CN113929660B - Ring opening method of ethylene oxide derivative - Google Patents
Ring opening method of ethylene oxide derivativeDownload PDFInfo
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- CN113929660B CN113929660BCN202111212177.4ACN202111212177ACN113929660BCN 113929660 BCN113929660 BCN 113929660BCN 202111212177 ACN202111212177 ACN 202111212177ACN 113929660 BCN113929660 BCN 113929660B
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- oxide derivative
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Technical Field
The application belongs to the technical field of organic synthesis, and particularly relates to a ring opening method of an ethylene oxide derivative.
Background
The triazole oxirane compound is a very important key intermediate of a conazole medicament, a large number of medicaments are synthesized by the triazole oxirane, and as shown in figure 3, the compound shown in formula 1 can be used for preparing itraconazole, voriconazole, abaconazole and fluconazole. Such as: representative triazole antifungal drug fluconazole developed by feverre in 1981; voriconazole developed by feverfew 2002; isaconazole developed by ASTELLAS corporation in 2015; the drug abaconazole and the like developed by the spanish Palau pharmacy in 2018 can be synthesized by triazole oxirane (a compound shown in a formula 1).
At present, various synthetic methods for synthesizing the conazole compound by triazole oxirane (a compound shown in a formula 1) are reported.
The prior literature reports that: the synthesis of 1-triazole-2-butanol derivative is carried out by ring-opening reaction of triazole oxirane and side chain under DIPEA and isopropyl magnesium bromide condition to obtain target product, which has strict reaction condition, high requirement for industrial production condition, and is not suitable for large scale production. Later, a method for obtaining the 1-triazole-2-butanol derivative by side chain ring-opening triazole oxirane under the condition of tert-butyl alcohol magnesium is developed, but the tert-butyl alcohol magnesium used in the reaction has low commercialization degree and high price, is not suitable for commercial production, and cannot obtain a target product with a single configuration.
Disclosure of Invention
In view of the above, the application provides a ring opening method for ethylene oxide derivatives, which effectively solves the technical problems of harsh conditions, high cost and low selectivity of synthesized target products of the existing triazole ethylene oxide ring opening.
The application provides an ethylene oxide derivative ring-opening method, which comprises the following steps:
taking an ethylene oxide derivative and a side chain compound as initial raw materials, and carrying out a ring-opening addition reaction on the ethylene oxide derivative under the conditions of alkali, calcium salt and a reaction solvent to obtain a compound shown in a formula 2;
or, taking an ethylene oxide derivative and a side chain compound as starting raw materials, and carrying out a ring-opening addition reaction on the ethylene oxide derivative under the conditions of calcium hydride and a reaction solvent to obtain a compound shown in a formula 2;
the oxirane derivative has a structural formula shown in a formula 1;
wherein R is1 Can be H or CH3 Ar is aryl, R2 Is an azapolycyclic compound;
the side chain compound is selected from one or more of 4-methylene piperidine or hydrochloride thereof, triazole, 5-fluoropyrimidine and 7-chloro-4 (3H) -quinazolinone.
Specifically, as shown in fig. 1, an ethylene oxide derivative and a side chain compound are used as starting materials, and the ethylene oxide derivative is subjected to a ring-opening addition reaction under the conditions of a base, a calcium salt and a reaction solvent to obtain a compound shown in formula 2.
Specifically, as shown in fig. 2, an ethylene oxide derivative and a side chain compound are used as starting materials, and the ethylene oxide derivative is subjected to a ring-opening addition reaction under the conditions of calcium hydride and a reaction solvent to obtain a compound represented by formula 2.
In another embodiment, the base is selected from one or more of lithium hydroxide, lithium hydroxide monohydrate, lithium tert-butoxide, lithium carbonate, DIPEA, tetramethylguanidine, and calcium carbonate.
In another embodiment, the calcium salt is selected from one or more of calcium chloride, calcium bromide, calcium iodide, and calcium carbonate.
Specifically, the calcium salt is calcium chloride.
In another embodiment, the reaction solvent is selected from one or more of acetonitrile, water, aqueous acetonitrile, ethanol, DMF, and DMSO.
Specifically, the reaction solvent is acetonitrile.
In another embodiment, the molar ratio of the ethylene oxide derivative to the side chain compound is 1 (1.0 to 2.0).
Specifically, the molar ratio of the ethylene oxide derivative to the side chain compound is 1.5.
In another embodiment, the molar ratio of the ethylene oxide derivative to the base is 1 (1.0 to 4.0).
