CN118108697A - Crystalline spirocyclic methylene carbonate derivative and preparation method and application thereof - Google Patents

Crystalline spirocyclic methylene carbonate derivative and preparation method and application thereof Download PDF

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CN118108697A
CN118108697A CN202410252519.2A CN202410252519A CN118108697A CN 118108697 A CN118108697 A CN 118108697A CN 202410252519 A CN202410252519 A CN 202410252519A CN 118108697 A CN118108697 A CN 118108697A
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crystalline
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carbonate derivative
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齐若德
汪梓义
宋伟健
郭雯倩
赵剑天
聂嘉谦
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East China University of Science and Technology
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    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
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Abstract

The invention belongs to the technical field of organic synthesis and preparation, and particularly relates to a crystalline spirocyclic methylene carbonate derivative, and a preparation method and application thereof. The invention provides a crystalline spiro methylene carbonate derivative, which has a structure shown in a formula I or a formula II: in the formula I, R 1-R6 is independently hydrogen, chlorine, bromine, hydroxyl and C1-C10 alkyl; in formula II, R 7-R10 is independently hydrogen, chlorine, bromine, hydroxyl, C1-C10 alkyl. The crystalline spiro methylene carbonate derivative provided by the invention is more beneficial to crystallization-driven self-assembly, and can be used for realizing micelle core functionalization by linking other chain segments through functional end groups when being used for crystallization-driven self-assembly.

Description

Crystalline spirocyclic methylene carbonate derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of organic synthesis and preparation, and particularly relates to a crystalline spirocyclic methylene carbonate derivative, and a preparation method and application thereof.
Background
In recent years, crystallization-driven self-assembly has become an effective means of preparing nano-supermolecular materials and has rapidly progressed. By incorporating at least one crystalline block into the block copolymer, a crystalline block copolymer can be obtained. The crystalline-amorphous block copolymer can self-assemble in a selective solution, the selective solvent selected being a good solvent for the amorphous block and at the same time being capable of initiating the crystallization behavior of the crystalline block, a process known as crystallization driven self-assembly. Due to the crystallinity of the crystalline block, the crystalline-amorphous block copolymer is capable of forming nano-scale micelles by crystallization-driven self-assembly. The crystal-driven self-assembly can obtain various structures such as rod-shaped, flake-shaped, branched and the like and is applied to the field of medicine carriers.
Most of the functionalization in the field of crystallization-driven self-assembly has been concentrated on amorphous blocks and has been demonstrated to be capable of exhibiting surprising application prospects. Meanwhile, the crystalline blocks of the block copolymer are gathered and wrapped inside, so that the application with wide prospect can be expanded. The polyfluorene methylene carbonate generated by ring opening polymerization of fluorene methylene carbonate is used as a crystallization block to drive self-assembly by crystallization, but the current method for preparing the fluorene methylene carbonate monomer has the defects of incapability of being realized in China, complex reaction process, high toxicity of the used catalyst, high cost and the like. Therefore, the efficient synthesis of the crystalline monomer which can be applied to the crystallization-driven self-assembled block copolymer and the expansion of micelle functionalization through the modification of the crystalline nucleation monomer have very important significance for the expansion of the field of nano drug carrier materials.
Disclosure of Invention
In view of the above, the present invention aims to provide a crystalline spiromethylene carbonate derivative, a preparation method and an application thereof, wherein the crystalline spiromethylene carbonate derivative provided by the present invention is more favorable for crystallization-driven self-assembly, and can realize micelle core functionalization by linking other chain segments through functional end groups when being used for crystallization-driven self-assembly.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a crystalline spiro methylene carbonate derivative, which has a structure shown in a formula I or a formula II:
In formula I, R 1-R6 is independently hydrogen, chlorine, bromine, hydroxyl, or C1-C10 alkyl;
in formula II, R 7-R10 is independently hydrogen, chlorine, bromine, hydroxyl or C1-C10 alkyl.
