CN111548275A - Synthetic method of 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride - Google Patents
Synthetic method of 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride Download PDFInfo
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- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C07C209/50—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of carboxylic acid amides
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- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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Abstract
The invention provides a method for synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride, which comprises the following steps: s1, reacting malonic acid dicarboxylic acid with DMF-DMA to generate an intermediate 1; s2, carrying out nickel hydrogenation on the intermediate 1 to obtain an intermediate 2; s3, carrying out amine ester exchange on the intermediate 2 in benzylamine to obtain an intermediate 3; s4, reducing the intermediate 3 by lithium aluminum hydride to obtain an intermediate 4; s5, hydrogenation of intermediate 4 under acidic conditions to give 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride. The raw materials adopted by the synthesis method of the 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride provided by the invention are conventional chemical reagents, are easy to obtain and cheap, and the reaction in the whole synthesis process belongs to a common reaction type, is relatively stable and easy to repeat, and has high yield, so that the method is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride.
Background
AP20187 is a cell permeable molecule that dimerizes FK506 binding proteins (FKBPs), initiates biological signaling cascades and gene expression, or disrupts protein-protein interactions. The AP20187 can be widely applied to clinical and medicine research and development. 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride is an important intermediate of an active molecule AP20187, and the chemical structure of the intermediate is as follows in the field of medicine:
the existing synthetic route is as follows, malononitrile is condensed to obtain an intermediate 1, the intermediate 1 is hydrogenated to obtain a free product, and the free product has quite large water solubility and cannot be purified; and continuously adding a protecting group in a free state of the crude product, then carrying out purification treatment, and removing the protecting group under an acidic condition to obtain a pure hydrochloric acid product.
In the above synthetic route, the yield of the intermediate 1 in the hydrogenation process is only below 5%, even no product can be seen, and the subsequent reaction purification cannot be carried out at all, thereby causing the failure of the whole route and obtaining no target product.
Therefore, there is a need for a method for successfully synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a synthesis method of 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride, the synthesis method has the advantages of easily available and cheap raw materials, common reaction types of functional group conversion and high yield of target products.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a synthetic method of 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride, which comprises the following synthetic route and synthetic steps:
step one, synthesizing an intermediate 1:
dissolving dimethyl malonate in DMF-DMA (N, N-dimethylformamide dimethyl acetal), and heating to 40-55 ℃ for reaction for 4-6 hours; after the reaction is finished, removing excessive DMF-DMA by spinning to obtain a crude product, purifying by column chromatography, and then eluting to obtain an intermediate 1;
step two, synthesizing an intermediate 2:
dissolving the intermediate 1 in an organic solvent, adding raney nickel and organic alkali, and heating to 60-80 ℃ under the protection of hydrogen to react for 14-18 hours; after the reaction is finished, cooling the reaction system to room temperature, pouring out supernatant, cleaning the solid with an organic solvent, and pouring out the supernatant; mixing the supernatants, and spin-drying to obtain crude intermediate 2;
step three, synthesizing an intermediate 3:
dissolving the intermediate 2 in an organic solvent, adding benzylamine and organic base, heating to 50-70 ℃, and carrying out reflux reaction for 6-10 hours; then carrying out vacuum spin drying and purifying to obtain an intermediate 3;
step four, synthesizing an intermediate 4:
under the protection of nitrogen, adding a reducing agent into an anhydrous dry reaction bottle, sequentially and respectively adding a solvent and an intermediate 3 at the temperature of 0 ℃, slowly raising the temperature to 40-60 ℃ and reacting for 15-20 hours; after the reaction is finished, cooling, slowly dripping water, a sodium hydroxide aqueous solution and water in sequence, stirring, filtering and spin-drying to obtain an intermediate 4;
step five, synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride:
dissolving the intermediate 4 in an organic solvent, adding an acidic solvent and palladium carbon, heating to 40-60 ℃ under the protection of hydrogen, and reacting for 16-20 hours to obtain 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride.
Further, the eluent used in column chromatography in step one is petroleum ether: ethyl acetate ═ 3: 1.
further, the reaction conditions in the first step were 50 ℃ and the reaction was carried out for 5 hours.