Specifically, the molar ratio of the ethylene oxide derivative to the base is 1.
In another embodiment, the molar ratio of the ethylene oxide derivative to the calcium salt is 1 (1.0 to 3.0).
Specifically, the molar ratio of the ethylene oxide derivative to the calcium salt is 1.
In another embodiment, the mass ratio of the ethylene oxide derivative to the reaction solvent is 1 (2.5 to 6.5).
Specifically, the mass ratio of the ethylene oxide derivative to the reaction solvent is 1.
In another embodiment, the molar ratio of the ethylene oxide derivative to the calcium hydride is 1 (0.75-3.0).
Specifically, the molar ratio of the ethylene oxide derivative to the calcium hydride is 1.
In another embodiment, the temperature of the ring-opening addition reaction is 60-100 ℃; the reaction time of the ring-opening addition reaction is 1-72h.
Specifically, the temperature of the ring-opening addition reaction is 80-90 ℃; the reaction time of the ring-opening addition reaction is 16-24h.
According to the method for opening the ring of the ethylene oxide derivative, the ethylene oxide derivative (a compound shown in a formula 1, such as triazole ethylene oxide) can be directly opened without an additive, and a target product (a compound shown in a formula 2) can be obtained in a high-selectivity manner under the conditions of specific alkali and a side chain compound; the applicability of the side chain compound is strong, particularly the side chain hydrochloride can obtain excellent reaction effect, and amine impurities caused by iodine and bromine can be effectively avoided.
Drawings
In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 is a scheme of a process for ring opening ethylene oxide derivatives provided herein;
FIG. 2 is a route to another ethylene oxide derivative ring opening process provided herein;
FIG. 3 is a synthetic route of preparing itraconazole, voriconazole, abaconazole and fluconazole from triazole oxirane disclosed in the prior art.
Detailed Description
The application provides a route of an oxirane derivative ring-opening method, which is used for solving the technical defects of harsh triazole oxirane ring-opening conditions, high cost and low selectivity of a synthesized target product in the prior art.
The technical solutions in the embodiments of the present application will be described clearly and completely below, and it should be understood that the described embodiments are only a part of the embodiments of the present application, and not all embodiments. All other embodiments obtained by a person of ordinary skill in the art based on the embodiments in the present application without making any creative effort belong to the protection scope of the present application.
The raw materials and reagents used in the following examples are commercially available or self-made.
The oxirane derivative shown in the formula 1 is (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazole-1-yl) methyl ] oxirane.
The (2R,3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] ethylene oxide used in the following examples was obtained by the method described in Japanese patent laid-open No. 2-191262. 4-Methylenepiperidine hydrochloride is commercially available from Shandong Wei Zhi pharmaceuticals, inc.
Bulk prices for some of the feedstocks of the following examples are shown in table 1.
TABLE 1 bulk price of materials
| Material(s) | Price/yuan/kg |
| Calcium hydride | 15 |
| Magnesium tert-butoxide | 450 |
| Lithium hydroxide monohydrate | 50 |
Example 1
The embodiment of the application provides an ethylene oxide derivative ring opening method, which comprises the following specific steps:
a100 mL three-necked flask was charged with 9.94g (0.09 mol) of calcium chloride, 11.97g (0.09 mol) of 4-methylenepiperidine hydrochloride, 7.52g (0.18 mol) of lithium hydroxide monohydrate, and 60mL of acetonitrile, stirred at room temperature for 30min, charged with 15g (0.06 mol) of (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] ethylene oxide, stirred, and heated to 80-85 ℃ to react for 20H. After the reaction is finished, concentrating, extracting with ethyl acetate, crystallizing with ethanol and water, and drying to obtain white solid efinaconazole 19.3g, with the yield of 93% and the purity of 99.91%.
Example 2
The embodiment of the application provides an ethylene oxide derivative ring opening method, which comprises the following specific steps:
a100 mL three-necked flask was charged with 3.77g (0.09 mol) of calcium hydride, 11.97g (0.09 mol) of 4-methylenepiperidine hydrochloride and 60mL of acetonitrile, stirred at room temperature for 30min, charged with 15g (0.06 mol) of (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] ethylene oxide, stirred and heated to 80-85 ℃ for 20H. After the reaction is finished, concentrating, extracting with ethyl acetate, crystallizing with ethanol and water, and drying to obtain 20.2g of white solid efinaconazole, wherein the yield is 97% and the purity is 99.98%.
