CN111960983A - N-methyl-3- (1-methylpyrrolidine-3-yl) propyl-1-amine and synthetic method thereof - Google Patents
N-methyl-3- (1-methylpyrrolidine-3-yl) propyl-1-amine and synthetic method thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
Abstract
The invention belongs to the technical field of organic synthesis, and relates to N-methyl-3- (1-methylpyrrolidine-3-yl) propane-1-amine and a synthesis method thereof. The compound provided by the invention can be used as an important medical intermediate, and the synthesis method comprises the following steps: the N-methyl-3- (1-methylpyrrolidine-3-yl) propan-1-amine is prepared by taking diethyl cyanomethylphosphonate and 3-formylpyrrolidine-1-carboxylic acid tert-butyl ester as raw materials and carrying out olefin, catalytic hydrogenation, reduction, substitution and reduction reactions, and the synthesis method has the advantages of simple synthesis path, low cost and high efficiency.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and discloses N-methyl-3- (1-methylpyrrolidine-3-yl) propane-1-amine and a synthesis method thereof.
Background
The pyrrole derivatives are an important nitrogen heterocyclic compound, are used as an important alkaloid and widely exist in the whole natural world, wherein a large number of derivatives have good physiological and pharmacological activities. As such, pyrrole derivatives are widely used in the design of many drugs as important pharmaceutical intermediates. In addition, the pyrrole derivatives are important fine chemical product intermediates and have wide application in the fields of pesticides and the like. Therefore, the synthesis of pyrrole derivatives is of great significance.
Disclosure of Invention
The invention aims to provide a synthetic method of N-methyl-3- (1-methylpyrrolidin-3-yl) propane-1-amine serving as a compound of a medical intermediate, and the synthetic method is simple and high in yield.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a compound is N-methyl-3- (1-methylpyrrolidin-3-yl) propan-1-amine, and the molecular structure is shown as formula 1:
the invention also provides a synthesis method of the compound, which takes the cyano-methyl diethyl phosphonate and the 3-formyl pyrrolidine-1-carboxylic acid tert-butyl ester as raw materials to synthesize the compound through five steps of alkene, catalytic hydrogenation, reduction, substitution and reduction reaction, and the synthesis route is shown as the following formula:
the synthesis method comprises the following steps:
s1, dissolving diethyl cyanomethylphosphonate and 3-formyl pyrrolidine-1-carboxylic acid tert-butyl ester in tetrahydrofuran to obtain a mixed solution, cooling to 0 ℃ after the mixed solution is clarified, adding potassium tert-butoxide in batches, slowly heating to room temperature, and stirring for reaction for 12 hours to obtain E-3- (1-acrylonitrile group) pyrrole-1-carboxylic acid tert-butyl ester;
s2, dissolving the E-3- (1-acrylonitrile group) pyrrole-1-tert-butyl formate obtained in the step S1 in methanol, adding a catalyst Pd/C under the protection of nitrogen, filling hydrogen, and stirring and reacting at room temperature for 12 hours to obtain E-3- (1-acrylonitrile group) pyrrole-1-tert-butyl formate;
s3, adding lithium aluminum hydride into a reaction bottle, slowly dropwise adding tetrahydrofuran, controlling the reaction temperature to be 60-70 ℃, slowly dropwise adding a tetrahydrofuran solution of the E-3- (1-propionitrile) pyrrole-1-tert-butyl formate obtained in the step S2, and reacting for 12 hours to obtain (3- (1-methylpyrrolidin-3-yl) propane-1-amine;
s4, adding the 3- (1-methylpyrrolidin-3-yl) propan-1-amine obtained in the step S3 into a reaction bottle, adding triethylamine and sodium bicarbonate, adding a dichloromethane solution containing Boc2O, and stirring at room temperature for reaction for 12 hours to obtain 3- (1-methylpyrrolidin-3-yl) propyl carbamic acid tert-butyl ester;
s5, adding lithium aluminum hydride into a reaction bottle, dropwise adding DMF, heating to 60-70 ℃, slowly dropwise adding a tetrahydrofuran solution containing 3- (1-methylpyrrolidin-3-yl) propyl carbamic acid tert-butyl ester, and reacting for 12h to obtain N-methyl-3- (1-methylpyrrolidin-3-yl) propyl-1-amine.
