CN108117564B - Process method for preparing cryptate 222 - Google Patents
Process method for preparing cryptate 222 Download PDFInfo
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- CN108117564B CN108117564B CN201711380707.XA CN201711380707A CN108117564B CN 108117564 B CN108117564 B CN 108117564B CN 201711380707 A CN201711380707 A CN 201711380707A CN 108117564 B CN108117564 B CN 108117564B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
Abstract
The invention discloses a process method for preparing cryptate 222, which comprises the following steps: step one, taking tris [ (2-ethyleneoxy) ethyl ] amine as a raw material, and reacting under the catalytic action of a Grubbs catalyst and an alkali metal salt to obtain an intermediate; and step two, adding the intermediate obtained in the step one into a hydrogen source under the catalytic action of a hydrogenation catalyst to react to obtain the cryptate 222. The method has the advantages of shorter synthesis period and higher yield.
Description
Technical Field
The invention belongs to the field of a preparation method of a supramolecular compound cryptate 222, and particularly relates to a process method for preparing cryptate 222.
Background
The three-dimensional internal cavity of cryptates can be tightly bound to foreign ions, and the resulting complex is called cryptate. The most strongly binding cations are the harder cations, including NH4+(ammonium ion) and cations of lanthanides, alkali metals, alkaline earth metals. The cryptate utilizes nitrogen and oxygen in molecules to coordinate with the ions, and different alkali metal cations can be distinguished or separated by selecting proper cryptate due to different binding capacities of different ions and different three-dimensional structures of the cryptate.
However, cryptates bind alkali metal ions more tightly and are more selective than other complexing agents such as crown ethers. By coordination, the cryptate ether can dissolve salts which are not dissolved in an organic solvent in general in another phase, and can be used as a phase transfer catalyst to accelerate the rate of chemical reaction, and can also stabilize alkali metal negative ions, so that an alkalide and an electronic salt can be synthesized.
Cryptate 222 is the most widely used of all cryptates. For example, potassium ions can be captured by cryptic ether 222 in serum assays to determine the amount of potassium ions in serum. In addition, in the preparation of fluorodeoxyglucose (abbreviated as FDG) which is a drug for imaging required by radiology, the cryptic ether 222 is used to complex potassium ions in the reactant KF, so as to improve the nucleophilicity of radioactive fluoride ions, thereby linking fluorine to deoxyglucose.
The current industrial method for preparing the cryptate 222 mainly adopts the following synthetic route:
prepared by reacting 1, 2-bis (2-aminoethoxy) ethane with triethylene glycol, both end groups of which are substituted by strong leaving groups (such as halogen, methanesulfonic acid group, p-toluenesulfonic acid group and the like), under the action of sodium carbonate or potassium carbonate. The preparation method has the obvious defects that the reaction time is very long, and reflux reaction is usually required for more than 6 days, so that the synthesis period is long, and the equipment cost and the energy cost are high. In addition, the yield is also relatively low, generally not exceeding 40%.
In view of the problems of long synthesis period, low yield, high equipment and energy costs, and the like in the process for preparing the cryptate 222. Therefore, the urgent need in the art is to find an industrial production method for synthesizing the cryptate 222 with shorter synthesis period and higher yield, which is of great significance.
Disclosure of Invention
The invention aims to provide a process method for preparing cryptate 222, which can solve the technical problems of long synthesis period, high equipment use cost and high energy use cost in the preparation process.
In order to solve the above technical problems, the present invention provides a process for preparing cryptate 222, wherein the process comprises the following steps:
step one, taking tris [ (2-ethyleneoxy) ethyl ] amine as a raw material, and reacting under the catalytic action of a Grubbs catalyst and an alkali metal salt to obtain an intermediate;
and step two, adding the intermediate obtained in the step one into a hydrogen source under the catalytic action of a hydrogenation catalyst to react to obtain the cryptate 222.
Preferably, the Grubbs catalyst in step one is one or more of a Grubbs primary catalyst, a Grubbs secondary catalyst, a Grubbs tertiary catalyst.