Further, the organic solvent in the second step is methanol, ethanol or isopropanol.
Further preferably, the organic solvent of step two is methanol.
Further, the organic base in the second step is triethylamine, dipropylethylamine or N-methylmorpholine.
Further preferably, the organic base of step two is triethylamine.
Further, the reaction conditions of the second, fourth and fifth steps are all 60 ℃ and the reaction is carried out for 16 hours.
Further, the organic solvent in the third step is dioxane, chloroform, methanol or ethanol.
Further preferably, the organic solvent of step three is methanol.
Further, the organic base in the third step is diisopropylethylamine, triethylamine or DBU.
Further preferably, the organic base of step three is triethylamine.
Further, the reaction conditions in the third step were 60 ℃ and the reaction was performed under reflux for 6 hours.
Further, the reducing agent in the fourth step is lithium aluminum hydride or borane.
Further preferably, the reducing agent of step four is lithium aluminum hydride.
Further, the solvent of step four is tetrahydrofuran or methyltetrahydrofuran.
Further preferably, the solvent of step four is tetrahydrofuran.
Further, the organic solvent in the fifth step is methanol or ethanol.
Further preferably, the organic solvent of step five is methanol.
Further, the acidic solvent in the fifth step is hydrogen chloride methanol, hydrogen chloride dioxane or hydrogen chloride ethanol.
Further preferably, the acidic solvent of step five is hydromethanol.
Further, step five also includes: after the reaction is finished, cooling the reaction system, filtering the palladium-carbon, leaching a filter cake once by using methanol, carrying out vacuum spin-drying on mother liquor to obtain a white solid, pulping and filtering the white solid by using acetic acid and acetic acid, and drying the white solid to obtain 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride.
By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:
the raw materials adopted by the synthesis method of the 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride provided by the invention are conventional chemical reagents, are easy to obtain and cheap, and the reaction in the whole synthesis process belongs to a common reaction type, is relatively stable and easy to repeat, and has high yield, so that the method is suitable for large-scale industrial production.
Detailed Description
The invention provides a synthetic method of 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride, which comprises the following synthetic route and synthetic steps:
step one, synthesizing an intermediate 1:
dissolving dimethyl malonate in DMF-DMA (N, N-dimethylformamide dimethyl acetal), and heating to 40-55 ℃ for reaction for 4-6 hours; after the reaction is finished, removing excessive DMF-DMA by spinning to obtain a crude product, purifying by column chromatography, and then eluting to obtain an intermediate 1;
step two, synthesizing an intermediate 2:
dissolving the intermediate 1 in an organic solvent, adding raney nickel and organic alkali, and heating to 60-80 ℃ under the protection of hydrogen to react for 14-18 hours; after the reaction is finished, cooling the reaction system to room temperature, pouring out supernatant, cleaning the solid with an organic solvent, and pouring out the supernatant; mixing the supernatants, and spin-drying to obtain crude intermediate 2;
step three, synthesizing an intermediate 3:
dissolving the intermediate 2 in an organic solvent, adding benzylamine and organic base, heating to 50-70 ℃, and carrying out reflux reaction for 6-10 hours; then carrying out vacuum spin drying and purifying to obtain an intermediate 3;
step four, synthesizing an intermediate 4:
under the protection of nitrogen, adding a reducing agent into an anhydrous dry reaction bottle, sequentially and respectively adding a solvent and an intermediate 3 at the temperature of 0 ℃, slowly raising the temperature to 40-60 ℃ and reacting for 15-20 hours; after the reaction is finished, cooling, slowly dripping water, a sodium hydroxide aqueous solution and water in sequence, stirring, filtering and spin-drying to obtain an intermediate 4;
step five, synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride:
dissolving the intermediate 4 in an organic solvent, adding an acidic solvent and palladium carbon, heating to 40-60 ℃ under the protection of hydrogen, and reacting for 16-20 hours to obtain 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride.
In a preferred embodiment of the present invention, the eluent used in column chromatography in step one is petroleum ether: ethyl acetate ═ 3: 1.
in a preferred embodiment of the present invention, the reaction conditions in step one are 50 ℃ and the reaction time is 5 hours.
