CN109665982B - Synthetic method of nefiracetam intermediate 2-pyrrolidone - Google Patents
Synthetic method of nefiracetam intermediate 2-pyrrolidone Download PDFInfo
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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
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Abstract
The invention discloses a synthetic method of a nefiracetam intermediate 2-pyrrolidone, which comprises the steps of reacting 4-halogenated butyryl chloride with carbamate under the action of a catalyst to obtain 2-pyrrolidone; 1) uniformly mixing 4-halobutyryl chloride, a catalyst and a solvent A under protective gas, heating to 100-125 ℃, heating to 3-5 atmospheric pressures, dropwise adding a solution of carbamate and a solvent B for 40-60 min, maintaining the conditions to continuously react for 5-7 h after finishing reaction, heating to 135-160 ℃, heating to 5-7 atmospheric pressures, reacting for 6-8 h, cooling to 40-60 ℃, cooling to normal pressure, dropping 20-30 min of alkaline water, heating to 120-140 ℃, and reacting for 3-6 h; heating to 140-160 ℃, and reacting for 4-6 hours under the pressure of 7-10 atmospheric pressures; 2) and cooling, pouring into water with the volume of 3-4 times, adding a solvent C, extracting and layering, washing and drying an organic layer, and concentrating and evaporating to remove the solvent to obtain a product. Low cost and high yield.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a synthetic method of a nefiracetam intermediate 2-pyrrolidone.
Background
In recent years, with the increasing of the population of the elderly, the incidence of senile dementia in China is increasing continuously. The causes of senile dementia are different, and the treatment method and the drug selection are also different. According to conservative estimation, about 600 ten thousand of senile dementia patients exist in China. Senile dementia is a progressive disease, and no specific medicine or cure method exists at present. There is still a need for appropriate medical treatment of patients to delay the development of dementia, improve the quality of life of the patients, reduce the occurrence of complications and prolong life. Since the 90 s of the 20 th century, drugs for treating alzheimer's disease have been emerging, and several clinical trials of drugs have been available. The aminobutyrate medicine has good clinical treatment value on Alzheimer disease and cerebrovascular sequelae, can promote the synthesis of phosphorylcholine and phosphorylethanolamine, promote brain metabolism for enhancing metabolism and learning capacity, and is considered to be more effective and safe. Clinical trials in patients with dementia secondary to cerebrovascular disease have shown that nefiracetam can enhance cognitive function and improve certain symptoms in mental aspects.
Nefiracetam, known as N- (2, 6-dimethylphenyl) -2- (2-oxo-1-pyrrolidinyl) acetamide, is a novel pyrrolidone drug developed by Daiich Seiyaku, japan and has the following chemical structure:
the existing literature reports a synthetic route of nefiracetam, which is mainly characterized in that 2-pyrrolidone is adopted to be subjected to alkylation reaction with ethyl chloroacetate under the catalysis of sodium hydride, an obtained intermediate is subjected to esterification to obtain 2-oxopyrrolidine acetic acid, and then the 2-oxopyrrolidine acetic acid and 2, 6-dimethylaniline are subjected to amidation under the action of a condensing agent Dicyclohexylcarbodiimide (DCC) to synthesize the nefiracetam, wherein the reaction route is as follows:
from the above formula, it is known that 2-pyrrolidone is a main intermediate for the synthesis of nefiracetam.
The preparation of 2-pyrrolidone has been reported in several documents, mainly: lee, Han Won et al, U.S. Pat. No. 5, 296466, reported the formation of 2-pyrrolidone from gamma-butyrolactone with aqueous ammonia; gellrich, Urs et al J.Am.chem.Soc. [2015,137(14),4851](AcrPNP) is reported in a mixed solvent of dioxane and tolueneiPr) RuH (CO) Cl reacts with sodium hydroxide solution under catalysis to generate 2-pyrrolidone; myriant corporation in WO2013/33649 reports that succinimide reacts with hydrogen at high temperature and high pressure in ethylene glycol dimethyl ether to produce 2-pyrrolidone. In general, the above methods for preparing 2-pyrrolidone have disadvantages of expensive raw materials and catalysts, low yield, and the like, which are not favorable for industrial production, and thus, it is necessary to develop a novel method for synthesizing 2-pyrrolidone.
