CN117603196A - Purification method of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol - Google Patents
Purification method of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol Download PDFInfo
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- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 title claims abstract description 83
- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000000746 purification Methods 0.000 title claims abstract description 23
- 239000012535 impurity Substances 0.000 claims abstract description 149
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 84
- 239000002904 solvent Substances 0.000 claims description 53
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 50
- 238000001816 cooling Methods 0.000 claims description 45
- 239000012043 crude product Substances 0.000 claims description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 238000002425 crystallisation Methods 0.000 claims description 24
- 230000008025 crystallization Effects 0.000 claims description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 19
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 14
- 239000013078 crystal Substances 0.000 claims description 13
- 238000004090 dissolution Methods 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000012264 purified product Substances 0.000 abstract description 25
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000001914 filtration Methods 0.000 description 33
- 238000003756 stirring Methods 0.000 description 33
- 239000012065 filter cake Substances 0.000 description 24
- 238000001035 drying Methods 0.000 description 19
- 239000000047 product Substances 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 9
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- ZXKXJHAOUFHNAS-FVGYRXGTSA-N (S)-fenfluramine hydrochloride Chemical compound [Cl-].CC[NH2+][C@@H](C)CC1=CC=CC(C(F)(F)F)=C1 ZXKXJHAOUFHNAS-FVGYRXGTSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 3
- 229960004130 itraconazole Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- -1 triazole compound Chemical class 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention provides a process for the purification of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol comprising the step of removing other mono-and/or isomeric impurities. The purification method disclosed by the invention is simple to operate, low in raw material cost and suitable for industrial mass production, and other single impurities and isomer impurities contained in 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol can be simultaneously and effectively removed, so that the purity of the finally obtained purified product is higher, and the content of the isomer impurities is obviously reduced compared with the prior art.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a purification method of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol.
Background
The structural formula of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol is shown as a formula I, is a key intermediate in chemical synthesis methods of compounds such as itraconazole and the like, the quality of the compound can have important influence on the product quality of the final product itraconazole, and the quality is limited by a purification method, so that the conventional 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol has the problems that the content of other single impurities is high (generally about 10 percent), the content of isomer impurities is high (generally about 15 percent), the content of isomer impurities of an intermediate triazole compound disclosed in China patent CN101391994B is reduced, but still about 10 percent, and the purity is low, so that the prepared final product can meet the standard pharmacopoeia of China only after being purified for multiple times.
Disclosure of Invention
In view of the above-mentioned shortcomings in the background art, the present invention aims to provide a purification method of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, so as to solve the technical problems of high content of other single impurities or high content of isomer impurities or both of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol in the prior art, and improve the purity of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, thereby reducing the quality risk of the final product itraconazole prepared from the intermediate.
In order to achieve the above object, the present invention provides a purification method of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, the purification method comprising the step of removing other mono-impurities and/or removing isomer impurities.
Wherein the structure of the isomer impurity is as follows:
the other single impurity refers to other impurities than the above-mentioned isomer impurities.
Preferably, the step of recrystallizing the crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol with a mixed solvent of the first good solvent and the poor solvent is used as the impurity;
preferably, in the step of removing the other single impurities, the first good solvent is selected from any one of methanol, ethanol, acetone, dichloromethane and ethyl acetate, preferably ethanol or ethyl acetate.
Preferably, in the step of removing the other mono-impurities, the poor solvent is selected from any one of methyl tert-butyl ether, n-hexane and n-heptane, preferably methyl tert-butyl ether or n-hexane.
Preferably, in the step of removing the other single impurities, a volume ratio between the first good solvent and the poor solvent is 1:1 to 10, preferably 1:3 to 5, more preferably 1:5.
preferably, in the step of removing other single impurities, the crystallization temperature is-10 ℃ to 30 ℃, preferably-10 ℃ to 5 ℃.
Preferably, in the step of removing other single impurities, when the poor solvent is methyl tertiary butyl ether, the crystallization temperature is-10 ℃ to-5 ℃; when the poor solvent is n-hexane, the crystallization temperature is 0-5 ℃.
The inventors have found that too much amount of the good solvent may cause the product to be less likely to precipitate and the yield to be lost to be large, too little amount may cause the crude product to be insufficiently dissolved, resulting in weakening of the impurity removing ability, preferably, in the step of removing other single impurities, the volume of the first good solvent is 1 to 5 times, preferably 2 to 3 times, more preferably 2 times the mass of the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol.