Preferably, in the step S1, the molar ratio of diethyl cyanomethylphosphonate to tert-butyl 3-formylpyrrolidine-1-carboxylate to potassium tert-butoxide is 1:1.1: 1.2;
preferably, in the step S3, the molar ratio of the E-3- (1-propionitrile) pyrrole-1-carboxylic acid tert-butyl ester to the lithium aluminum hydride is 1: 4.
Preferably, in the step S4, the molar ratio of the 3- (1-methylpyrrolidin-3-yl) propan-1-amine to the Boc2O is 1: 2.
Compared with the prior art, the invention provides a new medical intermediate, and the synthesis method provided by the invention has the advantages of simple synthesis path, low cost and high efficiency.
Detailed description of the invention
The following detailed description will provide specific embodiments of the present invention. These embodiments are merely illustrative and not intended to limit the scope or the principles of the invention, which is defined by the claims and includes obvious modifications and variations based thereon.
Example 1
S1, and E-3- (1-acrylonitrile) pyrrole-1-carboxylic acid tert-butyl ester synthesis:
in a 500mL four-neck flask, 17.7g of diethyl cyanomethylphosphonate and 21.92g of tert-butyl 3-formylpyrrolidine-1-carboxylate are dissolved in 150mL of tetrahydrofuran to obtain a mixed solution, after the mixed solution is clarified, the temperature is reduced to 0 ℃, 13.4g of potassium tert-butoxide is added in 5 batches, the temperature is slowly raised to room temperature for reaction for 12 hours, after the reaction is completely analyzed by thin-layer chromatography, 200mL of saturated ammonium chloride solution is added, ethyl acetate is extracted for 3 times (3X 500mL), anhydrous sodium sulfate is dried, the filtrate is concentrated to dryness, and the mixture passes through a column to obtain 20.15g of tert-butyl E-3- (1-acrylonitrile) pyrrole-1-carboxylate, wherein the yield is 85%.
S2, and E-3- (1-propionitrile) pyrrole-1-carboxylic acid tert-butyl ester synthesis:
and (2) dissolving 20g of the E-3- (1-propionitrile) pyrrole-1-carboxylic acid tert-butyl ester obtained in the step S1 in 160mL of methanol in a 500mL hydrogenation bottle, adding 2g of catalyst Pd/C under the protection of nitrogen, introducing hydrogen, stirring at room temperature, reacting for 12h, completely analyzing and reacting through liquid phase mass spectrum and thin layer chromatography, filtering the reaction liquid, and concentrating the filtrate obtained by filtering to obtain 18.12g of E-3- (1-propionitrile) pyrrole-1-carboxylic acid tert-butyl ester, wherein the yield is 91%.
S3 synthesis of (3- (1-methylpyrrolidine) -1-propylamine:
adding 11.4g of lithium aluminum hydride into a 500mL reaction bottle, dropwise adding 200mL of DMF, heating to 60 ℃, slowly dropwise adding 20mL of tetrahydrofuran solution containing 18.12g E-3- (1-propionitrile) pyrrole-1-carboxylic acid tert-butyl ester, reacting for 12h, analyzing the reaction completion of raw materials through thin layer chromatography, cooling the reaction liquid to room temperature, adding 6mL of 2M sodium hydroxide solution and 12mL of water, mechanically stirring for 30min until a large amount of solid is generated, filtering, concentrating the filtrate obtained by filtering to dryness to obtain a crude product, and further distilling to obtain 5.46g of (3- (1-methylpyrrolidine) -1-propylamine with the yield of 51%.
S4 Synthesis of tert-butyl 3- (1-methylpyrrolidin-3-yl) propylcarbamate:
a250 mL reaction flask was charged with 5.46g of (3- (1-methylpyrrolidine) -1-propylamine, 3.7g of triethylamine and 2.4mL of sodium bicarbonate, and charged with a solution containing 7.98g of Boc2O in dichloromethane (48 mL) and the reaction stirred at room temperature for 12 h. The reaction of the starting materials was completed by TLC analysis, and the reaction solution was separated into layers, and the aqueous layer was extracted with methylene chloride 3 times (3X 500mL), washed with citric acid 3 times (3X 500mL), washed with saturated brine 3 times (3X 500mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a crude product, which was passed through a column to give 4.5g of tert-butyl 3- (1-methylpyrrolidin-3-yl) propylcarbamate in a yield of 76.8%.
