CN114835610A - Preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine - Google Patents
Preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine Download PDFInfo
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Abstract
The invention discloses a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, belonging to the technical field of organic compound preparation, and the preparation method comprises the following steps of reacting trans-1, 4-cyclohexanediamine with acyl chloride or sulfonyl chloride under the action of a catalyst 1 to obtain an intermediate 1; second, intermediate 1 was reacted with (Boc) 2 Reacting O in the presence of an acid-binding agent to obtain an intermediate 2; and thirdly, reacting the intermediate 2 under the conditions of a catalyst 2 and hydrogen to obtain the N-Boc-trans-1, 4-cyclohexanediamine. The preparation method adopts trans-1, 4-cyclohexanediamine as a raw material, 1 amino group in the raw material is protected, the proportion of a protective agent to 1 is not required to be strictly controlled, multi-position substitution is avoided, byproducts are less, and the purification is simple and convenient; the preparation method has the advantages of mild reaction conditions, high yield, high purity and good economic benefit.
Description
Technical Field
The invention belongs to the technical field of organic compound preparation, and particularly relates to a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine.
Background
N-Boc-trans-1, 4-cyclohexanediamine is widely used as a medical raw material, and downstream products of the N-Boc-trans-1, 4-cyclohexanediamine comprise a kinase inhibitor intermediate or a poly ADP ribosylation protein inhibition drug intermediate; the upstream product trans-1, 4-cyclohexanediamine is used as chiral organic amine with a symmetrical heterocyclic structure, is widely applied to the field of medicines, is an important medical intermediate, and plays an important role in medicine preparation. The trans-1, 4-cyclohexanediamine has two amino groups, and one of the amino groups is generally required to be protected in the reaction and then subjected to subsequent reaction.
The existing N-Boc-trans-1, 4-cyclohexanediamine is directly synthesized by adopting trans-1, 4-cyclohexanediamine and Boc anhydride, the Boc anhydride has multi-position substitution, a plurality of reaction byproducts are generated, and the purity is low; yet another method is to protect the 1-amino group with an equivalent amount of benzophenone with trans-1, 4-cyclohexanediamine, followed by reaction with Boc anhydride under basic conditions; and then reacting in an alcohol solvent under the catalysis of boron trifluoride diethyl etherate to obtain the N-Boc-trans-1, 4-cyclohexanediamine, but the method needs strict control of the dosage of the benzophenone, cannot judge whether the reaction is complete, and has harsh reaction conditions. In addition, the chinese patent application with application publication No. CN 112898178A in the prior art discloses a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, wherein trans-1, 4-cyclohexanediamine is protected with 1-amino group by equal equivalent of benzophenone, and then reacts with Boc anhydride under alkaline conditions; then reacting in an alcohol solvent under the catalysis of boron trifluoride diethyl etherate to obtain the N-Boc-trans-1, 4-cyclohexanediamine. The method avoids the technical defect that the mono-substituted product is mainly controlled only by needing a large excess of trans-1, 4-cyclohexanediamine, is beneficial to the full utilization of the expensive main raw material trans-1, 4-cyclohexanediamine and is beneficial to industrial production.
Disclosure of Invention
One of the purposes of the invention is to provide a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, which avoids multi-position substitution and has high yield and high purity.
The technical scheme adopted by the invention for realizing the purpose is as follows:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following steps,
firstly, reacting trans-1, 4-cyclohexanediamine with acyl chloride or sulfonyl chloride under the action of a catalyst 1 to obtain an intermediate 1;
second, intermediate 1 was reacted with (Boc) 2 O is obtained by reaction in the presence of an acid-binding agentIntermediate 2;
step three, reacting the intermediate 2 under the conditions of a catalyst 2 and hydrogen to obtain N-Boc-trans-1, 4-cyclohexanediamine;
catalyst 1 is pyridine or triethylamine;
the intermediate 1 is represented by formula (1-1) or formula (1-2), wherein R is C1-C12 alkyl or substituted C1-C12 alkyl, R is 1 Is C1-C12 alkyl, substituted C1-C12 alkyl, phenyl or benzyl;
the intermediate 2 is represented by formula (2-1) or formula (2-2), wherein R is C1-C12 alkyl or substituted C1-C12 alkyl, R is 1 Is C1-C12 alkyl, substituted C1-C12 alkyl, phenyl or benzyl;
The preparation method adopts trans-1, 4-cyclohexanediamine as a raw material to protect 1 amino group, does not need to strictly control the proportion of a protective agent to be 1:1, avoids multi-position substitution, has few byproducts and is simple and convenient to purify; the preparation method has the advantages of mild reaction conditions, high yield, high purity and good economic benefit.
Alternatively, in the first step, the molar ratio of trans-1, 4-cyclohexanediamine, acid chloride and catalyst 1 is from 1:1.0 to 1.2:1.5 to 3, or the molar ratio of trans-1, 4-cyclohexanediamine, acid chloride and catalyst 1 is from 1:1.0 to 1.2:1.5 to 3.
Alternatively, in the first step, the yield of intermediate 1 is greater than 93%.
Alternatively, in the second step, intermediate 1 is reacted with (Boc) 2 The molar ratio of O to the acid-binding agent is 1:1.0-2.0:1.5-3.5。
Optionally, in the second step, the acid-binding agent is NaOH aqueous solution, KOH aqueous solution, triethylamine or DMAP.
Alternatively, the yield of intermediate 2 in the second step is greater than 93%.
Optionally, in the third step, the catalyst 2 is one of palladium hydroxide, palladium on carbon, raney nickel, lithium aluminum hydride, sodium borohydride/nickel dichloride or red aluminum.
Optionally, in the third step, the hydrogen conditions are 0.5 to 5.0MPa hydrogen pressure.
Alternatively, in the third step, the yield of N-Boc-trans-1, 4-cyclohexanediamine is greater than 80%.
The preparation method of the invention has the following beneficial effects: the preparation method adopts trans-1, 4-cyclohexanediamine as a raw material to protect 1 amino group, does not need to strictly control the proportion of a protective agent to be 1:1, avoids multi-position substitution, has few byproducts and is simple and convenient to purify; the preparation method has the advantages of mild reaction conditions, high yield, high purity and good economic benefit.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to specific embodiments.
The embodiment of the invention discloses a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, which comprises the following steps of,
wherein R is C1-C12 alkyl or substituted C1-C12 alkyl.
