithium nitride and water vigorous reaction, can burn in atmosphere, and dangerous large, price is high to be not easy to obtain, and usage quantity is large, is difficult to realize industrialization.
Summary of the invention
Highly to be not easy to obtain to overcome lithium nitride price in existing technique, reaction conditions is comparatively harsh, yield is low, high in cost of production shortcoming, the invention provides low, easy-operating 3, the 5-dicyano-4-of a kind of cost to the preparation method of fluorophenyl-2,6-dioxopiperidine.
The present invention with secondary amine or tertiary amine for catalyzer, p-Fluorobenzenecarboxaldehyde, methyl cyanoacetate, Malonamide nitrile and catalyzer are dissolved in solvent, control not drip ammoniacal liquor higher than under the condition of 15 DEG C, stirring at room temperature reaction 7-10h, thin up, acidifying, filtration, washing, dry obtained 3,5-dicyano-4-is to fluorophenyl-2,6-dioxopiperidine.Product yield more than 83%, content in crude product more than 95%.
Wherein secondary amine catalyst comprises piperidines, morpholine, piperazine, tetramethyleneimine and di-n-propylamine, and wherein tertiary amine catalyst comprises N-methyl piperidine, N-methylmorpholine, 1-methylpiperazine, Isosorbide-5-Nitrae-lupetazin, N-crassitude and triethylamine.
Wherein solvent is methyl alcohol or ethanol or Virahol or water, or the mixture of water and any one alcohol aforementioned.
Wherein p-Fluorobenzenecarboxaldehyde: methyl cyanoacetate: between the preferred 1:1.1:1 to 1:1:1.2 of mol ratio of Malonamide nitrile.
One pot reaction of the present invention, comprises the Knoevenagel condensation of p-Fluorobenzenecarboxaldehyde and methyl cyanoacetate, the Michael addition of condensation product and Malonamide nitrile, the molecule inner ring condensation of ester and acid amides, and salify, the steps such as acidifying, reaction formula is as follows.
Methyl cyanoacetate of the present invention also can be ethyl cyanoacetate, cyanoacetic acid isopropyl ester etc., but the consumption of methyl cyanoacetate and price minimum, there is industrial production prospect.
Post-treating method of the present invention, just thin up, hcl acidifying, filtration, washing, drying after the completion of reaction, whole process is simple and convenient, consumption is economized during joint, conversion unit comprises reactor and pipeline etc. and directly carries out next batch reaction without the need to drying, to solve in prior art relevant device after every batch reaction and must carry out the step dehydrated, improve production efficiency.
The present invention proposes 3,5-dicyano-4-to the preparation method of fluorophenyl-2,6-dioxopiperidine, and its key character is: it is ammonia source that (1) ammoniacal liquor substitutes lithium nitride, cheap and easy to get, easy to use, and reaction system does not need strictly to control anhydrous, air tight condition, and security is good; (2) reaction times is short, product yield is high, three-waste pollution is few; (3) aftertreatment of reacting is simple and convenient, and reaction system is without the need to drying, and economize consumption during joint, production efficiency is high.
The present invention with p-Fluorobenzenecarboxaldehyde, methyl cyanoacetate, Malonamide nitrile, ammoniacal liquor for raw material, under secondary amine or tertiary amine catalytic, one pot reaction, acidifying, filtration etc. obtained 3 in the mixture of methyl alcohol or ethanol or Virahol or water or water and any one alcohol aforementioned, 5-dicyano-4-is to fluorophenyl-2,6-dioxopiperidine, there is the advantages such as raw material is cheap and easy to get, simple to operate, mild condition, yield are high, cost is low, energy-saving consumption, there is higher industrial production value.