Preferably, the process for removing other single impurities comprises adding a first good solvent and a poor solvent into the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, stirring and dissolving at the temperature of 40-70 ℃, cooling to-10-30 ℃, preferably-10-5 ℃, preserving heat and crystallizing for 1-3 hours, preferably 2 hours, filtering, and collecting a filter cake.
Preferably, in the step of removing other single impurities, the dissolution temperature is preferably 50-60 ℃, and too low temperature leads to insufficient dissolution of the crude product, so that the impurity removing capability is weakened, and the product quality is affected if the temperature is too high.
Preferably, in the step of removing the other single impurities, the filter cake is rinsed with a poor solvent.
Preferably, in the step of removing other single impurities, the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol is 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol to be purified or a product after removal of isomer impurities.
Preferably, the isomer-removing impurity is a step of recrystallizing the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol with a mixed solvent of the second good solvent and water.
Preferably, in the step of removing the isomer impurities, the second good solvent is selected from any one of methanol, ethanol, acetone, tetrahydrofuran and 1, 4-dioxane, preferably methanol or acetone, more preferably acetone.
Preferably, in the step of removing the isomer impurities, the volume ratio of the second good solvent to water is 1:1 to 8, preferably 1:5 to 8, more preferably 1:5.
Preferably, in the step of removing the isomer impurities, the crystallization temperature is 0 to 30 ℃, preferably 10 to 15 ℃.
Preferably, in the step of removing the isomer impurities, the volume of the second good solvent is 1 to 5 times, preferably 2 to 3 times, more preferably 2 times the mass of the crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol.
Preferably, the isomer impurity removal comprises adding a second good solvent and water with the total water content of 0-40 v/v% to the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, stirring and dissolving at the temperature of 40-70 ℃, preferably 50-60 ℃, cooling to 0-30 ℃, preferably 10-15 ℃ after dissolving, preserving heat and crystallizing for 1-3 hours, preferably 2 hours, filtering, collecting filter cakes, and adding the rest water before cooling after dissolving or adding the rest water before crystallizing after cooling.
Preferably, the isomer impurity removal comprises adding a second good solvent and water accounting for 0-40 v/v% of the total water amount into the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, stirring and dissolving at the temperature of 40-70 ℃, preferably 50-60 ℃, cooling to 0-30 ℃, preferably 10-15 ℃ after dissolving, adding the rest water at the maintenance temperature, preserving heat and crystallizing for 1-3 hours, preferably 2 hours, filtering, and collecting filter cakes. Compared with the technical scheme of adding the residual water before cooling after dissolving, the technical scheme of adding the residual water after cooling can effectively avoid the phenomenon of agglomeration of the precipitated crystals.
Preferably, the isomer impurity removal comprises adding a second good solvent and water accounting for 10-20 v/v% of the total water amount into the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, stirring and dissolving at the temperature of 40-70 ℃, preferably 50-60 ℃, cooling to 0-30 ℃, preferably 10-15 ℃, maintaining the temperature, adding the rest water, preserving heat and crystallizing for 1-3 hours, preferably 2 hours, filtering, and collecting a filter cake. The technical proposal of controlling the primary water adding amount to be 10-20 v/v percent can obviously improve the removal effect of the isomer impurities and further improve the yield.
Preferably, the isomer impurity removal comprises adding a second good solvent and water accounting for 10-20 v/v% of the total water amount into the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, stirring and dissolving at the temperature of 40-70 ℃, preferably 50-60 ℃, adding 30-60 v/v% of the residual water after dissolving, cooling to 0-30 ℃, preferably 10-15 ℃, maintaining the temperature, adding the residual water, preserving the temperature and crystallizing for 1-3 hours, preferably 2 hours, filtering, and collecting filter cakes. The technical scheme of adding the water three times can further improve the removal effect and the yield of the isomer impurities.
Preferably, the isomer removing impurities comprise adding a second good solvent and water accounting for 10-20 v/v% of the total water amount to the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, stirring and dissolving at the temperature of 40-70 ℃, preferably 50-60 ℃, adding 30-60 v/v% of the residual water amount after dissolving, crystallizing for 0.5-2 hours, preferably 1 hour, cooling to 0-30 ℃, preferably 10-15 ℃, maintaining the temperature, adding the residual water, preserving heat and crystallizing for 1-3 hours, preferably 1 hour, filtering, and collecting filter cakes. The technical proposal of adding the crystal growth before cooling ensures that the finally obtained crystal has better character, uniform grain diameter and powder shape.