The embodiment of the invention discloses a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, which comprises the following steps,
firstly, reacting trans-1, 4-cyclohexanediamine with acyl chloride under the action of a catalyst 1 to obtain an intermediate 1;
second, intermediate 1 was reacted with (Boc) 2 Reacting O in the presence of an acid-binding agent to obtain an intermediate 2;
and thirdly, reacting the intermediate 2 under the conditions of a catalyst 2 and hydrogen to obtain the N-Boc-trans-1, 4-cyclohexanediamine.
As an embodiment of the present invention, in the first step, the acyl chloride is selected from acetyl chloride, propionyl chloride, butyryl chloride, tert-butyryl chloride, isobutyryl chloride, valeryl chloride, isovaleryl chloride, hexanoyl chloride, isohexanoyl chloride, heptanoyl chloride, isoheptanoyl chloride, octanoyl chloride, isooctanoyl chloride, nonanoyl chloride, isononanoyl chloride, decanoyl chloride or isodecanoyl chloride.
In the first step, catalyst 1 is pyridine as an example of the present invention.
As an example of the present invention, in the first step, the molar ratio of trans-1, 4-cyclohexanediamine, acid chloride and catalyst 1 is 1:1.0-1.2: 1.5-3.
As an embodiment of the invention, in the first step, the reaction temperature is 0 ℃ to room temperature, and the reaction time is 4 to 12 hours.
As an example of the invention, in the first step, the yield of intermediate 1 is greater than 93%.
As an example of the invention, in the second step, intermediate 1 is reacted with (Boc) 2 The molar ratio of the O to the acid-binding agent is 1:1.0-2.0: 1.5-3.5.
In the second step, the acid-binding agent is NaOH aqueous solution, KOH aqueous solution, triethylamine or DMAP.
As an embodiment of the present invention, in the second step, the reaction temperature is room temperature and the reaction time is 12-72 h.
As an example of the invention, the yield of intermediate 2 in the second step is greater than 93%.
In the third step, the catalyst 2 is one of palladium hydroxide, palladium on carbon, raney nickel, lithium aluminum hydride, sodium borohydride/nickel dichloride or red aluminum.
As an embodiment of the present invention, in the third step, the hydrogen condition is 0.5 to 5.0MPa of hydrogen pressure.
In the third step, the mass ratio of the intermediate 2 to the catalyst 2 is 1: 0.05-0.5.
As an embodiment of the present invention, in the second step, the reaction temperature is room temperature and the reaction time is 12-48 h.
As an example of the present invention, in the third step, the yield of N-Boc-trans-1, 4-cyclohexanediamine was more than 80%.
As an example of the present invention, in the third step, the purity of N-Boc-trans-1, 4-cyclohexanediamine was more than 99%.
As an example of the present invention, TLC was used to check the completion of the reaction of the starting materials.
As an embodiment of the present invention, a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following steps,
firstly, adding trans-1, 4-cyclohexanediamine and a catalyst 1 into dichloromethane, dropwise adding acyl chloride at 0 ℃, wherein the molar ratio of the trans-1, 4-cyclohexanediamine to the acyl chloride to the catalyst 1 is 1:1.0-1.2:1.5-3, the solid-to-liquid ratio of the trans-1, 4-cyclohexanediamine to the dichloromethane is 1g:1-10mL, reacting at room temperature for 4-12h, spin-drying after the reaction is finished, dissolving with dichloromethane or ethyl acetate, and washing under a weak acid condition to obtain an intermediate 1;
second, intermediate 1 was reacted with (Boc) 2 Adding O into organic solvent, slowly adding acid-binding agent, reacting at room temperature for 12-72h, reacting intermediate 1 with (Boc) 2 The molar ratio of O to the acid-binding agent is 1:1.0-2.0:1.5-3.5, the solid-liquid ratio of the intermediate 1 to the organic solvent is 1g:1-10mL, the pH value is adjusted to be weak acid after the reaction is finished, dichloromethane is added to extract a reaction system, the organic phase is evaporated and concentrated, and the intermediate 2 is obtained after recrystallization and filtration;
and thirdly, dissolving the intermediate 2 in methanol, adding a catalyst 2, reacting at room temperature for 12-48h under the condition of 0.5-5.0MPa of hydrogen pressure, filtering to remove palladium-carbon after the reaction is finished, evaporating the methanol, washing by using a sodium bicarbonate aqueous solution, extracting by using dichloromethane, and drying an organic phase to obtain the N-Boc-trans-1, 4-cyclohexanediamine, wherein the mass ratio of the intermediate 2 to the catalyst 2 is 1:0.05-0.5, and the solid-liquid ratio of the intermediate 2 to the methanol is 1g:1-10 mL.
For the second step of one embodiment of the invention, the organic solvent is dichloromethane, methanol, tetrahydrofuran, or 1, 4-dioxane.
For the third step of one embodiment of the invention, catalyst 2 is palladium on carbon. Preferably, catalyst 2 is palladium on carbon with a palladium content of 1-10% by weight.
For the third step of one embodiment of the present invention, the catalyst 2 is a novel magnetic palladium-carbon, which comprises palladium and a magnetic polymer modified on the surface of the palladium-carbon, and the reaction monomers of the magnetic polymer comprise acrylic acid, acrylamide and vinyl Fe 3 O 4 Magnetic nanoparticles. The novel magnetic palladium-carbon catalyst can be used for hydrogenation reaction of an intermediate 2, has high catalytic activity, and can improve the yield of a target product to N-Boc-trans-1, 4-cyclohexanediamine. In addition, the novel magnetic palladium-carbon catalyst is easy to separate from a target product to N-Boc-trans-1, 4-cyclohexanediamine under the action of an external magnetic field, has cyclic usability, and still has high catalytic activity after being repeatedly used for 10 times.
The preparation method of the magnetic palladium-carbon of the embodiment of the invention comprises the following steps:
step 1), preparing Fe by taking ferric chloride hexahydrate, trisodium citrate and anhydrous sodium acetate as raw materials and adopting a hydrothermal reaction 3 O 4 Magnetic nanoparticles;
step 2), adding Fe 3 O 4 Reacting the magnetic nano particles with a vinyl silane coupling agent to obtain vinyl Fe 3 O 4 Magnetic nanoparticles;
step 3), mixing acrylic acid, allylamine, sodium vinylsulfonate and vinyl Fe 3 O 4 Carrying out polymerization reaction on the magnetic nanoparticles under an initiator to obtain a magnetic polymer;
and 4) modifying the palladium carbon by a magnetic polymer to obtain the novel magnetic palladium carbon.
Preferably, in the step 1), the mass ratio of ferric chloride hexahydrate, trisodium citrate, anhydrous sodium acetate and glycol is 2-4:1: 3-6.
Preferably, in the step 1), the hydrothermal reaction temperature is 180-240 ℃ and the time is 6-12 h.