Embodiment
Following examples are raw materials used, solvent etc. is technical grade product, without being further purified.Assay uses high performance liquid chromatography (HPLC) normalization method.Infrared, nuclear-magnetism and mass spectroscopy structural characterize and use infrared spectrometer, nuclear magnetic resonance spectrometer and mass spectrograph respectively.
embodiment 1
3,5-dicyano-4-is to the synthesis of fluorophenyl-2,6-dioxopiperidine
P-Fluorobenzenecarboxaldehyde 24.8g (0.20mol), Malonamide nitrile 20.2g (0.24mol), methyl cyanoacetate 19.8g (0.20mol), morpholine 1.0g and methyl alcohol 120mL is added in four-hole bottle, stir lower dropping ammoniacal liquor 170g (1.98mol), drip process control temp below 15 DEG C.Drip off stirring at room temperature reaction 7h, add water 120mL, hcl acidifying to pH less than 5.Filtration, washing, drying obtain beige to off-white color powdered product 3,5-dicyano-4-to fluorophenyl-2,6-dioxopiperidine 45.6g, yield 83.2%, content 96.8%.
embodiment 2
3,5-dicyano-4-is to the synthesis of fluorophenyl-2,6-dioxopiperidine
P-Fluorobenzenecarboxaldehyde 24.8g (0.20mol), Malonamide nitrile 17.6g (0.21mol), methyl cyanoacetate 19.8g (0.20mol), piperidines 0.85g, ethanol 80mL, water 20mL is added in four-hole bottle, stir lower dropping ammoniacal liquor 160g (1.65mol), drip process control temp below 10 DEG C.Drip off stirring at room temperature reaction 9h, add water 160mL, hcl acidifying to pH less than 5.Filtration, washing, drying obtain beige to off-white color powdered product 3,5-dicyano-4-to fluorophenyl-2,6-dioxopiperidine 47.5g, yield 86.7%, content 96.2%.
embodiment 3
3,5-dicyano-4-is to the synthesis of fluorophenyl-2,6-dioxopiperidine
P-Fluorobenzenecarboxaldehyde 24.8g (0.20mol), Malonamide nitrile 16.8g (0.20mol), methyl cyanoacetate 19.8g (0.20mol), triethylamine 1.2g and Virahol 100mL is added in four-hole bottle, stir lower dropping ammoniacal liquor 100g (1.65mol), drip process control temp below 10 DEG C.Drip off stirring at room temperature reaction 8h, add water 300mL, hcl acidifying to pH less than 5.Filtration, washing, drying obtain beige to off-white color powdered product 3,5-dicyano-4-to fluorophenyl-2,6-dioxopiperidine 46.9g, yield 85.5%, content 97.1%.
embodiment 4
3,5-dicyano-4-is to the synthesis of fluorophenyl-2,6-dioxopiperidine
P-Fluorobenzenecarboxaldehyde 24.8g (0.20mol), Malonamide nitrile 16.8g (0.20mol), methyl cyanoacetate 21.8g (0.22mol), di-n-propylamine 1.0g, ethanol 100mL is added in four-hole bottle, stir lower dropping ammoniacal liquor 90g (1.48mol), drip process control temp below 15 DEG C.Drip off stirring at room temperature reaction 10h, add water 280mL, hcl acidifying to pH less than 5.Filtration, washing, drying obtain beige to off-white color powdered product 3,5-dicyano-4-to fluorophenyl-2,6-dioxopiperidine 47.9g, yield 87.4%, content 97.5%.
embodiment 5
3,5-dicyano-4-is to the synthesis of fluorophenyl-2,6-dioxopiperidine
P-Fluorobenzenecarboxaldehyde 24.8g (0.20mol), Malonamide nitrile 17.6g (0.21mol), methyl cyanoacetate 19.8g (0.20mol), N-crassitude 0.9g, water 100mL is added in four-hole bottle, stir lower dropping ammoniacal liquor 120g (1.98mol), drip process control temp below 5 DEG C.Drip off stirring at room temperature reaction 8h, add water 260mL, hcl acidifying to pH less than 5.Filtration, washing, drying obtain beige to off-white color powdered product 3,5-dicyano-4-to fluorophenyl-2,6-dioxopiperidine 46.2g, yield 84.3%, content 95.4%.
embodiment 6
3,5-dicyano-4-is to the synthesis of fluorophenyl-2,6-dioxopiperidine
P-Fluorobenzenecarboxaldehyde 24.8g (0.20mol), Malonamide nitrile 16.8g (0.20mol), methyl cyanoacetate 21.8g (0.22mol), 1-methylpiperazine 1.0g, methyl alcohol 120mL, water 20mL is added in four-hole bottle, stir lower dropping ammoniacal liquor 110g (1.32mol), drip process control temp below 0 DEG C.Drip off stirring at room temperature reaction 7h, add water 230mL, hcl acidifying to pH less than 5.Filtration, washing, drying obtain beige to off-white color powdered product 3,5-dicyano-4-to fluorophenyl-2,6-dioxopiperidine 46.9g, yield 85.6%, content 96.6%.