Example 3
The embodiment of the application provides an ethylene oxide derivative ring opening method, which comprises the following specific steps:
a100 mL three-necked flask was charged with 17.9g (0.09 mol) of calcium bromide, 11.97g (0.09 mol) of 4-methylenepiperidine hydrochloride, 7.52g (0.18 mol) of lithium hydroxide monohydrate, and 60mL of acetonitrile, stirred at room temperature for 30min, charged with 15g (0.06 mol) of (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] ethylene oxide, stirred, and heated to 80-85 ℃ to react for 20H. After the reaction is finished, concentrating, extracting with ethyl acetate, crystallizing with ethanol and water, and drying to obtain white solid efinaconazole 19.76g, with the yield of 95% and the purity of 99.82%.
Example 4
The embodiment of the application provides an ethylene oxide derivative ring opening method, which comprises the following specific steps:
a100 mL three-necked flask was charged with 3.77g (0.09 mol) of calcium hydride, 16.2g (0.09 mol) of 7-chloro-4 (3H) -quinazolinone, and 60mL of acetonitrile, stirred at room temperature for 30min, charged with 15g (0.06 mol) of (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] ethylene oxide, stirred and heated to 80-85 ℃ for 20H. After the reaction is finished, concentrating, extracting by ethyl acetate, crystallizing by ethanol and water, and drying to obtain 25g of white solid abaconazole, wherein the yield is 95% and the purity is 99.93%.
Example 5
The embodiment of the application provides an ethylene oxide derivative ring opening method, which comprises the following specific steps:
a100 mL three-necked flask was charged with 3.77g (0.09 mol) of calcium hydride, 11.9g (0.09 mol) of 4-chloro-5-fluoropyrimidine and 60mL of acetonitrile, stirred at room temperature for 30min, charged with 15g (0.06 mol) of (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] ethylene oxide, stirred, warmed to 80-85 ℃ and reacted for 20H. After the reaction is finished, concentrating, extracting by ethyl acetate, crystallizing by ethanol and water, and drying to obtain 20.2g of white solid voriconazole, wherein the yield is 96 percent, and the purity is 99.96 percent.
Example 6
The embodiment of the application provides an ethylene oxide derivative ring opening method, which comprises the following specific steps:
a100 mL three-necked flask was charged with 9.94g (0.09 mol) of calcium chloride, 11.97g (0.09 mol) of 4-methylenepiperidine hydrochloride, 14.3g (0.18 mol) of lithium tert-butoxide, and 60mL of acetonitrile, stirred at room temperature for 30min, charged with 15g (0.06 mol) of (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] oxirane, stirred, and heated to 80-85 ℃ to react for 20H. After the reaction is finished, concentrating, extracting with ethyl acetate, crystallizing with ethanol and water, and drying to obtain 18.1g of white solid efinaconazole, wherein the yield is 87%, and the purity is 99.89%.
Example 7
The embodiment of the application provides an ethylene oxide derivative ring-opening method, which comprises the following specific steps:
a100 mL three-necked flask was charged with 9.94g (0.09 mol) of calcium chloride, 11.97g (0.09 mol) of 4-methylenepiperidine hydrochloride, 20.63g (0.18 mol) of tetramethylguanidine, and 60mL of acetonitrile, stirred at room temperature for 30min, charged with 15g (0.06 mol) of (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] ethylene oxide, stirred, and heated to 80-85 ℃ for 20H of reaction. After the reaction is finished, concentrating, extracting by ethyl acetate, crystallizing by ethanol and water, and drying to obtain 17.68g of white solid efinaconazole, wherein the yield is 85 percent, and the purity is 99.73 percent.
Example 8
The embodiment of the application provides an ethylene oxide derivative ring-opening method, which comprises the following specific steps:
a100 mL three-necked flask was charged with 9.94g (0.09 mol) of calcium chloride, 11.97g (0.09 mol) of 4-methylenepiperidine hydrochloride, 10.05g (0.18 mol) of potassium hydroxide, and 60mL of acetonitrile, stirred at room temperature for 30min, charged with 15g (0.06 mol) of (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] ethylene oxide, stirred, and heated to 80-85 ℃ to react for 20H. After the reaction is finished, concentrating, extracting with ethyl acetate, crystallizing with ethanol and water, and drying to obtain 17.89g of white solid itraconazole, wherein the yield is 86% and the purity is 99.73%.
