CN109988092B - Preparation method of nefiracetam for treating Alzheimer disease - Google Patents
Preparation method of nefiracetam for treating Alzheimer disease Download PDFInfo
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- CN109988092B CN109988092B CN201910204417.2A CN201910204417A CN109988092B CN 109988092 B CN109988092 B CN 109988092B CN 201910204417 A CN201910204417 A CN 201910204417A CN 109988092 B CN109988092 B CN 109988092B
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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Abstract
The invention belongs to the field of western medicine synthesis, and particularly discloses a preparation method of a medicine nefiracetam for treating Alzheimer disease. The preparation method increases the reaction activity, improves the reaction rate, reduces the occurrence of side reactions, obtains the product with high yield and high purity, reduces the production cost and is beneficial to industrial production by activating the carboxyl in the 2-oxo-pyrrolidine acetic acid by the N' N-dicarbonyl imidazole (CDI).
Description
Technical Field
The application relates to a preparation method of a medicine nefiracetam for treating Alzheimer disease, belonging to the field of western medicine synthesis.
Background
With the aging of the world population, the quality of life of the elderly becomes a problem of increasing concern. Senile dementia is a major factor that causes the quality of life of the elderly to decline. It is a progressive degenerative disease of the nervous system with occult onset. Clinically, the overall dementia such as dysmnesia, aphasia, disuse, agnosia, impairment of visual spatial skills, dysfunction in execution, and personality and behavior changes are characterized, and the etiology is unknown. It can be classified into Alzheimer's Disease (AD), Vascular Dementia (VD), dementia with lewy bodies, dementia with parkinson's disease, pick's disease, motor nerve disease, etc., with AD being the most common. Medical studies have found that AD is characterized by a pathological hallmark: the degeneration of cholinergic neurons causes irreversible damage to neurons, deposition of beta-amyloid, microglial cell proliferation, neurofibrillary tangles, and hindered ability of cell membranes to pump calcium ions. However, it is also known that genetic factors, environmental factors, psychological factors and physiological factors can all cause AD, the causes and pathogenesis of AD are very complex and not clear up to now, and the occurrence of AD is hidden, so that there is no practical and reliable treatment means so far, and the clinical application mainly includes drug control.
Nefiracetam (Nefiracetam), chemical name N- (2, 6-dimethylphenyl) -2-oxo-1-pyrrolidineacetamide, as white crystals, was developed by japan first pharmaceutical company. The medicine can enhance cognitive ability and prevent learning and memory damage through the effect on cerebral cortex, has the functions of improving brain energy metabolism and nerve transmission, and has good clinical treatment value on AD and cerebrovascular sequelae.
The chemical structural formula of nefiracetam is shown as follows:
many documents research on the synthesis of nefiracetam, and two main ways of synthesizing nefiracetam are reported in the documents. One is pyrrolidone acetic acid method, which is carried out by condensation reaction of pyrrolidone acetic acid and 2, 6-dimethylaniline under dehydration action of N, N-dicyclohexyl carbonyl Diimine (DCC). However, dehydrating agents DCC are expensive and excess DCC and dicyclohexylurea derived therefrom are difficult to remove, resulting in low final yields and high impurities. Secondly, chloroacetyl chloride reacts with 2, 6-dimethylaniline to generate N, (2, 6-dimethylphenyl) -alpha-chloroacetamide, and then reacts with alpha-pyrrolidone under the action of strong alkali to generate nefiracetam. However, the process of the route is long, strong alkali is needed in the reaction, the requirement on equipment is high, and the total yield is low.
In order to solve the technical problems, the invention provides a preparation method of nefiracetam with high yield and high purity, which increases the reaction activity, improves the reaction rate and reduces the occurrence of side reactions by activating carboxyl in 2-oxopyrrolidine acetic acid by N' N-dicarbonyl imidazole (CDI), and the obtained product has high yield and high purity.
Disclosure of Invention
The invention aims to solve the technical problems that in the prior art, the nefiracetam reaction route is long, part of reaction conditions are harsh, the raw materials are expensive, the yield is low, the product purity is not high, and the like.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
the preparation method of nefiracetam comprises the following steps:
the method specifically comprises the following steps:
1) reacting 2-oxopyrrolidineacetic acid with N' N-dicarbonyl imidazole (CDI) in an organic solvent in the presence of a base to obtain a solution containing an intermediate compound;
2) directly adding 2, 6-dimethylaniline into the solution, and reacting to obtain the nefiracetam.
