CN113999197A - Preparation method of 4-aminomethyl tetrahydropyran - Google Patents
Preparation method of 4-aminomethyl tetrahydropyran Download PDFInfo
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- CN113999197A CN113999197A CN202111409943.6A CN202111409943A CN113999197A CN 113999197 A CN113999197 A CN 113999197A CN 202111409943 A CN202111409943 A CN 202111409943A CN 113999197 A CN113999197 A CN 113999197A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a preparation method of 4-aminomethyl tetrahydropyran, which comprises the following steps: the method comprises the following steps: step one, adding 150ml of dichloromethane, 1g of DMAP and 50g of tetrahydropyran-4-formic acid into a 500ml three-neck flask, stirring and dropwise adding 73g of oxalyl chloride in an ice water bath, and heating to room temperature after dropwise adding is finished, and stirring and reacting for 2 hours; after the reaction is finished, dropwise adding the reaction solution into 100ml of ammonia water, continuously stirring for 1 hour and separating the solution; extracting in 100ml of water phase dichloromethane, combining organic phases, washing with water, then washing with brine, drying and filtering by using anhydrous sodium sulfate, and spin-drying the liquid to obtain 46g of 4-formamido tetrahydropyran; and step two, under the operation of no water and no oxygen, adding 120ml of anhydrous tetrahydrofuran into a 500ml three-necked bottle, and adding 40g of 4-formamido tetrahydropyran. The preparation method of the drug intermediate 4-aminomethyl tetrahydropyran has mild reaction conditions and high yield, and is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the technical field of intermediate synthesis, and particularly relates to a preparation method of 4-aminomethyl tetrahydropyran.
Background
4-aminomethyl tetrahydropyran is an intermediate fragment of venetocalax, an anticancer drug on the market, and is also a molecular composition of anticancer drugs based on a series of Bcl-2 protein inhibitors (CN 201810661179.3).
The literature reports that 4-cyanotetrahydropyran is reduced by lithium aluminum hydride (WO 2005066126) or is subjected to catalytic hydrogenation (WO 2018029711), and the method has the disadvantages of expensive raw materials and high danger of lithium aluminum hydride and is not easy to realize commercial production.
Disclosure of Invention
In view of the problems mentioned in the background, it is an object of the present invention to provide a method for preparing 4-aminomethyl tetrahydropyran, which solves the problems mentioned in the background.
The technical purpose of the invention is realized by the following technical scheme:
a preparation method of 4-aminomethyl tetrahydropyran comprises the following steps:
step one, adding 150ml of dichloromethane, 1g of DMAP and 50g of tetrahydropyran-4-formic acid into a 500ml three-neck flask, stirring and dropwise adding 73g of oxalyl chloride in an ice water bath, and heating to room temperature after dropwise adding is finished, and stirring and reacting for 2 hours; after the reaction is finished, dropwise adding the reaction solution into 100ml of ammonia water, continuously stirring for 1 hour and separating the solution; extracting in 100ml of water phase dichloromethane, combining organic phases, washing with water, then washing with brine, drying and filtering by using anhydrous sodium sulfate, and spin-drying the liquid to obtain 46g of 4-formamido tetrahydropyran;
step two, under the anhydrous and anaerobic operation, adding 120ml of anhydrous tetrahydrofuran into a 500ml three-necked bottle, adding 40g of 4-formamido tetrahydropyrane, dropwise adding 134 g of 70% toluene solution containing red aluminum at the temperature controlled by an ice water bath below 10 ℃, heating to room temperature after adding, reacting and stirring for 15-17 hours, and finishing the reaction; controlling the temperature below 5 ℃ in an ice water bath, dropwise adding 30ml of saturated ammonium chloride aqueous solution into the reaction solution, continuously stirring for half an hour, filtering the reaction solution, washing filter cakes with tetrahydrofuran, combining mother liquor, drying magnesium sulfate, filtering, and then spin-drying the solution to obtain a crude product, and obtaining 32g of a pure 4-aminomethyl tetrahydropyran product after reduced pressure distillation, wherein the yield is 91.5%, and the specific reaction is as follows:
preferably, in the first step, the yield of the 4-formamido tetrahydropyran is 92.0%.
Preferably, in the second step, 134 g of 70% toluene solution containing red aluminum is added dropwise in an ice-water bath at the temperature of below 10 ℃, and after the addition is finished, the temperature is raised to room temperature, the reaction is stirred for 16 hours, and the reaction is finished.