In a preferred embodiment of the present invention, the organic solvent in step two is methanol, ethanol or isopropanol. Further, the organic solvent of the second step is methanol.
In a preferred embodiment of the present invention, the organic base of step two is triethylamine, dipropylethylamine or N-methylmorpholine. Further, the organic base in the second step is triethylamine.
In a preferred embodiment of the present invention, the reaction conditions of steps two, four and five are all 60 ℃ for 16 hours.
In a preferred embodiment of the present invention, the organic solvent in step three is dioxane, chloroform, methanol or ethanol. Further, the organic solvent in the third step is methanol.
In a preferred embodiment of the present invention, the organic base of step three is diisopropylethylamine, triethylamine or DBU. Further, the organic base in the third step is triethylamine.
In a preferred embodiment of the present invention, the reaction conditions in step three are 60 ℃ and the reaction is performed under reflux for 6 hours.
In a preferred embodiment of the present invention, the reducing agent of step four is lithium aluminum hydride or borane. Further, the reducing agent in the fourth step is lithium aluminum hydride.
In a preferred embodiment of the present invention, the solvent of step four is tetrahydrofuran or methyltetrahydrofuran. Further, the solvent of step four is tetrahydrofuran.
In a preferred embodiment of the present invention, the organic solvent in step five is methanol or ethanol. Further, the organic solvent of the fifth step is methanol.
In a preferred embodiment of the present invention, the acidic solvent in step five is hydrogen chloride methanol, hydrogen chloride dioxane or hydrogen chloride ethanol. Further, the acidic solvent of step five is hydromethanol.
In a preferred embodiment of the present invention, step five further includes: after the reaction is finished, cooling the reaction system, filtering the palladium-carbon, leaching a filter cake once by using methanol, carrying out vacuum spin-drying on mother liquor to obtain a white solid, pulping and filtering the white solid by using acetic acid and acetic acid, and drying the white solid to obtain 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride.
The present invention will be described in detail and specifically with reference to the following examples to facilitate better understanding of the present invention, but the following examples do not limit the scope of the present invention.
Example 1
This example provides a preferred method for synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride, comprising the steps of:
step one, dissolving 26.4g (0.2mol) of dimethyl malonate in 50ml of DMF-DMA, heating to 55 ℃ for reaction for 4 hours, after the reaction is finished, removing excessive DMF-DMA to obtain a crude product, and purifying by column chromatography, wherein an eluent is petroleum ether: ethyl acetate ═ 3: 1 to give intermediate 1(30g) in 80% yield as a pale yellow liquid.
And step two, dissolving 130 g (0.16mol) of the intermediate in 300ml of methanol, adding leini mud (20g, wet weight) and triethylamine (5ml) to the mixture, heating the mixture to 60 ℃ under the protection of hydrogen, reacting for 16 hours, cooling the reaction system to room temperature after the reaction is finished, pouring out supernatant, washing the solid with methanol twice, pouring out the supernatant, combining the supernatants, and performing spin drying to obtain a crude intermediate 2(25g), wherein the yield is 82.5 percent, the crude intermediate is light yellow liquid, and the crude intermediate is directly used for the next reaction.
Step three, dissolving 225 g (0.13mol) of the intermediate in 200ml of anhydrous methanol, adding benzylamine (35g, 0.33mol) and triethylamine (26.26g, 0.26mol), then heating to 70 ℃, refluxing for 6 hours, and after the reaction is finished, performing vacuum rotation on the methanol and the triethylamine to obtain a crude intermediate 3. Purifying by column chromatography, wherein an eluent is petroleum ether: ethyl acetate: triethylamine ═ 3: 1: 0.1, pure intermediate 3(25.6g) was obtained in 56% yield as a pale yellow solid.