Example 9
The embodiment of the application provides an ethylene oxide derivative ring opening method, which comprises the following specific steps:
a100 mL three-necked flask was charged with 9.94g (0.09 mol) of calcium chloride, 11.97g (0.09 mol) of 4-methylenepiperidine hydrochloride, 7.52g (0.18 mol) of lithium hydroxide monohydrate, and 60mL of water, stirred at room temperature for 30min, charged with 15g (0.06 mol) of (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] ethylene oxide, stirred, and heated to 80-85 ℃ to react for 20H. After the reaction is finished, concentrating, extracting by ethyl acetate, crystallizing by ethanol and water, and drying to obtain 17.68g of white solid efinaconazole, wherein the yield is 85 percent, and the purity is 99.54 percent.
Example 10
The embodiment of the application provides an ethylene oxide derivative ring opening method, which comprises the following specific steps:
a100 mL three-necked flask was charged with 9.94g (0.09 mol) of calcium chloride, 11.97g (0.09 mol) of 4-methylenepiperidine hydrochloride, 7.52g (0.18 mol) of lithium hydroxide monohydrate, and 60mL of ethanol, stirred at room temperature for 30min, charged with 15g (0.06 mol) of (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] ethylene oxide, stirred, and heated to 80-85 ℃ to react for 20H. After the reaction is finished, concentrating, extracting with ethyl acetate, crystallizing with ethanol and water, and drying to obtain 18.51g of white solid efinaconazole, wherein the yield is 89% and the purity is 99.63%.
Example 11
The embodiment of the application provides an ethylene oxide derivative ring opening method, which comprises the following specific steps:
a100 mL three-necked flask was charged with 9.94g (0.09 mol) of calcium chloride, 11.97g (0.09 mol) of 4-methylenepiperidine hydrochloride, 7.52g (0.18 mol) of lithium hydroxide monohydrate, and 60mL of DMF, stirred at room temperature for 30min, charged with 15g (0.06 mol) of (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] ethylene oxide, stirred, and heated to 80-85 ℃ to react for 20H. After the reaction is finished, concentrating, extracting with ethyl acetate, crystallizing with ethanol and water, and drying to obtain 18.1g of white solid efinaconazole, wherein the yield is 87% and the purity is 99.77%.
Example 12
The embodiment of the application provides an ethylene oxide derivative ring-opening method, which comprises the following specific steps:
a100 mL three-necked flask was charged with 17.9g (0.09 mol) of calcium bromide, 11.97g (0.09 mol) of 4-methylenepiperidine hydrochloride, 7.52g (0.18 mol) of lithium hydroxide monohydrate, and 60mL of DMF, stirred at room temperature for 30min, charged with 15g (0.06 mol) of (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] ethylene oxide, stirred, and heated to 80-85 ℃ to react for 20H. After the reaction is finished, concentrating, extracting with ethyl acetate, crystallizing with ethanol and water, and drying to obtain white solid efinaconazole 19.76g, with the yield of 95% and the purity of 99.92%.
Example 13
The embodiment of the application provides an ethylene oxide derivative ring opening method, which comprises the following specific steps:
a100 mL three-necked flask was charged with 9.94g (0.09 mol) of calcium chloride, 11.97g (0.09 mol) of 4-methylenepiperidine hydrochloride, 13.23g (0.18 mol) of lithium carbonate, and 60mL of acetonitrile, stirred at room temperature for 30min, charged with 15g (0.06 mol) of (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] oxirane, stirred, and heated to 80-85 ℃ to react for 20H. After the reaction is finished, concentrating, extracting with ethyl acetate, crystallizing with ethanol and water, and drying to obtain 17.68g of white solid efinaconazole, wherein the yield is 85% and the purity is 99.94%.
Example 14
The embodiment of the application provides an oxirane derivative ring-opening method, which comprises the following steps:
according to the synthesis reaction conditions and starting materials shown in Table 2, (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] oxirane and 4-methylenepiperidine hydrochloride were used as starting materials to prepare itraconazole according to the method of example 1, and the yield of itraconazole was measured, and the results are shown in Table 2.
Table 2 influence of different reaction conditions on the yield of efinaconazole
Eq in Table 2 refers to the molar ratio of 4-methylenepiperidine hydrochloride to (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] ethylene oxide.
In Table 2, "/" indicates no addition.
Example 15
The embodiment of the application provides an oxirane derivative ring-opening method, which comprises the following steps:
the target product was prepared according to the synthesis reaction conditions and starting materials shown in Table 3 using (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl- [ (1H-1,2,4-triazol-1-yl) methyl ] ethylene oxide as the starting material according to the method of example 2, and the yield of the target product was measured, and the results are shown in Table 3.