Disclosure of Invention
The invention aims to provide a synthetic method of a nefiracetam intermediate 2-pyrrolidone, which has the advantages of low cost and high yield.
In order to achieve the purpose, the invention adopts the following technical scheme:
X-Cl or Br-R-Me or Et
The method for synthesizing the nefiracetam intermediate 2-pyrrolidone is characterized in that 4-halogenated butyryl chloride and carbamate react under the action of a catalyst to obtain the 2-pyrrolidone, and the reaction process comprises the following steps:
1) uniformly mixing p-4-halobutyryl chloride, a catalyst and a solvent A under a protective gas, controlling the reaction temperature to rise to 100-125 ℃, the pressure to rise to 3-5 atmospheric pressures, dropwise adding a solution of carbamate and a solvent B, controlling the dropwise adding time to be 40-60 min, maintaining the conditions to continue to react for 5-7 h after the dropwise adding is finished, then raising the temperature to 135-160 ℃, raising the pressure to 5-7 atmospheric pressures, reacting for 6-8 h, then cooling to 40-60 ℃, reducing the pressure to normal pressure, dropwise adding alkaline water, controlling the dropwise adding time to be 20-30 min, then raising the temperature to 120-140 ℃, reacting for 3-6 h, then controlling the temperature to rise to 140-160 ℃, raising the pressure to 7-10 atmospheric pressures, and finishing the reaction for 4-6 h;
2) and cooling the system, pouring the cooled system into water with the volume of 3-4 times, adding a solvent C for extraction, layering, washing an organic layer, drying a drying agent, and concentrating and evaporating to remove the solvent to obtain the product.
The 4-halobutyryl chloride is 4-chlorobutyryl chloride or 4-bromobutyryl chloride; the carbamate is methyl carbamate or ethyl carbamate.
The preparation method of the catalyst comprises the following steps: dissolving organic base in an organic solvent D, adding 300-500-mesh silica gel, stirring at 40-50 ℃ for 30-50 min, cooling, concentrating, evaporating to remove the solvent, uniformly grinding the rest solid, and sieving with a 200-300-mesh sieve to obtain the product; the dosage ratio of the organic base to the silica gel to the organic solvent D is 1mol, (200-300) g, (900-1000) mL; the organic base is sodium methoxide or sodium ethoxide; the organic solvent D is absolute methanol or absolute ethanol.
The molar ratio of the 4-halobutyryl chloride to the carbamate is 1 (1.02-1.1); the weight ratio of the 4-halobutyryl chloride to the catalyst is 1 (0.05-0.12); the dosage ratio of the 4-halobutyryl chloride to the solvent A is 1g (3.5-5.5) mL; the dosage ratio of the carbamate to the solvent B is 1g (4-6) mL; the dosage ratio of the 4-halobutyryl chloride to the solvent C is 1g (3-5) mL.
The solvent A is absolute methanol or absolute ethanol; the solvent B is anhydrous isopropanol or anhydrous isobutanol; the solvent C is dichloromethane or chloroform; the protective gas is nitrogen or argon; the drying agent is anhydrous sodium sulfate or anhydrous magnesium sulfate.
The alkaline water is an aqueous solution of sodium hydroxide or potassium hydroxide, and the concentration is 15% by mass; the molar ratio of the 4-halobutyryl chloride to sodium hydroxide or potassium hydroxide in the alkaline water is 1 (1.5-2).
The reaction principle of the invention is shown as the following formula:
under the action of a supported alkali catalyst and under the conditions of heating and pressurizing, 4-halobutyryl chloride and carbamate firstly carry out substitution reaction on the surface of the catalyst; because the substitution reaction with the halogen atom is easier, the amino group reacts with the halogen atom first to generate a transition state 1; the reaction temperature and pressure are increased, the substituted amino further generates the reaction of substituting chlorine atoms in acyl chloride groups to generate a transition state 2, the conditions of the step are harsh, and the reaction can be generated only by the action of a catalyst; after the substitution reaction is finished, adding alkaline water, and further reacting to generate a salt 3; and (3) decarboxylating the salt 3 under the conditions of heating and pressurizing to generate the target product 2-pyrrolidone.