Preferably, the compound has a structure shown in formula I-1, formula I-2, formula I-3, formula II-1 or formula II-2:
The invention also provides a preparation method of the crystalline spirocyclic methylene carbonate derivative, which comprises the following steps:
After the compound A or the compound B and paraformaldehyde are first dissolved, carrying out a methylolation reaction under the catalysis of an alkaline catalyst to obtain an intermediate III or an intermediate IV with a structure shown in a formula III or IV;
Secondly dissolving the intermediate III or the intermediate IV and carbonyl diimidazole, and carrying out substitution reaction under an acidic condition to obtain the crystalline spirocyclic methylene carbonate derivative with the structure shown in the formula I or the formula II;
preferably, when the compound a is subjected to a methylolation reaction, the basic catalyst is sodium methoxide; the molar ratio of the compound A to the sodium methoxide is 1: (0.05 to 0.5);
the molar ratio of the compound A to the paraformaldehyde is 1: (1-10); the temperature of the methylolation reaction is between 25 ℃ below zero and 35 ℃ and the time is between 5 and 1000 seconds.
Preferably, when the compound B is subjected to a methylolation reaction, the basic catalyst is potassium carbonate; the molar ratio of the compound B to the potassium carbonate is 1: (0.05 to 0.5);
The molar ratio of the compound B to the paraformaldehyde is 1: (1-10); the temperature of the methylolation reaction is between 25 ℃ below zero and 35 ℃ below zero and the time is between 1 and 1000 minutes.
Preferably, when the intermediate III undergoes a substitution reaction, the molar ratio of intermediate III to carbonyldiimidazole is 1: (1-9).
Preferably, when the compound IV undergoes a substitution reaction, the molar ratio of the intermediate IV to carbonyldiimidazole is 1: (1-10).
Preferably, the temperature of the substitution reaction is 0-150 ℃; the time is 0.1-48 h.
The invention also provides an application of the crystalline spiromethylene carbonate derivative or the crystalline spiromethylene carbonate derivative prepared by the preparation method in preparing a nano supermolecular material by crystallization-driven self-assembly.
The invention provides a crystalline spiro methylene carbonate derivative, which has a structure shown in a formula I or a formula II:
In the formula I, R 1-R6 is independently hydrogen, chlorine, bromine, hydroxyl and C1-C10 alkyl; in formula II, R 7-R10 is independently hydrogen, chlorine, bromine, hydroxyl, C1-C10 alkyl. The crystalline monomer micromolecular material with biocompatibility provided by the invention uses fluorene and indenone with excellent biocompatibility as core parts of derivatives, and uses secondary carbon atoms on a fluorene center five-membered ring and secondary carbon atoms ortho to carbonyl carbon on an indenone five-membered ring to carry out methylolation reaction with nucleophile and formaldehyde respectively, so that a compound product of hexacyclic methylene carbonate with a spiro structure and center fluorene and indenone is further constructed by using carbonyl diimidazole. The six-membered ring methylene carbonate contained in the structure can carry out ring-opening polymerization, and fluorene and indenone parts in the molecule are vertical to the main chain of the polymer after the ring-opening polymerization due to the existence of spiro carbon, so that the six-membered ring methylene carbonate is orderly arranged in a three-dimensional space to drive the formation of crystals. Such crystalline homopolymers are copolymerized with other crystalline homopolymers or amorphous homopolymers to obtain crystalline block copolymers for crystallization driven self-assembly. In the invention, the biocompatible crystalline spirocyclic methylene carbonate derivative small molecule mainly comprises methylene carbonate and fluorene and derivatives thereof or indenone and derivatives thereof. The fluorene and indenone derivatives are functional groups provided by mono-substitution or poly-substitution of different atoms or alkanes on the benzene rings. When the crystalline spirocyclic methylene carbonate derivative small molecule is made into a crystalline block copolymer and used for crystallization-driven self-assembly, micelle core functionalization can be achieved by linking other segments through functional end groups.
The crystalline spirocyclic methylene carbonate derivative provided by the invention has the advantages of simple synthesis steps, high purity, low cost, functionalization and mass production, is expected to expand the selectable range of a crystalline polymer block suitable for crystallization driving self-assembly based on the steps, and introduces a method for preparing a functionalized core crystalline micelle.
Detailed Description
The invention provides a crystalline spirocyclic methylene carbonate derivative, which has a structure shown in a formula I or a formula II:
In the formula I, R 1-R6 is independently hydrogen, chlorine, bromine, hydroxyl and C1-C10 alkyl;
In formula II, R 7-R10 is independently hydrogen, chlorine, bromine, hydroxyl, C1-C10 alkyl.