More preferably, in the above-mentioned isomer-removing impurities, the crystal growth temperature is 50 to 55 ℃.
Preferably, in the step of removing the isomer impurities, the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol is 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol to be purified or a product after removal of other single impurities.
Namely, the purification method of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol provided by the invention can be used for performing other single impurity removal operations on 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol to be purified; or performing isomer removal operation on 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol to be purified; or performing other single impurity removal operation on the 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol to be purified, and then performing isomer removal operation on the product after the other single impurity removal operation; or the method can also be that the isomer removal operation is firstly carried out on the 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol to be purified, and then the other single impurity removal operation is carried out on the product after the isomer removal operation.
In the purification method of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol provided by the present invention, the 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol to be purified refers to a synthetic product prepared by a chemical synthesis method using a formula II (cis-bromoester) or a precursor of formula II as a raw material, that is, in a process of synthesizing 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, when the raw material adopts the formula II or the precursor of formula II, any chemical synthesis route is used, such as a chemical synthesis route disclosed in chinese patent document CN101391994B, no. Journal of Medicinal Chemistry,1983, vol.26, vol.4: 611-613, or chemical synthetic routes employed in experimental examples of the present application, etc., all of which can be purified by the purification method provided by the present invention.
Preferably, in the step of removing the isomer impurities, the obtained filter cake is rinsed with water.
Preferably, the operation of removing the isomer impurities of the present invention may be repeated as many times as necessary to obtain 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol having an isomer impurity content conforming to a predetermined target.
Advantageous effects
Compared with the prior art, the purification method of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol provided by the invention is simple to operate, has low raw material cost, is suitable for industrial mass production, can independently remove other single impurity or isomer impurities contained in 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, and can simultaneously and effectively remove other single impurity and isomer impurities contained in 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, so that the purity of the finally obtained purified product is higher, the isomer impurity content is obviously reduced compared with the prior art, and the isomer impurity can be lower than 1.0% at the lowest by adopting the purification method, thereby ensuring that the impurity content of the purified intermediate is not in accordance with the standard of the final product B of Chinese medicine, namely, the impurity content of the purified product is higher than 0.5%.
Detailed Description
The present invention will be described in further detail with reference to the following examples, which are illustrative of the present invention and are not intended to limit the present invention thereto.
The crude products in the following examples, unless specified, were all crude products of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol triazole prepared by the synthetic method disclosed in the Chinese patent No. CN101391994B, and the crude products were detected to have a purity of 82.13%, an isomer impurity content of 10.23% and a total content of other single impurities of 7.64%.
The purification method of the invention, removing isomer impurities
Example I-1
Taking 10g of crude product, adding 20ml of acetone, stirring and dissolving at 50-60 ℃, cooling to 10-15 ℃ after dissolving, adding 100ml of water, preserving heat and crystallizing for 2 hours, filtering and drying to obtain 8.0g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 80%, the purity is 90.25%, and the content of isomer impurity is 2.96%.
Example I-2
Adding 20ml of acetone and 20ml of water into 10g of crude product, stirring and dissolving at 50-60 ℃, adding 80ml of water after dissolving, cooling to 10-15 ℃, preserving heat and crystallizing for 2 hours, filtering and drying to obtain 9.2g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 92%, the purity is 92.32%, the content of isomer impurities is 0.91%, and the purified product has caking.
Example I-3
Taking 10g of crude product, adding 20ml of acetone and 20ml of water, stirring and dissolving at 50-60 ℃, cooling to 10-15 ℃ after dissolving, adding 80ml of water, preserving heat and crystallizing for 2 hours, filtering and drying to obtain 9.1g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 91%, the purity is 92.34%, and the content of isomer impurity is 0.90%.
Example I-4
Taking 10g of crude product, adding 20ml of acetone and 20ml of water, stirring and dissolving at 50-60 ℃, adding 40ml of water after dissolving, cooling to 10-15 ℃, adding 40ml of water, preserving heat and crystallizing for 2 hours, filtering and drying to obtain 9.2g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 92%, the purity is 92.71%, and the content of isomer impurities is 0.67%.