Step four, under the protection of nitrogen, adding lithium aluminum hydride (8.6g, 0.23mol) into an anhydrous dry reaction bottle, cooling to 0 ℃ in an ice bath, firstly dropwise adding 20ml of anhydrous tetrahydrofuran, uniformly stirring, dropwise adding the intermediate 3(25.6g, 0.075mol) into the anhydrous dry reaction bottle, dissolving the intermediate in 200ml of anhydrous tetrahydrofuran, controlling the temperature to be below 20 ℃, and slowly raising the temperature to 60 ℃ for reaction for 16 hours after dropwise adding; after the reaction is finished, cooling to 0 ℃, slowly dropwise adding 8.6ml of water, dropwise adding 8.6ml of 10% sodium hydroxide aqueous solution, finally dropwise adding 25.8ml of water, controlling the temperature in the whole dropwise adding process to be below 5 ℃, stirring for 1 hour at 0 ℃ after the dropwise adding is finished, filtering the reaction system, leaching a filter cake twice by using acetic acid, drying the mother liquor anhydrous sodium sulfate again, filtering, and spin-drying to obtain an intermediate 4(13.8g) with yield of 58% which is light yellow liquid.
Step five, dissolving the intermediate 4(13.8g, 0.044mol) in 120ml of methanol, adding 30ml of hydrogen chloride methanol solution and palladium-carbon (1.0g), heating to 60 ℃ under the protection of hydrogen, and adding reflux for reaction for 16 hours; after the reaction is finished, cooling the reaction system to room temperature, filtering the palladium-carbon, leaching a filter cake once by using methanol, carrying out vacuum spin-drying on a mother solution to obtain a white solid, pulping the white solid by using acetic acid (20ml), filtering the white solid, and drying the white solid to obtain 5.3g of 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride.
LC-MS(ESI):(M+H+)＝132.2
1H NMR(400MHz,MeOD)2.63(d，J＝8.4Hz,4H)，2.31(s，6H)2.13(d，J＝11.2Hz，2H)1.41-1.36(m，1H).
The 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride obtained in this example was a white solid with a yield of 50%.
Example 2
This example provides a preferred method for synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride, comprising the steps of:
step one, dissolving 26.4g (0.2mol) of dimethyl malonate in chloroform (30ml), adding 50ml of DMF-DMA, heating to 50 ℃ for reaction for 4.5 hours, after the reaction is finished, removing the chloroform and excessive DMF-DMA to obtain a crude product, and purifying by column chromatography, wherein an eluent is petroleum ether: ethyl acetate ═ 3: 1 to give intermediate 1(30g) in 80% yield as a pale yellow liquid.
Step two, dissolving 130 g (0.16mol) of the intermediate in 300ml of isopropanol, adding leini mud (20g, wet weight) and dipropylethylamine (5ml) under the protection of hydrogen, heating to 60 ℃ for reaction for 16 hours, cooling the reaction system to room temperature after the reaction is finished, pouring out supernatant, washing the solid twice with isopropanol, pouring out supernatant, combining the supernatants, and performing spin drying to obtain a crude intermediate 2(23g), wherein the yield is 76.7 percent, and the crude intermediate is a light yellow liquid and is directly used for the next reaction.
Step three, dissolving 223 g (0.12mol) of the intermediate in 200ml of anhydrous methanol, adding benzylamine (35g, 0.33mol) and dipropylethylamine (33.5g, 0.26mol), then heating to 65 ℃, carrying out reflux reaction for 7 hours, and after the reaction is finished, carrying out vacuum rotation on the methanol and the dipropylethylamine to obtain a crude intermediate 3. Purifying by column chromatography, wherein an eluent is petroleum ether: ethyl acetate: triethylamine ═ 3: 1: 0.1, obtaining a pure intermediate 3(24.2g), with the yield of 60.5 percent and light yellow solid.
Step four, under the protection of nitrogen, adding lithium aluminum hydride (8.1g, 0.21mol) into an anhydrous dry reaction bottle, cooling to 0 ℃ in an ice bath, firstly dropwise adding 20ml of anhydrous tetrahydrofuran, uniformly stirring, dropwise adding the intermediate 3(24.2g, 0.071mol) and dissolving in 200ml of anhydrous tetrahydrofuran, controlling the temperature to be below 20 ℃, and slowly raising the temperature to 60 ℃ for reacting for 16 hours after dropwise adding; after the reaction is finished, cooling to 0 ℃, slowly dropwise adding 8.1ml of water, dropwise adding 8.1ml of 10% sodium hydroxide aqueous solution, finally dropwise adding 24.3ml of water, controlling the temperature in the whole dropwise adding process to be below 5 ℃, stirring for 1 hour at 0 ℃ after the dropwise adding is finished, filtering the reaction system, leaching a filter cake twice by using acetic acid, drying the mother liquor anhydrous sodium sulfate again, filtering, and spin-drying to obtain an intermediate (11.3g) with the yield of 51% which is light yellow liquid.