Wherein the organic solvent is selected from dichloromethane, tetrahydrofuran, DMF, dioxane, chloroform, and dichloroethane; the base is selected from triethylamine, pyridine, picoline, DBU, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; the base is used in an amount of 1 to 3 equivalents based on 2-oxopyrrolidineacetic acid.
Wherein the molar ratio of the 2-oxopyrrolidineacetic acid to the N' -dicarbonyl imidazole (CDI) to the 2, 6-dimethylaniline is 1:1-2: 1-2.
Wherein the reaction temperature is 20-50 ℃.
Wherein, TLC monitors the reaction process, after the reaction is finished, water is added for extraction, organic phase saturated sodium chloride is washed, dried, decompressed and concentrated, and the nefiracetam product is obtained after column chromatography and vacuum drying.
Or, monitoring the reaction process by TLC, adding water for extraction after the reaction is finished, washing the organic phase with saturated sodium chloride, drying, concentrating under reduced pressure, dissolving in ethanol by heating, cooling for crystallization, and drying in vacuum to obtain the nefiracetam product.
The invention has the beneficial effects that:
the invention provides a synthetic route of nefiracetam, which has the advantages of short reaction route, cheap and easily-obtained raw materials, easy operation of the reaction process, high yield of each step, total reaction yield of more than 97 percent, product purity of more than 99.8 percent, stronger reaction selectivity, reduction of byproducts, high purity of the obtained product, reduction of production cost and contribution to industrial production.
Drawings
Figure 1 is a synthetic route for nefiracetam.
Detailed Description
The invention discloses a preparation method of nefiracetam, and a person skilled in the art can appropriately improve process parameters by referring to the content. It is expressly intended that all such alterations and modifications which are obvious to those skilled in the art are deemed to be incorporated herein by reference, and that the techniques of the invention may be practiced and applied by those skilled in the art without departing from the spirit, scope and range of equivalents of the invention.
In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings that are commonly understood by those skilled in the art.
In order to make those skilled in the art better understand the technical solution of the present invention, the following detailed description of the present invention is provided with reference to specific embodiments.
Example 1:
in 250mL of tetrahydrofuran, 14.3 g (about 0.1mol) of 2-oxopyrrolidineacetic acid, 17.7 g (about 0.11mol) of CDI and 20.2 g (about 0.2mol) of triethylamine were added, and the mixture was heated to 40 ℃ to react for 1.5 hours to obtain a solution containing an intermediate compound;
and (2) directly adding 13.3 g (about 0.11mol) of 2, 6-dimethylaniline into the solution, carrying out heat preservation reaction for half an hour, monitoring the reaction process by TLC, adding 150mL of water for extraction after the reaction is finished, washing twice by using organic phase saturated sodium chloride, drying by using anhydrous magnesium sulfate, concentrating under reduced pressure, carrying out column chromatography, concentrating eluent to remove a solvent, and drying in vacuum to obtain 24.0 g (about 0.0974mol) of a nefiracetam product with the HPLC purity of 99.81%.
Example 2:
in 250mL of methylene chloride, 14.3 g (about 0.1mol) of 2-oxopyrrolidineacetic acid, 17.7 g (about 0.11mol) of CDI and 23.7 g (about 0.3mol) of pyridine were added, heated to 35 ℃ and reacted for 1.5 hours to obtain an intermediate-containing compound solution;
14.5 g (about 0.12mol) of 2, 6-dimethylaniline is directly added into the solution, the reaction is kept for half an hour, TLC monitors the reaction process, when the reaction is finished, 150mL of water is added for extraction, the organic phase is washed twice by saturated sodium chloride, anhydrous magnesium sulfate is dried, the mixture is concentrated under reduced pressure, ethanol is hot-dissolved, cooling and crystallization are carried out at the temperature of 0 ℃, filtration and vacuum drying are carried out, so that 23.9 g (about 0.097mol) of nefiracetam product is obtained, and the HPLC purity is 99.88%.