S5, Synthesis of N-methyl-3- (1-methylpyrrolidin-3-yl) propan-1-amine:
adding 2.9g of lithium aluminum hydride into a 250mL reaction bottle, dropwise adding 70mL of DMF, heating to 60 ℃, slowly dropwise adding 10mL of tetrahydrofuran solution containing 4.5g of 3- (1-methylpyrrolidin-3-yl) propyl carbamic acid tert-butyl ester, reacting for 12h, analyzing the reaction completion of raw materials through thin layer chromatography, cooling the reaction liquid to room temperature, adding 6mL of 2M sodium hydroxide solution and 12mL of water, mechanically stirring for 30min, generating a large amount of solid, filtering, concentrating the filtrate obtained by filtering to dryness to obtain a crude product, and further distilling to obtain 2.16g N-methyl-3- (1-methylpyrrolidin-3-yl) propan-1-amine with the yield of 51%.
Example 2
S1, and E-3- (1-acrylonitrile) pyrrole-1-carboxylic acid tert-butyl ester synthesis:
in a 500mL four-neck flask, 17.7g of diethyl cyanomethylphosphonate and 21.92g of tert-butyl 3-formylpyrrolidine-1-carboxylate are dissolved in 150mL of tetrahydrofuran to obtain a mixed solution, after the mixed solution is clarified, the temperature is reduced to 0 ℃, 13.4g of potassium tert-butoxide is added in 5 batches, the temperature is slowly increased to room temperature for reaction for 12 hours, after the reaction is completely analyzed by thin-layer chromatography, 200mL of saturated ammonium chloride solution is added, ethyl acetate is extracted for 3 times (3X 500mL), anhydrous sodium sulfate is dried, the filtrate is concentrated to dryness, and the mixture passes through a column to obtain 20.41g of tert-butyl E-3- (1-acrylonitrile) pyrrole-1-carboxylate, wherein the yield is 86.1%.
S2, and E-3- (1-propionitrile) pyrrole-1-carboxylic acid tert-butyl ester synthesis:
and (2) dissolving 20g of the E-3- (1-propionitrile) pyrrole-1-carboxylic acid tert-butyl ester obtained in the step S1 in 160mL of methanol in a 500mL hydrogenation bottle, adding 2g of catalyst Pd/C under the protection of nitrogen, introducing hydrogen, stirring at room temperature, reacting for 12h, completely analyzing and reacting through liquid phase mass spectrum and thin layer chromatography, filtering the reaction liquid, and concentrating the filtrate obtained by filtering to obtain 18.12g of E-3- (1-propionitrile) pyrrole-1-carboxylic acid tert-butyl ester, wherein the yield is 91%.
S3 synthesis of (3- (1-methylpyrrolidine) -1-propylamine:
adding 11.4g of lithium aluminum hydride into a 500mL reaction bottle, dropwise adding 200mL of DMF, heating to 66 ℃, slowly dropwise adding 20mL of tetrahydrofuran solution containing 18.12g E-3- (1-propionitrile) pyrrole-1-carboxylic acid tert-butyl ester, reacting for 12h, analyzing the reaction completion of raw materials through thin layer chromatography, cooling the reaction liquid to room temperature, adding 6mL of 2M sodium hydroxide solution and 12mL of water, mechanically stirring for 30min, generating a large amount of solid, filtering, concentrating the filtrate obtained by filtering to dryness to obtain a crude product, and further distilling to obtain 5.6g of (3- (1-methylpyrrolidine) -1-propylamine with the yield of 52.3%.
S4 Synthesis of tert-butyl 3- (1-methylpyrrolidin-3-yl) propylcarbamate:
a250 mL reaction flask was charged with 5.46g of (3- (1-methylpyrrolidine) -1-propylamine, 3.7g of triethylamine and 2.4mL of sodium bicarbonate, and charged with a solution containing 7.98g of Boc2O in dichloromethane (48 mL) and the reaction stirred at room temperature for 12 h. The reaction of the starting materials was completed by TLC analysis, and the reaction solution was separated into layers, and the aqueous layer was extracted with methylene chloride 3 times (3X 500mL), washed with citric acid 3 times (3X 500mL), washed with saturated brine 3 times (3X 500mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give a crude product, which was passed through a column to give 4.5g of tert-butyl 3- (1-methylpyrrolidin-3-yl) propylcarbamate in a yield of 76.8%.