Preferably, the alkali metal salt in step one is one or more of sodium chloride, sodium bromide, sodium iodide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium chloride, potassium bromide, potassium iodide, potassium hydroxide, potassium carbonate and potassium bicarbonate.
Preferably, the reaction in the first step is carried out in an organic solvent, wherein the organic solvent is one or more of dichloromethane, chloroform, acetonitrile, methanol, ethanol, acetone, ethyl acetate, butyl acetate, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, 2-butanone and NMP.
Preferably, the reaction in the first step is carried out under the protection of inert gas, and the inert gas is nitrogen or helium.
Preferably, the hydrogenation catalyst in the second step is one or more of palladium carbon, palladium hydroxide carbon, platinum dioxide and raney nickel.
Preferably, the hydrogenation catalytic reaction of the intermediate and the hydrogenation catalyst in the second step is carried out in an organic solvent, and the organic solvent is one or more of dichloromethane, chloroform, acetonitrile, methanol, ethanol, acetone, ethyl acetate, butyl acetate, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, 2-butanone and NMP.
Preferably, the hydrogen source in the second step is one or more of hydrogen, sodium formate, formic acid and hydrazine formate.
Preferably, the Grubbs catalyst is used in an amount of 0.0001 to 1 equivalent and the alkali metal salt is used in an amount of 0.0001 to 5 equivalents in step one;
the dosage of the hydrogenation catalyst in the second step is 0.0001-1 equivalent.
Preferably, the reaction temperature in the first step is-20 to 200 ℃; and the reaction temperature in the second step is-20-200 ℃.
Compared with the prior art, the process method for preparing the cryptate 222 has the following advantages that:
1. the process method has short reaction period, and can complete the reaction within 2 days.
2. The process method disclosed by the invention is simple in synthesis process, mild in reaction conditions, higher in yield of the product of the cryptate 222, simple and convenient in reaction operation, wider in application range and capable of fully meeting the requirements of industrial production of the product.
Drawings
In order to illustrate the present invention examples or prior art solutions more clearly, the drawings that are needed in the examples or prior art descriptions will be briefly described below, it is obvious that the drawings in the following description are only some examples of the present invention, and it is obvious for a person skilled in the art that other drawings can be obtained from these drawings without inventive effort.
Fig. 1 is a schematic flow structure diagram of the process for preparing cryptate 222 according to the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings in combination with the embodiments. It should be understood that the description is intended to be exemplary only, and is not intended to limit the scope of the present invention. Moreover, in the following description, descriptions of well-known structures and techniques are omitted so as to not unnecessarily obscure the concepts of the present invention.
Fig. 1 is a schematic flow structure diagram of a process for preparing cryptate 222 according to the present invention, and as shown in fig. 1, the present invention provides a process for preparing cryptate 222, wherein the process comprises the following steps:
step one, taking tris [ (2-ethyleneoxy) ethyl ] amine as a raw material, and reacting under the catalytic action of a Grubbs catalyst and an alkali metal salt to obtain an intermediate;
and step two, adding the intermediate obtained in the step one into a hydrogen source under the catalytic action of a hydrogenation catalyst to react to obtain the cryptate 222.
It should be noted that the supramolecular compound cryptate 222 prepared by the invention can be widely applied to the fields of analysis and detection, phase transfer catalysis, life science and the like.
In a further embodiment of the present invention, the Grubbs catalyst in the first step is one or more of a Grubbs primary catalyst, a Grubbs secondary catalyst, a Grubbs tertiary catalyst, or other Grubbs catalysts, and the details thereof are not repeated herein.
In a further embodiment of the present invention, the alkali metal salt in step one is one or more of sodium chloride, sodium bromide, sodium iodide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium chloride, potassium bromide, potassium iodide, potassium hydroxide, potassium carbonate, potassium bicarbonate.
In a further embodiment of the present invention, the reaction in the first step is carried out in an organic solvent, wherein the organic solvent is one or more of dichloromethane, chloroform, acetonitrile, methanol, ethanol, acetone, ethyl acetate, butyl acetate, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, 2-butanone and NMP.