Example I-5
Adding 20ml of acetone and 20ml of water into 10g of crude product, stirring and dissolving at 50-60 ℃, adding 40ml of water after dissolving, maintaining the temperature of 50-55 ℃ for crystal growth for 1 hour, cooling to 10-15 ℃, adding 40ml of water, preserving heat and crystallizing for 2 hours, filtering and drying to obtain 9.2g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 92%, the purity is 92.80%, the content of isomer impurity is 0.63%, and the purified product has better crystal property, uniform particle size and is in powder shape.
Example I-6
Taking 10g of crude product, adding 20ml of acetone and 20ml of water, stirring and dissolving at 50-60 ℃, cooling to 10-15 ℃ after dissolving, adding 80ml of water, preserving heat and crystallizing for 2 hours, filtering, and collecting a filter cake.
Adding 20ml of acetone and 20ml of water into the filter cake, stirring and dissolving at 50-60 ℃, cooling to 10-15 ℃ after dissolving, adding 80ml of water, preserving heat and crystallizing for 2 hours, filtering and drying to obtain 8.7g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, wherein the yield is 87%, the purity is 94.35%, and the content of isomer impurities is 0.26%.
Comparative example I-1
Adding 20ml of acetone into 10g of crude product, stirring and dissolving at 50-60 ℃, cooling to 10-15 ℃ after dissolving, preserving heat and crystallizing for 2 hours, filtering and drying to obtain 5.6g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 56%, the purity is 83.89%, and the content of isomer impurity is 8.95%.
Comparative example I-2
Taking 10g of crude product, adding 20ml of acetone and 100ml of water, stirring and dissolving at 50-60 ℃, cooling to 10-15 ℃ after dissolving, preserving heat and crystallizing for 2 hours, filtering and drying to obtain 8.6g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 86%, the purity is 85.11%, and the content of isomer impurity is 8.12%.
The purification method of the invention-except other single impurities
Example II-1
Adding 20ml of ethanol and 100ml of methyl tertiary butyl ether into 10g of crude product, heating to 50-60 ℃ for stirring and dissolving, cooling to-10 to-5 ℃ after dissolving, crystallizing for 2 hours, filtering and drying to obtain 9.1g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 91%, the purity is 90.56%, and the content of other single impurities is 0.88%.
Example II-2
Reference Journal of Medicinal Chemistry,1983, vol.26, no.4:611-613 to obtain crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, wherein the purity of the crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol is 80.26%, and the total content of other single impurities is 10.56%.
Taking 10g of the crude product, adding 20ml of ethyl acetate and 100ml of methyl tertiary butyl ether, heating to 50-60 ℃ for stirring and dissolving, cooling to-10 to-5 ℃ after dissolving, crystallizing for 2 hours, filtering and drying to obtain 8.9g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 89%, the purity is 90.39%, and the content of other single impurities is 0.86%.
Example II-3
Adding 20ml of ethanol and 60ml of normal hexane into 10g of crude product, heating to 50-60 ℃ for stirring and dissolving, cooling to 0-5 ℃ after dissolving, crystallizing for 2 hours, filtering and drying to obtain 9.0g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 90%, the purity is 90.58%, and the content of other single impurities is 0.89%.
Example II-4
Reference Journal of Medicinal Chemistry,1983, vol.26, no.4:611-613 to obtain crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, wherein the purity of the crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol is 80.26%, and the total content of other single impurities is 10.56%.
10g of the crude product is taken, 20ml of ethyl acetate and 60ml of normal hexane are added, the temperature is raised to 50-60 ℃ for stirring and dissolution, the temperature is reduced to 0-5 ℃ after dissolution, crystallization is carried out for 2 hours, and 8.8g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol is obtained after filtration and drying, the yield is 88%, the purity is 90.33%, and the content of other single impurities is 0.91%.
The purification method of the invention-simultaneously removing isomer impurities and other single impurities
Example III-1
Removing other single impurities: taking 10g of crude product, adding 20ml of ethanol and 100ml of methyl tertiary butyl ether, heating to 50-60 ℃, stirring for dissolution, cooling to-10 to-5 ℃ after dissolution, crystallizing for 2 hours, filtering, and collecting filter cakes.