S5, Synthesis of N-methyl-3- (1-methylpyrrolidin-3-yl) propan-1-amine:
adding 2.9g of lithium aluminum hydride into a 250mL reaction bottle, dropwise adding 70mL of DMF, heating to 66 ℃, slowly dropwise adding 10mL of tetrahydrofuran solution containing 4.5g of 3- (1-methylpyrrolidin-3-yl) propyl carbamic acid tert-butyl ester, reacting for 12h, analyzing the reaction completion of raw materials through thin layer chromatography, cooling the reaction liquid to room temperature, adding 6mL of 2M sodium hydroxide solution and 12mL of water, mechanically stirring for 30min until a large amount of solid is generated, filtering, concentrating the filtrate obtained by filtering to dryness to obtain a crude product, and further distilling to obtain 2.24g N-methyl-3- (1-methylpyrrolidin-3-yl) propan-1-amine with the yield of 53%.
Example 3
S1, and E-3- (1-acrylonitrile) pyrrole-1-carboxylic acid tert-butyl ester synthesis:
in a 500mL four-neck flask, 17.7g of diethyl cyanomethylphosphonate and 21.92g of tert-butyl 3-formylpyrrolidine-1-carboxylate are dissolved in 150mL of tetrahydrofuran to obtain a mixed solution, after the mixed solution is clarified, the temperature is reduced to 0 ℃, 13.4g of potassium tert-butoxide is added in 5 batches, the temperature is slowly increased to room temperature for reaction for 12 hours, after the reaction is completely analyzed by thin-layer chromatography, 200mL of saturated ammonium chloride solution is added, ethyl acetate is extracted for 3 times (3X 500mL), anhydrous sodium sulfate is dried, the filtrate is concentrated to dryness, and the mixture passes through a column to obtain 19.98g of tert-butyl E-3- (1-acrylonitrile) pyrrole-1-carboxylate, wherein the yield is 84.3%.
S2, and E-3- (1-propionitrile) pyrrole-1-carboxylic acid tert-butyl ester synthesis:
and (2) dissolving 20g of the E-3- (1-propionitrile) pyrrole-1-carboxylic acid tert-butyl ester obtained in the step S1 in 160mL of methanol in a 500mL hydrogenation bottle, adding 2g of catalyst Pd/C under the protection of nitrogen, introducing hydrogen, stirring at room temperature, reacting for 12h, completely analyzing and reacting through liquid phase mass spectrum and thin layer chromatography, filtering the reaction liquid, and concentrating the filtrate obtained by filtering to obtain 18.12g of E-3- (1-propionitrile) pyrrole-1-carboxylic acid tert-butyl ester, wherein the yield is 91%.
S3 synthesis of (3- (1-methylpyrrolidine) -1-propylamine:
adding 11.4g of lithium aluminum hydride into a 500mL reaction bottle, dropwise adding 200mL of DMF, heating to 70 ℃, slowly dropwise adding 20mL of tetrahydrofuran solution containing 18.12g E-3- (1-propionitrile) pyrrole-1-carboxylic acid tert-butyl ester, reacting for 12h, analyzing the reaction completion of raw materials through thin layer chromatography, cooling the reaction liquid to room temperature, adding 6mL of 2M sodium hydroxide solution and 12mL of water, mechanically stirring for 30min, generating a large amount of solid, filtering, concentrating the filtrate obtained by filtering to dryness to obtain a crude product, and further distilling to obtain 5.56g of (3- (1-methylpyrrolidine) -1-propylamine with the yield of 51.9%.
S4 Synthesis of tert-butyl 3- (1-methylpyrrolidin-3-yl) propylcarbamate:
a250 mL reaction flask was charged with 5.46g of (3- (1-methylpyrrolidine) -1-propylamine, 3.7g of triethylamine and 2.4mL of sodium bicarbonate, and charged with a solution containing 7.98g of Boc2O in dichloromethane (48 mL) and the reaction stirred at room temperature for 12 h. The reaction of the starting materials was analyzed by thin layer chromatography, the reaction solution was separated into layers, the aqueous layer was extracted with methylene chloride 3 times (3X 500mL), washed with citric acid 3 times (3X 500mL), and washed with saturated brine3 times (3X 500mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness to give the crude product, which was passed through a column to give 4.5g of tert-butyl 3- (1-methylpyrrolidin-3-yl) propylcarbamate in 76.8% yield.