In a further embodiment of the present invention, the reaction in step one is carried out under an inert gas atmosphere, and the inert gas is nitrogen or helium. The reaction is carried out under the inert gas protection condition, so that the reaction is purer, and is not easily interfered by air, and the reaction result is more accurate.
In a further embodiment of the present invention, the hydrogenation catalyst in the second step is one or more of palladium carbon, palladium hydroxide carbon, platinum dioxide and raney nickel.
In a further embodiment of the present invention, the hydrogenation catalytic reaction of the intermediate in the second step and the hydrogenation catalyst is performed in an organic solvent, wherein the organic solvent is one or more of dichloromethane, chloroform, acetonitrile, methanol, ethanol, acetone, ethyl acetate, butyl acetate, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, 2-butanone, and NMP.
In a further embodiment of the present invention, the hydrogen source in step two is selected from one or more of hydrogen, sodium formate, formic acid, hydrazine formate.
In a further embodiment of the invention, the Grubbs catalyst is used in an amount of 0.0001 to 1 equivalent in step one, the alkali metal salt is used in an amount of 0.0001 to 5 equivalents, and the hydrogenation catalyst is used in an amount of 0.0001 to 1 equivalent in step two. The reaction carried out in this range gives higher yields and faster reaction times.
In a further embodiment of the present invention, the reaction temperature in the first step is-20 to 200 ℃, and the reaction temperature in the second step is-20 to 200 ℃. The reaction is carried out under the condition of the reaction temperature, the yield is higher, and the reaction time is faster.
The present invention is further illustrated below with reference to specific examples, which are, of course, intended to illustrate the invention and are not intended to limit the scope of the invention.
EXAMPLE 1 Process for the preparation of cryptate 222
This example is a process for making cryptate 222, comprising the steps of:
the method comprises the following steps: preparation of intermediates
In this example, this step was carried out under nitrogen protection.
Firstly, 10L of dichloromethane, 100g of sodium iodide and 3kg of tris [ (2-ethyleneoxy) ethyl ] amine are sequentially added into a 20L reaction kettle and stirred uniformly;
then, 10g of Grubbs-generation catalyst was further added thereto, and the reaction was stirred at room temperature for 6 hours, and the reaction was completed.
And finally, filtering the reaction solution by using kieselguhr and alumina in sequence, and spin-drying the filtrate to obtain a slurry-like intermediate.
Step two: preparation of cryptate 222
First, 10L of ethanol and the slurry intermediate obtained in the previous step were sequentially added to a 20L reactor while stirring at room temperature, and the mixture was stirred.
Then, 25g of palladium-carbon catalyst was added thereto, and the reaction was completed by hydrogenation reaction for 6 hours under a hydrogen atmosphere of 2 atmospheres.
Finally, the reaction solution was filtered sequentially with celite and alumina, and the filtrate was spin-dried to obtain slurry cryptand 222.
Incidentally, this slurry of cryptate 222 was recrystallized from toluene-ethanol to give 1.75kg of a pure white solid, 99.5% HPLC purity, 70.44% yield, 1H NMR (400MHz, CDCl 3): 3.69(s, 12H), 3.60(t, 12H), 2.64(t, 12H).
EXAMPLE 2 Process for the preparation of cryptate 222
This example is a process for making cryptate 222, comprising the steps of:
the method comprises the following steps: preparation of intermediates
In this example, this step is performed under the protection of helium.
Firstly, 10L of methanol, 120g of sodium chloride and 3kg of tris [ (2-ethyleneoxy) ethyl ] amine are sequentially added into a 20L reaction kettle and stirred uniformly;
then, 10g of Grubbs' second generation catalyst was further added thereto, and the reaction was stirred at room temperature for 6 hours, and the reaction was completed.
And finally, filtering the reaction solution by using kieselguhr and alumina in sequence, and spin-drying the filtrate to obtain a slurry-like intermediate.