Removing isomer impurities: adding 20ml of acetone and 20ml of water into the filter cake, stirring and dissolving at 50-60 ℃, adding 40ml of water after dissolving, maintaining the temperature of 50-55 ℃ for crystal growth for 1 hour, cooling to 10-15 ℃, adding 40ml of water, preserving heat and crystallizing for 2 hours, filtering and drying to obtain 8.5g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 85%, the purity is 99.23%, the impurity content of isomers is 0.56%, and the total content of other single impurities is 0.21%.
Example III-2
Reference Journal of Medicinal Chemistry,1983, vol.26, no.4:611-613 to obtain crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, the crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol was detected to have a purity of 80.26%, an isomer impurity content of 9.18%, and a total content of other single impurities of 10.56%.
Removing other single impurities: taking 10g of the crude product, adding 20ml of ethyl acetate and 100ml of methyl tertiary butyl ether, heating to 50-60 ℃ for stirring and dissolving, cooling to-10 to-5 ℃ after dissolving, crystallizing for 2 hours, filtering, and collecting a filter cake.
Removing isomer impurities: adding 20ml of acetone and 20ml of water into the filter cake, stirring and dissolving at 50-60 ℃, adding 40ml of water after dissolving, maintaining the temperature of 50-55 ℃ for crystal growth for 1 hour, cooling to 10-15 ℃, adding 40ml of water, preserving heat and crystallizing for 2 hours, filtering and drying to obtain 8.3g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 83%, the purity is 99.15%, the impurity content of isomers is 0.62%, and the total content of other single impurities is 0.23%.
Example III-3
Removing other single impurities: taking 10g of crude product, adding 20ml of ethanol and 60ml of normal hexane, heating to 50-60 ℃, stirring for dissolution, cooling to 0-5 ℃ after dissolution, crystallizing for 2 hours, filtering, and collecting a filter cake.
Removing isomer impurities: adding 20ml of acetone and 20ml of water into the filter cake, stirring and dissolving at 50-60 ℃, adding 40ml of water after dissolving, maintaining the temperature of 50-55 ℃ for crystal growth for 1 hour, cooling to 10-15 ℃, adding 40ml of water, preserving heat and crystallizing for 2 hours, filtering and drying to obtain 8.5g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, wherein the yield is 85%, the purity is 99.20%, the impurity content of isomers is 0.55%, and the total content of other single impurities is 0.25%.
Example III-4
Reference Journal of Medicinal Chemistry,1983, vol.26, no.4:611-613 to obtain crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, the crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol was detected to have a purity of 80.26%, an isomer impurity content of 9.18%, and a total content of other single impurities of 10.56%.
Removing other single impurities: taking 10g of the crude product, adding 20ml of ethyl acetate and 60ml of normal hexane, heating to 50-60 ℃ for stirring and dissolving, cooling to 0-5 ℃ after dissolving, crystallizing for 2 hours, filtering, and collecting a filter cake.
Removing isomer impurities: adding 20ml of acetone and 20ml of water into the filter cake, stirring and dissolving at 50-60 ℃, adding 40ml of water after dissolving, maintaining the temperature of 50-55 ℃ for crystal growth for 1 hour, cooling to 10-15 ℃, adding 40ml of water, preserving heat and crystallizing for 2 hours, filtering and drying to obtain 8.4g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 84%, the purity is 99.12%, the impurity content of isomers is 0.65%, and the total content of other single impurities is 0.23%.
Example III-5
Removing isomer impurities: taking 10g of crude product, adding 20ml of acetone and 20ml of water, stirring and dissolving at 50-60 ℃, adding 40ml of water after dissolving, maintaining the temperature of 50-55 ℃ for crystal growth for 1 hour, cooling to 10-15 ℃, adding 40ml of water, preserving heat and crystallizing for 2 hours, filtering, and collecting a filter cake.
Removing other single impurities: adding 20ml of ethanol and 100ml of methyl tertiary butyl ether into the filter cake, heating to 50-60 ℃ for stirring and dissolving, cooling to-10 to-5 ℃ after dissolving, crystallizing for 2 hours, filtering and drying to obtain 8.3g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 83%, the purity is 99.19%, the isomer impurity content is 0.54%, and the total content of other single impurities is 0.27%.
Example III-6
Reference Journal of Medicinal Chemistry,1983, vol.26, no.4:611-613 to obtain crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, the crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol was detected to have a purity of 80.26%, an isomer impurity content of 9.18%, and a total content of other single impurities of 10.56%.