Compared with the prior art, the invention has the advantages that:
1. the raw materials are easy to obtain, and the cost is low;
2. the reaction yield is high;
3. the pollution emission is less.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
The synthesis method of the 2-pyrrolidone comprises the following steps:
1) under the protection of argon, uniformly mixing p-4-bromobutyryl chloride, a catalyst and anhydrous methanol, controlling the reaction temperature to rise to 120 ℃, the pressure to rise to 4 atmospheric pressures, dropwise adding a solution of methyl carbamate and anhydrous isopropanol, controlling the dropwise adding time to be 50min, after the dropwise adding is finished, continuously reacting for 6h under the condition, then raising the temperature to 150 ℃, raising the pressure to 6 atmospheric pressures, reacting for 7h, then cooling to 50 ℃, reducing the pressure to normal pressure, dropwise adding a sodium hydroxide aqueous solution with the concentration of 15% by mass fraction, controlling the dropwise adding time to be 25min, then raising the temperature to 135 ℃, reacting for 5h, then raising the temperature to 152 ℃, raising the pressure to 9 atmospheric pressures, and finishing the reaction for 5 h.
The molar ratio of 4-bromobutyryl chloride to methyl carbamate is 1:1.08, the weight ratio of 4-bromobutyryl chloride to catalyst is 1:0.1, the dosage ratio of 4-bromobutyryl chloride to anhydrous methanol is 1g:4.5mL, the dosage ratio of methyl carbamate to anhydrous isopropanol is 1g:5mL, and the molar ratio of 4-bromobutyryl chloride to sodium hydroxide in the aqueous solution of sodium hydroxide is 1: 1.8.
The preparation method of the catalyst comprises the following steps: dissolving sodium ethoxide in anhydrous ethanol, adding 450 mesh silica gel, stirring at 46 deg.C for 40min, cooling, concentrating, evaporating to remove solvent, grinding the rest solid uniformly, and sieving with 250 mesh sieve to obtain the final product; the dosage ratio of the sodium ethoxide to the silica gel to the absolute ethyl alcohol is 1mol:260g:950 mL.
2) And cooling the system, pouring the cooled system into 3.5 times volume of water, adding dichloromethane for extraction, wherein the dosage ratio of 4-bromobutyryl chloride to dichloromethane is 1g:4mL, layering, washing an organic layer with water, drying the organic layer with anhydrous sodium sulfate, and concentrating and evaporating the organic layer by using a rotary evaporator to remove the solvent to obtain the product. The molar yield was 98.9% and the GC purity was 99.3%.
Example 2
The synthesis method of the 2-pyrrolidone comprises the following steps:
1) under the protection of nitrogen, uniformly mixing 4-chlorobutyryl chloride, a catalyst and absolute ethyl alcohol, controlling the reaction temperature to rise to 100 ℃, the pressure to rise to 3 atmospheric pressures, dropwise adding a solution of ethyl carbamate and absolute isobutanol, controlling the dropwise adding time to be 40min, after the dropwise adding is finished, maintaining the conditions to continue to react for 5h, raising the temperature to 135 ℃, raising the pressure to 5 atmospheric pressures, reacting for 6h, then cooling to 40 ℃, reducing the pressure to normal pressure, controlling the dropwise adding time to be 20min, then raising the temperature to 120 ℃, reacting for 3h, then raising the temperature to 140 ℃, raising the pressure to 7 atmospheric pressures, and finishing the reaction for 4 h.
The preparation method of the catalyst comprises the following steps: dissolving sodium methoxide in anhydrous methanol, adding 300-mesh silica gel, stirring at 40 ℃ for 30min, cooling, concentrating, evaporating to remove the solvent, grinding the residual solid uniformly, and sieving with a 200-mesh sieve to obtain the sodium methoxide/silica gel composite material; the dosage ratio of the sodium methoxide, the silica gel and the anhydrous methanol is 1mol:200g:900 mL.