In the present invention, the crystalline spirocyclic methylene carbonate derivative preferably has a structure represented by the formula I-1, the formula I-2, the formula I-3, the formula II-1, and the formula II-2.
The invention also provides a preparation method of the crystalline spirocyclic methylene carbonate derivative, which comprises the following steps:
After the compound A or the compound B and paraformaldehyde are first dissolved, carrying out a methylolation reaction under the catalysis of an alkaline catalyst to obtain an intermediate III or an intermediate IV with a structure shown in a formula III or IV;
Secondly dissolving the intermediate III or the intermediate IV and carbonyl diimidazole, and carrying out substitution reaction under an acidic condition to obtain the crystalline spirocyclic methylene carbonate derivative with the structure shown in the formula I or the formula II;
After the compound A or the compound B and paraformaldehyde are first dissolved, carrying out a methylolation reaction under the catalysis of an alkaline catalyst to obtain an intermediate III or an intermediate IV with a structure shown in a formula III or IV.
When the compound a is subjected to a methylolation reaction, the basic catalyst is preferably sodium methoxide; the first solvent is preferably dimethyl sulfoxide and/or absolute ethanol. In the present invention, when the first dissolved solvent is dimethyl sulfoxide and absolute ethanol, the volume ratio of dimethyl sulfoxide to absolute ethanol is preferably 9:11.
In the present invention, the molar ratio of the compound a to sodium methoxide is preferably 1: (0.05 to 0.5), more preferably 1: (0.1 to 0.4); the molar ratio of the compound a to paraformaldehyde is preferably 1: (1 to 10), more preferably 1: (2-9); the mass ratio of the compound A to the solvent for dissolution is preferably 1: (10 to 50), more preferably 1: (20-50).
In the present invention, when the compound a is subjected to the methylolation reaction, the temperature of the methylolation reaction is preferably-25 to 35 ℃, more preferably 0 to 30 ℃; the time is preferably 5 to 1000 seconds, more preferably 50 to 800 seconds.
When the compound B is subjected to a methylolation reaction, the basic catalyst is preferably potassium carbonate; the first dissolved solvent is preferably methanol and water.
In the present invention, the molar ratio of the compound B to potassium carbonate is preferably 1: (0.05 to 0.5), more preferably 1: (0.1 to 0.4); the molar ratio of the compound B to paraformaldehyde is preferably 1: (1 to 10), more preferably 1: (2-9); the mass ratio of the compound B to the methanol is preferably 1: (1 to 100), more preferably 1: (20-80); the mass ratio of the compound B to water is preferably 1: (1 to 100), more preferably 1: (20-80); the volumes of methanol and water are preferably the same.
In the present invention, when the compound B is subjected to the methylolation reaction, the temperature of the methylolation reaction is preferably-25 to 35 ℃, more preferably 0 to 30 ℃, and the time is preferably 1 to 1000 minutes, more preferably 50 to 600 minutes.
After obtaining an intermediate III or an intermediate IV, the intermediate III or the intermediate IV and carbonyl diimidazole are dissolved for the second time, and substitution reaction is carried out under an acidic condition, so that the crystalline spiro methylene carbonate derivative with the structure shown in the formula I or the formula II is obtained.
When the intermediate III undergoes a substitution reaction, the second dissolving reagent is preferably acetonitrile; the acidic conditions are provided by acetic acid;
The molar ratio of intermediate III to carbonyldiimidazole is preferably 1: (1 to 9), more preferably 1: (2-7); the molar ratio of intermediate III to acetic acid is preferably 1: (5 to 100), more preferably 1: (10-80); the mass ratio of the intermediate III to the acetonitrile is preferably 1: (10 to 250), more preferably 1: (50-150).
When the intermediate IV undergoes a substitution reaction, the second dissolving reagent is preferably acetonitrile; the acidic conditions are provided by acetic acid;
The molar ratio of intermediate IV to carbonyldiimidazole is preferably 1: (1 to 10), more preferably 1: (3-7); the molar ratio of intermediate IV to acetic acid is preferably 1: (1 to 40), more preferably 1: (10-30); the mass ratio of the intermediate IV to acetonitrile is preferably 1: (10 to 350), more preferably 1: (50-250).
In the present invention, the temperature at which the substitution reaction of the intermediate III or IV is performed is preferably 0 to 150 ℃, more preferably 20 to 50 ℃; the time is preferably 0.1 to 48 hours, more preferably 1 to 20 hours.