Preferably, in the second step, 134 g of 70% toluene solution containing red aluminum is added dropwise in an ice-water bath with the temperature controlled to be 3-6 ℃.
Preferably, in the first step, the organic phases are combined and washed by water and then by brine, and the mass concentration of the brine used is 1%.
Preferably, in the second step, 30ml of saturated ammonium chloride aqueous solution is added dropwise to the reaction solution, stirring is continued for half an hour, the reaction solution is filtered, and filtering operation is performed by using filter paper during filtering.
In summary, the invention mainly has the following beneficial effects:
the preparation method of the drug intermediate 4-aminomethyl tetrahydropyran takes tetrahydropyran-4-formic acid as a raw material, and obtains the product 4-aminomethyl tetrahydropyran through amidation reaction and red aluminum reduction.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A preparation method of 4-aminomethyl tetrahydropyran comprises the following steps:
step one, adding 150ml of dichloromethane, 1g of DMAP and 50g of tetrahydropyran-4-formic acid into a 500ml three-neck flask, stirring and dropwise adding 73g of oxalyl chloride in an ice water bath, and heating to room temperature after dropwise adding is finished, and stirring and reacting for 2 hours; after the reaction is finished, dropwise adding the reaction solution into 100ml of ammonia water, continuously stirring for 1 hour and separating the solution; extracting in 100ml of water phase dichloromethane, combining organic phases, washing with water, then washing with brine, drying and filtering by using anhydrous sodium sulfate, and spin-drying the liquid to obtain 46g of 4-formamido tetrahydropyran;
step two, under the anhydrous and anaerobic operation, adding 120ml of anhydrous tetrahydrofuran into a 500ml three-necked bottle, adding 40g of 4-formamido tetrahydropyrane, dropwise adding 134 g of 70% toluene solution containing red aluminum at the temperature controlled by an ice water bath below 10 ℃, heating to room temperature after adding, reacting and stirring for 15-17 hours, and finishing the reaction; controlling the temperature below 5 ℃ in an ice water bath, dropwise adding 30ml of saturated ammonium chloride aqueous solution into the reaction solution, continuously stirring for half an hour, filtering the reaction solution, washing filter cakes with tetrahydrofuran, combining mother liquor, drying magnesium sulfate, filtering, and then spin-drying the solution to obtain a crude product, and obtaining 32g of a pure 4-aminomethyl tetrahydropyran product after reduced pressure distillation, wherein the yield is 91.5%, and the specific reaction is as follows:
wherein, in the first step, the yield of the 4-formamido tetrahydropyran is 92.0%.
In the second step, 134 g of 70% toluene solution containing red aluminum is added dropwise in an ice-water bath at the temperature of below 10 ℃, and then the temperature is raised to room temperature after the addition, the reaction is stirred for 16 hours, and the reaction is finished.
In the second step, 134 g of a 70% toluene solution containing red aluminum is added dropwise at the temperature of 3 ℃ in an ice-water bath.
In the first step, the organic phases are combined and washed by water and then washed by brine, wherein the mass concentration of the brine is 2%.
And in the second step, 30ml of saturated ammonium chloride aqueous solution is dropwise added into the reaction solution, the reaction solution is continuously stirred for half an hour, the reaction solution is filtered, and the filtering operation is performed by using filter paper during filtering.
The preparation method of the drug intermediate 4-aminomethyl tetrahydropyran uses tetrahydropyran-4-formic acid as a raw material, and obtains the product 4-aminomethyl tetrahydropyran through amidation reaction and red aluminum reduction.
Example 2
A preparation method of 4-aminomethyl tetrahydropyran comprises the following steps:
step one, adding 150ml of dichloromethane, 1g of DMAP and 50g of tetrahydropyran-4-formic acid into a 500ml three-neck flask, stirring and dropwise adding 73g of oxalyl chloride in an ice water bath, and heating to room temperature after dropwise adding is finished, and stirring and reacting for 2 hours; after the reaction is finished, dropwise adding the reaction solution into 100ml of ammonia water, continuously stirring for 1 hour and separating the solution; extracting in 100ml of water phase dichloromethane, combining organic phases, washing with water, then washing with brine, drying and filtering by using anhydrous sodium sulfate, and spin-drying the liquid to obtain 46g of 4-formamido tetrahydropyran;
step two, under the anhydrous and anaerobic operation, adding 120ml of anhydrous tetrahydrofuran into a 500ml three-necked bottle, adding 40g of 4-formamido tetrahydropyrane, dropwise adding 134 g of 70% toluene solution containing red aluminum at the temperature controlled by an ice water bath below 10 ℃, heating to room temperature after adding, reacting and stirring for 15-17 hours, and finishing the reaction; controlling the temperature below 5 ℃ in an ice water bath, dropwise adding 30ml of saturated ammonium chloride aqueous solution into the reaction solution, continuously stirring for half an hour, filtering the reaction solution, washing filter cakes with tetrahydrofuran, combining mother liquor, drying magnesium sulfate, filtering, and then spin-drying the solution to obtain a crude product, and obtaining 32g of a pure 4-aminomethyl tetrahydropyran product after reduced pressure distillation, wherein the yield is 91.5%, and the specific reaction is as follows:
wherein, in the first step, the yield of the 4-formamido tetrahydropyran is 92.0%.