The molar ratio of the 4-chlorobutyryl chloride to the ethyl carbamate is 1: 1.02; the weight ratio of the 4-chlorobutyryl chloride to the catalyst is 1: 0.05; the dosage ratio of the 4-chlorobutyryl chloride to the absolute ethyl alcohol is 1g:3.5 mL; the dosage ratio of the ethyl carbamate to the absolute isobutanol is 1g to 4 mL; the molar ratio of 4-chlorobutyryl chloride to potassium hydroxide in the aqueous solution of potassium hydroxide is 1: 1.5.
2) And cooling the system, pouring the cooled system into 3 times volume of water, adding chloroform for extraction, wherein the dosage ratio of 4-chlorobutyryl chloride to chloroform is 1g:3mL, layering, washing an organic layer, drying the organic layer by anhydrous magnesium sulfate, and concentrating and evaporating the organic layer by using a rotary evaporator to remove the solvent to obtain the product. The molar yield was 97.5% and the GC purity 98.5%.
Example 3
The synthesis method of the 2-pyrrolidone comprises the following steps:
1) under the protection of argon, uniformly mixing p-4-bromobutyryl chloride, a catalyst and absolute ethyl alcohol, controlling the reaction temperature to rise to 125 ℃, the pressure to rise to 5 atmospheric pressures, dropwise adding a solution of carbamate and absolute isopropyl alcohol, controlling the dropwise adding time to be 60min, after the dropwise adding is finished, maintaining the conditions to continue to react for 7h, raising the temperature to 160 ℃, raising the pressure to 7 atmospheric pressures, reacting for 8h, then cooling to 60 ℃, reducing the pressure to normal pressure, controlling the dropwise adding time to be 30min, then raising the temperature to 140 ℃, reacting for 6h, then raising the temperature to 160 ℃, raising the pressure to 10 atmospheric pressures, and finishing the reaction for 6 h.
The preparation method of the catalyst comprises the following steps: dissolving sodium ethoxide in anhydrous ethanol, adding 500 mesh silica gel, stirring at 50 deg.C for 50min, cooling, concentrating, evaporating to remove solvent, grinding the rest solid, and sieving with 300 mesh sieve to obtain the final product; the dosage ratio of the sodium ethoxide to the silica gel to the absolute ethyl alcohol is 1mol:300g:1000 mL.
The molar ratio of 4-bromobutyryl chloride to carbamate is 1: 1.1; the weight ratio of the 4-bromobutyryl chloride to the catalyst is 1: 0.12; the dosage ratio of the 4-bromobutyryl chloride to the absolute ethyl alcohol is 1g to 5.5 mL; the dosage ratio of the carbamate to the anhydrous isopropanol is 1g to 6 mL; the molar ratio of 4-bromobutyryl chloride to sodium hydroxide in the aqueous sodium hydroxide solution is 1: 2.
2) And (3) cooling the system, pouring the cooled system into 4 times volume of water, adding dichloromethane for extraction, wherein the dosage ratio of the 4-bromobutyryl chloride to the dichloromethane is 1g:5mL, layering, washing an organic layer with water, drying the organic layer with anhydrous sodium sulfate, and concentrating and evaporating the organic layer by using a rotary evaporator to remove the solvent to obtain the product. The molar yield was 98.5% and the GC purity was 99.1%.
Example 4
The reaction pressure before the addition of the carbamate was set to 2 atmospheres, the reaction temperature was set to 70 ℃, and other reaction conditions and material use ratios were the same as in example 1, with a molar yield of 45.2% and a GC purity of 69.3%.
Example 5
The reaction pressure before the addition of the carbamate was set to 6 atmospheres, the reaction temperature was set to 140 ℃, and other reaction conditions and material use ratios were the same as in example 1, the molar yield was 73.1%, and the GC purity was 77.2%.
Example 6
The reaction pressure after the carbamate addition was continued for 5 hours was set to 3 atm, the reaction temperature was set to 120 ℃, the other reaction conditions and the material ratio were the same as in example 1, the molar yield was 62.6%, and the GC purity was 72.5%.
Example 7
The reaction pressure after the carbamate addition was continued for 5 hours was set to 9 atm, the reaction temperature was set to 175 ℃, other reaction conditions and the material ratio were the same as in example 1, the molar yield was 82.6%, and the GC purity was 89.2%.