Preferably, the specific steps of step 1) are adding ferric chloride hexahydrate, trisodium citrate and anhydrous sodium acetate into ethylene glycol, stirring for 1-3h at room temperature, then carrying out hydrothermal reaction for 6-12h at 180-240 ℃, cooling to room temperature, washing with ethanol and deionized water respectively2-5 times, vacuum drying to obtain Fe 3 O 4 Magnetic nanoparticles. More preferably, the dosage ratio of ferric chloride hexahydrate, trisodium citrate, anhydrous sodium acetate and glycol is 2-4g:1g:3-6g:50-100 mL.
Preferably, in step 2), the vinylsilane coupling agent is selected from the group consisting of vinyltrimethoxysilane, allyltrimethoxysilane, 3- (methacryloyloxy) propyltrimethoxysilane and acryloxymethyltrimethoxysilane.
Preferably, in step 2), Fe 3 O 4 The mass ratio of the magnetic nanoparticles to the vinyl silane coupling agent is 1: 1-3.
Preferably, the specific steps of step 2) are,
step 21), uniformly mixing absolute ethyl alcohol and deionized water, wherein the volume ratio of the absolute ethyl alcohol to the deionized water is 3-6:1, and obtaining mixed liquid-1;
step 22), adding Fe 3 O 4 Magnetic nanoparticles are added into the mixed solution-1, Fe 3 O 4 The dosage ratio of the magnetic nano particles to the mixed solution-1 is 1g:100- 3 O 4 The dosage ratio of the magnetic nano particles to the strong ammonia water is 1g:1-5mL, the magnetic nano particles and the strong ammonia water are uniformly mixed, and the mixture is-2;
step 23), dropwise adding the vinyl silane coupling agent solution into the mixed solution-2, wherein Fe is 3 O 4 The mass ratio of the magnetic nano particles to the vinyl silane coupling agent is 1:2-5, the vinyl silane coupling agent solution is ethanol solution of the vinyl silane coupling agent, the concentration of the ethanol solution is 0.1-0.3g/mL, the mixture is stirred and reacted for 4-6h at the temperature of 40-60 ℃, the mixture is uniformly dispersed, cooled to room temperature, magnetically separated, washed by ethanol and deionized water for 2-5 times respectively, and dried in vacuum, and then the vinyl Fe is obtained 3 O 4 Magnetic nanoparticles.
Preferably, in step 3), acrylic acid, allylamine, sodium vinylsulfonate and vinyl Fe 3 O 4 The mass ratio of the magnetic nano particles is 1:0.2-2:0.05-0.2: 0.1-0.5.
Preferably, in the step 3), the initiator is potassium persulfate, ammonium persulfate or sodium bisulfite, and the dosage of the initiator is propaneOlefine acid, allylamine, sodium vinylsulfonate and vinyl Fe 3 O 4 1-5wt% of the total mass of the magnetic nanoparticles.
Preferably, in step 3), the polymerization reaction temperature is 50-60 ℃ and the time is 2-8 h.
Preferably, the specific step of the step 3) is to mix acrylic acid, allylamine, sodium vinylsulfonate and vinyl Fe 3 O 4 Adding magnetic nanoparticles into deionized water, acrylic acid, allylamine, sodium vinylsulfonate and vinyl Fe 3 O 4 The mass ratio of the magnetic nano particles is 1:0.2-2:0.05-0.2:0.1-0.5, the magnetic nano particles are uniformly stirred, then the temperature is raised to 50-60 ℃, initiator aqueous solution with the concentration of 1-5g/mL is slowly added dropwise, and the dosage of the initiator is acrylic acid, allylamine, sodium vinylsulfonate and vinyl Fe 3 O 4 1-5wt% of the total mass of the magnetic nanoparticles, carrying out polymerization reaction for 2-8h, cooling, washing with ethanol and deionized water for 2-5 times respectively, drying, and crushing to obtain the magnetic polymer.
Preferably, in the step 4), the mass ratio of palladium to the magnetic polymer in the palladium on carbon is 1: 0.1-0.5.
Preferably, the specific step of the step 4) is to add palladium carbon and a magnetic polymer into methanol, wherein the mass ratio of palladium to the magnetic polymer in the palladium carbon is 1:0.1-0.5, and the dosage ratio of the palladium carbon to the methanol is 1g:5-20mL, stir for 12-24h, pump-filter, wash for 2-5 times with ethanol and deionization respectively, dry, and modify to obtain the novel magnetic palladium carbon.
The embodiment of the invention discloses a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, which comprises the following steps of,
in the formula, R 1 Is C1-C12 alkyl, substituted C1-C12 alkyl, phenyl or benzyl.
The embodiment of the invention discloses a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, which comprises the following steps,
firstly, reacting trans-1, 4-cyclohexanediamine with sulfonyl chloride under the action of a catalyst 1 to obtain an intermediate 1;
second, intermediate 1 was reacted with (Boc) 2 Reacting O in the presence of an acid-binding agent to obtain an intermediate 2;
and thirdly, reacting the intermediate 2 under the conditions of a catalyst 2 and hydrogen to obtain the N-Boc-trans-1, 4-cyclohexanediamine.
As an embodiment of the present invention, in the first step, the sulfonyl chloride is selected from benzenesulfonyl chloride, benzylsulfonyl chloride, 2-phenethylsulfonyl chloride, sulfonyl chloride, ethanesulfonyl chloride, propylsulfonyl chloride or butylsulfonyl chloride.
In the first step, catalyst 1 is triethylamine as an example of the present invention.
As an example of the present invention, in the first step, the molar ratio of trans-1, 4-cyclohexanediamine, sulfonyl chloride and catalyst 1 is 1:1.0-1.2: 1.5-3.
As an embodiment of the present invention, in the first step, the reaction temperature is 0 ℃ to room temperature.
As an example of the invention, in the first step, the yield of intermediate 1 is greater than 93%.
As an example of the invention, in the second step, intermediate 1 is reacted with (Boc) 2 The molar ratio of the O to the acid-binding agent is 1:1.0-2.0: 1.5-3.5.
In the second step, the acid-binding agent is NaOH aqueous solution, KOH aqueous solution, triethylamine or DMAP.
As an example of the invention, the yield of intermediate 2 in the second step is greater than 93%.
In the third step, the catalyst 2 is one of palladium hydroxide, palladium on carbon, raney nickel, lithium aluminum hydride, sodium borohydride/nickel dichloride or red aluminum.
As an embodiment of the present invention, in the third step, the hydrogen condition is 0.5 to 5.0MPa of hydrogen pressure.