Step two: preparation of cryptate 222
First, stirring was carried out at room temperature, and 10L of ethylene glycol diethyl ether and the slurry intermediate obtained in the previous step were sequentially added to a 20L reactor and stirred.
Then, 25g of platinum carbon catalyst was added thereto, and hydrogenation reaction was carried out for 6 hours under a hydrogen atmosphere of 2 atmospheres, and the reaction was completed.
Finally, the reaction solution was filtered sequentially with celite and alumina, and the filtrate was spin-dried to obtain slurry cryptand 222.
Incidentally, this slurry of the cryptic ether 222 was recrystallized from toluene-ethanol to obtain 1.94kg of a pure white solid, with an HPLC purity of 99.2%, a yield of 78.14%, 1H NMR (400MHz, CDCl 3): 3.69(s, 12H), 3.60(t, 12H), 2.64(t, 12H).
It is to be understood that the above-described embodiments of the present invention are merely illustrative of or illustrative of the principles of the present invention and are not to be construed as limiting the invention. Therefore, any modification, equivalent replacement, improvement and the like made without departing from the spirit and scope of the present invention shall be included in the protection scope of the present invention. Further, it is intended that the appended claims cover all such variations and modifications as fall within the scope and boundaries of the appended claims or the equivalents of such scope and boundaries.
Claims (9)
1. A process for preparing cryptate 222, comprising the steps of:
step one, taking tris [ (2-ethyleneoxy) ethyl ] amine as a raw material, and reacting under the catalytic action of a Grubbs catalyst and an alkali metal salt to obtain an intermediate;
step two, adding the intermediate obtained in the step one into a hydrogen source under the catalytic action of a hydrogenation catalyst to react to obtain the cryptate 222,
wherein, after the reaction in the first step and the second step, diatomite and alumina are sequentially used for filtering;
the alkali metal salt in the step one is one or more of sodium chloride, sodium bromide, sodium iodide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium chloride, potassium bromide, potassium iodide, potassium hydroxide, potassium carbonate and potassium bicarbonate.
2. The process of claim 1, wherein said Grubbs catalyst in step one is one or more of a Grubbs primary catalyst, a Grubbs secondary catalyst, and a Grubbs tertiary catalyst.
3. The process of claim 1, wherein the reaction in step one is carried out in an organic solvent, and the organic solvent is one or more of dichloromethane, chloroform, acetonitrile, methanol, ethanol, acetone, ethyl acetate, butyl acetate, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, 2-butanone, and NMP.
4. The process of claim 1, wherein the reaction of step one is carried out under an inert gas atmosphere, and the inert gas is nitrogen or helium.
5. The process of claim 1, wherein the hydrogenation catalyst in step two is one or more of palladium on carbon, palladium on carbon hydroxide, platinum on carbon, platinum dioxide, and raney nickel.
6. The process for preparing cryptate 222 of claim 1, wherein the hydrogenation catalytic reaction of the intermediate and the hydrogenation catalyst in step two is carried out in an organic solvent, and the organic solvent is one or more of dichloromethane, chloroform, acetonitrile, methanol, ethanol, acetone, ethyl acetate, butyl acetate, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, 2-butanone, and NMP.
7. The process of claim 1, wherein the hydrogen source in step two is one or more of hydrogen, sodium formate, formic acid, and hydrazine formate.
8. The process of claim 1, wherein,
the Grubbs catalyst is used in an amount of 0.0001-1 equivalent, and the alkali metal salt is used in an amount of 0.0001-5 equivalents;
the dosage of the hydrogenation catalyst in the second step is 0.0001-1 equivalent.
9. The process of claim 1, wherein,
the reaction temperature in the first step is-20-200 ℃;
and the reaction temperature in the second step is-20-200 ℃.
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| US4156683A (en) * | 1973-03-26 | 1979-05-29 | Schering Corporation | Complexes of macrocyclic compounds |
| CN1703401A (en) * | 2001-05-22 | 2005-11-30 | 神经原公司 | Melanin concentrating hormone receptor ligands: substituted 1-benzyl-4-aryl piperazine analogues |
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