The characterization data of product is as follows: IR(KBr)/cm
-1: 3315(NH), 2274(cyano group), 1726,1702(carbonyl).
1H NMR(DMSO-d
6,300MHz)/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 technician of the industry should be appreciated that, the present invention is not restricted to the described embodiments, describe in above-described embodiment and specification sheets just in order to principle of the present invention is described.Without departing from the spirit and scope of the present invention, the present invention also has various changes and modifications, and these all fall in the scope of protection of present invention.
Claims (5)
1. one kind 3,5-dicyano-4-is to fluorophenyl-2, the preparation method of 6-dioxopiperidine, it is characterized in that: with secondary amine or tertiary amine for catalyzer, p-Fluorobenzenecarboxaldehyde, methyl cyanoacetate, Malonamide nitrile and catalyzer are dissolved in solvent, control not drip ammoniacal liquor higher than under the condition of 15 DEG C, stirring at room temperature reaction 7-10h, thin up, acidifying, filtration, washing, dry obtained 3,5-dicyano-4-are to fluorophenyl-2,6-dioxopiperidine.
2. 3,5-dicyano-4-as claimed in claim 1 are to the preparation method of fluorophenyl-2,6-dioxopiperidine, it is characterized in that: described secondary amine catalyst is piperidines, morpholine, piperazine, tetramethyleneimine and di-n-propylamine.
3. as claimed in claim 13,5-dicyano-4-is to fluorophenyl-2, the preparation method of 6-dioxopiperidine, is characterized in that: described tertiary amine catalyst is N-methyl piperidine, N-methylmorpholine, 1-methylpiperazine, Isosorbide-5-Nitrae-lupetazin, N-crassitude and triethylamine.
4. 3,5-dicyano-4-as claimed in claim 1 are to the preparation method of fluorophenyl-2,6-dioxopiperidine, it is characterized in that: described solvent is methyl alcohol or ethanol or Virahol or water, or the mixture of water and any one alcohol aforementioned.
5. 3,5-dicyano-4-as claimed in claim 1 are to the preparation method of fluorophenyl-2,6-dioxopiperidine, it is characterized in that: described p-Fluorobenzenecarboxaldehyde: methyl cyanoacetate: the mol ratio of Malonamide nitrile is between 1:1.1:1 to 1:1:1.2.
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| CN201510169133.6A CN104710348B (en) | 2015-04-13 | 2015-04-13 | Preparation method of 3,5-dicyano-4-p-fluorophenyl-2,6-dioxopiperidine |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554010A (en) * | 2013-11-05 | 2014-02-05 | 衢州学院 | Synthetic process of 1-alkyl-4-p-fluorophenyl-2,6-piperadinedione-3-formic ester |
| CN104311536A (en) * | 2014-10-24 | 2015-01-28 | 上海应用技术学院 | Method for preparing lenalidomide |
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- 2015-04-13 CN CN201510169133.6A patent/CN104710348B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554010A (en) * | 2013-11-05 | 2014-02-05 | 衢州学院 | Synthetic process of 1-alkyl-4-p-fluorophenyl-2,6-piperadinedione-3-formic ester |
| CN104311536A (en) * | 2014-10-24 | 2015-01-28 | 上海应用技术学院 | Method for preparing lenalidomide |
Non-Patent Citations (2)
| Title |
|---|
| S. A. EL BATRAN，等: "Synthesis and evaluation of 2,6-piperidinedione derivatives as potentially novel compounds with analgesic and other CNS activities", 《INFLAMMOPHARMACOLOGY》 * |
| WU, LIQIANG，等，: "Synthesis of 4-substituted 3,5-dicyano-2,6-piperidinediones using lithium nitride as a convenient source of ammonia", 《HETEROCYCLES》 * |
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