S5, Synthesis of N-methyl-3- (1-methylpyrrolidin-3-yl) propan-1-amine:
adding 2.9g of lithium aluminum hydride into a 250mL reaction bottle, dropwise adding 70mL of DMF, heating to 70 ℃, slowly dropwise adding 10mL of tetrahydrofuran solution containing 4.5g of 3- (1-methylpyrrolidin-3-yl) propyl carbamic acid tert-butyl ester, reacting for 12h, analyzing the reaction completion of raw materials through thin layer chromatography, cooling the reaction liquid to room temperature, adding 6mL of 2M sodium hydroxide solution and 12mL of water, mechanically stirring for 30min, generating a large amount of solid, filtering, concentrating the filtrate obtained by filtering to dryness to obtain a crude product, and further distilling to obtain 2.22g N-methyl-3- (1-methylpyrrolidin-3-yl) propan-1-amine with the yield of 52.3%.
While there have been shown and described what are at present considered the fundamental principles and essential features of the invention and its advantages, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but is capable of other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (5)
1. A compound, wherein the compound is N-methyl-3- (1-methylpyrrolidin-3-yl) propan-1-amine, and the molecular structure is shown as formula I:
2. the method for synthesizing the compound according to claim 1, wherein the compound is synthesized by olefin, catalytic hydrogenation, reduction, substitution and reduction reactions using diethyl cyanomethylphosphonate and tert-butyl 3-formylpyrrolidine-1-carboxylate as raw materials, and the synthetic route is shown as the following formula:
the synthesis method comprises the following steps:
s1, dissolving diethyl cyanomethylphosphonate and 3-formyl pyrrolidine-1-carboxylic acid tert-butyl ester in tetrahydrofuran to obtain a mixed solution, cooling to 0 ℃ after the mixed solution is clarified, adding potassium tert-butoxide in batches, slowly heating to room temperature, and stirring for reaction for 12 hours to obtain E-3- (1-acrylonitrile group) pyrrole-1-carboxylic acid tert-butyl ester;
s2, dissolving the E-3- (1-acrylonitrile group) pyrrole-1-tert-butyl formate obtained in the step S1 in methanol, adding a catalyst Pd/C under the protection of nitrogen, filling hydrogen, and stirring and reacting at room temperature for 12 hours to obtain E-3- (1-acrylonitrile group) pyrrole-1-tert-butyl formate;
s3, adding lithium aluminum hydride into a reaction bottle, slowly dropwise adding tetrahydrofuran, controlling the reaction temperature to be 60-70 ℃, slowly dropwise adding a tetrahydrofuran solution of the E-3- (1-propionitrile) pyrrole-1-tert-butyl formate obtained in the step S2, and reacting for 12 hours to obtain (3- (1-methylpyrrolidin-3-yl) propane-1-amine;
s4, adding the 3- (1-methylpyrrolidin-3-yl) propan-1-amine obtained in the step S3 into a reaction bottle, adding triethylamine and sodium bicarbonate, adding a dichloromethane solution containing Boc2O, and stirring at room temperature for reaction for 12 hours to obtain 3- (1-methylpyrrolidin-3-yl) propyl carbamic acid tert-butyl ester;
s5, adding lithium aluminum hydride into a reaction bottle, dropwise adding DMF, heating to 60-70 ℃, slowly dropwise adding a tetrahydrofuran solution containing 3- (1-methylpyrrolidin-3-yl) propyl carbamic acid tert-butyl ester, and reacting for 12h to obtain N-methyl-3- (1-methylpyrrolidin-3-yl) propyl-1-amine.
3. The method of claim 2, wherein in step S1, the molar ratio of diethyl cyanomethylphosphonate, tert-butyl 3-formylpyrrolidine-1-carboxylate and potassium tert-butoxide is 1:1.1: 1.2.
4. The method of claim 2, wherein in step S3, the molar ratio of E-3- (1-propionitrile) pyrrole-1-carboxylic acid tert-butyl ester to lithium aluminum hydride is 1: 4.
5. The method of claim 2, wherein in step S4, the molar ratio of 3- (1-methylpyrrolidin-3-yl) propan-1-amine to Boc2O is 1: 2.
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Application publication date: 20201120 |