The invention also provides an application of the crystalline spiromethylene carbonate derivative or the crystalline spiromethylene carbonate derivative prepared by the preparation method in preparing a nano supermolecular material by crystallization-driven self-assembly.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The synthetic route for preparing the crystalline spirocyclic methylene carbonate derivative FTMC is as follows:
(1) Synthesis of monomer 1 (corresponding to the specific Structure of intermediate III) in example 1:
Paraformaldehyde (2.7 g,90.24mmol,1.5 eq) and a methanolic solution of sodium methoxide (mass concentration 30%, sodium methoxide 3.24g,18.06mmol,0.3 eq) were added to a 1L round bottom flask which was sufficiently dried in advance and dissolved with 100mL of anhydrous dimethyl sulfoxide (DMSO), and mixed well at room temperature under stirring. Another flask was charged with 9H-fluorene (10 g,60.16mmol,1 eq) and 50mL of anhydrous DMSO was added and heated by sonication to dissolve it completely. Subsequently, a round bottom flask containing a DMSO solution of paraformaldehyde and sodium methoxide uniformly mixed was placed in a cold water bath at 5℃and after adding a DMSO solution of 9H-fluorene and stirring for 2 minutes, 5mL of an aqueous solution of hydrochloric acid with a mass concentration of 37% was added to terminate the reaction to obtain a pale yellow transparent liquid. After the reaction was returned to room temperature, it was poured into 800mL of brine, the aqueous phase was extracted 3 times with diethyl ether, the organic phase was dried over anhydrous magnesium sulfate, the diethyl ether was removed after filtration using a rotary evaporator, and 3 times of recrystallization using 240mL of toluene gave monomer 1 as a white powdery solid (8.2 g,36.24mmol, yield 60.2%).
(2) Synthesis of crystalline spirocyclic methylene carbonate derivative FTMC:
Monomer 1 (1 g,4.43mmol,1 eq) and carbonyldiimidazole (4.3 g,26.55mmol,6 eq) were added to a screw spherical reaction flask sufficiently dried in advance and dissolved with 50mL of anhydrous acetonitrile, mixed with stirring at room temperature for 1 minute, followed by addition of acetic acid (12.2 mL,212.4mmol,48 eq) and heating to 60 ℃ for reaction for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature to obtain a pale yellow transparent liquid, the crude reaction mixture was added dropwise to 800mL of ultrapure water to obtain a white precipitate, the white precipitate was collected by filtration under reduced pressure, and then dissolved with chloroform, dried over anhydrous magnesium sulfate, filtered off, and then removed with a rotary evaporator to obtain a white powdery solid, namely, fluorene spiro methylene carbonate FTMC (925 mg,3.67mmol, yield 83%).
The nuclear magnetic hydrogen spectrum information of the final product fluorene spiro methylene carbonate FTMC is:
1HNMR(chloroform-d,298K,400MHz,δ/ppm):7.81(d,2H),7.50(m,4H),7.38(t,2H),4.58(s,4H)。
Example 2
The synthetic route for preparing the crystalline spiromethylene carbonate derivative DTBFTMC is as follows:
Synthesis of monomer 1 in example 2:
Paraformaldehyde (3.2 g,107.74mmol,3 eq) and a methanolic solution of sodium methoxide (mass concentration 30%, sodium methoxide 2.58g,14.36mmol,0.4 eq) were added to a 1L round bottom flask that was sufficiently dried in advance and dissolved using 120mL anhydrous DMSO and mixed well with stirring at room temperature. Another flask was charged with 2, 7-di-tert-butylfluorene (10 g,35.91mmol,1 eq) and 120mL of anhydrous DMSO was added and heated by sonication to dissolve completely. Subsequently, a round bottom flask containing a DMSO solution of paraformaldehyde and sodium methoxide uniformly mixed was placed in a water bath at 20℃and a DMSO solution of 2, 7-di-t-butylfluorene was added and stirred for 1 minute, and a little white precipitate was precipitated during the reaction, and after 1 minute, an aqueous hydrochloric acid solution (37%, 5 mL) was added to terminate the reaction to obtain a pale yellow liquid. After the reaction was returned to room temperature, it was poured into 800mL of brine, the aqueous phase was extracted 3 times with diethyl ether, the organic phase was dried over anhydrous magnesium sulfate, the diethyl ether was removed after filtration using a rotary evaporator, and recrystallized 3 times from toluene (240 mL) to give monomer 1 as a white powdery solid (7.5 g,22.01mmol, yield 61.3%).