In the third step, the mass ratio of the intermediate 2 to the catalyst 2 is 1: 0.05-0.5.
As an example of the present invention, in the third step, the yield of N-Boc-trans-1, 4-cyclohexanediamine was more than 85%.
As an embodiment of the present invention, a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following steps,
firstly, adding trans-1, 4-cyclohexanediamine and a catalyst 1 into dichloromethane, dropwise adding sulfonyl chloride at 0 ℃, wherein the molar ratio of the trans-1, 4-cyclohexanediamine to the sulfonyl chloride to the catalyst 1 is 1:1.0-1.2:1.5-3, the solid-to-liquid ratio of the trans-1, 4-cyclohexanediamine to the dichloromethane is 1g:1-10mL, reacting at room temperature for 4-12h, spin-drying a solvent after the reaction is finished, dissolving the solvent by using dichloromethane or ethyl acetate, and washing the solvent under a weak acid condition to obtain an intermediate 1;
second, intermediate 1 was reacted with (Boc) 2 Adding O into organic solvent, slowly adding acid-binding agent, reacting at room temperature for 12-72h, reacting intermediate 1 with (Boc) 2 The molar ratio of O to the acid-binding agent is 1:1.0-2.0:1.5-3.5, the solid-liquid ratio of the intermediate 1 to the organic solvent is 1g:1-10mL, the pH value is adjusted to be weak acid after the reaction is finished, dichloromethane is added to extract a reaction system, the organic phase is evaporated and concentrated, and the intermediate 2 is obtained after recrystallization and filtration;
and thirdly, dissolving the intermediate 2 in methanol, adding a catalyst 2, enabling the mass ratio of the intermediate 2 to the catalyst 2 to be 1:0.05-0.5, enabling the solid-liquid ratio of the intermediate 2 to the methanol to be 1g:1-10mL, reacting at room temperature for 12-48h under the condition of 0.5-5.0MPa of hydrogen pressure, filtering out palladium carbon after the reaction is finished, evaporating the methanol to dryness, washing with a sodium bicarbonate aqueous solution, extracting with dichloromethane, and drying an organic phase to obtain the N-Boc-trans-1, 4-cyclohexanediamine.
For the second step of one embodiment of the invention, the organic solvent is dichloromethane, methanol, tetrahydrofuran, or 1, 4-dioxane.
For the third step of one embodiment of the invention, catalyst 2 is palladium on carbon. Preferably, catalyst 2 is palladium on carbon with a palladium content of 1-10% by weight.
For the third step of one embodiment of the present invention, the catalyst 2 is a novel magnetic palladium-carbon, which comprises palladium and a magnetic polymer modified on the surface of the palladium-carbon, and the reaction monomers of the magnetic polymer comprise acrylic acid, acrylamide and vinyl Fe 3 O 4 Magnetic nanoparticles.
The experimental procedures in the following examples are conventional unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following steps:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following synthesis steps:
the first step is as follows: adding 100g of trans-1, 4-cyclohexanediamine and 103.91g of pyridine into 500mL of dichloromethane, dropwise adding 69.44g of acetyl chloride into the system at the temperature of 0 ℃, then reacting for 6h at room temperature, spin-drying the solvent after the reaction is finished, dissolving by using ethyl acetate, and washing under the weak acidic condition; the organic phase is dried, evaporated and purified to obtain 128.61g of intermediate 1, the yield is 94.7%; 1 H NMR (400MHz , DMSO) : 8.08 (s , 1H) , 5.17 (s , 2H) , 3.59 (m , 1H) , 2.62 (m , 1H) , 2.30 (m , 2H) , 1.90 (s , 3H), 1.76-1.54 (m , 8H)；
the second step is that: 128.61g of intermediate 1 were mixed with 188.65g of (Boc) 2 Adding O into 500mL of 1, 4-dioxane, slowly adding 49.41g of saturated aqueous solution prepared by NaOH into the system under the protection of nitrogen, reacting for 24h at room temperature, adding dilute hydrochloric acid to adjust the pH to be weak acid after the reaction is finished, adding dichloromethane to extract the reaction system, evaporating and concentrating an organic phase, recrystallizing, and filtering to obtain 196.25g of intermediate 2, wherein the yield is 93.4%; 1 H NMR (400MHz , DMSO) : 8.11 (s , 2H) , 3.62 (m , 2H) , 1.88 (s , 3H), 1.78-1.58 (m , 8H) , 1.43 (s , 9H)；
the third step: 196.25g of intermediate 2 is dissolved in 500mL of methanol, 29.31g of palladium carbon with the weight percentage content of 5% of palladium is added into the system, the reaction is carried out for 16h at room temperature under the condition of 2.0MPa of hydrogen pressure, the palladium carbon is filtered after the reaction is finished, the methanol is evaporated to dryness, sodium bicarbonate water solution is adopted for washing, dichloromethane is used for extraction, an organic phase is dried and the solvent is removed, 144.38g of N-Boc-trans-1, 4-cyclohexanediamine is obtained, the yield is 78.5%, and the purity is 99.1%; 1 H NMR (400MHz , DMSO) : 8.07 (s , 1H) , 5.10 (s , 2H) , 3.55 (m , 1H) , 2.61 (m , 1H) , 1.73-1.52 (m , 8H) , 1.42 (s , 9H)。
example 2:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, and the synthetic route is the same as that of example 1.
A preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following synthesis steps:
the first step is as follows: adding 100g of trans-1, 4-cyclohexanediamine and 159.32g of pyridine into 500mL of dichloromethane, dropwise adding 75.63g of acetyl chloride into the system at the temperature of 0 ℃, then reacting for 6h at room temperature, spin-drying the solvent after the reaction is finished, dissolving by using dichloromethane, and washing under a weak acid condition; the organic phase was dried, evaporated and purified to obtain 130.94g of intermediate 1 with a yield of 95.7%;
the second step is that: 130.94g of intermediate 1 were mixed with 201.20g of (Boc) 2 Adding O into 500mL of 1, 4-dichloromethane, slowly adding 73.77g of saturated aqueous solution prepared by NaOH into the system, reacting for 24h at room temperature, adding dilute hydrochloric acid after the reaction is finished to adjust the pH value to be weak acidity, adding dichloromethane to extract the reaction system, evaporating and concentrating an organic phase, recrystallizing, and filtering to obtain 203.02g of intermediate 2, wherein the yield is 94.5%;
the third step: 203.02g of intermediate 2 is dissolved in 500mL of methanol, 31.76g of palladium carbon with the weight percentage content of 5% of palladium is added into the system, the reaction is carried out for 16h at room temperature under the condition of 2.0MPa of hydrogen pressure, the palladium carbon is filtered after the reaction is finished, the methanol is evaporated to dryness, sodium bicarbonate aqueous solution is adopted for washing, dichloromethane is used for extraction, and an organic phase is dried and subjected to solvent removal to obtain 156.83g of N-Boc-trans-1, 4-cyclohexanediamine, wherein the yield is 82.4% and the purity is 99.3%.