Removing isomer impurities: taking 10g of the crude product, adding 20ml of acetone and 20ml of water, stirring and dissolving at 50-60 ℃, adding 40ml of water after dissolving, maintaining the temperature of 50-55 ℃ for crystal growth for 1 hour, cooling to 10-15 ℃, adding 40ml of water, preserving heat and crystallizing for 2 hours, filtering, and collecting a filter cake.
Removing other single impurities: adding 20ml of ethyl acetate and 60ml of normal hexane into the filter cake, heating to 50-60 ℃ for stirring and dissolving, cooling to 0-5 ℃ after dissolving, crystallizing for 2 hours, filtering and drying to obtain 8.2g of purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, wherein the yield is 82%, the purity is 99.10%, the impurity content of isomers is 0.67%, and the total content of other single impurities is 0.23%.
Experimental example 1: influence experiments of different factors
Preparation of crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol: the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol is prepared by taking cis-bromo-ester (formula II) as a raw material, and the purity of the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol is 77.55%, the isomer impurity content is 14.36% and the total content of other single impurities is 8.09% according to the detection.
The crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol described above was purified as follows, with specific parameters and results shown in tables 1-7.
(1) Removing other single impurities: adding a first good solvent and a poor solvent into the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, stirring and dissolving at the temperature of 40-70 ℃, cooling to-10-30 ℃ after dissolving, preserving heat and crystallizing for 2 hours, filtering, collecting a filter cake, and detecting the purity, the isomer impurity content, the total content of other single impurities and the yield;
(2) Removing isomer impurities: adding a second good solvent and water accounting for 0-40 v/v% of the total water into the filter cake, stirring and dissolving the mixture at the temperature of 40-70 ℃, cooling the mixture to 0-30 ℃ after dissolving, maintaining the temperature, adding the rest water, preserving heat and crystallizing for 2 hours, filtering and drying the mixture to obtain a purified product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, and detecting the purity, the isomer impurity content, the total content of other single impurities and the yield of the purified product.
1. Influence of mixed solvents of different systems
The procedure of step (1) was carried out according to the parameters shown in Table 1 to remove other impurities, and the results are shown in Table 1.
Table 1 (except for other single impurities)
Conclusion: the first good solvent is ethanol or ethyl acetate, and the poor solvent is methyl tertiary butyl ether or n-hexane
The product obtained by taking the sequence number 2 in Table 1 after removing other single impurities was operated according to the method for removing isomers in the above step (2) and the parameters in Table 2, and the results are shown in Table 2.
Table 2 (isomeride removal)
Conclusion: the second good solvent is methanol or acetone
2. Effects of different solvent ratios
TABLE 3 (except for other single impurities)
Conclusion: the ratio of the first good solvent to the poor solvent is suitably selected to be 1:3 to 5.
The product obtained by taking the number 7 in Table 3 after removing other single impurities was subjected to the above-mentioned method for removing isomer and recrystallizing in the step (2) and the parameters in Table 4, and the results are shown in Table 4.
Table 4 (isomeride removal)
Conclusion: the ratio of the second good solvent to the poor solvent is 1:1-8.
3. Influence of different crystallization temperatures
Table 5 (except for other single impurities)
Conclusion: the crystallization temperature is suitably selected to be-10 to 5 ℃.
The product obtained by taking the sequence number 1 in Table 5 after removing other single impurities was subjected to the isomer removing method of the above step (2) and the parameters of Table 6, and the results are shown in Table 6.
Table 6 (isomeride removal)
Conclusion: the crystallization temperature is selected to be 0-30 ℃, preferably 10-15 ℃.
4. Influence of different primary water addition amounts
The product obtained by taking the sequence number 1 in Table 5 after removing other single impurities was subjected to the isomer removing method of the above step (2) and the parameters of Table 7, and the results are shown in Table 7.
Table 7 (isomeride)
Conclusion: the primary water addition amount is suitably selected to be 10-20 v/v%.
Claims (10)
1. A process for the purification of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol comprising the step of removing additional mono-and/or isomeric impurities, wherein the isomeric impurities have the structure:
the other single impurity refers to other impurities than the above-mentioned isomer impurities.