Synthesis of crystalline spirocyclic methylene carbonate derivative small molecule DTBFTMC:
monomer 1 (1 g,2.95mmol,1 eq) and carbonyldiimidazole (2.87 g,17.73mmol,6 eq) were added to a screw spherical reaction flask sufficiently dried in advance and dissolved using 93mL of anhydrous acetonitrile, mixed with stirring at room temperature for 1 minute, and a large amount of white precipitate appeared in the solution. Acetic acid (8.2 mL,141.80mmol,48 eq) was then added and the reaction was continued for 20 hours at 100℃with the addition of acetic acid and the white precipitate disappeared. After the completion of the reaction, the reaction mixture was cooled to room temperature to obtain a pale yellow transparent liquid, the crude reaction mixture was added dropwise to 800mL of ultrapure water to obtain a white precipitate, the white precipitate was collected by filtration under reduced pressure, and after washing the white precipitate 5 times with 200mL of ultrapure water, it was dissolved with chloroform, dried with anhydrous magnesium sulfate, and after removing the anhydrous magnesium sulfate by filtration, the chloroform was removed with a rotary evaporator to obtain a white powdery solid, namely, the final product di-t-butylfluorene methylene carbonate DTBFTMC (915 mg,2.51mmol, yield 85%).
The nuclear magnetic hydrogen spectrum information of the final product di-tert-butylfluorene methylene carbonate DTBFTMC is:
1HNMR(chloroform-d,298K,400MHz,δ/ppm):7.68(d,2H),7.51(d,2H),7.47(d,2H),4.59(s,4H),1.37(s,18H).
Example 3
The synthetic route for preparing the crystalline spiromethylene carbonate derivative DCFTMC is as follows:
example 3 synthesis of monomer 1:
Paraformaldehyde (3.8 g,127.60mmol,3 eq) and a methanolic solution of sodium methoxide (mass concentration 30%, sodium methoxide 3.06g,17.02mmol,0.4 eq) were added to a 1L round bottom flask that was sufficiently dried in advance and dissolved using 50mL of mixed solvent (anhydrous DMSO/anhydrous etoh=45/55), and thoroughly stirred and mixed at room temperature. Another flask was charged with 2, 7-dichlorofluorene (10 g,42.53mmol,1 eq) and 50mL of the mixed solvent was added, and heated by ultrasonic to dissolve completely. Subsequently, a round bottom flask containing a uniformly mixed paraformaldehyde and sodium methoxide solution was placed in an ice-water bath at 5℃and 2, 7-dichlorofluorene solution was added and stirred for 8 minutes, followed by addition of aqueous hydrochloric acid (37%, 5 mL) to terminate the reaction to give a transparent pale yellow liquid. After the reaction was returned to room temperature, a white precipitate was obtained by pouring 300mL of brine, collecting the white precipitate by filtration under reduced pressure and washing with 200mL of ultrapure water 5 times, dissolving with Tetrahydrofuran (THF) and drying with the addition of anhydrous magnesium sulfate, removing THF by filtration using a rotary evaporator after removing anhydrous magnesium sulfate, drying the crude product at 30℃for 1 hour using a vacuum oven, and recrystallizing with 150mL of toluene 3 times to obtain a white lump solid, namely monomer 1 (7.4 g,25.09mmol, yield%).
Synthesis of crystalline spirocyclic methylene carbonate derivative DCFTMC:
Monomer 1 (1 g,3.39mmol,1 eq) and carbonyldiimidazole (3.30 g,20.33mmol,6 eq) were added to a screw spherical reaction flask sufficiently dried in advance and dissolved using 70mL of anhydrous acetonitrile, and mixed with stirring at room temperature for 1 hour. Acetic acid (9.2 mL,162.62mmol,48 eq) was then added and reacted for 2 hours at 80 ℃. After the completion of the reaction, the reaction mixture was cooled to room temperature to obtain a pale yellow transparent liquid, the crude reaction mixture was added dropwise to 800mL of ultrapure water to obtain a white precipitate, the white precipitate was collected by filtration under reduced pressure, and after washing the white precipitate 5 times with 200mL of ultrapure water, it was dissolved with chloroform, dried with anhydrous magnesium sulfate, and after removing the anhydrous magnesium sulfate by filtration, chloroform was removed with a rotary evaporator to obtain a white powdery solid, namely, the final product dichlorofluorene methylene carbonate DCFTMC (881 mg,2.74mmol, yield 81%).