Example 3:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, and the synthetic route is the same as that of example 1.
A preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following synthesis steps:
the first step is as follows: adding 100g of trans-1, 4-cyclohexanediamine and 207.81g of pyridine into 500mL of dichloromethane, dropwise adding 82.5g of acetyl chloride into the system at the temperature of 0 ℃, then reacting for 6h at room temperature, spin-drying the solvent after the reaction is finished, dissolving by using ethyl acetate, and washing under the weak acidic condition; the organic phase was dried, evaporated and purified to obtain 130.05g of intermediate 1 with a yield of 95.0%;
the second step is that: 130.05g of intermediate 1 were mixed with 217.89g of (Boc) 2 Adding O into 500mL of tetrahydrofuran, slowly adding 99.86g of saturated aqueous solution prepared by NaOH into the system, reacting at room temperature for 24h, adding dilute hydrochloric acid after the reaction is finished to adjust the pH value to be weak acidity, adding dichloromethane to extract the reaction system, evaporating and concentrating an organic phase, recrystallizing, and filtering to obtain 220.90g of intermediate 2, wherein the yield is 94.2%;
the third step: 220.90g of intermediate 2 is dissolved in 500mL of methanol, 34.29g of palladium carbon with the weight percentage content of 5% of palladium is added into the system, the reaction is carried out for 16h at room temperature under the condition of 2.0MPa of hydrogen pressure, the palladium carbon is filtered after the reaction is finished, the methanol is evaporated to dryness, sodium bicarbonate aqueous solution is adopted for washing, dichloromethane is used for extraction, and an organic phase is dried and subjected to solvent removal to obtain 154.69g of N-Boc-trans-1, 4-cyclohexanediamine, wherein the yield is 82.1% and the purity is 99.3%.
Example 4:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following steps:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following synthesis steps:
the first step is as follows: adding 100g of trans-1, 4-cyclohexanediamine and 138.54g of pyridine into 500mL of dichloromethane, dropwise adding 85.08g of propionyl chloride into the system at the temperature of 0 ℃, reacting for 6 hours at room temperature, spin-drying the solvent after the reaction is finished, dissolving by using dichloromethane, and washing under a weak acid condition; the organic phase was dried, evaporated and purified to obtain 142.70g of intermediate 1 with a yield of 94.6%; 1 H NMR (400MHz , DMSO) : 8.15 (s , 1H) , 5.20 (s , 2H) , 3.53 (m , 1H) , 2.55 (m , 1H) , 2.30 (m , 2H) , 1.70-1.45 (m , 8H) , 1.12 (t , 3H)；
the second step: 142.70g of intermediate 1 were mixed with 198.89g of (Boc) 2 Adding O into tetrahydrofuran, and adding the mixture into tetrahydrofuran,slowly adding an aqueous solution prepared by 92.95g of KOH into the system, reacting at room temperature for 24 hours, adding dilute hydrochloric acid after the reaction is finished to adjust the pH value to be weak acid, adding dichloromethane to extract the reaction system, evaporating and concentrating an organic phase, recrystallizing, and filtering to obtain 209.87g of intermediate 2, wherein the yield is 93.7%; 1 H NMR (400MHz , DMSO) : 8.05 (s , 2H) , 3.63 (m , 2H) , 2.30 (m , 2H) , 1.72-1.45 (m , 8H) , 1.45 (s , 9H) , 1.09 (t , 3H)；
the third step: 209.87g of intermediate 2 is dissolved in 500mL of methanol, 32.22g of palladium-carbon with the weight percentage content of 5% of palladium is added into the system, the reaction is carried out for 16h at room temperature under the condition of 2.0MPa of hydrogen pressure, the palladium-carbon is filtered after the reaction is finished, the methanol is evaporated to dryness, sodium bicarbonate water solution is adopted for washing, dichloromethane is used for extraction, and an organic phase is dried and subjected to solvent removal to obtain 150.39g of N-Boc-trans-1, 4-cyclohexanediamine, wherein the yield is 80.4%, and the purity is 99.2%.
Example 5:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, and the synthetic route is the same as that of example 4.
A preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following synthesis steps:
the first step is as follows: adding 100g of trans-1, 4-cyclohexanediamine and 152.39g of pyridine into 500mL of dichloromethane, dropwise adding 87.51g of propionyl chloride into the system at the temperature of 0 ℃, reacting for 6 hours at room temperature, spin-drying the solvent after the reaction is finished, dissolving by using dichloromethane, and washing under a weak acid condition; the organic phase is dried, evaporated and purified to obtain 144.06g of intermediate 1, the yield is 95.5%;
the second step: 144.06g of intermediate 1 were mixed with 213.56g of (Boc) 2 Adding O into methanol, slowly adding 103.22g of KOH-prepared aqueous solution into the system, reacting at room temperature for 24h, adding dilute hydrochloric acid after the reaction is finished to adjust the pH value to be weak acid, adding dichloromethane to extract the reaction system, evaporating and concentrating an organic phase, recrystallizing and filtering to obtain 213.23g of intermediate 2, wherein the yield is 94.3%;
the third step: 213.23g of intermediate 2 is dissolved in 500mL of methanol, 34.91g of palladium carbon with the weight percentage content of 5% of palladium is added into the system, the reaction is carried out for 16h at room temperature under the condition of 2.0MPa of hydrogen pressure, the palladium carbon is filtered after the reaction is finished, the methanol is evaporated to dryness, sodium bicarbonate aqueous solution is adopted for washing, dichloromethane is used for extraction, and an organic phase is dried and subjected to solvent removal to obtain 151.27g of N-Boc-trans-1, 4-cyclohexanediamine, wherein the yield is 80.5%, and the purity is 99.0%.