Step five, dissolving the intermediate 4(11.3g, 0.036mol) in 100ml ethanol, adding 20ml ethanol solution of hydrogen chloride and palladium-carbon (1.1g), heating to 60 ℃ under the protection of hydrogen, and adding reflux to react for 17 hours; after the reaction is finished, cooling the reaction system to room temperature, filtering the palladium-carbon, leaching a filter cake once by using methanol, carrying out vacuum spin-drying on a mother solution to obtain a white solid, pulping and filtering the white solid by using acetic acid (20ml), and drying the white solid to obtain 4.4g of 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride.
LC-MS(ESI):(M+H+)＝132.2
1H NMR(400MHz,MeOD)2.63(d，J＝8.4Hz,4H)，2.31(s，6H)2.13(d，J＝11.2Hz，2H)1.41-1.36(m，1H).
The 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride obtained in this example was a white solid with a yield of 51%.
Example 3
This example provides a preferred method for synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride, comprising the steps of:
step one, dissolving 26.4g (0.2mol) of dimethyl malonate in carbon tetrachloride (30ml), adding into 50ml of DMF-DMA, heating to 40 ℃ for reaction for 5 hours, after the reaction is finished, removing the carbon tetrachloride and the excessive DMF-DMA by spinning to obtain a crude product, purifying by column chromatography, wherein an eluent is petroleum ether: ethyl acetate ═ 3: 1 to give intermediate 1(28g) in 74.8% yield as a pale yellow liquid.
And step two, dissolving 128 g (0.15mol) of the intermediate in 300ml of ethanol, adding Raney nickel (20g, wet weight) and N-methylmorpholine (5ml) under the protection of hydrogen, heating to 60 ℃ for reacting for 16 hours, cooling the reaction system to room temperature after the reaction is finished, pouring out supernatant, washing the solid twice with ethanol, pouring out supernatant, combining the supernatants, and performing spin drying to obtain a crude intermediate 2(22.6g), wherein the yield is 80%, the crude intermediate is light yellow liquid, and the crude intermediate is directly used for the next reaction.
Step three, dissolving 222.6 g (0.12mol) of the intermediate in 200ml of anhydrous methanol, adding benzylamine (32g, 0.30mol) and triethylamine (24.15g, 0.24mol), then heating to 60 ℃, carrying out reflux reaction for 8 hours, and after the reaction is finished, carrying out vacuum rotation on the methanol and the triethylamine to obtain a crude intermediate 3. Purifying by column chromatography, wherein an eluent is petroleum ether: ethyl acetate: triethylamine ═ 3: 1: 0.1, intermediate 3(22.3g) was obtained as a pure product in 55% yield as a pale yellow solid.
Step four, adding lithium aluminum hydride (7.5g, 0.20mol) into an anhydrous dry reaction bottle under the protection of nitrogen, cooling to 0 ℃ in an ice bath, firstly dropwise adding 15ml of anhydrous tetrahydrofuran, uniformly stirring, dropwise adding the intermediate 3(22.3g, 0.066mol) into 200ml of anhydrous tetrahydrofuran, controlling the temperature to be below 20 ℃, and slowly raising the temperature to 60 ℃ for reacting for 16 hours after dropwise adding; after the reaction is finished, cooling to 0 ℃, slowly dropwise adding 7.5ml of water, dropwise adding 7.5ml of 10% sodium hydroxide aqueous solution, finally dropwise adding 22.5ml of water, controlling the temperature in the whole dropwise adding process to be below 5 ℃, stirring for 1 hour at 0 ℃ after the dropwise adding is finished, filtering the reaction system, leaching a filter cake twice by using acetic acid, drying the mother liquor again by using anhydrous sodium sulfate, filtering, and spin-drying to obtain an intermediate 4(12.3g) with the yield of 60%, wherein the yield is light yellow liquid.