Table 3 comparison of the solution of the present application with the prior art solution
The side-chain hydrobromide, side-chain hydroiodide salts in the above table were synthesized according to the method described in patent CN103080100 a.
From the above data, it can be seen that the side chain compounds employed in the present application are well commercialized, and are less expensive than the side chain hydrogen bromides and hydrogen iodides of the prior art; the ring opening of the ethylene oxide derivative is carried out by using calcium hydride as an alkali and a side chain hydrochloride compound, a side chain hydrobromide compound and a side chain hydroiodide compound as side chain compounds, so as to obtain a target product with high purity and high yield. However, when calcium hydroxide is used as a base and a side chain hydrochloride compound, a side chain hydrobromide compound and a side chain hydroiodide compound are used as side chain compounds, the target product cannot be obtained in high purity and high yield, and the side chain of hydrogen bromide and hydrogen iodide must be used to complete the conversion.
Obviously, the product yield of the existing scheme is low, the purity is poor and the separation is complex, wherein the triazole oxirane and a side chain undergo a ring-opening reaction under the condition of a metal hydroxide salt to obtain a target product; the side chain requires hydrobromide and hydroiodide, so the existing ring opening method has high cost and cannot be applied to the hydrochloride form with lower cost.
Therefore, the present application discloses a highly efficient ring-opening method of an ethylene oxide derivative, in which a specific ethylene oxide derivative and a specific side chain compound undergo a ring-opening addition reaction under specific alkali or/and calcium salt conditions, so that the ethylene oxide derivative is ring-opened to obtain a target product with high selectivity, and the method can obtain the target product with high purity and high yield.
The foregoing is only a preferred embodiment of the present application and it should be noted that those skilled in the art can make several improvements and modifications without departing from the principle of the present application, and these improvements and modifications should also be considered as the protection scope of the present application.
Claims (6)
1. A process for ring-opening an oxirane derivative, comprising: taking an ethylene oxide derivative and a side chain compound as initial raw materials, and carrying out a ring-opening addition reaction on the ethylene oxide derivative under the conditions of alkali, calcium salt and a reaction solvent to obtain a compound shown in a formula 2;
or, taking an ethylene oxide derivative and a side chain compound as starting raw materials, and carrying out a ring-opening addition reaction on the ethylene oxide derivative under the conditions of calcium hydride and a reaction solvent to obtain a compound shown in a formula 2;
the oxirane derivative has a structural formula shown in formula 1;
wherein R is1 Can be H or CH3 Ar is aryl, R2 Is an azapolycyclic compound;
the side chain compound is selected from one or more of 4-methylene piperidine hydrochloride, triazole, 5-fluoropyrimidine and 7-chloro-4 (3H) -quinazolinone;
the azapolycyclic compound is 4-methylene piperidyl, triazolyl, 5-fluoropyrimidinyl or 7-chloro-4 (3H) -quinazolinone;
the calcium salt is selected from calcium bromide;
the temperature of the ring-opening addition reaction is 80-85 ℃; the reaction time of the ring-opening addition reaction is 1-72h;
the alkali is selected from one or more of lithium hydroxide, lithium hydroxide monohydrate, lithium tert-butoxide, lithium carbonate, DIPEA, tetramethylguanidine and calcium carbonate;
the reaction solvent is selected from one or more of acetonitrile, water, acetonitrile water solution, ethanol, DMF and DMSO.
2. The method of opening a ring of an ethylene oxide derivative according to claim 1, wherein the molar ratio of the ethylene oxide derivative to the side chain compound is 1 (1.0 to 2.0).
3. The method for ring-opening an ethylene oxide derivative according to claim 1, wherein the molar ratio of the ethylene oxide derivative to the base is 1 (1.0 to 4.0).
4. The method for ring-opening an ethylene oxide derivative according to claim 1, wherein the molar ratio of the ethylene oxide derivative to the calcium salt is 1 (1.0 to 3.0).
5. The method for ring-opening an ethylene oxide derivative according to claim 1, wherein the mass ratio of the ethylene oxide derivative to the reaction solvent is 1 (2.5 to 6.5).
6. The process for opening a cyclic ring of an oxirane derivative according to claim 1, wherein a molar ratio of the oxirane derivative to the calcium hydride is 1 (0.75 to 3.0).
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