Example 6:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following steps:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following synthesis steps:
the first step is as follows: adding 100g of trans-1, 4-cyclohexanediamine and 138.54g of pyridine into 500mL of dichloromethane, dropwise adding 115.07g of butyryl chloride into the system at the temperature of 0 ℃, reacting for 6 hours at room temperature, spin-drying the solvent after the reaction is finished, dissolving by using dichloromethane, and washing under a weak acid condition; the organic phase was dried, evaporated and purified to obtain 142.70g of intermediate 1 with a yield of 94.2%; 1 H NMR (400MHz , DMSO) : 8.17 (s , 1H) , 5.06 (s , 2H) , 3.66 (m , 1H) , 2.59 (m , 1H) , 2.42 (t , 2H) , 1.79-1.58 (m , 8H) , 1.37 (m , 2H) , 0.96 (t , 3H)；
the second step is that: 142.70g of intermediate 1 were mixed with 198.89g of (Boc) 2 Adding O into tetrahydrofuran, slowly adding an aqueous solution prepared by 92.95g of KOH into the system, reacting at room temperature for 24 hours, adding dilute hydrochloric acid after the reaction is finished to adjust the pH value to be weak acidity, adding dichloromethane to extract the reaction system, evaporating and concentrating an organic phase, recrystallizing, and filtering to obtain 209.87g of intermediate 2, wherein the yield is 93.1%; 1 H NMR (400MHz , DMSO) : 8.10 (s , 2H) , 3.65 (m , 2H) , 2.37 (t , 2H) , 1.78-1.57 (m , 8H) , 1.42 (s , 9H) , 1.30 (m , 2H) , 0.95 (t , 3H)；
the third step: 209.87g of intermediate 2 is dissolved in 500mL of methanol, 32.22g of palladium-carbon with the weight percentage content of 5% of palladium is added into the system, the reaction is carried out for 16h at room temperature under the condition of 2.0MPa of hydrogen pressure, the palladium-carbon is filtered after the reaction is finished, the methanol is evaporated to dryness, sodium bicarbonate water solution is adopted for washing, dichloromethane is used for extraction, and an organic phase is dried and subjected to solvent removal to obtain 150.39g of N-Boc-trans-1, 4-cyclohexanediamine, wherein the yield is 80.3%, and the purity is 99.1%.
Example 7:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following steps:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following synthesis steps:
the first step is as follows: adding 100g of trans-1, 4-cyclohexanediamine and 177.24g of triethylamine into 500mL of dichloromethane, dropwise adding 170.13g of benzenesulfonyl chloride into the system at the temperature of 0 ℃, reacting for 6 hours at room temperature, spin-drying the solvent after the reaction is finished, dissolving by using dichloromethane, and washing under a weak acid condition; the organic phase was dried, evaporated and purified to give 211.6g of intermediate 1 with a yield of 95.0%; 1 H NMR (400MHz , DMSO) : 7.92 (d , 2H) , 7.79 (s , 1H) , 7.72 (t, 1H) , 7.68 (t, 2H) , 5.16 (s , 2H) , 3.04 (m , 1H) , 2.66 (m , 1H) , 1.76-1.50 (m , 8H)；
the second step is that: 211.60g of intermediate 1 were mixed with 199.73g of (Boc) 2 Adding O into tetrahydrofuran, slowly adding 185.22g of triethylamine into the system, reacting at room temperature for 24h, adding dilute hydrochloric acid after the reaction is finished to adjust the pH value to be subacidity, adding dichloromethane to extract the reaction system, evaporating and concentrating an organic phase, recrystallizing and filtering to obtain 278.09g of intermediate 2, wherein the yield is 94.3%; 1 H NMR (400MHz , DMSO) : 8.08 (s , 1H) , 7.95 (d , 2H) , 7.81 (s , 1H) , 7.74 (t, 1H) , 7.66 (t, 2H) , 3.62 (m , 1H) , 3.07 (m , 1H) , 1.78-1.55 (m , 8H) , 1.47 (s , 9H)；
the third step: 278.09g of intermediate 2 is dissolved in 500mL of methanol, 69.83g of palladium carbon with the weight percentage content of 5% of palladium is added into the system, the reaction is carried out for 16h at room temperature under the condition of 2.0MPa of hydrogen pressure, the palladium carbon is filtered after the reaction is finished, the methanol is evaporated to dryness, sodium bicarbonate aqueous solution is adopted for washing, dichloromethane is used for extraction, and an organic phase is dried and subjected to solvent removal to obtain 155.52g of N-Boc-trans-1, 4-cyclohexanediamine, the yield is 82.5%, and the purity is 99.3%.
Example 8:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, and the synthetic route is the same as that of example 7.
A preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following synthesis steps:
the first step is as follows: adding 100g of trans-1, 4-cyclohexanediamine and 177.24g of triethylamine into 500mL of dichloromethane, dropwise adding 170.13g of benzenesulfonyl chloride into the system at the temperature of 0 ℃, reacting for 6 hours at room temperature, spin-drying the solvent after the reaction is finished, dissolving by using dichloromethane, and washing under a weak acid condition; the organic phase was dried, evaporated and purified to give 211.6g of intermediate 1 with a yield of 95.0%;
the second step is that: 211.60g of intermediate 1 were mixed with 199.73g of (Boc) 2 Adding O into 500mL of tetrahydrofuran, slowly adding 203.28g of DMAP into the system, reacting at room temperature for 24h, adding dilute hydrochloric acid after the reaction is finished to adjust the pH value to be weak acid, adding dichloromethane to extract the reaction system, evaporating and concentrating an organic phase, recrystallizing and filtering to obtain 276.62g of intermediate 2, wherein the yield is 93.8%;
the third step: 276.62g of intermediate 2 is dissolved in 500mL of methanol, 53.89g of palladium-carbon with the weight percentage content of 5% of palladium is added into the system, the reaction is carried out for 16h at room temperature under the condition of 2.0MPa of hydrogen pressure, the palladium-carbon is filtered after the reaction is finished, the methanol is evaporated to dryness, sodium bicarbonate water solution is adopted for washing, dichloromethane is used for extraction, and an organic phase is dried and subjected to solvent removal to obtain 154.03g of N-Boc-trans-1, 4-cyclohexanediamine, wherein the yield is 82.1% and the purity is 99.4%.