EXAMPLE 8 nuclear magnetic hydrogen Spectroscopy of the product
Taking the product of the example 1 as an example,1H-NMR (DMSO): δ 7.72(1H), δ 3.42(2H), δ 2.26 (2H), δ 2.13 (2H). The various hydrogens are assigned to the product structure as follows:
and (4) performing nuclear magnetic analysis, wherein the structure of the product conforms to the target object, namely the 2-pyrrolidone.
Claims (5)
1. The method for synthesizing the nefiracetam intermediate 2-pyrrolidone is characterized in that 4-halogenated butyryl chloride and carbamate react under the action of a catalyst to obtain the 2-pyrrolidone, and the reaction process comprises the following steps:
1) uniformly mixing p-4-halobutyryl chloride, a catalyst and a solvent A under a protective gas, controlling the reaction temperature to rise to 100-125 ℃, the pressure to rise to 3-5 atmospheric pressures, dropwise adding a solution of carbamate and a solvent B, controlling the dropwise adding time to be 40-60 min, maintaining the conditions to continue to react for 5-7 h after the dropwise adding is finished, then raising the temperature to 135-160 ℃, raising the pressure to 5-7 atmospheric pressures, reacting for 6-8 h, then cooling to 40-60 ℃, reducing the pressure to normal pressure, dropwise adding alkaline water, controlling the dropwise adding time to be 20-30 min, then raising the temperature to 120-140 ℃, reacting for 3-6 h, then controlling the temperature to rise to 140-160 ℃, raising the pressure to 7-10 atmospheric pressures, and finishing the reaction for 4-6 h;
2) cooling the system, pouring the cooled system into water with the volume of 3-4 times, adding a solvent C for extraction, layering, washing an organic layer, drying a drying agent, and concentrating and evaporating to remove the solvent to obtain a product;
the preparation method of the catalyst comprises the following steps: dissolving organic base in an organic solvent D, adding 300-500 meshes of silica gel, stirring at 40-50 ℃ for 30-50 min, cooling, concentrating, evaporating to dryness, uniformly grinding the rest solid, and sieving with a 200-300-mesh sieve to obtain the solid-phase organic silica gel; the dosage ratio of the organic base to the silica gel to the organic solvent D is 1mol, (200-300) g, (900-1000) mL; the organic base is sodium methoxide or sodium ethoxide; the organic solvent D is absolute methanol or absolute ethanol.
2. A method of synthesizing nefiracetam intermediate, 2-pyrrolidone as in claim 1, wherein said 4-halobutyryl chloride is 4-chlorobutyryl chloride or 4-bromobutyryl chloride; the carbamate is methyl carbamate or ethyl carbamate.
3. The method for synthesizing nefiracetam intermediate 2-pyrrolidone as claimed in claim 1, wherein the molar ratio of 4-halobutyryl chloride to carbamate is 1 (1.02-1.1); the weight ratio of the 4-halobutyryl chloride to the catalyst is 1 (0.05-0.12); the dosage ratio of the 4-halobutyryl chloride to the solvent A is 1g (3.5-5.5) mL; the dosage ratio of the carbamate to the solvent B is 1g (4-6) mL; the dosage ratio of the 4-halobutyryl chloride to the solvent C is 1g (3-5) mL.
4. The method of synthesizing nefiracetam intermediate 2-pyrrolidone of claim 1, wherein said solvent a is absolute methanol or absolute ethanol; the solvent B is anhydrous isopropanol or anhydrous isobutanol; the solvent C is dichloromethane or chloroform; the protective gas is nitrogen or argon; the drying agent is anhydrous sodium sulfate or anhydrous magnesium sulfate.
5. The method for synthesizing nefiracetam intermediate 2-pyrrolidone of claim 1, wherein the aqueous alkali is an aqueous solution of sodium hydroxide or potassium hydroxide, and the concentration is 15% by mass; the molar ratio of the 4-halobutyryl chloride to the sodium hydroxide or the potassium hydroxide in the alkaline water is 1 (1.5-2).
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