The nuclear magnetic hydrogen spectrum information of the final product dichlorofluorene methylene carbonate DCFTMC is:
1H NMR(chloroform-d,298K,400MHz,δ/ppm):7.75(d,2H),7.44(m,2H),7.28(d,2H),4.71(s,4H)。
Example 4
The synthetic route for preparing the crystalline spiromethylene carbonate derivative ITMC is as follows:
example 4 synthesis of monomer 1:
1-indenone (5 g,37.832mmol,1 eq) was added to a 500mL round bottom flask sufficiently dried in advance and dissolved with 25mL of methanol, followed by addition of potassium carbonate (5.23 g,37.82mmol,1 eq) and rapid addition of 25mL of ultrapure water, after addition of paraformaldehyde, reaction at room temperature for 5 minutes and direct addition of 100mL of ethyl acetate for extraction 3 times, the organic phase was collected and residual moisture was removed by addition of anhydrous magnesium sulfate, and after removal of anhydrous magnesium sulfate by filtration, ethyl acetate was removed by rotary evaporator to give monomer 1 as a white powdery solid (4.73 g,24.59mmol, 65% yield).
(2) Synthesis of crystalline trimethylene carbonate derivatives:
Monomer 1 (1 g,5.20mmol,1 eq) and carbonyldiimidazole (5.01 g,31.21mmol,6 eq) were added to a screw spherical reaction flask sufficiently dried in advance and dissolved using 120mL of anhydrous acetonitrile, and mixed with stirring at room temperature for 3 minutes. Acetic acid (2.4 mL,41.62mmol,12 eq) was then added and the reaction was carried out at 120℃for 4 hours to give a pale yellow transparent solution. Acetonitrile was then removed directly using a rotary evaporator until a small amount of oily residue, 200mL of diethyl ether was added and sonicated to give a white precipitate. The white precipitate was collected by distillation under reduced pressure, and was dissolved in methylene chloride after washing 5 times with 50mL of diethyl ether, dried over anhydrous magnesium sulfate was added, and after removing the anhydrous magnesium sulfate by filtration, methylene chloride was removed by using a rotary evaporator to give a white crystalline powder as a final product (969 mg,4.53mmol, yield 87%).
The nuclear magnetic hydrogen spectrum information of the final product indenone trimethylene carbonate ITMC is:
1H NMR(chloroform-d,298K,400MHz,δ/ppm):7.80(d,1H),7.73(t,1H),7.58(d,1H),4.48(t,1H),4.71(d,2H),4.22(d,2H),3.43(s,2H).
Example 5
The synthetic route for preparing the crystalline spiromethylene carbonate derivative DMITMC is as follows:
example 5 synthesis of monomer 1:
5, 6-dimethoxy-1-indenone (5 g,26.01mmol,1 eq) was added to a 500mL round bottom flask sufficiently dried in advance, and dissolved with 60mL of methanol, followed by addition of anhydrous potassium carbonate K 2CO3 (7.19 g,52.02mmol,2 eq) and rapid addition of 60mL of ultrapure water, after addition of paraformaldehyde, reaction at room temperature for 30 minutes, direct addition of dichloromethane (60 mL) to extract the aqueous phase 1 time, followed by further extraction of the aqueous phase 3 times with 60mL of ethyl acetate, collection of all organic phases and addition of anhydrous magnesium sulfate to remove residual moisture, filtration to remove anhydrous magnesium sulfate. The dichloromethane solution obtained after extraction was filtered to remove anhydrous magnesium sulfate, and then dichloromethane was removed by using a rotary evaporator and 50mL of ethyl acetate was added to recrystallize 3 times to obtain a white powdery solid, namely monomer 1. The ethyl acetate solution obtained after recrystallization was filtered to remove anhydrous magnesium sulfate, and then ethyl acetate was directly removed by a rotary evaporator to obtain a white powdery solid, namely, monomer 1. The total was obtained as a white powdery solid monomer 1 (3.61 g,14.30mmol, yield 55%).