Step five, dissolving the intermediate 4(12.3g, 0.039mol) in 100ml ethanol, adding 20ml of hydrogen chloride ethanol solution and palladium-carbon (1.0g), heating to 50 ℃ under the protection of hydrogen, and adding reflux for reacting for 18 hours; after the reaction is finished, cooling the reaction system to room temperature, filtering the palladium-carbon, leaching a filter cake with ethanol once, carrying out vacuum spin-drying on a mother solution to obtain a white solid, pulping the white solid with acetic acid (20ml), filtering the white solid, and drying the white solid to obtain 4.7g of 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride.
LC-MS(ESI):(M+H+)＝132.2
1H NMR(400MHz,MeOD)2.63(d，J＝8.4Hz,4H)，2.31(s，6H)2.13(d，J＝11.2Hz，2H)1.41-1.36(m，1H).
The 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride obtained in this example was a white solid with a yield of 49.5%.
Example 4
This example provides a preferred method for synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride, comprising the steps of:
step one, dissolving 26.4g (0.2mol) of dimethyl malonate in 50ml of DMF-DMA, heating to 50 ℃ for reaction for 6 hours, after the reaction is finished, removing excessive DMF-DMA to obtain a crude product, and purifying by column chromatography, wherein an eluent is petroleum ether: ethyl acetate ═ 3: 1 to give intermediate 1(29g) in 77.3% yield as a pale yellow liquid.
Step two, dissolving 129 g (0.15.5mol) of the intermediate in 290ml of methanol, adding Raney nickel (19.3g, wet weight) and triethylamine (5ml) to the mixture, heating the mixture to 65 ℃ under the protection of hydrogen, reacting for 16 hours, cooling the reaction system to room temperature after the reaction is finished, pouring out supernatant, washing the solid with methanol twice, pouring out the supernatant, combining the supernatants, and spin-drying to obtain a crude intermediate 2(23g), wherein the yield is 78.5 percent, and the crude intermediate is light yellow liquid and is directly used for the next reaction.
Step three, dissolving 223 g (0.12mol) of the intermediate in 190ml of anhydrous methanol, adding benzylamine (28.6g, 0.0.27mol) and triethylamine (24.58g, 0.24mol), then heating to 50 ℃, reacting for 10 hours, and after the reaction is finished, performing vacuum rotation on methanol and triethylamine to obtain a crude intermediate 3. Purifying by column chromatography, wherein an eluent is petroleum ether: ethyl acetate: triethylamine ═ 3: 1: 0.1, intermediate 3(22.6g) was obtained as a pure product in 55% yield as a pale yellow solid.
Step four, adding lithium aluminum hydride (7.6g, 0.20mol) into an anhydrous dry reaction bottle under the protection of nitrogen, cooling to 0 ℃ in an ice bath, firstly dropwise adding 20ml of anhydrous tetrahydrofuran, uniformly stirring, dropwise adding the intermediate 3(22.6g, 0.067mol) into 180ml of anhydrous tetrahydrofuran, controlling the temperature to be below 20 ℃, and slowly raising the temperature to 50 ℃ for reaction for 20 hours after dropwise adding; after the reaction is finished, cooling to 0 ℃, slowly dropwise adding 7.6ml of water, dropwise adding 7.6ml of 10% sodium hydroxide aqueous solution, finally dropwise adding 22.8ml of water, controlling the temperature in the whole dropwise adding process to be below 5 ℃, stirring for 1 hour at 0 ℃ after the dropwise adding is finished, filtering the reaction system, leaching a filter cake twice by using acetic acid, drying the mother liquor anhydrous sodium sulfate again, filtering, and spin-drying to obtain an intermediate 4(11.8g) with the yield of 57%, wherein the yield is light yellow liquid.