Example 9:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following steps:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following synthesis steps:
the first step is as follows: 100g of trans-1, 4-cyclohexanediamine and 177.24g of triethylamine are added into 500mL of dichloromethane, 183.64g of benzylsulfonyl chloride is added into the system at 0 ℃, then the reaction is carried out for 6h at room temperature, and the solution is dried after the reaction is finishedDissolving the agent by using dichloromethane, and washing the agent under a weak acid condition; the organic phase was dried, evaporated and purified to give 211.6g of intermediate 1 with a yield of 93.9%; 1 H NMR (400MHz , DMSO) : 7.83 (s , 1H) , 7.45 (d , 2H) , 7.38 (t, 2H) , 7.32 (t, 1H) , 5.26 (s , 2H) , 4.45 (s , 2H) , 3.07 (m , 1H) , 2.70 (m , 1H) , 1.69-1.45 (m , 8H)；
5 .45(s , 2H) ,3.09-3.06(m ,1H) ,2.57-2.54(m ,1H) ,1 .87-1 .84(m ,4H) ,1 .49-1 .46(m ,4H) .
the second step is that: 211.60g of intermediate 1 were mixed with 199.73g of (Boc) 2 Adding O into tetrahydrofuran, slowly adding 185.22g of triethylamine into the system, reacting at room temperature for 24h, adding dilute hydrochloric acid after the reaction is finished to adjust the pH value to be weak acidity, adding dichloromethane to extract the reaction system, evaporating and concentrating an organic phase, recrystallizing and filtering to obtain 278.09g of intermediate 2, wherein the yield is 93.2%; 1 H NMR (400MHz , DMSO) : 8.11 (s , 1H) , 7.79 (s , 1H) , 7.47 (d , 2H) , 7.35 (t, 2H) , 7.28 (t, 1H) , 4.39 (s , 2H) , 3.61 (m , 1H) , 3.05 (m , 1H) , 1.75-1.52 (m , 8H) , 1.46 (s , 9H)；
the third step: 278.09g of intermediate 2 is dissolved in 500mL of methanol, 69.83g of palladium carbon with the weight percentage content of 5% of palladium is added into the system, the reaction is carried out for 16h at room temperature under the condition of 2.0MPa of hydrogen pressure, the palladium carbon is filtered after the reaction is finished, the methanol is evaporated to dryness, sodium bicarbonate aqueous solution is adopted for washing, dichloromethane is used for extraction, and an organic phase is dried and subjected to solvent removal to obtain 155.52g of N-Boc-trans-1, 4-cyclohexanediamine, the yield is 81.7%, and the purity is 99.1%.
Example 10:
the preparation method of the novel magnetic palladium-carbon comprises the following steps:
step 1), adding 5.2g of ferric chloride hexahydrate, 2g of trisodium citrate and 9.6g of anhydrous sodium acetate into 120mL of ethylene glycol, stirring at room temperature for 2h, performing hydrothermal reaction at 200 ℃ for 8h, cooling to room temperature, washing with ethanol and deionized water for 4 times respectively, and performing vacuum drying to obtain Fe 3 O 4 Magnetic nanoparticles;
step 21), uniformly mixing 200mL of absolute ethyl alcohol and 40mL of deionized water to obtain a mixed solution-1;
step 22), 2g of Fe 3 O 4 Adding the magnetic nanoparticles into 240mL of mixed solution-1, uniformly dispersing, then dropwise adding 3.5mL of concentrated ammonia water, and uniformly mixing to obtain mixed solution-2;
step 23), dropwise adding 30mL of 0.2g/mL ethanol solution of 3- (methacryloyloxy) propyltrimethoxysilane into 240mL of mixed solution-2, stirring and reacting at 50 ℃ for 6h, uniformly dispersing, cooling to room temperature, carrying out magnetic separation, washing with ethanol and deionized water for 4 times respectively, and carrying out vacuum drying to obtain the vinyl Fe 3 O 4 Magnetic nanoparticles;
step 3), 10g of acrylic acid, 5g of allylamine, 1g of sodium vinylsulfonate and 2g of vinyl Fe 3 O 4 Adding magnetic nanoparticles into deionized water, uniformly stirring, heating to 50 ℃, dropwise and slowly adding 18mL of potassium persulfate aqueous solution with the concentration of 0.02g/mL, carrying out polymerization reaction for 6 hours, cooling, washing for 4 times by using ethanol and deionized water respectively, drying, and crushing to obtain a magnetic polymer; characterization of magnetic polymers by Fourier transform infrared spectroscopy at 3500cm -1 The stretching vibration peak of N-H appears nearby, and is 3420cm -1 The expansion vibration peak of N-H appears nearby, and is at 1725cm -1 An expansion vibration peak of C = O appears in the vicinity of the ester group, and the peak is 1455cm -1 The stretching vibration peak of Si-C appears nearby at 1230cm -1 An S = O expansion and contraction vibration peak at 625cm appears nearby -1 The expansion vibration peak of Fe-O-Si appears nearby, at 575cm -1 A stretching vibration peak of Fe — O appears in the vicinity, and a characteristic absorption peak of C = C does not appear, indicating successful acquisition of the magnetic polymer.
And 4), adding 20g of palladium-carbon with palladium weight percentage content of 5% and 0.3g of magnetic polymer into 100mL of methanol, stirring for 12h, carrying out suction filtration, washing for 4 times by using ethanol and deionized water respectively, drying, and modifying to obtain the novel magnetic palladium-carbon.
A preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, and the synthetic route is the same as that of example 4.
A preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following synthesis steps:
the first step is as follows: the same as example 4;
the second step is that: the same as example 4;
the third step: 209.87g of intermediate 2 is dissolved in 500mL of methanol, 32.22g of novel magnetic palladium carbon is added into the system, the reaction is carried out for 16h at room temperature under the condition of 2.0MPa of hydrogen pressure, the palladium carbon is filtered out after the reaction is finished, the methanol is evaporated to dryness, sodium bicarbonate aqueous solution is adopted for washing, dichloromethane is adopted for extraction, and 150.39g of N-Boc-trans-1, 4-cyclohexanediamine is obtained after an organic phase is dried and desolventized, wherein the yield is 92.8%, and the purity is 99.7%. The yield of N-Boc-trans-1, 4-cyclohexanediamine in this example is significantly higher than that in example 4, which shows that the novel magnetic palladium carbon prepared in this example has higher catalytic activity and can improve the yield of the target product to N-Boc-trans-1, 4-cyclohexanediamine.
Example 11:
the preparation method of the novel magnetic palladium-carbon is the same as that of example 10.
A preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, and the synthetic route is the same as that of example 7.
A preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following synthesis steps:
the first step is as follows: the same as in example 7;
the second step is that: the same as in example 7;
the third step: 278.09g of intermediate 2 is dissolved in 500mL of methanol, 69.83g of novel magnetic palladium carbon is added into the system, the reaction is carried out for 16h at room temperature under the condition of 2.0MPa of hydrogen pressure, the palladium carbon is filtered out after the reaction is finished, the methanol is evaporated to dryness, sodium bicarbonate aqueous solution is adopted for washing, dichloromethane is adopted for extraction, and 155.52g of N-Boc-trans-1, 4-cyclohexanediamine is obtained after an organic phase is dried and desolventized, wherein the yield is 93.4%, and the purity is 99.7%. The yield of N-Boc-trans-1, 4-cyclohexanediamine in this example is significantly higher than that in example 7, which shows that the novel magnetic palladium carbon prepared in this example has higher catalytic activity and can improve the yield of the target product to N-Boc-trans-1, 4-cyclohexanediamine.