Synthesis of crystalline spirocyclic methylene carbonate derivative DMITMC:
Monomer 1 (1 g,3.96mmol,1 eq) and carbonyldiimidazole (3.85 g,23.78mmol,6 eq) were added to a screw spherical reaction flask sufficiently dried in advance and dissolved using 75mL of anhydrous acetonitrile, and mixed with stirring at room temperature for 1 minute. Acetic acid (7.2 mL,124.84mmol,48 eq) was then added and the reaction was carried out at 80℃for 2 hours to give a pale yellow transparent solution. Acetonitrile was then removed directly using a rotary evaporator until a small amount of oily residue, 200mL of diethyl ether was added and sonicated to give a white precipitate. The white precipitate was collected by distillation under reduced pressure, and was dissolved in methylene chloride after washing 5 times with 50mL of diethyl ether, dried over anhydrous magnesium sulfate was added, and after removing the anhydrous magnesium sulfate by filtration, methylene chloride was removed by a rotary evaporator to give a white powdery solid as a final product, dimethoxyindenone methylene carbonate DMITMC (924 mg,3.37mmol, yield 85%).
The nuclear magnetic hydrogen spectrum information of the final product dimethoxy indenone methylene carbonate DMITMC is:
1HNMR(dmso-d,298K,400MHz,δ/ppm):7.20(s,1H),7.11(s,1H),4.54(d,2H),4.40(d,2H),3.89(s,3H),3.80(s,3H),3.12(s,2H).
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (9)

1. A crystalline spirocyclic methylene carbonate derivative having a structure represented by formula I or formula II:
In formula I, R 1-R6 is independently hydrogen, chlorine, bromine, hydroxyl, or C1-C10 alkyl;
in formula II, R 7-R10 is independently hydrogen, chlorine, bromine, hydroxyl or C1-C10 alkyl.
2. The crystalline spirocyclic methylene carbonate derivative according to claim 1, which has a structure represented by formula I-1, formula I-2, formula I-3, formula II-1 or formula II-2:
3. The process for producing a crystalline spirocyclic methylene carbonate derivative according to claim 1, which comprises the steps of:
After the compound A or the compound B and paraformaldehyde are first dissolved, carrying out a methylolation reaction under the catalysis of an alkaline catalyst to obtain an intermediate III or an intermediate IV with a structure shown in a formula III or IV;
Secondly dissolving the intermediate III or the intermediate IV and carbonyl diimidazole, and carrying out substitution reaction under an acidic condition to obtain the crystalline spirocyclic methylene carbonate derivative with the structure shown in the formula I or the formula II;
4. A production method according to claim 3, wherein when the compound a is subjected to a methylolation reaction, the basic catalyst is sodium methoxide; the molar ratio of the compound A to the sodium methoxide is 1: (0.05 to 0.5);
the molar ratio of the compound A to the paraformaldehyde is 1: (1-10); the temperature of the methylolation reaction is between 25 ℃ below zero and 35 ℃ and the time is between 5 and 1000 seconds.
5. The production method according to claim 3, wherein when the compound B is subjected to a methylolation reaction, the basic catalyst is potassium carbonate; the molar ratio of the compound B to the potassium carbonate is 1: (0.05 to 0.5);
The molar ratio of the compound B to the paraformaldehyde is 1: (1-10); the temperature of the methylolation reaction is between 25 ℃ below zero and 35 ℃ below zero and the time is between 1 and 1000 minutes.
6. A process according to claim 3, wherein when the intermediate III undergoes a substitution reaction, the molar ratio of intermediate III to carbonyldiimidazole is 1: (1-9).
7. A process according to claim 3, wherein when the compound IV undergoes a substitution reaction, the molar ratio of intermediate IV to carbonyldiimidazole is 1: (1-10).
8. The method according to claim 1, 6 or 7, wherein the temperature of the substitution reaction is 0 to 150 ℃; the time is 0.1-48 h.
9. Use of the crystalline spiromethylene carbonate derivative according to claim 1 or 2 or the crystalline spiromethylene carbonate derivative prepared by the preparation method according to any one of claims 3 to 8 in the preparation of nano-supermolecular materials by crystallization-driven self-assembly.
CN202410252519.2A 2024-03-06 2024-03-06 Crystalline spirocyclic methylene carbonate derivative and preparation method and application thereof Pending CN118108697A (en)

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