In the second step, 134 g of 70% toluene solution containing red aluminum is added dropwise in an ice-water bath at the temperature of below 10 ℃, and then the temperature is raised to room temperature after the addition, the reaction is stirred for 16 hours, and the reaction is finished.
In the second step, 134 g of a 70% toluene solution containing red aluminum is added dropwise at the temperature of 5 ℃ in an ice-water bath.
In the first step, the organic phases are combined and washed by water and then washed by brine, wherein the mass concentration of the brine is 1%.
And in the second step, 30ml of saturated ammonium chloride aqueous solution is dropwise added into the reaction solution, the reaction solution is continuously stirred for half an hour, the reaction solution is filtered, and the filtering operation is performed by using filter paper during filtering.
The preparation method of the drug intermediate 4-aminomethyl tetrahydropyran uses tetrahydropyran-4-formic acid as a raw material, and obtains the product 4-aminomethyl tetrahydropyran through amidation reaction and red aluminum reduction.
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 (6)
1. A preparation method of 4-aminomethyl tetrahydropyran is characterized by comprising the following steps: the method comprises the following steps:
step one, adding 150ml of dichloromethane, 1g of DMAP and 50g of tetrahydropyran-4-formic acid into a 500ml three-neck flask, stirring and dropwise adding 73g of oxalyl chloride in an ice water bath, and heating to room temperature after dropwise adding is finished, and stirring and reacting for 2 hours; after the reaction is finished, dropwise adding the reaction solution into 100ml of ammonia water, continuously stirring for 1 hour and separating the solution; extracting in 100ml of water phase dichloromethane, combining organic phases, washing with water, then washing with brine, drying and filtering by using anhydrous sodium sulfate, and spin-drying the liquid to obtain 46g of 4-formamido tetrahydropyran;
step two, under the anhydrous and anaerobic operation, adding 120ml of anhydrous tetrahydrofuran into a 500ml three-necked bottle, adding 40g of 4-formamido tetrahydropyrane, dropwise adding 134 g of 70% toluene solution containing red aluminum at the temperature controlled by an ice water bath below 10 ℃, heating to room temperature after adding, reacting and stirring for 15-17 hours, and finishing the reaction; controlling the temperature below 5 ℃ in an ice water bath, dropwise adding 30ml of saturated ammonium chloride aqueous solution into the reaction solution, continuously stirring for half an hour, filtering the reaction solution, washing filter cakes with tetrahydrofuran, combining mother liquor, drying magnesium sulfate, filtering, and then spin-drying the solution to obtain a crude product, and obtaining 32g of a pure 4-aminomethyl tetrahydropyran product after reduced pressure distillation, wherein the yield is 91.5%, and the specific reaction is as follows:
2. the process according to claim 1, wherein the reaction mixture comprises: in the first step, the yield of the 4-formamido tetrahydropyran is 92.0 percent.
3. The process according to claim 1, wherein the reaction mixture comprises: in the second step, 134 g of 70% toluene solution containing red aluminum is added dropwise at the temperature controlled by ice water bath below 10 ℃, and then the temperature is raised to room temperature after the addition, the reaction is stirred for 16 hours, and the reaction is finished.
4. The process according to claim 1, wherein the reaction mixture comprises: in the second step, 134 g of 70% toluene solution containing red aluminum is added dropwise in an ice-water bath at the temperature of 3-6 ℃.
5. The process according to claim 1, wherein the reaction mixture comprises: in the first step, the organic phases are combined and washed by water and then by brine, wherein the mass concentration of the brine is 1%.
6. The process according to claim 1, wherein the reaction mixture comprises: and in the second step, 30ml of saturated ammonium chloride aqueous solution is dropwise added into the reaction solution, the reaction solution is continuously stirred for half an hour, the reaction solution is filtered, and the filtering operation is carried out by using filter paper during filtering.
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