Step five, dissolving the intermediate 4(11.8g, 0.038mol) in 110ml of methanol, adding 28ml of hydrogen chloride methanol solution and palladium-carbon (0.9g), and heating to 40 ℃ under the protection of hydrogen to react for 20 hours; after the reaction is finished, cooling the reaction system to room temperature, filtering the palladium-carbon, leaching a filter cake once with methanol, carrying out vacuum spin-drying on a mother solution to obtain a white solid, pulping the white solid with acetic acid acetate (18ml), filtering, and drying to obtain 4.5g of 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride.
LC-MS(ESI):(M+H+)＝132.2
1H NMR(400MHz,MeOD)2.63(d，J＝8.4Hz,4H)，2.31(s，6H)2.13(d，J＝11.2Hz，2H)1.41-1.36(m，1H).
The 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride obtained in this example was a white solid with a yield of 49.5%.
The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.
Claims (10)
1. The synthesis method of 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride is characterized by comprising the following synthetic route and synthetic steps:
step one, synthesizing an intermediate 1:
dissolving dimethyl malonate in DMF-DMA, heating to 40-55 deg.c and reacting for 4-6 hr; after the reaction is finished, removing excessive DMF-DMA by spinning to obtain a crude product, purifying by column chromatography, and then eluting to obtain an intermediate 1;
step two, synthesizing an intermediate 2:
dissolving the intermediate 1 in an organic solvent, adding raney nickel and organic alkali, and heating to 60-80 ℃ under the protection of hydrogen to react for 14-18 hours; after the reaction is finished, cooling the reaction system to room temperature, pouring out supernatant, cleaning the solid with an organic solvent, and pouring out the supernatant; mixing the supernatants, and spin-drying to obtain a crude product, namely the intermediate 2;
step three, synthesizing an intermediate 3:
dissolving the intermediate 2 in an organic solvent, adding benzylamine and organic base, heating to 50-70 ℃, and carrying out reflux reaction for 6-10 hours; then carrying out vacuum spin drying and purifying to obtain an intermediate 3;
step four, synthesizing an intermediate 4:
under the protection of nitrogen, adding a reducing agent into an anhydrous dry reaction bottle, sequentially and respectively adding a solvent and the intermediate 3 at the temperature of 0 ℃, and slowly raising the temperature to 40-60 ℃ for reaction for 15-20 hours; after the reaction is finished, cooling, adding water, sodium hydroxide aqueous solution and water slowly and dropwise in sequence, stirring, filtering and spin-drying to obtain an intermediate 4;
step five, synthesizing the 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride:
dissolving the intermediate 4 in an organic solvent, adding an acidic solvent and palladium carbon, heating to 40-60 ℃ under the protection of hydrogen, and reacting for 16-20 hours to obtain the 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride.
2. The method for synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride according to claim 1, wherein the reaction conditions in the first step are 50 ℃ and 5 hours.
3. The method for synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride according to claim 1, wherein the organic solvent in step two is methanol, ethanol or isopropanol.
4. The method for synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride according to claim 1, wherein the organic base in step two is triethylamine, dipropylethylamine or N-methylmorpholine.
5. The method for synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride according to claim 1, wherein the reaction conditions in the second, fourth and fifth steps are 60 ℃ and 16 hours.
6. The method for synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride according to claim 1, wherein the organic solvent in step three is dioxane, chloroform, methanol or ethanol.
7. The method for synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride according to claim 1, wherein the reaction conditions in step three are 60 ℃ and the reaction is performed under reflux for 6 hours.
8. The method for synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride according to claim 1, wherein the reducing agent in step four is lithium aluminum hydride or borane.
9. The method for synthesizing 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride according to claim 1, wherein the acidic solvent in step five is hydrogen chloride methanol, hydrogen chloride dioxane or hydrogen chloride ethanol.
10. The method of claim 1 for the synthesis of 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride, wherein step five further comprises: and after the reaction is finished, cooling the reaction system, filtering the palladium-carbon, leaching a filter cake once by using methanol, carrying out vacuum spin-drying on the mother liquor to obtain a white solid, pulping and filtering the white solid by using acetic acid and acetic acid, and drying the white solid to obtain the 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride.
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