Example 3:
in 250mL of chloroform, 14.3 g (about 0.1mol) of 2-oxopyrrolidineacetic acid, 18.1 g (about 0.11mol) of CDI and 30.1 g (about 0.3mol) of potassium hydrogencarbonate were added, heated to 50 ℃ and reacted for 1.5 hours to obtain an intermediate-containing compound solution;
and (2) directly adding 13.3 g (about 0.11mol) of 2, 6-dimethylaniline into the solution, carrying out heat preservation reaction for half an hour, monitoring the reaction process by TLC, adding 150mL of water for extraction after the reaction is finished, washing twice by using organic phase saturated sodium chloride, drying by using anhydrous magnesium sulfate, concentrating under reduced pressure, carrying out column chromatography, concentrating eluent to remove a solvent, and drying in vacuum to obtain 24.2 g (about 0.0982mol) of a nefiracetam product with the HPLC purity of 99.83%.
Example 4:
in 250mL of methylene chloride, 14.3 g (about 0.1mol) of 2-oxopyrrolidineacetic acid, 17.4 g (about 0.11mol) of CDI and 21.2 g (about 0.2mol) of sodium carbonate were added, heated to 25 ℃ and reacted for 1.5 hours to obtain an intermediate-containing compound solution;
14.6 g (about 0.12mol) of 2, 6-dimethylaniline is directly added into the solution, the reaction is kept for half an hour, TLC monitors the reaction progress, when the reaction is finished, 150mL of water is added for extraction, organic phase saturated sodium chloride is washed twice, anhydrous magnesium sulfate is dried, reduced pressure concentration is carried out, ethanol is used for hot dissolution, cooling crystallization is carried out at the temperature of 0 ℃, filtration and vacuum drying are carried out, and 24.3 g (about 0.0987mol) of nefiracetam product is obtained, and the HPLC purity is 99.89%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (6)
1. The method for synthesizing nefiracetam is characterized by comprising the following synthetic route:
1) reacting 2-oxopyrrolidineacetic acid with N' N-dicarbonyl imidazole (CDI) in an organic solvent in the presence of a base to obtain a solution containing an intermediate compound;
the base is selected from triethylamine, pyridine, picoline, DBU, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate;
2) directly adding 2, 6-dimethylaniline into the solution, and reacting to obtain the nefiracetam.
2. A process for the preparation of nefiracetam according to claim 1, wherein: the organic solvent is selected from dichloromethane, tetrahydrofuran, DMF, dioxane, chloroform, and dichloroethane; the base is used in an amount of 1 to 3 equivalents based on 2-oxopyrrolidineacetic acid.
3. A process for the preparation of nefiracetam according to claim 1, wherein: the molar ratio of the 2-oxopyrrolidineacetic acid, N' -dicarbonylimidazole (CDI) and 2, 6-dimethylaniline is 1:1-2: 1-2.
4. A process for the preparation of nefiracetam according to claim 1, wherein: the reaction temperature is 20-50 ℃.
5. A process for the preparation of nefiracetam according to claim 1, wherein: and monitoring the reaction process by TLC, adding water for extraction after the reaction is finished, washing with organic phase saturated sodium chloride, drying, concentrating under reduced pressure, performing column chromatography, and performing vacuum drying to obtain the nefiracetam product.
6. A process for the preparation of nefiracetam according to claim 1, wherein: and monitoring the reaction process by TLC, adding water for extraction after the reaction is finished, washing the organic phase with saturated sodium chloride, drying, concentrating under reduced pressure, thermally dissolving in ethanol, cooling for crystallization, and drying in vacuum to obtain the nefiracetam product.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4341790A (en) * | 1979-06-13 | 1982-07-27 | A. Nattermann & Cie. Gmbh | Pyrrolidinylalkylcarboxylic acid amide derivatives, their preparation and pharmaceutical compositions containing them |
| WO2000004905A1 (en) * | 1998-07-21 | 2000-02-03 | American Biogenetic Sciences, Inc. | Benzoquinolizidine and benzoindolizidine derivatives and therapeutic uses thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4341790A (en) * | 1979-06-13 | 1982-07-27 | A. Nattermann & Cie. Gmbh | Pyrrolidinylalkylcarboxylic acid amide derivatives, their preparation and pharmaceutical compositions containing them |
| WO2000004905A1 (en) * | 1998-07-21 | 2000-02-03 | American Biogenetic Sciences, Inc. | Benzoquinolizidine and benzoindolizidine derivatives and therapeutic uses thereof |
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