Example 12:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, and the synthetic route is the same as that of example 10.
A preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following synthesis steps:
the third step: 209.87g of intermediate 2 is dissolved in 500mL of methanol, 32.22g of novel magnetic palladium carbon (prepared in example 10 and subjected to 10 cycles of example 10) is added into the system, the mixture is reacted at room temperature under the condition of hydrogen pressure of 2.0MPa for 16h, after the reaction, the palladium carbon is filtered out, the methanol is evaporated, the obtained product is washed by sodium bicarbonate aqueous solution, dichloromethane is used for extraction, and after an organic phase is dried and the solvent is removed, 150.39g of N-Boc-trans-1, 4-cyclohexanediamine is obtained, wherein the yield is 91.8% and the purity is 99.5%. The yield of the N-Boc-trans-1, 4-cyclohexanediamine in the example is almost equivalent to that in the example 10, and is obviously higher than that in the example 4, which shows that the novel magnetic palladium carbon prepared in the example has higher catalytic activity, can improve the yield of the target product to the N-Boc-trans-1, 4-cyclohexanediamine, has cyclic usability, and still has higher catalytic activity after being repeatedly used for 10 times.
Example 13:
a preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine, and the synthetic route is the same as that of example 11.
A preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine comprises the following synthesis steps:
the third step: 278.09g of intermediate 2 is dissolved in 500mL of methanol, 69.83g of novel magnetic palladium carbon (prepared in example 10 and subjected to 10 cycles of example 11) is added into the system, the mixture is reacted at room temperature under the condition of hydrogen pressure of 2.0MPa for 16 hours, after the reaction is finished, the palladium carbon is filtered, the methanol is evaporated, the obtained product is washed by sodium bicarbonate aqueous solution and extracted by dichloromethane, and an organic phase is dried and desolventized to obtain 155.52g of N-Boc-trans-1, 4-cyclohexanediamine, wherein the yield is 92.7% and the purity is 99.6%. The yield of the N-Boc-trans-1, 4-cyclohexanediamine in the example is almost equivalent to that in the example 11, and is obviously higher than that in the example 4, which shows that the novel magnetic palladium carbon prepared in the example has higher catalytic activity, can improve the yield of the target product to the N-Boc-trans-1, 4-cyclohexanediamine, has cyclic usability, and still has higher catalytic activity after being repeatedly used for 10 times.
Conventional operations in the operation steps of the present invention are well known to those skilled in the art and will not be described herein.
The embodiments described above are intended to illustrate the technical solutions of the present invention in detail, and it should be understood that the above-mentioned embodiments are only specific embodiments of the present invention, and are not intended to limit the present invention, and any modification, supplement or similar substitution made within the scope of the principles of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. A preparation method for synthesizing N-Boc-trans-1, 4-cyclohexanediamine is characterized by comprising the following steps of,
firstly, reacting trans-1, 4-cyclohexanediamine with acyl chloride or sulfonyl chloride under the action of a catalyst 1 to obtain an intermediate 1;
second, intermediate 1 was reacted with (Boc) 2 Reacting O in the presence of an acid-binding agent to obtain an intermediate 2;
step three, reacting the intermediate 2 under the conditions of a catalyst 2 and hydrogen to obtain N-Boc-trans-1, 4-cyclohexanediamine;
the catalyst 1 is pyridine or triethylamine;
the intermediate 1 is shown as a formula (1-1) or a formula (1-2), wherein R is C1-C12 alkyl or substituted C1-C12 alkyl, and R is 1 Is C1-C12 alkyl, substituted C1-C12 alkyl, phenyl or benzyl;
the intermediate 2 is shown as a formula (2-1) or a formula (2-2), wherein R is C1-C12 alkyl or substituted C1-C12 alkyl, and R is 1 Is C1-C12 alkyl, substituted C1-C12 alkyl, phenyl or benzyl;
2. The preparation method of claim 1, wherein in the first step, the molar ratio of trans-1, 4-cyclohexanediamine to acid chloride to catalyst 1 is 1:1.0-1.2:1.5-3, or the molar ratio of trans-1, 4-cyclohexanediamine to acid chloride to catalyst 1 is 1:1.0-1.2: 1.5-3.
3. The process of claim 1, wherein the yield of intermediate 1 in the first step is greater than 93%.
4. The process of claim 1, wherein in the second step, intermediate 1 is reacted with (Boc) 2 The molar ratio of the O to the acid-binding agent is 1:1.0-2.0: 1.5-3.5.
5. The method of claim 1, wherein in the second step, the acid-binding agent is NaOH, KOH, triethylamine, or DMAP.
6. The process of claim 1, wherein the yield of intermediate 2 in the second step is greater than 93%.
7. The method as claimed in claim 1, wherein in the third step, the catalyst 2 is one of palladium hydroxide, palladium on carbon, raney nickel, lithium aluminum hydride, sodium borohydride/nickel dichloride or red aluminum.
8. The process of claim 1, wherein the hydrogen pressure in the third step is 0.5-5.0 MPa.
9. The method as claimed in claim 1, wherein the yield of N-Boc-trans-1, 4-cyclohexanediamine in the third step is greater than 80%.
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| CN102432780A (en) * | 2011-09-16 | 2012-05-02 | 复旦大学 | Surface carboxyl-functionalized core-shell type magnetic composite microballoons and preparation method thereof |
| CN111867592A (en) * | 2018-01-04 | 2020-10-30 | G1治疗公司 | Heterocyclic compounds for the treatment of abnormal cell proliferation |
| CN112898178A (en) * | 2021-01-25 | 2021-06-04 | 蚌埠产品质量监督检验研究院 | Preparation method of N-Boc-trans-1, 4-cyclohexanediamine |
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| CN110114353B (en) * | 2016-12-27 | 2022-04-22 | 山东大学 | Benzo [ b ] thiophene amide derivative and application thereof |
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| CN102432780A (en) * | 2011-09-16 | 2012-05-02 | 复旦大学 | Surface carboxyl-functionalized core-shell type magnetic composite microballoons and preparation method thereof |
| CN111867592A (en) * | 2018-01-04 | 2020-10-30 | G1治疗公司 | Heterocyclic compounds for the treatment of abnormal cell proliferation |
| CN112898178A (en) * | 2021-01-25 | 2021-06-04 | 蚌埠产品质量监督检验研究院 | Preparation method of N-Boc-trans-1, 4-cyclohexanediamine |
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