2. The method according to claim 1, wherein the step of removing the other single impurities is a step of recrystallizing a crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol with a mixed solvent of the first good solvent and the poor solvent;
preferably, in the step of removing the other single impurities, the first good solvent is selected from any one of methanol, ethanol, acetone, dichloromethane and ethyl acetate, preferably ethanol or ethyl acetate;
preferably, in the step of removing the other mono-impurities, the poor solvent is selected from any one of methyl tertiary butyl ether, n-hexane and n-heptane, preferably methyl tertiary butyl ether or n-hexane;
preferably, in the step of removing the other single impurities, a volume ratio between the first good solvent and the poor solvent is 1:1 to 10, preferably 1:3 to 5.
3. Purification process according to claim 1 or 2, characterized in that in the step of removing the other single impurities, the crystallization temperature is-10 ℃ to 30 ℃, preferably-10 ℃ to 5 ℃;
preferably, in the step of removing other single impurities, when the poor solvent is methyl tertiary butyl ether, the crystallization temperature is-10 ℃ to-5 ℃; when the poor solvent is n-hexane, the crystallization temperature is 0-5 ℃.
4. A purification method according to any one of claims 1 to 3, wherein in the step of removing the other single impurities, the volume of the first good solvent is 1 to 5 times, preferably 2 to 3 times, the crude mass of the 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol.
5. The method according to any one of claims 1 to 4, wherein the removal of the other single impurities comprises adding a first good solvent and a poor solvent to the crude 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol, dissolving at a temperature of 40 to 70 ℃, cooling to a crystallization temperature after the dissolution, and preserving the heat for 1 to 3 hours.
6. The purification method according to any one of claims 1 to 5, wherein the isomer-removing impurity is a step of recrystallizing a crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol with a mixed solvent of a second good solvent and water;
preferably, in the step of removing the isomer impurities, the second good solvent is selected from any one of methanol, ethanol, acetone, tetrahydrofuran and 1, 4-dioxane, preferably methanol or acetone.
7. The method according to claim 6, wherein in the step of removing the isomer impurities, the volume ratio of the second good solvent to water is 1:1 to 8, preferably 1:5 to 8.
8. The method according to claim 6 or 7, wherein in the step of removing the isomer impurities, the crystallization temperature is 0 to 30 ℃.
9. The purification method according to any one of claims 6 to 8, wherein in the step of removing the isomer impurities, the volume of the second good solvent is 1 to 5 times, preferably 2 to 3 times, the crude mass of the 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolan-4-methanol.
10. The purification method according to any one of claims 6 to 9, wherein the removing of the isomer impurities comprises adding a second good solvent and water in an amount of 0 to 40v/v% of the total amount of water to the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, dissolving at a temperature of 40 to 70 ℃, cooling to crystallization temperature after dissolving, and incubating for crystallization for 1 to 3 hours, during which the remaining water is added before cooling after dissolving or the remaining water is added before crystallization after cooling;
preferably, the isomer impurity removal comprises adding a second good solvent and water accounting for 0-40 v/v% of the total water into the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, dissolving at the temperature of 40-70 ℃, cooling to crystallization temperature after dissolving, maintaining the temperature, adding the rest water, and preserving the temperature for crystallization for 1-3 hours;
preferably, the isomer impurity removal comprises adding a second good solvent and water accounting for 10-20 v/v% of the total water into the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, dissolving at the temperature of 40-70 ℃, cooling to crystallization temperature after dissolving, maintaining the temperature, adding the rest water, and preserving the temperature for crystallization for 1-3 hours;
preferably, the isomer impurity removal comprises adding a second good solvent and 10-20 v/v% of water of total water into the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, dissolving at the temperature of 40-70 ℃, adding 30-60 v/v% of the residual water after dissolving, cooling to a crystallization temperature, maintaining the temperature, adding the residual water, and preserving heat for crystallization for 1-3 hours;
preferably, the isomer impurity removal comprises adding a second good solvent and 10-20 v/v% of water of total water into the crude product of 2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazole-1-methyl) -1, 3-dioxolane-4-methanol, dissolving at the temperature of 40-70 ℃, adding 30-60 v/v% of the residual water after dissolving, crystallizing for 0.5-2 hours, cooling to the crystallization temperature, maintaining the temperature, adding the residual water, and preserving the temperature for crystallization for 1-3 hours;
more preferably, in the above-mentioned isomer-removing impurities, the crystal growth temperature is 50 to 55 ℃.
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